A Global Analysis of the Receptor Tyrosine Kinase-Protein Phosphatase Interactome.

Receptor tyrosine kinases (RTKs) and protein phosphatases comprise protein families that play crucial roles in cell signaling. We used two protein-protein interaction (PPI) approaches, the membrane yeast two-hybrid (MYTH) and the mammalian membrane two-hybrid (MaMTH), to map the PPIs between human RTKs and phosphatases. The resulting RTK-phosphatase interactome reveals a considerable number of previously unidentified interactions and suggests specific roles for different phosphatase families. Additionally, the differential PPIs of some protein tyrosine phosphatases (PTPs) and their mutants suggest diverse mechanisms of these PTPs in the regulation of RTK signaling. We further found that PTPRH and PTPRB directly dephosphorylate EGFR and repress its downstream signaling. By contrast, PTPRA plays a dual role in EGFR signaling: besides facilitating EGFR dephosphorylation, it enhances downstream ERK signaling by activating SRC. This comprehensive RTK-phosphatase interactome study provides a broad and deep view of RTK signaling.

The distinct spatiotemporal evolutionary landscape of HBV and HDV largely determines the unique epidemic features of HDV globally.

Chronic infection of hepatitis B virus (HBV) and hepatitis D virus (HDV) causes the most severe form of viral hepatitis. Due to the dependence on HBV, HDV was deemed to co-evolve and co-migrate with HBV. However, we previously found that the naturally occurred HDV/HBV combinations do not always reflect the most efficient virological adaptation (Wang et al., 2021). Moreover, regions with heavy HBV burden do not always correlate with high HDV prevalence (e.g., East Asia), and vice versa (e.g., Central Asia). Herein, we systematically elucidated the spatiotemporal evolutionary landscape of HDV to understand the unique epidemic features of HDV. We found that the MRCA of HDV was from South America around the late 13th century, was globally dispersed mainly via Central Asia, and evolved into eight genotypes from the 19th to 20th century. In contrast, the MRCA of HBV was from Europe ∼23.7 thousand years ago (Kya), globally dispersed mainly via Africa and East Asia, and evolved into eight genotypes ∼1100 years ago. When HDV stepped in, all present-day HBV genotypes had already formed and its global genotypic distribution had stayed stable geographically. Nevertheless, regionalized HDV adapted to local HBV genotypes and human lineages, contributing to the global geographical separation of HDV genotypes. Additionally, a sharp increase in HDV infections was observed after the 20th century. In conclusion, HDV exhibited a distinct spatiotemporal distribution path compared with HBV. This unique evolutionary relationship largely fostered the unique epidemic features we observe nowadays. Moreover, HDV infections may continue to ramp up globally, thus more efforts are urgently needed to combat this disease.

Rapid migration of Mongolian oak into the southern Asian boreal forest.

The migration of trees induced by climatic warming has been observed at many alpine treelines and boreal-tundra ecotones, but the migration of temperate trees into southern boreal forest remains less well documented. We conducted a field investigation across an ecotone of temperate and boreal forests in northern Greater Khingan Mountains of northeast China. Our analysis demonstrates that Mongolian oak (Quercus mongolica), an important temperate tree species, has migrated rapidly into southern boreal forest in synchrony with significant climatic warming over the past century. The average rate of migration is estimated to be 12.0 ± 1.0 km decade-1 , being slightly slower than the movement of isotherms (14.7 ± 6.4 km decade-1 ). The migration rate of Mongolian oak is the highest observed among migratory temperate trees (average rate 4.0 ± 1.0 km decade-1 ) and significantly higher than the rates of tree migration at boreal-tundra ecotones (0.9 ± 0.4 km decade-1 ) and alpine treelines (0.004 ± 0.003 km decade-1 ). Compared with the coexisting dominant boreal tree species, Dahurian larch (Larix gmelinii), temperate Mongolian oak is observed to have significantly lower capacity for light acquisition, comparable water-use efficiency but stronger capacity to utilize nutrients especially the most limiting nutrient, nitrogen. In the context of climatic warming, and in addition to a high seed dispersal capacity and potential thermal niche differences, the advantage of nutrient utilization, reflected by foliar elementomes and stable nitrogen isotope ratios, is also likely a key mechanism for Mongolian oak to coexist with Dahurian larch and facilitate its migration toward boreal forest. These findings highlight a rapid deborealization of southern Asian boreal forest in response to climatic warming.

FSMN-Net: a free space matching network based on manifold convolution for optical molecular tomography.

Optical molecular tomography (OMT) can monitor glioblastomas in small animals non-invasively. Although deep learning (DL) methods have made remarkable achievements in this field, improving its generalization against diverse reconstruction systems remains a formidable challenge. In this Letter, a free space matching network (FSMN-Net) was presented to overcome the parameter mismatch problem in different reconstruction systems. Specifically, a novel, to the best of our knowledge, manifold convolution operator was designed by considering the mathematical model of OMT as a space matching process. Based on the dynamic domain expansion concept, an end-to-end fully convolutional codec further integrates this operator to realize robust reconstruction with voxel-level accuracy. The results of numerical simulations and in vivo experiments demonstrate that the FSMN-Net can stably generate high-resolution reconstruction volumetric images under different reconstruction systems.

Distinct latitudinal patterns and drivers of topsoil nitrogen and phosphorus across urban forests in eastern China.

Nitrogen (N) and phosphorus (P) are the two most important macronutrients supporting forest growth. Unprecedented urbanization has created growing areas of urban forests that provide key ecosystem services for city dwellers. However, the large-scale patterns of soil N and P content remain poorly understood in urban forests. Based on a systematic soil survey in urban forests from nine large cities across eastern China, we examined the spatial patterns and key drivers of topsoil (0-20 cm) total N content, total P content, and N:P ratio. Topsoil total N content was found to change significantly with latitude in the form of an inverted parabolic curve, while total P content showed an opposite latitudinal pattern. Variance partition analysis indicated that regional-scale patterns of topsoil total N and P contents were dominated by climatic drivers and partially regulated by time and pedogenic drivers. Conditional regression analyses showed a significant increase in topsoil total N content with lower mean annual temperature (MAT) and higher mean annual precipitation (MAP), while topsoil total P content decreased significantly with higher MAP. Topsoil total N content also increased significantly with the age of urban park and varied with pre-urban soil type, while no such effects were found for topsoil total P content. Moreover, topsoil N:P ratio showed a latitudinal pattern similar to that of topsoil total N content and also increased significantly with lower MAT and higher MAP. Our findings demonstrate distinct latitudinal trends of topsoil N and P contents and highlight a dominant role of climatic drivers in shaping the large-scale patterns of topsoil nutrients in urban forests.

PUM2 regulates the formation of thoracic aortic dissection through EFEMP1.

Thoracic aortic dissection (TAD) is a severe cardiovascular disease attributed to the abnormal phenotypic switch of vascular smooth muscle cells (VSMCs). We found that the RNA-binding protein PUM2 and the fibulin protein EFEMP1 were significantly decreased at the TAD anatomical site. Therefore, we constructed expression and silencing vectors for PUM2 and EFEMP1 to analyze differential expression. Overexpression of PUM2 inhibited VSMC proliferation and migration. Western blot analysis indicated that PUM2 overexpression in VSMCs upregulated α-SMA and SM22α and downregulated OPN and MMP2. Immunofluorescence demonstrated that PUM2 and EFEMP1 were co-expressed in VSMCs. Immunoprecipitation confirmed that PUM2 bound to EFEMP1 mRNA to promote EFEMP1 expression. An Ang-II-induced aortic dissection mouse model showed that PUM2 impedes the development of aortic dissection in vivo. Our study demonstrates that PUM2 inhibits the VSMC phenotypic switch to prevent aortic dissection by targeting EFEMP1 mRNA. These findings could assist the development of targeted therapy for TAD.

Fluorescence molecular tomography based on an online maximum a posteriori estimation algorithm.

Fluorescence molecular tomography (FMT) is a non-invasive, radiation-free, and highly sensitive optical molecular imaging technique for early tumor detection. However, inadequate measurement information along with significant scattering of near-infrared light within the tissue leads to high ill-posedness in the inverse problem of FMT. To improve the quality and efficiency of FMT reconstruction, we build a reconstruction model based on log-sum regularization and introduce an online maximum a posteriori estimation (OPE) algorithm to solve the non-convex optimization problem. The OPE algorithm approximates a stationary point by evaluating the gradient of the objective function at each iteration, and its notable strength lies in the remarkable speed of convergence. The results of simulations and experiments demonstrate that the OPE algorithm ensures good reconstruction quality and exhibits outstanding performance in terms of reconstruction efficiency.

Polyhedral Oligomeric Silsesquioxane-Based Nanoparticles for Efficient Chemotherapy of Glioblastoma.

Glioblastoma (GBM) is the most common lethal brain tumor with dismal treatment outcomes and poor response to chemotherapy. As the regulatory center of cytogenetics and metabolism, most tumor chemotherapeutic molecules exert therapeutic effects in the nucleus. Nanodrugs showing the nuclear aggregation effect are expected to eliminate and fundamentally suppress tumor cells. In this study, a nanodrug delivery system based on polyhedral oligomeric silsesquioxane (POSS) is introduced to deliver drugs into the nuclei of GBM cells, effectively enhancing the therapeutic efficacy of chemotherapy. The nanoparticles are modified with folic acid and iRGD peptides molecules to improve their tumor cell targeting and uptake via receptor-mediated endocytosis. Nuclear aggregation allows for the direct delivery of chemotherapeutic drug temozolomide (TMZ) to the tumor cell nuclei, resulting in more significant DNA damage and inhibition of tumor cell proliferation. Herein, TMZ-loaded POSS nanoparticles can significantly improve the survival of GBM-bearing mice. Therefore, the modified POSS nanoparticles may serve as a promising drug-loaded delivery platform to improve chemotherapy outcomes in GBM patients.

3D-deep optical learning: a multimodal and multitask reconstruction framework for optical molecular tomography.

Optical molecular tomography (OMT) is an emerging imaging technique. To date, the poor universality of reconstruction algorithms based on deep learning for various imaged objects and optical probes limits the development and application of OMT. In this study, based on a new mapping representation, a multimodal and multitask reconstruction framework-3D deep optical learning (3DOL), was presented to overcome the limitations of OMT in universality by decomposing it into two tasks, optical field recovery and luminous source reconstruction. Specifically, slices of the original anatomy (provided by computed tomography) and boundary optical measurement of imaged objects serve as inputs of a recurrent convolutional neural network encoded parallel to extract multimodal features, and 2D information from a few axial planes within the samples is explicitly incorporated, which enables 3DOL to recognize different imaged objects. Subsequently, the optical field is recovered under the constraint of the object geometry, and then the luminous source is segmented by a learnable Laplace operator from the recovered optical field, which obtains stable and high-quality reconstruction results with extremely few parameters. This strategy enable 3DOL to better understand the relationship between the boundary optical measurement, optical field, and luminous source to improve 3DOL's ability to work in a wide range of spectra. The results of numerical simulations, physical phantoms, and in vivo experiments demonstrate that 3DOL is a compatible deep-learning approach to tomographic imaging diverse objects. Moreover, the fully trained 3DOL under specific wavelengths can be generalized to other spectra in the 620-900 nm NIR-I window.

A distinctive latitudinal trend of nitrogen isotope signature across urban forests in eastern China.

Rapid urbanization has greatly altered nitrogen (N) cycling from regional to global scales. Compared to natural forests, urban forests receive much more external N inputs with distinctive abundances of stable N isotope (δ15 N). However, the large-scale pattern of soil δ15 N and its imprint on plant δ15 N remain less well understood in urban forests. By collecting topsoil (0-20 cm) and leaf samples from urban forest patches in nine large cities across a north-south transect in eastern China, we analyzed the latitudinal trends of topsoil C:N ratio and δ15 N as well as the correlations between tree leaf δ15 N and topsoil δ15 N. We further explored the spatial variation of topsoil δ15 N explained by corresponding climatic, edaphic, vegetation-associated, and anthropogenic drivers. Our results showed a significant increase of topsoil C:N ratio towards higher latitudes, suggesting lower N availability at higher latitudes. Topsoil δ15 N also increased significantly at higher latitudes, being opposite to the latitudinal trend of soil N availability. The latitudinal trend of topsoil δ15 N was mainly explained by mean annual temperature, mean annual precipitation, and atmospheric deposition of both ammonium and nitrate. Consequently, tree leaf δ15 N showed significant positive correlations with topsoil δ15 N across all sampled plant species and functional types. Our findings reveal a distinctive latitudinal trend of δ15 N in urban forests and highlight an important role of anthropogenic N sources in shaping the large-scale pattern of urban forest 15 N signature.

Coordination Tuning of Metal Porphyrins for Improved Oxygen Evolution Reaction.

The nucleophilic attack of water or hydroxide on metal-oxo units forms an O-O bond in the oxygen evolution reaction (OER). Coordination tuning to improve this attack is intriguing but has been rarely realized. We herein report on improved OER catalysis by metal porphyrin 1-M (M=Co, Fe) with a coordinatively unsaturated metal ion. We designed and synthesized 1-M by sterically blocking one porphyrin side with a tethered tetraazacyclododecane unit. With this protection, the metal-oxo species generated in OER can maintain an unoccupied trans axial site. Importantly, 1-M displays a higher OER activity in alkaline solutions than analogues lacking such an axial protection by decreasing up to 150-mV overpotential to achieve 10 mA/cm2 current density. Theoretical studies suggest that with an unoccupied trans axial site, the metal-oxo unit becomes more positively charged and thus is more favoured for the hydroxide nucleophilic attack as compared to metal-oxo units bearing trans axial ligands.

lncRNA XLOC013218 promotes cell proliferation and TMZ resistance by targeting the PIK3R2-mediated PI3K/AKT pathway in glioma.

The discovery of long noncoding RNAs (lncRNAs) has improved the understanding of development and progression in various cancer subtypes. However, the role of lncRNAs in temozolomide (TMZ) resistance in glioblastoma multiforme (GBM) remains largely undefined. In this present study, the differential expression of lncRNAs was identified between U87 and U87 TMZ-resistant (TR) cells. lncRNA XLOC013218 (XLOC) was drastically upregulated in TR cells and was associated with poor prognosis in glioma. Overexpression of XLOC markedly increased TMZ resistance, promoted proliferation, and inhibited apoptosis in vitro and in vivo. In addition, RNA-seq analysis and gain-of-function or loss-of-function studies revealed that PIK3R2 was the potential target of XLOC. Mechanistically, XLOC recruited specificity protein 1 (Sp1) transcription factor and promoted the binding of Sp1 to the promoters of PIK3R2, which elevated the expression of PIK3R2 in both mRNA and protein levels. Finally, PIK3R2-mediated activation of the PI3K/AKT signaling pathway promoted TMZ resistance and cell proliferation, but inhibited cell apoptosis. In conclusion, these data highlight the vital role of the XLOC/Sp1/PIK3R2/PI3K/AKT axis in GBM TMZ resistance.

Total Variation Constrained Graph Manifold Learning Strategy for Cerenkov Luminescence Tomography.

Harnessing the power and flexibility of radiolabeled molecules, Cerenkov luminescence tomography (CLT) provides a novel technique for non-invasive visualisation and quantification of viable tumour cells in a living organism. However, owing to the photon scattering effect and the ill-posed inverse problem, CLT still suffers from insufficient spatial resolution and shape recovery in various preclinical applications. In this study, we proposed a total variation constrained graph manifold learning (TV-GML) strategy for achieving accurate spatial location, dual-source resolution, and tumour morphology. TV-GML integrates the isotropic total variation term and dynamic graph Laplacian constraint to make a trade-off between edge preservation and piecewise smooth region reconstruction. Meanwhile, the tetrahedral mesh-Cartesian grid pair method based on the k-nearest neighbour, and the adaptive and composite Barzilai-Borwein method, were proposed to ensure global super linear convergence of the solution of TV-GML. The comparison results of both simulation experiments and in vivo experiments further indicated that TV-GML achieved superior reconstruction performance in terms of location accuracy, dual-source resolution, shape recovery capability, robustness, and in vivo practicability. Significance: We believe that this novel method will be beneficial to the application of CLT for quantitative analysis and morphological observation of various preclinical applications and facilitate the development of the theory of solving inverse problem.

VoxDMRN: a voxelwise deep max-pooling residual network for bioluminescence tomography reconstruction.

Bioluminescence tomography (BLT) has extensive applications in preclinical studies for cancer research and drug development. However, the spatial resolution of BLT is inadequate because the numerical methods are limited for solving the physical models of photon propagation and the restriction of using tetrahedral meshes for reconstruction. We conducted a series of theoretical derivations and divided the BLT reconstruction process into two steps: feature extraction and nonlinear mapping. Inspired by deep learning, a voxelwise deep max-pooling residual network (VoxDMRN) is proposed to establish the nonlinear relationship between the internal bioluminescent source and surface boundary density to improve the spatial resolution in BLT reconstruction. The numerical simulation and in vivo experiments both demonstrated that VoxDMRN greatly improves the reconstruction performance regarding location accuracy, shape recovery capability, dual-source resolution, robustness, and in vivo practicability.

Pentraxin 3 secreted by human adipose-derived stem cells promotes dopaminergic neuron repair in Parkinson's disease via the inhibition of apoptosis.

Although adipose-derived human mesenchymal stem cell (hADSC) transplantation has recently emerged as a promising therapeutic modality for Parkinson's disease (PD), its underlying mechanism of action has not been fully elucidated. This study evaluated the therapeutic effects of stereotaxic injection of hADSCs in the striatum of the 6-OHDA-induced mouse model. Furthermore, an in vitro PD model was constructed using tissue-organized brain slices. The therapeutic effect was also evaluated using a co-culture of the hADSCs and 6-OHDA-treated brain slice. The analysis of hADSC exocrine proteins using RNA-sequencing, human protein cytokine arrays, and label-free quantitative proteomics identified key extracellular factors in the hADSC secretion environment. The degeneration and apoptosis of the dopaminergic neurons were measured in the PD samples in vivo and in vitro, and the beneficial effects were evaluated using quantitative reverse transcription-polymerase chain reaction, western blotting, Fluoro-Jade C, TUNEL assay, and immunofluorescence analysis. This study found that hADSCs protected the dopaminergic neurons in the in vivo and vitro models. We identified Pentraxin 3 (PTX3) as a key extracellular factor in the hADSC secretion environment. Moreover, we found that human recombinant PTX3 (rhPTX3) treatment could rescue the pathophysiological behavior of the PD mice in vivo, prevent dopaminergic neuronal death, and increase neuronal terminals in the ventral tegmental area + substantia nigra pars compacta and striatum in the PD brain slices in vitro. Furthermore, testing of the pro-apoptotic markers in the PD mouse brain following rhPTX3 treatment revealed that rhPTX3 can prevent apoptosis and degeneration of the dopaminergic neurons. This study discovered that PTX3, a hADSC-secreted protein, potentially protected the dopaminergic neurons against apoptosis and degeneration during PD progression and improved motor performance in PD mice, indicating the possible mechanism of action of hADSC replacement therapy for PD. Thus, our study discovered potential translational implications for the development of PTX3-based therapeutics for PD.

Accurate and fast reconstruction for bioluminescence tomography based on adaptive Newton hard thresholding pursuit algorithm.

As a promising noninvasive medical imaging technique, bioluminescence tomography (BLT) dynamically offers three-dimensional visualization of tumor distribution in living animals. However, due to the high ill-posedness caused by the strong scattering property of biological tissues and the limited boundary measurements with noise, BLT reconstruction still cannot meet actual preliminary clinical application requirements. In our research, to recover 3D tumor distribution quickly and precisely, an adaptive Newton hard thresholding pursuit (ANHTP) algorithm is proposed to improve the performance of BLT. The ANHTP algorithm fully combines the advantages of sparsity constrained optimization and convex optimization to guarantee global convergence. More precisely, an adaptive sparsity adjustment strategy was developed to obtain the support set of the inverse system matrix. Based on the strong Wolfe line search criterion, a modified damped Newton algorithm was constructed to obtain optimal source distribution information. A series of numerical simulations and phantom and in vivo experiments show that ANHTP has high reconstruction accuracy, fast reconstruction speed, and good robustness. Our proposed algorithm can further increase the practicality of BLT in biomedical applications.

Facile synthesis of a novel magnetic covalent organic frameworks for extraction and determination of five fungicides in Chinese herbal medicines.

A novel magnetic covalent organic framework was synthesized via a one-step coating approach with solvothermal reaction employing 2,4,6-tris(4-aminophen-yl)-1,3,5-triazine and 2,4,6-triformylphloroglucinol as two building blocks by covalent bonding. The prepared magnetic covalent organic frameworks were properly characterized by different techniques and employed as adsorbents of magnetic solid-phase extraction. An analytical method was developed for the simultaneous determination of five fungicides in two Chinese herbal medicine samples via magnetic solid-phase extraction coupled to ultra high performance liquid chromatography with tandem mass spectrometry analysis. Under optimized magnetic solid-phase extraction conditions, the method exhibited satisfactory recoveries (74.0-109.6%) with relative standard deviations of 0.4-4.6%, low limits of detection (0.003-0.015 µg/kg), and good linearity (R2 > 0.9960). Compared with the traditional extraction method, the proposed method required a lower amount of adsorbent (3 mg) and extraction time (5 min). The adsorbent also had favorable reusability (not less than eight times). Therefore, the magnetic covalent organic frameworks could be a promising adsorbent for the extraction and quantitation of fungicides in Chinese herbal medicines.

Green sulfidated iron oxide nanocomposites for efficient removal of Malachite Green and Rhodamine B from aqueous solution.

A green and facile pathway was described using Viburnum odoratissimum leaf extract in the presence of sodium thiosulfate for the synthesis of sulfidated iron oxide nanocomposites (S-Fe NCs) adsorbents. The prepared S-Fe NCs can be used for the efficient removal of Malachite Green (MG) and Rhodamine B (RhB) from aqueous solution. Analytical techniques by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR), and X-ray photoelectron spectroscopy (XPS) were applied to understand the morphologies and compositions of S-Fe NCs. The stability of the adsorption capacity on S-Fe NCs was studied. Results from the characterization studies showed that S-Fe NCs were mainly composed of iron oxides, iron sulfides and biomolecules. The S-Fe NCs displayed high adsorption capacity for a wide range of pH values. The Koble-Corrigan isotherm model and Elovich model well described the adsorption process. The maximum adsorption capacity for MG and RhB was 4.31 mmol g-1 and 2.88 mmol g-1 at 303 K, respectively. The adsorption mechanism may be attributed to the electrostatic interaction, the hydrogen bonding, the π-π stacking interactions, the inner-sphere surface complexation or the cation bridging among the S-Fe NCs and dye molecules.

Role-Specialized Division of Labor in CO2 Reduction with Doubly-Functionalized Iron Porphyrin Atropisomers.

In enzymes, the active site residues function differently to promote chemical reactions. Such a role-specialized division of labor has been rarely realized by synthetic catalysts. We report herein on catalytic CO2 reduction with Fe porphyrins decorated with two cationic N,N,N-trimethylbenzylamine groups in cis- or trans-arrangement. The cis-isomer outperforms the trans-isomer and reaches a TOFmax of 4.4×105  s-1 in acetonitrile using phenol proton source. Theoretical studies revealed that the two cationic units in the cis-isomer are more effective than a single cationic unit to improve the CO2 binding, and more importantly, they function differently but cooperatively to promote the C-O bond cleavage: one interacts with the CO2 -adduct, while the other one interacts with the phenol molecule through electrostatic interactions. This work therefore presents a significant example of synthetic catalysts, which boost chemical reactions using a role-specialized strategy for substrate activation.

Metal-Corrole-Based Porous Organic Polymers for Electrocatalytic Oxygen Reduction and Evolution Reactions.

Integrating molecular catalysts into designed frameworks often enables improved catalysis. Compared with porphyrin-based frameworks, metal-corrole-based frameworks have been rarely developed, although monomeric metal corroles are usually more efficient than porphyrin counterparts for the electrocatalytic oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). We herein report on metal-corrole-based porous organic polymers (POPs) as ORR and OER electrocatalysts. M-POPs (M=Mn, Fe, Co, Cu) were synthesized by coupling metal 10-phenyl-5,15-(4-iodophenyl)corrole with tetrakis(4-ethynylphenyl)methane. Compared with metal corrole monomers, M-POPs displayed significantly enhanced catalytic activity and stability. Co-POP outperformed other M-POPs by achieving four-electron ORR with a half-wave potential of 0.87 V vs. RHE and reaching 10 mA cm-2 OER current density at 340 mV overpotential. This work is unparalleled to develop and explore metal-corrole-based POPs as electrocatalysts.