Plasmodium falciparum isolates were obtained from Thai patients attending a malaria clinic on the Thai-Kampuchean border over 4 cross-sectional surveys carried out at 3-monthly intervals. The genetic structure of the parasite populations was determined by nested polymerase chain reaction (PCR) amplification of polymorphic regions of 3 P. falciparum antigen genes: msp1, msp2 and glurp. Although a high degree of diversity characterized these isolates, the overall population structure of the parasites associated with patent malaria infections was observed to remain relatively stable over time. The highest degree of polymorphism was observed with msp2, and the mean number of lines per infection (multiplicity of infection) calculated with this marker was higher than that obtained using msp1 or glurp alone, or combined. Infections with > or = 2 parasite lines were seen in 76% of the samples, and were proportionally more numerous at the start and end of the rainy season. Two interesting exceptions to the random distribution were observed and involved 2 allelic variants which in one case were found dissociated (msp1 MAD20-family) and in the other were associated (msp2 FC27-family). The epidemiological significance of these types of data is discussed.
Olmsted syndrome (OS) is a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching. The genetic basis for OS remained unidentified. Using whole-exome sequencing of case-parents trios, we have identified a de novo missense mutation in TRPV3 that produces p.Gly573Ser in an individual with OS. Nucleotide sequencing of five additional affected individuals also revealed missense mutations in TRPV3 (which produced p.Gly573Ser in three cases and p.Gly573Cys and p.Trp692Gly in one case each). Encoding a transient receptor potential vanilloid-3 cation channel, TRPV3 is primarily expressed in the skin, hair follicles, brain, and spinal cord. In transfected HEK293 cells expressing TRPV3 mutants, much larger inward currents were recorded, probably because of the constitutive opening of the mutants. These gain-of-function mutations might lead to elevated apoptosis of keratinocytes and consequent skin hyperkeratosis in the affected individuals. Our findings suggest that TRPV3 plays essential roles in skin keratinization, hair growth, and possibly itching sensation in humans and selectively targeting TRPV3 could provide therapeutic potential for keratinization or itching-related skin disorders.
We propose that the exciton condensate may form in a well-controlled way in appropriately arranged semiconductor quantum well structures. The mean-field theory of Keldysh and Kopaev, exact in both the high density and the low density limits, is solved numerically to illustrate our proposal. The electron-hole pairing gap and the excitation spectrum of the exciton condensate are obtained. The energy scales of the condensate are substantial at higher densities. We discuss how such densities could be achieved experimentally by generating an effective pressure.
Background: Mutations in GJB2 are the most common molecular defects responsible for autosomal recessive nonsyndromic hearing impairment (NSHI). The mutation spectra of this gene vary among different ethnic groups.
A large number of extracellular polypeptides bound to their cognate receptors activate the transcription factor STAT3 by phosphorylation of tyrosine 705. Supplemental activation occurs when serine 727 is also phosphorylated. STAT3 deletion in mice leads to embryonic lethality. We have produced mice with alanine substituted for serine 727 in STAT3 (the SA allele) to examine the function of serine 727 phosphorylation in vivo. Embryonic fibroblasts from SA/SA mice had ϳ50% of the transcriptional response of wild-type cells. However, SA/SA mice were viable and grossly normal. STAT3 wild-type/null (؉/؊) animals were also normal and were interbred with SA/SA mice to study SA/؊ mice. The SA/؊ mice progressed through gestation, showing 10 to 15% reduced birth weight, three-fourths died soon after birth, and the SA/؊ survivors reached only 50 to 60% of normal size at 1 week of age. The lethality and decreased growth were accompanied by altered insulin-like growth factor 1 (IGF-1) levels in serum, establishing a role for the STAT3 serine phosphorylation acting through IGF-1 in embryonic and perinatal growth. The SA/؊ survivors have decreased thymocyte number associated with increased apoptosis, but unexpectedly normal STAT3-dependent liver acute phase response. These animals offer the opportunity to study defined reductions in the transcriptional capacity of a widely used signaling pathway.The utility of hypomorphic mutations in delineating signaling pathways has been amply proven: such mutations are widely used in detecting gene interactions which intensify or ameliorate a mutant phenotype. Many, perhaps most, extracellular ligand-activated signaling pathways report to a more limited number of transcription factors (7). To learn the quantitative importance of a given transcription factor in a particular cellular or developmental event, it would be valuable to introduce mutations with known stepwise reductions in transcription factor activity. We have constructed a mouse strain with the aim of producing reduced STAT3 activity.The STAT (signal transducers and activators of transcription) proteins are latent transcription factors activated through receptors that bind cytokines, growth factors, or peptides, triggering intracellular tyrosine phosphorylation of the STATs (23). STAT3 is ubiquitously expressed and transiently activated by a large number of different ligands, including cytokines of the interleukin-6 (IL-6) family that also includes ciliary neurotrophic factor (CNTF), oncostatin M (OSM), and leukemia inhibitory factor (LIF), as well as noncytokine ligands such as the growth factors epidermal growth factor, platelet-derived growth factor, hepatocyte growth factor, and granulocyte colony-stimulating factor (1, 24). Many genes are known to be induced in response to STAT3 activation. The STAT3 gene is the only member of this family that results in embryonic lethality when removed in mice (43). Tissue-specific removal has revealed a broad spectrum of biological functions of STAT3 in adult tissues based on disturbed cel...
Paraneoplastic pemphigus (PNP) is a life-threatening autoimmune blistering skin disease. Clinically, it is characterized by severe mucosal erosions and various cutaneous lesions associated with lymphoproliferative neoplasmas. Suprabasal acantholysis and clefts with scattered necrotic keratinocytes are the unique histopathological features. PNP patient sera recognize multiple antigens, which have been identified as the plakin protein family that includes desmoplakin, bullous pemphigoid antigen I (BPAG1), envoplakin and periplakin, and desmogleins 1 and 3. Castleman's tumor, non-Hodgkin's lymphoma, thymoma, follicular dendritic cell sarcoma and chronic lymphocytic leukemia are the commonly associated neoplasmas in PNP. We have also demonstrated that the autoantibodies reacting to epidermal proteins are directly produced by the cells in the associated tumors. Bronchiolitis obliterans is frequently found in PNP and may cause respiratory failure and death. In our experience, the early detection and removal of the tumor and i.v. administration of immunoglobulin are critical for the treatment of PNP.
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