Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome.

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses and spreads by metastasis to the liver1. Cancer-associated fibroblasts, the extracellular matrix and type I collagen (Col I) support2,3 or restrain the progression of PDAC and may impede blood supply and nutrient availability4. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers to escape nutrient limitation, remain poorly understood. Here we show that matrix-metalloprotease-cleaved Col I (cCol I) and intact Col I (iCol I) exert opposing effects on PDAC bioenergetics, macropinocytosis, tumour growth and metastasis. Whereas cCol I activates discoidin domain receptor 1 (DDR1)-NF-κB-p62-NRF2 signalling to promote the growth of PDAC, iCol I triggers the degradation of DDR1 and restrains the growth of PDAC. Patients whose tumours are enriched for iCol I and express low levels of DDR1 and NRF2 have improved median survival compared to those whose tumours have high levels of cCol I, DDR1 and NRF2. Inhibition of the DDR1-stimulated expression of NF-κB or mitochondrial biogenesis blocks tumorigenesis in wild-type mice, but not in mice that express MMP-resistant Col I. The diverse effects of the tumour stroma on the growth and metastasis of PDAC and on the survival of patients are mediated through the Col I-DDR1-NF-κB-NRF2 mitochondrial biogenesis pathway, and targeting components of this pathway could provide therapeutic opportunities.

Histone Modifications Regulate Chromatin Compartmentalization by Contributing to a Phase Separation Mechanism.

Eukaryotic chromosomes contain compartments of various functions, which are marked by and enriched with specific histone modifications. However, the molecular mechanisms by which these histone marks function in chromosome compartmentalization are poorly understood. Constitutive heterochromatin is a largely silent chromosome compartment characterized in part by H3K9me2 and 3. Here, we show that heterochromatin protein 1 (HP1), an H3K9me2 and 3 "reader," interacts with SUV39H1, an H3K9me2 and 3 "writer," and with TRIM28, an abundant HP1 scaffolding protein, to form complexes with increased multivalent engagement of H3K9me2 and 3-modified chromatin. H3K9me2 and 3-marked nucleosomal arrays and associated complexes undergo phase separation to form macromolecule-enriched liquid droplets. The droplets are reminiscent of heterochromatin as they are highly dense chromatin-containing structures that are resistant to DNase and exclude the general transcription factor TFIIB. Our data suggest a general mechanism by which histone marks regulate chromosome compartmentalization by promoting phase separation.

Genome evolution of the ancient hexaploid Platanus × acerifolia (London planetree).

Whole-genome duplication (WGD; i.e., polyploidy) and chromosomal rearrangement (i.e., genome shuffling) significantly influence genome structure and organization. Many polyploids show extensive genome shuffling relative to their pre-WGD ancestors. No reference genome is currently available for Platanaceae (Proteales), one of the sister groups to the core eudicots. Moreover, Platanus × acerifolia (London planetree; Platanaceae) is a widely used street tree. Given the pivotal phylogenetic position of Platanus and its 2-y flowering transition, understanding its flowering-time regulatory mechanism has significant evolutionary implications; however, the impact of Platanus genome evolution on flowering-time genes remains unknown. Here, we assembled a high-quality, chromosome-level reference genome for P. × acerifolia using a phylogeny-based subgenome phasing method. Comparative genomic analyses revealed that P. × acerifolia (2n = 42) is an ancient hexaploid with three subgenomes resulting from two sequential WGD events; Platanus does not seem to share any WGD with other Proteales or with core eudicots. Each P. × acerifolia subgenome is highly similar in structure and content to the reconstructed pre-WGD ancestral eudicot genome without chromosomal rearrangements. The P. × acerifolia genome exhibits karyotypic stasis and gene sub-/neo-functionalization and lacks subgenome dominance. The copy number of flowering-time genes in P. × acerifolia has undergone an expansion compared to other noncore eudicots, mainly via the WGD events. Sub-/neo-functionalization of duplicated genes provided the genetic basis underlying the unique flowering-time regulation in P. × acerifolia. The P. × acerifolia reference genome will greatly expand understanding of the evolution of genome organization, genetic diversity, and flowering-time regulation in angiosperms.

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.

Design of Ultrasound-Driven Charge Interference Therapy for Wound Infection.

Wound infections, especially those caused by pathogenic bacteria, present a considerable public health concern due to associated complications and poor therapeutic outcomes. Herein, we developed antibacterial nanoparticles, namely, PGTP, by coordinating guanidine derivatives with a porphyrin-based sonosensitizer. The synthesized PGTP nanoparticles, characterized by their strong positive charge, effectively disrupted the bacterial biosynthesis process through charge interference, demonstrating efficacy against both Gram-negative and Gram-positive bacteria. Additionally, PGTP nanoparticles generated reactive oxygen species under ultrasound stimulation, resulting in the disruption of biofilm integrity and efficient elimination of pathogens. RNA-seq analysis unveiled the detailed mechanism of wound healing, revealing that PGTP nanoparticles, when coupled with ultrasound, impair bacterial metabolism by interfering with the synthesis and transcription of amino acids. This study presents a novel approach to combatting wound infections through ultrasound-driven charge-interfering therapy, facilitated by advanced antibacterial nanomaterials.

p21 restricts influenza A virus by perturbing the viral polymerase complex and upregulating type I interferon signaling.

Many cellular genes and networks induced in human lung epithelial cells infected with the influenza virus remain uncharacterized. Here, we find that p21 levels are elevated in response to influenza A virus (IAV) infection, which is independent of p53. Silencing, pharmacological inhibition or deletion of p21 promotes virus replication in vitro and in vivo, indicating that p21 is an influenza restriction factor. Mechanistically, p21 binds to the C-terminus of IAV polymerase subunit PA and competes with PB1 to limit IAV polymerase activity. Besides, p21 promotes IRF3 activation by blocking K48-linked ubiquitination degradation of HO-1 to enhance type I interferons expression. Furthermore, a synthetic p21 peptide (amino acids 36 to 43) significantly inhibits IAV replication in vitro and in vivo. Collectively, our findings reveal that p21 restricts IAV by perturbing the viral polymerase complex and activating the host innate immune response, which may aid the design of desperately needed new antiviral therapeutics.

Neighboring mutation-mediated enhancement of dengue virus infectivity and spread.

Frequent turnover of dengue virus (DENV) clades is one of the major forces driving DENV persistence and prevalence. In this study, we assess the fitness advantage of nine stable substitutions within the envelope (E) protein of DENV serotypes. Two tandem neighboring substitutions, threonine to lysine at the 226th (T226K) and glycine to glutamic acid at the 228th (G228E) residues in the DENV2 Asian I genotype, enhance virus infectivity in either mosquitoes or mammalian hosts, thereby promoting clades turnover and dengue epidemics. Mechanistic studies indicate that the substitution-mediated polarity changes in these two residues increase the binding affinity of E for host C-type lectins. Accordingly, we predict that a G228E substitution could potentially result in a forthcoming epidemic of the DENV2 Cosmopolitan genotype. Investigations into the substitutions associated with DENV fitness in hosts may offer mechanistic insights into dengue prevalence, thus providing a warning of potential epidemics in the future.

A seamless phase II/III design with dose optimization for oncology drug development.

The US FDA's Project Optimus initiative that emphasizes dose optimization prior to marketing approval represents a pivotal shift in oncology drug development. It has a ripple effect for rethinking what changes may be made to conventional pivotal trial designs to incorporate a dose optimization component. Aligned with this initiative, we propose a novel seamless phase II/III design with dose optimization (SDDO framework). The proposed design starts with dose optimization in a randomized setting, leading to an interim analysis focused on optimal dose selection, trial continuation decisions, and sample size re-estimation (SSR). Based on the decision at interim analysis, patient enrollment continues for both the selected dose arm and control arm, and the significance of treatment effects will be determined at final analysis. The SDDO framework offers increased flexibility and cost-efficiency through sample size adjustment, while stringently controlling the Type I error. This proposed design also facilitates both accelerated approval (AA) and regular approval in a "one-trial" approach. Extensive simulation studies confirm that our design reliably identifies the optimal dosage and makes preferable decisions with a reduced sample size while retaining statistical power.

A stochastic dynamic programming model for the optimal policy mix of the carbon tax and decarbonization subsidy.

Carbon tax and decarbonization subsidy are an effective policy mix in reducing carbon emissions. However, there is a research gap between the deterministic and static analysis related to carbon reduction policy instruments and the dynamic green transition influenced by stochastic factors. This research investigates the optimal dynamic carbon reduction strategies that develop green technologies, increase abatement inputs, and reduce carbon emissions by applying the stochastic optimal control theory. Firms that are incentivized by decarbonization subsidies and regulated by carbon tax choose optimal closed-loop control strategies of abatement inputs to achieve profit-maximizing objectives with carbon reduction constraints. The explicit solutions of the optimal carbon tax and decarbonization subsidy are provided. The simulation results illustrate that the optimal policy mix is feasible in the effective period when the carbon emission decreases significantly, which indicates that the abatement policy mix can effectively promote carbon reduction. Our results reveal that the dynamic optimal policy mix is conducive to achieving carbon abatement goals with capital uncertainty. The government should implement a dynamic carbon tax and decarbonization subsidy policy mix simultaneously associated with optimal closed-loop carbon reduction strategies. Firms with asymmetric decarbonization efficiency can transfer progressively into a cleaner productive pattern.

[Influence of telemedicine on the operation of public hospitals in China].

OBJECTIVE: Telemedicine, as an information-based tool, is widely recognized as an effective solution for compensating for the imbalanced allocation of medical resources in China. This study specifi-cally aimed to analyze the impact of telemedicine functions on the operational efficiency of public hospitals, with a particular focus on their heterogeneous effects on hospitals of different levels. METHODS: A cross-sectional research design was used based on the 2022 Health Informatization Statistical Survey data, and 8 944 public hospitals were used as research objects to analyze the impact of telemedicine on hospital revenues and business capacity. Multivariate linear model, propensity score matching (PSM), and grouped regression methods were employed to evaluate the impact of telemedicine on hospital revenues, number of consultations, and the number of discharges. RESULTS: The descriptive results showed that telemedicine was available in 35.51% of public hospitals. The analysis also demonstrated that various factors, such as hospital level, academic category, area of the hospital, administrational level and number of beds all had a significant influence on the operation of the hospital. Moreover, the regression results showed that opening telemedicine could increase hospital revenues by 0.140 (P < 0.01), hospital consultations by 0.136 (P < 0.01), and the number of discharges by 0.316 (P < 0.01). After correcting for endogeneity using the propensity score matching, the results showed that the effect of opening telemedicine on hospital revenues, consultations, and the number of discharges was 0.191 (P < 0.01), 0.216 (P < 0.01), and 0.353 (P < 0.01), respectively. Further heterogeneity analysis was conducted to explore the differential effects of telemedicine on hospitals of different levels. Grouped regression showed that telemedicine had a positive impact on the income of secondary hospitals, with a coefficient of 0.088 (P < 0.05), and it had a more significant positive impact on hospital consultations in secondary hospitals, with a coefficient of 0.127 (P < 0.01). An even greater impact on the number of discharges in primary hospitals, with a coefficient of 1.203 (P < 0.01). Telemedicine, on the other hand, did not have a significant positive impact on the overall revenue and operational capacity of tertiary hospitals. CONCLUSION: Telemedicine had a significant promoting effect on hospital revenues, hospital consultations and the number of discharges, and this effect was differentiated between hospitals of different levels. Through the construction of telemedicine, primary hospitals were able to significantly improve their business capacity and revenue, which played a positive role in improving the operation of primary public hospitals.

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Alpha-ketoglutarate (α-KG), an endogenous intermediate of the tricarboxylic acid cycle, is involved in a variety of cellular metabolic pathways. It serves as an energy donor, a precursor of amino acid biosynthesis, and an epigenetic regulator. α-KG plays physiological functions in immune regulation, oxidative stress, and anti-aging as well. In recent years, it has been reported that the level of α-KG in the body is closely associated with metabolic syndrome, including obesity, hyperglycemia, and other pathological factors. Exogenous supplementation of α-KG improves obesity, blood glucose levels, and cardiovascular disease risks associated with metabolic syndrome. Furthermore, α-KG regulates the common pathological mechanisms of metabolic syndrome, suggesting the potential application prospect of α-KG in metabolic syndrome. In order to provide a theoretical basis for further exploration of the application of α-KG in metabolic syndrome, we focused on α-KG and metabolic syndrome in this article and summarized the latest research progress in the role of α-KG in improving the pathological condition and disease progression of metabolic syndrome. For the next step, researchers may focus on the co-pathogenesis of metabolic syndrome and investigate whether α-KG can be used to achieve the therapeutic goal of "homotherapy for heteropathy" in the treatment of metabolic syndrome.

Water-Resistance-Based S-Scheme Heterojunction for Deep Mineralization of Toluene.

Deep mineralization of low concentration toluene (C7 H8 ) is one of the most significant but challenging reactions in photocatalysis. It is generally assumed that hydroxyl radicals (⋅OH) as the main reactive species contribute to the enhanced photoactivity, however, it remains ambiguous at this stage. Herein, a S-scheme ZnSn(OH)6 -based heterojunction with AlOOH as water resistant surface layer is in situ designed for tuning the free radical species and achieving deep mineralization of C7 H8 . By employing a combination of in situ DRIFTS and materials characterization techniques, we discover that the dominant intermediates such as benzaldehyde and benzoic acid instead of toxic phenols are formed under the action of holes (h+ ) and superoxide radicals (⋅O2 - ). These dominant intermediates turn out to greatly decrease the ring-opening reaction barrier. This study offers new possibilities for rationally tailoring the active species and thus directionally producing dominant intermediates via designing water resistant surface layer.

Asynchronous Ring Opening of Cyclic Carbonate and Glycidyl Ether Induced Phase Evolution Towards Heat-Free and Rapid-Bonding Superior Epoxy Adhesive.

Structural adhesives that do not require heating are in high demand in the automotive and electronics industries. However, it remains a challenge to develop robust adhesives that rapidly achieve super adhesion near ambient temperature. Herein, a room-temperature curable, fast-bonding, and super strong epoxy-based structural adhesive was designed from the perspective of cross-scale structure, which lies in threefold pivotal aspects: (i) high branching topology of glycerol carbonate-capped polyurethane (PUGC) increases the kinetics of the ring-opening reaction, contributing to fast crosslinking and the formation of abundant urethane and hydroxyl moieties; (ii) asynchronous crosslinking of epoxy and PUGC synergistically induces phase separation of PUGC within the epoxy resin and the resulting PUGC domains surrounded by interpenetrated shell serves to efficiently toughen the matrix; (iii) abundant dynamic hydrogen bonds including urethane and hydroxyl moieties, along with the elastomeric PUGC domains, dissipate energy of shearing force. As a result, the adhesive strength rapidly grows to 16 MPa within 4 hours, leveling off to 21 MPa after 7 hours, substantially outperforming commercial room-temperature curable epoxy adhesives. The results of this study could advance the field of high-performance adhesives and provide valuable insights into designing materials for efficient curing at room temperature.

Vertically Concentrated Quantum Wells Enabling Highly Efficient Deep-Blue Perovskite Light-Emitting Diodes.

Deep-blue perovskite light-emitting diodes (PeLEDs) based on quasi-two-dimensional (quasi-2D) systems exist heightened sensitivity to the domain distribution. The top-down crystallization mode will lead to a vertical gradient distribution of quantum well (QW) structure, which is unfavorable for deep-blue emission. Herein, a thermal gradient annealing treatment is proposed to address the polydispersity issue of vertical QWs in quasi-2D perovskites. The formation of large-n domains at the upper interface of the perovskite film can be effectively inhibited by introducing a low-temperature source in the annealing process. Combined with the utilization of NaBr to inhibit the undesirable n=1 domain, a vertically concentrated QW structure is ultimately attained. As a result, the fabricated device delivers a narrow and stable deep-blue emission at 458 nm with an impressive external quantum efficiency (EQE) of 5.82 %. Green and sky-blue PeLEDs with remarkable EQE of 21.83 % and 17.51 % are also successfully achieved, respectively, by using the same strategy. The findings provide a universal strategy across the entire quasi-2D perovskites, paving the way for future practical application of PeLEDs.

Surficial Homogenic Effect Enables Highly Stable Deep-Blue Perovskite Light-Emitting Diodes.

The device performance of deep-blue perovskite light-emitting diodes (PeLEDs) is primarily constrained by low external quantum efficiency (EQE) especially poor operational stability. Herein, we develop a facile strategy to improve deep-blue emission through rational interface engineering. We innovatively reported the novel electron transport material, 4,6-Tris(4-(diphenylphosphoryl)phenyl)-1,3,5-triazine (P-POT2T), and utilized a sequential wet-dry deposition method to form homogenic gradient interface between electron transport layer (ETL) and perovskite surface. Unlike previous reports that achieved carrier injection balance by inserting new interlayers, our strategy not only passivated uncoordinated Pb in the perovskite via P=O functional groups but also reduced interfacial carrier recombination without introducing new interfaces. Additionally, this strategy enhanced the interface contact between the perovskite and ETL, significantly boosting device stability. Consequently, the fabricated deep-blue PeLEDs delivered an external quantum efficiency (EQE) exceeding 5% (@ 460 nm) with an exceptional halftime extended to 31.3 minutes. This straightforward approach offers a new strategy to realize highly efficient especially stable PeLEDs.

Chemical Reaction Modulated Low-Dimensional Phase Toward Highly Efficient Sky-Blue Perovskite Light-Emitting Diodes.

Blue perovskite light-emitting diodes (PeLEDs) are crucial avenues for achieving full-color displays and lighting based on perovskite materials. However, the relatively low external quantum efficiency (EQE) has hindered their progression towards commercial applications. Quasi-two-dimensional (quasi-2D) perovskites stand out as promising candidates for blue PeLEDs, with optimized control over low-dimensional phases contributing to enhanced radiative properties of excitons. Herein, the impact of organic molecular dopants on the crystallization of various n-phase structures in quasi-2D perovskite films. The results reveal that the highly reactive bis(4-(trifluoromethyl)phenyl)phosphine oxide (BTF-PPO) molecule could effectively restrain the formation of organic spacer cation-ordered layered perovskite phases through chemical reactions, simultaneously passivate those uncoordinated Pb2+ defects. Consequently, the prepared PeLEDs exhibited a maximum EQE of 16.6 % (@ 490 nm). The finding provides a new route to design dopant molecules for phase modulation in quasi-2D PeLEDs.

Role of Mutual Diffusion in the Dissolution Behavior of One Primary Bulk Gas Nanobubble in Liquid: A Molecular Dynamics Study.

Dissolution of one primary bulk gas nanobubble in an undersaturated liquid constitutes one of the underlying issues of the exceptional stability of bulk gas nanobubble population. In this paper, the mutual diffusion coefficient at the gas-liquid interface of one primary bulk gas nanobubble is investigated via all-atom molecular dynamics simulation, and the applicability of the Epstein-Plesset theory is verified. The mutual diffusion coefficient, different from the self-diffusion coefficient in bulk gas or bulk liquid, is essentially determined by the chemical potential due to its driving role in the mass transfer across the interface. We could ascribe the low-rate dissolution of one primary bulk gas nanobubble in an undersaturated liquid to the slight attenuation of the mutual diffusion coefficient at the interface. The results show that the dissolution process of one primary bulk gas nanobubble in an undersaturated liquid fundamentally obeys the Epstein-Plesset theory and that the macroscopic dissolution rate is intrinsically determined by the gas mutual diffusion coefficient at the interface rather than the self-diffusion coefficient in the bulk phase. The mass transfer viewpoint from the present study might actively promote subsequent studies on the super-stability of bulk gas nanobubble population in liquid.

Catalyst-Free α-Allylation of Dihydroisoquinolines with Morita-Baylis-Hillman Carbonates and Its Applications in the Construction of Benzo[a]quinolizidines.

In this work, a mild and efficient catalyst-free α-allylation of 3,4-dihydroisoquinoline imines with Morita-Baylis-Hillman (MBH) carbonates was reported. The scopes of 3,4-dihydroisoquinolines and MBH carbonates as well as gram-scale synthesis were investigated, and densely functionalized adducts were obtained in moderate to good yields. The synthetic utility of these versatile synthons was further demonstrated by the facile synthesis of diverse benzo[a]quinolizidine skeletons.

Analysis of the epidemiological trends of enterovirus A in Asia and Europe.

BACKGROUND: Enteroviruses have been in massive, cyclical epidemics worldwide. An in-depth understanding of the international epidemiological characteristics of Enterovirus A (EVA) is critical to determining its clinical significance and total disease burden. Although much research has been conducted on EVA epidemiology, there is still a lack of a comprehensive overview of EVA epidemiological characteristics and trends. OBJECTIVE: EVA nucleic acid sequences from the NCBI virus database were used to summarize the epidemic time (based on the time of specimen collection), spatial and serotype distribution of EVA, and to analyze EVA isolated from cerebrospinal fluid specimens. METHODS: EVA sequences were searched in NCBI Virus by keyword ("Enterovirus A″ or "EVA") to screen sequences released before December 2021 and sort them to analyze EVA by year, geographic region and serotype prevalence. RESULTS: The results found 23,041 retrieved nucleic acid sequences with precise collection dates and geographical regions as of December 2021, with Asia accounting for 87%, Europe for 11% and Africa and the Americas for only 2%. Overall, EV-A71, CVA6 and CVA16 are a few of the main prevalent serotypes; and the prevalence characteristics of the different serotypes change over time from place to place. CONCLUSION: The prevalence of different serotypes of EVA varies considerably over time and space, and we focused on analysing the epidemiological characteristics of EVAs in Asia and Europe and EVAs that invade the nervous system. This study will likely provide important clues for prevention, control and future research in virological surveillance, disease management and vaccine development.