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IntroductionAnimal waste proteins have been increasing in the past decade, along with consumer demands. Their huge volume and the environmental issues caused by improper treatment probably pose a massive threat to human health. These animal waste proteins contain many valuable bioactive peptides and can be used not only as nutrient substances but also as primary functional ingredients in many industries, including agriculture, food, and pharmaceuticals. However, the advancement of the value-added application of animal waste proteins within the past 10 years has not been elucidated yet. In this regard, this paper scrutinized the studies on the applications of hydrolysates and peptides from animal waste proteins throughout the last decade, hoping to display a whole picture of their value-adding applications.MethodsThe Web of Science and Google Scholar were searched from January 1, 2013, to December 12, 2023. This review included field trials, in vitro and in vivo assays, and in silico analysis based on literature surveys or proteolysis simulation. The quality of the included studies was evaluated by Journal Citation Reports, and the rationality of the discussion of studies included.ResultsNumerous studies were performed on the application potential of hydrolysates and peptides of animal waste proteins in agricultural, food, and medicinal industries. Particularly, due to the nutritional value, safety, and especially competitive effects, the peptide with antioxidant, antimicrobial, antihypertensive, antidiabetic, or antithrombotic activities can be used as a primary functional ingredient in food and pharmaceuticals.DiscussionThese value-added applications of animal waste proteins could be a step towards sustainable animal by-products management, and simultaneously, open new avenues in the rapid development of nutraceuticals and pharmaceuticals. However, further studies on the bioavailability and structure-activity relationship are required to verify their therapeutic effects.

Abstract Gliomas are the most common primary intracranial tumor worldwide. The maintenance of telomeres serves as an important biomarker of some subtypes of glioma. In order to investigate the biological role of RTEL1 in glioma. Relative telomere length (RTL) and RTEL1 mRNA was explored and regression analysis was performed to further examine the relationship of the RTL and the expression of RTEL1 with clinicopathological characteristics of glioma patients. We observed that high expression of RTEL1 is positively correlated with telomere length in glioma tissue, and serve as a poor prognostic factor in TERT wild-type patients. Further in vitro studies demonstrate that RTEL1 promoted proliferation, formation, migration and invasion ability of glioma cells. In addition, in vivo studies also revealed the oncogene role of RTEL1 in glioma. Further study using RNA sequence and phospho-specific antibody microarray assays identified JNK/ELK1 signaling was up-regulated by RTEL1 in glioma cells through ROS. In conclusion, our results suggested that RTEL1 promotes glioma tumorigenesis through JNK/ELK1 cascade and indicate that RTEL1 may be a prognostic biomarker in gliomas.

Stress granules (SGs), formed by untranslated messenger ribonucleoproteins (mRNPs) during cellular stress in eukaryotes, have been linked to flavivirus interference without clear understanding. This study reveals the role of Zika virus (ZIKV) NS2B as a scaffold protein mediating interaction between protein phosphatase 1α (PP1α) and eukaryotic initiation factor 2α (eIF2α). This interaction promotes eIF2α dephosphorylation by PP1α, inhibiting SG formation. The NS2B-PP1α complex exhibits remarkable stability, resisting ubiquitin-induced degradation and amplifying eIF2α dephosphorylation, thus promoting ZIKV replication. In contrast, the NS2BV35A mutant, interacting exclusively with eIF2α, fails to inhibit SG formation, resulting in reduced viral replication and diminished impact on brain organoid growth. These findings reveal PP1α's dual role in ZIKV infection, inducing interferon production as an antiviral factor and suppressing SG formation as a viral promoter. Moreover, we found that NS2B also serves as a versatile mechanism employed by flaviviruses to counter host antiviral defenses, primarily by broadly inhibiting SG formation. This research advances our comprehension of the complex interplay in flavivirus-host interactions, offering potential for innovative therapeutic strategies against flavivirus infections.

BackgroundAcute promyelocytic leukemia (APL) is rarely caused by the PLZF::RARα fusion gene. While APL patients with PLZF::RARα fusion commonly exhibit diverse hematologic symptoms, the presentation of myeloid sarcoma (MS) as an initial manifestation is infrequent.Case presentationA 61-year-old patient was referred to our hospital with 6-month history of low back pain and difficulty walking. Before this admission, spine magnetic resonance imaging (MRI) conducted at another hospital revealed multiple abnormal signals in the left iliac bone and vertebral bodies spanning the thoracic (T11-T12), lumbar (L1-L4), and sacral (S1/S3) regions. This led to a provisional diagnosis of bone tumors with an unknown cause. On admission, complete blood count (CBC) test and peripheral blood smear revealed a slightly increased counts of monocytes. Immunohistochemical staining of both spinal and bone marrow (BM) biopsy revealed positive expression for CD117, myeloperoxidase (MPO), and lysozyme. BM aspirate showed a significant elevation in the percentage of promyelocytes (21%), which were morphologically characterized by round nuclei and hypergranular cytoplasm. Multiparameter flow cytometry of BM aspirate revealed that blasts were positive for CD13, CD33, CD117, and MPO. Through the integrated application of chromosome analysis, fluorescence in situ hybridization (FISH), reverse transcriptase polymerase chain reaction (RT-PCR), and Sanger sequencing, it was determined that the patient possessed a normal karyotype and a rare cryptic PLZF::RARα fusion gene, confirming the diagnosis of APL.ConclusionIn the present study, we report the clinical features and outcome of a rare APL patient characterized by a cryptic PLZF::RARα fusion and spinal myeloid sarcoma (MS) as the initial presenting symptom. Our study not only offers valuable insights into the heterogeneity of APL clinical manifestations but also emphasizes the crucial need to promptly consider the potential link between APL and MS for ensuring a timely diagnosis and personalized treatments.

Herein, we constructed innovative reduction-sensitive and targeted gelatin-based micelles for doxorubicin (DOX) delivery in tumor therapy. AS1411 aptamer-modified gelatin-ss-tocopherol succinate (AGSST) and the control GSST without AS1411 modification were synthesized and characterized. Antitumor drug DOX-containing AGSST (AGSST-D) and GSST-D nanoparticles were prepared, and their shapes were almost spherical. Reduction-responsive characteristics of DOX release in vitro were revealed in AGSST-D and GSST-D. Compared with non-targeted GSST-D, AGSST-D demonstrated better intracellular uptake and stronger cytotoxicity against nucleolin-overexpressed A549 cells. Importantly, AGSST-D micelles showed more effective killing activity in A549-bearing mice than GSST-D and DOX⋅HCl. It was revealed that AGSST-D micelles had no obvious systemic toxicity. Overall, AGSST micelles would have the potential to be an effective drug carrier for targeted tumor therapy.

Sepsis, a complex clinical syndrome characterized by an exaggerated host response to infection, often necessitates hospitalization and intensive care unit admission. Delayed or inaccurate diagnosis of sepsis, coupled with suboptimal treatment strategies, can result in unfavorable outcomes, including mortality. Maresins, a newly discovered family of lipid mediators synthesized from docosahexaenoic acid by macrophages, have emerged as key players in promoting inflammation resolution and the termination of inflammatory processes. Extensive evidence has unequivocally demonstrated the beneficial effects of maresins in modulating the inflammatory response associated with sepsis; however, their bioactivity and functions exhibit remarkable diversity and complexity. This article presents a comprehensive review of recent research on the role of maresins in sepsis, aiming to enhance our understanding of their effectiveness and elucidate the specific mechanisms underlying their actions in sepsis treatment. Furthermore, emerging insights into the management of patients with sepsis are also highlighted.

Nickel-based superalloys have been widely used in the aerospace industry, and regulating the reinforcing phases is the key to improving the high-temperature strength of the alloy. In this study, a series of aging treatments (650 °C, 750 °C, 850 °C and 950 °C for 8 h) were designed to study different thermal deformation behaviors and microstructure evolutions for a novel nickel-based superalloy. Among the aged samples, the 950 °C aged sample achieved the peak stress of ~323 MPa during the thermal deformation and the highest microhardness of ~315 HV after thermal compression, which were the greatest differences compared to before deformation. In addition, the grains of the 950 °C sample exhibit deformed fibrous shapes, and the grain orientation is isotropic, while the other samples exhibited isotropy. In the 850 °C and 950 °C high-temperature aging samples, the γ′ precipitate (about 20 nm in size) is gradually precipitated, which inhibits the movement of dislocation in the grain during compression, thus inhibiting the occurrence of dynamic recrystallization and improving the high-temperature mechanical properties of the alloy.

In this work, a three-dimensional electrode material (FeN@BC) was prepared by doping iron-nitrogen sites into biochar for activating peroxydisulfate (E-FeN@BC-PS). The scanning electron microscope, x-ray diffractometer, Fourier transform infrared spectroscopy, and x-ray photoelectron spectroscopy results of FeN@BC proved that Fe–N sites were successful doped into BC. Electrochemical analysis indicated that FeN@BC could enhance the electron transfer in the electrochemical process. A significant synergistic effect (SI = 12.46) was observed in the E-FeN@BC-PS system. Tetracycline (TC) was almost removed completely within 30 min in optimal operating parameters. Radical scavenging experiments showed that ·OH, SO4●−, O2●−, and 1O2 all contributed to TC degradation. The cyclic experiment and characterizations before and after the recycle showed that the FeN@BC in the three-dimensional electrode system exhibited excellent stability and reusability, and electricity had an obvious protective effect on the FeN@BC materials. This study revealed the synergistic catalytic mechanism of metal and heteroatomic hybrid materials as three-dimensional electrodes in persulfate activation, promising the development of sustainable and efficient water treatment technology.

Synchronization is a very important phenomenon in the nervous system, which is closely related to the encoding, integration and transmission of information. In this paper, synchronization and transition of a two-compartment respiratory neuron model under transcranial magnetic stimulation (TMS) are studied from the perspective of synchronization degree for the first time. We are established the correlation degree with synchronization, and discussed the firing mode and transition rule of the neurons in the two-compartment compartment pre-Bötzinger complex (PBC) by means of bifurcation theory and Lyapunov index. The results show that the synchronization of neurons has a great influence under TMS, which is embodied in the fact that the somatic will experience a peak firing and a transition from bursting to resting under the magnetic stimulation,which was a phenomenon never before shown in PBC neurons. These results fully reveal the dynamic behavior of PBC nervous system under TMS, and provide theoretical value for further understanding of respiratory rhythm.

ContextDiabetic retinopathy (DR) and diabetic nephropathy (DN), are major microvascular complications of diabetes. DR is an important predictor of DN, but the relationship between the severity of DR and the pathological severity of diabetic glomerulopathy remains unclear.ObjectiveTo investigate the relationship between severity of diabetic retinopathy (DR) and histological changes and clinical indicators of diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM)MethodsPatients with T2DM (n=272) who underwent a renal biopsy were eligible. Severity of DR was classified as non-diabetic retinopathy, non-proliferative retinopathy, and proliferative retinopathy (PDR). Relationship between DN and DR and the diagnostic efficacy of DR for DN were explored.ResultsDN had a higher prevalence of DR (86.4%) and DR was more severe. The sensitivity and specificity of DR in DN were 86.4% and 78.8%, while PDR was 26.4% and 98.5%, respectively. In DN patients, the severity of glomerular lesions (p=0.001) and prevalence of KW nodules (p

Abstract Solute carrier family 39 member 10 (SLC39A10) belongs to a subfamily of zinc transporters and plays a key role in B-cell development. Previous studies have reported that its upregulation promotes breast cancer metastasis by enhancing the influx of zinc ions (Zn2+); however, its role in gastric cancer remains totally unclear. Here, we found that SLC39A10 expression was frequently increased in gastric adenocarcinomas and that SLC39A10 upregulation was strongly associated with poor patient outcomes; in addition, we identified SLC39A10 as a direct target of c-Myc. Functional studies showed that ectopic expression of SLC39A10 in gastric cancer cells dramatically enhanced the proliferation, colony formation, invasiveness abilities of these gastric cancer cells and tumorigenic potential in nude mice. Conversely, SLC39A10 knockdown inhibited gastric cancer cell proliferation and colony formation. Mechanistically, SLC39A10 exerted its carcinogenic effects by increasing Zn2+ availability and subsequently enhancing the enzyme activity of CK2 (casein kinase 2). As a result, the MAPK/ERK and PI3K/AKT pathways, two major downstream effectors of CK2, were activated, while c-Myc, a downstream target of these two pathways, formed a vicious feedback loop with SLC39A10 to drive the malignant progression of gastric cancer. Taken together, our data demonstrate that SLC39A10 is a functional oncogene in gastric cancer and suggest that targeting CK2 is an alternative therapeutic strategy for gastric cancer patients with high SLC39A10 expression.

Abstract Previous studies disclosed that a high thyroid stimulating hormone level is an independent risk factor for diabetes peripheral neuropathy (DPN) in subclinical hypothyroidism (SCH) patients with type 2 diabetes mellitus (T2DM). However, whether thyroid metabolism has an effect on DPN in euthyroid T2DM patients remains unknown. The aim of this study was to identify the association between thyroid function and DPN in euthyroid T2DM patients. A set of 580 euthyroid T2DM patients was enrolled in the current study and stratified into DPN and Non-DPN groups. Mann–Whitney U test was performed to analyze the continuous variables of biochemical and thyroid metabolism indicators, and the Chi-square test was used to compare the categorical variables. Spearman correlation analysis was performed to analyze the relationship between clinical indicators and free thyroxine (FT4). By using the logistic regression analysis, the prevalence of DPN in different thyroid function indicators were evaluated. T2DM patients with DPN had obviously lower levels of aspartate aminotransferase (AST), alpha-hydroxybutyric dehydrogenase (α-HBDH), superoxide dismutase (SOD), calcium (Ca), creatinine (Cr), uric acid (UA), retinol binding protein (RBP), total protein (TP), albumin (ALB), alanine aminotransferase (ALT) and FT4 than the T2DM patients without DPN (P

Abstract Chemotherapy remains as the first-choice treatment option for triple-negative breast cancer (TNBC). However, the limited tumor penetration and low cellular internalization efficiency of current nanocarrier-based systems impede the access of anticancer drugs to TNBC with dense stroma and thereby greatly restricts clinical therapeutic efficacy, especially for TNBC bone metastasis. In this work, biomimetic head/hollow tail nanorobots were designed through a site-selective superassembly strategy. We show that nanorobots enable efficient remodeling of the dense tumor stromal microenvironments (TSM) for deep tumor penetration. Furthermore, the self-movement ability and spiky head markedly promote interfacial cellular uptake efficacy, transvascular extravasation, and intratumoral penetration. These nanorobots, which integrate deep tumor penetration, active cellular internalization, near-infrared (NIR) light-responsive release, and photothermal therapy capacities into a single nanodevice efficiently suppress tumor growth in a bone metastasis female mouse model of TNBC and also demonstrate potent antitumor efficacy in three different subcutaneous tumor models.

Abstract STAG2, an important subunit in cohesion complex, is involved in the segregation of chromosomes during the late mitosis and the formation of sister chromatids. Mutational inactivation of STAG2 is a major cause of the resistance of BRAF-mutant melanomas to BRAF/MEK inhibitors. In the present study, we found that STAG2 was frequently down-regulated in thyroid cancers compared with control subjects. By a series of in vitro and in vivo studies, we demonstrated that STAG2 knockdown virtually had no effect on malignant phenotypes of BRAF-mutant thyroid cancer cells such as cell proliferation, colony formation and tumorigenic ability in nude mice compared with the control. In addition, unlike melanoma, STAG2 knockdown also did not affect the sensitivity of these cells to MEK inhibitor. However, we surprisingly found that STAG2-knockdown cells exhibited more sensitive to glutamine deprivation or glutaminase inhibitor BPTES compared with control cells. Mechanistically, knocking down STAG2 in BRAF-mutant thyroid cancer cells decreases the protein stability of c-Myc via the ERK/AKT/GSK3β feedback pathway, thereby impairing glutamine metabolism of thyroid cancer cells by down-regulating its downstream targets such as SCL1A5, GLS and GLS2. Our data, taken together, demonstrate that STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells, thereby improving their cellular response to glutaminase inhibitor. This study will provide a potential therapeutic strategy for BRAF-mutant thyroid cancers.

Abstract China has implemented a series of long-term measures to control the spread of COVID-19, however, the effects of these measures on other chronic and acute respiratory infectious diseases remain unclear. Tuberculosis (TB) and scarlet fever (SF) serve as representatives of chronic and acute respiratory infectious diseases, respectively. In China’s Guizhou province, an area with a high prevalence of TB and SF, approximately 40,000 TB cases and hundreds of SF cases are reported annually. To assess the impact of COVID-19 prevention and control on TB and SF in Guizhou, the exponential smoothing method was employed to establish a prediction model for analyzing the influence of COVID-19 prevention and control on the number of TB and SF cases. Additionally, spatial aggregation analysis was utilized to describe spatial changes in TB and SF before and after the COVID-19 outbreak. The parameters of the TB and SF prediction models are R2 = 0.856, BIC = 10.972 and R2 = 0.714, BIC = 5.325, respectively. TB and SF cases declined rapidly at the onset of COVID-19 prevention and control measures, with the number of SF cases decreasing for about 3–6 months and the number of TB cases remaining in decline for 7 months after the 11th month. The spatial aggregation of TB and SF did not change significantly before and after the COVID-19 outbreak but exhibited a marked decrease. These findings suggest that China’s COVID-19 prevention and control measures also reduced the prevalence of TB and SF in Guizhou. These measures may have a long-term positive impact on TB, but a short-term effect on SF. Areas with high TB prevalence may continue to experience a decline due to the implementation of COVID-19 preventive measures in the future.

Abstract Toxoplasma gondii (T. gondii) is an obligate intracellular parasite with a wide range of hosts, including humans and many warm-blooded animals. The parasite exists in two interconvertible forms, namely tachyzoites and bradyzoites in intermediate hosts that are responsible for acute and chronic infections respectively. Mature bradyzoites accumulate large amounts of amylopectin granules but their roles have not been fully characterized. In this study, the predicted key enzymes involved in amylopectin synthesis (UDP-sugar pyrophospharylase, USP) and degradation (alpha-glucan water dikinase, GWD) of ME49 strain were individually knocked out, and then bradyzoite-related phenotyping experiments in vitro and in vivo were performed to dissect their roles during parasite growth and development. Deletion of the usp or gwd gene in the type II strain ME49 reduced the replication rates of tachyzoites in vitro and parasite virulence in vivo, suggesting that amylopectin metabolism is important for optimal tachyzoite growth. Interestingly, the Δusp mutant grew slightly faster than the parental strain under stress conditions that induced bradyzoite transition, which was likely due to the decreased efficiency of bradyzoite formation of the Δusp mutant. Although the Δgwd mutant could convert to bradyzoite robustly in vitro, it was significantly impaired in establishing chronic infection in vivo. Both the Δusp and Δgwd mutants showed a dramatic reduction in the reactivation of chronic infection in an in vitro model. Together, these results suggest that USP and GWD, which are involved in amylopectin synthesis and degradation have important roles in tachyzoite growth, as well as in the formation and reactivation of bradyzoites in T. gondii.

Abstract Background Primary immune thrombocytopenia (ITP) is characterized for the skewed Th differentiation towards Th1 and Th17 cells as well as the impaired number and function of regulatory T cells (Tregs). Tregs are capable of co-expressing effector Th markers in different inflammatory milieu, which probably indicates Treg dysfunction and incompetence to counter over-activated immune responses. Methods Ninety-two primary ITP patients from March 2013 to December 2018 were included, and proinflammatory plasticity in different Treg compartments, age groups, and TGFBR2 variant carrier status were investigated. Results Patients were categorized into elderly (n = 44) and younger (n = 48) groups according to an age of 50 years at disease onset. The overall remission rate was 82.6% after first-line regimens, including 47.8% complete remission. TGFBR2 variants were found in 7 (7.6%) patients with three V216I and four T340M heterozygote carriers. ITP patients demonstrated elevated co-expression of IL-17 and decreased co-expression of both IFN-γ and IL-13 than health control (all p

Abstract Memristive devices with threshold switching characteristics can be effectively utilized to mimic biological neurons acting as one of the key building blocks for constructing advanced hardware neural networks. In this work, the emulation of leaky integrate‐and‐fire memristive neuron is realized in one single cell with Ag/Ag−In−Zn−S/silk sericin/W architecture without the need for additional auxiliary circuits. The studied devices demonstrate excellent electrical properties, such as stably repeatable threshold switching, concentratedly low threshold voltage (≈0.4 V), and relatively small device‐to‐device variation. In addition, multiple neural features, such as leaky integrate‐and‐fire neuron functionality and strength‐modulated spike frequency characteristic, have been successfully emulated owing to the forming‐free volatile threshold switching effect. The stable volatile threshold switching behaviors and regular firing event may be attributed to the controllable metallic Ag filamentary mechanism. Furthermore, a solid accuracy of 91.44% of the pattern recognition of Modified National Institute of Standards and Technology (MNIST) data is obtained via a trained spiking neural network (SNN) based on the leaky integrate‐and‐fire behavior of sericin‐based device. These achievements shed light on the fact that employing sericin biomaterials has great application potential in advanced neuromorphic computation.

Lung cancer is a malignancy with high incidence and mortality rates globally, and it has a 5-year survival rate of only 10%–20%. The significant heterogeneity in clinical presentation, histological features, multi-omics findings, and drug sensitivity among different lung cancer patients necessitate the development of personalized treatment strategies. The current precision medicine for lung cancer, primarily based on pathological and genomic multi-omics testing, fails to meet the needs of patients with clinically refractory lung cancer. Lung cancer organoids (LCOs) are derived from tumor cells within tumor tissues and are generated through three-dimensional tissue culture, enabling them to faithfully recapitulate in vivo tumor characteristics and heterogeneity. The establishment of a series of LCOs biobanks offers promising platforms for efficient screening and identification of novel targets for anti-tumor drug discovery. Moreover, LCOs provide supplementary decision-making factors to enhance the current precision medicine for lung cancer, thereby addressing the limitations associated with pathology-guided approaches in managing refractory lung cancer. This article presents a comprehensive review on the construction methods and potential applications of LCOs in both preclinical and clinical research. It highlights the significance of LCOs in biomarker exploration, drug resistance investigation, target identification, clinical precision drug screening, as well as microfluidic technology-based high-throughput drug screening strategies. Additionally, it discusses the current limitations and future prospects of this field.

Abstract Introduction Due to the high recurrence, the HCC prognosis remains poor. Yet, the biomarkers for predicting the recurrence of high‐risk patients are currently lacking. We aimed to develop a signature to predict the recurrence of HCC based on NKG2D ligands. Methods The multivariate Cox proportional hazards regression was used to select recurrence‐related variables of NKG2D ligands in HCC patients from The Cancer Genome Atlas (TCGA). HCC patients from the OEP000321 dataset and Guilin cohort were used to validate the predictive signature. The mRNA expression of NKG2D ligands was measured by QRT‐PCR. Immunohistochemistry analysis of HCC tissue microarray samples was used to identify the expression of NKG2D ligands. Results In this study, NKG2D ligands expression in the mRNA and protein level was both abnormally expressed in HCC and associated with recurrence‐free survival (RFS). Then, the recurrence‐related variables of NKG2D ligands in HCC were selected by the multivariate Cox proportional hazards regression. Among the eight NKG2D ligands, MICA (HR = 1.347; 95% CI = 1.012–1.793; p = 0.041), ULBP3 (HR = 0.453; 95% CI = 0.231–0.889; p = 0.021) and ULBP5 (HR = 3.617; 95% CI = 1.819–7.194; p

Background & Aims: Hepatic immune system disorder plays a critical role in the pathogenesis of acute liver injury. The intrinsic signaling mechanisms responsible for dampening excessive activation of liver macrophages are not completely understood. The Notch and Hippo-YAP signaling pathways have been implicated in immune homeostasis. In this study, we investigated the interactive cell signaling networks of Notch1/YAP pathway during acute liver injury. Methods: Myeloid-specific Notch1 knockout (Notch1M-KO) mice and the floxed Notch1 (Notch1FL/FL) mice were subjected to lipopolysaccharide/D-galactosamine toxicity. Some mice were injected via the tail vein with bone marrow–derived macrophages transfected with lentivirus-expressing YAP. Some mice were injected with YAP siRNA using an in vivo mannose-mediated delivery system. Results: We found that the activated Notch1 and YAP signaling in liver macrophages were closely related to lipopolysaccharide/D-galactosamine-induced acute liver injury. Macrophage/neutrophil infiltration, proinflammatory mediators, and hepatocellular apoptosis were markedly ameliorated in Notch1M-KO mice. Importantly, myeloid Notch1 deficiency depressed YAP signaling and facilitated M2 macrophage polarization in the injured liver. Furthermore, YAP overexpression in Notch1M-KO livers exacerbated liver damage and shifted macrophage polarization toward the M1 phenotype. Mechanistically, macrophage Notch1 signaling could transcriptionally activate YAP gene expression. Reciprocally, YAP transcriptionally upregulated the Notch ligand Jagged1 gene expression and was essential for Notch1-mediated macrophage polarization. Finally, dual inhibition of Notch1 and YAP in macrophages further promoted M2 polarization and alleviated liver damage. Conclusions: Our findings underscore a novel molecular insight into the Notch1-YAP circuit for controlling macrophage polarization in acute liver injury, raising the possibility of targeting macrophage Notch1-YAP circuit as an effective strategy for liver inflammation–related diseases.

Abstract Accumulating evidence supports evolutionary trait of drug resistance. Like resilience in other systems, most tumor cells experience drug-tolerant state before full resistance acquired. However, the underlying mechanism is still poorly understood. Here, we identify that EGF like domain multiple 7 (EGFL7) is a responsive gene to epidermal growth factor receptor (EGFR) kinase inhibition during a period when tumors are decimated. Moreover, our data reveal that the adaptive increase of EGFL7 during this process is controlled by the depression of nonsense-mediated mRNA decay (NMD) pathway. Upregulation of EGFL7 activates NOTCH signaling in lung cancer cells, which slows down the decrease of c-Myc caused by EGFR inhibition, thereby helping the survival of cancer cells. Our data, taken together, demonstrate that EGFL7 is a driver gene for resistance to EGFR kinase inhibition, and suggest that targeting EGFL7/NOTCH signaling may improve the clinical benefits of EGFR inhibitors in patients with EGFR mutant tumors.

Abstract Breast cancer is the most common female tumors arising worldwide, and genetic and epigenetic events are constantly accumulated in breast tumorigenesis. The melastatin-related transient receptor potential 7 channel (TRPM7) is a nonselective cation channel, mainly maintaining Zn2+, Ca2+ and Mg2+ homeostasis. It is also involved in regulating proliferation and migration in various cancers including breast cancer. However, epigenetic alterations (such as promoter methylation) of TRPM7 and their correlation with clinical outcomes in breast cancer patients remain largely unclear. In this study, we found that TRPM7 was highly expressed in the luminal A subtype of breast cancers but no other subtypes compared with GTEx (Genotype-Tissue Expression Rad) or normal samples by analyzing the TCGA database. Correspondingly, TRPM7 was methylated in 42.7% (93 of 219) of breast cancers. Further studies found that promoter methylation of TRPM7 were significantly associated with better clinical outcomes in breast cancer patients, especially in the Luminal A subtype. Besides, methylated TRPM7 was correlated with less number of metastatic lymph nodes and longer local failure free survival time in this subtype. In summary, our data indicate that promoter methylation of TRPM7 may predict poor prognosis in patients with luminal A breast cancer.

Abstract Enantioselective recognition and separation are the most important issues in the fields of chemistry, pharmacy, agrochemical, and food science. Here, we developed two optically active diamines showing aggregation‐induced emission (AIE) that can discriminate 5 kinds of chiral acids with high enantioselectivity. Especially, a very high fluorescence intensity ratio (Il/Id) of 281 for (±)‐Dibenzoyl‐d/l‐tartaric acid was obtained through the collection of fluorescence change after interaction with chiral AIE‐active diamine. By virtue of AIE property and intermolecular acid‐base interaction, enantioselective separation was facilely realized by simple filtration of the precipitates formed by chiral AIE luminogen (AIEgen) and one enantiomer in the racemic solution. The chiral HPLC data indicated that the precipitates of AIEgen/chiral acid possessed 82% l‐analyte (the enantiomeric excess value was assessed to be 64% ee). Therefore, this method can serve as a simple, convenient, and low‐cost tool for chiral detection and separation.

Summary: Spaceflight is rigorous and dangerous environment which can negatively affect astronauts’ health and the entire mission. The 60 days of 6° head-down bed rest (HDBR) experiment provided us with an opportunity to trace the change of gut microbiota under simulated microgravity. The gut microbiota of volunteers was analyzed and characterized by 16S rRNA gene sequencing and metagenomic sequencing. Our results showed that the composition and function of the volunteers’ gut microbiota were markedly was affected by 60 days of 6° HDBR. We further confirmed the species and diversity fluctuations. Resistance and virulence genes in the gut microbiota were also affected by 60 days of 6° HDBR, but the species attributions remained stable. The human gut microbiota affected by 60 days of 6° HDBR which was partially consistent with the effect of spaceflight, this implied that HDBR was a simulation of how spaceflight affects the human gut microbiota.

Background Previous studies confirmed that most neoantigens predicted by algorithms do not work in clinical practice, and experimental validations remain indispensable for confirming immunogenic neoantigens. In this study, we identified the potential neoantigens with tetramer staining, and established the Co-HA system, a single-plasmid system coexpressing patient human leukocyte antigen (HLA) and antigen, to detect the immunogenicity of neoantigens and verify new dominant hepatocellular carcinoma (HCC) neoantigens.Methods First, we enrolled 14 patients with HCC for next-generation sequencing for variation calling and predicting potential neoantigens. Then, the Co-HA system was established. To test the feasibility of the system, we constructed target cells coexpressing HLA-A*11:01 and the reported KRAS G12D neoantigen as well as specific T-cell receptor (TCR)-T cells. The specific cytotoxicity generated by this neoantigen was shown using the Co-HA system. Moreover, potential HCC-dominant neoantigens were screened out by tetramer staining and validated by the Co-HA system using methods including flow cytometry, enzyme-linked immunospot assay and ELISA. Finally, antitumor test in mouse mode and TCR sequencing were performed to further evaluate the dominant neoantigen.Results First, 2875 somatic mutations in 14 patients with HCC were identified. The main base substitutions were C>T/G>A transitions, and the main mutational signatures were 4, 1 and 16. The high-frequency mutated genes included HMCN1, TTN and TP53. Then, 541 potential neoantigens were predicted. Importantly, 19 of the 23 potential neoantigens in tumor tissues also existed in portal vein tumor thrombi. Moreover, 37 predicted neoantigens restricted by HLA-A*11:01, HLA-A*24:02 or HLA-A*02:01 were performed by tetramer staining to screen out potential HCC-dominant neoantigens. HLA-A*24:02-restricted epitope 5'-FYAFSCYYDL-3' and HLA-A*02:01-restricted epitope 5'-WVWCMSPTI-3' demonstrated strong immunogenicity in HCC, as verified by the Co-HA system. Finally, the antitumor efficacy of 5'-FYAFSCYYDL-3'-specific T cells was verified in the B-NDG-B2mtm1Fcrntm1(mB2m) mouse and their specific TCRs were successfully identified.Conclusion We found the dominant neoantigens with high immunogenicity in HCC, which were verified with the Co-HA system.

Emerging research underscores the substantial link between gut flora and various inflammatory skin diseases. We hypothesize that there exists a complex gut–skin axis, possibly affecting the progression of conditions such as eczema, acne, psoriasis, and rosacea. However, the precise nature of the causal connection between gut flora and skin diseases remains unestablished. In this study, we started by compiling summary data from genome-wide association studies (GWAS) featuring 211 unique gut microbiota and four types of skin conditions. We scrutinized these data across different taxonomic strata. Subsequently, we leveraged Mendelian randomization (MR) to ascertain if there is a causal link between gut microbiota and these skin conditions. We also performed a bidirectional MR analysis to identify the causality’s direction. By utilizing Mendelian randomization, we identified 26 causal connections between the gut microbiome and four recognized inflammatory skin conditions, including 9 positive and 17 negative causal directions. Additional sensitivity analyses of these results revealed no evidence of pleiotropy or heterogeneity. Our MR analysis suggests a causal connection between gut microbiota and skin diseases, potentially providing groundbreaking perspectives for future mechanistic and clinical studies on microbiota-affected skin conditions.

Summary: IgA nephropathy (IgAN) is a heterogeneous disease, which poses a series of challenges to accurate diagnosis and personalized therapy. Herein, we constructed a systematic quantitative proteome atlas from 59 IgAN and 19 normal control donors. Consensus sub-clustering of proteomic profiles divided IgAN into three subtypes (IgAN-C1, C2, and C3). IgAN-C2 had similar proteome expression patterns with normal control, while IgAN-C1/C3 exhibited higher level of complement activation, more severe mitochondrial injury, and significant extracellular matrix accumulation. Interestingly, the complement mitochondrial extracellular matrix (CME) pathway enrichment score achieved a high diagnostic power to distinguish IgAN-C2 from IgAN-C1/C3 (AUC>0.9). In addition, the proteins related to mesangial cells, endothelial cells, and tubular interstitial fibrosis were highly expressed in IgAN-C1/C3. Most critically, IgAN-C1/C3 had a worse prognosis compared to IgAN-C2 (30% eGFR decline, p = 0.02). Altogether, we proposed a molecular subtyping and prognostic system which could help to understand IgAN heterogeneity and improve the treatment in the clinic.

This article provides a comprehensive overview of the fairness issues in artificial intelligence (AI) systems, delving into its background, definition, and development process. The article explores the fairness problem in AI through practical applications and current advances and focuses on bias analysis and fairness training as key research directions. The paper explains in detail the concept, implementation, characteristics, and use cases of each method. The paper explores strategies to reduce bias and improve fairness in AI systems, reviews challenges and solutions to real-world AI fairness applications, and proposes future research directions. In addition, this study provides an in-depth comparative analysis of the various approaches, utilizing cutting-edge research information to elucidate their different characteristics, strengths, and weaknesses. The results of the comparison provide guidance for future research. The paper concludes with an overview of existing challenges in practical applications and suggests priorities and solutions for future research. The conclusions provide insights for promoting fairness in AI systems. The information reviewed in this paper is drawn from reputable sources, including leading academic journals, prominent conference proceedings, and well-established online repositories dedicated to AI fairness. However, it is important to recognize that research nuances, sample sizes, and contextual factors may create limitations that affect the generalizability of the findings.

Cholecystokinin (CCK) can make the human body feel full and has neurotrophic and anti-inflammatory effects. It is beneficial in treating obesity, Parkinson’s disease, pancreatic cancer, and cholangiocarcinoma. Traditional biological experiments are costly and time-consuming when it comes to finding and identifying novel CCK-secretory peptides, and there is an urgent need to develop a new computational method to predict new CCK-secretory peptides. This study combines the transfer learning method with the SMILES enumeration data augmentation strategy to solve the data scarcity problem. It establishes a fusion model of the hierarchical attention network (HAN) and bidirectional long short-term memory (BiLSTM), which fully extracts peptide chain features to predict CCK-secretory peptides efficiently. The average accuracy of the proposed method in this study is 95.99%, with an AUC of 98.07%. The experimental results show that the proposed method is significantly superior to other comparative methods in accuracy and robustness. Therefore, this method is expected to be applied to the preliminary screening of CCK-secretory peptides.

BackgroundLupus nephritis (LN) is one of the most common and serious complications of systemic lupus erythaematosus (SLE). Genetic factors play important roles in the pathogenesis of LN and could be used to predict who might develop LN. The purpose of this study was to screen for susceptible candidates of LN across the whole genome in the Han Chinese population.Methods592 LN patients and 453 SLE patients without renal damage were genotyped at 492,970 single nucleotide polymorphisms (SNPs) in the genome-wide association study (GWAS). Fifty-six SNPs were selected for replication in an independent cohort of 188 LN and 171 SLE without LN patients. Further quantitative real-time (qRT) PCR was carried out in 6 LN patients and 6 healthy controls. Gene-based analysis was conducted using the versatile gene-based test for GWAS. Subsequently, enrichment and pathway analyses were performed in the DAVID database.ResultsThe GWAS analysis and the following replication research identified 9 SNPs showing suggestive correlation with LN (P

Abstract Background Chronic kidney disease (CKD) has become a global public health problem. Accumulating evidence suggested that vitamins play important roles in the progression of CKD. Methods A cross-sectional study was conducted to investigate the vitamin status of patients with CKD at stage 1–5. The serum concentrations of 9 vitamins, vitamin A, B1, B2, B6, B9, B12, C, D, and E were measured by electroanalytical method with a Multi-Vitamin Analyzer. Pearson correlation and multiple linear regression between serum level of vitamins were analyzed. Results The median levels of vitamin A, B1, B2, B6, B9, B12, C and E were within the reference ranges or on the borderline. Vitamin D deficiency was found in all patients. Weak correlation was found between vitamin A or vitamin D and estimated glomerular filtration rate (eGFR). The Pearson correlation coefficient were − 0.21766 and 0.19752, respectively. Hypertension, diabetes mellitus, and atherosclerosis were the major comorbidities. Conclusions For the first time, the serum levels of 9 vitamins were measured simultaneously in patients with CKD at different stages. Vitamin D deficiency was found in all patients. Weak correlation between vitamin A or vitamin D and eGFR was found.

Background: Conventional animal models used in corresponding basic studies are distinct from humans in terms of the brain’s development trajectory, tissue cytoarchitecture and cell types, making it difficult to accurately evaluate the potential adverse effects of anesthetic treatments on human fetal brain development. This study investigated the effects of sevoflurane on the midbrain’s development and cytopathology using human physiologically-relevant midbrain organoids.Methods: Monolayer human induced pluripotent stem cells (hiPSC)-derived human floor plate cells and three-dimensional hiPSC-derived midbrain organoids (hMBOs) were exposed to 2% (v/v) sevoflurane for 2 or 6 h, followed by expansion or differentiation culture. Then, immunofluorescence, real-time PCR, EdU assay, Tunnel assay, and transcriptome sequencing were performed to examine the effects of sevoflurane on the midbrain’s development.Results: We found that 2% sevoflurane exposure inhibited hFPCs’ proliferation (differentiation culture: 7.2% ± 0.3% VS. 13.3% ± 0.7%, p = 0.0043; expansion culture: 48% ± 2.2% VS. 35.2% ± 1.4%, p = 0.0002) and increased their apoptosis, but did not affect their differentiation into human dopaminergic neurons After 6 h, 2% sevoflurane exposure inhibited cell proliferation (62.8% ± 5.6% VS. 100% ± 5.5%, p = 0.0065) and enhanced the premature differentiation of hMBOs (246% ± 5.2% VS. 100% ± 28%, p = 0.0065). The RNA-seq results showed long-term exposure to sevoflurane up regulates some transcription factors in the differentiation of dopaminergic neurons, while short-term exposure to sevoflurane has a weak up-regulation effect on these transcription factors.Conclusion: This study revealed that long-term exposure to sevoflurane could promote the premature differentiation of hMBOs, while short-term exposure had negligible effects, suggesting that long-term exposure to sevoflurane in pregnant women may lead to fetals’ midbrain development disorder.

Summary: Organoids are considered a game-changing paradigm of research models for human physiology and disease, which provides unsurpassed opportunities across disciplines in basic medical research, drug development, and personalized medicine. Here, we made a deep investigation for global patents of organoid technologies in the past decade using bibliometric analysis for the first time. We have identified a total of 672 patents related to organoid technology. The number of annual patent applications exhibits an overall upward growth trend over the past decade, especially entering an exponential growth since 2015. Notably, 76.64% of patents are related to the construction of organoid models. Liver, brain, and intestinal models take up the first three places in the physiological models, while tumor models account for 76.30% of the total patents for disease models. Furthermore, drug screening is the most preferred application, revealing the great commercial value of organoid technologies in precision medicine and preclinical drug screening.

Human pluripotent stem cell-derived liver organoids are emerging as more human-relevant in vitro models for studying liver diseases and hepatotoxicity than traditional hepatocyte cultures and animal models. The generation of liver organoids is based on the Matrigel dome method. However, the organoids constructed by this method display significant heterogeneity in their morphology, size, and maturity. Additionally, the formed organoid is randomly encapsulated in the Matrigel dome, which is not convenient for in situ staining and imaging. Here, we demonstrate an approach to generate a novel type of liver organoids via micropatterning technique. This approach enables the reproducible and high-throughput formation of bioengineered fetal liver organoids with uniform morphology and deterministic size and location in a multiwell plate. The liver organoids constructed by this technique closely recapitulate some critical features of human liver development at the fetal stage, including fetal liver-specific gene and protein expression, glycogen storage, lipid accumulation, and protein secretion. Additionally, the organoids allow whole-mount in-situ staining and imaging. Overall, this new type of liver organoids is compatible with the pharmaceutical industry’s widely-used preclinical drug discovery tools and will facilitate liver drug screening and hepatotoxic assessment.

BackgroundThe disease pathology for diabetes mellitus patients with chronic kidney disease (CKD) may be diabetic nephropathy (DN), non-diabetic renal disease (NDRD), or DN combined with NDRD. Considering that the prognosis and treatment of DN and NDRD differ, their differential diagnosis is of significance. Renal pathological biopsy is the gold standard for diagnosing DN and NDRD. However, it is invasive and cannot be implemented in many patients due to contraindications. This article constructed a new noninvasive evaluation model for differentiating DN and NDRD.MethodsWe retrospectively screened 1,030 patients with type 2 diabetes who has undergone kidney biopsy from January 2005 to March 2017 in a single center. Variables were ranked according to importance, and the machine learning methods (random forest, RF, and support vector machine, SVM) were then used to construct the model. The final model was validated with an external group (338 patients, April 2017–April 2019).ResultsIn total, 929 patients were assigned. Ten variables were selected for model development. The areas under the receiver operating characteristic curves (AUCROCs) for the RF and SVM methods were 0.953 and 0.947, respectively. Additionally, 329 patients were analyzed for external validation. The AUCROCs for the external validation of the RF and SVM methods were 0.920 and 0.911, respectively.ConclusionWe successfully constructed a predictive model for DN and NDRD using machine learning methods, which were better than our regression methods.Clinical Trial RegistrationClinicalTrial.gov, NCT03865914.

BackgroundUnderstanding the acute kidney injury (AKI) microenvironment changes and the complex cellular interaction is essential to elucidate the mechanisms and develop new targeted therapies for AKI.MethodsWe employed unbiased single-cell RNA sequencing to systematically resolve the cellular atlas of kidney tissue samples from mice at 1, 2 and 3 days after ischemia-reperfusion AKI and healthy control. The single-cell transcriptome findings were validated using multiplex immunostaining, western blotting, and functional experiments.ResultsWe constructed a systematic single-cell transcriptome atlas covering different AKI timepoints with immune cell infiltration increasing with AKI progression. Three new proximal tubule cells (PTCs) subtypes (PTC-S1-new/PTC-S2-new/PTC-S3-new) were identified, with upregulation of injury and repair-regulated signatures such as Sox9, Vcam1, Egr1, and Klf6 while with downregulation of metabolism. PTC-S1-new exhibited pro-inflammatory and pro-fibrotic signature compared to normal PTC, and trajectory analysis revealed that proliferating PTCs were the precursor cell of PTC-S1-new, and part of PTC-S1-new cells may turn into PTC-injured and then become fibrotic. Cellular interaction analysis revealed that PTC-S1-new and PTC-injured interacted closely with infiltrating immune cells through CXCL and TNF signaling pathways. Immunostaining validated that injured PTCs expressed a high level of TNFRSF1A and Kim-1, and functional experiments revealed that the exogenous addition of TNF-α promoted kidney inflammation, dramatic injury, and specific depletion of TNFRSF1A would abrogate the injury.ConclusionsThe single-cell profiling of AKI microenvironment provides new insight for the deep understanding of molecular changes of AKI, and elucidates the mechanisms and developing new targeted therapies for AKI.

BackgroundEarly prediction of acute kidney injury (AKI) can allow for timely interventions, but there are still few methods that are easy and convenient to apply in predicting AKI, specially targeted at patients with minimal change disease (MCD). Motivated by this, we aimed to develop a predicting model for AKI in patients with MCD within the KDIGO criteria.MethodsData on 401 hospitalized adult patients, whose biopsy was diagnosed as MCD from 12/31/2010 to 15/7/2021, were retrospectively collected. Among these data, patients underwent biopsy earlier formed the training set (n = 283), while the remaining patients formed the validation set (n = 118). Independent risk factors associated with AKI were analyzed. From this, the prediction model was developed and nomogram was plotted.ResultsAKI was found in 55 of 283 patients (19%) and 15 of 118 patients (13%) in the training and validation cohorts, respectively. According to the results from lasso regression and logistic regression, it was found that four factors, including mean arterial pressure, serum albumin, uric acid, and lymphocyte counts, were independent of the onset of AKI. Incorporating these factors, the nomogram achieved a reasonably good concordance index of 0.84 (95%CI 0.77–0.90) and 0.75 (95%CI 0.62–0.87) in predicting AKI in the training and validation cohorts, respectively. Decision curve analysis suggested clinical benefit of the prediction models.ConclusionsOur predictive nomogram provides a feasible approach to identify high risk MCD patients who might develop AKI, which might facilitate the timely treatment.

The pandemic of coronavirus disease 2019 (COVID-19) is changing the world like never before. This crisis is unlikely contained in the absence of effective therapeutics or vaccine. The papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays essential roles in virus replication and immune evasion, presenting a charming drug target. Given the PLpro proteases of SARS-CoV-2 and SARS-CoV share significant homology, inhibitor developed for SARS-CoV PLpro is a promising starting point of therapeutic development. In this study, we sought to provide structural frameworks for PLpro inhibitor design. We determined the unliganded structure of SARS-CoV-2 PLpro mutant C111S, which shares many structural features of SARS-CoV PLpro. This crystal form has unique packing, high solvent content and reasonable resolution 2.5 Å, hence provides a good possibility for fragment-based screening using crystallographic approach. We characterized the protease activity of PLpro in cleaving synthetic peptide harboring nsp2/nsp3 juncture. We demonstrate that a potent SARS-CoV PLpro inhibitor GRL0617 is highly effective in inhibiting protease activity of SARS-CoV-2 with the IC50 of 2.2 ± 0.3 μmol/L. We then determined the structure of SARS-CoV-2 PLpro complexed by GRL0617 to 2.6 Å, showing the inhibitor accommodates the S3–S4 pockets of the substrate binding cleft. The binding of GRL0617 induces closure of the BL2 loop and narrows the substrate binding cleft, whereas the binding of a tetrapeptide substrate enlarges the cleft. Hence, our results suggest a mechanism of GRL0617 inhibition, that GRL0617 not only occupies the substrate pockets, but also seals the entrance to the substrate binding cleft hence prevents the binding of the LXGG motif of the substrate.

Abstract The activating TERT promoter mutations and BRAF V600E mutation are well-established oncogenic alterations in human cancers. Coexistence of BRAF V600E and TERT promoter mutations is frequently found in multiple cancer types, and is strongly associated with poor patient prognosis. Although the BRAFV600E-elicited activation of ERK has been demonstrated to contribute to TERT reactivation by maintaining an active chromatin state, it still remains to be addressed how activated ERK is selectively recruited to mutant TERT promoter. Here, we report that transcription factor GABPA mediates the regulation of BRAFV600E/MAPK signaling on TERT reactivation by selectively recruiting activated ERK to mutant TERT promoter, where activated ERK can phosphorylate Sp1, thereby resulting in HDAC1 dissociation and an active chromatin state. Meanwhile, phosphorylated Sp1 further enhances the binding of GABPA to mutant TERT promoter. Taken together, our data indicate that GABPA and Sp1 synergistically activate mutant TERT promoter, contributing to tumorigenesis and cancer progression, particularly in the BRAFV600E-driven human cancers. Thus, our findings identify a direct mechanism that bridges two frequent oncogenic alterations together in TERT reactivation.

The synthetic strategies of oxime derivatives participating in radical-type reactions have been rapidly developed in the last few decades. Among them, the N–O bond cleavage of oxime esters leading to formation of nitrogen-centered radicals triggers adjacent C–C bond cleavage to produce carbon-centered free radicals, which has been virtually used in organic synthesis in recent years. Herein, we summarized the radical reactions involving oxime N–O bond and C–C bond cleavage through this special reaction form, including those from acyl oxime ester derivatives and cyclic ketoxime ester derivatives. These contents were systematically classified according to different reaction types. In this review, the free radical reactions involving acyl oxime esters and cyclic ketoxime esters after 2021 were included, with emphasis on the substrate scope and reaction mechanism.

Abstract Background Graves' disease (GD) is a clinical autoimmune thyroid disease. During the treatment of GD, antithyroid drug‐induced agranulocytosis (TIA) is a common and even life‐threatening adverse drug reaction. Previous studies suggested that susceptibility to TIA is strongly associated with HLA‐B*27:05, HLA‐B*38:02, and HLA‐DRB1*08:03 genetic variation and six single nucleotide polymorphisms (SNPs) in MICA genes. Aims The purpose of this study is to further study the associations between TIA, HLA‐B and MICA. Materials & Methods We genotyped MICA‐STR and MICA‐129 variants in 41 TIA and 308 control patients with GD and investigated the linkage effect among SNPs and short tandem repeat (STR) of MICA and HLA‐B alleles. Results The results showed that MICA*A5.1 was significantly associated with TIA (p = .007, odd ratio = 1.958, 95% confidence interval, 1.192–3.214). In addition, high linkage among MICA‐129 and six SNPs MICA and HLA‐B was detected, and two haplotypes (AAAACAAAAACGGCCTA and AACAAAAAAAACATTAA (p = 5.14E−07 and p = 3.42E−08, respectively)) were significantly associated with TIA. Furthermore, when we analyzed only MICA‐129 and HLA‐B separately, the haplotypes (AAAACAAAAAA with p = 2.49E−07 and AACAAAAAAAA with p = 2.14E−09) were identified with more significant effects. MICA‐129 was completely linked to six SNPs with haplotypes ACATTACA (p = 2.05E−05) significantly associated with TIA. Conclusion These data indicated that there was a significant linkage effect between MICA‐129 and other alleles, suggesting that they exert interactive effects as risk factors for the development of TIA.

Understanding the behavior of consumers and especially the purchase-related behavior has been a focus of research for the past decades. Thus, researchers and practitioners are curious to know how purchase patterns are different under different conditions such as product category, price, feeling, and so on. The primary focus of this study was to examine how the price of the products influences the purchase behavior of consumers across hedonic and utilitarian categories under regulatory focus theory (RFT). The secondary insight was to examine how mood can moderate this impact. We conducted three experimental studies to examine these research questions regarding the preference of consumers of hedonic (utilitarian) products when the price is low (high) and at different mood conditions in this purchase process. The results confirmed our hypothesis that product category has a significant impact on purchase choice of products and mood can mediate this impact. In the last section, we discussed the theoretical contribution, strategic insights for product designers and marketers, and possible future research directions.

Chemokines are a family of cytokines that orchestrate the migration and positioning of immune cells within tissues and are critical for the function of the immune system. CCR2 participates in liver pathology, including acute liver injury, chronic hepatitis, fibrosis/cirrhosis, and tumor progression, by mediating the recruitment of immune cells to inflammation and tumor sites. Although a variety of chemokines have been well studied in various diseases, there is no comprehensive review presenting the roles of all known chemokine ligands of CCR2 (CCL2, CCL7, CCL8, CCL12, CCL13, CCL16, and PSMP) in liver disease, and this review aims to fill this gap. The introduction of each chemokine includes its discovery, its corresponding chemotactic receptors, physiological functions and roles in inflammation and tumors, and its impact on different immune cell subgroups.

Alongshan virus (ALSV) is an emerging human pathogen that was identified in China and rapidly spread to the European continent in 2019, raising concerns about public health. ALSV belongs to the distinct Jingmenvirus group within the Flaviviridae family with segmented RNA genomes. While segments 2 and 4 of the ALSV genome encode the VP1–VP3 proteins of unknown origin, segments 1 and 3 encode the NS2b–NS3 and NS5 proteins, which are related to Flavivirus nonstructural proteins, suggesting an evolutionary link between segmented and unsegmented viruses within the Flaviviridae family. Here, the enzymatic activity of the ALSV NS3-like helicase (NS3-Hel) was characterized and its crystal structure was determined to 2.9 Å resolution. ALSV NS3-Hel exhibits an ATPase activity that is comparable to those measured for Flavivirus NS3 helicases. The structure of ALSV NS3-Hel exhibits an overall fold similar to those of Flavivirus NS3 helicases. Despite the limited amino-acid sequence identity between ALSV NS3-Hel and Flavivirus NS3 helicases, structural features at the ATPase active site and the RNA-binding groove remain conserved in ALSV NS3-Hel. These findings provide a structural framework for drug design and suggest the possibility of developing a broad-spectrum antiviral drug against both Flavivirus and Jingmenvirus.

A new species of the Rhododendron (Ericaceae) in subgen. Tsutsusi sect. Tsutsusi from Puding county of Guizhou, China, is described and illustrated. The new species, R. pudingense X.Y. Dai, C.H. Yang & Y.P. Ma, is similar to R. myrsinifolium Ching ex Fang et M. Y. He and R. minutiflorum Hu, but it can be easily distinguished by its length and being pubescent on inner surface of corolla tube, sparse hairs below the middle of filament and the glabrous style.