Common and Rare Variants in TMEM175 Gene Concur to the Pathogenesis of Parkinson's Disease in Italian Patients.

Parkinson's disease (PD) represents the most common neurodegenerative movement disorder. We recently identified 16 novel genes associated with PD. In this study, we focused the attention on the common and rare variants identified in the lysosomal K channel TMEM175.

Identification of sixteen novel candidate genes for late onset Parkinson's disease.

Background: Parkinson's disease (PD) is a neurodegenerative movement disorder affecting 1-5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD.

Methods: The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls).

Direct repression of Nanog and Oct4 by OTX2 modulates the contribution of epiblast-derived cells to germline and somatic lineage.

In mammals, the pre-gastrula proximal epiblast gives rise to primordial germ cells (PGCs) or somatic precursors in response to BMP4 and WNT signaling. Entry into the germline requires activation of a naïve-like pluripotency gene regulatory network (GRN). Recent work has shown that suppression of OTX2 expression in the epiblast by BMP4 allows cells to develop a PGC fate in a precise temporal window.

Functional Antagonism between OTX2 and NANOG Specifies a Spectrum of Heterogeneous Identities in Embryonic Stem Cells.

Embryonic stem cells (ESCs) cultured in leukemia inhibitory factor (LIF) plus fetal bovine serum (FBS) exhibit heterogeneity in the expression of naive and primed transcription factors. This heterogeneity reflects the dynamic condition of ESCs and their versatility to promptly respond to signaling effectors promoting naive or primed pluripotency. Here, we report that ESCs lacking Nanog or overexpressing Otx2 exhibit an early primed identity in LIF + FBS and fail to convert into 2i-induced naive state.

Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth.

The mechanistic target of rapamycin complex 1 (mTORC1) is recruited to the lysosome by Rag guanosine triphosphatases (GTPases) and regulates anabolic pathways in response to nutrients. We found that MiT/TFE transcription factors-master regulators of lysosomal and melanosomal biogenesis and autophagy-control mTORC1 lysosomal recruitment and activity by directly regulating the expression of RagD. In mice, this mechanism mediated adaptation to food availability after starvation and physical exercise and played an important role in cancer growth.

Loss of the Otx2-Binding Site in the Nanog Promoter Affects the Integrity of Embryonic Stem Cell Subtypes and Specification of Inner Cell Mass-Derived Epiblast.

Mouse embryonic stem cells (ESCs) and the inner cell mass (ICM)-derived epiblast exhibit naive pluripotency. ESC-derived epiblast stem cells (EpiSCs) and the postimplantation epiblast exhibit primed pluripotency. Although core pluripotency factors are well-characterized, additional regulators, including Otx2, recently have been shown to function during the transition from naive to primed pluripotency.

Increased dopaminergic innervation in the brain of conditional mutant mice overexpressing Otx2: effects on locomotor behavior and seizure susceptibility.

The homeobox-containing transcription factor Otx2 controls the identity, fate and proliferation of mesencephalic dopaminergic (mesDA) neurons. Transgenic mice, in which Otx2 was conditionally overexpressed by a Cre recombinase expressed under the transcriptional control of the Engrailed1 gene (En1(Cre/+); tOtx2(ov/+)), show an increased number of mesDA neurons during development. In adult mice, Otx2 is expressed in a subset of neurons in the ventral tegmental area (VTA) and its overexpression renders mesDA more resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-HCl (MPTP) neurotoxin.

Otx2 cell-autonomously determines dorsal mesencephalon versus cerebellum fate independently of isthmic organizing activity.

During embryonic development, the rostral neuroectoderm is regionalized into broad areas that are subsequently subdivided into progenitor compartments with specialized identity and fate. These events are controlled by signals emitted by organizing centers and interpreted by target progenitors, which activate superimposing waves of intrinsic factors restricting their identity and fate. The transcription factor Otx2 plays a crucial role in mesencephalic development by positioning the midbrain-hindbrain boundary (MHB) and its organizing activity.

Otx2 is an intrinsic determinant of the embryonic stem cell state and is required for transition to a stable epiblast stem cell condition.

Mouse embryonic stem cells (ESCs) represent the naïve ground state of the preimplantation epiblast and epiblast stem cells (EpiSCs) represent the primed state of the postimplantation epiblast. Studies have revealed that the ESC state is maintained by a dynamic mechanism characterized by cell-to-cell spontaneous and reversible differences in sensitivity to self-renewal and susceptibility to differentiation. This metastable condition ensures indefinite self-renewal and, at the same time, predisposes ESCs for differentiation to EpiSCs.

Otx2 selectively controls the neurogenesis of specific neuronal subtypes of the ventral tegmental area and compensates En1-dependent neuronal loss and MPTP vulnerability.

Understanding the molecular basis underlying the neurogenesis of mesencephalic-diencephalic Dopaminergic (mdDA) neurons is a major task fueled by their relevance in controlling locomotor activity and emotion and their involvement in neurodegenerative and psychiatric diseases. Increasing evidence suggests that mdDA neurons of the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) represent two main distinct neuronal populations, which, in turn, include specific neuronal subsets. Relevant studies provided important results on mdDA neurogenesis, but, nevertheless, have not yet clarified how the identity of mdDA neuronal subtypes is established and, in particular, whether neurogenic factors may direct progenitors towards the differentiation of specific mdDA neuronal subclasses.

Dedifferentiated endometrioid adenocarcinoma of the uterus: a clinicopathologic study of a case.

Dedifferentiation confers more aggressive malignant behaviour than would be otherwise shown by the original tumor if present alone. This phenomenon has been described in several tumors, both mesenchymal and epithelial. Dedifferentiated endometrioid carcinoma either ovarian or endometrial is the latest addition to this family of tumors.

Otx genes in neurogenesis of mesencephalic dopaminergic neurons.

Mesencephalic-diencephalic dopaminergic (mdDA) neurons play a relevant role in the control of movement, behavior, and cognition. Indeed loss and/or abnormal functioning of mdDA neurons are responsible for Parkinson's disease as well as for addictive and psychiatric disorders. In the last years a wealth of information has been provided on gene functions controlling identity, fate, and proliferation of mdDA progenitors.

Modulation of CD20 antigen expression after rituximab treatment: a retrospective study in patients with chronic lymphocytic leukemia.

Background: CD20 antigen down-modulation by anti-CD20 rituximab treatment is a well-recognized phenomenon in patients with non-Hodgkin's lymphoma. However, few data are currently available on this topic in other lymphoproliferative disorders, in particular in chronic lymphocytic leukemia (CLL).

Objective: The aim of this study was to establish how many patients with CLL show a disappearance of CD20 antigen after salvage treatment with rituximab and its possible clinical significance.

The role of otx2 in adult mesencephalic-diencephalic dopaminergic neurons.

Mesencephalic and diencephalic dopaminergic (mdDA) progenitors generate two major groups of neurons corresponding to the A9 neurons of the substantia nigra pars compacta (SNpc) and the A10 neurons of the ventral tegmental area (VTA). MdDA neurons control motor, sensorimotor and motivated behaviour and their degeneration or abnormal functioning is associated to Parkinson's disease and psychiatric disorders. Although relevant advances have been made, the molecular basis controlling identity, survival and vulnerability to neurodegeneration of SNpc and VTA neurons remains poorly understood.

Otx2 controls neuron subtype identity in ventral tegmental area and antagonizes vulnerability to MPTP.

Mesencephalic-diencephalic dopaminergic neurons control locomotor activity and emotion and are affected in neurodegenerative and psychiatric diseases. The homeoprotein Otx2 is restricted to ventral tegmental area (VTA) neurons that are prevalently complementary to those expressing Girk2 and glycosylated active form of the dopamine transporter (Dat). High levels of glycosylated Dat mark neurons with efficient dopamine uptake and pronounced vulnerability to Parkinsonian degeneration.

A neuronal migratory pathway crossing from diencephalon to telencephalon populates amygdala nuclei.

Neurons usually migrate and differentiate in one particular encephalic vesicle. We identified a murine population of diencephalic neurons that colonized the telencephalic amygdaloid complex, migrating along a tangential route that crosses a boundary between developing brain vesicles. The diencephalic transcription factor OTP was necessary for this migratory behavior.

Otx2 expression is restricted to dopaminergic neurons of the ventral tegmental area in the adult brain.

Mesencephalic-diencephalic dopaminergic (mdDA) neurons control motor, sensorimotor and motivated behaviour and their degeneration or abnormal functioning is associated with important pathologies, such as Parkinsons disease and psychiatric disorders. Despite great efforts, the molecular basis and the genetic factors differentially controlling identity, survival and vulnerability to neurodegeneration of mdDA neurons of the substantia nigra (SN) and ventral tegmental area (VTA) are poorly understood. We have previously shown that the transcription factor Otx2 is required for identity, fate and proliferation of mesencephalic DA (mesDA) progenitors.

Selective inactivation of Otx2 mRNA isoforms reveals isoform-specific requirement for visceral endoderm anteriorization and head morphogenesis and highlights cell diversity in the visceral endoderm.

Genetic and embryological experiments demonstrated that the visceral endoderm (VE) is essential for positioning the primitive streak at one pole of the embryo and head morphogenesis through antagonism of the Wnt and Nodal signaling pathways. The transcription factor Otx2 is required for VE anteriorization and specification of rostral neuroectoderm at least in part by controlling the expression of Dkk1 and Lefty1. Here, we investigated the relevance of the Otx2 transcriptional control in these processes.

Anterior-posterior graded response to Otx2 controls proliferation and differentiation of dopaminergic progenitors in the ventral mesencephalon.

Meso-diencephalic dopaminergic (mdDA) neurons control voluntary movement, cognition and the reward response, and their degeneration is associated with Parkinson's disease (PD). Prospective cell transplantation therapies for PD require full knowledge of the developmental pathways that control mdDA neurogenesis. We have previously shown that Otx2 is required for the establishment of the mesencephalic field and molecular code of the entire ventral mesencephalon (VM).

Serotonin hyperinnervation abolishes seizure susceptibility in Otx2 conditional mutant mice.

The homeobox-containing transcription factor Otx2 is crucially involved in fate determination of midbrain neurons. Mutant mice, in which Otx2 was conditionally inactivated by a Cre recombinase expressed under the transcriptional control of the Engrailed1 (En1) gene (En1(cre/+); Otx2(flox/flox)), show a reduced number of dopaminergic neurons and an increased number of serotonergic neurons in the ventral midbrain. Despite these developmental anatomical alterations, En1(cre/+); Otx2(flox/flox) adult mice display normal motor function.

N-terminal amino acid sequences of intact and cleaved forms of mung bean nuclease.

We report, for the first time, the N-terminal amino acid sequences of both intact and cleaved forms (fragments A and B) of Mung bean nuclease, purified from sprouts of Vigna radiata or purchased from Amersham Biosciences. The N-terminal sequence of Mung bean nuclease shows high similarity with the putative bifunctional nuclease from Arabidopsis thaliana (AC: AAM63596).

[Primary malignant schwannoma of the uterine cervix: a malignant tumor with unusual behaviour. A case report].

Malignant tumors of peripheral nerves (MPNST) represent approximately 5-10% of all soft tissue sarcomas and usually are in relationship with a major nerve. Primary cervical malignant Schwannomas are very rare neural sheat tumors that, grossly and clinically, are misdiagnosed for other more frequent lesions of the uterine cervix. We report a case of primary cervical malignant Schwannoma in a 27 years old female with atypical bleeding.

[Retroperitoneal Pacinian neuroma: report of a rare lesion in an uncommon location].

Pacinian neuroma is an extremely rare benign tumor which has only occasionally been reported in the literature. To date, this lesion has usually been observed in the hand and foot; only one had intra-abdominal localization. Local trauma is reported in the most of these cases.

[Angiodysplasia of the gastrointestinal tract: description of 2 cases].

Gastrointestinal angiodysplasia is an acquired and degenerative lesion characterized by proliferation and ectasias of the vessels of the mucosa and submucosa. It's thought to be one of the most common causes of lower gastrointestinal bleeding in the elderly. We describe two cases of angiodysplasia and review the related literature.