RNA aggregates harness the danger response for potent cancer immunotherapy.

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Construction of a human cell landscape at single-cell level.

Single-cell analysis is a valuable tool for dissecting cellular heterogeneity in complex systems1. However, a comprehensive single-cell atlas has not been achieved for humans. Here we use single-cell mRNA sequencing to determine the cell-type composition of all major human organs and construct a scheme for the human cell landscape (HCL). We have uncovered a single-cell hierarchy for many tissues that have not been well characterized. We established a 'single-cell HCL analysis' pipeline that helps to define human cell identity. Finally, we performed a single-cell comparative analysis of landscapes from human and mouse to identify conserved genetic networks. We found that stem and progenitor cells exhibit strong transcriptomic stochasticity, whereas differentiated cells are more distinct. Our results provide a useful resource for the study of human biology.

Harnessing endogenous transcription factors directly by small molecules for chemically induced pluripotency inception.

Chemistry-alone approach has recently been applied for incepting pluripotency in somatic cells, representing a breakthrough in biology. However, chemical reprogramming is hampered by low efficiency, and the underlying molecular mechanisms remain unclear. Particularly, chemical compounds do not have specific DNA-recognition domains or transcription regulatory domains, and then how do small molecules work as a driving force for reinstating pluripotency in somatic cells? Furthermore, how to efficiently clear materials and structures of an old cell to prepare the rebuilding of a new one? Here, we show that small molecule CD3254 activates endogenous existing transcription factor RXRα to significantly promote mouse chemical reprogramming. Mechanistically, CD3254-RXRα axis can directly activate all the 11 RNA exosome component genes (Exosc1-10 and Dis3) at transcriptional level. Unexpectedly, rather than degrading mRNAs as its substrates, RNA exosome mainly modulates the degradation of transposable element (TE)-associated RNAs, particularly MMVL30, which is identified as a new barrier for cell-fate determination. In turn, MMVL30-mediated inflammation (IFN-γ and TNF-α pathways) is reduced, contributing to the promotion of successful reprogramming. Collectively, our study provides conceptual advances for translating environmental cues into pluripotency inception, particularly, identifies that CD3254-RXRα-RNA exosome axis can promote chemical reprogramming, and suggests modulation of TE-mediated inflammation via CD3254-inducible RNA exosome as important opportunities for controlling cell fates and regenerative medicine.

Inhibition of Syk promotes chemical reprogramming of fibroblasts via metabolic rewiring and H2 S production.

Chemical compounds have recently been introduced as alternative and non-integrating inducers of pluripotent stem cell fate. However, chemical reprogramming is hampered by low efficiency and the molecular mechanisms remain poorly characterized. Here, we show that inhibition of spleen tyrosine kinase (Syk) by R406 significantly promotes mouse chemical reprogramming. Mechanistically, R406 alleviates Syk / calcineurin (Cn) / nuclear factor of activated T cells (NFAT) signaling-mediated suppression of glycine, serine, and threonine metabolic genes and dependent metabolites. Syk inhibition upregulates glycine level and downstream transsulfuration cysteine biosynthesis, promoting cysteine metabolism and cellular hydrogen sulfide (H2 S) production. This metabolic rewiring decreased oxidative phosphorylation and ROS levels, enhancing chemical reprogramming. In sum, our study identifies Syk-Cn-NFAT signaling axis as a new barrier of chemical reprogramming and suggests metabolic rewiring and redox homeostasis as important opportunities for controlling cell fates.

Adipose Triglyceride Lipase-Mediated Adipocyte Lipolysis Exacerbates Acute Pancreatitis Severity in Mouse Models and Patients.

Dyslipolysis of adipocytes has played a critical role in various diseases. Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme in adipocyte autonomous lipolysis. However, whether the degree of adipocyte lipolysis relates to the prognoses in acute pancreatitis (AP) and the role of ATGL-mediated lipolysis in the pathogenesis of AP remain elusive. The visceral adipose tissue consumption rate in the acute stage was measured in both patients with AP and mouse models. Lipolysis levels and ATGL expression were detected in caerulein-induced AP models. CL316,243, a lipolysis stimulator, and adipose tissue-specific ATGL knockout mice were used to further investigate the role of lipolysis in AP. The ATGL-specific inhibitor, atglistatin, was used in C57Bl/6N and ob/ob AP models. This study found that increased visceral adipose tissue consumption rate in the acute phase was independently associated with adverse prognoses in patients with AP, which was validated in mice AP models. Lipolysis of adipocytes was elevated in AP mice. Stimulation of lipolysis could aggravate AP. Genetic blockage of ATGL specifically in adipocytes was able to alleviate the damage to AP. The application of atglistatin could effectively protect against AP in both lean and obese mice. These findings demonstrated that ATGL-mediated adipocyte lipolysis exacerbates AP and highlighted the therapeutic potential of ATGL as a drug target for AP.

Multicolor Long-Term Single-Particle Tracking Using 10 nm Upconverting Nanoparticles.

Single-particle tracking (SPT) is a powerful technique to unveil molecular behaviors crucial to the understanding of many biological processes, but it is limited by factors such as probe photostability and spectral orthogonality. To overcome these limitations, we develop upconverting nanoparticles (UCNPs), which are photostable over several hours at the single-particle level, enabling long-term multicolor SPT. We investigate the brightness of core-shell UCNPs as a function of inert shell thickness to minimize particle size while maintaining sufficient signal for SPT. We explore different rare-earth dopants to optimize for the brightest probes and find that UCNPs doped with 2% Tm3+/30% Yb3+, 10% Er3+/90% Yb3+, and 15% Tm3+/85% Yb3+ represent the optimal probes for blue, green, and near-infrared emission, respectively. The multiplexed 10 nm probes enable three-color single-particle tracking on live HeLa cells for tens of minutes using a single, near-infrared excitation source. These photostable and multiplexed probes open new avenues for numerous biological applications.

Associations of Intrapancreatic Fat Deposition With Incident Diseases of the Exocrine and Endocrine Pancreas: A UK Biobank Prospective Cohort Study.

INTRODUCTION: To investigate whether increased intrapancreatic fat deposition (IPFD) heightens the risk of diseases of the exocrine and endocrine pancreas. METHODS: A prospective cohort study was conducted using data from the UK Biobank. IPFD was quantified using MRI and a deep learning-based framework called nnUNet. The prevalence of fatty change of the pancreas (FP) was determined using sex- and age-specific thresholds. Associations between IPFD and pancreatic diseases were assessed with multivariate Cox-proportional hazard model adjusted for age, sex, ethnicity, body mass index, smoking and drinking status, central obesity, hypertension, dyslipidemia, liver fat content, and spleen fat content. RESULTS: Of the 42,599 participants included in the analysis, the prevalence of FP was 17.86%. Elevated IPFD levels were associated with an increased risk of acute pancreatitis (hazard ratio [HR] per 1 quintile change 1.513, 95% confidence interval [CI] 1.179-1.941), pancreatic cancer (HR per 1 quintile change 1.365, 95% CI 1.058-1.762) and diabetes mellitus (HR per 1 quintile change 1.221, 95% CI 1.132-1.318). FP was also associated with a higher risk of acute pancreatitis (HR 3.982, 95% CI 2.192-7.234), pancreatic cancer (HR 1.976, 95% CI 1.054-3.704), and diabetes mellitus (HR 1.337, 95% CI 1.122-1.593, P = 0.001). DISCUSSION: FP is a common pancreatic disorder. Fat in the pancreas is an independent risk factor for diseases of both the exocrine pancreas and endocrine pancreas.

Comparative mitochondrial genome analysis provides new insights into the classification of Modiolinae.

BACKGROUND: Mitochondrial genomes have become a powerful tool for studying molecular genetics and phylogeny of mollusks. Currently, the position of Modiolinae within Mytilidae and the taxonomic and phylogenetic relationships within Modiolinae were still controversial. This study focuses on the complete mitochondrial genomes of two species: Modiolus modulaides (Röding, 1798) and Modiolus auriculatus Krauss, 1848, which have not been sequenced before. METHODS AND RESULTS: We assembled and characterized the mitochondrial genomes of M. modulaides and M. auriculatus and then analyzed the phylogenetic relationships. The mitochondrial genomes of M. modulaides and M. auriculatus were 15,422 bp and 16,027 bp, respectively. Both of them were composed of 36 functional genes, including 12 protein-coding genes, 22 transfer RNAs, and 2 ribosomal RNAs. All protein-coding genes showed A + T bias, positive GC skews, and negative AT skews in nucleotide composition. Phylogenetic analysis based on the mitochondrial genomes showed that Modiolinae and Bathymodiolinae clustered together to form a sister relationship. Seven Modiolinae species were divided into two clades: L1 (M. modulaides, M. auriculatus and Modiolus philippinarum Hanley, 1843) and L2 [Modiolus modiolus (Linnaeus, 1758), Modiolus kurilensis Bernard, 1983, Modiolus nipponicus (Oyama, 1950), and Modiolus comptus (Sowerby III, 1915)]. The divergence time of the two clades was approximately 105.75 Ma. Furthermore, the transfer RNA gene rearrangement, longer genetic distance, and greater genetic differentiation were confirmed between the L1 and L2 clades, as well as differences in the external characteristics of the shells of the two clades. CONCLUSIONS: Based on the molecular data, it was speculated that species from the L1 clade might belong to other genera or new genera. This study provides molecular information for further taxonomic and phylogenetic studies of Mytilidae.

Histological study of Bactrian camel cryptorchidism and expression of immunoglobulin λ light chain in the testicular and epididymis of cryptorchid Bactrian camel.

Lambda light chains (λ-LCs) are frequently responsible for triggering the activation of inflammatory factors in autoimmune disorders, and an increase in their levels will cause various pathological changes in serum. The aim of this study was to determine the histological differences between the epididymis and testis of normal and cryptorchid Bactrian camels and the differences in λ-LC expression in the epididymis and testis of normal and cryptorchid Bactrian camels. Haematoxylin and eosin (H&E) staining was used to examine the pathological changes in cryptorchidism. The gene and protein levels of λ-LC were determined using RT-qPCR and western blot. The distribution of λ-LCs was assessed by immunohistochemistry and immunofluorescence. Compared with that in normal Bactrian camels, the diameter of the epididymal lumen and the thickness of the epithelium were decreased in the epididymis of cryptorchidic animals. Additionally, no sperm was detected in the cavity of the cryptorchidic epididymis. Meanwhile, the expression of λ-LC was significantly increased in the cryptorchidic epididymis at both the mRNA and protein levels (p < .05). The highest protein expression of λ-LC was found in epididymal epithelial halo cells and testicular Sertoli cells. These findings suggested that the structural changes observed in the epididymal epithelium of cryptorchidic camels affect its secretory and absorptive functions. Additionally, the high level of λ-LC expression recorded in halo cells suggested that these cells play an important role in epithelial immunity in cryptorchidic Bactrian camels. Furthermore, the high λ-LC expression levels detected in normal testicular Sertoli cells indicated that λ-LCs may be involved in spermatogenesis. The results of this study provide clues for an in-depth study of immunological sterility in cryptorchidic Bactrian camels.

[Relationship Between Cerebrovascular Reactivity and Depression in Patients With End-Stage Renal Disease].

Objective To investigate the relationship between cerebrovascular reactivity (CVR) and emotional disorders in the patients undergoing continuous hemodialysis for end-stage renal disease (ESRD).Methods The clinical data of the ESRD patients undergoing continuous hemodialysis were collected.Anxiety and depression of the patients were assessed by the Hamilton anxiety scale (HAMA) and Beck depression inventory,respectively.The cerebral hemodynamic changes during the breath holding test were monitored by transcranial Doppler sonography,and the breath-holding index (BHI) was calculated.The BHI≥0.69 and BHI<0.69 indicate normal CVR and abnormal CVR,respectively.Binary Logistic regression was employed to analyze the factors affecting the depressive state of ESRD patients.Results The group with abnormal CVR exhibited higher total cholesterol level (P=0.010),low density lipoprotein level (P=0.006),and incidence of depression (P=0.012) than the group with normal CVR.Compared with the non-depression group,the depression group displayed prolonged disease course (P=0.039),reduced body mass index (P=0.048),elevated HAMA score (P=0.001),increased incidence of anxiety (P<0.001),decreased BHI (P=0.015),and increased incidence of abnormal CVR (P=0.012).Binary Logistic regression analysis indicated anxiety as a contributing factor (OR=22.915,95%CI=2.653-197.956,P=0.004) and abnormal CVR as a risk factor (OR=0.074,95%CI=0.008-0.730,P=0.026) for depression.Conclusion Impaired CVR could pose a risk for depression in the patients with ESRD.

Chiroptical Activity of An Achiral Emissive Eu Metal-Organic Framework.

Chiroptical activity of achiral crystals is theoretically allowed but very unusual. There is a particularly scarcity of empirical studies on optically active achiral metal-organic frameworks (MOFs). Herein we report an achiral emissive Eu MOF and its chiroptical properties both in the ground and excited states. The framework crystallizes in an achiral space group (Pna21 ) belonging to the polar point group (mm2), where the asymmetric arrangement of racemic trinuclear Eu-oxo clusters is responsible for the optical activity. A pair of circular dichroisms (CD) and circularly polarized luminescence (CPL) peaks with opposite signs were observed for single crystals. Importantly, the luminescence dissymmetry factor can reach up to 1.1×10-3 , which is comparable in magnitude to the value of most of the chiral-linker-bridged MOFs. This work gives the first example of achiral MOFs with CPL response and should be instructive for the discovery of more CPL emitters from racemic MOF family.

Biliary sepsis complication with congenital hepatic fibrosis: an unexpected outcome.

BACKGROUND: CHF (Congenital hepatic fibrosis) is a rare hereditary disease characterized by periportal fibrosis and ductal plate malformation. Little is known about the clinical presentations and outcome in CHF patients with an extraordinary complication with biliary sepsis. Our case described a 23-year-old female diagnosed as CHF combined with biliary sepsis. Her blood culture was positive for KP (Klebsiella pneumoniae), and with a high level of CA19-9 (> 1200.00 U/ml, ref: <37.00 U/ml). Meanwhile, her imaging examinations showed intrahepatic bile duct dilatation, portal hypertension, splenomegaly, and renal cysts. Liver pathology revealed periportal fibrosis and irregularly shaped proliferating bile ducts. Whole-exome sequencing identified two heterozygous missense variants c.3860T > G (p. V1287G) and c.9059T > C (p. L3020P) in PKHD1 gene. After biliary sepsis relieved, her liver function test was normal, and imaging examination results showed no significant difference with the results harvested during her biliary sepsis occurred. CONCLUSION: The diagnosis of CHF complicated with biliary sepsis in the patient was made. Severely biliary sepsis due to KP infection may not inevitably aggravate congential liver abnormality in young patients. Our case provides a good reference for timely treatment of CHF patients with biliary sepsis.

Association between the location of social medical insurance and social integration among China's elderly rural migrants: a nationwide cross-sectional study.

BACKGROUND: Universal social medical insurance coverage is viewed as a major factor in promoting social integration, but insufficient evidence exists on the integration of elderly rural migrants (ERM), generally aged 60 years and above, in low- and middle-income countries. To address this problem, we explore the relationship between the location of social medical insurance (SMI), such as a host city, and social integration in the context of Chinese ERM. METHODS: This study is based on data from the 2017 National Internal Migrant Dynamic Monitoring Survey in China. The study participants were Chinese ERM. An integration index was constructed to measure the degree of social integration in a multi-dimensional manner using a factor analysis method. This study used descriptive statistics and one-way analysis of variance to explore the differences in social integration between ERM with SMI from host cities and hometowns. Stepwise multiple linear regression analysis was used to test the correlation between SMI location and social integration level in the overall sample. Finally, the results were verified by propensity score matching. RESULTS: It was found that 606 (18.2%) of the insured ERM chose host city SMI, while 2727 (81.8%) chose hometown SMI. The level of social integration was lower among ERM with hometown SMI (-1.438 ± 32.795, F = 28.311, p ≤ 0.01) than those with host city SMI (6.649 ± 34.383). Among the dimensions of social integration, social participation contributed more than other factors, with a contribution rate of 45.42%. Host city SMI increased the probability of the social integration index by 647% among ERM (k-nearest neighbor caliper matched (n = 4, caliper = 0.02), with a full sample ATT value of 6.47 (T = 5.32, SE = 1.48, p < 0.05)). CONCLUSIONS: ERM with host city SMI have a higher social integration level than those with hometowns SMI. That is, host city SMI positively affects social integration. Policymakers should focus on the access of host city SMI for ERM. Removing the threshold of host city SMI coverage for ERM can promote social integration.

Clinical observational study on the efficacy of induction chemotherapy sequential concurrent radiotherapy combined with targeted therapy in patients with locally advanced EGFR-positive nasopharyngeal carcinoma: prediction model construction and efficacy testing.

OBJECTIVE: To establish a nomogram for prediction of prognosis in EGFR-positive advanced nasopharyngeal carcinoma (NPC) patients who were treated with induction chemotherapy (IC) and concurrent chemoradiotherapy (CCRT). The clinical data of 124 NPC patients who received IC sequential CCRT combined with targeted therapy at the Department of Oncology of the Affiliated Hospital of North Sichuan Medical College between June 2017 and September 2022 were retrospectively reviewed. Logistic regression analysis was used to identify the prognostic factors for building the nomogram. RESULTS: Multifactorial regression analysis showed that the use of targeted drugs and T stage were independent factors of prognosis (p < 0.05) and the equation Y = 0.476 + 2.733X1 + - 0.758 × 2 (Y = efficacy, X1 = targeted drug therapy, X2 = T stage) was obtained. Then, a prognostic nomogram prediction model was constructed. The prediction model was validated internally for 1000 times using the Bootstrap resampling method with an accuracy of 79.29%. The calibration curve suggests that the predicted values fit well with the true values. The clinical decision curve (DCA) shows that the model has good clinical predictive value. CONCLUSION: The use of targeted therapy significantly improved the prognosis of patients with EGFR-positive advanced NPC. For advanced NPC patients with T1 and T2 stages, IC sequenced with CCRT is more effective, and the addition of targeted therapy can further improve patients' prognosis. For advanced NPC patients with T3 and T4 stages, IC sequenced with CCRT is ineffective, and the addition of targeted therapy can significantly improve patient prognosis.

Disease mechanisms of X-linked cone dystrophy caused by missense mutations in the red and green cone opsins.

Cone photoreceptors are responsible for the visual acuity and color vision of the human eye. Red/green cone opsin missense mutations N94K, W177R, P307L, R330Q, and G338E have been identified in subjects with congenital blue cone monochromacy or color-vision deficiency. Studies on disease mechanisms due to these cone opsin mutations have been previously carried out exclusively in vitro, and the reported impairments were not always consistent. Here we expressed these mutants via AAV specifically in vivo in M-opsin knockout mouse cones to investigate their subcellular localization, the pathogenic effects on cone structure, function, and cone viability. We show that these mutations alter the M-opsin structure, function, and localization. N94K and W177R mutants appeared to be misfolded since they localized exclusively in cone inner segments and endoplasmic reticulum. In contrast, P307L, R330Q, and G338E mutants were detected predominately in cone outer segments. Expression of R330Q and G338E, but not P307L opsins, also partially restored expression and correct localization of cone PDE6α' and cone transducin γ and resulted in partial rescue of M-cone-mediated light responses. Expression of W177R and P307L mutants significantly reduced cone viability, whereas N94K, R330Q, and G338E were only modestly toxic. We propose that although the underlying biochemical and cellular defects caused by these mutants are distinct, they all seem to exhibit a dominant phenotype, resembling autosomal dominant retinitis pigmentosa associated with the majority of rhodopsin missense mutations. The understanding of the molecular mechanisms associated with these cone opsin mutants is fundamental to developing targeted therapies for cone dystrophy/dysfunction.

Generation of Environmentally Persistent Free Radicals on Metal-Organic Frameworks.

Environmentally persistent free radicals (EPFRs) have been recognized as one of the important emerging contaminants with biological toxicity, environmental persistence, and global mobility. Previous studies have identified the catalytic role of surface metal oxides in EPFRs formation and illustrated the metal-dependence of EPFRs by studying on various metal oxide nanoparticles and single crystals. However, there is still lack of an understanding on the formation of EPFRs from the point of view of metal sites. Various factors (e.g., crystalline phases and surface species) of metal oxides are regarded to contribute to the generation of EPFRs, which present profound difficulties for scientists to tease apart the impact of metal type. Herein, a laboratory investigation, in terms of the acidity and oxidation strength of metal cations, was conducted by selecting metal-variable isostructural metal-organic frameworks as material platforms. Specifically, we evaluated EPFRs generation on MIL-100(M) (M = Al, Cr, Fe) from chlorine-substituted phenol vapor and catechol under thermal conditions. It is found that high Lewis acidity of metal sites is crucial for capturing the above two phenolic precursors, activating the O-H bond and promoting EPFRs formation. Radical species with half-life as long as 70 days were generated on MIL-100 rich in 5-fold coordinated Al3+ sites. The unpaired electron spin density donation was further confirmed by using 27Al solid-state nuclear magnetic resonance spectroscopy. Despite their higher oxidation power than Al3+, the exposed Cr3+ and Fe3+ sites show undetectable catalytic activity for the formation of EPFRs, because of their insufficient Lewis acidity. Our results suggest that the surface species rather than Lewis acid sites may be a major contributor to the formation of EPFRs on metal oxides like Fe2O3.

Genetic spectrum of CAKUT and risk factors for kidney failure: a pediatric multicenter cohort study.

BACKGROUND: Congenital anomalies of the kidney and urinary tracts (CAKUT) are the leading cause of kidney failure in children with phenotypic and genotypic heterogeneity. Our objective was to describe the genetic spectrum and identify the risk factors for kidney failure in children with CAKUT. METHODS: Clinical and genetic data were derived from a multicenter network (Chinese Children Genetic Kidney Disease Database, CCGKDD) and the Chigene database. A total of 925 children with CAKUT who underwent genetic testing from 2014 to 2020 across China were studied. Data for a total of 584 children wereobtained from the CCGKDD, including longitudinal data regarding kidney function. The risk factors for kidney failure were determined by the Kaplan-Meier method and Cox proportional hazards models. RESULTS: A genetic diagnosis was established in 96 out of 925 (10.3%) children, including 72 (8%) with monogenic variants, 20 (2%) with copy number variants (CNVs), and 4 (0.4%)with major chromosomal anomalies. Patients with skeletal abnormalities were more likely to have large CNVs or abnormal karyotypes than monogenic variants. Eighty-two patients from the CCGKDD progressed to kidney failure at a median age of 13.0 (95% confidence interval, 12.4-13.6) years, and twenty-four were genetically diagnosed with variants of PAX2, TNXB, EYA1, HNF1B and GATA3 or the 48, XXYY karyotype. The multivariate analysis indicated that solitary kidney, posterior urethral valves, bilateral hypodysplasia, the presence of certain variants and premature birth were independent prognostic factors. CONCLUSIONS: The genetic spectrum of CAKUT varies among different subphenotypes. The identified factors indicate areas that require special attention.

The Proresolving Lipid Mediator Maresin1 Alleviates Experimental Pancreatitis via Switching Macrophage Polarization.

METHOD: Repeated caerulein injection was used to induce AP and chronic pancreatitis (CP) models in mice. The histopathological and serological changes were examined for evaluating the severity of the AP model, and flow cytometry was used for detecting macrophage phagocytosis and phenotype. Meanwhile, clodronate liposomes were used for macrophage depletion in mice. Finally, the CP model was adopted to further observe the protective effect of MaR1. RESULT: MaR1 administration manifested the improved histopathological changes and the lower serum levels of amylase and lipase. However, MaR1 played no protective role in the pancreatic acinar cell line in vitro. It obviously reduced the macrophage infiltration in the injured pancreas, especially M1-type macrophages. After macrophage clearance, MaR1 showed no further protection in vivo. This study also demonstrated that MaR1 could alleviate fibrosis to limit AP progression in the CP model. CONCLUSION: Our data suggests that MaR1 was a therapeutic and preventive target for AP in mice, likely operating through its effects on decreased macrophage infiltration and phenotype switch.

Metal-Organic Framework Films and Their Potential Applications in Environmental Pollution Control.

Metal-organic frameworks (MOFs), an emerging class of porous hybrid inorganic-organic crystals, exhibit very important application prospects in gas storage and separation, heterogeneous catalysis, sensing, drug release, environmental decontamination, etc., due to their competitive advantages over other traditional porous materials (e.g., activated carbon and zeolite), including high surface areas, adjustable pore size, uniformly distributed metal centers, and tunable functionalities. However, MOF particles are usually difficult to be processed into application-specific devices because of their brittleness, insolubility, difficulty in molding, and low compatibility with other materials. It is an urgent need to shape MOF nanocrystals into various useful configurations by developing effective fabrication methods. Specifically, versatile functional MOF films with robustness and operation flexibility are highly desired. Although an increasing number of MOF films and their diverse applications have been demonstrated, this field is still at an emerging stage with challenging issues. In this Account, we describe our recent research progress on controllable synthesis of MOF films, highlighting postsynthetic polymerization, in situ interweaving, and solvent-free hot-pressing methods. Basically, two main synthesis concepts are involved, including incorporation of the performed MOF particles into polymer matrix and in situ growth of MOF coatings on surface. In MOF/polymer hybrid films, MOF nanocrystals were covalently linked by flexible polymer chains via graft copolymerization, interconnected by functional polymer chains via in situ polymerization, or adhered to polymer matrix via specific interactions at interface, consequently leading to a molecular-level homogeneous membrane or functional coating layer or foam. In these examples, the existence of polymer endows MOF films with favorable features of processability and flexibility, along with new functions. Moreover, we developed an in situ solvent-free hot-pressing method as a general approach for efficient fabrication of MOF coatings on various commercial substrates (e.g., cloth and metal foils), where metal ions or ligands were chemically bonded to the surface functional groups or metal sites at the early stage of nucleation and subsequently assembled into continuous, uniform, and stable MOF layers under confined conditions. We further extended it to a scalable manufacturing method, roll-to-roll production. MOF films severing as filters (MOFilters) have significant applications in air and water purification. They show high and stable performance in PM capture along with a low pressure drop, holding promise of application in both industrial and residential environments. Moreover, MOFilters can remove SO2 and O3 from air by adsorption and catalytic decomposition, respectively. Given the functional diversity of MOFs, mixed pollutants in solution could also be efficiently trapped by multifunctional MOF hollow tubes. We believe this Account will offer new insights for design and preparation of functional MOF films and coatings and accelerate the practical applications of MOFs.

Discovery and Biosynthesis of Pepticinnamins G-M Featuring Three Enzymes-Catalyzed Nonproteinogenic Amino Acid Formation.

Since pepticinnamin E was discovered almost 30 years ago, no other pepticinnamin family of natural products has been reported to date. Here, we report the discovery of pepticinnamins G-I (1-3) from a marine Streptomyces sp. PKU-MA01144 and pepticinnamins J-M (4-7) from several mutants, and these new compounds contain different N-methyl-l-alanine and l-tyrosine residues compared to pepticinnamin E. Genome sequencing, heterologous expression, gene deletion, and reconstitution of enzymatic reaction in vitro identified the biosynthetic gene cluster of 1-7 and first experimentally established the biosynthesis of the nonproteinogenic 2-chloro-3-hydroxy-4-methoxy-l-phenylalanine residue by a biopterin-dependent hydroxylase Pep10, an O-methyltransferase Pep9, and a flavin-dependent halogenase Pep1. The biosynthetic research and heterologous expression system in this study set the stage for pathway engineering for more pepticinnamins generation in the future.