Stability and Bifurcation in a Delayed Holling-Tanner Predator-Prey System with Ratio-Dependent Functional Response

We analyze a delayed Holling-Tanner predator-prey system with ratio-dependent functional response. The local asymptotic stability and the existence of the Hopf bifurcation are investigated. Direction of the Hopf bifurcation and the stability of the bifurcating periodic solutions are studied by deriving the equation describing the flow on the center manifold. Finally, numerical simulations are presented for the support of our analytical findings

Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] P\u3c0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] P\u3c0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] P\u3c0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] P\u3c0.001), and CK was 3.56 ([95% CI, 2.53-5.02] P\u3c0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials

Redefining cardiac biomarkers in predicting mortality and adverse outcomes of inpatients with COVID-19

The prognostic power of circulating cardiac biomarkers, their utility and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multi-centered retrospective study, we enrolled 3,219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effect Cox model, after adjusting for age, gender and comorbidities, the adjusted hazard ratios of 28-day mortality for high-sensitivity cardiac troponin I (hs-cTnI) was 7.12 (95%CI, 4.60-11.03; P<0.001), NT-proB-type natriuretic peptide (NT-proBNP) was 5.11 (95%CI, 3.50-7.47; P<0.001), CK-MB was 4.86 (95%CI, 3.33-7.09; P<0.001), myoglobin was 4.50 (95%CI, 3.18-6.36; P < 0.001), and CK was 3.56 (95%CI, 2.53-5.02; P < 0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 49% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoffs for of these values might be much lower than the current reference standards. These findings can assist better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19 associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials

Oncogenic signalling in BRAF/RAS wild type melanoma

Theoretical thesis.Bibliography: pages 160-199.Chapter 1. Introduction -- Chapter 2. Mitogen-activated protein kinase dependency in BRAF/RAS wild type melanoma: a rationale for combination inhibitors -- Chapter 3. Influence of p53 on melanoma responses to trametinib -- Chapter 4. Multiple signaling pathways are active in BRAF/RAS wild type melanoma -- Chapter 5. Conclusion.Selective inhibition of the mitogen-activated protein kinase (MAPK) pathway has significantly improved the survival of patients with BRAF V600 - mutant advanced melanoma. However, BRAF / RAS wild type (WT) melanomas have no known actionable mutations, and immune checkpoint inhibitors remain the only effective therapy for patients with this melanoma subtype. In this PhD project, we explored the signalling activity and response of BRAF / RAS WT melanomas to combination small molecule inhibitors. In Chapter 2, we investigated MAPK dependency in 23 melanoma cell lines, including 10 BRAF V600 - mutant and 13 BRAF / RAS WT (seven NF1 - mutant and six triple WT) melanomas. Melanoma cell lines were treated with the MEK inhibitor trametinib, and the impact of MEK inhibition on cell survival and proliferation were examined. We showed that BRAF / RAS WT melanomas had variable responses to MEK inhibition; 23% were highly sensitive, indicating dependency on MAPK signalling for survival and proliferation, whereas 38% were resistant, and this was commonly associated with high mutation burden and loss - of - function mutation s in NF1. We demonstrated that NF1 loss conferred MEK inhibitor resistance in BRAF V600 - mutant cells but not in BRAF / RAS WT melanomas. The mutational profiles of BRAF / RAS WT melanomas revealed concurrent mutations in RASopathy genes, and enrichment of TP53 mutations. In Chapter 3, we explored the precise contribution of p53 loss to MEK inhibitor resistance in our panel of melanoma cells. We also examined the efficacy of a p53 activator in combination with MEK inhibition on suppressing melanoma proliferation. Finally, in Chapter 4, the activity of oncogenic signalling pathways in BRAF/RAS WT melanoma cell lines was examined and the activity of combination inhibitors targeting activated cascades w as tested .1 online resource (xvii, 199 pages) illustration

A mathematical model for container port integrated scheduling and optimization problem

International audienceTraditionally, container terminal optimizations are excused separately and sequentially. As the seaside and landside operations interact intensively, the sequential planning approaches often hinder obtaining sufficient resource utilization, especially for transshipment hubs. Facing the challenge of simultaneous optimization of berth allocation, quay crane assignment and yard allocation, this paper makes an attempt to remedy the situation of sub-optimizations made by different agents, by devising a comprehensive mathematical model, with the aim of benefiting port operators. Regarding that some transit containers typically require temporary yard stowage, the effect of yard stowage allocation, a major factor to the port operational cost, is elaborated in the paper. The main contribution of this work is the presentation of a compact mixed integer linear programming model

A polynomial-time heuristic for the quay crane double-cycling problem with internal-reshuffling operations

International audienceOne of great challenges in seaport management is how to handle containers under reshuffling, called reshuffles. Repositioning reshuffles in a bay (internal reshuffling) can improve the efficiency of quay cranes and help ports to reduce ship turn-around time. This paper studies the quay crane double-cycling problem with internal-reshuffling operations, and presents a fast solution algorithm. To reduce the number of operations necessary to turn around a bay of a vessel, the problem is first formulated as a new integer program. A polynomial-time heuristic is then developed. The analysis is made on the worst-case error bound of the proposed algorithm. Results are presented for a suite of combinations of problem instances with different bay sizes and workload scenarios. Comparisons are made between our algorithm and the start-of-the-art heuristic. The computational results demonstrate that our model can be solved more efficiently with CPLEX than the model proposed by Meisel and Wichmann (2010), and the proposed algorithm can well solve real-world problem instances within several seconds

The Spatiotemporal Variation in Biodiversity and Its Response to Different Future Development Scenarios: A Case Study of Guilin as an Internationally Renowned Tourist Destination in China

The preservation of biodiversity is crucial for maintaining ecological balance and promoting the harmonious development of mankind and nature. To formulate a biodiversity conservation plan for Guilin in China and accurately evaluate the impact of conservation measures on regional biodiversity, this study combined the InVEST model (v 3.7.0), the GeoSOS-FLUS model (v 2.3), and the landscape pattern index, analyzing the spatiotemporal changes in biodiversity from 2000 to 2020 in Guilin and simulating biodiversity under different development scenarios in 2040. The results showed the following: (1) The biodiversity index in Guilin displayed a declining trend, with the average annual value decreasing from 0.875 in 2000 to 0.870 in 2020. The area experiencing a reduction in biodiversity was primarily concentrated around the city. (2) The biodiversity level of each district and county had a large spatiotemporal difference, with the overall distribution characteristics of “higher in the northwest, southwest, and east, and lower in the northeast, southeast and central”. (3) The biodiversity hotspots were identified as priority areas for conservation; woodland and wetland were effectively protected, and the expansion of construction land and arable land was limited under the ecological protection scenario compared with the natural development scenario. (4) The annual average value of the biodiversity index of Guilin could reach 0.872 in 2040 after the adoption of ecological conservation measures, which is 0.013 higher than the natural development scenario. The results of this study can provide guidance for the construction of a national sustainable development model city and land use planning in Guilin, as well as a scientific reference for the creation of biodiversity conservation policies

Melanoma Cell State-Specific Responses to TNFα

Immune checkpoint inhibitors that target the programmed cell death protein 1 (PD1) pathway have revolutionized the treatment of patients with advanced metastatic melanoma. PD1 inhibitors reinvigorate exhausted tumor-reactive T cells, thus restoring anti-tumor immunity. Tumor necrosis factor alpha (TNFα) is abundantly expressed as a consequence of T cell activation and can have pleiotropic effects on melanoma response and resistance to PD1 inhibitors. In this study, we examined the influence of TNFα on markers of melanoma dedifferentiation, antigen presentation and immune inhibition in a panel of 40 melanoma cell lines. We report that TNFα signaling is retained in all melanomas but the downstream impact of TNFα was dependent on the differentiation status of melanoma cells. We show that TNFα is a poor inducer of antigen presentation molecules HLA-ABC and HLA-DR but readily induces the PD-L2 immune checkpoint in melanoma cells. Our results suggest that TNFα promotes dynamic changes in melanoma cells that may favor immunotherapy resistance

Effect of Methionine Analogues on Growth Performance, Serum Biochemical Parameters, Serum Free Amino Acids and Rumen Fermentation of Yaks

This experiment was conducted to investigate the effects of methionine analogues 2-hydroxy-4-methylthio butanoic acid isopropyl ester (HBMi) on growth performance, nutrient apparent digestibility, serum metabolite, serum free amino acids, and rumen fermentation parameters of yaks. Twenty-four male Maiwa yaks (252.79 ± 15.95 kg) were randomly allocated to four dietary treatments: basic diet (CON), or three HBMi (MetaSmart (MS); Adisseo Inc., Antony, France) supplementation treatments: MS1 (5 g), MS2 (10 g), and MS3 (15 g). The results showed that the increase in the supplemented MS levels linearly increased the average daily gain (p p p p p < 0.05). In summary, a diet supplemented with 10 g/d MS could be an effective way to improve the growth performance of fattening yaks without negative effects