Single Cycle Research Articles

Analysis of Stress Characteristics of a Vertical Centrifugal Pump Based on Fluid-Structure Interaction

Vertical centrifugal pumps play a crucial role in numerous water conservancy projects. However, their continuous operation can lead to the development of cracks or even fractures in some centrifugal pump blades, resulting in a substantial adverse impact on the operation of the pumping station unit and jeopardizing safe production. This study employs the fluid-structure interaction method to comprehensively investigate the modal characteristics of the impeller, both in an air environment and immersed in water. Furthermore, the analysis of static and dynamic stress attributes is conducted. The natural frequency of the impeller when submerged in water is significantly lower than its frequency in an air medium, typically accounting for approximately 0.35 to 0.46 of the air-based natural frequency. There are conspicuous stress concentrations at specific locations within the system, specifically at the rounded corners of the blade back exit edge, the impeller front cover, the middle of the blade inlet edge, and the junction where the blade interfaces with the front and back cover. It is crucial to underscore that when the system operates under high-flow or low-flow conditions, there is a pronounced stress concentration at the interface between the impeller and the rear cover plate. Any deviation from the intended design conditions results in an escalation of equivalent stress levels. Through dynamic stress calculations during a single rotational cycle of the impeller, it is discerned that the cyclic nature of stress at the point of maximum stress is primarily influenced by the number of blades and the rotational velocity of impeller. This research carries significant implications for effectively mitigating blade fractures and cyclic fatigue damage, thereby enhancing the operational reliability of vertical centrifugal pumps in water conservancy applications.

In-sequence tectonic evolution of Ediacaran nappes in the southeastern branch of the Brasília Orogen (SE Brazil): Constraints from metamorphic iterative thermodynamic modeling and monazite petrochronology

The metamorphic and kinematic evolution of medium-high grade rocks of the Andrelândia Nappe System (ANS), the orogenic wedge of the Southern Brasilia Orogen (SBO), was investigated in this work. Field and microstructural observations were combined with metamorphic petrology (i.e., iterative thermodynamic modeling) and monazite petrochronology to reconstruct the tectono-metamorphic history of the ANS rocks. The Liberdade Nappe experienced prograde metamorphism at ca. 610 Ma, achieving peak metamorphic conditions of ca. 650 °C and 9.5–10 kbar. This stage was followed by isothermal decompression linked to tectonic transport toward SE, at ca. 570 Ma. On the contrary, the Andrelândia Nappe experienced prograde metamorphism later, at ca. 580 Ma, reaching peak metamorphic conditions of ca. 680 °C and 11–12 kbar. The obtained results indicate that each nappe of the Andrelândia System records a single metamorphic cycle of burial and decompression, although it took place at different ages over a period of ca. 60 myr, from 630 to 570 Ma. The nappes experienced prograde and retrograde metamorphism whose ages progressively decreased toward the bottom of the nappe stack. We attribute this pattern to propagation of older buried material from the orogenic wedge (i.e., Liberdade Nappe), via thrust-and-fold, upon recently accreted rocks (i.e., Andrelândia Nappe), conducting a younger metamorphism event on the footwall of the ductile thrusted nappes. This mechanism is consistent with the ANS in-sequence fold-and-thrust architecture.

Metallurgical patterns of the formation of W–Zr surface alloys via pulsed electron-beam processing

In this study, W–Zr surface alloys (SAs) were synthesized by low-energy high-current electron beam (LEHCEB) processing of preliminary deposited tungsten films on zirconium substrates in a single vacuum cycle. Then, their microstructure, as well as both chemical and phase compositions were investigated. Also, computer simulation of the dynamics of temperature fields was carried out. After LEHCEB processing of the Zr substrate with the preliminary deposited W film, the constituent element distributions were non-uniform over the surface of the W–Zr SA at the energy density of 3.5 J/cm2. Rising the energy density up to 5.5 J/cm2 resulted in a smoother and more homogeneous W–Zr SA. At the energy density of 3.5 J/cm2, the average tungsten content over the surface was 53 ± 39 at.%, while it was only 26 ± 2 at.% at 5.5 J/cm2. All W–Zr SAs consisted of the W phase (in different proportions), tungsten-rich solid solutions in the stabilized β-Zr phase, and the W2Zr intermetallic compound. The contents of the β-Zr and W2Zr phases enhanced with rising the energy density due to a greater amount of dissolved tungsten. Based on the obtained results, a scheme was proposed describing the formation of the SAs upon LEHCEB processing.

In-situ Raman spectroscopic study of conformational reorganization during heat treatment for high-density polyethylene solid

We investigated in-situ conformational reorganization in a quenched high-density polyethylene solid during heat treatments at various temperatures using in-situ Raman spectroscopic technique. The heat-treatment cycle included three steps: heating from room temperature, maintaining at a fixed sub-melting temperature (tempering), and cooling to room temperature. The heating process caused a conformational transformation from orthorhombic crystalline trans conformers to non-crystalline long trans segments outside the crystalline lattice, which were then amorphized. During the tempering or isothermal duration region, the amorphized long trans segments were steadily subjected to crystalline rearrangement. Finally, the cooling process modified the long trans component (including the amorphized component) into crystalline trans conformers. Overall, a single heat-treatment cycle increased the crystallinity through reorganization of non-crystalline long-trans segments without changing the interfacial content where the original amorphous content remained the same.

Switched "On" Transient Fluorescence Output from a Pulsed-Fuel Molecular Ratchet.

We report the synthesis and operation of a molecular energy ratchet that transports a crown ether from solution onto a thread, along the axle, over a fluorophore, and off the other end of the thread back into bulk solution, all in response to a single pulse of a chemical fuel (CCl3CO2H). The fluorophore is a pyrene residue whose fluorescence is normally prevented by photoinduced electron transfer (PET) to a nearby N-methyltriazolium group. However, crown ether binding to the N-methyltriazolium site inhibits the PET, switching on pyrene fluorescence under UV irradiation. Each pulse of fuel results in a single ratchet cycle of transient fluorescence (encompassing threading, transport to the N-methyltriazolium site, and then dethreading), with the onset of the fluorescent time period determined by the amount of fuel in each pulse and the end-point determined by the concentration of the reagents for the disulfide exchange reaction. The system provides a potential alternative signaling approach for artificial molecular machines that read symbols from sequence-encoded molecular tapes.

Abstract B132: Addition of AMXT1501 (polyamine uptake inhibitor) plus DFMO (polyamine synthesis inhibitor) to standard-of-care chemotherapy/anti-GD2 antibody in the TH-MYCN mouse neuroblastoma model, enhances efficacy compared to addition of DFMO alone

Abstract Background: We used the TH-MYCN mouse model of neuroblastoma (NB) to determine the importance of simultaneously inhibiting both polyamine uptake and synthesis when added to standard-of-care chemotherapy/immunotherapy. Polyamines are essential cations frequently upregulated in tumors. We have shown the benefit of adding DFMO, an irreversible polyamine synthesis inhibitor, to standard-of-care chemotherapy in several NB mouse models (Evageliou, Clin Cancer Res 2016). Based on our work, a randomized Phase 2 COG trial of DFMO, added to chemotherapy/anti-GD2 immunotherapy, is ongoing for relapsed NB (NCT03794349). We recently showed in NB mouse models that DFMO efficacy is enhanced by adding the polyamine uptake inhibitor AMXT1501 (Gamble, Sci Transl Med, 2019). DFMO/AMXT1501 is now in adult clinical trial (NCT05500508). Preclinical modelling of polyamine-targeted therapeutics in TH-MYCN mice has been invaluable for supporting clinical trial design but has yet to include anti-GD2 immunotherapy. Methods: TH-MYCN mice were used to optimize DFMO/AMXT1501 therapy combined with temozolomide/irinotecan (TEM/IRI) or cyclophosphamide/topotecan (CYCLO/TOPO), and anti-GD2 (14G2a) antibody. We studied escalating doses of DFMO and AMXT1501 (n=10/group), with or without TEM/IRI or CYCLO/TOPO. 14G2a regimen was titrated toward human-relevant pharmacokinetic exposures to establish suitable conditions for combination therapies. Results: In the absence of chemo-immunotherapy, highest-dose DFMO (1.5%) and AMXT1501 (2.5 mg/kg/d) had greatest efficacy without increased toxicity. Median mouse survival was 2-fold greater compared with lower dose DFMO/AMXT1501 combinations, suggesting that maximising DFMO dose is critical. Similar improved efficacy was observed in combination with TEM/IRI or CYCLO/TOPO. Combining 14G2a (100ug 2x/wk, 18 wks; McNerney, Oncoimmunology, 2022) with either CYCLO/TOPO (single 5-day chemo cycle) or DFMO/AMXT1501 (1.5%/2.5 mg/kg/d) increased survival compared with either treatment alone. Combining all 5 drugs resulted in 100% survival at 1 year, with minimal toxicity. However substantial dose reductions of 14G2a (<25µg, 2 doses) and TEM/IRI or CYCLO/TOPO (single 2-day chemo cycle) were needed to identify clinically relevant backbones which achieved human-relevant 14G2a pharmacokinetics. Addition of DFMO alone to the clinically relevant CYCLO/TOPO/14G2a backbone did not result in benefit compared to backbone alone. In contrast, addition of AMXT1501 plus DFMO to the backbone significantly extended survival (P< 0.001). Conclusions: We have increased the utility of the TH-MYCN mouse model for preclinical modelling of polyamine inhibition, and other investigational treatments, by pharmacokinetics-driven optimization of anti-GD2 therapy with standard-of-care chemotherapy backbones. This approach will improve optimisation for future NB clinical trials. Our data highlight the importance of adding AMXT1501 to DFMO for polyamine inhibition and support a planned international DFMO/AMXT1501/chemotherapy/anti-GD2 trial for refractory NB. Citation Format: Jayne Murray, Ruby Pandher, Lin Xiao, Klaartje Somers, Jennifer Brand, Erin Mosmann, Stephanie Alfred, Frances Kusuma, Adam Kearns, Julie R Park, Lynley V Marshall, Chiara Gorrini, Louis Chesler, Michael D Hogarty, Andrew D J Pearson, Mark Burns, Jamie I Fletcher, David Ziegler, Murray D Norris, Michelle Haber. Addition of AMXT1501 (polyamine uptake inhibitor) plus DFMO (polyamine synthesis inhibitor) to standard-of-care chemotherapy/anti-GD2 antibody in the TH-MYCN mouse neuroblastoma model, enhances efficacy compared to addition of DFMO alone [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B132.

Application of novel constrained friction processing method to produce fine grained biomedical Mg-Zn-Ca alloy

In order to obtain Mg alloys with fine microstructures and high mechanical performances, a novel friction-based processing method, name as “constrained friction processing (CFP)”, was investigated. Via CFP, defect-free Mg-Zn-Ca rods with greatly refined grains and high mechanical properties were produced. Compared to the previous as-cast microstructure, the grain size was reduced from more than 1 mm to around 4 µm within 3 s by a single process cycle. The compressive yield strength was increased by 350% while the ultimate compressive strength by 53%. According to the established material flow behaviors by “tracer material”, the plastic material was transported by shear deformation. From the base material to the rod, the material experienced three stages, i.e. deformation by the tool, upward flow with additional tilt, followed by upward transportation. The microstructural evolution was revealed by “stop-action” technique. The microstructural development at regions adjacent to the rod is mainly controlled by twinning, dynamic recrystallization (DRX) as well as particle stimulated nucleation, while that within the rod is related to DRX combined with grain growth.

#37 : Improved Pregnancy Prediction Performance in an Updated Deep-Learning-Based Embryo Selection Model: A Retrospective Independent Validation Study Using 3,960 Single Blastocyst Transfer Cycles

Background and Aims: Generally, the performance of deep learning models is improved by increasing the size of the training dataset. However, to the best of our knowledge, there has been no study on the effect of increasing training data on the performance of pregnancy prediction using the same deep-learning model. Method: A total of 3,960 blastocyst transfer cycles (1 patient, 1 cycle) were retrospectively analyzed. Embryos were stratified according to SART age groups. The quality and scoring of embryos were assessed by iDAScore v2.0 (iDA-V2; Vitrolife, Sweden), v1.0 (iDA-V1; Vitrolife, Sweden), and Gardner grading (GG). The discriminative performance of pregnancy prediction for each embryo scoring model was compared using the area under the curve (AUC) of the receiver operating characteristic curve for each maternal age group. Results: In the AUCs of the < 35 years age group (n = 757) for pregnancy prediction, the AUC of iDAV2 was significantly higher than that of GG (0.718 vs. 0.694, p = 0.015). For the 35-37 years age group (n = 821), the AUC of iDA-V2 was significantly higher than that of iDA-V1 (0.712 vs. 0.696, p = 0.035). In the AUCs of the 41–42 years age group (n = 715), the AUC of iDA-V2 was significantly different from that of GG (0.745 vs. 0.696, P = 0.007). In the > 42 years age group (n = 660) and 38–40 years age group (n = 1,007), there were no significant difference among the groups. Conclusion: The present study suggests that the performance of deep learning models for pregnancy prediction will be improved by increasing the size of the training data. Therefore, in a deep-learning model for pregnancy prediction, continuously collecting training data is an important step for improving the performance of updated AI models.

#175 : Cohort Study of Post-Thawed Blastocyst Morphology is Associated with the Clinical Pregnancy of the Single Embryo Transfer Cycle

Background and Aims: Frozen Embryo Transfer is the final step in undergoing IVF treatment. One of the important parts in the success of the FET cycle is the quality of the transferred embryos. The ability of blastocyst post-thawed recovery indicated embryo potential. However, there is limited understanding of the factors that influence recovery of post-thawed blastocyst embryos. This study aims to examine whether blastocyst morphology post-thawed correlates with clinical pregnancy rate. Method: In a retrospective cohort study, analysis data of Morula IVF Surabaya was conducted from January 2022 – February 2023, thawed blastocyst with a post-thaw cell survival rate of 50%–100% were observed for morphological characteristics prior to transfer. Then, recovery of blastocoel expansion was graded as A, fully expanded; B, re-expanded; and C, not expanded. Results: The primary outcome was the clinical pregnancy rate per cycle. In the 134 cycles reviewed, the clinical pregnancy rate (CPR) reached 5.5% of the not expanded; 29.4% of the re-expanded; and 56.92% of the full expanded blastocyst group (p<0.005). Conclusion: Post-thawed fully expanded blastocysts are associated with a higher clinical pregnancy rate. However, embryos with a poor morphology post-thawed still demonstrate a considerable probability of clinical pregnancy.

Unlocking the Power of Multicatalytic Synergistic Transformation: toward Environmentally Adaptable Organohydrogel.

A sustainable and efficient multicatalytic chemical transformation approach is devised for the development of all-biobased environmentally adaptable polymers and gels with multifunctional properties. The catalytic system, utilizing Lignin aluminum nanoparticles (AlNPs)-aluminum ions (Al3+ ), synergistically combines multiple catalytic cycles to create robust, mechanically stable, and versatile organohydrogels. Single catalytic cycles alone fail to achieve desired results, highlighting the importance of cooperatively combining different cycles for successful outcomes. The transformation involves free radical crosslinking, reversible quinone-catechol reactions, and an autocatalytic mechanism, resulting in a dual crosslinking strategy that incorporates both covalent and ionic crosslinking. This approach creates a dynamic gel system with combined energy dissipation and storage mechanisms. The engineered organohydrogels demonstrate vital multifunctionalities such as good thermal stability, self-healing, and adhesive properties, flame-retardancy, mechanical resilience and durability, conductivity, viscoelastic properties, environmental adaptability, and resistance to extreme conditions such as freezing and drying. The developed catalytic technology and resulting gels hold significant potential for applications in flexible electronics, energy storage, actuators, and sensors.

A Phase 2 Study of Minimal Residual Disease (MRD)-Adapted Front Line Venetoclax and Obinutuzumab in Fit Patients with Chronic Lymphocytic Leukemia (CLL): Effect of Obinutuzumab on Tumor Lysis Syndrome (TLS) Risk and Safety of Outpatient Venetoclax Dose Escalation

Introduction: Venetoclax (V) / Obinutuzumab (O) is an effective one-year fixed duration therapy for patients (pts) requiring first-line CLL treatment (tx). In CLL14, tumor lysis syndrome (TLS) risk assessment (including lymph node measurements by imaging and ALC) was required once prior to tx initiation, and O's impact on TLS risk prior to introduction of V was not a pre-planned study endpoint. Therefore, TLS prophylaxis (ppx) and tx setting for V dose escalation did not account for the possibility that O may decrease TLS risk prior to V escalation. Based on this approach, 22% of pts in the CLL14 study were high risk for TLS, thus requiring hospitalization for intensive laboratory monitoring during V dose escalation. (Fischer, NEJM 2019) We hypothesized that cycle (C) 1 of O would significantly decrease TLS risk prior to V escalation and that all pts, regardless of TLS risk category, could safely undergo a standard 5-week V dose escalation in the outpatient setting. Methods: We are conducting a Phase 2 study (NCT04447768) designed to examine the efficacy of a minimal residual disease (MRD)-adapted approach to V/O combination for fit pts in the front-line setting (study schema, Figure 1). A planned secondary study endpoint is to evaluate the effect of O monotherapy in C1 on TLS risk. Here we present interim results of TLS risk modification for the first 80 patients. Per protocol, TLS risk assessment including CT imaging and ALC measurement was performed at two defined timepoints: (1) prior to C1 day (D) 1 and (2) immediately prior to V initiation on C1D22. Key eligibility criteria: adult pts with CLL requiring first line tx per iwCLL guidelines, CIRS score ≤ 6, adequate heme function (Hgb ≥8 g/dL, ANC ≥1 x 10 9/L, Plt ≥30 x 10 9/L), creatinine clearance >50 mL/min. O was administered on C1 D1/2, 8 and 15. Per protocol, pts underwent V dose escalation in the outpatient setting, regardless of TLS risk. For pts with low and medium (med) tumor burden, TLS ppx was per FDA label. For pts who remained high TLS risk at the time of V initiation, TLS ppx throughout dose escalation included allopurinol to start at least 3 days prior to V initiation, sevelamer to start 12 hours prior to V initiation, and oral intake of ≥2 L water daily. On days of dose escalation, ppx additionally included kayexalate, rasburicase, and IV normal saline on D1 and D2 of each dose escalation. TLS labs were monitored according to FDA label guidance. Statistical analysis of TLS risk and adverse events was descriptive. Results: As of 5/2023, 80 pts have enrolled in this study. Seventy-eight pts completed the 5-week V ramp-up. Two pts were removed after receiving at least one dose of O but before repeat assessment of TLS risk and initiation of V (1 death unrelated to tx/disease, 1 patient with recurrent grade 3 (G3) O infusion-related reaction (IRR) leading to consent withdrawal). Median pt age was 57.5 years, 68% male, 95% white. Prior to tx initiation, TLS risk categories were low: 16%, med: 58%, and high: 26% (n=80). Change in TLS risk from baseline to C1D22 is detailed in Figure 2. Of the 20 pts who had sequential assessments with high baseline TLS risk, TLS risk after C1 O (C1D22) was low: 55%, med: 35%, high: 10%. For pts with med TLS risk at baseline with sequential assessments (n=45), TLS risk at C1D22 was low: 82%, med: 18%. One patient developed laboratory TLS on C1D3 following administration of O; no clinical TLS was observed. All pts accomplished V dose escalation in the outpatient setting with no observed laboratory or clinical TLS as defined by Howard Criteria. Grade 3 / 4 tx emergent AEs that occurred in >5% between C1D1 and C3D1 included neutropenia (35% G3, 11% G4), IRR (11% G3, 0% G4), and thrombocytopenia (9% G3, 3% G4). Conclusions: A single cycle of O effectively reduced TLS risk prior to introduction of V escalation with most pts achieving low or med TLS risk by C1D22. Notably, 90% of pts with high pre-tx TLS risk converted to low or med risk following C1 of O allowing for outpatient V escalation per FDA label. Further, we demonstrate that V dose escalation can be safely accomplished in the outpatient setting with close monitoring regardless of TLS risk. With this strategy, we observed no laboratory or clinical TLS during V dose escalation. Eliminating the need for hospitalization during V dose escalation may enhance patient and provider convenience and decrease the economic burden of this regimen. This study is ongoing; efficacy results of this MRD-guided approach to V/O are forthcoming.

Safety and Efficacy of Single Cycle Blinatumomab Plus VP Chemotherapy for High Tumor Burden Acute Lymphoblastic Leukemia in Adults

Background: Blinatumomab, a CD3×CD19 T cell-engaging antibody was developed for immunotherapy in patients with relapsed/refractory B-lineage acute lymphoblastic leukemia (R/R B-ALL) and positive minimal residual disease complete remission. However, high tumor burden is thought able to predict a lower object response rate (ORR) after treatment with blinatumomab monotherapy, so combination treatment regimens are needed to improve the therapeutic effect of blinatumomab. Previous studies have reported the clinical trial results of adding blinatumomab to chemotherapy such as Mini-hyper-CVD and CAM for the treatment of adult or infant R/R B-ALL patients. In this retrospective study, we set out to test the safety and efficacy of single-cycle blinatumomab plus VP scheme in adult R/R B-ALL patients with high tumor burden. Method: Adult patients (≥18 years of age) diagnosed as R/R B-ALL with a high tumor burden (blast count in the bone marrow >50%), previously received 1 to 3 lines of chemotherapy, and received single-cycle blinatumomab plus VP were enrolled. These patients were given blinatumomab (9μg/d in d1-d7, 28μg/d in d8-d28), vincristine 2mg/week and dexamethasone (10mg/d in d1-d14, 5mg/d in d15-d28), for a total of 28 days. For patients with Philadelphia chromosome-positive, a BTK kinase inhibitor (TKI), including imatinib/dasatinib/olverembatinib, etc., was administered simultaneously. Eligible patients were treated with allo-HSCT or CAR-T therapy after they achieved remission with single-cycle blinatumomab plus VP. All patients underwent bone marrow examination before and after treatment to determine tumor burden and therapeutic effect. Flow cytometry was used to monitor patients' MRD status, with abnormal cells ≤0.01% defined as MRD-negative. OS is defined as the time from the initiation of the treatment to death for any cause. RFS is defined as the time from achievement of CR to disease recurrence or death after the treatment. Results: Sixteen patients started this treatment between August 2021 and February 2023. The median age of the 16 patients were 29.5 years (range, 20-72), and their baseline characteristics were shown in the table. Seven of the patients were Philadelphia chromosome-positive. Prior to receiving blinatumomab, all patients had received at least first-line chemotherapy and had refractory or recurrent events. At the end of single-cycle blinatumomab plus VP treatment, 12 patients (75%) achieved objective response (CR+CRi), 1 patient (6.25%) achieved PR, 3 patients (18.75%) did not achieve response, and no patients died during treatment. Of the 12 patients in objective response, 3 patients (18.75%) achieved CR with MRD-negative, 2 patients achieved CRi with MRD-negative, and 7 patients achieved CRi with MRD-positive. Six patients were bridged with allo-HSCT after the treatment, and four patients were subsequently treated with CD19 CAR T cells. With a median follow-up of 11.07 months, the median overall survival was 23.13 months and the median RFS was 17.23 months. The majority of adverse events during treatment were mild and acceptable. Twelve patients (75%) developed fever, of which nine patients (56.25%) were diagnosed with febrile neutropenia, and eight patients (50.00%) had an infection requiring antibiotic treatment, but none required high-flow oxygen (≥6L/min) or vasoactive agents to maintain blood pressure. Almost all patients (93.75%) had myelosuppression during treatment (neutrophil in peripheral blood <1.0×10 9/L), the median time was 17.5 days (range, 0d~28d). Elevated ALT/AST was observed in only one patient. No above grade 3 cytokine release syndrome (CRS) and any grade of immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. Conclusion: Blinatumomab combined with VP resulted in a higher response rate in adult R/R B-ALL patients with high tumor burden and increased tolerability and safety of the treatment.

The infill of tunnel valleys in the central North Sea: Implications for sedimentary processes, geohazards, and ice-sheet dynamics

Tunnel valleys are widespread in formerly glaciated regions such as the North Sea and record sediment transport beneath ice sheets undergoing deglaciation. However, their complex infill architecture often makes their implications for ice-sheet processes difficult to unravel. Here, we use high resolution 3D (HR3D) seismic-reflection data, improved-resolution conventional 3D seismic-reflection data, and geotechnical information from industry-acquired boreholes to image the infill architecture of buried Quaternary tunnel valleys in the North Sea in unprecedented detail. Ten cross-cutting generations of tunnel valleys are mapped beneath the seafloor of the North Sea where only seven were visible previously. Each generation of tunnel valleys potentially reflects a different glaciation, although our evidence may imply that it is possible to rapidly erode and infill multiple generations of tunnel valleys within a single glacial cycle. The infill of the oldest tunnel valley generations reflects sedimentation during relatively gradual ice-sheet retreat, with occasional episodes of overriding by re-advancing grounded ice. Tunnel valleys formed in more recent glaciations are characterised by more variable sedimentation patterns that reflect dynamic fluctuations of the ice margin, including readvances and stagnation, during valley filling and ice retreat. Numerous subglacial landforms are also imaged within the tunnel valleys; these sometimes contain shallow gas accumulations that represent geohazards for seafloor infrastructure installations. In addition, we document examples where salt diapirism has caused fluids to migrate upwards from depth through faults and into the near-surface tunnel valleys. In instances where this occurs, the relatively porous and often highly continuous subglacial landforms present within their infill may allow these fluids to spread laterally for kilometres or even escape from the seafloor; it is therefore important to consider tunnel valleys when monitoring possible CO2 leakage from carbon capture and storage efforts.

Super-stable Kneading Sequences with Double Cycles in 1D Bimodal Maps

It is well known that a super-stable kneading sequence (SSKS) is an important concept, all SSKSs in bimodal maps forms joints in the corresponding symbolic dynamics, it decides the multiplication table of star products, which the n-tupling bifurcations to chaos can be investigated and Feigenbaum’s metric universalities can be measured and reconstructed, this SSKSs have form which are periodic with single cycle. However, in fact, the SSKSs in bimodal maps have another form with double cycles which are little mentioned and researched, they have the same position and significance as the single cycle SSKS. In the paper, we presented the number of admissible SSKSs with period-n and the joints graph on the parameter plane.

Research on nonlinear dynamic characteristics of high-speed gear in two-speed transmission system

The working performance and service life of the two-speed transmission system directly affects the performance and service life of helicopters and other equipment. One of the main tasks of the two-speed transmission system research is to improve its dynamic characteristics. For the two-speed transmission system in high-speed gear, a purely torsional nonlinear dynamic differential equation set considering the number of planetary gears, backlash, and clutch dynamic load is established by using the lumped parameter method, and the equations are dimensionless. Then the dimensionless differential equation set is solved by using the variable step-size fourth-order Runge–Kutta method, and the phase diagram and Poincare diagram of high-speed gear are obtained. By changing the dynamic friction coefficient of the friction clutch and the backlash of the gear pair, the influence of parameter change on the nonlinear dynamic characteristics of the system is analyzed. The results show that, with the increase of excitation frequency, the system has experienced single cycle, quasi-cycle, chaos, and double cycle, then changed from double cycle to chaotic motion, and then changed from chaotic motion to double cycle and single cycle motion in turn, and found the path to chaos. In the low-frequency band, reducing the friction coefficient of the friction clutch can reduce vibration amplitude; In the middle-frequency band, reducing the friction coefficient will make the system tend to unstable vibration. In the high-frequency band, it is a single-cycle movement, which is not affected by friction coefficient.

Novel 3D integrated microfluidic device: Design, construction, and application to the preparation of liposomes for vaccine delivery

As a kind of nanovesicles, liposomes are considered to be the most promising delivery vehicles for drugs and vaccines. The preparation of liposomes using microfluidic chips is one of the most effective and feasible methods. Removal of solvents and non-encapsulated drugs is usually required after liposome formation, which will affect the storage stability and medical safety of liposomes, thus hindering their industrial production and clinical application. Therefore, innovative preparation techniques with multiple integrated functions are of practical significance to address the challenges of traditional and latest developed liposome preparation technologies. A novel three-dimensional integrated microfluidic device (3D-mf device) reported here can be used as a continuous process flow system for liposome preparation and purification. The microchannel array of the microdevice is 4 × 3, and the computational fluid dynamics simulation is used to determine that the ratio of the four filter area channels is 1: 0.75: 0.5: 0.2. Drug-loaded liposomes with an average particle size of 208 nm and polydispersity index (PDI) of 0.211 were prepared by adjusting the total flow rate (TFR) and flow rate ratio (FRR). The removal rates of ethanol and polyinosinic acid: polycytidylic acid [poly (I: C)] after a single cycle were 66.8 % and 56.3 %, respectively. The size distribution and zeta potential of liposomes keep stable within 28 days. Finally, in an immunization study in rats, hemagglutination inhibition titers (HI, ≥512) were found to be significantly higher than those required for protection after two rounds of immunization with 6 μg of hemagglutinin from a split influenza vaccine with poly (I: C) liposomes. This innovative integrated device shows the potential for industrial production of nano-pharmaceutical applications.

Corrigendum: Association between endometrial blood and clinical outcome in frozen single blastocyst transfer cycles

Corrigendum: Association between endometrial blood and clinical outcome in frozen single blastocyst transfer cycles

A Peptide-Based Oscillator.

Living organisms are replete with rhythmic and oscillatory behavior at all levels, to the extent that oscillations have been termed as a defining attribute of life. Recent studies of synthetic oscillators that mimic such functions have shown decayed cycles in batch-mode reactions or sustained oscillatory kinetics under flow conditions. Considering the hypothesized functionality of peptides in early chemical evolution and their central role in current bio-nanotechnology, we now reveal a peptide-based oscillator. Oscillatory behavior was achieved by coupling coiled-coil-based replication processes as positive feedback to controlled initiation and inhibition pathways in a continuously stirred tank reactor (CSTR). Our results stress that assembly into the supramolecular structure and specific interactions with the replication substrates are crucial for oscillations. The replication-inhibition processes were first studied in batch mode, which produced a single damped cycle. Thereafter, combined experimental and theoretical characterization of the replication process in a CSTR under different flow and environmental (pH, redox) conditions demonstrated reasonably sustained oscillations. We propose that studies in this direction might pave the way to the design of robust oscillation networks that mimic the autonomous behavior of proteins in cells (e.g., in the cyanobacterial circadian clock) and hence hint at feasible pathways that accelerated the transition from simple peptides to extant enzymes.

Phase field modeling of fatigue crack growth retardation under single cycle overloads

A zone-based crack retardation model that responds to single cycle overloads is applied to a phase field fatigue framework. Fatigue crack growth is incorporated through the degradation of fracture toughness in the phase field fracture model where a representative loading strategy is followed instead of explicit cyclic loading. The model is demonstrated to capture Paris-Erdogan law type behavior. Crack growth retardation following an overload cycle is simulated through a zone ahead of the crack tip taking inspiration from existing plastic zone-based retardation models. The retardation zone is described through a strain energy density limit, with the overload ratio controlling the extent to which the fatigue damage accumulation rate is slowed inside the retardation zone. The model is implemented utilizing user subroutines in Abaqus with coupled-temperature displacement elements where temperature acts as a stand in for the phase field parameter. The model is found capable of reproducing experimental levels of fatigue life gains and reduction in crack growth rate for compact tension and center-cracked tension panel specimens when various overload levels are applied. Furthermore, the model is demonstrated to be able to capture complex crack paths with great accuracy.

A Novel Strategy to Generate a Recombinant, Live-Virus, Replication Incompetent Congenital Cytomegalovirus Vaccine Candidate

Abstract Background Preventing congenital cytomegalovirus (cCMV) infection, the most common infectious cause of disability in pediatrics, is a high public health priority. Subunit vaccine studies based on single viral proteins (usually envelope glycoproteins) have yielded disappointing results in clinical trials. In contrast, Disabled infectious single cycle (DISC) recombinant viruses are promising vaccine candidates, offering the potential for a robust immune response against multiple viral immunogens while maintaining an attenuated phenotype. These studies sought to examine the safety and immunogenicity of this strategy in an animal model of vaccine-preventable cCMV infection, the guinea pig cytomegalovirus (GPCMV) model. Design/Methods Vaccine design consisted of introducing a ligand-regulatable FKBP protein destabilization domain, ddFKBP, into an essential viral gene. This domain directs degradation of the tagged protein in cells unless the synthetic compound Shield-1 is present, allowing generation of viral particles capable of single-cycle replication. Two such essential genes, the GPCMV homologs of CMV genes UL51 and UL52 (GP51 and GP52), were targeted for vaccine design. In this study, we sought to test: 1) whether the DISC viruses GP51 and GP52 were attenuated for replication in a guinea pig model; and 2) whether the replication-incompetent viruses retained immunogenicity comparable to a wild-type virus. GPCMV-seronegative guinea pigs were challenged with DISC vaccines GP51 or GP52. Control animals were challenged with wild-type GPCMV (SG24). Animals (3 per group) were infected by subcutaneous injection and boosted at day 21. Blood collected at days 0, 7, 14, 21, 28, 35, 42, and 84 was used for PCR (to gauge attenuation) and serology (to examine immunogenicity). Results Real-time PCR showed a mean viral load of 8.5 x 105 genome copies/mL of blood at day 7 and 9.3 x 104 genome copies/mL at day 14 in guinea pigs that received SG24 compared to 2.9 x 104 and 1.9 x 103 genome copies/mL at days 7 and 14 respectively in recipients of GP51. No viral DNA was detected in recipients of GP52 at either day 7 or 14. These data demonstrate significantly lower viremia in the GP51 and GP52 groups compared to SG24 by two-way ANOVA (p<0.01; Fig. 1A). In spite of marked attenuation, no statistically significant difference in immune response was noted, with equivalent ELISA responses detected upon comparison of animals that received GP51, GP52, or SG24 CMV strains at days 14, 35, or 84 (Fig. 1B). Western blot analysis of sera used to probe fractions containing wild-type viral particles likewise demonstrated induction of a robust antibody response by GP51 and GP52. Conclusion(s) These data suggest that GP51 and GP52 are attenuated for replication but induce an immune response comparable to wild-type infection. Thus, they are promising options in the development of a vaccine to prevent cCMV. Examination of the extent of attenuation against vertical transmission of these DISC viruses, as well as their efficacy as vaccine candidates against cCMV, is warranted. These questions have important implications for potential future human clinical trials. Funding: Supported by 5 T35 AI118620-07, Medical Student Summer Research Program in Infection and Immunity