Studying tissue composition and function in non-human primates (NHPs) is crucial to understand the nature of our own species. Here we present a large-scale cell transcriptomic atlas that encompasses ...over 1 million cells from 45 tissues of the adult NHP Macaca fascicularis. This dataset provides a vast annotated resource to study a species phylogenetically close to humans. To demonstrate the utility of the atlas, we have reconstructed the cell-cell interaction networks that drive Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases, and intersected our data with human genetic disease orthologues to establish potential clinical associations. Our M. fascicularis cell atlas constitutes an essential reference for future studies in humans and NHPs.
Aims
Ansamycins are a family of macrolactams that are synthesized by type I polyketide synthase (PKS) using 3‐amino‐5‐hydroxybenzoic acid (AHBA) as the starter unit. Most members of the family have ...strong antimicrobial, antifungal, anticancer and/or antiviral activities. We aimed to discover new ansamycins and/or other AHBA‐containing natural products from actinobacteria.
Methods and Results
Through PCR screening of AHBA synthase gene, we identified 26 AHBA synthase gene–positive strains from 206 plant‐associated actinomycetes (five positives) and 688 marine‐derived actinomycetes (21 positives), representing a positive ratio of 2·4–3·1%. Twenty‐five ansamycins, including eight new compounds, were isolated from six AHBA synthase gene–positive strains through TLC‐guided fractionations followed by repeated column chromatography. To gain information about those potential ansamycin gene clusters whose products were unknown, seven strains with phylogenetically divergent AHBA synthase genes were subjected to fosmid library construction. Of the seven gene clusters we obtained, three show characteristics for typical ansamycin gene clusters, and other four, from Micromonospora spp., appear to lack the amide synthase gene, which is unusual for ansamycin biosynthesis. The gene composition of these four gene clusters suggests that they are involved in the biosynthesis of a new family of hybrid PK‐NRP compounds containing AHBA substructure.
Conclusions
PCR screening of AHBA synthase is an efficient approach to discover novel ansamycins and other AHBA‐containing natural products.
Significance and Impact of the Study
This work demonstrates that the AHBA‐based screening method is a useful approach for discovering novel ansamycins and other AHBA‐containing natural products from new microbial resources.
MicroRNAs (miRNAs) are believed to have fundamental roles in tumorigenesis and have great potential for the diagnosis and treatment of cancer. However, the roles of miRNAs in hepatocellular ...carcinogenesis are still not fully elucidated. We investigated the aberrantly expressed miRNAs involved in hepatoma by comparison of miRNA expression profiles in cancerous hepatocytes with normal primary human hepatocytes, and 37 dysregulated miRNAs were screened out by twofold change with a significant difference (P<0.05). Clustering analysis based on 13 miRNAs with changes over 15-folds showed that the miRNA expression patterns between the cancerous and normal hepatocytes were clearly different. Among the 13 miRNAs, we found that miR-375 was significantly downregulated in hepatocellular carcinoma (HCC) tissues and cell lines. Overexpression of miR-375 in liver cancer cells decreased cell proliferation, clonogenicity, migration/invasion and also induced G1 arrest and apoptosis. To unveil the molecular mechanism of miR-375-mediated phenotype in hepatoma cells described above, we examined the putative targets using bioinformatics tools and found that astrocyte elevated gene-1 (AEG-1) was a potential target of miR-375. Then we demonstrated that miR-375 bound directly to the 3'-untranslated region of AEG-1 and inhibited the expression of AEG-1. TaqMan quantitative reverse transcriptase-PCR and western blot analysis showed that miR-375 expression was inversely correlated with AEG-1 expression in HCC tissues. Knockdown of AEG-1 by RNAi in HCC cells, similar to miR-375 overexpression, suppressed tumor properties. Ectopic expression of AEG-1, conversely, could partially reverse the antitumor effects of miR-375. In a mouse model, therapeutic administration of cholesterol-conjugated 2'-O-methyl-modified miR-375 mimics (Chol-miR-375) could significantly suppress the growth of hepatoma xenografts in nude mice. In conclusion, our findings indicate that miR-375 targets AEG-1 in HCC and suppresses liver cancer cell growth in vitro and in vivo, and highlight the therapeutic potential of miR-375 in HCC treatment.
Background
The prevalence of allergic rhinitis (AR) has increased worldwide in recent decades. This study was conducted to investigate the prevalence of self‐reported AR and profiles of AR‐related ...comorbidities in the adult population of China over time.
Methods
This study surveyed residents of 18 major cities in mainland China. Telephone interviews were conducted with study participants after sampling target telephone numbers by random digit dialing. The questions asked during telephone interviews were based on those included in validated questionnaires and focused on topics regarding AR, nonallergic rhinitis (NAR), acute/chronic rhinosinusitis (ARS/CRS), asthma, and atopic dermatitis (AD).
Results
During 2011, a total of 47 216 telephone interviews were conducted, and the overall response rate was 77.5%. When compared with the AR prevalence in 11 cities surveyed in 2005, there was a significant increase in self‐reported adult AR in eight of those cities (P < 0.01). In 2011, the standardized prevalence of self‐reported adult AR in the 18 cities was 17.6%. The concentration of SO2 was positively correlated with the prevalence of AR (r = 0.504, P = 0.033). A multiple regression model showed that the absolute change in household yearly income was significantly associated with the change in the prevalence of AR (R2 = 0.68), after adjusting for PM10, SO2, NO2, temperature, and humidity. The overall prevalences of NAR, ARS, CRS, asthma, and AD in the general population were 16.4%, 5.4%, 2.1%, 5.8%, and 14%, respectively.
Conclusion
During a 6‐year period, there was a significant increase in the prevalence of self‐reported AR in the general Chinese adult population. The incidence of AR being accompanied by rhinosinusitis, asthma, or AD was significantly higher among individuals having self‐reported AR compared with the general population.
Metastasis is the predominant cause of death in breast cancer patients. Several lines of evidence have shown that microRNAs (miRs) can have an important role in cancer metastasis. Using isogenic ...pairs of low and high metastatic lines derived from a human breast cancer line, we have identified miR-149 to be a suppressor of breast cancer cell invasion and metastasis. We also identified GIT1 (G-protein-coupled receptor kinase-interacting protein 1) as a direct target of miR-149. Knockdown of GIT1 reduced migration/invasion and metastasis of highly invasive cells. Re-expression of GIT1 significantly rescued miR-149-mediated inhibition of cell migration/invasion and metastasis. Expression of miR-149 impaired fibronectin-induced focal adhesion formation and reduced phosphorylation of focal adhesion kinase and paxillin, which could be restored by re-expression of GIT1. Inhibition of GIT1 led to enhanced protein degradation of paxillin and α5β1 integrin via proteasome and lysosome pathways, respectively. Moreover, we found that GIT1 depletion in metastatic breast cancer cells greatly reduced α5β1-integrin-mediated cell adhesion to fibronectin and collagen. Low level of miR-149 and high level of GIT1 was significantly associated with advanced stages of breast cancer, as well as with lymph node metastasis. We conclude that miR-149 suppresses breast cancer cell migration/invasion and metastasis by targeting GIT1, suggesting potential applications of the miR-149-GIT1 pathway in clinical diagnosis and therapeutics.
Cytokine storm syndrome (CSS) is a critical clinical condition induced by a cascade of cytokine activation, characterized by overwhelming systemic inflammation, hyperferritinaemia, haemodynamic ...instability and multiple organ failure (MOF). At the end of 2019, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) emerged in Wuhan, China, and rapidly developed into a global pandemic. More and more evidence shows that there is a dramatic increase of inflammatory cytokines in patients with COVID‐19, suggesting the existence of cytokine storm in some critical illness patients. Here, we summarize the pathogenesis, clinical manifestation of CSS, and highlight the current understanding about the recognition and potential therapeutic options of CSS in COVID‐19.
Abstract We report the timing analysis of PSR J1846−0513, a pulsar discovered by the Five-hundred-meter Aperture Spherical radio Telescope (FAST) in Commensal Radio Astronomy FAST Survey. The pulsar ...possesses a spin period of 23.36 ms and a spin-down rate ( P ̇ ) of 1.0106(3) × 10 −18 s s −1 , and it is located in an eccentric orbit ( e ∼0.208) with an orbital period of 0.61 days. The characteristic age and surface magnetic field of the pulsar are found to be 366.62 Myr and 4.9178 × 10 9 G, respectively, indicating that it is a recycled pulsar. Using over two years of timing data, we measure the periastron advance ω ̇ = 0.8956(8) deg yr −1 . By assuming that this effect is purely relativistic, we have estimated the total mass M = 2.6287(35) M ⊙ and obtained an upper limit for the pulsar mass and a lower limit for the companion’s mass. Our results indicate that this is a double neutron star system.
Auroral arcs and diffuse auroras are common phenomena at high latitudes, though characteristics of their source plasma and fields have not been well understood. We report the first observation of ...fields and particles including their pitch‐angle distributions in the source region of auroral arcs and diffuse auroras, using data from the Arase satellite at L ~ 6.0–6.5. The auroral arcs appeared and expanded both poleward and equatorward at local midnight from ~0308 UT on 11 September 2018 at Nain (magnetic latitude: 66°), Canada, during the expansion phase of a substorm, while diffuse auroras covered the whole sky after 0348 UT. The top part of auroral arcs was characterized by purple/blue emissions. Bidirectional field‐aligned electrons with structured energy‐time spectra were observed in the source region of auroral arcs, while source electrons became isotropic and less structured in the diffuse auroral region afterwards. We suggest that structured bidirectional electrons at energies below a few keV were caused by upward field‐aligned potential differences (upward electric field along geomagnetic field) reaching high altitudes (~30,000 km) above Arase. The bidirectional electrons above a few keV were probably caused by Fermi acceleration associated with the observed field dipolarization. Strong electric‐field fluctuations and earthward Poynting flux were observed at the arc crossing and are probably also caused by the field dipolarization. The ions showed time‐pitch‐angle dispersion caused by mirror reflection. These results indicate a clear contrast between auroral arcs and diffuse auroras in terms of source plasma and fields and generation mechanisms of auroral arcs in the inner magnetosphere.
Plain Language Summary
Auroral arcs or curtains are a familiar phenomenon seen at high latitudes, and aurora is also present in diffuse form. In near‐Earth space, plasmas and electric and magnetic fields are known to have interactions that cause the auroral phenomena, but a direct link between measurements in space and the corresponding auroras near the surface has been hard to make. The Arase satellite carries advanced plasma and field instruments allowing detailed study of conditions in space, so campaign observations were carried out at Nain, Canada, in September 2018, at a time when it was expected to be connected to the region by following magnetic field lines. Both discrete and diffuse auroras were observed from the ground, while in space electrons and ions were observed, whose characteristics changed depending on whether the spacecraft was lined up with discrete auroras, or later, with diffuse auroras. The auroras and particles changed with time due to a “substorm,” which made the auroras brighten while making the particles more energetic. The observations suggest mechanisms by which the particles may be energized during substorms, with direct measurements in the source region.
Key Points
This is the first observation of the source plasma features of auroral arcs and diffuse auroras in the inner magnetosphere by Arase
Unique purple/blue auroral arcs appeared in association with an arrival of corotating interaction region (CIR) in the solar wind
During the arc crossing, field‐aligned electrons, time‐pitch‐angle dispersion of ions, and strong electric field variations were observed
Abstract
The minimum value of the geomagnetic
aa
index has served as a remarkably successful predictor of solar cycle amplitude. This value is reached near or just after sunspot minimum, when both ...the near-Earth solar wind speed and interplanetary magnetic field (IMF) strength fall to their lowest values. At this time, the heliospheric current sheet is flattened toward the heliographic equator and the dominant source of the IMF is the Sun’s axial dipole moment, which, in turn, has its source in the polar fields. As recognized previously, the success of
aa
min
as solar cycle precursor provides support for dynamo models in which the sunspots of a given cycle are produced by winding up the poloidal field built up during the previous cycle. Because they are highly concentrated toward the poles by the surface meridional flow, the polar fields are difficult to measure reliably. Here we point out that the observed value of the radial IMF strength at solar minimum can be used to constrain the polar field measurements, and that this parameter, which is directly proportional to the Sun’s axial dipole strength, may be an even better solar cycle predictor than geomagnetic activity.
PDF
