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As a new family of two-dimensional (2D) nanomaterials, MXenes have recently attracted much attention because of high performance in versatile applications including energy storage and electrochemistry, but their specific application to biomedicine has been rarely reported, especially for theranostic nanomedicine, i.e., concurrent diagnostic imaging and therapy. This study shows for the first time surface engineering and functionalization of 2D Ti 3 C 2 MXene nanosheets by the integration of GdW 10 -based polyoxometalates (POMs). These multifunctional GdW 10 @Ti 3 C 2 composite nanosheets provide hyperthermal treatment with magnetic resonance (MR) and/or computed tomography (CT) imaging guidance toward tumor cells or xenografts. A tumor was effectively eradicated without further reoccurrence during the observation period. GdW 10 nanoclusters that were integrated onto the surface of Ti 3 C 2 nanosheets were demonstrated to serve as a contrast agent for contrast-enhanced CT and MR imaging based on their unique composition, thus showing the potential for diagnostic-imaging guidance and monitoring for tumor hyperthermia nanotherapy. The high in vivo biocompatibility of GdW 10 @Ti 3 C 2 composite nanosheets was demonstrated to guarantee their subsequent translation into a medical treatment. This study provides a novel strategy for broadening the biomedical applications of MXenes by surface engineering and multifunctionalization, which is expected to promote further exploration of biomedical applications of MXenes in nanotheranostics.

The utilization of recycled brick aggregate (RBA) and recycled brick powder (RBP) in cementitious materials helps the reclamation of clay brick waste in construction and demolition waste. This work studied the properties of cementitious materials with RBA as aggregate and RBP as supplementary cementitious material. The RBA has lower apparent density and higher water absorption than natural aggregate, and RBP with an irregular micro-structure contains high content of silicon and aluminum oxides and possesses excellent pozzolanic activity. Incorporating RBP decreases the fluidity and increases the setting time, but the incorporated RBP improves the pore structure and decreases the average pore diameter of cementitious materials, thereby decreasing the permeability. Utilizing RBA increases the drying shrinkage, while the incorporated RBP decreases the drying shrinkage of cementitious materials; the mortar with 50% RBA and 30% RBP has the lower drying shrinkage than the common mortar without RBA and RBP. Incorporating RBA and high-volume RBP decreases the mechanical strength, while there is no obvious decrease in the mechanical strength for the mortar with 50% RBA and 30% RBP. Moreover, the flexural strength to compressive strength ratio increases with RBA and RBP incorporating. Utilizing RBA increases the water transport, while the water transport properties decrease with the RBP incorporation; incorporating appropriate content of RBA and RBP can obtain the cementitious materials with low permeability. Particularly, a significant decrease in chloride ingress occurs with the substitution of RBP.

Background Photothermal therapy (PTT) frequently cause thermal resistance in tumor cells by inducing the heat shock response, limiting its therapeutic effect. Hydrogen sulfide (H 2 S) with appropriate concentration can reverse the Warburg effect in cancer cells. The combination of PTT with H 2 S gas therapy is expected to achieve synergistic tumor treatment. Methods Here, sulourea (Su) is developed as a thermosensitive/hydrolysable H 2 S donor to be loaded into Pd nanocubes through in-depth coordination for construction of the Pd-Su nanomedicine for the first time to achieve photo-controlled H 2 S release, realizing the effective combination of photothermal therapy and H 2 S gas therapy. Results The Pd-Su nanomedicine shows a high Su loading capacity (85 mg g −1 ), a high near-infrared (NIR) photothermal conversion efficiency (69.4%), and NIR-controlled H 2 S release by the photothermal-triggered hydrolysis of Su. The combination of photothermal heating and H 2 S produces a strong synergetic effect by H 2 S-induced inhibition of heat shock response, thereby effectively inhibiting tumor growth. Moreover, high intratumoral accumulation of the Pd-Su nanomedicine after intravenous injection also enables photothermal/photoacoustic dual-mode imaging-guided tumor treatment. Conclusions The proposed NIR-responsive heat/H 2 S release strategy provides a new approach for effective cancer therapy. Graphic abstract

To evaluate the efficacy of baricitinib in combination therapy for managing refractory, rapidly progressive systemic sclerosis (SSc) with severe cardiac conduction defects and interstitial lung disease (ILD). A 48-year-old male patient with SSc complicated by significant cardiac enlargement, third-degree atrioventricular block, heart failure, progressive ILD, and partial intestinal obstruction was included in the study. Prior treatments with mycophenolate mofetil (MMF), tacrolimus, and cyclophosphamide (CTX) had shown limited efficacy. The patient subsequently received a combination regimen of glucocorticoids, intravenous immunoglobulins, CTX, and baricitinib (4 mg daily). The patient exhibited significant clinical improvements, including a reduction in cardiac size, restoration of sinus rhythm, and resolution of heart failure symptoms. ILD and skin sclerosis showed substantial regression. Pulmonary function tests indicated significant recovery in lung capacity and diffusion capacity. Additionally, gastrointestinal symptoms such as abdominal pain and bloating were completely resolved. This case highlights the potential of baricitinib as an adjunctive therapy for refractory SSc with multiorgan involvement. The observed improvements in cardiac conduction defects, ILD, and skin fibrosis suggest that JAK inhibitors may offer a promising therapeutic avenue for severe SSc cases resistant to conventional treatments.

Background and aimsRadiotherapy for neoplastic disease is associated with significant adverse enteric effects associated with excessive cell death. Ionising radiation induces cell death by a mechanism that is dependent on JNK (c-jun N-terminal kinase) pathway signalling. Additionally, it is known that cells exposed to extracellular bacterial products such as flagellin, pleiotropically activate a number of innate immune pathways, including that of JNK. The JNK pathway controls its own activity by inducing the transcription of mitogen-activated protein kinase phosphatase-7 (MKP-7) which directly targets phosphorylated JNK, thus functioning as a negative feedback loop. Previously, it has been shown that flagellin limits ionising radiation-induced mortality in mice, but the cellular mechanism of protection remained unknown.MethodsWild-type C57BL/6 or tlr5−/− C57BL/6 were injected with flagellin 2 h before exposure to irradiation, and their intestines were examined for apoptosis. Candidate proteins mediating cytoprotection from irradiation were identified by expression profiling. One of these candidates, MKP-7, was cloned and packaged into adenovirus particles, used to infect cultured cells, and examined for the extent to which its activity reduced cellular apoptosis by flow cytometry or immunoblot analysis.ResultsFlagellin pretreatment protected mice from radiation-induced intestinal mucosal injury and apoptosis via a Toll-like receptor 5 (TLR5)-dependent mechanism. Expression profiling of flagellin-treated mice showed upregulation of MKP-7, an inducible repressor of the JNK pathway. MKP-7 expression reached a maximum at 2 h after flagellin treatment, coinciding with suppression of phosphorylated JNK and JNK pathway inhibition. Furthermore, constitutive MKP-7 expression protected cultured cells from radiation-induced apoptosis.ConclusionsFlagellin is a promising adjuvant for suppressing ionising radiation-induced injury. MKP-7 activity exhibits cytoprotective effects, and is thus a candidate cellular molecule for limiting the damaging effect of radiotherapy on the gastreointestinal system.

Mimetics of bacterial DNA, given orally or subcutaneously, protect mice from experimental colitis via a toll-like receptor (TLR)-9-dependent mechanism. The goal of the study was to define whether synthetic viral RNA, polyinosinic acid:cytidylic acid [poly(I:C)], which is also a potent immunomodulator, might also affect murine colitis and, if so, define whether such effects were mediated by TLR3, which is one of at least 4 known receptors for this viral RNA analog.MethodsMice (C57BL6, IL-10KO, or TLR3 KO) were administered 1.5% dextran sodium sulfate (DSS) in drinking water for 7 days. Two hours before treatment with DSS, mice were given phosphate-buffered saline (PBS) or poly(I:C) 20 μg subcutaneously (s.c.), or 100 μg intragastrically (i.g.).ResultsIn wildtype mice s.c. administration of poly(I:C) dramatically protected against DSS-induced colitis as assessed by every parameter analyzed, which included body weight, rectal bleeding, colonic myeloperoxidase, histopathology, serum keratinocyte-derived chemokine, serum amyloid A, and lipocalin-2. In contrast, i.g. administration of poly(I:C) offered no protection in this colitis model nor did its administration activate the innate immune system as assessed by serologic parameters. Subcutaneous poly(I:C) protected against DSS-induced colitis equally well in C57BL6 and IL-10KO mice, indicating that this antiinflammatory cytokine is not required for such protection. Protection against colitis given by poly(I:C) treatment was ablated in TLR3 KO, indicating that the protective action of this viral RNA analog was mediated by this receptor.ConclusionsActivation of TLR3 on cells that are accessible by systemic, but not oral, administration of synthetic viral RNA results in protection against the acute inflammation that can ensue upon damage of the gut epithelium. Thus, this viral RNA analog, which is under clinical trials for other inflammatory disorders (e.g., lupus), may also have therapeutic value for inflammatory bowel disease.

Genetic transformation of wheat, using biolistics or Agrobacterium , underpins a range of specific research methods for identifying genes and studying their function in planta . Transgenic approaches to study and modify traits in durum wheat have lagged behind those for bread wheat. Here we report the use of Agrobacterium strain AGL1, with additional vir genes housed in a helper plasmid, to transform and regenerate the durum wheat variety Ofanto. The use of the basic pSoup helper plasmid with no additional vir genes failed to generate transformants, whereas the presence of either vir G 542 or the 15 kb Komari fragment containing vir B, vir C and vir G 542 produced transformation efficiencies of between 0.6 and 9.7%. Of the 42 transgenic plants made, all but one (which set very few seeds) appeared morphologically normal and produced between 100 and 300 viable seeds. The transgene copy number and the segregation ratios were found to be very similar to those previously reported for bread wheat. We believe that this is the first report describing successful genetic transformation of tetraploid durum wheat ( Triticum turgidum L. var. durum ) mediated by Agrobacterium tumefaciens using immature embryos as the explant.

Bifunctional magnetic-luminescent dansylated Fe 3 O 4 @SiO 2 (Fe 3 O 4 @SiO 2 -DNS) nanoparticles were fabricated by the nucleophilic substitution of dansyl chloride with primary amines of aminosilane-modified Fe 3 O 4 @SiO 2 core–shell nanostructures. The morphology and properties of the resultant Fe 3 O 4 @SiO 2 -DNS nanoparticles were investigated by transmission electron microscopy, FT–IR spectra, UV–vis spectra, photoluminescence spectra, and vibrating sample magnetometry. The Fe 3 O 4 @SiO 2 -DNS nanocomposites exhibit superparamagnetic behavior at room temperature, and can emit strong green light under the excitation of UV light. They show very low cytotoxicity against HeLa cells and negligible hemolysis activity. The T 2 relaxivity of Fe 3 O 4 @SiO 2 -DNS in water was determined to be 114.6 Fe mM −1  s −1 . Magnetic resonance (MR) imaging analysis coupled with confocal microscopy shows that Fe 3 O 4 @SiO 2 -DNS can be uptaken by the cancer cells effectively. All these positive attributes make Fe 3 O 4 @SiO 2 -DNS a promising candidate for both MR and fluorescent imaging applications.

Commensal bacterial colonization of the intestine is essential for normal intestinal development, renewal, and repair. Injury to the intestinal mucosa can occur with infection, surgical trauma, and in idiopathic inflammatory bowel disease (IBD). Repair of mucosal injury, termed restitution, as well as restoration of intestinal homeostasis involves induced and coordinated proliferation and migration of intestinal epithelial cells. N-formyl peptide receptors (FPRs) are widely expressed pattern recognition receptors that can specifically bind and induce responses to host-derived and bacterial peptides and small molecules during repair of mucosal injury in a redox dependent manner. However, little is known about the host-microbiota crosstalk mediated by FPRs during repair of gut mucosal injuries. We hypothesized that distinct members of the gut microbiota preferentially colonize the restitutive mucosa and influence wound repair processes in a FPR1-dependent fashion.MethodsTo study restitution of epithelial wounds, defined mechanical wounds were inflicted in mouse distal colon by using a miniature endoscope and forceps. Microbiota studies were performed by high throughput sequencing of the V4 region of 16s rRNA gene of the bacteria harvested from mucosal wounds undergoing different stages of restitutive events.ResultsHere we report that the high throughput sequencing analysis of bacterial 16s rDNA revealed a spatiotemporal shift in the composition and diversity of microbiota. Importantly, the community structure of the microbiota associated with restitutive mucosa is distinctly different from that of luminal contents or intact mucosa. Moreover, our data demonstrated that FPR1 is required for the changes in microenvironment of mucosal wounds. These changes include depletion of oxygen, expression of muc 3 mucin, as well as, rapid enrichment of a distinct commensal species Akkermansia, an anaerobic, mucinophilic bacterium. We demonstrated that A. mucinophila, in turn, stimulates FPR1 on intestinal epithelial cells to generate reactive oxygen species (ROS) via enterocyte NADPH oxidase 1 (NOX1), enhancing migration and proliferation of enterocytes, ultimately eventuating in rapid closure of colonic wounds.ConclusionsTaken together, these findings identify a novel role of FPR1 to promote changes in the wound microenvironment to such extent that enriches a specific mucosa-associated bacterium to enhance enterocyte migration and proliferation in a FPR1-mediated and redox-dependent fashion. Herein, we propose to advance the knowledge of the function of gut microbiota during restitution of mucosal wounds by elucidating molecular mechanism of microbial interaction with the host intestinal epithelial cells that could be harnessed to develop therapeutics for inflammatory bowel disease (IBD).

Using eco-friendly recycled brick powder (RBP) derived from waste brick to prepare strain hardening cementitious composites (SHCC) provides a new way of recycling the construction and demolition waste (CDW), and the dosage of cement in SHCC can be decreased. This paper investigated the micro-properties and mechanical properties of SHCC containing RBP by a series of experiments. The results showed that RBP had typical characteristics of supplementary cementitious material (SCM). The addition of RBP increased the SiO2 content and decreased the hydration products in cementitious materials; in this case, the mechanical properties of mortar decreased with increasing RBP replacements, and a linear relationship was observed between them. It was noticed that the adverse effect of RBP on the mechanical properties decreased with increasing PVA fiber content in mortar. For SHCC containing various RBP replacements, the ultimate load increased, and the ultimate displacement decreased with increasing curing days. When using RBP to replace cement by weight, the ultimate displacement increased with the addition of RBP. Meanwhile, there was no significant reduction in the ultimate load of SHCC. When using RBP to replace fly ash (FA) by weight, the incorporation of RBP decreased the ultimate displacement of SHCC, whereas the ultimate load was improved. For example, the ultimate load and displacement of SHCC with 54%RBP were 17.6% higher and 16.4% lower, respectively, than those of SHCC with 54% FA.