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Using detailed exposure information on COVID-19 cases, we estimated the mean latent period to be 5.5 (95% CI: 5.1–5.9) days, shorter than the mean incubation period (6.9 days). Laboratory testing may allow shorter quarantines since 95% of COVID-19 cases shed virus within 10.6 (95% CI: 9.6–11.6) days of infection.

We estimated the symptomatic, PCR-confirmed secondary attack rate (SAR) for 2,382 close contacts of 476 symptomatic persons with coronavirus disease in Yichang, Hubei Province, China, identified during January 23–February 25, 2020. The SAR among all close contacts was 6.5%; among close contacts who lived with an index case-patient, the SAR was 10.8%; among close-contact spouses of index case-patients, the SAR was 15.9%. The SAR varied by close contact age, from 3.0% for those 60 years of age. Multilevel logistic regression showed that factors significantly associated with increased SAR were living together, being a spouse, and being >60 years of age. Multilevel regression did not support SAR differing significantly by whether the most recent contact occurred before or after the index case-patient’s onset of illness (p = 0.66). The relatively high SAR for coronavirus disease suggests relatively high virus transmissibility.

Diabetic retinopathy (DR) is one of the most serious microvascular complications of diabetes mellitus (DM). MicroRNAs (miRNAs) have been discovered to play a crucial role in DR, but the mechanisms underlying the effects of miR-301a-3p on DR are poorly understood. This paper was designed to explore the possible role of miR-301a-3p in DR. The diabetic rat model was established by a single intraperitoneal injection of streptozotocin (STZ). The effects of miR-301a-3p on the biological functions of HRECs were determined through a series of experiments in vitro/vivo. The results revealed that interference with miR-301a-3p could decrease the expressions of inflammatory factors and apoptosis in the retinal tissue of DR. Furthermore, it can alleviate the oxidative stress in DR serum, reduce VEGF expression, increase endothelial cell marker expression, and inhibit (High Glucose) HG-induced apoptosis of HRECs. Six-transmembrane epithelial antigen of prostate 4 (STEAP4) was the target of miR-301a-3p. All the effects of miR-301a-3p in DR model were reversed by STEAP4 inhibitor. miR-301a-3p promotes diabetic retinopathy via regulation of STEAP4. The findings in this study may provide a vital reference for the drug research and development in DR treatment.

Cough is induced by inhaled prostacyclin analogues including treprostinil (TRE), and, at higher doses, treprostinil palmitil (TP), a prodrug of TRE. In this report, we have investigated mechanisms involved in TRE- and TP-induced cough, using a dry powder formulation of TP (TPIP) to supplement previous data obtained with an aqueous suspension formulation of TP (TPIS). Experiments in guinea pigs and rats investigated the prostanoid receptor subtype producing cough and whether it involved activation of sensory nerves in the airways and vasculature. Experiments involved treatment with prostanoid, tachykinin and bradykinin receptor antagonists, a cyclooxygenase inhibitor and TRE administration to the isolated larynx or intravenously. In guinea pigs, cough with inhaled TRE (1.23 µg·kg−1) was not observed with an equivalent dose of TPIP and required higher inhaled doses (12.8 and 35.8 µg·kg−1) to induce cough. TRE cough was blocked with IP and tachykinin NK1 receptor antagonists but not with EP1, EP2, EP3, DP1 or bradykinin B2 antagonists or a cyclooxygenase inhibitor. TRE administered to the isolated larynx or intravenously in rats produced no apnoea or swallowing, whereas citric acid, capsaicin and hypertonic saline had significant effects. The mechanisms inducing cough with inhaled TRE likely involves the activation of prostanoid IP receptors on jugular C-fibres in the tracheobronchial airways. Cough induced by inhaled dry powder and nebulised formulations of TP occurs at higher inhaled doses than TRE, presumably due to the slow, sustained release of TRE from the prodrug resulting in lower concentrations of TRE at the airway sensory nerves., Cough induced by inhaled treprostinil and treprostinil palmitil involves the activation of prostacyclin (IP) receptors located on airway tachykinin nerves https://bit.ly/37sXz1I

Introduction: Alternatively using gradient lower-body negative pressure (LBNP) and ergometer exercise (LBNP + ergo) under a flight schedule framework was explored to detect its orthostatic capacity maintenance effects in female subjects after 15 days of -6° head-down bed rest (HDBR). Methods: Twenty-two female university students were divided into a control group (n = 8), an LBNP group (n = 7), and an LBNP + ergo group (n = 7). Ergometer exercise consisted of an interval exercise protocol with 2 min intervals alternating between 41% and 70% VO2max. Gradient LBNP was decompressed in 10 mm Hg intervals to -40 mmHg every 5 min. intermittent ergometer exercise and LBNP were alternatively performed. Tilt test was performed 2 days before HDBR (R-2), on the day of HDBR termination (R+1), and 5 days after HDBR (R+5). Results: Fifty percent of the participants (11/22) did not pass the tilt test on R+1. The orthostatic tolerance time decreased from 20 to 16.1 ± 2.1 min in the control group, to 10.0 ± 2.7 min in the LBNP group (p = 0.01) and to 16.3 ± 2.0 min in the LBNP + ergo group. The HRs and BPs were at similar level among three groups during tilt test on different test days. Compared with the control group, the LBNP + ergo group had higher SV and CO percentage changes at R+1(p < 0.023) and R+5 (p < 0.00001) during the tilt test. Conclusion: LBNP combined with ergometer exercises fails to prevent orthostatic intolerance but it induced some positive hemodynamic changes during tilt test after 15 days HDBR.

Deep learning methods have boosted the performance of a series of visual tasks. However, the aerial image scene classification remains challenging. The object distribution and spatial arrangement in aerial scenes are often more complicated than in natural image scenes. Possible solutions include highlighting local semantics relevant to the scene label and preserving more discriminative features. To tackle this challenge, in this letter, we propose an attention pooling-based dense connected convolutional network (APDC-Net) for aerial scene classification. First, it uses a simplified dense connection structure as the backbone to preserve features from different levels. Then, we propose a trainable pooling to down-sample the feature maps and to enhance the local semantic representation capability. Finally, we introduce a multi-level supervision strategy, so that features from different levels are all allowed to supervise the training process directly. Exhaustive experiments on three aerial scene classification benchmarks demonstrate that our proposed APDC-Net outperforms other state-of-the-art methods with much fewer parameters and validate the effectiveness of our attention-based pooling and multi-level supervision strategy.

Background Between mid‐January and early February, provinces of mainland China outside the epicentre in Hubei province were on high alert for importations and transmission of COVID‐19. Many properties of COVID‐19 infection and transmission were still not yet established. Methods We collated and analysed data on 449 of the earliest COVID‐19 cases detected outside Hubei province to make inferences about transmission dynamics and severity of infection. We analysed 64 clusters to make inferences on serial interval and potential role of pre‐symptomatic transmission. Results We estimated an epidemic doubling time of 5.3 days (95% confidence interval (CI): 4.3, 6.7) and a median incubation period of 4.6 days (95% CI: 4.0, 5.2). We estimated a serial interval distribution with mean 5.7 days (95% CI: 4.7, 6.8) and standard deviation 3.5 days, and effective reproductive number was 1.98 (95% CI: 1.68, 2.35). We estimated that 32/80 (40%) of transmission events were likely to have occurred prior to symptoms onset in primary cases. Secondary cases in clusters had less severe illness on average than cluster primary cases. Conclusions The majority of transmissions are occurring around illness onset in an infected person, and pre‐symptomatic transmission does play a role. Detection of milder infections among the secondary cases may be more reflective of true disease severity.

This study aimed to report the occurrence of benign paroxysmal positional vertigo (BPPV) in a 90-day head-down bed rest experiment and evaluate the potential relationship between BPPV-related seizures and bone metabolic changes. Five cases of lateral semicircular canal (LSC) BPPV were diagnosed during a 90-day head-down bed rest experiment. Five age-matched subjects who participated in this experiment and never felt dizziness or vertigo were assigned as controls. The differences between the BPPV and the controls in lumbar bone mineral density, 25-hydroxyvitamin D level, corrected serum calcium, potassium, sodium, phosphorus, iron, uric acid and N-terminal osteocalcin were analyzed to determine the cause of LSC-BPPV. BPPV occurred from Day 17 to Day 42 during head-down bed rest. The occurrences of BPPV were related to low 25-hydroxyvitamin D level (BPPV:20.70 ± 1.95 ng/L vs. control: 30.59 ± 2.75 ng/L at Day 30 during HDBR, p

The accuracy and efficiency of scene classification have immensely improved with the extensive application of deep convolutional neural networks (CNNs). However, standard CNNs classify images mostly based on the global features from the last fully connected layer, which may cause the negligence of discriminative local information and the sensitivity to various spatial transformations. In this article, we consider the problem of scene classification from the perspective of multiple instance learning (MIL) and propose an end-to-end multiple instance CNN (MI-CNN) for learning more robust scene representations. In MI-CNN, a scene is represented as a bag of local patches (instances). An instance-level classifier is trained to obtain the label of each patch in an MIL fashion, which makes the classifier more sensitive to the discriminative local patches. The patch labels are then aggregated into an image label by an MIL pooling layer, which is invariant to the order of local patches and helps construct more robust representations. We present extensive experiments on UC Merced Land use (UCM), Aerial Image data set (AID), and NWPU-RESISC (NWPU) data sets. Experimental results show that the proposed method achieves 1.17%, 1.70%, and 3.61% accuracy improvements with 90% parameter reduction compared with the standard CNNs.

With rapid development of satellite and airplane platforms, aerial image has become more and more accessible. Aerial image scene classification plays an important role in many remote sensing and geo-science applications. Deep learning methods, especially convolutional neural network (CNN), have boosted the performance of aerial image scene classification significantly because of the strong feature representation ability. However, the distribution of geo-spatial objects and the spatial arrangement of aerial image scenes is often more complicated than natural image scenes. While current CNNs usually highlight the global semantics, more local semantics and more discriminative features need to be preserved to deal with the aforementioned challenges in aerial scenes. In this paper, we propose a residual attention based dense connected convolutional neural network (RADC-Net) to tackle this problem. This framework contains three dense block each followed by an attention block and an enhanced classification layer. Firstly, we simplify the current dense connection structure so that our dense block has much fewer parameters while maintaining discriminative convolutional feature representation ability. Then, we propose a novel residual attention block for our framework to highlight the local semantics relevant to the aerial scenes. Finally, we introduce an enhanced classification layer in our framework to further refine the extracted convolutional features and highlight local semantic information. We comprehensively evaluate the performance of our proposed RADC-Net on three publicly available benchmark datasets. Experimental results demonstrate that our proposed RADC-Net outperforms some state-of-the-art methods with much fewer parameters.

Inflammatory bowel disease (IBD) is an important risk factor for colon cancer. Novel serum immunoinflammation-related protein complexes (IIRPCs) have shown associations with early cancer detection. Herein, we investigated the potential of serum IIRPCs for discriminating between IBD and colorectal cancer (CRC) patients. Serum protein complexes of 65 healthy controls, 57 CRC, 69 (ulcerative colitis) UC, and 67 (Crohn's disease) CD patients were isolated by native-PAGE. The gray values of serum IIRPCs bands in the gel were quantified using Quantity One software. The receiver-operating characteristic (ROC) curves were constructed to assess the discriminating ability by calculating the area under the ROC curve. The serum IIRPCs levels in IBD and CRC patients were significantly elevated compared to healthy controls. ROC analysis indicated certain diagnostic ability of serum IIRPCs in differentiating IBD from CRC. Specifically, “a3” complex discriminated UC from CRC, with an AUC value of 0.722, sensitivity of 69.4% and specificity of 63.8%. Similarly, “b4” complex discriminated UC from CRC, with an AUC value of 0.709, sensitivity of 70.4%, and specificity of 60.0%. In addition, the “a3” complex also discriminated CD from CRC, with an AUC value of 0.785, sensitivity of 73.1%, and specificity of 74.1%, while the “b4” complex showed a tendency to discriminate CD from CRC, with an AUC value of 0.663, sensitivity of 67.9% and specificity of 50.0%. Thus, an equation based on multiple IIRPCs was built to further improve the discriminating power. Serum IIRPCs can be used to discriminate IBD from CRC and may also be associated with early screening of colitis-associated cancer.

Chronic pulmonary methicillin-resistant Staphylococcus aureus (MRSA) disease in cystic fibrosis (CF) has a high probability of recurrence following treatment with standard-of-care antibiotics and represents an area of unmet need associated with reduced life expectancy. We developed a lipoglycopeptide therapy customized for pulmonary delivery that not only demonstrates potent activity against planktonic MRSA, but also against protected colonies of MRSA in biofilms and within cells, the latter of which have been linked to clinical antibiotic failure. A library of next-generation potent lipoglycopeptides was synthesized with an emphasis on attaining superior pharmacokinetics (PK) and pharmacodynamics to similar compounds of their class. Our strategy focused on hydrophobic modification of vancomycin, where ester and amide functionality were included with carbonyl configuration and alkyl length as key variables. Candidates representative of each carbonyl attachment chemistry demonstrated potent activity in vitro, with several compounds being 30 to 60 times more potent than vancomycin. Selected compounds were advanced into in vivo nose-only inhalation PK evaluations in rats, where RV94, a potent lipoglycopeptide that utilizes an inverted amide linker to attach a 10-carbon chain to vancomycin, demonstrated the most favorable lung residence time after inhalation. Further in vitro evaluation of RV94 showed superior activity to vancomycin against an expanded panel of Gram-positive organisms, cellular accumulation and efficacy against intracellular MRSA, and MRSA biofilm killing. Moreover, in vivo efficacy of inhaled nebulized RV94 in a 48 h acute model of pulmonary MRSA (USA300) infection in neutropenic rats demonstrated statistically significant antibacterial activity that was superior to inhaled vancomycin.

Background: Bone loss induced by microgravity is a serious problem in space flight. However, the effects of acupuncture stimulation on osteoporosis induced by microgravity have not been studied. With the goal of developing an effective countermeasure, our aim was to evaluate the effects of electroacupuncture (EA) stimulation at BL20, BL23, and SP6 on osteoporosis induced by simulated microgravity in rats. Methods: Thirty male Wistar rats (aged 10 weeks) were randomly divided into three groups: healthy control group (CON, n = 10), hind limb unloading by tail-suspension group (T-S, n = 10), and EA treatment group (TRE, n = 10). Rats in the T-S and TRE groups were subjected to tail-suspension at −30° for 30 days, while the CON group experienced freedom of activity. In this period, the TRE group received EA treatment at BL20, BL23, and SP6 for 30 min every other day, which continued for 30 days. The microarchitecture of the proximal tibia and the biomechanical features of the femur in the rats were analyzed. In addition, the levels of serum biomarkers bone alkaline phosphatase (BALP) and osteocalcin (BGP) were measured. Results: Compared with the CON group, the value of bone volume/total volume (BV/TV) and trabecular number (Tb.N) of the tibias in the TRE group remarkably decreased ( p Conclusions: These findings indicate that EA stimulation at BL20, BL23, and SP6 retards osteoporosis induced by hind limb unloading in rats.

Background and aims Early diagnosis is key to improving the prognosis of gastric cancer. Altered phospholipid metabolism has been observed in different types of cancer. This study assessed serum phospholipid levels of patients with gastric cancer to explore biomarkers for its early diagnosis. Materials and methods A total of 199 participants were enrolled, including patients with early gastric cancer or precancerous gastric lesions and healthy controls. Serum phospholipids were extracted and identified using mass spectrometry. The relative abundances of these phospholipids were compared among patients at different disease stages. Twenty-four patients with early gastric cancer were followed up, and their serum phospholipid levels were compared beween before and after resection. Results Fifty-four phospholipids were identified. Phosphatidylethanolamine (36:3), phosphatidylethanolamine (36:2), phosphatidylcholine (32:0), and sphingomyelin (d18:0/18:1(9Z)) were more abundant in patients with early gastric cancer than in healthy controls. The area under the receiver operating curve of sphingomyelin (d18:0/18:1(9Z)) reached 0.883 in the training set (sensitivity 81.08%, specificity 78.82%) and 0.874 in the validation set. The levels of phosphatidylethanolamine (36:2), phosphatidylcholine (32:0), and sphingomyelin (d18:0/18:1(9Z)) significantly declined after the cancerous lesions were resected. Conclusion Serum phospholipids can serve as potential biomarkers for the early diagnosis of gastric cancer.

[Objectives] By studying the plasma metabolomics of patients with different pulmonary nodules and healthy people, we can find the difference in plasma low-molecular metabolites among them. [Methods] Patients with pulmonary nodules admitted to our department were divided into three groups: pulmonary metastatic carcinoma (PMC), benign pulmonary nodules (BPN), and primary lung cancer (PLC). Meanwhile healthy people were enrolled as healthy population group (HPG). PLC and HPG were equally divided into the Discovery Set and Validation set. [Results] Five significant low-molecular metabolites were found by comparison of four groups as a whole. Four to six metabolites were selected by comparison of the three pulmonary nodule groups with healthy people respectively. The AUC of ROC of these metabolites were all＞0.93. Each pairwise comparison within the three pulmonary nodule groups all found three metabolites, whose AUC of ROC were all＞0.83. From the comparison of PLC and HPG in the discovery set, six metabolites were selected. Their AUC of ROC were all greater than 0.95 in the validation set, indicating that they had a strong ability to differentiate between primary lung cancer and healthy people. [Conclusions] We can find the significant changes of some low-molecular metabolites among three pulmonary nodules and healthy people. These metabolites had the potential to be biomarkers for screening and differential diagnosis of lung cancer.

Background The relative contributions of asymptomatic, presymptomatic, and symptomatic transmission of severe acute respiratory syndrome coronavirus 2 have not been clearly measured, although control measures may differ in response to the risk of spread posed by different types of cases. Methods We collected detailed information on transmission events and symptom status based on laboratory-confirmed patient data and contact tracing data from 4 provinces and 1 municipality in China. We estimated the variation in risk of transmission over time and the severity of secondary infections by symptomatic status of the infector. Results There were 393 symptomatic index cases with 3136 close contacts and 185 asymptomatic index cases with 1078 close contacts included in the study. The secondary attack rates among close contacts of symptomatic and asymptomatic index cases were 4.1% (128 of 3136) and 1.1% (12 of 1078), respectively, corresponding to a higher transmission risk from symptomatic cases than from asymptomatic cases (odds ratio, 3.79; 95% confidence interval, 2.06–6.95). Approximately 25% (32 of 128) and 50% (6 of 12) of the infected close contacts were asymptomatic from symptomatic and asymptomatic index cases, respectively, while more than one third (38%) of the infections in the close contacts of symptomatic cases were attributable to exposure to the index cases before symptom onset. Conclusions Asymptomatic and presymptomatic transmissions play an important role in spreading infection, although asymptomatic cases pose a lower risk of transmission than symptomatic cases. Early case detection and effective test-and-trace measures are important to reduce transmission.

Treprostinil palmitil (TP) is a prodrug of treprostinil (TRE), a pulmonary vasodilator that has been previously formulated for inhaled administration via a nebulizer. TP demonstrates a sustained presence in the lungs with reduced systemic exposure and prolonged inhibition of hypoxia-induced pulmonary vasoconstriction in vivo. Here, we report on re-formulation efforts to develop a more convenient solution-based metered-dose inhaler (MDI) formulation of TP, a treprostinil palmitil inhalation aerosol (TPIA) that matches the pharmacokinetic (PK) and efficacy profile of a nebulized TP formulation, treprostinil palmitil inhalation suspension (TPIS). MDI canisters were manufactured using a two-stage filling method. Aerosol performance, formulation solubility, and chemical stability assays were utilized for in vitro evaluation. For in vivo studies, TPIA formulations were delivered to rodents using an inhalation tower modified for MDI delivery. Using an iterative process involving evaluation of formulation performance in vitro (TP and excipient solubility, chemical stability, physical stability, and aerosol properties) and confirmatory testing in vivo (rat PK and efficacy, guinea pig cough), a promising formulation was identified. The optimized formulation, TPIA-W, demonstrates uniform in vitro drug delivery, a PK profile suitable for a once-daily administration, efficacy lasting at least 12 h in a hypoxic challenge model, and a significantly higher cough threshold than the parent drug treprostinil.

Influenza endangers human health but can be prevented in part by vaccination. Assessing influenza vaccine effectiveness (VE) provides scientific evidence for developing influenza vaccination policy. We conducted a systematic review and meta-analysis of studies that evaluated influenza VE in mainland China. We searched six relevant databases as of 30 August 2019 to identify studies and used Review Manager 5.3 software to analyze the included studies. The Newcastle–Ottawa scale was used to assess the risk of publication bias. We identified 1408 publications, and after removing duplicates and screening full texts, we included 21 studies in the analyses. Studies were conducted in Beijing, Guangzhou, Suzhou, and Zhejiang province from the 2010/11 influenza season through the 2017/18 influenza season. Overall influenza VE for laboratory confirmed influenza was 36% (95% CI: 25–46%). In the subgroup analysis, VE was 45% (95% CI: 18–64%) for children 6–35 months who received one dose of influenza vaccine, and 57% (95% CI: 50–64%) who received two doses. VE was 47% (95% CI: 39–54%) for children 6 months to 8 years, and 18% (95% CI: 0–33%) for adults ≥60 years. For inpatients, VE was 21% (95% CI: −11–44%). We conclude that influenza vaccines that were used in mainland China had a moderate effectiveness, with VE being higher among children than the elderly. Influenza VE should be continuously monitored in mainland China to provide evidence for policy making and improving uptake of the influenza vaccine.

We introduce the concept of third-order Riemann pulses in nonlinear optical fibers. These pulses are generated when properly tailored input pulses propagate through optical fibers in the presence of higher-order dispersion and Kerr nonlinearity. The local propagation speed of these optical wave packets is governed by their local amplitude, according to a rule that remains unchanged during propagation. Analytical and numerical results exhibit a good agreement, showing controllable pulse steepening and subsequent shock wave formation. Specifically, we found that the pulse steepening dynamic is predominantly determined by the action of higher-order dispersion, while the contribution of group velocity dispersion is merely associated with a shift of the shock formation time relative to the comoving frame of the pulse evolution. Unlike standard Riemann waves, which exclusively exist within the strong self-defocusing regime of the nonlinear Schrödinger equation, such third-order Riemann pulses can be generated under both anomalous and normal dispersion conditions. In addition, we show that the third-order Riemann pulse dynamics can be judiciously controlled by a phase chirping parameter directly included in the initial chirp profile of the pulse.

Introduction: Sugen/Hypoxia (Su/Hx) challenge to rats produces many pathophysiological markers of human pulmonary arterial hypertension (PAH). Aim: Compare the effects of TPIS, a long-acting prodrug of treprostinil (TRE) and the PDE5 inhibitor Sild on the increase in pulmonary arterial blood pressure, right heart size (Fulton index), decrease in cardiac output (CO), and pulmonary vascular and cardiac histopathology in Su/Hx challenged rats. Methods: Male Sprague Dawley rats were injected with subcutaneous Su (20 mg/kg) followed by 3-week exposure to Hx (10% O2) and normoxia (Nx) for 10-weeks. The rats received daily nose-only inhalation of TPIS (daily total delivered doses of 52 and 135 mg/kg, QD) or oral Sild (50 mg/kg, BID) during the Nx exposure. Pulmonary vascular hemodynamics, Fulton index, CO and histopathology were assessed along with pharmacokinetic data of plasma TRE and lung treprostinil palmitil (TP) concentrations. Results: TPIS not only reduced the increase in pulmonary vascular hemodynamics, Fulton index, and the decrease in CO but also reduced the increases in wall thickness, muscularization and occlusion in pulmonary arteries and collagen deposition in the heart. TPIS almost completely restores vascular hemodynamics and Fulton index to normal values with the 135 µg/kg dose. Sild had only partial effects on all parameters. TPIS produced dose-dependent increases in plasma TRE and lung TP concentrations. Conclusions: These results demonstrate beneficial effects of TPIS to ameliorate the pathophysiology and histopathology in the pulmonary blood vessels and heart of Su/Hx challenged rats with effects superior to that produced by Sild.

Introduction: Continuous infusion with intravenous (IV) treprostinil (TRE) results in desensitization of the prostacyclin receptor and requires dose escalation to maintain its efficacy over time. It is unknown if desensitization to TPIS, a long-acting prodrug of TRE, occurs after repeat administration. Aim: Determine if desensitization occurs with TPIS after daily inhalation for 32-consecutive days. Methods: Male Sprague Dawley rats with a telemetry probe inserted in the right ventricle were exposed to acute inhaled hypoxia (Hx). The Hx-induced increase in right ventricular pulse pressure (∆RVPP) was measured before and every 4th day after daily TPIS (total daily delivered dose of 40 µg/kg) for 32-consecutive days. A comparison was made to continuous IV TRE (250 ng/kg/min) for 16-consecutive days. Blood samples were collected at each Hx challenge to measure the plasma TRE concentration. Results: There was no diminution in the ∆RVPP response to Hx after exposure to TPIS which averaged 15.49 mmHg before TPIS, and 5.01 mmHg on Day 0, 6.83 mmHg on day 16 and 7.01 mmHg on day 32. In contrast, the ∆RVPP response to Hx with IV TRE averaged 15.02 mmHg before IV TRE, and 7.77 mmHg on day 0 and 13.97 mmHg on day 16 indicating a diminution of effect by day 16 for IV TRE. The plasma TRE concentrations after TPIS ranged from 0.02 to 0.21 ng/ml but were higher with IV infused TRE and ranged from 2.54 to 13.35 ng/ml. Conclusions: Unlike IV infused TRE, there was no evidence for desensitization with TPIS for inhibition of Hx-induced pulmonary vasoconstriction in rats after daily adminstration via inhalation for 32-consecutive days.

Background The goal of this study was to detect novel modified forms of hemoglobin using mass spectrometry (MS) and to investigate the effect of modified hemoglobin on HbA1c and fasting plasma glucose (FPG). Methods This study was conducted on 1200 subjects aged >25 years. Hemoglobin from the above-mentioned subjects was detected using direct-infusion electrospray ionization-MS, and HbA1c and FPG were measured according to the manufacturer's instructions. Regression analysis was performed to estimate the correlations and interactions among HbA1c, FPG, and modified hemoglobin. Results Multiple modified forms (α1, α2, α3, β1, β2, and β3) of hemoglobin were observed using MS. Statistical analyses indicated that modified hemoglobin was significantly correlated with FPG (p ≤ .01). The association of FPG with α1% (p = .021) and β3% (p Conclusions This MS-based method is an effective tool for monitoring glycated forms of hemoglobin than traditional approaches. For the Han Chinese population, multiple-glycated hemoglobin affects the association of FPG with HbA1c%, and the correlation between FPG and HbA1c% in females is different from that in males. These data suggest that the HbA1c criteria for the diagnosis and monitoring of diabetes should be established according to genders and modified types of hemoglobin.

International audience; We report on the generation of third-order Riemann pulses in nonlinear optical fiber, obtained by tailoring the initial pulse in presence of high-order dispersion and Kerr nonlinearity. Analytical and numerical results show controllable pulse steepening and shock formation. OCIS codes: (190.0190) Nonlinear optics; (070.7345) Wave propagation; (190.3270) Kerr effect Simple Riemann waves (RWs), solutions of the Inviscid Burgers' Equation (IBE), are of fundamental importance to study shock formation in different physical frameworks beyond hydrodynamics [1]. Experimental demonstration and control of RW signatures have been recently reported in nonlinear optics, in both the temporal [2-5 ] and spatial [6-7] domains. Nevertheless, standard RWs are achieved under both week dispersion/diffraction and strong nonlinearity, and have been only demonstrated in the self-defocusing regime of the nonlinear Schrödinger equation (NLSE). High-order dispersive effects in fibers can affect the RW dynamics by significantly deteriorating their expected temporal profiles. Here, we propose a conceptually new class of optical RWs which can be implemented in nonlinear optical fibers, namely, third-order Riemann pulses (TORPs). Such RW packets arise from the interplay between high-order dispersion and nonlinearity, and can be realized by properly tailoring the phase profile of an input ultrashort light pulse. Our analysis starts by considering the NLSE that describes pulse propagation in a nonlinear optical fiber with Kerr nonlinearity, considering also both second-and third-order dispersions (SOD and TOD), as follows: 2 3 3 2 2 2 3 0. 26 A A i A i A A Z TT      − − + =   (1) In Eq. (1), A(T, Z) is the dimensionless electric field envelope, while T = t / T 0 and Z=z/L NL , are the normalized temporal and propagation coordinates, respectively. We scale the pulse duration by T 0 , and its peak power by P 0. 2 20 2 0 / () PT    = and 33 3 0 0 / () PT    = are the dimensionless SOD and TOD terms, where γ = k 0 n 2 is the nonlinear Kerr coefficient, k 0 is the vacuum wavenumber, n 0 and n 2 are the linear and nonlinear refractive index, and β 2 and β 3 denote the SOD and TOD coefficients of the fiber. Arbitrary solutions to Eq. (1) can be found by expressing the pulse envelope in a polar form by means of the Madelung transformation: () () () , , exp , , T

Background Deregulation of circulating microRNAs (miRNAs) is always associated with development and progression of human diseases. We aimed to assess whether patients with brain arteriovenous malformations (BAVMs) possess a distinct miRNA signature compared with healthy subjects. Methods Three patients with unruptured BAVMs and 3 normal control subjects were recruited as case and control groups. Peripheral blood was collected, and miRNA signature was obtained by next-generation sequencing, followed by comparative, functional, and network analyses. Quantitative reverse transcription polymerase chain reaction was performed to validate expression of specific miRNAs. Results Deep sequencing detected 246 differentially expressed miRNAs in blood samples of patients with BAVMs compared with normal control subjects. For the top 5 miRNAs, 946 target genes were predicted, and a BAVM-specific miRNA-target gene regulatory network was constructed. Functional annotation suggested that 15 of the predicted miRNA-targeted genes were involved in vascular endothelial growth factor signaling, in which 3 critical miRNAs were involved: miR-7-5p, miR-199a-5p, and miR-200b-3p. Conclusions We explored the miRNA expression signature of BAVMs, which will provide an important foundation for future studies on the regulation of miRNAs involved in BAVMs.

INS1009 is a long acting pulmonary vasodilator prodrug of treprostinil (TRE) that is formulated in a lipid nanoparticle for inhaled delivery by nebulization. This study examined the ability of INS1009 to inhibit vasoconstriction in the pulmonary vasculature of rats and dogs and the extent to which local activity within the lung contributes to its activity. Rats received a single dose of INS1009 by nose-only inhalation or were given a continuous intravenous (i.v.) infusion of TRE, followed by an i.v. challenge of the thromboxane mimetic pulmonary vasoconstrictor U46619 and the increase in pulmonary arterial pressure (PAP) was measured. In beagle dogs, INS1009 was given by inhalation via face mask and TRE was given by continuous i.v. infusion; vasoconstriction was then induced by inhaled hypoxia with reduction of FIO2 to 0.10. Changes in the dog's right ventricular pulse pressure (RVPP) were measured using implanted telemetry probes. Blood samples were collected in rats and dogs immediately after the challenge to measure the plasma TRE concentration. Exposure of rats to inhaled INS1009 (0.5, 3.0 and 20.9 μg/kg) inhibited the U46619-induced increase in PAP at all doses up to 6 h with statistically significant inhibition up to 24 h with the pooled dose-response data. The concentration of TRE in the plasma at which PAP was reduced by 50% was approximately 60-fold lower for INS1009 (EC50 = 0.08 ng/mL) as compared to i.v. TRE (EC50 = 4.9 ng/mL). In dogs, INS1009 (2.7–80.9 μg/kg) inhibited the hypoxia-induced increase in RVPP at all doses up to 6 h with activity once again observed with the pooled dose-response of 10 μg/kg and higher at 24 h. The concentration of TRE in the plasma at which RVPP was reduced by 50% was approximately 550-fold lower for INS1009 (EC50 = 0.0075 ng/mL) as compared to i.v. TRE (EC50 = 4.1 ng/mL). These studies, in two species and by two different pulmonary vasoconstrictor challenges, demonstrate that inhaled INS1009 not only has long-acting vasodilatory effects but also that the local activity within the lung contributes to this response. Therefore, INS1009 may offer the opportunity to effect pulmonary vasodilation for long periods but with substantially lower systemic exposure than infused TRE.

We constructed an all-fiber pulsed vortex laser based on a nonlinear amplifying loop mirror (NALM) and a coupler that was fused with a single-mode fiber (SMF) and a few-mode fiber (FMF). The cavity, including an NALM, was in charge of the generation of pulses. The coupler inserted into the cavity acted as a mode converter. The produced 393-fs vortex beam had a spectrum width of 12 nm and centered at 1567 nm.

Background Genetic risk factors can contribute to the etiology of intracranial aneurysms (IAs), and the genetic predisposition of IAs is largely unknown. Our study aimed to explore the role of rare variations in IA susceptibility. Methods Whole-exome sequencing (WES) was performed in a representative family with a history of multiple cases of IAs. WES variants were prioritized by various filtering strategies, including frequency, predicted pathogenicity, and functional prediction. Sanger sequencing also was performed in an additional 2 families and sporadic IA cases. Results After WES and filtering, 15 single-nucleotide variants and 3 insertion/deletions (indels) were prioritized in the family. Among them, we selected 5 candidate variants (located in DHRS3, OR2G3, LOXL2, FGL1, and KLC3) by considering known disease genes or ontology association with cardiovascular morphogenesis or other known diseases. Genotyping results revealed that only c.C133T/p.H45Y in exon 2 of LOXL2 gene was segregated fully with definite IA phenotypes in the family. Moreover, LOXL2 has been reported as a susceptibility gene for IAs. Conclusions LOXL2 c.C133T is a pathogenic mutation that is responsible for a fraction of familial IAs.

Long exposure to the microgravity will lead to muscle atrophy and bone loss. Treadmill exercise could mitigate the musculoskeletal decline. But muscle atrophy remains inevitable. The constraint loading applied on astronauts could affect the muscle force and its atrophy severity. However, the quantitative correlation between constraint loading mode and muscle forces remains unclear. This study aimed to characterize the influence of constraint loading mode on the lower limb muscle forces in weightless treadmill exercise. The muscle forces in the full gait cycle were calculated with the inverse dynamic model of human musculoskeletal system. The calculated muscle forces at gravity were validated with the EMG data. Muscle forces increased at weightlessness compared with those at the earth’s gravity. The increasing percentage from high to low is as follows: biceps femoris, gastrocnemius, soleus, vastus, and rectus femoris, which was in agreement with the muscle atrophy observed in astronauts. The constraint loading mode had an impact on the muscle forces in treadmill exercise and thus could be manipulated to enhance the effect of the muscle training in spaceflight. The findings could provide biomechanical basis for the optimization of treadmill constraint system and training program and improve the countermeasure efficiency in spaceflight.

This article describes the preclinical pharmacology and pharmacokinetics (PK) of hexadecyl-treprostinil (C16TR), a prodrug of treprostinil (TRE), formulated in a lipid nanoparticle (LNP) for inhalation as a pulmonary vasodilator. C16TR showed no activity (>10 µM) in receptor binding and enzyme inhibition assays, including binding to prostaglandin E2 receptor 2, prostaglandin D2 receptor 1, prostaglandin I2 receptor, and prostaglandin E2 receptor 4; TRE potently bound to each of these prostanoid receptors. C16TR had no effect (up to 200 nM) on platelet aggregation induced by ADP in rat blood. In hypoxia-challenged rats, inhaled C16TR-LNP produced dose-dependent (0.06-6 µg/kg), sustained pulmonary vasodilation over 3 hours; inhaled TRE (6 µg/kg) was active at earlier times but lost its effect by 3 hours. Single- and multiple-dose PK studies of inhaled C16TR-LNP in rats showed proportionate dose-dependent increases in TRE Cmax and area under the curve (AUC) for both plasma and lung; similar results were observed for dog plasma levels in single-dose PK studies. In both species, inhaled C16TR-LNP yielded prolonged plasma TRE levels and a lower plasma TRE Cmax compared with inhaled TRE. Inhaled C16TR-LNP was well tolerated in rats and dogs; TRE-related side effects included cough, respiratory tract irritation, and emesis and were seen only after high inhaled doses of C16TR-LNP in dogs. In guinea pigs, inhaled TRE (30 µg/ml) consistently produced cough, but C16TR-LNP (30 µg/ml) elicited no effect. These results demonstrate that C16TR-LNP provides long-acting pulmonary vasodilation, is well tolerated in animal studies, and may necessitate less frequent dosing than inhaled TRE with possibly fewer side effects.

An evanescent-wave quartz-enhanced photoacoustic spectroscopy (EW-QEPAS) CO sensor was developed using a tapered fiber integrated with the quartz tuning fork (QTF) and micro-resonator (mR) tubes. The fiber taper was inserted through the two mR tubes with the taper waist located between the QTF prongs. A fiber-coupled continuous-wave distributed feedback (DFB) laser at 2.3 μm was connected with the fiber taper fabricated by the flame-brushing method. The fiber taper has negligible influence on the resonant frequency and Q -factor of the QTF, but significantly reduces the background noise compared with the recently developed fiber tip-based EW-QEPAS sensor. In the EW-QEPAS detection with wavelength modulation spectroscopy, we investigated the optimal modulation depth and gas pressure, which are different from that of the conventional free-space QEPAS detection. The current CO sensor achieved a minimum detection limit of ∼20 ppm at the 210-s averaging time, corresponding to a normalized noise equivalent absorption (NNEA) coefficient of 1.44 × 10 −8 cm −1 W/√Hz.

Manipulative dual-microsphere lasing based on a nanosilica waveguide integrated in a simplified hollow-core microstructured optical fiber (SHMOF) is proposed and demonstrated. The SHMOF, which has a silica-branch structure, provides a nanoscale waveguide array and offers a versatile platform for selective lasing. Emissions at 600 and 640 nm are produced by excitation of different dye-coated microspheres, enabling a laser array with an ultralow nJ-level threshold. Because the transitive energy is bridged by the silica ring, the microsphere lasing could be controlled by another microsphere laser because of the interaction between and dependence of their thresholds. In addition, semidirectional lasing is also achieved by deliberately embedding a microsphere against the hexagonal silica wall.

In contrast with nature scenes, aerial scenes are often composed of many objects crowdedly distributed on the surface in bird’s view, the description of which usually demands more discriminative features as well as local semantics. However, when applied to scene classification, most of the existing convolution neural networks (ConvNets) tend to depict global semantics of images, and the loss of low- and mid-level features can hardly be avoided, especially when the model goes deeper. To tackle these challenges, in this paper, we propose a multiple-instance densely-connected ConvNet (MIDC-Net) for aerial scene classification. It regards aerial scene classification as a multiple-instance learning problem so that local semantics can be further investigated. Our classification model consists of an instance-level classifier, a multiple instance pooling and followed by a bag-level classification layer. In the instance-level classifier, we propose a simplified dense connection structure to effectively preserve features from different levels. The extracted convolution features are further converted into instance feature vectors. Then, we propose a trainable attention-based multiple instance pooling. It highlights the local semantics relevant to the scene label and outputs the bag-level probability directly. Finally, with our bag-level classification layer, this multiple instance learning framework is under the direct supervision of bag labels. Experiments on three widely-utilized aerial scene benchmarks demonstrate that our proposed method outperforms many state-of-the-art methods by a large margin with much fewer parameters.

Recent advances in high-throughput (HTP) computational power and machine learning have led to great achievements in exploration of new thermoelectric materials. However, experimental discovery and optimization of thermoelectric materials have long relied on the traditional Edisonian trial and error approach. Herein, we demonstrate that ultrahigh thermoelectric performance in a Cu-doped PbSe-PbS system can be realized by HTP experimental screening and precise property modulation. Combining the HTP experimental technique with transport model analysis, an optimal Se / S ratio showing high thermoelectric performance has been efficiently screened out. Subsequently, based on the screened Se / S ratio, the doping content of Cu has been subtly adjusted to reach the optimum carrier concentration. As a result, an outstanding peak zT ~ 1.6 is achieved at 873 K for a 1.8 at% Cu-doped PbSe 0.6 S 0.4 sample, which is the superior value among the n -type Te-free lead chalcogenides. We anticipate that current work will stimulate large-scale unitization of the HTP experimental technique in the thermoelectric field, which can greatly accelerate the research and development of new high-performance thermoelectric materials.

Objective. Renal ischemia/reperfusion injury (RI/RI) is the main cause of acute kidney injury. Total glucosides of paeony (TGP) are a traditional Chinese medicine. This study was aimed at exploring the role of TGP in RI/RI and its underlying mechanism of action. Methods. Rat RI/RI models were constructed by surgical operation. Serum creatinine (Scr) and blood urea nitrogen (BUN) were used to evaluate renal function. The levels of proinflammatory cytokines were detected by ELISA. RI/RI was simulated by hypoxia/reoxygenation (H/R) treatment in renal cells in vitro. The lncRNA XIST (XIST) expression was analyzed by qRT-PCR. Then, the viability and apoptosis of renal cells were detected by MTT and flow cytometry assay. Additionally, dual-luciferase reporter assay was used to determine the interactions among XIST, microRNA-124-3p (miR-124-3p), and ITGB1. Results. TGP improved renal function and inhibited inflammatory responses after RI/RI. XIST expression was highly expressed in rat RI/RI models and H/R-treated renal cells, whereas treatment with TGP downregulated the XIST expression. Additionally, TGP increased viability and attenuated apoptosis and inflammation of H/R-treated renal cells via inhibiting XIST. Moreover, XIST was competitively bound to miR-124-3p, and ITGB1 was a target of miR-124-3p. miR-124-3p overexpression or ITGB1 inhibition rescued the reduction effect on viability and mitigated the promoting effects on cell apoptosis and inflammation caused by XIST overexpression in H/R-treated renal cells. Conclusions. In vivo, TGP attenuated renal dysfunction and inflammation in RI/RI rats. In vitro, TGP inhibited XIST expression to modulate the miR-124-3p/ITGB1 axis, alleviating the apoptosis and inflammation of H/R-treated renal cells.

Treprostinil palmitil (TP) is an inhaled long-acting pulmonary vasodilator prodrug of treprostinil (TRE) that has been formulated for delivery as a suspension (treprostinil palmitil inhalation suspension; TPIS) and as a dry powder (treprostinil palmitil inhalation powder; TPIP). In humans, tachyphylaxis is frequently observed with continuous intravenous (IV) or subcutaneous (SC) infusion of TRE and requires dosage escalation to maintain activity. The aim of the present study was to determine whether tachyphylaxis occurs with repeat daily administration of inhaled TPIS.Experiments were performed in male Sprague-Dawley rats prepared with a telemetry probe implanted into the right ventricle to measure the change in right ventricular pulse pressure (ΔRVPP) induced by exposure to a 10% oxygen gas mixture. TPIS (6 mL) at concentrations of 0.25, 0.5, and 1 mM was given by nose-only inhalation using an Aeroneb Pro nebulizer, either as a single administration or daily for 16 or 32 consecutive days. In studies involving consecutive daily administrations of TPIS, the delivered TP dosage was 140.3 μg/kg at 1 mM and ranged from 40.2 to 72.2 μg/kg at 0.5 mM. A separate cohort of telemetered rats received continuous IV infusion of TRE via an Alzet mini-pump at a dosage rate of 250 ng/kg/min for 16 days. Blood and lung tissue samples were obtained, and the concentration of TRE in the plasma and TRE and TP in the lungs were measured approximately 1 h after TPIS administration.Dose-response studies with TPIS administered as a single administration inhibited the hypoxia-induced increase in RVPP in both a concentration-dependent (0.25, 0.5, and 1 mM) and time-dependent (1-24 h) manner. TPIS, given QD or BID at inhaled doses ranging from 40.2 to 140.3 μg/kg for 16 or 32 consecutive days, produced statistically significant (P .05) inhibition of the increase of RVPP due to hypoxia over the full duration of the dosing periods. By contrast, the inhibition of the hypoxia-induced increase in RVPP observed with IV TRE infusion (250 ng/kg/min) disappeared after 16 days of infusion. The plasma concentrations of TRE were significantly higher after IV TRE (range, 2.85-13.35 ng/mL) compared to inhaled TPIS (range, 0.22-0.73 ng/mL) CONCLUSIONS: There was no evidence of tachyphylaxis with repeat daily dosing of TPIS for a period of up to 32 days. The absence of tachyphylaxis with TPIS is likely related to its local vasodilatory effects within the lungs, combined with an absence of sustained high plasma concentrations of TRE.

Convolutional neural networks (CNN) have made rapid progress for a series of visual tasks, but the bottom-up convolutional feature extraction process is not qualified to mimic the human visual perception process, which takes advantages of discriminative features. Although attention modules extract the top-down discriminative features and have been widely investigated in the past few years, current attention modules interrupt the bottom-up convolutional feature extraction process. To tackle this challenge, in this paper, we introduce dense connection structure to fuse discriminative features from attention modules and convolutional features, which we term as dense attention learning. Also, to alleviate the over-fitting problem caused by rapid feature dimension growth, we propose a channel-wise attention module to compress and refine the convolutional features. Based on these strategies, we build a dense attention convolutional neural network (DA-CNN) for visual recognition. Exhaustive experiments on four challenging datasets including CIFAR-10, CIFAR-100, SVHN and ImageNet demonstrate that our DA-CNN outperforms many state-of-the-art methods. Moreover, the effectiveness of our dense attention learning and channel-wise attention module is also validated.

Building extraction plays a significant role in many high-resolution remote sensing image applications. Many current building extraction methods need training samples while it is common knowledge that different samples often lead to different generalization ability. Morphological building index (MBI), representing morphological features of building regions in an index form, can effectively extract building regions especially in Chinese urban regions without any training samples and has drawn much attention. However, some problems like the heavy computation cost of multi-scale and multi-direction morphological operations still exist. In this paper, a multi-scale filtering building index (MFBI) is proposed in the hope of overcoming these drawbacks and dealing with the increasing noise in very high-resolution remote sensing image. The profile of multi-scale average filtering is averaged and normalized to generate this index. Moreover, to fully utilize the relatively little spectral information in very high-resolution remote sensing image, two scenarios to generate the multi-channel multi-scale filtering index (MMFBI) are proposed. While no high-resolution remote sensing image building extraction dataset is open to the public now and the current very high-resolution remote sensing image building extraction datasets usually contain samples from the Northern American or European regions, we offer a very high-resolution remote sensing image building extraction datasets in which the samples contain multiple building styles from multiple Chinese regions. The proposed MFBI and MMFBI outperform MBI and the currently used object based segmentation method on the dataset, with a high recall and F-score. Meanwhile, the computation time of MFBI and MBI is compared on three large-scale very high-resolution satellite image and the sensitivity analysis demonstrates the robustness of the proposed method.

With the development of deep learning, many state-of-the-art natural image scene classification methods have demonstrated impressive performance. While the current convolution neural network tends to extract global features and global semantic information in a scene, the geo-spatial objects can be located at anywhere in an aerial image scene and their spatial arrangement tends to be more complicated. One possible solution is to preserve more local semantic information and enhance feature propagation. In this paper, an end to end multiple instance dense connected convolution neural network (MIDCCNN) is proposed for aerial image scene classification. First, a 23 layer dense connected convolution neural network (DCCNN) is built and served as a backbone to extract convolution features. It is capable of preserving middle and low level convolution features. Then, an attention based multiple instance pooling is proposed to highlight the local semantics in an aerial image scene. Finally, we minimize the loss between the bag-level predictions and the ground truth labels so that the whole framework can be trained directly. Experiments on three aerial image datasets demonstrate that our proposed methods can outperform current baselines by a large margin., Comment: 5 pages,3 figures, a conference paper accepted by IEEE ICIP 2019

Background: The association of pathological states with N-glycosylation of haptoglobin-β has attracted increasing attention. Materials & Methods: In the present study, disease-specific haptoglobin-β (DSHp-β) was separated from serum immunoinflammation-related protein complexes (IIRPCs) of 600 participants including 300 patients with benign lung diseases (BLDs) and 300 patients with non-small cell lung cancer (NSCLC). The enriched glycopeptides of the tryptic digests of the DSHp-β were analyzed using matrix assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FTICR MS). Results: 20 of glycopeptides were detected for each sample. The statistical analysis has indicated that significant changes in the sialylation of DSHp-β between BLDs and NSCLC patients were observed. The age- and sex-matched participants were randomly clarified into the training set and the validation set. Receiver operating characteristic (ROC) analysis has revealed that the level ratio of glycopeptides (G2G3/G2G3S4) at the sites of Asn207/211 has potential capability to distinguish BLDs from NSCLC, with the sensitivity of 74.4%, the specificity of 82.8%, and the area under curve (AUC) of 0.805. Conclusion: The glycosylation of DSHp-β can distinguish NSCLC from BLDs with high diagnostic accuracy compared with current clinical available serum markers.

Background Treadmill exercise is commonly used as an alternative to over-ground walking or running. Increasing evidence indicated the kinetics of treadmill exercise is different from that of over-ground. Biomechanics of treadmill or over-ground exercises have been investigated in terms of energy consumption, ground reaction force, and surface EMG signals. These indexes cannot accurately characterize the musculoskeletal loading, which directly contributes to tissue injuries. This study aimed to quantify the differences of lower limb joint angles and muscle forces in treadmills and over-ground exercises. 10 healthy volunteers were required to walk at 100 and 120 steps/min and run at 140 and 160 steps/min on treadmill and ground. The joint flexion angles were obtained from the motion capture experiments and were used to calculate the muscle forces with an inverse dynamic method. Results Hip, knee, and ankle joint motions of treadmill and over-ground conditions were similar in walking, yet different in running. Compared with over-ground running, joint motion ranges in treadmill running were smaller. They were also less affected by stride frequency. Maximum Gastrocnemius force was greater in treadmill walking, yet maximum Rectus femoris and Vastus forces were smaller. Maximum Gastrocnemius and Soleus forces were greater in treadmill running. Conclusions Treadmill exercise results in smoother joint kinematics. In terms of muscle force, treadmill exercise requires lower loading on knee extensor, yet higher loading on plantar flexor, especially on Gastrocnemius. The findings and the methodology can provide the basis for rehabilitation therapy customization and sophistic treadmill design. Electronic supplementary material The online version of this article (10.1186/s12938-019-0708-4) contains supplementary material, which is available to authorized users.

Introduction: Cough and airway irritation are adverse effects (AEs) associated with inhaled treprostinil (TRE). The site of action causing these AEs is unknown. Aim: Nebulized TRE, at a concentration that causes cough in guinea pigs, was administered to the isolated laryngeal airway of rats and guinea pigs to determine if the actions of TRE involved activation of laryngeal reflexes. Methods: The laryngeal airway was isolated in anesthetized male Sprague Dawley rats and Dunkin Hartley guinea pigs for administration (20 sec) of either nebulized TRE (30 µg/mL), citric acid (CA), hypertonic saline (HS) or phosphate buffered saline (PBS). Pulmonary airflow and expiratory duration (TE) were measured with a pneumotachograph connected to a tracheal catheter. The apneic index (TE post-challenge/TE pre-challenge), mean arterial blood pressure (MAP), heart rate (HR), arterial oxygen saturation (SaO2) and the number of swallows were measured before and after drugs. Results: In rats, nebulized CA (0, 0.01, 0.1 and 1 M) increased the apneic index (1, 32, 90, 101, respectively), MAP and swallowing and decreased SaO2 and HR. Similar effects occurred with nebulized HS (1.5, 3, 5 and 7 %). However, nebulized TRE (30 µg/mL), like nebulized PBS had no effects. In guinea pigs, nebulized CA (0, 0.1 and 1 M) increased the apneic index (2, 3 and 15, respectively) and produced cough and swallowing. Nebulized TRE (30 µg/mL) had no effects. Conclusions: These results demonstrate that nebulization of TRE to the laryngeal airway of rats and guinea pigs does not produce cough and airway irritation and suggest that sites more distal in the tracheobronchial tree and lung are involved.

Supplemental Digital Content is available in the text, Background: Heat shock proteins (HSP) might be useful as biomarkers for bipolar disorder (BD) which would be clinically valuable since no reliable biomarker for BD has so far been identified. The purpose of this study was to assess the heat shock proteins CPN10, CPN60, and CPN70 as potential biomarkers of BD. Methods: The study included 100 BD patients recruited from a hospital during 2012 and 2013. The study also included 94 healthy controls. Among the BD patients, 33 had abnormal hypothalamic-pituitary-adrenal (HPA) axis activity. Blood samples were obtained from the patients and controls. The chemiluminescence method, mass spectrometry, and flow cytometry were used for analysis. Results: The BD patients compared with the controls had a significantly lower level of CPN10 and significantly higher levels of CPN60 and CPN70. The BD patients with abnormal HPA axis activity had a significantly lower level of CPN60 compared with the normal HPA axis activity group of BD patients. The CPN60 level significantly inversely correlated with adrenocorticotropic hormone (ACTH) level in patients with bipolar depression and in patients with bipolar hypomania, and CPN70 significantly correlated with ACTH level in patients with bipolar depression and hypomania. Conclusions: Our findings suggest that the heat shock proteins CPN10, CPN60, and CPN70 might have potential as biomarkers for BD and CPN60 blood level might distinguish patients with abnormal HPA axis activity from those with normal HPA axis activity.

Treprostinil (TRE), a prostanoid analogue approved in the USA for the treatment of pulmonary arterial hypertension, requires continuous infusion or multiple dosing sessions per day for inhaled and oral routes of administration due to its short half-life. The inhaled drug is known to induce adverse systemic and local effects including headache, nausea, cough, and throat irritation which may be due at least in part to transiently high drug concentrations in the lungs and plasma immediately following administration [1]. To ameliorate these side effects and reduce dosing frequency we designed an inhaled slow-release TRE formulation. TRE was chemically modified to be an alkyl prodrug (TPD) which was then packaged into a lipid nanoparticle (LNP) carrier. Preclinical screening in a rat model of hypoxia-induced pulmonary vasoconstriction led to selection of a 16-carbon alkyl ester derivative of TRE. The TPD-LNP demonstrated approximately 10-fold lower TRE plasma Cmax compared to inhaled TRE solution while maintaining an extended vasodilatory effect. The favorable PK profile is attributed to gradual dissociation of TPD from the LNP and subsequent conversion to TRE. Together, this sustained presentation of TRE to the lungs and plasma is consistent with a once- or twice-daily dosing schedule in the absence of high Cmax-associated adverse events which could provide patients with an improved treprostinil therapy.

Background: To screen biomarkers to differentiate early-stage colorectal cancer (CRC) from benign colorectal disease (BCD) and healthy controls. Materials & Methods: Quantitative and qualitative analysis of C16:1, C18:3, C18:2, C18:1, C20:4, and C22:6 in 185 healthy controls, 55 patients with BCD, and 139 patients with CRC was performed. Comparisons of their levels in between CRC patients, BCD patients, and healthy controls were performed using Mann-Whitney U test. Results: Serum levels of C16:1, C18:3, C18:2, C18:1, C20:4, and C22:6 in CRC patients were significantly decreased compared with healthy controls and BCD patients. A combination of C16:1, C18:2, C20:4, and C22:6 has excellent diagnostic performance to differentiate early-stage CRC patients from healthy controls plus BCD patients, with an AUC of 0.926, a sensitivity of 84.6%, and a specificity of 89.8%. Conclusions: Serum levels of C16:1, C18:2, C20:4, and C22:6 could be diagnostic indicators of early-stage CRC patients.

Idiopathic pulmonary fibrosis is a progressive and lethal disease and while there are now two approved drugs (Esbriet ® and Ofev ® ) additional effective treatments are still needed. Recently, prostacyclin analogs such as iloprost and treprostinil (TRE) have been shown to exert some protection against bleomycin-induced pulmonary fibrosis in mice when administered in a prophylactic regimen. In this study, we evaluated the effect of the inhaled treprostinil prodrug hexadecyl-treprostinil (C16TR) formulated in a lipid nanoparticle (INS1009) administered therapeutically in a fibrotic rat model. Male Fischer 344 rats challenged with intra-tracheal saline instillation were then treated with daily inhaled phosphate buffered saline (PBS) while rats challenged with bleomycin sulfate (3.5–4.0 mg/kg) instillation were treated with either daily inhaled PBS, daily inhaled INS1009 (10, 30, or 100 μg/kg), or twice-daily orally with the anti-fibrotic compound pirfenidone (100 mg/kg). Dosing started on day 10 post-bleomycin challenge and continued until day 27 after bleomycin. Lungs were harvested 24 h after the last dose of treatment for evaluation of lung hydroxyproline content and pulmonary histology. Lung hydroxyproline content increased from 421 μg/lung lobe in saline challenged and PBS treated animals to 673 μg/lung lobe in bleomycin challenged and PBS treated rats. Treatment of bleomycin challenged rats with 10, 30, or 100 μg/kg INS1009 dose-dependently reduced lung hydroxyproline content to 563, 501, and 451 μg/lung lobe, respectively, and pirfenidone decreased hydroxyproline content to 522 μg/lung lobe. Histologically, both INS1009 (100 μg/kg) and pirfenidone (100 mg/kg) reduced the severity of subepithelial fibrosis . Single dose pharmacokinetic (PK) studies of inhaled INS1009 in bleomycin challenged rats showed dose-dependent increases in lung C16TR concentration and plasma TRE on day 10 post-bleomycin challenge. Multiple dose PK studies of inhaled INS1009 showed dose-dependent increases only in lung C16TR concentration on day 27 post-bleomycin challenge. We also investigated the effects of TRE on the cytokine transforming growth factor-β 1 (TGF-β1 )-stimulated collagen gene and protein expressions in cultured human lung fibroblasts , assessed by real-time PCR and Sirius Red staining, respectively. In human fibroblasts, TRE (0.001–10 μM) inhibited TGF-β 1 (20 ng/mL)-induced expression of collagen mRNA and protein in a concentration-dependent manner. These results demonstrated that inhaled INS1009, administered in a therapeutic dosing paradigm, dose-dependently (10–100 μg/kg) inhibited bleomycin-induced pulmonary fibrosis in rats. This effect may involve direct actions of TRE in suppressing collagen expression in lung fibroblasts.

We developed a photothermal interferometry-based trace gas sensor by coupling a mid-infrared pump laser and a near-infrared probe laser into a hollow-core optical fiber.

Introduction: Inhaled treprostinil (TRE) is used in the US to treat pulmonary arterial hypertension but is often associated with cough. Recently we found that a nebulized hexadecyl-treprostinil (C16TR) prodrug in a lipid nanoparticle, which provided prolonged pulmonary vasodilation in animals, evoked no cough in guinea pigs. We have now made a dry powder inhaled version of that formulation (DP-INS1009) that has comparable lung and plasma PK. Here we provide data on the effect of DP-INS1009 on cough. Aim: To evaluate inhaled DP-INS1009 on cough in guinea pigs. Methods: Guinea pigs were placed in a whole body plethysmograph and exposed to nebulized phosphate buffered saline (PBS) and TRE for 10 min and to dry powder lactose (DP-L) and DP-INS1009 for 15 min. Coughs were detected by visual observations and plethysmograph recordings. Drug doses were calculated based on aerosol concentrations of TRE and C16TR collected on a filter. Results: Exposure to inhaled TRE (1.2 µg/kg) produced cough (n=4) with a total of 53 ± 11 coughs. Inhaled TRE at 3.3 µg/kg (n=5) produced no further increase in cough (50 ± 6 coughs). No cough was observed after inhaled TRE (≈0.3 µg/kg, n=4) and PBS (n=10). In contrast, inhaled DP-L (n=5) and DP-INS1009 (3.8-17.3 µg/kg, treprostinil equivalent, n=5) did not induce cough (zero coughs). Conclusions: DP-INS1009 does not activate the cough reflex in guinea pigs at a dose up to 14-fold higher than inhaled nebulized TRE. Similar results have been previously found with nebulized INS1009 in guinea pigs and suggest that INS 1009 would be less likely to cause cough than inhaled TRE.

Objective: To screen novel biomarkers in the levels of protein complexes for type 2 diabetes mellitus (T2DM). Methods: Serum immunoinflammation-related protein complexes (IIRPCs) and diabetes-related protein complexes (DRPCs) in 1537 serum samples including 504 healthy controls, 320 patients with prediabetes, and 713 patients with T2DM were analyzed using an optimized native polyacrylamide gel electrophoresis (native-PAGE). Results: Seven patterns of serum IIRPCs and four patterns of serum DRPCs were observed in the study population, respectively. Significant increase in the levels of serum IIRPCs in T2DM was detected relative to healthy controls. Change trends of serum DRPCs are as below: patients with T2DM>patients with prediabetes> healthy controls. Conclusion: Our findings suggest that increased levels of serum IIRPCs and DRPCs were associated with T2DM.

Cherenkov radiation is a ubiquitous phenomenon in nature. It describes electromagnetic radiation from a charged particle moving in a medium with a uniform velocity larger than the phase velocity of light in the same medium. Such a picture is typically adopted in the investigation of traditional Cherenkov radiation as well as its counterparts in different branches of physics, including nonlinear optics, spintronics and plasmonics. In these cases, the radiation emitted spreads along a “cone”, making it impractical for most applications. Here, we employ a self-accelerating optical pump wave-packet to demonstrate controlled shaping of one type of generalized Cherenkov radiation - dispersive waves in optical fibers. We show that, by tuning the parameters of the wave-packet, the emitted waves can be judiciously compressed and focused at desired locations, paving the way to such control in any physical system.

Due to the lone-pair-induced anharmonic rattling, InTe exhibits intrinsically ultralow thermal conductivity, which was considered as a candidate for thermoelectric application. However, the poor electrical transport properties result in low thermoelectric conversion efficiency. In this work, Cd doping in InTe have been performed with the aim to optimize the carrier concentration and increase the power factor. Furthermore, an essential enhancement of carrier mobility can be realized via prolonging the annealing time, leading to improved thermoelectric performance. As a result, the maximum thermoelectric figure of merit zT of 0.87 at 773 K has been achieved for In0.98Cd0.02Te undergoing 7 days annealing treatment (In0.98Cd0.02Te-7days), which is 67% higher than the value of InTe after 2 days annealing (InTe-2days, zT = 0.52@773 K). The average zT increases significantly from 0.26 for InTe-2days to 0.53 for In0.98Cd0.02Te-7days in the temperature range of 323–823 K. Thus, both introducing Cd dopant and regulating the annealing time have obvious effects on improving the thermoelectric performance of InTe.