Moon-forming impactor as a source of Earth's basal mantle anomalies.

Seismic images of Earth's interior have revealed two continent-sized anomalies with low seismic velocities, known as the large low-velocity provinces (LLVPs), in the lowermost mantle1. The LLVPs are often interpreted as intrinsically dense heterogeneities that are compositionally distinct from the surrounding mantle2. Here we show that LLVPs may represent buried relics of Theia mantle material (TMM) that was preserved in proto-Earth's mantle after the Moon-forming giant impact3. Our canonical giant-impact simulations show that a fraction of Theia's mantle could have been delivered to proto-Earth's solid lower mantle. We find that TMM is intrinsically 2.0-3.5% denser than proto-Earth's mantle based on models of Theia's mantle and the observed higher FeO content of the Moon. Our mantle convection models show that dense TMM blobs with a size of tens of kilometres after the impact can later sink and accumulate into LLVP-like thermochemical piles atop Earth's core and survive to the present day. The LLVPs may, thus, be a natural consequence of the Moon-forming giant impact. Because giant impacts are common at the end stages of planet accretion, similar mantle heterogeneities caused by impacts may also exist in the interiors of other planetary bodies.

Dapagliflozin alleviates high glucose-induced injury of endothelial cells via inducing autophagy.

Hyperglycaemia is a key factor in the progression of diabetes complications. Dapagliflozin (DAPA), a new type of hypoglycaemic agent, has been shown to play an important role in anti-apoptotic, anti-inflammatory and antioxidant activities. Previous studies have demonstrated an endothelial protective effect of DAPA, but the underlying mechanism was still unclear. Autophagy is a homeostatic cellular mechanism that circulates unfolded proteins and damaged organelles through lysosomal dependent degradation. In this study, we aimed to investigate whether DAPA plays a protective role against high glucose (HG)-induced endothelial injury through regulating autophagy. The results showed that DAPA treatment resulted in increased cell viability. Additionally, DAPA treatment decreased interleukin (IL)-1ß, IL-6, and tumour necrosis factor-α levels in endothelial cells subjected to HG conditions. We observed that HG inhibited autophagy, and DAPA increased the autophagy level by inhibiting the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway. Chloroquine reversed all of these beneficial effects as an autophagy inhibitor. In summary, the endothelial protective effect of DAPA in HG can be attributed in part to its role in activating of autophagy via the AKT/mTOR signalling pathway. Therefore, suggesting that the activation of autophagy by DAPA may be a novel target for the treatment of HG-induced endothelial cell injury.

The Role of Inflammasome in Abdominal Aortic Aneurysm and Its Potential Drugs.

Abdominal aortic aneurysm (AAA) has been recognized as a serious chronic inflammatory degenerative aortic disease in recent years. At present, there is no other effective intervention except surgical treatment for AAA. With the aging of the human population, its incidence is increasing year by year, posing a serious threat to human health. Modern studies suggest that vascular chronic inflammatory response is the core process in AAA occurrence and development. Inflammasome, a multiprotein complex located in the cytoplasm, mediates the expression of various inflammatory cytokines like interleukin (IL)-1ß and IL-18, and thus plays a pivotal role in inflammation regulation. Therefore, inflammasome may exert a crucial influence on the progression of AAA. This article reviews some mechanism studies to investigate the role of inflammasome in AAA and then summarizes several potential drugs targeting inflammasome for the treatment of AAA, aiming to provide new ideas for the clinical prevention and treatment of AAA beyond surgical methods.

Plastome variations reveal the distinct evolutionary scenarios of plastomes in the subfamily Cereoideae (Cactaceae).

BACKGROUND: The cactus family (Cactaceae) has been reported to have evolved a minimal photosynthetic plastome size, with the loss of inverted-repeat (IR) regions and NDH gene suites. However, there are very limited genomic data on the family, especially Cereoideae, the largest subfamily of cacti. RESULTS: In the present study, we assembled and annotated 35 plastomes, 33 of which were representatives of Cereoideae, alongside 2 previously published plastomes. We analyzed the organelle genomes of 35 genera in the subfamily. These plastomes have variations rarely observed in those of other angiosperms, including size differences (with ~ 30 kb between the shortest and longest), dramatic dynamic changes in IR boundaries, frequent plastome inversions, and rearrangements. These results suggested that cacti have the most complex plastome evolution among angiosperms. CONCLUSION: These results provide unique insight into the dynamic evolutionary history of Cereoideae plastomes and refine current knowledge of the relationships within the subfamily.

Complete mitochondrial genome of Thuja sutchuenensis and its implications on evolutionary analysis of complex mitogenome architecture in Cupressaceae.

BACKGROUND: The complex physical structure and abundant repeat sequences make it difficult to assemble the mitogenomes of seed plants, especially gymnosperms. Only approximately 33 mitogenomes of gymnosperms have been reported. However, as the most widely distributed and the second largest family among gymnosperms, Cupressaceae has only six assembled mitogenomes, including five draft mitogenomes and one complete mitogenome, which has greatly hindered the understanding of mitogenome evolution within this large family, even gymnosperms. RESULTS: In this study, we assembled and validated the complete mitogenome of Thuja sutchuenensis, with a size of 2.4 Mb. Multiple sequence units constituted its complex structure, which can be reduced to three linear contigs and one small circular contig. The analysis of repeat sequences indicated that the numbers of simple sequence repeats increased during the evolutionary history of gymnosperms, and the mitogenome of Thuja sutchuenensis harboured abundant extra-long repeats (more than 5 kb). Additionally, the longest repeat sequence identified in these seven gymnosperms also came from the mitogenome of Thuja sutchuenensis, with a length of up to 47 kb. The analysis of colinear blocks and gene clusters both revealed that the orders of mitochondrial genes within gymnosperms was not conserved. The comparative analysis showed that only four tRNAs were shared by seven gymnosperms, namely, trnD-GUC, trnE-UUC, trnI-CAU and trnY-GUA. Furthermore, four genes have undergone potential positive selection in most gymnosperm species, namely, atp8, ccmB, mttB and sdh4. CONCLUSION: We successfully assembled the second complete mitogenome within Cupressaceae and verified that it consisted of multiple sequence units. Our study also indicated that abundant long repeats may contribute to the generation of the complex conformation of the mitogenome of Thuja sutchuenensis. The investigation of Thuja sutchuenensis's mitogenome in our study provides new insight into further understanding the complex mitogenome architecture within gymnosperms.

Short-term function and immune-protection of microencapsulated adult porcine islets with alginate incorporating CXCL12 in healthy and diabetic non-human primates without systemic immune suppression: A pilot study.

Replacement of insulin-producing pancreatic beta-cells by islet transplantation offers a functional cure for type-1 diabetes (T1D). We recently demonstrated that a clinical grade alginate micro-encapsulant incorporating the immune-repellent chemokine and pro-survival factor CXCL12 could protect and sustain the integrity and function of autologous islets in healthy non-human primates (NHPs) without systemic immune suppression. In this pilot study, we examined the impact of the CXCL12 micro encapsulant on the function and inflammatory and immune responses of xenogeneic islets transplanted into the omental tissue bilayer sac (OB; n = 4) and diabetic (n = 1) NHPs. Changes in the expression of cytokines after implantation were limited to 2-6-fold changes in blood, most of which did not persist over the first 4 weeks after implantation. Flow cytometry of PBMCs following transplantation showed minimal changes in IFNγ or TNFα expression on xenoantigen-specific CD4+  or CD8+  T cells compared to unstimulated cells, and these occurred mainly in the first 4 weeks. Microbeads were readily retrievable for assessment at day 90 and day 180 and at retrieval were without microscopic signs of degradation or foreign body responses (FBR). In vitro and immunohistochemistry studies of explanted microbeads indicated the presence of functional xenogeneic islets at day 30 post transplantation in all biopsied NHPs. These results from a small pilot study revealed that CXCL12-microencapsulated xenogeneic islets abrogate inflammatory and adaptive immune responses to the xenograft. This work paves the way toward future larger scale studies of the transplantation of alginate microbeads with CXCL12 and porcine or human stem cell-derived beta cells or allogeneic islets into diabetic NHPs without systemic immunosuppression.

Perspective of SGLT2i in the Treatment of Abdominal Aortic Aneurysms.

ABSTRACT: The incidence of abdominal aortic aneurysm (AAA) in the elderly is increasing year by year with high mortality. Current treatment is mainly through surgery or endovascular intervention, which is not sufficient to reduce future risk. Therefore, we still need to find an effective conservative measure as an adjunct therapy or early intervention to prevent AAA progression. Traditional therapeutic agents, such as ß-receptor blockers, calcium channel blockers, and statins, have been shown to have limited effects on the growth of AAA. Recently, sodium-glucose cotransport proteins inhibitors (SGLT2is), a new class hypoglycemic drug, have shown outstanding beneficiary effects on cardiovascular diseases by plasma volume reduction, vascular tone regulation, and various unidentified mechanisms. It has been demonstrated that SGLT2i is abundantly expressed in the aorta, and some studies also showed promising results of SGLT2i in treating animal AAA models. This article aims to summarize the recent progress of AAA studies and look forward to the application of SGLT2i in AAA treatment for early intervention or adjunct therapy after surgical repair or stent graft.

Developing long-term conservation priority planning for medicinal plants in China by combining conservation status with diversity hotspot analyses and climate change prediction.

BACKGROUND: Medicinal plants have always played an important role in the history of human health. However, the populations and sustainable use of medicinal plants have been severely affected by human activities and climate change. Little is known about the current conservation status and distribution pattern of medicinal plants. In this study, based on accurate geographical distribution information of 9756 medicinal plants, we identified diversity hotspots and conservation gaps, evaluated conservation effectiveness of nature reserves, and predicted suitable habitat areas for medicinal plants in China to provide scientific guidance for their long-term conservation and sustainable use. RESULTS: A total of 150 diversity hotspot grid cells, mainly concentrated in central and southern China, were identified. These only accounted for 5% of the total distribution area but contained 96% of the medicinal plants of the country. The hotspot grid cells included all traditional hotspot areas, but we also detected three new hotspots, namely Mufu-Lushan Mountains, Tianshan-Altai Mountains, and Changbai Mountains. The current national and provincial nature reserves protect 125 hotspot grid cells, which harbor 94% of all medicinal plants. However, 25 hotspot grid cells, distributed in the Tianshan-Altai Mountains and Hengduan Mountains, are located outside the national and provincial nature reserves. An analysis of the predicted effects of climate change indicated that the suitable habitat areas will shift from southern to northern China, and that southern China will face a considerable loss of suitable habitat areas, while the east and west parts of China will encompass remarkably more suitable habitat areas in the future. CONCLUSIONS: The current conservation networks have achieved high conservation effectiveness with regard to medicinal plants; however, the conservation gaps we identified should not be neglected, and conservation planning needs to take into account the predicted shifts of some hotspots of medicinal plants due to climate change.

Assembly of the Complete Mitochondrial Genome of Pereskia aculeata Revealed That Two Pairs of Repetitive Elements Mediated the Recombination of the Genome.

Pereskia aculeata is a potential new crop species that has both food and medicinal (antinociceptive activity) properties. However, comprehensive genomic research on P. aculeata is still lacking, particularly concerning its organelle genome. In this study, P. aculeata was studied to sequence the mitochondrial genome (mitogenome) and to ascertain the assembly, informational content, and developmental expression of the mitogenome. The findings revealed that the mitogenome of P. aculeata is circular and measures 515,187 bp in length with a GC content of 44.05%. It contains 52 unique genes, including 33 protein-coding genes, 19 tRNA genes, and three rRNA genes. Additionally, the mitogenome analysis identified 165 SSRs, primarily consisting of tetra-nucleotides, and 421 pairs of dispersed repeats with lengths greater than or equal to 30, which were mainly forward repeats. Based on long reads and PCR experiments, we confirmed that two pairs of long-fragment repetitive elements were highly involved with the mitogenome recombination process. Furthermore, there were 38 homologous fragments detected between the mitogenome and chloroplast genome, and the longest fragment was 3962 bp. This is the first report on the mitogenome in the family Cactaceae. The decoding of the mitogenome of P. aculeata will provide important genetic materials for phylogenetic studies of Cactaceae and promote the utilization of species germplasm resources.

Intrapleural transplantation of allogeneic pancreatic islets achieves glycemic control in a diabetic non-human primate.

Clinical islet transplantation has relied almost exclusively on intraportal administration of pancreatic islets, as it has been the only consistent approach to achieve robust graft function in human recipients. However, this approach suffers from significant loss of islet mass from a potent immediate blood-mediated inflammatory response (IBMIR) and a hypoxic environment. To avoid these negative aspects of the portal site, we explored an alternative approach in which allogeneic islets were transplanted into the intrapleural space of a non-human primate (NHP), treated with an immunosuppression regimen previously reported to secure routine survival and tolerance to allogeneic islets in NHP. Robust glycemic control and graft survival were achieved for the planned study period of >90 days. Our observations suggest the intrapleural space provides an attractive locale for islet transplantation due to its higher oxygen tension, ability to accommodate large transplant tissue volumes, and a lack of IBMIR-mediated islet damage. Our preliminary results reveal the promise of the intrapleural space as an alternative site for clinical islet transplantation in the treatment of type 1 diabetes.

Development of Atropa belladonna L. Plants with High-Yield Hyoscyamine and without Its Derivatives Using the CRISPR/Cas9 System.

Atropa belladonna L. is one of the most important herbal plants that produces hyoscyamine or atropine, and it also produces anisodamine and scopolamine. However, the in planta hyoscyamine content is very low, and it is difficult and expensive to independently separate hyoscyamine from the tropane alkaloids in A. belladonna. Therefore, it is vital to develop A. belladonna plants with high yields of hyoscyamine, and without anisodamine and scopolamine. In this study, we generated A. belladonna plants without anisodamine and scopolamine, via the CRISPR/Cas9-based disruption of hyoscyamine 6ß-hydroxylase (AbH6H), for the first time. Hyoscyamine production was significantly elevated, while neither anisodamine nor scopolamine were produced, in the A. belladonna plants with homozygous mutations in AbH6H. In summary, new varieties of A. belladonna with high yields of hyoscyamine and without anisodamine and scopolamine have great potential applicability in producing hyoscyamine at a low cost.

The application of Temporary Ark Hospitals in controlling COVID-19 spread: The experiences of one Temporary Ark Hospital, Wuhan, China.

Coronavirus disease 2019 (COVID-19) had its evolution in Wuhan, Hubei Province, China, and now it has spread around the world, resulting in a large number of deaths. Temporary Ark hospitals (TAHs) have played an important role in controlling the spread of the epidemic in the city of Wuhan. Taking one TAH with 800 beds as an example, we summarized details of the layout, setting, working mode of medical staff, patient management, admission standards, discharge standards, and standards for transferring to another hospital, hospital operation, and so on. Over the period of operation, a total of 1124 patients were admitted for treatment. Of these, 833 patients were cured and discharged from the hospital and 291 patients were transferred to other designated hospitals, owing to aggravation of their condition. The achievement was to have zero infection for medical staff, zero in-hospital deaths among admitted patients, and zero readmission for discharged patients. The rapid deployment of TAH provided a suitable place for treating mild/moderate or no asymptomatic COVID-19 patients, which successfully helped to control the infection in Wuhan. The successful model of TAH would rapidly and effectively control the spread of COVID-19 in other cities.

The Role of the Gut Microbiota in Coronary Heart Disease.

PURPOSE OF REVIEW: This review focuses on recent evidence examining the role gut microbiota play in coronary heart disease. It also provides a succinct overview of current and future therapies targeting the gut microbiota for coronary heart disease risk reduction. RECENT FINDINGS: A consensus has been reached that differences exist in the gut microbiotas of patients with coronary heart disease. Studies have shown that the gut microbiota is associated with obesity, diabetes, dyslipidemia, and hypertension, which are risk factors for coronary heart disease. The gut microbiota is involved in mediating basic metabolic processes, such as cholesterol metabolism, uric acid metabolism, oxidative stress, and inflammatory reactions, through its metabolites, which can induce the development of atherosclerosis and coronary heart disease. Interfering with the composition of gut microbiota, supplementing probiotics, and fecal donation are active areas of research to potentially prevent and treat coronary heart disease. Gut microbiota are causally associated with coronary heart disease. We analyzed the gut microbiota's effects on risk factors for coronary heart disease and studied the effects of gut microbiota metabolites on coronary heart disease. Gut microbiota is a potential target for preventing and treating coronary heart disease.

A pro-gastrin-releasing peptide imprinted photoelectrochemical sensor based on the in situ growth of gold nanoparticles on a MoS2 nanosheet surface.

Lamellar MoS2 nanosheets were successfully prepared by hydrothermal synthesis using 1-(3-mercaptopropyl)-3-methyl-imidazolium bromine (MIMBr) ionic liquid as a sulfur source and a morphology control agent, and sodium molybdate as a molybdenum source. Gold nanoparticles were assembled on the surface of MoS2 nanosheets by the in situ reduction of chloroauric acid at low temperatures to successfully fabricate AuNP/2D-MoS2 nanocomposites, thus improving photoelectrochemical response. AuNP/2D-MoS2 nanocomposites were used as photoelectrically active materials modified onto a glassy carbon electrode surface to construct a photoelectrochemical (PEC) sensor. Then, using 1-(N-pyrrolpropyl)-3-methyl-imidazolium bromine (PMIMBr) ionic liquid as a functional monomer and pro-gastrin-releasing peptide (Pro-GRP) as a template, a molecularly imprinted polymerized ionic liquid film was electrochemically deposited on an AuNP/2D-MoS2/GCE surface. Upon removing the templates, a molecularly imprinted photoelectrochemical sensor was constructed for the sensing of a tumor marker, pro-gastrin-releasing peptide. Experimental conditions including ascorbic acid concentration, polymerization conditions, incubation time, and pH value of the incubation solution have been optimized. Under the optimized conditions, the molecularly imprinted photoelectrochemical sensor can specifically detect the target protein Pro-GRP in the range of 0.02 ng mL-1-5 ng mL-1 with a detection limit of 0.0032 ng mL-1 (S/N = 3). The practicability of this photoelectrochemical sensor was demonstrated by accurately determining Pro-GRP in human serum samples.

Endoplasmic Reticulum-Targeted Fluorescent Nanodot with Large Stokes Shift for Vesicular Transport Monitoring and Long-Term Bioimaging.

Herein, a highly stable aggregation-induced emission (AIE) fluorescent nanodot assembled by an amphiphilic quinoxalinone derivative-peptide conjugate, namely Quino-1-Fmoc-RACR (also termed as Q1-PEP), which exhibits large Stokes shift and an endoplasmic reticulum (ER)-targeting capacity for bioimaging is reported. It is found that the resulting nanodot can effectively enter the ER with high fluorescent emission. As the ER is mainly involved in the transport of synthesized proteins in vesicles to the Golgi or lysosomes, the Q1-PEP nanodot with ER-targeting capacity can be used to monitor vesicular transport inside the cells. Compared to conventional fluorescent dyes with small Stokes shifts, the self-assembled fluorescent nanodot shows superior resistance to photobleaching and aggregation-induced fluorescence quenching, and elimination of the spectra overlap with autofluorescence of biosubstrate owning to their AIE-active and red fluorescence emission characteristics. All these optical properties make the fluorescent nanodot suitable for noninvasive and long-term imaging both in vitro and in vivo.

Microtubing-Reactor-Assisted Aliphatic C-H Functionalization with HCl as a Hydrogen-Atom-Transfer Catalyst Precursor in Conjunction with an Organic Photoredox Catalyst.

Chlorine radical, which is classically generated by the homolysis of Cl2 under UV irradiation, can abstract a hydrogen atom from an unactivated C(sp3 )-H bond. We herein demonstrate the use of HCl as an effective hydrogen-atom-transfer catalyst precursor activated by an organic acridinium photoredox catalyst under visible-light irradiation for C-H alkylation and allylation. The key to success relied on the utilization of microtubing reactors to maintain the volatile HCl catalyst. This photomediated chlorine-based C-H activation protocol is effective for a variety of unactivated C(sp3 )-H bond patterns, even with primary C(sp3 )-H bonds, as in ethane. The merit of this strategy is illustrated by rapid access to several pharmaceutical drugs from abundant unfunctionalized alkane feedstocks.

Eosin†Y as a Direct Hydrogen-Atom Transfer Photocatalyst for the Functionalization of C-H Bonds.

Eosin Y, a well-known economical alternative to metal catalysts in visible-light-driven single-electron transfer-based organic transformations, can behave as an effective direct hydrogen-atom transfer catalyst for C-H activation. Using the alkylation of C-H bonds with electron-deficient alkenes as a model study revealed an extremely broad substrate scope, enabling easy access to a variety of important synthons. This eosin Y-based photocatalytic hydrogen-atom transfer strategy is promising for diverse functionalization of a wide range of native C-H bonds in a green and sustainable manner.

Photoinduced Nickel-Catalyzed Chemo- and Regioselective Hydroalkylation of Internal Alkynes with Ether and Amide α-Hetero C(sp3)-H Bonds.

A direct hydroalkylation of disubstituted alkynes with unfunctionalized ethers and amides was achieved in an atom-efficient and additive-free manner through the synergistic combination of photoredox and nickel catalysis. The protocol was effective with a wide range of internal alkynes, providing products in a highly selective fashion. Notably, the observed regioselectivity is complementary to conventional radical addition processes. Mechanistic investigations suggest that the photoexcited iridium catalyst facilitated the nickel activation via single-electron transfer.

A Molecular Recognition Approach To Synthesize Nucleoside Analogue Based Multifunctional Nanoparticles for Targeted Cancer Therapy.

Tumor-targeted drug delivery with simultaneous cancer imaging is highly desirable for personalized medicine. Herein, we report a supramolecular approach to design a promising class of multifunctional nanoparticles based on molecular recognition of nucleobases, which combine excellent tumor-targeting capability via aptamer, controlled drug release, and efficient fluorescent imaging for cancer-specific therapy. First, an amphiphilic prodrug dioleoyl clofarabine was self-assembled into micellar nanoparticles with hydrophilic nucleoside analogue clofarabine on their surface. Thereafter, two types of single-stranded DNAs that contain the aptamer motif and fluorescent probe Cy5.5, respectively, were introduced onto the surface of the nanoparticles via molecular recognition between the clofarabine and the thymine on DNA. These drug-containing multifunctional nanoparticles exhibit good capabilities of targeted clofarabine delivery to the tumor site and intracellular controlled drug release, leading to a robust and effective antitumor effect in vivo.

"Bottom-up" Construction of Multi-Polyprodrug-Arm Hyperbranched Amphiphiles for Cancer Therapy.

Despite the great advantages of polymer-drug conjugates (PDC) in cancer therapy, control of the drug loading site and degree via a facile approach remains a great challenge. Herein, by combining the controllability of the "bottom-up" strategy and the stability of multiarm hyperbranched amphiphiles, we have developed novel multi-polyprodrug-arm hyperbranched amphiphiles (H40-star-(PHCPTMA-b-PMPC), hPCM) via reversible addition-fragmentation chain transfer (RAFT) polymerization for cancer therapy. The hPCM was constructed via two-step polymerization of an acid-labile prodrug monomer and a zwitterionic monomer, respectively. By using an H40 macroRAFT agent, 10-hydroxycamptothecine (HCPT) prodrug monomers were directly polymerized via the "bottom-up" strategy as a polyprodrug-arm inner-shell of hPCM with homogeneous drug distribution. The drug loading content can be facilely tuned through variation of the feed ratio of HCPTMA/H40 macroRAFT agent. Finally, the poly-zwitterionic hydrophilic outer-shell of hPCM was formed by RAFT polymerization of zwitterionic monomer to ensure preferable biocompatibility. By dissolving in dilute solution, unimolecular micelles of hPCM can be obtained, which endow desirable stability for the micelles. The effective cellular internalization, extended blood retention time, considerable accumulation in tumor tissue, and excellent anticancer activity of the hPCM micelles have been evaluated both in vitro and in vivo. This novel multi-polyprodrug-arm hyperbranched amphiphile constructed via the "bottom-up" strategy may open up new horizons for exploring next-generation PDC-based drug delivery systems.