Inferring redox conditions for ancient marine environments is critical to our understanding of biogeochemical cycles over Earth history. Because of the redox sensitivity of cerium (Ce) relative to ...other rare earth elements (REEs) and its uptake in marine carbonates, the Ce anomaly (Ce/Ce*) is widely applied to ancient carbonates as a proxy for local redox conditions in the water column. However, carbonate sediments and rocks are particularly vulnerable to multiple stages and styles of post-depositional diagenetic alteration where the diagenetic redox conditions and fluid compositions can vary widely from overlying seawater. Evaluations of the effects of this post-depositional alteration for the Ce anomaly have mostly been limited to ancient carbonate rocks rather than recent, well-characterized analog facies. Here, we report on analyses of REE plus yttrium concentrations (REY) and Ce anomalies in bulk carbonate samples from drill cores collected in the Bahamas (Clino and Unda) that allow us to track loss or retention of primary signals of initial oxic deposition through a range of subsequent alteration scenarios mostly under anoxic conditions. Specifically, these materials have experienced well-constrained overprints linked to meteoric processes and marine burial diagenesis, including dolomitization. Our results show that, regardless of mineralogy, diagenetic fluid composition, and redox state, the REY patterns in these carbonates, including the Ce anomaly, are similar to those of modern oxic seawater, indicating that they likely record the seawater signatures of primary deposition. As such, the Ce anomaly in shallow marine carbonates has the potential to preserve records of primary deposition even when subject to multiple stages and styles of diagenetic alteration, confirming its utility in studies of ancient marine redox.
Switching materials in channels of nonlinear optics (NLOs) are of particular interest in NLO material science. Numerous crystalline NLO switches based on structural phase transition have emerged, but ...most of them reveal a single‐step switch between two different second‐harmonic‐generation (SHG) states, and only very rare cases involve three or more SHG states. Herein, we report a new organic‐inorganic hybrid salt, (Me3NNH2)2CdI4, which is an unprecedented case of a reversible three‐step NLO switch between SHG‐silent, ‐medium, ‐low, and ‐high states, with high contrasts of 25.5/4.3/9.2 in a temperature range of 213–303 K. By using the combined techniques of variable‐temperature X‐ray single‐crystal structural analyses, dielectric constants, solid‐state 13C nuclear magnetic resonance spectroscopy, and Hirshfeld surface analyses, we disclose that this four‐state switchable SHG behavior is highly associated with the stepwise‐changed molecular dynamics of the polar organic cations. This finding demonstrates well the complexity of molecular dynamics in simple hybrid salts and their potential in designing new advanced multistep switching materials.
A new simple hybrid salt has been synthesized that exhibits reversible multistep phase transitions and an unprecedented thermally induced three‐step “silent‐medium‐low‐high” second‐harmonic‐generation switching behavior. This behavior arises from complex and stepwise molecular dynamic changes of the polar organic cations.
Damaged or dysfunctional mitochondria are toxic to the cell by producing reactive oxygen species and releasing cell death factors. Therefore, timely removal of these organelles is critical to ...cellular homeostasis and viability. Mitophagy is the mechanism of selective degradation of mitochondria via autophagy. The significance of mitophagy in kidney diseases, including ischemic acute kidney injury (AKI), has yet to be established, and the involved pathway of mitophagy remains poorly understood. Here, we show that mitophagy is induced in renal proximal tubular cells in both in vitro and in vivo models of ischemic AKI. Mitophagy under these conditions is abrogated by Pink1 and Park2 deficiency, supporting a critical role of the PINK1-PARK2 pathway in tubular cell mitophagy. Moreover, ischemic AKI is aggravated in pink1 andpark2 single- as well as double-knockout mice. Mechanistically, Pink1 and Park2 deficiency enhances mitochondrial damage, reactive oxygen species production, and inflammatory response. Taken together, these results indicate that PINK1-PARK2-mediated mitophagy plays an important role in mitochondrial quality control, tubular cell survival, and renal function during AKI.
The typical chalcopyrite AgGaQ2 (Q = S, Se) are commercial infrared (IR) second‐order nonlinear optical (NLO) materials; however, they suffer from unexpected laser‐induced damage thresholds (LIDTs) ...primairy due to their narrow band gaps. Herein, what sets this apart from previously reported chemical substitutions is the utilization of an unusual cationic substitution strategy, represented by SZn4S12 + S4Zn13S24 + 11ZnS4 ⇒ MS12+ M4ClS24 + 11GaS4, in which the covalent SxZny units in the diamond‐like sphalerite ZnS are synergistically replaced by cationic MxCly units, resulting in two novel salt‐inclusion sulfides, MM4ClGa11S20 (M = A/Ba, A = K, 1; Rb, 2). As expected, the introduction of mixed cations in the GaS4 anionic frameworks of 1 and 2 leads to wide band gaps (3.04 and 3.01 eV), which exceeds the value of AgGaS2, facilitating the improvement of high LIDTs (9.4 and 10.3 × AgGaS2@1.06 µm, respectively). Furthermore, compounds 1 and 2 exhibit moderate second‐harmonic generation intensities (0.84 and 0.78 × AgGaS2@2.9 µm, respectively), mainly originating from the orderly packing tetrahedral GaS4 units. Importantly, this study demonstrates the successful application of the cationic substitution strategy based on diamond‐like structures to provide a feasible chemical design insight for constructing high‐performance NLO materials.
What sets this apart from previously reported chemical substitutions is the utilization of an unusual cationic substitution strategy, offers two excellent infrared nonlinear optical materials, which provides a feasible chemical design insight for constructing high‐performance nonlinear optical materials.
Strontium isotope ratios (87Sr/86Sr) are gaining considerable interest as a geolocation tool and are now widely applied in archaeology, ecology, and forensic research. However, their application for ...provenance requires the development of baseline models predicting surficial 87Sr/86Sr variations ("isoscapes"). A variety of empirically-based and process-based models have been proposed to build terrestrial 87Sr/86Sr isoscapes but, in their current forms, those models are not mature enough to be integrated with continuous-probability surface models used in geographic assignment. In this study, we aim to overcome those limitations and to predict 87Sr/86Sr variations across Western Europe by combining process-based models and a series of remote-sensing geospatial products into a regression framework. We find that random forest regression significantly outperforms other commonly used regression and interpolation methods, and efficiently predicts the multi-scale patterning of 87Sr/86Sr variations by accounting for geological, geomorphological and atmospheric controls. Random forest regression also provides an easily interpretable and flexible framework to integrate different types of environmental auxiliary variables required to model the multi-scale patterning of 87Sr/86Sr variability. The method is transferable to different scales and resolutions and can be applied to the large collection of geospatial data available at local and global levels. The isoscape generated in this study provides the most accurate 87Sr/86Sr predictions in bioavailable strontium for Western Europe (R2 = 0.58 and RMSE = 0.0023) to date, as well as a conservative estimate of spatial uncertainty by applying quantile regression forest. We anticipate that the method presented in this study combined with the growing numbers of bioavailable 87Sr/86Sr data and satellite geospatial products will extend the applicability of the 87Sr/86Sr geo-profiling tool in provenance applications.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chemokines play a key role in orchestrating the recruitment and positioning of myeloid cells within the tumor microenvironment. However, the tropism regulation and functions of these cells in ...hepatocellular carcinoma (HCC) are not completely understood. Herein, by scrutinizing the expression of all chemokines in HCC cell lines and tissues, we found that CCL15 was the most abundantly expressed chemokine in human HCC. Further analyses showed that CCL15 expression was regulated by genetic, epigenetic, and microenvironmental factors, and negatively correlated with patient clinical outcome. In addition to promoting tumor invasion in an autocrine manner, CCL15 specifically recruited CCR1+ cells toward HCC invasive margin, approximately 80% of which were CD14+ monocytes. Clinically, a high density of marginal CCR1+CD14+ monocytes positively correlated with CCL15 expression and was an independent index for dismal survival. Functionally, these tumor‐educated monocytes directly accelerated tumor invasion and metastasis through bursting various pro‐tumor factors and activating signal transducer and activator of transcription 1/3, extracellular signal‐regulated kinase 1/2, and v‐akt murine thymoma viral oncogene homolog signaling in HCC cells. Meanwhile, tumor‐derived CCR1+CD14+ monocytes expressed significantly higher levels of programmed cell death‐ligand 1, B7‐H3, and T‐cell immunoglobulin domain and mucin domain‐3 that may lead to immune suppression. Transcriptome sequencing confirmed that tumor‐infiltrating CCR1+CD14+ monocytes were reprogrammed to upregulate immune checkpoints, immune tolerogenic metabolic enzymes (indoleamine and arginase), inflammatory/pro‐angiogenic cytokines, matrix remodeling proteases, and inflammatory chemokines. Orthotopic animal models confirmed that CCL15‐CCR1 axis forested an inflammatory microenvironment enriched with CCR1+ monocytes and led to increased metastatic potential of HCC cells. Conclusion: A complex tumor‐promoting inflammatory microenvironment was shaped by CCL15‐CCR1 axis in human HCC. Blockade of CCL15‐CCR1 axis in HCC could be an effective anticancer therapy.
Materials with hysteretic multi‐step spin‐crossover (SCO) have potential application in high‐order data storage. Here, an unprecedented hysteretic four‐step SCO behavior with the sequence of ...LS↔HS0.25LS0.75↔HS0.5LS0.5↔ HS0.75LS0.25↔HS is found in a three‐dimensional (3D) Hofmann‐type metal–organic framework (MOF), which is evidenced by magnetic, differential scanning calorimetry, and crystal data. Further experiments involving guest exchange leads to the first reversible modulation of four‐, two‐, and one‐stepped SCO behaviors, which provides a new strategy for developing multi‐step SCO materials.
Hysteretic four‐step SCO behavior, LS↔HS0.25LS0.75↔HS0.5LS0.5↔HS0.75LS0.25↔HS, is evidenced by magnetic, differential scanning calorimetry, and crystal data. Furthermore, reversible modulation of four‐, two‐, and one‐stepped SCO behaviors is realized through guest exchange.
Pancreatic cancer (PC) is one of the most lethal cancers known worldwide, and its prognosis is poor in most patients. Exosomes are nanosized extracellular vesicles, which are released from various ...cell types. They are involved in cellular communication. The diagnosis and treatment of PC were improved substantially with exosomes. In this study, we isolated PC‐derived exosomes and investigated their proteomic profile. Then, we conducted bioinformatic analysis on proteomic data. Differential ultracentrifugation was performed to isolate exosomes from human serum samples and four PC cell lines. Transmission electron microscopy and Western blot analysis were used to characterize the isolated exosomes. Liquid chromatography coupled with tandem mass spectrometry was conducted to identify the proteome of serum exosomes. Proteomic analysis demonstrated that all the serum exosomes were derived from three cohorts of human subjects; these serum exosomes contained a total of 655 proteins, out of which 315 proteins overlapped with ExoCarta database. Gene oncology and kyoto encyclopedia of genes and genomes analyses provided the functional annotation of the proteome. Interestingly, 18 or 14 proteins were upregulated and 11 or 14 proteins were downregulated in serum exosomes derived from patients with PC as compared with in serum exosomes derived from healthy volunteers or from pancreatitis patients respectively. Annexin A11, a calcium‐dependent phospholipid‐binding protein, was expressed in a PC cell line (CFPAC‐1)‐derived exosomes and in tumor tissues of patients with PC, respectively. Our data provided a basic foundation for further studies on the protein composition of PC‐derived exosomes and its involvement in PC biology.
Necroptosis, a form of inflammation‐related programmed cell death, is a major mechanism of proximal tubular cell injury in acute kidney injury (AKI). Blockade of necroptosis signalling represents a ...promising strategy for clinical therapy of AKI. Previously, we identified a small molecular receptor‐interacting protein kinases (RIPK)1 inhibitor Cpd‐71 with nephroprotective activities. To discover more nephroprotective agents, in this study, 20 chalcone derivatives were synthesized and evaluated for their anti‐necroptosis and nephroprotective activities. Among the chalcone derivatives, Cpd‐2 exhibited the most potent anti‐necroptosis activity (IC50 = 1.08 μM) and protective activity (EC50 = 1.49 μM) through directly binding to RIPK1 and blocking RIPK1‐RIPK3‐mixed‐lineage kinase domain‐like protein (MLKL) signalling pathway. Furthermore, Cpd‐2 effectively attenuated cisplatin or hypoxia/reoxygenation (H/R)‐induced injury and necroptotic inflammation in renal cell models. Moreover, in cisplatin‐ or ischemia/reperfusion (I/R) induced AKI mouse model, detection of creatinine and urea nitrogen in blood showed that Cpd‐2 improved kidney function. Periodic acid–Schiff (PAS) staining and immunofluorescence analysis indicated that Cpd‐2 also reduced pathological damage and inhibited inflammatory development in kidney tissues. In summary, although some chalcone derivatives have been reported to prevent kidney injury previously, our present study not only discovered a promising leading compound Cpd‐2, but also provided a novel and successful practice for the development of necroptosis inhibitors from natural products derivatives as AKI therapeutic agents.
Acute kidney injury (AKI) is a destructive clinical condition induced by multiple insults including ischemic reperfusion, nephrotoxic drugs and sepsis. It is characterized by a sudden decline in ...renal function, in addition to excessive inflammation, oxidative stress and programmed cell death of renal tubular epithelial cells. RIPK1-mediated necroptosis plays an important role in AKI. In the present study, we evaluated the treatment effects of Compound-71 (Cpd-71), a novel RIPK1 inhibitor, by comparing with Necrostatin-1 (Nec-1), a classic RIPK1 inhibitor, which has several drawbacks like the narrow structure-activity relationship (SAR) profile, moderate potency and non-ideal pharmacokinetic properties,
and
Our results showed that pretreatment of Cpd-71 attenuated cisplatin-induced renal injury, restored renal function and suppressed renal inflammation, oxidative stress and cell necroptosis. In addition, Cpd-71 inhibited renal damage while reducing the up-regulated serum creatinine (Cr) and blood urea nitrogen (BUN) levels in established AKI mice model. Consistently, we confirmed that Cpd-71 exhibited more effectively suppressive effect on cisplatin-induced renal tubular cell necroptosis than Nec-1, by physically binding to the allosteric type III ligand binding site of RIPK1, thereby reduced RIPK1 kinase activity, RIPK1/RIPK3 complex formation and phosphor-MLKL membrane translocation by molecular docking, Western blot, co-immunoprecipitation and cellular thermal shift assay (CETSA). Taken together, we currently showed that targeting RIPK1 with Cpd-71 may serve as a promising clinical candidate for AKI treatment.
PDF
