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Abstract Esophageal squamous cell carcinoma (ESCC) possesses a poor prognosis and treatment outcome. Dysregulated metabolism contributes to unrestricted growth of multiple cancers. However, abnormal metabolism, such as highly activated pentose phosphate pathway (PPP) in the progression of ESCC remains largely unknown. Herein, we report that high-mobility group AT-hook 1 (HMGA1), a structural transcriptional factor involved in chromatin remodeling, promoted the development of ESCC by upregulating the PPP. We found that HMGA1 was highly expressed in ESCC. Elevated HMGA1 promoted the malignant phenotype of ESCC cells. Conditional knockout of HMGA1 markedly reduced 4-nitroquinoline-1-oxide (4NQO)-induced esophageal tumorigenesis in mice. Through the metabolomic analysis and the validation assay, we found that HMGA1 upregulated the non-oxidative PPP. With the transcriptome sequencing, we identified that HMGA1 upregulated the expression of transketolase (TKT), which catalyzes the reversible reaction in non-oxidative PPP to exchange metabolites with glycolytic pathway. HMGA1 knockdown suppressed the PPP by downregulating TKT, resulting in the reduction of nucleotides in ESCC cells. Overexpression of HMGA1 upregulated PPP and promoted the survival of ESCC cells by activating TKT. We further characterized that HMGA1 promoted the transcription of TKT by interacting with and enhancing the binding of transcription factor SP1 to the promoter of TKT. Therapeutics targeting TKT with an inhibitor, oxythiamine, reduced HMGA1-induced ESCC cell proliferation and tumor growth. Together, in this study, we identified a new role of HMGA1 in ESCCs by upregulating TKT-mediated activation of PPP. Our results provided a new insight into the role of HMGA1/TKT/PPP in ESCC tumorigenesis and targeted therapy.

Objective: The Theory of Planned Behavior (TPB) was used to compile a questionnaire to determine the relationship between knowledge, attitude, subjective norm, perceived behavioral control and the intention of university students to perform cardiopulmonary resuscitation (CPR) for strangers, and the factors influencing them. Methods: We recruited 575 university students who completed an online questionnaire within 30 min to assess knowledge, attitude, subjective norm, and perceived behavioral control related to bystander CPR. Factor analysis was used to evaluate the reliability of the extended questionnaire. Multivariate analysis, correlation analysis, and path analysis were used to determine the differences of intra-group and inter-group. Results: The Cronbach's α of knowledge, attitude, subjective norm, perceived behavioral control and intention were 0.770, 0.797, 0.909, 0.619 and 0.899 respectively, indicating that the extended scale reliability of the TPB was adequate. χ2/df = 3.463, GFI = 0.977, CFI = 0.968, IFI = 0.969, RMSEA = 0.066, indicating that the extended scale of the TPB had a good fit. Path analysis showed that the influencing factors of intention were “Families of medical workers”, “Experience in administering CPR first aid training”, “Gender”, “Ability to master CPR skills”, “Knowledge”, “Subjective norm” and “Attitude”, with effect values of 0.019, 0.063, 0.069, 0.122, 0.187, 0.361 and 0.386, respectively. All the factors together accounted for 57.00 % of the variation in intention. Conclusions: Knowledge, attitude and subjective norm regarding to bystander CPR among university students are the determinants of intention, while perceived behavioral control does not play a major role. This study has implications for future CPR training. In order to improve the CPR implementation rate of university students, we should strengthen the relevant knowledge about CPR, maintain positive attitude and refine the related criteria of CPR implementation.

Abstract Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance. Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy.

Abstract Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract. The absorption of SCFAs is mediated by substrate transporters, such as monocarboxylate transporter 1 and sodium-coupled monocarboxylate transporter 1, which promote cellular metabolism. An increasing number of studies have implicated metabolites produced by microorganisms as crucial executors of diet-based microbial influence on the host. SCFAs are important fuels for intestinal epithelial cells (IECs) and represent a major carbon flux from the diet, that is decomposed by the gut microbiota. SCFAs play a vital role in multiple molecular biological processes, such as promoting the secretion of glucagon-like peptide-1 by IECs to inhibit the elevation of blood glucose, increasing the expression of G protein-coupled receptors such as GPR41 and GPR43, and inhibiting histone deacetylases, which participate in the regulation of the proliferation, differentiation, and function of IECs. SCFAs affect intestinal motility, barrier function, and host metabolism. Furthermore, SCFAs play important regulatory roles in local, intermediate, and peripheral metabolisms. Acetate, propionate, and butyrate are the major SCFAs, they are involved in the regulation of immunity, apoptosis, inflammation, and lipid metabolism. Herein, we review the diverse functional roles of this major class of bacterial metabolites and reflect on their ability to affect intestine, metabolic, and other diseases. Video Abstract

BackgroundEmerging evidence reveals that SARS-CoV-2 possesses the capability to disrupt the gastrointestinal (GI) homeostasis, resulting in the long-term symptoms such as loss of appetite, diarrhea, gastroesophageal reflux, and nausea. In the current review, we summarized recent reports regarding the long-term effects of COVID-19 (long COVID) on the gastrointestine.ObjectiveTo provide a narrative review of abundant clinical evidence regarding the development and management of long-term GI symptoms in COVID-19 patients.ResultsLong-term persistent digestive symptoms are exhibited in a majority of long-COVID patients. SARS-CoV-2 infection of intestinal epithelial cells, cytokine storm, gut dysbiosis, therapeutic drugs, psychological factors and exacerbation of primary underlying diseases lead to long-term GI symptoms in COVID-19 patients. Interventions like probiotics, prebiotics, fecal microbiota transplantation, and antibiotics are proved to be beneficial in preserving intestinal microecological homeostasis and alleviating GI symptoms.ConclusionTimely diagnosis and treatment of GI symptoms in long-COVID patients hold great significance as they may contribute to the mitigation of severe conditions and ultimately lead to the improvement of outcomes of the patients.

ABSTRACTIntestinal dysbiosis frequently occurs in abdominal radiotherapy and contributes to irradiation (IR)-induced intestinal damage and inflammation. Akkermansia muciniphila (A. muciniphila) is a recently characterized probiotic, which is critical for maintaining the dynamics of the intestinal mucus layer and preserving intestinal microbiota homeostasis. However, the role of A. muciniphila in the alleviation of radiation enteritis remains unknown. In this study, we reported that the abundance of A. muciniphila was markedly reduced in the intestines of mice exposed to abdominal IR and in the feces of patients who received abdominal radiotherapy. Abundance of A. muciniphila in feces of radiotherapy patients was negatively correlated with the duration of diarrhea in patients. Administration of A. muciniphila substantially mitigated IR-induced intestinal damage and prevented mouse death. Analyzing the metabolic products of A. muciniphila revealed that propionic acid, a short-chain fatty acid secreted by the microbe, mediated the radioprotective effect. We further demonstrated that propionic acid bound to G-protein coupled receptor 43 (GRP43) on the surface of intestinal epithelia and increased histone acetylation and hence enhanced the expression of tight junction proteins occludin and ZO-1 and elevated the level of mucins, leading to enhanced integrity of intestinal epithelial barrier and reduced radiation-induced intestinal damage. Metformin, a first-line agent for the treatment of type II diabetes, promoted intestinal epithelial barrier integrity and reduced radiation intestinal damage through increasing the abundance of A. muciniphila. Together, our results demonstrated that A. muciniphila plays a critical role in the reduction of abdominal IR-induced intestinal damage. Application of probiotics or their regulators, such as metformin, could be an effective treatment for the protection of radiation exposure-damaged intestine.

研究者繼Atayal部落國小低年級文化回應課程（ culturally responsive curriculum, CRC）知識選擇探究之後，本研究延續教育現場資料聚焦討論CRC知識傳輸方式及其教學特徵。本研究依據臺灣北部宜蘭地區Atayal部落國小B低年級實施CRC之質性資料，分析與詮釋個案教師如何提升學童語文及認識文化能力的歷程。歸納個案教師傳遞課程知識之策略與特徵有五點： 一、本案「Atayal男狩獵、女織布」主題課程能統整適合二年級學童學習的文化內容；二、以敘事之認識論規劃敘事文本閱讀、聆聽敘事與敘說經驗及模擬傳統技能等活動是恰當的文化傳輸策略；三、應用現代科技及學科概念教學，學童能獲得文化相關之學科知識；四、多樣的閱讀活動設計，能提升學童參與程度及國字正確率；五、個案教師課室師、生話語權分配比例趨向均等。本研究討論與建議︰一、文化認同度高的教師能積極轉化文化知識及均等分配學童學習機會；二、傳輸CRC知識之教師應具備閱讀教學、跨文化理解、學科教學等能力，較易達成CRC的多重目標。 This study is based on the author’s previous exploration of knowledge selection in a culturally responsive curriculum (CRC) for students in lower grades of the Atayal tribal elementary schools. The present manuscript provides a focused discussion of knowledge transfer methods and teaching features based on on-site CRC educational materials. A qualitative research approach explored the implementation of CRC for lower-grade students at the Atayal tribal elementary school in northern Taiwan in order to analyze and interpret the processes by which the teachers successfully improved students’ language outcomes and cultural understanding. Five key findings can be summarized in terms of the strategies and teaching features used by teachers for CRC knowledge transfer: (1) the curriculum topic of “Atayal boys to become hunters and girls to become weavers” suitably integrated cultural content for the second grade students’ learning; (2) cultural transmission strategies involved the design of learning activities based on the epistemology of narrative, including reading ethnic texts, listening to elders’ narratives, and simulating traditional skills; (3) modern technology and subject-based concept instruction were used to help students successfully acquire culturally relevant subject knowledge; (4) the design of diverse literacy activities encouraged students to actively participate in ethnicnarrative discussions, enhancing Chinese literacy strategies, and improving their accuracy in writing Chinese characters; and (5) the distribution of discourse power between teachers and students in the classroom tended to be equal. This paper discusses and proposes two recommendations: (1) teachers with high levels of cultural identity are best able to actively transform CRC knowledge and ensure equality of learning opportunities for students; and (2) teachers responsible for CRC knowledge transmission should possess skills related to literacy instruction, ethnic cultural identity, cross-cultural understanding, and subject teaching in order to easily achieve the multiple goals of the CRC.

Abdominal irradiation (IR) destroys the intestinal mucosal barrier, leading to severe intestinal infection. There is an urgent need to find safe and effective treatments to reduce IR-induced intestinal injury. In this study, we reported that metformin protected mice from abdominal IR-induced intestinal injury by improving the composition and diversity of intestinal flora. The elimination of intestinal microbiota (Abx) abrogated the protective effects of metformin on irradiated mice. We further characterized that treatment of metformin increased the murine intestinal abundance of Lactobacillus, which mediated the radioprotective effect. The administration of Lactobacillus or fecal microbiota transplantation (FMT) into Abx mice considerably lessened IR-induced intestinal damage and restored the radioprotective function of metformin in Abx mice. In addition, applying the murine intestinal organoid model, we demonstrated that IR inhibited the formation of intestinal organoids, and metformin alone bore no protective effect on organoids after IR. However, a combination of metformin and Lactobacillus or Lactobacillus alone displayed a strong radioprotection on the organoid formation. We demonstrated that metformin/Lactobacillus activated the farnesoid X receptor (FXR) signaling in intestinal epithelial cells and hence upregulated tight junction proteins and mucins in intestinal epithelia, increased the number of goblet cells, and augmented the mucus layer thickness to maintain the integrity of intestinal epithelial barrier, which eventually contributed to reduced radiation intestinal injury. In addition, we found that Lactobacillus abundance was significantly increased in the intestine of patients receiving metformin while undergoing abdominal radiotherapy and the abundance was negatively correlated with the diarrhea duration of patients. In conclusion, our results demonstrate that metformin possesses a protective effect on IR-induced intestinal injury by upregulating the abundance of Lactobacillus in the intestine.

Magnetism in two-dimensional (2D) materials has attracted much attention recently. However, intrinsic magnetic 2D materials are rare and mostly unstable in ambient. Although heteroatom doping can introduce magnetism, the basic property especially the electrical-magnetic coupling property has been rarely revealed. Herein, both iron (Fe)-doped and vanadium (V)-doped MoS2 films were grown by chemical vapor deposition. Through studying the structure and electrical property of Fe-doped and V-doped MoS2, it was found that both Fe and V doping would decrease the electron concentration, exhibiting a p-type doping effect. Significantly, V-doped MoS2 displays a p-type conduction behavior. Although the carrier mobility decreases after heteroatom doping, both Fe and V doping could endow MoS2 with magnetism, in which the transfer curves of both MoS2 transistors exhibit a strong magnetic-dependent behavior. It is found that the magnetic response of Fe-doped MoS2 can be tuned from ~0.2 ​nA/T to ~1.3 ​nA/T, with the tunability much larger than that of V-doped MoS2. At last, the magnetic mechanism is discussed with the local magnetic property performed by magnetic force microscopy. The typical morphology-independent magnetic signal demonstrates the formed magnetic domain structure in Fe-doped MoS2. This study opens new potential to design novel magnetic-electrical devices.