Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes.

Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. C1q activates canonical Wnt signaling by binding to Frizzled receptors and subsequently inducing C1s-dependent cleavage of the ectodomain of Wnt coreceptor low-density lipoprotein receptor-related protein 6. Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging.

The red flower wintersweet genome provides insights into the evolution of magnoliids and the molecular mechanism for tepal color development.

Wintersweet (Chimonanthus praecox) is one of the most important ornamental plants. Its color is mainly determined by the middle tepals. However, the molecular mechanisms underlying the intriguing flower color development among different wintersweet groups are still largely unknown. In addition, wintersweet belongs to magnoliids, and the phylogenetic position of magnoliids remains to be determined conclusively. Here, the whole genome of red flower wintersweet, a new wintersweet type, was sequenced and assembled with high quality. The genome comprised 11 super-scaffolds (chromosomes) with a total size of 737.03 Mb. Based on the analyses of the long branch attraction, incomplete lineage sorting, sparse taxon sampling, and other factors, we suggest that a bifurcating tree may not fully represent the complex early diversification of the angiosperms and that magnoliids are most likely sister to the eudicots. The wintersweet genome appears to have undergone two whole-genome duplication (WGD) events: a recent WGD event representing an independent event specific to the Calycanthaceae and an ancient WGD event shared by Laurales. By integrating genomic, transcriptomic, and metabolomic data, CpANS1 and the transcription factor CpMYB1 were found to play key roles in regulating tepal color development, whereas CpMYB1 needs to form a complex with bHLH and WD40 to fully perform its regulatory function. The present study not only provides novel insights into the evolution of magnoliids and the molecular mechanism for flower color development, but also lays the foundation for subsequent functional genomics study and molecular breeding of wintersweet.

NOD1 modulates decidual stromal cell function to maintain pregnancy in the early trimester.

We sought to explore the functions and modulated factors of NOD1 in normal decidual stromal cells (DSCs) derived from the first trimester pregnancy and whether existed different expression of NOD1 between normal and unexplained recurrent pregnancy loss (URPL) in DSCs. Twenty-six patients with normal pregnancies that required abortion and 12 URPL patients at first trimester were enrolled for the study. As a result, we found lower levels of NOD1 in the DSCs derived from URPL compared with those from normal early trimester pregnancy. Furthermore, increased NOD1 expression in the normal DSCs induced apoptosis and increased monocyte chemotactic protein-1 (MCP-1) and IL-1ß (interleukin 1 beta) secretion but decreased their invasion capacity. In addition, several cytokines such as IL-1ß, tumour necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-17 (IL-17) were present at the maternal-fetal interface in RPL and were found to regulate NOD1 expression in primary DSCs. Our study indicates that RPL may be associated with NOD1 aberrant expression in DSCs, which plays a significant role in maintaining pregnancy via infection control and regulation of immune responses that might affect the pregnancy outcome. We expect that our results will bring more comprehensively understanding about the connection between NOD1 and RPL for researchers.

Effectiveness and potential mechanisms of intralipid in treating unexplained recurrent spontaneous abortion.

AIM: Abnormal natural killer (NK) cell activity has been suggested to be a high-risk factor associated with unexplained recurrent spontaneous abortion (URSA). Intralipid, like immunoglobulin, is able to lower the activity of NK cells, which has been reported to be useful for improving URSA outcomes in pregnancy. This study aimed to determine whether intralipid could be used as an alternative treatment to intravenous immunoglobulin (IVIG) which is expensive and has many side-effects. METHODS: A prospective, randomized clinical trial was conducted from December 2010 to December 2012. Eligible participants were matched and sorted randomly into the intralipid and the IVIG group. The primary outcome was the rate of successful pregnancy. In addition, comparisons of peripheral NK cell activities were accessed by flow cytometry. Moreover, the effects of intralipid on trophoblasts were investigated using a Matrigel assay with the JEG-3 cell line. RESULTS: Seventy-six patients in the intralipid group and 78 in the IVIG group completed the trial. There were no statistically significant differences in successful pregnancy rates between the two groups (92.1 vs 88.2 %, P = 0.415). The reduced NK cell concentrations revealed the cytotoxic effects of the treatments in both groups. The invasive ability of JEG-3 cells was inhibited during co-culture with patient PBMCs. However, the inhibitory effect could be alleviated if the patient PBMCs were stimulated with intralipid. CONCLUSIONS: Intralipid can be used as an alternative treatment to IVIG for URSA, and its potential mechanism of action may occur by regulating NK cell function and promoting trophoblast invasion.

Regeneration of the Cardiac Conduction System by Adipose Tissue-Derived Stem Cells.

BACKGROUND: Adipose tissue is one of the sources of mesenchymal stem cells, which have the potential to differentiate into various types of cells, including myocytes. Whether brown adipose tissue (BAT)-derived cells might differentiate into the cardiac pacemaking-conducting cells, and have the potential to regenerate the cardiac conduction system (CCS), is investigated in this study. METHODS AND RESULTS: BAT was isolated from the interscapular area of mice and enzymatically digested before culture. Round or fusiform cells showed spontaneous beating at 4-7 days after culturing of BAT-derived cells. Reverse transcriptase-polymerase chain reaction analysis and immunocytochemical analysis revealed that BAT-derived cells expressed several cardiomyocytes, the CCS and pacemaker (PM) cell marker genes and proteins. Patch-clamp techniques revealed that spontaneous electrical activity and the shape of the action potential showed properties of cardiac PM cells. Next, a complete atrioventricular (AV) block was created in mice and green fluorescent protein-positive (GFP (+)) BAT-derived cells were injected intramyocardially around the AV node. At 1 week after transplantation, 50% of BAT-derived cells injected mice showed a sinus rhythm or a 2:1 AV block. Immunohistochemical analysis revealed that injected GFP (+) cells were engrafted and some GFP (+) cells co-expressed several cardiac PM cell marker proteins. CONCLUSIONS: BAT-derived cells differentiate into the CCS and PM-like cells in vitro and in vivo, and may become a useful cell source for arrhythmia therapy.

Targeted radiosensitization with PARP1 inhibition: optimization of therapy and identification of biomarkers of response in breast cancer.

Sustained locoregional control of breast cancer is a significant issue for certain patients. Inhibition of PARP1 is a promising strategy for radiosensitization (RS). We sought to optimize therapy with PARP1 inhibition and radiation (RT) by establishing the most effective treatment schedule, degree of PARP1-mediated RS, and identify early biomarkers predictive of efficacy in breast cancer models. Using clonogenic survival assays, we assessed intrinsic radiosensitivity and RS induced by PARP1 inhibition in breast cancer cell lines. Potential biomarkers of response were evaluated using western blotting, flow cytometry, and immunofluorescence with validation in vivo using tumor xenograft experiments. Across a panel of BC and normal breast epithelial cell lines, the PARP1 inhibitor ABT-888 preferentially radiosensitizes breast cancer (vs. normal) cells with enhancement ratios (EnhR) up to 2.3 independent of intrinsic BC subtype or BRCA mutational status. Concurrent and adjuvant therapy resulted in the highest EnhR of all schedules tested. The degree of RS did not correlate with pretreatment markers of PARP1 activity, DNA damage/repair, or cell cycle distribution. Increases in PARP1 activity 24 h after RT were associated with sensitivity after combination treatment. Findings were confirmed in breast cancer xenograft models. Our study demonstrates that PARP1 inhibition improves the therapeutic index of RT independent of BC subtype or BRCA1 mutational status and that PARP1 activity may serve as a clinically relevant biomarker of response. These studies have led to a clinical trial (TBCRC024) incorporating intratreatment biomarker analyses of PARP1 inhibitors and RT in breast cancer patients.

Evaluation of the clinical efficacy of Zhuanggu Zhitong Recipe in treatment of postmenopausal osteoporosis and its correlation with the AMPK/mTOR autophagy signaling pathway.

OBJECTIVE: To evaluate the efficacy of bone strengthening and pain relieving capsules in the treatment of postmenopausal osteoporosis and its correlation with AMPK/mTOR autophagy signaling pathway. METHODS: Between January 2021 and December 2022, 100 patients with postmenopausal osteoporosis of liver-kidney yin deficiency and qi stagnation and blood stasis type were retrospectively screened in the outpatient and inpatient departments of the Department of Orthopaedics and Traumatology of Liuzhou Hospital of Traditional Chinese Medicine, Guangxi Zhuang Autonomous Region, and were randomly divided into 2 groups of 50 patients each according to the order of the timing of the consultation, namely, the Strong Bone Pain Relief Capsules Treatment Group and the Alendronate Sodium Control Group. Bone mineral density of the left femur, Chinese medicine evidence points, serum AMPK level, E2 level before and after treatment, Ca2+ level, IL-17, serum phosphorus level, ALP, PTH, OC, PINP, NTX and TRAP-5b level before and after drug intervention were detected in the two groups. RESULTS: Both groups achieved a lower TCM syndrome score, NRS score of low back pain, and AMPK level after treatment (P<0.001). Both groups had increased Ca2+ concentration and E2 level (P<0.001), and reduced IL-17 and serum P level (P<0.001). Both groups had significantly increased ALP, PTH, OC, PINP level, NTX and TRAP-5b level (P<0.001). The difference between the two groups was significant (P<0.05) and for TRAP-5b levels, (P<0.001). Efficacy for osteoporosis differed between the two groups (P<0.05). CONCLUSION: Strong Bone Pain Relief Capsules may negatively regulate the level of AMPK and increase the level of cellular autophagy so as to play a role in the improvement of osteoporosis.

Genome assembly and resequencing shed light on evolution, population selection, and sex identification in Vernicia montana.

Vernicia montana is a dioecious plant widely cultivated for high-quality tung oil production and ornamental purposes in the Euphorbiaceae family. The lack of genomic information has severely hindered molecular breeding for genetic improvement and early sex identification in V. montana. Here, we present a chromosome-level reference genome of a male V. montana with a total size of 1.29 Gb and a contig N50 of 3.69 Mb. Genome analysis revealed that different repeat lineages drove the expansion of genome size. The model of chromosome evolution in the Euphorbiaceae family suggests that polyploidization-induced genomic structural variation reshaped the chromosome structure, giving rise to the diverse modern chromosomes. Based on whole-genome resequencing data and analyses of selective sweep and genetic diversity, several genes associated with stress resistance and flavonoid synthesis such as CYP450 genes and members of the LRR-RLK family, were identified and presumed to have been selected during the evolutionary process. Genome-wide association studies were conducted and a putative sex-linked insertion and deletion (InDel) (Chr 2: 102 799 917-102 799 933 bp) was identified and developed as a polymorphic molecular marker capable of effectively detecting the gender of V. montana. This InDel is located in the second intron of VmBASS4, suggesting a possible role of VmBASS4 in sex determination in V. montana. This study sheds light on the genome evolution and sex identification of V. montana, which will facilitate research on the development of agronomically important traits and genomics-assisted breeding.

Clonal growth characteristics and diversity patterns of different Clintonia udensis (Liliaceae) diploid and tetraploid cytotypes in the Hualongshan Mountains.

Polyploidization plays an important role in plant evolution and biodiversity. However, intraspecific polyploidy compared to interspecific polyploidy received less attention. Clintonia udensis (Liliaceae) possess diploid (2n = 2x = 14) and autotetraploid (2n = 4x = 28) cytotypes. In the Hualongshan Mountains, the autotetraploids grew on the northern slope, while the diploids grew on the southern slopes. The clonal growth characteristics and clonal architecture were measured and analyzed by field observations and morphological methods. The diversity level and differentiation patterns for two different cytotypes were investigated using SSR markers. The results showed that the clonal growth parameters, such as the bud numbers of each rhizome node and the ratio of rhizome branches in the autotetraploids were higher than those in the diploids. Both the diploids and autotetraploids appeared phalanx clonal architectures with short internodes between ramets. However, the ramets or genets of the diploids had a relatively scattered distribution, while those of the autotetraploids were relatively clumping. The diploids and autotetraploids all allocated more biomass to their vegetative growth. The diploids had a higher allocation to reproductive organs than that of autotetraploids, which indicated that the tetraploids invested more resources in clonal reproduction than diploids. The clone diversity and genetic diversity of the autotetraploids were higher than that of the diploids. Significant genetic differentiation between two different cytotypes was observed (P < 0.01). During establishment and evolution, C. udensis autotetraploids employed more clumping phalanx clonal architecture and exhibited more genetic variation than the diploids.

Orientation selectivity mapping in the visual cortex.

The orientation map is one of the most well-studied functional maps of the visual cortex. However, results from the literature are of different qualities. Clear boundaries among different orientation domains and blurred uncertain distinctions were shown in different studies. These unclear imaging results will lead to an inaccuracy in depicting cortical structures, and the lack of consideration in experimental design will also lead to biased depictions of the cortical features. How we accurately define orientation domains will impact the entire field of research. In this study, we test how spatial frequency (SF), stimulus size, location, chromatic, and data processing methods affect the orientation functional maps (including a large area of dorsal V4, and parts of dorsal V1) acquired by intrinsic signal optical imaging. Our results indicate that, for large imaging fields, large grating stimuli with mixed SF components should be considered to acquire the orientation map. A diffusion model image enhancement based on the difference map could further improve the map quality. In addition, the similar outcomes of achromatic and chromatic gratings indicate two alternative types of afferents from LGN, pooling in V1 to generate cue-invariant orientation selectivity.

Longistylin A from Cajanus cajan (L.) Millsp. disturbs glycerophospholipid metabolism and cytokinin biosynthesis of Nocardia seriolae.

ETHNOPHARMACOLOGICAL RELEVANCE: Nocardiosis is an uncommon infectious disease that bears certain similarities to tuberculosis, with a continuous increase in its incidence and a poor prognosis. In traditional Chinese medicine, the leaves of Cajanus cajan (L.) Millsp. are employed to treat wounds, malaria, coughs, and abdominal pain. AIM OF THE STUDY: In this study, we investigated the effects and mechanisms of longistylin A (LGA), a natural stilbene isolated from C. cajan, as a potential antibiotic against nocardiosis. MATERIALS AND METHODS: LGA was isolated from the leaves of C. cajan and assessed using a minimum bactericidal concentration (MBC) determination against Nocardia seriolae. Multi-omics analysis encompassing genes, proteins, and metabolites was conducted to investigate the impact of LGA treatment on N. seriolae. Additionally, quantitative analysis of 40 cytokinins in N. seriolae mycelium was performed to assess the specific effects of LGA treatment on cytokinin levels. Cryo-scanning electron microscopy was utilized to examine morphological changes induced by LGA treatment, particularly in the presence of exogenous trans-zeatin-O-glucoside (tZOG). The therapeutic effect of LGA was investigated by feeding N. seriolae-infected largemouth bass. RESULTS: LGA exhibited significant efficacy against N. seriolae, with MBC value of 2.56 µg/mL. Multi-omics analysis revealed that LGA disrupted glycerophospholipid metabolism and hormone biosynthesis by notably reducing the expression of glycerol-3-phosphate dehydrogenase and calmodulin-like protein. Treatment with LGA markedly disrupted 12 distinct cytokinins in N. seriolae mycelium. Additionally, the addition of exogenous tZOG counteracted the inhibitory effects of LGA on filamentous growth, resulting in mycelial elongation and branching. Furthermore, LGA treatment improved the survival rate of largemouth bass infected with N. seriolae. CONCLUSIONS: We found for the first time that LGA from C. cajan exhibited significant efficacy against N. seriolae by interfering with glycerophospholipid metabolism and cytokinin biosynthesis.

[Modulation of low molecular weight heparin and heparin-binding epidermal growth factor on biological functions of human first trimester trophoblast].

OBJECTIVE: To evaluate the effects of low molecular weight heparin (LMWH) and heparin-binding epidermal growth factor (HB-EGF) on the biological function of human trophoblast in first trimester. METHODS: From Feb. 2011 to Nov. 2011, the trophoblast isolated from human first trimester chorionic villi was cultured in vitro. Based on variation of LMWH concentration, the trophoblast was classified into 0.025 U/ml group, 0.25 U/ml group, 2.5 U/ml group, 25 U/ml group and 250 U/ml group. In the mean time, based on treatment of heparin, the trophoblast was classified into LMWH group (0.25 U/ml), HB-EGF group (10 µg/L), combination group (LMWH at 0.25 U/ml + HB-EGF at 10 µg/L) and add with DMEM as control group. Cell proliferation was assessed by the methyl thiazolyl tetrazolium (MTT) test, which was showed with the mean absorbance as A value. Cell invasion was measured by transwell, which counted the number of cells migrated to the superficies inferia of filter membrane. Cell differentiation was assessed by the concentration of hCG secretion. RESULTS: Compared with control group, the trophoblast proliferation and invasion treated by LMWH at 0.025 U/ml did not show significant difference (P > 0.05). When treated by LWMH at 0.25 U/ml and 2.5 U/ml, trophoblast proliferation and invasion was increased significantly (P < 0.05). When LMWH at 25 U/ml and 250 U/ml, it could inhibit trophoblast proliferation and invasion (P < 0.05). When compared with A value of 0.44 ± 0.04 in control group, the increased A value were 0.51 ± 0.05 in LMWH group, 0.56 ± 0.04 in HB-EGF group and 0.69 ± 0.06 in combination group (P < 0.05). In the transwell test, the cell number were 511 ± 78 in LMWH group, 669 ± 67 in HB-EGF group and 872 ± 64 in combination group, which were significantly higher than 405 ± 67 in control group (P < 0.05), respectively. And the hCG concentration were (7143 ± 649) U/L in LMWH group, (11 762 ± 1059) U/L in HB-EGF group and (11 015 ± 1084) U/L in combination group, which showed statistical difference with (8182 ± 666) U/L in control group (P < 0.05). CONCLUSION: LMWH could modulate trophoblast proliferation, invasion, and differentiation. HB-EGF is one of important factors involved in effects of LMWH on trophoblast function.

Phylogenetic Analysis of the PR-4 Gene Family in Euphorbiaceae and Its Expression Profiles in Tung Tree (Vernicia fordii).

Pathogenesis-related protein-4 (PR-4) is generally believed to be involved in physiological processes. However, a comprehensive investigation of this protein in tung tree (Vernicia fordii) has yet to be conducted. In this study, we identified 30 PR-4 genes in the genomes of Euphorbiaceae species and investigated their domain organization, evolution, promoter cis-elements, expression profiles, and expression profiles in the tung tree. Sequence and structural analyses indicated that VF16136 and VF16135 in the tung tree could be classified as belonging to Class II and I, respectively. Phylogenetic and Ka/Ks analyses revealed that Hevea brasiliensis exhibited a significantly expanded number of PR-4 genes. Additionally, the analysis of promoter cis-elements suggested that two VfPR-4 genes may play a role in the response to hormones and biotic and abiotic stress of tung trees. Furthermore, the expression patterns of VfPR-4 genes and their responses to 6-BA, salicylic acid, and silver nitrate in inflorescence buds of tung trees were evaluated using qRT-PCR. Notably, the expression of two VfPR-4 genes was found to be particularly high in leaves and early stages of tung seeds. These results suggest that VF16136 and VF16135 may have significant roles in the development of leaves and seeds in tung trees. Furthermore, these genes were found to be responsive to 6-BA, salicylic acid, and silver nitrate in the development of inflorescence buds. This research provides valuable insights for future investigation into the functions of PR-4 genes in tung trees.

Promotion of CHIP-mediated p53 degradation protects the heart from ischemic injury.

RATIONALE: The number of patients with coronary heart disease, including myocardial infarction, is increasing and novel therapeutic strategy is awaited. Tumor suppressor protein p53 accumulates in the myocardium after myocardial infarction, causes apoptosis of cardiomyocytes, and plays an important role in the progression into heart failure. OBJECTIVES: We investigated the molecular mechanisms of p53 accumulation in the heart after myocardial infarction and tested whether anti-p53 approach would be effective against myocardial infarction. METHODS AND RESULTS: Through expression screening, we found that CHIP (carboxyl terminus of Hsp70-interacting protein) is an endogenous p53 antagonist in the heart. CHIP suppressed p53 level by ubiquitinating and inducing proteasomal degradation. CHIP transcription was downregulated after hypoxic stress and restoration of CHIP protein level prevented p53 accumulation after hypoxic stress. CHIP overexpression in vivo prevented p53 accumulation and cardiomyocyte apoptosis after myocardial infarction. Promotion of CHIP function by heat shock protein (Hsp)90 inhibitor, 17-allylamino-17-demethoxy geldanamycin (17-AAG), also prevented p53 accumulation and cardiomyocyte apoptosis both in vitro and in vivo. CHIP-mediated p53 degradation was at least one of the cardioprotective effects of 17-AAG. CONCLUSIONS: We found that downregulation of CHIP level by hypoxia was responsible for p53 accumulation in the heart after myocardial infarction. Decreasing the amount of p53 prevented myocardial apoptosis and ameliorated ventricular remodeling after myocardial infarction. We conclude that anti-p53 approach would be effective to treat myocardial infarction.

Magnetic Resonance Image in Monitor and Diagnosis of Patients with Neuromyelitis Optica.

This study was aimed to investigate the craniocerebral magnetic resonance imaging (MRI) measurement and clinical characteristics of patients with neuromyelitis optica (NMO) and multiple sclerosis (MS). 50 patients with NMO (NMO group) and 50 patients with MS (MS group) were studied. The clinical manifestations, brain injury morphology, MRI signal characteristics, brain distribution characteristics, and related laboratory tests (serum aquaporin 4 [AQP4] antibody) were statistically analyzed. The results showed that the analysis of clinical manifestations of patients revealed that optic neuritis (37 cases) was the most common disease in NMO patients, and myelitis (16 cases) was more common in MS patients than NMO patients. There were significant differences in gender ratio, abnormal expression of brain MR1, positive serum AQP4-IgG, and other immune diseases and symptoms between the two groups (P < 0.05). When the lesions measured by MRI were located in the white matter area of the cerebral hemisphere, the image showed blurred edges and a relatively symmetrical distribution. When the lesions measured by MRI were located around the medulla oblongata, the lesions mainly involved the central gray matter and white matter of the spinal cord, with patchy and line-like long T1 and long T2 signals. Moreover, in the late stage of recurrence of spinal cord disease, severe spinal cord atrophy may occur. In conclusion, craniocerebral MRI measurement in NMO patients can provide more basis for the diagnosis and differential diagnosis of the disease, so as to improve the diagnostic level of NMO.

Genome-wide identification and transcriptional profiling of the basic helix-loop-helix gene family in tung tree (Vernicia fordii).

The basic helix-loop-helix (bHLH) transcription factor gene family is one of the largest gene families and is extensively involved in plant growth, development, biotic and abiotic stress responses. Tung tree (Vernicia fordii) is an economically important woody oil plant that produces tung oil rich in eleostearic acid. However, the characteristics of the bHLH gene family in the tung tree genome are still unclear. Hence, VfbHLHs were first searched at a genome-wide level, and their expression levels in various tissues or under low temperature were investigated systematically. In this study, we identified 104 VfbHLHs in the tung tree genome, and these genes were classified into 18 subfamilies according to bHLH domains. Ninety-eight VfbHLHs were mapped to but not evenly distributed on 11 pseudochromosomes. The domain sequences among VfbHLHs were highly conserved, and their conserved residues were also identified. To explore their expression, we performed gene expression profiling using RNA-Seq and RT-qPCR. We identified five, 18 and 28 VfbHLH genes in female flowers, male flowers and seeds, respectively. Furthermore, we found that eight genes (VfbHLH29, VfbHLH31, VfbHLH47, VfbHLH51, VfbHLH57, VfbHLH59, VfbHLH70, VfbHLH72) were significant differential expressed in roots, leaves and petioles under low temperature stress. This study lays the foundation for future studies on bHLH gene cloning, transgenes, and biological mechanisms.

Metabolome Analysis under Aluminum Toxicity between Aluminum-Tolerant and -Sensitive Rice (Oryza sativa L.).

Aluminum (Al) solubilizes into trivalent ions (Al3+) on acidic soils, inhibiting root growth. Since about 13% of global rice cultivation is grown on acidic soils, improving Al tolerance in rice may significantly increase yields. In the present study, metabolome analysis under Al toxicity between the Al-tolerant variety Nipponbare and the Al-sensitive variety H570 were performed. There were 45 and 83 differential metabolites which were specifically detected in Nipponbare and H570 under Al toxicity, respectively. Furthermore, the results showed that 16 lipids out of 45 total metabolites were down-regulated, and 7 phenolic acids as well as 4 alkaloids of 45 metabolites were up-regulated in Nipponbare, while 12 amino acids and their derivatives were specifically detected in H570, of which 11 amino acids increased, including L-homoserine and L-methionine, which are involved in cysteine synthesis, L-ornithine and L-proline, which are associated with putrescine synthesis, and 1-aminocyclopropane-1-carboxylate, which is associated with ethylene synthesis. The contents of cysteine and s-(methyl) glutathione, which were reported to be related to Al detoxification in rice, decreased significantly. Meanwhile, putrescine was accumulated in H570, while there was no significant change in Nipponbare, so we speculated that it might be an intermediate product of Al detoxification in rice. The differential metabolites detected between Al-tolerant and -sensitive rice variants in the present study might play important roles in Al tolerance. These results provide new insights in the mechanisms of Al tolerance in rice.

Association of thyroid peroxidase antibodies with the rate of first-trimester miscarriage in euthyroid women with unexplained recurrent spontaneous abortion.

Background: Unexplained recurrent spontaneous abortion is a serious reproductive problem of unknown etiology. Thyroid peroxidase antibodies (TPO-Ab) may be associated with pregnancy outcomes in unexplained recurrent spontaneous abortion with normal thyroid function. Objective: This study aimed to investigate the relationship between TPO-Ab and the first trimester miscarriage rate/live birth rate in women of unexplained recurrent spontaneous abortion with normal thyroid function. Methods: We retrospectively analyzed the clinical data of 297 women who met our strict inclusion criteria, comparing the first trimester miscarriage rate/live birth rate between the TPO-Ab positive and TPO-Ab negative groups. For the same purpose, we also performed subgroup analysis. Results: Of the included women, 76 (25.6%) were TPO-Ab positive, and 221 (74.4%) were negative. First trimester miscarriage rate differed between the two groups (36.8% vs 24.0%, RR = 1.54, 95% CI: 1.05-2.24, P = 0.030). In the younger subgroup (<35 years) and the primary RSA subgroup, First trimester miscarriage rate was also higher in the TPO-Ab positive group (33.3% vs 19.0%, RR = 1.75, 95% CI: 1.07-2.87, P = 0.030; 36.5% vs 21.7%, RR = 1.69, 95% CI: 1.10-2.58, P = 0.020). While the live birth rate was lower in women with TPO-Ab positive, the difference did not reach statistical significance, even in the subgroup analysis. Conclusion: Our results suggest that TPO-Ab is associated with first trimester miscarriage rate in euthyroid women with unexplained recurrent spontaneous abortion.

RB expression confers sensitivity to CDK4/6 inhibitor-mediated radiosensitization across breast cancer subtypes.

Standard radiation therapy (RT) does not reliably provide locoregional control for women with multinode-positive breast cancer and triple-negative breast cancer (TNBC). We hypothesized that CDK4/6 inhibition (CDK4/6i) would increase the radiosensitivity not only of estrogen receptor-positive (ER+) cells, but also of TNBC that expresses retinoblastoma (RB) protein. We found that CDK4/6i radiosensitized RB WT TNBC (n = 4, radiation enhancement ratio [rER]: 1.49-2.22) but failed to radiosensitize RB-null TNBC (n = 3, rER: 0.84-1.00). RB expression predicted response to CDK4/6i + RT (R2 = 0.84), and radiosensitization was lost in ER+/TNBC cells (rER: 0.88-1.13) after RB1 knockdown in isogenic and nonisogenic models. CDK4/6i suppressed homologous recombination (HR) in RB WT cells but not in RB-null cells or isogenic models of RB1 loss; HR competency was rescued with RB reexpression. Radiosensitization was independent of nonhomologous end joining and the known effects of CDK4/6i on cell cycle arrest. Mechanistically, RB and RAD51 interact in vitro to promote HR repair. CDK4/6i produced RB-dependent radiosensitization in TNBC xenografts but not in isogenic RB1-null xenografts. Our data provide the preclinical rationale for a clinical trial expanding the use of CDK4/6i + RT to difficult-to-control RB-intact breast cancers (including TNBC) and nominate RB status as a predictive biomarker of therapeutic efficacy.