Sutureless and Rapid Deployment Prosthesis in Redo-Bentall Endocarditis.

Aortic valve replacement (AVR) in a patient with a bio-Bentall conduit can be very challenging, especially if there was a previous endocarditis process for significant morbidity and mortality. We report a case of sutureless AVR in an old patient with a bio-Bentall conduit (Carpentier-Edwards Perimount Magna Ease 25 aortic valve and Hemashield 30 aortic conduit), who developed an endocarditis on aortic prosthesis valve. We believe that sutureless AVR is the best option for redo-operation in older patients with a high surgical risk because it allows for easy rapid deployment implantation, avoids anchoring sutures on a fragile aortic anulus, and reduces cardiopulmonary and aortic cross-clamp times.

Unleashing the Power of Reliance for Post-Approval Changes: A Journey with 48 National Regulatory Authorities.

Post-approval changes (PACs) to marketed products are routinely introduced to continuously enhance the product lifecycle management. However, bringing a chemistry, manufacturing and control (CMC) change through the global health authorities can be a complex and lengthy process taking up to several years, therefore negatively impacting supply continuity. In order to accelerate the review and approval of regulatory submissions and ensure continuous supply to patients, the World Health Organization (WHO) is strongly supporting the implementation of reliance among National Regulatory Authorities (NRAs).

Standford type A aortic dissection in a patient with situs inversus totalis, with critical clinical presentation: a case report.

Unlabelled: The association of Standford type A acute aortic dissection with situs inversus totalis (SIT) is extremely rare and only a few cases are reported in the literature to date. Due to the particular rarity, this unusual condition, if not diagnosed quickly and correctly, can generate both clinical and surgical difficulties.

Case Presentation: We describe the case of a male Caucasian patient with SIT and aortic dissection type A, who occurred to our Emergency Department with a severe clinical condition of shock.

Regulation of human mTOR complexes by DEPTOR.

The vertebrate-specific DEP domain-containing mTOR interacting protein (DEPTOR), an oncoprotein or tumor suppressor, has important roles in metabolism, immunity, and cancer. It is the only protein that binds and regulates both complexes of mammalian target of rapamycin (mTOR), a central regulator of cell growth. Biochemical analysis and cryo-EM reconstructions of DEPTOR bound to human mTOR complex 1 (mTORC1) and mTORC2 reveal that both structured regions of DEPTOR, the PDZ domain and the DEP domain tandem (DEPt), are involved in mTOR interaction.

The 3.2-Å resolution structure of human mTORC2.

The protein kinase mammalian target of rapamycin (mTOR) is the central regulator of cell growth. Aberrant mTOR signaling is linked to cancer, diabetes, and neurological disorders. mTOR exerts its functions in two distinct multiprotein complexes, mTORC1 and mTORC2.

Hybrid histidine kinase activation by cyclic di-GMP-mediated domain liberation.

Cytosolic hybrid histidine kinases (HHKs) constitute major signaling nodes that control various biological processes, but their input signals and how these are processed are largely unknown. In , the HHK ShkA is essential for accurate timing of the G1-S cell cycle transition and is regulated by the corresponding increase in the level of the second messenger c-di-GMP. Here, we use a combination of X-ray crystallography, NMR spectroscopy, functional analyses, and kinetic modeling to reveal the regulatory mechanism of ShkA.

Protein kinase Akt2/PKBβ is involved in blastomere proliferation of preimplantation mouse embryos.

Activation of Akt/Protein Kinase B (PKB) by phosphatidylinositol-3-kinase (PI3K) controls several cellular functions largely studied in mammalian cells, including preimplantation embryos. We previously showed that early mouse embryos inherit active Akt from oocytes and that the intracellular localization of this enzyme at the two-cell stage depends on the T-cell leukemia/lymphoma 1 oncogenic protein, Tcl1. We have now investigated whether Akt isoforms, namely Akt1, Akt2 and Akt3, exert a specific role in blastomere proliferation during preimplantation embryo development.

Experimental evidence for the enhanced and reduced stopping regimes for protons propagating through hot plasmas.

Our understanding of the dynamics of ion collisional energy loss in a plasma is still not complete, in part due to the difficulty and lack of high-quality experimental measurements. These measurements are crucial to benchmark existing models. Here, we show that such a measurement is possible using high-flux proton beams accelerated by high intensity short pulse lasers, where there is a high number of particles in a picosecond pulse, which is ideal for measurements in quickly expanding plasmas.

Involvement of sperm acetylated histones and the nuclear isoform of Glutathione peroxidase 4 in fertilization.

We previously demonstrated that the nuclear form of Glutathione peroxidase 4 (nGPx4) has a peculiar distribution in sperm head, being localized to nuclear matrix and acrosome and that sperm lacking nGPx4 are more prone to decondensation in vitro. In this study we have hypothesized that sperm retained acetylated histones and nGPx4 are implicated in paternal chromatin decondensation and male pronucleus formation at fertilization. Indeed, significant higher amounts of acetylated histone H4 and acetylated histone H3 were observed by both immunofluorescence and western blotting in nGPx4-KO sperm vs WT ones.

Shortened primary cilium length and dysregulated Sonic hedgehog signaling in Niemann-Pick C1 disease.

The Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder due to mutations in the NPC1 gene, encoding a transmembrane protein related to the Sonic hedgehog (Shh) receptor, Patched, and involved in intracellular trafficking of cholesterol. We have recently found that the proliferation of cerebellar granule neuron precursors is significantly reduced in Npc1-/- mice due to the downregulation of Shh expression. This finding prompted us to analyze the formation of the primary cilium, a non-motile organelle that is specialized for Shh signal transduction and responsible, when defective, for several human genetic disorders.

Sexually Dimorphic Expression of Reelin in the Brain of a Mouse Model of Alzheimer Disease.

Recent evidence highlights the protective role of reelin against amyloid β (Aβ)-induced synaptic dysfunction and cognitive impairment in Alzheimer disease (AD). In this study, exploiting TgCRND8 mice that overexpress a mutant form of amyloid β precursor protein (AβPP) and display an early onset of AD neuropathological signs, we addressed the question whether changes of reelin expression eventually precede the appearance of Aβ-plaques in a sex-dependent manner. We show that sex-associated and brain region-specific differences in reelin expression appear long before Aβ-plaque formation.

Developmental delay in motor skill acquisition in Niemann-Pick C1 mice reveals abnormal cerebellar morphogenesis.

Niemann-Pick type C1 (NPC1) disease is a lysosomal storage disorder caused by defective intracellular trafficking of exogenous cholesterol. Purkinje cell (PC) degeneration is the main sign of cerebellar dysfunction in both NPC1 patients and animal models. It has been recently shown that a significant decrease in Sonic hedgehog (Shh) expression reduces the proliferative potential of granule neuron precursors in the developing cerebellum of Npc1 (-/-) mice.

Surgery of the Ascending Aorta with or without Combined Procedures through an Upper Ministernotomy: Outcomes of a Series of More Than 100 Patients.

Background: Use of a minimally invasive approach for isolated aortic valve surgery is increasing. However, management of the root and/or ascending aorta through a mini-invasive incision is not so frequent. The aim of this study is to report our initial experience with surgery of the ascending aorta through a ministernotomy approach.

Visual evoked potentials of Niemann-Pick type C1 mice reveal an impairment of the visual pathway that is rescued by 2-hydroxypropyl-ß-cyclodextrin.

Background: The lysosomal storage disorder, Niemann Pick type C1 (NPC1), presents a variable phenotype including neurovisceral and neurological symptoms. 2-Hydroxypropyl-ß-cyclodextrin (HPßCD)-based therapies are presently the most promising route of intervention. While severe cerebellar dysfunction remains the main disabling feature of NPC1, sensory functions including auditory and olfactory ones are also affected.

The nuclear form of glutathione peroxidase 4 colocalizes and directly interacts with protamines in the nuclear matrix during mouse sperm chromatin assembly.

The testis-specific nuclear form of Phospholipid Hydroperoxide Glutathione Peroxidase (nGPx4) is associated with the nuclear matrix during spermiogenesis and is implicated in sperm chromatin condensation. In this study, we have addressed the question whether nGPx4 directly interacts with protamines by transiently sharing a nuclear matrix localization. We first expressed tagged protamine 1-myc and protamine 2-V5 in HeLa and COS-1 cells and showed by both confocal microscopy and immunoblotting analyses that protamines were produced in vitro and colocalized correctly to the nucleus.

A marked paucity of granule cells in the developing cerebellum of the Npc1(-/-) mouse is corrected by a single injection of hydroxypropyl-β-cyclodextrin.

In this study we show that postnatal development of cerebellar granule neurons (GNs) is defective in Npc1(-/-) mice. Compared to age-matched wild-type littermates, there is an accelerated disappearance of the external granule layer (EGL) in these mice. This is due to a premature exit from the cell cycle of GN precursors residing at the level of the EGL.

Monochromatic short pulse laser produced ion beam using a compact passive magnetic device.

High-intensity laser accelerated protons and ions are emerging sources with complementary characteristics to those of conventional sources, namely high charge, high current, and short bunch duration, and therefore can be useful for dedicated applications. However, these beams exhibit a broadband energy spectrum when, for some experiments, monoenergetic beams are required. We present here an adaptation of conventional chicane devices in a compact form (10 cm × 20 cm) which enables selection of a specific energy interval from the broadband spectrum.

Multiple TSC22D4 iso-/phospho-glycoforms display idiosyncratic subcellular localizations and interacting protein partners.

Proteins of the TSC22 domain (TSC22D) family, including TSC22D1 and TSC22D4, play pivotal roles in cell proliferation, differentiation and apoptosis, interacting with other factors in a still largely unknown manner. This study explores this issue by biochemically characterizing various TSC22D4 forms (both iso- and glyco-phospho-, namely the splice variants 42 and 55 kDa and the post-translationally modified 67 and 72 kDa forms) and their subcellular localization and protein partners during cerebellar granule neuron (CGN) differentiation. The TSC22D4-42 form is mostly cytosolic, and is the only TSC22D4 form that associates with TSC22D1.

The nuclear form of glutathione peroxidase 4 is associated with sperm nuclear matrix and is required for proper paternal chromatin decondensation at fertilization.

The nuclear isoform of the selenoprotein Phospholipid Hydroperoxide Glutathione Peroxidase (nGPx4) is expressed in haploid male germ cells, contains several cysteines and is able to oxidize protein thiols, besides glutathione. In this study we have investigated the subnuclear localization of this isoform in isolated mouse male germ cells at different steps of maturation. Immunoblotting and confocal microscopy analyses of subnuclear fractions showed that nGPx4 is localized to the nuclear matrix together with well known markers of this subnuclear compartment like lamin B and topoisomerase IIβ at all stages of germ cell differentiation.

Subcellular TSC22D4 localization in cerebellum granule neurons of the mouse depends on development and differentiation.

We previously demonstrated that TSC22D4, a protein encoded by the TGF-β1-activated gene Tsc22d4 (Thg-1pit) and highly expressed in postnatal and adult mouse cerebellum with multiple post-translationally modified protein forms, moves to nucleus when in vitro differentiated cerebellum granule neurons (CGNs) are committed to apoptosis by hyperpolarizing KCl concentrations in the culture medium. We have now studied TSC22D4 cytoplasmic/nuclear localization in CGNs and Purkinje cells: (1) during CGN differentiation/maturation in vivo, (2) during CGN differentiation in vitro, and (3) by in vitro culturing ex vivo cerebellum slices under conditions favoring/inhibiting CGN/Purkinje cell differentiation. We show that TSC22D4 displays both nuclear and cytoplasmic localizations in undifferentiated, early postnatal cerebellum CGNs, irrespectively of CGN proliferation/migration from external to internal granule cell layer, and that it specifically accumulates in the somatodendritic and synaptic compartments when CGNs mature, as indicated by TSC22D4 abundance at the level of adult cerebellum glomeruli and apparent lack in CGN nuclei.

THG-1pit moves to nucleus at the onset of cerebellar granule neurons apoptosis.

Thg-1pit (Tsc22d4), a murine gene belonging to the TGF-beta1-stimulated clone 22 domain (TSC22D) family, is expressed in developing and adult cerebellar granule neurons and mature Purkinje cells. We have studied THG-1pit function in primary cultures of mouse cerebellar granule neurons maintained in vitro in the presence of a medium containing 25 mM K+ (differentiating condition) or 5 mM K+ (pro-apoptotic condition), and determined the effect of culture medium, TGF-beta1 and IGF-1 on THG-1pit expression and intracellular localization. Thg-1pit encoded a 42 kDa MW protein and other, higher MW and developmentally-regulated forms.