Functions and mechanisms of adenosine and its receptors in sleep regulation.

Sleep is a natural and recurring state of life. Long-term insomnia can lead to physical and mental fatigue, inattention, memory loss, anxiety, depression and other symptoms, imposing immense public health and economic burden worldwide. The sleep and awakening regulation system is composed of many nerve nuclei and neurotransmitters in the brain, and it forms a neural network that interacts and restricts each other to regulate the occurrence and maintenance of sleep-wake. Adenosine (AD) is a neurotransmitter in the central nervous system and a driver of sleep. Meanwhile, the functions and mechanisms underlying sleep-promoting effects of adenosine and its receptors are still not entirely clear. However, in recent years, the increasing evidence indicated that adenosine can promote sleep through inhibiting arousal system and activating sleep-promoting system. At the same time, astrocyte-derived adenosine in modulating sleep homeostasis and sleep loss-induced related cognitive and memory deficits plays an important role. This review, therefore, summarizes the current research on the functions and possible mechanisms of adenosine and its receptors in the regulation of sleep and homeostatic control of sleep. Understanding these aspects will provide us better ideas on clinical problems such as insomnia, hypersomnia and other sleep disorders.

Determination of anthocyanins, organic acids, and phenolic acids in hibiscus market products using LC/UV/MS.

Hibiscus sabdariffa has gained increasing attention from consumers as a natural, healthy food ingredient, leading to a myriad of available products, yet there is a lack of understanding of the quality and chemical diversity among commercially available hibiscus products. Here, we conducted a survey on the chemistry of 29 hibiscus products (calyces, beverages, and extracts). UHPLC-DAD and UHPLC-QQQ/MS methods with high sensitivity and selectivity were developed to evaluate the chemical profiles pertaining to the sensory attributes (color and taste). Two major anthocyanins (delphinidin-3-sambubioside and cyanindin-3-sambubioside), eight organic acids, and 23 phenolic acids were identified and quantified in hibiscus market products. The results showed that hibiscus samples contained < 0.001-2.372% of total anthocyanins, 0.073-78.002% of total organic acids, and 0.001-1.041% of total phenolic acids, and demonstrated significant variations in market products. This is the first time that an in-depth organic acid profiling was conducted on hibiscus products using UHPLC-QQQ/MS. This method can also be extended to chemical profiling, sensory analysis, quality control, authentication, and standardization of other natural products.

Glycosaminoglycans: Participants in Microvascular Coagulation of Sepsis.

Sepsis represents a syndromic response to infection and frequently acts as a common pathway leading to fatality in the context of various infectious diseases globally. The pathology of severe sepsis is marked by an excess of inflammation and activated coagulation. A substantial contributor to mortality in sepsis patients is widespread microvascular thrombosis-induced organ dysfunction. Multiple lines of evidence support the notion that sepsis induces endothelial damage, leading to the release of glycosaminoglycans, potentially causing microvascular dysfunction. This review aims to initially elucidate the relationship among endothelial damage, excessive inflammation, and thrombosis in sepsis. Following this, we present a summary of the involvement of glycosaminoglycans in coagulation, elucidating interactions among glycosaminoglycans, platelets, and inflammatory cells. In this section, we also introduce a reasoned generalization of potential signal pathways wherein glycosaminoglycans play a role in clotting. Finally, we discuss current methods for detecting microvascular conditions in sepsis patients from the perspective of glycosaminoglycans. In conclusion, it is imperative to pay closer attention to the role of glycosaminoglycans in the mechanism of microvascular thrombosis in sepsis. Dynamically assessing glycosaminoglycan levels in patients may aid in predicting microvascular conditions, enabling the monitoring of disease progression, adjustment of clinical treatment schemes, and mitigation of both acute and long-term adverse outcomes associated with sepsis.

Immune-Related Molecules CD3G and FERMT3: Novel Biomarkers Associated with Sepsis.

Sepsis ranks among the most common health problems worldwide, characterized by organ dysfunction resulting from infection. Excessive inflammatory responses, cytokine storms, and immune-induced microthrombosis are pivotal factors influencing the progression of sepsis. Our objective was to identify novel immune-related hub genes for sepsis through bioinformatic analysis, subsequently validating their specificity and potential as diagnostic and prognostic biomarkers in an animal experiment involving a sepsis mice model. Gene expression profiles of healthy controls and patients with sepsis were obtained from the Gene Expression Omnibus (GEO) and analysis of differentially expressed genes (DEGs) was conducted. Subsequently, weighted gene co-expression network analysis (WGCNA) was used to analyze genes within crucial modules. The functional annotated DEGs which related to the immune signal pathways were used for constructing protein-protein interaction (PPI) analysis. Following this, two hub genes, FERMT3 and CD3G, were identified through correlation analyses associated with sequential organ failure assessment (SOFA) scores. These two hub genes were associated with cell adhesion, migration, thrombosis, and T-cell activation. Furthermore, immune infiltration analysis was conducted to investigate the inflammation microenvironment influenced by the hub genes. The efficacy and specificity of the two hub genes were validated through a mice sepsis model study. Concurrently, we observed a significant negative correlation between the expression of CD3G and IL-1ß and GRO/KC. These findings suggest that these two genes probably play important roles in the pathogenesis and progression of sepsis, presenting the potential to serve as more stable biomarkers for sepsis diagnosis and prognosis, deserving further study.

A novel method to quantify chitosan in aqueous solutions by ultrahigh-performance liquid chromatography-tandem mass spectrometry.

In this study, a novel and accurate quantitative analysis method for the direct determination of chitosan (CS) in aqueous solutions using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) is presented. By detecting the mass spectrum response intensity of a series of CS characteristic ion pairs, the sample concentration (abscissa) was linearly fitted with the total ion current (TIC) response intensity of its characteristic ion pairs (ordinate). A reliable standard curve was derived for quantifying CS in the range of 125-4000 ng/mL. Under the detection conditions, this CS quantification method yielded acceptable specificity (no interference peak), linearity (with correlation coefficient (r2) values >0.999), precision (acceptable limit RSDr < 3 %, RSDR < 6 %), accuracy (RE within the acceptable limits of ±5 %), and stability (acceptable limit RE within ±5 %, RSDr < 3 %). Moreover, the applicability of measurement was verified when a series of substrates did not interact with CS in the solution. Results have verified the applicability of this method for determining CS content in different composites. This study provides a method for determining CS content with significant practical value and economic benefit.

M2 Macrophage-Derived Exosomal lncRNA MIR4435-2HG Promotes Progression of Infantile Hemangiomas by Targeting HNRNPA1.

Purpose: Infantile hemangiomas (IHs) are commonly observed benign tumors that can cause serious complications. M2-polarized macrophages in IHs promote disease progression. In this study, we investigated the role of M2 macrophage-derived exosomal lncRNA MIR4435-2HG in IHs. Patients and Methods: Exosomes derived from M2 polarized macrophages were extracted. Next, using cell co-culture or transfection, we investigated whether M2 polarized macrophage-derived exosomes (M2-exos) can transport MIR4435-2HG to regulate the proliferation, migration, invasion, and angiogenesis of hemangioma-derived endothelial cells (HemECs). RNA-seq and RNA pull-down assays were performed to identify targets and regulatory pathways of MIR4435-2HG. We explored the possible mechanisms through which MIR4435-2HG regulates the biological function of HemECs. Results: M2-exos significantly enhanced the proliferation, migration, invasion, and angiogenesis of HemECs. Thus, HemECs uptake M2-exos and promote biological functions through the inclusion of MIR4435-2HG. RNA-seq and RNA pull-down experiments confirmed that MIR4435-2HG regulates of HNRNPA1 expression and directly binds to HNRNPA1, consequently affecting the NF-κB signal pathway. Conclusion: MIR4435-2HG of M2-exos promotes the progression of IHs and enhances the proliferation, migration, invasion, and angiogenesis of HemECs by directly binding to HNRNPA1. This study not only reveals the mechanism of interaction between M2 macrophages and HemECs, but also provides a promising therapeutic target for IHs.

The role of sclerostin in lipid and glucose metabolism disorders.

Lipid and glucose metabolism are critical for human activities, and their disorders can cause diabetes and obesity, two prevalent metabolic diseases. Studies suggest that the bone involved in lipid and glucose metabolism is emerging as an endocrine organ that regulates systemic metabolism through bone-derived molecules. Sclerostin, a protein mainly produced by osteocytes, has been therapeutically targeted by antibodies for treating osteoporosis owing to its ability to inhibit bone formation. Moreover, recent evidence indicates that sclerostin plays a role in lipid and glucose metabolism disorders. Although the effects of sclerostin on bone have been extensively examined and reviewed, its effects on systemic metabolism have not yet been well summarized. In this paper, we provide a systemic review of the effects of sclerostin on lipid and glucose metabolism based on in vitro and in vivo evidence, summarize the research progress on sclerostin, and prospect its potential manipulation for obesity and diabetes treatment.

Pain mediates the improvement of social functions of repeated intravenous ketamine in patients with unipolar and bipolar depression.

OBJECTIVE: Previous research has shown that ketamine can improve social functions. In addition, evidence also suggests that ketamine can alleviate pain. Herein, we propose that ketamine-induced improvements in pain and depression are partially mediated by a reduction in pain. We aimed to determine whether improvements in pain-mediated changes in psychological function were associated with ketamine treatment. METHOD: This trial included unipolar or bipolar patients (n = 103) who received 6 intravenous infusions (0.5 mg/kg) of ketamine over 2 weeks. The severity of current depressive symptoms and social function were evaluated by the Montgomery-Åsberg Depression Scale (MADRS), Self-Rating Depression Scale (SDS) and Global Assessment Function (GAF), respectively, at baseline and on day 13 and day 26. At the same time points, the three dimensions of pain, including the sensory index, affective index and present pain intensity (PPI), were measured by the Simple McGill Pain Scale (SF-MPQ). RESULTS: The mixed model results showed that ketamine plays an important role in improving the psychosocial functioning of patients. There was a significant decrease from baseline to the day 13 and day 26, indicating that the pain index of the patient improved significantly. Mediation analysis showed that for SDS score (coef = -5.171, 95 % CI[-6.317, -4.025]) and GAF score (coef = 1.021, 95 % CI[0.848, 1.194]), the overall effect of ketamine was observable. The overall indirect and direct effects of ketamine on social functioning were significant (SDS: direct: coef = -1949 to -2114; total indirect: from 0.594 to 0.664; GAF: from 0.399 to 0.427; total indirect: coef = 0.593 to 0.664). The MADRS total score and emotional index were important mediators of the association between ketamine treatment and improvements in subjective and objective social functioning. CONCLUSION: Depressive symptom severity and the affective index of pain partially mediated improvements in social function after six repeated ketamine treatments among patients with bipolar or unipolar depressive disorder.

The roles of hepatokine and osteokine in liver-bone crosstalk: Advance in basic and clinical aspects.

Both the liver and bone are important secretory organs in the endocrine system. By secreting organ factors (hepatokines), the liver regulates the activity of other organs. Similarly, bone-derived factors, osteokines, are created during bone metabolism and act in an endocrine manner. Generally, the dysregulation of hepatokines is frequently accompanied by changes in bone mass, and osteokines can also disrupt liver metabolism. The crosstalk between the liver and bone, particularly the function and mechanism of hepatokines and osteokines, has increasingly gained notoriety as a topic of interest in recent years. Here, based on preclinical and clinical evidence, we summarize the potential roles of hepatokines and osteokines in liver-bone interaction, discuss the current shortcomings and contradictions, and make recommendations for future research.

Using deeply time-series semantics to assess depressive symptoms based on clinical interview speech.

Introduction: Depression is an affective disorder that contributes to a significant global burden of disease. Measurement-Based Care (MBC) is advocated during the full course management, with symptom assessment being an important component. Rating scales are widely used as convenient and powerful assessment tool, but they are influenced by the subjectivity and consistency of the raters. The assessment of depressive symptoms is usually conducted with a clear purpose and restricted content, such as clinical interviews based on the Hamilton Depression Rating Scale (HAMD), so that the results are easy to obtain and quantify. Artificial Intelligence (AI) techniques are used due to their objective, stable and consistent performance, and are suitable for assessing depressive symptoms. Therefore, this study applied Deep Learning (DL)-based Natural Language Processing (NLP) techniques to assess depressive symptoms during clinical interviews; thus, we proposed an algorithm model, explored the feasibility of the techniques, and evaluated their performance. Methods: The study included 329 patients with Major Depressive Episode. Clinical interviews based on the HAMD-17 were conducted by trained psychiatrists, whose speech was simultaneously recorded. A total of 387 audio recordings were included in the final analysis. A deeply time-series semantics model for the assessment of depressive symptoms based on multi-granularity and multi-task joint training (MGMT) is proposed. Results: The performance of MGMT is acceptable for assessing depressive symptoms with an F1 score (a metric of model performance, the harmonic mean of precision and recall) of 0.719 in classifying the four-level severity of depression and an F1 score of 0.890 in identifying the presence of depressive symptoms. Disscussion: This study demonstrates the feasibility of the DL and the NLP techniques applied to the clinical interview and the assessment of depressive symptoms. However, there are limitations to this study, including the lack of adequate samples, and the fact that using speech content alone to assess depressive symptoms loses the information gained through observation. A multi-dimensional model combing semantics with speech voice, facial expression, and other valuable information, as well as taking into account personalized information, is a possible direction in the future.

Energy and exergy analysis of a modified three-stage auto-cascade refrigeration cycle using low-GWP refrigerants for sustainable development.

This study proposed a modified three-stage auto-cascade refrigeration cycle (MTARC) operating with environmentally benign zeotropic mixture of R1234yf/R170/R14 at the refrigeration temperature level of - 80 °C. Compared with the conventional three-stage auto-cascade refrigeration cycle (CTARC), MTARC incorporates an additional pressure regulator between the condenser and separator to realize phase separation at a lower pressure and temperature. A comprehensive evaluation of energy and exergy performance of the two cycles was conducted theoretically. Under a typical working condition, the cooling capacity, COP and exergy efficiency of the MTARC are improved by 15.85%, 11.69% and 7.65% in comparison with the CTARC, respectively. In addition, a lower evaporating temperature was also obtained by the MTARC under the same operating condition. When the intermediate pressure drops from 2 to 1 MPa, the cooling capacity, COP and exergy efficiency are improved by 35.43%, 25.25% and 16.74%, respectively, for the MTARC, meanwhile the compressor outlet temperature increases 19.93 °C from 92.27 to 112.20 °C. Therefore, the selection of the intermediate pressure should be comprehensively considered to ensure a desirable cycle performance and a proper working condition for the compressor. The proposed modified cycle offers new pathways for designing innovative cryogenic refrigeration systems, thereby potentially improving the energy economy in a myriad of modern energy applications for sustainability concerns.

Handgrip strength and the risk of major depressive disorder: a two-sample Mendelian randomisation study.

Background: Major depressive disorder (MDD) is a common psychiatric disease and a leading cause of disability worldwide. Handgrip strength (HGS) as an objective physical fitness test is a practical index for identifying many diseases. Previous studies drew different conclusions about the relationship between HGS and MDD. Aims: We aim to explore whether HGS has an effect on the risk of MDD. Methods: HGS-related single-nucleotide polymorphisms identified by a genome-wide association study were used as instrumental variables in this Mendelian randomisation (MR) study. Summary data on MDD were obtained from the Psychiatric Genomics Consortium. Four methods were applied, including inverse variance weighted (IVW), MR Egger, weighted median and weighted mode. Additional sensitivity analyses, including leave-one-out, heterogeneity test, pleiotropy test and confounders identification, were conducted to test the robustness of our results. Results: Each 1 kg increase in left HGS is associated with a 21.95% reduction in the risk of MDD (ORIVW = 0.781, 95% CI: 0.650 to 0.937, p=0.009), while no significant correlation exists in the estimation of right HGS (p=0.146). Sensitivity analyses demonstrated statistical significance (ßIVW = -0.195, p=0.023) after excluding some genetic loci that cause pleiotropy. Conclusions: Increased left HGS is associated with a reduced risk of MDD. In the future, it may be used as an index for the clinical screening, observation and treatment of MDD.

Association between vitamin D serum levels and insulin resistance assessed by HOMA-IR among non-diabetic adults in the United States: Results from NHANES 2007-2014.

Insulin resistance, a pathological response to insulin hormone in insulin-dependent cells, is characterized by the presence of high glucose and insulin concentrations. The homeostasis model of insulin resistance (HOMA-IR) is one of the most used indexes to estimate insulin resistance by assessing the fasting glucose and insulin levels. An association was observed between vitamin D levels and insulin resistance, which varied in different ethnic groups, and there is some evidence that vitamin D supplementation could contribute to the improvement of insulin resistance. This study assessed the association between 25-hydroxyvitamin D (25[OH]D) concentration and HOMA-IR in American adults aged 20 years and older, without diabetes and other chronic diseases that can influence insulin resistance. The data from the National Health and Nutrition Examination Survey (NHANES) 2007-2014 were used by exploiting the free and publicly-accessible web datasets. Linear regression models were performed to evaluate the association between serum 25(OH)D concentration and HOMA-IR, and a negative association was observed, which remained significant following the adjustment for age, gender, race/ethnicity, education, body mass index (BMI), physical activity, the season of examination, current smoking, hypertension, the use of drugs which can influence insulin resistance, serum bicarbonates, triglycerides, and calcium and phosphorus levels. Only in non-Hispanic Blacks was this inverse association between vitamin D and HOMA-IR not observed in the fully adjusted model. Further studies are needed to explain the mechanisms of the observed ethnic/racial differences in the association of vitamin D levels with HOMA-IR.

High levels of triglycerides, apolipoprotein B, and the number of colorectal polyps are risk factors for colorectal polyp recurrence after endoscopic resection: a retrospective study.

Background: The recurrence of polyps after endoscopic treatment is a difficult problem and there may be an association between blood lipid levels and colorectal polyps, but this is controversial and the aim of this study is to explore the risk factors for colorectal polyp recurrence. Methods: A total of 357 patients who underwent intestinal polypectomy from January 1, 2019 to June 1, 2020 in Sichuan Provincial People's Hospital were included in this retrospective study to analyze the potential association between blood indices and recurrence risk. Polyp recurrence was defined as the detection of 1 or more polyps at any time after polypectomy, regardless of site. Follow-up was performed through the electronic medical record system. Patients' age, gender, tobacco and alcohol liking, duration of follow-up, body mass index (BMI), polyp size, number, type of pathology, and lipid profiles (triglycerides, cholesterol, apolipoprotein B, and apolipoprotein A) were collected. Results: Triglycerides (1.54±0.95 vs. 1.25±1.01, P=0.036) and apolipoprotein B (0.87±0.26 vs. 0.79±0.16 mL, P=0.001) were significantly different in both the recurrence and non-recurrence groups. Binary logistic regression identified 3 independent risk factors for recurrence: triglycerides [odds ratio (OR): 1.763, 95% confidence interval (CI): 1.003 to 3.098, P=0.049], apolipoprotein B (OR: 5.438, 95% CI: 1.411 to 20.961, P=0.014), and the number of polyps (OR: 2.540, 95% CI: 1.649 to 3.911, P<0.001). Conclusions: High levels of triglycerides, apolipoprotein B, and the number of colorectal polyps are risk factors for colorectal polyp recurrence after endoscopic resection. Therefore, for patients at high risk of polyp recurrence, we recommend aggressive control of triglyceride and apolipoprotein B levels.

A novel hypoxia-driven gene signature that can predict the prognosis and drug resistance of gliomas.

Hypoxia spontaneously forms in the interior of glioma tissues and regulates the expression of various genes. However, the status of hypoxia-driven genes in glioma tissues is not completely known. In the current study, RNA-seq data of 695 glioma tissues in The Cancer Genome Atlas (TCGA) were set as a discovery cohort and were used to identify hypoxia-driven genes and construct a novel gene signature. The prognostic values of that signature were verified in data from the TCGA and the Chinese Glioma Genome Atlas (CGGA). The expression and diagnostic values of hypoxia-driven genes were analyzed using immunohistochemistry and receiver operator characteristic curves. Finally, the effects of hypoxia-driven genes on temozolomide (TMZ) resistance were analyzed by western blot, CCK-8 and colony formation assay. A total of 169 hypoxia-driven genes were identified, which were associated with a poor outcome in glioma patients. Among them, 22 genes had a degree score ≥10 and 6 genes (WT1, HOXA2, HOXC6, MMP9, SHOX2 and MYOD1) were selected to construct a signature to classify glioma patients into low- or high-risk groups. That signature had a remarkable prognostic value for glioma patients in TCGA and CGGA. The expression of HOXC6, MMP9, SHOX2 and MYOD1 was associated with hypoxia degree in glioma tissues and in recurrent cases, had a remarkable diagnostic value and a significant relationship with disease free survival in glioma patients. Moreover, SHOX2 was highly expressed in glioma tissues with O-6-methylguanine-DNA methyltransferase (MGMT)-unmethylation and temozolomide (TMZ) resistant glioma cell lines, and associated with MGMT expression. Knockdown the expression of SHOX2 significantly reduced the TMZ-resistance induced by hypoxia in glioma cells. Ultimately, we identified six novel hypoxia-driven genes for reliable prognostic prediction in gliomas and found that SHOX2 might be a potential target to overcome the TMZ resistance induced by hypoxia.

Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice.

Rationale: Sclerostin inhibition demonstrated bone anabolic potential in osteogenesis imperfecta (OI) mice, whereas humanized therapeutic sclerostin antibody romosozumab for postmenopausal osteoporosis imposed clinically severe cardiac ischemic events. Therefore, it is desirable to develop the next generation sclerostin inhibitors to promote bone formation without increasing cardiovascular risk for OI. Methods and Results: Our data showed that sclerostin suppressed inflammatory responses, prevented aortic aneurysm (AA) and atherosclerosis progression in hSOSTki.Col1a2+/G610C.ApoE-/- mice. Either loop2&3 deficiency or inhibition attenuated sclerostin's suppressive effects on expression of inflammatory cytokines and chemokines in vitro, whilst loop3 deficiency maintained the protective effect of sclerostin on cardiovascular system both in vitro and in vivo. Moreover, loop3 was critical for sclerostin's antagonistic effect on bone formation in Col1a2+/G610C mice. Accordingly, a sclerostin loop3-specific aptamer aptscl56 was identified by our lab. It could recognize both recombinant sclerostin and sclerostin in the serum of OI patients via targeting loop3. PEG40k conjugated aptscl56 (Apc001PE) demonstrated to promote bone formation, increase bone mass and improve bone microarchitecture integrity in Col1a2+/G610C mice via targeting loop3, while did not show influence in inflammatory response, AA and atherosclerosis progression in Col1a2+/G610C.ApoE-/- mice with Angiotensin II infusion. Further, Apc001PE had no influence in the protective effect of sclerostin on cardiovascular system in hSOSTki.Col1a2+/G610C.ApoE-/- mice, while it inhibited the antagonistic effect of sclerostin on bone formation in hSOSTki.Col1a2+/G610C mice via targeting loop3. Apc001PE was non-toxic to healthy rodents, even at ultrahigh dose. Apc001PE for OI was granted orphan drug designation by US-FDA in 2019 (DRU-2019-6966). Conclusion: Sclerostin loop3-specific aptamer Apc001PE promoted bone formation without increasing cardiovascular risk in OI mice.

Sigma-1 Receptors in Depression: Mechanism and Therapeutic Development.

Depression is the most common type of neuropsychiatric illness and has increasingly become a major cause of disability. Unfortunately, the recent global pandemic of COVID-19 has dramatically increased the incidence of depression and has significantly increased the burden of mental health care worldwide. Since full remission of the clinical symptoms of depression has not been achieved with current treatments, there is a constant need to discover new compounds that meet the major clinical needs. Recently, the roles of sigma receptors, especially the sigma-1 receptor subtype, have attracted increasing attention as potential new targets and target-specific drugs due to their translocation property that produces a broad spectrum of biological functions. Even clinical first-line antidepressants with or without affinity for sigma-1 receptors have different pharmacological profiles. Thus, the regulatory role of sigma-1 receptors might be useful in treating these central nervous system (CNS) diseases. In addition, long-term mental stress disrupts the homeostasis in the CNS. In this review, we discuss the topical literature concerning sigma-1 receptor antidepressant mechanism of action in the regulation of intracellular proteostasis, calcium homeostasis and especially the dynamic Excitatory/Inhibitory (E/I) balance in the brain. Furthermore, based on these discoveries, we discuss sigma-1 receptor ligands with respect to their promise as targets for fast-onset action drugs in treating depression.

Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation.

Sclerostin negatively regulates bone formation by antagonizing Wnt signalling. An antibody targeting sclerostin for the treatment of postmenopausal osteoporosis was approved by the U.S. Food and Drug Administration, with a boxed warning for cardiovascular risk. Here we demonstrate that sclerostin participates in protecting cardiovascular system and inhibiting bone formation via different loops. Loop3 deficiency by genetic truncation could maintain sclerostin's protective effect on the cardiovascular system while attenuating its inhibitory effect on bone formation. We identify an aptamer, named aptscl56, which specifically targets sclerostin loop3 and use a modified aptscl56 version, called Apc001PE, as specific in vivo pharmacologic tool to validate the above effect of loop3. Apc001PE has no effect on aortic aneurysm and atherosclerotic development in ApoE-/- mice and hSOSTki.ApoE-/- mice with angiotensin II infusion. Apc001PE can promote bone formation in hSOSTki mice and ovariectomy-induced osteoporotic rats. In summary, sclerostin loop3 cannot participate in protecting the cardiovascular system, but participates in inhibiting bone formation.

Correlation Between Word Frequency and 17 Items of Hamilton Scale in Major Depressive Disorder.

Objective: To explore the correlation between word frequency and 17 items of the Hamilton Depression Scale (HAMD-17) in assessing the severity of depression in clinical interviews. Methods: This study included 70 patients with major depressive disorder (MDD) who were hospitalized in the Beijing Anding Hospital. Clinicians interviewed eligible patients, collected general information, disease symptoms, duration, and scored patients with HAMD-17. The words used by the patients during the interview were classified and extracted according to the HowNet sentiment dictionary, including positive evaluation words, positive emotional words, negative evaluation words, negative emotional words. Symptom severity was grouped according to the HAMD-17 score: mild depressive symptoms is 8-17 points, moderate depressive symptoms is 18-24 points and severe depressive symptoms is >24 points. Analysis of Variance (ANOVA) was used to analyze the four categories of words among the groups, and partial correlation analysis was used to analyze the correlation between the four categories of word frequencies based on HowNet sentiment dictionary and the HAMD-17 scale to evaluate the total score. Receiver operating characteristic (ROC) curves were used to determine meaningful cut-off values. Results: There was a significant difference in negative evaluation words between groups (p = 0.032). After controlling for gender, age and years of education, the HAMD-17 total score was correlated with negative evaluation words (p = 0.009, r = 0.319) and negative emotional words (p = 0.027, r = 0.272), as the severity of depressive symptoms increased, the number of negative evaluation and negative emotional words in clinical interviews increased. Negative evaluation words distinguished patients with mild and moderate-severe depression. The area under the curve is 0.693 (p = 0.006) when the cut-off value is 8.48, the Youden index was 0.41, the sensitivity was 55.2%, and the specificity was 85.4%. Conclusion: In the clinical interview with MDD patients, the number of word frequencies based on HowNet sentiment dictionary may be beneficial in evaluating the severity of depressive symptoms.

A Rapid Protocol for Direct Isolation of Osteoclast Lineage Cells from Mouse Bone Marrow.

Osteoclast lineage cells (OLCs), including osteoclast precursors (OCPs) and mature osteoclasts (MOCs), participate in bone remodeling and mediate pathologic bone loss. Thus, it is essential to obtain OLCs for exploring their molecular features in both physiological and pathological conditions in vivo. However, the conventional protocols for obtaining OLCs ex vivo are not only time-consuming, but also unable to capture the cellular status of OLCs in vivo. In addition, the current antibody-based isolation approaches, such as fluorescence-/ magnetic-activated cell sorting, are not able to obtain pure osteoclasts because no unique surface antigen for osteoclasts has been identified. Here, we develop a rapid protocol for directly isolating OLCs from mouse bone marrow through magnetic-activated cell sorting (MACS). This protocol can rapidly enrich OCPs and MOCs, respectively, depending on the expression of the distinctive surface markers at their differentiation stages. It is optimized to isolate OLCs from four mice concurrently, of which sorting procedure could be completed within ~5 h.