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PNAS Nexus
Number of Followers: 3  

  This is an Open Access Journal Open Access journal
ISSN (Online) 2752-6542
Published by Oxford University Press Homepage  [419 journals]
  • Historical prevalence of slavery predicts contemporary American gun
           ownership

    • Abstract: AbstractAmerican gun-owners, uniquely, view firearms as a means of keeping themselves safe from dangers both physical and psychological. We root this belief in the experience of White Southerners during Reconstruction—a moment when a massive upsurge in the availability of firearms co-occurred with a worldview threat from the emancipation and the political empowerment of Black Southerners. We show that the belief-complex formed in this historical moment shapes contemporary gun culture: The prevalence of slavery in a Southern county (measured in 1860) predicts the frequency of firearms in the present day. This relationship holds above and beyond a number of potential covariates, including contemporary crime rates, police spending, degree of racial segregation and inequality, socioeconomic conditions, and voting patterns in the 2016 Presidential election; and is partially mediated by the frequency of people in the county reporting that they generally do not feel safe. This Southern origin of gun culture may help to explain why we find that worries about safety do not predict county-level gun ownership outside of historically slave-owning counties, and why we find that social connection to historically slaveholding counties predicts county-level gun ownership, even outside of the South.
      PubDate: Fri, 05 Aug 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac117
      Issue No: Vol. 1, No. 3 (2022)
       
  • Argonaute 2 modulates EGFR–RAS signaling to promote mutant HRAS and
           NRAS-driven malignancies

    • Abstract: AbstractActivating mutations in RAS GTPases drive nearly 30% of all human cancers. Our prior work described an essential role for Argonaute 2 (AGO2), of the RNA-induced silencing complex, in mutant KRAS-driven cancers. Here, we identified a novel endogenous interaction between AGO2 and RAS in both wild-type (WT) and mutant HRAS/NRAS cells. This interaction was regulated through EGFR-mediated phosphorylation of Y393-AGO2, and utilizing molecular dynamic simulation, we identified a conformational change in pY393-AGO2 protein structure leading to disruption of the RAS binding site. Knockdown of AGO2 led to a profound decrease in proliferation of mutant HRAS/NRAS-driven cell lines but not WT RAS cells. These cells demonstrated oncogene-induced senescence (OIS) as evidenced by β-galactosidase staining and induction of multiple downstream senescence effectors. Mechanistically, we discovered that the senescent phenotype was mediated via induction of reactive oxygen species. Intriguingly, we further identified that loss of AGO2 promoted a novel feed forward pathway leading to inhibition of the PTP1B phosphatase and activation of EGFR–MAPK signaling, consequently resulting in OIS. Taken together, our study demonstrates that the EGFR–AGO2–RAS signaling axis is essential for maintaining mutant HRAS and NRAS-driven malignancies.
      PubDate: Thu, 28 Jul 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac084
      Issue No: Vol. 1, No. 3 (2022)
       
  • Quarantine and serial testing for variants of SARS-CoV-2 with benefits of
           vaccination and boosting on consequent control of COVID-19

    • Abstract: AbstractQuarantine and serial testing strategies for a disease depend principally on its incubation period and infectiousness profile. In the context of COVID-19, these primary public health tools must be modulated with successive SARS CoV-2 variants of concern that dominate transmission. Our analysis shows that (1) vaccination status of an individual makes little difference to the determination of the appropriate quarantine duration of an infected case, whereas vaccination coverage of the population can have a substantial effect on this duration, (2) successive variants can challenge disease control efforts by their earlier and increased transmission in the disease time course relative to prior variants, and (3) sufficient vaccine boosting of a population substantially aids the suppression of local transmission through frequent serial testing. For instance, with Omicron, increasing immunity through vaccination and boosters—for instance with 100% of the population is fully immunized and at least 24% having received a third dose—can reduce quarantine durations by up to 2 d, as well as substantially aid in the repression of outbreaks through serial testing. Our analysis highlights the paramount importance of maintaining high population immunity, preferably by booster uptake, and the role of quarantine and testing to control the spread of SARS CoV-2.
      PubDate: Wed, 27 Jul 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac100
      Issue No: Vol. 1, No. 3 (2022)
       
  • Primary cicatricial alopecias are characterized by dysregulation of shared
           gene expression pathways

    • Abstract: AbstractThe primary forms of cicatricial (scarring) alopecia (PCA) are a group of inflammatory, irreversible hair loss disorders characterized by immune cell infiltrates targeting hair follicles (HFs). Lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), and centrifugal cicatricial alopecia (CCCA) are among the main subtypes of PCAs. The pathogenesis of the different types of PCAs are poorly understood, and current treatment regimens yield inconsistent and unsatisfactory results. We performed high-throughput RNA-sequencing on scalp biopsies of a large cohort PCA patients to develop gene expression-based signatures, trained into machine-learning-based predictive models and pathways associated with dysregulated gene expression. We performed morphological and cytokine analysis to define the immune cell populations found in PCA subtypes. We identified a common PCA gene signature that was shared between LPP, FFA, and CCCA, which revealed a significant over-representation of mast cell (MC) genes, as well as downregulation of cholesterogenic pathways and upregulation of fibrosis and immune signaling genes. Immunohistological analyses revealed an increased presence of MCs in PCAs lesions. Our gene expression analyses revealed common pathways associated with PCAs, with a strong association with MCs. The indistinguishable differences in gene expression profiles and immune cell signatures between LPP, FFA, and CCCA suggest that similar treatment regimens may be effective in treating these irreversible forms of hair loss.
      PubDate: Mon, 11 Jul 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac111
      Issue No: Vol. 1, No. 3 (2022)
       
  • Mechanisms of phase-separation-mediated cGAS activation revealed by dcFCCS

    • Abstract: AbstractCyclic GMP–AMP synthase (cGAS), as a DNA sensor, plays an important role in cGAS–STING pathway, which further induces expression of type I interferon as the innate immune response. Previous studies reported that liquid–liquid phase separation (LLPS) driven by cGAS and long DNA is essential to promote catalytic activity of cGAS to produce a second messenger, cyclic GMP–AMP (cGAMP). However, the molecular mechanism of LLPS promoting cGAS activity is still unclear. Here, we applied dual-color fluorescence cross-correlation spectroscopy (dcFCCS), a highly sensitive and quantitative method, to characterize phase separation driven by cGAS and DNA from miscible individual molecule to micronscale. Thus, we captured nanoscale condensates formed by cGAS at close-to-physiological concentration and quantified their sizes, molecular compositions and binding affinities within condensates. Our results pinpointed that interactions between DNA and cGAS at DNA binding sites A, B, and C and the dimerization of cGAS are the fundamental molecular basis to fully activate cGAS in vitro. Due to weak binding constants of these sites, endogenous cGAS cannot form stable interactions at these sites, leading to no activity in the absence of LLPS. Phase separation of cGAS and DNA enriches cGAS and DNA by 2 to 3 orders of magnitude to facilitate these interactions among cGAS and DNA and to promote cGAS activity as an on/off switch. Our discoveries not only shed lights on the molecular mechanisms of phase-separation-mediated cGAS activation, but also guided us to engineer a cGAS fusion, which can be activated by 15 bp short DNA without LLPS.
      PubDate: Fri, 08 Jul 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac109
      Issue No: Vol. 1, No. 3 (2022)
       
  • Single-crystal-like germanium thin films on large-area, compliant,
           light-weight, flexible, single-crystal-like substrates

    • Abstract: AbstractGermanium (Ge) films were heteroepitaxially grown on flexible, large-area, single-crystal-like metallic substrates. Multiple, heteroepitaxial, buffer layers of nanoscale dimensions were deposited on the triaxially textured, single-crystal-like, thermo-mechanically processed Ni–W alloy substrates. Ge films were deposited on a CeO2-terminated, heteroepitaxial buffer stack on the metallic substrate using electron beam evaporation. X-ray diffraction θ–2θ scans showed a very strong Ge (400) peak and the full width at half-maximum (FWHM) of the Ge (400) rocking curve was 0.93°. The Ge (111) ϕ-scan showed a FWHM value ∼4°. Based on the X-ray ω-scan, ϕ-scan and (111), (110), and (001) X-ray pole-figures, the Ge film deposited on the flexible, metallic substrate had a cube-on-cube heteroepitaxial relationship with the single-crystal-like metallic substrate. Reflection-high-energy-diffraction (RHEED) patterns from the Ge layer was streaky indicative of a smooth and essentially single-crystal-like Ge film. Cross-section TEM examination revealed a sharp interface between the Ge film and the topmost buffer layer, CeO2, with a low defect density. The CeO2 layer serves as a highly compliant layer that modulates its lattice parameter to attain excellent lattice-matching to the heteroepitaxial Ge layer. Ge films grown on these flexible metal substrates exhibited electron mobilities in the range of 175–250 cm2V–1s–1. Such single-crystal-like semiconductor films on low-cost, flexible, large-area, scalable, single-crystal-like metallic substrates could potentially enable high-performance electronic devices for a range of applications.
      PubDate: Tue, 05 Jul 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac098
      Issue No: Vol. 1, No. 3 (2022)
       
  • Quantifying the immunological distinctiveness of emerging SARS-CoV-2
           variants in the context of prior regional herd exposure

    • Abstract: AbstractThe COVID-19 pandemic has seen the persistent emergence of immune-evasive SARS-CoV-2 variants under the selection pressure of natural and vaccination-acquired immunity. However, it is currently challenging to quantify how immunologically distinct a new variant is compared to all the prior variants to which a population has been exposed. Here, we define “Distinctiveness” of SARS-CoV-2 sequences based on a proteome-wide comparison with all prior sequences from the same geographical region. We observe a correlation between Distinctiveness relative to contemporary sequences and future change in prevalence of a newly circulating lineage (Pearson r = 0.75), suggesting that the Distinctiveness of emergent SARS-CoV-2 lineages is associated with their epidemiological fitness. We further show that the average Distinctiveness of sequences belonging to a lineage, relative to the Distinctiveness of other sequences that occur at the same place and time (n = 944 location/time data points), is predictive of future increases in prevalence (Area Under the Curve, AUC = 0.88 [95% confidence interval 0.86 to 0.90]). By assessing the Delta variant in India versus Brazil, we show that the same lineage can have different Distinctiveness-contributing positions in different geographical regions depending on the other variants that previously circulated in those regions. Finally, we find that positions that constitute epitopes contribute disproportionately (20-fold higher than the average position) to Distinctiveness. Overall, this study suggests that real-time assessment of new SARS-CoV-2 variants in the context of prior regional herd exposure via Distinctiveness can augment genomic surveillance efforts.
      PubDate: Mon, 04 Jul 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac105
      Issue No: Vol. 1, No. 3 (2022)
       
  • A potent tumor-selective ERK pathway inactivator with high therapeutic
           index

    • Abstract: AbstractFDA-approved BRAF and MEK small molecule inhibitors have demonstrated some level of efficacy in patients with metastatic melanomas. However, these “targeted” therapeutics have a very low therapeutic index, since these agents affect normal cells, causing undesirable, even fatal, side effects. To address these significant drawbacks, here, we have reengineered the anthrax toxin-based protein delivery system to develop a potent, tumor-selective MEK inactivator. This toxin-based MEK inactivator exhibits potent activity against a wide range of solid tumors, with the highest activity seen when directed toward tumors containing the BRAFV600E mutation. We demonstrate that this reengineered MEK inactivator also exhibits an extremely high therapeutic index (>15), due to its in vitro and in vivo activity being strictly dependent on the expression of multiple tumor-associated factors including tumor-associated proteases matrix metalloproteinase, urokinase plasminogen activator, and anthrax toxin receptor capillary morphogenesis protein-2. Furthermore, we have improved the specificity of this MEK inactivator, restricting its enzymatic activity to only target the ERK pathway, thereby greatly diminishing off-target toxicity. Together, these data suggest that engineered bacterial toxins can be modified to have significant in vitro and in vivo therapeutic effects with high therapeutic index.
      PubDate: Fri, 01 Jul 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac104
      Issue No: Vol. 1, No. 3 (2022)
       
  • Mitigating long queues and waiting times with service resetting

    • Abstract: AbstractWhat determines the average length of a queue, which stretches in front of a service station' The answer to this question clearly depends on the average rate at which jobs arrive at the queue and on the average rate of service. Somewhat less obvious is the fact that stochastic fluctuations in service and arrival times are also important, and that these are a major source of backlogs and delays. Strategies that could mitigate fluctuations-induced delays are, thus in high demand as queue structures appear in various natural and man-made systems. Here, we demonstrate that a simple service resetting mechanism can reverse the deleterious effects of large fluctuations in service times, thus turning a marked drawback into a favorable advantage. This happens when stochastic fluctuations are intrinsic to the server, and we show that service resetting can then dramatically cut down average queue lengths and waiting times. Remarkably, this strategy is also useful in extreme situations where the variance, and possibly even mean, of the service time diverge—as resetting can then prevent queues from “blowing up.” We illustrate these results on the M/G/1 queue in which service times are general and arrivals are assumed to be Markovian. However, the main results and conclusions coming from our analysis are not specific to this particular model system. Thus, the results presented herein can be carried over to other queueing systems: in telecommunications, via computing, and all the way to molecular queues that emerge in enzymatic and metabolic cycles of living organisms.
      PubDate: Fri, 01 Jul 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac070
      Issue No: Vol. 1, No. 3 (2022)
       
  • Sustained timber yield claims, considerations, and tradeoffs for
           selectively logged forests

    • Abstract: ABSTRACTWhat is meant by sustainability depends on what is sustained and at what level. Sustainable forest management, for example, requires maintenance of a variety of values not the least of which is sustained timber yields (STYs). For the 1 Bha of the world's forests subjected to selective or partial logging, failure to maintain yields can be hidden by regulatory requirements and questionable auditing practices such as increasing the number of commercial species with each harvest, reducing the minimum size at which trees can be harvested and accepting logs of lower quality. For assertions of STY to be credible, clarity is needed about all these issues, as well as about the associated ecological and economic tradeoffs. Lack of clarity about sustainability heightens risks of unsubstantiated claims and unseen losses. STY is possible but often requires cutting cycles that are longer and logging intensities that are lower than prescribed by law, as well as effective use of low-impact logging practices and application of silvicultural treatments to promote timber stock recovery. These departures from business-as-usual practices will lower profit margins but generally benefit biodiversity and ecosystem services.
      PubDate: Fri, 01 Jul 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac102
      Issue No: Vol. 1, No. 3 (2022)
       
  • Cash-like vouchers improve psychological well-being of vulnerable and
           displaced persons fleeing armed conflict

    • Abstract: AbstractThe psychological burden of conflict-induced displacement is severe. Currently, there are 80 million displaced persons around the world, and their number is expected to increase in upcoming decades. Yet, few studies have systematically assessed the effectiveness of programs that assist displaced persons, especially in settings of extreme vulnerability. We focus on eastern Democratic Republic of Congo, where myriad local armed conflicts have driven cycles of displacement for over 20 years. We conducted a within-village randomized field experiment with 976 households, across 25 villages, as part of the United Nations’ Rapid Response to Population Movements program. The program provided humanitarian relief to over a million people each year, including vouchers for essential nonfood items, such as pots, pans, cloth, and mattresses. The vouchers led to large improvements in psychological well-being: a 0.32 standard deviation unit (SDU) improvement at 6 weeks, and a 0.18 SDU improvement at 1 year. There is no evidence that the program undermined social cohesion within the village, which alleviates worries related to programs that target some community members but not others. Finally, there was no improvement in child health.
      PubDate: Thu, 30 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac101
      Issue No: Vol. 1, No. 3 (2022)
       
  • Heterosis of fitness and phenotypic variance in the evolution of a diploid
           gene regulatory network

    • Abstract: AbstractHeterosis describes the phenomenon, whereby a hybrid population has higher fitness than an inbred population, which has previously been explained by either Mendelian dominance or overdominance under the general assumption of a simple genotype–phenotype relationship. However, recent studies have demonstrated that genes interact through a complex gene regulatory network (GRN). Furthermore, phenotypic variance is reportedly lower for heterozygotes, and the origin of such variance-related heterosis remains elusive. Therefore, a theoretical analysis linking heterosis to GRN evolution and stochastic gene expression dynamics is required. Here, we investigated heterosis related to fitness and phenotypic variance in a system with interacting genes by numerically evolving diploid GRNs. According to the results, the heterozygote population exhibited higher fitness than the homozygote population, indicating fitness-related heterosis resulting from evolution. In addition, the heterozygote population exhibited lower noise-related phenotypic variance in expression levels than the homozygous population, implying that the heterozygote population is more robust to noise. Furthermore, the distribution of the ratio of heterozygote phenotypic variance to homozygote phenotypic variance exhibited quantitative similarity with previous experimental results. By applying dominance and differential gene expression rather than only a single gene expression model, we confirmed the correlation between heterosis and differential gene expression. We explain our results by proposing that the convex high-fitness region is evolutionarily shaped in the genetic space to gain noise robustness under genetic mixing through sexual reproduction. These results provide new insights into the effects of GRNs on variance-related heterosis and differential gene expression.
      PubDate: Wed, 29 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac097
      Issue No: Vol. 1, No. 3 (2022)
       
  • Experimental reductions in subdaily flow fluctuations increased gross
           primary productivity for 425 river kilometers downstream

    • Abstract: AbstractAquatic primary production is the foundation of many river food webs. Dams change the physical template of rivers, often driving food webs toward greater reliance on aquatic primary production. Nonetheless, the effects of regulated flow regimes on primary production are poorly understood. Load following is a common dam flow management strategy that involves subdaily changes in water releases proportional to fluctuations in electrical power demand. This flow regime causes an artificial tide, wetting and drying channel margins and altering river depth and water clarity, all processes that are likely to affect primary production. In collaboration with dam operators, we designed an experimental flow regime whose goal was to mitigate negative effects of load following on ecosystem processes. The experimental flow contrasted steady-low flows on weekends with load following flows on weekdays. Here, we quantify the effect of this experimental flow on springtime gross primary production (GPP) 90-to-425 km downstream of Glen Canyon Dam on the Colorado River, AZ, USA. GPP during steady-low flows was 41% higher than during load following flows, mostly owing to nonlinear reductions in sediment-driven turbidity. The experimental flow increased weekly GPP even after controlling for variation in weekly mean discharge, demonstrating a negative effect of load following on GPP. We estimate that this environmental flow increased springtime carbon fixation by 0.27 g C m−2 d−1, which is ecologically meaningful considering median C fixation in 356 US rivers of 0.44 g C m−2 d−1 and the fact that native fish populations in this river are food-limited.
      PubDate: Sat, 25 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac094
      Issue No: Vol. 1, No. 3 (2022)
       
  • At the nexus of science, engineering, and medicine: Pasteur's quadrant
           reconsidered

    • Abstract: AbstractThere has been a sea change in the scientific world, advanced even more rapidly by the recent compounded public crises. Accelerated discovery, and impact from such discoveries have come from convergence approaches across disciplines, sectors, institutions, and the multiple communities seeking the common goal of innovations that transform. The classic simultaneous pursuit of fundamental understanding and application has been termed  Pasteur's quadrant, where use-inspired basic research occurs. In the classic schematic developed by Donald Stokes, three quadrants  represent research approaches using a 2D plane in which the vertical dimension represents the quest for understanding (basic research) and the horizontal dimension represents the consideration of use (applied research). The three outer quadrants are Bohr's (pure basic research), Edison's (pure applied research), and Pasteur's (use-inspired  basic research). Viewing each of these axes as a continuum, we label the previously unnamed but contributory cell as the Innominate quadrant, where a nonzero amount of discovery and applied research also has value in generating scientific tools, novel processes or products that inform the other quadrants. More importantly, a reimagined Pasteur's quadrant schema shows a third dimension of Transformations over Time, occurring through a continuous fluid interchange among the quadrants.  Transformative innovations may originate from any single quadrant.  While work in Pasteur's quadrant has been shown to be highly productive, a dynamic fluid interchange among the quadrants is often involved and generates transformative advances at a faster rate. This should inform how we fund science, engineeering, and medicine and educate the next generation of innovators.
      PubDate: Thu, 23 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac092
      Issue No: Vol. 1, No. 3 (2022)
       
  • Perceived movement of nonrigid motion patterns

    • Abstract: AbstractNonrigid materials such as liquids or smoke deform over time. Little is known about the visual perception of nonrigid motion other than that many motion cues associated with rigid motion perception are not reliable for nonrigid motion. Nonrigid motion patterns lack clear borders and their movement can be inconsistent with the motion of their parts. We developed a novel stimulus that creates a nonrigid vortex motion pattern in a random dot distribution and decouples the movement of the vortex from the first-order motion of the dots. We presented three moving vortices that entailed consecutively fewer motion cues, eliminating occlusion, motion borders, and velocity field gradients in the process. Subjects were well able to report the end position and travel path in all cases, showing that nonrigid motion is perceived through an analysis of the temporal evolution of visual motion patterns and does not require borders or speed differences. Adding a coherent global motion did not hamper perception, but adding local noise did, indicating that the visual system uses mid-level features that are on a local scale. We also found that participants judged the movement of the nonrigid motion patterns slower than a rigid control, revealing that speed perception was based on a combination of motion of the parts and movement of the pattern. We propose that the visual system uses the temporal evolution of a motion pattern for the perception of nonrigid motion and suggest a plausible mechanism based on the curl of the motion field.
      PubDate: Wed, 22 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac088
      Issue No: Vol. 1, No. 3 (2022)
       
  • Sporadic, late-onset, and multistage diseases

    • Abstract: AbstractMultistage disease processes are often characterized by a linear relationship between the log of incidence rates and the log of age. Examples include sequences of somatic mutations, that can cause cancer, and have recently been linked with a range of non-malignant diseases. Using a Weibull distribution to model diseases that occur through an ordered sequence of stages, and another model where stages can occur in any order, we characterized the age-related onset of disease in UK Biobank data. Despite their different underlying assumptions, both models accurately described the incidence of over 450 diseases, demonstrating that multistage disease processes cannot be inferred from this data alone. The parametric models provided unique insights into age-related disease, that conventional studies of relative risks cannot. The rate at which disease risk increases with age was used to distinguish between “sporadic” diseases, with an initially low and slowly increasing risk, and “late-onset” diseases whose negligible risk when young rapidly increases with age. “Relative aging rates” were introduced to quantify how risk factors modify age-related risk, finding the effective age-at-risk of sporadic diseases is strongly modified by common risk factors. Relative aging rates are ideal for risk-stratification, allowing the identification of ages with equivalent-risk in groups with different exposures. Most importantly, our results suggest that a substantial burden of sporadic diseases can be substantially delayed or avoided by early lifestyle interventions.
      PubDate: Wed, 22 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac095
      Issue No: Vol. 1, No. 3 (2022)
       
  • Pleiotropic opposing dominance within a color gene block contributes to a
           nascent species boundary via its influence on hybrid male territorial
           behavior

    • Abstract: AbstractThe divergence of plumage color genes contributes to songbird radiation. However, the mechanisms by which color gene divergence counteracts gene flow to maintain reproductive isolation during the formation of new species boundaries remain elusive. The hybrid zone between Setophaga occidentalis (SOCC) and S. townsendi (STOW) in the Cascade Range provides a natural observatory to investigate potential behavioral mechanisms underlying divergent selection on color genes. Recently, we found that selection within a single gene block associated with plumage color variation has maintained a stable and narrow hybrid zone. Here, we investigated the potential role of plumage signals in moderating a behavioral mechanism of selection. Specifically, we assessed whether two plumage traits are associated with body size among breeding males and if trait mismatch predicted aggressive behavior within hybrid and parental individuals in response to simulated territorial intrusion. The two plumage signals, cheek and flank coloration, though associated with the same gene block, reflect opposing dominance of SOCC and STOW alleles. We found that both plumage traits significantly predict the body size in the territorial sex (i.e. males). The opposing dominance of the single color gene block resulted in plumage signal discordance in heterozygotes, which in turn was associated with reduced hybrid territorial performance, an important proxy of fitness in this system. Taken together, these observations point to a single-locus-two-alleles mechanism of incompatibility in shaping a natural species boundary in the early stage of speciation.
      PubDate: Mon, 11 Jul 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac074
       
  • Deadly gun violence, neighborhood collective efficacy, and adolescent
           neurobehavioral outcomes

    • Abstract: AbstractGun violence is a major public health problem and costs the United States $280 billion annually (1). Although adolescents are disproportionately impacted (e.g. premature death), we know little about how close adolescents live to deadly gun violence incidents and whether such proximity impacts their socioemotional development (2, 3). Moreover, gun violence is likely to shape youth developmental outcomes through biological processes—including functional connectivity within regions of the brain that support emotion processing, salience detection, and physiological stress responses—though little work has examined this hypothesis. Lastly, it is unclear if strong neighborhood social ties can buffer youth from the neurobehavioral effects of gun violence. Within a nationwide birth cohort of 3,444 youth (56% Black, 24% Hispanic) born in large US cities, every additional deadly gun violence incident that occurred within 500 meters of home in the prior year was associated with an increase in behavioral problems by 9.6%, even after accounting for area-level crime and socioeconomic resources. Incidents that occurred closer to a child's home exerted larger effects, and stronger neighborhood social ties offset these associations. In a neuroimaging subsample (N = 164) of the larger cohort, living near more incidents of gun violence and reporting weaker neighborhood social ties were associated with weaker amygdala–prefrontal functional connectivity during socioemotional processing, a pattern previously linked to less effective emotion regulation. Results provide spatially sensitive evidence for gun violence effects on adolescent behavior, a potential mechanism through which risk is biologically embedded, and ways in which positive community factors offset ecological risk.
      PubDate: Thu, 07 Jul 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac061
       
  • SARS-CoV-2 and influenza coinfection throughout the COVID-19 pandemic: an
           assessment of coinfection rates, cohort characteristics, and clinical
           outcomes

    • Abstract: AbstractCase reports of patients infected with COVID-19 and influenza virus (“flurona”) have raised questions around the prevalence and severity of coinfection. Using data from HHS Protect Public Data Hub, NCBI Virus, and CDC FluView, we analyzed trends in SARS-CoV-2 and influenza hospitalized coinfection cases and strain prevalences. We also characterized coinfection cases across the Mayo Clinic Enterprise from January 2020 to April 2022. We compared expected and observed coinfection case counts across different waves of the pandemic and assessed symptoms and outcomes of coinfection and COVID-19 monoinfection cases after propensity score matching on clinically relevant baseline characteristics. From both the Mayo Clinic and nationwide datasets, the observed coinfection rate for SARS-CoV-2 and influenza has been higher during the Omicron era (2021 December 14 to 2022 April 2) compared to previous waves, but no higher than expected assuming infection rates are independent. At the Mayo Clinic, only 120 coinfection cases were observed among 197,364 SARS-CoV-2 cases. Coinfected patients were relatively young (mean age: 26.7 years) and had fewer serious comorbidities compared to monoinfected patients. While there were no significant differences in 30-day hospitalization, ICU admission, or mortality rates between coinfected and matched COVID-19 monoinfection cases, coinfection cases reported higher rates of symptoms including congestion, cough, fever/chills, headache, myalgia/arthralgia, pharyngitis, and rhinitis. While most coinfection cases observed at the Mayo Clinic occurred among relatively healthy individuals, further observation is needed to assess outcomes among subpopulations with risk factors for severe COVID-19 such as older age, obesity, and immunocompromised status.
      PubDate: Mon, 04 Jul 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac071
       
  • Crop genetic diversity uncovers metabolites, elements, and gene networks
           predicted to be associated with high plant biomass yields in maize

    • Abstract: AbstractRapid population growth and increasing demand for food, feed, and bioenergy in these times of unprecedented climate change require breeding for increased biomass production on the world's croplands. To accelerate breeding programs, knowledge of the relationship between biomass features and underlying gene networks is needed to guide future breeding efforts. To this end, large-scale multiomics datasets were created with genetically diverse maize lines, all grown in long-term organic and conventional cropping systems. Analysis of the datasets, integrated using regression modeling and network analysis revealed key metabolites, elements, gene transcripts, and gene networks, whose contents during vegetative growth substantially influence the build-up of plant biomass in the reproductive phase. We found that S and P content in the source leaf and P content in the root during the vegetative stage contributed the most to predicting plant performance at the reproductive stage. In agreement with the Gene Ontology enrichment analysis, the cis-motifs and identified transcription factors associated with upregulated genes under phosphate deficiency showed great diversity in the molecular response to phosphate deficiency in selected lines. Furthermore, our data demonstrate that genotype-dependent uptake, assimilation, and allocation of essential nutrient elements (especially C and N) during vegetative growth under phosphate starvation plays an important role in determining plant biomass by controlling root traits related to nutrient uptake. These integrative multiomics results revealed key factors underlying maize productivity and open new opportunities for efficient, rapid, and cost-effective plant breeding to increase biomass yield of the cereal crop maize under adverse environmental factors.
      PubDate: Mon, 04 Jul 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac068
       
  • Modeling pandemic to endemic patterns of SARS-CoV-2 transmission using
           parameters estimated from animal model data

    • Abstract: AbstractThe contours of endemic coronaviral disease in humans and other animals are shaped by the tendency of coronaviruses to generate new variants superimposed upon nonsterilizing immunity. Consequently, patterns of coronaviral reinfection in animals can inform the emerging endemic state of the SARS-CoV-2 pandemic. We generated controlled reinfection data after high and low risk natural exposure or heterologous vaccination to sialodacryoadenitis virus (SDAV) in rats. Using deterministic compartmental models, we utilized in vivo estimates from these experiments to model the combined effects of variable transmission rates, variable duration of immunity, successive waves of variants, and vaccination on patterns of viral transmission. Using rat experiment-derived estimates, an endemic state achieved by natural infection alone occurred after a median of 724 days with approximately 41.3% of the population susceptible to reinfection. After accounting for translationally altered parameters between rat-derived data and human SARS-CoV-2 transmission, and after introducing vaccination, we arrived at a median time to endemic stability of 1437 (IQR = 749.25) days with a median 15.4% of the population remaining susceptible. We extended the models to introduce successive variants with increasing transmissibility and included the effect of varying duration of immunity. As seen with endemic coronaviral infections in other animals, transmission states are altered by introduction of new variants, even with vaccination. However, vaccination combined with natural immunity maintains a lower prevalence of infection than natural infection alone and provides greater resilience against the effects of transmissible variants.
      PubDate: Fri, 01 Jul 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac096
       
  • Insight into 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced disruption of
           zebrafish spermatogenesis via single cell RNA-seq

    • Abstract: Abstract2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent and environmentally persistent endocrine disrupting chemical. Our previous work demonstrated the latent reproductive maladies of early-life TCDD exposure in zebrafish. Zebrafish acutely exposed to low, environmentally relevant levels of TCDD (50 pg/mL) during two windows of sexual differentiation in development (1 hour of exposure at 3 and 7 weeks postfertilization) were later infertile, showed a reduction in sperm, and exhibited gene expression consistent with an altered microenvironment, even months after exposure. Due to the highly heterogeneous cell- type and -stage landscape of the testes, we hypothesized various cell types contribute markedly different profiles toward the pathology of TCDD exposure. To investigate the contributions of the diverse cell types in the adult zebrafish testes to TCDD-induced pathology, we utilized single-cell RNA-seq and the 10x Genomics platform. The method successfully captured every stage of testicular germ cell development. Testes of adult fish exposed during sexual differentiation to TCDD contained sharply decreased populations of late spermatocytes, spermatids, and spermatozoa. Spermatogonia and early spermatocyte populations were, in contrast, enriched following exposure. Pathway analysis of differentially expressed genes supported previous findings that TCDD exposure resulted in male infertility, and suggested this outcome is due to apoptosis of spermatids and spermatozoa, even years after exposure cessation. Increased germ cell apoptosis was confirmed histologically. These results provide support for an environmental exposure explanation of idiopathic male infertility.
      PubDate: Wed, 22 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac060
       
  • Steady-like topology of the dynamical hydrogen bond network in supercooled
           water

    • Abstract: AbstractWe investigate the link between topology of the hydrogen bond network (HBN) and large-scale density fluctuations in water from ambient conditions to the glassy state. We observe a transition from a temperature-dependent topology at high temperatures, to a steady-like topology below the Widom temperature TW ∼ 220 K signaling the fragile-to-strong crossover and the maximum in structural fluctuations. As a consequence of the steady topology, the network suppresses large-scale density fluctuations much more efficiently than at higher temperatures. Below TW, the contribution of coordination defects of the kind A2D1 (two acceptors and one donor) to the kinetics of the HBN becomes progressively more pronounced, suggesting that A2D1 configurations may represent the main source of dynamical heterogeneities. Below the vitrification temperature, the freezing of rotational and translational degrees of freedom allow for an enhanced suppression of large-scale density fluctuations and the sample reaches the edges of nearly hyperuniformity. The formed network still hosts coordination defects, hence implying that nearly hyperuniformity goes beyond the classical continuous random network paradigm of tetrahedral networks and can emerge in scenarios much more complex than previously assumed. Our results unveil a hitherto undisclosed link between network topology and properties of water essential for better understanding water’s rich and complex nature. Beyond implications for water, our findings pave the way to a better understanding of the physics of supercooled liquids and disordered hyperuniform networks at large.
      PubDate: Fri, 17 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac090
       
  • An intranasally administrated SARS-CoV-2 beta variant subunit booster
           vaccine prevents beta variant replication in rhesus macaques

    • Abstract: AbstractEmergence of SARS-CoV-2 variants and waning of vaccine/infection-induced immunity pose threats to curbing the COVID-19 pandemic. Effective, safe, and convenient booster vaccines are in need. We hypothesized that a variant-modified mucosal booster vaccine might induce local immunity to prevent SARS-CoV-2 infection at the port of entry. The beta-variant is one of the hardest to cross-neutralize. Herein, we assessed the protective efficacy of an intranasal booster composed of beta variant-spike protein S1 with IL-15 and TLR agonists in previously immunized macaques. The macaques were first vaccinated with Wuhan strain S1 with the same adjuvant. A total of 1 year later, negligibly detectable SARS-CoV-2-specific antibody remained. Nevertheless, the booster induced vigorous humoral immunity including serum- and bronchoalveolar lavage (BAL)-IgG, secretory nasal- and BAL-IgA, and neutralizing antibody against the original strain and/or beta variant. Beta-variant S1-specific CD4+ and CD8+ T cell responses were also elicited in PBMC and BAL. Following SARS-CoV-2 beta variant challenge, the vaccinated group demonstrated significant protection against viral replication in the upper and lower respiratory tracts, with almost full protection in the nasal cavity. The fact that one intranasal beta-variant booster administrated 1 year after the first vaccination provoked protective immunity against beta variant infections may inform future SARS-CoV-2 booster design and administration timing.
      PubDate: Fri, 17 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac091
       
  • Abnormal antibodies to self-carbohydrates in SARS-CoV-2-infected patients

    • Abstract: AbstractOur immune system is critical for preventing and treating SARS-CoV-2 infections, but aberrant immune responses can have deleterious effects. While antibodies to glycans could recognize the virus and influence the clinical outcome, little is known about their roles. Using a carbohydrate antigen microarray, we profiled serum antibodies in healthy control subjects and COVID-19 patients from two separate cohorts. COVID-19 patients had numerous autoantibodies to self-glycans, including antiganglioside antibodies that can cause neurological disorders. Additionally, nearly all antiglycan IgM signals were lower in COVID-19 patients, indicating a global dysregulation of this class of antibodies. Autoantibodies to certain N-linked glycans correlated with more severe disease, as did low levels of antibodies to the Forssman antigen and ovalbumin. Collectively, this study indicates that expanded testing for antiglycan antibodies could be beneficial for clinical analysis of COVID-19 patients and illustrates the importance of including host and viral carbohydrate antigens when studying immune responses to viruses.
      PubDate: Fri, 17 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac062
       
  • Apo and ligand-bound high resolution Cryo-EM structures of the human Kv3.1
           channel reveal a novel binding site for positive modulators

    • Abstract: AbstractKv3 ion-channels constitute a class of functionally distinct voltage-gated ion channels characterized by their ability to fire at a high frequency. Several disease relevant mutants, together with biological data, suggest the importance of this class of ion channels as drug targets for CNS disorders, and several drug discovery efforts have been reported. Despite the increasing interest for this class of ion channels, no structure of a Kv3 channel has been reported yet. We have determined the cryo-EM structure of Kv3.1 at 2.6 Å resolution using full-length wild type protein. When compared to known structures for potassium channels from other classes, a novel domain organization is observed with the cytoplasmic T1 domain, containing a well-resolved Zinc site and displaying a rotation by 35°. This suggests a distinct cytoplasmic regulation mechanism for the Kv3.1 channel. A high resolution structure was obtained for Kv3.1 in complex with a novel positive modulator Lu AG00563. The structure reveals a novel ligand binding site for the Kv class of ion channels located between the voltage sensory domain and the channel pore, a region which constitutes a hotspot for disease causing mutations. The discovery of a novel binding site for a positive modulator of a voltage-gated potassium channel could shed light on the mechanism of action for these small molecule potentiators. This finding could enable structure-based drug design on these targets with high therapeutic potential for the treatment of multiple CNS disorders.
      PubDate: Thu, 16 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac083
       
  • Switching charge states in quasi-2D molecular conductors

    • Abstract: Abstract2D molecular entities build next-generation electronic devices, where abundant elements of organic molecules are attractive due to the modern synthetic and stimuli control through chemical, conformational, and electronic modifications in electronics. Despite its promising potential, the insufficient control over charge states and electronic stabilities must be overcome in molecular electronic devices. Here, we show the reversible switching of modulated charge states in an exfoliatable 2D-layered molecular conductor based on bis(ethylenedithio)tetrathiafulvalene molecular dimers. The multiple stimuli application of cooling rate, current, voltage, and laser irradiation in a concurrent manner facilitates the controllable manipulation of charge crystal, glass, liquid, and metal phases. The four orders of magnitude switching of electric resistance are triggered by stimuli-responsive charge distribution among molecular dimers. The tunable charge transport in 2D molecular conductors reveals the kinetic process of charge configurations under stimuli, promising to add electric functions in molecular circuitry.
      PubDate: Mon, 13 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac089
       
  • Biodegradable iron oxide nanoparticles for intraoperative parathyroid
           gland imaging in thyroidectomy

    • Abstract: AbstractParathyroid gland (PG) injury is the most common complication of thyroidectomy owing to the lack of approaches for surgeons to effectively distinguish PGs from surrounding thyroid glands (TGs) in the operation room. Herein, we report the development of biodegradable iron oxide nanoparticles (IONPs) as a promising contrast agent candidate for intraoperative PG visualization. We elucidated that locally administrated dark-colored IONPs readily diffuse in TGs but cannot infiltrate tissue-dense PGs, yielding a distinguishable contrast enhancement between PGs and TGs by naked eye observation. We performed unbiased and quantitative in vivo screenings to optimize particle size and concentration of IONPs for PG/TG contrast enhancement. Moreover, in vivo applications of IONPs via the local administration route demonstrate no adverse toxicities and can be biodegraded in the thyroid microenvironment within 3 months. To our knowledge, these promising findings provide the first in vivo evidence that IONPs can serve as a safe, biodegradable, and effective contrast agent candidate for improving PG visualization in thyroidectomy.
      PubDate: Sat, 11 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac087
       
  • Signatures of muscle disuse in spaceflight and bed rest revealed by single
           muscle fiber proteomics

    • Abstract: AbstractAstronauts experience dramatic loss of muscle mass, decreased strength, and insulin resistance, despite performing daily intense physical exercise that would lead to muscle growth on Earth. Partially mimicking spaceflight, prolonged bed rest causes muscle atrophy, loss of force, and glucose intolerance. To unravel the underlying mechanisms, we employed highly sensitive single fiber proteomics to detail the molecular remodeling caused by unloading and inactivity during bed rest and changes of the muscle proteome of astronauts before and after a mission on the International Space Station. Muscle focal adhesions, involved in fiber–matrix interaction and insulin receptor stabilization, are prominently downregulated in both bed rest and spaceflight and restored upon reloading. Pathways of antioxidant response increased strongly in slow but not in fast muscle fibers. Unloading alone upregulated markers of neuromuscular damage and the pathway controlling EIF5A hypusination. These proteomic signatures of mechanical unloading in muscle fiber subtypes contribute to disentangle the effect of microgravity from the pleiotropic challenges of spaceflight.
      PubDate: Sat, 11 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac086
       
  • Emergent expression of fitness-conferring genes by phenotypic selection

    • Abstract: AbstractGenotypic and phenotypic adaptation is the consequence of ongoing natural selection in populations and is key to predicting and preventing drug resistance. Whereas classic antibiotic persistence is all-or-nothing, here we demonstrate that an antibiotic resistance gene displays linear dose-responsive selection for increased expression in proportion to rising antibiotic concentration in growing Escherichia coli populations. Furthermore, we report the potentially wide-spread nature of this form of emergent gene expression (EGE) by instantaneous phenotypic selection process under bactericidal and bacteriostatic antibiotic treatment, as well as an amino acid synthesis pathway enzyme under a range of auxotrophic conditions. We propose an analogy to Ohm’s law in electricity (V = IR), where selection pressure acts similarly to voltage (V), gene expression to current (I), and resistance (R) to cellular machinery constraints and costs. Lastly, mathematical modeling using agent-based models of stochastic gene expression in growing populations and Bayesian model selection reveal that the EGE mechanism requires variability in gene expression within an isogenic population, and a cellular “memory” from positive feedbacks between growth and expression of any fitness-conferring gene. Finally, we discuss the connection of the observed phenomenon to a previously described general fluctuation–response relationship in biology.
      PubDate: Fri, 10 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac069
       
  • Feasibility of hybrid in-stream generator–photovoltaic systems for
           Amazonian off-grid communities

    • Abstract: AbstractWhile there have been efforts to supply off-grid energy in the Amazon, these attempts have focused on low upfront costs and deployment rates. These “get-energy-quick” methods have almost solely adopted diesel generators, ignoring the environmental and social risks associated with the known noise and pollution of combustion engines. Alternatively, it is recommended, herein, to supply off-grid needs with renewable, distributed microgrids comprised of photovoltaics (PV) and in-stream generators (ISG). Utilization of a hybrid combination of renewable generators can provide an energetically, environmentally, and financially feasible alternative to typical electrification methods, depending on available solar irradiation and riverine characteristics, that with community engagement allows for a participatory codesign process that takes into consideration people’s needs. A convergent solution development framework that includes designers—a team of social scientists, engineers, and communication specialists—and communities as well as the local industry is examined here, by which the future negative impacts at the human–machine–environment nexus can be minimized by iterative, continuous interaction between these key actors.
      PubDate: Thu, 09 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac077
       
  • N-linked glycosylation enhances hemagglutinin stability in avian H5N6
           influenza virus to promote adaptation in mammals

    • Abstract: AbstractClade 2.3.4.4 avian H5Ny viruses, namely H5N2, H5N6, and H5N8, have exhibited unprecedented intercontinental spread in poultry. Among them, only H5N6 viruses are frequently reported to infect mammals and cause serious human infections. In this study, the genetic and biological characteristics of surface hemagglutinin (HA) from clade 2.3.4.4 H5Ny avian influenza viruses (AIVs) were examined for adaptation in mammalian infection. Phylogenetic analysis identified an amino acid (AA) deletion at position 131 of HA as a distinctive feature of H5N6 virus isolated from human patients. This single AA deletion was found to enhance H5N6 virus replication and pathogenicity in vitro and in mammalian hosts (mice and ferrets) through HA protein acid and thermal stabilization that resulted in reduced pH threshold from pH 5.7 to 5.5 for viral-endosomal membrane fusion. Mass spectrometry and crystal structure revealed that the AA deletion in HA at position 131 introduced an N-linked glycosylation site at 129, which increases compactness between HA monomers, thus stabilizes the trimeric structure. Our findings provide a molecular understanding of how HA protein stabilization promotes cross-species avian H5N6 virus infection to mammalian hosts.
      PubDate: Wed, 08 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac085
       
  • Excess natural-cause deaths in California by cause and setting: March 2020
           through February 2021

    • Abstract: AbstractExcess mortality has exceeded reported deaths from Covid-19 during the pandemic. This gap may be attributable to deaths that occurred among individuals with undiagnosed Covid-19 infections or indirect consequences of the pandemic response such as interruptions in medical care; distinguishing these possibilities has implications for public health responses. In the present study, we examined patterns of excess mortality over time and by setting (in-hospital or out-of-hospital) and cause of death using death certificate data from California. The estimated number of excess natural-cause deaths from 2020 March 1 to 2021 February 28 (69,182) exceeded the number of Covid-19 diagnosed deaths (53,667) by 29%. Nearly half, 47.4% (32,775), of excess natural-cause deaths occurred out of the hospital, where only 28.6% (9,366) of excess mortality was attributed to Covid-19. Over time, increases or decreases in excess natural non-Covid-19 mortality closely mirrored increases or decreases in Covid-19 mortality. The time series were positively correlated in out-of-hospital settings, particularly at time lags when excess natural-cause deaths preceded reported Covid-19 deaths; for example, when comparing Covid-19 deaths to excess natural-cause deaths in the week prior, the correlation was 0.73. The strong temporal association of reported Covid-19 deaths with excess out-of-hospital deaths from other reported natural-cause causes suggests Covid-19 deaths were undercounted during the first year of the pandemic.
      PubDate: Wed, 08 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac079
       
  • Partners in crime: Tbf1 and Vid22 promote expansions of long human
           telomeric repeats at an interstitial chromosome position in yeast

    • Abstract: AbstractIn humans, telomeric repeats (TTAGGG)n are known to be present at internal chromosomal sites. These interstitial telomeric sequences (ITSs) are an important source of genomic instability, including repeat length polymorphism, but the molecular mechanisms responsible for this instability remain to be understood. Here, we studied the mechanisms responsible for expansions of human telomeric (Htel) repeats that were artificially inserted inside a yeast chromosome. We found that Htel repeats in an interstitial chromosome position are prone to expansions. The propensity of Htel repeats to expand depends on the presence of a complex of two yeast proteins: Tbf1 and Vid22. These two proteins are physically bound to an interstitial Htel repeat, and together they slow replication fork progression through it. We propose that slow progression of the replication fork through the protein complex formed by the Tbf1 and Vid22 partners at the Htel repeat cause DNA strand slippage, ultimately resulting in repeat expansions.
      PubDate: Wed, 08 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac080
       
  • Development of a nonhuman primate model for mammalian bornavirus infection

    • Abstract: AbstractUntil recently, it was assumed that members of the family Bornaviridae could not induce severe disease in humans. Today, however, Borna disease virus 1 (BoDV-1), as well as the more recently emerged variegated squirrel bornavirus 1 (VSBV-1), are known as causative agents of lethal encephalitis in humans. In order to establish animal models reflecting the pathogenesis in humans and for countermeasure efficacy testing, we infected twelve rhesus macaques (Macaca mulatta) either with VSBV-1 or with BoDV-1. For each virus, three monkeys each were inoculated with 2 × 104 focus forming units by the intracerebral route or by multiple peripheral routes (intranasal, conjunctival, intramuscular, and subcutaneous; same dose in total). All BoDV-1 and VSBV-1 intracerebrally infected monkeys developed severe neurological signs around 5 to 6 or 8 to 12 weeks postinfection, respectively. Focal myoclonus and tremors were the most prominent observations in BoDV-1 and VSBV-1-infected animals. VSBV-1-infected animals also showed behavioral changes. Only one BoDV-1 peripherally infected animal developed similar disease manifestations. All animals with severe clinical disease showed high viral loads in brain tissues and displayed perivascular mononuclear cuffs with a predominance of lymphocytes and similar meningeal inflammatory infiltrates. In summary, rhesus macaques intracerebrally infected with mammalian bornaviruses develop a human-like disease and may serve as surrogate models for human bornavirus infection.
      PubDate: Wed, 08 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac073
       
  • Durability analysis of the highly effective BNT162b2 vaccine against
           COVID-19

    • Abstract: AbstractCOVID-19 vaccines are effective, but breakthrough infections have been increasingly reported. We conducted a test-negative case-control study to assess the durability of protection after full vaccination with BNT162b2 against polymerase chain reaction (PCR)-confirmed symptomatic SARS-CoV-2 infection, in a national medical practice from January 2021 through January 2022. We fit conditional logistic regression (CLR) models stratified on residential county and calendar time of testing to assess the association between time elapsed since vaccination and the odds of symptomatic infection or non-COVID-19 hospitalization (negative control), adjusted for several covariates. There were 5,985 symptomatic individuals with a positive test after full vaccination with BNT162b2 (cases) and 32,728 negative tests contributed by 27,753 symptomatic individuals after full vaccination (controls). The adjusted odds of symptomatic infection were higher 250 days after full vaccination versus at the date of full vaccination (Odds Ratio [OR]: 3.62, 95% CI: 2.52 to 5.20). The odds of infection were still lower 285 days after the first BNT162b2 dose as compared to 4 days after the first dose (OR: 0.50, 95% CI: 0.37 to 0.67), when immune protection approximates the unvaccinated status. Low rates of COVID-19 associated hospitalization or death in this cohort precluded analyses of these severe outcomes. The odds of non-COVID-19 associated hospitalization (negative control) decreased with time since vaccination, suggesting a possible underestimation of waning protection by this approach due to confounding factors. In summary, BNT162b2 strongly protected against symptomatic SARS-CoV-2 infection for at least 8 months after full vaccination, but the degree of protection waned significantly over this period.
      PubDate: Wed, 08 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac082
       
  • Vaccinating children against COVID-19 is crucial to protect schools and
           communities

    • Abstract: AbstractTo evaluate the joint impact of childhood vaccination rates and school masking policies on community transmission and severe outcomes due to COVID-19, we utilized a stochastic, agent-based simulation of North Carolina to test 24 health policy scenarios. In these scenarios, we varied the childhood (ages 5 to 19) vaccination rate relative to the adult's (ages 20 to 64) vaccination rate and the masking relaxation policies in schools. We measured the overall incidence of disease, COVID-19-related hospitalization, and mortality from 2021 July 1 to 2023 July 1. Our simulation estimates that removing all masks in schools in January 2022 could lead to a 31% to 45%, 23% to 35%, and 13% to 19% increase in cumulative infections for ages 5 to 9, 10 to 19, and the total population, respectively, depending on the childhood vaccination rate. Additionally, achieving a childhood vaccine uptake rate of 50% of adults could lead to a 31% to 39% reduction in peak hospitalizations overall masking scenarios compared with not vaccinating this group. Finally, our simulation estimates that increasing vaccination uptake for the entire eligible population can reduce peak hospitalizations in 2022 by an average of 83% and 87% across all masking scenarios compared to the scenarios where no children are vaccinated. Our simulation suggests that high vaccination uptake among both children and adults is necessary to mitigate the increase in infections from mask removal in schools and workplaces.
      PubDate: Wed, 08 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac081
       
  • Long-term preservation of biomolecules in lake sediments: potential
           importance of physical shielding by recalcitrant cell walls

    • Abstract: AbstractEven though lake sediments are globally important organic carbon (OC) sinks, the controls on long-term OC storage in these sediments are unclear. Using a multiproxy approach, we investigate changes in diatom, green algae, and vascular plant biomolecules in sedimentary records from the past centuries across five temperate lakes with different trophic histories. Despite past increases in the input and burial of OC in sediments of eutrophic lakes, biomolecule quantities in sediments of all lakes are primarily controlled by postburial microbial degradation over the time scales studied. We, moreover, observe major differences in biomolecule degradation patterns across diatoms, green algae, and vascular plants. Degradation rates of labile diatom DNA exceed those of chemically more resistant diatom lipids, suggesting that chemical reactivity mainly controls diatom biomolecule degradation rates in the lakes studied. By contrast, degradation rates of green algal and vascular plant DNA are significantly lower than those of diatom DNA, and in a similar range as corresponding, much less reactive lipid biomarkers and structural macromolecules, including lignin. We propose that physical shielding by degradation-resistant cell wall components, such as algaenan in green algae and lignin in vascular plants, contributes to the long-term preservation of labile biomolecules in both groups and significantly influences the long-term burial of OC in lake sediments.
      PubDate: Wed, 08 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac076
       
  • Big data from a popular app reveals that fishing creates superhighways for
           aquatic invaders

    • Abstract: AbstractHuman activities are the leading cause of biological invasions that cause ecologic and economic damage around the world. Aquatic invasive species (AIS) are often spread by recreational anglers who visit two or more bodies of water within a short time frame. Movement data from anglers are, therefore, critical to predicting, preventing, and monitoring the spread of AIS. However, the lack of broad-scale movement data has restricted efforts to large and popular lakes or small geographic extents. Here, we show that recreational fishing apps are an abundant, convenient, and relatively comprehensive source of “big” movement data across the contiguous United States. Our analyses revealed a dense network of angler movements that was dramatically more interconnected and extensive than the network that is formed naturally by rivers and streams. Short-distanced movements by anglers combined to form invasion superhighways that spanned the contiguous United States. We also identified possible invasion fronts and invaded hub lakes that may be superspreaders for two relatively common aquatic invaders. Our results provide unique insight into the national network through which AIS may be spread, increase opportunities for interjurisdictional coordination that is essential to addressing the problem of AIS, and highlight the important role that anglers can play in providing accurate data and preventing invasions. The advantages of mobile devices as both sources of data and a means of engaging the public in their shared responsibility to prevent invasions are probably general to all forms of tourism and recreation that contribute to the spread of invasive species.
      PubDate: Wed, 08 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac075
       
  • Coherent polaron dynamics of electrons solvated in polar liquids

    • Abstract: AbstractAn electron solvated in a polar liquid is an elementary quantum system with properties governed by electric interactions with a fluctuating molecular environment. In the prevailing single particle picture, the quantum ground and excited states are determined by a self-consistent potential, as defined by the particular local configuration of the solvation shell. This description neglects collective many-body excitations, which arise from the coupling of electronic degrees of freedom and nuclear motions of the environment. While recent experiments have demonstrated collective nonequilbrium electronic–nuclear motion, i.e. polaron excitations in liquid water, their relevance in the broader context of polar liquids has remained unexplored. Here, we study the nonequilibrium dielectric response of the, compared to water, less polar alcohols isopropanol, and ethylene glycol, that also display a different hydrogen bond pattern. We demonstrate that ultrafast relaxation of photogenerated electrons impulsively induces coherent charge oscillations, which persist for some 10 ps. They emit electric waves in a frequency range from 0.1 to 2 THz, depending on electron concentration. Oscillation frequencies and line shapes are reproduced by a unified polaron picture for alcohols and water, which is based on a Clausius–Mossotti local field approach for the THz dielectric function. The analysis suggests a longitudinal character of many-body polaron excitations and a weak coupling to transverse excitations, supported by the underdamped character of charge oscillations. Polaron dynamics are governed by the long-range Coulomb interaction between an excess electron and several thousands of polar solvent molecules, while local electron solvation geometries play a minor role.
      PubDate: Tue, 07 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac078
       
  • Human IgE monoclonal antibody recognition of mite allergen Der p 2 defines
           structural basis of an epitope for IgE cross-linking and anaphylaxis in
           vivo

    • Abstract: AbstractImmunoglobulin E (IgE) antibody is a critical effector molecule for adaptive allergen-induced immune responses, which affect up to 40% of the population worldwide. Allergens are usually innocuous molecules but induce IgE antibody production in allergic subjects. Allergen cross-linking of IgE bound to its high affinity receptor (FcεRI) on mast cells and basophils triggers release of histamine and other mediators that cause allergic symptoms. Little is known about the direct allergen–IgE antibody interaction due to the polyclonal nature of serum IgE and the low frequency of IgE-producing B cells in blood. Here, we report the X-ray crystal structure of a house dust mite allergen, Der p 2, in complex with Fab of a human IgE monoclonal antibody (mAb) isolated by hybridoma technology using human B cells from an allergic subject. This IgE mAb, 2F10, has the correct pairing of heavy and light chains as it occurs in vivo. Key amino acids forming the IgE epitope on Der p 2 were identified. Mutation of these residues ablated their functional ability to cross-link IgE in a mouse model of passive systemic anaphylaxis. These analyses revealed an important conformational epitope associated with the IgE antibody repertoire to a major mite allergen.
      PubDate: Thu, 02 Jun 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac054
       
  • Deep-learning microscopy image reconstruction with quality control reveals
           second-scale rearrangements in RNA polymerase II clusters

    • Abstract: AbstractFluorescence microscopy, a central tool of biological research, is subject to inherent trade-offs in experiment design. For instance, image acquisition speed can only be increased in exchange for a lowered signal quality, or for an increased rate of photo-damage to the specimen. Computational denoising can recover some loss of signal, extending the trade-off margin for high-speed imaging. Recently proposed denoising on the basis of neural networks shows exceptional performance but raises concerns of errors typical of neural networks. Here, we present a work-flow that supports an empirically optimized reduction of exposure times, as well as per-image quality control to exclude images with reconstruction errors. We implement this work-flow on the basis of the denoising tool Noise2Void and assess the molecular state and 3D shape of RNA polymerase II (Pol II) clusters in live zebrafish embryos. Image acquisition speed could be tripled, achieving 2-s time resolution and 350-nm lateral image resolution. The obtained data reveal stereotyped events of approximately 10 s duration: initially, the molecular mark for recruited Pol II increases, then the mark for active Pol II increases, and finally Pol II clusters take on a stretched and unfolded shape. An independent analysis based on fixed sample images reproduces this sequence of events, and suggests that they are related to the transient association of genes with Pol II clusters. Our work-flow consists of procedures that can be implemented on commercial fluorescence microscopes without any hardware or software modification, and should, therefore, be transferable to many other applications.
      PubDate: Mon, 23 May 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac065
       
  • Functional connectivity signatures of political ideology

    • Abstract: AbstractEmerging research has begun investigating the neural underpinnings of the biological and psychological differences that drive political ideology, attitudes, and actions. Here, we explore the neurological roots of politics through conducting a large sample, whole-brain analysis of functional connectivity (FC) across common fMRI tasks. Using convolutional neural networks, we develop predictive models of ideology using FC from fMRI scans for nine standard task-based settings in a novel cohort of healthy adults (n = 174, age range: 18 to 40, mean = 21.43) from the Ohio State University Wellbeing Project. Our analyses suggest that liberals and conservatives have noticeable and discriminative differences in FC that can be identified with high accuracy using contemporary artificial intelligence methods and that such analyses complement contemporary models relying on socio-economic and survey-based responses. FC signatures from retrieval, empathy, and monetary reward tasks are identified as important and powerful predictors of conservatism, and activations of the amygdala, inferior frontal gyrus, and hippocampus are most strongly associated with political affiliation. Although the direction of causality is unclear, this study suggests that the biological and neurological roots of political behavior run much deeper than previously thought.
      PubDate: Mon, 23 May 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac066
       
  • Stochastic block models reveal a robust nested pattern in healthy human
           gut microbiomes

    • Abstract: AbstractA key question in human gut microbiome research is what are the robust structural patterns underlying its taxonomic composition. Herein, we use whole metagenomic datasets from healthy human guts to show that such robust patterns do exist, albeit not in the conventional enterotype sense. We first introduce the concept of mixed-membership enterotypes using a network inference approach based on stochastic block models. We find that gut microbiomes across a group of people (hosts) display a nested structure, which has been observed in a number of ecological systems. This finding led us to designate distinct ecological roles to both microbes and hosts: generalists and specialists. Specifically, generalist hosts have microbiomes with most microbial species, while specialist hosts only have generalist microbes. Moreover, specialist microbes are only present in generalist hosts. From the nested structure of microbial taxonomies, we show that these ecological roles of microbes are generally conserved across datasets. Our results show that the taxonomic composition of healthy human gut microbiomes is associated with robustly structured combinations of generalist and specialist species.
      PubDate: Mon, 23 May 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac055
       
  • SLC46A3 is a lysosomal proton-coupled steroid conjugate and bile acid
           transporter involved in transport of active catabolites of T-DM1

    • Abstract: AbstractAntibody–drug conjugates (ADCs) represent a new class of cancer therapeutics that enable targeted delivery of cytotoxic drugs to cancer cells. Although clinical efficacy has been demonstrated for ADC therapies, resistance to these conjugates may occur. Recently, SLC46A3, a lysosomal membrane protein, was revealed to regulate the efficacy of trastuzumab emtansine (T-DM1), a noncleavable ADC that has been widely used for treating breast cancer. However, the role of SLC46A3 in mediating T-DM1 cytotoxicity remains unclear. In this study, we discovered the function of SLC46A3 as a novel proton-coupled steroid conjugate and bile acid transporter. SLC46A3 preferentially recognized lipophilic steroid conjugates and bile acids as endogenous substrates. In addition, we found that SLC46A3 directly transports Lys-SMCC-DM1, a major catabolite of T-DM1, and potent SLC46A3 inhibitors attenuate the cytotoxic effects of T-DM1, suggesting a role in the escape of Lys-SMCC-DM1 from the lysosome into the cytoplasm. Our findings reveal the molecular mechanism by which T-DM1 kills cancer cells and may contribute to the rational development of ADCs that target SLC46A3.
      PubDate: Fri, 20 May 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac063
       
  • Population health, not individual health, drives support for populist
           parties

    • Abstract: AbstractRecent electoral shifts toward populist parties may have been partly driven by deteriorating health, although empirical evidence on this link is primarily confined to ecological designs. We performed both ecological- and individual-level analyses to investigate whether changes in health are associated with changes in the support for populist parties. Data were used on the strategic Dutch case, the only liberal democracy featuring leftist and rightist populist politicians in parliament for over a decade. We used: (a) fixed effects models to examine whether changes in the standardized mortality ratios and self-assessed health (SAH) in municipalities were associated with changes in the populist vote share in four parliamentary elections (2006/2010/2012/2017); and (b) 10 waves of panel data collected in 2008 to 2018 to investigate if changes in individual-level SAH were linked to movement in the sympathy, intention to vote, and actual voting for populist parties. The ecological analyses showed that: changes in municipality mortality ratios were positively linked to changes in the vote share of right-wing populist parties, while changes in the prevalence of less-than-good SAH were negatively associated with changes in the vote share for left-wing populist parties. The individual-level analyses identified no such associations. Our findings imply that support for populist parties may be driven by health concerns at the ecological, but not the individual, level. This suggests that sociotropic (e.g. perceiving population health issues as a social problem), but not egotropic (e.g. relating to personal health issues like experienced stigma), concerns may underlie rising support for populist parties.
      PubDate: Thu, 19 May 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac057
       
  • Domino effect of a natural cascade alpine lake system on the Third Pole

    • Abstract: AbstractThird Pole natural cascade alpine lakes (NCALs) are exceptionally sensitive to climate change, yet the underlying cryosphere-hydrological processes and associated societal impacts are largely unknown. Here, with a state-of-the-art cryosphere-hydrology-lake-dam model, we quantified the notable high-mountain Hoh-Xil NCALs basin (including Lakes Zonag, Kusai, Hedin Noel, and Yanhu, from upstream to downstream) formed by the Lake Zonag outburst in September 2011. We demonstrate that long-term increased precipitation and accelerated ice and snow melting as well as short-term heavy precipitation and earthquake events were responsible for the Lake Zonag outburst; while the permafrost degradation only had a marginal impact on the lake inflows but was crucial to lakeshore stability. The quadrupling of the Lake Yanhu area since 2012 was due to the tripling of inflows (from 0.25 to 0.76 km3/year for 1999 to 2010 and 2012 to 2018, respectively). Prediction of the NCALs changes suggests a high risk of the downstream Qinghai–Tibet Railway, necessitating timely adaptions/mitigations.
      PubDate: Mon, 16 May 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac053
       
  • Statistical electromagnetics for industrial pharmaceutical lyophilization

    • Abstract: AbstractLyophilization is a common unit operation in pharmaceutical manufacturing but is a prolonged vacuum drying process with poor energy utilization. Microwave-assisted vacuum drying has been investigated to accelerate the lyophilization process. However, the literature lacks methodical approaches that consider the lyophilizer, the lyophilizate, the microwave power uniformity, the resulting heat uniformity, and the scalability. We present a microwave–vacuum drying method based on the statistical electromagnetics theory. The method offers an optimum frequency selection procedure that accounts for the lyophilizer and the lyophilizate. The 2.45 GHz frequency conventionally utilized is proven to be far from optimum. The method is applied in a microwave-assisted heating configuration to pharmaceutical excipients (sucrose and mannitol) and different myoglobin formulations in a lab-scale lyophilizer. At 18 GHz frequency and 60 W microwave power, the method shows nearly three times speed-up in the primary drying stage of sucrose relative to the conventional lyophilization cycle for typical laboratory batches. The uniformity of the microwave power inside the chamber is controlled within ± 1 dB. The resulting heating uniformity measured through residual moisture analysis shows 12.7% of normalized SD of moisture level across the batch in a microwave-assisted cycle as opposed to 15.3% in the conventional cycle. Conventional and microwave lyophilized formulations are characterized using solid-state hydrogen-deuterium exchange-mass spectrometry (ssHDX-MS), solid-state Fourier transform infrared spectroscopy (ssFTIR), circular dichroism (CD), and accelerated stability testing (AST). Characterization shows comparable protein structure and stability. Heat and mass transfer simulations quantify further effects of optimal volumetric heating via the high-frequency statistical microwave heating.
      PubDate: Mon, 16 May 2022 00:00:00 GMT
      DOI: 10.1093/pnasnexus/pgac052
       
 
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