Left ventricular noncompaction (LVNC) is a primary congenital cardiomyopathy characterized by prominent trabeculation and intra-trabecular recesses in the ventricular wall. Its genetic basis and pathologic mechanism remain largely unknown. Here it is shown that Irx3;Irx4 double knockout (DKO) mouse mutants represent a novel model of LVNC. Irx3 and Irx4 belong to the family of Iroquois homeobox (Irx) genes, encoding transcription factors important for cardiac function. Mice lacking either Irx3 or Irx4 do not have gross cardiac malformations. In contrast, Irx3;Irx4DKO mice exhibit postnatal lethality and thinner ventricular walls as early as E14.5. By P14, DKO mice have prominent noncompacted trabeculation and abnormal muscular growth that resemble human LVNC. Furthermore, Irx3;Irx4DKO hearts exhibit increased expression of heart failure marker genes, elevated Bmp10 pathway activity, and altered pattern of cardiomyocyte proliferation, each of which are implicated in the pathogenesis of LVNC. Taken together, these studies suggest that Irx3 and Irx4 possess overlapping functions, which are essential to myocardial compaction.%%%%M.Sc.%%%%2019-11-07 00:00:00

Purpose: We evaluated the association of hypospadias and 17 susceptibility loci previously identified by a European genome-wide association study in a cohort of Japanese patients. We also examined the expression of candidate genes in male mouse embryos to determine the possible underlying mechanisms of this disease. Materials and Methods: We enrolled 169 Japanese patients (mean age at surgery 3.7 years) who underwent repair of hypospadias. Genotyping of 17 single nucleotide polymorphisms was performed using a multiplex polymerase chain reaction invader assay. We also performed in situ hybridization to determine whether candidate genes were expressed in the male genital tubercle during embryonic development of the external genitalia in mice. Results: Single nucleotide polymorphism rs3816183 of HAAO was significantly associated with susceptibility to hypospadias in general (p = 0.0019) and to anterior/middle hypospadias (p = 0.0283) and posterior hypospadias (p + 0.0226), while single nucleotide polymorphism rs6499755 of IRX6 showed an association with susceptibility to anterior/middle hypospadias (p = 0.0472). In mouse embryos there was no significant upregulation of Haao expression in the developing male external genitalia. Irx3 and Irx5, which are linked to Irx6 within the IrxB cluster, were expressed in the mesenchyme remote from the urethral plate epithelium during the critical embryonic period for masculinization. Irx6 was expressed in the ectodermal epithelium, demonstrating prominent dorsal ectodermal expression without expression in the ventral ectoderm adjacent to the urethral plate during the same period. Conclusions: Genetic variations of HAAO and IRX6 influence susceptibility to hypospadias in the Japanese population. Further research is needed to clarify the mechanism by which variations in these genes contribute to the pathogenesis of hypospadias.

Mutations of the X-linked gene PTCHD1 are associated with autism spectrum disorders and intellectual disability.

A fundamental question in stem cell research is whether cultured multipotent adult stem cells represent endogenous multipotent precursor cells. Here we address this question, focusing on SKPs, a cultured adult stem cell from the dermis that generates both neural and mesodermal progeny. We show that SKPs derive from endogenous adult dermal precursors that exhibit properties similar to embryonic neural-crest stem cells. We demonstrate that these endogenous SKPs can first be isolated from skin during embryogenesis and that they persist into adulthood, with a niche in the papillae of hair and whisker follicles. Furthermore, lineage analysis indicates that both hair and whisker follicle dermal papillae contain neural-crest-derived cells, and that SKPs from the whisker pad are of neural-crest origin. We propose that SKPs represent an endogenous embryonic precursor cell that arises in peripheral tissues such as skin during development and maintains multipotency into adulthood.

nel to be dynamically modulated by inflammatory products that activate PLC. Finally, it is interesting to note that the C-terminal domain of TRPV3, a warm-sensitive channel with an activation threshold of 35°C (21–23), conspicuously lacks a region corresponding to the 777–792 domain of TRPV1, the minimal essential core of the predicted PIP2 binding site. Thus, modification of this PIP2 regulatory domain by genetic, biochemical, or pharmacological mechanisms may have profound effects on sensitivity of primary afferent nerve fibers to chemical and thermal stimuli under normal or pathological conditions.

. Iroquois homeoproteins are prepatterning factors that positively regulate proneural genes and control neurogenesis. We have identified a zebrafish Iroquois gene, irx1 , which is highly homologous to Xenopus Xiro1 , Gallus c-Irx1 and mouse Irx1 . Expression of irx1 was initially detected at the bud stage. By 16 h post-fertilization (hpf), irx1 expression was exclusively limited to the prospective midbrain and hindbrain. By 24 hpf, irx1 expression was clearly detected in the acousticovestibual ganglia, tectum, tegmentum, cerebellum and rhombomere 1 but not in rhombomere 2 or mid-hindbrain boundary.

Summary: The Nkx‐6.1 homeodomain transcription factor was previously shown to be expressed in ventral neural progenitor cells and subsequently subsets of unidentified motor neurons during early neural development. In this study, we identify a specific subpopulation of motor neurons, the median half of the lateral motor neuron column (LMCm), that retain a strong expression of Nkx‐6.1. In addition, we report novel patterns of Nkx‐6.1 expression in several mesenchymal tissues surrounding Sonic hedgehog (Shh)‐expressing cells, including ventral spinal meninges, esophageal mesenchyme, and dorsal tracheal mesenchyme. Whereas Shh signaling is required for Nkx‐6.1 expression in the ventral neural tube and spinal meninges, an Shh‐independent pathway appears to operate in regulating Nkx‐6.1 expression in the foregut. The persistent and robust expression of Nkx‐6.1 in motor neurons and mesenchymal cells suggests an important role for Nkx‐6.1 in controlling cell fate specification and differentiation. genesis 27:6–11, 2000. © 2000 Wiley‐Liss, Inc.

This paper investigates dynamic load balancing issues in the multidomain environment where local area networks (LANs) are interconnected by the Internet. Because of the much slower Internet communication speed and limited bandwidth, existing load balancing algorithms for LANs are unsuitable for the multidomain environment. New issues such as lag time in updating load information and network cost of transferring jobs must be addressed. To tackle these problems, the conventional least load scheduler is extended to the multidomain environment by employing a hierarchical structure, and several quick update techniques are proposed. Also, a heuristic taking both the machine load and the network cost into consideration is developed to evaluate the benefits of sending jobs to computers in different domains. A set of experiments conducted on the BALANCE testbed showed that the proposed techniques provide significant performance improvement over existing algorithms.

The authors propose two strategies for dynamic load balancing: one takes network delay into account to avoid errors in scheduling jobs; the other also delays job execution when the system is fully used. These strategies are general and can augment existing algorithms.

This paper presents a hydrodynamic framework to solving the dynamic load balancing problem in heterogeneous distributed systems. In this approach, each processor is viewed as a liquid cylinder where the cross-sectional area corresponds to the capacity of the processor, the communication links are modeled as liquid channels between the cylinders, the workload is represented by liquid, and the load balancing algorithm manages the flow of the liquid. It is proven that all algorithms under this framework converge geometrically to the state of equilibrium, in which the heights of the liquid columns are the same in all the cylinders. In this way, each processor obtains an amount of workload proportional to its capacity. A hydrodynamic algorithm is presented and its performance is evaluated. The algorithm is applied to solve several practical applications to demonstrate the applicability of the framework.

A homologue of the segment polarity gene wnt-1 from Bombyx mori (Bmwnt-1) has been characterized. The segmentally reiterated pattern of Bmwnt-1 transcrip9t distribution in B. mori embryos suggested its segment polarity function. Maximal levels of Bmwnt-1 RNA during embryonic development were reached by stage 21A. In the larval stages, Bmwnt-1 was expressed in the fore- and hindwing discs, ovaries, testes and gut, reminiscent of the expression domains in Drosophila. Bmwnt-1 was expressed in the wing-margin area of both the fore- and hindwing discs. The pattern of wnt-1 expression in the hindwing discs was similar to that in the butterfly Precis coenia but subtle differences existed in forewing discs of the two species, which correlated well with the absence of proximal bands of pigmentation in the adult Bombyx wings. In addition, Bmwnt-1 was expressed in the silkglands and the expression was confined to the anterior sub-compartment within the middle silkglands throughout development from the embryonic to late larval stages. This domain of Bmwnt-1 expression overlapped with those of Cubitus interruptus (BmCi) and sericin-2 but excluded the Engrailed expression domain viz. the middle and posterior sub-compartments of middle silkglands. Bmwnt-1 expression was detected only during the intermoults and not in the moulting periods.

This paper investigates the issue of building software in the Internet environment, where local area network (LAN) based systems are interconnected by links with different bandwidth and do not share file systems. The software is modeled as a directed acyclic graph. Each node in the graph represents a logical step in processing the software while the edges describe the order of execution. The problem is to construct the software at a particular LAN with minimum Internet communication cost. An optimal polynomial algorithm, SOFTCON, with time complexity \({\cal O}(N C + E + {\cal A}(N, N + E))\) is presented, where \(N\) and \(E\) are the number of nodes and edges in the graph describing the software respectively, \(C\) is the number of LANs in the Internet environment, and \({\cal O}({\cal A}({\cal N}, {\cal E}))\) is the time complexity of the network flow algorithm on the flow network with \({\cal N}\) nodes and \({\cal E}\) edges transformed from the directed acyclic graph of the software.