WTAP-induced N6-methyladenosine of PD-L1 blocked T-cell-mediated antitumor activity under hypoxia in colorectal cancer.

N6-Methyladenosine (m6A) is a important process regulating gene expression post-transcriptionally. Programmed death ligand 1 (PD-L1) is a major immune inhibitive checkpoint that facilitates immune evasion and is expressed in tumor cells. In this research we discovered that Wilms' tumor 1-associated protein (WTAP) degradation caused by ubiquitin-mediated cleavage in cancer cells (colorectal cancer, CRC) under hypoxia was inhibited by Pumilio homolog 1 (PUM1) directly bound to WTAP. WTAP enhanced PD-L1 expression in a way that was m6A-dependent. m6A "reader," Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) identified methylated PD-L1 transcripts and subsequently fixed its mRNA. Additionally, we found that T-cell proliferation and its cancer cell-killing effects were prevented by overexpression of WTAP in vitro and in vivo. Overexpression prevented T cells from proliferating and killing CRC by maintaining the expression of PD-L1. Further evidence supporting the WTAP-PD-L1 regulatory axis was found in human CRC and organoid tissues. Tumors with high WTAP levels appeared more responsive to anti-PD1 immunotherapy, when analyzing samples from patients undergoing treatment. Overall, our findings demonstrated a novel PD-L1 regulatory mechanism by WTAP-induced mRNA epigenetic regulation and the possible application of targeting WTAP as immunotherapy for tumor hypoxia.

An Ion-Pumping Quasi-Solid Electrolyte Enabled by Electrokinetic Effects for Stable Aqueous Zinc Metal Batteries.

The practical application of aqueous zinc (Zn) metal batteries (ZMBs) is hindered by the complicated hydrogen evolution, passivation reactions, and dendrite growth of Zn metal anodes. Here, an ion-pumping quasi-solid electrolyte (IPQSE) with high Zn2+ transport kinetics enabled by the electrokinetic phenomena to realize high-performance quasi-solid state Zn metal batteries (QSSZMBs) is reported. The IPQSE is prepared through the in situ ring-opening polymerization of tetramethylolmethane-tri-ß-aziridinylpropionate in the aqueous electrolyte. The porous polymer framework with high zeta potential provides the IPQSE with an electrokinetic ion-pumping feature enabled by the electrokinetic effects (electro-osmosis and electrokinetic surface conduction), which significantly accelerates the Zn2+ transport, reduces the concentration polarization and overcomes the diffusion-limited current. Moreover, the Zn2+ affinity of the polymer and hydrogen bonding interactions in the IPQSE changes the Zn2+ coordination environment and reduces the amount of free H2O, which lowers the H2O activity and inhibits H2O-induced side reactions. Consequently, the highly reversible and stable Zn metal anodes are achieved. The assembled QSSZMBs based on the IPQSE display excellent cycling stability with high capacity retention and Coulombic efficiency. The high-performance quasi-solid state Zn metal pouch cells are demonstrated, showing great promise for the practical application of the IPQSE.

Modulating the Inner Helmholtz Plane towards Stable Solid Electrolyte Interphase by Anion-π Interactions for High-Performance Anode-Free Lithium Metal Batteries.

Anode-free lithium (Li) metal batteries (AFLBs) featured high energy density are viewed as the viable future energy storage technology. However, the irregular Li deposition and unstable solid electrolyte interphase (SEI) on anode current collectors reduce their cycling performance. Here, we propose a concept of anion-recognition electrodes enabled by anion-π interactions to regulate the inner Helmholtz plane (IHP) and electrolyte solvation chemistry for high-performance AFLBs. By engineering the electrodes with electron-deficient aromatic-π systems that possess high permanent quadrupole moment (Qzz ), the anion-π interactions can be generated to concentrate the anions on the electrode surface and tune the IHP structure to construct a stable anion-derived SEI layer, thus achieving highly reversible Li plating/stripping process. Through designing various current collectors with different Qzz values, the intimate correlations among the surface charge of the electrode, competitive adsorption of the IHP, and SEI structures are demonstrated. Particularly, the modified carbon cloth current collector with a high Qzz value (+35.1) delivers a high average Li stripping/plating Coulombic efficiency of 99.1% over 230 cycles in the carbonated electrolyte, enabling a long lifespan and high capacity retention of LiNi0.8Co0.1Mn0.1O2-based AFLBs with a commercial-level areal capacity (4.1 mA h cm-2).

Breaking Mass Transport Limitations by Iodized Polyacrylonitrile Anodes for Extremely Fast-Charging Lithium-Ion Batteries.

The fast-charging capability of rechargeable batteries is greatly limited by the sluggish ion transport kinetics in anode materials. Here we develop an iodized polyacrylonitrile (I-PAN) anode that can boost the bulk/interphase lithium (Li)-ion diffusion kinetics and accelerate Li-ion desolvation process to realize high-performance fast-charging Li-ion batteries. The iodine immobilized in I-PAN framework expands ion transport channels, compresses the electric double layer, and changes the inner Helmholtz plane to form LiF/LiI-rich solid electrolyte interphase layer. The dissolved iodine ions in the electrolyte self-induced by the interfacial nucleophilic substitution of PF6 - not only promote the Li-ion desolvation process, but also reuse the plated/dead Li formed on the anode under fast-charging conditions. Consequently, the I-PAN anode exhibits a high capacity of 228.5 mAh g-1 (39 % of capacity at 0.5 A g-1 delivered in 18 seconds) and negligible capacity decay for 10000 cycles at 20 A g-1 . The I-PAN||LiNi0.8 Co0.1 Mn0.1 O2 full cell shows excellent fast-charging performance with attractive capacities and negligible capacity decay for 1000 cycles at extremely high rates of 5 C and 10 C (1 C=180 mA g-1 ). We also demonstrate high-performance fast-charging sodium-ion batteries using I-PAN anodes.

Responses of nickel bioavailability and toxicity of Prorocentrum Donghaienses to dissolved organic matter (DOM) fractions incubated in urea.

Urea, nickel (Ni) and dissolved organic matter (DOM) from land varied with different sources have a great impact on the offshore ecosystem. The heterogeneity of Ni bioavailability and toxicity of Prorocentrum donghaiense influenced by DOM fractions incubated in urea was investigated in this study. On the occasion, chlorophyll (Chl a) concentration, growth rate, and photosynthesis parameters were monitored to track changes occurring in the test organism. Chl a concentration and photosynthesis parameters in the treatment of hydrophilic DOM (HPI) with Ni-free was significantly higher than that in the control treatment, and similar data were shown in the treatment of hydrophobic DOM（HPO）with the low Ni environment (0.17µmol L-1). However, the opposite phenomena were observed in the treatments of HPO with the higher Ni environment (over 170µmol L-1). Moreover, the EC50 of Ni for P.donghaiense incubated in HPO was relatively lower than that in HPI and control treatment, which implied that HPO elevated the toxicity of Ni. Therefore, the varied DOM compositions because of different origins, as a chelating agent and potential nutrient source in coastal waters, shows the significantly different bioavailability and toxicity of Ni with the increasing inputs of urea, which in turn influences the dynamics of phytoplankton.

Hepatitis B virus X protein promotes liver cell pyroptosis under oxidative stress through NLRP3 inflammasome activation.

OBJECTIVE: Hepatitis B virus X protein (HBx) is a pivotal factor for HBV-induced hepatitis. Herein, we sought to investigate HBx-mediated NLR pyrin domain containing 3 (NLRP3) inflammasome activation and pyroptosis under oxidative stress. METHODS: The effect of HBx on the NLRP3 inflammasome was analyzed by enzyme-linked immunosorbent assays, quantitative reverse transcription-polymerase chain reaction, western blotting, and immunofluorescence in hepatic HL7702 cells. Pyroptosis was evaluated by western blotting, lactate dehydrogenase release, propidium iodide staining, and transmission electron microscopy. NLRP3 expression in the inflammasome from liver tissues was assessed by immunohistochemistry. RESULTS: In hydrogen peroxide (H2O2)-stimulated HL7702 cells, HBx triggered the release of pro-inflammatory mediators apoptosis-associated speck-like protein containing a CARD (ASC), interleukin (IL)-1ß, IL-18, and high-mobility group box 1 (HMGB1); activated NLRP3; and initiated pro-inflammatory cell death (pyroptosis). HBx localized to the mitochondria, where it induced mitochondrial damage and production of mitochondrial reactive oxygen species (mitoROS). Treatment of HL7702 cells with a mitoROS scavenger attenuated HBx-induced NLRP3 activation and pyroptosis. Expression levels of NLRP3, ASC, and IL-1ß in liver tissues from patients were positively correlated with HBV DNA concentration. CONCLUSIONS: The NLRP3 inflammasome was activated by elevated mitoROS levels and mediated HBx-induced liver inflammation and hepatocellular pyroptosis under H2O2-stress conditions.

Increased soil moisture aggravated the competitive effects of the invasive tree Rhus typhina on the native tree Cotinus coggygria.

BACKGROUND: Invasive exotic species have caused significant problems, and the effects of extreme precipitation and drought, which might occur more frequently under the global climate change scenarios, on interspecific relationship between invasive and native species remain unclear. RESULTS: We conducted a greenhouse experiment with three soil water levels (30-40%, 50-60%, and 70-80% of field capacity) and two cultivation treatments (monoculture pots, one seedling of either species and mixture pots, one seedling of each species) to investigate soil water content effects on the relationship between invasive Rhus typhina and native Cotinus coggygria. Rhus typhina had lower height but bigger crown area than C. coggygria in the monoculture treatment. Rhus typhina had higher height, bigger crown area and total biomass than C. coggygria in the mixture treatment. Drought decreased the growth parameters, total chlorophyll concentration, and leaf biomass, but did not change gas exchange and other biomass parameters in R. typhina. The growth parameters, leaf area index, biomass parameters, total chlorophyll concentration, and net photosynthetic rate of C. coggygria decreased under drought conditions. The log response ratio (lnRR), calculated as ln (total biomass of a target plant grown in monoculture/total biomass of a target plant grown in mixed culture), of R. typhina was lower than that of C. coggygria. The lnRR of R. typhina and C. coggygria decreased and increased with increase in soil water content, respectively. CONCLUSIONS: Rhus typhina has greater capacity to relatively stable growth to the drought condition than C. coggygria and has strong competition advantages in the mixture with C. coggygria, especially in the drought condition. Our study will help understand the causes of invasiveness and wide distribution of R. typhina under various moisture conditions and predict its expansion under climate change scenarios.

[Chemical constituents and their biosynthesis mechanisms of Polygonum cuspidatum].

This article reviews the research progress of the chemical constituents and biosynthesis mechanisms of Polygonum cuspidatum. The chemistry components isolated from P. cuspidatum are mainly anthraquinones, naphthoquinones, stilbenes, flavonoids, and other compounds. The synthase genes involved in the biosynthesis process were summarized. The biosynthesis mechanism of stilbenes and anthraquinones was discussed. This article hopefully to provide a reference for further research, development and utilization of P. cuspidatum.

Metaproteomics reveals major microbial players and their metabolic activities during the blooming period of a marine dinoflagellate Prorocentrum donghaiense.

Interactions between bacteria and phytoplankton during bloom events are essential for both partners, which impacts their physiology, alters ambient chemistry and shapes ecosystem diversity. Here, we investigated the community structure and metabolic activities of free-living bacterioplankton in different blooming phases of a dinoflagellate Prorocentrum donghaiense using a metaproteomic approach. The Fibrobacteres-Chlorobi-Bacteroidetes group, Rhodobacteraceae, SAR11 and SAR86 clades contributed largely to the bacterial community in the middle-blooming phase while the Pseudoalteromonadaceae exclusively dominated in the late-blooming phase. Transporters and membrane proteins, especially TonB-dependent receptors were highly abundant in both blooming phases. Proteins involved in carbon metabolism, energy metabolism and stress response were frequently detected in the middle-blooming phase while proteins participating in proteolysis and central carbon metabolism were abundant in the late-blooming phase. Beta-glucosidase with putative algicidal capability was identified from the Pseudoalteromonadaceae only in the late-blooming phase, suggesting an active role of this group in lysing P. donghaiense cells. Our results indicated that diverse substrate utilization strategies and different capabilities for environmental adaptation among bacteria shaped their distinct niches in different bloom phases, and certain bacterial species from the Pseudoalteromonadaceae might be crucial for the termination of a dinoflagellate bloom.

Solasodine Induces Apoptosis, Affects Autophagy, and Attenuates Metastasis in Ovarian Cancer Cells.

Solasodine, a steroidal alkaloid isolated from solanaceous species, exhibits anticancer activities on several cell lines. This study aimed to explore the antitumor potential of solasodine on ovarian cancer cells. The MTT assay, lactate dehydrogenase release assay, Hoechst 33342 staining, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine staining assay, and Annexin V/PI assay were conducted to investigate the antiproliferation and apoptosis-inducing effects of solasodine. Monodansylcadaverine staining was performed to label the acidic puncta on ovarian cancer HEY cells. A wound healing assay and Transwell assay were carried out to determine whether solasodine elicits an antimetastatic effect on HEY cells. A gelatin zymography assay was applied to detect the enzymatic activities of matrix metalloproteinases. Western blot was employed to examine relevant protein expression. Results revealed that solasodine inhibited cell viabilities in a time- and dose-dependent manner, triggered apoptotic body formation, reduced cell mitochondrial membrane potential, and interfered with autolysosome degradation in ovarian cancer cells. Solasodine also suppressed the migration and invasion of HEY cells by downregulating matrix metalloproteinase expression and activities. This study could be used as a basis for further studies on the molecular mechanisms of the antiproliferation, apoptosis-inducing, autophagy-modifying, and antimetastatic activities of solasodine.

Trigonelline Inhibits Inflammation and Protects ß Cells to Prevent Fetal Growth Restriction during Pregnancy in a Mouse Model of Diabetes.

BACKGROUND: As an active component from traditional Chinese medicine, trigonelline has a protective effect on diabetes. This study evaluated the protective effects of trigonelline on diabetic mice during pregnancy. METHODS: Diabetes was induced in female mice by intraperitoneal injection for continuous 5-day of 40 mg/kg/day streptozotocin. Female mice were divided into 4 groups after they were allowed to mate with normal male mice: nondiabetic, nondiabetic treated with trigonelline (70 mg/kg) for 18 days, diabetic, and diabetic treated with trigonelline (70 mg/kg). RESULTS: Diabetic pregnant mice had significantly higher levels of blood glucose, serum total cholesterol, triglyceride, insulin, and leptin but lower serum omentin-1 level and insulin sensitivity index than the nondiabetic ones. Trigonelline improved the hyperglycemia, dyslipidemia, insulin resistance, and adipocytokine of diabetic pregnant mice. Diabetic pregnant mice had significantly reduced fetus numbers, fetal weight, and fetal/placental ratio, which were reversed by trigonelline. Trigonelline prevented the increase in proinflammatory cytokines and reduced interleukin-10 level in placenta of diabetic pregnant mice. Trigonelline increased ß-cell replication and the decreased ß-cell mass, and decreased the ß-cell apoptosis of diabetic pregnant mice. CONCLUSION: These findings suggest that trigonelline protects diabetic pregnancy partly by suppressing inflammation, regulating the secretion of adipocytokines, increasing ß-cell mass, replication, and decreasing ß-cell apoptosis.

Saponins from Chinese Medicines as Anticancer Agents.

Saponins are glycosides with triterpenoid or spirostane aglycones that demonstrate various pharmacological effects against mammalian diseases. To promote the research and development of anticancer agents from saponins, this review focuses on the anticancer properties of several typical naturally derived triterpenoid saponins (ginsenosides and saikosaponins) and steroid saponins (dioscin, polyphyllin, and timosaponin) isolated from Chinese medicines. These saponins exhibit in vitro and in vivo anticancer effects, such as anti-proliferation, anti-metastasis, anti-angiogenesis, anti-multidrug resistance, and autophagy regulation actions. In addition, related signaling pathways and target proteins involved in the anticancer effects of saponins are also summarized in this work.

Platycodin D induces apoptosis and triggers ERK- and JNK-mediated autophagy in human hepatocellular carcinoma BEL-7402 cells.

AIM: Platycodin D, the main saponin isolated from Chinese herb Platycodonis Radix, exhibits anticancer activities against various cancer cell lines. Here we evaluated its anticancer action against human hepatocellular carcinoma cells in vitro and in vivo, and elucidated the relationship between platycodin D-induced apoptosis and autophagy. METHODS: The viability of human hepatocellular carcinoma BEL-7402 cells was evaluated with MTT assay, and the apoptosis was examined using Annexin V/PI and Hoechst 33342 staining assays. Monodansylcadaverine (MDC) staining was used to label autophagic vacuoles. The proteins were detected using Western blot analysis. For studying its anticancer action in vivo, platycodin D (5 and 10 mg· kg(-1)·d(-1)) was intraperitoneally injected to BEL-7402-bearing mice for 21 days. RESULTS: Platycodin D (5-40 µmol/L) inhibited the cell proliferation in vitro with IC50 values of 37.70±3.99, 24.30±2.30 and 19.70±2.36 µmol/L at 24, 48 and 72 h, respectively. Platycodin D (5-20 µmol/L) dose-dependently increased BEL-7402 cell apoptosis, increased the Bax/Bcl-2 ratio and the levels of cleaved PARP and cleaved caspase-3, and decreased the level of Bcl-2. Furthermore, platycodin D (5-20 µmol/L) induced autophagy in BEL-7402 cells, as evidenced by formation of cytoplasmic vacuoles, increased amounts of LC3-II, and increased numbers of MDC-positive cells. Pretreatment with the autophagy inhibitor chloroquine (5 µmol/L) or BAF (50 nmol/L) significantly enhanced platycodin D-induced proliferation inhibition and apoptosis. Moreover, platycodin D (20 µmol/L) activated the ERK and JNK pathways in BEL-7402 cells, and simultaneous blockage of the two pathways effectively suppressed platycodin D-induced autophagy and enhanced platycodin D-induced apoptosis. In BEL-7402-bearing mice, platycodin D (10 mg·kg(-1)•d(-1)) significantly reduced relative tumor volume with decreased body weight. CONCLUSION: Platycodin D not only inhibits the proliferation of BEL-7402 cells but also suppresses BEL-7402 xenograft tumor growth. Platycodin D-induced cell proliferation inhibition and apoptosis are amplified by co-treatment with autophagy inhibitors.

"Fast track" rehabilitation after gastric cancer resection: experience with 80 consecutive cases.

BACKGROUND: To evaluate the safety, efficacy and outcomes of fast-track rehabilitation applied to gastric cancer proximal, distal and total gastrectomy. METHODS: Eighty consecutive patients undergoing gastric cancer resection performed by a single surgeon, received perioperative multimodal rehabilitation. Demographic and operative data, gastrointestinal function, postoperative hospital stays, surgical and general complications and mortality were assessed prospectively. RESULTS: Of the 80 patients (mean age 56.3 years), 10 (12.5%) received proximal subtotal gastrectomy (Billroth I), 38 (47.5%) received distal (Billroth II), and 32 (40%) received total gastrectomy (Roux-en-Y). Mean operative time was 104.9 minutes and intraoperative blood loss was 281.9 ml. Time to first flatus was 2.8 ± 0.5 postoperative days. Patients were discharged at a mean of 5.3 ± 2.2 postoperative days; 30-day readmission rate was 3.8%. In-hospital mortality was 0%; general and surgical complications were both 5%. CONCLUSIONS: Fast-track multimodal rehabilitation is feasible and safe in patients undergoing gastric cancer resection and may reduce time to first flatus and postoperative hospital stays.

Andrographolide protects against lipopolysaccharide-induced vascular hyporeactivity by suppressing the expression of inducible nitric oxide in periaortic adipose.

This study investigated the role of perivascular adipose tissue (PVAT) in the beneficial effects of andrographolide on vascular reactivity in endotoxaemic rats. After being challenged by lipopolysaccharide (4 mg/kg intraperitoneally), the rats were treated with andrographolide (1 mg/kg intraperitoneally). The response to phenylephrine of aortic rings with or without PVAT was recorded. Vascular relaxing effect of PVAT was determined by bioassay experiments. Inducible nitric oxide synthase (iNOS) in aortic PVAT was tested by Western blot, immunofluorescence, and quantitative polymerase chain reaction. Lipopolysaccharide injection lowered the contraction force induced by phenylephrine in aortic rings with or without PVAT and andrographolide treatment reversed these effects. In bioassay experiments, transferring bathing solution incubated with a PVAT+ ring to a PVAT- ring induced relaxation in the recipient. This relaxing effect of PVAT from endotoxaemic rats was more potent than the rats treated with vehicles. Andrographolide treatment decreased the relaxing effect of PVAT in endotoxaemic rats. The levels of iNOS protein and messenger RNA in PVAT were significantly higher in endotoxaemic rats than in the rats treated with vehicles. Andrographolide treatment decreased PVAT iNOS protein and messenger RNA levels in endotoxaemic rats. Our results suggest that andrographolide restores vascular reactivity in endotoxaemic rats by downregulation of iNOS in PVAT.

[Correlation of methylation of CpG island in cystathionine beta synthase promoter and clinicopathological features in colorectal cancer].

OBJECTIVE: To explore the association between methylation of cystathionine-beta-synthase (CBS) promoter and clinicopathological features in colorectal cancer. METHODS: Bisulfate sequencing PCR, real-time RT-PCR, and immunohistochemistry were used to investigate the methylation of CpG island in CBS promoter of 95 sporadic colorectal cancers. Software SPSS PASW Statistics was used to analyze the data of the hypermethylation levels in the malignant tissues and the correlation with pathological parameters and clinical outcome. RESULTS: Methylation levels in tumor tissue of patients [(64.9 ± 14.3)%]with colorectal cancer were significantly higher than that in normal tissues[(27.5 ± 13.1)%, P < 0.001]. The CBS mRNA levels in the hypomethylation group (7.22 ± 1.91) were significantly higher than that in the hypermethylation group (2.78 ± 1.12, P < 0.01). Univariate analysis showed that age, pT stage, pN stage, liver metastases, pTNM stage, and CBS hypermethylation level significantly correlated with the survival and recurrence rates of colorectal cancer patients (All P < 0.05). Multivariate analysis showed that CBS hypermethylation level and liver metastasis were independent factors significantly correlated with the recurrence rate and overall survival of the patients (All P < 0.05). CONCLUSIONS: Our study indicates that methylation of CpG island in CBS promoter is correlated with the occurrence and progression of colorectal cancer and plays a role in its tumorigenesis. It might serve as a useful marker for early diagnosis, targeted therapy and prediction of prognosis in colorectal cancer.

Up-regulation of PUM1 by miR-218-5p promotes colorectal tumor-initiating cell properties and tumorigenesis by regulating the PI3K/AKT axis.

Background: Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Advanced stage CRC, during the recent past, had a dismal prognosis and only a few available treatments. Pumilio homologous protein 1 (PUM1) is reportedly aberrant in human malignancies, including CRC. However, the role of PUM1 in the regulation of tumor-initiating cells (T-ICs) remains unknown. Methods: The levels of messenger RNAs (mRNAs) were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunoblot analyses. Statistical analyses were performed to determine the associations between the levels of PUM1 and tumor features and patient outcomes. Whether PUM1 is a downstream target of miR-218-5p was verified by bioinformatics target gene prediction and qRT-PCR. Results: Herein, it was found that T-ICs, chemoresistance, and recurrent CRC samples all manifest increased PUM1 expression. Functional investigations have shown that PUM1 increased the self-renewal, tumorigenicity, malignant proliferation, and chemoresistance of colorectal cells. PUM1 activates the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway biochemically. Furthermore, it was discovered that miR-218-5p specifically targets T-ICs' PUM1 3'-untranslated region (3'-UTR). More importantly, the PUM1/PI3K/AKT axis regulates CRC cells' responses to treatment with cetuximab, and PUM1 overexpression increased cetuximab resistance. More evidence points to the possibility that low PUM1 may predict cetuximab benefits in CRC patients after analysis of the patient cohort, patient-derived tumor organoids, and patient-derived xenografts (PDXs). Conclusions: Taken together, the result of this work points to the critical function of the miR-218-5p/PUM1/PI3K/AKT regulatory circuit in regulating T-ICs characteristics and thus suggests possible therapeutic targets for CRC.

Improving the genome and proteome annotations of the marine model diatom Thalassiosira pseudonana using a proteogenomics strategy.

Diatoms are unicellular eukaryotic phytoplankton that account for approximately 20% of global carbon fixation and 40% of marine primary productivity; thus, they are essential for global carbon biogeochemical cycling and climate. The availability of ten diatom genome sequences has facilitated evolutionary, biological and ecological research over the past decade; however, a complimentary map of the diatom proteome with direct measurements of proteins and peptides is still lacking. Here, we present a proteome map of the model marine diatom Thalassiosira pseudonana using high-resolution mass spectrometry combined with a proteogenomic strategy. In-depth proteomic profiling of three different growth phases and three nutrient-deficient samples identified 9526 proteins, accounting for ~ 81% of the predicted protein-coding genes. Proteogenomic analysis identified 1235 novel genes, 975 revised genes, 104 splice variants and 234 single amino acid variants. Furthermore, our quantitative proteomic analysis experimentally demonstrated that a considerable number of novel genes were differentially translated under different nutrient conditions. These findings substantially improve the genome annotation of T. pseudonana and provide insights into new biological functions of diatoms. This relatively comprehensive diatom proteome catalog will complement available diatom genome and transcriptome data to advance biological and ecological research of marine diatoms. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-022-00161-y.

Protective effect of total flavonoids of seabuckthorn (Hippophae rhamnoides) in simulated high-altitude polycythemia in rats.

Seabuckthorn (Hippophae rhamnoides L.) has been used to treat high altitude diseases. The effects of five-week treatment with total flavonoids of seabuckthorn (35, 70, 140 mg/kg, ig) on cobalt chloride (5.5 mg/kg, ip)- and hypobaric chamber (simulating 5,000 m)-induced high-altitude polycythemia in rats were measured. Total flavonoids decreased red blood cell number, hemoglobin, hematocrit, mean corpuscular hemoglobin levels, span of red blood cell electrophoretic mobility, aggregation index of red blood cell, plasma viscosity, whole blood viscosity, and increased deformation index of red blood cell, erythropoietin level in serum. Total flavonoids increased pH, pO2, Sp(O2), pCO2 levels in arterial blood, and increased Na⁺, HCO3⁻, Cl⁻, but decreased K⁺ concentrations. Total flavonoids increased mean arterial pressure, left ventricular systolic pressure, end-diastolic pressure, maximal rate of rise and decrease, decreased heart rate and protected right ventricle morphology. Changes in hemodynamic, hematologic parameters, and erythropoietin content suggest that administration of total flavonoids from seabuckthorn may be useful in the prevention of high altitude polycythaemia in rats.

Efficacy and Safety of Dapagliflozin versus Liraglutide in Patients with Overweight or Obesity and Type 2 Diabetes Mellitus: A Randomised Controlled Clinical Trial in Tianjin, China.

Objective: We aimed to clarify the efficacy of dapagliflozin versus liraglutide in patients with overweight or obesity and type 2 diabetes mellitus (T2DM) at the beginning of the coronavirus disease 2019 (COVID-19) pandemic. Methods: T2DM patients with overweight or obesity who visited the Metabolic Disease Management Center at Tianjin Fourth Central Hospital from October 2019 to January 2020 were recruited and randomised to receive dapagliflozin or liraglutide for 24 weeks. Changes in blood glucose and lipid levels, blood pressure, and body weight, as well as the occurrence of hypoglycaemia and other adverse events, were compared. Results: 309 patients completed the study (143 in liraglutide group and 166 in dapagliflozin group). After 24 weeks, HbA1c, fasting blood glucose (FPG), and 2 h postprandial blood glucose (2hPG) levels significantly decreased from 8.80% ± 1.41% to 7.02% ± 1.05%, 10.41 ± 3.13 to 7.59 ± 2.16 mmol/L, and 17.90 ± 4.39 to 10.12 ± 2.47 mmol/L, respectively, in the dapagliflozin group, and from 8.92% ± 1.49% to 6.78% ± 1.00%, 10.04 ± 2.99 to 7.20 ± 1.63 mmol/L, and 17.30 ± 4.39 to 10.13 ± 4.15 mmol/L, respectively, in the liraglutide group. Changes in HbA1c, FPG, and 2hPG levels between groups were not significantly different. Systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) level significantly decreased from 144.1 ± 19.1 to 139.7 ± 16.2 mmHg (p = 0.001) and from 3.21 ± 0.94 to 2.98 ± 0.89 mmol/L (p = 0.014), respectively, in the dapagliflozin group. After COVID-19 outbreak, the number of patients taking sleep-promoting drugs increased from 4.9% to 9.4% (p = 0.029). Conclusions: Liraglutide and dapagliflozin had strong hypoglycaemic effects in patients with overweight or obesity and T2DM at the beginning of the COVID-19 pandemic. Dapagliflozin may be beneficial in improving SBP and LDL-C levels; however, further research is warranted.