The Noonan Syndrome Gene Lztr1 Controls Cardiovascular Function by Regulating Vesicular Trafficking.

RATIONALE: Noonan syndrome (NS) is one of the most frequent genetic disorders. Bleeding problems are among the most common, yet poorly defined complications associated with NS. A lack of consensus on the management of bleeding complications in patients with NS indicates an urgent need for new therapeutic approaches. OBJECTIVE: Bleeding disorders have recently been described in patients with NS harboring mutations of LZTR1 (leucine zipper-like transcription regulator 1), an adaptor for CUL3 (CULLIN3) ubiquitin ligase complex. Here, we assessed the pathobiology of LZTR1-mediated bleeding disorders. METHODS AND RESULTS: Whole-body and vascular specific knockout of Lztr1 results in perinatal lethality due to cardiovascular dysfunction. Lztr1 deletion in blood vessels of adult mice leads to abnormal vascular leakage. We found that defective adherent and tight junctions in Lztr1-depleted endothelial cells are caused by dysregulation of vesicular trafficking. LZTR1 affects the dynamics of fusion and fission of recycling endosomes by controlling ubiquitination of the ESCRT-III (endosomal sorting complex required for transport III) component CHMP1B (charged multivesicular protein 1B), whereas NS-associated LZTR1 mutations diminish CHMP1B ubiquitination. LZTR1-mediated dysregulation of CHMP1B ubiquitination triggers endosomal accumulation and subsequent activation of VEGFR2 (vascular endothelial growth factor receptor 2) and decreases blood levels of soluble VEGFR2 in Lztr1 haploinsufficient mice. Inhibition of VEGFR2 activity by cediranib rescues vascular abnormalities observed in Lztr1 knockout mice Conclusions: Lztr1 deletion phenotypically overlaps with bleeding diathesis observed in patients with NS. ELISA screening of soluble VEGFR2 in the blood of LZTR1-mutated patients with NS may predict both the severity of NS phenotypes and potential responders to anti-VEGF therapy. VEGFR inhibitors could be beneficial for the treatment of bleeding disorders in patients with NS.

Stress-induced lncRNA LASTR fosters cancer cell fitness by regulating the activity of the U4/U6 recycling factor SART3.

Dysregulated splicing is a common event in cancer even in the absence of mutations in the core splicing machinery. The aberrant long non-coding transcriptome constitutes an uncharacterized level of regulation of post-transcriptional events in cancer. Here, we found that the stress-induced long non-coding RNA (lncRNA), LINC02657 or LASTR (lncRNA associated with SART3 regulation of splicing), is upregulated in hypoxic breast cancer and is essential for the growth of LASTR-positive triple-negative breast tumors. LASTR is upregulated in several types of epithelial cancers due to the activation of the stress-induced JNK/c-JUN pathway. Using a mass-spectrometry based approach, we identified the RNA-splicing factor SART3 as a LASTR-interacting partner. We found that LASTR promotes splicing efficiency by controlling SART3 association with the U4 and U6 small nuclear ribonucleoproteins (snRNP) during spliceosome recycling. Intron retention induced by LASTR depletion downregulates expression of essential genes, ultimately decreasing the fitness of cancer cells.

A risk-based approach for the safety analysis of eight trace elements in Chinese flowering cabbage (Brassica parachinensis L.) in China.

BACKGROUND: Most countries set regulatory values for the total trace element (TE) concentrations in soil, although there is growing interest in using a risk-based approach to evaluate the bioavailable TE using dilute salt extractants or other soil parameters, including pH and organic carbon. The present study compares the current regulatory system (based on total TEs and pH) and a risk-based approach using 0.01 mol L-1 CaCl2 to estimate the bioavailable fraction. RESULTS: In total, 150 paired samples of Chinese flowering cabbages (Brassica parachinensis) and their growth soils were collected, and the total and extractable concentrations of chromium (Cr), cadmium (Cd), lead (Pb), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As) and mercury (Hg), as well as soil pH and organic matter content, were measured. No more than 3.33% of the edible parts exceeded Chinese food safety standards, even when growing in soils exceeding the current regulatory thresholds by over 50%. The total soil Cd (1.5 mg kg-1 ), as well as the extractable concentrations of Cd (0.1 mg kg-1 ), Ni (0.03 mg kg-1 ) and Zn (0.1 mg kg-1 ), are the key factors affecting the TE concentrations in B. parachinensis. CONCLUSION: Our findings suggest that the current soil regulatory guidelines for safe production of B. parachinensis are overly strict and conservative. A risk-based approach based on the extractable TE concentrations would provide a better indication for plant uptake of soil TEs and avoid the waste of farmlands that can still produce safe vegetables. Future research should focus on providing crop-specific available TE concentration guidelines to promote effective utilization of farmlands. © 2021 Society of Chemical Industry.

Radiosensitization approaches for HPV-positive and HPV-negative head and neck squamous carcinomas.

Radiotherapy is one of the most used treatment approaches for head and neck squamous cell carcinoma (HNSCC). Targeted inhibition of DNA repair machinery has the potential to improve treatment response by tailoring treatment to cancer cells lacking specific DNA repair pathways. Human papillomavirus (HPV)-negative and HPV-positive HNSCCs respond differently to radiotherapy treatment, suggesting that different approaches of DNA repair inhibition should be employed for these HNSCC groups. Here, we searched for optimal radiosensitization approaches for HPV-positive and HPV-negative HNSCCs by performing a targeted CRISPR-Cas9 screen. We found that inhibition of base excision repair resulted in a better radiotherapy response in HPV-positive HNSCC, which is correlated with upregulation of genes involved in base excision repair. In contrast, inhibition of nonhomologous end-joining and mismatch repair showed strong effects in both HNSCC groups. We validated the screen results by combining radiotherapy with targeted inhibition of DNA repair in several preclinical models including primary and recurrent patient-derived HNSCC xenografts. These findings underline the importance of stratifying HNSCC patients for combination treatments.

Sterically Stabilized Terminal Hydride of a Diiron Dithiolate.

The kinetically robust hydride [t-HFe2(Me2pdt)(CO)2(dppv)2]+ ([t-H1]+) (Me2pdt2- = Me2C(CH2S-)2; dppv = cis-1,2-C2H2(PPh2)2) and related derivatives were prepared with 57Fe enrichment for characterization by NMR, FT-IR, and NRVS. The experimental results were rationalized using DFT molecular modeling and spectral simulations. The spectroscopic analysis was aimed at supporting assignments of Fe-H vibrational spectra as they relate to recent measurements on [FeFe]-hydrogenase enzymes. The combination of bulky Me2pdt2- and dppv ligands stabilizes the terminal hydride with respect to its isomerization to the 5-16 kcal/mol more stable bridging hydride ([µ-H1]+) with t1/2(313.3 K) = 19.3 min. In agreement with the nOe experiments, the calculations predict that one methyl group in [t-H1]+ interacts with the hydride with a computed CH···HFe distance of 1.7 Å. Although [t-H571]+ exhibits multiple NRVS features in the 720-800 cm-1 region containing the bending Fe-H modes, the deuterated [t-D571]+ sample exhibits a unique Fe-D/CO band at ∼600 cm-1. In contrast, the NRVS spectra for [µ-H571]+ exhibit weaker bands near 670-700 cm-1 produced by the Fe-H-Fe wagging modes coupled to Me2pdt2- and dppv motions.

Comparison of foliar silicon and selenium on cadmium absorption, compartmentation, translocation and the antioxidant system in Chinese flowering cabbage.

Silicon (Si) and selenium (Se) are beneficial for many higher plants when grown on stress conditions. However, the mechanisms underlying the differential effects between foliar Si and Se in alleviation of plant toxicity exposed to cadmium (Cd) stress are remained unclear. In this study, we investigated the discrepant mechanisms of foliar Si and Se on Cd absorption and compartmentation by roots, its translocation in xylem, and the antioxidant system within Chinese flowering cabbage (Brassica campestris L. ssp. chinensis var. utilis) under low and high Cd stress. Results showed that plant growth was significantly enhanced by foliar additions of Si or/and Se according to an increased plant tissue biomass at high Cd exposure. In addition, the foliar coupled addition of Si and Se showed little effects on the concentrations of Si or Se in plant tissues in comparison with the single addition of foliar Si or Se respectively. The foliar Si alone or combined with Se markedly reduced the Cd concentrations in plant shoots under two Cd treatments. This might be explained by the lower Cd concentrations in symplast and apoplast and the higher Cd concentrations in cell walls of plant roots, and the lower Cd concentrations in xylem sap. However, no great changes in these values were observed under the treatments of foliar Se alone. Moreover, the foliar additions of Si or/and Se all increased the antioxidant enzyme activities of SOD, CAT and APX in plant tissues, especially at high Cd dosage. No significant differences in the increasing degrees of these three antioxidant enzymes were found between the foliar Si and Se treatments. However, only the foliar Se alone or combined with Si markedly promoted the antioxidant enzyme activities of GR and DHAR in plant tissues. Our findings demonstrate that the alleviation of Cd toxicity by foliar Si maybe mainly responsible for inhibition of Cd absorption and its translocation to plant shoots, reinforcing its compartmentation into root cell walls, whilst enhancing the antioxidant enzyme system may be employed by foliar Se.

Rational Synthesis of the Carbonyl(perthiolato)diiron [Fe2(S3CPh2)(CO)6] and Related Complexes.

The photochemical reaction of Fe2(S2)(CO)6 and Ph2CS affords the perthiolate Fe2(S3CPh2)(CO)6 (1) in good yield. As confirmed crystallographically, 1 contains a previously elusive perthiolate ligand. The related reaction of Fe2(S2)(CO)5-(PPh3) and Ph2CS gave Fe2(S3CPh2)(CO)5(PPh3). Although Fe3S2(CO)9 and Ph2CS failed to efficiently give Fe2(S2CPh2)(CO)6, this compound could be prepared by desulfurization of 1 using PPh3.

Synthesis of self-supported NiCoFe(OH)x via fenton-like effect corrosion for highly efficient water oxidation.

Efficientandinexpensiveoxygenevolutionreaction(OER)catalysts are essential for the electrochemical splitting of water into hydrogen fuel. Herein, we have successfully synthesized NiCoFe(OH)x nanosheets on Ni-Fe foam (NFF) by exploiting the Fenton-like effect of Co2+ and S2O82- to corrode the NFF foam. The as-prepared NiCoFe(OH)x/NFF exhibits the porous structure with the interconnected nanosheets that are firmly bonded to the conductive substrate of NFF, thereby enhancing ions and charge transfer kinetics. The unique structure and composition of NiCoFe(OH)x/NFF result in the low overpotentials of 200 and 262 mV at current densities of 10 and 100 mA cm-2, respectively, as well as a low Tafel slope of 53.25 mV dec-1. In addition, NiCoFe(OH)x/NFF displays low overpotentials of 267 and 294 mV at a high current density of 100 mA cm-2 in simulated and real seawater, respectively. Furthermore, the assembled NiCoFe(OH)x//Pt/C water electrolysis cell has achieved a current density of 10 mA cm-2 at a low voltage of 1.49 V, and displayed the good stability with slight attenuation for 110 h. The high OER performance of NiCoFe(OH)x is attributed to the co-catalytic effect of the three metal ions and the interconnected porous nanosheet structure.

Facile synthesis of amorphous/crystalline Ni-Fe thiophenedicarboxylate coordination polymer nanobelts for efficient water oxidation.

The oxygen evolution reaction (OER) is a complex four-electron transfer process that poses a significant challenge to the efficient production of hydrogen through water splitting. However, developing non-noble metal electrocatalyst with excellent OER performance is still a big challenge. Herein, we propose a new strategy for the in-situ growth of two-dimensional amorphous/crystalline thiophene-based Ni-Fe metal-organic frameworks (MOFs) using Ni-Fe foam (NFF) as metal source and current collector, and thiophene-2,5-dicarboxylic acid (TDC) as corrosion agent and ligand. TDC was ionized at high temperature to produce H+ ions that etch NFF to release Ni2+ and Fe2+ ions, which were coordinated with TDC to in situ synthesize two-dimensional Ni-Fe thiophenedicarboxylate coordination polymer (NiFe-TDC) nanobelts on NFF. The unique structure and synergistic effect of Ni and Fe ions of NiFe-TDC0.05 result in the excellent OER performance with an overpotential of 224 and 256 mV at current densities of 10 and 100 mA cm-2, respectively, and it can run stably for 100 h at a current density of 100 mA cm-2, indicating the outstanding stability. Furthermore, NiFe-TDC0.05 remains the excellent OER performance with an extremely low potential of 196 and 271 mV at current densities of 10 and 100 mA cm-2 in seawater with 1 mol L-1 (M) KOH, respectively. The assembled NiFe-TDC0.05 || Pt/C water electrolysis cell achieves a current density of 100 mA cm-2 at a low voltage of 1.78 V. The work provides a new method to prepare two dimensional MOFs for efficient water oxidation.

Research on the Shale Reservoir Sensitivity by Using the Mineral Analysis Method.

Shale reservoirs have diverse mineral types, and analyzing the sensitivity of the mineral composition to shale pores is of great scientific and engineering significance. In this paper, first, X-ray diffraction (XRD) experiments on shale mineral compositions are carried out, and the characteristics of pore structure changes after shale mineral compositions interacted with external fluids (slick water and backflow fluid) are elucidated. Then, the effects of quartz, kaolinite, and pyrite on the pore structure and permeability of shale on the susceptibility to slick water are studied. The results show that (a) quartz and clay minerals are the dominant constituents of each core, with some cores containing minor amounts of plagioclase feldspar and rhodochrosite. (b) The composition of the shale changed significantly following the action of external fluids. The average quartz content of pure shale decreased from 31.62% to 29.1%. The average content of quartz in siliceous shale decreased from 36.53% to 33.5%. The average content of quartz in carbonaceous shale decreased from 9.15% to 8.05%. (c) Factors affecting the sensitivity of shale pore structure and permeability to slick water are mainly quartz, kaolinite, and pyrite. The contents of quartz, kaolinite, and pyrite decreased by an average of 5.1%, 4.6%, and 0.9%, respectively, after slick water action.

Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer.

Activating mutations in PIK3CA are frequently found in estrogen-receptor-positive (ER+) breast cancer, and the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with anti-ER inhibitors is approved for therapy. We have previously demonstrated that the PI3K pathway regulates ER activity through phosphorylation of the chromatin modifier KMT2D. Here, we discovered a methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding and alpelisib-mediated changes in gene expression, including ER-dependent transcription. Knockdown or pharmacological inhibition of SMYD2 sensitizes breast cancer cells, patient-derived organoids, and tumors to PI3K/AKT inhibition and endocrine therapy in part through KMT2D K1330 methylation. Together, our findings uncover a regulatory crosstalk between post-translational modifications that fine-tunes KMT2D function at the chromatin. This provides a rationale for the use of SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors in the treatment of ER+/PIK3CA mutant breast cancer.

TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer.

PURPOSE: TIPRL1 (target of rapamycin signaling pathway regulator-like 1) is a known interactor and inhibitor of protein phosphatases PP2A, PP4 and PP6 - all pleiotropic modulators of the DNA Damage Response (DDR). Here, we investigated the role of TIPRL1 in the radiotherapy (RT) response of Head and Neck Squamous Cell Carcinoma (HNSCC). METHODS: TIPRL1 mRNA (cBioportal) and protein expression (immunohistochemistry) in HNSCC samples were linked with clinical patient data. TIPRL1-depleted HNSCC cells were generated by CRISPR/Cas9 editing, and effects on colony growth, micronuclei formation (microscopy), cell cycle (flow cytometry), DDR signaling (immunoblots) and proteome (mass spectrometry) following RT were assessed. Mass spectrometry was used for TIPRL1 phosphorylation and interactomics analysis in irradiated cells. RESULTS: TIPRL1 expression was increased in tumor versus non-tumor tissue, with high tumoral TIPRL1 expression associating with lower locoregional control and decreased survival of RT-treated patients. TIPRL1 deletion in HNSCC cells resulted in increased RT sensitivity, a faster but prolonged cell cycle arrest, increased micronuclei formation and an altered proteome-wide DDR. Upon irradiation, ATM phosphorylates TIPRL1 at Ser265. A non-phospho Ser265Ala mutant could not rescue the increased radiosensitivity phenotype of TIPRL1-depleted cells. While binding to PP2A-like phosphatases was confirmed, DNA-dependent protein kinase (DNA-PKcs), RAD51 recombinase and nucleosomal histones were identified as novel TIPRL1 interactors. Histone binding, although stimulated by RT, was adversely affected by TIPRL1 Ser265 phosphorylation. CONCLUSIONS: Our findings underscore a clinically relevant role for TIPRL1 and its ATM-dependent phosphorylation in RT resistance through modulation of the DDR, highlighting its potential as a new HNSCC predictive marker and therapeutic target.

Breast tumors interfere with endothelial TRAIL at the premetastatic niche to promote cancer cell seeding.

Endothelial cells (ECs) grant access of disseminated cancer cells to distant organs. However, the molecular players regulating the activation of quiescent ECs at the premetastatic niche (PMN) remain elusive. Here, we find that ECs at the PMN coexpress tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its cognate death receptor 5 (DR5). Unexpectedly, endothelial TRAIL interacts intracellularly with DR5 to prevent its signaling and preserve a quiescent vascular phenotype. In absence of endothelial TRAIL, DR5 activation induces EC death and nuclear factor κB/p38-dependent EC stickiness, compromising vascular integrity and promoting myeloid cell infiltration, breast cancer cell adhesion, and metastasis. Consistently, both down-regulation of endothelial TRAIL at the PMN by proangiogenic tumor-secreted factors and the presence of the endogenous TRAIL inhibitors decoy receptor 1 (DcR1) and DcR2 favor metastasis. This study discloses an intracrine mechanism whereby TRAIL blocks DR5 signaling in quiescent endothelia, acting as gatekeeper of the vascular barrier that is corrupted by the tumor during cancer cell dissemination.

(E)-1-Phenyl-3-[4-(trifluoro-meth-yl)phen-yl]prop-2-en-1-one.

In the title compound, C(16)H(11)F(3)O, the dihedral angle between the two rings is 48.8 (2)°. The crystal packing exhibits no classical inter-molecular inter-actions between the mol-ecules.

Diphenyl-methyl isothio-cyanate.

The asymmetric unit of the title compound, C(14)H(11)NS, contains two mol-ecules in which the dihedral angles between the phenyl rings are 77.23 (7) and 86.30 (7)°. No aromatic π-π stacking inter-actions are observed.

3-Nitro-2-phenyl-chroman.

In the title compound, C(15)H(13)NO(3), the dihedral angle between the two aromatic rings is 79.25 (16)°.

Bulky oxadithiolate-bridged [FeFe]­hydrogenase mimics [Fe2(µ-R2odt)(CO)4(κ2-diphosphine)] (R = Ph and H) with chelating diphosphines.

In order to develop an attractive generation of bulky oxadithiolate-bridged [FeFe]­hydrogenase mimics with chelating diphosphines, two new series of asymmetrically diphosphine-substituted diiron model complexes [Fe2(µ-R2odt)(CO)4(κ2-diphosphine)] (3-5) with bulky Ph2odt bridge and their reference counterparts (6-8) with common odt bridge were obtained from the Me3NO-assisted substitutions of diiron hexacarbonyl precursors [Fe2(µ-R2odt)(CO)6] (R2odt = (SCHR)2O, R = Ph (1) and H (2)) with different diphosphines such as (Ph2P)2NBn (labelled PNBnP, Bn = benzyl), (Ph2PCH2)2NBn (PCNBnCP), and (Ph2PCH2)2CH2 (DPPP)), respectively. All the as-prepared complexes have been characterized by elemental analysis, IR plus NMR spectroscopies, and particularly by X-ray crystallography for 3-8. It is interesting to note that complexes 3 and 6 chelating by small bite-angle PNBnP diphosphine have the favorable dibasal isomer whereas analogues 4, 5 and 7, 8 chelating by flexible backbone PCNBnCP or DPPP ligands possess the main apical-basal isomer in solution or in the solid state. Further, the electrochemical properties of two pairs of representative complexes 3, 6 and 5, 8 are explored and compared by cyclic voltammetry (CV) in the absence and presence of trifluoroacetic acid (CF3CO2H) as proton source, indicating that the complete protonations of 3, 6 and 5, 8 with higher concentration of CF3CO2H lead to two new catalytic waves for the electrocatalytic proton reduction to hydrogen (H2).

Biochar-based molybdenum slow-release fertilizer enhances nitrogen assimilation in Chinese flowering cabbage (Brassica parachinensis).

Low molybdenum (Mo) bioavailability in acidic soil obstructs vegetable nitrogen assimilation and thus increases the health risk of vegetable ingestion due to nitrate accumulation. Constantly providing available Mo in acidic soil is a challenge for decreasing nitrate accumulation in vegetables. In this study, three Mo application methods, including biochar-based Mo slow-release fertilizer (Mo-biochar), seed dressing, and basal application, were investigated to enhance Mo bioavailability in acidic soil and nitrogen assimilation in Chinese flowering cabbage (Brassica parachinensis). The results showed that Mo-biochar constantly and sufficiently supplied Mo nutrients throughout the growing period of Brassica parachinensis, as evidenced by the soil available Mo, plant Mo uptake, and Mo values. The improved Mo supply was attributed to the alleviation of acidic soil (pH from 5.10 to 6.99) and the slow release of Mo adsorbed on biochar. Mo-biochar increased the nitrate reductase (NR) activity by 238.6% and glutamate dehydrogenase activity by 27.5%, indicating an enhancement of the rate-limiting steps of nitrogen assimilation, especially for nitrate reduction and amino acid synthesis. The increase in Mo-containing NR could be directly ascribed to the high level of Mo in Brassica parachinensis. Compared with the control, the nitrate content of Brassica parachinensis decreased by 42.9% due to the nitrate reduction induced by increased NR. Additionally, Mo-biochar was beneficial to vegetable growth and quality. In contrast, the transformation from NO3- to NH4+ was blocked with Mo seed dressing and basal application because of low Mo bioavailability in the soil, resulting in a high nitrate content in Brassica parachinensis. Conclusively, Mo-biochar can slowly release Mo and improve the neutral environment for Mo bioavailability, which is an effective strategy to mitigate the high nitrate accumulation of vegetables planted in acidic soil.

The long non-coding RNA SAMMSON is essential for uveal melanoma cell survival.

Long non-coding RNAs (lncRNAs) can exhibit cell-type and cancer-type specific expression profiles, making them highly attractive as therapeutic targets. Pan-cancer RNA sequencing data revealed broad expression of the SAMMSON lncRNA in uveal melanoma (UM), the most common primary intraocular malignancy in adults. Currently, there are no effective treatments for UM patients with metastatic disease, resulting in a median survival time of 6-12 months. We aimed to investigate the therapeutic potential of SAMMSON inhibition in UM. Antisense oligonucleotide (ASO)-mediated SAMMSON inhibition impaired the growth and viability of a genetically diverse panel of uveal melanoma cell lines. These effects were accompanied by an induction of apoptosis and were recapitulated in two uveal melanoma patient derived xenograft (PDX) models through subcutaneous ASO delivery. SAMMSON pulldown revealed several candidate interaction partners, including various proteins involved in mitochondrial translation. Consequently, inhibition of SAMMSON impaired global, mitochondrial and cytosolic protein translation levels and mitochondrial function in uveal melanoma cells. The present study demonstrates that SAMMSON expression is essential for uveal melanoma cell survival. ASO-mediated silencing of SAMMSON may provide an effective treatment strategy to treat primary and metastatic uveal melanoma patients.