ANGPTL4 binds to the leptin receptor to regulate ectopic bone formation.

Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR [db/db (diabetes)] and leptin [ob/ob (obese)] are not identical, and the cause remains unclear. Here, we show that db/db, but not ob/ob, mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4 (angiopoietin-like protein 4), a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1+ mesenchymal cells at the HO site, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1+ cells, or lineage ablation of LepR+ cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Together, these findings identify ANGPTL4 as a ligand for LepR to regulate the formation of acquired HO.

Total infectome characterization of respiratory infections in pre-COVID-19 Wuhan, China.

At the end of 2019 Wuhan witnessed an outbreak of "atypical pneumonia" that later developed into a global pandemic. Metagenomic sequencing rapidly revealed the causative agent of this outbreak to be a novel coronavirus denoted SARS-CoV-2. To provide a snapshot of the pathogens in pneumonia-associated respiratory samples from Wuhan prior to the emergence of SARS-CoV-2, we collected bronchoalveolar lavage fluid samples from 408 patients presenting with pneumonia and acute respiratory infections at the Central Hospital of Wuhan between 2016 and 2017. Unbiased total RNA sequencing was performed to reveal their "total infectome", including viruses, bacteria and fungi. We identified 35 pathogen species, comprising 13 RNA viruses, 3 DNA viruses, 16 bacteria and 3 fungi, often at high abundance and including multiple co-infections (13.5%). SARS-CoV-2 was not present. These data depict a stable core infectome comprising common respiratory pathogens such as rhinoviruses and influenza viruses, an atypical respiratory virus (EV-D68), and a single case of a sporadic zoonotic pathogen-Chlamydia psittaci. Samples from patients experiencing respiratory disease on average had higher pathogen abundance than healthy controls. Phylogenetic analyses of individual pathogens revealed multiple origins and global transmission histories, highlighting the connectedness of the Wuhan population. This study provides a comprehensive overview of the pathogens associated with acute respiratory infections and pneumonia, which were more diverse and complex than obtained using targeted PCR or qPCR approaches. These data also suggest that SARS-CoV-2 or closely related viruses were absent from Wuhan in 2016-2017.

Sinhcaf-dependent histone deacetylation is essential for primordial germ cell specification.

Primordial germ cells (PGCs) are the progenitor cells that give rise to sperm and eggs. Sinhcaf is a recently identified subunit of the Sin3 histone deacetylase complex (SIN3A-HDAC). Here, we provide evidence that Sinhcaf-dependent histone deacetylation is essential for germ plasm aggregation and primordial germ cell specification. Specifically, maternal-zygotic sinhcaf zebrafish mutants exhibit germ plasm aggregation defects, decreased PGC abundance and male-biased sex ratio, which can be rescued by re-expressing sinhcaf. Overexpression of sinhcaf results in excess PGCs and a female-biased sex ratio. Sinhcaf binds to the promoter region of kif26ab. Loss of sinhcaf epigenetically switches off kif26ab expression by increasing histone 3 acetylation in the promoter region. Injection of kif26ab mRNA could partially rescue the germ plasm aggregation defects in sinhcaf mutant embryos. Taken together, we demonstrate a role of Sinhcaf in germ plasm aggregation and PGC specialization that is mediated by regulating the histone acetylation status of the kif26ab promoter to activate its transcription. Our findings provide novel insights into the function and regulatory mechanisms of Sinhcaf-mediated histone deacetylation in PGC specification.

Combined effects of cadmium and simulated acid rain on soil microbial communities in the early cultivation of Populus beijingensis seedlings.

The combined cadmium (Cd) and acid rain pollution poses a significant threat to the global ecological environment. Previous studies on the combined adverse effects have predominantly focused on the aboveground plant physiological responses, with limited reports on the microbial response in the rhizosphere soil. This study employed Populus beijingensis seedlings and potting experiments to simulate the impacts of combined mild acid rain (pH=4.5, MA) or highly strong acid rain (pH=3.0, HA), and soil Cd pollution on the composition and diversity of microbial communities, as well as the physiochemical properties in the rhizosphere soil. The results showed that Cd decreased the content of inorganic nitrogen, resulting in an overall decrease of 49.10 % and 46.67 % in ammonium nitrogen and nitrate nitrogen, respectively. Conversely, acid rain was found to elevate the content of total potassium and soil organic carbon by 4.68 %-6.18 % and 8.64-19.16 %, respectively. Additionally, simulated acid rain was observed to decrease the pH level by 0.29-0.35, while Cd increased the pH level by 0.11. Moreover, Cd alone reduced the rhizosphere bacterial diversity, however, when combined with acid rain, regardless of its intensity, Cd was observed to increase the diversity. Fungal diversity was not influenced by the acid rain, but Cd increased fungal diversity to some extend under HA as observed in bacterial diversity. In addition, composition of the rhizosphere bacterial community was primarily influenced by the inorganic nitrogen components, while the fungal community was driven mainly by soil pH. Furthermore, "Metabolism" was emerged as the most significant bacterial function, which was markedly affected by the combined pollution, while Cd pollution led to a shift from symbiotroph to other trophic types for fungi. These findings suggest that simulated acid rain has a mitigating effect on the diversity of rhizosphere bacteria affected by Cd pollution, and also alters the trophic type of these microorganisms. This can be attributed to the acid rain-induced direct acidic environment, as well as the indirect changes in the availability or sources of carbon, nitrogen, or potassium.

Interspecific variations in growth, physiology and Cd accumulation between Populus deltoides and P. × canadensis in response to Cd pollution under two soil types.

Both acid and alkaline purple soils in China are increasingly affected by Cd contamination. The selection of fast-growing trees suitable for remediating different soil types is urgent, yet there is a severe lack of relevant knowledge. In this study, we conducted a controlled pot experiment to compare the growth, physiology, and Cd accumulation efficiency of two widely recognized poplar species, namely Populus deltoides and P. × canadensis, under Cd contamination (1 mg kg-1) in acid and alkaline purple soils. The objective was to determine which poplar species is best suited for remediating different soil types. Our findings are as follows: (1) the total biomass of both poplars remained largely unaffected by Cd pollution in both soil types. Notably, under Cd pollution, the total biomass of P. deltoides in acid purple soil was 1.53 times greater than that in alkaline purple soil. (2) Cd pollution did not significantly induce oxidative damage in the leaves of either poplar species in both soil types. However, in acid purple soil, Cd contamination led to a 21% increase in NO3- concentration and a 44% increase in NH4+ concentration in P. × canadensis leaves, whereas in alkaline purple soil, it led to a 59% increase in NH4+ concentration in P. deltoides leaves. (3) Cd concentrations in all root orders of P. × canadensis were significantly higher than those in P. deltoides, especially in the first three root orders, under alkaline purple soil. The total Cd accumulation by P. × canadensis in Cd-polluted alkaline purple soil was 2.18 times higher than that in Cd-polluted acid purple soil, a difference not observed in P. deltoides. (4) redundancy analysis indicated that the sequestration effect of higher soil organic matter on Cd availability in acid purple soil was more pronounced than the release effects caused by lower pH. In conclusion, P. × canadensis is better suited for remediating alkaline purple soil due to its higher capacity for Cd uptake, while P. deltoides is more suitable for remediating Cd-contaminated acid purple soil due to its better growth conditions and greater Cd enrichment capability.

Interleukin 9 prevents immune thrombocytopenia in mice via JAK/STAT5 signaling.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by autoimmune-mediated platelet destruction and impaired platelet production, which can lead to an increased risk of bleeding. The clinical management of ITP currently remains a challenge for hematologists. We explored the role of interleukin-9 (IL-9) in the treatment of CD41-induced ITP, and investigated its underlying mechanisms in a CD41-induced ITP mouse model. IL-9 treatment increased the numbers of mature megakaryocytes (CD41+CD42d+) and CD41+Sca-1+ cells in the bone marrow in these model mice, while IL-9 receptor (IL-9R) small interfering RNA (siRNA) inhibited the process. Moreover, phosphorylated signal transducer and activator of transcription 5 (STAT5), as a downstream molecule of IL-9R, was increased after IL-9 treatment. We next investigated the source of IL-9 in bone marrow, osteoblasts produced the highest level of IL-9. These results confirmed that IL-9 could prevent CD41-induced ITP in BALB/c mice by regulating osteoblasts and activating IL-9R/STAT5 signaling in megakaryocytes, thus providing further evidence for IL-9 as a promising therapeutic agent for the treatment of ITP.

AGE receptor 1 silencing enhances advanced oxidative protein product-induced epithelial-to-mesenchymal transition of human kidney proximal tubular epithelial cells via RAGE activation.

Advanced oxidative protein products (AOPPs) are novel uremic toxins whose concentrations continuously increases in patients with chronic kidney disease (CKD). Epithelial-to-mesenchymal transition (EMT) of tubular cells is the main mechanism underlying CKD pathogenesis. Studies have shown that AOPPs can induce EMT and promote renal fibrosis. However, the mechanism through which AOPPs induce tubular cell-EMT is poorly understood. In this study, we aimed to clarify the mechanisms underlying AOPP-induced EMT in human kidney proximal tubular (HKC-8) epithelial cells. Small molecule inhibitor, CRISPR-Cas9 knockout technology, siRNA knockdown technology, western blot, and reverse transcription-quantitative polymerase chain reaction were applied to investigate the mechanisms underlying AOPP-induced EMT in HKC-8 cells. AOPP treatment was found to significantly induce EMT, as evidenced by increased α-smooth muscle actin (α-SMA) and decreased E-cadherin levels, and upregulated Wnt1, ß-catenin, Tcf4, and Gsk-3ß expression. Conversely, blockade of Wnt/ß-catenin signaling using small molecule inhibitor ICG-001 hindered AOPP-induced EMT. Moreover, knockout of receptor of advanced glycation end-products (RAGE) reversed these aforementioned effects, whereas AGE receptor 1 (AGER1)-specific siRNA transfection enhanced them. Taken together, these data suggested that AOPPs could induce HKC-8 cell EMT by activating the RAGE/Wnt/ß-catenin signaling pathway and AGER1 could restore EMT by antagonizing the role of RAGE. These results may provide a new theoretical basis for EMT and help identify new therapeutic targets for suppressing CKD progression.

Characterization of Ethyl Acetate and Trichloromethane Extracts from Phoebe zhennan Wood Residues and Application on the Preparation of UV Shielding Films.

In this work, ethyl acetate (EA) and trichloromethane (TR) extracts were extracted from Phoebe zhennan wood residues and the extracts were then applied to the preparation of UV shielding films (UV-SF). The results revealed that substances including olefins, phenols and alcohols were found in both EA and TR extracts, accounting for about 45% of all the detected substances. The two extracts had similar thermal stability and both had strong UV shielding ability. When the relative percentage of the extract is 1 wt% in solution, the extract solution almost blocked 100% of the UV-B (280-315 nm), and UV-A (315-400 nm). Two kinds of UV-SF were successfully prepared by adding the two extracts into polylactic acid (PLA) matrix. The UV-SF with the addition of 24 wt% of the extractive blocked 100% of the UV-B (280-315 nm) and more than 80% of the UV-A (315-400 nm). Moreover, the UV shielding performance of the UV-SF was still stable even after strong UV irradiation. Though the addition of extracts could somewhat decrease the thermal stability of the film, its effect on the end-use of the film was ignorable. EA extracts had less effect on the tensile properties of the films than TR extracts as the content of the extract reached 18%. The results of this study could provide fundamental information on the potential utilization of the extracts from Phoebe zhennan wood residues on the preparation of biobased UV shielding materials.

Effect of Dual-track Interactive Nursing Intervention Model on Anxiety and Depression in Patients with Coronary Heart Disease.

BACKGROUND: Elderly patients with coronary heart disease often suffer adverse psychological reactions, such as anxiety and depression. The dual-track interactive nursing model is a nursing intervention aimed to provide specific and community nursing. For patients with chronic diseases, this model can improve the patients' self-management and rehabilitation. The effect of this model on the mental health of patients with chronic diseases has been unanimously recognized by researchers. In this study, a dual-track interactive nursing model intervention was conducted on the anxiety and depression in elderly patients with coronary heart disease to verify the psychological effect of the model. SUBJECTS AND METHODS: From June 2018 to June 2019, 136 elderly patients with coronary heart disease (mean age of 63.5±8.26 years) from three communities in Changsha, Hunan Province, China were selected as subjects. A total of 53 and 50 patients were identified in the intervention and the control groups, respectively. The control group underwent routine longitudinal referral, whereas the intervention group was subjected to a two-track interactive nursing model intervention. The Short Form-36 Health Survey (SF-36) and related questionnaires were used to monitor and compare the two groups before and after the intervention and employed for scoring and comparative analysis. RESULTS: After the intervention, the mental health scores of the intervention group in total score, somatization, obsessive-compulsive symptoms, interpersonal sensitivity, depression, anxiety, hostility, and paranoia are significantly lower than those of the control group (P<0.05). The intervention group has scored significantly higher in coping style but significantly lower in negative coping than the control group (P<0.05). CONCLUSIONS: The application of the dual-track interactive nursing model intervention in the management of patients with coronary heart disease can improve the self-management and the mental health of patients with coronary heart disease.

Qiliqiangxin Protects against Renal Injury in Rat with Cardiorenal Syndrome Type I through Regulating the Inflammatory and Oxidative Stress Signaling.

Cardiorenal syndrome (CRS) is a frequently encountered clinical condition when the dysfunction of either the heart or kidneys amplifies the failure progression of the other organ. CRS remains a major global health problem. Qiliqiangxin (QLQX) is a traditional Chinese herbs medication, which can improve cardiac function, urine volume, and subjective symptoms in patients with chronic heart failure. In the present study, we aim to investigate the role of QLQX in the treatment of CRS type I and the possible mechanism through establishment of a rat model of myocardial infarction. Rats in CRS-Q group were orally treated with QLQX daily for 2 weeks or 4 weeks, while in sham group and CRS-C group were treated with saline at the same time. Enzyme-linked immunosorbent assay (ELISA) analysis showed that QLQX significantly reduced the levels of angiotensin II (AngII), brain natriuretic peptides (BNP), creatinine (CRE), cystatin C (CysC), tumor necrosis factor (TNF)-α, interleukin (IL)-6, microalbuminuria (MAU), and neutrophil gelatinase-associated lipocalin (NGAL) in plasma induced by myocardial infarction. Western blot analysis showed that QLQX significantly reduced the expressions of AngII, non-phagocytic cell oxidase (NOX)2, and B-cell lymphoma (Bcl)2 associated X protein (Bax), and increased the expressions of Bcl2 and Angiotensin II Type 1 receptor (ATR) in the kidney as compared with the CRS-C group. Fluorescence microscopy showed that the content of reactive oxygen species (ROS) was significantly reduced in the kidney as compared with the CRS-C group. We also examined the apoptosis level in kidney by using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, and the result showed that QLQX significantly reduced the apoptosis level in kidney induced by myocardial infarction. Taken together, we suggest that QLQX may be a potentially effective drug for the treatment of CRS by regulating inflammatory/oxidative stress signaling.

[Value of Pediatric Early Warning Score in identifying the condition of critically ill children].

OBJECTIVE: To study the value of Pediatric Early Warning Score (PEWS) in identifying the condition of critically ill children. METHODS: A total of 120 children who were transferred to the pediatric intensive care unit (PICU) from the general ward during hospitalization or admitted to the PICU after emergency treatment in the Xiangya Hospital of Central South University from January to December, 2016 were enrolled as the PICU group. The other 120 children who were admitted to the general ward in the hospital were used as the control group. According to the disease type, the PICU group was further divided into two subgroups: respiratory/circulatory system diseases (n=55) and nervous/other system diseases (n=65). The PEWS score on admission was recorded, and the receiver operating characteristic (ROC) curve was used to analyze the value of PEWS in evaluating patients' condition. RESULTS: The PICU group had a significantly higher PEWS score than the control group (P<0.05). The respiratory/circulatory system disease subgroup had a significantly higher PEWS score than the nervous/other system disease subgroup (P<0.05). In predicting whether the child was admitted to the PICU, PEWS had a sensitivity of 85%, a specificity of 95%, and an area under the ROC curve (AUC) of 0.951 (95% confidence interval: 0.923-0.980) at the optimal cut-off value of 3.5 (PEWS score). The AUC of PEWS was 0.768 in the nervous/other system disease subgroup and 0.968 in the respiratory/circulatory system disease subgroup. The mortality rate of children with a PEWS score of >6, 4-6 and ≤3 was 40%, 21% and 0 respectively (P<0.001). CONCLUSIONS: PEWS can well identify disease severity in critically ill children, and it has different sensitivities in children with different varieties of diseases. PEWS has a good value in predicting children's prognosis.

Potential therapeutic targets for hypoxia-induced pulmonary artery hypertension.

BACKGROUND: Hypoxic pulmonary artery hypertension (PAH) as a severe pulmonary disease is characterized by changes of pulmonary vascular reconstruction. Mitochondrial ATP-sensitive potassium channel (mitoKATP) was considered as one of factors responsible for the proliferation of hypoxic pulmonary arterial smooth muscle cells (PASMCs), although the exact mechanisms remain unclear. METHODS: Pulmonary artery hypertension was induced in rats with or without 5-hydroxydecanoate (5-HD). The mean pulmonary artery pressure, morphologic changes, mRNA and protein expressions of voltage-gated potassium channels (Kv1.5 channel), were measured. The concentrations of monocyte chemo-attractant protein-1 (MCP-1) and transforming growth factor-beta1 (TGF-ß1) were detected. Furthermore, pulmonary arterial smooth muscle cells (PASMCs) were isolated and cultured with or without hypoxia pretreated with or without 5-HD or/and Kv1.5 inhibitor 4-aminopyridine (4-AP). Mitochondrial membrane potential (Δψm) and the proliferation of PASMCs were detected. RESULTS: 5-HD significantly prevented the development of PAH by blocking the mitochondrial membrane depolarization, increased the expression of voltage-gated potassium channels, and reduced pulmonary hypertension mediated by TGF-ß1 or MCP-1 signaling pathway. CONCLUSION: The MitoKATP plays an important role in the development of PAH and may be therapeutic target for the treatment of disease.

RanGAP1 maintains chromosome stability in limb bud mesenchymal cells during bone development.

BACKGROUND: Bone development involves the rapid proliferation and differentiation of osteogenic lineage cells, which makes accurate chromosomal segregation crucial for ensuring cell proliferation and maintaining chromosomal stability. However, the mechanism underlying the maintenance of chromosome stability during the rapid proliferation and differentiation of Prx1-expressing limb bud mesenchymal cells into osteoblastic precursor cells remains unexplored. METHODS: A transgenic mouse model of RanGAP1 knockout of limb and head mesenchymal progenitor cells was constructed to explore the impact of RanGAP1 deletion on bone development by histomorphology and immunostaining. Subsequently, G-banding karyotyping analysis and immunofluorescence staining were used to examine the effects of RanGAP1 deficiency on chromosome instability. Finally, the effects of RanGAP1 deficiency on chromothripsis and bone development signaling pathways were elucidated by whole-genome sequencing, RNA-sequencing, and qPCR. RESULTS: The ablation of RanGAP1 in limb and head mesenchymal progenitor cells expressing Prx1 in mice resulted in embryonic lethality, severe cartilage and bone dysplasia, and complete loss of cranial vault formation. Moreover, RanGAP1 loss inhibited chondrogenic or osteogenic differentiation of mesenchymal stem cells (MSCs). Most importantly, we found that RanGAP1 loss in limb bud mesenchymal cells triggered missegregation of chromosomes, resulting in chromothripsis of chromosomes 1q and 14q, further inhibiting the expression of key genes involved in multiple bone development signaling pathways such as WNT, Hedgehog, TGF-ß/BMP, and PI3K/AKT in the chromothripsis regions, ultimately disrupting skeletal development. CONCLUSIONS: Our results establish RanGAP1 as a critical regulator of bone development, as it supports this process by preserving chromosome stability in Prx1-expressing limb bud mesenchymal cells.

The Molecular and Functional Characterization of Sensory Neuron Membrane Protein 1b (SNMP1b) from Cyrtotrachelus buqueti (Coleoptera: Curculionidae).

Sensory neuron membrane proteins (SNMPs) play important roles in insect chemoreception and SNMP1s have been reported to be essential in detecting sex pheromones in Drosophila and some lepidopteran species. However, SNMPs for Cyrtotrachelus buqueti (Coleoptera: Curculionidae), a major insect pest of bamboo plantations, remain uncharacterized. In this study, a novel SNMP gene, CbuqSNMP1b, from C. buqueti was functionally characterized. The expression of CbuqSNMP1b was significantly higher in antennae than in other tissues of both sexes and the expression level was significantly male-biased. Additionally, CbuqSNMP1b showed significantly higher transcription levels in the adult stage and very low transcription levels in other stages, suggesting that CbuqSNMP1b is involved in the process of olfaction. Fluorescence binding assays indicated that CbuqSNMP1b displayed the strongest binding affinity to dibutyl phthalate (Ki = 9.03 µM) followed by benzothiazole (Ki = 11.59 µM) and phenol (Ki = 20.95 µM) among fourteen C. buqueti volatiles. Furthermore, molecular docking revealed key residues in CbuqSNMP1b that interact with dibutyl phthalate, benzothiazole, and phenol. In conclusion, these findings will lay a foundation to further understand the olfactory mechanisms of C. buqueti and promote the development of novel methods for controlling this pest.

Mature tertiary lymphoid structures: important contributors to anti-tumor immune efficacy.

Tertiary lymphoid structures (TLS) represent the ectopic aggregations of immune cells arising during chronic inflammation or tumor progression. In cancer, TLS are often associated with beneficial clinical outcomes in patients undergoing immunotherapy, underscoring their prognostic and predictive significance. Mature TLS, characterized by germinal centers and areas of T-cell and B-cell aggregation, are considered primary locations for activating and maintaining both humoral and cellular anti-tumor immune effects. Despite their recognized importance, the mechanisms driving the formation of mature TLS in cancer and their influence on the immune response within tumors remain insufficiently understood. Therefore, this review aims to comprehensively explore the structural composition, development mechanisms, maturity impact factors, immunological function, and innovative therapeutic strategies of mature TLS within the tumor microenvironment. The research summarized herein offers novel insights and considerations for therapeutic approaches to promote TLS generation and maturation in patients with cancer, representing a promising avenue for future cancer therapies.

Whitening of brown adipose tissue inhibits osteogenic differentiation via secretion of S100A8/A9.

The mechanism by which brown adipose tissue (BAT) regulates bone metabolism is unclear. Here, we reveal that BAT secretes S100A8/A9, a previously unidentified BAT adipokine (batokine), to impair bone formation. Brown adipocytes-specific knockout of Rheb (RhebBAD KO), the upstream activator of mTOR, causes BAT malfunction to inhibit osteogenesis. Rheb depletion induces NF-κB dependent S100A8/A9 secretion from brown adipocytes, but not from macrophages. In wild-type mice, age-related Rheb downregulation in BAT is associated with enhanced S100A8/A9 secretion. Either batokines from RhebBAD KO mice, or recombinant S100A8/A9, inhibits osteoblast differentiation of mesenchymal stem cells in vitro by targeting toll-like receptor 4 on their surfaces. Conversely, S100A8/A9 neutralization not only rescues the osteogenesis repressed in the RhebBAD KO mice, but also alleviates age-related osteoporosis in wild-type mice. Collectively, our data revealed an unexpected BAT-bone crosstalk driven by Rheb-S100A8/A9, uncovering S100A8/A9 as a promising target for the treatment, and potentially, prevention of osteoporosis.

Transient low T3 syndrome in patients with COVID-19: a new window for prediction of disease severity.

Objective: To investigate the relationship of low T3 syndrome with disease severity in patients with COVID-19. Methods: The clinical data of 145 patients with COVID-19 were retrospectively collected, and patients were divided into a low T3 group and a normal T3 group. Logistic regression models were used to assess predictive performance of FT3. Receiver operating characteristic (ROC) analysis was used to evaluate the use of low T3 syndrome in predicting critical disease. Kaplan-Meier analysis was used to analyze the impact of low T3 syndrome on mortality. Results: The prevalence of low T3 level among COVID-19 patients was 34.48%. The low T3 group was older, and had lower levels of hemoglobin, lymphocytes, prealbumin, and albumin, but higher levels of white blood cells, neutrophils, CRP, ESR, and D-dimer (all p<0.05). The low T3 group had greater prevalences of critical disease and mortality (all p <0.05). Multivariate logistic regression analysis showed that the Lymphocytes, free T3 (FT3), and D-dimer were independent risk factors for disease severity in patients with COVID-19. ROC analysis showed that FT3, lymphocyte count, and D-dimer, and all three parameters together provided reliable predictions of critical disease. Kaplan-Meier analysis showed the low T3 group had increased mortality (p<0.001). Six patients in the low T3 group and one patient in the normal T3 group died. All 42 patients whose T3 levels were measured after recovery had normal levels after discharge. Conclusion: Patients with COVID-19 may have transient low T3 syndrome at admission, and this may be useful for predicting critical illness.

Loss of RanGAP1 drives chromosome instability and rapid tumorigenesis of osteosarcoma.

Chromothripsis is a catastrophic event of chromosomal instability that involves intensive fragmentation and rearrangements within localized chromosomal regions. However, its cause remains unclear. Here, we show that reduction and inactivation of Ran GTPase-activating protein 1 (RanGAP1) commonly occur in human osteosarcoma, which is associated with a high rate of chromothripsis. In rapidly expanding mouse osteoprogenitors, RanGAP1 deficiency causes chromothripsis in chr1q, instant inactivation of Rb1 and degradation of p53, consequent failure in DNA damage repair, and ultrafast osteosarcoma tumorigenesis. During mitosis, RanGAP1 anchors to the kinetochore, where it recruits PP1-γ to counteract the activity of the spindle-assembly checkpoint (SAC) and prevents TOP2A degradation, thus safeguarding chromatid decatenation. Loss of RanGAP1 causes SAC hyperactivation and chromatid decatenation failure. These findings demonstrate that RanGAP1 maintains mitotic chromosome integrity and that RanGAP1 loss drives tumorigenesis through its direct effects on SAC and decatenation and secondary effects on DNA damage surveillance.

Bindarit Reduces Bone Loss in Ovariectomized Mice by Inhibiting CCL2 and CCL7 Expression via the NF-κB Signaling Pathway.

OBJECTIVE: To investigate the changes in proinflammatory cytokines and chemokines, namely, C-C motif ligand (CCL) 2 and CCL7, in postmenopausal osteoporosis (PMOP) and to develop a new drug, bindarit (Bnd), for PMOP in an ovariectomized (OVX) mouse model. METHODS: Bone marrow macrophages (BMMs) from the femurs of five women with PMOP and five premenopausal women without osteoporosis were detected by RNA sequencing. BMMs from mice were differentiated into osteoclasts and treated with a synthetic inhibitor of CCL2 and CCL7, Bnd, or 17 beta estradiol (E2 ). Mouse BMMs were differentiated into osteoclasts with or without Bnd for 7 days and analyzed by RNA sequencing. Osteoblasts of mice were induced to undergo osteoblastogenesis and treated with Bnd. OVX mice were treated with E2 or Bnd after surgery. The protein and mRNA expression of CCL2 and CCL7 was detected using immunostaining and qPCR, respectively, in OVX and aged mice and in cells cultured in vitro. Osteoclast formation was detected using a tartrate-resistant acid phosphatase (TRAP) assay in vitro and in vivo. Alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) were detected using immunostaining to evaluate osteogenesis. Microcomputed tomography was conducted to analyze trabecular bone parameters, the structure model index, bone mineral density and other variables. Nuclear factor-κB (NF-κB) signaling pathway-related protein phosphorylation of IKKα/ß (p-IKKα/ß) and p-NFκB p65 was examined using western blotting. RESULTS: CCL2, CCL7 and their receptor of C-C chemokine receptor-2 (CCR2), and the NF-κB signaling pathway, were significantly increased in women with PMOP. CCL2 and CCL7 protein and mRNA expression was increased in OVX mice and aged female mice, but the increases were attenuated by E2 and Bnd. E2 and Bnd effectively inhibited osteoclastogenesis and the protein expression of CCL2 and CCL7 both in vitro and in vivo and reduced bone loss in OVX mice. Bnd did not affect the mineralization of osteoblasts directly in vitro but reduced bone turnover in vivo. p-IKKα/ß and p-NFκB p65 levels were increased in BMMs of mice after differentiation into osteoclasts but were significantly decreased by Bnd. CONCLUSION: The proinflammatory cytokines and chemokines CCL2, CCL7 and CCR2 were correlated with PMOP. Bnd attenuated the increases in CCL2 and CCL7 levels to affect osteoporosis in OVX mice via the NFκB signaling pathway. Thus, Bnd may be useful as a new therapeutic for the prevention of PMOP.

Identification of a Six-Gene SLC Family Signature With Prognostic Value in Patients With Lung Adenocarcinoma.

Given the importance of solute carrier (SLC) proteins in maintaining cellular metabolic homeostasis and that their dysregulation contributes to cancer progression, here we constructed a robust SLC family signature for lung adenocarcinoma (LUAD) patient stratification. Transcriptomic profiles and relevant clinical information of LUAD patients were downloaded from the TCGA and GEO databases. SLC family genes differentially expressed between LUAD tissues and adjacent normal tissues were identified using limma in R. Of these, prognosis-related SLC family genes were further screened out and used to construct a novel SLC family-based signature in the training cohort. The accuracy of the prognostic signature was assessed in the testing cohort, the entire cohort, and the external GSE72094 cohort. Correlations between the prognostic signature and the tumor immune microenvironment and immune cell infiltrates were further explored. We found that seventy percent of SLC family genes (279/397) were differentially expressed between LUAC tissues and adjacent normal. Twenty-six genes with p-values < 0.05 in univariate Cox regression analysis and Kaplan-Meier survival analysis were regarded as prognosis-related SLC family genes, six of which were used to construct a prognostic signature for patient classification into high- and low-risk groups. Kaplan-Meier survival analysis in all internal and external cohorts revealed a better overall survival for patients in the low-risk group than those in the high-risk group. Univariate and multivariate Cox regression analyses indicated that the derived risk score was an independent prognostic factor for LUAD patients. Moreover, a nomogram based on the six-gene signature and clinicopathological factors was developed for clinical application. High-risk patients had lower stromal, immune, and ESTIMATE scores and higher tumor purities than those in the low-risk group. The proportions of infiltrating naive CD4 T cells, activated memory CD4 T cells, M0 macrophages, resting dendritic cells, resting mast cells, activated mast cells, and eosinophils were significantly different between the high- and low-risk prognostic groups. In all, the six-gene SLC family signature is of satisfactory accuracy and generalizability for predicting overall survival in patients with LUAD. Furthermore, this prognostics signature is related to tumor immune status and distinct immune cell infiltrates in the tumor microenvironment.