Proceedings of the National Academy of Sciences of the United States of America最新文献

Cultivation studies evaluating land-use histories and coevolutionary dynamics between humans and plants focus predominantly on domesticated species. Traditional anthropological divisions of "foragers" and "farmers" have shaped our understanding of ancient cultivation practices but have several limitations, including how people stewarded and managed nondomesticated species. To investigate the long-term effects of plant management in the Pacific Northwest, this study focuses on beaked hazelnut (Corylus cornuta) which has a long, precolonial history of management, transportation, and cultivation in British Columbia (BC, Canada). In particular, isolated hazelnut populations in northwestern BC are thought to be the result of historical transplanting and management. We sampled individual hazelnuts (n = 219) representing three distinct regions in and assessed 9,650 genome-wide SNPs identified with nextRAD genotyping-by-sequencing libraries to test for population genetic structure. We used linear measurements of individuals to assess morphological phenotypes and to identify variation between individuals and lineages. These data reveal shared genetic clusters in distant and disjunct northwestern and interior regions consistent with the movement of humans across the landscape. We also find several small genetically distinct populations in the northwestern region. The Genetic structure of hazelnut in the previously labeled "disjunct" region in Gitxsan, Ts'msyen, and Nisga'a homelands is consistent with the enduring influence of people on the distribution of purportedly "wild" plant species. Our results support the hypothesis that hazelnut was likely transplanted long distances and also managed in situ. This study highlights the often-overlooked agency of Indigenous Peoples in shaping species range distributions in North America.

A critical host response against viral infections entails the activation of innate immune signaling that culminates in the production of antiviral proteins. DNA viruses are sensed by the cytosolic pattern recognition receptor cyclic GMP-AMP synthase (cGAS), which initiates a signaling pathway that results in production of proinflammatory cytokines such as Interferon-β (IFN-β) and activation of the antiviral response. Precise regulation of the antiviral innate immune response is required to avoid deleterious effects of its overactivation. We previously reported that the 4EHP/GIGYF2 translational repressor complex reduces the translation of Ifnb1 mRNA, which encodes IFN-β, upon RNA viral infections. Here, we report a distinct regulatory mechanism by which 4EHP controls replication of DNA viruses by translational repression of the Cgas mRNA, which encodes the DNA viral sensor cGAS. We show that 4EHP is required for effective translational repression of Cgas mRNA triggered by miR-23a. Upon infection, 4EHP deficiency bolsters the elicited innate immune response against the diverse DNA viruses Herpes simplex virus 1 (HSV-1) and Vaccinia Virus (VacV) and concomitantly reduces their rate of replication in vitro and in vivo. This study elucidates an intrinsic regulatory mechanism of the host response to DNA viruses which may provide unique opportunities for countering viral infections.

The Civil War was the deadliest conflict in US history. However, incomplete records have made it difficult to estimate the exact death toll both nationally, and especially, at the state level. In this article, we leverage the recently released full count of individual census returns and a sample of linked records across multiple censuses to provide i) the most precise national estimate of excess mortality to date and ii) reliable state-level estimates of excess mortality among native-born white males. Our national estimate is 698,000 Civil War deaths. This is substantially higher than the conventional historical estimate of 618,000 but lower than the most recent estimate of around 750,000 deaths based on a 1% census sample. Leveraging a novel migration-adjusted census comparison method, we document the extent to which the war's toll was much greater in the Confederate states than in the Union.

Delineating a protein's essential and dispensable domains provides critical insight into how it carries out its function. Here, we developed a high-throughput method to synthesize and test the functionality of all possible in-frame and continuous deletions in a gene of interest, enabling rapid and unbiased determination of protein domain importance. Our approach generates precise deletions using a CRISPR library framework that is free from constraints of gRNA target site availability and efficacy. We applied our method to AcrIIA4, a phage-encoded anti-CRISPR protein that robustly inhibits SpCas9. Extensive structural characterization has shown that AcrIIA4 physically occupies the DNA-binding interfaces of several SpCas9 domains; nonetheless, the importance of each AcrIIA4 interaction for SpCas9 inhibition is unknown. We used our approach to determine the essential and dispensable regions of AcrIIA4. Surprisingly, not all contacts with SpCas9 were required, and in particular, we found that the AcrIIA4 loop that inserts into SpCas9's RuvC catalytic domain can be deleted. Our results show that AcrIIA4 inhibits SpCas9 primarily by blocking PAM binding and that its interaction with the SpCas9 catalytic domain is inessential.

2'-O-methylation is one of the most prevalent RNA modifications found in different RNA types. However, the identities of enzymes participating in the transfer of methyl groups are not well defined. To date, fibrillarin (FBL) is the only known small nucleolar ribonucleoprotein (snoRNP) 2'-O-methyltransferase. Whether other snoRNP 2'-O-methyltransferases exist and their functions in targeting RNAs to determine cell differentiation and function need to be elucidated. Here, we identify FBL-like protein 1 (FBLL1) as a 2'-O-methyltransferase and find its function in promoting neuronal differentiation. We show that FBLL1 is a key snoRNP complex enzyme that transfers methyl groups to substrate RNAs both in vitro and in vivo. Moreover, FBLL1 exhibits different 2'-O-methyltransferase site selectivity from FBL and tissue-specific distribution. FBLL1 is preferentially expressed in the brain, especially in human neuron cells, and promotes neuronal differentiation through 2'-O-methylation of GAP43 messenger RNA (mRNA). Knockdown of FBLL1, but not FBL, reduced 2'-O-methylation levels in GAP43 mRNA, decreased expression of GAP43 proteins, and eventually repressed neuronal differentiation. Our finding of neuron-specific FBLL1 adds insights into RNA modification in neurobiology and provides clues for understanding 2'-O-methylation in health and disease.

In response to the disruption of gas supplies from Russia following the invasion of Ukraine in 2022, European politicians and public utilities appealed to citizens and customers to conserve natural gas. Moreover, they strengthened economic incentives for gas conservation. In fact, a substantial amount of natural gas was saved during the winter of 2022/23. This raises the question to what extent this success is attributable to government and corporate means to foster energy conservation in the crisis, including energy policies such as the German government's "gas price brake," gas-saving programs launched by public utilities, and consumers' individual pricing schemes. We analyzed the effectiveness of these means using a survey and a field experiment with a German gas supplier and show that, while household savings during the crisis were substantial, economic incentives did not significantly change behavior. Indeed, demand for gas is largely price inelastic. A large majority of consumers do not understand the incentives arising from the gas price brake, and when they do, they do not respond. Likewise, consumers do not react to the design of the utilities' gas-saving program. These findings suggest that i) citizens' response to marginal individual economic incentives contributes little to overall gas savings, and ii) the crisis, along with the extensive societal engagement it generated, likely shifted the public's mindset about energy consumption, making conservation a social priority.

Indirect reciprocity is a key explanation for the exceptional magnitude of cooperation among humans. This literature suggests that a large proportion of human cooperation is driven by social norms and individuals' incentives to maintain a good reputation. This intuition has been formalized with two types of models. In public assessment models, all community members are assumed to agree on each others' reputations; in private assessment models, people may have disagreements. Both types of models aim to understand the interplay of social norms and cooperation. Yet their results can be vastly different. Public assessment models argue that cooperation can evolve easily and that the most effective norms tend to be stern. Private assessment models often find cooperation to be unstable, and successful norms show some leniency. Here, we propose a model that can organize these differing results within a single framework. We show that the stability of cooperation depends on a single quantity: the extent to which individual opinions turn out to be correlated. This correlation is determined by a group's norms and the structure of social interactions. In particular, we prove that no cooperative norm is evolutionarily stable when individual opinions are statistically independent. These results have important implications for our understanding of cooperation, conformity, and polarization.

Odors are key signals for guiding spatial behaviors such as foraging and navigation in rodents. Recent findings reveal that odor representations in the piriform cortex (PCx) also encode spatial context information. However, the brain origins of this information and its integration into PCx microcircuitry remain unclear. This study investigates the lateral entorhinal cortex (LEC) as a potential source of spatial contextual information affecting the PCx microcircuit and its olfactory responses. Using mice brain slices, we performed patch-clamp recordings on superficial (SP) and deep (DP) pyramidal neurons, as well as parvalbumin (PV) and somatostatin (SOM) inhibitory interneurons. Concurrently, we optogenetically stimulated excitatory LEC projections to observe their impact on PCx activity. Results show that LEC inputs are heterogeneously distributed in the PCx microcircuit, evoking larger excitatory currents in SP and PV neurons due to higher monosynaptic connectivity. LEC inputs also differentially affect inhibitory circuits, activating PV while suppressing SOM interneurons. Studying the interaction between LEC inputs and sensory signals from the lateral olfactory tract (LOT) revealed that simultaneous LEC and LOT activation increases spiking in SP and DP neurons, with DP neurons showing a sharpened response due to LEC-induced inhibition that suppresses delayed LOT-evoked spikes. This suggests a regulatory mechanism where LEC inputs inhibit recurrent activity by activating PV interneurons. Our findings demonstrate that LEC afferents reconfigure PCx activity, aiding the understanding of how odor objects form within the PCx by integrating olfactory and nonolfactory information.