The manufacturer who is a supplier of trade credit may face non-payment risk from customers and a capital shortage problem simultaneously. Trade credit insurance, as one of the most important risk ...management tools, has been widely used in companies’ daily operation. In this study, the manufacturer who allows customers to delay payment for goods already delivered purchases trade credit insurance to transfer and reduce non-payment risk and borrows money from a bank to accommodate the capital constraint problem. The Stackelberg game and loss-averse theory are used to establish a newsboy model including trade credit insurance, and the optimal insurance coverage and total sales of the manufacturer are thereby investigated. Subsequently, the interest rate decision of the bank under different risk-averse situations is also characterized. We find that the interest rate set by a loss-averse bank is equal to or greater than that given by a risk-neutral bank. The use of trade credit insurance can help the manufacturer expand sales and dramatically reduce its default risk. Both the bank and the manufacturer are better off due to the use of trade credit insurance, but contrary to what one might expect, the bank prefers giving a higher interest rate to the manufacturer when the premium rate is in a reasonable region, which indicates that the manufacturer cannot use the insurance to negotiate better financing terms.
•This study investigates a parking reservation problem in parking-sharing programs.•A novel real-time parking reservation approach is developed.•Our approach assigns multiple demands to a single ...supply to better utilize slots.•An iterative two-stage heuristics is developed for the problem.
This paper studies a real-time parking-sharing program with which owners of private parking spaces can lend out their parking spaces to other drivers to park when these are not in use. Compared with curbside and garage parking problems, the information of supplies and demands is randomly announced by drivers and owners respectively via a parking-sharing APP installed on their smartphones. Besides, the parking spaces made available by independent owners are usually heterogeneous in terms of their locations and available time intervals. Thus, two critical issues need to be resolved: (a) appropriately matching demands and supplies under an uncertain setting; and (b) efficiently scheduling the demands matched to avoid potential parking conflicts. We propose a novel real-time reservation approach based on a rolling-horizon framework, which can assign multiple drivers to a single parking space in order to better utilize scarce parking resources. For each period, an integrated optimal matching-and-scheduling problem is formulated as a mixed integer programming model and proved to be strongly NP-hard. To fast generate a near-optimal solution to the problem, a two-stage heuristics derived from the minimum-cost flow problem is developed. The computational results validate the efficiency and effectiveness of the proposed approach. Some operational insights are also presented and discussed.
TET2 is mutated/deleted with high frequencies in multiple forms of myeloid malignancies including MDS, CMML, MPN, and AML. However, little is known regarding the biological function of TET2 and its ...role in the pathogenesis of myeloid malignancies. To study the function of TET2 in vivo, we generated a Tet2 knock out mouse model. Deletion of Tet2 in mice led to dramatic reduction in the 5-hydroxymethylcytosine levels and concomitant increase in the 5-methylcytosine levels in the genomic DNA of BM cells. The Tet2−/− mice contained an increased Lin−Sca-1+c-Kit+ (LSK) cell pool before the development of myeloid malignancies. A competitive reconstitution assay revealed that Tet2−/− LSK cells had an increased hematopoietic repopulating capacity with an altered cell differentiation skewing toward monocytic/granulocytic lineages. Approximately 1/3 of Tet2−/− and 8% of Tet2+/− mice died within 1 year of age because of the development of myeloid malignancies resembling characteristics of CMML, MPD-like myeloid leukemia, and MDS. Furthermore, transplantation of Tet2−/−, but not wild-type (WT) or Tet2+/− BM cells, led to increased WBC counts, monocytosis, and splenomegaly in WT recipient mice. These data indicate that Tet2-deficient mice recapitulate patients with myeloid malignancies, implying that Tet2 functions as a tumor suppressor to maintain hematopoietic cell homeostasis.
In this article, we discuss the optimal scheduling problem of the recently introduced model for partial loss due to machine breakdowns, which fills up a significant gap in the existing literature. ...More specifically, we consider the problem of processing a number of jobs with arbitrary random processing times by a machine subject to general stochastic breakdowns, where each breakdown may cause an uncertain loss of the work achieved on the job being processed. The objective is to maximize the expected weighted discounted reward of completing the jobs in the class of unrestricted dynamic policies. We obtain the optimal dynamic polices using multi-armed bandit process methodology, which are characterized by a set of Gittins indices as solutions to a system of integral equations. Optimal solutions for a number of problems with specific loss patterns are derived. Application of the theory to the classical no-loss model is also discussed which leads to new results.
Chondrocyte hypertrophy is the terminal step in chondrocyte differentiation and is crucial for endochondral bone formation. How signaling pathways regulate chondrocyte hypertrophic differentiation ...remains incompletely understood. In this study, using a Tbx18:Cre (Tbx18Cre/+) gene-deletion approach, we selectively deleted the gene for the signaling protein SMAD family member 4 (Smad4f/f) in the limbs of mice. We found that the Smad4-deficient mice develop a prominent shortened limb, with decreased expression of chondrocyte differentiation markers, including Col2a1 and Acan, in the humerus at mid-to-late gestation. The most striking defects in these mice were the absence of stylopod elements and failure of chondrocyte hypertrophy in the humerus. Moreover, expression levels of the chondrocyte hypertrophy–related markers Col10a1 and Panx3 were significantly decreased. Of note, we also observed that the expression of runt-related transcription factor 2 (Runx2), a critical mediator of chondrocyte hypertrophy, was also down-regulated in Smad4-deficient limbs. To determine how the skeletal defects arose in the mouse mutants, we performed RNA-Seq with ChIP-Seq analyses and found that Smad4 directly binds to regulatory elements in the Runx2 promoter. Our results suggest a new mechanism whereby Smad4 controls chondrocyte hypertrophy by up-regulating Runx2 expression during skeletal development. The regulatory mechanism involving Smad4-mediated Runx2 activation uncovered here provides critical insights into bone development and pathogenesis of chondrodysplasia.
The regeneration capacity of neonatal mouse heart is controversial. In addition, whether epicardial cells provide a progenitor pool for de novo heart regeneration is incompletely defined. Following ...apical resection of the neonatal mouse heart, we observed limited regeneration potential. Fate-mapping of Tbx18MerCreMer mice revealed that newly formed coronary vessels and a limited number of cardiomyocytes were derived from the T-box transcription factor 18 (Tbx18) lineage. However, further lineage tracing with SM-MHCCreERT2 and Nfactc1Cre mice revealed that the new smooth muscle and endothelial cells are in fact derivatives of pre-existing coronary vessels. Our data show that neonatal mouse heart can regenerate but that its potential is limited. Moreover, although epicardial cells are multipotent during embryogenesis, their contribution to heart repair through “stem” or “progenitor” cell conversion is minimal after birth. These observations suggest that early embryonic heart development and postnatal heart regeneration are distinct biological processes. Multipotency of epicardial cells is significantly decreased after birth.
Display omitted
•Limited regeneration occurs in the neonatal mouse heart upon ventricular apex amputation•Progenitor cell differentiation from epicardium is very minimal during heart repair•New coronary vessels are generated through angiogenesis after injury
The regeneration potential of the newborn mouse heart is controversial, and whether epicardial cells provide progenitors for coronary vascular regeneration is unclear. Cai et al. demonstrate a limited regeneration capacity of the neonatal heart upon injury. Epicardial cells do not convert into functional cardiac cells, including coronary vessels, during repair.
The vertebrate heart develops from mesoderm and requires inductive signals secreted from early endoderm. During embryogenesis, Nkx2.5 acts as a key transcription factor and plays essential roles for ...heart formation from Drosophila to human. In mice, Nkx2.5 is expressed in the early first heart field, second heart field pharyngeal mesoderm, as well as pharyngeal endodermal cells underlying the second heart field. Currently, the specific requirements for Nkx2.5 in the endoderm versus mesoderm with regard to early heart formation are incompletely understood. Here, we performed tissue-specific deletion in mice to dissect the roles of Nkx2.5 in the pharyngeal endoderm and mesoderm. We found that heart development appeared normal after endodermal deletion of Nkx2.5 whereas mesodermal deletion engendered cardiac defects almost identical to those observed on Nkx2.5 null embryos (Nkx2.5−/−). Furthermore, re-expression of Nkx2.5 in the mesoderm rescued Nkx2.5−/− heart defects. Our findings reveal that Nkx2.5 in the mesoderm is essential while endodermal expression is dispensable for early heart formation in mammals.
•Nkx2.5 is a key cardiac transcription factor expressed in the early FHF, SHF and pharyngeal endoderm.•Mouse heart development appears normal after endodermal deletion of Nkx2.5.•Mesodermal disruption of Nkx2.5 engenders almost identical cardiac defects to Nkx2.5 null mice.•Specific re-expression of Nkx2.5 in the mesoderm rescues Nkx2.5 null cardiac defects.•Nkx2.5 expression in the mesoderm is essential but its endodermal expression is dispensable for early SHF development.
How dermal papilla (DP) niche cells regulate hair follicle progenitors to control hair growth remains unclear. Using Tbx18Cre to target embryonic DP precursors, we ablate the transcription factor ...Sox2 early and efficiently, resulting in diminished hair shaft outgrowth. We find that DP niche expression of Sox2 controls the migration speed of differentiating hair shaft progenitors. Transcriptional profiling of Sox2 null DPs reveals increased Bmp6 and decreased BMP inhibitor Sostdc1, a direct Sox2 transcriptional target. Subsequently, we identify upregulated BMP signaling in knockout hair shaft progenitors and demonstrate that Bmp6 inhibits cell migration, an effect that can be attenuated by Sostdc1. A shorter and Sox2-negative hair type lacks Sostdc1 in the DP and shows reduced migration and increased BMP activity of hair shaft progenitors. Collectively, our data identify Sox2 as a key regulator of hair growth that controls progenitor migration by fine-tuning BMP-mediated mesenchymal-epithelial crosstalk.
► Sox2 ablation in the dermal papilla niche diminishes hair outgrowth ► Migration of differentiating hair shaft progenitors is reduced ► Sox2-controlled Bmp pathway regulators regulate progenitor migration ► Sox2 controls mesenchymal-epithelial crosstalk during hair growth
Mesenchymal-epithelial crosstalk is a prominent feature of hair follicle development and regeneration. Clavel et al. find that Sox2 regulates the ability of the dermal papilla niche to control hair shaft progenitor migration and thus hair outgrowth. Sox2 fine-tunes BMP signal output, which in turn attenuates progenitor migration rates.
The sinoatrial node （SAN） is essential for rhythmic beating of the heart; however, our understanding of what con- trols proper functioning of the SAN remains primitive. To explore molecular control ...of SAN function, we specifically deleted Baj250a, a key regulatory component of the ATP-dependent chromatin remodeling complex SWI/SNF, in the SAN. Deletion of Baf250a in the SAN led to sinus bradycardia. Time series analysis of dysregulated genes after deletion of Baf250a reveals a transcriptional hierarchy maintaining pacemaker cell identity, i.e., Baf250a activates the expression of Tbx3, and Baf250a, Thx3 and histone deacetylase 3 coordinately repress the expression of Nkx2.5. Disruption of this repressive pathway switches on expression of Nkx2.5, which stimulates expression of Gata4 and Tbx5. These three cardiac transcription factors further turn on a contractile cardiomyocyte program in the SAN, which eventually leads to sick sinus disease （SSD）. Our study suggests that disruption of key genetic pathways regulating cardiac lineage segregation may cause SSD and cardiac arrhythmias in general.
We consider an outsourcing problem where a group of manufacturers outsource jobs to a single third party who owns a specialized facility needed to process these jobs. The third party announces the ...time slots available on her facility, and the associated prices. Manufacturers reserve, on a first-come-first-book basis, time slots that they desire to utilize. Booking of overtime is possible, at a higher cost. A job completed after its due date incurs a tardiness cost. Each manufacturer books chunks of facility time and sequences his jobs over the time slots booked to minimize his booking, overtime, and tardiness costs. This model captures the main features of outsourcing operations in industries such as semiconductor manufacturing, biotechnology, and drug R&D. In current practice, the third party executes all outsourced jobs without performing optimization and coordination. We investigate the issue of the third party serving as a coordinator to create a win-win solution for all. We propose a model based on a cooperative game as follows: (i) Upon receiving the booking requests from the manufacturers, the third party derives an optimal solution if manufacturers cooperate, and computes the savings achieved. (ii) She devises a savings sharing scheme so that, in monetary terms, every manufacturer is better off to coordinate than to act independently or coalesce with a subgroup of manufacturers. (iii) For her work, the third party withholds a portion ρ of the booking revenue paid by the manufacturers for time slots that are released after coordination. We further design a truth-telling mechanism that can prevent any self-interested manufacturer from purposely reporting false job data to take advantage of the coordination scheme. Finally, we perform a computational experiment to assess the value of coordination to the various parties involved.
PDF
