Inhibition of spinal BRD4 alleviates pyroptosis and M1 microglia polarization via STING-IRF3 pathway in morphine-tolerant rats.

BACKGROUND: Morphine tolerance has been a challenging medical issue. Neuroinflammation is considered as a critical mechanism for the development of morphine tolerance. Bromodomain-containing protein 4 (BRD4), a key regulator in cell damage and inflammation, participates in the development of chronic pain. However, whether BRD4 is involved in morphine tolerance and the underlying mechanisms remain unknown. METHODS: The morphine-tolerant rat model was established by intrathecal administration of morphine twice daily for 7 days. Behavior test was assessed by a tail-flick latency test. The roles of BRD4, pyroptosis, microglia polarization and related signaling pathways in morphine tolerance were elucidated by Western blot, real-time quantitative polymerase chain reaction, and immunofluorescence. RESULTS: Repeated morphine administration upregulated BRD4 level, induced pyroptosis, and promoted microglia M1-polarization in spinal cord, accompanied by the release of proinflammatory cytokines, such as TNF-α and IL-1ß. JQ-1, a BRD4 antagonist, alleviated the development of morphine tolerance, diminished pyroptosis and induced the switch of microglia from M1 to M2 phenotype. Mechanistically, stimulator of interferon gene (STING)- interferon regulatory factor 3 (IRF3) pathway was activated and the protective effect of JQ-1 against morphine tolerance was at least partially mediated by inhibition of STING-IRF3 pathway. CONCLUSION: This study demonstrated for the first time that spinal BRD4 contributes to pyroptosis and switch of microglia polarization via STING-IRF3 signaling pathway during the development of morphine tolerance, which extend the understanding of the neuroinflammation mechanism of morphine tolerance and provide an alternative strategy for the precaution against of this medical condition.

The mechanisms, regulations, and functions of histone lysine crotonylation.

Histone lysine crotonylation (Kcr) is a new acylation modification first discovered in 2011, which has important biological significance for gene expression, cell development, and disease treatment. In the past over ten years, numerous signs of progress have been made in the research on the biochemistry of Kcr modification, especially a series of Kcr modification-related "reader", "eraser", and "writer" enzyme systems are identified. The physiological function of crotonylation and its correlation with development, heredity, and spermatogenesis have been paid more and more attention. However, the development of disease is usually associated with abnormal Kcr modification. In this review, we summarized the identification of crotonylation modification, Kcr-related enzyme system, biological functions, and diseases caused by abnormal Kcr. This knowledge supplies a theoretical basis for further exploring the function of crotonylation in the future.

Photo-thermal waxgels with fast wax layer regeneration ability for anti-icing.

Waxgels are known for their unique ability to generate sacrificial wax layers during anti-icing. To address the severe slow regrowth of the wax layer, here, carbon black is incorporated in the waxgel network to endow photothermal function. The rate of the regrowth of the wax layer is raised by >6 times under natural light conditions. Meanwhile, the photothermal waxgel showed improved anti-icing performances in terms of delayed ice formation and lower ice adhesion strength.

Interleukin-18 in chronic pain: Focus on pathogenic mechanisms and potential therapeutic targets.

Chronic pain has been proven to be an independent disease, other than an accompanying symptom of certain diseases. Interleukin-18 (IL-18), a pro-inflammatory cytokine with pleiotropic biological effects, participates in immune modulation, inflammatory response, tumor growth, as well as the process of chronic pain. Compelling evidence suggests that IL-18 is upregulated in the occurrence of chronic pain. Antagonism or inhibition of IL-18 expression can alleviate the occurrence and development of chronic pain. And IL-18 is located in microglia, while IL-18R is mostly located in astrocytes in the spinal cord. This indicates that the interaction between microglia and astrocytes mediated by the IL-18/IL-18R axis is involved in the occurrence of chronic pain. In this review, we described the role and mechanism of IL-18 in different types of chronic pain. This review provides strong evidence that IL-18 is a potential therapeutic target in pain management.

Rich-Carbonyl Carbon Catalysis Facilitating the Li2 CO3 Decomposition for Cathode Lithium Compensation Agent.

The active lithium loss of lithium-ion batteries can be well addressed by adding a cathode lithium compensation agent. Due to the poor conductivity and electrochemical activity, lithium carbonate (Li2 CO3 ) is not considered as a candidate. Herein, an effective cathode lithium compensation agent, the recrystallized Li2 CO3 combined with large specific surface area disordered porous carbon (R-LCO@SPC) is prepared. The screened SPC makes it easier for nano-sized Li2 CO3 to adsorb and decompose on carbon substrate, meantime, exposing plenty of catalytic active sites of C═O, which can significantly improve the electrochemical activity and conductivity of Li2 CO3 , thus greatly reducing the decomposition potential of Li2 CO3 (4.0 V) and releasing high irreversible capacity (580 mAh g-1 ) compared to the unmodified Li2 CO3 (nearly no capacity above 4.6 V). Meantime, the Li2 CO3 can disappear completely without any by-product after the initial cycle accompanied by partially dissolved in electrolyte, optimizing the composition of SEI. The resultant lithium compensation agent applied to LMFP//graphite full cell exhibits a 19.1% increase in energy density, enhancing the rate and cycling performance, demonstrating great practical applications potential in high energy density lithium-ion batteries.

Prognostic factors and benefit populations of ovarian function suppression in premenopausal HR+/HER2+ early-stage breast cancer patients who received trastuzumab: Evidence from a real-world study with long-term follow-up.

BACKGROUND: Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-positive (HER2+) breast cancer exhibits considerable heterogeneity, and it is of great interest whether patients with premenopausal HR+/HER2+ breast cancer treated with trastuzumab can benefit from ovarian function suppression (OFS) therapy similarly to HR+/HER2- breast cancer. Here, we conducted a real-world study in this population to identify both who would derive substantial benefits from the addition of OFS and clinicopathological factors with potential prognostic value. METHODS: Multicenter data from 253 premenopausal patients with HR+/HER2+ early-stage breast cancer who received trastuzumab from October 2009 to October 2018 were retrospectively included. The Kaplan-Meier method was used for survival analysis, while the log-rank test was used to compare the survival rates. Univariate and multifactor Cox regression analyses were performed to analyze the independent risk factors affecting invasive disease-free survival (IDFS). RESULTS: After a median follow-up of 98.50 months, compared with tamoxifen/toremifene alone, tamoxifen/toremifene/aromatase inhibitors plus OFS demonstrated significant benefits in the overall study population (HR = 0.289, 95% CI: 0.100-0.835, p = 0.022, 8-year IDFS rate: 90.78% vs. 95.54%), especially in the lymph node-positive subgroup and age ≤40 years subgroup. Age ≤40 years, histological grade >2, lymph node involvement, PR ≤50%, and tamoxifen alone were independent prognostic factors. CONCLUSIONS: For premenopausal HR+ breast cancer patients, HER2 positivity alone is an indication for the addition of OFS in adjuvant endocrine therapy. Age, histological grade, lymph node status, the expression of PR, and OFS treatment were independent prognostic factors in this population.

Double-Network Organohydrogels Toughened by Solvent Exchange.

Double-network hydrogels based on calcium alginate are extensively exploited. Unfortunately, their low strength and unstable constitution to open environments limit their application potential. Herein, a new type of double-network organohydrogel (OHG) is proposed. By solvent exchange, a stable physical network is established based on dimethyl sulfoxide (DMSO)-alginate in the presence of a polyacrylamide network. The DMSO content endows tunable mechanical properties, with a maximum tensile strength of ≈1.7 MPa. Importantly, the OHG shows much better environmental stability compared to the conventional double-network hydrogels. Due to the reversible association of hydrogen bonds, the OHG possesses some unique properties, including free-shapeability, shape-memory, and self-adhesion, that offers several promising ways to utilize alginate-based gels for wide applications.

Liquid-based biomarkers in breast cancer: looking beyond the blood.

In recent decades, using circulating tumor cell (CTC), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), exosomes and etc. as liquid biomarkers has received enormous attention in various tumors, including breast cancer (BC). To date, efforts in the area of liquid biopsy predominantly focus on the analysis of blood-based markers. It is worth noting that the identifications of markers from non-blood sources provide unique advantages beyond the blood and these alternative sources may be of great significance in offering supplementary information in certain settings. Here, we outline the latest advances in the analysis of non-blood biomarkers, predominantly including urine, saliva, cerebrospinal fluid, pleural fluid, stool and etc. The unique advantages of such testings, their current limitations and the appropriate use of non-blood assays and blood assays in different settings are further discussed. Finally, we propose to highlight the challenges of these alternative assays from basic to clinical implementation and explore the areas where more investigations are warranted to elucidate its potential utility.

Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers.

BACKGROUND: Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ microenvironment affects the clinically-predictive value of this model. We implemented a GSC monolayer system to investigate in situ-in vitro molecular correspondence and the relationship between in vitro and patient response to temozolomide (TMZ). METHODS: DNA/RNA-sequencing was performed on 56 glioblastoma tissues and 19 derived GSC cultures. Sensitivity to TMZ was screened across 66 GSC cultures. Viability readouts were related to clinical parameters of corresponding patients and whole-transcriptome data. RESULTS: Tumour DNA and RNA sequences revealed strong similarity to corresponding GSCs despite loss of neuronal and immune interactions. In vitro TMZ screening yielded three response categories which significantly correlated with patient survival, therewith providing more specific prediction than the binary MGMT marker. Transcriptome analysis identified 121 genes related to TMZ sensitivity of which 21were validated in external datasets. CONCLUSION: GSCs retain patient-unique hallmark gene expressions despite loss of their natural environment. Drug screening using GSCs predicted patient response to TMZ more specifically than MGMT status, while transcriptome analysis identified potential biomarkers for this response. GSC drug screening therefore provides a tool to improve drug development and precision medicine for glioblastoma.

Construction of the Stable Lubricant Film on One-Dimensional Cone-Structured Surfaces for Directional Liquid Transport.

Directional liquid transport along one-dimensional structures finds vast applications in fog harvest, liquid separation, sensing, chemical synthesis, and numerous other scenarios. Dynamically, the liquid transport speed is boosted by the driving force and retarded by the hysteresis from the liquid/substrate interface. A capillary force-relied lubricant film or a covalently attached polymer brush on the surface could increase liquid mobility temporarily by reducing the interfacial hysteresis. However, the easy depletion of the lubricant film and the stringent restriction of the substrate severely hamper droplet's directional transport in a long run. Herein, we report a feasible and durable hysteresis reduction design with the polymer-brush stabilized lubricating surface (PBSLS). The PBSLS is achieved through incorporating liquid-like polydimethylsiloxane brushes (b-PDMS) and the liquid PDMS oligomer (o-PDMS). The covalent attached b-PDMS "locks" the lubricant oil o-PDMS to the cone surface via strong intermolecular van der Waals force in between. The PBSLS on the cone surface can be sustained under constant shearing force from liquid transport for at least 6 h. A cone with such PBSLS shows increased ability of droplet transport and enhanced fog collection performance in the long run. This design supplies an effective way toward regulating macro-level interfacial performance through surface design on the molecular level.

Toll-like Receptor 2-Melatonin Feedback Loop Regulates the Activation of Spinal NLRP3 Inflammasome in Morphine-Tolerant Rats.

BACKGROUND AND PURPOSE: Morphine is amongst the most effective analgesics available for the management of severe pain. However, prolonged morphine treatment leads to analgesic tolerance which limits its clinical usage. Previous studies have demonstrated that melatonin ameliorates morphine tolerance by reducing neuroinflammation. However, little is known about the relationship between Toll like receptor 2 (TLR2) and neuroinflammation in morphine tolerance. The aim of this study was to explore the role of TLR2 in morphine tolerance and its connections with melatonin and Nod-like receptor protein 3 (NLRP3) inflammasome. METHODS: Sprague-Dawley rats were treated with morphine for 7 days and tail-flick latency test was performed to identify the induction of analgesic tolerance. The roles of TLR2 in microglia activation and morphine tolerance were assessed pharmacologically, and the possible interactions between melatonin, TLR2 and NLRP3 inflammasome were investigated. KEY RESULTS: Morphine tolerance was accompanied by increased TLR2 expression and NLRP3 inflammasome activation in spinal cord. whereas melatonin level was down-regulated. Chronic melatonin administration resulted in a reduced TLR2 expression and NLRP3 inflammasome activation. Moreover, the analgesic effect of morphine was partially restored. Inhibition of TLR2 suppressed the microglia and NLRP3 inflammasome activation, as well as restored the spinal melatonin level while attenuated the development of morphine tolerance. Furthermore, the inhibition of microglia activation ameliorated morphine tolerance via inhibiting TLR2-NLRP3 inflammasome signaling in spinal cord. CONCLUSION: In this study, we directly demonstrate a TLR2-melatonin negative feedback loop regulating microglia and NLRP3 inflammasome activation during the development of morphine tolerance.

Circular RNA FEACR inhibits ferroptosis and alleviates myocardial ischemia/reperfusion injury by interacting with NAMPT.

BACKGROUND: Emerging research has reported that circular RNAs (circRNAs) play important roles in cardiac cell death after myocardial ischemia and reperfusion (I/R). Ferroptosis, a new form of cell death discovered in recent years, has been proven to participate in the regulation of myocardial I/R. This study used circRNA sequencing to explore the key circRNA in the regulation of cardiac ferroptosis after I/R and study the mechanisms of potential circRNA function. METHODS: We performed circRNA sequencing to explore circRNAs differentially expressed after myocardial I/R. We used quantitative polymerase chain reactions to determine the circRNA expression in different tissues and detect the circRNA subcellular localization in the cardiomyocyte. Gain- and loss-of-function experiments were aimed to examine the function of circRNAs in cardiomyocyte ferroptosis and cardiac tissue damage after myocardial I/R. RNA pull-down was applied to explore proteins interacting with circRNA. RESULTS: Here, we identified a ferroptosis-associated circRNA (FEACR) that has an underlying regulatory role in cardiomyocyte ferroptosis. FEACR overexpression suppressed I/R-induced myocardial infarction and ameliorated cardiac function. FEACR inhibition induces ferroptosis in cardiomyocytes and FEACR overexpression inhibits hypoxia and reoxygenation-induced ferroptosis. Mechanistically, FEACR directly bound to nicotinamide phosphoribosyltransferase (NAMPT) and enhanced the protein stability of NAMPT, which increased NAMPT-dependent Sirtuin1 (Sirt1) expression, which promoted the transcriptional activity of forkhead box protein O1 (FOXO1) by reducing FOXO1 acetylation levels. FOXO1 further upregulated the transcription of ferritin heavy chain 1 (Fth1), a ferroptosis suppressor, which resulted in the inhibition of cardiomyocyte ferroptosis. CONCLUSIONS: Our finding reveals that the circRNA FEACR-mediated NAMPT-Sirt1-FOXO1-FTH1 signaling axis participates in the regulation of cardiomyocyte ferroptosis and protects the heart function against I/R injury. Thus, FEACR and its downstream factors could be novel targets for alleviating ferroptosis-related myocardial injury in ischemic heart diseases.

Combined chemo-endocrine therapy as a potential new option for HR+/HER2- advanced breast cancer: a prospective study of fulvestrant plus oral vinorelbine.

OBJECTIVE: Endocrine therapy with fulvestrant has shown synergistic antitumor effects with some chemotherapy drugs in vitro. This study evaluated the efficacy and safety of fulvestrant with vinorelbine in patients with hormone receptor positive (HR+)/human epidermal growth factor receptor-2-negative (HER2-) recurrent or metastatic breast cancer. METHODS: Patients were intramuscularly administered fulvestrant 500 mg (day 1 per cycle for 28 days) and oral vinorelbine (60 mg/m2 on days 1, 8, and 15 of each cycle). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, objective response rate, disease control rate, duration of response, and safety. RESULTS: A total of 38 patients with HR+/HER2- advanced breast cancer included in the study were followed up for a median time of 25.1 months. The overall median PFS was 9.86 months [95% confidence interval (CI) 7.2-23.13], and the median PFS of the first-line and the second-line treatment population was 20.73 months (95% CI 9.82 to NR) and 4.27 months (95% CI 3.68 to NR), respectively. Most adverse events reported were of grade 1/2, and none were of grade 4/5. CONCLUSIONS: This is the first exploratory study of a fulvestrant and oral vinorelbine regimen in the treatment of HR+/HER2- recurrent and metastatic breast cancer. The combination chemo-endocrine therapy was efficacious, safe, and promising for patients with HR+/HER2- advanced breast cancer.

Nacre-inspired layered composite gels with broad tunable mechanical strength and structural color for stress visualization.

The brick-and-mortar architecture of nacre shells brings radiant structural colors, high toughness, and strength, inspiring numerous designs for structural and optical materials. However, constructing structural color is not always easy, especially among soft materials where aligning components against random and dynamically active environments is generally difficult. Here, we propose a composite organohydrogel capable of visualizing multiple levels of stress, featuring broad tunable mechanical properties, dynamic mechanochromism, deep low working temperatures, and anti-drying attributes. In the composite gels, the intercalation between α-zirconium phosphate (α-ZrP) nanoplates and poly-(diacetone acrylamide-co-acrylamide) is induced by shear-orientation-assisted self-assembly followed by solvent replacement. The highly tailorable (from ∼780 nm to ∼445 nm) range of colors was achieved by regulating the concentration of α-ZrP and glycerol inside the matrix. With the help from glycerol, the composite gels exhibited long-term stability (7 d) in the arid condition and remarkable low-temperature tolerance (-80 °C). The extraordinary mechanical property (compressive strength up to 119 MPa) of composite gels is achieved by the assembled α-ZrP plates with a small aspect ratio, high negative charge repulsion, and abundant hydrogen bonding sites. As a result, the mechanochromic sensor based on the composite gel enjoys a wide range of stress detection (0-1862 KPa). This study provides a new strategy for constructing high strength structural-colored gels, opening up opportunities for sensitive yet strong mechanochromic sensors in extreme environments.

Cre-loxP-mediated genetic lineage tracing: Unraveling cell fate and origin in the developing heart.

The Cre-loxP-mediated genetic lineage tracing system is essential for constructing the fate mapping of single-cell progeny or cell populations. Understanding the structural hierarchy of cardiac progenitor cells facilitates unraveling cell fate and origin issues in cardiac development. Several prospective Cre-loxP-based lineage-tracing systems have been used to analyze precisely the fate determination and developmental characteristics of endocardial cells (ECs), epicardial cells, and cardiomyocytes. Therefore, emerging lineage-tracing techniques advance the study of cardiovascular-related cellular plasticity. In this review, we illustrate the principles and methods of the emerging Cre-loxP-based genetic lineage tracing technology for trajectory monitoring of distinct cell lineages in the heart. The comprehensive demonstration of the differentiation process of single-cell progeny using genetic lineage tracing technology has made outstanding contributions to cardiac development and homeostasis, providing new therapeutic strategies for tissue regeneration in congenital and cardiovascular diseases (CVDs).

Clinicopathologic characteristics and prognostic significance of HER2-low expression in patients with early breast cancer: A systematic review and meta-analysis.

Background: HER2-low expression breast cancer (BC) accounts for approximately 45%-55% of all BC cases. The purpose of this study was to investigate the prognostic difference between patients with HER2-low expression and HER2-zero BC. Methods: An electronic search of Pubmed, Embase, Cochrane Library, and Web of Science databases was performed to screen studies that included prognostic comparisons between HER2-zero and HER2-low expression groups. A total of 14 studies involving 52106 patients were included. Results: Our results indicated that HER2-low expression was associated with a significant benefit in OS among all patients with early BC (HR, 0.83; 95% CI, 0.78-0.88), patients with hormone-receptor positive BC (HR, 0.83; 95% CI, 0.77-0.89), and patients with TNBC (HR, 0.78; 95% CI, 0.70-0.87). HER2-low expression was associated with a significant benefit in DFS among all patients (HR, 0.81; 95% CI, 0.71-0.93), patients with hormone receptor-positive BC (HR, 0.81; 95% CI, 0.72-0.90), but no significant difference in DFS was found in patients with TNBC (HR, 0.87; 95% CI, 0.65-1.17). HER2-low expression was associated with a significant benefit in RFS among all patients (HR, 0.90; 95% CI, 0.85-0.95), patients with hormone receptor-positive BC (HR, 0.90; 95% CI, 0.84-0.96), but no significant difference in RFS was found in patients with TNBC (HR, 0.80; 95% CI, 0.55-1.16). Conclusions: Among patients with early-stage BC, patients with HER2-low expression BC had better OS in the overall population, hormone receptor-positive and TNBC subgroups. Besides, favorable DFS and RFS were observed in both the overall population and hormone receptor-positive subgroup. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier (CRD 42022349458).

ABRO1 arrests cardiomyocyte proliferation and myocardial repair by suppressing PSPH.

The role of Abraxas 2 (ABRO1 or KIAA0157), a component of the lysine63-linked deubiquitinating system, in the cardiomyocyte proliferation and myocardial regeneration is unknown. Here, we found that ABRO1 regulates cardiomyocyte proliferation and cardiac regeneration in the postnatal heart by targeting METTL3-mediated m6A methylation of Psph mRNA. The deletion of ABRO1 increased cardiomyocyte proliferation in hearts and restored the heart function after myocardial injury. On the contrary, ABRO1 overexpression significantly inhibited the neonatal cardiomyocyte proliferation and cardiac regeneration in mouse hearts. The mechanism by which ABRO1 regulates cardiomyocyte proliferation mainly involved METTL3-mediated Psph mRNA methylation and CDK2 phosphorylation. In the early postnatal period, METTL3-dependent m6A methylation promotes cardiomyocyte proliferation by hypermethylation of Psph mRNA and upregulating PSPH expression. PSPH dephosphorylates cyclin-dependent kinase 2 (CDK2), a positive regulator of cell cycle, at Thr14/Tyr15 and increases its activity. Upregulation of ABRO1 restricts METTL3 activity and halts the cardiomyocyte proliferation in the postnatal hearts. Thus, our study reveals that ABRO1 is an essential contributor in the cell cycle withdrawal and attenuation of proliferative response in the postnatal cardiomyocytes and could act as a potential target to accelerate cardiomyocyte proliferation and cardiac repair in the adult heart.

Assessing early changes in plasma HER2 levels is useful for predicting therapeutic response in advanced breast cancer: A multicenter, prospective, noninterventional clinical study.

BACKGROUND: Early prediction of treatment response is crucial for the optimal treatment of advanced breast cancer. We aimed to explore whether monitoring early changes in plasma human epidermal growth factor receptor 2 (HER2) levels using digital PCR (dPCR) could predict the treatment response in advanced breast cancer. METHODS: This was a multicenter, prospective, noninterventional clinical study of patients with advanced breast cancer. All enrolled patients underwent blood testing to measure the HER2 levels by digital PCR before treatment initiation and once every 3 weeks during the study. The primary endpoints werea the diagnostic value of dPCR for detecting HER2 status in the blood andb the relevance of potential changes in the plasma HER2 level at 3 weeks from baseline for predicting treatment response. RESULTS: Overall, 85 patients were enrolled between October 9, 2018, and January 23, 2020. dPCR had a specificity of 91.67% (95% CI: 80.61% to 97.43%) for detecting HER2 amplification, and the area under the receiver operating characteristic (ROC) curve was 0.84 (p < 0.01). A clinically relevant specificity threshold of approximately 90%, which was equivalent to a ≥15% decrease in the plasma HER2 ratio at 3 weeks from baseline, showed a positive predictive value of 97.37% (95% CI: 77.11% to 98.65%) in terms of predicting clinical benefit. Patients whose plasma HER2 ratio was reduced by ≥15% had a longer median progression-free survival (PFS) than those whose ratio was reduced by <15% (9.20 months vs. 4.50 months, p < 0.01). CONCLUSIONS: Early changes in the plasma HER2 ratio may predict the treatment response in patients with advanced breast cancer and could facilitate optimal treatment selection.

Conjugated Poly(ionic liquid)-Based Nanoporous Membrane for Rapid Moisture Response.

Stimuli-responsive nanoporous materials represent a newly emerging category of functional materials, for which instant and significant response behavior is strongly demanded but still challenging. Herein, a new kind of conjugated poly(ionic liquid)s (PILs) synthesized via a simple one-pot spontaneous nucleophilic substitution and polymerization between 4,4'-vinylenedipyridine and propargyl bromide is reported. A nanoporous membrane actuator is further developed via ionic complexation between the current PIL and trimesic acid. The actuator carries a gradient density in the hydrophobicity content along the membrane cross-section, which results in a fast response to moisture.

A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis.

Intestinal epithelial cells (IECs) are implicated in the propagation of T-cell-mediated inflammatory diseases, including graft-versus-host disease (GVHD), but the underlying mechanism remains poorly defined. Here, we report that IECs require receptor-interacting protein kinase-3 (RIPK3) to drive both gastrointestinal (GI) tract and systemic GVHD after allogeneic hematopoietic stem cell transplantation. Selectively inhibiting RIPK3 in IECs markedly reduces GVHD in murine intestine and liver. IEC RIPK3 cooperates with RIPK1 to trigger mixed lineage kinase domain-like protein-independent production of T-cell-recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell-produced interferon gamma enhances this RIPK1/RIPK3 action in IECs through a JAK/STAT1-dependent mechanism, creating a feed-forward inflammatory cascade. RIPK1/RIPK3 forms a complex with JAK1 to promote STAT1 activation in IECs. The RIPK1/RIPK3-mediated inflammatory cascade of alloreactive T-cell responses results in intestinal tissue damage, converting the local inflammation into a systemic syndrome. Human patients with severe GVHD showed highly activated RIPK1 in the colon epithelium. Finally, we discover a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis, and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1/RIPK3 in IECs represents an effective nonimmunosuppressive strategy for GVHD treatment and potentially for other diseases involving GI tract inflammation.