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Exosomes are nanosized membrane vesicles released from cells after fusion of multivesicular bodies (MVBs) with the plasma membrane (PM) and play important roles in intercellular communication and numerous biological processes. However, the molecular mechanisms regulating exosome secretion remain poorly understood. Here we identify KIBRA as an adaptor-like protein that stabilizes Rab27a, which in turn controls exosome secretion both in vitro and in vivo. Knockdown or overexpression of KIBRA in neuronal and podocyte cell lines leads to a decrease or increase of exosome secretion, respectively, and KIBRA depletion increases MVB size and number. Comparing protein profiles between KIBRA knockout and wild-type mouse brain showed significantly decreased Rab27a, a small GTPase that regulates MVB-PM docking. Rab27a is stabilized by interacting with KIBRA, which prevents ubiquitination and degradation via the ubiquitin-proteasome pathway. In conclusion, we show that KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a. Exosomes are intercellular signaling vesicles created by fusion of multivesicular bodies (MVBs) and the plasma membrane (PM), but secretory regulation is ill-defined. Song et al. show that KIBRA controls exosome secretion by protecting Rab27a from proteasomal degradation, promoting MVB-PM docking.

Nanocelluloses, including cellulose nanocrystals (CNCs), bacterial nanocellulose (BNC), and cellulose nanofibrils (CNFs), have attracted much attention in recent years all over the world. However, commercial applications of nanocelluloses are still limited due to the high cost of nanocelluloses. In this study, we developed a novel method to prepare lignocellulose nanofibrils (LCNF) directly from bamboo chips (BC), which can readily be scaled up. The method developed consists of three primary steps, which are as follows: glycerol pretreatment, screw extrusion, and mechanical refining/milling in a colloid mill. Glycerol can readily penetrate into bamboo chips and it is used as an effective reaction medium for fibrillation and delignification. The LCNF yield is about 77.2% based on bone dry bamboo chips. The morphology of the LCNF was investigated by transmission electron microscopy (TEM), which shows that the LCNFs have a diameter of 20–80 nm and a length of several thousand nanometers. X-ray diffraction (XRD) analysis shows that the crystallinity of the LCNF was 52.7%, which was slightly lower than that of the bamboo raw material. This process can be easily scaled up for commercial production of LCNF.

Gastrointestinal (GI) cancers impose a substantial global health burden, highlighting the necessity for deeper understanding of their intricate pathogenesis and treatment strategies. This review explores the interplay between intratumoral microbiota, tumor metabolism, and major types of GI cancers (including esophageal, gastric, liver, pancreatic, and colorectal cancers), summarizing recent studies and elucidating their clinical implications and future directions. Recent research revealed altered microbial signatures within GI tumors, impacting tumor progression, immune responses, and treatment outcomes. Dysbiosis-induced alterations in tumor metabolism, including glycolysis, fatty acid metabolism, and amino acid metabolism, play critical roles in cancer progression and therapeutic resistance. The integration of molecular mechanisms and potential biomarkers into this understanding further enhances the prognostic significance of intratumoral microbiota composition and therapeutic opportunities targeting microbiota-mediated tumor metabolism. Despite advancements, challenges remain in understanding the dynamic interactions within the tumor microenvironment (TME). Future research directions, including advanced omics technologies and prospective clinical studies, offer promising avenues for precision oncology and personalized treatment interventions in GI cancer. Overall, integrating microbiota-based approaches and molecular biomarkers into GI cancer management holds promise for improving patient outcomes and survival.

This paper takes the unexpected event of the new coronavirus as the research background, selects the daily closing price data of the financial sectors (banking, insurance, securities, and multifinance) from 20 June 2017 to 31 December 2023. It then applies the TVP-VAR-DY model to empirically study the risk spillover effect among financial sectors. The study identified three distinct stages: before, during, and after the epidemic. It revealed that the total systematic spillover exhibited an initial increase, followed by a subsequent decrease. Notably, the fluctuation in this phenomenon intensified significantly during the epidemic. The securities sector emerged as the most susceptible to spillover risks from other sectors and, in turn, the most vulnerable to risk contagion from other sectors. Conversely, the banking sector demonstrated relative stability. Furthermore, the multifinance sector is more susceptible to risk contagion from other sectors during the pre-epidemic and mid-epidemic stages. However, following the epidemic, as the economy has not yet fully recovered, the multifinance sector is more likely to experience spillover risks from other sectors, and the insurance sector also primarily acts as a risk spillover. Finally, five different lag orders were selected to test the robustness of the empirical results of the model. The test results demonstrated that the model was valid and the results were feasible.

Thrombocytopenia is a major complication in a subset of patients with multiple myeloma (MM). However, little is known about its development and significance during MM. Here, we show thrombocytopenia is linked to poor prognosis in MM. In addition, we identify serine, which is released from MM cells into the bone marrow microenvironment, as a key metabolic factor that suppresses megakaryopoiesis and thrombopoiesis. The impact of excessive serine on thrombocytopenia is mainly mediated through the suppression of megakaryocyte (MK) differentiation. Extrinsic serine is transported into MKs through SLC38A1 and downregulates SVIL via SAM-mediated tri-methylation of H3K9, ultimately leading to the impairment of megakaryopoiesis. Inhibition of serine utilization or treatment with TPO enhances megakaryopoiesis and thrombopoiesis and suppresses MM progression. Together, we identify serine as a key metabolic regulator of thrombocytopenia, unveil molecular mechanisms governing MM progression, and provide potential therapeutic strategies for treating MM patients by targeting thrombocytopenia. The molecular mechanisms underlying the development of thrombocytopenia in multiple myeloma (MM) remain to be explored. Here, the authors show an association of thrombocytopenia with poor prognosis in MM and identify serine as a key metabolic regulator of thrombocytopenia.

The rapid development of urbanization has had a dramatic impact on the economy, society and environment in China. In this context, the coordination relationship between population urbanization and land urbanization is essential for achieving sustainable urbanization. Based on the statistical data from 2007–2017 in the Yangtze River Economic Belt (YEB), this paper established the multi-dimensional coordination evaluation (MDCE) model by using the speed coordination evaluation (SCE) model, the level consistency evaluation (LCE) model, the entropy method and the space matching evaluation (SME) model to evaluate the coordination relationship between population urbanization and land urbanization from the speed-level-space perspective. The results showed that from 2007 to 2017: 1) the development speed of population urbanization and land urbanization in the YEB were more and more coordinated, and the speed of population urbanization lagged behind that of land urbanization. In addition, the overall development speed of the 11 provinces declined, and most of them were characterized by excessive development of land urbanization. 2) the development level of population urbanization and land urbanization in the YEB were all high, but the development level of population urbanization was lower than that of land urbanization. Further, the development level of the 11 provinces remained stable and high, and continuously improved. 3) the space matching of population urbanization and land urbanization in the YEB had a high degree of coordination, and the space matching degree of population urbanization was higher than that of land urbanization. Moreover, the space matching of most provinces in the region had declined, but the change was small. Finally, this paper proposes the policy recommendations on the coordinated development of population and land urbanization at the institutional, market and management levels to achieve coordinated and sustainable urbanization.

This study investigated the changes in serum tumor marker levels in patients with breast cancer (BC) after neoadjuvant chemotherapy (NACT) and their potential as prognostic factors in NACT. A total of 134 consecutive patients with BC treated at our hospital between January 2019 and December 2021 were retrospectively analyzed. Patients were treated with NACT based on the docetaxel, epirubicin, and cyclophosphamide (TEC) regimen and assessed for marker levels, T cell subsets, and therapeutic outcomes. Receiver operating characteristic (ROC) curves were constructed to evaluate the predictive performance of the markers. Outcome assessments showed that NACT effectively reduced the tumor size, leading to increased complete remission, partial remission, stable disease, and significantly reduced disease progression. Improved immune function has also been observed after NACT. The levels of two (E-cadherin and HMGB1) out of five markers (CA153, CK19, CEA, E-cadherin, and HMGB1) were significantly reduced after NACT before surgery compared with those at admission, suggesting that NACT modulates the levels of biomarkers. ROC analysis revealed that the area under the curve (AUC) of HMGB1 and E-cadherin combination was 0.87 for discrimination of therapeutic response with a sensitivity and specificity of 91.3% and 88.4%, respectively. Serum tumor marker levels were reduced after NACT in patients with BC. The reduction was most prominent for HMGB1, followed by E-cadherin. These biomarkers can be used to predict the therapeutic response to NACT with an AUC of 0.87, thus offering a new tool to monitor treatment progress in NACT for patients with BC.

BackgroundThe standard neoadjuvant treatments in patients with esophageal squamous cell carcinoma (ESCC) still have either poor safety or efficacy. Better therapies are needed in China.MethodsThis was an open-label, single-arm, phase 2 trial. Patients with potentially resectable ESCC (cT1b-3, Nany, M0 or T4a, N0-1, or M0) received preoperative intravenous sintilimab plus triplet chemotherapy (liposomal paclitaxel, cisplatin, and S-1) every 3 weeks for two cycles. The primary endpoints were safety and surgical feasibility; the secondary endpoint was major pathological response (MPR) rate. Genomic biomarkers (genetic mutations, tumor mutational burden (TMB), circulating tumor DNA status and immune microenvironment) in baseline tumor samples were investigated.ResultsAll 30 patients completed two cycles of neoadjuvant treatment and underwent surgical resection. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 36.7% (11/30) of patients. The most frequent TRAEs were decreased white cell count (76.7%), anemia (76.7%), and decreased neutrophil count (73.3%). All TRAEs were hematological toxicities; none caused ≥30 days surgical delay. The MPR and pathological complete response (pCR) rates were 50.0% (15/30; 95% CI 33.2 to 66.9) and 20.0% (6/30; 95% CI 9.5 to 37.3), respectively. Patients with higher TMB and more clonal mutations were more likely to respond. ERBB2 alterations and ctDNA high-releaser status have a negative correlation with neoadjuvant ICI response. No significant difference was observed between therapeutic response and tumor immune microenvironment.ConclusionsNeoadjuvant sintilimab plus platinum-based triplet chemotherapy appeared safe and feasible, did not delay surgery and induced a pCR rate of 20.0% in patients with potentially resectable ESCC.Trial registration numberNCT03946969.

The model mushroom Coprinopsis cinerea exhibits remarkable photomorphogenesis during fruiting body development. This study reports that the C. cinerea transcription factor CcNsdD2 promotes primary hyphal knot formation by upregulating cfs1 , cfs2 , cgl1 , and hyd1 . Coprinopsis cinerea has seven homologs of the Aspergillus nidulans transcription factor NsdD. Of these, CcNsdD1 and CcNsdD2 from C. cinerea show the best identities of 62 and 50% to A. nidulans NsdD, respectively. After 4 days of constant darkness cultivation, CcnsdD2 , but not CcnsdD1 , was upregulated on the first day of light/dark cultivation to induce fruiting bodies, and overexpression of CcnsdD2 , but not CcnsdD1 , produced more fruiting bodies under a light/dark rhythm. Although single knockdown of CcnsdD2 did not affect fruiting body production due to upregulation of its homolog CcnsdD1 , the double-knockdown CcNsdD1/NsdD2-RNAi transformant showed defects in fruiting body formation under a light/dark rhythm. Knockdown of CcnsdD1 / nsdD2 led to the differentiation of primary hyphal knots into sclerotia rather than secondary hyphal knots under a light/dark rhythm, similar to the differentiation of primary hyphal knots into sclerotia of the wild-type strain under darkness. The CcNsdD2-overexpressing transformant produced more primary hyphal knots, secondary hyphal knots, and fruiting bodies under a light/dark rhythm but only more primary hyphal knots and sclerotia under darkness. RNA-seq revealed that some genes reported previously to be involved in formation of hyphal knots and primordia, cyclopropane-fatty-acyl-phospholipid synthases cfs1-3 , galectins cgl1-3 , and hydrophobins hyd1-3 were downregulated in the CcNsdD1/NsdD2-RNAi transformant compared to the mock transformant. ChIP-seq and electrophoretic mobility shift assay demonstrated that CcNsdD2 bound to promoter regulatory sequences containing a GATC motif in cfs1 , cfs2 , cgl1 , and hyd1 . A molecular mechanism by which CcNsdD2 regulates the developmental fate of C. cinerea under dark or light conditions is proposed. IMPORTANCE The model mushroom Coprinopsis cinerea exhibits remarkable photomorphogenesis during fruiting body development. This study reports that the C. cinerea transcription factor CcNsdD2 promotes primary hyphal knot formation by upregulating cfs1 , cfs2 , cgl1 , and hyd1 . Although the induction of CcnsdD2 is not under direct control of light and photoreceptors, the CcNsdD2-mediated developmental fates of the primary hyphal knots depend on the following light/dark rhythm cultivation or dark cultivation after full growth of mycelia in the constant dark cultivation. This study provides new insight into the molecular mechanism by which CcNsdD2 regulates the developmental fate of C. cinerea under dark or light conditions. In addition, the result that overexpression of CcnsdD2 induced more secondary hyphal knots, primordia, and fruiting bodies under light/dark rhythm cultivation conditions has potential applied value in the edible mushroom industry.

Platelets, the chief effector of hemostasis, are small anucleate blood cells generated from megakaryocytes (MKs), and the defects in platelet production or function lead to a variety of bleeding complications. Emerging evidence indicates that MKs and platelets are much more diverse than previously appreciated and involved in many physiological and pathological processes besides hemostasis, such as innate and adaptive immune responses, angiogenesis, and tumor metastasis, while the ontogenic variations in MK and platelet function have also become a focus in the field. However, whether MKs and platelets fulfill these distinct functions by utilizing distinct subpopulations remains poorly understood. New studies aimed at deciphering the MK transcriptome at the single‐cell level have provided some key insights into the functional heterogeneity of MKs. In this review, we will discuss some of the recent discoveries of functional and developmental heterogeneity of MKs and its potential link to the heterogeneity of platelets. We will also discuss the implications of these findings while focusing on the ex vivo generation of platelets from human pluripotent stem cells. The improved understanding of the heterogeneity underlying human MK development and platelet production should open new avenues for future platelet regeneration and clinical treatment of related diseases. The comprehensive elucidation of megakaryocyte (MK) heterogeneity and improved understanding of its potential link with platelet heterogeneity will provide new insights into the platelet production from human pluripotent stem cells. It would be extremely attractive to produce platelet‐biased MKs and subsequent platelet subpopulations with distinct functions for future clinical applications, such as those with hemostatic, antineoplastic, or pro‐angiogenic functions.