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

Language is a productive system--we routinely produce well-formed utterances that we have never heard before. It is, however, difficult to assess when children first achieve linguistic productivity simply because we rarely know all the utterances a child has experienced. The onset of linguistic productivity has been at the heart of a long-standing theoretical question in language acquisition--do children come to language learning with abstract categories that they deploy from the earliest moments of acquisition? We address the problem of when linguistic productivity begins by marrying longitudinal behavioral observations and computational modeling to capitalize on the strengths of each. We used behavioral data to assess when a sample of 64 English-learning children began to productively combine determiners and nouns, a linguistic construction previously used to address this theoretical question. After the onset of productivity, the children produced determiner-noun combinations that were not attested in our sample of their linguistic input from caregivers. We used computational techniques to model the onsets and trajectories of determiner-noun combinations in these 64 children, as well as characteristics of their utterances in which the determiner was omitted. Because we knew exactly what input the model was trained on, we could, with confidence, know that the model had gone beyond its input. The parallels found between child and model in the timing and number of novel combinations suggest that the children too were creatively going beyond their input.

In the late spring to summer season of 2023, Canada witnessed unprecedented wildfires, with an extensive burning area and smoke spreading as far as the East Coast of the United States and Europe. Here, using multisource data analysis and climate model simulations, we show that an abnormally warm North Atlantic, as well as an abnormally low Barents Sea ice concentration (SIC), are likely key climate drivers of this Canadian fire season, contributing to ~80% of the fire weather anomaly over Canada from June to August 2023. Specifically, the warm North Atlantic forms an anomalous regional zonal cell with ascending air over the Atlantic and descending air encircling Canada, creating hot and dry local conditions. Meanwhile, reduced Barents SIC leads to a high-pressure center and reinforces the dry northern winds in Canada through Rossby wave dynamics. These exacerbated dry and hot conditions create a favorable environment for the ignition and spread of fires, thus contributing to the prolonged and extreme fire season in Canada. These teleconnections can extend to decadal scales and have important implications for understanding and predicting decadal fire activity in Canada and the surrounding regions.

Erectile dysfunction (ED) is a major threat to male fertility and quality of life, and mesenchymal stromal cells (MSCs) are a promising therapeutic option. However, therapeutic outcomes are compromised by low MSC retention and survival rates in corpus cavernosum tissue. Here, we developed an innovative magnetic soft microrobot comprising an ultrasoft hydrogel microsphere embedded with a magnetic nanoparticle chain for MSC delivery. This design also features phenylboronic acid groups for scavenging reactive oxygen species (ROS). With a Young's modulus of less than 1 kPa, the ultrasoft microrobot adapts its shape within narrow blood vessels, ensuring a uniform distribution of MSCs within the corpus cavernosum. Our findings showed that compared with traditional MSC injections, the MSC delivery microrobot (MSC-Rob) significantly enhanced MSC retention and survival. In both rat and beagle ED models, MSC-Rob treatment accelerated the repair of corpus cavernosum tissue and restored erectile function. Single-cell RNA sequencing (scRNA-seq) revealed that MSC-Rob treatment facilitates nerve and blood vessel regeneration in the corpus cavernosum by increasing the presence of regenerative macrophages. Overall, our MSC-Rob not only advances the clinical application of MSCs for ED therapy but also broadens the scope of microrobots for other cell therapies.

Antibiotic resistance is a global public health threat. Many factors contribute to this issue, with human antibiotic consumption being significant among them. Analyzing trends and patterns in consumption can aid in developing policies to mitigate the burden of antimicrobial resistance and global disparities in access to antibiotics. Using pharmaceutical sales data licensed from IQVIA, we estimate national-level trends in antibiotic consumption in 67 countries during 2016-2023 and analyze the effects of economic growth and the COVID-19 pandemic. Finally, we estimate global human consumption and project growth through 2030 assuming current trends. We find that estimated antibiotic consumption in reported countries increased 16.3% from 29.5 to 34.3 billion defined daily doses (DDDs) from 2016 to 2023, reflecting a 10.6% increase in the consumption rate from 13.7 to 15.2 DDDs per 1,000 inhabitants per day. Increases were most pronounced in upper-middle- and lower-middle-income countries. While the COVID-19 pandemic significantly reduced consumption globally, this was most pronounced in high-income countries, and in these countries, reductions in antibiotic use in 2020 were sharper, and lasted longer, than in other countries. By 2030, we project that, without reductions in rapidly developing nations, such as investments to improve infrastructure, particularly water and sanitation, along with improved access to vaccination, global antibiotic consumption will increase by 52.3% from an estimated 49.3 billion in 2023 to 75.1 billion DDDs.

The ability to follow the evolutionary trajectories of specific neuronal cell types has led to major insights into the evolution of the vertebrate brain. Here, we study how cave life in the Mexican tetra (Astyanax mexicanus) has affected an identified giant multisensory neuron, the Mauthner neuron (MN). Because this neuron is crucial in driving rapid escapes, the absence of predation risk in the cave forms predicts a massive reduction in this neuron. Moreover, the absence of functional eyes in the A. mexicanus Pachón form predicts an even stronger reduction in the cell's large ventral dendrite that receives visual inputs in sighted fish species. We succeeded in recording in vivo from this neuron in the blind cavefish and two surface tetra (A. mexicanus and Astyanax aeneus), which offers unique chances to simultaneously study evolutionary changes in morphology and function in this giant neuron. In contrast to the predictions, we find that cave life, while sufficient to remove vision, has neither affected the cell's morphology nor its functional properties. This specifically includes the cell's ventral dendrite. Furthermore, cave life did not increase the variance in morphological or functional features. Rather, variability in surface and cave forms was the same, which suggests a complex stabilizing selection in this neuron and a continued role of its ventral dendrite. We found that adult cavefish are potent predators that readily attack smaller fish. So, one of the largely unknown stabilizing factors could be using the MN in such attacks and, in the young fish, escaping them.

Since their domestication, horses have accompanied mankind, and humans have constantly shaped horses according to their needs through stallion-centered breeding. Consequently, the male-specific portion of the Y chromosome (MSY) is extremely uniform in modern horse breeds. The majority of stallions worldwide carry MSY haplotypes (HT) attributed to an only ~1,500-y-old, so-called, "Crown" haplogroup. The predominance of the Crown in modern horse breeds is thought to represent a footprint of the vast impact of stallions of "Oriental origin" in the past millennium. Here, we report the results of a fine-scaled MSY haplotyping of large datasets of patrilines comprising 1,517 males of 189 modern horse breeds, covering a broad phenotypic and geographic spectrum. We can disentangle the multilayered influence of Oriental stallions over the last few hundred years, exposing the intense linebreeding and the wide-ranging impact of Arabian, English Thoroughbred, and Coldblood sires. Iberian and New World horse breeds contain a wide range of diversified Crown lineages. Their broad HT spectrum illustrates the spread of horses of Oriental origin via the Iberian Peninsula after the Middle Ages, which is commonly referred to as the "Spanish influence." Our survey also revealed a second major historical dissemination of horses from Western Asia, attributed to the expansion of the Ottoman Empire. Our analysis shows that MSY analysis can uncover the complex history of horse breeds and can be used to establish the paternal ancestry of modern horse breeds.

Why microbes harm their hosts is a fundamental question in evolutionary biology with broad relevance to our understanding of infectious diseases. Several hypotheses have been proposed to explain this "evolution of virulence." In this perspective, we reexamine one of these hypotheses in the specific context of the human gut microbiome, namely short-sighted evolution. According to the short-sighted evolution hypothesis, virulence is a product of niche expansion within a colonized host, whereby variants of commensal microbes establish populations in tissues and sites where the infection causes morbidity or mortality. This evolution is short-sighted in that the evolved variants that infect those tissues and sites are not transmitted to other hosts. The specific hypothesis that we propose is that some bacteria responsible for invasive infections and disease are the products of the short-sighted evolution of commensal bacteria residing in the gut microbiota. We present observations in support of this hypothesis and discuss the challenges inherent in assessing its general application to infections and diseases associated with specific members of the gut microbiota. We then describe how this hypothesis can be tested using genomic data and animal model experiments and outline how such studies will serve to provide fundamental information about both the evolution and genetic basis of virulence, and the bacteria of intensively studied yet poorly understood habitats including the gut microbiomes of humans and other mammals.

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.

KCTD10, a member of the potassium channel tetramerization domain (KCTD) family, is implicated in neuropsychiatric disorders and functions as a substrate recognition component within the RING-type ubiquitin ligase complex. A rare de novo variant of KCTD10, p.C124W, was identified in schizophrenia cases, yet its underlying pathogenesis remains unexplored. Here, we demonstrate that heterozygous KCTD10 C124W mice display pronounced synaptic abnormalities and exhibit schizophrenia-like behaviors. Mechanistically, we reveal that KCTD10 undergoes liquid-liquid phase separation (LLPS), a process orchestrated by its intrinsically disordered region (IDR). p.C124W mutation disrupts this LLPS capability, leading to diminished degradation of RHOB and subsequent excessive accumulation in the postsynaptic density fractions. Notably, neither IDR deletion nor p.C124W mutation in KCTD10 mitigates the synaptic abnormalities caused by Kctd10 deficiency. Thus, our findings implicate that LLPS may be associated with the pathogenesis of KCTD10-associated brain disorders and highlight the potential of targeting RHOB as a therapeutic strategy for diseases linked to mutations in KCTD10 or RHOB.