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The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) mandates the development of improved therapies. As KRAS mutations are found in 95% of PDAC and are critical for tumor maintenance, one promising strategy involves exploiting KRAS-dependent metabolic perturbations. The macrometabolic process of autophagy is upregulated in KRAS-mutant PDAC, and PDAC growth is reliant on autophagy. However, inhibition of autophagy as monotherapy using the lysosomal inhibitor hydroxychloroquine (HCQ) has shown limited clinical efficacy. To identify strategies that can improve PDAC sensitivity to HCQ, we applied a CRISPR-Cas9 loss-of-function screen and found that a top sensitizer was the receptor tyrosine kinase (RTK) insulin-like growth factor 1 receptor (IGF1R). Additionally, reverse phase protein array pathway activation mapping profiled the signaling pathways altered by chloroquine (CQ) treatment. Activating phosphorylation of RTKs, including IGF1R, was a common compensatory increase in response to CQ. Inhibition of IGF1R increased autophagic flux and sensitivity to CQ-mediated growth suppression both in vitro and in vivo. Cotargeting both IGF1R and pathways that antagonize autophagy, such as ERK–MAPK axis, was strongly synergistic. IGF1R and ERK inhibition converged on suppression of glycolysis, leading to enhanced dependence on autophagy. Accordingly, concurrent inhibition of IGF1R, ERK, and autophagy induced cytotoxicity in PDAC cell lines and decreased viability in human PDAC organoids. In conclusion, targeting IGF1R together with ERK enhances the effectiveness of autophagy inhibitors in PDAC.Significance:Compensatory upregulation of IGF1R and ERK–MAPK signaling limits the efficacy of autophagy inhibitors chloroquine and hydroxychloroquine, and their concurrent inhibition synergistically increases autophagy dependence and chloroquine sensitivity in pancreatic ductal adenocarcinoma.

Supplementary Tables

The fungal communities provide the nutrients and drive the cycles of elements in nature, and the rare fungal taxa are proved to be crucial for these communities in many environments. However, the ecological functions of rare taxa for the fungal communities in mangrove ecosystems are poorly assessed until now. This work aims to reveal the importance of rare taxa for the assembly of fungal communities in mangrove sediments by using the amplicon sequencing analysis of different spatiotemporal samples collected from Sanya mangroves, China. The results showed that Ascomycota and Basidiomycota were the dominant phyla in the conditionally rare taxa (CRT). The fungal communities possessed outstanding stability against the spatiotemporal variation and most collected environmental factors. The CRT possessed narrower niches and were more affected by the environmental variables than the abundant taxa. The current work demonstrated that the CRT had significantly higher relative abundances, degrees (the number of adjacent edges), clustering coefficients, and closeness centralities in the top 8 modules of the co-occurrence network (p 0.05), indicating the important role of the CRT for the interaction of fungal communities in mangrove sediments. These findings indicate the importance of the CRT for the fungal community structures in mangrove sediments, and would deepen our understanding of dynamic functions of mangrove fungi, thereby facilitating the management, utilization, and protection of mangrove ecosystems. KEY POINTS: • Fungal communities in mangrove sediments are stable against environment variations. • The conditionally rare taxa (CRT) possessed narrower niches than the abundant fungal taxa. • The CRT are central for the co-occurrence network and interaction of fungal communities.

Objective: To analyze the risk of perioperative complications associated with preoperative risk factors in patients who underwent anastomosis of free head and neck flaps using a vascular stapler. Methods: We reviewed the data of all patients who underwent anastomosis of free head and neck flaps using a vascular stapler in our hospital between 2019 and 2020 (n=171). They were grouped according to age, weight, smoking, alcohol consumption, diabetes, and high blood pressure. Logistic regression analysis was used to evaluate the relationship between these factors and flap necrosis. Results: Among the 171 patients who underwent single vein anastomotic reconstruction of free head and neck flaps with a vascular stapler, five exhibited flap necrosis. Age,smoking,alcohol consumption, diabetes, and hypertension were found to affect the prognosis of surgery; among these, diabetes was a risk factor for flap necrosis. Conclusion: Attention should be paid to the control of blood glucose in patients undergoing free vascularized flaps using a stapler.

Additional file 1: Supplementary Table 1. Data sources and search strategies. Supplementary Method 1. Data extraction and quality assessment.

Additional file 1: Supplementary Figure 1. Distributionof 19-mer frequency in Ridgeia piscesaegenome. The short-insert paired-end reads (180 bp) were used to generate the19-mer frequency curve. Theheterozygous rate and the genome size were determined based on the k-merdistribution. Supplementary Figure 2. The phylogenetic tree of R.piscesae and 14 other lophotrochozoans.The tree wasreconstructed with single-copy orthologs using a maximum likelihood approach.The ultrafast bootstrap (UFBoots) value is listed above each of the nodes.Supplementary Figure 3. Genomic organization of Hox gene clusters in 4vestimentiferan tubeworms and 11 other metazoans. Hox genes are indicated as rectangles.The orientations of genes are indicated by arrows below the genes. The genecomposition and orientation of Hox clusters are consistent between two vent-dwellingtubeworms (R. pachyptila and R. piscesae), but slightly differentbetween vent- and seep-dwelling tubeworms. Supplementary Figure 4.Alignment of hemoglobins in four tubeworms. Each tubeworm has two copies of A1 chain, one copy of A2 chain, and onecopy of B2 chain in hemoglobins of tubeworms. A group of B1 chain in hemoglobinwere found in each of four species. Free cysteine was found in A2, B2, and B1chains in hemoglobin. Supplementary Table 1. Statistics of the genome sequencing data of Ridgeia piscesae. Supplementary Table 2. Statistic of the R. piscesae genome assembly. Supplementary Table 3. Assessment of genome coverage ratebased on short-insert paired-end reads remapping analysis. SupplementaryTable 4. Assessment of gene coveragerate using Trinity assembled sequences (Unigenes). SupplementaryTable 5. BUSCO evaluationof R. piscesae genome assembly. Supplementary Table 6. Summary of annotated repeats in R.piscesae genome. Supplementary Table 7. Statistics of functional annotated gene models in the genome of R.piscesae. Supplementary Table 8. Information of genomes used to perform phylogenomic analysis. Supplementary Table 9. Exon and intronlengths of genes in four Vestimentiferan tubeworms. Supplementary Table 10. Expression levels of hemoglobin genes withfree cysteine in R. piscesae. Supplementary Table 11. Gene families were significantly expandedin the genomes of all four tubeworms. SupplementaryTable 12. Gene families were significantly expanded in the genomes of twoseep-dwelling tubeworms. Supplementary Table 13. Positively selected genes (PSGs) in R.piscesae. Supplementary Table 14. Summary of genome assemblies using two other assemblers

Tumor-associated macrophages (TAMs) are crucially associated with tumor development and progression; however, it remains unclear how the tumor microenvironment (TME) rewires the metabolic circuits and preferentially induces TAMs to polarize toward a protumoral phenotype. Here, we report that polyunsaturated fatty acids (PUFAs) in malignant ascites promote protumoral M2-like TAMs deposition and facilitate peritoneal metastases of epithelial ovarian cancer (EOC). We demonstrated that PUFAs in the lipid-enriched malignant ascites inactivate RhoA, reducing nuclear YAP1 in macrophages and promoting protumoral M2-like TAMs polarization with OXPHOS metabolism. Conditional Yap1 depletion in murine MΦs leads to skew macrophage polarization toward protumoral M2-like TAMs that, in turn, suppress CD8+ T cell infiltration and aggravate tumor colonization in vivo. Noticeably, the significance of nuclear YAP1 depletion was evinced in the infiltrating TAMs in tumor spheroids of malignant ascites from EOC patients. In contrast, restored nuclear YAP1 expression in TAMs by pharmacological suppression of MST1/2 enhances tumoricidal M1-like TAMs population and CD8+ T cells infiltration, restricting EOC peritoneal metastasis. These results indicate that PUFAs are a key player in promoting tumor-infiltrated TAMs polarization that, in turn, facilitates EOC tumor growth and metastasis.

Objective The upregulation of long noncoding RNA intersectin 1-2 (lnc ITSN1-2) is associated with poor prognosis in acute ischemic stroke (AIS) patients, but the role and mechanism of lnc ITSN1-2 in AIS are rarely reported, which, thus, are highlighted in this study. Methods AIS cell model was constructed by oxygen glucose deprivation and reoxygenation (OGD/R). The quantitative real-time PCR was used to detect the expression of lnc ITSN1-2 in HT22 cells. The effects of lnc ITSN1-2 overexpression or knockdown on viability, LDH release, apoptosis, inflammatory and apoptotic factor expressions in OGD/R-induced HT22 cells were measured by cell counting kit-8 assay, LDH release kit, flow cytometry, ELISA and western blot, respectively. Starbase was used to screen the target genes of lnc ITSN1-2. The targeting relationship between lnc ITSN1-2 and miR-195-5p was predicted by starbase and verified by dual-luciferase report assay. The above assays were conducted again to study the function of miR-195-5p. Lastly, the levels of activated mitogen-activated protein kinases (MAPK) pathway-related proteins were determined by western blot. Results OGD/R treatment reduced the HT22 cell viability and enhanced LDH release rate and lnc ITSN1-2 expression. Lnc ITSN1-2 overexpression promoted the cell injury, apoptosis and inflammation in OGD/R-induced HT22 cells, while lnc ITSN1-2 knockdown generated the opposite effect and deactivated the MAPK pathways. However, the effect of lnc ITSN1-2 knockdown in OGD/R-induced HT22 cells was reversed by miR-195-5p inhibitor. Conclusion Lnc ITSN1-2 knockdown suppressed the inflammation and apoptosis in OGD/R-induced HT22 cells by regulating the miR-195-5p-mediated MAPK pathways.

Our work aims to investigate the functions of a natural compound, Albiflorin (AF) in cerebral ischemia-reperfusion (IR) injury. The cerebral IR models were established by OGD/R in PC12 cells and MCAO/IR in rats. The cells in a glucose-free medium were placed in an anaerobic chamber containing 95% N₂ and 5% CO₂ for 3 h at 37°C, returned to a normal medium, and incubated for 24 h to accomplish OGD/R. Focal cerebral ischemia was conducted by thread occlusion of the right middle cerebral artery for 2 h followed by 24 h reperfusion in rats. CCK-8 assay indicated that AF had no toxicity to PC12 cells. Flow cytometry, Western blot, or TUNEL showed that AF treatment reduced apoptosis of cells or rat brain tissues. qRT-PCR and ELISA showed that AF decreased IL-1β, IL-6, and TNF-α levels in vitro and in vivo. Elevated levels of MDA, SOD, and ROS induced by IR injury were mitigated by AF in vitro and in vivo. HE and TTC staining revealed that AF ameliorated pathological injury in MCAO/IR rats. Western blot showed that Nrf2, NQO1, and HO-1 expression was activated by AF, and ML385 treatment suppressed the inhibition effects of AF in cerebral IR injury models. Overall, AF alleviates cerebral IR injury via regulating the Nrf2/HO-1 pathway.

China has proposed the Renewable Portfolio Standard (RPS) policy to advance the stable development of renewable energy. The RPS requires each province to achieve a stated minimum share of renewable energy power in the total provincial power generation. However, there is an obvious mismatch between the actual capability of generating renewable power and the assigned responsibility for the share of renewable energy power based on the RPS in some provinces. Therefore, this study aims to optimize the renewable power dispatching strategy across provinces for satisfying the RPS requirements in China and to assess the corresponding pressure for each province. A renewable energy power dispatching model is developed, and an economically feasible strategy for dispatching renewable energy power in Chinese provinces in 2020–2022 was obtained. The results indicate that it is necessary to dispatch 395.2 and 140.4 TWh of hydropower and non-hydropower nationwide, respectively, in 2022 to fulfill the RPS target when the COVID-19 is effectively controlled worldwide. If COVID-19 cannot be effectively controlled, 376.6 and 127.8 TWh of hydropower and non-hydropower must be dispatched nationwide to fill the gap. Beijing, Tianjin, Shanghai, and Zhejiang are faced with a relatively high pressure under the RPS target. Finally, a path for each province to achieve its RPS target is proposed.

Treated dentin matrix (TDM) is an ideal scaffold material containing multiple extracellular matrix factors. The canonical Wnt signaling pathway is necessary for tooth regeneration. Thus, this study investigated whether the TDM can promote the odontogenic differentiation of human dental pulp stem cells (hDPSCs) and determined the potential role of Wnt/β-catenin signaling in this process. Different concentrations of TDM promoted the dental differentiation of the hDPSCs and meanwhile, the expression of GSK3β was decreased. Of note, the expression of the Wnt/β-catenin pathway-related genes changed significantly in the context of TDM induction, as per RNA sequencing (RNA seq) data. In addition, the experiment showed that new dentin was visible in rat mandible cultured with TDM, and the thickness was significantly thicker than that of the control group. In addition, immunohistochemical staining showed lower GSK3β expression in new dentin. Consistently, the GSK3β knockdown hDPSCs performed enhanced odotogenesis compared with the control groups. However, GSK3β overexpressing could decrease odotogenesis of TDM-induced hDPSCs. These results were confirmed in immunodeficient mice and Wistar rats. These suggest that TDM promotes odontogenic differentiation of hDPSCs by directly targeting GSK3β and activating the canonical Wnt/β-catenin signaling pathway and provide a theoretical basis for tooth regeneration engineering., Graphical abstract Image 1, Highlights • TDM promotes odontogenic differentiation of hDPSCs by targeting GSK3β and activating the canonical Wnt/β-catenin signaling.

Cold atmospheric plasma-based plasma medicine has been expanding the diversity of its specialties. As an emerging branch, plasma dermatology takes advantage of the beneficial complexity of plasma constituents (e.g., reactive oxygen and nitrogen species, UV photons, and electromagnetic emission), technical versatility (e.g., direct irradiation and indirect aqueous treatment), and practical feasibility (e.g., hand-held compact device and clinician-friendly operation). The objective of this comprehensive review is to summarize recent advances in the CAP-dominated skin therapy by broadly covering three aspects. We start with plasma optimisation of intact skin, detailing the effect of CAP on skin lipids, cells, histology, and blood circulation. We then conduct a clinically oriented and thorough dissection of CAP treatment of various skin diseases, focusing on the wound healing, inflammatory disorders, infectious conditions, parasitic infestations, cutaneous malignancies, and alopecia. Finally, we conclude with a brief analysis on the safety aspect of CAP treatment and a proposal on how to mitigate the potential risks. This comprehensive review endeavors to serve as a mini textbook for clinical dermatologists and a practical manual for plasma biotechnologists. Our collective goal is to consolidate plasma dermatology’s lead in modern personalized medicine.

Mangrove is among the most carbon-rich biomes on earth, and viruses are believed to play a significant role in modulating local and global carbon cycling. However, few viruses have been isolated from mangrove sediments to date. Here, we report the isolation of a novel Bacillus phage (named phage vB_BviS-A10Y) from mangrove sediments. Phage vB_BviS-A10Y has a hexameric head with a diameter of ~ 79.22 nm and a tail with a length of ~ 548.56 nm, which are typical features of siphophages. vB_BviS-A10Y initiated host lysis at 3.5 h postinfection with a burst size of 25 plaque-forming units (PFU)/cell. The genome of phage vB_BviS-A10Y is 162,435 bp long with 225 predicted genes, and the GC content is 34.03%. A comparison of the whole genome sequence of phage vB_BviS-A10Y with those of other phages from the NCBI viral genome database showed that phage vB_BviS-A10Y has the highest similarity (73.7% identity with 33% coverage) to Bacillus phage PBC2. Interestingly, abundant auxiliary metabolic genes (AMGs) were identified in the vB_BviS-A10Y genome. The presence of a β-1,3-glucosyltransferase gene in the phage genome supported our previous hypothesis that mangrove viruses may manipulate carbon cycling directly through their encoded carbohydrate-active enzyme (CAZyme) genes. Therefore, our study will contribute to a better understanding of the diversity and potential roles of viruses in mangrove ecosystems.