Urban Fringe Land Use Transitions in Hong Kong: From New Towns to New Development Areas.

Land in urban fringe area is the primary source for land supply and development. In Hong Kong (HK), nine new towns have been built in New Territories since 1970s, providing 172.6 km2 built-up land and large amount of residences for 3.4 million people. However, due to land scarcity, development restriction, and social opposition, New Development Area (NDA), as the small-scale extension of New Town (NT), was designated as one of the main approaches for HK medium and long term land supply. To demonstrate the characteristics of urban fringe land use transitions in Hong Kong, literature review and case study were used in this research. The history of new town development and the scheme of new development areas were introduced firstly. Afterwards, the land use features of NT and NDA were compared and the case of Hung Shui Kiu NDA was illustrated. It is concluded that while housing, infrastructure and facility were the main elements in NTs, employment, vibrancy and environment were suggested to be the new compulsory elements in NDAs integrated to the traditional planning concepts. As for the development approach, lease modification was adopted in NDA to allow private landowners directly develop their land, in addition to the traditional development approach of land resumption in NT. It is suggested to ensure the development of NDA, the proposed development plan should be persuasive to provide the optimal land use distribution as a trade-off among the profits of developers, the interests of local villager, government concern and the provision of land for future residents. Also, community engagement will play a more important role in NDA planning process. Referring to the analysis of urban fringe land use transitions and strategies for planning and development, the study would also be helpful to others growing cities.

Polycomb repressive complex 2 component Suz12 is required for hematopoietic stem cell function and lymphopoiesis.

Polycomb repressive complex 2 (PRC2) is a chromatin modifier that regulates stem cells in embryonic and adult tissues. Loss-of-function studies of PRC2 components have been complicated by early embryonic dependence on PRC2 activity and the partial functional redundancy of enhancer of zeste homolog 1 (Ezh1) and enhancer of zeste homolog 2 (Ezh2), which encode the enzymatic component of PRC2. Here, we investigated the role of PRC2 in hematopoiesis by conditional deletion of suppressor of zeste 12 protein homolog (Suz12), a core component of PRC2. Complete loss of Suz12 resulted in failure of hematopoiesis, both in the embryo and the adult, with a loss of maintenance of hematopoietic stem cells (HSCs). In contrast, partial loss of PRC2 enhanced HSC self-renewal. Although Suz12 was required for lymphoid development, deletion in individual blood cell lineages revealed that it was dispensable for the development of granulocytic, monocytic, and megakaryocytic cells. Collectively, these data reveal the multifaceted role of PRC2 in hematopoiesis, with divergent dose-dependent effects in HSC and distinct roles in maturing blood cells. Because PRC2 is a potential target for cancer therapy, the significant consequences of modest changes in PRC2 activity, as well as the cell and developmental stage-specific effects, will need to be carefully considered in any therapeutic context.

SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition.

Mutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2's normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2, which triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in the splicing of key regulators, and impaired hematopoiesis.

MOZ regulates B-cell progenitors and, consequently, Moz haploinsufficiency dramatically retards MYC-induced lymphoma development.

The histone acetyltransferase MOZ (MYST3, KAT6A) is the target of recurrent chromosomal translocations fusing the MOZ gene to CBP, p300, NCOA3, or TIF2 in particularly aggressive cases of acute myeloid leukemia. In this study, we report the role of wild-type MOZ in regulating B-cell progenitor proliferation and hematopoietic malignancy. In the Eµ-Myc model of aggressive pre-B/B-cell lymphoma, the loss of just one allele of Moz increased the median survival of mice by 3.9-fold. MOZ was required to maintain the proliferative capacity of B-cell progenitors, even in the presence of c-MYC overexpression, by directly maintaining the transcriptional activity of genes required for normal B-cell development. Hence, B-cell progenitor numbers were significantly reduced in Moz haploinsufficient animals. Interestingly, we find a significant overlap in genes regulated by MOZ, mixed lineage leukemia 1, and mixed lineage leukemia 1 cofactor menin. This includes Meis1, a TALE class homeobox transcription factor required for B-cell development, characteristically upregulated as a result of MLL1 translocations in leukemia. We demonstrate that MOZ localizes to the Meis1 locus in pre-B-cells and maintains Meis1 expression. Our results suggest that even partial inhibition of MOZ may reduce the proliferative capacity of MEIS1, and HOX-driven lymphoma and leukemia cells.

Polycomb repressive complex 2 (PRC2) suppresses Eµ-myc lymphoma.

Deregulation of polycomb group complexes polycomb repressive complex 1 (PRC1) and 2 (PRC2) is associated with human cancers. Although inactivating mutations in PRC2-encoding genes EZH2, EED, and SUZ12 are present in T-cell acute lymphoblastic leukemia and in myeloid malignancies, gain-of-function mutations in EZH2 are frequently observed in B-cell lymphoma, implying disease-dependent effects of individual mutations. We show that, in contrast to PRC1, PRC2 is a tumor suppressor in Eµ-myc lymphomagenesis, because disease onset was accelerated by heterozygosity for Suz12 or by short hairpin RNA-mediated knockdown of Suz12 or Ezh2. Accelerated lymphomagenesis was associated with increased accumulation of B-lymphoid cells in the absence of effects on apoptosis or cell cycling. However, Suz12-deficient B-lymphoid progenitors exhibit enhanced serial clonogenicity. Thus, PRC2 normally restricts the self-renewal of B-lymphoid progenitors, the disruption of which contributes to lymphomagenesis. This finding provides new insight regarding the functional contribution of mutations in PRC2 in a range of leukemias.

Involvement of TRP-like channels in the acute ischemic response of hippocampal CA1 neurons in brain slices.

During a period of acute ischemia in vivo or oxygen-glucose deprivation (OGD) in vitro, CA1 neurons depolarize, swell and become overloaded with calcium. Our aim was to test the hypothesis that the initial responses to OGD are at least partly due to transient receptor potential (TRP) channel activation. As some TRP channels are temperature-sensitive, we also compared the effects of pharmacological blockade of the channels with the effects of reducing temperature. Acute hippocampal slices (350 mum) obtained from Wistar rats were submerged in ACSF at 36 degrees C. CA1 neurons were monitored electrophysiologically using extracellular, intracellular or whole-cell patch-clamp recordings. Cell swelling was assessed by recording changes in relative tissue resistance, and changes in intracellular calcium were measured after loading neurons with fura-2 dextran. Blockers of TRP channels (ruthenium red, La3+, Gd3+, 2-APB) or lowering temperature by 3 degrees C reduced responses to OGD. This included: (a) an increased delay to negative shifts of extracellular DC potential; (b) reduction in rate of the initial slow membrane depolarization, slower development of OGD-induced increase in cell input resistance and slower development of whole-cell inward current; (c) reduced tissue swelling; and (d) a smaller rise in intracellular calcium. Mild hypothermia (33 degrees C) and La3+ or Gd3+ (100 microM) showed an occlusion effect when delay to extracellular DC shifts was measured. Expression of TRPM2/TRPM7 (oxidative stress-sensitive) and TRPV3/TRPV4 (temperature-sensitive) channels was demonstrated in the CA1 subfield with RT-PCR. These results indicate that TRP or TRP-like channels are activated by cellular stress and contribute to ischemia-induced membrane depolarization, intracellular calcium accumulation and cell swelling. We also hypothesize that closing of some TRP channels (TRPV3 and/or TRPV4) by lowering temperature may be partly responsible for the neuroprotective effect of hypothermia.

Prostaglandin EP receptors: targets for treatment and prevention of colorectal cancer?

The importance of the prostaglandin (PG) synthesis pathway, particularly the rate-limiting enzymatic step catalyzed by cyclooxygenase, to colorectal carcinogenesis and development of novel anticolorectal cancer therapy is well established. The predominant PG species in benign and malignant colorectal tumors is PGE2. PGE2 acts via four EP receptors termed EP1 to EP4. Recently, EP receptors have been identified as potential targets for treatment and/or prevention of colorectal cancer. This review summarizes existing knowledge of the expression and function of the EP receptor subtypes in human and rodent intestine during tumorigenic progression and describes the current literature on targeting EP receptor signaling during intestinal tumorigenesis.

Paracrine cyclooxygenase-2-mediated signalling by macrophages promotes tumorigenic progression of intestinal epithelial cells.

In human colorectal adenomas or polyps, cyclooxygenase-2 is expressed predominantly by stromal (or interstitial) macrophages. Therefore, we tested the hypothesis that macrophage cyclooxygenase-2 has paracrine pro-tumorigenic activity using in vitro models of macrophage-epithelial cell interactions. We report that macrophages can promote tumorigenic progression of intestinal epithelial cells (evidenced by decreased cell-cell contact inhibition, increased proliferation and apoptosis, gain of anchorage-independent growth capability, decreased membranous E-cadherin expression, up-regulation of cyclooxygenase-2 expression, down-regulation of transforming growth factor-beta type II receptor expression and resistance to the anti-proliferative activity of transforming growth factor-beta(1)) in a paracrine, cyclooxygenase-2-dependent manner. Pharmacologically relevant concentrations (1-2 microM) of a selective cyclooxygenase-2 inhibitor had no detectable, direct effect on intestinal epithelial cells but inhibited the macrophage-epithelial cell signal mediating tumorigenic progression. Cyclooxygenase-2-mediated stromal-epithelial cell signalling during the early stages of intestinal tumorigenesis provides a novel target for chemoprevention of colorectal cancer (and other gastro-intestinal epithelial malignancies, which arise on a background of chronic inflammation, such as gastric cancer) and may explain the discrepancy between the concentrations of cyclooxygenase inhibitors required to produce anti-neoplastic effects in vitro and in vivo.

Adverse neurodevelopmental outcome after extracorporeal membrane oxygenation among neonates with bronchopulmonary dysplasia.

OBJECTIVE: The relationship between bronchopulmonary dysplasia (BPD) and neurodevelopmental outcome after extracorporeal membrane oxygenation (ECMO) has not been extensively reported. We compared the outcomes in a large series of infants with and without BPD after ECMO. STUDY DESIGN: Hospital charts and follow-up records of 145 infants treated with ECMO (1985 through 1990) were reviewed. Complete long-term respiratory and follow-up outcome data were available in 64 infants. BPD occurred in 17 survivors; the remaining 47 did not have BPD. RESULTS: Babies with BPD were more likely to have had respiratory distress syndrome. Mean (+/- SD) age at ECMO initiation was later for the BPD group (127+/-66 vs 53+/-39 hours, p < 0.001), and the duration of ECMO treatment was longer (192+/-68 vs 119+/-53 hours, p < 0.001). Bayley Scales of Infant Development scores at <30 months were lower in infants with BPD (p < 0.001), as were three of four Mullen Scales of Early Learning scores (> or = 30 months, p < 0.001 or p = 0.01). At 57+/-16 months 11 (64%) patients with BPD had mild neurologic disabilities, and 3 (18%) had severe disabilities. At a similar age (53+/-16 months, p = NS) 16 (34%) patients without BPD had mild disabilities, whereas 2 (4%) had severe disabilities (p < 0.01). CONCLUSIONS: The occurrence of BPD after ECMO is associated with adverse neurodevelopmental outcome. Patients with BPD after ECMO merit close long-term follow-up.