Long-term hematopoietic transfer of the anti-cancer and lifespan-extending capabilities of a genetically engineered blood system by transplantation of bone marrow mononuclear cells.

A causal relationship exists among the aging process, organ decay and disfunction, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed Klf1K74R/K74R or Klf1(K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/EKLF has been generated that possesses extended lifespan and healthy characteristics, including cancer resistance. We show that the healthy longevity characteristics of the Klf1(K74R) mice, as exemplified by their higher anti-cancer capability, are likely gender-, age-, and genetic background-independent. Significantly, the anti-cancer capability, in particular that against melanoma as well as hepatocellular carcinoma, and lifespan-extending property of Klf1(K74R) mice, could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells at a young age of the latter. Furthermore, NK(K74R) cells carry higher in vitro cancer cell-killing ability than wild-type NK cells. Targeted/global gene expression profiling analysis has identified changes in the expression of specific proteins, including the immune checkpoint factors PDCD and CD274, and cellular pathways in the leukocytes of the Klf1(K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a transferable hematopoietic/blood system for long-term anti-cancer and, potentially, for anti-aging.

A Positive Regulatory Feedback Loop between EKLF/KLF1 and TAL1/SCL Sustaining the Erythropoiesis.

The erythroid Krüppel-like factor EKLF/KLF1 is a hematopoietic transcription factor binding to the CACCC DNA motif and participating in the regulation of erythroid differentiation. With combined use of microarray-based gene expression profiling and the promoter-based ChIP-chip assay of E14.5 fetal liver cells from wild type (WT) and EKLF-knockout (Eklf-/-) mouse embryos, we identified the pathways and direct target genes activated or repressed by EKLF. This genome-wide study together with the molecular/cellular analysis of the mouse erythroleukemic cells (MEL) indicate that among the downstream direct target genes of EKLF is Tal1/Scl. Tal1/Scl encodes another DNA-binding hematopoietic transcription factor TAL1/SCL, known to be an Eklf activator and essential for definitive erythroid differentiation. Further identification of the authentic Tal gene promoter in combination with the in vivo genomic footprinting approach and DNA reporter assay demonstrate that EKLF activates the Tal gene through binding to a specific CACCC motif located in its promoter. These data establish the existence of a previously unknow positive regulatory feedback loop between two DNA-binding hematopoietic transcription factors, which sustains mammalian erythropoiesis.

Negative Regulation of the Differentiation of Flk2- CD34- LSK Hematopoietic Stem Cells by EKLF/KLF1.

Erythroid Krüppel-like factor (EKLF/KLF1) was identified initially as a critical erythroid-specific transcription factor and was later found to be also expressed in other types of hematopoietic cells, including megakaryocytes and several progenitors. In this study, we have examined the regulatory effects of EKLF on hematopoiesis by comparative analysis of E14.5 fetal livers from wild-type and Eklf gene knockout (KO) mouse embryos. Depletion of EKLF expression greatly changes the populations of different types of hematopoietic cells, including, unexpectedly, the long-term hematopoietic stem cells Flk2- CD34- Lin- Sca1+ c-Kit+ (LSK)-HSC. In an interesting correlation, Eklf is expressed at a relatively high level in multipotent progenitor (MPP). Furthermore, EKLF appears to repress the expression of the colony-stimulating factor 2 receptor ß subunit (CSF2RB). As a result, Flk2- CD34- LSK-HSC gains increased differentiation capability upon depletion of EKLF, as demonstrated by the methylcellulose colony formation assay and by serial transplantation experiments in vivo. Together, these data demonstrate the regulation of hematopoiesis in vertebrates by EKLF through its negative regulatory effects on the differentiation of the hematopoietic stem and progenitor cells, including Flk2- CD34- LSK-HSCs.

An iterative expanding and shrinking process for processor allocation in mixed-parallel workflow scheduling.

Parallel computation has been widely applied in a variety of large-scale scientific and engineering applications. Many studies indicate that exploiting both task and data parallelisms, i.e. mixed-parallel workflows, to solve large computational problems can get better efficacy compared with either pure task parallelism or pure data parallelism. Scheduling traditional workflows of pure task parallelism on parallel systems has long been known to be an NP-complete problem. Mixed-parallel workflow scheduling has to deal with an additional challenging issue of processor allocation. In this paper, we explore the processor allocation issue in scheduling mixed-parallel workflows of moldable tasks, called M-task, and propose an Iterative Allocation Expanding and Shrinking (IAES) approach. Compared to previous approaches, our IAES has two distinguishing features. The first is allocating more processors to the tasks on allocated critical paths for effectively reducing the makespan of workflow execution. The second is allowing the processor allocation of an M-task to shrink during the iterative procedure, resulting in a more flexible and effective process for finding better allocation. The proposed IAES approach has been evaluated with a series of simulation experiments and compared to several well-known previous methods, including CPR, CPA, MCPA, and MCPA2. The experimental results indicate that our IAES approach outperforms those previous methods significantly in most situations, especially when nodes of the same layer in a workflow might have unequal workloads.

SLA-constrained service selection for minimizing costs of providing composite cloud services under stochastic runtime performance.

Composite cloud services based on the methodologies of Software as a Service and Service-Oriented Architecture are transforming how people develop and use software. Cloud service providers are confronting the service selection problem when composing composite cloud services. This paper deals with an important type of service selection problem, minimizing the total cost of providing a composite cloud service with respect to the constraints of service level agreement (SLA). Two types of SLA are considered in the study: per-request-based SLA and ratio-based SLA. We present three service selection approaches for dynamic cloud environments where services' performance might vary with time. The first two are iterative compound approaches for per-request-based SLA and the third approach is a one-step method for ratio-based SLA based on the Chebyshev's theorem and nonlinear programming. Experimental results show that our approaches outperform the previous method significantly in terms of total cost reduction.

Wave intensity analysis of para-aortic counterpulsation.

Wave intensity analysis (WIA) was used to delineate and maximize the efficacy of a newly developed para-aortic blood pump (PABP). The intra-aortic balloon pump (IABP) was employed as the comparison benchmark. Acute porcine experiments using eight pigs, randomly divided into IABP (n = 4) and PABP (n = 4) groups, were conducted to compare the characteristics of intra- and para-aortic counterpulsation. We measured pressure and velocity with probes installed in the left anterior descending coronary artery and aorta, during and without PABP assistance. Wave intensity for aortic and left coronary waves were derived from pressure and flow measurements with synchronization correction applied. To achieve maximized support efficacy, deflation timings ranging from 25 ms ahead of to 35 ms after the R-wave were tested. Similar to those associated with IABP counterpulsation, the PABP-generated backward-traveling waves predominantly drove aortic and coronary blood flows. However, in contrast with IABP counterpulsation, the nonocclusive nature of the PABP allowed systolic unloading to be delayed into early systole, which resulted in near elimination of coronary blood steal without diminution of systolic left ventricular ejection wave intensities. WIA can elucidate subtleties among different counterpulsatile support means with high sensitivity. Total accelerating wave intensity (TAWI), which was defined as the sum of the time integration of accelerated parts of the positive and negative wave intensities, was used to quantify counterpulsation efficacy. In general, the larger the TAWI gain, the better the counter-pulsatile support efficacy. However, when PABP deflation timings were delayed to after the R-wave, the TAWI was found to be inversely correlated with coronary perfusion. In this delayed deflation timing setting, greater wave cancellation occurred, which led to decreased TAWI but increased coronary perfusion attributed to blood regurgitation reduction.

Wave energy patterns of counterpulsation: a novel approach with wave intensity analysis.

BACKGROUND: In counterpulsation, diastolic augmentation increases coronary blood flow and systolic unloading reduces left ventricular afterload. We present a new approach with wave intensity analysis to revisit and explain counterpulsation principles. METHODS: In an acute porcine model, a standard intra-aortic balloon pump was placed in descending aorta in 4 pigs. We measured pressure and velocity with probes in left anterior descending artery and aorta during and without intra-aortic balloon pump assistance. Wave intensities of aortic and left coronary waves were derived from pressure and flow measurements with synchronization correction. RESULTS: We identified predominating waves in counterpulsation. In the aorta, during diastolic augmentation, intra-aortic balloon inflation generated a backward compression wave, with a "pushing" effect toward the aortic root that translated to a forward compression wave into coronary circulation. During systolic unloading, intra-aortic balloon pump deflation generated a backward expansion wave that "sucked" blood from left coronary bed into the aorta. While this backward expansion wave translated to reduced left ventricular afterload, the "sucking" effect resulted in left coronary blood steal, as demonstrated by a forward expansion wave in left anterior descending coronary flow. The waves were sensitive to inflation and deflation timing, with just 25 ms delay from standard deflation timing leading to weaker forward expansion wave and less coronary regurgitation. CONCLUSIONS: Intra-aortic balloon pumps generate backward-traveling waves that predominantly drive aortic and coronary blood flow during counterpulsation. Wave intensity analysis of arterial circulations may provide a mechanism to explain diastolic augmentation and systolic unloading of intra-aortic balloon pump counterpulsation.

Hemodynamic and metabolic effects of para- versus intraaortic counterpulsatile circulation supports.

Despite the success of intraaortic balloon counterpulsation, data on physiologic indices and optimal inflation/deflation timing control of chronic counterpulsation devices are unclear. This study explored the acute hemodynamic and metabolic efficacy of a novel 40-ml stroke volume paraaortic blood pump (PABP) versus a standard intraaortic balloon pump (IABP). Acute porcine model was used with eight pigs randomly divided into PABP (n = 4) and IABP (n = 4) groups. Hemodynamic and metabolic measurements were obtained with and without mechanical assistance. In one pig, the inflation/deflation control was adjusted to different settings, with corresponding performance indices measured. The PABP significantly improved classical counterpulsation indices (p ≤ 0.05) and achieved an average beneficial effect on these indices 1.5-3.5 times greater than that of the IABP. Classical metabolic indices (tension time index and endocardial viability ratio [EVR]), and indices new to chronic counterpulsation research (coronary perfusion, left ventricular stroke work (SW), and a newly derived EVR) were also used in assessment. Both IABP assistance and PABP assistance improved these physiologic indices, with a trend toward PABP superiority in reducing left ventricular SW (p = 0.08). An optimal PABP deflation timing occurs during systole (25 milliseconds after the R-wave) and can minimize coronary regurgitation.