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Abstract Reconfigurable phototransistors featuring bipolar photoresponses are favorable for manipulating high-performance neuromorphic vision sensory. Here, we present a momentum-conserved reconfigurable phototransistor based on the van der Waals heterojunction between methylammonium lead iodide perovskite and two-dimensional Bi2O2Se semiconductor, which exhibits a synergistic interplay of interband hot-carrier transitions and reconfigurable heterointerface band alignments, eventually achieving the ultrahigh bipolar optoelectronic performances with the photoresponsivity of 6×107 AW−1, accompanied by the specific detectivity of 5.2×1011 Jones, and the dynamic range of 110 dB. Moreover, A 3×3 heterotransistor array is fabricated to perform in-sensor analog multiply-accumulate operations even under the challenging dim illumination of 0.1 μWcm−2 that comparable to natural moonlight. The reconfigurable heterotransistor array can be further adopted to enhance the traffic-light detection under dim-light conditions. Our advancement in momentum-conserved reconfigurable heterotransistor signifies a leap forward in real-time, energy-efficient, and low-light image processing for neuromorphic vision sensors.

Portal vein tumor thrombosis (PVTT), a severe complication of hepatocellular carcinoma (HCC), markedly influences patient prognosis by fostering a hypercoagulable state. However, its molecular underpinnings remain largely unexplored. This study sheds light on the critical role of the KIT ligand (KITLG) in modulating expression of the collagen gene COL4A1 via the STAT3-SMAD2 signaling pathway, thereby influencing platelet activation and PVTT development. Extensive analysis of PVTT tissue samples, alongside in vitro and in vivo experiments including cell-platelet interaction assays and PVTT animal models, revealed the mechanism through which KITLG regulates COL4A1 expression, as well as its downstream effects on platelet behavior and the coagulation cascade. Our findings revealed that marked upregulation of COL4A1 expression, mediated by KITLG through the STAT3-SMAD2 pathway, led to increased platelet activation and PVTT formation. KITLG and COL4A1 expression was markedly higher in PVTT tissues than primary HCC tissues, thus highlighting their critical role in the pathophysiological trajectory leading to thrombosis. The finding that the KITLG-COL4A1 signaling axis is a crucial mediator in PVTT development may offer promising new directions for developing targeted diagnostic and therapeutic strategies. This study underscores the importance of the KITLG-COL4A1 axis in PVTT formation and its potential as a therapeutic target in HCC treatment protocols.

Abstract Background Bedtime procrastination refers to an individual’s inability to go to bed at a predetermined time without external obstacles. Previous researchers have found that the bedtime procrastination is harmful to human physical and mental health, but these research on bedtime procrastination have mostly focused on exploring individual factors, while ignoring the external environmental factors. Therefore, this is the first study to investigate bedtime procrastination from the perspective of family environments. Methods The study was conducted using a convenient sampling method and online questionnaires. Family Cohesion Scale, Coping Styles Questionnaire, Mobile Phone Addiction Tendency Scale and Bedtime Procrastination Scale were used to measure sleep and psychological condition of 1,048 college students. Results Family cohesion negatively predicted bedtime procrastination. Additionally, positive coping style and mobile phone addiction had significant independent mediating effects. Furthermore, positive coping style and mobile phone addiction had chain mediating effects between family cohesion and bedtime procrastination. Conclusion This study revealed the effect of coping styles and mobile phone addiction on the relationship between family cohesion and bedtime procrastination among Chinese college students. These findings explained the mechanisms of bedtime procrastination from the perspective of environment, so as to effectively intervene the bedtime procrastination of college students from the perspective of external environment.

Abstract The Xinjiang unearthed brocade as a significant cultural heritage records the historical and cultural information of diverse ethnic groups, and it also influences cultural product development. However, the existing knowledge concerning these brocades is disorganized, fragmented, and incomplete, hindering a comprehensive understanding of their intricate relationships. To address these issues, this study has developed an integrated ontological model for Xinjiang’s unearthed brocades (XJUBontology). By applying Conceptual Reference Model of International Committee for Documentation (CIDOC CRM) ontology and the Remanufactured Process Planning (RPP) approach, this XJUBontology comprises knowledge about both the brocades and their cultural derivatives, and knowledge in these two domains are able to be organized and refined. The implementation of XJUBontology in Protégé and validation via SPARQL queries not only centralize and manage Xinjiang unearthed brocade-related knowledge but also establish vital connections among this fragmented information. The contribution is to help in associating, managing, and sharing knowledge in the domain of Xinjiang unearthed brocades, providing a framework for establishing related data repository, and helping researchers, apparel and accessories designers, museums, and other cultural and tourism institutions to access a more systematic information to assist their works.

IntroductionBispecific antibodies (BsAbs) can simultaneously target two epitopes of different antigenic targets, bringing possibilities for diversity in antibody drug design and are promising tools for the treatment of cancers and other diseases. T-cell engaging bsAb is an important application of the bispecific antibody, which could promote T cell-mediated tumor cell killing by targeting tumor-associated antigen (TAA) and CD3 at the same time.MethodsThis study comprised antibodies purification, Elisa assay for antigen binding, cytotoxicity assays, T cell activation by flow cytometry in vitro and xenogenic tumor model in vivo.ResultsWe present a novel bsAb platform named PHE-Ig technique to promote cognate heavy chain (HC)-light chain (LC) pairing by replacing the CH1/CL regions of different monoclonal antibodies (mAbs) with the natural A and B chains of PHE1 fragment of Integrin β2 based on the knob-in-hole (KIH) technology. We had also verified that PHE-Ig technology can be effectively used as a platform to synthesize different desired bsAbs for T-cell immunotherapy. Especially, BCMA×CD3 PHE-Ig bsAbs exhibited robust anti-multiple myeloma (MM) activity in vitro and in vivo.DiscussionMoreover, PHE1 domain was further shortened with D14G and R41S mutations, named PHE-S, and the PHE-S-based BCMA×CD3 bsAbs also showed anti BCMA+ tumor effect in vitro and in vivo, bringing more possibilities for the development and optimization of different bsAbs. To sum up, PHE1-based IgG-like antibody platform for bsAb construction provides a novel strategy for enhanced T-cell immunotherapy.

Impaired differentiation of megakaryocytes constitutes the principal etiology of thrombocytopenia. The signal transducer and activator of transcription 3 (STAT3) is a crucial transcription factor in regulating megakaryocyte differentiation, yet the precise mechanism of its activation remains unclear. PALLD, an actin-associated protein, has been increasingly recognized for its essential functions in multiple biological processes. This study revealed that megakaryocyte/plateletspecific knockout of PALLD in mice exhibited thrombocytopenia due to diminished platelet biogenesis. In megakaryocytes, PALLD deficiency led to impaired proplatelet formation and polyploidization, ultimately weakening their differentiation for platelet production. Mechanistic studies demonstrated that PALLD bound to STAT3 and interacted with its DNA-binding domain (DBD) and Src homology 2 (SH2) domain via Immunoglobulin domain 3 (Ig3). Moreover, the absence of PALLD attenuated STAT3 Y705 phosphorylation and impeded STAT3 nuclear translocation. Based on the PALLD-STAT3 binding sequence, we designed a peptide C-P3, which can facilitate megakaryocyte differentiation and accelerate platelet production in vivo. In conclusion, this study highlights the pivotal role of PALLD in megakaryocyte differentiation and proposes a novel approach for treating thrombocytopenia by targeting the PALLD-STAT3 interaction.

Inspired by classical experiments that uncovered the inherent properties of light waves, Young’s Double-Slit Experiment (YDSE) optimization algorithm represents a physics-driven meta-heuristic method. Its unique search mechanism and scalability have attracted much attention. However, when facing complex or high-dimensional problems, the YDSE optimizer, although striking a good balance between global and local searches, does not converge as fast as it should and is prone to fall into local optimums, thus limiting its application scope. A fractional-order boosted hybrid YDSE, called FYDSE, is proposed in this article. FYDSE employs a multi-strategy mechanism to jointly address the YDSE problems and enhance its ability to solve complex problems. First, a fractional-order strategy is introduced into the dark edge position update of FYDSE to ensure more efficient use of the search potential of a single neighborhood space while reducing the possibility of trapping in a local best. Second, piecewise chaotic mapping is constructed at the initial stage of the population to obtain better-distributed initial solutions and increase the convergence rate to the optimal position. Moreover, the low exploration space is extended by using a dynamic opposition strategy, which improves the probability of acquisition of a globally optimal solution. Finally, by introducing the vertical operator, FYDSE can better balance global exploration and local exploitation and explore new unknown areas. The numerical results show that FYDSE outperforms YDSE in 11 (91.6%) of cec2022 sets. In addition, FYDSE performs best in 8 (66.6%) among all algorithms. Compared with the 11 methods, FYDSE obtains the optimal best and average weights for the 20-bar, 24-bar, and 72-bar truss problems, which proves its efficient optimization capability for difficult optimization cases.

Based on a meta-heuristic secretary bird optimization algorithm (SBOA), this paper develops a multi-strategy improvement secretary bird optimization algorithm (MISBOA) to further enhance the solving accuracy and convergence speed for engineering optimization problems. Firstly, a feedback regulation mechanism based on incremental PID control is used to update the whole population according to the output value. Then, in the hunting stage, a golden sinusoidal guidance strategy is employed to enhance the success rate of capture. Meanwhile, to keep the population diverse, a cooperative camouflage strategy and an update strategy based on cosine similarity are introduced into the escaping stage. Analyzing the results in solving the CEC2022 test suite, the MISBOA both get the best comprehensive performance when the dimensions are set as 10 and 20. Especially when the dimension is increased, the advantage of MISBOA is further expanded, which ranks first on 10 test functions, accounting for 83.33% of the total. It illustrates the introduction of improvement strategies that effectively enhance the searching accuracy and stability of MISBOA for various problems. For five real-world optimization problems, the MISBOA also has the best performance on the fitness values, indicating a stronger searching ability with higher accuracy and stability. Finally, when it is used to solve the shape optimization problem of the combined quartic generalized Ball interpolation (CQGBI) curve, the shape can be designed to be smoother according to the obtained parameters based on MISBOA to improve power generation efficiency.

Air purifier use, shift work, and long-term exposure to fine particulate matter (PM2.5) are linked to platelet abnormality. However, the role of air purifier use and shift work in the individual or joint associations of PM2.5 and its components with platelet indices are largely unknown. A total of 8772 participants were recruited from a population of subway workers in China. PM2.5 and its component data were obtained from the Tracking Air Pollution in China dataset. The role of air purifier use and shift work in the association between PM2.5 and its components and platelet indices were analyzed. Among shift workers without air purifier use, positive associations of PM2.5 and each component in PM2.5 with the mean platelet volume (MPV) or platelet counts (PLT) were observed, whereas negative associations of PM2.5 and each component in PM2.5 with the platelet distribution width (PDW) were observed. Furthermore, estimated changes (95%CIs) in PLT, MPV, and PDW in response to each 10th percentile increment in the mixture of PM2.5 and its components were 0.8657 (0.2496, 1.4819), 0.0192 (0.0054, 0.0329), and −0.0648 (−0.0945, −0.0351), respectively, and sulfate in PM2.5 was the major contributor to those associations. Long-term exposure to PM2.5 and its components was related to increased platelet disorders among shift workers without air purifier use, and those associations were mainly attributed to sulfate in PM2.5.

Hyperuricemia, i.e., increased plasma uric acid concentration, is a common problem in clinical practice, leading to gout or nephrolithiasis, and is associated with other disorders, such as metabolic syndrome, cardiovascular disease, and chronic renal disease. Xanthine oxidoreductase (XOR) is a critical rate-limiting enzyme involved in uric acid synthesis and a promising target for hyperuricemia therapy. However, XOR inhibitors currently face clinical problems such as a short half-life and side effects. Here, we found that specifically targeting liver Xor with GalNAc-siRNAs had a good therapeutic effect on hyperuricemia. First, siRNAs were designed to target various sites in the homologous region between Homo sapiens and Mus musculus Xor mRNA and were screened in primary mouse hepatocytes. Then, the siRNAs were modified to increase their stability in vivo and conjugated with GalNAc for liver-specific delivery. The effects of GalNAc-siRNAs were evaluated in three hyperuricemia mouse models, including potassium oxonate and hypoxanthine administration in WT and humanized XDH mice and Uox knockout mice. Febuxostat, a specific XOR inhibitor used for hyperuricemia treatment, was used as a positive control. Targeting liver Xor with GalNAc-siRNAs by subcutaneous administration reduced plasma uric acid levels, uric acid accumulation in the kidney, renal inflammation, and fibrosis, thereby alleviating kidney damage in hyperuricemia mouse models without hepatoxicity. The results demonstrated that targeting liver Xor with GalNAc-siRNAs was a promising strategy for hyperuricemia therapy.

Abstract Aberrant coagulation and thrombosis are associated with severe COVID-19 post-SARS-CoV-2 infection, yet the underlying mechanism remains obscure. Here we show that serum levels of SARS-CoV-2 envelope (E) protein are associated with coagulation disorders of COVID-19 patients, and intravenous administration of the E protein is able to potentiate thrombosis in mice. Through protein pull-down and mass spectrometry, we find that CD36, a transmembrane glycoprotein, directly binds with E protein and mediates hyperactivation of human and mouse platelets through the p38 MAPK-NF-κB signaling pathway. Conversely, the pharmacological blockade of CD36 or p38 notably attenuates human platelet activation induced by the E protein. Similarly, the genetic deficiency of CD36, as well as the pharmacological inhibition of p38 in mice, significantly diminishes E protein-induced platelet activation and thrombotic events. Together, our study reveals a critical role for the CD36-p38 axis in E protein-induced platelet hyperactivity, which could serve as an actionable target for developing therapies against aberrant thrombotic events related to the severity and mortality of COVID-19.

Breakthrough treatment for refractory and relapsed immune thrombocytopenia (ITP) patients is urgently needed. Autoantibody-mediated platelet clearance and megakaryocyte dysfunction are important pathogenic mediators of ITP. Glycoprotein (GP) Ibα is a significant autoantigen found in ITP patients and is associated with poor response to standard immunosuppressive treatments. Here, we engineered human T cells to express a chimeric autoantibody receptor (CAAR) with GPIbα constructed into the ligand-binding domain fused to the CD8 transmembrane domain and CD3ζ-4-1BB signaling domains. We performed cytotoxicity assays to assess GPIbα CAAR-T-cell selective cytolysis of cells expressing anti-GPIbα B-cell receptors (BCRs) in vitro. Furthermore, we demonstrated the potential of GPIbα CAAR-T cells to persist and precisely eliminate GPIbα-specific B cells in vivo. In summary, we present a proof of concept for CAAR-T-cell therapy to eradicate autoimmune B cells while sparing healthy B cells with GPIbα CAAR-T cells that function like a Trojan horse. GPIbα CAAR-Tcell therapy is a promising treatment for refractory and relapsed ITP patients.

Polysaccharides and saponins are the main active components of Polygonati Rhizoma. Studying the molecular mechanism of their synthesis pathway is helpful in improving the content of active components at the molecular level. At present, transcriptome analysis of three Polygonatum species (Polygonatum sibiricum Red., Polygonatum cyrtonema Hua, Polygonatum kingianum Coll. et Hemsl.) has been reported, but no comparative study has been found on the transcriptome data of the three species. Transcriptome sequencing was performed on the rhizomes of three Polygonatum species based on high-throughput sequencing technology, and all transcripts were assembled. A total of 168,108 unigenes were generated after the removal of redundancy, of which 121,642 were annotated in seven databases. Through differential analysis and expression analysis of key enzyme genes in the synthesis pathway of three Polygonatum polysaccharides and steroidal saponins, 135 differentially expressed genes encoding 18 enzymes and 128 differentially expressed genes encoding 28 enzymes were identified, respectively. Numerous transcription factors are involved in the carbohydrate synthesis pathway. Quantitative real-time PCR was used to further verify the gene expression level. In this paper, we present a public transcriptome dataset of three medicinal plants of the genus Polygonatum, and analyze the key enzyme genes of polysaccharide and steroidal saponins synthesis pathway, which lays a foundation for improving the active component content of Polygonati Rhizoma by molecular means.

Abstract Background Oligodendrocytes have robust regenerative ability and are key players in remyelination during physiological and pathophysiological states. However, the mechanisms of brain microenvironmental cue in regulation of the differentiation of oligodendrocytes still needs to be further investigated. Results We demonstrated that myelin-associated glycoprotein (MAG) was a novel receptor for angiopoietin-like protein 2 (ANGPTL2). The binding of ANGPTL2 to MAG efficiently promoted the differentiation of oligodendrocytes in vitro, as evaluated in an HCN cell line. Angptl2-null mice had a markedly impaired myelination capacity in the early stage of oligodendrocyte development. These mice had notably decreased remyelination capacities and enhanced motor disability in a cuprizone-induced demyelinating mouse model, which was similar to the Mag-null mice. The loss of remyelination ability in Angptl2-null/Mag-null mice was similar to the Angptl2-WT/Mag-null mice, which indicated that the ANGPTL2-mediated oligodendrocyte differentiation effect depended on the MAG receptor. ANGPTL2 bound MAG to enhance its phosphorylation level and recruit Fyn kinase, which increased Fyn phosphorylation levels, followed by the transactivation of myelin regulatory factor (MYRF). Conclusion Our study demonstrated an unexpected cross-talk between the environmental protein (ANGPTL2) and its surface receptor (MAG) in the regulation of oligodendrocyte differentiation, which may benefit the treatment of many demyelination disorders, including multiple sclerosis.

Abstract Background Multiple myeloma (MM) is a hematological malignancy characterized by clonal proliferation of malignant plasma cells. Despite extensive research, molecular mechanisms in MM that drive drug sensitivity and clinic outcome remain elusive. Results Single-cell RNA sequencing was applied to study tumor heterogeneity and molecular dynamics in 10 MM individuals before and after 2 cycles of bortezomib–cyclophosphamide–dexamethasone (VCD) treatment, with 3 healthy volunteers as controls. We identified that unfolded protein response and metabolic-related program were decreased, whereas stress-associated and immune reactive programs were increased after 2 cycles of VCD treatment. Interestingly, low expression of the immune reactive program by tumor cells was associated with unfavorable drug response and poor survival in MM, which probably due to downregulation of MHC class I mediated antigen presentation and immune surveillance, and upregulation of markers related to immune escape. Furthermore, combined with immune cells profiling, we uncovered a link between tumor intrinsic immune reactive program and immunosuppressive phenotype in microenvironment, evidenced by exhausted states and expression of checkpoint molecules and suppressive genes in T cells, NK cells and monocytes. Notably, expression of YBX1 was associated with downregulation of immune activation signaling in myeloma and reduced immune cells infiltration, thereby contributed to poor prognosis. Conclusions We dissected the tumor and immune reprogramming in MM during targeted therapy at the single-cell resolution, and identified a tumor program that integrated tumoral signaling and changes in immune microenvironment, which provided insights into understanding drug sensitivity in MM.

Background: Glioma is the most common primary brain tumor, but its therapeutic effect is not very ideal up to now. The point of this study was to recognize the potential gene involved in lower-grade glioma (LGG) and to promote the treatment and prognosis for LGG patients. Method: During the investigation, we first studied the differential expression and the survival analysis of GNG5 in patients with glioma, LGG, and GBM, respectively. Then, independent prognostic analysis, the clinical relevance characteristics and the differential expressed genes (DEGs) were also evaluated. In addition, Metascape and GSEA analyses were carried out to achieve potential mechanism. Co-expression and immune infiltration analysis were finally conducted. Results: The results indicated that GNG5 as an independent prognostic indicator was negatively associated with the overall survival of LGG patients. Metascape and GSEA analyses showed that GNG5 may participate in complement and coagulation cascades pathway. The co-expression analysis was concluded that GNG5 was positively correlated with the following factors: C4B, PLAU, C1R, C1QC, C4A, SERPINA1, C1QB, CFI, C3. Conclusions: This study demonstrated that the highly expression of GNG5 in LGG may lead to poor prognosis. Besides, our research also revealed that GNG5 may be a promising immune-related biomarker for LGG patients.

Currently, there is a lack of effective drugs for the treatment of pulmonary fibrosis. Here, the authors reveal a novel role of PEAR1 in fibroblast activation and demonstrate that activating PEAR1 by monoclonal antibodies might be a promising therapeutic approach for pulmonary fibrosis.

The logistics carbon emission efficiency takes into account the two goals of economic development and carbon emission reduction, and is an indicator for evaluating the development of a low-carbon economy. This paper mainly discusses the interaction between international trade and logistics carbon emissions. It firstly reviews and sorts out the relevant literature on technology spillovers and carbon emission efficiency in international trade. Then, by analyzing the current situation of China’s economic belt’s import trade and export trade, and by calculating the import trade technology spillover and export trade technology spillover of China’s economic belt from 2017 to 2021, it analyzes the current situation of China’s economic belt and each region of China’s economic belt absorbing technology spillovers from international trade. By analyzing the CO2 emission and economic development of China’s economic belt, the carbon emission efficiency of China’s economic belt can be calculated by using the relationship model between carbon emission and various economic indicators. Then, the panel data model is used to empirically analyze the impact of import trade technology spillovers and export trade technology spillovers on the carbon emission efficiency of China’s economic belt and make regional comparisons. Textile, sewing and leather product manufacturing, chemical industry, metal product manufacturing and machinery and equipment manufacturing saw the largest increases in embodied carbon. In 2017, the embodied carbon in the export trade of textile, sewing and leather product manufacturing increased from 26,761,122 tons to 98,311,041 tons in 2021, and the chemical industry in 2017 increased from 26,413,981 tons to 107,493,401 tons in 2021. This research will help to rationally formulate the carbon emission quota system and improve the supervision system of the carbon trading market.

The use of messenger RNA (mRNA) enables the transient production of therapeutic proteins with stable and predictable translational kinetics and without the risk of insertional mutagenesis. Recent findings highlight the enormous potential of mRNA-based therapeutics. Here, we describe the synthesis of chemically modified thrombopoietin (TPO) mRNA through in vitro transcription and in vivo delivery via lipid nanoparticles (LNPs). After delivery of TPO mRNA in mice, compared with normal physiological values, plasma TPO protein levels increased over 1000-fold in a dose-dependent manner. Moreover, through a single intravenous dose of TPO mRNA-loaded LNPs, both reticulated and total platelet count increased significantly in mice, demonstrating that TPO protein derived from the exogenous mRNA was able to maintain normal activity. Submicrogram quantity of N1-methylpseudouridine-modified TPO mRNA showed a similar effect in promoting thrombopoiesis as that by the TPO receptor agonist romiplostim. In addition, a therapeutic value was established in anti-GPIbα (CD42b) antibody-induced thrombocytopenia mouse models that showed a fast recovery of platelet count. Our study demonstrated chemically modified in-vitro-transcribed TPO mRNA as a potentially safe therapeutic intervention to stimulate thrombopoiesis.

The efficient conversion and utilization of CO2 is imminent due to the increase of global CO2 emissions year by year, so the strategy of electrocatalytic CO2 reduction to high value‐added chemicals comes into being. The CO2 reduction reaction (CO2RR) can yield diversified products, including C1 (like CO, CH4, etc.), C2 (like C2H4, C2H5OH, etc.), and other multicarbon compounds. Thereinto, selective transformation to C2 compounds is relatively significative by reason of high industrial value but being greatly challenging, particularly involving complex CC coupling. Herein, the reaction mechanisms of several C2 products (including C2H4, C2H5OH, and H2C2O4) and corresponding latest research progress are summarized and discussed. Besides, N atoms, from N2, nitrates, and nitrites, are integrated into CO2RR to yield nitrogen‐containing organics (like urea, amides, and amines), broadening the application field of CO2RR. Therefore, the part on the electrocatalytic coupling of CO2 and nitrogen sources (including N2, NO3−, NO2−) by CN bonds is also delved in this review, including recent advances, reaction mechanisms, and related key intermediates.

Vegetable oil is an important part of the human diet and has multiple industrial uses. The rapid increase in vegetable oil consumption has necessitated the development of viable methods for optimizing the oil content of plants. The key genes regulating the biosynthesis of maize grain oil remain mostly uncharacterized. In this study, by analyzing oil contents and performing bulked segregant RNA sequencing and mapping analyses, we determined that su1 and sh2-R mediate the shrinkage of ultra-high-oil maize grains and contribute to the increase in the grain oil content. Functional kompetitive allele-specific PCR (KASP) markers developed for su1 and sh2-R detected su1su1Sh2Sh2, Su1Su1sh2sh2, and su1su1sh2sh2 mutants among 183 sweet maize inbred lines. An RNA sequencing (RNA-seq) analysis indicated that genes differentially expressed between two conventional sweet maize lines and two ultra-high-oil maize lines were significantly associated with linoleic acid metabolism, cyanoamino acid metabolism, glutathione metabolism, alanine, aspartate, and glutamate metabolism, and nitrogen metabolism. A bulk segregant analysis and sequencing (BSA-seq) analysis identified another 88 genomic intervals related to grain oil content, 16 of which overlapped previously reported maize grain oil-related QTLs. The combined analysis of BSA-seq and RNA-seq data enabled the identification of candidate genes. The KASP markers for GRMZM2G176998 (putative WD40-like beta propeller repeat family protein), GRMZM2G021339 (homeobox-transcription factor 115), and GRMZM2G167438 (3-ketoacyl-CoA synthase) were significantly related to maize grain oil content. Another candidate gene, GRMZM2G099802 (GDSL-like lipase/acylhydrolase), catalyzes the final step of the triacylglycerol synthesis pathway and was expressed at significantly higher levels in the two ultra-high-oil maize lines than in the two conventional sweet maize lines. These novel findings will help clarify the genetic basis of the increased oil production in ultra-high-oil maize lines with grain oil contents exceeding 20%. The KASP markers developed in this study may be useful for breeding new high-oil sweet maize varieties.

Platelets have been shown to alter immune cell function but it is not clear if this includes autoimmunity. Here the authors show that phosphatase and tensin homolog (PTEN) deficient platelets promote autoimmunity in mouse models through excessive activation of TFH cells and systemic autoimmune pathology.

With the increasing depth of metal mining, thermal damage has become a serious problem that restricts mining. The thermal management system of refrigeration and ventilation is an indispensable technology in the mining of deep metal mines, which plays a key role in improving the thermal and humid environment of mines. Optimizing the performance of refrigeration and ventilation systems to reduce energy consumption has become a focus of researchers’ attention. Based on the heat current method, this research establishes the overall heat transfer and flow constraint model of the refrigeration and ventilation system, and proposes an iterative algorithm that combines the refrigerator energy consumption model and the artificial neural network model of heat exchangers. The Lagrange multiplier method is used to optimize the system with the goal of minimizing the total power consumption of the system. The results show that under 9.1 kW cooling load conditions, the total energy consumption of the system reduces by 16.5%, and the COP of the refrigerator increases by 11.6%. The optimization results provide significant guidance for the production and energy consumption reduction of the deep metal mines.

Abstract Objectives To analyze the relationship between the dietary preparation status prior to contrast-enhanced CT (CECT) and adverse drug reactions (ADR) and emetic complications. Methods Non-emergency adult patients who underwent routine CECT in our hospital from January 2019 to December 2020 were retrospectively analyzed. Stratified dietary preparation regimens were implemented for different clinical scenarios. The relationship between actual dietary preparation status and ADR and emetic complications was analyzed. Results A total of 127,200 cases were enrolled, including 49,676 cases in the fasting group (57 years ± 13, 56.79% men) and 77,524 cases in the non-fasting group (60 years ± 13, 54.55% men). No statistical difference was found in the overall incidence of ADR (0.211% vs. 0.254%, p = 0.126) or emetic complications (0.030% vs. 0.046%, p = 0.158) between the two groups, and no aspiration pneumonia or death occurred. For patients with an ICM-ADR history, the ADR incidence in non-fasting group was significantly lower than fasting group (2.424% vs. 12.371%, p = 0.002). For patients with hypertension, injection dose ≥ 100 mL, injection rate ≥ 5 mL/s, and Iopromide 370 usage, non-fasting was associated with higher ADR incidence (p

Teratomas often occur in the gonads, while Extragonadal mature cystic teratomas are reported occasionally, with the most common site being the omentum. Teratoma in the Douglas sac is extremely rare. we report a rare case of mature cystic Teratoma in the Douglas sac in a 71-year-old woman who underwent laparoscopic surgery. A cyst with a diameter of approximately 6 cm from Douglas was found during surgery, and the mass was separated from both ovaries. Microscopically, the cyst was a mature cystic teratoma that did not originate from the ovary.

Rhizosphere microorganisms are the main factors affecting the formation of high quality medicinal materials and promoting the accumulation of secondary metabolites. However, the composition, diversity, and function of rhizosphere microbial communities in endangered wild and cultivated Rhizoma Atractylodis Macrocephalae (RAM) and their relationships with active component accumulation have remained unclear. In this study, high-throughput sequencing and correlation analysis were used to study the rhizosphere microbial community diversity (bacteria and fungi) of three RAM species and its correlation with the accumulation of polysaccharides, atractylone, and lactones (I, II, and III). A total of 24 phyla, 46 classes, and 110 genera were detected. The dominant taxa were Proteobacteria, Ascomycota, and Basidiomycota. The microbial communities in both wild and artificially cultivated soil samples were extremely species-rich, but there were some differences in their structure and the relative abundances of microorganism taxa. Meanwhile, the contents of effective components in wild RAM were significantly higher than those in cultivated RAM. Correlation analysis showed that 16 bacterial and 10 fungal genera were positively or negatively correlated with active ingredient accumulation. These results showed that rhizosphere microorganisms could play an important role in component accumulation and might lay a foundation for future research on endangered materials.

Polygonatum cyrtonema Hua is a perennial herbaceous plant of the Polygonatum genus, belonging to the Liliaceae family, with significant medicinal and nutritional value. In China, this species is a traditional medicinal and edible herb with a long history of application and is widely appreciated by the people. However, as the demand for medicinal herbs continues to grow, excessive harvesting has led to the depletion of wild resources and the risk of genetic erosion. In addition, the chaotic cultivation of varieties and the lack of high quality germplasm resources have led to inconsistent quality of medical materials. Therefore, it is urgent to conduct genetic diversity evaluation of this species and establish a sound conservation plan. This study assessed the genetic diversity and population structure of 96 samples collected from seven regions in China using the simple sequence repeat (SSR) molecular marker technology. In this study, a total of 60 alleles (Na) were detected across the 10 polymorphic SSR markers used, with an average of 6.0 alleles generated per locus. The values of polymorphic information content (PIC) values ranged from 0.3396 to 0.8794, with an average value of 0.6430. The average value of the effective number of alleles (Ne) was 2.761, and the average value of the Shannon’s information index (I) was 1.196. The population structure analysis indicates that the Polygonatum cyrtonema Hua germplasm can be classified into three subpopulations (JZ, QY, JD) at the molecular level, which corresponds to the previous subgroups identified based on individual plant phenotypic traits. Analysis of Molecular Variance (AMOVA) showed that 74% of the genetic variation was between individuals within populations in different regions. The phylogenetic analysis of the 96 germplasm samples divided them into three main populations. The QY and JD subpopulations are largely clustered together, which could be attributed to their mountainous distribution and the local climate environment. The genetic differentiation coefficient (Fst) value was low at 0.065, indicating relatively low population differentiation. The ratio of the genetic differentiation coefficient (Fst) between the JZ population and the other two populations (QY and JD) is much higher than the ratio between the QY and JD populations. Based on the clustering results and the ratio of the genetic differentiation coefficient (Fst), it can be inferred that the genetic relationship between the QY and JD subpopulations is closer, with a certain degree of genetic differentiation from the JZ subpopulation. This study supports the conservation of germplasm resources of Polygonatum cyrtonema Hua in China and provides new parental material for germplasm genetic improvement and breeding programs.

IntroductionLung cancer is a serious global health concern, and its subtypes are closely linked to lifestyle and dietary habits. Recent research has suggested that malnutrition, over-nutrition, electrolytes, and granulocytes have an effect on the development of cancer. This study investigated the impact of combining patient nutritional indicators, electrolytes, and granulocytes as comprehensive predictors for lung cancer treatment outcomes, and applied a machine learning algorithm to predict lung cancer.Methods6,336 blood samples were collected from lung cancer patients classified as lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), and small cell lung cancer (SCLC). 2,191 healthy individuals were used as controls to compare the differences in nutritional indicators, electrolytes and granulocytes among different subtypes of lung cancer, respectively.ResultsOur results demonstrated significant differences between men and women in healthy people and NSCLC, but no significant difference between men and women in SCLC patients. The relationship between indicators is basically that the range of indicators for cancer patients is wider, including healthy population indicators. In the process of predicting lung cancer through nutritional indicators by machine learning, the AUC of the random forest model was as high as 93.5%, with a sensitivity of 75.9% and specificity of 96.5%.DiscussionThis study supports the feasibility and accuracy of nutritional indicators in predicting lung cancer through the random forest model. The successful implementation of this novel prediction method could guide clinicians in providing both effective diagnostics and treatment of lung cancers.

Abstract Solitary wave is often used to simulate tsunami propagating in deep water and breaking solitary wave is often used to simulate tsunami bore propagating in shallow water or on land. The breaking solitary wave force on box-girder, which has been widely used in bridge engineering in coastal areas of China, receives few attentions. This study aims to investigate characteristics and generation mechanism of breaking solitary wave force on box-girder numerically. A numerical wave flume with a 1:20 slope was built firstly, then the solitary wave generation ability, wave deformation and wave breaking on the slope, as well as wave force calculation precision, are validated. The water depth 0.6 m, the slope gradient 1:20 and the distance between slope top and box-girder 2.0 m remain unchanged, while the wave height and clearance changes in different cases. The time histories of horizontal force and vertical force on box-girder can be divided into three and four stages respectively according to their characteristics. The surface of box-girder is decomposed into a series of panels to facilitate exploring tsunami bore force generation mechanism. Results show horizontal force is dominated by static pressure on upstream vertical panels and vertical force is mainly contributed by static pressure on upstream horizontal panels and on panels in the chambers. Tsunami bore overtopping the box-girder deck impacts the top panel vigorously and results in the peak value of negative vertical force.

Abstract Protein acetylation has emerged to play pivotal roles in alcoholic liver disease (ALD). Sirutin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase involved in the regulation of aging, metabolism, and stress. However, the role of SIRT2 in ALD remains unclear. Here, we report that the SIRT2-mediated deacetylation–deubiquitination switch of CCAAT/enhancer-binding protein beta (C/EBPβ) prevents ALD. Our results showed that hepatic SIRT2 protein expression was negatively correlated with the severity of alcoholic liver injury in ALD patients. Liver-specific SIRT2 deficiency sensitized mice to ALD, whereas transgenic SIRT2 overexpression in hepatocytes significantly prevented ethanol-induced liver injury via normalization of hepatic steatosis, lipid peroxidation, and hepatocyte apoptosis. Mechanistically, we identified C/EBPβ as a critical substrate of SIRT2 implicated in ALD. SIRT2-mediated deacetylation at lysines 102 and 211 decreased C/EBPβ ubiquitination, resulting in enhanced protein stability and subsequently increased transcription of C/EBPβ-target gene LCN2. Importantly, hepatic deacetylated C/EBPβ and LCN2 compensation reversed SIRT2 deletion-induced ALD aggravation in mice. Furthermore, C/EBPβ protein expression was positively correlated with SIRT2 and LCN2 expression in the livers of ALD patients and was inversely correlated with ALD development. Therefore, activating SIRT2-C/EBPβ-LCN2 signaling pathway is a potential therapy for ALD.

Abstract Backgrounds Decreased cytotoxicity of natural killer (NK) cells has been shown in multiple myeloma (MM). However, the underlying molecular mechanisms remain unclear. Here, by using single‐cell RNA sequencing analysis and in vitro experiments, we aim to uncover and validate molecularly distinctive insights into identifying regulators for NK cell exhaustion and provide potential targets for novel immune therapies in MM. Methods Single‐cell RNA sequencing was conducted in the bone marrow and peripheral blood samples from 10 newly diagnosed MM patients and three healthy volunteers. Based on the cluster‐defining differentially expressed genes, we named and estimated functional states of each cluster via bioinformatics analyses. Functional significance of key findings obtained from sequencing analysis was examined in a series of in vitro experiments, including luciferase reporter assay, lentiviral expression vector construction, NK cell transfection, RT‐qPCR, flow cytometry, and cytotoxicity assay. Results We classified NK cells into seven distinct clusters and confirmed that a subset of ZNF683+ NK cells were enriched in MM patients with ‘exhausted’ transcriptomic profile, featuring as decreased expression of activating receptors and cytolytic molecules, as well as increased expression of inhibitory receptors. Next, we found a significant downregulation of SH2D1B gene that encodes EAT‐2, an adaptor protein of activating receptor SLAMF7, in ZNF683+ NK cells from MM patients versus healthy volunteers. We further proved that ZNF683 transfection in NK cells significantly downregulated SH2D1B expression via directly binding to the promoter of SH2D1B, leading to NK cell cytotoxic activity impairment and exhausted phenotypes acquisition. In contrast, ZNF683 knockout in NK cells from MM patients increased cytotoxic activity and reversed NK cell exhaustion. Conclusions In summary, our findings uncover an important mechanism of ZNF683+ NK cell exhaustion and suggest that transcriptional suppressor ZNF683 as a potential useful therapeutic target in immunotherapy of MM.

The evidence linking sleep duration and metabolic body size phenotypes is limited, especially in young adulthood. In this study, we aimed to examine the association between sleep duration and metabolic body size phenotypes among Chinese young workers and investigate whether discrepancies exist among shift and non-shift workers. A cross-sectional study was performed between 2018 and 2019 in Wuhan, China and 7,376 young adults aged 20–35 years were included. Self-reported sleep duration was coded into four groups:

Abstract Background Chest X-rays are the most commonly available and affordable radiological examination for screening thoracic diseases. According to the domain knowledge of screening chest X-rays, the pathological information usually lay on the lung and heart regions. However, it is costly to acquire region-level annotation in practice, and model training mainly relies on image-level class labels in a weakly supervised manner, which is highly challenging for computer-aided chest X-ray screening. To address this issue, some methods have been proposed recently to identify local regions containing pathological information, which is vital for thoracic disease classification. Inspired by this, we propose a novel deep learning framework to explore discriminative information from lung and heart regions. Result We design a feature extractor equipped with a multi-scale attention module to learn global attention maps from global images. To exploit disease-specific cues effectively, we locate lung and heart regions containing pathological information by a well-trained pixel-wise segmentation model to generate binarization masks. By introducing element-wise logical AND operator on the learned global attention maps and the binarization masks, we obtain local attention maps in which pixels are are 1 for lung and heart region and 0 for other regions. By zeroing features of non-lung and heart regions in attention maps, we can effectively exploit their disease-specific cues in lung and heart regions. Compared to existing methods fusing global and local features, we adopt feature weighting to avoid weakening visual cues unique to lung and heart regions. Our method with pixel-wise segmentation can help overcome the deviation of locating local regions. Evaluated by the benchmark split on the publicly available chest X-ray14 dataset, the comprehensive experiments show that our method achieves superior performance compared to the state-of-the-art methods. Conclusion We propose a novel deep framework for the multi-label classification of thoracic diseases in chest X-ray images. The proposed network aims to effectively exploit pathological regions containing the main cues for chest X-ray screening. Our proposed network has been used in clinic screening to assist the radiologists. Chest X-ray accounts for a significant proportion of radiological examinations. It is valuable to explore more methods for improving performance.

BackgroundEndometriosis (EMS) is a relapsing and estrogen-dependent disease. For endometriosis such as deep endometriosis and ovarian endometrioid cysts, surgery is the most effective treatment. Long-term follow-up showed that the recurrence rate of endometriosis after surgical treatment was high, so postoperative drugs were needed to reduce recurrence, and Gonadotropin-releasing hormone agonists (GnRH-a) were the most commonly used drug for postoperative management.GnRH-a may reduce the post-treatment endometriosis relapses by lowering the hormone levels in the body. However, the use of GnRH-a can give rise to perimenopausal symptoms, especially osteoporosis, bone loss, and bone pain, for which reason GnRH-a use is often limited. The add-back therapy is often used to alleviate the untoward effects caused by GnRH-a. However, long-term use of hormone drugs may lead to EMS recurrence, thrombosis, and breast cancer. Therefore, a safer and more effective drug is urgently needed to alleviate the untoward effects caused by GnRH-a. In recent years, scholars at home and abroad have found that isopropanolic Cimicifuga racemosa extract (ICR), as a plant extract, can better relieve the symptoms of perimenopausal women. At the same time, some studies have initially confirmed that black cohosh preparations can relieve the perimenopausal symptoms caused by GnRH-a treatment in EMS patients.ObjectiveTo investigate the effect of black cohosh preparations on the bone metabolism of rat models with GnRH-a-induced perimenopausal symptoms.MethodsThe rat models of perimenopausal symptoms were established by GnRH-a injection. and normal saline (NS injection) was used as the control. According to the modeling method and drug intervention, the rats were randomly divided into four groups: GnRH-a injection + saline intervention group (GnRH-a + NS), saline injection control + saline intervention group (NS + NS), GnRH-a injection + estradiol intervention group (GnRH-a + E2), and GnRH-a injection + black cohosh preparation intervention group (GnRH-a + ICR). The rat models were identified with the vaginal smear method, and then the corresponding drug intervention was administrated for 28 days. After the intervention, the rats were sacrificed. The rats’ bone mineral density (BMD) of the distal femur was detected by a dual-energy X-ray bone density scanner. Rat tibia bone tissues were decalcified and made into slices. The pathological and morphological changes of rat tibial bones in each group were observed through HE staining. Histomorphometry parameters of rat tibial bones in each group, such as trabecular bone volume (TBV), trabecular thickness (TbTh), trabecular number (TbN), and trabecular spacing (TbSp), were detected and analyzed by using an automatic image analysis system.Results(1) The BMD level of the distal femur in the GnRH-a + NS group was significantly lower than the NS + NS, GnRH-a + E2, and GnRH-a + ICR groups (P0.05). (2) The pathological changes of the tibia bones under the microscope in different groups were as follows: The tibia bone trabecular structure was normal in the NS + NS group, without trabecular thinning or fracture, and the arch structure was normal. In the GnRH-a + NS group, some trabecular structures tapered, the arch structure disappeared, but no obvious bone fracture was observed in the trabecula. In the GnRH-a + E2 and GnRH-a + ICR groups, the trabecular structures were normal, without trabecular bone thinning or fracture, and the arch structures were normal. (3) The TBV level of the GnRH-a + INS group was significantly lower than that of the NS + NS, GnRH-a + E2 and GnRH-a + ICR groups (P0.05). (4) The TbTh levels in the four groups had no significant difference (P>0.05). Compared with the NS + NS group, the TbTh levels in the GnRH-a + NS, GnRH-a + E2, and GnRH-a + ICR groups showed a descending tendency, while the TbTh levels in the GnRH-a + E2 and GnRH-a + ICR groups were slightly higher than that of the GnRH-a + NS group. However, such differences were not significant statistically (P>0.05). (5) Compared with the NS + NS group, the TbN levels in the GnRH-a + NS, GnRH-a + E2, and GnRH-a + ICR groups decreased remarkably (P0.05). (6) The TbSp level of the GnRH-a + NS group was significantly higher than that of the NS + NS, GnRH-a + E2, and GnRH-a + ICR groups (P0.05).ConclusionThe GnRH-a injection could achieve the desired effect. GnRH-a injection may lead to the loss of bone mass in rats. Black cohosh preparations, like estrogen, may have a protective effect on bone mass loss caused by GnRH-a injection.

Biocatalyzed asymmetric reduction of ketones is an environmentally friendly approach and one of the most cost-effective routes for producing chiral alcohols. In comparison with the well-studied reduction of prochiral ketones to generate chiral alcohols with one chiral center, resolution of racemates by ketoreductases (KREDs) to produce chiral compounds with at least two chiral centers is also an important strategy in asymmetric synthesis. The development of protein engineering and the combination with chemo-catalysts further enhanced the application of KREDs in the efficient production of chiral alcohols with high stereoselectivity. This review discusses the advances in the research area of KRED catalyzed asymmetric synthesis for biomanufacturing of chiral chemicals with at least two chiral centers through the kinetic resolution (KR) approach and the dynamic kinetic resolution (DKR) approach.

Summary: The suppressive function of regulatory T (Treg) cells is tightly controlled by nutrient-fueled mechanistic target of rapamycin complex 1 (mTORC1) activation, yet its dynamics and negative regulation remain unclear. Here we show that Treg-specific depletion of vacuolar protein sorting 33B (Vps33B) in mice results in defective Treg cell suppressive function and acquisition of effector phenotype, which in turn leads to disturbed T cell homeostasis and boosted antitumor immunity. Mechanistically, Vps33B binds with lysosomal nutrient-sensing complex (LYNUS) and promotes late endosome and lysosome fusion and clearance of the LYNUS-containing late endosome/lysosome, and therefore suppresses mTORC1 activation. Vps33B deficiency in Treg cells results in disordered endosome lysosome fusion, which leads to accumulation of LYNUS that causes elevated mTORC1 activation and hyper-glycolytic metabolism. Taken together, our study reveals that Vps33B maintains Treg cell suppressive function through sustaining endolysosomal homeostasis and therefore restricting amino acid-licensed mTORC1 activation and metabolism.

Polygonati rhizoma (Huangjing in Chinese) is a traditional and classic dual-purpose material used in food and medicine. Herbalists in China and Japan have noticed several different rhizome types in Huangjing with different qualities. Rhizome of Polygonatum cyrtonema Hua and P. sibiricum Red. is divided into five types: “Jitou-type” Polygonati rhizoma (JTPR), atypical “Jitou-type” Polygonati rhizoma (AJTPR), “Jiang-type” Polygonati rhizoma (JPR), “Cylinder-type” Polygonati rhizoma (CPR), and “Baiji-type” Polygonati rhizoma (BJPR). This study observed the microstructure and histochemical localization of polysaccharides, saponins, and proteins in Huangjing. Nutritional and medicinal component data and antioxidant capacity (DPPH and ABTS) were analyzed to evaluate the quality of different types of Huangjing. The results showed that the comprehensive quality of the rhizomes, BJPR and JTPR, was better, regardless of their nutritional or medicinal values. Altogether, these results could recommend future breeding efforts to produce Huangjing with improved nutritional and medicinal qualities.

Study ObjectiveThe aim was to investigate the outcome of vaginal delivery of full-term pregnancies in patients after transvaginal-natural orifice transluminal endoscopic surgery (vNOTES) treatment for gynecological disorders.DesignA case series report.SettingA medical university hospital.Patients12 cases of successful delivery after transvaginal-natural orifice transluminal endoscopic surgery.InterventionsLong-term follow-up of patients with fertility needs after transvaginal-natural orifice transluminal endoscopic surgery.Measurements and Main ResultsFrom 2018 to 2021, 163 cases of gynecological diseases were treated by vNOTES. One hundred forty-seven patients were followed up, with a follow-up rate of 90.1%. The average follow-up time was 28 (15–47) months, including 66 cases with fertility requirements. Among these 66 patients, 12 patients successfully got pregnant and completed delivery, including 10 cases of vaginal delivery and 2 cases of cesarean section, with no adverse pregnancy outcomes associated with vNOTES arising.ConclusionVaginal delivery of a full-term pregnancy after transvaginal-natural orifice transluminal endoscopic surgery appears to be safe and feasible and would not be one of the bases for elective cesarean delivery.

ObjectiveThe purpose of the study is to explore the mechanism of NRAGE enhancing radioresistance of esophageal squamous cell carcinoma (ESCC) in 2D and 3D levels.MethodsStably NRAGE-overexpressed ESCC cells and 3D-printing models for ESCC cells were established. Then, cellular malignancy indexes, such as cell morphology, proliferation, radioresistance, motility, apoptosis, cell cycle, and proteins of the Wnt/β-catenin pathway, were compared between radioresistant and its parental cells in 2D and 3D levels. Additionally, 44 paraffin ESCC specimens with radical radiotherapy were selected to examine NRAGE and β-catenin protein expression and analyze the clinical correlation.ResultsExperiments in 2D culture showed that morphology of the Eca109/NRAGE cells was more irregular, elongated spindle-shaped and disappeared polarity. It obtained faster growth ability, stronger resistance to irradiation, enhanced motility, reduced apoptosis ratio and cell cycle rearrangement. Moreover, Western blot results showed β-catenin, p-Gsk-3β and CyclinD1 expressions were induced, while p-β-catenin and Gsk-3β expressions decreased in Eca109/NRAGE cells. Experiments in the 3D-printing model showed Eca109/NRAGE cell-laden 3D scaffolds had the advantage on growth and spheroiding according to the brightfield observation, scanning electron microscopy and Ki-67 IHC staining, and higher expression at the β-catenin protein. Clinical analysis showed that NRAGE expression was higher in tumor tissues than in control tissues of ESCC patients from the Public DataBase. Compared with radiotherapy effective group, both NRAGE total and nuclear and β-catenin nuclear expressions were significantly upregulated from ESCC specimens in invalid group. Further analysis showed a positive and linear correlation between NRAGE nuclear and β-catenin nuclear expressions. Additionally, results from univariate and multivariate analyses revealed NRAGE nuclear expression could serve as a risk factor for ESCC patients receiving radical radiotherapy.ConclusionESCC cells with NRAGE nuclear accumulation demonstrated greater radioresistance, which may be related to the activation of the Wnt/β-catenin signaling pathway. It indicated that NRAGE nuclear expression was a potential biomarker for monitoring radiotherapeutic response.

Loss of vision due to progressive retinal degeneration is a hallmark of neuronal ceroid lipofuscinoses (NCL), a group of fatal neurodegenerative lysosomal storage diseases. Enzyme substitution therapies represent promising treatment options for NCLs caused by dysfunctions of soluble lysosomal enzymes. Here, we compared the efficacy of a cell-based enzyme substitution strategy and a gene therapy approach to attenuate the retinal pathology in cathepsin D- (CTSD) deficient mice, an animal model of CLN10 disease. Levels of enzymatically active CTSD in mutant retinas were significantly higher after an adeno-associated virus vector-mediated CTSD transfer to retinal glial cells and retinal pigment epithelial cells than after intravitreal transplantations of a CTSD overexpressing clonal neural stem cell line. In line with this finding, the gene therapy treatment restored the disrupted autophagy-lysosomal pathway more effectively than the cell-based approach, as indicated by a complete clearance of storage, significant attenuation of lysosomal hypertrophy, and normalized levels of the autophagy marker sequestosome 1/p62 and microtubule-associated protein 1 light chain 3-II. While the cell-based treatment did not prevent the rapidly progressing loss of various retinal cell types, the gene therapy approach markedly attenuated retinal degeneration as demonstrated by a pronounced rescue of photoreceptor cells and rod bipolar cells.

BackgroundEndometriosis (EMS) is an estrogen-dependent disease, which easily recurs after operation. Gonadotropin-releasing hormone agonist (GnRH-a), an estrogen-inhibiting drug, can effectively inhibit the secretion of gonadotropin by pituitary gland, so as to significantly decrease the ovarian hormone level and facilitate the atrophy of ectopic endometrium, playing a positive role in preventing postoperative recurrence. The application of GnRH-a can lead to the secondary low estrogen symptoms, namely the perimenopausal symptoms, and is a main reason for patients to give up further treatment. The add-back therapy based on sex hormones can well address the perimenopausal symptoms, but long-term use of hormones may cause the recurrence of EMS, as well as liver function damage, venous embolism, breast cancer and other risks, which has long been a heated topic in the industry. Therefore, it is necessary to find effective and safe anti-additive drugs soon. Studies at home and abroad show that, as a plant extract, isopropanolic extract of cimicifuga racemosa (ICR) can well relieve the perimenopausal symptoms caused by natural menopause. Some studies have preliminarily confirmed that black cohosh preparations can antagonize perimenopausal symptoms of EMS patients treated with GnRH-a after operation.ObjectiveTo establish a rat model of perimenopausal symptoms induced by GnRH-a injection, for the purposes of laying a foundation for further research and preliminarily exploring the effect of black cohosh preparations on reproductive endocrine of the rat model.MethodThe rat model of perimenopausal symptoms was established by GnRH-a injection, and normal saline (NS injection) was used as the control. The rats were randomly divided into four groups according to different modeling methods and drug intervention schemes. GnRH-a injection + normal saline intervention group (GnRH-a + NS), normal saline injection control + normal saline intervention group (NS + NS), GnRH-a injection + estradiol intervention group (GnRH-a + E2), and GnRH-a injection + black cohosh preparations intervention group (GnRH-a + ICR). After modelling was assessed to be successful with the vaginal smear method, the corresponding drugs were given for intervention for 28d. In the process of rat modeling and drug intervention, the skin temperature and anus temperature of the rat tails were measured every other day, the body weights of the rats were measured every other day, and the dosage was adjusted according to the body weight. After the intervention was over, the serum sex hormone level, the uterine weight, the uterine index, and the endometrial histomorphology changes, as well as the ovarian weight, the ovarian index, and the morphological changes of ovarian tissues of each group were measured.Results(1) The vaginal cell smears of the control group (NS + NS) showed estrous cycle changes, while other model rats had no estrous cycle of vaginal cells. (2) The body weight gains of the GnRH-a + NS, GnRH-a + E2 and GnRH-a + ICR groups were significantly higher than that of the NS + NS control group. The intervention with E2 and ICR could delay the weight gain trend of rats induced by GnRH-A. (3) After GnRH-a injection, the temperature of the tail and anus of rats showed an overall upward trend, and the intervention with E2 and ICR could effectively improve such temperature change. (4) The E2, FSH, and LH levels in the GnRH-a + NS, GnRH-a + E2, and GnRH-a + ICR groups were significantly lower than those in the NS + NS group (P < 0.01). The E2 level was significantly higher and the LH level was significantly lower in the GnRH-a + E2 group than those in the GnRH-a + NS and GnRH-a + ICR groups (P < 0.05). Compared with those of the GnRH-a + NS and GnRH-a + ICR groups, the FSH level of the GnRH-a + E2 group showed a slight downward trend, but the difference was not statistically significant (P > 0.05). There was no significant difference in the levels of sex hormones between the GnRH-a + NS group and GnRH-a + ICR group (P > 0.05). (5) Compared with those of the NS + NS group, the uterine weight and uterine index of the GnRH-a + NS, GnRH-a + E2 and GnRH-a + ICR groups significantly decreased (P < 0.01). In a comparison between the groups, the uterine weight and uterine index in the GnRH-a + NS and GnRH-a + ICR groups were significantly lower than those in the GnRH-a + E2 group (P < 0.01). There was a statistical difference in the uterine weight and uterine index between the GnRH-a + NS group and GnRH-a + ICR group (P > 0.05). (6) Compared with those of the NS + NS group, the ovarian weight and ovarian index of the GnRH-a + NS, GnRH-a + E2 and GnRH-a + ICR groups significantly decreased (P < 0.01). There was no statistical difference in the ovarian weight and ovarian index among the GnRH-a + E2, GnRH-a + NS and GnRH-a + ICR groups (P > 0.05). (7) Compared with those in the NS + NS group, the number of primordial follicles increased significantly, while the number of growing follicles and mature follicles decreased significantly in the GnRH-a + NS, GnRH-a + E2, and GnRH-a + ICR groups (P < 0.01), but there was a statistical difference in the total number of follicles among the four groups (P > 0.05).ConclusionsThe GnRH-a injection could achieve the desired effect. The animal model successfully achieved a significant decrease in the E2, FSH, and LH levels in rats, and could cause the rats to have rising body surface temperature similar to hot flashes in the perimenopausal period. The intervention with E2 and ICR could effectively relieve such “perimenopausal symptoms”, and ICR had no obvious effect on the serum sex hormone level in rats.

Abstract: Platelet activation requires fully functional mitochondria, which provide a vital energy source and control the life span of platelets. Previous reports have shown that both general autophagy and selective mitophagy are critical for platelet function. However, the underlying mechanisms remain incompletely understood. Here, we show that Nix, a previously characterized mitophagy receptor that plays a role in red blood cell maturation, also mediates mitophagy in platelets. Genetic ablation of Nix impairs mitochondrial quality, platelet activation, and FeCl3-induced carotid arterial thrombosis without affecting the expression of platelet glycoproteins (GPs) such as GPIb, GPVI, and αIIbβ3. Metabolic analysis revealed decreased mitochondrial membrane potential, enhanced mitochondrial reactive oxygen species level, diminished oxygen consumption rate, and compromised adenosine triphosphate production in Nix−/− platelets. Transplantation of wild-type (WT) bone marrow cells or transfusion of WT platelets into Nix-deficient mice rescued defects in platelet function and thrombosis, suggesting a platelet-autonomous role (acting on platelets, but not other cells) of Nix in platelet activation. Interestingly, loss of Nix increases the life span of platelets in vivo, likely through preventing autophagic degradation of the mitochondrial protein Bcl-xL. Collectively, our findings reveal a novel mechanistic link between Nix-mediated mitophagy, platelet life span, and platelet physiopathology. Our work suggests that targeting platelet mitophagy Nix might provide new antithrombotic strategies.

Abstract Background This study aimed to confirm that blocking RasGRP4 can effectively slow down the growth of DLBCL both in vitro and in vivo and ascertain the role of RasGRP4 in the prognosis of DLBCL clinically. Methods RasGRP4 expression levels were examined in benign tissues and lymphomas. In order to verify somatic mutation in RasGRP4 gene, cDNA sequencing was performed in DLBCL patients. RasGRP4-dependent cell proliferation, mitochondrial membrane potential, oxidative stress levels and signaling pathway changes were measured by knockdown of RasGRP4. Tumor growth was monitored in xenografted lymphoma model. Clinical data were collected to confirm the role of RasGRP4 in DLBCL. Results RasGRP4 expression was significantly elevated in DLBCL while no somatic mutations were detected of this gene in DLBCL patients. Decreased RasGRP4 significantly inhibited cell proliferation by simultaneously reducing mitosis and promoting apoptosis and increased the oxidative stress levels. Mechanistically, reduced expression of RasGRP4 decreased ERK while increased JNK expression in SUDHL-4 cells. Knockdown of RasGRP4 also significantly inhibited tumor formation in vivo. Furthermore, RasGRP4 expression levels were significantly higher in patients with larger DLBCL lesions (P = 0.0004), high-risk international prognostic index score groups (P = 0.0042), and its expression was positively correlated with maximum standardized uptake value in DLBCL (P = 0.0004). Conclusions These findings indicate the oncogenic role of RasGRP4 in DLBCL, suggesting it as a prognostic biomarker and potential therapeutic target in DLBCL.

Summary: Under extreme conditions or by genetic modification, pancreatic α-cells can regenerate and be converted into β-cells. This regeneration holds substantial promise for cell replacement therapy in diabetic patients. The discovery of clinical therapeutic strategies to promote β-cell regeneration is crucial for translating these findings into clinical applications. In this study, we reported that treatment with REMD 2.59, a human glucagon receptor (GCGR) monoclonal antibody (mAb), lowered blood glucose without inducing hypoglycemia in normoglycemic, streptozotocin-induced type 1 diabetic (T1D) and non-obesity diabetic mice. Moreover, GCGR mAb treatment increased the plasma glucagon and active glucagon-like peptide-1 levels, induced pancreatic ductal ontogenic α-cell neogenesis, and promoted α-cell proliferation. Strikingly, the treatment also increased the β-cell mass in these two T1D models. Using α-cell lineage-tracing mice, we found that the neogenic β-cells were likely derived from α-cell conversion. Therefore, GCGR mAb-induced α- to β-cell conversion might represent a pre-clinical approach for improving diabetes therapy. : Diabetology; Endocrinology; Specialized Functions of Cells Subject Areas: Diabetology, Endocrinology, Specialized Functions of Cells

Abstract Background Several epidemiological studies have suggested that optimal obesity and visceral adiposity indicators and their cut-off values to predict cardio-metabolic risks varied among different ethnic groups. However, few studies have investigated the associations of anthropometric indices with cardio-metabolic risks in Chinese Uyghur adults, and the results were inconsistent. Methods Between May and September 2016, a total of 4664 subjects aged ≥18 years old were recruited from Northwest China. Anthropometric indices and cardio-metabolic risk factors were measured by trained personnel. Partial correlation analyses and logistic regression analyses were used to evaluate the associations of anthropometric indices with cardio-metabolic risk factors. Receiver operating characteristic analysis was used to compare the abilities of different anthropometric indices to predict cardio-metabolic risk factors, and to determine the optimal cut-off values. Results The prevalence of metabolic syndrome was 39.41% in Uyghur adults from Xinjiang Uyghur Autonomous Region. Waist circumference (WC) performed better than other obesity indices in predicting the cardio-metabolic risk factors, and the optimal cut-off value of WC to diagnose metabolic syndrome risk factors was 86.50 cm for women and 90.50 cm for men. Conclusions Our study suggests that WC had the strongest predictive power for identifying cardio-metabolic risks in Xinjiang Uyghur adults. Further well-designed longitudinal studies are needed to confirm our findings.

Background: Glucagon-like peptide-1 (GLP-1) and its based agents improve glycemic control. Although their attenuating effect on hepatic glucose output has drawn our attention for decades, the potential mechanisms remain unclear. Methods: Cytokine array kit was used to assess cytokine profiles in db/db mice and mouse primary hepatocytes treated with exenatide (exendin-4). Two diabetic mouse models (db/db and Pax6m/+) were treated with a GLP-1 analog exenatide or liraglutide. The expression and secretion of fibroblast growth factor 21 (FGF21) in the livers of diabetic mice, primary mouse and human hepatocytes, and the human hepatic cell line HepG2 treated with or without GLP-1 analog were measured. Blockage of FGF21 with neutralizing antibody or siRNA, or hepatocytes isolated from Fgf21 knockout mice were used, and the expression and activity of key enzymes in gluconeogenesis were analyzed. Serum FGF21 level was evaluated in patients with type 2 diabetes (T2D) receiving exenatide treatment. Findings: Utilizing the cytokine array, we identified that FGF21 secretion was upregulated by exenatide (exendin-4). Similarly, FGF21 production in hepatocytes was stimulated by exenatide or liraglutide. FGF21 blockage attenuated the inhibitory effects of the GLP-1 analogs on hepatic glucose output. Similar results were also observed in primary hepatocytes from Fgf21 knockout mice. Furthermore, exenatide treatment increased serum FGF21 level in patients with T2D, particularly in those with better glucose control. Interpretation: We identify that function of GLP-1 in inhibiting hepatic glucose output is mediated via the liver hormone FGF21. Thus, we provide a new extra-pancreatic mechanism by which GLP-1 regulates glucose homeostasis. Fund: National Key Research and Development Program of China, the National Natural Science Foundation of China, the Natural Science Foundation of Beijing and Peking University Medicine Seed Fund for Interdisciplinary Research. Keywords: Glucagon-like peptide-1, Fibroblast growth factor 21, Hepatic glucose output, Diabetes