A Tangled Web: Dual Diagnosis of Hereditary Hemorrhagic Telangiectasia and Familial Cerebral Cavernous Malformation

Anesthesia using remimazolam during coronary artery bypass surgery in a patient with decreased left ventricular functionShingo Narumi, Yusuke Ishida, Sae Igarashi, Shunya Sekiguchi, Aya Kawachi, and Mikiko TominoDepartment of Anesthesiology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, JapanCorresponding author: Yusuke IshidaDepartment of AnesthesiologyTokyo Medical University6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, JapanTel.: +81-03-3342-6111; Fax: +81-03-5381-6650Email: yishida14anes@gmail.com

Conflicts among non-functional requirements for robotic systems heavily depend on features of actual execution contexts. The main objective of this work is to design and experimentally evaluate a framework, called SCARS, providing: (a) a domain-specific language extending the ROS2 Domain Specific Language (DSL) concepts by considering the different environmental contexts in which the system has to operate, (b) support to analyze their impact on non-functional requirements, and (c) the computation of the optimal degree of non-functional requirement satisfaction that can be achieved within different system configurations. The effectiveness of SCARS has been validated on the Gazebo simulation for iRobot ® Create ®3 robot.

Antibiotic resistance is a major challenge in the clinical treatment of bacterial infectious diseases. Herein, we constructed a multifunctional DNA nanoplatform as a versatile carrier for bacteria-specific delivery of clinical antibiotic ciprofloxacin (CIP) and classic nanoantibiotic silver nanoparticles (AgNP). In our rational design, CIP was efficiently loaded in the self-assembly double-bundle DNA tetrahedron through intercalation with DNA duplex, and single-strand DNA-modified AgNP was embedded in the cavity of the DNA tetrahedron through hybridization. With the site-specific assembly of targeting aptamer in the well-defined DNA tetrahedron, the bacteria-specific dual-antibiotic delivery system exhibited excellent combined bactericidal properties. With enhanced antibiotic accumulation through breaking the out membrane of bacteria, the antibiotic delivery system effectively inhibited biofilm formation and promoted the healing of infected wounds in vivo. This DNA-based antibiotic delivery system provides a promising strategy for the treatment of antibiotic-resistant infections.

In order to develop the application of walnut kernel, the effect of steaming and roasting treatment on the physicochemical and functional properties of walnut kernel at 95 ºC for different time (15, 20 and 30 min) was investigated, and compared to those of untreated sample. Scanning electron microscopy suggested that heating treatment had a notable effect on the microstructure of walnut kernel, especially the steam heating. Both treatments significantly increased the enthalpy, vitro protein digestibility, viscosity, G′ and G″ (P < 0.05), the order from high to low was steaming > roasting > untreated. All samples contained the amounts of essential amino acids, the amino acid score (AAS) of samples by steaming was the highest compared to that of the untreated and roasting, and the only limiting amino acid of walnut kernel before or after heat treatment was lysine. In addition, the protein of walnut kernel after heating treatment with the extension of time contained more α-helix and random coil structures compared to the untreated sample, while β-sheet and β-turns structures decreased. Moreover, the thermal treatment could cause the changes of the water/oil holding capacity, foaming and emulsifying properties of walnut kernel flour. When there were differences between the results of steaming and roasting samples, it was concluded that the water played an important role in steaming. These results suggested that the thermal treatment as an effective approach could improve the physico-chemical, structural and functional properties of walnut kernel and be potentially applied in the food processing.

SARS-CoV2 infection has caused an increase in mortality and morbidity but with vaccination, the disease severity has significantly reduced. But with emergence of various variants of concerns (VOCs), the vaccine breakthrough infection has also increased. Here, we studied circulating spike specific T follicular response (cTfh) in infection naïve vaccinees and convalescent vaccinees (individuals who got delta breakthrough infection after 2 doses of BBV152 vaccine) to understand their response as they are the most crucial cells that are involve in vaccine mediated protection by helping in B-cell maturation. Our results indicated that cTfh cells in both the groups recognized wild type and delta spike protein but memory response to wild type spike was superior in infection naïve than in convalescent group. The cytokine response particularly IL-21 from cTfh cells was also higher in infection naïve than convalescent vaccines indicating a dampened cTfh response in convalescent vaccines after breakthrough infection. Also, there was positive correlation between IL-21 from cTfh cells and neutralizing antibodies of infection naïve vaccinees. Multiple cytokine analysis also revealed higher inflammation in convalescent vaccinees. Our data indicated necessity of third booster dose may be individual specific depending in the steady state functional phenotype of immune cells.

Hybridization is a natural process whereby two diverging evolutionary lineages reproduce and create offspring of mixed ancestry. Differences in mating systems (e.g., self-fertilization and outcrossing) are expected to affect the direction and extent of hybridization and introgression in hybrid zones. Among other factors, selfers and outcrossers are expected to differ in their mutation loads. This has been studied both theoretically and empirically; however, conflicting predictions have been made on the effects mutation loads of parental species with different mating systems can have on the genomic composition of hybrids. Here we develop a multi-locus, selective model to study how the different mutation load built up in selfers and outcrossers as a result of selective interference and homozygosity impact the long-term genetic composition of hybrid populations. Notably, our results emphasize that genes from the parental population with lesser mutation load get rapidly over-represented in hybrid genomes, regardless of the hybrids own mating system. When recombination tends to be more important than mutation, outcrossers’ genomes tend to be of higher quality and prevail. When recombination is small, however, selfers’ genomes may reach higher quality than outcrossers’ genomes and prevail. Taken together these results provide concrete insights into one of the multiple factors influencing hybrid genome composition and introgression patterns in hybrid zones with species containing species with different mating systems.

Protein domains are structural, functional, and evolutionary units. These domains bring out the diversity of functionality by means of interactions with other co-existing domains and provide stability. Hence, it is important to study intra-protein inter-domain interactions from the perspective of types of interactions. Domains within a chain could interact over short timeframes or permanently, rather like protein-protein interactions (PPIs). However, no systematic study has been carried out between two classes, namely permanent and transient domain-domain interactions (DDIs). In this work, we studied 264 two-domain proteins, belonging to either of these classes and their interfaces on the basis of several factors, such as interface area and details of interactions (number, strengths, and types of interactions). We also characterized them based on residue conservation at the interface, correlation of residue motions across domains, its involvement in repeat formation, and their involvement in particular molecular processes. Finally, we could analyse the interactions arising from domains in two-domain monomeric proteins, and we observed significant differences between these two classes of domain interactions and a few similarities. This study will help to obtain a better understanding of structure-function and folding principles of multi-domain proteins.

BACKGROUND: Intercostal nerve cryoablation (INC) has shown promise as an adjunct method for analgesia in adults undergoing thoracotomy but has yet to be widely used in children for this indication. We hypothesize that INC decreases opioid utilization in children undergoing thoracotomy for cancer operations. METHODS: A retrospective review was performed of children who underwent thoracotomy for a cancer diagnosis at a freestanding children’s hospital from 2018-2023. Patient characteristics, intraoperative data, and data on clinical course were collected. Patients were divided into those who underwent INC and those who underwent routine care for comparison. RESULTS: Twenty-six patients underwent 38 procedures at a median age of 16 years (range 5-21 years). INC was performed in 23 cases over a median of 5 intercostal levels (range 2-7). Total oral morphine equivalents (OME) during inpatient admission were significantly lower in INC patients (137.6mg versus 514.5mg, p=0.002). Routine care patients were more likely to be discharged with an opioid prescription (30.4% versus 80.0%, p=0.008). Length of stay was similar between patients with INC and routine care (4 versus 5 days, p=0.15). There were no differences in rates of reoperation or 30-day readmission (emergency department (ED) or inpatient). CONCLUSTIONS: INC is a feasible and safe adjunct for children undergoing thoracotomy for cancer. INC is associated with reduced postoperative opioid utilization with respect to both inpatient use and outpatient prescriptions.

Approximately 5% of colorectal cancers (CRCs) are hereditary. Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common form of recognized hereditary CRC. Although Iran, a developing country, has a high incidence of CRC, the spectrum of mutations has yet to be thoroughly investigated. Therefore, this study aimed to investigate pathogenic and non-pathogenic variants in MLH1 and MSH2 genes in Iranian patients with suspected Lynch syndrome (sLS). In the present study, 25 peripheral blood samples were collected from patients with sLS and high microsatellite instability (MSI-H). After DNA extraction, all samples underwent polymerase chain reaction (PCR) and Sanger sequencing to identify the variants in the exons of MLH1 and MSH2 genes. The identified variants were interpreted using prediction tools, including SIFT, CADD, PolyPhen, PROVEAN, REVEL, MetaLR, and Mutational Assessor. In our study population, 13 variants were found in the MLH1 gene and 8 in the MSH2 gene. Interestingly, 7 of the 13 MLH1 variants and 3 of the 8 MSH2 variants were novel, whereas the remaining variants were previously reported or available in databases. In addition, some patients with sLS did not have variants in the exons of the MLH1 and MSH2 genes. The variants detected in the MLH1 and MSH2 genes had specific characteristics regarding the number, area of occurrence, and their relationship with demographic and clinicopathologic features. We identified two novel pathogenic/likely pathogenic variants in these two genes. Overall, our results suggest that analysis of MLH1 and MSH2 genes alone is insufficient in the Iranian population, and more comprehensive tests are recommended for detecting LS.

For many fruit crops, the colour of the fruit outwardly defines its eating quality. Fruit pigments provide reproductive advantage for the plant as well as providing protection against unfavourable environmental conditions and pathogens. For consumers these colours are considered attractive and provide many of the dietary benefits derived from fruits. In the majority of species, the main pigments are either carotenoids and/or anthocyanins. They are produced in the fruit as part of the ripening process, orchestrated by phytohormones and an ensuing transcriptional cascade, culminating in pigment biosynthesis. Whilst this is a controlled developmental process, the production of pigments is also attuned to environmental conditions such as light quantity and quality, availability of water and ambient temperature. If these factors intensify to stress levels, fruit tissues respond by increasing (or ceasing) pigment production. In many cases, if the stress is not severe, this can have a positive outcome for fruit quality. Here, we focus on the principal environmental factors (light, temperature and water) that can influence fruit colour.

Limited axon regeneration following peripheral nerve injury may be related to activation of the lysosomal protease, asparaginyl endopeptidase (AEP, δ-secretase), and its degradation of the microtubule associated protein, Tau. Activity of AEP was increased at the site of sciatic nerve transection and repair but blocked in mice treated systemically with a specific AEP inhibitor, compound 11 (CP11). Treatments with CP11 enhanced axon regeneration in vivo. Amplitudes of compound muscle action potentials recorded four weeks after nerve transection and repair and two weeks after daily treatments with CP11 were double those of vehicle-treated mice. At that time after injury, axons of significantly more motor and sensory neurons had regenerated successfully and reinnervated the tibialis anterior and gastrocnemius muscles in CP11-treated mice than vehicle-treated controls. In cultured adult dorsal root ganglion neurons derived from wild type mice that were treated in vitro for 24 hours with CP11, neurites were nearly 50% longer than in vehicle-treated controls, and similar to neurite lengths in cultures treated with the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF). Combined treatment with CP11 and 7,8-DHF did not enhance outgrowth more than treatments with either one alone. Enhanced neurite outgrowth produced by CP11 was found also in the presence of the TrkB inhibitor, ANA-12, indicating that the enhancement was independent of TrkB signaling. Longer neurites were found after CP11 treatment in both TrkB+ and TrkB- neurons. Delta secretase inhibition by CP11 is a treatment for peripheral nerve injury with great potential.

In this paper, we investigate the successful transmission probability of an aerial cellular network in which an unmanned aerial vehicle (UAV) as a Macrocell Base Station (UAV-BS) serves other UAVs as aerial users. The beamforming capable antennas are mounted on the UAVs, to increase the throughput of the network. The random effects of inner forces such as controlling errors or outer forces like the air conditions result in the random fluctuations. We assume Rician fading distribution over the links between the UAVs, then, we calculate the distribution of the channels under hovering fluctuations. Also, we derive the closed form expressions for successful transmission probability. Defining an optimization problem on the average successful transmission probability of the network, we obtain the best placement of UAV-BS along with the resource allocation. The problem turns out to be a non-convex problem and time consuming via numerical exhaustive search methods. Instead, we solve the optimization problem for its lower bound. Maximization problem for the achieved lower bound is equivalent to maximize the main problem. Then, we use some approximations to convert it to a low complex problem to find the solution. We use the entity of the low complex problem to obtain the allocated power for each UAV and in the following, the problem becomes convex which is solved by KKT conditions to obtain the location of UAV-BS. The theoretical results show that optimizing the lower bound probability achieves the suboptimal solution for power assignment and placement problem, which is verified by simulation results.

Mustard seeds have been used since ancient times contributing great economic value to global agriculture. Canada, one of the world’s top producers, grows three main mustard varieties, white /yellow, (Brassica hirta/ Sinapis alba), black (Brassica nigra) and Oriental (Brassica juncea). Besides their high protein and lipid content, mustard varieties are a rich source of phenolic compounds. This review will cover mustard seed components including lipids, glucosinolates, and sinapates. The latter are the main phenolic compounds in mustard and include sinapine, sinapic acid and its conversion to canolol. The important bioactivities associated with mustard phenolics, has led to efforts to improve the methods for their extraction. The use of green technology is crucial for producing these phenolics while minimizing any detrimental effects to the environment. The important antioxidant and anticancer activities of these phenolics will also be reviewed.

Clinical Needs Should Drive InnovationJennifer N. Avari Silva, MD1, 2, 3, 4Affiliations: 1Division of Pediatric Cardiology, Washington University School of Medicine, St. Louis, MO;2Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO;3Sentiar, Inc, St. Louis, MO;4Excera, Inc, St. Louis, MOCorresponding Author:Jennifer N. Avari Silva, MD jennifersilva@wustl.eduDisclosures: I am the co-founder and co-inventor of Sentiar and Excera, Inc. The technology has been licensed from Washington University to both Sentiar and Excera.Words:Conflicts: I have no relevant conflicts of disclosure.The tried-and-true methodology for designing medical devices starts with product ideation and rapid prototyping. But the most vital step starts prior to product ideation—that is, identifying the unmet clinical need. Starting with clear identification of clinical need may take time to fully elucidate and, importantly, may change over time as clinical practices, medical knowledge, and scientific discoveries change the field. Developing tools to address these unmet needs is the goal for medical device developers. When we start with developing tools that address unmet needs, the tools inherently provide added value. Conversely, tools are often developed to implement new technologies without a clear understanding of the need being addressed. Often, these technologies are in search of a clinically relevant use case—these tools become proverbial hammers in search of nails.In this study from Kumthekar et al1 in this month’s JCE, we learn the results of early feasibility testing of PeriScope in an animal (porcine) study. PeriScope is a novel percutaneous access tool for epicardial access developed to aid in the implantation of epicardial cardiac implantable electronic devices (CIEDs) in both pediatric and congenital patients who require systems at a young age. The clinical conundrum is that young patients who need CIEDs will often require lifelong devices, with transvenous systems often being delayed into adolescence (or later) due to small stature, linear growth, and concerns for causing venous stenosis or occlusion2, 3. Additionally, patients with congenital heart disease often have abnormal vasculature and anatomy which may prohibit transvenous CIED systems4, 5 This clinical problem has been debated rigorously in the pediatric EP community, with reports of transvenous systems placed in some of our youngest and smallest of patients6. This has been a longstanding need in the pediatric and congenital community which members of this investigative team have spent years working towards7-10.The authors set out to address this issue by creating a tool to ease epicardial device lead placement, and the first step in this multistep plan is epicardial access. The current data presented by Kumthekar et al1 demonstrate the use of this tool in an immature porcine model (Yorkshire piglets) to test the implant procedure characteristics and efficiencies. Early results are promising, showing the time from skin nick to sheath access in the pericardium was <10 minutes with a mean total procedure time of 16 minutes. Lead characteristics were acceptable, though not excellent, speaking to the need to develop additional new tools. To address the long-term goal of minimally invasive epicardial device implantation, adjunctive technologies will need to be developed, including leads designed for implantation via a minimally invasive approach and tools to simplify minimally invasive generator implantation. Given the breadth of tools that will be required to meet this need, an academic-industry partnership may emerge as a viable path for co-development.As with all novel tools and procedures, there is a learning curve and PeriScope is no different. Even within this small study with 6 piglets, there was a learning curve for the operator with piglet #1 having a longer procedure time than the rest of the cohort. Understanding learning curves, or assessments of performance over experience, for new technologies/tools and procedures is itself an entire field of study11 which over time has created standard learning curve models for guidance with certain types of procedures, including laparoscopic surgical procedures. With PeriScope, there appeared to be a steep learning curve with increased competency after a short experience (n=1). More experience with a varied user group will be invaluable to determining the true learning curve for the device.Finally, like many innovations developed to a specific clinical need, creative physicians will find novel, often off-label, use cases for technologies that address their own clinical needs. With the growing performance of epicardial ablation, accessing the epicardial space is no longer a need relegated to pediatric and congenital device implants, but is now an emerging need in adult, pediatric and congenital ablation. These changing needs over time are to be expected and reflect advances in medical knowledge and scientific discovery.By nature, cardiac electrophysiologists are innovators. We are fortunate to practice our field at a time when there is an abundance of devices being developed and engineered to address the unmet clinical needs emerging as we learn more about mechanisms of various substrates and develop best practices. Our mission is to ensure that these novel devices are practical, useful and of benefit to us and our patients.References:1. Kumthekar RN OJ, Mass P, M JC, Berul CI. Percutaneous Epicardial Pacing in Infants Using Direct VIsualization: A Feasibility Animal Study. Journal of Cardiovascular Electrophysiology . 2023.2. Berul CI, Triedman JK, Forbess J, Bevilacqua LM, Alexander ME, Dahlby D, Gilkerson JO and Walsh EP. Minimally invasive cardioverter defibrillator implantation for children: an animal model and pediatric case report. Pacing Clin Electrophysiol . 2001;24:1789-94.3. Kwak JG, Kim SJ, Song JY, Choi EY, Lee SY, Shim WS, Lee CH, Lee C and Park CS. Permanent epicardial pacing in pediatric patients: 12-year experience at a single center. Ann Thorac Surg . 2012;93:634-9.4. Maginot KR, Mathewson JW, Bichell DP and Perry JC. Applications of pacing strategies in neonates and infants. Prog Pediatr Cardiol . 2000;11:65-75.5. Rao V, Williams WG, Hamilton RH, Williams MG, Goldman BS and Gow RM. Trends in pediatric cardiac pacing. Can J Cardiol . 1995;11:993-9.6. Konta L, Chubb MH, Bostock J, Rogers J and Rosenthal E. Twenty-Seven Years Experience With Transvenous Pacemaker Implantation in Children Weighing <10 kg. Circ Arrhythm Electrophysiol . 2016;9:e003422.7. Clark BC, Kumthekar R, Mass P, Opfermann JD and Berul CI. Chronic performance of subxiphoid minimally invasive pericardial Model 20066 pacemaker lead insertion in an infant animal model. J Interv Card Electrophysiol . 2020;59:13-19.8. Clark BC, Opfermann JD, Davis TD, Krieger A and Berul CI. Single-incision percutaneous pericardial ICD lead placement in a piglet model. J Cardiovasc Electrophysiol . 2017;28:1098-1104.9. Kumthekar RN, Opfermann JD, Mass P, Clark BC, Moak JP, Sherwin ED, Whitman T, Marshall M and Berul CI. Minimally invasive percutaneous epicardial placement of a prototype miniature pacemaker with a leadlet under direct visualization: A feasibility study in an infant porcine model. Heart Rhythm . 2019;16:1261-1267.10. Kumthekar RN, Opfermann JD, Mass P, Clark BC, Moak JP, Sherwin ED, Whitman T, Marshall M and Berul CI. Percutaneous epicardial placement of a prototype miniature pacemaker under direct visualization: An infant porcine chronic survival study. Pacing Clin Electrophysiol . 2020;43:93-99.11. Hopper AN, Jamison MH and Lewis WG. Learning curves in surgical practice. Postgrad Med J . 2007;83:777-9.

Peptide drugs are developed from endogenous or synthetic peptides with specific biological activities. They have advantages of strong target specificity, high efficacy and low toxicity, thus showing great promise in the treatment of many diseases such as cancer, infections and diabetes. Although an increasing number of peptide drugs have entered market in recent years, the preparation of peptide drug substances is yet a bottleneck problem for their industrial production. Comparing to the chemical synthesis method, peptide biosynthesis has advantages of simple synthesis, low cost, and low contamination. Therefore, the biosynthesis technology of peptide drugs has been widely used for manufacturing. Herein, we reviewed the development of peptide drugs and recent advances in peptide biosynthesis technology, in order to shed a light to the prospect of industrial production of peptide drugs based on biosynthesis technology.

Blue sucker ( Cycleptus elongatus) occurs in the Mississippi River and Gulf of Mexico drainages of North America and is negatively affected by habitat fragmentation and flow regime alteration caused by dams. During fish assemblage surveys in August of 2022, we collected five specimens of juvenile blue sucker (312-428 mm total length) in the Angelina River upstream of Sam Rayburn Reservoir in east Texas (46,335-hectare surface area) where the occurrence of the species was previously unconfirmed. Given this unexpected finding, we (1) analyzed blue sucker mesohabitat associations to compare habitats we sampled with reports in the literature, and (2) reviewed blue sucker occurrence in state, national, and global databases across historical (1950-1980) and contemporary (1981-2022) periods to assess occurrence across gradients of habitat fragmentation and streamflow regulation. The blue sucker population in the Angelina River upstream of Sam Rayburn Reservoir was previously unconfirmed but is within the native range of the species. Mesohabitats occupied by blue sucker were consistent with literature reports, including fast velocity, shallow depth, and coarse substrates. The low degree of regulation (19% of natural runoff stored by upstream reservoirs) and a high degree of habitat connectivity (287 rkm of mainstem habitat) for the Angelina River upstream of Sam Rayburn Reservoir matched range-wide patterns of persistence within relatively intact (unfragmented and unregulated) or remnant (fragmented but unregulated) riverscapes. Our review reveals that blue sucker populations might persist (1) in remnant river fragments where local habitat templates are appropriate and (2) where effects of habitat fragmentation and flow regulation are not coupled.

Chytridiomycosis caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd) is a major driver of amphibian decline worldwide. The global presence of Bd is driven by a synergy of factors, such as climate, species life history, and amphibian host susceptibility. Here, using a Bayesian data-mining approach, we modelled the epidemiological landscape of Bd to evaluate how the infection varies across several spatial, ecological, and phylogenetic scales. We compiled global information on Bd occurrence, climate, species ranges, and phylogenetic diversity to infer the potential distribution and prevalence of Bd. By calculating the degree of co-distribution between Bd and our set of environmental and biological variables (e.g., climate and species), we identified which factors could potentially be related to Bd presence and prevalence using a geographic correlation metric, epsilon (ε). We fitted five ecological models based on: i) amphibian species identity, ii) phylogenetic species variability values for a given species assemblage, iii) temperature, iv) precipitation, and v) all variables together. Our results extend the findings of previous studies by identifying the epidemiological landscape features of the presence of Bd. This ecological modelling framework allowed us to generate explicit spatial predictions for Bd prevalence at global scale and a ranked list of species with high/low probability of Bd presence. Our geographic model was able to identify areas with high potential for Bd prevalence as potential risk areas and areas with low potential Bd prevalence as potential refuges (free Bd). At the amphibian assemblage level, we found a non-relationship with amphibian phylogenetic signals, but a significantly negative correlation between observed species richness and Bd prevalence indicated a potential dilution effect at the landscape scale. Our model may identify potential susceptible species and areas at risk of Bd presence which could be used to prioritize regions for amphibian conservation efforts and assess species and assemblage risk