Enhanced Direct Exchange Interaction and Hybridization by Single-Atom Linkers for High Curie Temperature and Superior Visible-Light Harvesting in Cr3(CN3)2.

Designing two-dimensional (2D) ferromagnetic (FM) semiconductors with elevated Curie temperature, high carrier mobility, and strong light harvesting is challenging but crucial to the development of spintronics with multifunctionalities. Herein, we show first-principles computation evidence of the 2D metal-organic framework Kagome ferromagnet Cr3(CN3)2. Monolayer Cr3(CN3)2 is predicted to be an FM semiconductor with a record-high Curie temperature of 943 K owing to the use of a single-atom linker (N), which results in strong direct d-p exchange interaction and hybridization between dyz/xz and pz of Cr and N, as well as excellent matching characteristics in energy and symmetry. The single-atom linker structural feature also leads to notable band dispersion and a relatively high carrier mobility of 420 cm2 V-1 s-1. Moreover, under the in-plane strain, 2D Cr3(CN3)2 can be tuned to possess a strong visible-light-harvesting functionality. These novel properties render monolayer Cr3(CN3)2 a distinct 2D ferromagnet with high potential for the development of multifunctional spintronics.

GCN5 mediates DNA-PKcs crotonylation for DNA double-strand break repair and determining cancer radiosensitivity.

BACKGROUND: DNA double-strand break (DSB) induction and repair are important events for determining cell survival and the outcome of cancer radiotherapy. The DNA-dependent protein kinase (DNA-PK) complex functions at the apex of DSBs repair, and its assembly and activity are strictly regulated by post-translation modifications (PTMs)-associated interactions. However, the PTMs of the catalytic subunit DNA-PKcs and how they affect DNA-PKcs's functions are not fully understood. METHODS: Mass spectrometry analyses were performed to identify the crotonylation sites of DNA-PKcs in response to γ-ray irradiation. Co-immunoprecipitation (Co-IP), western blotting, in vitro crotonylation assays, laser microirradiation assays, in vitro DNA binding assays, in vitro DNA-PK assembly assays and IF assays were employed to confirm the crotonylation, identify the crotonylase and decrotonylase, and elucidate how crotonylation regulates the activity and function of DNA-PKcs. Subcutaneous xenografts of human HeLa GCN5 WT or HeLa GCN5 siRNA cells in BALB/c nude mice were generated and utilized to assess tumor proliferation in vivo after radiotherapy. RESULTS: Here, we reveal that K525 is an important site of DNA-PKcs for crotonylation, and whose level is sharply increased by irradiation. The histone acetyltransferase GCN5 functions as the crotonylase for K525-Kcr, while HDAC3 serves as its dedicated decrotonylase. K525 crotonylation enhances DNA binding activity of DNA-PKcs, and facilitates assembly of the DNA-PK complex. Furthermore, GCN5-mediated K525 crotonylation is indispensable for DNA-PKcs autophosphorylation and the repair of double-strand breaks in the NHEJ pathway. GCN5 suppression significantly sensitizes xenograft tumors of mice to radiotherapy. CONCLUSIONS: Our study defines K525 crotonylation of DNA-PKcs is important for the DNA-PK complex assembly and DSBs repair activity via NHEJ pathway. Targeting GCN5-mediated K525 Kcr of DNA-PKcs may be a promising therapeutic strategy for improving the outcome of cancer radiotherapy.

Strong Interfacial Chemical Bonding in Regulating Electron Transfer and Stabilizing Catalytic Sites in a Metal-Semiconductor Schottky Junction for Enhanced Photocatalysis.

The weak electronic interaction at metal-photocatalyst heterointerfaces often compromises solar-to-fuel performance. Here, a trifunctional Schottky junction, involving chemically stabilized ultrafine platinum nanoparticles (Pt NPs, ≈3 nm in diameter) on graphitic carbon nitride nanosheets (CNs) is proposed. The Pt-CN electronic interaction induces a 1.5% lattice compressive strain in Pt NPs and maintains their ultrafine size, effectively preventing their aggregation during photocatalytic reactions. Density functional theory calculations further demonstrate a significant reduction in the Schottky barrier at the chemically bonded CN-Pt heterointerface, facilitating efficient interfacial electron transfer, as supported by femtosecond transient absorption spectra (fs-TAS) measurements. The combined effects of lattice strain, stabilized Pt NPs, and efficient interfacial charge transport collaboratively enhance the photocatalytic performance, leading to over an 11-fold enhancement in visible light H2 production (8.52 mmol g-1 h-1) compared to the CN nanosheets with the in situ photo-deposited Pt NPs (0.76 mmol g-1 h-1). This study highlights the effectiveness of strong metal-semiconductor electronic interactions and underscores the potential for developing high-efficiency photocatalysts.

How two-child policy affects cesarean section in women with advanced maternal age (AMA): using the Robson classification system.

OBJECTIVES: To study the possible associations between advanced maternal age and cesarean section(CS) under the two child policy. METHODS: This study used a cohort study from Dongguan People's Hospital in Guangdong Province, China from 2017 to 2020. The cohort was restricted to women aged ≥ 20 who give birth to babies with a gestational age of > 28 weeks and a weight of > 1000 g. Divide the advanced maternal age (AMA) pregnant women into two age groups: 35-39 years old and 40 years old or older age. We analyzed CS rate and CS contribution using the modified Robson classification system. Frequency of cesarean was determined for each group and compared by using χ2 and prevalence ratio. RESULTS: Overall, 47654 women were included, of which 7924 (16.63%) were between the ages of 35 and 39, and 1529 (3.21%) were aged 40 or older. The total CS rate is 40.64%, with 36.10% for mothers aged 20 to 34, 57.90% for women aged 35 to 40, and 64.75% for women aged 40 or older age. In the AMA groups (n = 9453), Robson group 2' was the most common, followed by groups 5 and 10. Women at 40 years or older age were 3 times more likely to undergo a cesarean delivery in Robson group 1', and 1.76 times more likely in group 10. The CS rate in group 2' were statistically significantly higher in the very AMA group. CONCLUSIONS: The CS rates increased noticeably with maternal age under the two child policy. Based on the modified Robson classification system, AMA women should pay more attention to primiparous women with single pregnancy, uterine scars, and premature birth in multiple pregnancies.

H2S-driven chemotherapy and mild photothermal therapy induced mitochondrial reprogramming to promote cuproptosis.

The elevated level of hydrogen sulfide (H2S) in colon cancer hinders complete cure with a single therapy. However, excessive H2S also offers a treatment target. A multifunctional cascade bioreactor based on the H2S-responsive mesoporous Cu2Cl(OH)3-loaded hypoxic prodrug tirapazamine (TPZ), in which the outer layer was coated with hyaluronic acid (HA) to form TPZ@Cu2Cl(OH)3-HA (TCuH) nanoparticles (NPs), demonstrated a synergistic antitumor effect through combining the H2S-driven cuproptosis and mild photothermal therapy. The HA coating endowed the NPs with targeting delivery to enhance drug accumulation in the tumor tissue. The presence of both the high level of H2S and the near-infrared II (NIR II) irradiation achieved the in situ generation of photothermic agent copper sulfide (Cu9S8) from the TCuH, followed with the release of TPZ. The depletion of H2S stimulated consumption of oxygen, resulting in hypoxic state and mitochondrial reprogramming. The hypoxic state activated prodrug TPZ to activated TPZ (TPZ-ed) for chemotherapy in turn. Furthermore, the exacerbated hypoxia inhibited the synthesis of adenosine triphosphate, decreasing expression of heat shock proteins and subsequently improving the photothermal therapy. The enriched Cu2+ induced not only cuproptosis by promoting lipoacylated dihydrolipoamide S-acetyltransferase (DLAT) heteromerization but also performed chemodynamic therapy though catalyzing H2O2 to produce highly toxic hydroxyl radicals ·OH. Therefore, the nanoparticles TCuH offer a versatile platform to exert copper-related synergistic antitumor therapy.

Design and synthesis of doublecortin-like kinase 1 inhibitors and their bioactivity evaluation.

Doublecortin-like kinase 1 (DCLK) is a microtubule-associated serine/threonine kinase that is upregulated in a wide range of cancers and is believed to be related to tumour growth and development. Upregulated DCLK1 has been used to identify patients at high risk of cancer progression and tumours with chemotherapy-resistance. Moreover, DCLK1 has been identified as a cancer stem cell (CSC) biomarker in various cancers, which has received considerable attention recently. Herein, a series of DCLK1 inhibitors were prepared based on the previously reported XMD8-92 structure. Among all the synthesised compounds, D1, D2, D6, D7, D8, D12, D14, and D15 showed higher DCLK1 inhibitory activities (IC50 40-74 nM) than XMD8-92 (IC50 161 nM). Compounds D1 and D2 were selective DCLK1 inhibitors as they showed a rather weak inhibitory effect on LRRK2. The antiproliferative activities of these compounds were also preliminarily evaluated. The structure-activity relationship revealed by our compounds provides useful guidance for the further development of DCLK1 inhibitors.

High-Sensitivity Differential Sensor for Characterizing Complex Permittivity of Liquids Based on LC Resonators.

This paper proposes a high-sensitivity microstrip differential sensor for measuring the complex permittivity of liquids. The prototype of the differential sensor was formed by cascading two LC resonators on a microstrip transmission line based on stepped impedance. A strong electric field was found to be distributed in the circular patch of the LC resonator; therefore, a cylindrical micropore was set in the center of the circular LC resonator to measure the dielectric sample, which maximized the disturbance of the dielectric sample on the sensor. By optimizing the size of the circular LC resonator, a high-sensitivity sensor circuit was designed and manufactured. The complex permittivity of the test sample was calculated by measuring the transmission coefficient of different molar concentrations of ethanol-water solutions. The experimental results show that the designed differential sensor can accurately measure the complex permittivity of liquid materials with an average sensitivity of 0.76%.

Stereocontrolled Synthesis of α-3-Deoxy-d-manno-oct-2-ulosonic Acid (α-Kdo) Glycosides Using C3-p-Tolylthio-Substituted Kdo Donors: Access to Highly Branched Kdo Oligosaccharides.

3-Deoxy-d-manno-oct-2-ulosonic acid (Kdo) is an eight-carbon monosaccharide found widely in bacterial lipopolysaccharides (LPSs) and capsule polysaccharides (CPSs). We developed an indirect method for the stereoselective synthesis of α-Kdo glycosides with a C3-p-tolylthio-substituted Kdo phosphite donor. The presence of the p-tolylthio group enhanced the reactivity, suppressed the formation of elimination by-products (2,3-enes), and provided complete α-stereocontrol. A variety of Kdo α-glycosides were synthesized by our method in excellent yields (up to 98 %). After glycosylation, the p-tolylthio group can be efficiently removed by free-radical reduction. Subsequently, the orthogonality of the phosphite donor and thioglycoside donor was demonstrated by the one-pot synthesis of a trisaccharide in Helicobacter pylori and Neisseria meningitidis LPS. Moreover, an efficient total synthesis route to the challenging 4,5-branched Kdo trisaccharide in LPSs from several A. baumannii strains was highlighted. To demonstrate the high reactivity of our approach further, the highly crowded 4,5,7,8-branched Kdo pentasaccharide was synthesized as a model molecule for the first time. Additionally, the reaction mechanism was investigated by DFT calculations.

Promoting CO2 Electroreduction to Hydrocarbon Products via Sulfur-Enhanced Proton Feeding in Atomically Precise Thiolate-Protected Cu Clusters.

Thiolate-protected Cu clusters with well-defined structures and stable low-coordinated Cu+ species exhibit remarkable potential for the CO2RR and are ideal model catalysts for establishing structure-electrocatalytic property relationships at the atomic level. However, extant Cu clusters employed in the CO2RR predominantly yield 2e- products. Herein, two model Cu4(MMI)4 and Cu8(MMI)4(tBuS)4 clusters (MMI=2-mercapto-1-methylimidazole) are prepared to investigate the synergistic effect of Cu+ and adjacent S sites on the CO2RR. Cu4(MMI)4 can reduce CO2 to deep-reduced products with a 91.0 % Faradaic efficiency (including 53.7 % for CH4) while maintaining remarkable stability. Conversely, Cu8(MMI)4(tBuS)4 shows a remarkable preference for C2+ products, achieving a maximum FE of 58.5 % with a C2+ current density of 152.1 mA⋅cm-2. In situ XAS and ex situ XPS spectra reveal the preservation of Cu+ species in Cu clusters during CO2RR, extensively enhancing the adsorption capacity of *CO intermediate. Moreover, kinetic analysis and theoretical calculations confirm that S sites facilitate H2O dissociation into *H species, which directly participate in the protonation process on adjacent Cu sites for the protonation of *CO to *CHO. This study highlights the important role of Cu-S dual sites in Cu clusters and provides mechanistic insights into the CO2RR pathway at the atomic level.

Harnessing 4f Electron Itinerancy for Integrated Dual-Band Redox Systems Boosts Lithium-Oxygen Batteries Electrocatalysis.

In-depth comprehension and manipulation of band occupation at metal centers are crucial for facilitating effective adsorption and electron transfer in lithium-oxygen battery (LOB) reactions. Rare earth elements play a unique role in band hybridization due to their deep orbitals and strong localization of 4f electrons. Herein, we anchor single Ce atoms onto CoO, constructing a highly active and stable catalyst with d-f a dual-band redox center. It is discovered that the itinerant behavior of 4f electrons introduces an enhanced spin-orbit coupling effect, which facilitates ideal σ/π bonding and flexible adsorption between the Ce/Co active sites and *O. Simultaneously, the injection of localized Ce 4f electrons strengthens the orbital bonding capacity of Co-O, effectively inhibits the dissolution of Co sites and improves the structural stability of the cathode material. Bracingly, the Ce1/CoO-based LOB exhibits an ultra-low charge-discharge polarization (0.46 V) and stable cyclic performance (1088 hours). This work breaks through the traditional limitations in catalyst activity and stability, providing new strategies and theoretical insights for developing high-performance LOBs powered by rare-earth elements.

Oxfendazole Induces Apoptosis in Ovarian Cancer Cells by Activating JNK/MAPK Pathway and Inducing Reactive Oxygen Species Generation.

Ovarian cancer (OC) is one of the most common and high mortality type of cancer among women worldwide. The majority of patients with OC respond to chemotherapy initially; however, most of them become resistant to chemotherapy and results in a high level of treatment failure in OC. Therefore, novel agents for the treatment of OC are urgently required. Benzimidazole anthelmintics might have the promising efficacy for cancer therapy as their selectively binding activity to ß-tubulin. Recent study has shown that one of the benzimidazole anthelmintics oxfendazole inhibited cell growth of non-small cell lung cancer cells, revealing its anti-cancer activity; however, the pharmacological action and detailed mechanism underlying the effects of oxfendazole on OC cells remain unclear. Therefore, the present study investigated the cytotoxic effects of oxfendazole on OC cells. Our results demonstrated that oxfendazole significantly decreased the viability of OC cells. Oxfendazole inhibited the proliferation, induced G2/M phase arrest and apoptotic cell death in A2780 cells. The c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) pathway was activated and reactive oxygen species (ROS) generation was increased in OC cells treated with oxfendazole; oxfendazole-induced apoptosis was notably abrogated when co-treated with JNK inhibitor SP600125 and ROS scavenger N-acetyl-L-cysteine (NAC), indicating that JNK/MAPK pathway activation and ROS accumulation was associated with the oxfendazole-induced apoptosis of OC cells. Moreover, oxfendazole could also induce the proliferation inhibition and apoptosis of cisplatin resistant cells. Collectively, these results revealed that oxfendazole may serve as a potential therapeutic agent for the treatment of OC.

Humanized mouse models for inherited thrombocytopenia studies.

Inherited thrombocytopenia (IT) is a group of hereditary disorders characterized by a reduced platelet count as the main clinical manifestation, and often with abnormal platelet function, which can subsequently lead to impaired hemostasis. In the past decades, humanized mouse models (HMMs), that are mice engrafted with human cells or genes, have been widely used in different research areas including immunology, oncology, and virology. With advances of the development of immunodeficient mice, the engraftment, and reconstitution of functional human platelets in HMM permit studies of occurrence and development of platelet disorders including IT and treatment strategies. This article mainly reviews the development of humanized mice models, the construction methods, research status, and problems of using humanized mice for the in vivo study of human thrombopoiesis.

Humanized mouse models (HMMs) refer to immunodeficient mice that have been used for the investigation of human hematopoiesis and immunity for years. With engrafted human hematopoietic stem cells (HSCs), the differentiation process of HSCs and re-construction of platelets can be monitored in the mice. Until now, several strains of HMMs have been used in the studies of inherited thrombocytopenia (IT), a genetic disorder associated with low platelet count in the blood. In this study, we reviewed the development of these HMMs in IT studies, compared the different sources of HSCs transplanted into HMMs and summarize the strategies of HSC transplantation in HMMs. The Kit^−/− immunodeficient mice showed effectively long-term and stable implantation of human HSC without irradiation and higher implantation levels, and they also support multilinear differentiation of human HSC, such as platelets and red blood cells. The source and count of HSCs and the transplantation strategy may also impact the result. This study provides a basis information for HMMs used in IT and will help other investigators in this field choosing the right research plan.

Microvascular and neural alterations in carotid cavernous fistulas: An optical coherence tomography angiography study.

BACKGROUND: Current modalities for diagnosing carotid cavernous fistula (CCF) are inaccurate in analysing retinal microcirculations and nerve fibre changes. Retinal microvascular and neural alterations occur in CCF patients and can be quantitatively measured using optical coherence tomography angiography (OCTA). We measured the neurovascular changes in the eyes of CCF patients and used OCTA as a supplementary method. METHODS: This cross-sectional study studied 54 eyes of 27 unilateral CCF subjects and 54 eyes of 27 healthy age- and sex-matched controls. OCTA parameters in the macula and optic nerve head (ONH) were analysed using a one-way analysis of variance with further Bonferroni corrections. Parameters with statistical significance were included in a multivariable binary logistic regression analysis and receiver operating characteristic (ROC) curves were generated. RESULTS: There was significantly less deep-vessel density (DVD) and ONH-associated capillary density in both eyes of CCF patients than in controls, while the differences between the affected and contralateral eyes were insignificant. The retinal nerve fibre layer and ganglion cell complex thickness were lower in the affected eyes than in the contralateral or controlled eyes. ROC curves identified DVD and ONH-associated capillary density as significant parameters in both eyes of CCF patients. CONCLUSION: The retinal microvascular circulation was affected in both eyes of unilateral CCF patients. Microvascular alterations occurred before retinal neural damage. This quantitative study suggests a supplementary measurement for diagnosing CCF and detecting early neurovascular impairments.

Design, Synthesis, and Antitumor Activity Evaluation of Proteolysis-Targeting Chimeras as Degraders of Extracellular Signal-Regulated Kinases 1/2.

Inhibition of the extracellular signal-regulated kinases 1/2 (ERK1/2) alone or in combination with other targets has emerged as a promising treatment strategy for a variety of human tumors. In addition to the development of inhibitors, the development of ERK1/2 degraders is an alternative approach to decrease its activity. We synthesized proteolysis-targeting chimeras (PROTACs) as effective ERK1/2 degraders, among which B1-10J showed high degradative activity, with DC50 of 102 nM and cytotoxic IC50 of 2.2 µM against HCT116 cells. Moreover, B1-10J dose-dependently inhibited tumor cell migration. Xenograft experiments in nude mice demonstrated that B1-10J inhibited HCT116 tumor cell growth and achieved significant regression of tumors at a daily dose of 25 mg/kg.

mech2d: An Efficient Tool for High-Throughput Calculation of Mechanical Properties for Two-Dimensional Materials.

Two-dimensional (2D) materials have been a research hot topic in the passed decades due to their unique and fascinating properties. Among them, mechanical properties play an important role in their application. However, there lacks an effective tool for high-throughput calculating, analyzing and visualizing the mechanical properties of 2D materials. In this work, we present the mech2d package, a highly automated toolkit for calculating and analyzing the second-order elastic constants (SOECs) tensor and relevant properties of 2D materials by considering their symmetry. In the mech2d, the SOECs can be fitted by both the strain-energy and stress-strain approaches, where the energy or strain can be calculated by a first-principles engine, such as VASP. As a key feature, the mech2d package can automatically submit and collect the tasks from a local or remote machine with robust fault-tolerant ability, making it suitable for high-throughput calculation. The present code has been validated by several common 2D materials, including graphene, black phosphorene, GeSe2 and so on.

Iron parameters in pregnant women with beta-thalassaemia minor combined with iron deficiency anaemia compared to pregnant women with iron deficiency anaemia alone demonstrate the safety of iron supplementation in beta-thalassaemia minor during pregnancy.

In patients with beta-thalassaemia intermedia or major, hepcidin induces iron overload by continuously promoting iron absorption. There have been no studies in pregnant women with beta-thalassaemia minor combined with iron deficiency anaemia (IDA), examining whether hepcidin is inhibited by GDF15, as may occur in patients with beta-thalassaemia intermedia or major, or whether the iron metabolism characteristics and the effect of iron supplementation are consistent with simple IDA in pregnancy. We compared and analysed routine blood parameters, iron metabolism parameters, the GDF15 levels, and the hepcidin levels among four groups, namely the beta-thalassaemia (ß) + IDA, ß, IDA, and normal groups. In addition, the ß + IDA and IDA groups received iron supplementation for four weeks. We found no statistically significant correlation between hepcidin and GDF15 in any group, but a positive correlation was observed between hepcidin and ferritin. After iron supplementation, the routine blood parameters and iron metabolism parameters in the ß + IDA group were improved, and the hepcidin content was significantly increased. These results suggest that in pregnant women with beta-thalassaemia minor, hepcidin functions normally to maintain iron homeostasis, and that iron supplementation is effective and safe.

Potential biomarkers for inherited thrombocytopenia 2 identified by plasma proteomics.

Inherited thrombocytopenia 2 (THC2) is difficult to diagnose due to the lack of specific clinical characteristics and diagnostic methods. To identify potential plasma protein biomarkers for THC2, we collected the plasma samples from a THC2 family (9 THC2 and 15 non-THC2 members), enriched the medium and low abundant proteins using Proteominer and analyzed the protein profiles using the liquid chromatography-mass spectrometry in data independent acquisition mode. Initially, we detected 784 proteins in the plasma samples of this family and identified 27 up-regulated and 36 down-regulated in the THC2 group compared to the non-THC2 group (|log2 ratio| >1 and p-value <0.05). To improve the predictive power, top eight dysregulated proteins (B7Z2B4, LTF, HP, ERN1, IGHV1-8, A0A0X9V9C4, VH6DJ, and D3JV41) were selected by an area under the curve-based random forest process to construct a clinical model. Multivariate analysis with random forest and support vector machine showed that the prediction model provided high discrimination ability for THC2 diagnosis (AUC: 1.000 and 0.967, respectively). The potential plasma protein biomarkers will be tested in more THC2 patients and other thrombocytopenia patients to further validate their specificity and sensitivity.

EloA promotes HEL polyploidization upon PMA stimulation through enhanced ERK1/2 activity.

Megakaryocytes (MKs) are the unique non-pathological cells that undergo polyploidization in mammals. The polyploid formation is critical for understanding the MK biology, and transcriptional regulation is involved in the differentiation and maturation of MKs. However, little is known about the functions of transcriptional elongation factors in the MK polyploidization. In this study, we investigated the role of transcription elongation factor EloA in the polyploidy formation during the MK differentiation. We found that EloA was highly expressed in the erythroleukemia cell lines HEL and K562. Knockdown of EloA in HEL cell line was shown to impair the phorbol myristate acetate (PMA) induced polyploidization process, which was used extensively to model megakaryocytic differentiation. Selective over-expression of EloA mutants with Pol II elongation activity partially restored the polyploidization. RNA-sequencing revealed that knockdown of EloA decelerated the transcription of genes enriched in the ERK1/2 cascade pathway. The phosphorylation activity of ERK1/2 decreased upon the EloA inhibition, and the polyploidization process of HEL was hindered when ERK1/2 phosphorylation was inhibited by PD0325901 or SCH772984. This study evidenced a positive role of EloA in HEL polyploidization upon PMA stimulation through enhanced ERK1/2 activity.

CRIF1 as a potential target to improve the radiosensitivity of osteosarcoma.

Resistance to ionizing radiation (IR), which is a conventional treatment for osteosarcoma that cannot be resected, undermines the efficacy of this therapy. However, the mechanism by which IR induces radioresistance in osteosarcoma is not defined. Here, we report that CR6-interacting factor-1 (CRIF1) is highly expressed in osteosarcoma and undergoes nuclear-cytoplasmic shuttling of cyclin-dependent kinase 2 (CDK2) after IR. Osteosarcoma cells lacking CRIF1 show increased sensitivity to IR, which is associated with delayed DNA damage repair, inactivated G1/S checkpoint, and mitochondrial dysfunction. CRIF1 interacts with the DNA damage checkpoint regulator CDK2, and CRIF1 and CDK2 colocalize in the nucleus after IR. Nuclear localization of CDK2 is associated with phosphorylation changes that promote DNA repair and activation of the G1/S checkpoint. CRIF1 knockdown synergized with IR in an in vivo osteosarcoma model, leading to tumor regression. Based on these findings, we identify CRIF1 as a potential therapeutic target in osteosarcoma that can increase the efficacy of radiotherapy. More broadly, our findings may provide insights into the mechanism for other types of radioresistant cancers and be exploited for therapeutic ends.

In Utero Exposure to Fine Particles Decreases Early Birth Weight of Rat Offspring and TLR4/NF-κB Expression in Lungs.

Particulate matter (PM2.5) exposure is reported to have deleterious effects on health. Maternal PM2.5 exposure has been confirmed to damage the growth of somatic cells and enhance the incidence of chronic respiratory diseases in children. Here we aim to investigate the impact of in utero PM2.5 exposure on early birth weight and postnatal lung development. Pregnant Sprague-Dawley rats were administered PM2.5 (0.1, 0.5, 2.5, or 7.5 mg/kg) intraperitoneally every 3 days until birth. Maternal and birth outcomes and somatic growth were monitored. Lungs were collected on PND1 (where PND = postnatal day) and PND28; the lung wet-to-dry weight ratio (W/D) was analyzed, and reactive oxygen species (ROS) levels were measured. Expression of Toll-like receptor 4 (TLR4) and NF-κB were evaluated by Western blotting and quantitative RT-PCR. There were no significant intergroup differences for maternal outcomes; however, offspring exposed in utero to 2.5 and 7.5 mg/kg PM2.5 were significantly smaller in litter weight than the controls. In utero exposure to 2.5 and 7.5 mg/kg PM2.5 led to lower body weight after birth and disrupted lung development during infancy. ROS levels were significantly increased in the 7.5 mg/kg PM2.5 group. PM2.5-treated rats showed upregulated pulmonary expression of TLR4 and NF-κB. Maternal PM2.5 exposure enhances the risk of low birth weight and affects lung alveolar development. The underlying molecular mechanisms may involve TLR4/NF-κB signaling.