Dispersal patterns and influence of air travel during the global expansion of SARS-CoV-2 variants of concern.

The Alpha, Beta, and Gamma SARS-CoV-2 variants of concern (VOCs) co-circulated globally during 2020 and 2021, fueling waves of infections. They were displaced by Delta during a third wave worldwide in 2021, which, in turn, was displaced by Omicron in late 2021. In this study, we use phylogenetic and phylogeographic methods to reconstruct the dispersal patterns of VOCs worldwide. We find that source-sink dynamics varied substantially by VOC and identify countries that acted as global and regional hubs of dissemination. We demonstrate the declining role of presumed origin countries of VOCs in their global dispersal, estimating that India contributed <15% of Delta exports and South Africa <1%-2% of Omicron dispersal. We estimate that >80 countries had received introductions of Omicron within 100 days of its emergence, associated with accelerated passenger air travel and higher transmissibility. Our study highlights the rapid dispersal of highly transmissible variants, with implications for genomic surveillance along the hierarchical airline network.

Genomic surveillance reveals dynamic shifts in the connectivity of COVID-19 epidemics.

The maturation of genomic surveillance in the past decade has enabled tracking of the emergence and spread of epidemics at an unprecedented level. During the COVID-19 pandemic, for example, genomic data revealed that local epidemics varied considerably in the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage importation and persistence, likely due to a combination of COVID-19 restrictions and changing connectivity. Here, we show that local COVID-19 epidemics are driven by regional transmission, including across international boundaries, but can become increasingly connected to distant locations following the relaxation of public health interventions. By integrating genomic, mobility, and epidemiological data, we find abundant transmission occurring between both adjacent and distant locations, supported by dynamic mobility patterns. We find that changing connectivity significantly influences local COVID-19 incidence. Our findings demonstrate a complex meaning of "local" when investigating connected epidemics and emphasize the importance of collaborative interventions for pandemic prevention and mitigation.

Diversification of Antibodies: From V(D)J Recombination to Somatic Exon Shuffling.

Antibodies that gain specificity by a large insert encoding for an extra domain were described for the first time in 2016. In malaria-exposed individuals, an exon deriving from the leukocyte-associated immunoglobulin-like 1 (LAIR1) gene integrated via a copy-and-paste insertion into the immunoglobulin heavy chain encoding region. A few years later, a second example was identified, namely a dual exon integration from the leukocyte immunoglobulin-like receptor B1 (LILRB1) gene that is located in close proximity to LAIR1. A dedicated high-throughput characterization of chimeric immunoglobulin heavy chain transcripts unraveled, that insertions from distant genomic regions (including mitochondrial DNA) can contribute to human antibody diversity. This review describes the modalities of insert-containing antibodies. The role of known DNA mobility aspects, such as genomic translocation, gene conversion, and DNA fragility, is discussed in the context of insert-antibody generation. Finally, the review covers why insert antibodies were omitted from the past repertoire analyses and how insert antibodies can contribute to protective immunity or an autoreactive response.

Emergence of an early SARS-CoV-2 epidemic in the United States.

The emergence of the COVID-19 epidemic in the United States (U.S.) went largely undetected due to inadequate testing. New Orleans experienced one of the earliest and fastest accelerating outbreaks, coinciding with Mardi Gras. To gain insight into the emergence of SARS-CoV-2 in the U.S. and how large-scale events accelerate transmission, we sequenced SARS-CoV-2 genomes during the first wave of the COVID-19 epidemic in Louisiana. We show that SARS-CoV-2 in Louisiana had limited diversity compared to other U.S. states and that one introduction of SARS-CoV-2 led to almost all of the early transmission in Louisiana. By analyzing mobility and genomic data, we show that SARS-CoV-2 was already present in New Orleans before Mardi Gras, and the festival dramatically accelerated transmission. Our study provides an understanding of how superspreading during large-scale events played a key role during the early outbreak in the U.S. and can greatly accelerate epidemics.

Paleolithic to Bronze Age Siberians Reveal Connections with First Americans and across Eurasia.

Modern humans have inhabited the Lake Baikal region since the Upper Paleolithic, though the precise history of its peoples over this long time span is still largely unknown. Here, we report genome-wide data from 19 Upper Paleolithic to Early Bronze Age individuals from this Siberian region. An Upper Paleolithic genome shows a direct link with the First Americans by sharing the admixed ancestry that gave rise to all non-Arctic Native Americans. We also demonstrate the formation of Early Neolithic and Bronze Age Baikal populations as the result of prolonged admixture throughout the eighth to sixth millennium BP. Moreover, we detect genetic interactions with western Eurasian steppe populations and reconstruct Yersinia pestis genomes from two Early Bronze Age individuals without western Eurasian ancestry. Overall, our study demonstrates the most deeply divergent connection between Upper Paleolithic Siberians and the First Americans and reveals human and pathogen mobility across Eurasia during the Bronze Age.

Nucleoid Size Scaling and Intracellular Organization of Translation across Bacteria.

The scaling of organelles with cell size is thought to be exclusive to eukaryotes. Here, we demonstrate that similar scaling relationships hold for the bacterial nucleoid. Despite the absence of a nuclear membrane, nucleoid size strongly correlates with cell size, independent of changes in DNA amount and across various nutrient conditions. This correlation is observed in diverse bacteria, revealing a near-constant ratio between nucleoid and cell size for a given species. As in eukaryotes, the nucleocytoplasmic ratio in bacteria varies greatly among species. This spectrum of nucleocytoplasmic ratios is independent of genome size, and instead it appears linked to the average population cell size. Bacteria with different nucleocytoplasmic ratios have a cytoplasm with different biophysical properties, impacting ribosome mobility and localization. Together, our findings identify new organizational principles and biophysical features of bacterial cells, implicating the nucleocytoplasmic ratio and cell size as determinants of the intracellular organization of translation.

The Lateral Organization and Mobility of Plasma Membrane Components.

Over the last several decades, an impressive array of advanced microscopic and analytical tools, such as single-particle tracking and nanoscopic fluorescence correlation spectroscopy, has been applied to characterize the lateral organization and mobility of components in the plasma membrane. Such analysis can tell researchers about the local dynamic composition and structure of membranes and is important for predicting the outcome of membrane-based reactions. However, owing to the unresolved complexity of the membrane and the structures peripheral to it, identification of the detailed molecular origin of the interactions that regulate the organization and mobility of the membrane has not proceeded quickly. This Perspective presents an overview of how cell-surface structure may give rise to the types of lateral mobility that are observed and some potentially fruitful future directions to elucidate the architecture of these structures in more molecular detail.

LTR-Retrotransposon Control by tRNA-Derived Small RNAs.

Transposon reactivation is an inherent danger in cells that lose epigenetic silencing during developmental reprogramming. In the mouse, long terminal repeat (LTR)-retrotransposons, or endogenous retroviruses (ERV), account for most novel insertions and are expressed in the absence of histone H3 lysine 9 trimethylation in preimplantation stem cells. We found abundant 18 nt tRNA-derived small RNA (tRF) in these cells and ubiquitously expressed 22 nt tRFs that include the 3' terminal CCA of mature tRNAs and target the tRNA primer binding site (PBS) essential for ERV reverse transcription. We show that the two most active ERV families, IAP and MusD/ETn, are major targets and are strongly inhibited by tRFs in retrotransposition assays. 22 nt tRFs post-transcriptionally silence coding-competent ERVs, while 18 nt tRFs specifically interfere with reverse transcription and retrotransposon mobility. The PBS offers a unique target to specifically inhibit LTR-retrotransposons, and tRF-targeting is a potentially highly conserved mechanism of small RNA-mediated transposon control.

SLFN5-mediated chromatin dynamics sculpt higher-order DNA repair topology.

Repair of DNA double-strand breaks (DSBs) elicits three-dimensional (3D) chromatin topological changes. A recent finding reveals that 53BP1 assembles into a 3D chromatin topology pattern around DSBs. How this formation of a higher-order structure is configured and regulated remains enigmatic. Here, we report that SLFN5 is a critical factor for 53BP1 topological arrangement at DSBs. Using super-resolution imaging, we find that SLFN5 binds to 53BP1 chromatin domains to assemble a higher-order microdomain architecture by driving damaged chromatin dynamics at both DSBs and deprotected telomeres. Mechanistically, we propose that 53BP1 topology is shaped by two processes: (1) chromatin mobility driven by the SLFN5-LINC-microtubule axis and (2) the assembly of 53BP1 oligomers mediated by SLFN5. In mammals, SLFN5 deficiency disrupts the DSB repair topology and impairs non-homologous end joining, telomere fusions, class switch recombination, and sensitivity to poly (ADP-ribose) polymerase inhibitor. We establish a molecular mechanism that shapes higher-order chromatin topologies to safeguard genomic stability.

Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8+ T Cells.

Infections are thought to trigger CD8+ cytotoxic T lymphocyte (CTL) responses during autoimmunity. However, the transcriptional programs governing the tissue-destructive potential of CTLs remain poorly defined. In a model of central nervous system (CNS) inflammation, we found that infection with lymphocytic choriomeningitis virus (LCMV), but not Listeria monocytogenes (Lm), drove autoimmunity. The DNA-binding factor TOX was induced in CTLs during LCMV infection and was essential for their encephalitogenic properties, and its expression was inhibited by interleukin-12 during Lm infection. TOX repressed the activity of several transcription factors (including Id2, TCF-1, and Notch) that are known to drive CTL differentiation. TOX also reduced immune checkpoint sensitivity by restraining the expression of the inhibitory checkpoint receptor CD244 on the surface of CTLs, leading to increased CTL-mediated damage in the CNS. Our results identify TOX as a transcriptional regulator of tissue-destructive CTLs in autoimmunity, offering a potential mechanistic link to microbial triggers.

Understanding the relationship between intergenerational mobility and community violence.

Violence is a key mechanism in the reproduction of community disadvantage. The existing evidence indicates that violence in a community impacts the intergenerational mobility of its residents. The current study explores the possibility of a reverse relationship. This study provisionally tests the hypothesis that depressed intergenerational mobility in a community may also spark subsequent community violence. We deploy a county measure of intergenerational mobility captured during early adulthood for a cohort of youth born between 1980 and 1986 and raised in low-income families [R. Chetty, N. Hendren, Quart. J. Econom. 133, 1163-1228 (2018)]. We model the relationship between county mobility scores and two county-level outcomes: violent crime and homicide. We find that a county's level of intergenerational mobility as measured by the Chetty-Hendren data is a major predictor of its rate of violent crime and homicide in 2008, when the youth in Chetty's mobility cohort were young adults (the same age the mobility measure was captured). In fact, mobility is a significantly stronger and more consistent predictor of community violent crime and homicide rates than more commonly used factors like poverty, inequality, unemployment, and law enforcement presence.

Absolute income mobility obscures marginalized children's disadvantages.

Intergenerational mobility captures the distance between the socioeconomic positions of parents versus their adult children. Researchers measure this distance in absolute and relative units, such as absolute dollars and relative ranks. Absolute and relative mobility often diverge. For example, absolute mobility can rise while relative mobility declines. How should scholars and policymakers understand this divergence? We conclude that they should understand it as follows: absolute mobility is less reflective than relative mobility of marginalized children's socioeconomic disadvantages. We base this conclusion on analyses of survey, administrative, and simulated data on income mobility in the contemporary United States. We analyze multiple points of difference in mobility, which facilitates the recognition of several asymmetries. First, high-income children's experiences weigh more heavily in absolute-mobility trends than low-income children's experiences, particularly when economic growth is positive. Second, this asymmetry is more characteristic of absolute- than relative-mobility trends. Third, absolute-mobility differences across demographic groups are more prone than relative-mobility differences to obscure marginalized groups' socioeconomic disadvantages. These asymmetries have policy implications: We caution that focusing on absolute mobility as a policy target can divert attention away from society's most disadvantaged children.

The roles of geometry and viscosity in the mobilization of coarse sediment by finer sediment.

In rivers, the addition of finer sediment to a coarser riverbed is known to increase the mobility of the coarser fraction. Two mechanisms have been suggested for this: a geometric mechanism whereby smaller sizes smooth the bed, increasing near-bed velocity and thus mobility of the larger sizes, and a viscous mechanism whereby a transitionally smooth turbulent boundary layer forms, rendering the coarser grains more mobile. Here, we report on experiments using two sediment mixtures to better understand these proposed mechanisms. In Mixture 1, we used 0.5 and 5 mm grains, and in Mixture 2, we used 2 and 20 mm grains. If the entrainment of coarse gravel by finer sediment is a purely geometric effect, then the addition of finer material should produce the same effect on the mobility of the coarser material for both mixtures because they have the same size ratio. We show that addition of finer material has a different effect on the two mixtures. We observed an increase in the mobility of the coarse fraction for both mixtures, but the increase in coarse fraction mobility for Mixture 1 was almost twice that for Mixture 2. Our experiments show that in addition to the geometric effect, enhancement of coarse gravel transport by finer sediment is also driven by a viscous effect.

Migration, belonging, and the sustainability of atoll islands through a changing climate.

Climate change might catalyze and exacerbate the trend of outmigration from low-lying atoll islands. There is speculation that migration away from atolls may not stop until such islands are abandoned. Yet migration creates both opportunities and risks for the sustainability of atoll communities. There is a trade-off between reduced demographic pressure on increasingly fragile atoll island environments and the financial and human resources necessary to adapt to climate change that can result from migration. Here we propose and analyze belonging as the centripetal force that makes migration a process that enhances the sustainability of atoll populations. We examine the relationship between migration, belonging, and the sustainability of populations on atoll islands based on data collected in three atoll islands in the Pacific: the island state of Niue; Namdrik Atoll in the Republic of the Marshall Islands; and Budibudi atoll (Laughlan Islands) in Papua New Guinea. In each case, belonging binds the people who live in and migrate from these places into a collective commitment to their continuity, yet it does so to different degrees according to the economic opportunities available to migrants and the infrastructure that enables extended communities to remain connected.

The role of emerging elites in the formation and development of communities after the fall of the Roman Empire.

Elites played a pivotal role in the formation of post-Roman Europe on both macro- and microlevels during the Early Medieval period. History and archaeology have long focused on their description and identification based on written sources or through their archaeological record. We provide a different perspective on this topic by integrating paleogenomic, archaeological, and isotopic data to gain insights into the role of one such elite group in a Langobard period community near Collegno, Italy dated to the 6-8th centuries CE. Our analysis of 28 newly sequenced genomes together with 24 previously published ones combined with isotope (Sr, C, N) measurements revealed that this community was established by and organized around a network of biologically and socially related individuals likely composed of multiple elite families that over time developed into a single extended pedigree. The community also included individuals with diverse genetic ancestries, maintaining its diversity by integrating newcomers and groups in later stages of its existence. This study highlights how shifts in political power and migration impacted the formation and development of a small rural community within a key region of the former Western Roman Empire after its dissolution and the emergence of a new kingdom. Furthermore, it suggests that Early Medieval elites had the capacity to incorporate individuals from varied backgrounds and that these elites were the result of (political) agency rather than belonging to biologically homogeneous groups.

Residential mobility and persistently depressed voting among disadvantaged adults in a large housing experiment.

This study examines the impact of residential mobility on electoral participation among the poor by matching data from Moving to Opportunity, a US-based multicity housing-mobility experiment, with nationwide individual voter data. Nearly all participants in the experiment were Black and Hispanic families who originally lived in high-poverty public housing developments. Notably, the study finds that receiving a housing voucher to move to a low-poverty neighborhood decreased adult participants' voter participation for nearly two decades-a negative impact equal to or outpacing that of the most effective get-out-the-vote campaigns in absolute magnitude. This finding has important implications for understanding residential mobility as a long-run depressant of voter turnout among extremely low-income adults.

Parkinson's-linked LRRK2-G2019S derails AMPAR trafficking, mobility, and composition in striatum with cell-type and subunit specificity.

Parkinson's disease (PD) is a multifactorial disease that affects multiple brain systems and circuits. While defined by motor symptoms caused by degeneration of brainstem dopamine neurons, debilitating non-motor abnormalities in fronto-striatal-based cognitive function are common, appear early, and are initially independent of dopamine. Young adult mice expressing the PD-associated G2019S missense mutation in Lrrk2 also exhibit deficits in fronto-striatal-based cognitive tasks. In mice and humans, cognitive functions require dynamic adjustments in glutamatergic synapse strength through cell-surface trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs), but it is unknown how LRRK2 mutation impacts dynamic features of AMPAR trafficking in striatal projection neurons (SPNs). Here, we used Lrrk2G2019S knockin mice to show that surface AMPAR subunit stoichiometry is altered biochemically and functionally in mutant SPNs in dorsomedial striatum to favor the incorporation of GluA1 over GluA2. GluA1-containing AMPARs were resistant to internalization from the cell surface, leaving an excessive accumulation of GluA1 on the surface within and outside synapses. This negatively impacted trafficking dynamics that normally support synapse strengthening, as GluA1-containing AMPARs failed to increase at synapses in response to a potentiating stimulus and showed significantly reduced surface mobility. Surface GluA2-containing AMPARs were expressed at normal levels in synapses, indicating subunit-selective impairment. Abnormal surface accumulation of GluA1 was independent of PKA activity and was limited to D1R SPNs. Since LRRK2 mutation is thought to be part of a common PD pathogenic pathway, our data suggest that sustained, striatal cell-type specific changes in AMPAR composition and trafficking contribute to cognitive or other impairments associated with PD.

Migration and sustainable development.

To understand the implications of migration for sustainable development requires a comprehensive consideration of a range of population movements and their feedback across space and time. This Perspective reviews emerging science at the interface of migration studies, demography, and sustainability, focusing on consequences of migration flows for nature-society interactions including on societal outcomes such as inequality; environmental causes and consequences of involuntary displacement; and processes of cultural convergence in sustainability practices in dynamic new populations. We advance a framework that demonstrates how migration outcomes result in identifiable consequences on resources, environmental burdens and well-being, and on innovation, adaptation, and challenges for sustainability governance. We elaborate the research frontiers of migration for sustainability science, explicitly integrating the full spectrum of regular migration decisions dominated by economic motives through to involuntary displacement due to social or environmental stresses. Migration can potentially contribute to sustainability transitions when it enhances well-being while not exacerbating structural inequalities or compound uneven burdens on environmental resources.

Social mobility in the Tang Dynasty as the Imperial Examination rose and aristocratic family pedigree declined, 618-907 CE.

Data from the distant past are fertile ground for testing social science theories of education and social mobility. In this study, we construct a dataset from 3,640 tomb epitaphs of males in China's Tang Dynasty (618-907 CE), which contain granular and extensive information about the ancestral origins, family background, and career histories of the deceased elites. Our statistical analysis of the complete profiles yields evidence of the transition away from an aristocratic society in three key trends: 1) family pedigree (i.e., aristocracy) mattered less for career achievement over time, 2) passing the Imperial Examination (Keju) became an increasingly important predictor of one's career achievement, and 3) father's position always mattered throughout the Tang, especially for men who did not pass the Keju. The twilight of medieval Chinese aristocracy, according to the data, began in as early as the mid-seventh century CE.

Transcription-induced active forces suppress chromatin motion.

The organization of interphase chromosomes in a number of species is starting to emerge thanks to advances in a variety of experimental techniques. However, much less is known about the dynamics, especially in the functional states of chromatin. Some experiments have shown that the motility of individual loci in human interphase chromosome decreases during transcription and increases upon inhibiting transcription. This is a counterintuitive finding because it is thought that the active mechanical force (F) on the order of ten piconewtons, generated by RNA polymerase II (RNAPII) that is presumably transmitted to the gene-rich region of the chromatin, would render it more open, thus enhancing the mobility. We developed a minimal active copolymer model for interphase chromosomes to investigate how F affects the dynamical properties of chromatin. The movements of the loci in the gene-rich region are suppressed in an intermediate range of F and are enhanced at small F values, which has also been observed in experiments. In the intermediate F, the bond length between consecutive loci increases, becoming commensurate with the distance at the minimum of the attractive interaction between nonbonded loci. This results in a transient disorder-to-order transition, leading to a decreased mobility during transcription. Strikingly, the F-dependent change in the locus dynamics preserves the organization of the chromosome at [Formula: see text]. Transient ordering of the loci, which is not found in the polymers with random epigenetic profiles, in the gene-rich region might be a plausible mechanism for nucleating a dynamic network involving transcription factors, RNAPII, and chromatin.