Imbalanced lipid homeostasis caused by membrane αKlotho deficiency contributes to the acute kidney injury to chronic kidney disease transition.

After acute kidney injury (AKI), renal tubular epithelial cells (RTECs) are pathologically characterized by intracellular lipid droplet (LD) accumulation, which are involved in RTEC injury and kidney fibrosis. However, its pathogenesis remains incompletely understood. The protein, αKlotho, primarily expressed in RTECs, is well known as an anti-aging hormone wielding versatile functions, and its membrane form predominantly acts as a co-receptor for fibroblast growth factor 23. Here, we discovered a connection between membrane αKlotho and intracellular LDs in RTECs. Fluorescent fatty acid (FA) pulse-chase assays showed that membrane αKlotho deficiency in RTECs, as seen in αKlotho homozygous mutated (kl/kl) mice or in mice with ischemia-reperfusion injury (IRI)-induced AKI, inhibited FA mobilization from LDs by impairing adipose triglyceride lipase (ATGL)-mediated lipolysis and lipophagy. This resulted in LD accumulation and FA underutilization. IRI-induced alterations were more striking in αKlotho deficiency. Mechanistically, membrane αKlotho deficiency promoted E3 ligase peroxin2 binding to ubiquitin-conjugating enzyme E2 D2, resulting in ubiquitin-mediated degradation of ATGL which is a common molecular basis for lipolysis and lipophagy. Overexpression of αKlotho rescued FA mobilization by preventing ATGL ubiquitination, thereby lessening LD accumulation and fibrosis after AKI. This suggests that membrane αKlotho is indispensable for the maintenance of lipid homeostasis in RTECs. Thus, our study identified αKlotho as a critical regulator of lipid turnover and homeostasis in AKI, providing a viable strategy for preventing tubular injury and the AKI-to-chronic kidney disease transition.

B7-H4 is a potential diagnostic and prognostic biomarker in colorectal cancer and correlates with the epithelial-mesenchymal transition.

BACKGROUND: As a negative co-stimulatory molecule of the B7 family, B7-H4 has recently attracted increased attention. However, the clinical value of B7-H4 in colorectal cancer (CRC) remains controversial and requires further investigation. This study aimed to investigate the role of B7-H4 in the clinical diagnosis and survival prognosis of CRC. METHODS: The relationships between B7-H4 expression, immune cell infiltration, epithelial-mesenchymal transition (EMT), clinicopathological features, and survival prognosis were determined through the TCGA database and verified in a large CRC cohort (n = 1118). RESULTS: The results showed the level of B7-H4 mRNA expression was significantly increased in the CRC tumor tissues compared with normal tissues (P <  0.001). Immunohistochemistry showed that B7-H4 protein expression was also up-regulated in CRC. The positive rate of B7-H4 in CRC tumor tissues was 76.38%, which was significantly higher than that in non-tumor tissues (P <  0.001). Overexpression of B7-H4 was positively correlated with lymph node metastasis, advanced TNM stage, and poor tumor differentiation (P = 0.012; 0.009; 0.014). Prognostic analysis showed high B7-H4 expression was associated with significantly shorter OS. Multivariate analysis demonstrated the risk of death in CRC patients with high B7-H4 expression is 1.487 times that of low B7-H4 expression. In addition, B7-H4 expression was negatively correlated with the epithelial marker E-cadherin (P <  0.001) and positively correlated with the mesenchymal marker vimentin (P <  0.001) in CRC tissues. However, B7-H4 expression was not associated with the immunosuppressive microenvironment in CRC. CONCLUSION: B7-H4 may represent a potential biomarker for the diagnosis and prognosis of CRC and enhance CRC invasion by promoting EMT.

Efficacy of Three Renal Replacement Therapy Modalities for the Treatment of Acute Kidney Injury Caused by Wasp Sting.

BACKGROUND/AIM: This study mainly aimed to explore the therapeutic effects of 3 renal replacement therapy (RRT) modalities on acute kidney injury (AKI) caused by wasp stings. METHODS: A retrospective study from September 2016 to December 2019 was conducted. Thirty-one patients with AKIs caused by wasp sting were selected and divided into 3 groups according to the initial RRT modality received, namely, (1) the intermittent hemodialysis combined with hemoperfusion (IHD + HP) group, (2) the continuous veno-venous hemodiafiltration (CVVHDF) group, and (3) the CVVHDF combined with HP (CVVHDF + HP) group. The laboratory results were measured and analyzed before treatment on the 3rd, 7th, and 14th days of treatment. The renal function outcomes and survival of the patients were investigated at 3 months follow-up. RESULTS: The laboratory results of enzyme measures and inflammatory indicators in wasp sting patients increased significantly in the early stage and 3 RRT modalities were effective in reducing these indicators. In addition, continuous RRT modality (CVVHDF and CVVHDF + HP) showed better clearance of myoglobin than IHD + HP. The serum creatinine levels of patients in the 3 groups did not recover to baseline within 14 days after beginning treatment. Nevertheless, the CVVHDF + HP group was better than the CVVHDF group, and CVVHDF was better than the IHD + HP group on the 3rd day. The interleukin (IL)-6 and IL-10 levels in CVVHDF + HP and IHD + HP groups were obviously lower than those in the CVVHDF group on the 3rd day. In the follow-up study, the recovery rate of renal function in CVVHDF and CVVHDF + HP groups was significantly better than that in the IHD + HP group. CONCLUSION: Early RRT was effective in the treatment of patients with A KI caused by wasp sting. CVVHDF + HP and CVVHDF modalities were better than the IHD + HP group in venom clearance and renal function recovery.

Laser-induced graphene (LIG)-driven medical sensors for health monitoring and diseases diagnosis.

Laser-induced graphene (LIG) is a class of three-dimensional (3D) porous carbon nanomaterial. It can be prepared by direct laser writing on some polymer materials in the air. Because of its features of simplicity, fast production, and excellent physicochemical properties, it was widely used in medical sensing devices. This minireview gives an overview of the characteristics of LIG and LIG-driven sensors. Various methods for preparing graphene were compared and discussed. The applications of the LIG in biochemical sensors for ions, small molecules, microRNA, protein, and cell detection were highlighted. LIG-based physical physiological sensors and wearable electronics for medical applications were also included. Finally, our insights into current challenges and prospects for LIG-based medical sensing devices were presented.

E3 ubiquitin ligase PJA1 regulates lung adenocarcinoma apoptosis and invasion through promoting FOXR2 degradation.

Among all lung cancer cases, lung adenocarcinoma (LAC) represents nearly 40% and remains the leading cause of cancer deaths worldwide. Although the combination therapy of surgical treatment with radiotherapy, chemotherapy, and immunotherapy, has been used to treat LAC, unfortunately, high recurrence rates and poor survival remain. Therefore, novel prognostic markers and new targets for molecular targeted therapy in LAC is urgently needed. Fork-head box R2 (FOXR2) plays a key role in a wide range of cellular processes, including cellular proliferation, invasion, differentiation, and apoptosis, and it has been reported to be implicated in progression of LAC, thus inhibition of FOXR2 may be a novel targeting therapy for lung cancer. This current study found that E3 ligase PJA1 regulates ubiquitin-mediated degradation of FOXR2 and predicts good outcome of patients with LAC. In addition, it was showed force expression of PJA1 significantly inhibited LAC cells invasion and induced apoptosis in vitro through inactivating Wnt/ß-catenin signaling pathway. In short, our findings reveal that PJA1 could be a potential diagnostic and prognostic biomarkers and the PJA1- FOXR2 axis could be served as a promising target for LAC therapy.

Prevalence, characteristics, and distribution of HPV genotypes in women from Zhejiang Province, 2016-2020.

OBJECTIVE: To evaluate and understand the prevalence of HPV genotypes and characteristics of female populations in specific areas and the relationship with cervical lesions, which can effectively guide cervical cancer screening and formulate HPV vaccine prevention strategies. METHODS: A total of 77,443 women who visited gynecological clinics and underwent health examinations in the Second Affiliated Hospital of Zhejiang University School of Medicine during 2016-2020 were enrolled in this survey. Cervical samples were collected for HPV DNA genotyping and cervical cytology testing. Cervical biopsies were performed for patients with visible cervical abnormality or abnormal cytological results. RESULTS: The results showed the 5-year overall positive rate was 22.3%, of which the gynecology clinic group had significantly more positive results compared with the health examination group (P < 0.001). The five most common genotypes in Zhejiang Province were HPV 52, 58, CP8304, 16, and 51 (23.9%, 12.7%, 11.7%, 11.7% and 9.3%). HPV infection was age-specific, with the highest infection rate in the age group ≤ 20 compared to other age groups (P < 0.001). HPV infection was also season-specific, with the highest infection rate in spring or winter. The main HPV infection mode was single infection (P = 0.004), but patients ≤ 20 years old were more likely to develop multiple infections (51.0%). HPV 16, 52 and 58 were the main genotypes that caused cytological abnormalities and HPV16, 18, 56, 58 and 66 were independent risk factors for cervical lesions (OR = 2.352, 1.567, 2.000, 1.694, 1.889; all P < 0.05). Further analysis found HPV 16 and 18 were the main genotypes that cause cervical cancer histological abnormalities and were independent risk factors for cervical cancer (OR = 5.647, P < 0.001; OR = 3.495, P = 0.036). CONCLUSION: This article analyzed the prevalence of distribution characteristics of HPV infection and revealed the corelation between HPV infection and cytological and histological abnormalities. Comprehensive results of this survey will help Zhejiang Province to formulate public health policies and provide evidence for future selection of specific HPV vaccines.

Xeno nucleic acid probes mediated methylation-specific PCR for single-base resolution analysis of N6-methyladenosine in RNAs.

Reliable and cost-effective quantification of RNA modifications at a specific gene locus is essential to elucidate the pathogenic mechanism encoded by RNA epigenetics. Current methods to quantify N6-methyladenosine (m6A) at specific sites can hardly satisfy the requirement of clinical application because epigenetic information is easily lost through polymerase chain reaction (PCR) assay or other isothermal amplification methods unless tedious pretreatment is applied. Herein, we propose a simple xeno nucleic acid (XNA) as a blocker probe to mediate the methylation specific reverse transcription quantitative polymerase chain reaction (MsRT-qPCR) assay to directly magnify the minor differences between epigenetic bases and unmodified bases in RNA. Strand displacement reactions selectively initiated between the reverse transcription primer (RT-primer) and the XNA probe at the m6A template given the affinity differences between the blocker probes and the m6A-modified RNA (m6A-RNA) and unmodified RNA (A-RNA). Thus, preferential amplification of m6A-RNA was allowed. Integration of a well-established oligo-modified Fe3O4@UiO-66-NH4 allowed purification of mRNA and lncRNA from cellular total RNA samples and greatly reduced the non-specific interference of m6A detection in real samples. Multiple specific sites of m6A in mRNA and lncRNA samples are also successfully quantified. The XNA probe-based m6A assay required only common and available lab equipment and materials, which can be applied in m6A-related fundamental studies and clinical diagnosis.

RNF115-mediated ubiquitination of p53 regulates lung adenocarcinoma proliferation.

Lung adenocarcinoma (LAC) represents approximately 40% of all lung cancer cases and is the leading cause of cancer-associated mortality worldwide. Although combined treatment, including radiotherapy, chemotherapy, surgical treatment and immunotherapy, has been used in treating LAC, the five-year survival rate of patients with LAC has not significantly improved. Therefore, it is vital for cancer research to investigate novel prognostic markers and new targets for molecular targeted therapy in LAC. TP53 is an important tumor suppressor gene and is frequently inactivated in lung cancer, thus upregulation or activation of p53 may be a novel targeted therapy for LAC. The present study found that RNF115 mediates ubiquitination of p53 and predicts poor prognosis of patients with LAC. Functionally, it was demonstrated that disruption of RNF115 significantly inhibited cell viability in vitro through inducing G1 phase arrest of LAC cells, which reduced tumor growth in an xenograft model. Taken together, these results suggest that RNF115 could be a novel prognostic biomarker and the RNF115-p53 axis may be a potential target for LAC therapy.

Browning of white adipose tissue induced by the ß3 agonist CL-316,243 after local and systemic treatment - PK-PD relationship.

Transformation of white adipose tissue (WAT) to a brown adipose tissue-like (BAT-like) phenotype has emerged as an attractive approach against obesity e.g. using g ß3 adrenergic receptor agonists. These could however, produce side-effects following systemic exposure. The present study explored the possibility of local use of CL-316,243 - a selective ß3 agonist - to circumvent this problem. Rats treated s.c. for 2 weeks (0.3 and 1 mg/kg) showed decreased inguinal fat pad (IFP) weight/volume, increased UCP-1 staining and expressed BAT-like features in H&E stained micrographs. Interscapular BAT increased in weight/volume. In contrast, local treatment into the IFP was not efficacious in terms of weight/volume, despite slight increases in UCP-1 staining and changes in histological features. After local treatment, the exposure of the IFP was lower than after systemic treatment. In turn higher local doses (0.5 and 5 mg/ml) were then tested which produced a strong trend for decreased volume of the IFP, a significant increase in UCP-1 staining, and also a decrease in adipocytes size but increased number. However, after this treatment the systemic exposure was in the same range as following systemic treatment. In conclusion, we saw no evidence for the possibility of converting inguinal WAT to a BAT-phenotype solely through local activation of ß3 receptors. This is in concert with our in vitro experiments which detected direct effects of PPARγ agonists at the gene/protein expression and functional level, but were unable to detect any effect of CL-316,243.

Nitrogen-rich salts based on the energetic [monoaquabis(N,N-bis(1H-tetrazol-5-yl)amine)-zinc(II)] anion: a promising design in the development of new energetic materials.

Nitrogen-rich energetic salts involving various cations (lithium, 1; ammonium, 2; hydrazinium, 3; hydroxylammonium, 4; guanidinium, 5; aminoguanidinium, 6; diaminoguanidinium, 7; and triaminoguanidinium, 8) based on nitrogen-rich anion [Zn(BTA)2(H2O)](2-) (N% = 65.37, BTA = N,N-bis[1H-tetrazol-5-yl]amine anion) were synthesized with a simple method. The crystal structures of all compounds except 1, 2, and 6 were determined by single-crystal X-ray diffraction and fully characterized by elemental analysis and FT-IR spectroscopy. The thermal stabilities were investigated by differential scanning calorimetry (DSC). The DSC results show that all compounds exhibit high thermal stabilities (decomposition temperature >200 °C). Additionally, the heats of formation were calculated on the basis of the experimental constant-volume energies of combustion measured by using bomb calorimetry. Lastly, the sensitivities toward impact and friction were assessed according to Bundesamt für Materialforschung (BAM) standard methods.

CagA, a major virulence factor of Helicobacter pylori, promotes the production and underglycosylation of IgA1 in DAKIKI cells.

While Helicobacter pylori (Hp) infection is closely associated with IgA nephropathy (IgAN), the underlying molecular mechanisms remain to be elucidated. This study was to investigate the effect of cytotoxin associated gene A protein (CagA), a major virulence factor of Hp, on the production and underglycosylation of IgA1 in the B cell line DAKIKI cells. Cells were cultured and treated with recombinant CagA protein. We found that CagA stimulated cell proliferation and the production of IgA1 in a dose-dependent and time-dependent manner. Moreover, CagA promoted the underglycosylation of IgA1, which at least partly attributed to the downregulation of ß1,3-galactosyltransferase (C1GALT1) and its chaperone Cosmc. In conclusion, we demonstrated that Hp infection, at least via CagA, may participate in the pathogenesis of IgAN by influencing the production and glycosylation of IgA1 in B cells.

Invert global and China's terrestrial carbon fluxes over 2019-2021 based on assimilating richer atmospheric CO2 observations.

With China's commitment to reach carbon peak by 2030 and achieve carbon neutrality by 2060, it is particularly important to obtain terrestrial ecosystem carbon fluxes with low uncertainty both globally and in China. The use of more observation data may help reduce the uncertainty of inverting carbon fluxes. This study uses the observation data from global stations, background stations and provincial stations in China, as well as the OCO-2 satellite, and uses the China Carbon Monitoring, Verification and Supporting System for Global (CCMVS-G) to estimate the carbon fluxes of global and Chinese terrestrial ecosystems from 2019 to 2021. The results revealed that the global terrestrial ecosystem carbon sink was approximately -3.40 Pg C/yr from 2019 to 2021. The carbon sinks in the Northern Hemisphere are large, especially in Asia, North America, and Europe. From 2019 to 2021, the carbon sink of China's terrestrial ecosystem was approximately -0.44 Pg C/yr. Carbon sinks exhibit significant seasonal and interannual variations in China. After assimilating the observation data, the uncertainty of the posterior flux is smaller than that of the prior flux, a more reasonable distribution of carbon sources and sinks can be obtained, and more accurate boundary conditions can be provided for the China Carbon Monitoring, Verification and Supporting System for Regional (CCMVS-R). In the future, it is important to establish a well-designed CO2 ground-based observation network.

Ortho Effects of Tricarboxylate Linkers in Regulating Topologies of Rare-Earth Metal-Organic Frameworks.

A linker design strategy is developed to attain novel polynuclear rare-earth (RE) metal-organic frameworks (MOFs) with unprecedented topologies. We uncover the critical role of ortho-functionalized tricarboxylate ligands in directing the construction of highly connected RE MOFs. The acidity and conformation of the tricarboxylate linkers were altered by substituting with diverse functional groups at the ortho position of the carboxyl groups. For instance, the acidity difference between carboxylate moieties resulted in forming three hexanuclear RE MOFs with novel (3,3,3,10,10)-c wxl, (3,12)-c gmx, and (3,3,3,12)-c joe topologies, respectively. In addition, when a bulky methyl group was introduced, the incompatibility between the net topology and ligand conformation guided the co-appearance of hexanuclear and tetranuclear clusters, generating a novel 3-periodic MOF with a (3,3,8,10)-c kyw net. Interestingly, a fluoro-functionalized linker prompted the formation of two unusual trinuclear clusters and produced a MOF with a fascinating (3,8,10)-c lfg topology, which could be gradually replaced by a more stable tetranuclear MOF with a new (3,12)-c lee topology with extended reaction time. This work enriches the polynuclear clusters library of RE MOFs and unveils new opportunities to construct MOFs with unprecedented structural complexity and vast application potential.

Evaluation of qSOFA score, and conjugated bilirubin and creatinine levels for predicting 28-day mortality in patients with sepsis.

Sepsis is a dangerous disease that develops rapidly and has a high mortality rate. A timely and accurate assessment of the patient's condition is beneficial in improving prognosis and reducing mortality. Therefore, the present study was designed to investigate the potential association between quick sequential organ failure assessment (qSOFA) scores and biochemical indicators, such as conjugated bilirubin (CB) and creatinine levels, with the 28-day prognosis of patients with sepsis in a retrospective observational study. All cases were divided into survival and non-survival groups on the 28th day after diagnosis. The qSOFA scores, and CB and creatinine levels were significantly higher in the non-survival group than in the survival group (both P<0.01). Cox regression models identified CB [hazard ratio (HR), 1.006; P=0.002] and creatinine levels (HR, 1.002; P=0.024) as independent factors affecting 28-day mortality. The area under the curve (AUC) for CB and creatinine levels plus qSOFA score was 0.792 (95% confidence interval, 0.745-0.834), which was larger than the values for CB level, creatinine level and qSOFA score alone (all P<0.01) in the prognosis of 28-day mortality. The cut-off value of CB and creatinine levels plus qSOFA score for the 28-day mortality was 0.275 (-2.466 + 0.012 x CB + 0.002 x creatinine + 1.289 x qSOFA). Patients with lower combined predictor values had a better prognosis as demonstrated by Kaplan-Meier survival curves (log-rank test, 10.060; P=0.002). In both the septic shock and sepsis groups, the combined predictor value was higher in the non-survival group than in the survival group (P<0.001). Therefore, an increase in the combined predictor value of CB and creatinine levels plus qSOFA score may be an important predictor of disease progression and prognosis in patients with sepsis and septic shock.

A simultaneously quantitative profiling method for 40 endogenous amino acids and derivatives in cell lines using hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry.

Endogenous metabolites of amino acids and their derivatives in biosamples are frequently highlighted as the most differential metabolites in recent metabolomics studies. The method for the detection of amino acid derivatives such as N-acetyl amino acids and oligopeptides is rarely reported. We developed a rapid, high-throughput, sensitive and reliable quantitative method to simultaneously profile 40 underivatized amino acids and their derivatives including N-acetyl amino acids and oligopeptides in cell lines, based on ultra-high-performance liquid chromatography-electrospray tandem mass spectrometry (UHPLC- MS/MS) by using a hydrophilic interaction liquid chromatography (HILIC) column. The optimized method was successfully validated with satisfactory linearity, sensitivity, accuracy, precision, matrix effects, recovery and stability for all analytes. Only one compound (cysteine-glutathione disulfide) showed relatively low recoveries at three concentration levels (60.8-74.3%). The limit of quantification (LOQ) for most compounds was in the range of 0.6-10 ng/mL (6-100 pg on column). This method was successfully applied to the analysis of amino acids and their derivatives in breast cancer cell samples. Principal component analysis (PCA) and the orthogonal projections to latent structures (OPLS) showed a clear discrimination of the non-tumorigenic breast epithelial cell line MCF-10A from the breast cancer cell line HCC 1806. Characteristic metabolic changes in amino acid metabolism were observed in the breast cancer cell line. This quantified analytical method of 40 endogenous amino acids and their derivatives in cell lines meets the requirement of quantification in specific expanded metabolomics studies with good sensitivity.

Duration of a "Brown-Like" Phenotype of White Adipose Tissue Induced by the ß3 Agonist CL-316,243.

"Browning" i. e. the transformation of white adipose tissue into brown-like adipose tissue could induce efficient burning of excess fat reserves via induction of non-shivering thermogenesis. For example, activation of ß3 adrenergic receptors has been show to induce such changes, however, it is still not clear, how long after termination of such a treatment, beneficial effects might be maintained. To address this question, we treated rats s.c. for 2 weeks with the ß3 agonist CL-316,243 at 1 mg/kg and assessed interscapular brown fat and inguinal white fat pads weight, UCP-1 (a marker for the brown-like fat phenotype) using immunohistochemistry and H&E staining, at different intervals after treatment termination.One 1 day after the treatment cessation there was a decrease of inguinal white fat pad weight and increase of interscapular fat pad. This change vanished at 7 days for inguinal pad and at 14 days for interscapular pad. Histological analysis of interscapular pads showed increased UCP-1 staining and brown-like morphology in H&E staining slices at 1 day, but not other time points. In case of inguinal pad there were brown-like features in H&E slices at 1 day and less after 7 days, but absent at 14 days. UCP-1 staining was only detected 1 day after the treatment.In conclusion, the present results indicate that browning-like changes of white fat may be short lasting after treatment termination and could require maintenance treatment of inductor to achieve desired therapeutic effect. This might be a serious shortcoming of potential therapeutic use.

Elevated cytokine levels associated with acute kidney injury due to wasp sting.

This study mainly to explore the change of serum cytokines in wasp sting patients and the potential correlation between cytokines and acute kidney injury (AKI) due to wasp stings. The levels of IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ in 33 wasp sting and 24 healthy people were measured by flow cytometry, the level of IL-17 was detected by enzyme-linked immunosorbent assay and the laboratory examination including inflammatory indicators, muscle enzyme markers, and renal function were detected by automatic biochemical analyzer, blood analyzer, and urine analyzer. The wasp sting patients were divided into AKI (n = 10) and non-AKI groups (n = 23). The correlation between the levels of serum cytokines and laboratory examination results was analyzed. The levels of IL-2, IL-6, IL-10, IFN-γ, and IL-17 were statistically increased in wasp sting patients compared with the controls (P < 0.05). IL-6, IL-10, and IL-17 levels were markedly increased in the AKI group compared with the non-AKI group (P < 0.05). Moreover, compared with non-AKI group, inflammatory markers and muscle enzyme markers were more abnormal in the AKI group. The positive rate of urinary occult blood in the AKI group was higher than that in the non-AKI group. The levels of IL-2, IL-4, IL-6, IFN-γ, and IL-17 correlated positively with white blood cell counts. The levels of IL-2, IL-4, IL-10, IFN-γ, and IL-17 correlated positively with the levels of serum creatinine. The levels of IL-2, IL-4, IL-10, IL-10, and IFN-γ correlated positively with the levels of C-reactive protein. The levels of IL-10, and IFN-γ correlated positively with urinary occult blood. Conclusion: Elevated levels of cytokines in wasp sting patients might be involved in the development and progression of acute kidney injury.

Cooperative Sieving and Functionalization of Zr Metal-Organic Frameworks through Insertion and Post-Modification of Auxiliary Linkers.

A major goal of metal-organic framework (MOF) research is to control the structures and functions of materials in accordance with their specific applications. However, due to the flexible coordination modes between metal ions and organic linkers in MOFs, it is still challenging to rationally assemble a framework with deliberate structures and desired functional groups. Sometimes, two or more phases coexist in a one-pot reaction, making them difficult to separate. To this end, sieving and purification of MOF mixtures become vital for the following application. Herein, we demonstrate that the formation of zirconium-based MOFs (Zr-MOFs) can be regulated in a wider two-dimensional scale by thermodynamics using auxiliary linkers. The auxiliary linkers favor the formation of the targeted Zr-MOF by selectively binding to its coordination vacancies and therefore increasing its formation enthalpy to achieve the sieving of MOF mixture. Furthermore, the resulting mixed-linkers MOFs not only maintain porosities but also contain the installed auxiliary linkers as chemical handles to further incorporate functional groups, providing the possibility of introduction of active sites through post-modification. Finally, this synthetic strategy was applied to assemble a cooperative catalytic system in a MOF platform for CO2 cycloaddition with epoxides. To the best of our knowledge, this is the first example of sieving and functionalization of MOFs through insertion and post-modification of auxiliary linkers.

A simultaneously quantitative method to profiling twenty endogenous nucleosides and nucleotides in cancer cells using UHPLC-MS/MS.

Endogenous nucleosides and nucleotides in biosamples are frequently highlighted as the most differential metabolites in recent metabolomics studies. We developed a rapid, sensitive, high-throughput and reliable quantitative method to simultaneously profile 20 endogenous nucleosides and nucleotides in cancer cell lines based on ultra-high performance liquid chromatography-electrospray tandem mass spectrometry (UHPLC- MS/MS) by using a porous graphitic carbon column and basic mobile phase. The results indicated that high pH value of mobile phase containing 0.12% diethylamine (DEA) and 5mM NH4OAC (pH 11.5) was the critical factor to prevent the adsorption of multi-phosphorylated species, and significantly improved peak shape and sensitivity. The optimized method was successfully validated with satisfactory linearity, sensitivity, accuracy, precision, matrix effects, recovery and stability for all analytes. The limit of quantification (LOQ) was in the range of 0.6-6nM (6-60 fmol on column). The validated method was applied to the extract of three epithelial cancer cell lines, and the significant difference in the profiling of the nucleosides and nucleotides among the cancer cell lines enables discrimination of breast cancer cell line from the colon cancer cell line and the lung cancer cell line. This quantified analytical method of 20 endogenous nucleosides and nucleotides in cancer cell lines meets the requirement of quantification in specific expanded metabolomics studies, with good selectivity and sensitivity.

Rational Design, Synthesis, and Pharmacological Characterization of Novel Ghrelin Receptor Inverse Agonists as Potential Treatment against Obesity-Related Metabolic Diseases.

A new chemotype of ghrelin inverse agonists was discovered through chimeric design based on molecular scaffolds known as growth-hormone secretagogue receptor (GHSR) modulators but with divergent pharmacodynamic and pharmacokinetic properties. The structure-activities/properties exploration led to compound 47, which displayed potent human GHSR antagonism and inverse agonism in cellular assays (IC50 = 68 nM, EC50 = 29 nM), moderate oral bioavailability, and notable brain penetration in rat ( F = 27%, B/ P ratio = 1.9). First in vivo studies demonstrated effective reduction of food intake after oral or parenteral administration to mouse (78% at 1 h and 38% at 8 h, respectively). Further preclinical studies are needed to evaluate the most suited mode of administration with the aim of promoting a first central-acting ghrelin inverse agonist molecule to development, which would represent a significant step toward therapeutic agents to treat metabolic disorders related to obesity, such as type 2 diabetes mellitus.