The Identification of Enteric Fever-Specific Antigens for Population-Based Serosurveillance.

BACKGROUND: Enteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi A, is a major public health problem in low- and middle-income countries. Moderate sensitivity and scalability of current methods likely underestimate enteric fever burden. Determining the serological responses to organism-specific antigens may improve incidence measures. METHODS: Plasma samples were collected from blood culture-confirmed enteric fever patients, blood culture-negative febrile patients over the course of 3 months, and afebrile community controls. A panel of 17 Salmonella Typhi and Paratyphi A antigens was purified and used to determine antigen-specific antibody responses by indirect ELISAs. RESULTS: The antigen-specific longitudinal antibody responses were comparable between enteric fever patients, patients with blood culture-negative febrile controls, and afebrile community controls for most antigens. However, we found that IgG responses against STY1479 (YncE), STY1886 (CdtB), STY1498 (HlyE), and the serovar-specific O2 and O9 antigens were greatly elevated over a 3-month follow up period in S. Typhi/S. Paratyphi A patients compared to controls, suggesting seroconversion. CONCLUSIONS: We identified a set of antigens as good candidates to demonstrate enteric fever exposure. These targets can be used in combination to develop more sensitive and scalable approaches to enteric fever surveillance and generate invaluable epidemiological data for informing vaccine policies. CLINICAL TRIAL REGISTRATION: ISRCTN63006567.

Trap spaces of multi-valued networks: definition, computation, and applications.

MOTIVATION: Boolean networks are simple but efficient mathematical formalism for modelling complex biological systems. However, having only two levels of activation is sometimes not enough to fully capture the dynamics of real-world biological systems. Hence, the need for multi-valued networks (MVNs), a generalization of Boolean networks. Despite the importance of MVNs for modelling biological systems, only limited progress has been made on developing theories, analysis methods, and tools that can support them. In particular, the recent use of trap spaces in Boolean networks made a great impact on the field of systems biology, but there has been no similar concept defined and studied for MVNs to date. RESULTS: In this work, we generalize the concept of trap spaces in Boolean networks to that in MVNs. We then develop the theory and the analysis methods for trap spaces in MVNs. In particular, we implement all proposed methods in a Python package called trapmvn. Not only showing the applicability of our approach via a realistic case study, we also evaluate the time efficiency of the method on a large collection of real-world models. The experimental results confirm the time efficiency, which we believe enables more accurate analysis on larger and more complex multi-valued models. AVAILABILITY AND IMPLEMENTATION: Source code and data are freely available at https://github.com/giang-trinh/trap-mvn.

Genetic Foundation of Prostaglandin Metabolism Influences Patent Ductus Arteriosus Closure in Extremely Low Birth Weight Infants.

OBJECTIVE: Prostaglandins (PGs) play a major role in maintaining patency of the ductal arteriosus (DA). Pulmonary 15-hydroxyprostaglandin dehydrogenase (PGDH), which is ecoded by the hydroxyprostaglandin dehydrogenase (HPGD) gene, is the primary enzyme responsible for PG breakdown. Animal studies have shown HPGD-knockout mice have significantly higher prostaglandin E2 levels and no ductal remodeling. Functional variants of the HPGD gene that alter PG breakdown have not been studied in preterm infants with patent ductus arteriosus (PDA). STUDY DESIGN: This was an observational cohort study including extreme low birth weight (ELBW) infants classified as having spontaneous, medical, or procedural (transcatheter or surgical ligation) closure of their DA. Urine prostaglandin E metabolite (PGEM) levels were measured in ELBW infants following ibuprofen treatment using competitive ELISA. HPGD genetic variants rs8752, rs2612656, and rs9312555 were analyzed. Kruskal-Wallis, Fisher's exact, chi square, logistic regression, and Wilcoxon signed-rank tests were used; p < 0.05 was considered significant. RESULTS: Infants in the procedural closure group had a younger gestational age (GA). The incidence of spontaneous closure or medical closure was higher compared to procedural closure in the presence of any minor allele of rs8752 (67 and 27%, respectively; p = 0.01), when adjusted for GA and gender. Haplotype analysis of three variants of HPGD revealed differences when comparing the spontaneous and medical closure group to the procedural group (p < 0.05). Urinary PGEM levels dropped significantly in those ELBW infants who responded to ibuprofen (p = 0.003) in contrast to those who did not respond (p = 0.5). CONCLUSION: There was a different genotype distribution for the rs8752 genetic variant of the HPGD gene-as it relates to the mode of treatment for ELBW infants with PDA. We speculate that medical management in the presence of this variant facilitated additional PG breakdown, significantly abrogating the need for procedural closure. Additionally, differences in genotype and haplotype distributions implicate a specific HPGD genetic foundation for DA closure in ELBW infants. KEY POINTS: · PGs and their metabolism play a major role in PDA patency or closure.. · Genetic variants of the HPGD gene influence mode of treatment of PDA in ELBW infants.. · ELBW infants with PDA that responded to medical closure had significantly decreased urine PGEM levels..

A virtual library of small molecules mimicking dipeptides.

Virtual combinatorial libraries are prevalent in drug discovery due to improvements in the prediction of synthetic reactions that can be performed. This has gone hand in hand with the development of virtual screening capabilities to effectively screen the large chemical spaces spanned by exhaustive enumeration of reaction products. In this study, we generated a small-molecule dipeptide mimic library to target proteins binding small peptides. The library was created based on the general idea of peptide synthesis, that is, amino acid mimics were reacted in silico to form the dipeptide mimics, yielding 2,036,819 unique compounds. After docking calculations, two compounds from the library were synthesized and tested against WD repeat-containing protein 5 (WDR5) and histamine receptors H1-H4 to evaluate whether these molecules are viable in assays. The compounds showed the highest potency at the histamine H3 receptor, with Ki values in the two-digit micromolar range.

A simple and effective scaffold for mouse hepatic stellate cell primary culture.

Scaffold-based culture is necessary for hepatic stellate cells (HSCs) because HSCs are promptly autoactivated under plastic conditions. Our research aims to investigate the potential and role of fibrin scaffold in reducing autoactivation, maintaining cell function, and extending the in vitro culture time of primary HSCs. HSCs were isolated from BALB/c mice and cultured on the surface of plastic, Matrigel, and fibrin gel. HSC's characteristics, including recovery, morphology, proliferation, lipid droplet (LD) storage, and activation were evaluated. Cell recovery was 86%, 80%, and 60% in fibrin, Matrigel, and plastic, respectively (P < 0.05). HSCs cultured on a plastic dish were autoactivated until day 7 with high proliferation, loss of cytoplasmic LD lipid droplets, and increased expression of activation markers, including alpha-smooth muscle actin (α-sma) and collagen type I. In contrast, these phenomena were reduced in Matrigel and fibrin-based cultures (P < 0.05). HSC culture in fibrin scaffold was associated with altered expression of cell adhesion molecules, including increased E-cadherin and inhibited N-cadherin. HSCs were more stellate-like in morphology in fibrin than in the Matrigel scaffold. Interestingly, fibrin-scaffold-embedded culture was able to maintain HSC quiescent state for up to 14 days in vitro. Fibrin gel could provide a potential scaffold for primary HSC culture while preserving cell function and extending primary HSC in vitro culture time.NEW & NOTEWORTHY Fibrin gel is appropriate for maintaining quiescence characteristics in primary culture of mouse hepatic stellate cells. Embedded culture of hepatic stellate cells in fibrin gel simulates in vivo cell morphology. Stiffness and adhesion molecules of fibrin gel play a crucial role in the hepatic stellate cell's primary culture.

Safety and Efficacy of Immune Checkpoint Inhibitors in Patients with Cancer and Viral Hepatitis: The MD Anderson Cancer Center Experience.

BACKGROUND: Despite the clinical benefit of immune checkpoint inhibitors (ICIs), patients with a viral hepatitis have been excluded from clinical trials because of safety concerns. The purpose of this study was to determine the incidence rate of adverse events (AEs) in patients with viral hepatitis who received ICIs for cancer treatment. MATERIALS AND METHODS: We conducted a retrospective study in patients with cancer and concurrent hepatitis B or C, who had undergone treatment with ICI at MD Anderson Cancer Center from January 1, 2010 to December 31, 2019. RESULTS: Of the 1076 patients screened, we identified 33 with concurrent hepatitis. All 10 patients with HBV underwent concomitant antiviral therapy during ICI treatment. Sixteen of the 23 patients with HCV received it before the initiation of ICI. The median follow-up time was 33 months (95% CI, 23-45) and the median duration of ICI therapy was 3 months (IQR, 1.9-6.6). Of the 33 patients, 12 (39%) experienced irAEs (immune-related adverse events) of any grade, with 2 (6%) having grade 3 or higher. None of the patients developed hepatitis toxicities. CONCLUSION: ICIs may be a therapeutic option with an acceptable safety profile in patients with cancer and advanced liver disease.

Clinical activity of checkpoint inhibitors in angiosarcoma: A retrospective cohort study.

BACKGROUND: Systemic treatments for angiosarcoma remains an area of unmet clinical need. The authors conducted this retrospective study to assess the clinical activity of checkpoint inhibitors in patients with angiosarcoma. The primary objective was to assess the objective response rate, and the secondary objective was to assess the progression-free and overall survival durations and disease control rate. METHODS: Patient data were obtained using The University of Texas MD Anderson Cancer Center Tumor Registry database. The final study population was refined to only include patients who had undergone pembrolizumab monotherapy. The objective response rate was evaluated using RECIST/irRECIST version 1.1. Progression-free survival and overall survival were defined as the time from the initiation of immunotherapy to disease progression or recurrence, death, or last follow-up and to death or last follow-up, respectively. RESULTS: The final cohort comprised 25 patients. Most patients had metastatic disease (72%) and had undergone at least two lines of systemic therapy (80%) before starting pembrolizumab. The objective response rate was 18%, whereas the disease control rate was 59%. The median progression-free survival duration was 6.2 months and was not significantly different between the cutaneous (4.7 months) and visceral angiosarcoma (6.2 months) groups (p = .42). The median overall survival duration was 72.6 months. Toxicities were recorded for eight patients, with fatigue, anemia, constipation, and rash being the most common. CONCLUSIONS: Pembrolizumab shows durable clinical activity in angiosarcoma. These findings suggest that checkpoint inhibition as monotherapy or combination therapy is likely to have a high probability of success.© 2022 American Cancer Society. LAY SUMMARY: This is the largest retrospective study to assess the clinical activity of checkpoint inhibitor monotherapy in angiosarcomas. The study includes an adequate number of patients with visceral angiosarcoma that enabled to obtain meaningful clinical insights that were previously unavailable. Our findings indicate an improvement in progression-free survival with pembrolizumab that is comparable to other active agents in angiosarcoma. Pembrolizumab monotherapy in angiosarcomas also has a favorable tolerability profile. Our findings emphasize the need for prospective studies to evaluate the activity of pembrolizumab monotherapy and combination therapy.

Effects of autophagy inhibition by chloroquine on hepatic stellate cell activation in CCl4-induced acute liver injury mouse model.

BACKGROUND AND AIM: Hepatic stellate cells (HSCs) activation, a critical event in liver fibrosis, has been recently shown to be related to autophagy. Determine whether chloroquine (CQ) could affect (i) the activation of HSC in vivo and (ii) the hepatic damage in a mice acute liver injury model. METHODS: The acute liver injury was induced in BALB/c mice by carbon tetrachloride (CCl4 group); 24 h before and after CCl4 administration animals were treated by CQ (CCl4  + CQ group). As control, mice treated by olive oil were considered. After 48 h from CCl4 /olive oil administration, blood samples, liver tissues, and HSCs were harvested for analysis. RESULTS: In vivo, CQ attenuates CCl4 -induced acute liver damage as evidenced by (i) the reduction of liver enlargement, (ii) the reduction of liver swelling and necrosis also supported by a certain decrease of circulating transaminases level, and (iii) the reduction of liver fibrosis evaluated by collagen deposition and α-sma protein expression. In HSCs isolated from CQ treated group, we observed the inhibition of autophagy proved by the increase in p62 protein and the decrease of lc3 protein. In addition, CQ reduced the expression of the HSCs activation markers α-sma/collagen-I and down-regulated the expression of the proliferative marker ki67. CONCLUSION: The autophagy attenuation exerted by CQ together with the reduction of the expression of the proliferation marker in HSCs can lessen the acute liver damage potentially opening the way to novel therapeutic approaches for hepatic fibrosis.

Learning acoustic responses from experiments: A multiscale-informed transfer learning approach.

A methodology to learn acoustical responses based on limited experimental datasets is presented. From a methodological standpoint, the approach involves a multiscale-informed encoder used to cast the learning task in a finite-dimensional setting. A neural network model mapping parameters of interest to the latent variables is then constructed and calibrated using transfer learning and knowledge gained from the multiscale surrogate. The relevance of the approach is assessed by considering the prediction of the sound absorption coefficient for randomly-packed rigid spherical beads of equal diameter. A two-microphone method is used in this context to measure the absorption coefficient on a set of configurations with various monodisperse particle diameters and sample thicknesses, and a hybrid numerical approach relying on the Johnson-Champoux-Allard-Pride-Lafarge model is deployed as the multiscale-based predictor. It is shown that the strategy allows for the relationship between the micro-/structural parameters and the experimental acoustic response to be well approximated, even if a small physical dataset (comprised of ten samples) is used for training. The methodology, therefore, enables the identification and validation of acoustical models under constraints related to data limitation and parametric dependence. It also paves the way for an efficient exploration of the parameter space for acoustical materials design.

A 90 GHz Broadband Balanced 8-Way Power Amplifier for High Precision FMCW Radar Sensors in 65-nm CMOS.

We present a W-band 8-way wideband power amplifier (PA) for a high precision frequency modulated continuous wave (FMCW) radar in 65-nm CMOS technology. To achieve a broadband operation with an improved output power for a high range resolution and high distance coverage of FMCW radar sensors, a balanced architecture is employed with the Lange coupler which naturally combines the output powers from two 4-way push-pull PAs. By utilizing a transformer-based push-pull structure with a cross-coupled capacitive neutralization technique, the gate-drain capacitance of the 4-way PA is compensated for the stabilization with an improved power gain. Interstage matching was performed with transformers for a reduced loss from the matching network and minimal area occupation. The implemented balanced 8-way PA achieved a saturated output power (Psat) of 16.5 dBm, a 1-dB compressed output power (OP1dB) of 13.3 dBm, a power-added efficiency (PAE) of 9.9% at 90 GHz and 3-dB power bandwidth was 20.4 GHz (79.2-99.6 GHz).

A 78.8-84 GHz Phase Locked Loop Synthesizer for a W-Band Frequency-Hopping FMCW Radar Transceiver in 65 nm CMOS.

A W-band integer-N phase-locked loop (PLL) for a frequency hopping frequency modulation continuous wave (FMCW) radar is implemented in 65-nm CMOS technology. The cross-coupled voltage-controlled oscillator (VCO) was designed based on a systematic analysis of the VCO combined with its push-pull buffer to achieve high efficiency and high output power. To provide a frequency hopping functionality without any overhead in the implementation, the center frequency of the VCO is steeply controlled by the gate voltage of the buffer, which effectively modifies the susceptance of the VCO load. A stand-alone VCO with the proposed architecture is fabricated, and it achieves an output power of 13.5 dBm, a peak power efficiency of 9.6%, and a tuning range of 3.5%. The phase noise performance of the VCO is -92.6 dBc/Hz at 1-MHz and -106.1 dBc/Hz at 10 MHz offset. Consisting of a third-order loop filter and a divider chain with a total modulus of 48, the locking range of the implemented PLL with the cross-coupled VCO is recorded from 78.84 GHz to 84 GHz, and its phase noise is -85.2 dBc/Hz at 1-MHz offset.

Emotional Speech Recognition Using Deep Neural Networks.

The expression of emotions in human communication plays a very important role in the information that needs to be conveyed to the partner. The forms of expression of human emotions are very rich. It could be body language, facial expressions, eye contact, laughter, and tone of voice. The languages of the world's peoples are different, but even without understanding a language in communication, people can almost understand part of the message that the other partner wants to convey with emotional expressions as mentioned. Among the forms of human emotional expression, the expression of emotions through voice is perhaps the most studied. This article presents our research on speech emotion recognition using deep neural networks such as CNN, CRNN, and GRU. We used the Interactive Emotional Dyadic Motion Capture (IEMOCAP) corpus for the study with four emotions: anger, happiness, sadness, and neutrality. The feature parameters used for recognition include the Mel spectral coefficients and other parameters related to the spectrum and the intensity of the speech signal. The data augmentation was used by changing the voice and adding white noise. The results show that the GRU model gave the highest average recognition accuracy of 97.47%. This result is superior to existing studies on speech emotion recognition with the IEMOCAP corpus.

Selection of a density separation solution to study microplastics in tropical riverine sediment.

Microplastics (MPs) are small (< 5 mm) plastic particles that are widely found in marine, freshwater, terrestrial and atmospheric environments. Due to their prevalence and persistence, MPs are considered an emerging contaminant of environmental concern. The separation and quantitation of MPs from freshwater sediments is a challenging and critical issue. It is necessary to identify the fate and sources of MPs in the environment, minimise their release and adverse effects. Compared to marine sediments, standardised methods for extracting and estimating the amount of MPs in freshwater sediments are relatively limited. The present study focuses on MP recovery efficiency of four commonly used salt solutions (NaCl, NaI, CaCl2 and ZnCl2) for isolating MPs during the density separation step from freshwater sediment. Known combinations of artificial MP particles (PS, PE, PVC, PET, PP and HDPE) were spiked into standard river sediment. Extraction using NaI, ZnCl2 and NaCl solutions resulted in higher recovery rates from 37 to 97% compared to the CaCl2 solution (28-83%) and varied between polymer types. Low-density MPs (PE, HDPE, PP and PS) were more effectively recovered (> 87%) than the denser polymers (PET and PVC: 37 to 88.8%) using NaCl, NaI and ZnCl2 solutions. However, the effective flotation of ZnCl2 and NaI solutions is relatively expensive and unsafe to the environment, especially in the context of developing countries. Therefore, considering the efficiency, cost and environmental criteria, NaCl solution was selected. The protocol was then tested by extracting MPs from nine riverine sediment samples from the Red River Delta. Sediments collected from urban rivers were highly polluted by MPs (26,000 MPs items·kg-1 DW) compared to sediments located downstream. Using a NaCl solution was found to be effective in this case study and might also be used in long-term and large-scale MP monitoring programmes in Vietnam.

Using k-mer embeddings learned from a Skip-gram based neural network for building a cross-species DNA N6-methyladenine site prediction model.

KEY MESSAGE: This study used k-mer embeddings as effective feature to identify DNA N6-Methyladenine sites in plant genomes and obtained improved performance without substantial effort in feature extraction, combination and selection. Identification of DNA N6-methyladenine sites has been a very active topic of computational biology due to the unavailability of suitable methods to identify them accurately, especially in plants. Substantial results were obtained with a great effort put in extracting, heuristic searching, or fusing a diverse types of features, not to mention a feature selection step. In this study, we regarded DNA sequences as textual information and employed natural language processing techniques to decipher hidden biological meanings from those sequences. In other words, we considered DNA, the human life book, as a book corpus for training DNA language models. K-mer embeddings then were generated from these language models to be used in machine learning prediction models. Skip-gram neural networks were the base of the language models and ensemble tree-based algorithms were the machine learning algorithms for prediction models. We trained the prediction model on Rosaceae genome dataset and performed a comprehensive test on 3 plant genome datasets. Our proposed method shows promising performance with AUC performance approaching an ideal value on Rosaceae dataset (0.99), a high score on Rice dataset (0.95) and improved performance on Rice dataset while enjoying an elegant, yet efficient feature extraction process.

Molecular detection of blaCTX-M gene to predict phenotypic cephalosporin resistance and clinical outcome of Escherichia coli bloodstream infections in Vietnam.

BACKGROUND: Blood stream infections (BSI) caused by Extended Spectrum Beta-Lactamases (ESBLs) producing Enterobacteriaceae is a clinical challenge leading to high mortality, especially in developing countries. In this study, we sought to describe the epidemiology of ESBL-producing Escherichia coli strains isolated from Vietnamese individuals with BSI, to investigate the concordance of genotypic-phenotypic resistance, and clinical outcome of ESBL E. coli BSI. METHODS: A total of 459 hospitalized patients with BSI were screened between October 2014 and May 2016. 115 E. coli strains from 115 BSI patients were isolated and tested for antibiotic resistance using the VITEK®2 system. The ESBL phenotype was determined by double disk diffusion method following the guideline of Clinical and Laboratory Standards Institute. Screening for beta-lactamase (ESBL and carbapenemase) genes was performed using a multiplex-PCR assay. RESULTS: 58% (67/115) of the E. coli strains were ESBL-producers and all were susceptible to both imipenem and meropenem. Resistance to third-generation cephalosporin was common, 70% (81/115) were cefotaxime-resistant and 45% (52/115) were ceftazidime-resistant. blaCTX-M was the most common ESBL gene detected (70%; 80/115) The sensitivity and specificity of blaCTX-M-detection to predict the ESBL phenotype was 87% (76-93% 95% CI) and 54% (39-48% 95% CI), respectively. 28%% (22/80) of blaCTX-M were classified as non-ESBL producers by phenotypic testing for ESBL production. The detection of blaCTX-M in ESBL-negative E. coli BSI was associated with fatal clinical outcome (27%; 6/22 versus 8%; 2/26, p = 0.07). CONCLUSION: A high prevalence of ESBL-producing E. coli isolates harbouring blaCTX-M was observed in BSI patients in Vietnam. The genotypic detection of blaCTX-M may have added benefit in optimizing and guiding empirical antibiotic therapy of E. coli BSI to improve clinical outcome.

Decellularization of Bone Tissue.

Decellularization technology is a process that uses different methods such as physical, chemical or enzymatic methods in order to eliminate cellular remnants from original tissues or organs while minimizing any adverse effect on the structural properties, biological activity, and mechanical integrity of the remaining ECM. Regenerative medicine uses the most promising therapies to replace or regenerate tissues and organs in human, restore or establish normal functions lost due to disease or injury. By the combination between new biomaterials and cells, one of the goals of regenerative medicine is to create autologous grafts for transplantation therapies in the future.Various decellularization methods have been developed include chemical treatment, biological treatment and physical treatment. The aim of this chapter is to evaluate the decellularization method and all available materials that preserves the matrix without structural disruption.

The Role of Maternally Acquired Antibody in Providing Protective Immunity Against Nontyphoidal Salmonella in Urban Vietnamese Infants: A Birth Cohort Study.

Background: Nontyphoidal Salmonella (NTS) organisms are a major cause of gastroenteritis and bacteremia, but little is known about maternally acquired immunity and natural exposure in infant populations residing in areas where NTS disease is highly endemic. Methods: We recruited 503 pregnant mothers and their infants (following delivery) from urban areas in Vietnam and followed infants until they were 1 year old. Exposure to the dominant NTS serovars, Salmonella enterica serovars Typhimurium and Enteritidis, were assessed using lipopolysaccharide (LPS) O antigen-specific antibodies. Antibody dynamics, the role of maternally acquired antibodies, and NTS seroincidence rates were modeled using multivariate linear risk factor models and generalized additive mixed-effect models. Results: Transplacental transfer of NTS LPS-specific maternal antibodies to infants was highly efficient. Waning of transplacentally acquired NTS LPS-specific antibodies at 4 months of age left infants susceptible to Salmonella organisms, after which they began to seroconvert. High seroincidences of S. Typhimurium and S. Enteritidis LPS were observed, and infants born with higher anti-LPS titers had greater plasma bactericidal activity and longer protection from seroconversion. Conclusions: Although Vietnamese infants have extensive exposure to NTS, maternally acquired antibodies appear to play a protective role against NTS infections during early infancy. These findings suggest that prenatal immunization may be an appropriate strategy to protect vulnerable infants from NTS disease.

The EGF-LIKE domain of thrombospondin-4 is a key determinant in the development of pain states due to increased excitatory synaptogenesis.

Up-regulation of thrombospondin-4 (TSP4) or voltage-gated calcium channel subunit α2δ1 (Cavα2δ1) proteins in the spinal cord contributes to neuropathic pain development through an unidentified mechanism. We have previously shown that TSP4 interacts with Cavα2δ1 to promote excitatory synaptogenesis and the development of chronic pain states. However, the TSP4 determinants responsible for these changes are not known. Here, we tested the hypothesis that the Cavα2δ1-binding domains of TSP4 are synaptogenic and pronociceptive. We mapped the major Cavα2δ1-binding domains of TSP4 within the coiled-coil and epidermal growth factor (EGF)-like domains in vitro Intrathecal injection of TSP4 fragment proteins containing the EGF-like domain (EGF-LIKE) into naïve rodents was sufficient for inducing behavioral hypersensitivity similar to that produced by an equal molar dose of full-length TSP4. Gabapentin, a drug that binds to Cavα2δ1, blocked EGF-LIKE-induced behavioral hypersensitivity in a dose-dependent manner, supporting the notion that EGF-LIKE interacts with Cavα2δ1 and thereby mediates behavioral hypersensitivity. This notion was further supported by our findings that a peptide within EGF-LIKE (EGFD355-369) could block TSP4- or Cavα2δ1-induced behavioral hypersensitivity after intrathecal injections. Furthermore, only TSP4 proteins that contained EGF-LIKE could promote excitatory synaptogenesis between sensory and spinal cord neurons, which could be blocked by peptide EGFD355-369. Together, these findings indicate that EGF-LIKE is the molecular determinant that mediates aberrant excitatory synaptogenesis and chronic pain development. Blocking interactions between EGF-LIKE and Cavα2δ1 could be an alternative approach in designing target-specific pain medications.

Olaratumab in the management of advanced soft tissue sarcoma.

Olaratumab, the first-in-class anti-PDGFRα monoclonal antibody, has been contingently approved in combination with doxorubicin to treat adult patients with advanced soft tissue sarcoma for improving progression-free and overall survival. Olaratumab-doxorubicin combination has tolerable safety profile, which mimics that of doxorubicin monotherapy, with the exception of infusion-related reactions. Survival data of an ongoing confirmatory phase 3 trial are forthcoming to ascertain the optimal role of this product in the management algorithm of advanced soft tissue sarcoma. Active research is ongoing to identify biomarkers predictive of clinical benefit to olaratumab, to expand its utility to the pediatric population, and to explore its safety and efficacy in combination with other active regimens.

A Low-Profile High-Gain and Wideband Log-Periodic Meandered Dipole Array Antenna with a Cascaded Multi-Section Artificial Magnetic Conductor Structure.

This paper presents a low-profile log-periodic meandered dipole array (LPMDA) antenna with wideband and high gain characteristics. The antenna consists of 14 dipole elements. For compactness, a meander line structure is applied to each dipole element to reduce its physical length. As a result, a compact and wideband LPMDA antenna is realized, exhibiting a wide impedance bandwidth of 1.04-5.22 GHz (ratio bandwidth of 5.02:1) for | S 11| < -10 dB. To enhance the antenna gain performance while maintaining the wideband behavior, the LPMDA antenna is integrated with a new design of an artificial magnetic conductor (AMC) structure. The designed AMC is realized by combining three AMC structures of different sizes to form a cascaded multi-section AMC structure, of which its overall operating bandwidth can continuously cover the entire impedance bandwidth of the LPMDA antenna. The proposed AMC-backed LPMDA antenna is experimentally verified and its measured -10 dB reflection bandwidth is found to be in the range of 0.84-5.15 GHz (6.13:1). At the main beam direction within the operating frequency bandwidth, the gain of the proposed AMC-backed LPMDA antenna ranges from 7.15-11.43 dBi, which is approximately 4 dBi higher than that of an LPMDA antenna without an AMC. Moreover, the proposed antenna has a low profile of only 0.138 λ L. ( λ L is the free-space wavelength at the lowest operating frequency).