EPCR deficiency ameliorates inflammatory arthritis in mice by suppressing the activation and migration of T cells and dendritic cells.

OBJECTIVES: Endothelial protein C receptor (EPCR) is highly expressed in synovial tissues of patients with RA, but the function of this receptor remains unknown in RA. This study investigated the effect of EPCR on the onset and development of inflammatory arthritis and its underlying mechanisms. METHODS: CIA was induced in EPCR gene knockout (KO) and matched wild-type (WT) mice. The onset and development of arthritis was monitored clinically and histologically. T cells, dendritic cells (DCs), EPCR and cytokines from EPCR KO and WT mice, RA patients and healthy controls (HCs) were detected by flow cytometry and ELISA. RESULTS: EPCR KO mice displayed >40% lower arthritis incidence and 50% less disease severity than WT mice. EPCR KO mice also had significantly fewer Th1/Th17 cells in synovial tissues with more DCs in circulation. Lymph nodes and synovial CD4 T cells from EPCR KO mice expressed fewer chemokine receptors CXCR3, CXCR5 and CCR6 than WT mice. In vitro, EPCR KO spleen cells contained fewer Th1 and more Th2 and Th17 cells than WT and, in concordance, blocking EPCR in WT cells stimulated Th2 and Th17 cells. DCs generated from EPCR KO bone marrow were less mature and produced less MMP-9. Circulating T cells from RA patients expressed higher levels of EPCR than HC cells; blocking EPCR stimulated Th2 and Treg cells in vitro. CONCLUSION: Deficiency of EPCR ameliorates arthritis in CIA via inhibition of the activation and migration of pathogenic Th cells and DCs. Targeting EPCR may constitute a novel strategy for future RA treatment.

Blocking the IFN-gamma signal in the choroid plexus confers resistance to experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory infiltration and demyelination in the central nervous system (CNS). IFN-gamma (IFN-γ), a critically important immunomodulator, has been widely studied in MS pathology. The confusing and complex effects of IFN-γ in MS patients and rodent models, however, cause us to look more closely at its exact role in MS. In this study, we identified the role of the IFN-γ signaling in the choroid plexus (CP) in the experimental autoimmune encephalomyelitis (EAE) model. We found that the IFN-γ signal was rapidly amplified when CNS immune cell infiltration occurred in the CP during the progressive stage. Furthermore, using two CP-specific knockdown strategies, we demonstrated that blocking the IFN-γ signal via knockdown of IFN-γR1 in the CP could protect mice against EAE pathology, as evidenced by improvements in clinical scores and infiltration. Notably, knocking down IFN-γR1 in the CP reduced the local expression of adhesion molecules and chemokines. This finding suggests that IFN-γ signaling in the CP may participate in the pathological process of EAE by preventing pathological T helper (Th) 17+ cells from infiltrating into the CNS. Finally, we showed that the unbalanced state of IFN-γ signaling between peripheral lymphocytes and the choroid plexus may determine whether IFN-γ has a protective or aggravating effect on EAE pathology. Above all, we discovered that IFN-γR1-mediated IFN-γ signaling in the CP was a vital pathway in the pathological process of EAE.

A recombinant signalling-selective activated protein C that lacks anticoagulant activity is efficacious and safe in cutaneous wound preclinical models.

Various preclinical and clinical studies have demonstrated the robust wound healing capacity of the natural anticoagulant activated protein C (APC). A bioengineered APC variant designated 3K3A-APC retains APC's cytoprotective cell signalling actions with <10% anticoagulant activity. This study was aimed to provide preclinical evidence that 3K3A-APC is efficacious and safe as a wound healing agent. 3K3A-APC, like wild-type APC, demonstrated positive effects on proliferation of human skin cells (keratinocytes, endothelial cells and fibroblasts). Similarly it also increased matrix metollaproteinase-2 activation in keratinocytes and fibroblasts. Topical 3K3A-APC treatment at 10 or 30 µg both accelerated mouse wound healing when culled on Day 11. And at 10 µg, it was superior to APC and had half the dermal wound gape compared to control. Further testing was conducted in excisional porcine wounds due to their congruence to human skin. Here, 3K3A-APC advanced macroscopic healing in a dose-dependent manner (100, 250 and 500 µg) when culled on Day 21. This was histologically corroborated by greater collagen maturity, suggesting more advanced remodelling. A non-interference arm of this study found no evidence that topical 3K3A-APC caused either any significant systemic side-effects or any significant leakage into the circulation. However the female pigs exhibited transient and mild local reactions after treatments in week three, which did not impact healing. Overall these preclinical studies support the hypothesis that 3K3A-APC merits future human wound studies.

Novel CCR3-targeted cyclic peptides as potential therapeutic agents for age-related macular degeneration via inhibiting angiogenesis and reducing retinal photoreceptor damage.

The prolonged intravitreal administration of anti-vascular endothelial growth factor (VEGF) drugs is prone to inducing aberrant retinal vascular development and causing damage to retinal neurons. Hence, we have taken an alternative approach by designing and synthesizing a series of cyclic peptides targeting CC motif chemokine receptor 3 (CCR3). Based on the binding mode of the N-terminal region in CCR3 protein to CCL11, we used computer-aided identification of key amino acid sequence, conformational restriction through different cyclization methods, designed and synthesized a series of target cyclic peptides, and screened the preferred compound IB-2 through affinity. IB-2 exhibits excellent anti-angiogenic activity in HRECs. The apoptosis level of 661W cells demonstrated a significant decrease with the escalating concentration of IB-2. This suggests that IB-2 may have a protective effect on photoreceptor cells. In vivo experiments have shown that IB-2 significantly reduces retinal vascular leakage and choroidal neovascularization (CNV) area in a laser-induced mouse model of CNV. These findings indicate the potential of IB-2 as a safe and effective therapeutic agent for AMD, warranting further development.

The evolution of ancestral and species-specific adaptations in snowfinches at the Qinghai-Tibet Plateau.

Species in a shared environment tend to evolve similar adaptations under the influence of their phylogenetic context. Using snowfinches, a monophyletic group of passerine birds (Passeridae), we study the relative roles of ancestral and species-specific adaptations to an extreme high-elevation environment, the Qinghai-Tibet Plateau. Our ancestral trait reconstruction shows that the ancestral snowfinch occupied high elevations and had a larger body mass than most nonsnowfinches in Passeridae. Subsequently, this phenotypic adaptation diversified in the descendant species. By comparing high-quality genomes from representatives of the three phylogenetic lineages, we find that about 95% of genes under positive selection in the descendant species are different from those in the ancestor. Consistently, the biological functions enriched for these species differ from those of their ancestor to various degrees (semantic similarity values ranging from 0.27 to 0.5), suggesting that the three descendant species have evolved divergently from the initial adaptation in their common ancestor. Using a functional assay to a highly selective gene, DTL, we demonstrate that the nonsynonymous substitutions in the ancestor and descendant species have improved the repair capacity of ultraviolet-induced DNA damage. The repair kinetics of the DTL gene shows a twofold to fourfold variation across the ancestor and the descendants. Collectively, this study reveals an exceptional case of adaptive evolution to high-elevation environments, an evolutionary process with an initial adaptation in the common ancestor followed by adaptive diversification of the descendant species.

Jolkinolide B attenuates allergic airway inflammation and airway remodeling in asthmatic mice.

Asthma is a widely prevalent chronic disease that brings great suffering to patients and may result in death if it turns severe. Jolkinolide B (JB) is one diterpenoid component separated from the dried roots of Euphorbia fischeriana Steud (Euphorbiaceae), and has anti--inflammatory, antioxidative, and antitumor properties. However, the detailed regulatory role and associated regulatory mechanism in the progression of asthma remain elusive. In this work, it was demonstrated that the extensive infiltration of bronchial inflammatory cells and the thickening of airway wall were observed in ovalbumin (OVA)-induced mice, but these impacts were reversed by JB (10 mg/kg) treatment, indicating that JB relieved the provocative symptoms in OVA-induced asthma mice. In addition, JB can control OVA-triggered lung function and pulmonary resistance. Moreover, JB attenuated OVA-evoked inflammation by lowering the levels of interleukin (IL)-4, IL-5, and IL-13. Besides, the activated nuclear factor kappa B (NF-κB) and transforming growth factor-beta-mothers against decapentaplegic homolog 3 (TGFß/smad3) pathways in OVA-induced mice are rescued by JB treatment. In conclusion, it was disclosed that JB reduced allergic airway inflammation and airway remodeling in asthmatic mice by modulating the NF-κB and TGFß/smad3 pathways. This work could offer new opinions on JB for lessening progression of asthma.

Endothelial Protein C Receptor and 3K3A-Activated Protein C Protect Mice from Allergic Contact Dermatitis in a Contact Hypersensitivity Model.

Endothelial protein C receptor (EPCR) is a receptor for the natural anti-coagulant activated protein C (aPC). It mediates the anti-inflammatory and barrier-protective functions of aPC through the cleavage of protease-activated receptor (PAR)1/2. Allergic contact dermatitis is a common skin disease characterized by inflammation and defective skin barrier. This study investigated the effect of EPCR and 3K3A-aPC on allergic contact dermatitis using a contact hypersensitivity (CHS) model. CHS was induced using 1-Fluoro-2,4-dinitrobenzene in EPCR-deficient (KO) and matched wild-type mice and mice treated with 3K3A-aPC, a mutant form of aPC with diminished anti-coagulant activity. Changes in clinical and histological features, cytokines, and immune cells were examined. EPCRKO mice displayed more severe CHS, with increased immune cell infiltration in the skin and higher levels of inflammatory cytokines and IgE than wild-type mice. EPCR, aPC, and PAR1/2 were expressed by the skin epidermis, with EPCR presenting almost exclusively in the basal layer. EPCRKO increased the epidermal expression of aPC and PAR1, whereas in CHS, their expression was reduced compared to wild-type mice. 3K3A-aPC reduced CHS severity in wild-type and EPCRKO mice by suppressing immune cell infiltration/activation and inflammatory cytokines. In summary, EPCRKO exacerbated CHS, whereas 3K3A-aPC could reduce the severity of CHS in both EPCRKO and wild-type mice.

Translational repression of FZP mediated by CU-rich element/OsPTB interactions modulates panicle development in rice.

Panicle development is an important determinant of the grain number in rice. A thorough characterization of the molecular mechanism underlying panicle development will lead to improved breeding of high-yielding rice varieties. Frizzy Panicle (FZP), a critical gene for panicle development, is regulated by OsBZR1 and OsARFs at the transcriptional stage. However, the translational modulation of FZP has not been reported. We reveal that the CU-rich elements (CUREs) in the 3' UTR of the FZP mRNA are crucial for efficient FZP translation. The knockout of CUREs in the FZP 3' UTR or the over-expression of the FZP 3' UTR fragment containing CUREs resulted in an increase in FZP mRNA translation efficiency. Moreover, the number of secondary branches (NSB) and the grain number per panicle (GNP) decreased in the transformed rice plants. The CUREs in the 3' UTR of FZP mRNA were verified as the targets of the polypyrimidine tract-binding proteins OsPTB1 and OsPTB2 in rice. Both OsPTB1 and OsPTB2 were highly expressed in young panicles. The knockout of OsPTB1/2 resulted in an increase in the FZP translational efficiency and a decrease in the NSB and GNP. Furthermore, the over-expression of OsPTB1/2 decreased the translation of the reporter gene fused to FZP 3' UTR in vivo and in vitro. These results suggest that OsPTB1/2 can mediate FZP translational repression by interacting with CUREs in the 3' UTR of FZP mRNA, leading to changes in the NSB and GNP. Accordingly, in addition to transcriptional regulation, FZP expression is also fine-tuned at the translational stage during rice panicle development.

Cold-inducible PPA1 is critical for the adipocyte browning in mice.

Promoting the thermogenic capacity of brown/beige adipocytes is becoming a promising strategy to counteract obesity and related metabolic diseases. Inorganic pyrophosphatase 1 (PPA1) is an enzyme that catalyzes the hydrolysis of PPi to Pi, and its presence is required for anabolism to take place in cells. Our previous study demonstrated the importance of PPA1 in maintaining adipose tissue function and whole-body metabolic homeostasis. In this study, we found that the expression of PPA1 was positively associated with the thermogenic capacity of brown/beige adipocytes. PPA1+/- mice exhibited less browning capacity in subcutaneous white adipose tissue compared to wild-type mice and also showed apparent cold intolerance. We found that decreased PPA1 abundance may lead to mitochondrial dysfunction and inhibited adipocyte browning both in vivo and in vitro. Furthermore, our study also revealed that PPA1 worked as a new target gene of nuclear respiratory factor 1 (NRF1), a major transcription regulator of mitochondrial biogenesis. Together, our findings indicated an essential role of PPA1 in mitochondrial function and browning in adipocytes and suggested PPA1 as a new therapeutic target for increasing thermogenesis to combat obesity and metabolic diseases.

The effects of different endometrial preparation regimens on pregnancy outcomes in frozen-thawed embryo transfer cycles: a prospective randomized controlled study.

OBJECTIVE: An increasing number of research have emerged to compare the pregnancy outcomes between the natural cycle and the hormone replacement therapy (HRT) cycle in preparing the endometrium for frozen-thawed embryo transfer (FET), but the results are controversial. This prospective randomized controlled study was hence designed to obtain more solid evidence. MATERIALS AND METHODS: In this study, patients with regular menstrual cycle length (21-35 days) who underwent FET between January 2010 to December 2017 were recruited for this study. Upon further filtering with the selection criteria of patients being, a total of 405 patients were recruited and randomized. Finally, analysis was performed on 384 patients: 178 belonged to the natural cycle group whereas the remaining 206 were in the HRT group. The primary outcome was live birth rate, while the secondary outcomes were implantation rate, clinical pregnancy rate, early miscarriage rate, late miscarriage rate, multiple birth rate and low birth weight rate. RESULTS: The live birth rate (37.6% vs 30.1%, p = 0.119) of natural cycle group were higher than those of the hormone replacement therapy group, although the difference was not significant. The secondary outcomes were not found to differ significantly between the two groups. Nonetheless, the endometrium was found to be thicker in the natural cycle group (10.75 mm) than the HRT group (9.00 mm) (p < 0.001). CONCLUSION: No significant differences were observed between the pregnancy outcomes of the natural cycle group and the HRT group which comprised of patients with regular menstrual cycle length.

Physiological and genetic convergence supports hypoxia resistance in high-altitude songbirds.

Skeletal muscle plays a central role in regulating glucose uptake and body metabolism; however, highland hypoxia is a severe challenge to aerobic metabolism in small endotherms. Therefore, understanding the physiological and genetic convergence of muscle hypoxia tolerance has a potential broad range of medical implications. Here we report and experimentally validate a common physiological mechanism across multiple high-altitude songbirds that improvement in insulin sensitivity contributes to glucose homeostasis, low oxygen consumption, and relative activity, and thus increases body weight. By contrast, low-altitude songbirds exhibit muscle loss, glucose intolerance, and increase energy expenditures under hypoxia. This adaptive mechanism is attributable to convergent missense mutations in the BNIP3L gene, and METTL8 gene that activates MEF2C expression in highlanders, which in turn increases hypoxia tolerance. Together, our findings from wild high-altitude songbirds suggest convergent physiological and genetic mechanisms of skeletal muscle in hypoxia resistance, which highlights the potentially medical implications of hypoxia-related metabolic diseases.

Increased ammonium in culture medium may promote cellular apoptosis and negatively affect pluripotency of human blastocysts.

PURPOSE: To determine the association between ammonium concentration in culture medium and blastocyst development and to assess the influence of increased ammonium concentration on the expression of Bax, Bcl-2 and Oct4. METHODS: A total of 254 cleavage-stage embryos were individually cultured in 30µL G2-plus medium on Day 3, and then culture media samples were collected on Day 5 for ammonium concentration determination immediately after evaluating the embryos morphology. Poor-quality blastocysts (combined score of CC) were used for gene expression analysis. The blastocyst formation rate, good-quality blastocyst rate and relative expression levels of Bax, Bcl-2 and Oct4 were analyzed. RESULTS: Based on receiver operating characteristic curve, the cutoff value of ammonium concentration produced by embryos was 16.07 µmol/L (AUC = 0.722, 95% CI 0.637-0.807; P = 0.000), so all embryos were assigned to two groups according to the cutoff value: normal group (< 16.07 µmol/L) and increased group (≥ 16.07 µmol/L). There was a significant difference in blastocyst formation rate (80.5% vs 59.0%, P < 0.01) between normal group and increased group, as well as for good-quality blastocyst rate (21.0% vs 3.4%, P < 0.01). A significantly higher expression level of Bax (P < 0.05) and considerably lower expression level of Oct4 (P < 0.01) were observed in increased group compared to normal group. CONCLUSION: Our data demonstrated for the first time that increased ammonium concentration in culture medium may promote cellular apoptosis and negatively affect pluripotency of human blastocyst.

Low-intensity pulsed ultrasound enhances immunomodulation and facilitates osteogenesis of human periodontal ligament stem cells by inhibiting the NF-κB pathway.

Human periodontal ligament stem cells (hPDLSCs) are vital in cellular regeneration and tissue repair due to their multilineage differentiation potential. Low intensity pulsed ultrasound (LIPUS) has been applied for treating bone and cartilage defects. This study explored the role of LIPUS in the immunomodulation and osteogenesis of hPDLSCs. hPDLSCs were cultured in vitro, and the effect of different intensities of LIPUS (30, 60, and 90 mW/cm2) on hPDLSC viability was measured. hPDLSCs irradiated by LIPUS and stimulated by lipopolysaccharide (LPS) and LIPUS (90 mW/cm2) were co-cultured with peripheral blood mononuclear cells (PBMCs). Levels of immunomodulatory factors in hPDLSCs and inflammatory factors in PBMCs were estimated, along with determination of osteogenesis-related gene expression in LIPUS-irradiated hPDLSCs. The mineralized nodules and alkaline phosphatase (ALP) activity of hPDLSCs and levels of IκBα, p-IκBα, and p65 subunits of NF-κB were determined. hPDLSC viability was increased as LIPUS intensity increased. Immunomodulatory factors were elevated in LIPUS-irradiated hPDLSCs, and inflammatory factors were reduced in PBMCs. Osteogenesis-related genes, mineralized nodules, and ALP activity were promoted in LIPUS-irradiated hPDLSCs. The cytoplasm of hPDLSCs showed increased IκBα and p65 and decreased p-IκBα at increased LIPUS intensity. After LPS and LIPUS treatment, the inhibitory effect of LIPUS irradiation on the NF-κB pathway was partially reversed, and the immunoregulation and osteogenic differentiation of hPDLSCs were decreased. LIPUS irradiation enhanced immunomodulation and osteogenic differentiation abilities of hPDLSCs by inhibiting the NF-κB pathway, and the effect is dose-dependent. This study may offer novel insights relevant to periodontal tissue engineering.

Comparative Transcriptome Sequencing and Endogenous Phytohormone Content of Annual Grafted Branches of Zelkova schneideriana and Its Dwarf Variety HenTianGao.

Zelkova schneideriana is a fast-growing tree species endemic to China. Recent surveys and reports have highlighted a continued decline in its natural populations; therefore, it is included in the Red List of Threatened Species by The International Union for Conservation of Nature. A new variety "HenTianGao" (H) has been developed with smaller plant height, slow growth, and lower branching points. In this study, we attempted to understand the differences in plant height of Z. schneideriana (J) and its dwarf variety H. We determined the endogenous hormone content in the annual grafted branches of both J and H. J exhibited higher gibberellic acid (GA)-19 and trans-Zeatin (tZ) levels, whereas H had higher levels of indole-3-acetic acid (IAA) catabolite 2-oxindole-3-acetic acid (OxIAA), IAA-Glu conjugate, and jasmonic acid (JA) (and its conjugate JA-Ile). The transcriptome comparison showed differential regulation of 20,944 genes enriched in growth and development, signaling, and metabolism-related pathways. The results show that the differential phytohormone level (IAA, JA, tZ, and GA) was consistent with the expression of the genes associated with their biosynthesis. The differences in relative OxIAA, IAA-Glu, GA19, trans-Zeatin, JA, and JA-Ile levels were linked to changes in respective signaling-related genes. We also observed significant differences in the expression of cell size, number, proliferation, cell wall biosynthesis, and remodeling-related genes in J and H. The differences in relative endogenous hormone levels, expression of biosynthesis, and signaling genes provide a theoretical basis for understanding the plant height differences in Z. schneideriana.

Uncovering the prevalence and drivers of antibiotic resistance genes in soils across different land-use types.

The emergence and spread of antibiotic resistance genes (ARGs) in soil due to animal excreta and organic waste is a major threat to human health and ecosystems, and global efforts are required to tackle the issue. However, there is limited knowledge of the variation in ARG prevalence and diversity resulting from different land-use patterns and underlying driving factors in soils. This study aimed to comprehensively characterize the profile of ARGs and mobile genetic elements and their drivers in soil samples collected from 11 provinces across China, representing three different land-use types, using high-throughput quantitative polymerase chain reaction and 16S rRNA amplicon sequencing. Our results showed that agricultural soil had the highest abundance and diversity of ARGs, followed by tea plantation and forest land. A total of 124 unique ARGs were detected in all samples, with shared subtypes among different land-use patterns indicating a common origin or high transmission frequency. Moreover, significant differences in ARG distribution were observed among different geographical regions, with the greatest enrichment of ARGs found in southern China. Biotic and abiotic factors, including soil properties, climatic factors, and bacterial diversity, were identified as the primary drivers associated with ARG abundance, explaining 71.8% of total ARG variation. The findings of our study demonstrate that different land-use patterns are associated with variations in ARG abundance in soil, with agricultural practices posing the greatest risk to human health and ecosystems regarding ARGs. Our identification of biotic and abiotic drivers of ARG abundance provides valuable insights into strategies for mitigating the spread of these genes. This study emphasizes the need for coordinated and integrated approaches to address the global antimicrobial resistance crisis.

Systematic contributions of CFEM domain-containing proteins to iron acquisition are essential for interspecies interaction of the filamentous pathogenic fungus Beauveria bassiana.

Common in fungal extracellular membrane (CFEM) domain is unique in fungal proteins and some of which contribute to iron acquisition in yeast. However, their roles in iron acquisition remain largely unknown in filamentous fungi. In this study, 12 CFEM-containing proteins were bioinformatically identified in the filamentous entomopathogenic fungus Beauveria bassiana, and the roles of 11 genes were genetically characterized. Transmembrane helices were critical for their association with intracellular membranes, and their number varied among proteins. Eleven CFEM genes significantly contribute to vegetative growth under iron starvation and virulence. Notably, the virulence of most disruptants could be significantly weakened by a decrease in iron availability, in which the virulence of ΔBbcfem7 and 8 strains was partially recovered by exogenous hemin. ΔBbcfem7 and 8 mutants displayed defective competitiveness against the sister entomopathogenic fungus Beauveria brongniartii. All 11 disruptants displayed impaired growth in the antagonistic assay with the saprotrophic fungus Aspergillus niger, which could be repressed by exogenous ferric ions. These findings not only reveal the systematic contributions of CFEM proteins to acquire two forms of iron (i.e. heme and ferric ion) in the entire lifecycle of entomopathogenic fungi but also help to better understand the mechanisms of fungus-host and inter-fungus interactions.

Transcriptome profiling of two super hybrid rice provides insights into the genetic basis of heterosis.

BACKGROUND: Heterosis is a phenomenon that hybrids show superior performance over their parents. The successful utilization of heterosis has greatly improved rice productivity, but the molecular basis of heterosis remains largely unclear. RESULTS: Here, the transcriptomes of young panicles and leaves of the two widely grown two-line super hybrid rice varieties (Jing-Liang-You-Hua-Zhan (JLYHZ) and Long-Liang-You-Hua-Zhan (LLYHZ)) and their parents were analyzed by RNA-seq. Transcriptome profiling of the hybrids revealed 1,778 ~ 9,404 differentially expressed genes (DEGs) in two tissues, which were identified by comparing with their parents. GO, and KEGG enrichment analysis showed that the pathways significantly enriched in both tissues of two hybrids were all related to yield and resistance, like circadian rhythm (GO:0,007,623), response to water deprivation (GO:0,009,414), and photosynthetic genes (osa00196). Allele-specific expression genes (ASEGs) were also identified in hybrids. The ASEGs were most significantly enriched in ionotropic glutamate receptor signaling pathway, which was hypothesized to be potential amino acid sensors in plants. Moreover, the ASEGs were also differentially expressed between parents. The number of variations in ASEGs is higher than expected, especially for large effect variations. The DEGs and ASEGs are the potential reasons for the formation of heterosis in the two elite super hybrid rice. CONCLUSIONS: Our results provide a comprehensive understanding of the heterosis of two-line super hybrid rice and facilitate the exploitation of heterosis in hybrid rice breeding with high yield heterosis.

A peroxisomal sterol carrier protein 2 (Scp2) contributes to lipid trafficking in differentiation and virulence of the insect pathogenic fungus Beauveria bassiana.

Sterol carrier protein 2 (SCP2) represents a family of proteins binding a variety of lipids and plays essential roles in cellular physiology. However, its physiological roles are largely unknown in filamentous fungi. In this study, we functionally characterized an orthologous Scp2 gene in the filamentous insect pathogenic fungus Beauveria bassiana (BbScp2). BbScp2 was verified to be a peroxisomal protein and displayed different affinities to various lipids, with strong affinity to palmitic acid (PA) and ergosterol (ES). No significant binding activity was detected between protein and oleic acid (OA) or linoleic acid (LA). Ablation of BbScp2 did not cause significant effects on fungal growth on various carbon sources, but resulted in a modest reduction in conidial (49%) and blastospore yield (45%). In addition, exogenous lipids could recover the defectives in conidiation of ΔBbScp2 mutant strain. BbScp2 was required for the cytomembrane functionality in germlings, and its loss resulted in a more significant decrease in virulence indicated by cuticle infection assay than intrahemocoel injection assay. Our findings indicate that Scp2 links the lipid trafficking to the asexual differentiation and virulence of B. bassiana.

The influence of high-order chromatin state in the regulation of stem cell fate.

In eukaryotic cells, genomic DNA is hierarchically compacted by histones into chromatin, which is initially assembled by the nucleosome and further folded into orderly and flexible structures that include chromatin fiber, chromatin looping, topologically associated domains (TADs), chromosome compartments, and chromosome territories. These distinct structures and motifs build the three-dimensional (3D) genome architecture, which precisely controls spatial and temporal gene expression in the nucleus. Given that each type of cell is characterized by its own unique gene expression profile, the state of high-order chromatin plays an essential role in the cell fate decision. Accumulating evidence suggests that the plasticity of high-order chromatin is closely associated with stem cell fate. In this review, we summarize the biological roles of the state of high-order chromatin in embryogenesis, stem cell differentiation, the maintenance of stem cell identity, and somatic cell reprogramming. In addition, we highlight the roles of epigenetic factors and pioneer transcription factors (TFs) involved in regulating the state of high-order chromatin during the determination of stem cell fate and discuss how H3K9me3-heterochromatin restricts stem cell fate. In summary, we review the most recent progress in research on the regulatory functions of high-order chromatin dynamics in the determination and maintenance of stem cell fate.

Using different machine learning models to classify patients into mild and severe cases of COVID-19 based on multivariate blood testing.

COVID-19 is a serious respiratory disease. The ever-increasing number of cases is causing heavier loads on the health service system. Using 38 blood test indicators on the first day of admission for the 422 patients diagnosed with COVID-19 (from January 2020 to June 2021) to construct different machine learning (ML) models to classify patients into either mild or severe cases of COVID-19. All models show good performance in the classification between COVID-19 patients into mild and severe disease. The area under the curve (AUC) of the random forest model is 0.89, the AUC of the naive Bayes model is 0.90, the AUC of the support vector machine model is 0.86, and the AUC of the KNN model is 0.78, the AUC of the Logistic regression model is 0.84, and the AUC of the artificial neural network model is 0.87, among which the naive Bayes model has the best performance. Different ML models can classify patients into mild and severe cases based on 38 blood test indicators taken on the first day of admission for patients diagnosed with COVID-19.