Bronze Age cheese reveals human-Lactobacillus interactions over evolutionary history.

Despite the long history of consumption of fermented dairy, little is known about how the fermented microbes were utilized and evolved over human history. Here, by retrieving ancient DNA of Bronze Age kefir cheese (∼3,500 years ago) from the Xiaohe cemetery, we explored past human-microbial interactions. Although it was previously suggested that kefir was spread from the Northern Caucasus to Europe and other regions, we found an additional spreading route of kefir from Xinjiang to inland East Asia. Over evolutionary history, the East Asian strains gained multiple gene clusters with defensive roles against environmental stressors, which can be a result of the adaptation of Lactobacillus strains to various environmental niches and human selection. Overall, our results highlight the role of past human activities in shaping the evolution of human-related microbes, and such insights can, in turn, provide a better understanding of past human behaviors.

The deep population history of northern East Asia from the Late Pleistocene to the Holocene.

Northern East Asia was inhabited by modern humans as early as 40 thousand years ago (ka), as demonstrated by the Tianyuan individual. Using genome-wide data obtained from 25 individuals dated to 33.6-3.4 ka from the Amur region, we show that Tianyuan-related ancestry was widespread in northern East Asia before the Last Glacial Maximum (LGM). At the close of the LGM stadial, the earliest northern East Asian appeared in the Amur region, and this population is basal to ancient northern East Asians. Human populations in the Amur region have maintained genetic continuity from 14 ka, and these early inhabitants represent the closest East Asian source known for Ancient Paleo-Siberians. We also observed that EDAR V370A was likely to have been elevated to high frequency after the LGM, suggesting the possible timing for its selection. This study provides a deep look into the population dynamics of northern East Asia.

Human population history at the crossroads of East and Southeast Asia since 11,000 years ago.

Past human genetic diversity and migration between southern China and Southeast Asia have not been well characterized, in part due to poor preservation of ancient DNA in hot and humid regions. We sequenced 31 ancient genomes from southern China (Guangxi and Fujian), including two ∼12,000- to 10,000-year-old individuals representing the oldest humans sequenced from southern China. We discovered a deeply diverged East Asian ancestry in the Guangxi region that persisted until at least 6,000 years ago. We found that ∼9,000- to 6,000-year-old Guangxi populations were a mixture of local ancestry, southern ancestry previously sampled in Fujian, and deep Asian ancestry related to Southeast Asian Hòabìnhian hunter-gatherers, showing broad admixture in the region predating the appearance of farming. Historical Guangxi populations dating to ∼1,500 to 500 years ago are closely related to Tai-Kadai and Hmong-Mien speakers. Our results show heavy interactions among three distinct ancestries at the crossroads of East and Southeast Asia.

The Born in Guangzhou Cohort Study enables generational genetic discoveries.

Genomic research that targets large-scale, prospective birth cohorts constitutes an essential strategy for understanding the influence of genetics and environment on human health1. Nonetheless, such studies remain scarce, particularly in Asia. Here we present the phase I genome study of the Born in Guangzhou Cohort Study2 (BIGCS), which encompasses the sequencing and analysis of 4,053 Chinese individuals, primarily composed of trios or mother-infant duos residing in South China. Our analysis reveals novel genetic variants, a high-quality reference panel, and fine-scale local genetic structure within BIGCS. Notably, we identify previously unreported East Asian-specific genetic associations with maternal total bile acid, gestational weight gain and infant cord blood traits. Additionally, we observe prevalent age-specific genetic effects on lipid levels in mothers and infants. In an exploratory intergenerational Mendelian randomization analysis, we estimate the maternal putatively causal and fetal genetic effects of seven adult phenotypes on seven fetal growth-related measurements. These findings illuminate the genetic links between maternal and early-life traits in an East Asian population and lay the groundwork for future research into the intricate interplay of genetics, intrauterine exposures and early-life experiences in shaping long-term health.

Apical expansion of calvarial osteoblasts and suture patency is dependent on fibronectin cues.

The skull roof, or calvaria, is comprised of interlocking plates of bones that encase the brain. Separating these bones are fibrous sutures that permit growth. Currently, we do not understand the instructions for directional growth of the calvaria, a process which is error-prone and can lead to skeletal deficiencies or premature suture fusion (craniosynostosis, CS). Here, we identify graded expression of fibronectin (FN1) in the mouse embryonic cranial mesenchyme (CM) that precedes the apical expansion of calvaria. Conditional deletion of Fn1 or Wasl leads to diminished frontal bone expansion by altering cell shape and focal actin enrichment, respectively, suggesting defective migration of calvarial progenitors. Interestingly, Fn1 mutants have premature fusion of coronal sutures. Consistently, syndromic forms of CS in humans exhibit dysregulated FN1 expression, and we also find FN1 expression altered in a mouse CS model of Apert syndrome. These data support a model of FN1 as a directional substrate for calvarial osteoblast migration that may be a common mechanism underlying many cranial disorders of disparate genetic etiologies.

Mesenchymal Wnts are required for morphogenetic movements of calvarial osteoblasts during apical expansion.

Apical expansion of calvarial osteoblast progenitors from the cranial mesenchyme (CM) above the eye is integral to calvarial growth and enclosure of the brain. The cellular behaviors and signals underlying the morphogenetic process of calvarial expansion are unknown. Time-lapse light-sheet imaging of mouse embryos revealed calvarial progenitors intercalate in 3D in the CM above the eye, and exhibit protrusive and crawling activity more apically. CM cells express non-canonical Wnt/planar cell polarity (PCP) core components and calvarial osteoblasts are bidirectionally polarized. We found non-canonical ligand Wnt5a-/- mutants have less dynamic cell rearrangements and protrusive activity. Loss of CM-restricted Wntless (CM-Wls), a gene required for secretion of all Wnt ligands, led to diminished apical expansion of Osx+ calvarial osteoblasts in the frontal bone primordia in a non-cell autonomous manner without perturbing proliferation or survival. Calvarial osteoblast polarization, progressive cell elongation and enrichment for actin along the baso-apical axis were dependent on CM-Wnts. Thus, CM-Wnts regulate cellular behaviors during calvarial morphogenesis for efficient apical expansion of calvarial osteoblasts. These findings also offer potential insights into the etiologies of calvarial dysplasias.

The genomic origins of the Bronze Age Tarim Basin mummies.

The identity of the earliest inhabitants of Xinjiang, in the heart of Inner Asia, and the languages that they spoke have long been debated and remain contentious1. Here we present genomic data from 5 individuals dating to around 3000-2800 BC from the Dzungarian Basin and 13 individuals dating to around 2100-1700 BC from the Tarim Basin, representing the earliest yet discovered human remains from North and South Xinjiang, respectively. We find that the Early Bronze Age Dzungarian individuals exhibit a predominantly Afanasievo ancestry with an additional local contribution, and the Early-Middle Bronze Age Tarim individuals contain only a local ancestry. The Tarim individuals from the site of Xiaohe further exhibit strong evidence of milk proteins in their dental calculus, indicating a reliance on dairy pastoralism at the site since its founding. Our results do not support previous hypotheses for the origin of the Tarim mummies, who were argued to be Proto-Tocharian-speaking pastoralists descended from the Afanasievo1,2 or to have originated among the Bactria-Margiana Archaeological Complex3 or Inner Asian Mountain Corridor cultures4. Instead, although Tocharian may have been plausibly introduced to the Dzungarian Basin by Afanasievo migrants during the Early Bronze Age, we find that the earliest Tarim Basin cultures appear to have arisen from a genetically isolated local population that adopted neighbouring pastoralist and agriculturalist practices, which allowed them to settle and thrive along the shifting riverine oases of the Taklamakan Desert.

Historic dog Furs Unravel the Origin and Artificial Selection of Modern Nordic Lapphund and Elkhound dog Breeds.

The origins and extreme morphological evolution of the modern dog breeds are poorly studied because the founder populations are extinct. Here, we analyse eight 100 to 200 years old dog fur samples obtained from traditional North Swedish clothing, to explore the origin and artificial selection of the modern Nordic Lapphund and Elkhound dog breeds. Population genomic analysis confirmed the Lapphund and Elkhound breeds to originate from the local dog population, and showed a distinct decrease in genetic diversity in agreement with intense breeding. We identified eleven genes under positive selection during the breed development. In particular, the MSRB3 gene, associated with breed-related ear morphology, was selected in all Lapphund and Elkhound breeds, and functional assays showed that a SNP mutation in the 3'UTR region suppresses its expression through miRNA regulation. Our findings demonstrate analysis of near-modern dog artifacts as an effective tool for interpreting the origin and artificial selection of the modern dog breeds.

Ancient Mitogenomes Reveal the Maternal Genetic History of East Asian Dogs.

Recent studies have suggested that dogs were domesticated during the Last Glacial Maximum (LGM) in Siberia, which contrasts with previous proposed domestication centers (e.g. Europe, the Middle East, and East Asia). Ancient DNA provides a powerful resource for the study of mammalian evolution and has been widely used to understand the genetic history of domestic animals. To understand the maternal genetic history of East Asian dogs, we have made a complete mitogenome dataset of 120 East Asian canids from 38 archaeological sites, including 102 newly sequenced from 12.9 to 1 ka BP (1,000 years before present). The majority (112/119, 94.12%) belonged to haplogroup A, and half of these (55/112, 49.11%) belonged to sub-haplogroup A1b. Most existing mitochondrial haplogroups were present in ancient East Asian dogs. However, mitochondrial lineages in ancient northern dogs (northeastern Eurasia and northern East Asia) were deeper and older than those in southern East Asian dogs. Results suggests that East Asian dogs originated from northeastern Eurasian populations after the LGM, dispersing in two possible directions after domestication. Western Eurasian (Europe and the Middle East) dog maternal ancestries genetically influenced East Asian dogs from approximately 4 ka BP, dramatically increasing after 3 ka BP, and afterwards largely replaced most primary maternal lineages in northern East Asia. Additionally, at least three major mitogenome sub-haplogroups of haplogroup A (A1a, A1b, and A3) reveal at least two major dispersal waves onto the Qinghai-Tibet Plateau in ancient times, indicating eastern (A1b and A3) and western (A1a) Eurasian origins.

Copper Difluorocarbene Enables Catalytic Difluoromethylation.

Despite the synthetic versatility of difluorocarbene, its high reactivity severely regulates widespread applications of difluorocarbene in organic synthesis. Here, we report a copper difluorocarbene-involved catalytic coupling, representing a new mode of the difluoromethylation reaction. This method allows difluoromethylation of a wide range of readily available allyl/propargyl electrophiles with NaBH3CN and low-cost difluorocarbene precursor BrCF2CO2K, featuring high cost-efficiency, high stereo- and regioselectivities, and high functional group tolerance, even with complex drug-like molecules. Applying the method led to the efficient synthesis of deuterated difluoromethylated compounds of medicinal interest. The resulting difluoromethylated allyl and allenyl products can serve as versatile synthons for diverse transformations, rendering the approach attractive for synthesizing complex fluorinated structures. Experimental mechanistic studies and computational calculations reveal that the formation of a difluoromethylcopper(I) intermediate through the nucleophilic attack of boron hydride on the copper(I) difluorocarbene is the key step in the reaction.

Lamellipodia-Mediated Osteoblast Haptotaxis Guided by Fibronectin Ligand Concentrations on a Multiplex Chip.

Skull morphogenesis is a complex, dynamic process involving two different germ layers and progressing to the coordinated, directional growth of individual bones. The mechanisms underlying directional growth toward the apex are not completely understood. Here, a microfluidic chip-based approach is utilized to test whether calvarial osteoblast progenitors undergo haptotaxis on a gradient of Fibronectin1 (FN1) via lamellipodia. Mimicking the embryonic cranial mesenchyme's FN1 pattern, FN1 gradients is established in the chip using computer modeling and fluorescent labeling. Primary mouse calvarial osteoblast progenitors are plated in the chip along an array of segmented gradients of adsorbed FN1. The study performs single-cell tracking and measures protrusive activity. Haptotaxis is observed at an intermediate FN1 concentration, with an average directional migration index (yFMI) of 0.07, showing a significant increase compared to the control average yFMI of -0.01. A significant increase in protrusive activity is observed during haptotaxis. Haptotaxis is an Arp2/3-dependent, lamellipodia-mediated process. Calvarial osteoblast progenitors treated with the Arp2/3 (Actin Related Protein 2/3 complex) inhibitor CK666 show significantly diminished haptotaxis, with an average yFMI of 0.01. Together, these results demonstrate haptotaxis on an FN1 gradient as a new mechanism in the apical expansion of calvarial osteoblast progenitors during development and shed light on the etiology of calvarial defects.

Interferometry-Integrated Noise-Immune Quantum Memory.

A quantum memory with the performances of low noise, high efficiency, and high bandwidth is of crucial importance for developing practical quantum information technologies. However, the excess noises generated during the highly efficient processing of quantum information inevitably destroy quantum state. Here, we present a quantum memory with built-in excess-noise eraser by integrating a photon-correlated quantum interferometry in quantum memory, where the memory efficiency can be enhanced and the excess noises can be suppressed to the vacuum level via destructive interference. This quantum memory is demonstrated in a rubidium vapor cell with a 10-ns-long photonics signal. We observe ∼80% noise suppression, the write-in efficiency enhancement from 87% to 96.2% without and with interferometry, and the corresponding memory efficiency excluding the noises from 70% to 77%. The fidelity is 93.7% at the single-photon level, significantly exceeding the no-cloning limit. Such interferometry-integrated quantum memory, the first expansion of quantum interference techniques to quantum information processing, simultaneously enables low noise, high bandwidth, high efficiency, and easy operation.

Genetic Continuity of Bronze Age Ancestry with Increased Steppe-Related Ancestry in Late Iron Age Uzbekistan.

Although Uzbekistan and Central Asia are known for the well-studied Bronze Age civilization of the Bactria-Margiana Archaeological Complex (BMAC), the lesser-known Iron Age was also a dynamic period that resulted in increased interaction and admixture among different cultures from this region. To broaden our understanding of events that impacted the demography and population structure of this region, we generated 27 genome-wide single-nucleotide polymorphism capture data sets of Late Iron Age individuals around the Historical Kushan time period (∼2100-1500 BP) from three sites in South Uzbekistan. Overall, Bronze Age ancestry persists into the Iron Age in Uzbekistan, with no major replacements of populations with Steppe-related ancestry. However, these individuals suggest diverse ancestries related to Iranian farmers, Anatolian farmers, and Steppe herders, with a small amount of West European Hunter Gatherer, East Asian, and South Asian Hunter Gatherer ancestry as well. Genetic affinity toward the Late Bronze Age Steppe herders and a higher Steppe-related ancestry than that found in BMAC populations suggest an increased mobility and interaction of individuals from the Northern Steppe in a Southward direction. In addition, a decrease of Iranian and an increase of Anatolian farmer-like ancestry in Uzbekistan Iron Age individuals were observed compared with the BMAC populations from Uzbekistan. Thus, despite continuity from the Bronze Age, increased admixture played a major role in the shift from the Bronze to the Iron Age in southern Uzbekistan. This mixed ancestry is also observed in other parts of the Steppe and Central Asia, suggesting more widespread admixture among local populations.

3,3-Difluoroallyl Sulfonium Salts: Practical and Bench-Stable Reagents for Highly Regioselective gem-Difluoroallylations.

The site-selective introduction of the difluoromethylene group into organic molecules has important applications in producing pharmaceuticals and agrochemicals. However, the general and efficient methods that can construct both C(sp2 )-CF2 R and C(sp3 )-CF2 R bonds remain challenging. Here, we disclose a new type of practical and bench-stable difluoroalkylating reagent 3,3-difluoroallyl sulfonium salt (DFAS) that can be practically prepared from inexpensive and bulk chemical feedstock 3,3,3-trifluoropropene. This reagent allows highly regioselective gem-difluoroallylation of various organozinc reagents, including aryl, primary, secondary, and tertiary alkyl zinc reagents, via copper catalysis under mild reaction conditions with high efficiency. The reaction can also be extended to a series of substituted DFASs. Application of the approach leads to the short synthesis of complex analogs, showing the prospect of DFASs in medicinal chemistry.

Ancient mitogenomes show plateau populations from last 5200 years partially contributed to present-day Tibetans.

The clarification of the genetic origins of present-day Tibetans requires an understanding of their past relationships with the ancient populations of the Tibetan Plateau. Here we successfully sequenced 67 complete mitochondrial DNA genomes of 5200 to 300-year-old humans from the plateau. Apart from identifying two ancient plateau lineages (haplogroups D4j1b and M9a1a1c1b1a) that suggest some ancestors of Tibetans came from low-altitude areas 4750 to 2775 years ago and that some were involved in an expansion of people moving between high-altitude areas 2125 to 1100 years ago, we found limited evidence of recent matrilineal continuity on the plateau. Furthermore, deep learning of the ancient data incorporated into simulation models with an accuracy of 97% supports that present-day Tibetan matrilineal ancestry received partial contribution rather than complete continuity from the plateau populations of the last 5200 years.

Paleolithic genetic link between Southern China and Mainland Southeast Asia revealed by ancient mitochondrial genomes.

The genetic history of Southern East Asians is not well-known, especially prior to the Neolithic period. To address this, we successfully sequenced two complete mitochondrial genomes of 11,000-year-old human individuals from Southern China, thus generating the oldest ancient DNA sequences from this area. Integrating published mitochondrial genomes, we characterized M71d, a new subhaplogroup of haplogroup M71. Our results suggest a possible early migration between Southern China and mainland Southeast Asia by at least 22,000 BP.

Herpes Simplex Virus 1 Specifically Targets Human CD1d Antigen Presentation To Enhance Its Pathogenicity.

Herpes simplex virus 1 (HSV-1) is one of the most prevalent herpesviruses in humans and represents a constant health threat to aged and immunocompromised populations. How HSV-1 interacts with the host immune system to efficiently establish infection and latency is only partially known. CD1d-restricted NKT cells are a critical arm of the host innate immune system and play potent roles in anti-infection and antitumor immune responses. We discovered previously that upon infection, HSV-1 rapidly and efficiently downregulates CD1d expression on the cell surface and suppresses the function of NKT cells. Furthermore, we identified the viral serine/threonine protein kinase US3 as a major viral factor downregulating CD1d during infection. Interestingly, neither HSV-1 nor its US3 protein efficiently inhibits mouse CD1d expression, suggesting that HSV-1 has coevolved with the human immune system to specifically suppress human CD1d (hCD1d) and NKT cell function for its pathogenesis. This is consistent with the fact that wild-type mice are mostly resistant to HSV-1 infection. On the other hand, in vivo infection of CD1d-humanized mice (hCD1d knock-in mice) showed that HSV-1 can indeed evade hCD1d function and establish infection in these mice. We also report here that US3-deficient viruses cannot efficiently infect hCD1d knock-in mice but infect mice lacking all NKT cells at a higher efficiency. Together, these studies supported HSV-1 evasion of human CD1d and NKT cell function as an important pathogenic factor for the virus. Our results also validated the potent roles of NKT cells in antiherpesvirus immune responses and pointed to the potential of NKT cell ligands as adjuvants for future vaccine development.IMPORTANCE Herpes simplex virus 1 (HSV-1) is among the most common human pathogens. Little is known regarding the exact mechanism by which this virus evades the human immune system, particularly the innate immune system. We reported previously that HSV-1 employs its protein kinase US3 to modulate the expression of the key antigen-presenting molecule, CD1d, so as to evade the antiviral function of NKT cells. Here we demonstrated that the virus has coevolved with the human CD1d and NKT cell system and that NKT cells indeed play potent roles in anti-HSV immune responses. These studies point to the great potential of exploring NKT cell ligands as adjuvants for HSV vaccines.

Characterization of genome-wide segmental duplications reveals a common genomic feature of association with immunity among domestic animals.

BACKGROUND: Segmental duplications (SDs) commonly exist in plant and animal genomes, playing crucial roles in genomic rearrangement, gene innovation and the formation of copy number variants. However, they have received little attention in most livestock species. RESULTS: Aiming at characterizing SDs across the genomes of diverse livestock species, we mapped genome-wide SDs of horse, rabbit, goat, sheep and chicken, and also enhanced the existing SD maps of cattle and pig genomes based on the most updated genome assemblies. We adopted two different detection strategies, whole genome analysis comparison and whole genome shotgun sequence detection, to pursue more convincing findings. Accordingly we identified SDs for each species with the length of from 21.7 Mb to 164.1 Mb, and 807 to 4,560 genes were harboured within the SD regions across different species. More interestingly, many of these SD-related genes were involved in the process of immunity and response to external stimuli. We also found the existence of 59 common genes within SD regions in all studied species except goat. These common genes mainly consisted of both UDP glucuronosyltransferase and Interferon alpha families, implying the connection between SDs and the evolution of these gene families. CONCLUSIONS: Our findings provide insights into livestock genome evolution and offer rich genomic sources for livestock genomic research.

88% conversion efficiency with an atomic spin wave mediated mode selection.

In studying quantum correlation and quantum memory of continuous variables of light fields and atoms, a crucial step is the retrieval of the quantum fields by converting an atomic spin wave to light, and retrieval efficiency is a crucial parameter. In this Letter, we implement a double-pass Raman scheme in Rb87 by incorporating coherent feedback. We find that the transfer efficiency from an atomic spin wave, which is generated from a Raman process in a high gain regime, to light fields is enhanced by the double-pass scheme as compared to the commonly used single-pass scheme. An atomic spin wave as high as 88% is read out, limited only by decoherence of the atomic spin waves. Our analysis shows that the enhancement effect is because a double-pass scheme introduced the coherent feedback mechanism which selects the spatial mode of an atomic spin wave via the correlated optical field and enhances the coupling efficiency between the atom and light. The correlations between the write-in and readout signals generated in such a two-pass Raman process are also better than the single-pass case. We believe such a two-pass scheme with feedback mechanism should be useful for studying continuous variables in quantum systems.

Effects of environmental noise exposure on DNA methylation in the brain and metabolic health.

Environmental noise exposure is associated with adverse effects on human health including hearing loss, heart disease, and changes in stress-related hormone levels. Alteration in DNA methylation in response to environmental exposures is a well-known phenomenon and it is implicated in many human diseases. Understanding how environmental noise exposures affect DNA methylation patterns may help to elucidate the link between noise and adverse effects on health. In this pilot study we examined the effects of environmental noise exposure on DNA methylation of genes related to brain function and investigated whether these changes are related with metabolic health. We exposed four groups of male Wistar rats to moderate intensity noise (70-75dB with 20-4000Hz) at night for three days as short-term exposure, and for three weeks as long-term exposure. Noise exposure was limited to 45dB during the daytime. Control groups were exposed to only 45dB, day and night. We measured DNA methylation in the Bdnf, Comt, Crhr1, Mc2r, and Snca genes in tissue from four brain regions of the rats (hippocampus, frontal lobe, medulla oblongata, and inferior colliculus). Further, we measured blood pressure and body weight after long-term noise exposure. We found that environmental noise exposure is associated with gene-specific DNA methylation changes in specific regions of the brain. Changes in DNA methylation are significantly associated with changes in body weight (between Bdnf DNA methylation and Δ body weight: r=0.59, p=0.018; and between LINE-1 ORF DNA methylation and Δ body weight: =-0.80, p=0.0004). We also observed that noise exposure decreased blood pressure (p=0.038 for SBP, p=0.017 for DBP and p 0. 017 for MAP) and decreased body weight (ß=-26g, p=0.008). In conclusion, environmental noise exposures can induce changes in DNA methylation in the brain, which may be associated with adverse effects upon metabolic health through modulation of response to stress-related hormones.