Sld7, an Sld3-associated protein required for efficient chromosomal DNA replication in budding yeast.

Genetic screening of yeast for sld (synthetic lethality with dpb11) mutations has identified replication proteins, including Sld2, -3, and -5, and clarified the molecular mechanisms underlying eukaryotic chromosomal DNA replication. Here, we report a new replication protein, Sld7, identified by rescreening of sld mutations. Throughout the cell cycle, Sld7 forms a complex with Sld3, which associates with replication origins in a complex with Cdc45, binds to Dpb11 when phosphorylated by cyclin-dependent kinase, and dissociates from origins once DNA replication starts.

A pregnant woman with clinical and radiological findings compatible with posterior reversible encephalopathy syndrome in early pregnancy without discernable underlying disorders: atypical type of this syndrome?

Posterior reversible encephalopathy syndrome, if it occurs in late pregnancy, requires pregnancy termination. Here, we report a woman without a discernable underlying condition who developed neurological deficits at 14 weeks of pregnancy. Magnetic resonance imaging demonstrated an occipitoparietal brain lesion suggestive of posterior reversible encephalopathy syndrome.

Subregional 6-[18F]fluoro-ʟ-m-tyrosine uptake in the striatum in Parkinson's disease.

Background: In idiopathic Parkinson's disease (PD) the clinical features are heterogeneous and include different predominant symptoms. The aim of the present study was to determine the relationship between subregional aromatic l-amino acid decarboxylase (AADC) activity in the striatum and the cardinal motor symptoms of PD using high-resolution positron emission tomography (PET) with an AADC tracer, 6-[18F]fluoro-ʟ-m-tyrosine (FMT).

Methods: We assessed 101 patients with PD and 19 healthy volunteers.

Arid5a cooperates with Sox9 to stimulate chondrocyte-specific transcription.

SRY-box-containing gene 9 (Sox9) is an essential transcription factor in chondrocyte lineage determination and differentiation. Recent studies demonstrated that Sox9 controls the transcription of chondrocyte-specific genes in association with several other transcriptional regulators. To further understand the molecular mechanisms by which Sox9 influences transcriptional events during chondrocyte differentiation, we attempted to identify transcriptional partners of Sox9 and to examine their roles in chondrocyte differentiation.

Massive pleural effusion and bronchopleural fistula in Wegener's granulomatosis.

Wegener's granulomatosis (WG) is characterized by systemic granulomatous necrotizing vasculitis, primarily affecting the respiratory tract and kidneys. We describe a rare case in a 28-year-old woman with WG, presenting with a massive lateral pleural effusion, accompanied by an aseptic bronchopleural fistula formed during immunosuppressive treatment. Although any organ can be involved in WG, only left pleuritis and a purpuric lesion on the neck were detected in this case.

The transcription factor Znf219 regulates chondrocyte differentiation by assembling a transcription factory with Sox9.

Sox9 is an essential transcription factor for chondrogenesis by regulating the expression of chondrogenic genes. However, its regulatory mechanism is not fully understood. To address this, we attempted to identify the transcriptional partners of Sox9 by screening the cDNA library of the chondrogenic cell line ATDC5 using the collagen 2α1 (Col2α1) gene promoter fused to a luciferase reporter gene.

Retinoid x receptor gamma control of affective behaviors involves dopaminergic signaling in mice.

Abnormal signaling by retinoids or n-3 polyunsaturated fatty acids has been implicated in clinical depression. The converging point in activities of these two classes of molecules is transcriptional activation of retinoid X receptors (Rxr). We show here that ablation of Rxrgamma in mice leads to depressive-like behaviors including increased despair and anhedonia, which were accompanied by reduced expression of dopamine D2 receptor in the shell of nucleus accumbens (NAc) and altered serotonin signaling.

A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson's disease.

Gene transfer of dopamine-synthesizing enzymes into the striatal neurons has led to behavioral recovery in animal models of Parkinson's disease (PD). We evaluated the safety, tolerability, and potential efficacy of adeno-associated virus (AAV) vector-mediated gene delivery of aromatic L-amino acid decarboxylase (AADC) into the putamen of PD patients. Six PD patients were evaluated at baseline and at 6 months, using multiple measures, including the Unified Parkinson's Disease Rating Scale (UPDRS), motor state diaries, and positron emission tomography (PET) with 6-[(18)F]fluoro-L-m-tyrosine (FMT), a tracer for AADC.

[A case of recurrence with liver metastasis after total gastrectomy for StageIA gastric carcinoma successfully treated with S-1/CDDP combination followed by S-1 chemotherapy].

A 72-year-old man underwent total gastrectomy for gastric carcinoma. Postoperative staging was Stage IA. One year after operation, abdominal CT revealed a metastatic tumor in the left lateral posterior segment of the liver.

The current status of gene therapy for Parkinson's disease.

The recent development of viral vectors, especially vectors derived from adeno-associated virus (AAV), has translated gene therapy for Parkinson's disease (PD) from animal experiments into clinical trials. The current gene therapy protocols used are based on three major strategies. The first protocol involves local production of dopamine via the introduction of dopamine-synthesizing enzyme genes into the putamen.

CDK-dependent complex formation between replication proteins Dpb11, Sld2, Pol (epsilon}, and GINS in budding yeast.

Eukaryotic chromosomal DNA replication requires cyclin-dependent kinase (CDK) activity. CDK phosphorylates two yeast replication proteins, Sld3 and Sld2, both of which bind to Dpb11 when phosphorylated. These phosphorylation-dependent interactions are essential and are the minimal requirements for CDK-dependent activation of DNA replication.

Gene therapy in Alzheimer's disease - potential for disease modification.

Alzheimer's disease (AD) is the major cause of dementia in the elderly, leading to memory loss and cognitive decline. The mechanism underlying onset of the disease has not been fully elucidated. However, characteristic pathological manifestations include extracellular accumulation and aggregation of the amyloid beta-peptide (Abeta) into plaques and intracellular accumulation and aggregation of hyperphosphorylated tau, forming neurofibrillary tangles.

[Cell therapy for Parkinson disease].

Advances in the field of stem cell research have raised hopes of creating novel cell replacement therapies for Parkinson disease (PD), although double-blinded clinical trials have met with controversial success in patients implanted with fetal midbrain tissue and autopsy results have shown that some of the grafted fetal neurons displayed pathological changes typical of PD. Dopaminergic neurons have been efficiently derived from stem cells using various methods, and beneficial effects after transplantation have been demonstrated in animal models of PD. Some obstacles remain to be overcome before stem cell therapy can be routinely and safely used to treat PD in humans.

Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons.

Transcription factors involved in the specification and differentiation of neurons often continue to be expressed in the adult brain, but remarkably little is known about their late functions. Nurr1, one such transcription factor, is essential for early differentiation of midbrain dopamine (mDA) neurons but continues to be expressed into adulthood. In Parkinson's disease, Nurr1 expression is diminished and mutations in the Nurr1 gene have been identified in rare cases of disease; however, the significance of these observations remains unclear.

Colorectal cancer susceptibility associated with the hMLH1 V384D variant.

Lynch syndrome is an autosomal dominant colorectal cancer susceptibility syndrome caused by a dysfunction of DNA mismatch repair genes, including MLH1, MSH2, MSH6 and PMS2. However, the interpretation of certain changes in the mismatch repair genes is perplexing, as these changes do not necessarily affect the function of the protein. The pathogenicity of the hMLH1 1151T↷A variant, which results in an amino-acid substitution of valine for aspartic acid at codon 384 (V384D), is also controversial.

Isolation and characterization of patient-derived, toxic, high mass amyloid beta-protein (Abeta) assembly from Alzheimer disease brains.

Amyloid beta-protein (Abeta) assemblies are thought to play primary roles in Alzheimer disease (AD). They are considered to acquire surface tertiary structures, not present in physiologic monomers, that are responsible for exerting toxicity, probably through abnormal interactions with their target(s). Therefore, Abeta assemblies having distinct surface tertiary structures should cause neurotoxicity through distinct mechanisms.

A convenient enzyme-linked immunosorbent assay for rapid screening of anti-adeno-associated virus neutralizing antibodies.

Background: Recombinant adeno-associated virus vectors based on serotype 2 (AAV-2) have become leading vehicles for gene therapy. Most humans in the general population have anti-AAV-2 antibodies as a result of naturally acquired infections. Pre-existing immunity to AAV-2 might affect the functional and safety consequences of AAV-2 vector-mediated gene transfer in clinical applications.

ERas is expressed in primate embryonic stem cells but not related to tumorigenesis.

The ERas gene promotes the proliferation of and formation of teratomas by mouse embryonic stem (ES) cells. However, its human orthologue is not expressed in human ES cells. This implies that the behavior of transplanted mouse ES cells would not accurately reflect the behavior of transplanted human ES cells and that the use of nonhuman primate models might be more appropriate to demonstrate the safety of human ES cell-based therapies.

Self-contained induction of neurons from human embryonic stem cells.

Background: Neurons and glial cells can be efficiently induced from mouse embryonic stem (ES) cells in a conditioned medium collected from rat primary-cultured astrocytes (P-ACM). However, the use of rodent primary cells for clinical applications may be hampered by limited supply and risk of contamination with xeno-proteins.

Methodology/principal Findings: We have developed an alternative method for unimpeded production of human neurons under xeno-free conditions.

The cardiac pacemaker-specific channel Hcn4 is a direct transcriptional target of MEF2.

Aims: Hcn4, which encodes the hyperpolarization-activated, cyclic nucleotide-sensitive channel (I(h)), is a well-established marker of the cardiac sino-atrial node. We aimed to identify cis-elements in the genomic locus of the Hcn4 gene that regulate the transcription of Hcn4.

Methods And Results: We screened evolutionarily conserved non-coding sequences (CNSs) that are often involved in the regulation of gene expression.

Gonadal sex differentiation and expression of Sox9a2, Dmrt1, and Foxl2 in Oryzias luzonensis.

Oryzias luzonensis is closely related to the medaka, O. latipes. The sex of both species is determined by an XX-XY system.

Multitracer assessment of dopamine function after transplantation of embryonic stem cell-derived neural stem cells in a primate model of Parkinson's disease.

The ability of primate embryonic stem (ES) cells to differentiate into dopamine (DA)-synthesizing neurons has raised hopes of creating novel cell therapies for Parkinson's disease (PD). As the primary purpose of cell transplantation in PD is restoration of dopaminergic neurotransmission in the striatum, in vivo assessment of DA function after grafting is necessary to achieve better therapeutic effects. A chronic model of PD was produced in two cynomolgus monkeys (M-1 and M-2) by systemic administration of neurotoxin.

Variation in the incidence of teratomas after the transplantation of nonhuman primate ES cells into immunodeficient mice.

Embryonic stem (ES) cells have the ability to generate teratomas when transplanted into immunodeficient mice, but conditions affecting the generation remain to be elucidated. Nonhuman primate cynomolgus ES cells were transplanted into immunodeficient mice under different conditions; the number of transplanted cells, physical state (clumps or single dissociated cells), transplant site, differentiation state, and immunological state of recipient mice were all varied. The tumorigenicity was then evaluated.