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Purpose: Twins have been studied to estimate the magnitudes of genetic and environmental effects on human phenotypes. The aim was to evaluate the genetic and environmental contributions to the cortical thickness of the cingulate region using brain magnetic resonance imaging of normal twins. Methods: Three-dimensional T1-weighted brain imaging at 3T of 43 monozygotic pairs and 18 dizygotic pairs was performed. Cortical thickness was measured for each of the six regions of the cingulum. Twin analysis with a model involving the phenotype variance components of additive genetic effects (A), common environmental effects (C), and unique environmental effects (E) was performed to assess the magnitude of each genetic and environmental effect on cortical thickness. Results: The AE model including A and E factors was adopted in the twin analysis for most of the regions. The magnitude of the genetic effects was mostly high and varied in each region; the genetic effects were strong in both sides of the anterior cingulate region, and the environmental effects were slightly strong in both sides of the posterior and marginal cingulate regions. Conclusion: Cortical thickness was affected mainly by genetic factors in the cingulate region.

Metal-modulated croconium dyes with multimodal-imaging and synergistic therapy in the tumor microenvironment have exhibited great potential in tumor theranostics. However, their unideal structure optimization always weakened the efficacy of near-infrared fluorescence–photoacoustic (NIRF/PA) imaging and photothermal therapy (PTT). Here, we screened croconium dye containing two indole groups with better NIRF/PA imaging and PTT in their family, linked to two morpholine rings, and obtained CR-736, as a lysosome-targeting and Fe3+-modulated agent. The established CR-736-Fe3+nanoplatform was accurately delivered to the breast tumor site, released CR-736 and Fe3+in the lower acidic lysosome microenvironment, and activated pH-responsive NIRF/PA/magnetic resonance imaging and PTT. Furthermore, ferroptosis generated hydroxyl free radicals and lipid peroxide by consuming GSH and H2O2by dint of the accumulation of Fe3+in tumor cells, which resulted in the inhibition of the expression of heat shock proteins and the concomitant recovery of PTT. The synergistic therapy of PTT, ferroptosis, and chemodynamics was further optimized to the maximal extent in tumor lysosome acidic microenvironment and proved both in vitro and a mouse tumor model. This study opens a new avenue in designing excellent and unique croconium-based nanoplatforms, synergizing multiple tumor theranostic methods, and further optimizing the theranostic effects in tumor microenvironment.

Uncertainty exists about whether lowering systolic blood pressure to less than 120 mm Hg is superior to that of less than 140 mm Hg, particularly in patients with diabetes and patients with previous stroke.

Enterogenic infection is a common complication for patients with radiation injury and requires efficient therapeutics in the clinic. Herein, we evaluated the promising drug candidate T7E21RHD5, which is a peptide derived from intestinal Paneth cell-secreted human defensin 5. Oral administration of this peptide alleviated the diarrhea symptoms of mice that received total abdominal irradiation (TAI, γ-ray, 12 Gy) and improved survival. Pathologic analysis revealed that T7E21RHD5 elicited an obvious mitigation of ionizing radiation (IR)-induced epithelial damage and ameliorated the reduction in the levels of claudin, zonula occluden 1 and occludin, three tight junction proteins in the ileum. Additionally, T7E21RHD5 regulated the gut microbiota in TAI mice by remodeling β diversity, manifested as a reversal of the inverted proportion of Bacteroidotato Firmicutescaused by IR. T7E21RHD5 treatment also decreased the abundance of pathogenic Escherichia–Shigellabut significantly increased the levels of Alloprevotellaand Prevotellaceae_NK3B31, two short-chain fatty acid-producing bacterial genera in the gut. Accordingly, the translocation of enterobacteria and lipopolysaccharide to the blood, as well as the infectious inflammatory responses in the intestine after TAI, was all suppressed by T7E21RHD5 administration. Hence, this versatile antimicrobial peptide possesses promising application prospects in the treatment of IR-induced enterogenic infection.

Bioorthogonal reactions involving transition metals have diversified applications in imaging, drug development, chemical catalysis and other fields. Transition metals used to catalyze the bioorthogonal reaction mainly include ruthenium, palladium, copper, and gold. However, the great potential for translational applications of bioorthogonal reaction needs to be further expanded and their reaction efficiency should be improved. Therefore, it is an urgent need for the development of this field to find more suitable catalysts to efficiently catalyze existing biological orthogonal reactions and expand the types of biological orthogonal reactions. Thus, this review not only summarizes those transition metal complexes-based catalysts participating in bioorthogonal reaction and some bioorthogonal reactions involving transition metals inside the cells, but also sheds light into the discovery of new transition metal complexes and their future development in applications.

An upwind weak Galerkin finite element scheme was devised and analyzed in this article for convection-dominated Oseen equations. The numerical algorithm was based on the weak Galerkin method enhanced by upwind stabilization. The resulting finite element scheme uses equal-order, say k, polynomial spaces on each element for the velocity and the pressure unknowns. With finite elements of order k⩾1, the numerical solutions are proved to converge at the rate of O(hk+12)in an energy-like norm for convection-dominated Oseen equations. Numerical results are presented to demonstrate the accuracy and effectiveness of the upwind weak Galerkin scheme.

The pantograph-catenary system (PACs) is the only channel for high-speed trains to obtain electric energy, and its state is crucial to the safety of train operation. There are two key indicators to measure the PACs state: the tension state of the catenary dropper and the zig-zag value of the PACs contact point (CPT). With the development of deep learning, on- board vision inspection equipment has gradually become an effective means of PACs state inspection. However, since more and more deep-learning black boxes are used in the railway industry, the reliability estimation of their decisions has become an unavoidable challenge. As for PACs state detection, there are two other challenges: the lack of defective dropper sample and the difficulty in distinguishing between true and false contact points. To overcome the challenge of defective sample scarcity, this article proposes to detect dropper defect by the semantic features extracted by a multitask pantograph-catenary system state detection network (MPCN), which is trained using only normal droppers. Aiming at the contact point tracking, a multiple hypothesis tracking tree (MHTT) algorithm is proposed to track the contact points using the change rule of the contact point sequence. Meanwhile, in the semantic space, domain knowledge is combined with Bayesian hypothesis testing to monitor the runtime reliability of the MPCN. In this way, the PACs state detection and the MPCN reliability monitoring can be implemented in a unified framework. The effectiveness of our method has been verified in various scenarios of various railway lines.

The dangers of organic dye pollutants and environmental pollution improvement through photocatalytic degradation are important courses in applied chemistry programs in universities. Zinc oxide (ZnO)-based nanomaterials are potent catalytic agents against organic dyes, but few experiments are available for students to understand their role and mechanism in class. Herein, we designed a comprehensive experiment across 24 class hours for undergraduates to investigate the photodegradation of colored organic dyes, including methylene blue, methyl orange, methyl violet, rhodamine B, basic fuchsin, and thymolphthalein, by a nanocomposite composed of ZnO-coated graphene oxide (ZnO/GO). This nanomaterial was prepared using a facile heating reflux method within 1 h. Scanning electron microscopy, Fourier transform infrared spectroscopy, and X-ray diffraction were introduced to students to characterize the synthesized products. Students could observe the time- and dose-dependent degradation as well as the reusability of ZnO/GO. Additionally, the addition of t-butanol, benzoquinone, and triethanolamine, scavengers of hydroxyl radical (•OH), superoxide anion (•O2–), and hole (h+), respectively, to the degradation system allowed them to master the underlying catalytic mechanism of ZnO/GO. This experiment improves students’ understanding of the photocatalytic effect of ZnO nanomaterials and stimulates them to engage in the field of applied chemistry and thus is worth recommending to undergraduates.

Lipid oxidation can produce lipid oxidation products (LOPs), which further react with proteins and affect their structure and digestibility, although the underlying mechanism remains unclear. Herein, we investigated the conformation and digestibility of proteins induced by LOPs after thermal treatment. Digestibility of myoglobin (Mb) affected by trans,trans,-2,4-decadienal (2,4-Dec) was significantly reduced under high temperature (100–180 °C). The peptides digested from Mb modified with 2,4-Dec during thermal processing revealed that the quantity of peptides decreased with increasing 2,4-Dec concentrations. Proteomic analysis showed that 2,4-Dec covalently binds to Mb, and the extent of modification was in the following order: lysine > histidine > arginine. Moreover, the secondary structure, intrinsic fluorescence, and surface hydrophobicity results suggested that 2,4-Dec induced changes in Mb, leading to a tighter spatial structure and aggregation, and exposure of fewer recognition sites of the enzyme and thermal treatment assisted these changes in the structure. Meanwhile, molecular dynamics simulations elucidated the molecular mechanisms underlying the effect of 2,4-Dec and temperature on the digestion and structure of Mb.

Immune recognition of excessive neurotoxins by microglia is a trigger for the onset of neuroinflammation in the brain, leading to neurodegeneration in Alzheimer's disease (AD). Blocking active recognition of microglia while removing neurotoxins holds promise for fundamentally alleviating neurotoxin-induced immune responses, but is very challenging. Herein, an engineered macrophage-biomimetic versatile nanoantidote (OT-Lipo@M) is developed for inflammation-targeted therapy against AD by neurotoxin neutralization and immune recognition suppression. Coating macrophage membranes can not only endow OT-Lipo@M with anti-phagocytic and inflammation-tropism capabilities to target inflammatory lesions in AD brain, but also efficiently reduce neurotoxin levels to prevent them from activating microglia. The loaded oxytocin (OT) can be slowly released to downregulate the expression of immune recognition site Toll-like receptor 4 (TLR4) on microglia, inhibiting TLR4-mediated pro-inflammatory signalling cascade. Benefiting from this two-pronged immunosuppressive strategy, OT-Lipo@M exhibits outstanding therapeutic effects on ameliorating cognitive deficits, inhibiting neuronal apoptosis, and enhancing synaptic plasticity in AD mice, accompanied by the delayed hippocampal atrophy and brain microstructural disruption by in vivo9.4T MR imaging. This work provides new insights into potential AD therapeutics targeting microglia-mediated neuroinflammation at the source.

•MC5R deficiency impairs HSC proliferation after stress.•Melanocortin/MC5R axis promotes hematopoietic recovery in irradiated mice.

Hematopoietic stem cells (HSCs) reside at the top of the hematopoietic hierarchy, exhibiting a unique capacity to self-renew and differentiate into all blood cells throughout the lifetime. However, how to prevent HSC exhaustion during long-term hematopoietic output is not fully understood. Here, we show that the homeobox transcription factor Nkx2-3 is required for HSC self-renewal by preserving metabolic fitness. We found that Nkx2-3 is preferentially expressed in HSCs with excessive regenerative potential. Mice with conditional deletion of Nkx2-3 displayed a reduced HSC pool and long-term repopulating capacity as well as increased sensitivity to irradiation and 5-flurouracil treatment due to impaired HSC quiescence. In contrast, overexpression of Nkx2-3 improved HSC function both in vitro and in vivo. Furthermore, mechanistic studies revealed that Nkx2-3 can directly control the transcription of the critical mitophagy regulator ULK1, which is essential for sustaining metabolic homeostasis in HSCs by clearing activated mitochondria. More importantly, a similar regulatory role of NKX2-3 was observed in human cord blood-derived HSCs. In conclusion, our data demonstrate an important role of the Nkx2-3/ULK1/mitophagy axis in regulating the self-renewal of HSCs, therefore providing a promising strategy to improve the function of HSCs in the clinic.

Intracellular redox homeostasis is of indispensable importance in pathophysiology. In order to maintain the balance of the redox state within the cell, reactive oxygen species (ROS) and reactive sulfur species (RSS) react and transform with each other, and their levels also directly reflect the degree of oxidative stress and disease. Hypochlorous acid (HClO) and cysteine (Cys) usually co-exist in organisms, interacting with each other in many important physiological processes and synergistically maintaining the dynamic redox balance in the body. To understand the relevance and pathophysiological effects of these two signaling molecules in oxidative stress, unique fluorescence imaging tools are required. Herein, we designed and developed a dual-channel fluorescent probe HP, for the individual and continuous detection of HClO and Cys. This probe could simultaneously monitor the changes in the concentrations of HClO and Cys in cells, and was characterized by a fast response, high sensitivity and high selectivity, especially compared with glutathione (GSH) and homocysteine (Hcy), the probe had a good specificity for Cys. Importantly, probe HPsuccessfully observed dynamic changes in HClO- and Cys-mediated redox status in the oxygen-glucose deprivation/reperfusion (OGD/R) model of HeLa cells and dynamically monitored fluctuations in endogenous HClO levels in lipopolysaccharides (LPS)-induced peritonitis mice.

Comprehension of photon-triggered molecular processes is essential in the study of various important topics in physics, chemistry, and biology. Here we propose a correlated tunneling picture to understand the dissociative ionization process of molecules in intense laser fields based on a quantum model developed in the framework of many-body S-matrix theory including nuclear vibrational motion. In this quantum correlation picture, the single ionization of H2and the subsequent electron-ion recollision-induced dissociation are considered as an entangled correlated process. It enables us to attribute the interference pattern in the joint-energy spectra to combined effects of single-slit diffraction and multi-slit interference of correlated electron-nuclear wave packets in the time domain. Our work opens a new avenue to understanding molecular dissociative ionization processes in external fields.

Platelet shedding from mature megakaryocytes (MKs) in thrombopoiesis is the critical step for elevating circulating platelets fast and efficiently, however, the underlying mechanism is still not well-illustrated, and the therapeutic targets and candidates are even less.

This article extends a recently developed superconvergence result for weak Galerkin (WG) approximations for modeling partial differential equations from constant coefficients to variable coefficients. This superconvergence features a rate that is two-order higher than the optimal-order error estimates in the usual energy and L2norms. The extension from constant to variable coefficients for the modeling equations is highly non-trivial. The underlying technical analysis is based on the use of a sequence of projections and decompositions. Numerical results are presented to confirm the superconvergence theory for second-order elliptic problems with variable coefficients.

Rho GTPase-activating protein 4 (ARHGAP4) is an important Rho family GTPase-activating protein that is strongly associated with the onset and progression of some tumors. We found that ARHGAP4 mRNA and protein are overexpressed in human acute myeloid leukemia (AML) patients and are associated with a poor prognosis. ARHGAP4 knockdown significantly impairs viability and colony formation capacity and induces apoptosis in AML cells. Further results demonstrate that ARHGAP4 deletion impairs AML progression in vivo. Interestingly, DRAM1 signaling is significantly activated in AML cells with ARHGAP4 knockdown. Our results also indicated that ARHGAP4 might function in AML cells by binding with p53 to inhibit DRAM1. Moreover, knockdown of DRAM1 rescues the defects of ARHGAP4 in AML cells. This newly described role of the ARHGAP4/DRAM1 axis in regulating AML progression may have important therapeutic implications.

Hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) have robust self-renewal potential, which is responsible for sustaining normal and malignant hematopoiesis, respectively. Although considerable efforts have been made to explore the regulation of HSC and LSC maintenance, the underlying molecular mechanism remains obscure. Here, we observe that the expression of thymocyte-expressed, positive selection-associated 1 (Tespa1) is markedly increased in HSCs after stresses exposure. Of note, deletion of Tespa1 results in short-term expansion but long-term exhaustion of HSCs in mice under stress conditions due to impaired quiescence. Mechanistically, Tespa1 can interact with CSN subunit 6 (CSN6), a subunit of COP9 signalosome, to prevent ubiquitination-mediated degradation of c-Myc protein in HSCs. As a consequence, forcing c-Myc expression improves the functional defect of Tespa1-null HSCs. On the other hand, Tespa1 is identified to be highly enriched in human acute myeloid leukemia (AML) cells and is essential for AML cell growth. Furthermore, using MLL-AF9-induced AML model, we find that Tespa1 deficiency suppresses leukemogenesis and LSC maintenance. In summary, our findings reveal the important role of Tespa1 in promoting HSC and LSC maintenance and therefore provide new insights on the feasibility of hematopoietic regeneration and AML treatment.

Thrombosis and hemorrhage as two opposite pathologies are prevalent within the chronic kidney disease (CKD) population. Platelet homeostasis, which positions centrally in their pathogenesis, varies among the CKD population, while the underlying mechanism is poorly understood. To investigate the change character and mechanism of platelet homeostasis in CKD and its association with renal Klotho deficiency. The change character of platelet homeostasis and its association with renal Klotho deficiency were determined based on a cohort study as well as CKD mice and Klotho‐deficient mice with CKD. The effects on thrombopoiesis and platelet lifespan were examined by flow cytometry and platelet transfer. The underlying mechanism was explored by proteomics, flow cytometry, western blot, and immunoprecipitation. We show that platelet count declines both in patient and mouse models with advanced CKD (Adv‐CKD) and is positively associated with circulating Klotho levels. Mechanistically, we identify that ubiquitin ligase UBE2O governs Bcl‐xL ubiquitination and degradation in platelets, whereas Adv‐CKD–induced oxidative stress in platelets stimulates p38MAPK to promote Bcl‐xL phosphorylation, which facilitates UBE2O binding to Bcl‐xL and subsequent Bcl‐xL degradation. Consequently, platelet lifespan is shortened in Adv‐CKD, culminating in platelet count decline. However, kidney‐secreted soluble Klotho protein restricts oxidative stress in platelets, thereby preserving Bcl‐xL expression and platelet lifespan. Our findings uncover the mechanism of platelet count decline in Adv‐CKD and identify renal Klotho as a long‐range regulator of platelet lifespan, which not only provide a molecular mechanism underlying CKD‐associated thrombocytopenia and hemorrhage but also offer a promising therapy choice.

Hydroxyl radical (•OH)‐sensitive carbon dots (CDs) with an excitation wavelength of 390 nm and emission wavelength of 525 nm were synthesized by microwave in one‐step. Using CDs as fluorescent probes, an •OH‐enhanced fluorescence quenching detection signal based on horseradish peroxidasecatalyzed H2O2was introduced on the basis of enzyme‐linked immunoassay, and a •OH‐enhanced label‐free fluorescence quenching immunoassay (FQIA) was constructed for high‐sensitivity detection of six broad‐spectrum antibiotics. When used for nitrofuran Q2 metabolites (3‐amino‐1,3‐oxazolidin‐2‐one, 3‐amino‐5‐(morpholin‐4‐ylmethyl)‐1,3‐oxazolidin‐2‐one, 1‐aminohydantoin hydrochloride, semicarbazide hydrochloride), chloramphenicol (CAP) and florfenicol (FLR) detection, FQIAs achieved high sensitivity detection of 0.061, 0.0058, 0.064, 0.045, 0.015, and 0.01 ng/ml, respectively. Compared with ELISA, the detection sensitivity was improved by 2.03‐ to 7.8‐fold. On this basis, the sample pretreatment methods for six targets were optimized, and the simultaneous extraction and high‐sensitivity detection of six targets were achieved. The FQIA proposed in this work improved the detection sensitivity, reduced the sample consumption and pretreatment steps, shortened the extraction time, and improved the detection efficiency, which provided support for the development and application of new immunoassay products and the development of the rapid analysis industry. A label‐free fluorescence quenching immunoassays using hydroxyl radical‐sensitive carbon dots as fluorescence probe was established for simultaneous extraction and highly sensitive detection of six wide‐spectrum antibiotics (nitrofuran metabolites, chloramphenicol, and florfenicol) in animal‐derived food. The organic combination of •OH‐sensitive CDs, high‐sensitivity fluorescence quenching immunoassays, and efficient pretreatment methods provides support for the development and application of new immunoassay technology.

Thrombosis and hemorrhage as two opposite pathologies are prevalent within the chronic kidney disease (CKD) population. Platelet homeostasis, which positions centrally in their pathogenesis, varies among the CKD population, while the underlying mechanism is poorly understood.

Thioredoxin reductase (TrxR) is highly overexpressed in cancer cells to promote malignant tumor survival. Designing drugs that inhibit TrxR activity is a promising approach to achieve highly effective cancer chemotherapy. However, the selectivity of TrxR inhibitors continue to be a challenge for scientists. In this work, we demonstrate a new strategy to selectively inhibit TrxR through constructing electrophilic center −N–Se(δ+)–N– by using the polarization effect of the selenium atom. The constructed electrophilic center interacts noncovalently with the active motif of TrxR to avoid the interference of other residues in human tissues, thereby selectively inhibiting intracellular TrxR activity. Computational and experimental analysis confirms that the formed electrophilic selenium center preferred to attack the SeC residues in the redox active center of TrxR at the 498 site through strong noncovalent interactions. Both in vitro and in vivo experimental results confirmed that this strategy can significantly improve the anticancer effect. This study may provide a novel route to design highly effective and selective chemotherapeutic drugs.

Background:The microbial community in human milk is associated with many maternal and neonatal factors. This study aimed to investigate the effect of antibiotic exposure on the microbial community structure of colostrum.Methods:Twenty women with antibiotic treatment immediately after delivery and 10 age-matched control women were enrolled at the Guangdong Women and Children Hospital. Colostrum samples were collected within postpartum 30 hours. The V4 variable region of the bacterial 16S rRNA gene was sequenced to characterize the microbial profile using Illumina MiSeq platform.Results:Phyla Proteobacteriaand Firmicuteswere the predominant bacteria in colostrum samples. The core and abundant genera in colostrum included Streptococcus, Staphylococcus, and Pseudomonas. Compared with the control group, principal coordinate analysis based on the Bray-Curtis distance showed a significant difference in milk microbial community in women with antibiotic exposure, accompanied by a significantly lower alpha diversity and a different microbial ecological network. Furthermore, the relative abundances of genera Actinomyces, Anaerobacter, and Clostridium_sensu_strictosignificantly decreased after antibiotic treatment.Conclusions:This study provided evidence of alterations in the colostrum microbial community with antibiotic exposure, improving our understanding of the effects of antibiotic treatment on the milk microbiome.

The search of highly efficient drugs for overcoming cancer drug resistance continues to be a challenge for scientists. Constructing a metal drug based in situoxidation-state transition system to disturb the redox balance in cancer cells is a promising approach for overcoming cancer drug resistance. Inspired by natural redox-active copper enzyme centers, we developed a Cu(I)-Cu(II) in situtransition system in this work. Through atom engineering, we fine-tuned the thermodynamic stability of this system to investigate its anticancer activity The results indicated that the synthetic Cu(I)-Cu(II) system could under-go in situtransition in vitroand in vivo, to disrupt the intracellular redox balance and trigger mitochondrial dysfunction and G2/M arrest, leading to apoptosis and overcoming cancer drug resistance This study presents a feasible way to overcome cancer drug resistance by designing an in situoxidation-state transition metal drug system.

Hematopoietic stem cells (HSCs) employ a very unique metabolic pattern to maintain themselves, while the spectrum of their metabolic adaptations remains incompletely understood. Here, we uncover a distinct and heterogeneous serine metabolism within HSCs and identify mouse HSCs as a serine auxotroph whose maintenance relies on exogenous serine and the ensuing mitochondrial serine catabolism driven by the hydroxymethyltransferase 2 (SHMT2)-methylene-tetrahydrofolate dehydrogenase 2 (MTHFD2) axis. Mitochondrial serine catabolism primarily feeds NAD(P)H generation to maintain redox balance and thereby diminishes ferroptosis susceptibility of HSCs. Dietary serine deficiency, or genetic or pharmacological inhibition of the SHMT2-MTHFD2 axis, increases ferroptosis susceptibility of HSCs, leading to impaired maintenance of the HSC pool. Moreover, exogenous serine protects HSCs from irradiation-induced myelosuppressive injury by fueling mitochondrial serine catabolism to mitigate ferroptosis. These findings reframe the canonical view of serine from a nonessential amino acid to an essential niche metabolite for HSC pool maintenance.

Mitochondria are key regulators of hematopoietic stem cell (HSC) homeostasis. Our research identifies the transcription factor Nynrin as a crucial regulator of HSC maintenance by modulating mitochondrial function. Nynrin is highly expressed in HSCs under both steady-state and stress conditions. The knockout Nynrindiminishes HSC frequency, dormancy, and self-renewal, with increased mitochondrial dysfunction indicated by abnormal mPTP opening, mitochondrial swelling, and elevated ROS levels. These changes reduce HSC radiation tolerance and promote necrosis-like phenotypes. By contrast, Nynrinoverexpression in HSCs diminishes irradiation (IR)-induced lethality. The deletion of Nynrin activates Ppif, leading to overexpression of cyclophilin D (CypD) and further mitochondrial dysfunction. Strategies such as Ppifhaploinsufficiency or pharmacological inhibition of CypD significantly mitigate these effects, restoring HSC function in Nynrin-deficient mice. This study identifies Nynrin as a critical regulator of mitochondrial function in HSCs, highlighting potential therapeutic targets for preserving stem cell viability during cancer treatment.

The cell cycle progression of hematopoietic stem cells (HSCs) and acute myeloid leukemia (AML) cells is precisely controlled by multiple regulatory factors. However, the underlying mechanisms are not fully understood. Here, we find that cyclin-dependent kinase 19 (CDK19), not its paralogue CDK8, is relatively enriched in mouse HSCs, and its expression is more significantly increased than CDK8 after proliferative stresses. Furthermore, SenexinB (a CDK8/19 inhibitor) treatment impairs the proliferation and self-renewal ability of HSCs. Moreover, overexpression of CDK19 promotes HSC function better than CDK8 overexpression. Using CDK19 knockout mice, we observe that CDK19−/−HSCs exhibit similar phenotypes to those of cells treated with SenexinB. Interestingly, the p53 signaling pathway is significantly activated in HSCs lacking CDK19 expression. Further investigations show that CDK19 can interact with p53 to inhibit p53-mediated transcription of p21 in HSCs and treatment with a specific p53 inhibitor (PFTβ) partially rescues the defects of CDK19-null HSCs. Importantly, SenexinB treatment markedly inhibits the proliferation of AML cells. Collectively, our findings indicate that CDK19 is involved in regulating HSC and AML cell proliferation via the p53-p21 pathway, revealing a new mechanism underlying cell cycle regulation in normal and malignant hematopoietic cells.

ABSTRACTNumerous studies have reported the regulatory effects of miR-21-5p and reversine in human breast cancer (HBC). However, the mechanism of reversine and miR-21-5p has not been fully investigated in HBC. The aim of the current study was to assess the mechanism of action of reversine, with or without miR-21-5p, in HBC progression. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot results confirmed the upregulation of miR-21-5p and downregulation of sprouty RTK signaling antagonist 2 (SPRY2) in HBC. Bioinformatics analysis and luciferase assay identified the correlation between miR-21-5p and SPRY2. Cell function experiment results indicated a decrease in migration, proliferation, and invasion of HBC cells treated with miR-21-5p inhibitor and reversine; however, an increase in apoptosis was observed in these cells. Apoptotic ability was more enhanced and migration, proliferation, and invasion were more impaired in HBC cells treated with both miR-21-5p inhibitor and reversine than in those treated individually with either inhibitors. SPRY2, downstream of miR-21-5p, participated in HBC progression with reversine. Overall, our study proved that combining the miR-21-5p inhibitor with reversine produced a synergistic effect by regulating SPRY2, thereby limiting HBC progression. This knowledge might offer insights into the clinical therapy of HBC.

Hematopoietic stem cell (HSC) fate is tightly controlled by various regulators, whereas the underlying mechanism has not been fully uncovered due to the high heterogeneity of these populations. In this study, we identify tetraspanin CD63 as a novel functional marker of HSCs in mice. We show that CD63 is unevenly expressed on the cell surface in HSC populations. Importantly, HSCs with high CD63 expression (CD63hi) are more quiescent and have more robust self-renewal and myeloid differentiation abilities than those with negative/low CD63 expression (CD63-/lo). On the other hand, using CD63 knockout mice, we find that loss of CD63 leads to reduced HSC numbers in the bone marrow. In addition, CD63-deficient HSCs exhibit impaired quiescence and long-term repopulating capacity, accompanied by increased sensitivity to irradiation and 5-fluorouracil treatment. Further investigations demonstrate that CD63 is required to sustain TGFβ signaling activity through its interaction with TGFβ receptors I and II, thereby playing an important role in regulating the quiescence of HSCs. Collectively, our data not only reveal a previously unrecognized role of CD63 but also provide us with new insights into HSC heterogeneity.

Evaluation of the nutrition and determination of phosphoproteins is of great importance in different foods as aberrant phosphorylation changes many biological processes and can relate to health conditions. In this study, an ultrafast (5 min) and sensitive electrochemiluminescence (ECL) sensor was innovatively fabricated for the determination of phosphoproteins in foods on the basis of fluorescent probe NH2-TiO2/upconversion nanomaterials (UCNPs). Impressively, the ECL intensity of NH2-TiO2/UCNPs-rGO/GCE was remarkably enhanced by 29 times. Furthermore, the photoactive NH2-TiO2layer provided not only specific selectivity but also a large surface area as well as an unprecedented photocatalytic activity for the NH2-TiO2/UCNPs-rGO/GCE ECL sensor (TIECLS), which could serve as an identification element for trace phosphoproteins. Under optimal conditions, the TIECLS achieved a relatively low detection limit of 9.2 × 10–5mg/mL (S/N= 3). Practical application of this TIECLS was carried out in different food samples with satisfying results, which were validated by laser desorption ionization–time-of-flight mass spectrometry (MALDI-TOF MS).

Rapid and high-sensitive detection of mycotoxins is believed to be of vital importance in assuring food safety. In this study, we developed a novel fluorescence immunochromatographic sensor (ICS) for the mycotoxin of zearalenone (ZEN) in cereals. This was done by using a black phosphorus-Au nanocomposite (BP-Au) as the 2D quenching platform. Herein, gold nanoparticles (AuNPs) were directly reduced on the surface of BP nanosheets (BPNSs) to form BP-Au nanocomposites, showing higher fluorescence (quantum dots, λEm= 525 nm) quenching efficiency compared to the BPNSs and AuNPs. The fluorescence quenching efficiency of the prepared BP-Au nanocomposite reached 73.8%, which was 1.73-fold and 1.44-fold higher than AuNPs and BPNSs, respectively. The density functional theory was also successfully used to explore the formation mechanism of the BP-Au nanocomposite. By introducing the quantum dots/BP-Au signal/quencher pair, a high-sensitive fluorescence quenching ICS (B-FICS) was developed for the detection and discrimination of ZEN with the limit of detection of 0.1 μg/l in pure working buffer. This was 2.5-fold more sensitive than AuNPs-based FICS (A-FICS). The B-FICS was successfully applied in real cereals detection with the sample limit of detection of 2 μg/kg. The successful construction of B-FICS offers a novel method for a rapid and high-sensitive detection of ZEN in cereals. It also provides a new practical application of 2D BPNSs in food safety sensing.

Hematopoietic system is one of the main target organs of irradiation injury. Exposure to radiation can cause acute myelosuppression and long-term hematopoietic injury due to the direct and indirect damage of hematopoietic stem cells (HSCs) that can self-renew and differentiate into all types of blood cells. So far, many factors in the modulation of HSC biology at steady status have been revealed, while how to orchestrate HSCs in the context of radiation has not been well established. Recently, an increasing number of studies focus on the underlying mechanisms involved in regulating HSC fate after radiation exposure by affecting DNA damage response (DDR), including DNA-damage repair, cell-cycle arrest, apoptosis and senescence, or bone marrow (BM) microenvironment. In this review, we summarize recent findings on intrinsic and extrinsic factors in the regulation of HSC fate after radiation exposure, which may further deepen our understanding of the radioprotection of HSCs.

•Gradient-doped Yb: YAG green bodies have been fabricated by active mixing 3D printing.•Highly transparent gradient-doped Yb: YAG laser ceramic with 82.1 % in-line transmittance at 1100 nm has been obtained.•A 1030 nm laser output with an output power of 4.5 W with a slope efficiency of 41.3 % has been achieved pumped with 940 nm laser diode.

Cholangiocarcinoma (CCA) is characterized by early distant invasion and metastasis, whereas the underlying mechanism is still obscure. Increasing evidence shows that collagen type Ι alpha 1 (COL1A1) is a gene associated with the progression of multiple diseases. Here, we attempted to investigate the role of COL1A1 in CCA.

The activation and execution of cancer invasion and metastasis involves a complex network of intracellular and extracellular molecule levels (such as reactive oxygen species (ROS), matrix metalloproteinases (MMPs)) and signaling cascades. Fluorescence sensing is a powerful detection tool for analytes. However, for imaging the intracellular signal cascades involving multiple molecules, traditional fluorescence probes are unsuitable, because most of them can only determine the change of species rather than response of multiple species simultaneously. Herein we constructed a novel probe: a H2O2-responding fluorophore donor was linked to a MMP2-sensitive peptide tagged with a FRET Cy5 acceptor. Upon addition of H2O2, the system was subjected to green fluorescence emission (555 nm), further triggering a brighter red fluorescent emission (672 nm, belonging to Cy5 acceptor), owing to FRET. In contrast, in the presence of MMP2, the FRET was turned off, due to the special cleavage of the peptide linker. The stimulation with H2O2made the probe-loaded living cells emit multicolor fluorescence, mainly red fluorescence in normal RAW264.7 cells and poorly invasive MCF7 cells, and only green fluorescence in highly invasive MDA-MA-231 cells, owing to overexpressed MMP2. This means that after the activation with H2O2, the probe can be used to distinguish MDA-MA-231 cells from RAW264.7 macrophages and MCF7 cells. Therefore, this multicolor fluorescent probe is a powerful tool in monitoring cancer invasion and metastasis, which will provide precision information for cancer control and cure.