Haplotype-resolved chromosome-scale genomes of the Asian and African Savannah Elephants.

The Proboscidea, which includes modern elephants, were once the largest terrestrial animals among extant species. They suffered mass extinction during the Ice Age. As a unique branch on the evolutionary tree, the Proboscidea are of great significance for the study of living animals. In this study, we generate chromosome-scale and haplotype-resolved genome assemblies for two extant Proboscidea species (Asian Elephant, Elephas maximus and African Savannah Elephant, Loxodonta africana) using Pacbio, Hi-C, and DNBSEQ technologies. The assembled genome sizes of the Asian and African Savannah Elephant are 3.38 Gb and 3.31 Gb, with scaffold N50 values of 130 Mb and 122 Mb, respectively. Using Hi-C technology ~97% of the scaffolds are anchored to 29 pseudochromosomes. Additionally, we identify ~9 Mb Y-linked sequences for each species. The high-quality genome assemblies in this study provide a valuable resource for future research on ecology, evolution, biology and conservation of Proboscidea species.

Multi-omics analysis reveals GAPDH posttranscriptional regulation of IFN-γ and PHGDH as a metabolic checkpoint of microglia polarization.

A "switch" in the metabolic pattern of microglia is considered to be required to meet the metabolic demands of cell survival and functions. However, how metabolic switches regulate microglial function remains controversial. We found here that exposure to amyloid-ß triggers microglial inflammation accompanied by increasing GAPDH levels. The increase of GAPDH, a glycolysis enzyme, leads to the reduced release of interferon-γ (IFN-γ) from inflammatory microglia. Such alternation is translational and is regulated by the binding of glycolysis enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to IFN-γ mRNA. GAPDH, by engaging/disengaging glycolysis and through influencing IFN-γ expression, regulates microglia functions, including phagocytosis and cytokine production. Phosphoglycerate dehydrogenase (PHGDH), screened from different state microglia by metabolomics combined with METARECON analysis, is a metabolic enzyme adjacent downstream of GAPDH and synthesizes serine on the collateral pathway derived from glycolysis. Polarization of microglial with PHGDH as a metabolic checkpoint can be bidirectionally regulated by adding IL-4 or giving PHGDH inhibitors. Therefore, regulation of metabolic enzymes not only reprograms metabolic patterns, but also manipulates microglia functions. Further study should be performed to explore the mechanism of metabolic checkpoints in human microglia or more in vivo animal experiments, and may expand to the effects of various metabolic substrates or enzyme, such as lipids and amino acids, on the functions of microglia.

Menin Reduces Parvalbumin Expression and is Required for the Anti-Depressant Function of Ketamine.

Dysfunction of parvalbumin (PV) neurons is closely involved in depression, however, the detailed mechanism remains unclear. Based on the previous finding that multiple endocrine neoplasia type 1 (Protein: Menin; Gene: Men1) mutation (G503D) is associated with a higher risk of depression, a Menin-G503D mouse model is generated that exhibits heritable depressive-like phenotypes and increases PV expression in brain. This study generates and screens a serial of neuronal specific Men1 deletion mice, and found that PV interneuron Men1 deletion mice (PcKO) exhibit increased cortical PV levels and depressive-like behaviors. Restoration of Menin, knockdown PV expression or inhibition of PV neuronal activity in PV neurons all can ameliorate the depressive-like behaviors of PcKO mice. This study next found that ketamine stabilizes Menin by inhibiting protein kinase A (PKA) activity, which mediates the anti-depressant function of ketamine. These results demonstrate a critical role for Menin in depression, and prove that Menin is key to the antidepressant function of ketamine.

Single-nucleus transcriptome inventory of giant panda reveals cellular basis for fitness optimization under low metabolism.

BACKGROUND: Energy homeostasis is essential for the adaptation of animals to their environment and some wild animals keep low metabolism adaptive to their low-nutrient dietary supply. Giant panda is such a typical low-metabolic mammal exhibiting species specialization of extremely low daily energy expenditure. It has low levels of basal metabolic rate, thyroid hormone, and physical activities, whereas the cellular bases of its low metabolic adaptation remain rarely explored. RESULTS: In this study, we generate a single-nucleus transcriptome atlas of 21 organs/tissues from a female giant panda. We focused on the central metabolic organ (liver) and dissected cellular metabolic status by cross-species comparison. Adaptive expression mode (i.e., AMPK related) was prominently displayed in the hepatocyte of giant panda. In the highest energy-consuming organ, the heart, we found a possibly optimized utilization of fatty acid. Detailed cell subtype annotation of endothelial cells showed the uterine-specific deficiency of blood vascular subclasses, indicating a potential adaptation for a low reproductive energy expenditure. CONCLUSIONS: Our findings shed light on the possible cellular basis and transcriptomic regulatory clues for the low metabolism in giant pandas and helped to understand physiological adaptation response to nutrient stress.

Hypothalamic Menin regulates systemic aging and cognitive decline.

Aging is a systemic process, which is a risk factor for impaired physiological functions, and finally death. The molecular mechanisms driving aging process and the associated cognitive decline are not fully understood. The hypothalamus acts as the arbiter that orchestrates systemic aging through neuroinflammatory signaling. Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development. Here, we found that the hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of aged mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers, while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline. We further found that Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism. Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocampus neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.

Brain Energy Metabolism: Astrocytes in Neurodegenerative Diseases.

Astrocytes are the most abundant cells in the brain. They have many important functions in the central nervous system (CNS), including the maintenance of glutamate and ion homeostasis, the elimination of oxidative stress, energy storage in glycogen, tissue repair, regulating synaptic activity by releasing neurotransmitters, and participating in synaptic formation. Astrocytes have special highly ramified structure. Their branches contact with synapses of neurons inwardly, with fine structure and wrapping synapses; their feet contact with blood vessels of brain parenchyma outward, almost wrapping the whole brain. The adjacent astrocytes rarely overlap and communicate with each other through gap junction channels. The ideal location of astrocytes enables them to sense the weak changes of their surroundings and provide the structural basis for the energy supply of neurons. Neurons and astrocytes are closely coupled units of energy metabolism in the brain. Neurons consume a lot of ATPs in the process of neurotransmission. Astrocytes provide metabolic substrates for neurons, maintain high activity of neuron, and facilitate information transmission of neurons. This article reviews the characteristics of glucose metabolism, lipid metabolism, and amino acid metabolism of astrocytes. The metabolic interactions between astrocytes and neurons, astrocytes and microglia were also detailed discussed. Finally, we classified analyzed the role of metabolic disorder of astrocytes in the occurrence and development of neurodegenerative diseases.

Genomic investigation of the Chinese alligator reveals wild-extinct genetic diversity and genomic consequences of their continuous decline.

Critically endangered species are usually restricted to small and isolated populations. High inbreeding without gene flow among populations further aggravates their threatened condition and reduces the likelihood of their long-term survival. Chinese alligator (Alligator sinensis) is one of the most endangered crocodiles in the world and has experienced a continuous decline over the past c. 1 million years. In order to identify the genetic status of the remaining populations and aid conservation efforts, we assembled the first high-quality chromosome-level genome of Chinese alligator and explored the genomic characteristics of three extant breeding populations. Our analyses revealed the existence of at least three genetically distinct populations, comprising two breeding populations in China (Changxing and Xuancheng) and one breeding population in an American wildlife refuge. The American population does not belong to the last two populations of its native range (Xuancheng and Changxing), thus representing genetic diversity extinct in the wild and provides future opportunities for genetic rescue. Moreover, the effective population size of these three populations has been continuously declining over the past 20 ka. Consistent with this decline, the species shows extremely low genetic diversity, a large proportion of long runs of homozygous fragments, and mutational load across the genome. Finally, to provide genomic insights for future breeding management and conservation, we assessed the feasibility of mixing extant populations based on the likelihood of introducing new deleterious alleles and signatures of local adaptation. Overall, this study provides a valuable genomic resource and important genomic insights into the ecology, evolution, and conservation of critically endangered alligators.

The chromosome-scale genome of the raccoon dog: Insights into its evolutionary characteristics.

The raccoon dog (Nyctereutes procyonoides) is an invasive canid species native to East Asia with several distinct characteristics. Here, we report a chromosome-scale genome of the raccoon dog with high contiguity, completeness, and accuracy. The intact taste receptor genes, expanded gene families, and positively selected genes related to digestion, absorption, foraging, and detoxification likely support the omnivory of raccoon dogs. Several positively selected genes and raccoon dog-specific mutations in TDRD6 and ZP3 genes may explain their high reproductivity. Enriched GO terms in energy metabolism and positively selected immune genes were speculated to be closely related to the diverse immune system of raccoon dogs. In addition, we found that several expanded gene families and positively selected genes related to lipid metabolism and insulin resistance may contribute to winter sleep of the raccoon dog. This high-quality genome provides a valuable resource for understanding the evolutionary characteristics of this species.

Screening of cell-virus, cell-cell, gene-gene crosstalk among animal kingdom at single cell resolution.

BACKGROUND: The exact animal origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains obscure and understanding its host range is vital for preventing interspecies transmission. METHODS: Herein, we applied single-cell sequencing to multiple tissues of 20 species (30 data sets) and integrated them with public resources (45 data sets covering 26 species) to expand the virus receptor distribution investigation. While the binding affinity between virus and receptor is essential for viral infectivity, understanding the receptor distribution could predict the permissive organs and tissues when infection occurs. RESULTS: Based on the transcriptomic data, the expression profiles of receptor or associated entry factors for viruses capable of causing respiratory, blood, and brain diseases were described in detail. Conserved cellular connectomes and regulomes were also identified, revealing fundamental cell-cell and gene-gene cross-talks from reptiles to humans. CONCLUSIONS: Overall, our study provides a resource of the single-cell atlas of the animal kingdom which could help to identify the potential host range and tissue tropism of viruses and reveal the host-virus co-evolution.

Whole-genome resequencing of Chinese pangolins reveals a population structure and provides insights into their conservation.

Poaching and trafficking have a substantial negative impact on the population growth and range expansion of the Chinese pangolin (Manis pentadactyla). However, recently reported activities of Chinese pangolins in several sites of Guangdong province in China indicate a promising sign for the recovery of this threatened species. Here, we re-sequence genomes of 15 individuals and perform comprehensive population genomics analyses with previously published 22 individuals. These Chinese pangolins are found to be divided into three distinct populations. Multiple lines of evidence indicate the existence of a newly discovered population (CPA) comprises entirely of individuals from Guangdong province. The other two populations (CPB and CPC) have previously been documented. The genetic differentiation of the CPA and CPC is extremely large (FST = 0.541), which is larger than many subspecies-level differentiations. Even for the closer CPA and CPB, their differentiation (FST = 0.101) is still comparable with the population-level differentiation of many endangered species. Further analysis reveals that the CPA and CPB populations separate 2.5-4.0 thousand years ago (kya), and on the other hand, CPA and CPC diverge around 25-40 kya. The CPA population harbors more runs of homozygosity (ROHs) than the CPB and CPC populations, indicating that inbreeding is more prevalent in the CPA population. Although the CPC population has less mutational load than CPA and CPB populations, we predict that several Loss of Function (LoF) mutations will be translocated into the CPA or CPB populations by using the CPC as a donor population for genetic rescue. Our findings imply that the conservation of Chinese pangolins is challenging, and implementing genetic rescue among the three groups should be done with extreme caution.

The complete mitochondrial genome of Cerithidea tonkiniana (Mabille, 1887) in Guangxi, China.

Cerithidea tonkiniana is an amphibious gastropod mollusk that lives in brackish water habitats. In this study, the complete mitochondrial genome of Cerithidea tonkiniana collected from Guangxi, China was assembled for the first time based on the next generation sequencing. The length of this mitogenome is 15,617 base pair with a slightly biased AT content (63.1％). This circular genome contains 13 proterin-coding genes, 22 tRNA genes, and 2 rRNA genes. Phylogenetic analysis using the 10 Cerithioidea species showed that the C. tonkiniana is closely related with Cerithidea sinensis and Cerithidea obtuse, forming the Potamididae cluster.

Chromosome-Level Genome Assembly of the Green Peafowl (Pavo muticus).

The green peafowl (Pavo muticus) is facing a high risk of extinction due to the long-term and widespread threats of poaching and habitat conversion. Here, we present a high-quality chromosome-level genome assembly of the green peafowl with high contiguity and accuracy assembled by PacBio sequencing, DNBSEQ short-read sequencing, and Hi-C sequencing technologies. The final genome size was estimated to be 1.049 Gb, whereas 1.042 Gb of the genome was assigned to 27 pseudochromosomes. The scaffold N50 length was 75.5 Mb with a complete BUSCO score of 97.6%. We identified W and Z chromosomes and validated them by resequencing 14 additional individuals. Totally, 167.04 Mb repetitive elements were identified in the genome, accounting for 15.92% of the total genome size. We predicted 14,935 protein-coding genes, among which 14,931 genes were functionally annotated. This is the most comprehensive and complete de novo assembly of the Pavo genus, and it will serve as a valuable resource for future green peafowl ecology, evolution, and conservation studies.

Chromosome-scale assembly and whole-genome sequencing of 266 giant panda roundworms provide insights into their evolution, adaptation and potential drug targets.

Helminth diseases have long been a threat to the health of humans and animals. Roundworms are important organisms for studying parasitic mechanisms, disease transmission and prevention. The study of parasites in the giant panda is of importance for understanding how roundworms adapt to the host. Here, we report a high-quality chromosome-scale genome of Baylisascaris schroederi with a genome size of 253.60 Mb and 19,262 predicted protein-coding genes. We found that gene families related to epidermal chitin synthesis and environmental information processes in the roundworm genome have expanded significantly. Furthermore, we demonstrated unique genes involved in essential amino acid metabolism in the B. schroederi genome, inferred to be essential for the adaptation to the giant panda-specific diet. In addition, under different deworming pressures, we found that four resistance-related genes (glc-1, nrf-6, bre-4 and ced-7) were under strong positive selection in a captive population. Finally, 23 known drug targets and 47 potential drug target proteins were identified. The genome provides a unique reference for inferring the early evolution of roundworms and their adaptation to the host. Population genetic analysis and drug sensitivity prediction provide insights revealing the impact of deworming history on population genetic structure of importance for disease prevention.

Genetics of Severe Cutaneous Adverse Reactions.

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) are T cells-mediated life-threatening immune reactions, most commonly induced by drug. The last decade has seen significant progress in SCARs research. Recent studies have unveiled the pathogenesis of SCARs involved in susceptible genes, including human leukocyte antigens (HLA) and drugs-T cell receptor (TCR) interaction that may trigger T cell activation with downstream immune signaling of cytokines/chemokines and specific cytotoxic proteins releases. Advances in identification of multiple genetic alleles associated with specific drugs related SCARS in different populations is an important breakthrough in recent years for prevention of SCARs. This article summarized the findings on genetic factors related to SJS/TEN, especially for HLA.

Chromosome-Scale Genome of Masked Palm Civet (Paguma larvata) Shows Genomic Signatures of Its Biological Characteristics and Evolution.

The masked palm civet (Paguma larvata) is a small carnivore with distinct biological characteristics, that likes an omnivorous diet and also serves as a vector of pathogens. Although this species is not an endangered animal, its population is reportedly declining. Since the severe acute respiratory syndrome (SARS) epidemic in 2003, the public has been particularly concerned about this species. Here, we present the first genome of the P. larvata, comprising 22 chromosomes assembled using single-tube long fragment read (stLFR) and Hi-C technologies. The genome length is 2.41 Gb with a scaffold N50 of 105.6 Mb. We identified the 107.13 Mb X chromosome and one 1.34 Mb Y-linked scaffold and validated them by resequencing 45 P. larvata individuals. We predicted 18,340 protein-coding genes, among which 18,333 genes were functionally annotated. Interestingly, several biological pathways related to immune defenses were found to be significantly expanded. Also, more than 40% of the enriched pathways on the positively selected genes (PSGs) were identified to be closely related to immunity and survival. These enriched gene families were inferred to be essential for the P. larvata for defense against the pathogens. However, we did not find a direct genomic basis for its adaptation to omnivorous diet despite multiple attempts of comparative genomic analysis. In addition, we evaluated the susceptibility of the P. larvata to the SARS-CoV-2 by screening the RNA expression of the ACE2 and TMPRSS2/TMPRSS4 genes in 16 organs. Finally, we explored the genome-wide heterozygosity and compared it with other animals to evaluate the population status of this species. Taken together, this chromosome-scale genome of the P. larvata provides a necessary resource and insights for understanding the genetic basis of its biological characteristics, evolution, and disease transmission control.

Corrigendum to "The Epidemiology of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in China".

[This corrects the article DOI: 10.1155/2018/4320195.].

The Epidemiology of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in China.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are life-threatening disease. However, there are only few epidemiologic studies of SJS/TEN from China. To analyze the clinical characteristics, causality, and outcome of treatment for SJS/TEN in China, we reviewed case reports of patients with SJS/TEN from the China National Knowledge Infrastructure (CNKI) and Wanfang database from 2006 to 2016 and patients with SJS/TEN who were admitted to the First Affiliated Hospital of Fujian Medical University during the same period. There were 166 patients enrolled, including 70 SJS, 2 SJS/TEN overlap, and 94 TEN. The most common offending drugs were antibiotics (29.5%) and anticonvulsants (24.1%). Carbamazepine, allopurinol, and penicillins were the most common single offending drugs (17.5%, 9.6%, and 7.2%). Chinese patent medicines accounted for 5.4%. There were 76 (45.8%) patients receiving systemic steroid and intravenous immunoglobulin (IVIG) in combination therapy, especially for TEN (80.3%), and others were treated with systemic steroids alone. Mortality rate of combination treatment comparing with steroid alone in TEN patients had no statistical significance. In conclusion, carbamazepine and allopurinol were the leading causative drugs for SJS/TEN in China. Combination of IVIG and steroids is a common treatment for TEN, but its efficacy in improving mortality needs further investigation.