Experimental evidence for cancer resistance in a bat species.

Mammals exhibit different rates of cancer, with long-lived species generally showing greater resistance. Although bats have been suggested to be resistant to cancer due to their longevity, this has yet to be systematically examined. Here, we investigate cancer resistance across seven bat species by activating oncogenic genes in their primary cells. Both in vitro and in vivo experiments suggest that Myotis pilosus (MPI) is particularly resistant to cancer. The transcriptomic and functional analyses reveal that the downregulation of three genes (HIF1A, COPS5, and RPS3) largely contributes to cancer resistance in MPI. Further, we identify the loss of a potential enhancer containing the HIF1A binding site upstream of COPS5 in MPI, resulting in the downregulation of COPS5. These findings not only provide direct experimental evidence for cancer resistance in a bat species but also offer insights into the natural mechanisms of cancer resistance in mammals.

Hypoxic response patterns in lung tissue: An integrated analysis of comparative physiological and transcriptomic studies from Neodon fuscus and Lasiopodomys brandtii.

Oxygen (O2) is essential for the survival and reproduction of most species. However, in recent years, with global climate change and the increasing impact of human activities on the ecosystem, the frequency of extreme environmental events, such as heat waves, cold waves, droughts, and floods, has increased, resulting in dramatic changes in environmental oxygen concentration (hypoxic environment, etc.), threatening the survival of animals and pushing them toward extreme adaptation. In this context, how organisms, especially those with differences in original habitats, adapt to low oxygen environment is particularly important. In this study, we systematically analyzed hypoxic response patterns in lung tissues of small rodents Neodon fuscus, Lasiopodomys brandtii, and Mus musculus with different experiences of natural hypoxia tolerance through laboratory simulation of hypoxia environment, combined with hematological, histological, and transcriptomic analysis. Our results show that all three species exhibit increased antioxidant defense and damage repair ability to a certain extent under hypoxia, although the specific molecular mechanisms are not the same. L. brandtii showed better damage repair ability than the others, which is likely to be closely related to the intermittent hypoxia environment experienced in the natural environment, and genes such as Glrx5, Prdx2, Col1a1, Lama1, and Eln may play a crucial role in this process. In addition, we found that both N. fuscus and L. brandtii appropriately enhanced oxygen transport in tissues under hypoxic conditions, with a series of functional genes related to hemoglobin synthesis and vascular smooth muscle contraction were significantly up-regulated in both species of voles, such as Actg2, Ptgir, Alas2, Hba, Hbb and Bpgm. Our results, to a certain extent, reveal the differences and similarities of hypoxic response patterns in lung tissues of small rodents with different hypoxic life histories and provide a relatively perfect analytical paradigm for related studies.

Fuel source shift or cost reduction: Context-dependent adaptation strategies in closely related Neodon fuscus and Lasiopodomys brandtii against hypoxia.

Oxygen is essential for most life forms. Insufficient oxygen supply can disrupt homeostasis and compromise survival, and hypoxia-induced cardiovascular failure is fatal in many animals, including humans. However, certain species have adapted and evolved to cope with hypoxic environments and are therefore good models for studying the regulatory mechanisms underlying responses to hypoxia. Here, we explored the physiological and molecular responses of the cardiovascular system in two closely related hypoxia-adapted species with different life histories, namely, Qinghai voles ( Neodon fuscus) and Brandt's voles ( Lasiopodomys brandtii), under hypoxic (10% O 2 for 48 h) and normoxic (20.9% O 2 for 48 h) exposure. Kunming mice ( Mus musculus) were used for comparison. Qinghai voles live in plateau areas under hypoxic conditions, whereas Brandt's voles only experience periodic hypoxia. Histological and hematological analyses indicated a strong tolerance to hypoxia in both species, but significant cardiac tissue damage and increased blood circulation resistance in mice exposed to hypoxia. Comparative transcriptome analysis revealed enhanced oxygen transport efficiency as a coping mechanism against hypoxia in both N. fuscus and L. brandtii, but with some differences. Specifically, N. fuscus showed up-regulated expression of genes related to accelerated cardiac contraction and angiogenesis, whereas L. brandtii showed significant up-regulation of erythropoiesis-related genes. Synchronized up-regulation of hemoglobin synthesis-related genes was observed in both species. In addition, differences in cardiometabolic strategies against hypoxia were observed in the rodents. Notably, M. musculus relied on adenosine triphosphate (ATP) generation via fatty acid oxidation, whereas N. fuscus shifted energy production to glucose oxidation under hypoxic conditions and L. brandtii employed a conservative strategy involving down-regulation of fatty acid and glucose oxidation and a bradycardia phenotype. In conclusion, the cardiovascular systems of N. fuscus and L. brandtii have evolved different adaptation strategies to enhance oxygen transport capacity and conserve energy under hypoxia. Our findings suggest that the coping mechanisms underlying hypoxia tolerance in these closely related species are context dependent.

Antioxidant response to severe hypoxia in Brandt's vole Lasiopodomys brandtii.

The antioxidant defense system is essential for animals to cope with homeostasis disruption and overcome oxidative stress caused by adverse environmental conditions such as hypoxia. However, our understanding of how this system works in subterranean rodents remains limited. In this study, Brandt's vole Lasiopodomys brandtii was exposed to normoxia (21% O2 ) or hypoxia (mild or severe hypoxia: 10% or 5% O2 ) for 6 h. Changes in key enzymes of the classic enzymatic antioxidant system at both mRNA and enzyme activity levels, and tissue antioxidant levels of the low-molecular-weight antioxidant system were determined in brain, liver, and kidney. Transcript levels of the upstream regulator NF-E2-related factor 2 (Nrf2) were also measured. We found that the mRNA expression of Nrf2 and its downstream antioxidant enzyme genes in L. brandtii were relatively conserved in response to hypoxia in most tissues and genes tested, except in the liver. Hepatic Nrf2, Cu/Zn SOD, GPx1, and GPx3 levels were significantly upregulated in response to mild hypoxia, whereas Mn SOD level decreased significantly in severe hypoxia. Unmatched with changes at the RNA level, constitutively high and relatively stable antioxidant enzyme activities were maintained throughout. For the low-molecular-weight antioxidant system, an abrupt increase of cerebral ascorbic acid (AA) levels in hypoxia indicated a tissue-specific antioxidant response. Although hypoxia did not cause significant oxidative damage in most tissues tested, the significant decrease in antioxidant enzyme activities (GPX and GR) and increase in lipid peroxidation in the kidney suggest that prolonged hypoxia may pose a critical threat to this species.

Diverse energy metabolism patterns in females in Neodon fuscus, Lasiopodomys brandtii, and Mus musculus revealed by comparative transcriptomics under hypoxic conditions.

The effects of global warming and anthropogenic disturbance force animals to migrate from lower to higher elevations to find suitable new habitats. As such migrations increase hypoxic stress on the animals, it is important to understand how plateau- and plain-dwelling animals respond to low-oxygen environments. We used comparative transcriptomics to explore the response of Neodon fuscus, Lasiopodomys brandtii, and Mus musculus skeletal muscle tissues to hypoxic conditions. Results indicate that these species have adopted different oxygen transport and energy metabolism strategies for dealing with a hypoxic environment. N. fuscus promotes oxygen transport by increasing hemoglobin synthesis and reduces the risk of thrombosis through cooperative regulation of genes, including Fga, Fgb, Alb, and Ttr; genes such as Acs16, Gpat4, and Ndufb7 are involved in regulating lipid synthesis, fatty acid ß-oxidation, hemoglobin synthesis, and electron-linked transmission, thereby maintaining a normal energy supply in hypoxic conditions. In contrast, the oxygen-carrying capacity and angiogenesis of red blood cells in L. brandtii are promoted by genes in the CYP and COL families; this species maintains its bodily energy supply by enhancing the pentose phosphate pathway and mitochondrial fatty acid synthesis pathway. However, under hypoxia, M. musculus cannot effectively transport additional oxygen; thus, its cell cycle, proliferation, and migration are somewhat affected. Given its lack of hypoxic tolerance experience, M. musculus also shows significantly reduced oxidative phosphorylation levels under hypoxic conditions. Our results suggest that the glucose capacity of M. musculus skeletal muscle does not provide sufficient energy during hypoxia; thus, we hypothesize that it supplements its bodily energy by synthesizing ketone bodies. For the first time, we describe the energy metabolism pathways of N. fuscus and L. brandtii skeletal muscle tissues under hypoxic conditions. Our findings, therefore, improve our understanding of how vertebrates thrive in high altitude and plain habitats when faced with hypoxic conditions.

Phylogeny and evolution of Lasiopodomys in subfamily Arvivolinae based on mitochondrial genomics.

The species of Lasiopodomys Lataste 1887 with their related genera remains undetermined owing to inconsistent morphological characteristics and molecular phylogeny. To investigate the phylogenetic relationship and speciation among species of the genus Lasiopodomys, we sequenced and annotated the whole mitochondrial genomes of three individual species, namely Lasiopodomys brandtii Radde 1861, L. mandarinus Milne-Edwards 1871, and Neodon (Lasiopodomys) fuscus Büchner 1889. The nucleotide sequences of the circular mitogenomes were identical for each individual species of L. brandtii, L. mandarinus, and N. fuscus. Each species contained 13 protein-coding genes (PCGs), 22 transfer RNAs, and 2 ribosomal RNAs, with mitochondrial genome lengths of 16,557 bp, 16,562 bp, and 16,324 bp, respectively. The mitogenomes and PCGs showed positive AT skew and negative GC skew. Mitogenomic phylogenetic analyses suggested that L. brandtii, L. mandarinus, and L. gregalis Pallas 1779 belong to the genus Lasiopodomys, whereas N. fuscus belongs to the genus Neodon grouped with N. irene. Lasiopodomys showed the closest relationship with Microtus fortis Büchner 1889 and M. kikuchii Kuroda 1920, which are considered as the paraphyletic species of genera Microtus. TMRCA and niche model analysis revealed that Lasiopodomys may have first appeared during the early Pleistocene epoch. Further, L. gregalis separated from others over 1.53 million years ago (Ma) and then diverged into L. brandtii and L. mandarinus 0.76 Ma. The relative contribution of climatic fluctuations to speciation and selection in this group requires further research.

Genome and transcriptome of Papaver somniferum Chinese landrace CHM indicates that massive genome expansion contributes to high benzylisoquinoline alkaloid biosynthesis.

Opium poppy (Papaver somniferum) is a source of morphine, codeine, and semisynthetic derivatives, including oxycodone and naltrexone. Here, we report the de novo assembly and genomic analysis of P. somniferum traditional landrace 'Chinese Herbal Medicine'. Variations between the 2.62 Gb CHM genome and that of the previously sequenced high noscapine 1 (HN1) variety were also explored. Among 79,668 protein-coding genes, we functionally annotated 88.9%, compared to 68.8% reported in the HN1 genome. Gene family and 4DTv comparative analyses with three other Papaveraceae species revealed that opium poppy underwent two whole-genome duplication (WGD) events. The first of these, in ancestral Ranunculales, expanded gene families related to characteristic secondary metabolite production and disease resistance. The more recent species-specific WGD mediated by transposable elements resulted in massive genome expansion. Genes carrying structural variations and large-effect variants associated with agronomically different phenotypes between CHM and HN1 that were identified through our transcriptomic comparison of multiple organs and developmental stages can enable the development of new varieties. These genomic and transcriptomic analyses will provide a valuable resource that informs future basic and agricultural studies of the opium poppy.

Chloroplast Phylogenomic Analyses Reveal a Maternal Hybridization Event Leading to the Formation of Cultivated Peanuts.

Peanuts (Arachis hypogaea L.) offer numerous healthy benefits, and the production of peanuts has a prominent role in global food security. As a result, it is in the interest of society to improve the productivity and quality of peanuts with transgenic means. However, the lack of a robust phylogeny of cultivated and wild peanut species has limited the utilization of genetic resources in peanut molecular breeding. In this study, a total of 33 complete peanut plastomes were sequenced, analyzed and used for phylogenetic analyses. Our results suggest that sect. Arachis can be subdivided into two lineages. All the cultivated species are contained in Lineage I with AABB and AA are the two predominant genome types present, while species in Lineage II possess diverse genome types, including BB, KK, GG, etc. Phylogenetic studies also indicate that all allotetraploid cultivated peanut species have been derived from a possible maternal hybridization event with one of the diploid Arachis duranensis accessions being a potential AA sub-genome ancestor. In addition, Arachis monticola, a tetraploid wild species, is placed in the same group with all the cultivated peanuts, and it may represent a transitional species, which has been through the recent hybridization event. This research could facilitate a better understanding of the taxonomic status of various Arachis species/accessions and the evolutionary relationship among them, and assists in the correct and efficient use of germplasm resources in breeding efforts to improve peanuts for the benefit of human beings.

The complete mitochondrial genome of Lasiopodomys brandtii.

In this study, the complete mitochondrial (mt) genome sequence of Lasiopodomys brandtii was determined using Illumina NovaSeq platform. The assembled genome was 16,557 bp in length and included 13 protein-coding genes, 2 ribosomal RNA genes, and 22 transfer RNA genes. The total nucleotide composition frequencies present clearly the A-T skew (59.5%), which mostly in D-loop and PCGs regions. Whole mt genome phylogenetic analysis revealed a closely related among Lasiopodomys, Proedromys, and Microtus with high support. It would provide further evolutionary research for the subfamily Arvicolinae.

Genome-wide adaptive evolution to underground stresses in subterranean mammals: Hypoxia adaption, immunity promotion, and sensory specialization.

Life underground has provided remarkable examples of adaptive evolution in subterranean mammals; however, genome-wide adaptive evolution to underground stresses still needs further research. There are approximately 250 species of subterranean mammals across three suborders and six families. These species not only inhabit hypoxic and dark burrows but also exhibit evolved adaptation to hypoxia, cancer resistance, and specialized sensory systems, making them an excellent model of evolution. The adaptive evolution of subterranean mammals has attracted great attention and needs further study. In the present study, phylogenetic analysis of 5,853 single-copy orthologous gene families of five subterranean mammals (Nannospalax galili, Heterocephalus glaber, Fukomys damarensis, Condylura cristata, and Chrysochloris asiatica) showed that they formed fou distinct clusters. This result is consistent with the traditional systematics of these species. Furthermore, comparison of the high-quality genomes of these five subterranean mammalian species led to the identification of the genomic signatures of adaptive evolution. Our results show that the five subterranean mammalian did not share positively selected genes but had similar functional enrichment categories, including hypoxia tolerance, immunity promotion, and sensory specialization, which adapted to the environment of underground stresses. Moreover, variations in soil hardness, climate, and lifestyles have resulted in different molecular mechanisms of adaptation to the hypoxic environment and different degrees of visual degradation. These results provide insights into the genome-wide adaptive evolution to underground stresses in subterranean mammals, with special focus on the characteristics of hypoxia adaption, immunity promotion, and sensory specialization response to the life underground.

The reproductive inhibitory effects of levonorgestrel, quinestrol, and EP-1 in Brandt's vole (Lasiopodomys brandtii).

BACKGROUND: Rodent pests can inflict devastating impacts on agriculture and the environment, leading to significant economic damage associated with their high species diversity, reproductive rates and adaptability. Fertility control methods could indirectly control rodent pest populations as well as limit ecological consequences and environmental concerns caused by lethal chemical poisons. Brandt's voles, which are common rodent pests found in the grasslands of middle-eastern Inner Mongolia, eastern regions of Mongolia, and some regions of southern Russia, were assessed in the present study. METHODS: We evaluated the effects of a 2-mg/kg dose of levonorgestrel and quinestrol and a 1:1 mixture of the two (EP-1) on reproductive behavior as well as changes in the reproductive system, reproductive hormone levels, and toxicity in Brandt's voles. RESULTS: Our results revealed that all three fertility control agents can cause reproductive inhibition at a dosage of 2 mg/kg. However, quinestrol caused a greater degree of toxicity, as determined by visible liver damage and reduced expression of the detoxifying molecule CYP1A2. Of the remaining two fertility control agents, EP-1 was superior to levonorgestrel in inhibiting the secretion of follicle-stimulating hormone and causing reproductive inhibition. We believe that these findings could help promote the use of these fertility control agents and, in turn, reduce the use of chemical poisons and limit their detrimental ecological and environmental impacts.

Transcriptome analysis of the response provided by Lasiopodomys mandarinus to severe hypoxia includes enhancing DNA repair and damage prevention.

BACKGROUND: Severe hypoxia induces a series of stress responses in mammals; however, subterranean rodents have evolved several adaptation mechanisms of energy metabolisms and O2 utilization for hypoxia. Mammalian brains show extreme aerobic metabolism. Following hypoxia exposure, mammals usually experience irreversible brain damage and can even develop serious diseases, such as hypoxic ischemic encephalopathy and brain edema. To investigate mechanisms underlying the responses of subterranean rodents to severe hypoxia, we performed a cross-species brain transcriptomic analysis using RNA sequencing and identified differentially expressed genes (DEGs) between the subterranean rodent Lasiopodomys mandarinus and its closely related aboveground species L. brandtii under severe hypoxia (5.0% O2, 6 h) and normoxia (20.9% O2, 6 h). RESULTS: We obtained 361 million clean reads, including 69,611 unigenes in L. mandarinus and 69,360 in L. brandtii. We identified 359 and 515 DEGs by comparing the hypoxic and normoxia groups of L. mandarinus and L. brandtii, respectively. Gene Ontology (GO) analysis showed that upregulated DEGs in both species displayed similar terms in response to severe hypoxia; the main difference is that GO terms of L. brandtii were enriched in the immune system. However, in the downregulated DEGs, GO terms of L. mandarinus were enriched in cell proliferation and protein transport and those of L. brandtii were enriched in nuclease and hydrolase activities, particularly in terms of developmental functions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that upregulated DEGs in L. mandarinus were associated with DNA repair and damage prevention as well as angiogenesis and metastasis inhibition, whereas downregulated DEGs were associated with neuronal synaptic transmission and tumor-associated metabolic pathways. In L. brandtii, upregulated KEGG pathways were enriched in the immune, endocrine, and cardiovascular systems and particularly in cancer-related pathways, whereas downregulated DEGs were associated with environmental information processing and misregulation in cancers. CONCLUSIONS: L. mandarinus has evolved hypoxia adaptation by enhancing DNA repair, damage prevention, and augmenting sensing, whereas L. brandtii showed a higher risk of tumorigenesis and promoted innate immunity toward severe hypoxia. These results reveal the hypoxic mechanisms of L. mandarinus to severe hypoxia, which may provide research clues for hypoxic diseases.

Differential responses of Lasiopodomys mandarinus and Lasiopodomys brandtii to chronic hypoxia: a cross-species brain transcriptome analysis.

BACKGROUND: Subterranean rodents have evolved many features to adapt to their hypoxic environment. The brain is an organ that is particularly vulnerable to damage caused by exposure to hypoxic conditions. To investigate the mechanisms of adaption to a hypoxic underground environment, we carried out a cross-species brain transcriptome analysis by RNA sequencing and identified genes that are differentially expressed between the subterranean vole Lasiopodomys mandarinus and the closely related above-ground species Lasiopodomys brandtii under chronic hypoxia [10.0% oxygen (O2)] and normoxia (20.9% O2). RESULTS: A total of 355 million clean reads were obtained, including 69,611 unigenes in L. mandarinus and 69,360 in L. brandtii. A total of 235 and 92 differentially expressed genes (DEGs) were identified by comparing the hypoxic and control groups of L. mandarinus and L. brandtii, respectively. A Gene Ontology (GO) analysis showed that upregulated DEGs in both species had similar functions in response to hypoxia, whereas downregulated DEGs in L. mandarinus were enriched GO terms related to enzymes involved in aerobic reactions. In the Kyoto Encyclopedia of Genes and Genomes pathway analysis, upregulated DEGs in L. mandarinus were associated with angiogenesis and the increased O2 transport capacity of red blood cells, whereas downregulated DEGs were associated with immune responses. On the other hand, upregulated DEGs in L. brandtii were associated with cell survival, vascular endothelial cell proliferation, and neuroprotection, while downregulated genes were related to the synaptic transmission by neurons. CONCLUSIONS: L. mandarinus actively adapts its physiological functions to hypoxic conditions, for instance by increasing O2 transport capacity and modulating O2 consumption. In contrast, L. brandtii reacts passively to hypoxia by decreasing overall activity in order to reduce O2 consumption. These results provide insight into hypoxia adaptation mechanisms in subterranean rodents that may be applicable to humans living at high altitudes or operating in other O2-poor environments.

Historical Refugia and Isolation by Distance of the Mud Snail, Bullacta exarata (Philippi, 1849) in the Northwestern Pacific Ocean.

Many phylogeographic studies on marine organisms in the Northwestern Pacific have supported for the biogeographic hypotheses that isolation in the marginal seas of this region during the Pleistocene glaciation lower sea level led to population genetic divergence, and thus population expansion was a common phenomenon when the sea level rebounded. However, most of these studies were based on maternally inherited mitochondrial DNA markers with limited sample sites and therefore, were unable to reveal detailed pictures encompassing paternal line information covering of the entire range. In this study, we used the mitochondrial cytochrome c oxidase subunit I (COI) and nine nuclear microsatellite loci to investigate the phylogeography of the mud snail, Bullacta exarata (Philippi, 1849), a species endemic to the Northwestern Pacific. We sampled 14 natural populations spanning across 3800 km of the Chinese coastline, essentially covering most of the species distribution range. COI analysis identified a total of 149 haplotypes separated into two distinct groups with nine mutation steps, revealing a prominent phylogeographic structure. Nuclear microsatellite data also demonstrated a similar but weaker genetic structure. The estimated time to the most recent common ancestor between the two COI haplogroups is at ∼0.89 Ma, indicating that B. exarata populations survived the Pleistocene glaciation in the Sea of Japan and the Okinawa Trough, two marginal seas around the species range. The consistent significant patterns of isolation by distance of both COI and microsatellites suggests that limited mobility of adults and short planktonic stage of larvae may have played an important role in promoting or maintaining the genetic differentiation of B. exarata. Results from population demographic analyses support population expansion late in the Pleistocene era.