3D printable strong and tough composite organo-hydrogels inspired by natural hierarchical composite design principles.

Fabrication of composite hydrogels can effectively enhance the mechanical and functional properties of conventional hydrogels. While ceramic reinforcement is common in many hard biological tissues, ceramic-reinforced hydrogels lack a similar natural prototype for bioinspiration. This raises a key question: How can we still attain bioinspired mechanical mechanisms in composite hydrogels without mimicking a specific composition and structure? Abstracting the hierarchical composite design principles of natural materials, this study proposes a hierarchical fabrication strategy for ceramic-reinforced organo-hydrogels, featuring (1) aligned ceramic platelets through direct-ink-write printing, (2) poly(vinyl alcohol) organo-hydrogel matrix reinforced by solution substitution, and (3) silane-treated platelet-matrix interfaces. Unit filaments are further printed into a selection of bioinspired macro-architectures, leading to high stiffness, strength, and toughness (fracture energy up to 31.1 kJ/m2), achieved through synergistic multi-scale energy dissipation. The materials also exhibit wide operation tolerance and electrical conductivity for flexible electronics in mechanically demanding conditions. Hence, this study demonstrates a model strategy that extends the fundamental design principles of natural materials to fabricate composite hydrogels with synergistic mechanical and functional enhancement.

Genetically engineered membrane-based nanoengagers for immunotherapy of pancreatic cancer.

Modulating macrophages presents a promising avenue in tumor immunotherapy. However, tumor cells have evolved mechanisms to evade macrophage activation and phagocytosis. Herein, we introduced a bispecific antibody-based nanoengager to facilitate the recognition and phagocytosis of tumor cells by macrophages. Specifically, we genetically engineered two single chain variable fragments (scFv) onto cell membrane: anti-CD40 scFv for engaging with macrophages and anti-Claudin18.2 (CLDN18.2) scFv for interacting with tumor cells. These nanoengagers were further constructed by coating scFv-anchored membrane into PLGA nanoparticle core. Our developed nanoengagers significantly boosted immune responses, including increased recognition and phagocytosis of tumor cells by macrophages, enhanced activation and antigen presentation, and elevated cytotoxic T lymphocyte activity. These combined benefits resulted in enhancing antitumor efficacy against highly aggressive "cold" pancreatic cancer. Overall, this study offers a versatile nanoengager design for immunotherapy, achieved through genetically engineering to incorporate antibody-anchored membrane.

Two Novel Iboga-Type and an Oxindole Glucuronide Alkaloid from Tabernaemontana peduncularis Disclose Related Biosynthetic Pathways to Tabernaemontana divaricata.

Phytochemical investigation of the two Tabernaemontana species (Apocynaceae) T. peduncularis Wall. and T. divaricata (L.) R.Br. ex Roem. & Schult. indicated closely related biosynthetic pathways leading to lipophilic and hydrophilic alkaloids. In total, 18 specialized metabolites comprising indole-derived alkaloid aglycones, three oxindole-derived alkaloid glycosides, and two iridoid glucosides could be identified in the studied species. Among the alkaloids, the two Iboga-type alkaloids 3,7-coronaridine isoindolenine, coronaridine 3,4-iminium and a javaniside derivative bearing a glucuronic acid, named javanuronic acid, could be described by spectroscopic and spectrometric methods for the first time. A docking experiment using alpha-fold was performed to generate a protein model of the enzyme 7-deoxyloganetic acid glucosyl transferase. Performed bioassays exhibited a growth reduction of neonate Spodoptera littoralis larvae and reduced cell viability of HepG2 cells of the extracts containing Iboga alkaloids, whilst the javaniside derivatives containing hydrophilic fraction did not show any effects. These findings indicate a high flexibility in the formation of bioactive indole alkaloid aglycones by Tabernaemontana species and also evidence similar accumulation trends in both species as well as indicate that biosynthetic routes leading to oxindole alkaloids like javanisides are more widespread than reported. Furthermore, the incorporation of the three novel compounds into potential biosynthetic pathways is discussed.

SiP-heterocycles derived from a bulky phosphanylsilylene.

Bis(1-adamantyl)phosphanylsilylene 1 was reacted with ArCCR (Ar = Ph, 4-iPr-C6H4, 3-F-C6H4; R = H, Ph) at 80 °C under microwave irradiation to afford fluorescence-active SiP-heterocycles 3a-d, which may undergo unique isomerizations starting from silirene intermediates. Moreover, the treatment of 1 with AdCP furnished a heavy congener of cyclopentadiene (4), whose formation involves cleavage of the Si(II)-P bond that is rarely observed in silylene chemistry.

Prognostic role of radiological splenic vessel involvement in patients with resectable pancreatic ductal adenocarcinoma of the body and tail: A retrospective analysis based on a large population.

BACKGROUND: Tumors located in the pancreatic body or tail are more likely to invade splenic vessels; however, splenic artery (SpA) or vein (SpV) involvement is not included in the criteria for resectability. We aimed to analyze the prognostic role of radiological splenic vessel involvement in patients with resectable pancreatic ductal adenocarcinoma (PDAC) of the body and tail. METHODS: Patients with resetable PDAC were retrospectively reviewed and analyzed. SpA and SpV involvement were graded as clear, abutment and encasement. Multivariate Cox and logistic regression analyses were used to identify prognostic factors for overall survival (OS) and risk factors for early recurrence, respectively. RESULTS: Of the 234 patients, 94 patients had radiologic SpA invasion, including abutment in 47 patients and encasement in 47 patients, while 123 patients had radiological SpV invasion, including abutment in 69 patients and encasement in 54 patients. Patients with SpA or SpV encasement showed a significantly worse OS and recurrence-free survival than those with SpA or SpV clear (P < 0.001, respectively). In multivariate analysis, both SpA and SpV encasement were independently associated with poor OS (SpA: hazard ratio [HR] 1.89, P = 0.010; SpV: HR 2.01, P = 0.001) and early recurrence (SpA: odds ratio [OR] 4.98, P < 0.001; SpV: OR 3.71, P = 0.002). CONCLUSION: Radiological SpA or SpV encasement independently decreases OS, and is associated with early recurrence of resectable PDAC of the body/tail.

Strain-Stiffening Ionogel with High-Temperature Tolerance via the Synergy of Ionic Clusters and Hydrogen Bonds.

Highly stretchable and conductive ionogels have great potential in flexible electronics and soft robotic skins. However, current ionogels are still far from being able to accurately duplicate the mechanically responsive behavior of real human skin. Furthermore, durable robotic skins that are applicable under harsh conditions are still lacking. Herein, a strong noncovalent interaction, ionic clusters, is combined with hydrogen bonds to obtain a physically cross-linked ionogel (PCI). Benefiting from the strong ionic bonding of the ionic cluster, the PCI shows strain-stiffening behavior similar to that of human skin, thus enabling it to have a perception-strengthening ability. Additionally, the strong ionic clusters can also ensure the PCI remains stable at high temperatures. Even when the temperature is raised to 200 °C, the PCI can maintain the gel state. Moreover, the PCI exhibits high transparency, recyclability, good adhesion, and high conductivity. Such excellent features distinguish the PCI from ordinary ionogels, providing a new way to realize skin-like sensing in harsh environments for future bionic machines.

Time-Restricted Feeding Ameliorates Uterine Epithelial Estrogen Receptor α Transcriptional Activity at the Time of Embryo Implantation in Mice Fed a High-Fat Diet.

BACKGROUND: More than 30% of reproductive-age women are obese or overweight. Obesity and exposure to a high-fat diet (HFD) detrimentally affect endometrial development and embryo implantation. We previously reported that time-restricted feeding (TRF) improved ovarian follicular development, but whether and how TRF modulates embryo implantation are poorly understood. OBJECTIVE: We investigated the effect of TRF on embryo implantation. METHODS: In TRF group, mice had 10 h of food free access from 9 pm to 7 am, and fed a normal diet or a HFD. Tail vein injection of Chicago blue dye was used to examine embryo implantation sites at day 5.5 (D5.5) of pregnancy. Serum collected at D0.5 and D4.5 of pregnancy was used to examine the level of estradiol (E2) and progesterone. Uterine estrogen receptor (ER) and progesterone receptor levels and their targeted aquaporins (AQPs) were measured. LC-MS was used to analyze bile acid (BA) composition, and primary hepatocytes were used to test the effects of BA on the expression level of SULT1E1, a key enzyme in estrogen inactivation and elimination. RESULTS: We found that TRF prevented HFD-induced embryo loss and alleviated the defect in luminal closure on D4.5 of pregnancy. The cyclic changes of E2 level were lost in mice fed ad libitum but not in TRF mice on the HFD. The HFD increased ER-α expression and transcriptional activity, which induced AQP3 and AQP5 expression on D4.5 of pregnancy. TRF prevented the negative effect of the HFD on uterine luminal closure. Furthermore, in vitro and in vivo results showed that BA suppressed estrogen degradation by activating liver SULT1E1 expression. CONCLUSIONS: Our findings demonstrated that TRF prevented HFD-induced defects in luminal closure, thereby improving embryonic implantation, and provide novel insights into the effects of dietary intervention on obesity and associated infertility.

The Prevalence and Antibiotic-Resistant of Listeria monocytogenes in Livestock and Poultry Meat in China and the EU from 2001 to 2022: A Systematic Review and Meta-Analysis.

To compare the prevalence and antibiotic resistance rate of Listeria monocytogenes in livestock and poultry (beef, pork and chicken) meat between China and the European Union (EU), a meta-analysis was conducted. Ninety-one out of 2156 articles in Chinese and English published between January 2001 and February 2022 were selected from four databases. The prevalence of L. monocytogenes in livestock and poultry (beef, pork and chicken) meat in China and Europe was 7.1% (3152/56,511, 95% CI: 5.8-8.6%) and 8.3% (2264/889,309, 95% CI: 5.9-11.0%), respectively. Moreover, a decreasing trend was observed in both regions over time. Regarding antibiotic resistance, for the resistance to 15 antibiotics, the pooled prevalence was 5.8% (95% CI: 3.1-9.1%). In both regions, the highest prevalence was found in oxacillin, ceftriaxone and tetracycline, and a large difference was reported between China and the EU in ceftriaxone (52.6% vs. 17.3%) and cefotaxime (7.0% vs. 0.0%). Based on the above, it remains a significant challenge to enforce good control measures against the meat-sourced L. monocytogenes both in China and in the EU.

Tumor Cell Nanovaccines Based on Genetically Engineered Antibody-Anchored Membrane.

Despite the promise in whole-tumor cell vaccines, a key challenge is to overcome the lack of costimulatory signals. Here, agonistic-antibody-boosted tumor cell nanovaccines are reported by genetically engineered antibody-anchored membrane (AAM) technology, capable of effectively activating costimulatory pathways. Specifically, the AAM can be stably constructed following genetic engineering of tumor cell membranes with anti-CD40 single chain variable fragment (scFv), an agonistic antibody to induce costimulatory signals. The nanovaccines are versatilely designed and obtained based on the anti-CD40 scFv-anchored membrane and nanotechnology. Following vaccination, the anti-CD40 scFv-anchored membrane nanovaccine (Nano-AAM/CD40) significantly facilitates dendritic cell maturation in CD40-humanized transgenic mice and subsequent adaptive immune responses. Compared to membrane-based nanovaccines alone, the enhanced antitumor efficacy in both "hot" and "cold" tumor models of the Nano-AAM/CD40 demonstrates the importance of agonistic antibodies in development of tumor-cell-based vaccines. To expand the design of nanovaccines, further incorporation of cell lysates into the Nano-AAM/CD40 to conceptually construct tumor cell-like nanovaccines results in boosted immune responses and improved antitumor efficacy against malignant tumors inoculated into CD40-humanized transgenic mice. Overall, this genetically engineered AAM technology provides a versatile design of nanovaccines by incorporation of tumor-cell-based components and agonistic antibodies of costimulatory immune checkpoints.

Prevention and Treatment of Grade C Postoperative Pancreatic Fistula.

Postoperative pancreatic fistula (POPF) is a troublesome complication after pancreatic surgeries, and grade C POPF is the most serious situation among pancreatic fistulas. At present, the incidence of grade C POPF varies from less than 1% to greater than 9%, with an extremely high postoperative mortality rate of 25.7%. The patients with grade C POPF finally undergo surgery with a poor prognosis after various failed conservative treatments. Although various surgical and perioperative attempts have been made to reduce the incidence of grade C POPF, the rates of this costly complication have not been significantly diminished. Hearteningly, several related studies have found that intra-abdominal infection from intestinal flora could promote the development of grade C POPF, which would help physicians to better prevent this complication. In this review, we briefly introduced the definition and relevant risk factors for grade C POPF. Moreover, this review discusses the two main pathways, direct intestinal juice spillover and bacterial translocation, by which intestinal microbes enter the abdominal cavity. Based on the abovementioned theory, we summarize the operation techniques and perioperative management of grade C POPF and discuss novel methods and surgical treatments to reverse this dilemma.

Neoadjuvant therapy in resectable pancreatic cancer: A promising curative method to improve prognosis.

Currently, 15 randomized controlled trials (RCTs) have been designed to investigate whether neoadjuvant therapy (NAT) benefits patients with resectable pancreatic adenocarcinoma (R-PA) compared to surgery alone. Five of them have acquired results so far; however, corresponding conclusions have not been obtained. We speculated that the reason for this phenomenon could be that some prognostic factors had proven to be adverse through upfront surgery curative patterns, but some of them were not regarded as independent baseline characteristics, which is important to obtaining comparability between the NAT and upfront surgery groups. This fact could cause bias and lead to the difference in the outcomes of RCTs. In this review, we collate data about risk factors (such as tumor size, resection margin, and lymph node status) influencing the prognoses of patients with R-PA from five RCTs and discuss the possible reasons for the varying outcomes.

Challenges and Breakthroughs in Selective Amide Activation.

In contrast to ketones and carboxylic esters, amides are classically seen as comparatively unreactive members of the carbonyl family, owing to their unique structural and electronic features. However, recent decades have seen the emergence of research programmes focused on the selective activation of amides under mild conditions. In the past four years, this area has continued to rapidly develop, with new advances coming in at a fast pace. Several novel activation strategies have been demonstrated as effective tools for selective amide activation, enabling transformations that are at once synthetically useful and mechanistically intriguing. This Minireview comprises recent advances in the field, highlighting new trends and breakthroughs in what could be called a new age of amide activation.

Dual Inhibition of EGFR and IGF-1R Signaling Leads to Enhanced Antitumor Efficacy against Esophageal Squamous Cancer.

Both the epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-1R) have been implicated in the development of cancers, and the increased expression of both receptors has been observed in esophageal cancer. However, the tyrosine kinase inhibitors of both receptors have thus far failed to provide clinical benefits for esophageal cancer patients. Studies have confirmed the complicated crosstalks that exist between the EGFR and IGF-1R pathways. The EGFR and IGF-1R signals act as mutual compensation pathways, thereby conveying resistance to EGFR or IGF-1R inhibitors when used alone. This study evaluated the antitumor efficacy of the EGFR/HER2 inhibitors, gefitinib and lapatinib, in combination with the IGF-1R inhibitor, linsitinib, on the esophageal squamous cell carcinoma (ESCC). Gefitinib or lapatinib, in combination with linsitinib, synergistically inhibited the proliferation, migration, and invasion of ESCC cells, caused significant cell cycle arrest, and induced marked cell apoptosis. Their combination demonstrated stronger inhibition on the activation of EGFR, HER2, and IGF-1R as well as the downstream signaling molecules. In vivo, the addition of linsitinib to gefitinib or lapatinib also potentiated the inhibition effects on the growth of xenografts. Our results suggest the next clinical exploration of the combination of gefitinib or lapatinib with linsitinib in the treatment of ESCC patients.

Synthesis of α-Aryl Acrylamides via Lewis-Base-Mediated Aryl/Hydrogen Exchange.

Herein we report a method for the synthesis of α-aryl acrylamides leveraging polar S-to-C aryl migrations induced by a Lewis basic organocatalyst. In contrast to previously reported radical aryl migrations of sulfonyl acrylimides, this polar process enables subsequent elimination, ultimately leading to a formal aryl/hydrogen exchange including SO2 extrusion. This reaction is selective for electron-deficient aromatic groups, while tolerating a variety of substituents on nitrogen and in the ß-position, and it delivers useful building blocks for further transformations, including cycloaddition and cyclisation reactions. The mechanism was investigated in detail using quantum chemical calculations, which unexpectedly revealed the Lewis base to be involved in several decisive steps.

Active Model-Based Hysteresis Compensation and Tracking Control of Pneumatic Artificial Muscle.

The hysteretic nonlinearity of pneumatic artificial muscle (PAM) is the main factor that degrades its tracking accuracy. This paper proposes an efficient hysteresis compensation method based on the active modeling control (AMC). Firstly, the Bouc-Wen model is adopted as the reference model to describe the hysteresis of the PAM. Secondly, the modeling errors are introduced into the reference model, and the unscented Kalman filter is used to estimate the state of the system and the modeling errors. Finally, a hysteresis compensation strategy is designed based on AMC. The compensation performances of the nominal controller with without AMC were experimentally tested on a PAM. The experimental results show that the proposed controller is more robust when tracking different types of trajectories. In the transient, both the overshoot and oscillation can be successfully attenuated, and fast convergence is achieved. In the steady-state, the proposed controller is more robust against external disturbances and measurement noise. The proposed controller is effective and robust in hysteresis compensation, thus improving the tracking performance of the PAM.

Challenges and Breakthroughs in Selective Amide Activation.

In contrast to ketones and carboxylic esters, amides are classically seen as comparatively unreactive members of the carbonyl family, owing to their unique structural and electronic features. However, recent decades have seen the emergence of research programmes focused on the selective activation of amides under mild conditions. In the past four years, this area has continued to rapidly develop, with new advances coming in at a fast pace. Several novel activation strategies have been demonstrated as effective tools for selective amide activation, enabling transformations that are at once synthetically useful and mechanistically intriguing. This Minireview comprises recent advances in the field, highlighting new trends and breakthroughs in what could be called a new age of amide activation.

Nanozyme-Powered Giant Unilamellar Vesicles for Mimicry and Modulation of Intracellular Oxidative Stress.

The bottom-up construction of enzyme-based artificial cells is generating increasing interest, but achieving artificial cells for "all artificial modules" remains challenging in synthetic biology. Here, we introduce a fully synthetic cell system by integration of biomimetic nanozymes into giant unilamellar vesicles (GUVs). To mimic native peroxidase for free radical generation by taking advantage of Fenton catalysis reactions, we designed and prepared a de novo artificial nanozyme composed of ferritin heavy-chain scaffold protein and catalytic Fe3O4 nanoparticles as the active center. As two examples in bioapplications, we showed this nanozyme-powered GUV system not only mimics intracellular oxidative stress pathways but also induces tumor cell death by sensing and responding to external chemical signals. Specifically, we recreated intracellular biochemical events, including DNA damage and lipid peroxidation, in the compartmentalized GUVs by taking advantage of nanozyme induction of defined catalytic reactions. Additionally, the GUV system also actively induced DNA double-strand breakage and lipid damage of tumor cells, in response to the high expression of H2O2 within the tumor microenvironment. This concept-of-proof study offers a promising option for defining catalysis in biological systems and gives new insights into the de novo creation of artificial cells in a fully synthetic manner.

Particle-based artificial three-dimensional stem cell spheroids for revascularization of ischemic diseases.

Development of new approaches to biomimetically reconstruct vasculature networks remains challenging in regenerative medicine. We introduce a particle-based artificial stem cell spheroid (ASSP) technology that recapitulates paracrine functions of three-dimensional (3D) SSPs for vasculature regeneration. Specifically, we used a facile method to induce the aggregation of stem cells into 3D spheroids, which benefited from hypoxia microenvironment-driven and enhanced secretion of proangiogenic bioactive factors. Furthermore, we artificially reconstructed 3D spheroids (i.e., ASSP) by integration of SSP-secreted factors into micro-/nanoparticles with cell membrane-derived surface coatings. The easily controllable sizes of the ASSP particles provided superior revascularization effects on the ischemic tissues in hindlimb ischemia models through local administration of ASSP microparticles and in myocardial infarction models via the systemic delivery of ASSP nanoparticles. The strategy offers a promising therapeutic option for ischemic tissue regeneration and addresses issues faced by the bottlenecked development in the delivery of stem cell therapies.

A Novel Model System for Understanding Anticancer Activity of Hypoxia-Activated Prodrugs.

Reports on the comprehensive factors for design considerations of hypoxia-activated prodrugs (HAPs) are rare. We introduced a new model system composed of a series of highly water-soluble HAPs, providing a platform to comprehensively understand the interaction between HAPs and hypoxic biosystems. Specifically, four kinds of new HAPs were designed and synthesized, containing the same biologically active moiety but masked by different bioreductive groups. Our results demonstrated that the activity of the prodrugs was strongly dependent on not only the molecular structure but also the hypoxic tumor microenvironment. We found the presence of a direct linear relationship between cytotoxicity of the HAPs and the reduction potential of whole molecule/oxygen concentration/reductase expression. Moreover, limited blood vasculature in hypoxic regions was also a critical barrier for effective activation of the HAPs. This study offers a comprehensive insight into understanding the design factors required for HAPs.