Search Results (15)

Most electric vehicles use 400 V batteries, while some companies are moving to 800 V to reduce current in electric drives. More cars are expected to adopt 800 V at the DC terminals of the batteries, but 400 V will remain common for the duration of this transition, so future off-board chargers must support a wide voltage output range. Silicon carbide switches are used to keep the power–electronics interface compact and scalable. The AC/DC stage of a modular silicon carbide-based interface is designed using a T-type active front end and a dual active bridge. The T-type front end is optimized with a genetic algorithm. The resulting model is used to tune the inner current and outer voltage controllers. Bode analysis shows an inner current loop bandwidth of 4.25 kHz with a phase margin of ${53}^{°}$ and a gain margin of 30 dB. The outer voltage loop reaches 50 Hz with a phase margin of ${108}^{°}$ and a gain margin of 33 dB. The controller is implemented on a dSPACE MicroLabBox. Tests show peak efficiency of 98.5% in G2V mode and 98.3% V2G mode. THD stays under 5% above 4 kW and reaches 3% at peak power. Full article

Background: Acute and chronic pre-traumatic cigarette smoke exposure increases morbidity and mortality after trauma and hemorrhage. In mice with a genetic deletion of the H₂S-producing enzyme cystathione-γ-lyase (CSE^−/−), providing exogenous H₂S using sodium thiosulfate (Na₂S₂O₃) improved organ function after chest trauma and hemorrhagic shock. Therefore, we evaluated the effect of Na₂S₂O₃ during resuscitation from blunt chest trauma and hemorrhagic shock on CSE^−/− mice with pre-traumatic cigarette smoke (CS) exposure. Since H₂S is well established as being able to modify energy metabolism, a specific focus was placed on whole-body metabolic pathways and mitochondrial respiratory activity. Methods: Following CS exposure, the CSE^−/− mice underwent anesthesia, surgical instrumentation, blunt chest trauma, hemorrhagic shock for over 1 h (target mean arterial pressure (MAP) ≈ 35 ± 5 mmHg), and resuscitation for up to 8 h comprising lung-protective mechanical ventilation, the re-transfusion of shed blood, fluid resuscitation, and continuous i.v. noradrenaline (NoA) to maintain an MAP ≥ 55 mmHg. At the start of the resuscitation, the mice randomly received either i.v. Na₂S₂O₃ (0.45 mg/g_bodyweight; n = 14) or the vehicle (NaCl 0.9%; n = 11). In addition to the hemodynamics, lung mechanics, gas exchange, acid–base status, and organ function, we quantified the parameters of carbohydrate, lipid, and protein metabolism using a primed continuous infusion of stable, non-radioactive, isotope-labeled substrates (gas chromatography/mass spectrometry) and the post-mortem tissue mitochondrial respiratory activity (“high-resolution respirometry”). Results: While the hemodynamics and NoA infusion rates did not differ, Na₂S₂O₃ was associated with a trend towards lower static lung compliance (p = 0.071) and arterial PO₂ (p = 0.089) at the end of the experiment. The direct, aerobic glucose oxidation rate was higher (p = 0.041) in the Na₂S₂O₃-treated mice, which resulted in lower glycemia levels (p = 0.050) and a higher whole-body CO₂ production rate (p = 0.065). The mitochondrial respiration in the heart, kidney, and liver tissue did not differ. While the kidney function was comparable, the Na₂S₂O₃-treated mice showed a trend towards a shorter survival time (p = 0.068). Conclusions: During resuscitation from blunt chest trauma and hemorrhagic shock in CSE^−/− mice with pre-traumatic CS exposure, Na₂S₂O₃ was associated with increased direct, aerobic glucose oxidation, suggesting a switch in energy metabolism towards preferential carbohydrate utilization. Nevertheless, treatment with Na₂S₂O₃ coincided with a trend towards worsened lung mechanics and gas exchange, and, ultimately, shorter survival. Full article

The three spacecraft of the space gravitational wave antenna employ heterodyne interferometry to mitigate the effects of Doppler shift. Constrained by laser relative intensity noise (RIN) and the sampling frequency constraints of phase readout circuits, the widespread adoption of fixed offset frequencies effectively regulates the frequency of heterodyne interferometric beat notes within a reasonable frequency domain of [5 MHz, 25 MHz]. In this work, a high-precision fitness genetic algorithm for heterodyne interferometry is utilized to generate the initial offset frequency distribution scheme. To address issues with unreasonable switching times and offset frequency settings in the initial scheme for partial frequency domains, optimization strategies are proposed from three aspects: frequency domain selection extension, switch times control, and numerical low frequency. Results demonstrate that the optimization of frequency domain selection extension narrows the reasonable frequency domain to [5 MHz, 15 MHz] and [7 MHz, 17 MHz]. Optimization of switch times control ensures that switching times of offset frequency distribution scheme generated under the settings of [6 MHz, 17 MHz] and wider frequency domains can be controlled within a reasonable range of 6 to 13 times. Fixed offset frequency settings are generally reduced by 24.3% after low-frequency optimization. This methodology and result can provide a reliable reference for Program Taiji and even related space gravitational wave antenna projects. Full article

Fibrillin-1 and fibrillin-2, encoded by FBN1 and FBN2, respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families. We performed clinical phenotyping for two newborn infants with complex congenital heart defects. For genetic investigations, we employed next-generation sequencing strategies including whole-genome Single-Nucleotide Polymorphism (SNP) microarray for infant A with valvular insufficiency, aortic sinus dilatation, hydronephrosis, and dysmorphic features, and Trio whole-exome sequencing (WES) for infant B with dextro-transposition of the great arteries (D-TGA) and both parents. Infant A is a term male with neonatal marfanoid features, left-sided hydronephrosis, and complex congenital heart defects including tricuspid regurgitation, aortic sinus dilatation, patent foramen ovale, patent ductus arteriosus, mitral regurgitation, tricuspid regurgitation, aortic regurgitation, and pulmonary sinus dilatation. He developed severe persistent pulmonary hypertension and worsening acute hypercapnic hypoxemic respiratory failure, and subsequently expired on day of life (DOL) 10 after compassionate extubation. Cytogenomic whole-genome SNP microarray analysis revealed a deletion within the FBN1 gene spanning exons 7–30, which overlapped with the exon deletion hotspot region associated with neonatal Marfan syndrome. Infant B is a term male prenatally diagnosed with isolated D-TGA. He required balloon atrial septostomy on DOL 0 and subsequent atrial switch operation, atrial septal defect repair, and patent ductus arteriosus ligation on DOL 5. Trio-WES revealed compound heterozygous c.518C>T and c.8230T>G variants in the FBN2 gene. Zygosity analysis confirmed each of the variants was inherited from one of the parents who were healthy heterozygous carriers. Since his cardiac repair at birth, he has been growing and developing well without any further hospitalization. Our study highlights novel FBN1/FBN2 variants and signifies the phenotype–genotype association in two infants affected with complex congenital heart defects with and without dysmorphic features. These findings speak to the importance of next-generation high-throughput genomics for novel variant detection and the phenotypic variability associated with FBN1/FBN2 variants, particularly in the neonatal period, which may significantly impact clinical care and family counseling. Full article

A three-phase multilevel inverter (MLI), synthesized with 31 levels in regard to its output voltage, is used to provide the AC supply to a three-phase, squirrel cage induction motor. The gating angles required for the 30 power switches on the MLI are optimized using both the genetic algorithm (GA) and the grey wolf optimizer (GWO), in which the optimal angles are determined through solving the trigonometric equations taken from Fourier analysis to target the minimum total harmonic distortion (THD) at the MLI output. A simulation model and an experimental prototype are developed for performance analysis and validation. The results demonstrate that the MLI is effectively able to produce 31 levels of three-phase AC output voltage, with the THD not exceeding 5% when loaded with a resistive load and a three-phase induction motor. The voltage and current are measured and recorded for different loads and operating conditions, including the amount of energy consumed by the load. The results of the frequency analysis demonstrate that most of the triple harmonics, which can harm the efficiency of the inverter, are cancelled. Full article

Background: Multilocus sequence typing (MLST) is used to gain insight into the population genetics of bacteria in the form of sequence type (ST). MLST has been used to study the evolution and spread of virulent clones of Streptococcus pneumoniae in many parts of the world. Such data for S. pneumoniae are lacking for the countries of the Arabian Peninsula, including Kuwait. Methods: We determined the STs of all 31 strains of S. pneumoniae from invasive diseases received at a reference laboratory from various health centers in Kuwait during 2018 by MLST. The relationship among the isolates was determined by phylogenetic analysis. We also determined the serotypes by Quellung reaction, and antimicrobial susceptibility by Etest, against 15 antibiotics belonging to 10 classes. Results: There were 28 STs among the 31 isolates, of which 14 were new STs (45.2%) and 5 were rare STs (16.1%). Phylogenetic analysis revealed that 26 isolates (83.9%) were unrelated singletons, and the Kuwaiti isolates were related to those from neighboring countries whose information was gleaned from unpublished data available at the PubMLST website. Many of our isolates were resistant to penicillin, erythromycin, and azithromycin, and some were multidrug-resistant. Virulent serotype 8-ST53, and serotype 19A with new STs, were detected. Conclusions: Our study detected an unusually large number of novel STs, which may indicate that Kuwait provides a milieu for the evolution of novel STs. Novel STs may arise due to recombination and can result in capsular switching. This can impact the effect of vaccination programs on the burden of invasive pneumococcal disease. This first report from the Arabian Peninsula justifies the continuous monitoring of S. pneumoniae STs for the possible evolution of new virulent clones and capsular switching. Full article

Next-generation sequencing technologies have revolutionized the field of virology by enabling the reading of complete viral genomes, extensive metagenomic studies, and the identification of novel viral pathogens. Although metagenomic sequencing has the advantage of not requiring specific probes or primers, it faces significant challenges in analyzing data and identifying novel viruses. Traditional bioinformatics tools for sequence identification mainly depend on homology-based strategies, which may not allow the detection of a virus significantly different from known variants due to the extensive genetic diversity and rapid evolution of viruses. In this work, we performed metagenomic analysis of bat feces from different Russian cities and identified a wide range of viral pathogens. We then selected sequences with minimal homology to a known picornavirus and used “Switching Mechanism at the 5′ end of RNA Template” technology to obtain a longer genome fragment, allowing for more reliable identification. This study emphasizes the importance of integrating advanced computational methods with experimental strategies for identifying unknown viruses to better understand the viral universe. Full article

The emergence of recombinant PRRSV strains has been observed for more than a decade. These recombinant viruses are characterized by a genome that contains genetic material from at least two different parental strains. Due to the advanced sequencing techniques and a growing number of data bank entries, the role of PRRSV recombinants has become increasingly important since they are sometimes associated with clinical outbreaks. Chimeric viruses observed more recently are products of PRRSV wild-type and vaccine strains. Here, we report on three PRRSV-1 isolates from geographically distant farms with differing clinical manifestations. A sequencing and recombination analysis revealed that these strains are crossovers between different wild-type strains and the same modified live virus vaccine strain. Interestingly, the recombination breakpoint of all analyzed isolates appears at the beginning of open reading frame 5 (ORF5). RNA structure predictions indicate a conserved stem loop in close proximity to the recombination hotspot, which is a plausible cause of a polymerase template switch during RNA replication. Further research into the mechanisms of the stem loop is needed to help understand the PRRSV recombination process and the role of MLVs as parental strains. Full article

Disturbances in cardiac lipid metabolism are associated with the development of cardiac hypertrophy and heart failure. Spontaneously hypertensive rats (SHRs), a genetic model of primary hypertension and pathological left ventricular (LV) hypertrophy, have high levels of diacylglycerols in cardiomyocytes early in development. However, the exact effect of lipids and pathways that are involved in their metabolism on the development of cardiac dysfunction in SHRs is unknown. Therefore, we used SHRs and Wistar Kyoto (WKY) rats at 6 and 18 weeks of age to analyze the impact of perturbations of processes that are involved in lipid synthesis and degradation in the development of LV hypertrophy in SHRs with age. Triglyceride levels were higher, whereas free fatty acid (FA) content was lower in the LV in SHRs compared with WKY rats. The expression of de novo FA synthesis proteins was lower in cardiomyocytes in SHRs compared with corresponding WKY controls. The higher expression of genes that are involved in TG synthesis in 6-week-old SHRs may explain the higher TG content in these rats. Adenosine monophosphate-activated protein kinase phosphorylation and peroxisome proliferator-activated receptor α protein content were lower in cardiomyocytes in 18-week-old SHRs, suggesting a lower rate of β-oxidation. The decreased protein content of α/β-hydrolase domain-containing 5, adipose triglyceride lipase (ATGL) activator, and increased content of G0/G1 switch protein 2, ATGL inhibitor, indicating a lower rate of lipolysis in the heart in SHRs. In conclusion, the present study showed that the development of LV hypertrophy and myocardial dysfunction in SHRs is associated with triglyceride accumulation, attributable to a lower rate of lipolysis and β-oxidation in cardiomyocytes. Full article

Nowadays, novel oral anticoagulants (NOACs) have shown improved safety profile and efficacy compared to vitamin K antagonists in the prevention of thromboembolic events occurring during different pathological conditions. However, there are concerns and safety issues, mostly related to adverse events following interactions with other drugs, in real-world practice. We report the case of an 83-year-old woman who developed a non-bleeding leg ulcer not caused by trauma or other evident pathological conditions after 10 days of treatment with apixaban 5 mg/q.d. She was switched from apixaban to dabigatran and the leg ulcer rapidly improved and completely cicatrized in 40 days. The resolution of the ulcer and the toleration of dabigatran therapy suggest an apixaban-specific reaction; however, the pathological mechanism of ulcer onset is currently unclear. Careful evaluation of hospital databases of Molise region (Southern Italy) hospitals identified two similar cases between 2019 and 2021. These cases underline the necessity of careful post-marketing surveillance, considering the rapidly increasing number of patients treated with NOACs and patient’s risk factors such as old age, high polypharmacy rate, co-morbidities, and peculiar genetic background related to NOACs pharmacokinetic features. Full article

O80:H2 enterohemorrhagic Escherichia coli (EHEC) of sequence type ST301 is one of the main serotypes causing European hemolytic and uremic syndrome, but also invasive infections, due to extra-intestinal virulence factors (VFs). Here, we determined whether other such heteropathotypes exist among ST301. EnteroBase was screened for ST301 strains that were included in a general SNP-phylogeny. French strains belonging to a new heteropathotype clone were sequenced. ST, hierarchical clusters (HC), serotype, resistome, and virulome were determined using EnteroBase, the CGE website, and local BLAST. The ST301 general phylogeny shows two groups. Group A (n = 25) is mainly composed of enteropathogenic E. coli, whereas group B (n = 55) includes mostly EHEC. Three serotypes, O186:H2, O45:H2 and O55:H9, share the same virulome as one of the O80:H2 sub-clones from which they derive subsequent O-antigen switches. The O55:H9 clone, mainly present in France (n = 29), as well as in the UK (n = 5) and Germany (n = 1), has a low background of genetic diversity (four HC20), although it has three Stx subtypes, an H-antigen switch, and genes encoding the major extra-intestinal VF yersiniabactin, and extended-spectrum beta-lactamases. Diverse heteropathotype clones genetically close to the O80:H2 clone are present among the ST301, requiring close European monitoring, especially the virulent O55:H9 clone. Full article

Campylobacter jejuni has a large adaptive potential due to enormous genetic exchange. Factors regulating natural transformation in this food-borne pathogen are largely unknown but of interest for the application of sustained reduction strategies in the food-processing industry. Using a single cell DNA uptake assay, we visualized that recognition of methylated C. jejuni DNA was essential for the first step of DNA uptake into a DNase resistant state. Transformation rates using a resistance marker correlated with the fraction of competent bacteria, harboring one to maximally four locations of active DNA uptake, not necessarily being located at the cell pole. Competence developed with rising pH between 6.5 and 7.5 under microaerobic conditions and was nearly insensitive towards growth temperatures between 32 °C and 42 °C, CO₂ concentrations ranging from 0 to 50% and growth rates. However, competence development was abolished at pH 5 or under aerobic stress conditions, in which the bacteria ceased growth but fully survived. The DNA uptake machinery in competent bacteria shut down at slightly acidic pH and was reversibly switched on upon neutralization. It was dependent on the proton motive force and, in contrast to competence development, slightly enhanced under aerobic conditions. The results suggest that natural transformation in C. jejuni occurs in the neutral and microaerobic intestinal environment for enhanced genetic diversity and pre-adaption before host switch. In addition, highly competent bacteria might be shed into the environment, still able to acquire genetic material for increased survival. Full article

Hyaluronic acid (HA) is a biopolymer formed by UDP-glucuronic acid and UDP-N-acetyl-glucosamine disaccharide units linked by β-1,4 and β-1,3 glycosidic bonds. It is widely employed in medical and cosmetic procedures. HA is synthesized by hyaluronan synthase (HAS), which catalyzes the precursors’ ligation in the cytosol, elongates the polymer chain, and exports it to the extracellular space. Here, we engineer Ogataea (Hansenula) polymorpha for HA production by inserting the genes encoding UDP-glucose 6-dehydrogenase, for UDP-glucuronic acid production, and HAS. Two microbial HAS, from Streptococcus zooepidemicus (hasAs) and Pasteurella multocida (hasAp), were evaluated separately. Additionally, we assessed a genetic switch using integrases in O. polymorpha to uncouple HA production from growth. Four strains were constructed containing both has genes under the control of different promoters. In the strain containing the genetic switch, HA production was verified by a capsule-like layer around the cells by scanning electron microscopy in the first 24 h of cultivation. For the other strains, the HA was quantified only after 48 h and in an optimized medium, indicating that HA production in O. polymorpha is limited by cultivation conditions. Nevertheless, these results provide a proof-of-principle that O. polymorpha is a suitable host for HA production. Full article

Torque density is one of the major limiting factors in machine design. In this paper, we propose the hybrid excited partitioned stator switched flux machine3 (HE-PSSFM3). In HE-PSSFM3, armature winding is positioned on the outer stator whereas the permanent magnet (PM) and field winding are placed at the inner stator, while the rotor is free from excitation sources and armature winding. Moreover, concentrated field winding is replaced by toroidal winding. The power splitting ratio between two stators/rotor pole combinations is analytically optimized and are validated through genetic algorithm (GA) in order to enhance average torque and flux regulation capability. The electromagnetic characteristics of the improved and initial design are evaluated and compared with existing designs, i.e., HE-PSSFM1 and HE-PSSFM2. The proposed HE-PSSFM3 has achieved high average torque, i.e., 2.0015 Nm, at same armature and field current densities of 5 A/mm${}^2$. The results show that the average torques of the proposed design are 35% and 15% greater than HE-PSSFM1 and HE-PSSFM2, respectively. Furthermore, the analysis of various parameters such as flux linkage, flux regulation, electromagnetic performances, cogging torque, back EMF, electromagnetic torque, and torque ripples are investigated using two dimensional (2D) finite element analysis (FEA). Moreover, the simulation results of the proposed design are validated through GA and analytical modeling. Full article

Epigenetic events and genetic alterations under the control of the tumor microenvironment potentially mediate tumor induced angiogenesis involved in soft tissue sarcoma (STS) metastasis. Addition of antiangiogenic agent, such as bevacizumab, to standard chemotherapy in treatment of sarcoma has been studied in clinical trials, but most of the findings have not supported its use. We hypothesized the existence of an epigenetically mediated “angiogenic switch”, and the tumor microenvironment, prevents bevacizumab from truly blocking angiogenesis. The addition of valproic acid (VPA), a weak histone deacetylase inhibitor, and bevacizumab, a monoclonal antibody against vascular endothelial growth factor, together with the cytotoxic effects of gemcitabine and docetaxel, may enhance responses and alter chemoresistance. This was designed as a phase I/II trial with primary endpoints including safety of the treatment combination and tumor response. Unresectable or metastatic sarcoma patients >18 years of age, irrespective of number of prior treatments, received VPA 40 mg/kg orally for 5 days prior to day 1, bevacizumab at 15 mg/kg IV on day 1, gemcitabine 900 mg/m² (day 1, day 8), and docetaxel 75 mg/m² (day 8). Cycles were of 28 day duration. Bevacizumab and VPA were continued as maintenance after 6 cycles, until disease progression. A standard 3 + 3 phase I dose de-escalation design was utilized to evaluate safety. Gain of function p53 gene mutation testing was performed on available archival tissue specimens. A total of 46 patients (30 female, 16 male) with median age of 60 (range 24–81) years were enrolled; 34 (73.9%) patients received prior chemotherapy, 14 (30%) of which received prior gemcitabine and docetaxel. Patients received a median of 5.5 cycles (range 0–24 of treatment (min 0, one patient died prior to completing the first cycle; max: 24, one patient received 6 cycles and 18 maintenance cycles before progressing). Seventeen patients underwent dose reduction, of which VPA was reduced in 6 patients. Forty-one patients were evaluable for response. There was a confirmed complete response in 1 (epithelioid sarcoma), and a partial response (PR) in 6 (1 carcinosarcoma, 2 extrauterine leiomyosarcoma (LMS), 2 undifferentiated pleomorphic sarcoma, and 1 uterine LMS) patients. Stable disease (SD) was seen in 21 patients for at least 2 months. One subject with prior gemcitabine and docetaxel had PR, and 7 had SD. Median progression-free survival (PFS) was 5.7 months (95% CI: 2.1–8.0), and overall survival (OS) was 12.9 months (95% CI: 8.3–14.5). Three patients died due to tumor progression while on the study. The combination of VPA, bevacizumab, gemcitabine, and docetaxel appears to be moderately safe and well tolerated. Given that there are very limited options for patients with relapsed refractory STS, this drug combination may be an important therapy to consider. This combination treatment deserves further investigation in epithelioid and carcinosarcoma subtypes. Full article