Search

We summarize recent progress in the development of top-down control over bottom-up colloidal processes using a taxonomy based on how active control is used to guide equilibrium, near-equilibrium, and far-from-equilibrium assembly.

In Paul: The Pagans’ Apostle (2017), Paula Fredriksen reminds us that gods and their cults were intertwined with ancient ethnic groups so much so that, when Gentiles committed themselves exclusively to Israel’s God, some Jews considered this ‘tantamount to changing ethnicity’. Fredriksen claims, however, that Paul’s Gentile addressees – whom she terms ‘ex-pagan pagans’ – remain separate ethnically from Jews despite forsaking their ancestral gods for Israel’s. Given that gods and ethnicity were intertwined, this article examines if it is reasonable to conclude that Paul thinks Gentile Christ-followers remain strictly Gentiles after they have abandoned their ethnic gods and entered into a relationship with Israel and its God. I argue that, similar to Philo’s proselyte inclusion strategy, Paul incorporates Gentiles-in-Christ into ethnic Israel. As Abraham’s ‘offspring’, Paul suggests that his addressees not only gain membership in Israel’s covenant on account of Israel’s messiah, but that they also acquire a new ethnic identity despite that their prior identities as ‘the Gentiles’ are not erased. This study, then, seeks to destabilize the binary that Fredriksen posits between ethnic Israel and Paul’s Gentiles-in-Christ as ethnic ‘other’. In the end, I demonstrate that Paul’s ethnic reconfiguration of Gentile identities resembles Philo’s proselyte discourse and is more disruptive ethnically than Fredriksen’s phrase ‘ex-pagan pagans’ would suggest.

How race, ethnicity, and ancestry are used in genomic research has wide-ranging implications for how research is translated into clinical care and incorporated into public understanding. Correlation between race and genetic ancestry contributes to unresolved complexity for the scientific community, as illustrated by heterogeneous definitions and applications of these variables. Here, we offer commentary and recommendations on the use of race, ethnicity, and ancestry across the arc of genetic research, including data harmonization, analysis, and reporting. While informed by our experiences as researchers affiliated with the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, these recommendations are applicable to basic and translational genomic research in diverse populations with genome-wide data. Moving forward, considerable collaborative effort will be required to ensure that race, ethnicity, and ancestry are described and used appropriately to generate scientific knowledge that yields broad and equitable benefit.

ObjectivesMuscle wasting is a recognised extra-pulmonary complication in chronic obstructive pulmonary disease and has been associated with increased risk of death. Acute respiratory exacerbations are associated with reduction of muscle function, but there is a paucity of data on their long-term effect. This study explores the relationship between acute respiratory exacerbations and long-term muscle loss using serial measurements of CT derived pectoralis muscle area (PMA).Design and settingParticipants were included from two prospective, longitudinal, observational, multicentre cohorts of ever-smokers with at least 10 pack-year history.ParticipantsThe primary analysis included 1332 (of 2501) participants from Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) and 4384 (of 10 198) participants from Genetic Epidemiology of COPD (COPDGene) who had complete data from their baseline and follow-up visits.InterventionsPMA was measured on chest CT scans at two timepoints. Self-reported exacerbation data were collected from participants in both studies through the use of periodic longitudinal surveys.Main outcome measuresAge-related and excess muscle loss over time.ResultsAge, sex, race and body mass index were associated with baseline PMA. Participants experienced age-related decline at the upper end of reported normal ranges. In ECLIPSE, the exacerbation rate over time was associated with an excess muscle area loss of 1.3% (95% CI 0.6 to 1.9, pConclusionsExacerbations are associated with accelerated skeletal muscle loss. Each annual exacerbation was associated with the equivalent of 6 months of age-expected decline in muscle mass. Ameliorating exacerbation-associated muscle loss represents an important therapeutic target.

The 18 March 2020 Mw 5.7 Magna, Utah, earthquake was the largest earthquake in Utah since the 1992 ML 5.8 St. George earthquake. The geologic setting of the Magna earthquake is well documented by recent geologic mapping at 1:24,000 scale and 1:62,500 scale at and near the epicenter northeast of Magna, Utah. Subsurface fault modeling from surficial geologic mapping, structural cross sections, deep borehole data, and geophysical data reveals a complex system of faulting concentrated in the hanging wall of the Weber and Salt Lake City segments of the Wasatch fault zone including the Harkers fault, the West Valley fault zone, and the newly interpreted Saltair graben. Based on geologic and geophysical data (seismic and gravity), we interpret the mainshock of the Magna earthquake as having occurred on a relatively gently dipping part of the Salt Lake City segment, with aftershocks concentrated in the Saltair graben and West Valley fault zone. Postearthquake rapid reconnaissance of geological effects of the Magna earthquake documented liquefaction near the earthquake epicenter, along the Jordan River, and along the Great Salt Lake shoreline. Subaerial and subaqueous sand boils were identified in regions with roadway infrastructure and artificial fill, whereas collapse features were noted along the shores of the Great Salt Lake. Potential syneresis cracking and pooling in large areas indicated fluctuating groundwater likely related to earthquake ground shaking. The moderate magnitude of the Magna earthquake and minimal geological effects highlight the critical importance of earthquake research from multidisciplinary fields in the geosciences and preparedness on the Wasatch Front.

Cachexia is a commonly observed but frequently neglected extra-pulmonary manifestation in patients with chronic obstructive pulmonary disease (COPD). Cachexia is a multifactorial syndrome characterized by severe loss of body weight, muscle, and fat, as well as increased protein catabolism. COPD cachexia places a high burden on patients (eg, increased mortality risk and disease burden, reduced exercise capacity and quality of life) and the healthcare system (eg, increased number, length, and cost of hospitalizations). The etiology of COPD cachexia involves a complex interplay of non-modifiable and modifiable factors (eg, smoking, hypoxemia, hypercapnia, physical inactivity, energy imbalance, and exacerbations). Addressing these modifiable factors is needed to prevent and treat COPD cachexia. Oral nutritional supplementation combined with exercise training should be the primary multimodal treatment approach. Adding a pharmacological agent might be considered in some, but not all, patients with COPD cachexia. Clinicians and researchers should use longitudinal measures (eg, weight loss, muscle mass loss) instead of cross-sectional measures (eg, low body mass index or fat-free mass index) where possible to evaluate patients with COPD cachexia. Lastly, in future research, more detailed phenotyping of cachectic patients to enable a better comparison of included patients between studies, prospective longitudinal studies, and more focus on the impact of exacerbations and the role of biomarkers in COPD cachexia, are highly recommended.

The West Valley fault zone (WVFZ) and Salt Lake City segment (SLCS) of the Wasatch fault zone comprise Holoceneactive normal faults that bound an intrabasin graben in northern Salt Lake Valley, Utah. Both fault zones have evidence of recurrent Holocene surface-faulting earthquakes. A topic of recent research is the seismogenic relation of the antithetic (subsidiary) WVFZ to the Wasatch fault zone—specifically, to what degree are WVFZ earthquakes independent of slip on the SLCS, or other adjacent segments, of the Wasatch fault zone. To improve paleoseismic data for the WVFZ and better understand the seismogenic relation between the WVFZ and Wasatch fault zone, we conducted a fault-trench investigation at the Airport East site, developed new earthquake recurrence and fault sliprate estimates for the WVFZ, and compared WVFZ earthquake timing data with data from the Wasatch fault zone.

Rock avalanches are large-magnitude mass movements with high mobility and fluid-like runout; however, because of their scarcity, little information is typically available to describe the hazard posed by these events. Geologic records thus provide key data regarding rock avalanche size, timing, and dynamics. Here we present a detailed case history analysis of the Devils Castle rock avalanche located near the town of Alta in the Wasatch Mountains of Utah. The deposit is ∼1.5 km in length with a Fahrboeschung angle of 14 degrees (height-to-length ratio = 0.25). Through topographic reconstruction, we calculated a deposit volume of 1.7 million m3 with a maximum thickness of 25 m and an average thickness of 7 m. Cosmogenic surface exposure dating of six deposit boulders indicates a failure age of 14.4 ± 1.0 ka. The Devils Castle headwall displays no obvious evidence indicating precise source location and geometry; therefore, we reconstructed two plausible source volumes and performed numerical runout simulations for each. Results agree well with mapped deposit boundaries for both source scenarios; however, the east source model better represents material and dynamic characteristics of the deposit observed in the field. While the region is seismically active, the Late Pleistocene age for the rock avalanche precludes ascribing direct correlation with any currently known surface-rupturing paleoearthquakes. We identified and describe five similar events in the region highlighting the extent of the potential hazard. Individual case history analyses such as this allow us to better understand the processes and controls of large-scale mass movements in the region.

The immune system undergoes a progressive functional remodeling with age. Understanding how age bias shapes antitumor immunity is essential in designing effective immunotherapies, especially for pediatric patients. Here, we explore antitumor CD8+T cell responses generated in young (prepubescent) and adult (presenescent) mice. Using an MHCI-deficient tumor model, we observed that tumor-reactive CD8+T cells expanded in young tumor-bearing (TB) mice acquired a terminally differentiated phenotype characterized by overexpression of inhibitory receptors and the transcription factor Tox1. Furthermore, tumor-infiltrating CD8+T cells from young tumors yielded a poor cytokine response compared with CD8+T cells infiltrating adult tumors. Young migratory dendritic cells (migDCs) from the draining lymph nodes (dLNs), and mononuclear phagocytic cells (MPCs) infiltrating young tumors, were more competent in capturing and cross-presenting tumor antigen, leading to enhanced priming of CD8+T cells in dLNs and their subsequent terminal differentiation in the tumors. Single-cell transcriptional profiling of tumor-infiltrating MPCs demonstrated that young MPCs are polarized toward an inflammatory, effector phenotype. Consistent with our observations in young versus adult TB mice, analysis of immune infiltrates from pediatric solid tumors showed a correlation between tumor-infiltrating CD8+T cells with an exhaustion phenotype and the frequency of PD-L1–expressing monocytes/macrophages. Collectively, these data indicate that a young tissue microenvironment contributes to the generation of an immune response skewed toward a less pliable terminal effector state, thus narrowing the window for immunotherapeutic interventions.

Background: Black individuals have high incident diabetes risk, despite having paradoxically lower triglyceride and higher HDL (high-density lipoprotein) cholesterol levels. The basis of this is poorly understood. We evaluated the participants of SPRINT (Systolic Blood Pressure Intervention Trial) to assess the association of estimated European genetic ancestry with the risk of incident diabetes in self-identified Black individuals. Methods: Self-identified non-Hispanic Black SPRINT participants free of diabetes at baseline were included. Black participants were stratified into tertiles (T1–T3) of European ancestry proportions estimated using 106 biallelic ancestry informative genetic markers. The multivariable-adjusted association of European ancestry proportion with indices of baseline metabolic syndrome (ie, fasting plasma glucose, triglycerides, HDL cholesterol, body mass index, and blood pressure) was assessed. Multivariable-adjusted Cox regression determined the risk of incident diabetes (fasting plasma glucose ≥126 mg/dL or self-reported diabetes treatment) across tertiles of European ancestry proportion. Results: Among 2466 Black SPRINT participants, a higher European ancestry proportion was independently associated with higher baseline triglyceride and lower HDL cholesterol levels ( P P >0.05). Compared with the first tertile, those in the second (hazard ratio, 0.64 [95% CI, 0.45–0.90]) and third tertiles (hazard ratio, 0.61 [95% CI, 0.44–0.89]) of the European ancestry proportion had a lower risk of incident diabetes. A 5% point higher European ancestry was associated with a 29% lower risk of incident diabetes (hazard ratio, 0.71 [95% CI, 0.55–0.93]). There was no evidence of a differential association between the European ancestry proportion tertiles and incident diabetes between those randomized to intensive versus standard blood pressure treatment. Conclusions: The higher risk of incident diabetes in Black individuals may have genetic determinants in addition to adverse social factors. Further research may help understand the interplay between biological and social determinants of cardiometabolic health in Black individuals. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01206062.

Biological systems rely on chemical gradients to direct motion through both chemotaxis and signaling, but synthetic approaches for doing the same are still relatively naïve. Consequently, we present a novel method for using chemical gradients to manipulate the position and velocity of colloidal particles in a microfluidic device. Specifically, we show that a set of spatially localized chemical reactions that are sufficiently controllable can be used to steer colloidal particles via diffusiophoresis along an arbitrary trajectory. To accomplish this, we develop a control method for steering colloidal particles with chemical gradients using nonlinear model predictive control with a model based on the unsteady Green’s function solution of the diffusion equation. We illustrate the effectiveness of our approach using Brownian dynamics simulations that steer single particles along paths, such as circle, square, and figure-eight. We subsequently compare our results with published techniques for steering colloids using electric fields, and we provide an analysis of the physical parameter space where our approach is useful. Based on these findings, we conclude that it is theoretically possible to explicitly steer particles via chemical gradients in a microfluidics paradigm.

The Peterson quadrangle is located southeast of Ogden, Utah. The major geographic features in and near the map area are Morgan Valley, the northern Wasatch Range to the west, Durst Mountain to the east, the Weber River in Morgan Valley, and lower Weber Canyon cut into the Wasatch Range by the river.

Fibrosis is a leading cause of morbidity and mortality worldwide. Although fibrosis may involve different organ systems, transforming growth factor-β (TGFβ) has been established as a master regulator of fibrosis across organs. Pirfenidone and Nintedanib are the only currently-approved drugs to treat fibrosis, specifically idiopathic pulmonary fibrosis, but their mechanisms of action remain poorly understood. To identify novel drug targets and uncover potential mechanisms by which these drugs attenuate fibrosis, we performed an integrative 'omics analysis of transcriptomic and proteomic responses to TGFβ1-stimulated lung fibroblasts. Significant findings were annotated as associated with pirfenidone and nintedanib treatment in silico via Coremine. Integrative 'omics identified a co-expressed transcriptomic and proteomic module significantly correlated with TGFβ1 treatment that was enriched (FDR-p = 0.04) with genes associated with pirfenidone and nintedanib treatment. While a subset of genes in this module have been implicated in fibrogenesis, several novel TGFβ1 signaling targets were identified. Specifically, four genes (BASP1, HSD17B6, CDH11, and TNS1) have been associated with pirfenidone, while five genes (CLINT1, CADM1, MTDH, SYDE1, and MCTS1) have been associated with nintedanib, and MYDGF has been implicated with treatment using both drugs. Using the Clue Drug Repurposing Hub, succinic acid was highlighted as a metabolite regulated by the protein encoded by HSD17B6. This study provides new insights into the anti-fibrotic actions of pirfenidone and nintedanib and identifies novel targets for future mechanistic studies.

Author(s): Kane, Bryan G.; Totten, Vicken Y.; Kraus, Chadd K.; Allswede, Michael; Diercks, Deborah B.; Garg, Nidhi; Ling, Louis; McDonald, Eric N.; Rosenau, Alex M.; Wilk, Mike; Holmes, Alexandria D.; Hemminger, Adam; Greenberg, Marna Rayl | Abstract: Introduction: In the context of the upcoming single accreditation system for graduate medical education resulting from an agreement between the Accreditation Council for Graduate Medical Education (ACGME), American Osteopathic Association and American Association of Colleges of Osteopathic Medicine, we saw the opportunity for charting a new course for emergency medicine (EM) scholarly activity (SA). Our goal was to engage relevant stakeholders to produce a consensus document. Methods: Consensus building focused on the goals, definition, and endpoints of SA. Representatives from stakeholder organizations were asked to help develop a survey regarding the SA requirement. The survey was then distributed to those with vested interests. We used the preliminary data to find areas of concordance and discordance and presented them at a consensus-building session. Outcomes were then re-ranked. Results: By consensus, the primary role(s) of SA should be the following: 1) instruct residents in the process of scientific inquiry; 2) expose them to the mechanics of research; 3) teach them lifelong skills, including search strategies and critical appraisal; and 4) teach them how to formulate a question, search for the answer, and evaluate its strength. To meet these goals, the activity should have the general elements of hypothesis generation, data collection and analytical thinking, and interpretation of results. We also determined consensus on the endpoints, and acceptable documentation of the outcome. Conclusion: This consensus document may serve as a best-practices guideline for EM residency programs by delineating the goals, definitions, and endpoints for EM residents’ SA. However, each residency program must evaluate its available scholarly activity resources and individually implement requirements by balancing the ACGME Review Committee for Emergency Medicine requirements with their own circumstances.

Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.

Osteoarthritis is a common progressive joint disease. As no effective medical interventions are available, osteoarthritis often progresses to the end stage, in which only surgical options such as total joint replacement are available. A more thorough understanding of genetic influences of osteoarthritis is essential to develop targeted personalized approaches to treatment, ideally long before the end stage is reached. To date, there have been no large multiancestry genetic studies of osteoarthritis. Here, we leveraged the unique resources of 484,374 participants in the Million Veteran Program and UK Biobank to address this gap. Analyses included participants of European, African, Asian and Hispanic descent. We discovered osteoarthritis-associated genetic variation at 10 loci and replicated findings from previous osteoarthritis studies. We also present evidence that some osteoarthritis-associated regions are robust to population ancestry. Drug repurposing analyses revealed enrichment of targets of several medication classes and provide potential insight into the etiology of beneficial effects of antiepileptics on osteoarthritis pain.

How structural segment boundaries modulate earthquake behavior is an important scientific and societal question, especially for the Wasatch fault zone (WFZ) where urban areas lie along multiple fault segments. The extent to which segment boundaries arrest ruptures, host moderate magnitude earthquakes, or transmit ruptures to adjacent fault segments is critical for understanding seismic hazard. To help address this outstanding issue, we conducted a paleoseismic investigation at the Traverse Ridge paleoseismic site (TR site) along the ∼7-km-long Fort Canyon segment boundary, which links the Provo (59 km) and Salt Lake City (40 km) segments of the WFZ. At the TR site, we logged two trenches which were cut across sub-parallel traces of the fault, separated by ∼175 m. Evidence from these exposures leads us to infer that at least 3 to 4 earthquakes have ruptured across the segment boundary in the Holocene. Radiocarbon dating of soil material developed below and above fault scarp colluvial packages and within a filled fissure constrains the age of the events. The most recent event ruptured the southern fault trace between 0.2 and 0.4 ka, the penultimate event ruptured the northern fault trace between 0.6 and 3.4 ka, and two prior events occurred between 1.4 and 6.2 ka (on the southern fault trace) and 7.2 and 8.1 ka (northern fault trace). Colluvial wedge heights of these events ranged from 0.7 to 1.2 m, indicating the segment boundary experiences surface ruptures with more than 1 m of vertical displacement. Given these estimates, we infer that these events were greater than Mw 6.7, with rupture extending across the entire segment boundary and portions of one or both adjacent fault segments. The Holocene recurrence of events at the TR site is lower than the closest paleoseismic sites at the adjacent fault segment endpoints. The contrasts in recurrence rates observed within 15 km of the Fort Canyon fault segment boundary may be explained conceptually by a leaky segment boundary model which permits spillover events, ruptures centered on the segment boundary, and segmented ruptures. The TR site demonstrates the utility of paleoseismology within segment boundaries which, through corroboration of displacement data, can demonstrate rupture connectivity between fault segments and test the validity of rupture models.

Additional file 4: Supplementary Note. NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium Banner Authorship List.

Additional file 3: Figure S1. Associations between ACE2 gene expression and COPD, asthma, steroid use, and race. Figure S2. Associations between ACE2 gene expression and obesity. Figure S3. Associations between ACE2 gene expression and hypertension, and use of antihypertensives. Figure S4. Associations between age and ACE2 gene expression, and age and differential ACE2 exon usage. Figure S5. Associations between age and smoking status, hypertension, sex, and BMI in SPIROMICS. Figure S6. COVID-19 and other viral illness related gene set enrichment analyses in association with comorbidities in SPIROMICS, SARP, and MAST. Figure S7. Regulatory genetic effects of ACE2 and TMPRSS2, and the effect of smoking on TMPRSS2. Figure S8. Associations between COVID-19-related genes and comorbidities. Figure S9. Replication of cis-eQTLs in GTEx. Figure S10. Regulatory genetic effects of the candidate genes in the chr3 cluster associated with COVID-19. Figure S11. PheWAS associations for the 44 out of 108 lead cis-eQTLs associated with COVID-19-related genes with Phenoscanner v2.

Emotional reactions to a partner’s extradyadic romantic interests are assumed to be negative and characterized by jealousy, an emotional state that arises over a perceived threat to one’s relationship. Yet, reactions may also be positive, and involve compersion, or taking joy in one's partner's pleasure in other sexual and relational encounters. Although some have argued that compersion is the opposite of jealousy, research has shown that compersion and jealousy are not opposing constructs, despite being treated this way in both theoretical and empirical research. Using a convenience sample of polyamorous (N = 3,530) and monogamous (N = 1,358) individuals we draw on theories of jealousy, emotional ambivalence, and emotional forecasting to examine people’s anticipated affective responses to hypothetical situations involving a partner’s extradyadic relations, and assess whether experience with having a partner engage in extradyadic relations was associated with anticipating less jealousy and more compersion. Results suggest that people in polyamorous relationships report less jealousy and more compersion with their partners, and that personal experience involving a partner’s extradyadic romantic interests predicted more compersion and less jealousy, with experience predicting greater increases in compersion among monogamous than polyamorous participants. Finally, while anticipated compersion was associated with greater relationship satisfaction, neither jealousy nor ambivalence were associated with relationship satisfaction. These results further demonstrate that individuals can experience both positive and negative reactions to a partner’s extradyadic relations, both based on actual experience and projection of responses to future events, and that real-life experiences are important in anticipating these emotions.

Additional file 1. Supplementary Methods.

Context.— We previously examined pituitary adenomas with immunohistochemical (IHC) stains for steroidogenic factor 1, Pit-1, anterior pituitary hormones, cytokeratin CAM 5.2, and the α-subunit of human chorionic gonadotropin and found that a screening panel comprising stains for steroidogenic factor 1, Pit-1, and adrenocorticotropic hormone successfully classified most cases and reduced the overall number of stains required. Objectives.— To examine the potential role of IHC stain for T-box transcription factor (Tpit) in the classification of our series of pituitary adenomas and to update our screening panel as necessary. Design.— We collected 157 pituitary adenomas from 2 institutions and included these in tissue microarrays. Immunostains for Tpit were scored in a blinded fashion using the Allred system. Adenomas were assigned to a gold standard class based on IHC pattern followed by application of available clinical and serologic information. Test characteristics were calculated. Correlation analyses, cluster analyses, and classification tree analyses were used to see whether IHC staining patterns reliably reflected adenoma class. Results.— Of the cases collected, 147 (93.6%) had sufficient material for Tpit analysis. IHC stain for Tpit identified 8 null cell adenomas (all nonfunctioning clinically) as silent corticotrophs; Tpit stains showed better sensitivity, specificity, positive predictive value, and negative predictive value than IHC for adrenocorticotropic hormone and cytokeratin CAM 5.2. Correlation analyses continued to show the expected relationships among IHC stains. Cluster analyses showed grouping of adenomas into clinically consistent groups. Classification tree analysis underscored the central role of transcription factor IHC stains, including Tpit, in adenoma classification. Conclusions.— Substitution of Tpit stain for the adrenocorticotropic hormone stain improves our prior algorithm by reducing the number of false-negatives and false-positives. As a result, fewer adenomas are classified as null cell adenoma, and more adenomas are classified as silent corticotroph adenoma.

Additional file 1: Table S1. ECLIPSE Sample Demographics. Descriptive values for COPD patients (N = 114) in ECLIPSE with gene expression data by Cachectic (N = 9) and Non-Cachectic (N = 105) co-morbid status. Unless otherwise noted values denote mean (SD). Table S2. Gene set enrichment analysis of 23 significantly (FDR p-value