pGM-CSF as an adjuvant in DNA vaccination against SARS-CoV-2.

The emergence of SARS-CoV-2 presents a significant global public health dilemma. Vaccination has long been recognized as the most effective means of preventing the spread of infectious diseases. DNA vaccines have attracted attention due to their safety profile, cost-effectiveness, and ease of production. This study aims to assess the efficacy of plasmid-encoding GM-CSF (pGM-CSF) as an adjuvant to augment the specific humoral and cellular immune response elicited by DNA vaccines based on the receptor-binding domain (RBD) antigen. Compared to the use of plasmid-encoded RBD (pRBD) alone, mice that were immunized with a combination of pRBD and pGM-CSF exhibited significantly elevated levels of RBD-specific antibody titers in serum, BALF, and nasal wash. Furthermore, these mice generated more potent neutralization antibodies against both the wild-type and Omicron pseudovirus, as well as the ancestral virus. In addition, pGM-CSF enhanced pRBD-induced CD4+ and CD8+ T cell responses and promoted central memory T cells storage in the spleen. At the same time, tissue-resident memory T (Trm) cells in the lung also increased significantly, and higher levels of specific responses were maintained 60 days post the final immunization. pGM-CSF may play an adjuvant role by promoting antigen expression, immune cells recruitment and GC B cell responses. In conclusion, pGM-CSF may be an effective adjuvant candidate for the DNA vaccines against SARS-CoV-2.

The First Report of the Acrotretoid Brachiopod Hadrotreta from the Tsinghsutung Formation Cambrian (Series 2, Stage 4), Guizhou, South China.

Hadrotreta is a worldwide acrotretoid brachiopod reported from the Cambrian Series 2 to Miaolingian. Here, a number of well-preserved fossils of Hadrotreta, identified as Hadrotreta cf. H. timchristiorum, were found in the Protoryctocephalus arcticus Zone of the Tsinghsutung Formation of Cambrian Series 2, Stage 4 in Jianhe, Guizhou, south China. This is the first report of Hadrotreta in China, which enriches its global palaeogeographical distribution. Hadrotreta is very similar to acrotretoids such as Kostjubella, Vandalotreta, Linnarssonia, and Eohadrotreta. It differs from them with its well-developed ventral boss-like apical process, apical pits, and dorsal median sulcus. In view of the palaeogeography of Hadrotreta, this genus was mainly distributed in low-latitude regions. Hadrotreta was only found in south China and Laurentia during the Cambrian Age 4, then expanded its distribution to other regions such as Siberia, Baltica, the Kazakh Terranes, the Far East, and Gondwana Pange during the Miaolingian Epoch. Hadrotreta seems to have shifted from deeper water to shallow-water environments during the period from the Cambrian Series 2 to the Miaolingian.

Patient Engagement in a Multimodal Digital Phenotyping Study of Opioid Use Disorder.

BACKGROUND: Multiple digital data sources can capture moment-to-moment information to advance a robust understanding of opioid use disorder (OUD) behavior, ultimately creating a digital phenotype for each patient. This information can lead to individualized interventions to improve treatment for OUD. OBJECTIVE: The aim is to examine patient engagement with multiple digital phenotyping methods among patients receiving buprenorphine medication for OUD. METHODS: The study enrolled 65 patients receiving buprenorphine for OUD between June 2020 and January 2021 from 4 addiction medicine programs in an integrated health care delivery system in Northern California. Ecological momentary assessment (EMA), sensor data, and social media data were collected by smartphone, smartwatch, and social media platforms over a 12-week period. Primary engagement outcomes were meeting measures of minimum phone carry (≥8 hours per day) and watch wear (≥18 hours per day) criteria, EMA response rates, social media consent rate, and data sparsity. Descriptive analyses, bivariate, and trend tests were performed. RESULTS: The participants' average age was 37 years, 47% of them were female, and 71% of them were White. On average, participants met phone carrying criteria on 94% of study days, met watch wearing criteria on 74% of days, and wore the watch to sleep on 77% of days. The mean EMA response rate was 70%, declining from 83% to 56% from week 1 to week 12. Among participants with social media accounts, 88% of them consented to providing data; of them, 55% of Facebook, 54% of Instagram, and 57% of Twitter participants provided data. The amount of social media data available varied widely across participants. No differences by age, sex, race, or ethnicity were observed for any outcomes. CONCLUSIONS: To our knowledge, this is the first study to capture these 3 digital data sources in this clinical population. Our findings demonstrate that patients receiving buprenorphine treatment for OUD had generally high engagement with multiple digital phenotyping data sources, but this was more limited for the social media data. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.3389/fpsyt.2022.871916.

Identification of Fusarium sacchari Causing Foliar Blight on Begonia semperflorens in China.

Begonia semperflorens Link et Otto (Begoniaceae) is a flowering, ornamental plant widely cultivated in China. In April of 2020, a foliar blight disease on B. semperflorens was observed in plant nurseries (∼0.2 ha), with ~ 20% disease incidence (n = 150) in Nanning, Guangxi Province, China. Initial symptoms included irregular to circular, grayish white spots surrounded by a dark brown halo, mainly scattered on the edges the leaves. In severe infections, the spots frequently coalesced to form large, blighted areas, followed by defoliation. To isolate the pathogen, three representative plants exhibiting symptoms were collected from the nurseries. Leaf tissues (5 × 5 mm) were cut from the margin of necrotic lesions (n = 18), surface disinfected in 1% NaOCl for 2 min, then rinsed three times in sterile H2O. Then the tissues were plated on potato dextrose agar (PDA), and incubated at 28°C (12 h photoperiod) for 3 days. Hyphal tips from recently germinated spores were transferred to PDA to purify fungal isolates. A total of 11 isolates (85% isolation frequency) with similar morphological characteristics were obtained. Colonies on PDA plates were villose, had a dense growth of white aerial mycelia and appeared pale but becoming violet with age. On Spezieller Nährstoffarmer Agar (SNA), the macroconidia were slender, slight falcate, two to three septate, and 23.5 to 48.8 × 2.8 to 4.8 µm (n = 60), and the microconidia were abundant and formed in false heads on monophialides or polyphialides, slim, oval, zero to one septate, and 7.8 to 22.4 × 2.4 to 4.0 µm (n = 60). For molecular identification, the internal transcribed spacer (ITS) region of rDNA, and partial translation elongation factor-1 alpha (TEF-1α), and RNA polymerase second largest subunit (RPB2) genes of the representative isolate HT-2B were amplified and sequenced using primer pairs ITS1/ITS4 (White et al. 1990), EF-1/EF-2 (O'Donnell et al. 1998), and 5f2/11ar (Liu et al. 1999, Reeb et al. 2004), respectively. The obtained sequences were deposited in NCBI GenBank under the accession numbers OQ048268 (TIS), OP994260 (TEF-1α), OP994262 (RPB2) and showed 99.4%, 99.8%, and 99.4% similarity with the corresponding sequences (X94168，AF160278，and JX171580, respectively) of Fusarium sacchari from type material. In addition, a phylogenetic analysis showed that HT-2B was grouped with F. sacchari. Therefore, based on morphological (Leslie et al. 2005) and molecular characteristics, the isolates were identified as F. sacchari. To test pathogenicity, three healthy leaves on each of three B. semperflorens plants were stab-wounded with a sterile syringe and inoculated with a 10-µl droplet of a conidial suspension (106 spores/ml) of the isolate HT-2B. As a control, another three leaves were wound inoculated with sterilized dH2O. All plants were enclosed in transparent plastic bags and incubated in a greenhouse at 28°C (12 h photoperiod, ~ 80% relative humidity). Six days post-inoculation, symptoms appeared on the inoculated leaves. No symptoms were detected on control plants. Experiments were replicated three times with similar results. To fulfill Koch's postulates, the F. sacchari isolates were consistently re-isolated from symptomatic tissue and confirmed by morphology and sequencing, whereas no fungus was isolated from the control plants. To our knowledge, this is the first report of F. sacchari causing foliar blight on B. semperflorens in China. This result will help develop management strategies for this disease.

Graph Convolutional Neural Networks for Histologic Classification of Pancreatic Cancer.

CONTEXT.­: Pancreatic ductal adenocarcinoma has some of the worst prognostic outcomes among various cancer types. Detection of histologic patterns of pancreatic tumors is essential to predict prognosis and decide the treatment for patients. This histologic classification can have a large degree of variability even among expert pathologists. OBJECTIVE.­: To detect aggressive adenocarcinoma and less aggressive pancreatic tumors from nonneoplasm cases using a graph convolutional network-based deep learning model. DESIGN.­: Our model uses a convolutional neural network to extract detailed information from every small region in a whole slide image. Then, we use a graph architecture to aggregate the extracted features from these regions and their positional information to capture the whole slide-level structure and make the final prediction. RESULTS.­: We evaluated our model on an independent test set and achieved an F1 score of 0.85 for detecting neoplastic cells and ductal adenocarcinoma, significantly outperforming other baseline methods. CONCLUSIONS.­: If validated in prospective studies, this approach has a great potential to assist pathologists in identifying adenocarcinoma and other types of pancreatic tumors in clinical settings.

Improving Representation Learning for Histopathologic Images with Cluster Constraints.

Recent advances in whole-slide image (WSI) scanners and computational capabilities have significantly propelled the application of artificial intelligence in histopathology slide analysis. While these strides are promising, current supervised learning approaches for WSI analysis come with the challenge of exhaustively labeling high-resolution slides-a process that is both labor-intensive and timeconsuming. In contrast, self-supervised learning (SSL) pretraining strategies are emerging as a viable alternative, given that they don't rely on explicit data annotations. These SSL strategies are quickly bridging the performance disparity with their supervised counterparts. In this context, we introduce an SSL framework. This framework aims for transferable representation learning and semantically meaningful clustering by synergizing invariance loss and clustering loss in WSI analysis. Notably, our approach outperforms common SSL methods in downstream classification and clustering tasks, as evidenced by tests on the Camelyon16 and a pancreatic cancer dataset. The code and additional details are accessible at https://github.com/wwyi1828/CluSiam.

The Feasibility and Utility of Harnessing Digital Health to Understand Clinical Trajectories in Medication Treatment for Opioid Use Disorder: D-TECT Study Design and Methodological Considerations.

Introduction: Across the U.S., the prevalence of opioid use disorder (OUD) and the rates of opioid overdoses have risen precipitously in recent years. Several effective medications for OUD (MOUD) exist and have been shown to be life-saving. A large volume of research has identified a confluence of factors that predict attrition and continued substance use during substance use disorder treatment. However, much of this literature has examined a small set of potential moderators or mediators of outcomes in MOUD treatment and may lead to over-simplified accounts of treatment non-adherence. Digital health methodologies offer great promise for capturing intensive, longitudinal ecologically-valid data from individuals in MOUD treatment to extend our understanding of factors that impact treatment engagement and outcomes. Methods: This paper describes the protocol (including the study design and methodological considerations) from a novel study supported by the National Drug Abuse Treatment Clinical Trials Network at the National Institute on Drug Abuse (NIDA). This study (D-TECT) primarily seeks to evaluate the feasibility of collecting ecological momentary assessment (EMA), smartphone and smartwatch sensor data, and social media data among patients in outpatient MOUD treatment. It secondarily seeks to examine the utility of EMA, digital sensing, and social media data (separately and compared to one another) in predicting MOUD treatment retention, opioid use events, and medication adherence [as captured in electronic health records (EHR) and EMA data]. To our knowledge, this is the first project to include all three sources of digitally derived data (EMA, digital sensing, and social media) in understanding the clinical trajectories of patients in MOUD treatment. These multiple data streams will allow us to understand the relative and combined utility of collecting digital data from these diverse data sources. The inclusion of EHR data allows us to focus on the utility of digital health data in predicting objectively measured clinical outcomes. Discussion: Results may be useful in elucidating novel relations between digital data sources and OUD treatment outcomes. It may also inform approaches to enhancing outcomes measurement in clinical trials by allowing for the assessment of dynamic interactions between individuals' daily lives and their MOUD treatment response. Clinical Trial Registration: Identifier: NCT04535583.

Urothelial Calcium-Sensing Receptor Modulates Micturition Function via Mediating Detrusor Activity and Ameliorates Bladder Hyperactivity in Rats.

The urothelium displays mechano- and chemosensory functions via numerous receptors and channels. The calcium-sensing receptor (CaSR) detects extracellular calcium and modulates several physiological functions. Nonetheless, information about the expression and the role of CaSR in lower urinary tract has been absent. We aimed to determine the existence of urothelial CaSR in urinary bladder and its effect on micturition function. We utilized Western blot to confirm the expression of CaSR in bladder and used immunofluorescence to verify the location of the CaSR in the bladder urothelium via colocalization with uroplakin III A. The activation of urothelial CaSR via the CaSR agonist, AC-265347 (AC), decreased urinary bladder smooth muscle (detrusor) activity, whereas its inhibition via the CaSR antagonist, NPS-2143 hydrochloride (NPS), increased detrusor activity in in vitro myography experiments. Cystometry, bladder nerve activities recording, and bladder surface microcirculation detection were conducted to evaluate the effects of the urothelial CaSR via intravesical administrations. Intravesical AC inhibited micturition reflex, bladder afferent and efferent nerve activities, and reversed cystitis-induced bladder hyperactivity. The urothelial CaSR demonstrated a chemosensory function, and modulated micturition reflex via regulating detrusor activity. This study provided further evidence of how the urothelial CaSR mediated micturition and implicated the urothelial CaSR as a potential pharmacotherapeutic target in the intervention of bladder disorders.

Natural language processing for automated annotation of medication mentions in primary care visit conversations.

OBJECTIVES: The objective of this study is to build and evaluate a natural language processing approach to identify medication mentions in primary care visit conversations between patients and physicians. MATERIALS AND METHODS: Eight clinicians contributed to a data set of 85 clinic visit transcripts, and 10 transcripts were randomly selected from this data set as a development set. Our approach utilizes Apache cTAKES and Unified Medical Language System controlled vocabulary to generate a list of medication candidates in the transcribed text and then performs multiple customized filters to exclude common false positives from this list while including some additional common mentions of the supplements and immunizations. RESULTS: Sixty-five transcripts with 1121 medication mentions were randomly selected as an evaluation set. Our proposed method achieved an F-score of 85.0% for identifying the medication mentions in the test set, significantly outperforming existing medication information extraction systems for medical records with F-scores ranging from 42.9% to 68.9% on the same test set. DISCUSSION: Our medication information extraction approach for primary care visit conversations showed promising results, extracting about 27% more medication mentions from our evaluation set while eliminating many false positives in comparison to existing baseline systems. We made our approach publicly available on the web as an open-source software. CONCLUSION: Integration of our annotation system with clinical recording applications has the potential to improve patients' understanding and recall of key information from their clinic visits, and, in turn, to positively impact health outcomes.

A high-throughput and simultaneous determination of combretastatin A-4 phosphate and its metabolites in human plasma using HPLC-MS/MS: Application to a clinical pharmacokinetic study.

To investigate the clinical pharmacokinetics of CA4P, a high-throughput high-performance liquid chromatography-tandem mass spectrometry assay with an identical positive electrospray ionization (ESI) mode was developed for the simultaneous determination of CA4P, its active metabolite CA4, and CA4 glucuronide in human plasma. CA4P and CA4 were easier to protonate in positive ESI mode, whereas CA4G was reported to produce deprotonated ion in negative ESI mode. Because the baseline separation of CA4P and CA4G could not be achieved, using MS positive/negative ion switching is not feasible. In this study, an abundant ammonium adduct ion of CA4G in ESI+ was observed as an ideal precursor ion. The final precursor/product transition pairs chosen for CA4P, CA4, and CA4G were at m/z 397/350, 317/286, and 510/317, respectively. To the best of our knowledge, it is the first report on the simultaneous quantification of CA4P, CA4, and CA4G in biological samples. The proposed method was validated, which showed a wide linear dynamic range, high selectivity and sensitivity, good repeatability, and a short run time. Compared with the literatures, the lower limits of quantification were five- and two-fold more sensitive for CA4G and CA4, respectively. Therefore, this method was successfully applied to the pharmacokinetic study of CA4P in phase I clinical trial.

Silicon-containing water intake confers antioxidant effect, gastrointestinal protection, and gut microbiota modulation in the rodents.

We explored the effects of silicon-containing water (BT) intake on gastrointestinal function and gut microbiota. BT was obtained by pressuring tap water through silicon minerals (mullite, Al6Si2O13) column. BT decreased H2O2 chemiluminescence counts, indicating its antioxidant activity. Four weeks of BT drinking increased H2O2 scavenging activity and glutathione peroxidase activity of plasma. BT drinking did not affect the body weight but significantly reduced the weight of feces and gastrointestinal motility. BT drinking significantly suppressed pylorus ligation enhanced gastric juice secretion, gastric reactive oxygen species amount, erythrocyte extravasation, IL-1ß production by infiltrating leukocyte, and lipid peroxidation within gastric mucosa. Data from 16S rRNA sequencing revealed BT drinking significantly increased beneficial flora including Ruminococcaceae UCG-005, Prevotellaceae NK3B31, Weissella paramesenteroides, Lactobacillus reuteri, and Lactobacillus murinus and decreased harmful flora including Mucispirillum, Rodentibacter, and Staphylococcus aureus. This study pioneerly provided scientific evidences for the potential effects of water-soluble forms of silicon intake on antioxidant activity, gastrointestinal function, and gut microbiota modulation.

Acellular pericardium: A naturally hierarchical, osteoconductive, and osteoinductive biomaterial for guided bone regeneration.

There is great demand for an improved barrier membrane with osteogenic potential for guided bone regeneration (GBR). Natural acellular porcine pericardium (APP) is increasingly used in regenerative medicine as a kind of common extracellular matrix materials. This study aimed to investigate its potential application in GBR, especially its osteoconductive and osteoinductive properties. Bio-Gide (BG), a commercial collagen membrane, was set as the control group. APP samples were characterized by physicochemical analyses and their biological effects on human bone mesenchymal stem cells (hBMSCs) and human gingival fibroblasts (hGFs) were also examined. Additionally, the osteogenic potential of APP was tested on a bilateral critical-sized calvarial defect model. We discovered that the smooth surface of APP tended to recruit more hBMSCs. Moreover, promoted proliferation and osteogenic differentiation of hBMSCs was detected on this side of APP, with increased alkaline phosphatase activity and upregulated expression of bone-specific genes. Besides, the rough side of APP showed good biocompatibility and barrier function with hGFs. Histologic observation and analysis of calvarial defect healing over 4 weeks revealed enhanced bone regeneration under APP compared with BG and the control group. The results of this study indicate that APP is a potential osteoconductive and osteoinductive biomaterial for GBR.

Multi-Ontology Refined Embeddings (MORE): A hybrid multi-ontology and corpus-based semantic representation model for biomedical concepts.

OBJECTIVE: Currently, a major limitation for natural language processing (NLP) analyses in clinical applications is that concepts are not effectively referenced in various forms across different texts. This paper introduces Multi-Ontology Refined Embeddings (MORE), a novel hybrid framework that incorporates domain knowledge from multiple ontologies into a distributional semantic model, learned from a corpus of clinical text. MATERIALS AND METHODS: We use the RadCore and MIMIC-III free-text datasets for the corpus-based component of MORE. For the ontology-based part, we use the Medical Subject Headings (MeSH) ontology and three state-of-the-art ontology-based similarity measures. In our approach, we propose a new learning objective, modified from the sigmoid cross-entropy objective function. RESULTS AND DISCUSSION: We used two established datasets of semantic similarities among biomedical concept pairs to evaluate the quality of the generated word embeddings. On the first dataset with 29 concept pairs, with similarity scores established by physicians and medical coders, MORE's similarity scores have the highest combined correlation (0.633), which is 5.0% higher than that of the baseline model, and 12.4% higher than that of the best ontology-based similarity measure. On the second dataset with 449 concept pairs, MORE's similarity scores have a correlation of 0.481, based on the average of four medical residents' similarity ratings, and that outperforms the skip-gram model by 8.1%, and the best ontology measure by 6.9%. Furthermore, MORE outperforms three pre-trained transformer-based word embedding models (i.e., BERT, ClinicalBERT, and BioBERT) on both datasets. CONCLUSION: MORE incorporates knowledge from several biomedical ontologies into an existing corpus-based distributional semantics model, improving both the accuracy of the learned word embeddings and the extensibility of the model to a broader range of biomedical concepts. MORE allows for more accurate clustering of concepts across a wide range of applications, such as analyzing patient health records to identify subjects with similar pathologies, or integrating heterogeneous clinical data to improve interoperability between hospitals.

Associations Between Substance Use and Instagram Participation to Inform Social Network-Based Screening Models: Multimodal Cross-Sectional Study.

BACKGROUND: Technology-based computational strategies that leverage social network site (SNS) data to detect substance use are promising screening tools but rely on the presence of sufficient data to detect risk if it is present. A better understanding of the association between substance use and SNS participation may inform the utility of these technology-based screening tools. OBJECTIVE: This paper aims to examine associations between substance use and Instagram posts and to test whether such associations differ as a function of age, gender, and race/ethnicity. METHODS: Participants with an Instagram account were recruited primarily via Clickworker (N=3117). With participant permission and Instagram's approval, participants' Instagram photo posts were downloaded with an application program interface. Participants' past-year substance use was measured with an adapted version of the National Institute on Drug Abuse Quick Screen. At-risk drinking was defined as at least one past-year instance having "had more than a few alcoholic drinks a day," drug use was defined as any use of nonprescription drugs, and prescription drug use was defined as any nonmedical use of prescription medications. We used logistic regression to examine the associations between substance use and any Instagram posts and negative binomial regression to examine the associations between substance use and number of Instagram posts. We examined whether age (18-25, 26-38, 39+ years), gender, and race/ethnicity moderated associations in both logistic and negative binomial models. All differences noted were significant at the .05 level. RESULTS: Compared with no at-risk drinking, any at-risk drinking was associated with both a higher likelihood of any Instagram posts and a higher number of posts, except among Hispanic/Latino individuals, in whom at-risk drinking was associated with a similar number of posts. Compared with no drug use, any drug use was associated with a higher likelihood of any posts but was associated with a similar number of posts. Compared with no prescription drug use, any prescription drug use was associated with a similar likelihood of any posts and was associated with a lower number of posts only among those aged 39 years and older. Of note, main effects showed that being female compared with being male and being Hispanic/Latino compared with being White were significantly associated with both a greater likelihood of any posts and a greater number of posts. CONCLUSIONS: Researchers developing computational substance use risk detection models using Instagram or other SNS data may wish to consider our findings showing that at-risk drinking and drug use were positively associated with Instagram participation, while prescription drug use was negatively associated with Instagram participation for middle- and older-aged adults. As more is learned about SNS behaviors among those who use substances, researchers may be better positioned to successfully design and interpret innovative risk detection approaches.

Bone Augmentation of Peri-Implant Dehiscence Defects Using Multilaminated Small Intestinal Submucosa as a Barrier Membrane: An Experimental Study in Dogs.

OBJECTIVE: The aim of the study is to evaluate the effects of multilaminated small intestinal submucosa (mSIS) combined with bone substitute material to repair peri-implant defects during guided bone regeneration procedures. METHODS: Twelve implants were placed in bilateral lower premolars of three beagle dogs, and a peri-implant buccal bone defect (3 mm width and 4 mm height) was created at each implant site. A total of 12 sites were filled with a particulate bone substitute material and then randomly divided into three treatment groups: covered by mSIS membrane (mSIS group), covered by collagen membrane (BG group), and no treatment (control group), each group of four sites. After 12 weeks of healing, all of the animals were euthanized and dissected blocks were obtained for micro-computed tomography (micro-CT) and histological analyses. RESULTS: Micro-CT results revealed similar horizontal width of augmented tissue and new bone formation between mSIS and BG groups (P < 0.05). Histological analyses revealed that the differences in horizontal widths of newly formed bone and bone-to-implant contact between mSIS and BG groups were not significant (P > 0.05). All of these parameters were significantly different from those in the control group (P < 0.05). CONCLUSIONS: These findings confirmed that mSIS combined with the bone substitute material enhanced bone regeneration in peri-implant defects, in a manner similar to that of a collagen membrane.

Glycine tomentella hayata extract and its ingredient daidzin ameliorate cyclophosphamide-induced hemorrhagic cystitis and oxidative stress through the action of antioxidation, anti-fibrosis, and anti-inflammation.

We explored the therapeutic potential of intragastric administration of traditional Chinese medicine Glycine tomentella Hayata (I-Tiao-Gung [ITG]) extract and its major component Daidzin on cyclophosphamide (CYP)-induced cystitis, oxidative stress, fibrosis, inflammation, and bladder hyperactivity in rats. Female Wistar rats were divided into control, CYP (200 mg/kg), CYP+ITG (1.17 g/kg/day), and CYP+Daidzin (12.5 mg/kg/day) groups. We measured the voiding function by the transcystometrogram and evaluated the pathology with the hematoxylin and eosin and Masson stain. We determined the bladder reactive oxygen species (ROS) amount by an ultrasensitive chemiluminescence analyzer, the expression of 3-nitrotyrosine (3-NT) and NADPH oxidase 4 (NOX4) by Western blot and the expression of multiple cytokine profiles, including matrix metalloproteinase (MMP)-8 and tissue inhibitor of metalloproteinase (TIMP)-1 through a cytokine array. ITG extract contains 1.07% of Daidzin through high-performance liquid chromatography. The effect of ITG extract and Daidzin in scavenging hydrogen peroxide activity was more efficient than distilled water. CYP-induced higher urination frequency, shorter intercontraction interval, and lower maximal voiding pressure in the bladders and these symptoms were significantly ameliorated in CYP+ITG and CYP+Daidzin groups. The amount of in vivo bladder ROS and the expression of 3-NT and NOX4 expressions were significantly increased in CYP group but were efficiently decreased in the CYP+ITG and CYP+Daidzin groups. CYP-induced fibrosis, hemorrhage, leukocyte infiltration, and edema in the bladders were significantly attenuated in the CYP+ITG and CYP+Daidzin groups. These results suggested that ITG extract and its active component Daidzin effectively improved CYP-induced oxidative stress, inflammation, and fibrosis through inhibiting the MMP-8, TIMP-1, and oxidative stress.

Aromatherapy: Activating olfactory calcium-sensing receptors impairs renal hemodynamics via sympathetic nerve-mediated vasoconstriction.

AIM: This study determines whether the activation of olfactory calcium-sensing receptor initiates a sympathetic activation-dependent neurovascular reflex subsequently contributing to renal hemodynamic depression. METHODS: Immunohistochemistry and nose-loading calcium-sensitive dye were used to explore the location and function of calcium-sensing receptor on the olfactory sensory neuron. The renal sympathetic nervous activity, renal hemodynamics and the microcirculation of kidney, liver and intestine were evaluated after liquid-phase intranasal administrations of saline, lidocaine, calcium-sensing receptor agonists and antagonist in sham and bilateral renal denervated rats. Real-time renal glomerular filtration rate was measured by a magnetic resonance renography. RESULTS: Calcium-sensing receptors were expressed on the cilia the olfactory sensory neuron and their activation depolarized olfactory sensory neuron and induced the calcium influx in the terminal side on olfactory glomeruli. Activating olfactory calcium-sensing receptors significantly increased arterial blood pressure and renal sympathetic nervous activities and subsequently decreased renal blood flow, renal, hepatic and enteral microcirculation. Cotreatments with calcium-sensing receptor antagonist or lidocaine inhibited these physiological alterations. The renal hemodynamic depressions by olfactory calcium-sensing receptor activation were significantly blocked by bilateral renal denervation. The intranasal manganese administration decreased the glomerular filtration rate. CONCLUSION: Calcium-sensing receptor acts as a functional chemosensory receptor on olfactory sensory neuron, and its activation causes the global sympathetic enhancement contributing to systematic vasoconstriction and subsequently depresses renal blood flow and glomerular filtration rate. These data implicate a possibly clinical aspect that several environmental stimuli may activate olfactory calcium-sensing receptors to evoke a sympathetic nervous system-mediated neurovascular reflex to depress renal hemodynamics.

Effect of Multilaminate Small Intestinal Submucosa as a Barrier Membrane on Bone Formation in a Rabbit Mandible Defect Model.

A barrier membrane (BM) is essential for guided bone regeneration (GBR) procedures. Absorbable BMs based on collagen have been widely applied clinically due to their excellent biocompatibility. The extracellular matrix (ECM) provides certain advantages that can compensate for the rapid degradation and insufficient mechanical strength of pure collagen membrane due to the porous scaffold structure. Recently, small intestinal submucosa (SIS), one of the most widely used ECM materials, has drawn much attention in bone tissue engineering. In this study, we adopted multilaminate SIS (mSIS) as a BM and evaluated its in vivo and in vitro properties. mSIS exhibited a multilaminate structure with a smooth upper surface and a significantly coarser bottom layer according to microscopic observation. Tensile strength was 13.10 ± 2.56 MPa. In in vivo experiments, we selected a rabbit mandibular defect model and subcutaneous implantation to compare osteogenesis and biodegradation properties with one of the most commonly used commercial collagen membranes. mSIS was retained for up to 3 months and demonstrated longer biodegradation time than commercial collagen membrane. Quantification of bone regeneration revealed significant differences in each group. Micro-computed tomography (micro-CT) revealed that the quantity and maturity of bones in the mSIS group were significantly higher than those in the blank control group (P < 0.05) and were similar to those in a commercial collagen membrane group (P > 0.05) at 4 and 12 weeks after surgery. Hematoxylin and eosin staining revealed large amounts of mature lamellar bone at 12 weeks in mSIS and commercial collagen membrane groups. Therefore, we conclude that mSIS has potential as a future biocompatible BM in GBR procedures.

A Highly Efficient and Reusable Palladium(II)/Cationic 2,2'-Bipyridyl-Catalyzed Stille Coupling in Water.

A water-soluble PdCl2(NH3)2/cationic 2,2'-bipyridyl system was found to be a highly efficient catalyst for Stille coupling of aryl iodides and bromides with organostannanes. The coupling reaction was conducted at 110 °C in water, under aerobic conditions, in the presence of NaHCO3 as a base to afford corresponding Stille coupling products in good to high yields. When aryltributylstannanes were employed, the reactions proceeded smoothly under a very low catalyst loading (as little as 0.0001 mol %). After simple extraction, the residual aqueous phase could be reused in subsequent runs, making this Stille coupling economical. In the case of tetramethylstannane, however, a greater catalyst loading (1 mol %) and the use of tetraethylammonium iodide as a phase-transfer agent were required in order to obtain satisfactory yields.