The years 2021 and 2022 showed that maritime logistics are prone to interruptions. Especially the ports turned out to be bottlenecks with long queues of waiting vessels. This leads to the question of whether this can be (at least partly) mitigated by means of better and more flexible terminal operations. Digital Twins have been in use in production and logistics to increase flexibility in operations and are considered a reasonable fit. They are suitable for real-time data integration to support decision-making. However, the true potential of Digital Twins to enhance terminal operations still needs to be further investigated. A Delphi study is conducted to explore operational pain points, best practices to counter them, and how these best practices can be supported by Digital Twins. A questionnaire with 16 propositions is developed, and a panel of 17 experts is asked for their degrees of confirmation for each. The results indicate that today’s terminal operations are far from ideal and leave space for optimisation. The experts see great potential in analysing past working shifts data to identify reasons for poor terminal performance. Moreover, they agree on the proposed best practices and support the use of aiding IT solutions.

This paper proposes a multi-terminal adaptive collaborative operation method to solve the problem of unstable internal force tracking in clamping and handling unknown objects by multi-terminal robots. In the proposed method, the internal command force changes the complex internal force control problem into an internal force tracking problem from multi-slave to master. Moreover, we develop an algorithm for multi-slave setups to estimate object stiffness and motion uncertainty in the direction of the internal command force according to Lyapunov theory. Finally, the impedance control generates a reference trajectory for the multi-slave to maintain the desired internal force and track the master’s motion. Several experiments are conducted on a self-made robot equipped. The experimental results show that the oscillation amplitude of each slave end is less than 1 mm, the directional oscillation amplitude is less than 1 degree during the tracking of the desired commanded internal force. For objects with low stiffness, the error of the commanded internal force is less than 1 N (6%) per slave. The error in tracking the commanded internal force for objects with high stiffness is less than 2 N (8%). The results prove the feasibility and effectiveness of the proposed method.

Introduction: Isolated terminal ileitis (ITI) is commonly found associated with Crohn’s disease but it has other etiologies too. Other common causes of ITI include nonsteroidal anti-inflammatory drug (NSAID) use, tuberculosis and other bacterial/parasitic infections, neoplasia, radiation or other autoimmune disorders. Methods: After obtaining IRB approval, a retrospective chart review was conducted on patients with biopsy proven ITI from May 2011 to May 2016 at our academic medical Centre. Data was collected pertaining to demographics, body mass index (BMI), associated Crohn’s disease or ulcerative colitis, treatment received and other causes of ileitis noted. Data was analyzed using SPSS software with chi square used to analyze categorical variables. P<0.05 was considered statistically significant. Results: A total of 229 patients with clinical symptoms and ITI on biopsy were reviewed. The mean age of our patients was 43.7 years old. Of the patient group, 49% (n=113/229) were males and the rest were females. Only 42% of patients with ITI were eventually diagnosed with Crohn's disease. Stool cultures were performed in 37% (n=86/229) of patients with positive results in 0.04% (n=4/86) of the patients. Most patients were treated with antibiotics after diagnosis of ileitis without determination of the exact etiology of the condition. Amongst those evaluated, one had tuberculosis, one had ischemic ileitis and one had Meckel’s diverticulum. NSAID use accounted for 26% (n=59/229) of ITI cases. Treatment generally involved antibiotics, initiation of biologics or use of 5-aminosalicylic acid products. The mean length of hospitalization was 1.25 days. Mean BMI of our patients was 25 kg/m2 and there was no statistically significant association noted between ITI and BMI. Presence of Crohn’s disease with ITI had a statistically significant association with positive clostridium difficile infection and subsequent need for treatment with biologics for isolated disease (p<0.001). Conclusions: Isolated terminal ileitis is commonly associated with Crohn’s disease but there are other conditions that should be suspected and can mimic Crohn’s disease histologically and endoscopically in the Ileum. NSAIDS are an important cause of ITI and need to be specifically inquired from the patient. If not considered it can result in misdiagnosis of Crohn’s disease and inappropriate treatment. Hence being aware of the wide range of differential diagnoses that can present with inflammation of the terminal ileum is important to avoid this inadvertent mislabeling. This retrospective study highlights the importance of other differentials when considering the management of a patient with ITI and not just focusing on only Crohn’s disease as the possible etiology.

This study delves into the foundational aspects of electrocardiographic (ECG) lead systems, specifically focusing on Einthoven’s Triangle and Wilson’s Central Terminal. We introduce the innovative concept of a Precordial Central Terminal, a strategic arrangement of thoracic electrodes that establishes two Einthoven’s triangles within the horizontal plane, in accordance with physical-mathematical principles. Furthermore, we meticulously scrutinize Goldberger’s contributions to the field of ECG, particularly augmented leads, which shed light on the development of our theory. Additionally, we propose the implementation of a novel standardized electrocardiograph, characterized by its use of exclusively “precordial” electrodes, yet capable of providing a comprehensive three-dimensional perspective of cardiac electrical activity. By amalgamating theoretical underpinnings with empirical experimentation, our study lays the groundwork for future investigations, including the experimental validation of our innovative Precordial Terminal. This validation holds the promise of yielding substantial advancements in the realm of clinical electrocardiography.

The molecular clusters ((HO)3Si-O-Si(OH)3, and (HO)3Al-O-Si(OH)3 ) representative of aluminosilicate mineral surface were employed to study the dissolution of aluminosilicate in acidic condition via density functional theory with the M06-2X+G(d,p) methodology. The surface termination sites (Si and Al) were both tetra-coordinated and the terminal oxygen was protonated in acidic condition. In the dissolution reaction, the calculated barrier height of the six-membered ring transition state complex containing two water molecules was predicted to be lower than that of four-membered ring transition state complex containing one water molecule. In addition, the calculated barrier heights for Al-terminated sites were predicted to be lower than those for the Si-terminated sites, suggesting that breaking the Al-O bond is easier than Si-O bond in the aluminosilicate mineral surface; the barrier heights of the surface termination sites with protonated terminal oxygen were lower than those without protonated terminal oxygen. With the fracture of Si-O and Al-O bonds, the Si and Al release from the aluminosilicate. These results confirm the experimental conclusions that the acidic condition facilitates the release of Si and Al from the aluminosilicate, and the concentration of Al leaching from aluminosilicate is higher than Si.

The incorporation of unmanned aircraft terminal operations into the scope of Detect and Avoid systems necessitates analysis of the safety performance of those systems—principally, an assessment of how well those systems prevent loss of well clear from and collision with other aircraft. This type of analysis has typically been conducted by Monte Carlo simulation with synthetic, statistically representative encounters between aircraft drawn from an appropriate encounter model. While existing encounter models include terminal airspace classes, none explicitly represents the structure expected while engaged in terminal operations, e.g., aircraft in a traffic pattern. The work described herein is an initial model of such operations, scoped at this time specifically for assessment of unmanned aircraft landings and encounters with other aircraft either landing or taking off. The model shares the Bayesian network foundation of other MIT Lincoln Laboratory encounter models but tailors those networks to address structured terminal operations, i.e., correlations between trajectories and the airfield and each other. This initial model release is intended to elicit feedback from the standards-writing community.

The aim of this study was to evaluate the nature of relationship between service quality and customers’ satisfaction thorough SERVQUAL model. This study can be considered as an applied research, from purpose point of view and descriptive-survey, with regards to the nature and method. Passengers of Kaveh and Sofeh terminal in Isfahan have been considered as research population. Sample size included 200 passengers witch was determined by Cochran formula. Spss 19 was used to analyze collected data. Results show that there is a significant positive relationship between service quality and customers’ satisfaction. It is also proved that in terms of the importance of satisfactions’ dimensions, assurance is the most important aspect and then reliability, empathy, equipment appearance and responsiveness in sequence are the most important dimensions.

Djibouti shares an exceptional geostrategic position by being close to one of the busiest maritime routes, which makes it possible to have a crucial position for the movement of international trade transported by sea. This study analyses the influence of port development on Djibouti’s economic growth in the case of Doraleh Container Terminal and identifies other significant variable factors. In this paper, we analyze the existence of an influence port development on economic growth and other variables, by applying the perspective of the multiple regression model in the analysis using Eviews software. the selected datasets in the analysis cover the period from 2010 to 2020. The result show that port development has a direct and strongly positive influence on the economic growth of Djibouti. In addition, this study also reveals that imports and exports trade is a mediating variable with a significant influence on economic growth in Djibouti. Furthermore, foreign direct investment has not directly and positive influences on Djibouti's economic growth. Therefore, we recommend that the Government of Djibouti attract and promote the benefits of foreign direct investment to enhance the development of various economic sectors and achieve significant economic growth in the coming years.

Knowing the symbolizations constructed in people's consciousness, based on lived experiences, is crucial to understanding how they structure their lives. Palliative Sedation (PS) integrates treatment in terminal palliative care, with the purpose of offering support and relief of refractory symptoms that may occur at the end of life. This study aimed at interpreting psychic fantasies that permeate thoughts, as reported by a sample of nurses when administering palliative sedation to patients in the final stage of life. This is a clinical-qualitative study conducted in a large hospital in the city of São Paulo (state of São Paulo, Brazil), a national reference in oncology. The study included 11 nurses working in the care of cancer patients. For data collection, we used the technique of SDIOQD – Semi-Directed Interview with Open-ended Questions in-Depth. The treatment by CQCA - Clinical-Qualitative Content Analysis is grounded on psychodynamic concepts. The interpretation of the meaning cores found in the interviews, complemented by observation of the para-verbal and nonverbal manifestations of the interviewees, led to the construction of three categories: (1) to symbolically serve death on a tray; (2) the act of sedation and its unfortunate coincidences; (3) palliative sedation as an agent of mercy death. This study suggests that nurses face dilemmatic situations, going through periods of self-questioning and moments of the ambivalence of feelings of beneficence and maleficence. When sedating a patient, the nurses envision to be offering dignity in death. Euthanasia fantasies in the process of administering sedation are latent in consciousness.

Bread wheat (Triticum aestivum L.) is one of the most important cereal crops for food security. Of all the stresses that curtail wheat productivity, drought has the most detrimental effects. Especially terminal drought stress i.e. at the time of flowering imposes a big challenge to sustain grain production. In the current study, 339 pre-breeding lines derived from three-way crosses of exotics x elite lines were evaluated in the irrigated and drought stress environments at Obregon, Mexico for the year 2016 and 2018. Drought significantly reduced yield (Y), spike length (SL), number of grains per spikes (NGS) and thousand kernel weight (TKW) by 46.4, 19.2, 23.5 and 25.9%, respectively in comparison to irrigated conditions. Kernel abortion (KA), highly correlated with Y, increased significantly (11.6%) under drought stress environment. Population structure analysis in this panel revealed three sub-populations and a genome wide linkage disequilibrium (LD) decay was at 2.5 cM. Single marker and haplotypes-based genome wide association study (GWAS) revealed significant associations on three chromosomes; 4A (HB10.7), 2D (HB6.10) and 3B (HB8.12) with Y, SL and TKW, respectively. Likewise, associations on chromosomes 6B (HB17.1) and 3A (HB7.11) were identified for NGS and on 3A (HB7.12) for KA. Five traits i.e. normalized difference vegetation index (NDVI), canopy temperature depression (CTD) days to heading (DTH), NGS, KA were associated at chromosome 3A both under irrigated and drought conditions however, different haplotypes were estimated. Twenty-six SNPs were part of 10 haplotype blocks associated with Y, SL, TKW, NGS and KA. In silico analysis of the associated SNPs/haplotypes showed hits with candidate genes known to confer abiotic stress resistance in model species and crops. Potential candidate genes include those coding for sulfite exporter TauE/SafE family in Arabidopsis thaliana, TBC domain containing protein in Oryza sativa subsp. Japonica and heat shock proteins in Aegilops tauschii subsp. tauschii were revealed. The SNPs linked to the promising genes identified in the study can be used for marker-assisted selection.

At container terminals, many cargo handling processes are interconnected and take place in parallel. Within short time windows, many operational decisions need to be taken considering both time and equipment efficiency. During operation, many sources for disturbance exist. These are the reason why perfectly coordinated processes are possibly unraveled. An approach that considers disturbance factors while optimizing a given objective is simulation-based optimization. This study analyses simulation-based optimization as a procedure to simultaneously scale the number of utilized equipment and to adjust the choice and tuning of operational policies. The four meta-heuristics Tree-structured Parzen Estimator, Bayesian Optimization, Simulated Annealing, and Random Search guide the simulation-based optimization process. The results show that simulation-based optimization is suitable to identify the amount of required equipment and well-performing policies. Thereby, there is no clear ranking which of the meta-heuristics finds the best approximation of the optimum. The approximated optima suggest that pooling terminal trucks as well as a yard block assignment close to the quay crane is preferable. With an increasing number of quay cranes, the number of optimal terminal trucks for each quay crane decreases as well as the range of truck utilization within one experiment.

Melittin, a natural antimicrobial peptide, displays a broad-spectrum antimicrobial activity, which has caused increasing attention as a potential antibiotic alternative. However, melittin has not been used widely at present due to its high hemolysis and low proteolytic stability. In this study, N-terminal fatty acid was conjugated to melittin to develop new melittin-derived lipopep-tides (MDLs) for improving the limitation of melittin. Our results showed that, the antimicrobial activity of MDLs was increased by 2 to 16 times compared with native melittin, and the stability of these MDLs against trypsin and pepsin degradation was increased by 50 to 80%. Besides, the hemolytic of the MDLs decreased when the length of the carbon chain of fatty acids exceeded 10. Among them, the newly designed analog Mel-C8 showed optimal antimicrobial activity and protease stability. The antimicrobial mechanism studied revealed that the MDLs showed a rapid bactericidal effect by interacting with LPS or LTA and penetrating the bacterial cell membrane. In conclusion, we designed and synthesized a new class of MDLs with potent antimicrobial activity, high proteolytic stability, and low hemolysis through N-terminal fatty acid conjugation.

Brassica napus is an important vegetable and oil crop worldwide. The research is meaningful for yield and plant architecture in B. napus. In this study, one natural mutant (MT) line with determinate and capitulum-like inflorescence was chosen for further study. The paraffin sectioning detected that the inflorescence apex began to split and developed into one terminal flower, starting from five-leaf stage. Genetic analysis indicated that the segregation patterns of inflorescences in the F2 populations supported a digenic inheritance model, which was further approved by BSA-Seq technique. The BSA-Seq method detected two QTL region on C02 (14.27-18.41 Mb) and C06 (32.98-33.68 Mb) for the genetic control of determinate inflorescences in MT plants. In addition, the expression profile in MT compared with WT was analysized, and a total of 133 candidate genes for regulating the flower development (75 genes, 56.4%), shoot meristem development (29 genes, 21.8%) and inflorescence meristem development (13 genes, 9.8%) were identified. Then one joint analysis combing BSA-Seq and RNA-Seq identified two candidate gene of BncTFL1 and BncAP1 for regulating the MT phenotype. Besides, the potential utilization of the MT plants was also discussed.

To search for novel thermostable esterase for optimized industrial applications, esterase from a thermophilic eubacterium species, Thermoanaerobacter tengcongensis MB4 was purified and characterised in this work. Sequence analysis of T. tengcongensis esterase with other homologous esterases of the same family revealed an apparent tail at the C-terminal that is not conserved across the esterase family. Hence, it was hypothesized that the tail is unlikely to have an essential structural or catalytic role. However, there is no documented report of any role for this tail region. We probed the role of the C-terminal domain on the catalytic activity and substrate preference of Thermoanaerobacter tengcongensis esterase EstA3 with a view to see how it could be engineered for enhanced properties. To achieve this, we cloned, expressed, and purified the wild-type and the truncated version of the enzyme. In addition, a naturally occurring member of the family (from B. brevis) that lacks the C-terminal tail was also made. In vitro characterization of the purified enzymes showed that the C-terminal domain contributes significantly to the catalytic activity and distinct substrate preference of T. tengcongensis esterase EstA3. All the three recombinant enzymes showed highest preference to paranitrophenyl butyrate (pNPC4), which suggests they are true esterases, not lipases. kinetic data revealed that truncation had a slight effect on the substrate-binding affinity. Thus, the drop in preference towards long-chain substrates might not be a result of substrate binding affinity alone.

The outdoor field test of the 4-terminal on Si tandem photovoltaic module (specifically, InGaP/GaAs on Si) was investigated and performance model, considering spectrum change affected by fluctuation of atmospheric parameters, was developed and validated. The 4-terminal on Si tandem photovoltaic module had about 40 % advantage in seasonal performance loss compared with standard InGaP/GaAs/InGaAs 2-terminal tandem photovoltaic module. This advantage is expanded in (subarctic zone) < (temperate zone) < (subtropical zone). The developed and validated model used all-climate spectrum model and considered fluctuation of atmospheric parameters, and can be applied every type of on-Si tandem solar cells.

Helicobacter pylori cytotoxin-associated gene A protein (CagA) has been associated with the increase in virulence and risk of cancer. It has been demonstrated that CagA's translocation is dependent on its interaction with phosphatidylserine. We evaluated the variability of the N-terminal CagA in 127 sequences reported in NCBI, by referring to molecular interaction forces with the Phosphatidylserine and the docking of 3 mutations chosen from variations in specific positions. The major sites of conservation of the residues involved in CagA-Phosphatidylserine interaction were 617, 621 and 626 which had no amino acid variation. Position 636 had the lowest conservation score, so mutations in this position were evaluated to observe the differences in intermolecular forces of the CagA-Phosphatidylserine complex. We evaluated the docking of 3 mutations: K636A, K636R and K636N. The models of the crystal and mutations presented a ΔG of −8.919907, −8.665261, −8.701923, −8.515097 Kcal/mol, respectively, while mutations K636A, K636R, K636N and the crystal structure presented 0, 3, 4 and 1 H-bonds, respectively. Likewise, the bulk effect of the ΔG and amount of H-bonds was estimated in all of the docking models. The type of mutation affected both the ΔG (χ²(1) = 93.82, p-value < 2.2 × 10⁻¹⁶) and the H-bonds (χ²(1) = 91.93, p-value < 2.2 × 10⁻¹⁶). In all the data, 76.9% of the strains that exhibit the K636N mutation produced a severe pathology. The average H-bond count diminished when comparing the mutations with the crystal structure of all the docking models, which means that other molecular forces are involved in the CagA-Phosphatidylserine complex interaction.

In archaea, the interaction of HerA helicase and NurA nuclease is required for 3' end resection during DNA double-stranded break repair, and its disruption results in unfaithful DNA repair. Interactions transpire by the four conserved domains, including the N-terminal HAS domain (HerA-ATP synthase), which serves as a binding site for the exonuclease NurA. As a HerA hexamer between its two subunits, the conserved C-terminal brace extension functions as an adjacent brace. DBD serves as a location for DNA binding, which causes the DNA strands to be propelled into the HerA pocket to begin unwinding. The putative pore entrance is made up of four helix coils, which provide a suitable charged surface for guiding DNA into the pore. The crystal structure of the complex HerA-NurA allows for the identification of key residues for protein-protein interaction. This allows us to predict that most archaeal HerA orthologs will be able to interact with one another. Archaeal HerA is a homo-hexameric assembly featuring a DNA-binding domain that is conserved. It also features distinctive ATP and NurA binding domains. Following the structure and sequence conservation criteria, we find one HerA ortholog in Pyrobaculum calidifontis and multiple HerA paralogs, but the role of none is established yet.Interestingly, orthologous HerA is part of an Mre11-Rad50 gene neighborhood while paralogous HerA is not, which could be misleading. As a result, it sought to describe the criteria that may be used as a possible fingerprint for identifying orthologous genes, as well as the cloning procedures and tactics that would aid in the confirmation of the HerA helicase in P. calidifontis. Their confirmation is based on PCR cloning and characterization following HerA construct creation.

Nanoporous films of Eu-doped organosilicate glass (OSG) have been synthesized using sol-gel technology and spin-coating, employing evaporation-induced self-assembly (EISA), on silicon wafers. The Eu doping is achieved by dissolution of Eu(NO3)3·6H2O in the precursor solution. The deposited films are characterized by using Fourier transform infrared (FTIR) spectroscopy, ellipsometric porosimetry (EP), X-ray photoelectron spectroscopy (XPS) and photoluminescence spectroscopy. It is observed that Eu doping makes the films more hydrophilic and reduces the pore size and open porosity. The reduction Eu3+ → Eu2+ occurs in the pores of OSG films, which is confirmed by depth profiling XPS. However, Eu3+ still presents on the film’s top surface. Presence of Eu3+ and Eu2+ gives characteristic luminescence emission in the range of 600‒630 nm (Eu3+) and 290‒400 nm (Eu2+). The Eu2+/Eu3+ concentrations ratio depends on CH3 groups concentration in the films. Moreover, concentration of Eu2+ ions in the pores can be reduced by exposure in inductively coupled (ICP) oxygen plasma. The observed shift of the luminescence spectra towards the UV region, in comparison to previously reported Eu-doped organosilicate films, can be attributed to the energy transfer occurring between the host material and Eu2+ ions.

This paper presents the design and implementation of a digital control system for modular multilevel converters (MMC) and its use in a 5-kW small scale prototype. To achieve higher system control reliability and multi-functionality, the proposed architecture has been built with an effective split of the control tasks between a master controller and six slave controllers, one for each of the six arms of the converter. The MMC prototype have been used for testing both converter and system level controls in a reduced scale laboratory set up of a Multi-Terminal DC transmission network (MTDC). The whole control has been tested in order to validate the proposed control strategies. The tests performed at system level allowed to explore the advantages of using an MMC in a MTDC system.

: Airports are often the centers driving economic development of the local community in which they are located and have a significant impact on the national economy. Therefore, the infrastructural development of the airport is of great importance. On the other hand, passengers are becoming more experienced, more informed and more demanding in achieving their own satisfaction related to the level of quality of the service provided. The new airport infrastructure has an impact on improvement of customer experience, but with the assumption that certain physical and operational conditions are met. The research found that, in addition to the facilities that are part of the passenger operations, passengers pay significant attention to the commercial facilities, design and ambiance of the passenger terminal. It can be concluded that with the new airport infrastructure development such as passenger terminal, a wow effect at the customers will be achieved, but that only right design of ambient, simplified passenger flows and organization of commercial areas with a diverse offer and acceptable prices will ensure long term customer satisfaction and that the experience gap remains positive and sustainable.

In this work, we developed a highly sensitive multiplexed immunosensor for direct simultaneous detection of both N-terminal Natriuretic Peptide (NT-proBNP) and Cortisol in human artificial saliva (AS). The developed biosensor platform based on silicon nitride was composed from four gold working microelectrodes (WEs) and an integrated counter and reference electrode. Gold WEs were biofunctionalized through carboxyl diazonium (4-APA) to immobilize both anti- NT-proBNP and anti-Cortisol antibodies for simultaneous detection. The electroaddressing of the 4-APA onto the gold WE surfaces was realized by cyclic voltammetry (CV), while the interaction between antibodies and antigens in PBS was monitored by electrochemical impedance spectroscopy (EIS). The antigen detection in human AS was realized by EIS combined with the standard addition method. The immunesensor was highly sensitive and selective toward the corresponding biomarkers in both PBS and artificial human saliva as well as in the presence of other potential interfering biomarkers such as tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10). The limit of detection (LOD) was at 0.2pg/mL for NT-proBNP within the range 0.03 to 0.9pg/mL, while the LOD for Cortisol was 0.06 ng/mL within the range 0.02 to 0.6 ng/mL for Cortisol in artificial saliva. The developed immunosensor is very promising for significant detection time reducing as it allows the simultaneous detection of various biomarkers.

The objective of this study is to measure the crack propagation speed in three types of self-compacting concrete reinforced with steel fibers loaded under four different loading rates. Central-notched prismatic beams with two types of fibers (13 mm and 30 mm in length), three fiber volume ratios, 0.51%, 0.77% and 1.23%, were fabricated. Four strain gages were glued on one side of the specimen notch to measure the crack propagation velocity, a fifth one at the notch tip to estimate the strain rates upon the initiation of a cohesive crack and the stress-free crack. A servo-hydraulic testing machine and a drop-weight impact device were employed to conduct three-point bending tests at four loading-point displacement rates, the former to perform tests at 2.2 μm/s, 22 mm/s and the latter for those at 1.77 m/s, 2.66 m/s, respectively. With lower fiber contents, smooth mode-I cracks were formed, the crack speed reached the order of 1 mm/s and 20 m/s. However, crack velocities up to 1417 m/s were obtained for the concrete with high content of fibers under impact loading. This value is fairly close to the theoretically predicted terminal crack velocity of 1600–1700 m/s. Numerical simulations based on cohesive theories of fracture and preliminary results based on the technique of Digital Image Correlation are also presented to complement those obtained from the strain gages. In addition, the toughness indices are calculated under all four loading rates. Strain hardening (softening) behavior accounting from the initiation of the first crack is observed for all three types of concrete at low (high) loading rates. Significant enhancement in the energy absorption capacity is observed with increased fiber content.

Manzamines are complex polycyclic marine-derived β-carboline alkaloids with reported anticancer, immunostimulatory, anti-inflammatory, antibacterial, antiviral, antimalarial, neuritogenic, hyperlipidemia and atherosclerosis suppression bioactivities, putatively associated with inhibition of glycogen synthase kinase-3, cyclin-dependent kinase 5, and vacuolar ATPases. We hypothesized that additional and yet undiscovered molecular targets might be associated with Manzamine A (MZA) reported pharmacological properties. We report herein for the first time to our knowledge that MZA inhibited a 90kDa ribosomal protein kinase S6 (RSK1) when screened against a panel of 30 protein kinases. Furthermore in vitro RSK kinase assays demonstrated a 10-fold selectivity in potency of MZA against RSK1 versus RSK2. MZA’s differential binding and selectivity toward the two isoforms is also supported by computational docking experiments. Specifically, the RSK1-MZA (N- and C-termini) complexes appear to have stronger interactions and preferable energetics contrary to the RSK2-MZA ones. In addition, our computational strategy suggests that MZA binds to the N-terminal kinase domain of RSK1 rather than the C-terminal domain. RSK is a vertebrate family of cytosolic serine-threonine kinases that act downstream of the ras-ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway, which phosphorylates substrates shown to regulate several cellular processes including growth, survival and proliferation. Consequently, our findings have lead us to hypothesize that MZA and the 80 currently known manzamine-type alkaloids isolated from several sponge genera, may have novel pharmacological properties.

C-terminal Src kinase (CSK) is the major inhibitory kinase for Src family kinases (SFKs) through phosphorylation of their C-tail tyrosine site, and regulates various cellular activities in association with SFKs functions. As a cytoplasmic protein, CSK need be recruited to the plasma membrane to regulate SFKs activities. The regulatory mechanism for CSK activity and its subcellular localization remains largely unclear. In this work, we developed a genetically encoded biosensor based on fluorescence resonance energy transfer (FRET) to visualize CSK activity in live cells. The biosensor with optimized substrate peptide confirmed crucial Arg107 site in CSK SH2 domain, and displayed sensitivity and specificity to CSK activity while little responses to co-transfected Src and Fyn. FRET measurements showed CSK having relatively mild level of kinase activity in comparison to Src and Fyn ones in rat airway smooth muscle cells. The biosensor tagged with different submembrane-targeting signals detected CSK activity at both non-lipid raft and lipid raft microregions, while showed higher FRET level at non-lipid ones. Co-transfected receptor-type protein tyrosine phosphatase alpha (PTPα) had inhibitory effect on the CSK FRET response. The biosensor didn’t detect obvious changes of CSK activity between metastatic cancer cells and normal ones. In conclusion, a novel FRET biosensor was generated to monitor CSK activity, and demonstrated CSK activity existing in both non-lipid and lipid raft membrane microregions while more present at non-lipid ones.

There is a growing use of High Voltage Direct Current (HVDC) globally due to the many advantages of Direct Current (DC) transmission systems over Alternating Current (AC) transmission, including enabling transmission over long distances, higher transmission capacity and efficiency. Moreover, HVDC systems can be a great enabler in the transition to a low carbon electrical power system which is an important objective in today’s society. The objectives of the paper are to give a comprehensive overview of HVDC technology, its development, and present status, and to discuss its salient features, limitations and applications.

SORL1 gene encodes LR11/SorLA, a protein that binds -amyloid precursor protein (bAPP) and drives its intracellular trafficking. SORL1 mutations occurring frequently in a subset of familial cases of Alzheimer’s disease (AD) have been documented but their pathogenic potential is not yet clear and questions remain concerning their putative influence on the physiopathological processing of bAPP. We have assessed the influence of three SORL1 mutations that were described as likely disease-causing and that were associated with either benign (SorLA924) or severe (SorLA141 and SorLA511) AD phenotypes. We examined the influence of wild-type and mutants SorLA in transiently transfected HEK293 cells expressing either wild-type or Swedish mutated bAPP on bAPP expression, secreted Ab and sAPPa levels, intracellular Ab40 and Ab42 peptides, APP-CTFs (C99 and C83) expressions, a-, b- and g-secretases expressions and activities as well as Ab and CTFs-degrading enzymes. These paradigms were studied in control conditions or after pharmacological proteasomal modulation. We also established stably transfected CHO cells expressing wild-type SorLA and established the colocalization of wild-type SorLA and bAPP. Overall, although we mostly confirmed previous data concerning the influence of wild-type SorLA on bAPP processing, we were unable to evidence significant alterations triggered by our set of SorLA mutants, whatever the cells or pharmacological conditions examined. Our study however does not rule out the possibility that other AD-linked SORL1 mutations could indeed affect bAPP processing and that pathogenic mutations examined in the present study could interfere with other cellular pathways/triggers in AD.

This study focuses on mimicking constitutive phosphorylation in the N-terminus of the myosin regulatory light chain (S15D-RLC) as a rescue strategy for the mutation-induced cardiac dysfunction in transgenic (Tg) models of restrictive (RCM) and dilated (DCM) cardiomyopathy caused by mutations in myosin essential (ELC) or regulatory (RLC) light chains. S15D-RLC phosphomimetic was reconstituted in left ventricular papillary muscle (LVPM) fibers from two mouse models of cardiomyopathy, RCM-E143K ELC and DCM-D94A RLC, along with their corresponding Tg-ELC and Tg-RLC wild type (WT) mice. The beneficial effects of S15D-RLC in rescuing cardiac function were manifested by S15D-RLC-induced destabilization of the super-relaxed (SRX) state that was observed in both models of cardiomyopathy. S15D-RLC promoted a shift from the SRX state to the disordered relaxed (DRX) state, increasing the number of heads readily available to interact with actin and produce force. Additionally, S15D-RLC reconstituted fibers demonstrated significantly higher maximal isometric force per cross-section of muscle compared with reconstitution with WT-RLC protein. The effects of the phosphomimetic S15D-RLC were compared to those observed for Omecamtiv Mecarbil (OM), a myosin activator shown to bind to the catalytic site of cardiac myosin and increase myocardial contractility. A similar SRX↔DRX equilibrium shift was observed in OM=treated fibers as in S15D-RLC-reconstituted preparations. Additionally, treatment with OM resulted in significantly higher maximal pCa 4 force per cross-section of muscle fibers in both cardiomyopathy models. Our results suggest that both treatments with S15D-RLC and OM may improve the function of myosin motors and cardiac muscle contraction in RCM-ELC and DCM-RLC mice.

Over the last decades, cellular immunotherapy has revealed its curative potential. However, the inherent physiological characteristics of immune cells can limit the potency of this approach. Best defined in T cells, dysfunction associated with terminal differentiation, exhaustion, senescence, and activation-induced cell death undermine adoptive cell therapies. In this review, we concentrate on how the multiple mechanisms that articulate the various forms of immune dysfunction impact cellular therapies primarily involving conventional T cells, but also other lymphoid subtypes, in addition to the various strategies put in place to circumvent these effects. The repercussions of immune cell dysfunction across the full life cycle of cell therapy, from the source material, during manufacturing, and after adoptive transfer are discussed. Applicable to cellular products prepared from native and unmodified immune cells, as well as genetically engineered therapeutics, the understanding and potential modulation of dysfunctional features is key to the development of improved cellular immunotherapies.

As most of the current dynamic positioning systems are based on model ships, they cannot accu-rately reflect the motion state, position changes, and mutual influence of each part of the dynamic positioning system of actual ships in complex environments. Other actual ships such as cargo ships cannot add various sensors and auxiliary equipment to verify and analyze the positioning system. This article takes the intelligent research and training dual-use ship of Dalian Maritime University, which integrates scientific research and training, as the object of study. This ship will not be affected by the voyage period and route and can choose a suitable sea area for research. Therefore, in order to improve the accuracy and reliability of the dynamic positioning system, research on the ship’s dynamic positioning system was carried out. Firstly, an accurate mathematical model of ship motion was established, and the hydrodynamic derivatives of ship model motion were obtained by nu-merical calculation, and applied to the three-degree-of-freedom model of the intelligent research and training dual-use ship. Then, the model was used as part of the closed-loop simulation model of the ship’s dynamic positioning system, and the terminal sliding mode controller was used for sim-ulation and emulation, thereby obtaining ideal simulation test results. This research helps to im-prove the accuracy and reliability of the dynamic positioning system and provides new ideas and methods for ship motion control.

Both SARS-CoV-2 and SARS-CoV initially appeared in China and spread to other parts of the world. SARS-CoV-2 has generated a COVID-19 pandemic causing more than 6 million human deaths worldwide while the SARS outbreak quickly ended in six months with a global total of 774 reported deaths. One of the factors contributing to this stunning difference in the outcome between these two outbreaks is the inaccuracy of the RT-qPCR tests for SARS-CoV-2, which generated a large number of false-negative and false-positive test results that have misled patient management and public health policy-makers. This article presented Sanger sequencing evidence to show that the RT-PCR diagnostic protocol established in 2003 for SARS-CoV can in fact detect SARS-CoV-2 accurately due to the well-known nonspecific PCR amplification of DNAs with similar sequences. Using nested RT-PCR followed by Sanger sequencing to retest 50 patient samples collected in January, 2022 and sold as RT-qPCR positive reference confirmed 21 (42%) were false-positive. Although the other 29 positive isolates were categorized as Omicron variant by partial sequencing of the N gene, and the RBD and the NTD of the S gene, 9 (31%) showed focal to complete sequencing failure in the S gene segments due to multi-allelic SNPs. During the course of the study, an Omicron variant isolate containing a BA.1 NTD and a BA.2 RBD in its S gene was also detected. Routine partial S gene sequencing of all PCR-positive samples can timely discover multi-allelic SNPs and viral recombination in the circulating variants for investigation of their impacts on vaccine efficacies, therapeutics and diagnostics.

As SARS-CoV-2 continues to spread among human populations, genetic changes occur and accumulate in the circulating virus. Some of these genetic changes have caused amino acid mutations, including deletions, which may have potential impact on critical SARS-CoV-2 countermeasures, including vaccines, therapeutics, and diagnostics. Considerable efforts have been made to categorize the amino acid mutations of the angiotensin-converting enzyme 2 (ACE2) receptor binding domain (RBD) of the spike (S) protein along with certain mutations in other regions within the S protein as specific variants in an attempt to study the relationship between these mutations and the biological behavior of the virus. However, the currently used whole genome sequencing surveillance technologies can test only a small fraction of the positive specimens with high viral loads and often generate uncertainties in nucleic acid sequencing that needs additional verification for precision determination of mutations. This article introduces a generic protocol to routinely sequence a 437-bp nested RT-PCR cDNA amplicon of the ACE2 RBD and a 490-bp nested RT-PCR cDNA amplicon of the N-terminal domain (NTD) of the S gene for detection of the amino acid mutations needed for accurate determination of all variants of concern and variants of interest according to the definitions published by the U.S. Centers for Disease Control and Prevention. This protocol was able to amplify both nucleic acid targets into cDNA amplicons to be used as templates for Sanger sequencing on all 16 clinical specimens that were positive for SARS-CoV-2.

The article is devoted to the preliminary concept of the Future Planetary Defense System (FPDS), emphasizing Astroballistics. This paper is intended to support international efforts to improve the planetary security of the Earth. The work covers three areas of knowledge: Astronautics, Astrodynamics, and Astroballistics. The most important part of the presented article is dynamic, contact combat modeling against small, deformable celestial bodies. For these purposes, the original, proprietary hydrocode of the Free Particle Method (HEFPM-G) with gravity was used. The main aim of combat is to redirect the Potentially Hazardous Objects (PHOs) to orbits safe for the Earth or destroy them. This concept's first task is to find, prepare and use dynamic three-dimensional models of celestial bodies' motion and spacecraft or human-crewed spaceships in the Solar System's relativistic frame. The second task is to prepare the FPDS' architecture and computer simulation space missions' initial concepts in the internal part of the solar system. The third and main task covers simulating, using hydrocodes, selected methods of fighting 100 m and 140 m diameter asteroids. The order of the article is as follows. The first part of the article presents an architecture and FPDS' modus operandi. Preliminary design and development of FPDS' space missions, including navigation, mission dynamics simulation, is prepared using an open-source space mission analysis and design tool. E.g., Asterank and Trajectory Browser or GMAT are presented in the second part. The third part of the article is devoted to computer hydrocodes (HEFPM-G) and the modeling and simulation of asteroid–asteroid collision, laser radiation effects on an asteroid, and FPDS spacecraft's warhead contact interaction on the small celestial body. The authors formulated the Main Planetary Defense Problem (MPDP) in this paper. The proposition of this problem solving has been realized by preparing its concepts, architecture, and modus operandi of the FPDS mission. Finally, a series of realistic simulations were made using hydrocode to deflect or destroy dangerous asteroids. The summary and conclusions can be found in the fourth part of the article.