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Acute kidney injury (AKI), a common complication of sepsis, is characterized by a rapid loss of renal excretory function. A variety of etiologies and pathophysiological processes may contribute to AKI. Previously, mitogen-activated protein kinase 1 (MAPK1) was reported to regulate cellular processes in various sepsis-associated diseases. The current study aimed to further explore the biological function and regulatory mechanism of MAPK1 in sepsis-induced AKI. In our study, MAPK1 exhibited high expression in the serum of AKI patients. Functionally, knockdown of MAPK1 suppressed inflammatory response, cell apoptosis in response of lipopolysaccharide (LPS) induction in HK-2 cells. Moreover, MAPK1 deficiency alleviated renal inflammation, renal dysfunction, and renal injury in vivo. Mechanistically, MAPK1 could activate the downstream p38/NF-κB pathway. Moreover, long noncoding RNA potassium voltage-gated channel subfamily Q member 1 opposite strand/antisense transcript 1 (KCNQ1OT1) was identified to serve as a competing endogenous RNA for miR-212-3p to regulate MAPK1. Finally, rescue assays indicated that the inhibitory effect of KCNQ1OT1 knockdown on inflammatory response, cell apoptosis, and p38/NF-κB pathway was reversed by MAPK1 overexpression in HK-2 cells. In conclusion, KCNQ1OT1 aggravates acute kidney injury by activating p38/NF-κB pathway via miR-212-3p/MAPK1 axis in sepsis. Therefore, KCNQ1OT may serve as a potential biomarker for the prognosis and diagnosis of AKI patients.

MicroRNAs (miRNAs) are short non-coding RNAs that inhibit the expression of target genes by directly binding to their mRNAs. In animals, pri-miRNAs are cleaved by Drosha to generate pre-miRNAs, which are subsequently cleaved by Dicer to generate mature miRNAs. Instead of being cleaved by two different enzymes, both cleavages in plants are performed by Dicer-like 1 (DCL1). With a similar domain architecture as human Dicer, it is mysterious how DCL1 recognizes pri-miRNAs and performs two cleavages sequentially. Here, we report the single-particle cryo-electron microscopy structures of Arabidopsis DCL1 complexed with a pri-miRNA and a pre-miRNA, respectively, in cleavage-competent states. These structures uncover the plasticity of the PAZ domain, which is critical for the recognition of both pri-miRNA and pre-miRNA. These structures suggest that the helicase module serves as an engine that transfers the substrate between two sequential cleavage events. This study lays a foundation for dissecting the regulation mechanism of miRNA biogenesis in plants and provides insights into the dicing state of human Dicer. In plant miRNA biogenesis, DCL1 cleaves pri-miRNA and pre-miRNA sequentially. This study reports the cryo-EM structures of Arabidopsis DCL1 complexed with the two substrates and uncovers the domains that are key for substrate recognition and transfer.

Solute carrier organic anion transporter family member 1B3 (SLCO1B3) is a gene that encodes an organic anion-transporting polypeptide (OATP) 1B3, a membrane-bound multi-specific transporter in hepatocytes. SLCO1B3 was first reported in hepatocytes. Later, it was found that its expression is higher in colorectal cancer (CRC) than in the adjacent normal tissue. However, the role of SLCO1B3 in CRC is not well elucidated. In this study, the correlation between SLCO1B3 and the overall survival (OS) of CRC patients was evaluated using data from the GEO database. This study evaluated the relationship between SLCO1B3 and the clinicopathological characteristics and prognosis of CRC patients. The effects of SLCO1B3 knockdown, on human CRC cell proliferation, migration, and invasion in vitro and CRC tumorigenesis and metastasis in vivo were also examined. In addition, next-generation sequencing was used to identify SLCO1B3 mediators. The results confirmed the association between SLCO1B3 and poor OS of CRC patients, and SLCO1B3 was identified as the top hub gene associated with the OS. The study showed that high SLCO1B3 expression was associated with poor tumor differentiation, advanced disease stage, tumor invasion, lymph node metastasis, and poor OS. Next-generation sequencing revealed that SLCO1B3 knockdown affected the expression of several genes involved in cancer invasion, metastasis, and DNA repair. Moreover, the western blot analysis showed that SLCO1B3 knockdown downregulated p-STAT3, MMP-2, and MMP-9. In summary, we demonstrated that SLCO1B3 acts as a novel carcinogen in the CRC that drives the CRC tumorigenesis and metastasis. SLCO1B3 inhibitors, alone or in combination with current drugs, may have therapeutic benefits in CRC.

Macroautophagy/autophagy is an important innate and adaptive immune response that can clear microbial pathogens through guiding their degradation. Virus infection in animals and plants is also known to induce autophagy. However, how virus infection induces autophagy is largely unknown. Here, we provide evidence that the early phase of rice black-streaked dwarf virus (RBSDV) infection in Laodelphax striatellus can also induce autophagy, leading to suppression of RBSDV invasion and accumulation. We have determined that the main capsid protein of RBSDV (P10) is the inducer of autophagy. RBSDV P10 can specifically interact with GAPDH (glyceraldehyde-3-phosphate dehydrogenase), both in vitro and in vivo. Silencing of GAPDH in L. striatellus could significantly reduce the activity of autophagy induced by RBSDV infection. Furthermore, our results also showed that both RBSDV infection and RBSDV P10 alone can promote phosphorylation of AMP-activated protein kinase (AMPK), resulting in GAPDH phosphorylation and relocation of GAPDH from the cytoplasm into the nucleus in midgut cells of L. striatellus or Sf9 insect cells. Once inside the nucleus, phosphorylated GAPDH can activate autophagy to suppress virus infection. Together, these data illuminate the mechanism by which RBSDV induces autophagy in L. striatellus, and indicate that the autophagy pathway in an insect vector participates in the anti-RBSDV innate immune response. Abbreviations3-MA: 3-methyladenine; AMPK: AMP-activated protein kinase; ATG: autophagy-related; co-IP: co-immunoprecipitation; DAPI: 4ʹ,6-diamidino-2-phenylindole; dpf: days post-feeding; dsRNA: double-stranded RNA; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GST: glutathione-S-transferase; RBSDV: Rice black-streaked dwarf virus; TEM: transmission electron microscope.

Underground fires are a smoldering combustion with a slow spread rate, low temperatures and no flame. They can last from days to several months, and can even become overwintering fires. They are difficult to find, leading to considerable damage to the forests. The moisture content of combustible fuels is an important factor in the occurrence and persistence of underground forest fires. The Daxing’an Mountains are a hot spot for underground fires in China. This paper looks at the influence of different moisture contents on underground fire characteristics using simulation combustion experiments in the laboratory. The study showed that peak temperature and spread rate fluctuation of humus at different moisture levels increased with humus depth. Peak temperature and spread rate fluctuation of humus at different depths decreased with increased moisture; moisture content and depth of humus had a significant effect on peak temperature and spread rate fluctuation; peak temperature at different depths decreased with increased moisture; the spread rate in upper layers increased with moisture content, while the spread rate in the lower layers decreased with increased moisture content.

We evaluated the lipidomic profile of patients with very high-risk atherosclerotic cardiovascular disease (ASCVD) by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-MS). A total of 64 patients with a very high risk of ASCVD were recruited and randomLy divided into the atorvastatin group (20 mg, every night, 4 weeks) or the combined group (evolocumab, 140 mg, once every 2 weeks on top of atorvastatin (20 mg per day)). The level of serum lipids was detected before and after treatment for 4 weeks. The lipid classes of triacylglycerols, cholesteryl esters, and sphingomyelins were analyzed using an ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry system. There were 32 patients in each group. After 4 weeks of treatment, the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in both groups and the level of lipoprotein-a (Lp-a) in the combined group were lower. In the combined treatment group, the levels of TC, LDL-C, and Lp-a decreased significantly (P < 0.05) after 4 weeks of treatment. Most of the lipid classes in plasma decreased in the combined group at 4 weeks, especially sphingolipids. Only 1 patient had an adverse event (a rash) in the combined group, which improved after anti-allergic treatment. PCSK9 inhibitors can rapidly and effectively reduce most lipid classes in patients with very-high-risk ASCVD.

Underground fires are characterized by smouldering combustion with a slow rate of spread rate and without flames. Although smouldering combustion releases large amounts of gaseous pollutants, it is difficult to discover by today’s forest fire monitoring technologies. Carbon monoxide (CO), nitrogen oxides (NOx) and sulfur dioxide (SO2) were identified as high concentration marker gases of smouldering combustion-easily-be monitored. According to a two-way ANOVA, combustion time had a significant impact on CO and NOx emissions; smoldering -depth also had a significant impact on NOx emissions but not on CO emissions. Gas emission equations were established by multiple linear regression, Cco = 156.989 − 16.626 t and CNOx = 3.637 − 0.252 t − 0.039 h.

Three experiments were conducted to investigate the Cd tolerance and accumulation ability of a forage grass, Pterocypsela indica. P. indica accumulated 31.40 and 69.68 mg/kg Cd in roots and shoots, respectively, and plant biomass was unaffected by soil Cd as high as 50 mg/kg. Cd pollution obviously increased the Cd content of the cell wall fraction and decreased that of the soluble fraction in plant roots, but had little effect on the subcellular Cd content in plant shoots. When soil was co-contaminated by 2.29 mg/kg Cd, 526.83 mg/kg Zn, and 595.38 mg/kg Pb, P. indica accumulated 61.63 mg/kg Cd, 4261.00 mg/kg Zn, and 75.27 mg/kg Pb in plant shoots. The results indicated that P. indica mainly detoxified Cd stress by improving the fixation of Cd on the cell wall of plant roots rather than shoots. P. indica is a potential Cd accumulator that has a high phytoremediation efficiency in Cd-Zn-contaminated soil.

In this study, a ricin toxin (RT)-induced pulmonary intoxication model was established in mice by intratracheal-delivered RT at a dose of 2× LD50. Based on this model, the histopathological evaluation of the lungs at 24 h and 48 h post-exposure was executed, and the genome-wide transcriptome of the lungs at 4, 12, 24 and 48 h post-exposure was analyzed. Histopathological analysis showed that a large number of neutrophils infiltrated the lungs at 24 h post-exposure, and slight pulmonary edema and perivascular-peribronchiolar edema appeared in the lungs at 48 h. Transcriptome analysis showed that the expression of a large number of genes related to leukocyte migration and chemotaxis consistently increased in the lungs upon exposure to RT, and the expression of genes that participate in acute phase immune and/or inflammatory response, also increased within 12 h of exposure to RT, which could be confirmed by the measurement of cytokines, such as IL-1β, TNF-α and IL-6, in bronchoalveolar lavage fluid. While the expression of genes related to cellular components of the extracellular matrix and cell membrane integrity consistently decreased in the lungs, and the expression of genes related to antioxidant activity also decreased within the first 12 h. There are 17 differentially expressed genes (DEGs) that participate in ribotoxic stress response, endoplasmic reticulum stress response or immune response in the lungs at 4 h post-exposure. The expression of these DEGs was upregulated, and the number of these DEGs accounted for about 59 % of all DEGs at 4 h. The 17 DEGs may play an important role in the occurrence and development of inflammation. Notably, Atf3, Egr1, Gdf15 and Osm, which are poorly studied, may be important targets for the subsequent research of RT-induced pulmonary intoxication. This study provides new information and insights for RT-induced pulmonary intoxication, and it can provide a reference for the subsequent study of the toxicological mechanism and therapeutic approaches for RT-induced pulmonary intoxication.

Three new porphyrin derivatives were synthesized from tetra (4-aminophenyl) porphyrin (TAPP), namely tetra[p-(4-cyanophenylmethylene imino)]phenyl porphyrin (TCyPPP), tetra[p-(P-benzylidene)]phenyl porphyrin (TbePPP) and tetra[p-(4-pyridylimethylene imino)]phenyl porphyrin (TPyPPP). Based on the principle of self-assembly, three kinds of porphyrin derivatives were self-assembled to prepare three kinds of monomers. The structures were characterized clearly by UV-vis, FT-IR, 1H NMR and SEM. The photocatalytic performance study shows that the self-assemblies of the three porphyrin derivatives have stronger photocatalytic performance than their monomers. Moreover, the self-assemblies and their monomers have good photocatalytic stability.

Despite one SINE retrotransposon insertion polymorphism (sRTIP) in the vertebrae development-associated (VRTN) gene was identified in pigs, the structural variations (SVs) in VRTN gene and its proximal flank regions were largely unknown. VRTN genic and flanking sequences from 14 breeds were assembled or downloaded from whole-genome shotgun contings (WGS) database, and aligned to identify the SVs with Clustalx, and retrotransposons in VRTN gene were annotated by RepeatMasker, the splicing patterns of VRTN gene were predicted by Genescan, and large SVs were evaluated by PCR. A total of 12 small SVs and three large SVs in intron of VRTN, derived from SINE insertion polymorphisms, were identified, and two of them (VRTN-sRTIP2 and VRTN-sRTIP3) were not reported before. These VRTN-sRTIPs may affect the splicing patterns of VRTN. They displayed polymorphisms in most detected eight breeds. VRTN-sRTIP2 and VRTN-sRTIP3 showed Hardy-Weinberg equilibrium distributions in most populations except the Chinese local Erhualian pigs, while VRTN-sRTIP1 showed genetic equilibrium in Erhualian pigs. Three VRTN-sRTIPs were identified, and displayed polymorphisms in pigs, and two of them were not reported before. These SVs provide a useful molecular markers for genetic analysis in pigs, and offer new information to facilitate the understanding the SVs of VRTN gene and their putative roles in the variation of vertebral number.

Here, we comprehensively analysed the abundance, diversity, and activity of Tc1/mariner transposons in African coelacanth (Latimeria chalumnae). Fifteen Tc1/mariner autonomous transposons were identified and grouped into six clades: DD34E/Tc1, DD34D/mariner, DD35D/Fot, DD31D/pogo, DD30-31D/pogo-like, and DD32–36D/Tigger, belonging to three known families: DD34E/Tc1, DD34D/mariner, and DD×D/pogo (DD35D/Fot, DD31D/pogo, DD30-31D/pogo-like, and DD32-36D/Tigger). Thirty-one miniature inverted-repeat transposable element (MITE) transposons of Tc1/mariner were also identified, and 20 of them display similarity to the identified autonomous transposons. The structural organization of these full Tc1/mariner elements includes a transposase gene flanked by terminal inverted repeats (TIRs) with TA dinucleotides. The transposases contain N-terminal DNA binding domain and a C-terminal catalytic domain characterized by the presence of a conservative D(Asp)DE(Glu)/D triad that is essential for transposase activity. The Tc1/mariner superfamily in coelacanth exhibited very low genome coverage (0.3%), but it experienced an extraordinary difference of proliferation dynamics among the six clades identified; moreover, most of them exhibited a very recent and current proliferation, suggesting that some copies of these transposons are putatively active. Additionally, at least four functional genes derived from Tc1/mariner transposons were found. We provide an up-to-date overview of Tc1/mariner in coelacanth, which may be helpful in determining genome and gene evolution in this living fossil.

Callicarpins A-D (1-4), possessing an unprecedented A-homoent-clerodane scaffold with a bicyclo[5.4.0]undecane ring system, and callicarpins E-G (5-7), with 5/6-fused ent-clerodane diterpenoid skeletons, were isolated from Callicarpaarborea and C. integerrim. Their structures were elucidated by comprehensive spectroscopic data, X-ray crystal diffraction, chemical derivatization, and electronic circular dichroism (ECD) data. Putative biosynthetic pathways for these callicarpins are proposed. Compounds 2, 3b, and 6-8 showed potent inhibitory effects against the NLRP3 inflammasome with IC50 values from 1.4 to 5.3 μM, and 2 significantly blocked NLRP3 inflammasome-induced pyroptosis by inhibiting Casp-1 activation and IL-1β secretion in J774A.1 cells.

Aristolochia yachangensis B.G.Huang, Yan Liu & Y.S.Huang, a new species from limestone areas in Guangxi, China, is described and illustrated. It is morphologically most similar to A. fangchi Y.C.Wu ex L.D.Chow & S.M.Hwang, A. petelotii O.C. Schmidt and A. championii Merr. & Chun in shape of leaf blade, anther, gynostemium and inflorescence on old woody stems. However, it can be easily distinguished from the latter by shape of inflorescence, length of upper and lower portions of perianth tube, colour of the limb and throat. A table and a key to distinguish the new species from other morphologically similar Aristolochia species are also provided.

Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment syndrome, affecting a large proportion of the general population. Genetic susceptibility has been implicated in CTS, but the causative genes remain elusive. Here, we report the identification of two mutations in cartilage oligomeric matrix protein (COMP) that segregate with CTS in two large families with or without multiple epiphyseal dysplasia (MED). Both mutations impair the secretion of COMP by tenocytes, but the mutation associated with MED also perturbs its secretion in chondrocytes. Further functional characterization of the CTS-specific mutation reveals similar histological and molecular changes of tendons/ligaments in patients’ biopsies and the mouse models. The mutant COMP fails to oligomerize properly and is trapped in the ER, resulting in ER stress-induced unfolded protein response and cell death, leading to inflammation, progressive fibrosis and cell composition change in tendons/ligaments. The extracellular matrix (ECM) organization is also altered. Our studies uncover a previously unrecognized mechanism in CTS pathogenesis. Familial carpal tunnel syndrome (CTS) is common, but causal genes are not characterized. Here the authors report two CTS-related mutations in two large families that impair secretion of COMP in tenocytes, leading to ER stress-induced unfolded protein response, inflammation and fibrosis in patients and mouse models.

Although the DD41D (named as Visitor, VS) family of Tc1/mariner transposons was discovered in Arthropods and Mollusca, the evolution profile of this family is still largely unknown. We found that VS is widespread in the animal kingdom, including 140 species of 18 orders in invertebrates and 30 species of 12 orders in vertebrates, and one land plant species. Our data revealed multiple horizontal transfer events in both invertebrates and vertebrates and invasion into multiple lineages of mammals, including Chiroptera (seven species), Dasyuromorphia/Marsupialia (one species), Didelphimorphia/Marsupialia (one species), Diprotodontia/Marsupialia (two species), and Primates (one species). Phylogenetic analysis revealed a close relationship of VSs to DD37D/maT and DD34D/mariner and confirmed that VSs with the DD40D signature identified previously are not a distinct family but originated from DD41D/VS. Age analysis revealed that the most recent invasion of VSs was found in ray-finned fishes and a toad, followed by relatively young invasions in bats and marsupials, whereas VSs in mammals, jawless fishes, and lizards were mainly represented by ancient copies, suggesting old age. Phylogenetic analyses and comparison of pairwise distances between VSs and recombination-activating gene 1 (RAG1) support horizontal transfer events of VSs in vertebrates. The intact VSs from bats were nonfunctional as determined by the transposition activity assay. Some vertebrate lineages and species were identified as the hot hosts of Tc1/mariner transposons. Overall, our study presents the evolution profile of VSs and suggests that VSs play roles in diversifying and shaping the genomes of diverse animal lineages.

Non-coding RNAs (ncRNAs) are an abundant component of the human transcriptome. Their biological role, however, remains incompletely understood. Nevertheless, ncRNAs are highly associated with cancer development and progression due to their ability to modulate gene expression, protein translation and growth pathways. Immune-checkpoint inhibitors (ICIs) are considered one of the most promising and highly effective therapeutic approaches for cancer treatment. ICIs are monoclonal antibodies targeting immune checkpoints such as CTLA-4, PD-1 and PD-L1 signalling pathways that stimulate T cell cytotoxicity and can result in tumor growth suppression. This Review will summarize existing knowledge regarding ncRNAs and their role in cancer and ICI therapy. In addition, we will discuss potential mechanisms by which ncRNAs may influence ICI treatment outcomes.

Background/objective: Intervertebral disc degeneration (IDD) remains to be an intractable clinical challenge. Although IDD is characterised by loss of notochordal cells (NCs) and dysfunction of nucleus pulposus (NP) cells, little is known about the origin, heterogeneity, fate and maintenance of NCs and NP cells, which further stunts the therapeutic development. Thus, effective tools to spatially and temporally trace specific cell lineage and clarify cell functions in intervertebral disc (IVD) development and homoeostasis are urgently required. Methods: In this study, NP specimens were obtained from 20 patients with degenerative disc disease or scoliosis. LepR-Cre mice was crossed with R26R-Tdtomato mice to generate LepR-Cre; R26R-Tdtomato mice, which enabled fate-mapping of NPs from embryo stage to late adult. LMNA G609G/G609G mice was used to determine the effect of premature-aging induced IDD on LepR NPs. X-ray imaging was used to measure lumber disc height of mice. Results: Here, we provide the first evidence that the leptin receptor (LepR) is preferentially expressed in NCs at embryonic stages and notochord-derived cells in the postnatal IVD. By using R26R-Tdtomato fluorescent reporter mice, we systematically analysed the specificity of activity and targeting efficiency of leptin receptor-Cre (LepR-Cre) in IVD tissues from the embryonic stage E15.5 to 6-month-old LepR-Cre; Rosa26-Tdtomato (R26R-Tdtomato) mice. Specifically, LepR-Cre targets a distinct subpopulation of notochord-derived cells closely associated with disc homoeostasis. The percentage of LepR-expressing NP cells markedly decreases in the postnatal mouse IVD and, more importantly, in the human IVD with the progression of IDD. Moreover, both spine instability–induced and premature ageing–induced IDD mouse models display the phenotype of IDD with decreased percentage of LepR-expressing NP cells. These findings uncover a potential role of LepR-expressing notochord-derived cells in disc homoeostasis and open the gate for therapeutically targeting the NP cell subpopulation. Conclusion: In conclusion, our data prove LepR-Cre mice useful for mapping the fate of specific subpopulations of IVD cells and uncovering the underlying mechanisms of IDD. The translational potential of this article: The translation potential of article is that we first identified LepR as a candidate marker of subpopulation of nucleus pulposus (NP) cells and provided LepR as a potential target for the treatment of intervertebral disc degeneration (IDD), which have certain profound significance. Keywords: LepR, Lineage tracing, Notochordal cells, Nucleus pulposus cells, Subpopulation

The discovery of new members of the Tc1/mariner superfamily of transposons is expected based on the increasing availability of genome sequencing data. Here, we identified a new DD35E family termed Traveler (TR). Phylogenetic analyses of its DDE domain and full-length transposase showed that, although TR formed a monophyletic clade, it exhibited the highest sequence identity and closest phylogenetic relationship with DD34E/Tc1. This family displayed a very restricted taxonomic distribution in the animal kingdom and was only detected in ray-finned fish, anura, and squamata, including 91 vertebrate species. The structural organization of TRs was highly conserved across different classes of animals. Most intact TR transposons had a length of ∼1.5 kb (range 1,072–2,191 bp) and harbored a single open reading frame encoding a transposase of ∼340 aa (range 304–350 aa) flanked by two short-terminal inverted repeats (13–68 bp). Several conserved motifs, including two helix-turn-helix motifs, a GRPR motif, a nuclear localization sequence, and a DDE domain, were also identified in TR transposases. This study also demonstrated the presence of horizontal transfer events of TRs in vertebrates, whereas the average sequence identities and the evolutionary dynamics of TR elements across species and clusters strongly indicated that the TR family invaded the vertebrate lineage very recently and that some of these elements may be currently active, combining the intact TR copies in multiple lineages of vertebrates. These data will contribute to the understanding of the evolutionary history of Tc1/mariner transposons and that of their hosts.

Long noncoding RNAs (lncRNAs) participate in and regulate the biological process of colorectal cancer (CRC) progression. Our previous research identified differentially expressed lncRNAs in 10 CRC tissues and 10 matched nontumor tissues by next-generation sequencing (NGS). In this study, we identified an lncRNA, FEZF1 antisense RNA 1 (FEZF1-AS1), and further explored its function and mechanism in CRC. We verified that FEZF1-AS1 is highly expressed in CRC tissues and cell lines. Through functional experiments, we found that reduced levels of FEZF1-AS1 significantly suppressed CRC cell migration, invasion, and proliferation and inhibited tumor growth in vivo. Mechanistically, we discovered that reduced levels of the lncRNA FEZF1-AS1 inhibited the activation of epithelial‐mesenchymal transition (EMT); the overexpression of orthodenticle homeobox 1 (OTX1) partially rescued the FEZF1-AS1-induced inhibition of protein expression. It indicated that FEZF1-AS1 may play a role in the occurrence and development of CRC by regulating the FEZF1-AS1/OTX1/EMT pathway. Furthermore, it was reported that FEZF1-AS1 is located in both the nucleus and cytoplasm of HCT116 cells. Dual-luciferase reporter assays verified that FEZF1-AS1 directly binds miR-30a-5p and negatively regulated each other. Further, we showed that 5′-nucleotidase ecto (NT5E) is a direct target of miR-30a-5p, and the inhibition of miR-30a-5p expression partially rescued the inhibitory effect of FEZF1-AS1 on NT5E. Our results indicated that the mechanism by which FEZF1-AS1 positively regulates the expression of NT5E is through sponging miR-30a-5p. Our study demonstrated that lncRNA FEZF1-AS1 is involved in the development of CRC and may serve as a diagnostic and therapeutic target for CRC patients.

Callicarpa bodinieri is a Chinese traditional medicine herb with anti-inflammatory activity in clinic. Herein, we report two new 9,10-seco and etherified abietane diterpenoids bodinieric acids J and K (1 and 2) and one known compound (3) isolated from the leaves and twigs of this plant. Their chemical structures were elucidated by detailed spectrometry data analysis and DP4 + NMR calculation methods. Hypothetical biosynthetic pathways of 1−3 were preliminarily speculated. Compound 3 inhibited inflammasome activation and exhibited blockage of NLRP3 inflammasome activation at non-cytotoxic concentrations in vitro.

Molecular markers based on retrotransposon insertion polymorphisms (RTIPs) have great potential in studies of animal genetics and breeding. In this study, L1 RTIP markers were developed and evaluated by using microsatellite primers combined with L1 specific primers, and were further evaluated in four Chinese and three imported domestic pig breeds. Eight L1RTIP markers were obtained, and uneven distribution was observed among these breeds, with the Sujiang breed exhibiting the highest level of polymorphism with seven polymorphic sites, followed by Jiangquhai, Meishan, and Duroc with six, four, and four polymorphic sites, respectively. Both Landrace and Yorkshire pigs exhibited three polymorphic sites, while Chinese inbred Bama pig showed the lowest level of polymorphism with only one polymorphic site. Three polymorphic makers (L1-31-2, L1-31-5, and L1-31-11) were strongly associated with the economic traits in 462 Yorkshire pigs, with the L1-31-5+ genotype females had a significantly greater alive litter size (11.44 ± 2.80) compared with pigs with the L1-31-5– genotype (9.96 ± 2.89) (P < 0.05). L1-31-11– genotype pigs had significantly younger age at 100 kg of body weight (160.20 ± 10.26 days) than the L1-31-11+counter parts (162.47 ± 9.71 days) (P < 0.05). In summary, we demonstrated that it is feasible to develop markers based on L1 RTIP sin the pig, and these markers may have greater potential in the application of pig genetics and breeding compared to non-selective conventional breeding.

To evaluate the characteristics of microorganisms and the origin of organic matter of the Wufeng Formation and Longmaxi Formation (WF-LMX) in Sichuan Basin (South China), the type and number of microorganisms were determined in this study using scanning electron microscope (SEM) microphotographs and microbial extraction. The contribution of various microorganisms to organic matter was analyzed in combination with the data of biomarkers and total organic carbon (TOC). It can be deduced from the paleogeography and pristine/phytane (Pr/Ph) ratio that the microorganisms of WF-LMX resided in 60 m–200 m deep shelf with anoxic bottom water. From SEM microphotographs and microbial microscopy analysis, it was demonstrated that the microorganisms in the WF-LMX can be divided into 3 types: planktonic algae (mainly including acritarchs and green algae), fungi, and benthic algae. Acritarchs were the most common microorganisms in the WF-LMX with the average relative content of 60.5%. The average relative contents of benthic algae, fungi, and green algae were 17.6%, 18.0% and 3.9%, respectively. Since the acritarchs and green algae in the Wufeng Formation and the Longmaxi Formation basically belong to planktonic algae, the relative content of planktonic algae in them is about 64.4%. The strata of WF-LMX can be divided into 3 sections based on the distribution characteristics of various microorganisms. The relative content of acritarchs gradually decreased upwards, while that of benthic algae gradually increased. The multiple proxies of biomarkers proved that the planktonic algae was the main source of organic matter in the WF-LMX. Combining the statistical data of microorganisms, it was considered that the organic matter in WF-LMX was mainly derived from acritarchs, which might be the components of planktonic algae. The fungi had a significant contribution to the organic matter in organic-rich layers (TOC > 2.0%) rather than in organic-poor layers, while green algae and benthic algae made little contribution to the organic matters in WF-LMX.

Background Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disease caused by loss of function of the lysosomal trafficking regulator protein. The causative gene LYST/CHS1 was cloned and identified in 1996, which showed significant homology to other species such as bovine and mouse. To date, 74 pathogenic or likely pathogenic mutations had been reported. Case presentation Here we describe a compound heterozygote in LYST gene, which was identified in a 4-year-old female patient. The patient showed skin hypopigmentation, sensitivity to light, mild splenomegaly and reduction of platelets in clinical examination. Giant intracytoplasmic inclusions were observed in the bone marrow examination, suggesting the diagnosis of CHS. Amplicon sequencing was performed to detect pathogenic mutation in LYST gene. The result was confirmed by two-generation pedigree analysis base on sanger sequencing. Conclusion A compound heterozygote in LYST gene, consisting of a missense mutation c.5719A > G and an intron mutation c.4863-4G > A, was identified from the patient by using amplicon sequencing. The missense mutation is reported for the first time. Two-generation pedigree analysis showed these two mutations were inherited from the patient’s parents, respectively. Our result demonstrated that amplicon sequencing has great potential for accelerating and improving the diagnosis of rare genetic diseases.

Metallic 1T-phase MoS2 is considered to be the ideal electrocatalyst to carry out hydrogen evolution reaction (HER) because of favorable conductivity and sufficient active site compared with 2H-pha...

A complete orthogonal experiment using a pot test is conducted to investigate the effects of four amendments (biochar, peat, manure, and non-contaminated soil (NCS)) on the metal availability, mobility, and phytostabilization potential of an energy crop, king grass (Pennisetum purpureum × P. thyphoideum), in Pb/Zn mine tailings. The addition of amendments significantly increased the pH and fertility of the tailings, while significantly decreasing the heavy metal available contents in the tailings. The available Cd, Pb, Zn, and As concentrations in the tailings in the treatment amended with biochar+NCS+peat+manure were 51.00%, 36.62%, 50.57%, and 75.88%, respectively, lower than those in the treatment control. The king grass survived in the tailings without amendments, while amendments made the plant grow well or better in the tailings than in NCS. The addition of amendments significantly reduced the content of heavy metals and bioaccumulation factor (BCF) in the plant root but increased the translocation factor (TF) of Cd, Zn, and As and had little effect on the TF of Pb. The TF for heavy metals in plant were lower than one for all of the treatments. During a leaching period of 30 days, the pH of the leachate declined slowly and then maintained at 6.0~6.6. The addition of the amendments significantly reduced the metal concentrations of the leachates, and the highest declines were 50.46%, 20.04%, 41.58%, and 47.04% for Cd, Pb, Zn, and As, respectively. Biochar had a higher immobilization capacity for Cd, Pb, Zn, and As than manure, peat, and NCS. King grass could be used to aid phytostabilization for Cd- and Pb-polluted tailings, and biochar-rich amendments were effective for the in situ immobilization of metals. Further field monitoring is necessary to demonstrate the effectiveness of king grass and amendments under the climatic conditions of China.

The Chinese Imaging Genetics (CHIMGEN) study establishes the largest Chinese neuroimaging genetics cohort and aims to identify genetic and environmental factors and their interactions that are associated with neuroimaging and behavioral phenotypes. This study prospectively collected genomic, neuroimaging, environmental, and behavioral data from more than 7000 healthy Chinese Han participants aged 18–30 years. As a pioneer of large-sample neuroimaging genetics cohorts of non-Caucasian populations, this cohort can provide new insights into ethnic differences in genetic-neuroimaging associations by being compared with Caucasian cohorts. In addition to micro-environmental measurements, this study also collects hundreds of quantitative macro-environmental measurements from remote sensing and national survey databases based on the locations of each participant from birth to present, which will facilitate discoveries of new environmental factors associated with neuroimaging phenotypes. With lifespan environmental measurements, this study can also provide insights on the macro-environmental exposures that affect the human brain as well as their timing and mechanisms of action.

Confusion persists over pathogenesis of spondylolysis. To confirm pathogenicity of the previously identified causative mutation of spondylolysis and investigate the genetic etiology, we generate a new mouse line harboring D673V mutation in the Slc26a2 gene. D673V mutation induces delayed endochondral ossification characterized by transiently reduced chondrocyte proliferation in mice at the early postnatal stage. Adult D673V homozygotes exhibit dysplastic isthmus and reduced bone volume of the dorsal vertebra resembling the detached vertebral bony structure when spondylolysis occurs, including the postzygopophysis, vertebral arch, and spinous process, which causes biomechanical alterations around the isthmic region of L4-5 vertebrae indicated by finite element analysis. Consistently, partial ablation of Slc26a2 in vertebral skeletal cells using Col1a1-Cre; Slc26a2 fl/fl mouse line recapitulates a similar but worsened vertebral phenotype featured by lamellar isthmus. In addition, when reaching late adulthood, D673V homozygotes develop an evident bone-loss phenotype and show impaired osteogenesis. These findings support a multifactorial etiology, involving congenitally predisposed isthmic conditions, altered biomechanics, and age-dependent bone loss, which leads to SLC26A2-related spondylolysis.

Isochorismatase domain-containing 1 (ISOC1) is a coding gene that contains an isochorismatase domain. The precise functions of ISOC1 in humans have not been clarified; however, studies have speculated that it may be involved in unknown metabolic pathways. Currently, it is reported that ISOC1 is associated with breast cancer. In this research, the aim is to investigate the critical role of ISOC1 in colorectal cancer (CRC) and to explore its biological function and mechanism in colon cancer cells. In 106 paired clinical samples, we found that the levels of ISOC1 expression were widely increased in cancer tissues compared with matched adjacent non-tumor tissues and that increased expression of ISOC1 was significantly associated with tumor size, tumor invasion, local lymph node metastasis and Tumor, Node and Metastasis (TNM) stage. Moreover, higher expression levels of ISOC1 were correlated with shorter disease-free survival in patients 2 years after surgery. In vitro, ISOC1 knockdown inhibited the proliferation and migration and induced the apoptosis of colon cancer cells, and in vivo, the xenograft tumors were also inhibited by ISOC1 silencing. We also used MTS, Transwell and cell apoptosis assays to confirm that ISOC1 plays a critical role in regulating the biological functions of colon cancer cells through the AKT/GSK-3β pathway. Additionally, the results of confocal microscopy and western blot analysis indicated that ISOC1 knockdown could promote p-STAT1 translocation to the nucleus., Isochorismatase domain-containing 1 (ISOC1) plays a critical role in CRC. In colon cancer cells, silencing ISOC1 inhibited proliferation and migration and induced apoptosis via the AKT/GSK-3β pathway; additionally, the expression of p-STAT1 was increased in the cell nucleus after ISOC1 knockdown.

Background: The Uyghur is the fifth largest group in China and also the largest ethnic minority in Xinjiang.Aim: To explore the genetic variations of 27 forensic genetic markers included in the newly developed SureID® PanGlobal Human DNA Identification System and analyse the genetic relationship between Xinjiang Uyghur and their neighbours.Subjects and methods: We genotyped 27 markers in 2,189 unrelated Uyghur individuals from the Hotan Prefecture in Southwest Xinjiang. Comprehensive population genetic studies among Chinese populations and worldwide populations were conducted via various statistics.Results: The combined power of discrimination (CPD) and the combined power of exclusion (CPE) of the new-generation autosomal STR amplification system in the Hotan Uyghur are 9,9999-E01 and 9,9999-E01, respectively. Population genetic studies indicate that the Hotan Uyghur show a close genetic relationship with geographically different Uyghurs and Kazakhs, while significant genetic differentiation exists between the Hotan Uyghur and some ethnicities from other non-Turkic-speaking populations. The results of population comparisons among the 52 worldwide populations demonstrate that geographically approached intercontinental populations have close genetic relationships.Conclusions: 24 autosomal STRs are highly polymorphic and informative in the Uyghur and this system is suitable for forensic personal identification and paternity testing. Our findings not only reveal that Chinese Uyghur is a homogenous population based on forensic genetic markers, but also indicate that population genetic affinity is closely related to the adjacent populations with common ethnic origin.

Background Meat fraud and adulteration incidents occur frequently in almost all regions of the globe, especially with the increase in the world's population. To ensure the authenticity of meat products, we developed a 10-plex xMAP assay to simultaneously detect ten animal materials: bovine, caprine, poultry, swine, donkey, deer, horse, dog, fox and mink. Results This method was investigated by analyzing DNA extracts from raw muscle, muscle mixtures, meat products and animal feeds. Our results indicated that the species of interest can be identified, differentiated and detected down to 1 g kg-1 in binary mixtures or 0.01-0.001 ng of genomic DNA from specific species. Testing of 125 commercial samples showed a 97.4% coincidence rate with the method used in routine testing in our lab. Conclusion These results indicated that the method established in this study could detect ten animal materials simultaneously within 3 h, which provides a new, useful tool for animal ingredient analysis in meat products and animal feeds. © 2019 Society of Chemical Industry.

Background and aims Nuclear-located covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is a determining factor for HBV persistence and the key obstacle for a cure of chronic hepatitis B. However, it remains unclear whether and how the host immune system senses HBV cccDNA and its biological consequences. Approach and results Here, we demonstrated that interferon-inducible protein 16 (IFI16) could serve as a unique innate sensor to recognize and bind to HBV cccDNA in hepatic nuclei, leading to the inhibition of cccDNA transcription and HBV replication. Mechanistically, our data showed that IFI16 promoted the epigenetic suppression of HBV cccDNA by targeting an interferon-stimulated response element (ISRE) present in cccDNA. It is of interest that this ISRE was also revealed to play an important role in IFI16-activated type I interferon responses. Furthermore, our data revealed that HBV could down-regulate the expression level of IFI16 in hepatocytes, and there was a negative correlation between IFI16 and HBV transcripts in liver biopsies, suggesting the possible role of IFI16 in suppressing cccDNA function under physiological conditions. Conclusions The nuclear sensor IFI16 suppresses cccDNA function by integrating innate immune activation and epigenetic regulation by targeting the ISRE of cccDNA, and IFI16 may present as a therapeutic target against HBV infection.

BACKGROUND The aim of this study was to identify feature autophagy-related genes (ARGs) in systemic lupus erythematosus (SLE), evaluate their diagnostic value, and further explore DNA methylation and expression levels in the pathogenesis of SLE. MATERIAL AND METHODS WGCNA was used to construct network and selected hub genes based on gene expression dataset GSE81622. ARGS were overlapped with hub genes, and feature ARGs were identified. A diagnostic model was established by these feature ARGs using LASSO. GSE96879 was used to analyze the methylation levels of feature ARGs. The expression and methylation levels of feature ARGs were verified using RT-PCR and methylation-specific PCR. RESULTS We found that 55 hub genes were highly connected to the red module of WGCNA, and ARGs were extracted from the Human Autophagy Database and the GO_AUTOPHAGY gene set. Overlapping of 55 hub gene with ARGs resulted in 18 feature ARGs. S100A8, MyD88, and NCR3 from the 18 feature ARGs showed higher good diagnostic value for SLE. Five differentially methylated positions locating to S100A8, MyD88, and NCR3 genes were identified from GSE96879. After validation tests, RT-PCR showed that gene expressions of MyD88 and S100A8 were increased in the PBMCs samples of SLE patients compared with healthy controls, whereas NCR3 was the opposite. MSP found that cg24898863 (S100A8) was hypomethylated, while cg27490128 (NCR3) was hypermethylated in the SLE group, and S100A8 and NCR3 methylation were positively correlated with their expressions. CONCLUSIONS Our present study identified the potential roles of feature ARGs in SLE diagnosis, and shows correlation among DNA methylation and gene expressions of these feature ARGs in SLE.

Here, a new superfamily of IS630-Tc1-mariner (ITm) DNA transposons, termed Sailor, is identified, that is characterized by a DD82E catalytic domain and is distinct from all previously known superfamilies of the ITm group. Phylogenetic analyses revealed that Sailor forms a monophyletic clade with a more intimate link to the clades of Tc1/mariner and DD34E/Gambol. Sailor was detected in both prokaryotes and eukaryotes and invaded a total of 256 species across six kingdoms. Sailor is present in nine species of bacteria, two species of plantae, four species of protozoa, 23 species of Chromista, 12 species of Fungi and 206 species of animals. Moreover, Sailor is extensively distributed in invertebrates (a total of 206 species from six phyla) but is absent in vertebrates. Sailor transposons are 1.38–6.98 kb in total length and encoded transposases of ~676 aa flanked by TIRs with lengths between 18, 1362 and 4 bp (TATA) target-site duplications. Furthermore, our analysis provided strong evidence of Sailor transmissions from prokaryotes to eukaryotes and internal transmissions in both. These data update the classification of the ITm group and will contribute to the understanding of the evolution of ITm transposons and that of their hosts.

High‐throughput biological data has created an unprecedented opportunity for illuminating the mechanisms of tumor emergence and evolution. An important and challenging problem in deciphering cancers is to investigate the commonalities of driver genes and pathways and the associations between cancers. Aiming at this problem, a tool ComCovEx is developed to identify common cancer driver gene modules between two cancers by searching for the candidates in local signaling networks using an exclusivity‐coverage iteration strategy and outputting those with significant coverage and exclusivity for both cancers. The associations of the cancer pairs are further evaluated by Fisher's exact test. Being applied to 11 TCGA cancer datasets, ComCovEx identifies 13 significantly associated cancer pairs with plenty of biologically significant common gene modules. The novel results of cancer relationship and common gene modules reveal the relevant pathological basis of different cancer types and provide new clues to diagnosis and drug treatment in associated cancers., This article presents a network‐based method ComCovEx to predict the common driver gene modules between two cancer types. An exclusivity‐coverage iteration strategy is designed for identifying the gene modules with significant coverage and exclusivity for two cancers. Then the identified gene modules are evaluated by statistical analysis. The associations of cancer pairs are further evaluated by Fisher's exact test.

Despite comprising much of the genome, transposons were once thought of as junk. However, transposons play many roles in the eukaryotic genome, such as providing new proteins as domesticated genes, expressing during germline-soma differentiation, function in DNA rearrangement in the offspring, and so on. We sought to describe the distribution and structural organization of the two autonomous transposons (ZB and PS) in the zebrafish genome and examine their expression patterns in embryos and adult tissues. The intact copy of ZB and PS was queried by BLAST on NCBI and ENSEMBL using default parameters. Of the copies with coverage and identity, more than 90 % were downloaded to do structural analysis. Spatial and temporal expression patterns were detected by qRT-PCR and Whole-mount in situ hybridization (WISH). There are 19 intact copies of ZB, encoding 341 amino acid residues with DD34E catalytic domain and flanked by 201bp TIRs, and seven intact PS copies, containing 425 amino acid residues with DD35D catalytic domain flanked by 28bp TIRs, were detected in the genome of zebrafish respectively. Analysis of genomic insertions indicated that both ZB and PS transposons are prone to be retained in the intron and intergenic regions of the zebrafish genome. The sense and antisense transcripts of ZB and PS were detected during embryonic development stages and exhibited similar expression patterns. The difference is that the sense strand transcript of ZB was explicitly expressed in midbrain-hindbrain boundary (MHB) and otic vesicle (OV), and pharyngeal arches and pharyngeal pouches (PA&PP) at 48 hpf. In adult zebrafish, the expressions of ZB and PS in muscle and brain are much higher than in other tissues. Our study results indicate that ZB and PS transposons may be involved in the embryonic development and regulation of somatic cells of certain adult tissues, such as the brain and muscle.

To understand the effects of source-sink relationships on rice yield response to elevated CO2 levels (eCO2), we conducted a field study using a popular japonica cultivar grown in a free-air CO2 enrichment environment in 2017–2018. The source-sink ratio of rice was set artificially via source-sink treatments (SSTs) at the heading stage. Five SSTs were performed in 2017 (EXP1): cutting off the flag leaf (LC1) and the top three functional leaves (LC3), removing one branch in every three branches of a panicle (SR1/3) and one branch in every two branches of a panicle (SR1/2), and the control (CK) without any leaf cutting or spikelet removal. The eCO2 significantly increased grain yield by 15.7% on average over all treatments; it significantly increased grain yield of CK, LC1, LC3, SR1/3, and SR1/2 crops by 13.9, 18.1, 25.3, 12.0, and 10.9%, respectively. The yield response to eCO2 was associated with a significant increase of panicle number and fully-filled grain percentage (FGP), and the response of crops under different SSTs was significantly positively correlated with FGP and the average grain weight of the seeds. Two SSTs (CK and LC3) were performed in 2018 (EXP2), which confirmed that the yield response of LC3 crops (25.1%) to eCO2 was significantly higher than that of CK (15.9%). Among the different grain positions, yield response to eCO2 of grains attached to the lower secondary rachis was greater than that of grains attached to the upper primary rachis. Reducing the source-sink ratio via leaf-cutting enhanced the net photosynthetic rate response of the remaining leaves to eCO2 and increased the grain filling ability. Conversely, spikelet removal increased the non-structural carbohydrate (NSC) content of the stem, causing feedback inhibition and photosynthetic down-regulation. This study suggests that reducing the source-sink ratio by adopting appropriate management measures can increase the response of rice to eCO2.

In cancer, copy number aberrations (CNA) represent a type of nearly ubiquitous and frequently extensive structural genome variations. To disentangle the molecular mechanisms underlying tumorigenesis as well as identify and characterize molecular subtypes, the comparative and meta-analysis of large genomic variant collections can be of immense importance. Over the last decades, cancer genomic profiling projects have resulted in a large amount of somatic genome variation profiles, however segregated in a multitude of individual studies and datasets. The Progenetix project, initiated in 2001, curates individual cancer CNA profiles and associated metadata from published oncogenomic studies and data repositories with the aim to empower integrative analyses spanning all different cancer biologies.During the last few years, the fields of genomics and cancer research have seen significant advancement in terms of molecular genetics technology, disease concepts, data standard harmonization as well as data availability, in an increasingly structured and systematic manner. For the Progenetix resource, continuous data integration, curation and maintenance have resulted in the most comprehensive representation of cancer genome CNA profiling data with 138’663 (including 115’357 tumor) CNV profiles. In this article, we report a 4.5-fold increase in sample number since 2013, improvements in data quality, ontology representation with a CNV landscape summary over 51 distinctive NCIt cancer terms as well as updates in database schemas, and data access including new web front-end and programmatic data access. Database URL:progenetix.org

Heterotopic ossification (HO) occurs as a common complication after injury or in genetic disorders. The mechanisms underlying HO remain incompletely understood, and there are no approved prophylactic or secondary treatments available. Here, we identify a self-amplifying, self-propagating loop of Yes-associated protein (YAP)-Sonic hedgehog (SHH) as a core molecular mechanism underlying diverse forms of HO. In mouse models of progressive osseous heteroplasia (POH), a disease caused by null mutations in GNAS, we found that Gnas-/- mesenchymal cells secreted SHH, which induced osteoblast differentiation of the surrounding wild-type cells. We further showed that loss of Gnas led to activation of YAP transcription activity, which directly drove Shh expression. Secreted SHH further induced YAP activation, Shh expression, and osteoblast differentiation in surrounding wild-type cells. This self-propagating positive feedback loop was both necessary and sufficient for HO expansion and could act independently of Gnas in fibrodysplasia ossificans progressiva (FOP), another genetic HO, and nonhereditary HO mouse models. Genetic or pharmacological inhibition of YAP or SHH abolished HO in POH and FOP and acquired HO mouse models without affecting normal bone homeostasis, providing a previously unrecognized therapeutic rationale to prevent, reduce, and shrink HO.

X-linked deafness-2 (DFNX2) is cochlear incomplete partition type III (IP-III), one of inner ear malformations characterized by an abnormally wide opening in the bone separating the basal turn of the cochlea from the internal auditory canal, fixation of the stapes and cerebrospinal fluid (CSF) gusher upon stapedectomy or cochleostomy. The causative gene of DFNX2 was POU3F4. To investigate the genetic causes of DFNX2 and compare the efficiency of different sequencing methods, 12 unrelated patients were enrolled in the present study. Targeted next-generation sequencing (NGS) and long-read sequencing were used to analyze the genetic etiology of DFNX2. Six variants of POU3F4 were identified in this cohort by NGS. Three patients with a negative diagnosis based on NGS were enrolled in further long-read sequencing. Two of them were all found to carry structural variations (SVs) on chromosome X, consisting of an 870-kb deletion (DEL) at upstream of POU3F4 and an 8-Mb inversion (INV). The 870-kb DEL may have been due to non-homologous end joining (NHEJ), while non-allelic homologous recombination (NAHR) within a single chromatid may have accounted for the 8-Mb INV. Common POU3F4 mutations in DFNX2 included point mutations, small insertions and deletions (INDELs), and exon mutations, which can be detected by Sanger sequencing and NGS. Single-molecule long-read sequencing constitutes an additional and valuable method for accurate detection of pathogenic SVs in IP-III patients with negative NGS results.

Copy number aberrations (CNA) are one of the most important classes of genomic mutations related to oncogenetic effects. In the past three decades, a vast amount of CNA data has been generated by molecular-cytogenetic and genome sequencing based methods. While this data has been instrumental in the identification of cancer-related genes and promoted research into the relation between CNA and histo-pathologically defined cancer types, the heterogeneity of source data and derived CNV profiles pose great challenges for data integration and comparative analysis. Furthermore, a majority of existing studies have been focused on the association of CNA to pre-selected “driver” genes with limited application to rare drivers and other genomic elements.In this study, we developed a bioinformatics pipeline to integrate a collection of 44,988 high-quality CNA profiles of high diversity. Using a hybrid model of neural networks and attention algorithm, we generated the CNA signatures of 31 cancer subtypes, depicting the uniqueness of their respective CNA landscapes. Finally, we constructed a multi-label classifier to identify the cancer type and the organ of origin from copy number profiling data. The investigation of the signatures suggested common patterns, not only of physiologically related cancer types but also of clinico-pathologically distant cancer types such as different cancers originating from the neural crest. Further experiments of classification models confirmed the effectiveness of the signatures in distinguishing different cancer types and demonstrated their potential in tumor classification.

BackgroundArtemisinin-resistant genotypes have now emerged a minimum of five times on three continents despite recommendations that all artemisinins be deployed as artemisinin combination therapies (ACTs). Widespread resistance to the non-artemisinin partner drugs in ACTs has the potential to limit the clinical and resistance benefits provided by combination therapy.MethodsUsing a consensus modelling approach with three individual-based mathematical models of Plasmodium falciparum transmission, we evaluate the effects of pre-existing partner-drug resistance and ACT deployment on artemisinin resistance evolution. We evaluate settings where dihydroartemisinin-piperaquine (DHA-PPQ), artesunate-amodiaquine (ASAQ), or artemether-lumefantrine (AL) are deployed as first-line therapy. We use time until 0.25 artemisinin resistance allele frequency (the establishment time) as the primary outcome measure.FindingsHigher frequencies of pre-existing partner-drug resistant genotypes lead to earlier establishment of artemisinin resistance. Across all scenarios and pre-existing frequencies of partner-drug resistance explored, a 0.10 increase in partner-drug resistance frequency on average corresponded to 0.7 to 5.0 years loss of artemisinin efficacy. However, the majority of reductions in time to artemisinin establishment were observed after the first increment from 0.0 to 0.10 partner-drug resistance genotype frequency.InterpretationPartner-drug resistance in ACTs facilitates the early emergence of artemisinin resistance and is a major public health concern. Higher grade partner-drug resistance has the largest effect, with piperaquine-resistance accelerating early emergence of artemisinin-resistant alleles the most. Continued investment in molecular surveillance of partner-drug resistant genotypes to guide choice of first-line ACT is paramount.FundingBill and Melinda Gates Foundation; Wellcome Trust.

The soybean aphid, Aphis glycines Matsumura, is an important pest of soybean. During some years with occurrences of heavy aphid infestations in field, A. glycines can cause serious damage to soybeans. A. glycines has a heteroecious and holocyclic life cycle, with migration occurring between the primary and secondary hosts during each year. The primary hosts of A. glycines are Rhamnus spp., and the secondary hosts are soybean, Glycine max (L.) Merrill, and wild soybean species, Glycine soja Sieb & Zucc. In this study, A. glycines were fed on detached leaves and live plants of Trifolium repens L. and Metaplexis japonica (Thunb.) Makino, and their survival, development and reproduction were studied at five constant temperatures. These data were compared to those of controls fed on the known host plant G. max. When A. glycines were fed on detached leaves of T. repens and M. japonica, they showed vigorous development and reproduction. The novel and striking results were that: (1) A. glycines could not thrive on live plants of M. japonica, and only a few nymphs were deposited. (2) When A. glycines were fed on live plants of vegetative stage T. repens, adult longevity and fecundity were as long as 11.64 ± 1.17 days and as great as 12.92 ± 1.23 nymphs per adult, respectively. This work provides important evidence that M. japonica is not a host of A. glycines, but T. repens is probably an important host for this aphid.

Background Multiple incompatibility (Inc) groups of plasmids have been identified in Enterobacteriaceae species, but there are still quite a few sequenced plasmids that could not be assigned to any known Inc groups. Methods One IncFIIpKF727591β plasmid p205880-qnrS and two IncpKPHS1 plasmids p11219-CTXM and p205880-NR1 were fully sequenced in this work. Detailed genomic comparison was applied to all available sequenced plasmids of IncFIIpKF727591 or IncpKPHS1 group. Results p205880-qnrS carried a novel transposon Tn6396, which was an ISKpn19-compsite transposon and represented a prototype transposable element carrying a minimum core qnrS1 module. p11219-CTXM harbored a novel transposon Tn6559, which was generated from integration of a truncated IS903D-bla CTX-M-14 -ISEcp1 unit into the Tn3-family cryptic unit transposon Tn1722. Two Inc groups, IncFIIpKF727591 and IncpKPHS1, of plasmids from Enterobacteriaceae species were proposed, and IncFIIpKF727591 was further grouped into two subgroups IncFIIpKF727591α and IncFIIpKF727591β. Each of the 11 IncFIIpKF727591 plasmids carried multiple accessory modules including at least one resistance module, and the relatively small IncFIIpKF727591 backbones could acquire a wealth of foreign genetic contents. The modular structures of plasmid backbones were conserved within each of IncFIIpKF727591α and IncFIIpKF727591β subgroups but dramatically different, although with similar gene organizations, between these two subgroups. The IncpKPHS1 backbones were conserved with respect to modular structures, and only four of the 14 IncpKPHS1 plasmids carried accessory modules, two of which contained resistance genes. Conclusion A genomic comparison of sequenced IncpKPHS1 or IncFIIpKF727591 plasmids provides insights into modular differences and genetic diversification of these plasmids, some of which carries antimicrobial resistance genes.

1. In order to increase the efficiency of generating transgenic chicken, this trial focused on two points: primordial germ cells (PGCs）transfection in vivo and a germline-specific promoter.2. In order to transfect PGCs in vivo, two plasmids (pZB-CAG-GFP, pCMV-ZB）were co-injected into chicken embryos via the subgerminal cavity at Hamburger and Hamilton (HH) stage 2-3 or via blood vessel at HH stage 13-14. Results showed that the percentage of GFP+ embryos, viability and hatching rate of embryos injected at HH stage 13-14 were significantly higher than that at HH stage 2-3.3. Two plasmid transposon systems were used for chicken embryo micro-injections. The donor plasmid, with a green fluorescent protein (GFP) reporter gene, was mediated by the ZB transposon. The helper plasmid was a transposase expression vector driven by the promoter of the chicken vasa homologue (Cvh) gene or Human cytomegalovirus (CMV) promoter. Results showed that 60.98% of gonads in Cvh group expressed GFP, which was 52.50% higher than seen in the CMV group. Only gonad tissue from the Cvh group showed any GFP signal, whereas both gonads and other tissues in the CMV group showed green fluorescence.4. The data suggested that ZB transposon-mediated gene transfer was efficient for transfecting PGCs in vivo; the Cvh promoter drove the transposase gene specifically in the germline and increased the efficiency of germline transmission. Blood vessels injection at HH stage 13-14 may be a more efficient route for PGCs transfection in vivo.

Background Dominant deafness-onychodystrophy (DDOD) syndrome is a rare disorder mainly characterized by severe deafness, onychodystrophy and brachydactyly. We previously identified c.1516C > T (p.Arg506X) in ATP6V1B2 as cause of DDOD syndrome, accounting for all cases of this genetic disorder. Clinical follow-up of DDOD syndrome patients with cochlear implantation revealed the language rehabilitation was unsatisfactory although the implanted cochlea worked well, which indicates there might be learning and memory problems in DDOD syndrome patients. However, the underlying mechanisms were unknown. Methods atp6v1b2 knockdown zebrafish and Atp6v1b2 c.1516C > T knockin mice were constructed to explore the phenotypes and related mechanism. In mutant mice, auditory brainstem response test and cochlear morphology analysis were performed to evaluate the auditory function. Behavioral tests were used to investigate various behavioral and cognitive domains. Resting-state functional magnetic resonance imaging was used to evaluate functional connectivity in the mouse brain. Immunofluorescence, Western blot, and co-immunoprecipitation were performed to examine the expression and interactions between the subunits of V-ATPases. Findings atp6v1b2 knockdown zebrafish showed developmental defects in multiple organs and systems. However, Atp6v1b2 c.1516C > T knockin mice displayed obvious cognitive defects but normal hearing and cochlear morphology. Impaired hippocampal CA1 region and weaker interaction between the V1E and B2 subunits in Atp6v1b2Arg506X//Arg506X mice were observed. Interpretation Our study extends the phenotypic range of DDOD syndrome. The impaired hippocampal CA1 region may be the pathological basis of the behavioral defects in mutant mice. The molecular mechanism underlying V-ATPases dysfunction involves a weak interaction between subunits, although the assembly of V-ATPases can still take place.

Breast cancer is the most pervasive cancer tormenting women, with increasing incidence and mortality rates year after year. MicroRNAs (miRNAs) with abnormal expression has various effects in biological processes and progression in diverse tumors. Nevertheless, it is vitally crucial for us to inspect more underlying molecular mechanisms for the therapy of patients with breast cancer. In the paper, we inquired the expression level and potential regulation mechanism of miR‐374c‐5p in breast cancer. Our research found out that miR‐374c‐5p was low‐level expressed in breast cancer. Upregulation of miR‐374c‐5p repressed cell proliferation, migration, and also epithelial‐mesenchymal transition (EMT), and induced cell apoptosis of breast cancer cells. Further, we concluded that miR‐374c‐5p interacted with TAF7 and downregulated its expression. Moreover, miR‐374c‐5p modulated DEP domain containing 1 (DEPDC1) through mediating TAF7. Finally, rescue assays represented that miR‐374c‐5p suppressed breast cancer development via TAF7‐mediated transcriptional regulation of DEPDC1. We uncovered that overexpressed miR‐374c‐5p inhibited the development of breast cancer via TAF7‐regulated transcriptional regulation of DEPDC1, which may be a novel and vital proportion of cancer diagnosis and treatment strategies.

Background Retrotransposons are the major determinants of genome sizes and they have shaped both genes and genomes in mammalian organisms, but their overall activity, diversity, and evolution dynamics, particularly their impact on protein coding and lncRNA genes in pigs remain largely unknown. Results In the present study, we performed de novo detection of retrotransposons in pigs by using multiple pipelines, four distinct families of pig-specific L1 s classified into 51 distinct subfamilies and representing four evolution models and three expansion waves of pig-specific SINEs represented by three distinct families were identified. ERVs were classified into 18 families and found two most “modern” subfamilies in the pig genome. The transposition activity of pig L1 was verified by experiment, the sense and antisense promoter activities of young L1 5′UTRs and ERV LTRs and expression profiles of young retrotransposons in multiple tissues and cell lines were also validated. Furthermore, retrotransposons had an extensive impact on lncRNA and protein coding genes at both the genomic and transcriptomic levels. Most protein coding and lncRNA (> 80%) genes contained retrotransposon insertions, and about half of protein coding genes (44.30%) and one-fourth (24.13%) of lncRNA genes contained the youngest retrotransposon insertions. Nearly half of protein coding genes (43.78%) could generate chimeric transcripts with retrotransposons. Significant distribution bias of retrotransposon composition, location, and orientation in lncRNA and protein coding genes, and their transcripts, were observed. Conclusions In the current study, we characterized the classification and evolution profile of retrotransposons in pigs, experimentally proved the transposition activity of the young pig L1 subfamily, characterized the sense and antisense expression profiles and promoter activities of young retrotransposons, and investigated their impact on lncRNA and protein coding genes by defining the mobilome landscapes at the genomic and transcriptomic levels. These findings help provide a better understanding of retrotransposon evolution in mammal and their impact on the genome and transcriptome. Electronic supplementary material The online version of this article (10.1186/s13100-019-0161-8) contains supplementary material, which is available to authorized users.