Bencaosome [16:0 Lyso PA+XLGB28-sRNA] improves osteoporosis by simultaneously promoting osteogenesis and inhibiting osteoclastogenesis in mice.

Osteoporosis (OP) is a systemic metabolic bone disease resulting in reduced bone strength and increased susceptibility to fractures, making it a significant public health and economic problem worldwide. The clinical use of anti-osteoporosis agents is limited because of their serious side effects or the high cost of long-term use. The Xianlinggubao (XLGB) formula is an effective traditional Chinese herbal medicine commonly used in orthopedics to treat osteoporosis; however, its mechanism of action remains unclear. In this study, we screened 40 small RNAs derived from XLGB capsules and found that XLGB28-sRNA targeting TNFSF11 exerted a significant anti-osteoporosis effect in vitro and in vivo by simultaneously promoting osteogenesis and inhibiting osteoclastogenesis. Oral administration of bencaosome [16:0 Lyso PA+XLGB28-sRNA] effectively improved bone mineral density and reduced the damage to the bone microstructure in mice. These results suggest that XLGB28-sRNA may be a novel oligonucleotide drug that promotes osteogenesis and inhibits osteoclastogenesis in mice.

Oral administration of herbal oligonucleotide drug JGL-sRNA-h7 ameliorates hyperglycemia in db/db mice and beagle dogs.

Type 2 diabetes mellitus is a prevalent metabolic disease, posing a considerable threat to public health. Oligonucleotide drugs have proven to be a promising field of therapy for the diseases. In this study, we reported that a herbal small RNA (sRNA), JGL-sRNA-h7 (B34735529, F1439.L002444.A11), could exhibit potent hypoglycemic effects by targeting glucose-6-phosphatase. Oral administration of sphingosine (d18:1)-JGL-sRNA-h7 bencaosomes ameliorated hyperglycemia and diabetic kidney injury better than metformin in db/db mice. Furthermore, glucose tolerance was also improved in sphingosine (d18:1)-JGL-sRNA-h7 bencaosomes-treated beagle dogs. Our study indicates that JGL-sRNA-h7 could be a promising hypoglycemic oligonucleotide drug.

M1-type microglia-derived exosomes contribute to blood-brain barrier damage.

BACKGROUND: As a key substance for intercellular communication, exosomes could be a potential strategy for stroke treatment. Activated microglia disrupt the integrity of blood-brain barrier (BBB) to facilitate the stroke process. Hence, this study was designed to investigate the effect of microglia-derived exosomes on BBB cell model injury and to explore the underlying molecular mechanisms. METHODS: M1 polarization of BV2 cells was induced with LPS and their derived exosomes were isolated. Astrocytes were cultured in primary culture and constructed with End3 cells as a BBB cell model. After co-culture with exosomes, the BBB cell model was examined for changes in TEER, permeability, and expression of BBB-related proteins (Claudin-1, Occludin, ZO-1 and JAM). Resting and M1-type BV2 cell-derived exosomes perform small RNA sequences and differentially expressed miRNAs (DE-miRNAs) are identified by bioinformatics. RESULTS: M1-type BV2 cell-derived exosomes decreased End3 cell viability, and increased their apoptotic ratio. Moreover, M1 type BV2 cell-derived exosomes dramatically enhanced the permeability of BBB cell model, and diminished the TEER and BBB-related protein (Claudin-1, Occludin, ZO-1) expression. Notably, resting BV2 cell-derived exosomes had no effect on the integrity of BBB cell model. Sequencing results indicated that 71 DE-miRNAs were present in M1 BV2 cell-derived exosomes, and their targets mediated neurological development and signaling pathways such as MAPK and cAMP. RT-qPCR confirmed the differential expression of mmu-miR-125a-5p, mmu-miR-122b-3p, mmu-miR-139-3p, mmu-miR-330-3p, mmu-miR-3057-5p and mmu-miR-342-3p consistent with the small RNA sequence. Furthermore, Creb1, Jun, Mtor, Frk, Pabpc1 and Sdc1 are the most well-connected proteins in the PPI network. CONCLUSION: M1-type microglia-derived exosomes contribute to the injury of BBB cell model, which has the involvement of miRNAs. Our findings provide new perspectives and potential mechanisms for future M1 microglia-derived exosomes as therapeutic targets in stroke.

A Case of Cerebral Large-Vessel Vasculitis Concomitant Fahr Syndrome in Systemic Lupus Erythematosus.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a heterogenous, devastating autoimmune inflammatory disease with multiorgan involvement. A variety of neurological and psychiatric symptoms may be caused by nervous system involvement, termed neuropsychiatric systemic lupus erythematosus. CASE REPORT: We describe a young man newly diagnosed with SLE who had a stroke as an initial symptom and was found to have cerebral large-vessel vasculitis and Fahr syndrome. CONCLUSIONS: The novelties of this report are the extensive cerebral calcification demonstrated on head computerized tomography in a patient with SLE, and the depiction of an underlying vasculitis on high-resolution magnetic resonance vessel wall imaging. It is our aim to describe this atypical form of neuropsychiatric systemic lupus erythematosus onset and to make known the usefulness of the new magnetic resonance imaging techniques for the diagnosis of cerebral large-vessel vasculitis.

Nonlinear topological laser on the non-Hermitian Haldane model with higher-order corner states.

The non-Hermitian skin effect (NHSE) on the non-Hermitian Haldane model with gain and loss on the honeycomb lattice with the outline of a triangle is discussed. The NHSE only occurs on the edge of the lattice, transforming the edge modes into the higher-order corner modes. The NHSE can also occur on a lattice with only loss, which can be treated as a lattice with gain and loss as well as a global loss added to it. When the saturated gain is added to the three corner sites of the dissipative lattice, a single-mode laser system is obtained. When any one site is stimulated initially, the system will reach a saturated state depending on the distribution of the corner modes, and the stable laser light is emitted by sites at the corners.

Safety evaluation of INFAT® PLUS: Acute, genetic, teratogenic, and subchronic (90-day) toxicity studies.

INFAT®PLUS, is a sn-2 palmitate enriched fat ingredient intended for infant formula. A battery of toxicological studies was conducted in accordance with the Food Safety Toxicological Assessment GB-15193 (China), to confirm the safety of INFAT®PLUS. In the acute oral toxicity test, the LD50 of INFAT® PLUS was higher than 53.4 g /kg BW and 26.7 g/kg BW for ICR mice and SD rats, respectively. In a subchronic study, INFAT® PLUS was administered by oral gavage to SD rats with maximal daily dose of 8.90 g/kg BW for 90 days. No treatment-related clinical signs or mortalities were observed. The no-observed-adverse-effect level (NOAEL) was set at 8.90 g/kg BW. Similarly, no evidence of genotoxicity effect was noted in several in vitro and in vivo tests, including bacterial reverse mutation (Ames) test, mouse erythrocyte micronucleus test, and chromosome aberration test of mouse spermatogonia/spermatocyte. For the teratogenic evaluations, no toxicological signs were observed in both pregnant SD rat and fetuses, and the NOAEL of INFAT® PLUS was determined to be 8.90 g/kg BW. Based on the obtained results we concluded that INFAT® PLUS was found non-toxic under the experimental conditions, and the totality of the safety data supports its use for infant nutrition.

A comprehensive analysis of the Bencao (herbal) small RNA Atlas reveals novel RNA therapeutics for treating human diseases.

Cross-kingdom herbal miRNA was first reported in 2012. Using a modified herbal extraction protocol, we obtained 73,677,287 sequences by RNA-seq from 245 traditional Chinese Medicine (TCM), of which 20,758,257 were unique sequences. We constructed a Bencao (herbal) small RNA (sRNA) Atlas ( http://bencao.bmicc.cn ), annotated the sequences by sequence-based clustering, and created a nomenclature system for Bencao sRNAs. The profiles of 21,757 miRNAs in the Atlas were highly consistent with those of plant miRNAs in miRBase. Using software tools, our results demonstrated that all human genes might be regulated by sRNAs from the Bencao sRNA Atlas, part of the predicted human target genes were experimentally validated, suggesting that Bencao sRNAs might be one of the main bioactive components of herbal medicines. We established roadmaps for oligonucleotide drugs development and optimization of TCM prescriptions. Moreover, the decoctosome, a lipo-nano particle consisting of 0.5%-2.5% of the decoction, demonstrated potent medical effects. We propose a Bencao (herbal) Index, including small-molecule compounds (SM), protein peptides (P), nucleic acid (N), non-nucleic and non-proteinogenic large-molecule compounds (LM) and elements from Mendeleev's periodic table (E), to quantitatively measure the medical effects of botanic medicine. The Bencao sRNA Atlas is a resource for developing gene-targeting oligonucleotide drugs and optimizing botanical medicine, and may provide potential remedies for the theory and practice of one medicine.

Integrated analysis of single-cell and bulk RNA sequencing data reveals an immunostimulatory microenvironment in tumor thrombus of osteosarcoma.

Tumor thrombus of bone sarcomas represents a unique reservoir for various types of cancer and immune cells, however, the investigation of tumor thrombus at a single-cell level is very limited. And it is still an open question to identify the thrombus-specific tumor microenvironment that is associated with the tumor-adaptive immune response. Here, by analyzing bulk tissue and single-cell level transcriptome from the paired thrombus and primary tumor samples of osteosarcoma (OS) patients, we define the immunostimulatory microenvironment in tumor thrombus of OS with a higher proportion of tumor-associated macrophages with M1-like states (TAM-M1) and TAM-M1 with high expression of CCL4. OS tumor thrombus is found to have upregulated IFN-γ and TGF-ß signalings that are related to immune surveillance of circulating tumor cells in blood circulation. Further multiplexed immunofluorescence staining of the CD3/CD4/CD8A/CD68/CCL4 markers validates the immune-activated state in the tumor thrombus samples. Our study first reports the transcriptome differences at a single-cell level between tumor thrombus and primary tumor in sarcoma.

Risk assessment of mechanic thrombectomy on post-stroke seizures: a systematical review and meta-analysis.

PURPOSE: We conducted a systematic review and meta-analysis to evaluate the risk of early and late onset seizures following stroke mechanic thrombectomy (MT) compared with other systematic thrombolytic strategies. METHODS: A literature search was conducted to identify articles covering databases (PubMed, Embase, and Cochrane Library) published from 2000 to 2022. The primary outcome was the incidence of post-stroke epilepsy or seizures following MT or in combination with intravenous thrombolytics therapy. Risk of bias was assessed by recording study characteristics. The study was conducted according to the PRISMA guidelines. RESULTS: There were 1346 papers in the search results, and 13 papers were included in the final review.We identified 29,793 patients with stroke, of which 695 had seizures. Pooled incidence of post-stroke seizures had no significant difference between mechanic thrombolytic group and other thrombolytic strategy group (OR=0.95 (95%CI= 0.75-1.21); Z=0.43; p=0.67). In subgroup analysis, mechanic group have a lower risk of post-stroke early onset of seizures (OR=0.59 (95%CI=0.36-0.95); Z=2.18; p<0.05) but showed no significant difference in post-stroke late onset of seizures (OR=0.95 (95%CI= 0.68-1.32); Z=0.32; p=0.75). CONCLUSIONS: MT may be associated with a lower risk of post-stroke early onset of seizures, despite MT does not affect the pooled incidence of post-stroke seizures compared with other systematic thrombolytic strategies.

Influence of a topological artificial atom chain on the transmission properties of a cavity.

We explore the influence of the artificial atomic chain on the input-output relation of the cavity. Specifically, we extend the atom chain to the one-dimensional Su-Schrieffer-Heeger (SSH) chain to check the role of atomic topological non-trivial edge state on the transmission characteristics of the cavity. The superconducting circuits can realize the artificial atomic chain. Our results show that the atom chain is not equivalent to atom gas, and the transmission properties of the cavity containing the atom chain are entirely different from that of the cavity containing atom gas. When the atom chain is arranged in the form of topological non-trivial SSH model, the atom chain can be equivalent to the three-level atom, in which the edge state contributes to the second level and is resonant with the cavity, while the high-energy bulk state contributes to form the third level and is greatly detuned with the cavity. Therefore, the transmission spectrum shows no more than three peaks. This allows us to infer the topological phase of the atomic chain and the coupling strength between the atom and the cavity only from the profile of the transmission spectrum. Our work is helping to understand the role of topology in quantum optics.

Expression of OLR1 gene on tumor-associated macrophages of head and neck squamous cell carcinoma, and its correlation with clinical outcome.

Head and neck squamous cell carcinoma (HNSCC) is one of the most heavily immune infiltrated human tumors, having distinct immune subtypes associated with different molecular characteristics and clinical outcomes. The tumor microenvironment (TME) of HNSCC which was dominated by tumor-associated macrophages (TAMs) had a relatively inferior prognosis. High levels of oxidized low-density lipoprotein receptor 1 (OLR1) expression are associated with more aggressive and metastatic characteristics in multiple cancers. However, the link between the OLR1 expression and immunosuppression of TME, and the molecular mechanisms which govern intratumoral TAMs behavior are unclear. Here, we performed the transcriptional analysis based on a single-cell RNA-sequencing (scRNA-seq) dataset of HNSCC, and found that the OLR1 expression was specifically enriched on the TAMs. Evaluation of protein expression within histologic sections of primary HNSCC patient samples showed a co-expression pattern of OLR1 and CD68 on macrophages. A total of 498 tumor samples of HNSCC patients from The Cancer Genome Atlas (TCGA) database were also analyzed. Remarkably, OLR1 expression was dramatically higher in HNSCC tissues than that in adjacent normal tissues, and the patients with high levels of OLR1 expression had significantly unfavorable overall survival (Hazard Ratio = 1.724, log-rank P-value = 0.0066) when compared to patients harboring low expression levels of OLR1. In summary, we reported that the specific expression of OLR1 on the TAMs was significantly correlated with poor survival outcomes, revealing that OLR1 could serve as a potential prognosis marker and promising target for immunotherapy in HNSCC.

Oral administration of the herbal oligonucleotide XKC-sRNA-h3 prevents angiotensin II-induced hypertension in mice.

Hypertension has become a growing public health concern worldwide. In fact, hypertension is commonly associated with increased morbidity and mortality. Currently, oligonucleotide drugs have proven to be promising therapeutic agents for various diseases. In the present study, we aimed to demonstrate that a herbal small RNA (sRNA), XKC-sRNA-h3 (B55710460, F221. I000082.B11), exhibits potent antihypertensive effects by targeting angiotensin-converting enzyme (ACE) in mice. When compared with captopril, oral administration of the sphingosine (d18:1)-XKC-sRNA-h3 bencaosome more effectively prevented angiotensin II-induced hypertensive cardiac damage and alleviated kidney injury in mice. Such findings indicated that XKC-sRNA-h3 may be a novel orally available ACE inhibitor type oligonucleotide drug for hypertension.

Herbal small RNAs in patients with COVID-19 linked to reduced DEG expression.

In China, more than 80% of patients with coronavirus disease 2019 (COVID-19) received traditional Chinese medicine (TCM) as a treatment and their clinical efficacy have been reported. However, the underlying molecular mechanism remains unclear. Previous studies have identified herbal small RNAs (sRNAs) as novel functional components. In this study, a cohort of 22 patients with COVID-19 treated with Toujie Quwen (TQ) granules was analyzed. We observed thousands of herbal small RNAs that entered the blood cells of patients after the consumption of TQ granules. In response to this treatment, the reduced differentially expressed genes (DEGs) were highly correlated with the predicted target genes of the most prevalent herbal sRNAs detected in the blood. Moreover, the predicted target genes of the top 30 sRNAs from each of the 245 TCMs in the Bencao sRNA Atlas overlapped with 337 upregulated DEGs in patients with mild COVID-19, and 33 TCMs, with more than 50% overlapping genes were identified as effective TCMs. These predicted target genes of top 30 sRNAs from Juhong, Gualoupi and Foshou were confirmed experimentally. Our results not only elucidated a novel molecular mechanism of TCM potential clinical efficacy for COVID-19 patients, but also provided 33 effective COVID-19 TCMs for prescription optimization.

Topological laser with higher-order corner states in the 2-dimensional Su-Schrieffer-Heeger model.

A nonlinear non-Hermitian topological laser system based on the higher-order corner states of the 2-dimensional (2D) Su-Schrieffer-Heeger (SSH) model is investigated. The topological property of this nonlinear non-Hermitian system described by the quench dynamics is in accordance with that of a normal 2D SSH model. In the topological phase, all sites belonging to the topological corner states begin to emit stable laser light when a pulse is given to any one site of the lattice, while no laser light is emitted when the lattice is in the trivial phase. Furthermore, the next-nearest-neighbor (NNN) couplings are introduced into the strong-coupling unit cells of the 2D SSH model, which open a band gap in the continuous band structure. In the topological phase, similar to the case of 2D SSH model without NNN couplings, the corner sites can emit stable laser light due to the robustness of the higher-order corner states when the NNN couplings are regarded as the perturbation. However, amplitude of the stimulated site does not decay to zero in the trivial phase, because the existence of the NNN couplings in the strong-coupling unit cells make the lattice like one in the tetramer limit, and a weaker laser light is emitted by each corner.

Auxin contributes to jasmonate-mediated regulation of abscisic acid signaling during seed germination in Arabidopsis.

Abscisic acid (ABA) represses seed germination and postgerminative growth in Arabidopsis thaliana. Auxin and jasmonic acid (JA) stimulate ABA function; however, the possible synergistic effects of auxin and JA on ABA signaling and the underlying molecular mechanisms remain elusive. Here, we show that exogenous auxin works synergistically with JA to enhance the ABA-induced delay of seed germination. Auxin biosynthesis, perception, and signaling are crucial for JA-promoted ABA responses. The auxin-dependent transcription factors AUXIN RESPONSE FACTOR10 (ARF10) and ARF16 interact with JASMONATE ZIM-DOMAIN (JAZ) repressors of JA signaling. ARF10 and ARF16 positively mediate JA-increased ABA responses, and overaccumulation of ARF16 partially restores the hyposensitive phenotype of JAZ-accumulating plants defective in JA signaling in response to combined ABA and JA treatment. Furthermore, ARF10 and ARF16 physically associate with ABSCISIC ACID INSENSITIVE5 (ABI5), a critical regulator of ABA signaling, and the ability of ARF16 to stimulate JA-mediated ABA responses is mainly dependent on ABI5. ARF10 and ARF16 activate the transcriptional function of ABI5, whereas JAZ repressors antagonize their effects. Collectively, our results demonstrate that auxin contributes to the synergetic modulation of JA on ABA signaling, and explain the mechanism by which ARF10/16 coordinate with JAZ and ABI5 to integrate the auxin, JA, and ABA signaling pathways.

Biomechanical Study on Atlantoaxial Dislocation Combined with Basilar Invagination by Different Posterior Internal Fixation Methods / 医用生物力学

Objective To investigate biomechanical differences of two posterior occipitocervical internal fixation techniques for treating basilar invagination with atlantoaxial dislocation (BI-AAD). Methods Intra-articular cage + posterior occipital plate+C2 pedicle screw (Cage+C2PS+OP), and intra-articular cage+C1 lateral mass screw+C2PS (Cage+C1LMS+C2PS) models were established based on occipitocervical CT data of the BI-AAD and clinical operation scheme, and the stability of atlantoaxial joint and stress distribution characteristics of C2 endplate and implanted instruments under different motion states were analyzed. Results Compared with the Cage+C1LMS+C2PS model, the atlantoaxial range of motion ( ROM) under flexion, extension, lateral bending and axial rotation in the Cage+C2PS+OP model were reduced by 5. 26% , 33. 33% , 43. 75% , -5. 56% , and stress peak of screw-rod fixation system were reduced by 47. 81% , 60. 90% , 48. 45% , 39. 14% , respectively. Under two internal fixation modes, stresses of C2 endplate and cage were mainly distributed on the compressive side during the motion, and both the screw-bone interface and the caudal side of screw subjected to large loading. Conclusions Two internal fixation methods could provide similar stability. However, the stress concentration of screw-rod system was more obvious and the possibility of screw loosening and fracture was greater under Cage+ C1LMS+C2PS fixation.

Study on the correlation between marital status and mild cognitive impairment in older adults / 中华老年医学杂志

Objective:To explore the relationship between marital status and mild cognitive impairment in older adults.Methods:This study is a cluster random sampling.From January to December 2020, a questionnaire survey was conducted among older adults aged 60 years and over in four cities of Hebei Province.Finally, 2690 older adults with mild cognitive impairment and normal cognitive function were enrolled.The older adults were divided into 2 groups according to their marital status: married and living with their spouses(group E1), divorced or living alone(group E2). The mini-mental state examination(MMSE)scores of older adults in the two groups were compared.Moreover, the cognitive differences of older adults between the two groups and the interaction of marital status, social activities and life events on cognitive outcomes were analyzed.Results:The married older adults with partners had better cognitive preservation( P<0.01). The more life events were more likely to cause cognitive impairment( P<0.01), and the interaction of marital status, social activities and life events had a significant impact on cognition( P<0.01). Older men who were married and lived with spouse had better cognition than older women who were married and lived with spouse( P<0.05 in Model 3). The cognition of widowed elderly women was better than those of widowed elderly men( P<0.1 in Model 1; P<0.1 in Model 2). Among elderly men, the cognition of those married and living with spouse was better than that those of widowed( P<0.01 in models 1 and 2, P<0.1 in model 3). Among elderly women, those married and living with spouse had better cognitive outcomes than those widowed( P<0.01 in Model 1, P<0.01 in Model 2). Conclusions:Marital companionship is a protective factor for the cognition of older adults, and there are gender differences in the impact of marital status on cognition in late life.

Clinical analysis of 10 cases of multi-center tumor necrosis factor receptor-associated periodic syndrome / 中华儿科杂志

Objective: To summarize the clinical characteristics of tumour necrosis factor receptor-associated periodic syndrome (TRAPS) in children. Methods: The clinical manifestations, laboratory tests, genetic testing and follow-up of 10 children with TRAPS from May 2011 to May 2021 in 6 hospitals in China were retrospectively analyzed. Results: Among the 10 patients with TRAPS, including 8 boys and 2 girls. The age of onset was 2 (1, 5) years, the age of diagnosis was (8±4) years, and the time from onset to diagnosis was 3 (1, 7) years. A total of 7 types of TNFRSF1A gene variants were detected, including 5 paternal variations, 1 maternal variation and 4 de novo variations. Six children had a family history of related diseases. Clinical manifestations included recurrent fever in 10 cases, rash in 4 cases, abdominal pain in 6 cases, joint involvement in 6 cases, periorbital edema in 1 case, and myalgia in 4 cases. Two patients had hematological system involvement. The erythrocyte sedimentation rate and C-reactive protein were significantly increased in 10 cases. All patients were negative for autoantibodies. In the course of treatment, 5 cases were treated with glucocorticoids, 7 cases with immunosuppressants, and 7 cases with biological agents. Conclusions: TRAPS is clinically characterized by recurrent fever accompanied by joint, gastrointestinal, skin, and muscle involvement. Inflammatory markers are elevated, and autoantibodies are mostly negative. Treatment mainly involves glucocorticoids, immunosuppressants, and biological agents.