Morphologic and mechanical adaptive variations in Saiga tatarica calcaneus: A model for interpreting the bone functional adaptation of wild artiodactyl in captivity.

Background and Aim: Captivity alters the locomotor behavior of wild artiodactyls and affects the mechanical loading of the calcaneus; however, the resulting adaptive changes in calcaneus morphology have not been sufficiently studied to date. This study aimed to investigate the morphological and mechanical adaptive variations in the calcaneus of Saiga tatarica to understand further the functional adaptation of the calcaneus in wild artiodactyl to captivity. Materials and Methods: Paired calcanei from autopsy samples of six captive wild artiodactyls (S. tatarica) and six domesticated artiodactyls (Ovis aries) were divided into skeletally immature and mature groups using X-ray evaluation of growth plate closure. High-resolution microcomputed tomography revealed a calcaneal diaphyseal cross-section. The mechanical and nanomorphological characteristics of the trabecular bone were determined by atomic force microscopy. Results: The percent cortical bone area (%CA), cortical thickness ratio (CTR), and Young's modulus (E) differed between species in the immature groups but not in the mature groups. S. tatarica had significantly higher growth rates for %CA, CTR, and E in the mid-shaft than O. aries (p < 0.05). Conclusion: The calcaneus morphology of S. tatarica converges with that of domesticated O. aries during ontogeny. These results indicate that the calcaneus of wild artiodactyls can undergo potentially transitional changes during the short-term adaptation to captivity. The above parameters can be preliminarily identified as morphological signs of functional bone adaptation in artiodactyls.

Research strategies of small molecules as chemotherapeutics to overcome multiple myeloma resistance.

Multiple myeloma (MM), a cancer of plasma cells, is the second most common hematological malignancy which is characterized by aberrant plasma cells infiltration in the bone marrow and complex heterogeneous cytogenetic abnormalities. Over the past two decades, novel treatment strategies such as proteasome inhibitors, immunomodulators, and monoclonal antibodies have significantly improved the relative survival rate of MM patients. However, the development of drug resistance results in the majority of MM patients suffering from relapse, limited treatment options and uncontrolled disease progression after relapse. There are urgent needs to develop and explore novel MM treatment strategies to overcome drug resistance and improve efficacy. Here, we review the recent small molecule therapeutic strategies for MM, and introduce potential new targets and corresponding modulators in detail. In addition, this paper also summarizes the progress of multi-target inhibitor therapy and protein degradation technology in the treatment of MM.

Unraveling the Promise of RET Inhibitors in Precision Cancer Therapy by Targeting RET Mutations.

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.

Novel_circ_003686 regulates the osteogenic differentiation of MSCs in patients with myeloma bone disease through miR-142-5p/IGF1 axis.

Objectives: Circ_003686 is a novel_circRNA with abnormally low expression found in the samples of multiple myeloma bone disease (MBD) patients. The current research intended to investigate the effects of novel_circ_003686 in osteogenesis-induced differentiation of bone marrow mesenchymal stem cells (BMSCs) in MBD. Methods: BMSCs were extracted from MBD patients and normal participants, the pcDNA3.1 encoding the circ_003686 (ov-circ_003686), miR-142-5p-mimic/inhibitor and siRNA oligonucleotides targeting insulin like growth factor 1 (IGF1, si-IGF1) were applied to intervene circ_003686, miR-142-5p and IGF1 levels, respectively. Results: Results showed that ov-circ_003686 could mediate the osteogenesis-induced differentiation of MBD-BMSC, and luciferase assay and RIP experiments confirmed that circ_003686 could bind to miR-142-5p. MiR-142-5p-inhibitor helped osteogenesis-induced differentiation, while miR-142-5p-mimic inhibited osteogenesis-induced differentiation and reversed the promoting effect of ov-circ_003686, suggesting that circ_003686/miR-142-5p axis participated in osteogenesis-induced differentiation of MBD-BMSC. In addition, miR-142-5p binds to the target gene IGF1 and negatively adjust its expression. Si-IGF1 significantly inhibited the osteogenesis-induced differentiation and reversed the promotion effects of miR-142-5p-inhibitor and ov-circ_003686. Moreover, circ_003686/miR-142-5p/IGF1 axis meaningfully regulates protein expressions in the PI3K/AKT pathway. Conclusion: In conclusion, this research confirmed that circ_003686 regulated the osteogenesis-induced differentiation of MBD-BMSC by sponging miR-142-5p and mediating IGF1, and the PI3K/AKT pathway may also be involved.

Case report: Successful treatment of Chidamide in a refractory/recurrent SPTCL with ARID1A mutation on the basis of CHOP plus auto-HSCT.

RATIONALE: Subcutaneous panniculitis like T-cell lymphoma (SPTCL) is a rare primary cutaneous lymphoma that belongs to peripheral T cell lymphomas, of which the overall prognosis is poor. Chidamide, a deacetylase inhibitor, has been approved for the treatment of peripheral T cell lymphomas. However, due to the rare occurrence of SPTCL, it is currently unknown whether Chidamide is effective for all SPTCL patients and whether there are molecular markers that can predict its therapeutic effect on SPTCL. PATIENT CONCERNS AND DIAGNOSES: The patient was a sixteen-year-old male and underwent subcutaneous nodule biopsy which showed SPTCL. Next-generation sequencing revealed AT-rich interaction domain 1A (ARID1A) mutation, and positron emission tomography/computed tomography showed scattered subcutaneous fluorodeoxyglucose metabolic lesions throughout the body. INTERVENTIONS AND OUTCOMES: During the first 3 CHOP (cyclophosphamide, doxorubicin, vindesine, and prednisone) treatment, the patient relapsed again after remission, and the successive addition of methotrexate and cyclosporine did not make the patient relapsing again. Then, after adding Chidamide to the last 3 CHOP treatment, the patient was relieved again. The patient underwent autologous hematopoietic stem cell transplantation (auto-HSCT) after completing a total of 8 cycles of chemotherapy, and continued maintenance therapy with Chidamide after auto-HSCT. Currently, the patient has been in continuous remission for 35 months. LESSONS SUBSECTIONS: This case is the first report of a refractory/recurrent SPTCL with ARID1A mutation treated with Chidamide. The treatment of Chidamide on the basis of CHOP plus auto-HSCT therapy achieved good results, suggesting that ARID1A may act as a molecular marker to predict the therapeutic effect of Chidamide on SPTCL patients, which helps to improve the precision of SPTCL treatment and the overall prognosis of SPTCL patients.

[Progress of researches on acupuncture-moxibustion promoting wound repair].

Wound is a common surgical disease characterized by skin defect or functional limitation. Studies have found that acupuncture-moxibustion plays an important role in wound healing. In this paper, we reviewed the mechanisms of acupuncture-moxibustion in promoting wound repair. Outcomes display that acupuncture-moxibustion has an action in promoting wound restoration by improving wound flow perfusion, promoting angiogenesis, increasing the number of fibroblasts and regulating collagen synthesis. In addition, acupuncture can effectively promote wound healing by controlling the release of inflammatory cytokines, up-regulating the expression of growth factors such as vascular endothelial growth factor and transforming growth factor-ß1, and affecting phosphatidylinositol-3-kinase/protein kinase B, mitogen-activated protein kinase and advanced glycation end products/receptor for AGEs signaling pathways. Based on the above studies, it is highly recommended that future studies should pay more attention to the multi-mechanism coordinated regulation target center, and the therapeutic means and dose-effect relationship of acupuncture-moxibustion in tissue repair.

[Moxibustion at "Zusanli"(ST36) mitigates senescence in subacute aging rats via regulating SIRT1/p53 signaling pathway].

OBJECTIVE: To observe the effect of moxibustion at "Zusanli"(ST36) on the silent information regulator 1 (SIRT1) /p53 signaling pathway in subacute aging model rats, so as to reveal its mechanisms in delaying aortic aging. METHODS: Male SD rats were divided into blank group, model group, prevention group and treatment group, with 20 rats in each group. Subacute aging model was established by intraperitoneal injection of D-galactose(500 mg·kg-1·d-1). In the morning, rats in the prevention group received moxibustion at ST36 with 3 moxa cones after modeling operation, once every day for 42 d. From the day after the 42-day modeling, rats in the treatment group received the same moxibustion treatment as the prevent group for 28 d. Rats in the blank and model group were fixed in the similar way as the other two groups, for 5 min. Contents of serum SIRT1, p53, endothelial nitric oxide synthase(eNOS) and vascular endothelial growth factor(VEGF) were detected by ELISA. Histopathological changes of aortic tissue were observed after HE staining. Expressions of SIRT1 and p53 mRNAs and proteins in aortic tissue were detected by qPCR and Western blot. RESULTS: Compared with the blank group, the model group showed aging symptoms, the prevention group was similar to the blank group, and the treatment group was slightly better than the model group. Compared with the blank group, content of serum p53, expressions of p53 mRNA and protein in aortic tissues were significantly increased (P<0.05, P<0.01), while contents of serum SIRT1, VEGF, eNOS, and expressions of SIRT1 mRNA and protein in aortic tissues were significantly decreased (P<0.05, P<0.01) in the model group. Compared with the model group, content of serum p53, and expression of p53 mRNA and protein in aortic tissues were significantly decreased (P<0.05, P<0.01) in the prevention and treatment groups, while the contents of serum SIRT1, VEGF, eNOS, and the expressions of SIRT1 mRNA and protein in aortic tissues were significantly increased (P<0.05, P<0.01). Compared with the treatment group, rats in the prevention group displayed significant improvement of the above indexes (P<0.05). Compared with the blank group, the endothelial cells were disordered, the vessel wall was significantly thickened, and the senescent cells were increased in the model group; the blood vessel walls were thinner to varying degrees, and the senescent cells were reduced and unevenly distributed in the prevention and treatment groups. The histopathological lesion was improved more obviously in the prevention group than the treatment group. CONCLUSION: Moxibustion at ST36 can alleviate vascular endothelial injury and oxidative stress in subacute aging rats, which may be related to its effect in regulating the SIRT1/p53 signaling pathway.

[Effects of moxibustion on acupoints at "opening" time on testicular tissue apoptosis in aging rats].

OBJECTIVE: To observe the effect of "lingguibafa" moxibustion at "opening" time on the level of superoxide dismutase(SOD), malondialdehyde(MDA), the protein expressions of B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) in aging model rats. METHODS: SD rats were randomly divided into blank control, model and lingguibafa groups, with 8 rats in each group. The aging model was established by daily intraperitoneal injection of D-galactose (500 mg/kg) for 42 consecutive days. After successful modeling, moxibustion intervention was applied at"lingguibafa" acupoints, 3 moxa-cone for each acupoint, once a day for 28 consecutive days. The contents of SOD and MDA in serum were detected by ELISA. Morphological changes of testicular tissue and the number of Leydig cells were observed after HE staining. Apoptosis rate of testicular cells was detected by TUNEL staining. The protein expression levels of Bcl-2 and Bax in testis were detected by Western blot. RESULTS: Compared with the blank control group, the SOD content in the serum, the number of testicular Leydig cells, the expression level of Bcl-2 protein in testis were significantly decreased (P<0.01) in the model group, while the MDA content in the serum, the apoptosis rate of testicular cells and the expression level of Bax protein in testis were significantly increased (P<0.01). Compared with the model group, the SOD content in serum, the number of testicular Leydig cells, the Bcl-2 protein expression in testis were significantly increased (P<0.01), while the MDA content in serum, the apoptosis rate of testicular cells, the expression level of Bax protein in testis were significantly decreased(P<0.01) in the lingguibafa group. CONCLUSION: Moxibustion on acupoints at "opening" time can delay testicular aging, and the mechanism may be related to balancing the metabolism of free radicals, reducing oxidative damage, and inhibiting the apoptosis of testicular cells.

Discovery of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine derivatives as novel FLT3 covalent inhibitors for the intervention of acute myeloid leukemia.

Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. Among these derivatives, compound F15 displayed potent inhibition activities against FLT3 (IC50 = 123 nM) and FLT3-internal tandem duplication (ITD) by 80% and 26.06%, respectively, at the concentration of 1 µM. Besides, F15 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 253 nM) and MV4-11 (IC50 = 91 nM), as well as BaF3 cells with variety of secondary mutations. Furthermore, cellular mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. Notably, F15 could be considered for further development as potential drug candidate to treat AML.

ALDEFLUOR activity, ALDH isoforms, and their clinical significance in cancers.

High aldehyde dehydrogenase (ALDH) activity is a metabolic feature of adult stem cells and various cancer stem cells (CSCs). The ALDEFLUOR system is currently the most commonly used method for evaluating ALDH enzyme activity in viable cells. This system is applied extensively in the isolation of normal stem cells and CSCs from heterogeneous cell populations. For many years, ALDH1A1 has been considered the most important subtype among the 19 ALDH family members in determining ALDEFLUOR activity. However, in recent years, studies of many types of normal and tumour tissues have demonstrated that other ALDH subtypes can also significantly influence ALDEFLUOR activity. In this article, we briefly review the relationships between various members of the ALDH family and ALDEFLUOR activity. The clinical significance of these ALDH isoforms in different cancers and possible directions for future studies are also summarised.

Prophylactic use of interleukin 6 monoclonal antibody can reduce CRS response of CAR-T cell therapy.

Background: Chimeric antigen receptor T (CAR-T) cell immunotherapy is becoming one of the most promising treatments for hematological malignancies, however, complications such as cytokine release syndrome (CRS) seriously threaten the lives of patients. Interleukin 6(IL-6) monoclonal antibody is the common and useful treatment of CRS, however, it is not clear whether prophylactic use IL-6 monoclonal antibody before CAR-T therapy can reduce the incidence of CRS. Purpose: This study aims to systematically evaluate whether the prophylactic use of IL-6 monoclonal antibody can reduce the incidence of CRS. Data sources and methods: We searched the PubMed, Embase, web of Science, and Cochrane Library databases for studies that reported the prophylactic use of IL-6 monoclonal antibody in the treatment of CRS-related complications of CAR-T cell immunotherapy before December 2022. The literature is screened according to the established inclusion and exclusion criteria, relevant data are extracted, and the quality of the literature is evaluated using the scale Cochrane bias risk assessment tool, and the Review Manager 5.3 is used to draw for related charts. Since the two experimental data only provide the median, the maximum and minimum values of the data, the mean and standard (Standard Deviation, SD) are calculated by this document Delai, and finally use Review Manager for data processing, and STATA software for supplementation. Results: A total of 2 trials with a total of 37 participants were included in this study. Meta-analysis showed that compared with no use of IL-6 monoclonal antibody to prevent CRS, IL-6 monoclonal antibody was given to patients at 8 mg/kg one hour before CAR-T cell infusion, which reduced the incidence of CRS [RR: 0.41 95% confidence interval (0.20, 0.86) I[2] = 0.0% P = 0.338 z = -2.369 (p = 0.018)]. In subgroup analysis, compared with those who did not use IL-6 monoclonal antibody to prevent CRS, IL-6 monoclonal antibody was given to patients at 8 mg/kg one hour before CAR-T cell infusion, which reduced lactate dehydrogenase (LDH)[MD: -617.21, 95% confidence interval (-1104.41, -130.01) I[2] = 0% P = 0.88 Z = 2.48 (P = 0.01)], prophylactic use of IL-6 monoclonal antibody has a significant effect on reducing peak C-reactive protein (CRP) after CAR-T therapy [MD: -11.58, 95% confidence interval (-15.28, -7.88) I[2] = 0.0% P = 0.73 z = 6.14 (p < 0.00001)]. Conclusion: The prophylactic use of IL-6 monoclonal antibody can significantly reduce the incidence of CRS complications after CAR-T therapy, can also reduce LDH vaule and peak CRP vaule after CAR-T therapy. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023487662, identifier CRD42023487662.

The mitochondrial unfolded protein response (UPRmt) protects against osteoarthritis.

The mitochondrial unfolded protein response (UPRmt) is a mitochondrial-to-nuclear signaling pathway that is activated to maintain mitochondrial function when there is an accumulation of misfolded proteins within mitochondria. Mitochondrial function is essential for chondrocyte homeostasis, and mitochondrial dysfunction is a characteristic of osteoarthritis (OA). However, the role of the UPRmt in OA remains unclear. In the present study, the level of the UPRmt was examined in primary mouse chondrocytes subjected to different stresses and in the articular cartilage of OA model mice and OA patients. The relationship between UPRmt activation and OA progression was studied. The UPRmt was induced in primary mouse chondrocytes subjected to diverse stresses and in the cartilage of OA mice. Enhancement of the UPRmt with nicotinamide riboside (NR) significantly improved mitochondrial function, reduced chondrocyte death, attenuated OA pain, and ameliorated OA progression, and the protective effects decreased significantly in chondrocyte-specific Atf5 knockout (ATF5f/fCol2a1-CreERT2) mice. UPRmt induction was also identified in the articular cartilage of OA patients and was associated with reduced chondrocyte death, less severe hip pain, and lower levels of inflammation in synovial fluid. These findings identify the induction of the UPRmt in primary mouse chondrocytes exposed to pathological stresses and in the articular cartilage of OA model mice and OA patients. Enhancement of the UPRmt ameliorates OA progression, suggesting that the UPRmt exerts a protective effect against OA and may be a potential diagnostic and therapeutic strategy for OA.

Targeting PARK7 Improves Acetaminophen-Induced Acute Liver Injury by Orchestrating Mitochondrial Quality Control and Metabolic Reprogramming.

Mitochondrial dysfunction and oxidative stress are considered to be key events in acetaminophen (APAP)-induced acute liver injury. Mitochondrial quality control, including mitophagy and mitochondrial synthesis, can restore mitochondrial homeostasis and thus protect the liver. The role of PARK7, a mitochondrial stress protein, in regulating mitochondrial quality control in APAP-induced hepatotoxicity is unclear. In this study, L02 cells, AML12 cells and C57/BL6 mice were each used to establish models of APAP-induced acute liver injury. PARK7 was silenced in vitro by lentiviral transfection and knocked down in vivo by AAV adeno-associated virus. Changes in cell viability, apoptosis, reactive oxygen species (ROS) level, serum enzyme activity and pathological features were evaluated after APAP treatment. Western blotting, real-time PCR, immunofluorescence, electron microscopy and Seahorse assays were used to detect changes in key indicators of mitochondrial quality control. The results showed that APAP treatment decreased cell viability and increased the apoptosis rate, ROS levels, serum enzyme activity, pathological damage and PARK7 expression. PARK7 silencing or knockdown ameliorated APAP-induced damage to the cells and liver. Furthermore, PARK7 silencing enhanced mitophagy, increased mitochondrial synthesis, and led to a switch from oxidative phosphorylation to glycolysis. Taken together, these results suggest that PARK7 is involved in APAP-induced acute liver injury by regulating mitochondrial quality control and metabolic reprogramming. Therefore, PARK7 may be a promising therapeutic target for APAP-induced liver injury.

Metabolomic and Transcriptomic Analyses Reveal the Characteristics of Tea Flavonoids and Caffeine Accumulation and Regulation between Chinese Varieties (Camellia sinensis var. sinensis) and Assam Varieties (C. sinensis var. assamica).

Flavonoids and caffeine are the major secondary metabolites with beneficial bioactivity for human health in tea plants, and their biosynthesis pathway and regulatory networks have been well-deciphered. However, the accumulation traits of flavonoids and caffeine in different tea cultivars was insufficient in investigation. In this study, metabolomic and transcriptomic analyses were performed to investigate the differences of flavonoids and caffeine accumulation and regulation between Chinese varieties, including the 'BTSC' group with green leaf, the 'BTZY' group with purple foliage, and the 'MYC' group comprising Assam varieties with green leaf. The results showed that most of the flavonoids were down-regulated in the 'MYC' group; however, the total anthocyanin contents were higher than that of the 'BTSC' group while lower than that of the 'BTZY' group. An ANS (Anthocyanin synthase) was significantly up-regulated and supposed to play a key role for anthocyanin accumulation in the 'BTZY' group. In addition, the results showed that esterified catechins were accumulated in the 'BTSC' and 'BTZY' groups with high abundance. In addition, SCPL1A (Type 1A serine carboxypeptidase-like acyltransferases gene) and UGGT (UDP glucose: galloyl-1-O-ß-d-glucosyltransferase gene) potentially contributed to the up-accumulation of catechins esterified by gallic acid. Interestingly, the results found that much lower levels of caffeine accumulation were observed in the 'MYC' group. RT-qPCR analysis suggested that the expression deficiency of TCS1 (Tea caffeine synthase 1) was the key factor resulting in the insufficient accumulation of caffeine in the 'MYC' group. Multiple MYB/MYB-like elements were discovered in the promoter region of TCS1 and most of the MYB genes were found preferentially expressed in 'MYC' groups, indicating some of which potentially served as negative factor(s) for biosynthesis of caffeine in tea plants. The present study uncovers the characteristics of metabolite accumulation and the key regulatory network, which provide a research reference to the selection and breeding of tea varieties.

Lower lip recurrent keratoacanthoma: A case report.

BACKGROUND: This paper introduces a case of recurrent keratoacanthoma (KA). KA is a self-healing disease. Recurrence after surgical resection is rare. In this case, the local application of retinoic acid ointment after the second operation achieved a good prognosis after 2 years of follow-up. CASE SUMMARY: A 76-year-old male patient was admitted to the hospital for "lower lip rupture and scab for 3 mo". Treatment: A rectangular incision was made in the healthy tissue about 3 mm outside the periphery of the lower lip mass, and a modified Bernard sliding flap was designed to completely remove the mass. Pathology showed (lower lip) KA. When the patient returned 6 mo after surgery, the middle mucosa of the lower lip had a bulge with a diameter of about 0.5 cm. The boundary was still clear, the surface was ulcerated. A recurrence of lower lip KA was suspected and a fan-shaped incision was performed in the healthy tissue about 5 mm outside the lesion to completely resect. Pathological showed lower lip KA had recurred. Topical application of tretinoin cream was applied once a day for 3 mo. The lower lip wounds were clean at the 2-year postoperative follow-up and the mucosa was normal. CONCLUSION: Adjuvant retinoic acid treatment after KA surgical resection can achieve good results.

Characteristics of annual mold variations and association with childhood allergic symptoms/diseases via combining surveys and home visit measurements.

The presence of dampness and visible molds leads to concerns of poor indoor air quality which has been consistently linked with increased exacerbation and development of allergy and respiratory diseases. Due to the limitations of epidemiological surveys, the actual fungal exposure characteristics in residences has not been sufficiently understood. This study aimed to characterize household fungal diversity and its annual temporal and spatial variations. We developed combined cross-sectional survey, repeated air sampling around a year, and DNA sequencing methods. The questionnaire survey was conducted in 2019, and 4943 valid cases were received from parents; a follow-up case-control study (11 cases and 12 controls) was designed, and onsite measurements of indoor environments were repeated in typical summer, transient season, and winter; dust from floor and beddings in children's room were collected and ITS based DNA sequencing of totally 68 samples was conducted. Results from 3361 children without changes to their residences since birth verified the significant associations of indoor dampness/mold indicators and prevalence of children-reported diseases, with increased adjusted odd ratios (aORs) >1 for studied asthma, wheeze, allergic rhinitis, and eczema. The airborne fungal concentrations from air sampling were higher than 1000 CFU/m3 in summer, regardless of indoors and outdoors, indicating an intermediate pollution level. The DNA sequencing for dust showed the Aspergillus was the predominant at genus level and the Aspergillus_penicillioides was the most common at species level; while the fungal community and composition varied significantly in different homes and seasons, according to α and ß diversity analyses. The comprehensive research methods contribute to a holistic understanding of indoor fungal exposure, including the concentrations, seasonal variations, community, and diversity, and verifies the relations with children's adverse health outcomes. The study further elucidates the role of microbiome in human health, which helps setting health-protective thresholds and managing mold treatments in buildings, to promote indoor air quality and human well-beings.

Construction of a solid Cox model for AML patients based on multiomics bioinformatic analysis.

Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy. The bone marrow (BM) microenvironment in AML plays an important role in leukemogenesis, drug resistance and leukemia relapse. In this study, we aimed to identify reliable immune-related biomarkers for AML prognosis by multiomics analysis. We obtained expression profiles from The Cancer Genome Atlas (TCGA) database and constructed a LASSO-Cox regression model to predict the prognosis of AML using multiomics bioinformatic analysis data. This was followed by independent validation of the model in the GSE106291 (n=251) data set and mutated genes in clinical samples for predicting overall survival (OS). Molecular docking was performed to predict the most optimal ligands to the genes in prognostic model. The single-cell RNA sequence dataset GSE116256 was used to clarify the expression of the hub genes in different immune cell types. According to their significant differences in immune gene signatures and survival trends, we concluded that the immune infiltration-lacking subtype (IL type) is associated with better prognosis than the immune infiltration-rich subtype (IR type). Using the LASSO model, we built a classifier based on 5 hub genes to predict the prognosis of AML (risk score = -0.086×ADAMTS3 + 0.180×CD52 + 0.472×CLCN5 - 0.356×HAL + 0.368×ICAM3). In summary, we constructed a prognostic model of AML using integrated multiomics bioinformatic analysis that could serve as a therapeutic classifier.

Bioinformatic analysis of circular RNA expression profiles in a rat lumbosacral spinal root avulsion model.

Lumbosacral spinal root avulsion (LSRA) is a severe nerve injury that results in devastating dysfunction in the lower limb. Circular ribonucleic acids (circRNAs) have been reported to be implicated in a variety of diseases. However, the role of circRNAs in LSRA remains unclear. Here, we performed RNA sequencing (RNA-seq) to determine circRNA expression profiles in a rat LSRA model and further investigated their potential functions and the underlying mechanisms by bioinformatic analyses and in vitro experiments. In all, 1708 circRNAs were found to be differentially expressed in spinal cord tissues after LSRA (|fold change| ≥ 2 and p < 0.05), with 591 up-regulated 1117 down-regulated. Meanwhile, 2263 mRNAs were also indentified to be differentially expressed, of which 1471 were upregulated and 792 were downregulated. Eight randomly selected circRNAs and mRNA were successfully verified to be consistent the RNA-seq results by quantitative real-time polymerase chain reaction. Functional analyses based on gene ontology and Kyoto Encyclopedia of Genes and Genomes predicted the potential roles of differentially expressed circRNAs and mRNAs in LSRA, and circRNA/miRNA/mRNA interaction networks revealed that circRNA_7025, a down-regulated circRNA in LSRA, was targeted by two neuronal apoptosis-related miRNAs, rno-miR-1224 and rno-miR-326-5p. Further in vitro experiments revealed that circRNA_7025 protected against oxygen-glucose deprivation induced neuronal apoptosis via the circRNA_7025/miR-1224/miR-326-5p axis. In summary, our results revealed circRNA expression profiles and their potential functions in LSRA. These findings improve our understanding of the pathogenic mechanisms involved in LSRA and might enable us to identify new molecular targets for LSRA.

Time-trends for eczema prevalences among children and adults from 1985 to 2015 in China: a systematic review.

BACKGROUND: Several studies have reported that childhood prevalence of eczema has been increasing worldwide. However, none study quantitatively evaluated prevalence trends of eczema among children and adults in the last 30 years in China. METHODS AND FINDINGS: Via a systematic review of literature databases in English and Chinese, we summarized all studies reporting eczema prevalences from 1985 to 2015 in China as well as diagramed prevalence and eczematous population trends against year for different age groups. A total of 93 studies and 17 studies (16 for children and one for adults) were selected for qualitative and quantitative synthesis, respectively. Childhood lifetime-ever eczema prevalences ranged from 10.0% to 30.0%. Prevalences among 3-12-year-olds children showed increasing trends in most specific cities, but national lifetime-ever eczema prevalences among 13-14-year-olds children decreased from 10.6% in 2001 to 8.6% in 2009 in mainland China. We estimated that about 1.5 million children aged 13-14-year-olds in 2009 and 15.5 million children aged 3-6-year-olds in 2012 had lifetime-ever eczema in mainland China. Similar studies were too few to ascertain time-trends of eczema prevalence among adults. About 39.4, 20.0, and 11.6 million adults aged 15-86-year-olds in 2010 had contact dermatitis, seborrheic dermatitis, and atopic dermatitis in the mainland China, respectively. CONCLUSIONS: The burden of eczema became heavier in young children, whereas perhaps had been reduced in adolescent in China. More studies for eczema prevalence in adults are warranted.

Effect of miR-381-3p/FGF7 axis on the osteogenic differentiation of bone marrow mesenchymal stem cells through MEK/ERK signaling pathway.

Although microRNAs (miRNAs) exert an important role in the osteogenesis of mesenchymal stem cells (MSCs), the effect of miR-381-3p on the osteogenic differentiation in MBD­MSCs is still unclear. The BMMSCs from patients with MBD (MBD­MSC) or normal participants (Normal­MSC) were isolated and induced to differentiation with dexamethasone. BMMSCs were transfected with miR-381-3p mimic, miR-381-3p inhibitor, and FGF7 siRNA to regulate the expression of miR-381-3p or FGF7. The direct binding between miR-381-3p and FGF7 was predicted and confirmed by bioinformatics prediction and luciferase reporter assay. The effect of miR-381-3p on the osteogenic differentiation of BMMSCs was assessed by RT­qPCR, alizarin Red S staining and western blot assays. Isolated BMMSCs showed the regular morphology, and were positive for CD44, CD90 and CD105 but negative for CD34 and CD45 markers. The calcium deposition and the relative mRNA expression levels of ALP, OC and OPN after induction were markedly enhanced. MiR-381-3p was upregulated in BMMSCs. Also, inhibition of miR-381-3p notably promoted osteogenic differentiation, vice versa. Besides, miR-381-3p could directly target FGF7 and negatively modulate the expression of FGF7. Moreover, inhibition of FGF7 attenuated the increase of the calcium deposition, and the relative mRNA expression of ALP, OC and OPN caused by the downregulation of miR-381-3p. In addition, the miR-381-3p inhibitor-induced the enhancement of the relative protein expressions of FGFR2, p-MEK and p-ERK1/2 were significantly reduced by the co-transfection of si-FGF7. Furthermore, the application of LY3214996, the inhibitor of ERK also verified these outcomes. MiR-381-3p directly targeting FGF7 modulated the osteogenic differentiation via MEK/ERK signaling pathway in BMMSCs.