Wnt/ß-catenin signaling pathway in carcinogenesis and cancer therapy.

The Wnt/ß-catenin signaling pathway plays a crucial role in various physiological processes, encompassing development, tissue homeostasis, and cell proliferation. Under normal physiological conditions, the Wnt/ß-catenin signaling pathway is meticulously regulated. However, aberrant activation of this pathway and downstream target genes can occur due to mutations in key components of the Wnt/ß-catenin pathway, epigenetic modifications, and crosstalk with other signaling pathways. Consequently, these dysregulations contribute significantly to tumor initiation and progression. Therapies targeting the Wnt/ß-catenin signaling transduction have exhibited promising prospects and potential for tumor treatment. An increasing number of medications targeting this pathway are continuously being developed and validated. This comprehensive review aims to summarize the latest advances in our understanding of the role played by the Wnt/ß-catenin signaling pathway in carcinogenesis and targeted therapy, providing valuable insights into acknowledging current opportunities and challenges associated with targeting this signaling pathway in cancer research and treatment.

Single phage proteins sequester TIR- and cGAS-generated signaling molecules.

Prokaryotic anti-phage immune systems use TIR (toll/interleukin-1 receptor) and cGAS (cyclic GMP-AMP synthase) enzymes to produce 1"-3'/1"-2' glycocyclic ADPR (gcADPR) and cyclid di-/trinucleotides (CDNs and CTNs) signaling molecules that limit phage replication, respectively 1-3. However, how phages neutralize these common systems is largely unknown. Here, we show that Thoeris anti-defense proteins Tad1 4 and Tad2 5 both have anti-CBASS activity by simultaneously sequestering CBASS cyclic oligonucleotides. Strikingly, apart from binding Thoeris signals 1"-3' and 1"-2' gcADPR, Tad1 also binds numerous CBASS CDNs/CTNs with high affinity, inhibiting CBASS systems using these molecules in vivo and in vitro. The hexameric Tad1 has six binding sites for CDNs or gcADPR, which are independent from two high affinity binding sites for CTNs. Tad2 also sequesters various CDNs in addition to gcADPR molecules, inhibiting CBASS systems using these CDNs. However, the binding pockets for CDNs and gcADPR are different in Tad2, whereby a tetramer can bind two CDNs and two gcADPR molecules simultaneously. Taken together, Tad1 and Tad2 are both two-pronged inhibitors that, alongside anti-CBASS protein 2, establish a paradigm of phage proteins that flexibly sequester a remarkable breadth of cyclic nucleotides involved in TIR- and cGAS-based anti-phage immunity.

Successful Treatment of Prurigo Nodularis by Dupilumab: Report of 24 Patients.

BACKGROUND: Prurigo nodularis (PN) is a chronic pruritic skin disease which is difficult to treat. Current treatment options often lead to limited clinical benefit or severe side effects. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of dupilumab in the treatment of PN in adults. METHOD: This study is a retrospective cohort study. Twenty-four adult patients with PN were included and treated with dupilumab. The primary outcomes were the mean reduction in the Investigator's Global Assessment (IGA) score and pruritus numeric rating scale (p-NRS) score. Outcomes were assessed at baseline, week 4, week 16, and week 36. RESULTS: The study included 24 patients, of whom 9 (37.5%) were male, and the mean (SD) age of the enrolled patients was 49.88 ± 16.71 years. At the end of the 16-week treatment, the mean p-NRS score decreased from 7.50 ± 2.21 to 1.41 ± 0.91 (p < 0.001), sleeplessness numeric rating scale (s-NRS) score declined from 5.33 ± 3.29 to 0.18 ± 0.59 (p < 0.001), and Dermatology Life Quality Index (DLQI) score decreased from 13.32 ± 4.88 to 0.91 ± 0.81 (p < 0.001). Fourteen (63.6%) of 22 patients achieved IGA 0/1 and 21 (95.5%) patients achieved IGA activity 0/1. Among 14 patients who achieved IGA 0/1, 10 had an elevated serum IgE level, and patients with a high serum IgE level showed a more remarkable reduction in IGA (r = 0.52, p = 0.03). Patients with AD responded faster than those without AD (3.76 ± 1.71 weeks vs. 6.40 ± 1.67 weeks, p = 0.01). Adverse events were recorded in 4/24 (16.6%) patients, with conjunctivitis being the most frequent. CONCLUSION: This study demonstrated that dupilumab is effective and safe for PN and could be a potential therapeutic option.

Imaging crossing fibers in mouse, pig, monkey, and human brain using small-angle X-ray scattering.

Myelinated axons (nerve fibers) efficiently transmit signals throughout the brain via action potentials. Multiple methods that are sensitive to axon orientations, from microscopy to magnetic resonance imaging, aim to reconstruct the brain's structural connectome. As billions of nerve fibers traverse the brain with various possible geometries at each point, resolving fiber crossings is necessary to generate accurate structural connectivity maps. However, doing so with specificity is a challenging task because signals originating from oriented fibers can be influenced by brain (micro)structures unrelated to myelinated axons. X-ray scattering can specifically probe myelinated axons due to the periodicity of the myelin sheath, which yields distinct peaks in the scattering pattern. Here, we show that small-angle X-ray scattering (SAXS) can be used to detect myelinated, axon-specific fiber crossings. We first demonstrate the capability using strips of human corpus callosum to create artificial double- and triple-crossing fiber geometries, and we then apply the method in mouse, pig, vervet monkey, and human brains. We compare results to polarized light imaging (3D-PLI), tracer experiments, and to outputs from diffusion MRI that sometimes fails to detect crossings. Given its specificity, capability of 3-dimensional sampling and high resolution, SAXS could serve as a ground truth for validating fiber orientations derived using diffusion MRI as well as microscopy-based methods. STATEMENT OF SIGNIFICANCE: To study how the nerve fibers in our brain are interconnected, scientists need to visualize their trajectories, which often cross one another. Here, we show the unique capacity of small-angle X-ray scattering (SAXS) to study these fiber crossings without use of labeling, taking advantage of SAXS's specificity to myelin - the insulating sheath that is wrapped around nerve fibers. We use SAXS to detect double and triple crossing fibers and unveil intricate crossings in mouse, pig, vervet monkey, and human brains. This non-destructive method can uncover complex fiber trajectories and validate other less specific imaging methods (e.g., MRI or microscopy), towards accurate mapping of neuronal connectivity in the animal and human brain.

Nitrogen-Neighbored Single-Cobalt Sites Enable Heterogeneous Oxidase-Type Catalysis.

The development of biomimetic catalytic systems that can imitate or even surpass natural enzymes remains an ongoing challenge, especially for bioinspired syntheses that can access non-natural reactions. Here, we show how an all-inorganic biomimetic system bearing robust nitrogen-neighbored single-cobalt site/pyridinic-N site (Co-N4/Py-N) pairs can act cooperatively as an oxidase mimic, which renders an engaged coupling of oxygen (O2) reduction with synthetically beneficial chemical transformations. By developing this broadly applicable platform, the scalable synthesis of greater than 100 industrially and pharmaceutically appealing O-silylated compounds including silanols, borasiloxanes, and silyl ethers via the unprecedented aerobic oxidation of hydrosilane under ambient conditions is demonstrated. Moreover, this heterogeneous oxidase mimic also offers the potential for expanding the catalytic scope of enzymatic synthesis. We anticipate that the strategy demonstrated here will pave a new avenue for understanding the underlying nature of redox enzymes and open up a new class of material systems for artificial biomimetics.

SAXS imaging reveals optimized osseointegration properties of bioengineered oriented 3D-PLGA/aCaP scaffolds in a critical size bone defect model.

Healing large bone defects remains challenging in orthopedic surgery and is often associated with poor outcomes and complications. A major issue with bioengineered constructs is achieving a continuous interface between host bone and graft to enhance biological processes and mechanical stability. In this study, we have developed a new bioengineering strategy to produce oriented biocompatible 3D PLGA/aCaP nanocomposites with enhanced osseointegration. Decellularized scaffolds -containing only extracellular matrix- or scaffolds seeded with adipose-derived mesenchymal stromal cells were tested in a mouse model for critical size bone defects. In parallel to micro-CT analysis, SAXS tensor tomography and 2D scanning SAXS were employed to determine the 3D arrangement and nanostructure within the critical-sized bone. Both newly developed scaffold types, seeded with cells or decellularized, showed high osseointegration, higher bone quality, increased alignment of collagen fibers and optimal alignment and size of hydroxyapatite minerals.

3D bioprinted colorectal cancer models based on hyaluronic acid and signalling glycans.

In cancer microenvironment, aberrant glycosylation events of ECM proteins and cell surface receptors occur. We developed a protocol to generate 3D bioprinted models of colorectal cancer (CRC) crosslinking hyaluronic acid and gelatin functionalized with three signalling glycans characterized in CRC, 3'-Sialylgalactose, 6'-Sialylgalactose and 2'-Fucosylgalactose. The crosslinking, performed exploiting azide functionalized gelatin and hyaluronic acid and 4arm-PEG-dibenzocyclooctyne, resulted in biocompatible hydrogels that were 3D bioprinted with commercial CRC cells HT-29 and patient derived CRC tumoroids. The glycosylated hydrogels showed good 3D printability, biocompatibility and stability over the time. SEM and synchrotron radiation SAXS/WAXS analysis revealed the influence of glycosylation in the construct morphology, whereas MALDI-MS imaging showed that protein profiles of tumoroid cells vary with glycosylation, indicating that sialylation and fucosylation of ECM proteins induce diverse alterations to the proteome of the tumoroid and surrounding cells.

The Nature of Interfacial Catalysis over Pt/NiAl2O4 for Hydrogen Production from Methanol Reforming Reaction.

Reforming of methanol is one of the most favorable chemical processes for on-board H2 production, which alleviates the limitation of H2 storage and transportation. The most important catalytic systems for methanol reacting with water are interfacial catalysts including metal/metal oxide and metal/carbide. Nevertheless, the assessment on the reaction mechanism and active sites of these interfacial catalysts are still controversial. In this work, by spectroscopic, kinetic, and isotopic investigations, we established a compact cascade reaction model (ca. the Langmuir-Hinshelwood model) to describe the methanol and water activation over Pt/NiAl2O4. We show here that reforming of methanol experiences methanol dehydrogenation followed by water-gas shift reaction (WGS), in which two separated kinetically relevant steps have been identified, that is, C-H bond rupture within methoxyl adsorbed on interface sites and O-H bond rupture within OlH (Ol: oxygen-filled surface vacancy), respectively. In addition, these two reactions were primarily determined by the most abundant surface intermediates, which were methoxyl and CO species adsorbed on NiAl2O4 and Pt, respectively. More importantly, the excellent reaction performance benefits from the following bidirectional spillover of methoxyl and CO species since the interface and the vacancies on the support were considered as the real active component in methanol dehydrogenation and the WGS reaction, respectively. These findings provide deep insight into the reaction process as well as the active component during catalysis, which may guide the design of new catalytic systems.

Fully-exposed Pt-Fe cluster for efficient preferential oxidation of CO towards hydrogen purification.

Hydrogen is increasingly being discussed as clean energy for the goal of net-zero carbon emissions, applied in the proton-exchange-membrane fuel cells (PEMFC). The preferential oxidation of CO (PROX) in hydrogen is a promising solution for hydrogen purification to avoid catalysts from being poisoned by the trace amount of CO in hydrogen-rich fuel gas. Here, we report the fabrication of a novel bimetallic Pt-Fe catalyst with ultralow metal loading, in which fully-exposed Pt clusters bonded with neighbor atomically dispersed Fe atoms on the defective graphene surface. The fully-exposed PtFe cluster catalyst could achieve complete elimination of CO through PROX reaction and almost 100% CO selectivity, while maintaining good stability for a long period. It has the mass-specific activity of 6.19 (molCO)*(gPt)-1*h-1 at room temperature, which surpasses those reported in literatures. The exhaustive experimental results and theoretical calculations reveal that the construction of fully-exposed bimetallic Pt-Fe cluster catalysts with maximized atomic efficiency and abundant interfacial sites could facilitate oxygen activation on unsaturated Fe species and CO adsorption on electron-rich Pt clusters to hence the probability of CO oxidation, leading to excellent reactivity in practical applications.

Photocatalytic dehydrogenative C-C coupling of acetonitrile to succinonitrile.

The coupling of acetonitrile into succinonitrile, an important terminal dinitrile for value-added nylon production, via a dehydrogenative route is highly attractive, as it combines the valuable chemical synthesis with the production of green hydrogen energy. Here, we demonstrate that it is possible to achieve a highly selective light driven dehydrogenative coupling of acetonitrile molecules to synthesize succinonitrile using anatase TiO2 based photocatalysts in aqueous medium under mild conditions. Under optimized conditions, the formation rate of succinonitrile reaches 6.55 mmol/(gcat*h), with over 97.5% selectivity to target product. Mechanism studies reveal that water acts as cocatalyst in the reaction. The excited hole of anatase semiconductor oxidizes water forming hydroxyl radical, which subsequently assists the cleavage of sp3 C-H bond of acetonitrile to generate ·CH2CN radical for further C-C coupling. The synergy between TiO2 and Pt cocatalyst is important to enhance the succinonitrile selectivity and prevent undesirable over-oxidation and hydrolysis. This work offers an alternative route to prepare succinonitrile based on renewable energy under mild conditions and avoid the use of toxic reagents and stoichiometric oxidative radical initiators.

Primary Cutaneous Anaplastic Large Cell Lymphoma Arising in a Patient with Rhupus Syndrome and Sjogren's Syndrome.

Rhupus syndrome, as an overlap syndrome of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), is relatively rare because of their substantially different immunopathological mechanisms. Herein, we report the first case of primary cutaneous anaplastic large cell lymphoma (PC-ALCL) in a patient with rhupus syndrome and Sjogren's syndrome and review the relevant literature. A 52-year-old Chinese woman with a history of rhupus syndrome and Sjogren's syndrome was treated with methotrexate, who developed gradually increasing nodules on the waist. Histopathological studies showed that the dermis and subcutaneous tissue were infiltrated with medium-to-large, atypical lymphocytes with the oval nucleus. The tumor cells showed CD3-, CD4-, CD8-, CD30+, LCA+, and EBV-encoded RNA (EBER) in situ hybridization (ISH) was positive. Therefore, the patient was diagnosed with PC-ALCL. Both immune disorders and EBV infection may be related to the onset of PL-ALCL, and further studies are needed to clarify the pathogenesis.

Catalytic Synthesis of Formamides by Integrating CO2 Capture and Morpholine Formylation on Supported Iridium Catalyst.

Herein we report an efficient and recyclable catalytic system for tandem CO2 capture and N-formylation to value-added chemicals. CO2 is apt to be captured by morpholine solution, while a highly efficient heterogeneous catalyst, isolated iridium atoms supported over nanadiamond/graphene, is discovered to be highly reactive for the formylation of morpholine, leading to the formation of N-formylmorpholine with excellent productivity (with a turnover number of 5 120 000 in a single batch reaction) and selectivity (>99 %). In addition, the CO2 captured by morpholine under atmospheric conditions can be converted to N-formylmorpholine with decent conversion (51 %), which realizes the integration of CO2 capture and conversion to value-added chemicals.

Importance of Species Heterogeneity in Supported Metal Catalysts.

The structural heterogeneity of surface metal species, which is represented by the distribution in size, morphology, and local coordination environment of the active metal component, is almost inevitable in practical supported metal catalysts. This is often regarded as a major hindrance to the full utilization of metal loading and the high mass-specific catalytic activity. In this work, by quantitative evaluation of the individual reaction steps of a probe reaction, cyclohexanol dehydrogenation (an important reaction for hydrogen storage and transportation as well as high valued chemical production), we demonstrate that the inherent heterogeneity of supported Rhodium catalysts prepared by conventional synthesis has unique advantages in a complex heterogeneous catalytic reaction. The isolated Rh species (Rh1) is extremely active for the first step of dehydrogenation, the transformation of cyclohexanol to cyclohexanone, while the Rh ensemble sites (Rhe, including Rh clusters, Rhn, and Rh nanoparticles, Rhp) are highly efficient for the successive reaction step, cyclohexanone to phenol, for which the Rh1 sites are almost inactive. Only with the coexistence of both active structures could the optimal reaction performance be achieved, which ambiguously demonstrates the importance of species heterogeneity in some multistep catalytic reactions. Our study provides a new view of the benefits from structural heterogeneity in practical catalysts and sheds light on the catalyst design strategy for complex catalytic reactions.

Atomically dispersed Ir/α-MoC catalyst with high metal loading and thermal stability for water-promoted hydrogenation reaction.

Synthesis of atomically dispersed catalysts with high metal loading and thermal stability is challenging but particularly valuable for industrial application in heterogeneous catalysis. Here, we report a facile synthesis of a thermally stable atomically dispersed Ir/α-MoC catalyst with metal loading as high as 4 wt%, an unusually high value for carbide supported metal catalysts. The strong interaction between Ir and the α-MoC substrate enables high dispersion of Ir on the α-MoC surface, and modulates the electronic structure of the supported Ir species. Using quinoline hydrogenation as a model reaction, we demonstrate that this atomically dispersed Ir/α-MoC catalyst exhibits remarkable reactivity, selectivity and stability, for which the presence of high-density isolated Ir atoms is the key to achieving high metal-normalized activity and mass-specific activity. We also show that the water-promoted quinoline hydrogenation mechanism is preferred over the Ir/α-MoC, and contributes to high selectivity towards 1,2,3,4-tetrahydroquinoline. The present work demonstrates a new strategy in constructing a high-loading atomically dispersed catalyst for the hydrogenation reaction.

Reversing sintering effect of Ni particles on γ-Mo2N via strong metal support interaction.

Reversing the thermal induced sintering phenomenon and forming high temperature stable fine dispersed metallic centers with unique structural and electronic properties is one of the ever-lasting targets of heterogeneous catalysis. Here we report that the dispersion of metallic Ni particles into under-coordinated two-dimensional Ni clusters over γ-Mo2N is a thermodynamically favorable process based on the AIMD simulation. A Ni-4nm/γ-Mo2N model catalyst is synthesized and used to further study the reverse sintering effect by the combination of multiple in-situ characterization methods, including in-situ quick XANES and EXAFS, ambient pressure XPS and environmental SE/STEM etc. The under-coordinated two-dimensional layered Ni clusters on molybdenum nitride support generated from the Ni-4nm/γ-Mo2N has been demonstrated to be a thermally stable catalyst in 50 h stability test in CO2 hydrogenation, and exhibits a remarkable catalytic selectivity reverse compared with traditional Ni particles-based catalyst, leading to a chemo-specific CO2 hydrogenation to CO.

Ferritin-based targeted delivery of arsenic to diverse leukaemia types confers strong anti-leukaemia therapeutic effects.

Trivalent arsenic (AsIII) is an effective agent for treating patients with acute promyelocytic leukaemia, but its ionic nature leads to several major limitations like low effective concentrations in leukaemia cells and substantial off-target cytotoxicity, which limits its general application to other types of leukaemia. Here, building from our clinical discovery that cancerous cells from patients with different leukaemia forms featured stable and strong expression of CD71, we designed a ferritin-based As nanomedicine, As@Fn, that bound to leukaemia cells with very high affinity, and efficiently delivered cytotoxic AsIII into a large diversity of leukaemia cell lines and patient cells. Moreover, As@Fn exerted strong anti-leukaemia effects in diverse cell-line-derived xenograft models, as well as in a patient-derived xenograft model, in which it consistently outperformed the gold standard, showing its potential as a precision treatment for a variety of leukaemias.

Catalytic Amination of Polylactic Acid to Alanine.

In comparison to the traditional petroleum-based plastics, polylactic acid, the most popular biodegradable plastic, can be decomposed into carbon dioxide and water in the environment. However, the natural degradation of polylactic acid requires a substantial period of time and, more importantly, it is a carbon-emitting process. Therefore, it is highly desirable to develop a novel transformation process that can upcycle the plastic trash into value-added products, especially with high chemical selectivity. Here we demonstrate a one-pot catalytic method to convert polylactic acid into alanine by a simple ammonia solution treatment using a Ru/TiO2 catalyst. The process has a 77% yield of alanine at 140 °C, and an overall selectivity of 94% can be reached by recycling experiments. Importantly, no added hydrogen is used in this process. It has been verified that lactamide and ammonium lactate are the initial intermediates and that the dehydrogenation of ammonium lactate initiates the amination, while Ru nanoparticles are essential for the dehydrogenation/rehydrogenation and amination steps. The process demonstrated here could expand the application of polylactic acid waste and inspire new upcycling strategies for different plastic wastes.

Sparse ab initio x-ray transmission spectrotomography for nanoscopic compositional analysis of functional materials.

The performance of functional materials is either driven or limited by nanoscopic heterogeneities distributed throughout the material's volume. To better our understanding of these materials, we need characterization tools that allow us to determine the nature and distribution of these heterogeneities in their native geometry in 3D. Here, we introduce a method based on x-ray near-edge spectroscopy, ptychographic x-ray computed nanotomography, and sparsity techniques. The method allows the acquisition of quantitative multimodal tomograms of representative sample volumes at sub-30 nm half-period spatial resolution within practical acquisition times, which enables local structure refinements in complex geometries. To demonstrate the method's capabilities, we investigated the transformation of vanadium phosphorus oxide catalysts with industrial use. We observe changes from the micrometer to the atomic level and the formation of a location-specific defect so far only theorized. These results led to a reevaluation of these catalysts used in the production of plastics.

Nanostructure-specific X-ray tomography reveals myelin levels, integrity and axon orientations in mouse and human nervous tissue.

Myelin insulates neuronal axons and enables fast signal transmission, constituting a key component of brain development, aging and disease. Yet, myelin-specific imaging of macroscopic samples remains a challenge. Here, we exploit myelin's nanostructural periodicity, and use small-angle X-ray scattering tensor tomography (SAXS-TT) to simultaneously quantify myelin levels, nanostructural integrity and axon orientations in nervous tissue. Proof-of-principle is demonstrated in whole mouse brain, mouse spinal cord and human white and gray matter samples. Outcomes are validated by 2D/3D histology and compared to MRI measurements sensitive to myelin and axon orientations. Specificity to nanostructure is exemplified by concomitantly imaging different myelin types with distinct periodicities. Finally, we illustrate the method's sensitivity towards myelin-related diseases by quantifying myelin alterations in dysmyelinated mouse brain. This non-destructive, stain-free molecular imaging approach enables quantitative studies of myelination within and across samples during development, aging, disease and treatment, and is applicable to other ordered biomolecules or nanostructures.

Complications and management of penile augmentation with hyaluronic acid injection.

Hyaluronic acid injection is becoming a popular way for penile augmentation. However, only few studies and follow-ups have investigated the various complications of hyaluronic acid injection and their corresponding management. In this study, a total of 230 patients who had penile augmentation with hyaluronic acid injection from January 2018 to December 2019 were examined on follow-up for penile girth, complications, and their corresponding management. At 1-month, 3-month, and 6-month postoperative follow-ups, the penile circumference had increased by 2.66 ± 1.24 cm, 2.28 ± 1.02 cm, and 1.80 ± 0.83 cm, respectively. During the entire 6-month follow-up, 4.3% had complications such as subcutaneous bleeding, subcutaneous nodules, and infection. There were no systemic or local allergic reactions among all the patients. All complications were treated accordingly, and no further deterioration or severe sequelae were observed. Although complications of hyaluronic acid injections are mild and rare, these may affect the patient's satisfaction postoperatively. Preoperative redundant prepuce may increase the incidence of penile edema or postoperative gel migration. Standardization of the surgery protocol and elucidation of the effects of other injection parameters are still lacking. Nevertheless, it still highlights the importance of preoperative preparation and surgical technique.