bluuebunny/crossref_metadata_2025 huggingface dataset:
Final results on the $$0\nu \beta \beta $$ decay half-life limit of $$^{100}$$Mo from the CUPID-Mo experiment
Authors: Augier C. , Barabash A. S. , Bellini F. , Benato G. , Beretta M. , Bergé L. , Billard J. , Borovlev Yu. A. , Cardani L. , Casali N. , Cazes A. , Chapellier M. , Chiesa D. , Dafinei I. , Danevich F. A. , De Jesus M. , de Marcillac P. , Dixon T. , Dumoulin L. , Eitel K. , Ferri F. , Fujikawa B. K. , Gascon J. , Gironi L. , Giuliani A. , Grigorieva V. D. , Gros M. , Helis D. L. , Huang H. Z. , Huang R. , Imbert L. , Johnston J. , Juillard A. , Khalife H. , Kleifges M. , Kobychev V. V. , Kolomensky Yu. G. , Konovalov S. I. , Loaiza P. , Ma L. , Makarov E. P. , Mariam R. , Marini L. , Marnieros S. , Navick X.-F. , Nones C. , Norman E. B. , Olivieri E. , Ouellet J. L. , Pagnanini L. , Pattavina L. , Paul B. , Pavan M. , Peng H. , Pessina G. , Pirro S. , Poda D. V. , Polischuk O. G. , Pozzi S. , Previtali E. , Redon Th. , Rojas A. , Rozov S. , Sanglard V. , Scarpaci J. A. , Schmidt B. , Shen Y. , Shlegel V. N. , Singh V. , Tomei C. , Tretyak V. I. , Umatov V. I. , Vagneron L. , Velázquez M. , Welliver B. , Winslow L. , Xue M. , Yakushev E. , Zarytskyy M. , Zolotarova A. S.
Published: November 2022

The CUPID-Mo experiment to search for 0$$\nu \beta \beta $$

ν
β
β

decay in $$^{100}$$

100

Mo has been recently completed after about 1.5 years of operation at Laboratoire Souterrain de Modane (France). It served as a demonstrator for CUPID, a next generation 0$$\nu \beta \beta $$

ν
β
β

decay experiment. CUPID-Mo was comprised of 20 enriched $$\hbox {Li}_{{2}}$$

Li
2

$$^{100}$$

100

$$\hbox {MoO}_4$$

MoO
4

scintillating calorimeters, each with a mass of $$\sim 0.2$$

∼
0.2

 kg, operated at $$\sim 20$$

∼
20

 mK. We present here the final analysis with the full exposure of CUPID-Mo ($$^{100}$$

100

Mo exposure of 1.47 $$\hbox {kg} \times \hbox {year}$$

kg
×
year

) used to search for lepton number violation via 0$$\nu \beta \beta $$

ν
β
β

decay. We report on various analysis improvements since the previous result on a subset of data, reprocessing all data with these new techniques. We observe zero events in the region of interest and set a new limit on the $$^{100}$$

100

Mo 0$$\nu \beta \beta $$

ν
β
β

decay half-life of $$T_{1/2}^{0\nu }$$

T

1
/
2

0
ν

$$> {1.8}\times 10^{24}$$

>

1.8

×

10
24

 year (stat. + syst.) at 90% CI. Under the light Majorana neutrino exchange mechanism this corresponds to an effective Majorana neutrino mass of $$\left$$

m

β
β

 $$<~{(0.28{-}0.49)} $$

<

(
0.28
-
0.49
)

 eV, dependent upon the nuclear matrix element utilized.
Qubit noise deconvolution
Authors: Mangini Stefano , Maccone Lorenzo , Macchiavello Chiara
Published: November 2022

We present a noise deconvolution technique to remove a wide class of noises when performing arbitrary measurements on qubit systems. In particular, we derive the inverse map of the most common single qubit noisy channels, and exploit it at the data processing step to obtain noise-free estimates of observables evaluated on a qubit system subject to known noise. We illustrate a self-consistency check to ensure that the noise characterization is accurate providing simulation results for the deconvolution of a generic Pauli channel, as well as experimental evidence of the deconvolution of decoherence noise occurring on Rigetti quantum hardware.
Nonlocal quantum correlations in a bipartite quantum system coupled to a bosonic non-Markovian reservoir
Authors: Elghaayda Samira , Dahbi Zakaria , Mohamed A.-B. A. , Mansour Mostafa
Published: November 2022

In this paper, we explore the dynamics of nonlocal correlations in a two-qubit system, that is, first prepared in a Gisin state and then interacts with a bosonic non-Markovian environment. We employ uncertainty-induced nonlocality (UIN) and the Horodecki measure (Bell function) to characterize the degree of nonclassical correlations and quantum nonlocality in the system, taking into account the influence of the non-Markovian reservoir. The dynamics of the UIN and the Bell nonlocality are next examined using the various parameters that define the non-Markovian reservoir and the initial Gisin state. Our results show that the amount of nonlocal correlations and the degree of violation of Bell’s inequality can be modulated by varying the physical parameters characterizing the non-Markovian reservoir and the initial Gisin state. We also show that in some specific cases, the system exhibits nonclassical correlations while the evolved Gisin state does not violate Bell’s inequality. Our results also confirm that UIN is robust than Bell’s nonlocality in the presence of decoherence induced by the interaction with the non-Markovian reservoir.
Heat transfer performance of temperature-dependent Xue and Yamada–Ota hybrid nanofluid flow models past a curved stretching sheet with generalized Fourier law
Authors: Ramzan Muhammad , Shaheen Naila , Ghazwani Hassan Ali S , Nisar Kottakkaran Sooppy , Ahamed Saleel C.
Published: November 2022

In this exploration, temperature-dependent Yamada–Ota and Xue hybrid nanoliquid models are investigated over a curved stretchable surface embedded in an absorbent media. Hybrid nanofluids are formed by the combination of single and multi-walled carbon nanotubes (CNTs) as nanoparticles with engine oil as base fluid. The goal of this study is to interpret how the modified Fourier law combined with temperature-dependent thermal conductivity, Newtonian heating and variable heat source/sink enhances thermal performance. A mathematical formulation of the problem is illustrated in the curvilinear coordinates. Highly nonlinear dimensionless ODEs are solved numerically by engaging the bvp4c approach. The impression of the key parameters is illustrated graphically. Drag force coefficient and Nusselt number are highlighted through tables. It is comprehended that the fluid velocity decays on augmenting the velocity slip parameter while elevates on amplifying the curvature parameter. Furthermore, an enhancement in the temperature field is noted for the conjugate parameter. A significant correlation with the existing outcomes is perceived when a comparison with the existing literature is made.
Influence of magnetic force on physical treatment of nanofluid laminar flow developing numerical approach
Authors: Rothan Yahya Ali
Published: November 2022

This paper analyzes the employment of nanotechnology and FHD effect on the transportation of fluid within a container. Carrier fluid is a combination of H2O and iron oxide and homogeneous model was incorporated to guess the features. The complex equations can be achieved by incorporating the source terms of Kelvin force and gravity term and in order to solve them, the control volume-based FEM approach was applied. To examine the accuracy, previous article of on FHD flow was examined and the achieved data showed nice accuracy. Laminar flow was analyzed and the influences of Kelvin and gravity forces were examined along with the role of the nano-sized particles. As Mn[Formula: see text] augments, impingement of fluid with wall enhances and bigger Nu was obtained. The effect of Ra on the characteristics of ferrofluid is same as Mn[Formula: see text]. Disperse of nanosized material makes Nu to rise to about 12.8% owing to greater conductivity of ferrofluid. Given [Formula: see text]E4, the augment of Kelvin force causes Nu to intensify to about 27.09%.
Non-Fourier pseudoplastic nanofluidic transport under the impact of momentum slip and thermal radiation
Authors: Mehmood R. , Tufail Y. , Rana S. , Khan A. U. , Ijaz S.
Published: November 2022

In this modern era of research, fluid mechanics and particularly nanofluids flowing on the stretching surfaces are considered to be occurring more often due to their faster heat transfer mechanism. Mostly, the theoretical research related to nanofluids including this one contributed in studying the performance and reaction of nanomaterials against different physical constraints so that they have wide applications in several developed engineering industries like, atomic receptacles, transportation, microchip technology as well as biomedicine industry and food industry. Several fluids permeating in industrial and biological processes are pseudo-plastics. Their non-Newtonian behavior is usually related to structural reorganizations of the fluid molecules due to their flow. Keeping this in view, this study is an effort to investigate two-dimensional steady incompressible Cattaneo–Christov heat flux model of Carreau–Yasuda nanofluid in the presence of thermal radiation and velocity slip. The governed model is presented through partial differential equations which are transformed into ordinary differential equations by using similarity transformation. The final system of equations are solved numerically and the results are expressed through graphs and tables for fluid’s velocity temperature, concentration and physical quantities like heat and mass flux. It is observed that skin friction as well as local heat and mass flux decline with velocity slip parameter and heat transfer rises but mass flux at surface declines through increment in radiation parameter.
The sulfur solubility minimum and maximum in silicate melt
Authors: Hughes Ery C. , Saper Lee M. , Liggins Philippa , O'Neill Hugh St. C. , Stolper Edward M.
Published: November 2022

The behaviour of sulfur in magmas is complex because it dissolves as both sulfide (S
2−
) and sulfate (S
6+
) in silicate melt. Interesting aspects of the behaviour of sulfur are the solubility minimum (SS
min
) and maxima (SS
max
) observed with varying oxygen fugacity (

f

O

2

). We use a simple ternary model (silicate–S
2
–O
2
) to explore the varying

f

O

2

paths where these phenomena occur. Both SS
min
and SS
max
occur when S
2−
and S
6+
are present in the silicate melt in similar quantities owing to the differing solubility mechanisms of melt species containing these oxidation states of sulfur. At constant
T
, a minimum in dissolved total S content in vapour-saturated silicate melt (

w

S

T

m

) occurs along paths of increasing

f

O

2

and either constant

f

S

2

or constant
P
. For paths on which

w

S

T

m

is held constant with increasing

f

O

2

, the SS
min
is expressed as a maximum in
P
. The SS
min
occurs when the fraction of S
6+
in the melt ([S
6+
/S
T
]

m

) is 0.25 for constant

f

S

2

and [S
6+
/S
T
]

m

 

≈

 0.75 for constant

w

S

T

m

and
P
. A minimum in

w

S

T

m

is not encountered during closed- or open-system depressurization in the simple system we modelled. However, the SS
min
marks a change from reduction to oxidation during degassing. Various SS
max
occur when the silicate melt is multiply saturated with at least two phases: vapour, sulfide melt, and/or anhydrite. The SS
min
and SS
max
are potentially important features of magmatic process involving S, such as mantle melting, magma mixing, and degassing. These concepts influence calculations of the pressures of vapour-saturation,

f

O

2

, and SO
2
emissions using melt inclusions.

Supplementary material:
Additional information and data used to create the figures are available at
https://doi.org/10.6084/m9.figshare.c.6274527

Thematic collection:
This article is part of the Sulfur in the Earth system collection available at:
https://www.lyellcollection.org/topic/collections/sulfur-in-the-earth-system
Electrochemical Performance of LBO-coated Ni-rich NCM Cathode Material: Experimental and Numerical Approaches
Authors: Jeon Dong Hyup , Kim Sangwon , Kim Jae-Joong , Lee Suhyun , Kim Young Je , Nam Sang-Cheol , Song Jung-Hoon
Published: November 2022

Ni-rich NCM-based cathode materials have garnered significant research interest for the development of high-performance lithium-ion batteries (LIBs) owing to their high energy capacity and low cost. However, they undergo several electrochemical degradation reactions that deteriorate the cathode performance. To alleviate the deterioration of the cathode, researchers have adopted surface coating materials, especially Li3BO3 (LBO), which demonstrates a superior modification effect, for Ni-rich NCM. Here, we investigate the electrochemical characteristics of an LBO-coated Ni-rich NCM cathode via experimental and numerical approaches. The cathode is synthesized through a wet chemical deposition method, and electrochemical measurements are conducted using coin half-cells. To further understand the effect of coating layer on the electrochemical performance, we developed an electrode coating model with modifying the porous electrode model. The model employs an impurity layer (Li2CO3 and LiOH), a protective layer (LiF), and a coating layer (LBO) to predict the discharge performance of LIBs. The validation results of the model are consistent with the experimental results. Electrochemical prediction results demonstrate that the LBO-coated Ni-rich NCM cathode would increase the discharge capacity.
Atomic-Scale Friction Study by EC-AFM: Underpotential Deposition (UPD) of Ag on I-Modified Au(111) and Its Tip Penetration
Authors: Park Inhee , Baltruschat H.
Published: November 2022

The underpotential deposition (UPD) of Ag on an I-modified Au(111) surface is examined in perchloric acid solution by electrochemical lateral force microscopy (LFM). The transitions of ordered structures are observed as potential is swept and normal load changes. At low normal load, the structural changes with potential indicate that the iodine structure is very sensitive to the coverage of silver. At potentials positive of the 1st Ag UPD peak, the iodine forms a (

3

×

3

R30°) structure (θ

I
= 0.33) on Au(111). The structural transition to a 1 × 1 structure observed as the normal load increases demonstrates that the AFM tip penetrates the iodine adlayer. As the potential passes the 1st Ag UPD peak, the iodine forms a p(3 × 3) (θ

I
= 0.44) structure and also silver seems to form a p(3 × 3) (θ

Ag
= 0.44) structure, as suggested by LFM images at high load. At even higher load, also this Ag layer is penetrated and the 1 × 1 structure of the substrate is observed. At potentials slightly negative of the 2nd Ag UPD peak, even though the iodine structure is maintained as a p(3 × 3) (θ

I
= 0.44) structure, the atomic corrugations observed at high normal load indicate that silver completes a monolayer. The large-scale images clearly show that an Ag bilayer is formed at the 3rd Ag UPD peak. When the Ag bilayer completes, the iodine forms a (

3

×

3

R30°) (θ

I
= 0.33).
Insights into Chemical and Electrochemical Interactions between Zn Anode and Electrolytes in Aqueous Zn−ion Batteries
Authors: Rajabi Roya , Sun Shichen , Billings Aidan , Mattick Victoria F. , Khan Jamil , Huang Kevin
Published: November 2022

Aqueous Zn-ion batteries (ZIBs) have garnered significant interest in recent years due to their potential applications in large-scale stationary energy storage. Early ZIBs research has primarily focused on searching for better cathodes and understanding cathodic Zn2+ storage mechanisms. Only very recently has ZIBs research shifted to Zn anode. Here in this study, we report on insights into the interactions between Zn anode and aqueous Zn-salt electrolytes gained by a systematic investigation of bulk properties of electrolytes, surface properties of the reacted Zn, electrokinetics of Zn/Zn2+ redox reaction and cycle stability of Zn/electrolyte/Zn symmetrical cells. We found that Zn metal surface, regardless of electrolyte, are always covered by a layer of Zn-containing layered double hydroxides (Zn-LDHs) upon contact with aqueous Zn-electrolytes. We show that “OH− production” pathway resulted from the dissolved oxygen in Zn-electrolytes is the root cause for the Zn-LDHs formation. The electrokinetic studies reveal that Zn/Zn(ClO4)2 interface has the highest exchange current density, while the symmetrical cell tests show that Zn(OTf)2 is the most stable electrolyte for Zn-metal anode.
Noise Effects in the Design of Digital Circuits Based on CNTFET
Authors: Marani R. , Perri A. G.
Published: November 2022

In this paper initially we present two CNTFET models: the first, already proposed by us and the second the Stanford model, recalling our method to match the output characteristics and transconductance characteristics between these two models. Then we briefly recall a compact noise model, proposed by us, used to simulate the performance of some digital CNTFET circuits, for which we present the DC, transient and noise analysis. In particular we examine a inverter gate and the proposed analysis allows to determine the optimal value of input voltage which makes the noise effects negligible.
The Hypolipidemic Effect of Hawthorn Leaf Flavonoids through Modulating Lipid Metabolism and Gut Microbiota in Hyperlipidemic Rats
Authors: Hu Huiming , Weng Jiajun , Cui Can , Tang Fangrui , Yu Mengdan , Zhou Yujie , Shao Feng , Zhu Yanchen
Published: November 2022

Objective. The purpose of this study was to explore the potential mechanisms of the lipid-regulating effects and the effect on modulating the gut microbiota of hawthorn leaf flavonoids (HLF) in the high-fat diet-induced hyperlipidemic rats. Methods. The hypolipidemic effect of HLF was investigated in the high-fat diet-induced hyperlipidemic rats. The action targets of HLF in the treatment of hyperlipidemia were predicted by network pharmacology and KEGG enrichment bubble diagram, which were verified by the test of western blotting. Meanwhile, we used 16S rRNA sequencing to evaluate the effects of HLF on the microbes. Results. The results of animal experiments showed that HLF could reduce the body weight and regulate the levels of serum lipid in high-fat diet (HFD) rats. Meanwhile, for the related targets of cholesterol metabolism, HLF could significantly upregulate the expression of LDLR, NR1H3, and ABCG5/ABCG8; reduce the expression of PCSK9; and increase the level of CYP7A1 in the intestinal tissue, whereas cholesterol biosynthetic protein expressions including HMGCR and SCAP were lowered by HLF. In addition, HLF increased the activities of plasma SOD, CAT, and GSH-Px and decreased the levels of Casp 1, NLRP3, IL-1β, IL-18, and TNF-α, improving the degree of hepatocyte steatosis and inflammatory infiltration of rats. Notably, HLF significantly regulated the relative abundance of major bacteria such as g_Lactobacillus, g_Anaerostipes, g_[Eubacterium]_hallii_group, g_Fusicatenibacter, g_Akkermansia, and g_Collinsella. Synchronously, we found that HLF could regulate the disorder of plasma HEPC and TFR levels caused by HFD. Conclusion. This study demonstrates that HLF can regulate metabolic hyperlipidemia syndromes and modulate the relative abundance of major bacteria, which illustrated that it might be associated with the modulation of gut microbiota composition and metabolites.
Interaction between the Gut Microbiota and Intestinal Motility
Authors: Liu Qihong , Luo Yunfeng , Ke Xiao
Published: November 2022

The gut microbiota is the largest symbiotic ecosystem with the host and has been proven to play an important role in maintaining the stability of the intestinal environment. The imbalance of the gut microbiota is caused by the imbalance between the symbiotic microbiota and the pathogenic microbiota. The commensal microbiome regulates intestinal motility, while the pathogenic microbiome causes intestinal motility disorder, resulting in disease development. Intestinal motility is a relatively general term, and its meaning may include intestinal muscle contraction, intestinal wall biomechanics, intestinal compliance, and transmission. The role of intestinal microecology and intestinal motility are interrelated, intestinal flora disorder mediates intestinal motility, and abnormal intestinal motility affects colonization of the intestinal flora. In this review, we briefly outlined the interaction between gut microbiota and intestinal motility and provided a reference for future studies.
Visualization Method for Porous Groundwater Seepage Flow Field Based on Particle Flow: Case of Yancheng City in the East Coast of China
Authors: He Liang , Chen Ling , Chen Suozhong
Published: November 2022

Porous groundwater seepage flow field reflects the spatiotemporal dynamic characteristics of porous groundwater movement. The geometric point and vector line methods are the traditionally used visualization methods for groundwater seepage flow field; however, they exhibit difficulty in describing the characteristics and attributes of a seepage flow field. Therefore, a new particle flow method in the field of computer graphics is introduced in this study to visualize seepage flow field, including the storage conditions, transport mechanism, and seepage field properties of porous groundwater. This visualization method is discussed from four aspects: the generation of seed points, the life cycle of particles, the movement velocity of particles, and the formation of particle trajectory and smooth processing. The seepage field of confined aquifer III groundwater expressed via particle flow and the contour of critical groundwater level are superimposed and analyzed in Yancheng City in the east coast of China. Results show that particle flow can be effectively applied to the visualization of groundwater seepage flow field and provide spatial auxiliary decision-making support for the sustainable exploitation of groundwater and the formulation of geological environment protection measures.
Incisal Interference Correction after Severe Extrusive Luxation Trauma during Orthodontic Treatment
Authors: Aarts M. , Suttorp C. M.
Published: November 2022

This case report presents the treatment of a 12-year-old boy who suffered serious dental trauma, accompanied with buccal alveolar socket wall fractures, during orthodontic treatment. The maxillary right lateral incisor and canine were severely extruded and laterally luxated to the palatal side, resulting in an anterior crossbite and creating an incisal interference that prevented the jaws from closing in normal occlusion. During emergency treatment, the dentist attempted manual repositioning, but both severely extruded teeth were found to be immobile. One day after trauma, orthodontic repositioning was started using full fixed appliances with light 0.012″ nickel–titanium round wires, and this occlusal interference was corrected within 3 weeks. In the various internationally recognized treatment guidelines, the options for orthodontic repositioning for dental luxation trauma are only marginally described. Internationally accepted dental treatment guidelines may include immediate orthodontic repositioning after trauma as a treatment option in the management of dental extrusive and lateral luxation trauma.
A Detailed Study of a Fractal‐Fractional Transmission Dynamical Model of Viral Infectious Disease with Vaccination
Authors: Shah Kamal , Sinan Muhammad , Abdeljawad Thabet , El-Shorbagy M.A. , Abdalla Bahaaeldin , Abualrub Marwan S.
Published: November 2022

This article is devoted to investigate a mathematical model consisting on susceptible, exposed, infected, quarantined, vaccinated, and recovered compartments of COVID‐19. The concerned model describes the transmission mechanism of the disease dynamics with therapeutic measures of vaccination of susceptible people along with the cure of the infected population. In the said study, we use the fractal‐fractional order derivative to understand the dynamics of all compartments of the proposed model in more detail. Therefore, the first model is formulated. Then, two equilibrium points disease‐free (DF) and endemic are computed. Furthermore, the basic threshold number is also derived. Some sufficient conditions for global asymptotical stability are also established. By using the next‐generation matrix method, local stability analysis is developed. We also attempt the sensitivity analysis of the parameters of the proposed model. Finally, for the numerical simulations, the Adams–Bashforth method is used. Using some available data, the results are displayed graphically using various fractal‐fractional orders to understand the mechanism of the dynamics. In addition, we compare our numerical simulation with real data in the case of reported infected cases.
General Community Detection in Attributed Networks with Consistent-Module Constrained Nonnegative Matrix Factorization
Authors: Li Yafang , Liu Yuanda , Wei Jianwen , Zu Baokai , Wang Hongyuan
Published: November 2022

Nonnegative matrix factorization (NMF) model has been successfully applied to discover latent community structures due to its good performance and interpretability advantages in extracting hidden patterns. However, most previous studies explore only the structural information of the network while ignoring the rich attributes. Besides, they aim at detecting densely connected communities (also called community structures) and fail to identify general structures, such as bipartite structures and mixture structures. In this paper, we research on general structure discovery and propose a new method GCDNMF (General Community Detection based on Nonnegative Matrix Factorization), which integrates structural information and node attributes through consistency module constraint to capture the community interactions. It can discover the general community structures of nodes by iteratively updating the community-interaction matrix and the node-membership matrix. We also introduce matrix initialization based on centrality and dispersion of nodes for center selection to reduce the sensitivity of random initialization. Experimental results on real-world networks with a variety of characteristics validate the performance of our approach, especially on networks with general structures. In addition, the associated initialization evaluations demonstrate the effectiveness of our method in obtaining stable results.
Mechanical Behavior of High-Strength Bolted Joints Fabricated from Fire-Resistant Steel at Elevated Temperatures
Authors: Wang Yuedong , Li Xiaorun , Liu Peng , Wu Changdong , Liu Chuhan , Zeng Lijing , He Wentao , Yin Tiantian
Published: November 2022

The use of fire-resistant steel is an effective way to alleviate fire safety issues in steel structures. Considering the limited research on bolted joints fabricated from fire-resistant steel, this study presents the results of the experimental investigation on the mechanical behavior of 40 specimens of bolted joints at room temperature and elevated temperatures (20°C∼700°C). These specimens are assembled with fire-resistant steel plates and fire-resistant high-strength bolts (or ordinary high-strength bolts). The mechanical behavior of these specimens was investigated, which included the failure mode, deformation performance, and degradation of bearing capacity. The experimental results show that the treatment of the friction surface (specifically, impeller blasting and sprayed hard quartz sand) has a negligible effect on the ultimate strength of specimens and a relatively significant effect on the slip strength. In addition, reduction factors of the tensile strength (KN) and slip strength (KS) for both fire-resistant bolt specimens and ordinary high-strength bolt specimens decrease with the increase in temperature, especially in the case of elevated temperatures ranging from 400°C to 700°C. Prediction models with different reliability degrees are proposed to calculate the degradation of tensile strength under elevated temperatures, which has the potential to be used for the fire-resistant design of steel connections and structures.
The Effect of Bank Financing under Supply Chain-to-Chain Competition
Authors: Gu Li , Liang Guitian
Published: November 2022

We consider two supply chains, each consisting of one supplier and one retailer. The two retailers are involved in Cournot competition and purchase one single product only from the supplier in the same supply chain. The two suppliers are heterogenous in the production cost. In addition, both retailers are in short of capital, hence both of them need to raise bank loans. All players are risk neutral and their objectives are to maximize their own profit. Based on these features, we establish an analytical model and characterize each player’s optimal decision. Compared to the benchmark model when both retailers have sufficient capital, we find that, in optimal, each supplier provides a lower wholesale price to its own retailer. Moreover, when one of the supplier’s cost is small enough, the corresponding supply chain’s competitive advantage is amplified by the financial cost (i.e., loan interest), generating a larger selling quantity to the market. Therefore, the supply chain achieves a higher profit than the benchmark case, while the other supply chain is worse off. However, if the difference of the two suppliers’ costs is not that significant, all players in the two supply chains would be worse off. Moreover, the numerical experiment further shows that when each supplier’s cost is low enough, both retailers can be better off even if they are capital-constrained. Our results provide useful insights into the supply chain competition when retailers use bank loans to finance their operations.
The tRNA-Cys-GCA Derived tsRNAs Suppress Tumor Progression of Gliomas via Regulating VAV2
Authors: Ren Jian , Wu Xiaoling , Shang Fei-Fei , Qi Yingqiang , Tang Zhurong , Wen Chunjie , Cao Weiguo , Cheng Quan , Tan Lihong , Chen Huan , Zhou Hong-Hao , Zou Hecun
Published: November 2022

The tsRNAs (tRNA-derived small RNAs) are new types of small noncoding RNAs derived from tRNAs. Gliomas are well-known malignant brain tumors. The study focused on tsRNA characterizations within gliomas. Datasets processing, bioinformatics analyses, and visualizations were performed with the packages of Python and R. Cell proliferations were demonstrated via CCK8 assays and colony formation assays, and in vivo xenograft experiments. Dual-luciferase reporter assay was performed to confirm the binding of tsRNA with its targets. Via using bioinformatics approaches, the hundreds of tsRNAs with available expression abundance were identified in gliomas dataset, most of them derived from D-loop or T-loop fragments of tRNAs. Among tsRNAs derived from tRNA-Cys-GCA, tRFdb-3003a and tRFdb-3003b (tRFdb-3003a/b) were remarkably down-regulated in gliomas. The survival outcome of gliomas patients with low tRFdb-3003a/b expressions was notably worse than that of high-expression patients. In glioma cells, tRFdb-3003a could suppress cells proliferation and colony formation ability. In vivo, tRFdb-3003a suppressed the tumor growth of xenograft gliomas. Enrichment analyses displayed the tRFdb-3003a-related mRNAs were enriched in the specific GO terms, spliceosome and autophagy pathways, and three GSEA molecular signatures. Mechanically, 3’-UTR regions of VAV2 mRNA were predicted to contain the binding positions of tRFdb-3003a/b, tRFdb-3003a and tRFdb-3003b was effective to reduce the relative luciferase activity of cells with VAV2 wild-type reporter. Overexpression of tRFdb-3003a/b could down-regulated the expression levels of VAV2 protein and mRNA in glioma cells. The tRNA-Cys-GCA derived tRFdb-3003a and tRFdb-3003b might act as key player in tumor progressions of gliomas; tRFdb-3003a/b might directly bind to VAV2 and regulate VAV2 expressions in gliomas.
Running to Outcompete Metastasis
Authors: Zerhouni Marwa , Piskounova Elena
Published: November 2022

The role of exercise in cancer progression is an emerging field of research, with intriguing evidence for physical activity playing an inhibitory role in cancer onset. In their recent publication, Sheinboim and colleagues demonstrate the impact of physical exercise on melanoma primary tumor growth and metastasis. They establish that physical exercise decreases metastatic spread, using both human epidemiologic data and in vivo models of melanoma metastasis. Systemic metabolic reprogramming of organs, induced by exercise, leads to a decrease in melanoma growth and progression as healthy organs are able to outcompete melanoma cells for nutrients. Exercise led to systemic metabolic changes in carbohydrate metabolism, glycolysis, and oxidative phosphorylation as well as mitochondrial biogenesis. Interestingly, the “metabolic shield” created by exercise could be reversed using the mTOR inhibitor rapamycin. This study highlights the importance of metabolic plasticity in metastasis and uncovers a direct link between systemic metabolic reprogramming and mTOR signaling. Overall, the study by Sheinboim and colleagues provides a more detailed understanding of the metastatic requirements in the context of energy and nutrient availability and the impact of exercise on cancer progression, highlighting novel opportunities for therapeutic intervention.

See related article by Sheinboim et al., p. 4164
Abstract B014: TLR signaling coordinates SAA-dependent liver metastasis in pancreatic cancer
Authors: Lee Jesse , Stone Meredith L. , Choi Hana , Beatty Gregory L.
Published: November 2022

Metastasis remains the primary cause of mortality in cancer. This is especially true in pancreatic ductal adenocarcinoma (PDAC) - where the liver is the most common site of metastasis and the 5-year overall survival rate for these patients has remained <3% for the past 20 years. Accumulating evidence shows a critical role for a niche microenvironment in the liver, termed the pro-metastatic niche, that supports metastatic seeding and outgrowth. Our previous work demonstrated that hepatocytes orchestrate the formation of this pro-metastatic niche during early tumorigenesis through the release of Serum Amyloid A1 and 2 (SAA). However, the mechanisms by which SAA directs formation of a pro-metastatic niche in the liver, and the impact of this niche on the fate of disseminating tumor cells (DTCs) seeding the liver, remain ill-defined. To begin to identify the cellular determinants of niche formation, we first analyzed the expression of SAA receptors within the normal liver and found predominant expression of receptors on the resident F4/80+ macrophages. This is in line with current published work as SAA is well characterized to control liver biology through toll-like receptors (TLRs) expressed by liver resident immune cells and hepatic stellate cells. Consistent with this, we also found that SAA is a specific, potent agonist of TLR2 in vitro. In tumor bearing mice we then found increased expression of TLR2 transcripts as well as an accumulation of TLR2+ inflammatory monocytes within the niche. Together, these findings suggested that SAA might form a pro-metastatic niche in the liver withough a TLR2-dependent mechanism. To test this, we next examined the livers of TLR2-/- tumor bearing mice and found a decrease in the expression of surrogate markers of the pro-metastatic niche. We also sought to determine a role for TLR2 in metastatic outgrowth. Using TLR2-/- mice in a model of PDAC with direct metastasis to the liver, we found significantly decreased metastatic burden and outgrowth in the liver. Analysis of micro-metastatic lesions in TLR2-/- tumor bearing mice also revealed that DTCs demonstrated molecular markers of cellular dormancy. Altogether, our findings suggest the evolution of an inflammatory mechanism within the niche wherein SAA may continue to signal through TLR2+ inflammatory monocytes, which then act to coordinate metastatic outgrowth. Future work aims to further elucidate the role of TLR2+ resident macrophages and monocytes in the formation of a pro-metastatic niche in the liver and in regulating metastatic outgrowth.

Citation Format: Jesse Lee, Meredith L. Stone, Hana Choi, Gregory L. Beatty. TLR signaling coordinates SAA-dependent liver metastasis in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B014.
Abstract B020: Retinoic acid produced by hepatic stellate cells facilitates Netrin-1 mediated pancreatic cancer metastasis
Authors: Dudgeon Crissy , Casabianca Anthony , Harris Chris , Astsaturov Igor , Ogier Charline , Su Xiaoyang , Pitarresi Jason , Narrow Wade , Soliman Fady , Withers Tracy , Mehlen Patrick , Carpizo Darren
Published: November 2022

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its proclivity for metastasis as evidenced by the fact that 85% are stage IV at diagnosis. This highlights the need to better understand the biology of metastatic PDAC and identify novel therapies for this patient population. Axon guidance genes have been shown to be involved in PDAC progression, but their role is unclear. We have investigated the role of the axon guidance molecule Netrin-1 and its receptors Unc5b and DCC in PDAC. We found that in both murine and human samples that NTN1 expression is increased in metastatic PDAC and the quasi-mesenchymal subtype. Murine and TCGA data indicate that Unc5b is the dominant NTN1 receptor and genetic knock-down (KD) or knock-out (KO) of either Netrin-1 or Unc5b decreases migration, invasion, and cell survival in vitro and hepatic metastatic growth in vivo. The mechanism of Netrin-1 upregulation in metastatic PDAC is unknown. We found that hepatic stellate cell (HSC) secreted retinoic acid upregulates NTN1 through both an RXR/RAR and Elf mediated mechanism. To determine if NTN1 is involved in the process of HSC activation we found that recombinant NTN1 added to HSCs in vitro induced activation. We examined the livers of mice harboring orthotopic PDAC tumors using murine pancreatic cancer lines that were either NTN1 wild type (WT) or KO, and found that the NTN-expressing lines increased HSC activation providing evidence that NTN1 is important for long distance intercellular communication between primary pancreatic tumors and the pre-metastatic liver. We detected NTN1 within extracellular vesicles, and mice pre-conditioned with EVs from NTN1 KO cells demonstrated a decreased metastatic burden as compared mice preconditioned with NTN1 WT cells. Treatment of several murine PDAC models (autochthonous and metastatic) with a monoclonal antibody to NTN1 led to decreased metastases and increased survival. These studies reveal that NTN1 is upregulated in metastatic PDAC mediated by a novel mechanism that involves EVs, HSC activation and RXR/RAR signaling. These studies provide pre-clinical evidence to support a human clinical trial of anti-NTN1 therapy in PDAC.

Citation Format: Crissy Dudgeon, Anthony Casabianca, Chris Harris, Igor Astsaturov, Charline Ogier, Xiaoyang Su, Jason Pitarresi, Wade Narrow, Fady Soliman, Tracy Withers, Patrick Mehlen, Darren Carpizo. Retinoic acid produced by hepatic stellate cells facilitates Netrin-1 mediated pancreatic cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B020.
Abstract B065: Polymerase theta inhibition activates the cGAS-STING signaling pathway and elicits an immune response in homologous recombination-deficient pancreatic adenocarcinoma
Authors: Oh Grace , Wang Annie , Wang Lidong , Li Jiufeng , Werba Gregor , Weissinger Daniel , Zhao Ende , Dhara Surajit , Hernandez Rosmel , Ackermann Amanda , Kalfakakou Despoina , Kawaler Emily A. , Golan Talia , Welling Theodore H. , Sfeir Agnel , Simeone Diane M.
Published: November 2022

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that harbors mutations in homologous recombination (HR) repair genes in up to 25% of cases. Defects in HR impart to tumor cells a specific vulnerability to poly-ADP ribose polymerase inhibitors and platinum-based chemotherapy. However, not all patients respond, and some who initially respond develop resistance and progress. Thus, new therapies that are effective against HR-deficient PDAC are needed. Here, we show that inactivation of the HR pathway in PDAC is associated with overexpression of polymerase theta (Polθ, or POLQ), a key enzyme that regulates the alternative non-homologous end-joining (alt-NHEJ) pathway of double-strand break (DSB) DNA repair. Using both human and murine HR-deficient PDAC models, we find that POLQ knockdown is synthetically lethal with mutations in HR genes (BRCA1, BRCA2, and PALB2) as well as the DNA damage repair gene ATM. Further, we present the first findings that POLQ knockdown enhances cytosolic micronucleus formation and activates cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. In an in vivo murine model, POLQ inhibition also leads to STING-dependent recruitment of immune cells and enhanced CD8+ T cell infiltration in the BRCA2-deficient tumor microenvironment (TME). Through its role in the alt-NHEJ pathway, we thus find that POLQ is critical for DSB repair in HR-deficient PDAC, and its inhibition presents a novel synthetic lethal approach to suppress tumor growth while simultaneously stimulating an immune response in the PDAC TME.

Citation Format: Grace Oh, Annie Wang, Lidong Wang, Jiufeng Li, Gregor Werba, Daniel Weissinger, Ende Zhao, Surajit Dhara, Rosmel Hernandez, Amanda Ackermann, Despoina Kalfakakou, Emily A. Kawaler, Talia Golan, Theodore H. Welling, Agnel Sfeir, Diane M. Simeone. Polymerase theta inhibition activates the cGAS-STING signaling pathway and elicits an immune response in homologous recombination-deficient pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B065.
Abstract B069: Inhibiting pancreatic cancer growth by dual targeting of ERK and PI3K signaling
Authors: Nair Gauthami G. , Reindl Katie , Quadir Mohiuddin
Published: November 2022

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a dismal 5-year survival rate of only 11%. Due to its late-stage detection and metastasis, surgery is not an option in most cases, and chemotherapy has become the sought-after strategy to combat PDAC. Current treatment strategies involve combining chemotherapeutic agents; however, these drugs show limited response in some patients and frequently result in acquired drug resistance. There is a need for new treatment approaches to more specifically target molecules involved in PDAC growth. The KRAS gene is mutated in almost 95% of the pancreatic cancers resulting in hyperactivated K-ras protein, which activates downstream growth-promoting signaling pathways such as extracellular receptor kinase (ERK) and phosphatidylinositol 3 kinase (PI3K). Thus, we hypothesized that the combination of ERK and PI3K inhibitors would lead to enhanced PDAC growth inhibition compared to either drug alone. To test our hypothesis, we used SCH772984 (an ERK1/2 inhibitor) and pictilisib (a class I PI3K inhibitor) to perform a cell viability assay using human PDAC cell lines, MIA PaCa-2 and PANC-1, for both 2-D cells and 3-D spheroids. Our results indicated that the cancer cells treated with both drugs showed reduced cell proliferation compared to either of the drugs administered individually. Our next steps will involve evaluation of this combination in animal models as well as testing these drugs against clinical PDAC samples. This research may lead to a novel combination of pictilisib and SCH772984 to enhance treatment for PDAC patients.

Citation Format: Gauthami G. Nair, Katie Reindl, Mohiuddin Quadir. Inhibiting pancreatic cancer growth by dual targeting of ERK and PI3K signaling [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B069.
Abstract C018: Co-activation of myeloid signaling pathways for pancreatic cancer immunotherapy
Authors: Wattenberg Max M. , Coho Heather , Herrera Veronica M. , Graham Kathleen , Stone Meredith L. , Xue Yuqing , Chang Renee B. , Cassella Christopher , Liu Mingen , Choi-Bose Shaanti , Thomas Stacy K. , Choi Hana , Li Yan , Melendez Lauren , Giannone Michael , Bose Nandita , Beatty Gregory L.
Published: November 2022

Pancreatic ductal adenocarcinoma (PDA) is characterized by a robust myeloid cell infiltrate. Although myeloid cells in PDA most commonly associate with immunosuppression, they also show plasticity and possess the capacity to engage productive anti-tumor immunity, thereby providing a potential therapeutic vulnerability. Here, we show that distinct myeloid cell subsets infiltrating human PDA express non-redundant activating receptors. Among the most highly expressed receptors was the pattern recognition receptor CLEC7A, which was expressed by macrophages, monocytes, and immature myeloid cells. In contrast, the TNF superfamily member CD40, was expressed by dendritic cells (DC) and SPP1+ macrophages. We hypothesized that combinatory targeting of myeloid activating receptors might be needed to restore productive immunosurveillance in PDA. In immune checkpoint blockade-resistant mouse models of PDA, pharmacologic activation of CLEC7A, using beta glucan (BG) therapy was associated with upregulation of the CXCL2/3-CXCR2 axis and triggered increases in intra-tumoral macrophages and granulocytes. Conversely, CD40 agonist therapy induced activity of the CXCL9-CXCR3 axis and drove conventional DC type 1-dependent infiltration of CD4+ and CD8+ T cells into tumors. Neither myeloid agonist alone, though, was sufficient to trigger durable anti-tumor immunity. By contrast, induction of both myeloid and lymphoid immunosurveillance by co-activation of CLEC7A/CD40 pathways caused tumor eradication, durable tumor control and T cell dependent immunological memory. Depletion of CSF1R+ myeloid cells or T cells significantly reduced the anti-tumor activity of treatment thereby highlighting the cooperativity of innate and adaptive immunity for anti-tumor activity. Moreover, the efficacy of CLEC7A and CD40 co-activation was independent of immune checkpoint blockade. Thus, beyond inhibitory checkpoint molecules on T cells, combinatory activation of non-redundant myeloid signaling pathways can be leveraged to trigger durable anti-tumor immunity, suggesting a new immunotherapy paradigm. A clinical trial of CLEC7A and CD40 agonist therapy for the treatment of patients with PDA is under development.

Citation Format: Max M. Wattenberg, Heather Coho, Veronica M. Herrera, Kathleen Graham, Meredith L. Stone, Yuqing Xue, Renee B. Chang, Christopher Cassella, Mingen Liu, Shaanti Choi-Bose, Stacy K. Thomas, Hana Choi, Yan Li, Lauren Melendez, Michael Giannone, Nandita Bose, Gregory L. Beatty. Co-activation of myeloid signaling pathways for pancreatic cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C018.