Congenital malignant melanoma.

The diagnosis and management of a 3-day-old infant with an exophytic pigmented growth on her back and chest are discussed. At 3 days of age, the child underwent a complete surgical excision of this lesion with immediate coverage by partial-thickness skin grafts. Pathologically, the lesion proved to be a thoracolumbar congenital melanocytic nevus with multiple focal areas of malignant melanoma. The child is now 3 years past surgery and shows no evidence of recurrence or distant metastases. The importance of this case lies in the presence of overt malignant melanoma at birth within a giant congenital nevocytic nevus.     

Irregular fruiting in Fraxinus excelsior

Abstract. Data of fruit-set and fruit production of Fraxinus excelsior (ash) at two sites in the archipelago of Stockholm, Sweden, were recorded over six years (1980-85), with particular emphasis on the fruiting tendency of individual trees. The aim was to determine the grounds for the irregularity of fruiting. There was no support for the assumption that irregular fruiting originates as a consequence of the fruiting tendency being resource limited. The probability of fruiting in a certain year was neither negatively related to previous fruiting years, nor positively related to climatically favourable years. Seeds were infested by the monophagous moth larva Pseudar-gyrotoza conwagana. An increased seed survival was noted in times of large seed crops, indicating seed predator satiation. Date of leafing the preceding year determined whether individual trees fruited or not. This relationship may have significance in synchronizing the fruit production of ash trees.     

Bafilomycin A1 inhibits lysosomal,phagosomal, and plasma membrane H+-ATPase and induces lysosomal enzyme secretion in macrophages

Bafilomycin A₁, a specific inhibitor of H⁺-ATPases of the vacuolar type, was in the present study shown, at similar concentrations, to induce secretion of lysosomal enzyme and to elevate lysosomal pH in mouse macrophages. These results lend support to the previous suggestion of a triggering role for an increase in lysosomal pH and a permissive role for cytosolic pH in the exocytosis of macrophage lysosomal enzyme. Vacuolar H⁺-ATPases are present in the macrophage plasma membrane as well as in intracellular membranes, for example, those of the lysosomal and phagosomal compartments. Phagosomal acidification was shown to be achieved in part by a mechanism with a similar sensitivity to bafilomycin A₁ as lysosomal H⁺ transport and in part by an early, bafilomycin A₁-insensitive mechanism. We found a lesser sensitivity towards bafilomycin A₁ of the lysosomal and phagosomal H⁺-ATPase than that localized in the plasma membrane, indicating differences among H⁺-ATPases at the subcellular level. Also, by attempts to mobilize lysosomal H⁺-ATPase to the plasma membrane, support was obtained for the notion that subcellular H⁺-ATPase populations differ and thus possibly could be differentially regulated. © 1995 Wiley-Liss, Inc.     

Demography of persistent juveniles in Fraxinus excelsior

Seedling emergence, survival, growth, and juvenile development of Fraxinus excelsior were followed over 10 yr in permanent plots m a dense Alnus-Fraxinus woodland in the outer archipelago of Stockholm, Sweden Number of germinated seedlings varied between years, due to variation in total seed crop but was also affected by weather conditions Seedlings and juveniles showed high survivorship 39 2% of the emerged seedlings of the two oldest cohorts were alive in the 9th growth season Mortality was somewhat raised during the first two years, but was age-independent from the third year The density of the field-layer and climatic factors were the most important determinants of mortality The juveniles produced 1 2 pairs of leaves per year and had an annual height increment of 7 1 mm, on average, from their second growth season The ontogenetic development, e g the increase m leaf complexity, was correspondingly slow and included regressions to more simple leaves
Fraxinus excelsior shows a regenerative strategy involving persistent juveniles The divergence between this and previous studies may be due to the lack of rabbit grazing     

Different Requirements for Early and Late Phases of Azurophilic Granule–Phagosome Fusion

Phagocytosis and killing of microorganisms are complex processes that involve tightly regulated membrane traffic events. Because many signaling molecules associate with membrane rafts and because these structures can be found on azurophilic granules, we decided to investigate raft recruitment and the signaling requirements for azurophilic granule secretion during phagosome maturation. At the site of phagocytosis of immunoglobulin G-opsonized prey in human neutrophils, we found that early secretion of azurophilic granules was both raft- and calcium-dependent. Subsequently, rafts at the phagocytic site were internalized with the prey. At the fully formed phagosome, the fusion of azurophilic granules was no longer dependent on rafts or calcium. These findings were found to be true also when using Streptococcus pyogenes bacteria as prey, and depletion of calcium affected the kinetics of bacterial intracellular survival. These findings suggest that the mechanisms for delivery of azurophilic content to nascent and sealed phagosomes, respectively, differ in their dependence on calcium and membrane rafts.     

ACL/MCL transection affects knee ligament insertion distance of healing and intact ligaments during gait in the Ovine model

The objective of this study was to assess the impact of combined transection of the anterior cruciate and medial collateral ligaments on the intact and healing ligaments in the ovine stifle joint. In vivo 3D stifle joint kinematics were measured in eight sheep during treadmill walking (accuracy: 0.4±0.4 mm, 0.4±0.4°). Kinematics were measured with the joint intact and at 2, 4, 8, 12, 16 and 20 weeks after either surgical ligament transection (n=5) or sham surgery without transection (n=3). After sacrifice at 20 weeks, the 3D subject-specific bone and ligament geometry were digitized, and the 3D distances between insertions (DBI) of ligaments during the dynamic in vivo motion were calculated. Anterior cruciate ligament/medial collateral ligament (ACL/MCL) transection resulted in changes in the DBI of not only the transected ACL, but also the intact lateral collateral ligament (LCL) and posterior cruciate ligament (PCL), while the DBI of the transected MCL was not significantly changed. Increases in the maximal ACL DBI (2 week: +4.2 mm, 20 week: +5.7 mm) caused increases in the range of ACL DBI (2 week: 3.6 mm, 20 week: +3.8 mm) and the ACL apparent strain (2 week: +18.9%, 20 week: +24.0%). Decreases in the minimal PCL DBI (2 week: −3.2 mm, 20 week: −4.3 mm) resulted in increases in the range of PCL DBI (2 week: +2.7 mm, 20 week: +3.2 mm). Decreases in the maximal LCL DBI (2 week: −1.0 mm, 20 week: −2.0 mm) caused decreased LCL apparent strain (2 week: −3.4%, 20 week: −6.9%). Changes in the mechanical environment of these ligaments may play a significant role in the biological changes observed in these ligaments.     

Distinct subdomains of the KCNQ1 S6 segment determine channel modulation by different KCNE subunits

Modulation of voltage-gated potassium (K_V) channels by the KCNE family of single transmembrane proteins has physiological and pathophysiological importance. All five KCNE proteins (KCNE1–KCNE5) have been demonstrated to modulate heterologously expressed KCNQ1 (K_V7.1) with diverse effects, making this channel a valuable experimental platform for elucidating structure–function relationships and mechanistic differences among members of this intriguing group of accessory subunits. Here, we specifically investigated the determinants of KCNQ1 inhibition by KCNE4, the least well-studied KCNE protein. In CHO-K1 cells, KCNQ1, but not KCNQ4, is strongly inhibited by coexpression with KCNE4. By studying KCNQ1-KCNQ4 chimeras, we identified two adjacent residues (K326 and T327) within the extracellular end of the KCNQ1 S6 segment that determine inhibition of KCNQ1 by KCNE4. This dipeptide motif is distinct from neighboring S6 sequences that enable modulation by KCNE1 and KCNE3. Conversely, S6 mutations (S338C and F340C) that alter KCNE1 and KCNE3 effects on KCNQ1 do not abrogate KCNE4 inhibition. Further, KCNQ1-KCNQ4 chimeras that exhibited resistance to the inhibitory effects of KCNE4 still interact biochemically with this protein, implying that accessory subunit binding alone is not sufficient for channel modulation. These observations indicate that the diverse functional effects observed for KCNE proteins depend, in part, on structures intrinsic to the pore-forming subunit, and that distinct S6 subdomains determine KCNQ1 responses to KCNE1, KCNE3, and KCNE4.     

Support Vector Machine Classifier for Estrogen Receptor Positive and Negative Early-Onset Breast Cancer

Two major breast cancer sub-types are defined by the expression of estrogen receptors on tumour cells. Cancers with large numbers of receptors are termed estrogen receptor positive and those with few are estrogen receptor negative. Using genome-wide single nucleotide polymorphism genotype data for a sample of early-onset breast cancer patients we developed a Support Vector Machine (SVM) classifier from 200 germline variants associated with estrogen receptor status (p<0.0005). Using a linear kernel Support Vector Machine, we achieved classification accuracy exceeding 93%. The model indicates that polygenic variation in more than 100 genes is likely to underlie the estrogen receptor phenotype in early-onset breast cancer. Functional classification of the genes involved identifies enrichment of functions linked to the immune system, which is consistent with the current understanding of the biological role of estrogen receptors in breast cancer.     

Loss of p53 Ser18 and Atm results in embryonic lethality without cooperation in tumorigenesis

Phosphorylation at murine Serine 18 (human Serine 15) is a critical regulatory process for the tumor suppressor function of p53. p53Ser18 residue is a substrate for ataxia-telangiectasia mutated (ATM) and ATM-related (ATR) protein kinases. Studies of mice with a germ-line mutation that replaces Ser18 with Ala (p53(S18A) mice) have demonstrated that loss of phosphorylation of p53Ser18 leads to the development of tumors, including lymphomas, fibrosarcomas, leukemia and leiomyosarcomas. The predominant lymphoma is B-cell lymphoma, which is in contrast to the lymphomas observed in Atm(-/-) animals. This observation and the fact that multiple kinases phosphorylate p53Ser18 suggest Atm-independent tumor suppressive functions of p53Ser18. Therefore, in order to examine p53Ser18 function in relationship to ATM, we analyzed the lifespan and tumorigenesis of mice with combined mutations in p53Ser18 and Atm. Surprisingly, we observed no cooperation in survival and tumorigenesis in compound p53(S18A) and Atm(-/-) animals. However, we observed embryonic lethality in the compound mutant animals. In addition, the homozygous p53Ser18 mutant allele impacted the weight of Atm(-/-) animals. These studies examine the genetic interaction of p53Ser18 and Atm in vivo. Furthermore, these studies demonstrate a role of p53Ser18 in regulating embryonic survival and motor coordination.