Institut de Recherche en Informatique Fondamentale

Reactive oxygen species (ROS) modulate intracellular signaling but are also responsible for neuronal damage in pathological states. Microglia, the resident CNS macrophages, are prominent sources of ROS through expression of the phagocyte oxidase which catalytic subunit Nox2 generates superoxide ion (O2(.-)). Here we show that microglia also express Nox1 and other components of nonphagocyte NADPH oxidases, including p22(phox), NOXO1, NOXA1, and Rac1/2. The subcellular distribution and functions of Nox1 were determined by blocking Nox activity with diphenylene iodonium or apocynin, and by silencing the Nox1 gene in microglia purified from wild-type (WT) or Nox2-KO mice. [Nox1-p22(phox)] dimers localized in intracellular compartments are recruited to phagosome membranes during microglial phagocytosis of zymosan, and Nox1 produces O2(.-) in zymosan-loaded phagosomes. In microglia activated with lipopolysaccharide (LPS), Nox1 produces O2(.-), which enhances cell expression of inducible nitric oxide synthase and secretion of interleukin-1beta. Comparisons of microglia purified from WT, Nox2-KO, or Nox1-KO mice indicate that both Nox1 and Nox2 are required to optimize microglial production of nitric oxide. By injecting LPS in the striatum of WT and Nox1-KO mice, we show that Nox1 also enhances microglial production of cytotoxic nitrite species and promotes loss of presynaptic proteins in striatal neurons. These results demonstrate the functional expression of Nox1 in resident CNS phagocytes, which can promote production of neurotoxic compounds during neuroinflammation. Our study also shows that Nox1- and Nox2-dependent oxidases play distinct roles in microglial activation and that Nox1 is a possible target for the treatment of neuroinflammatory states.

Despite the clinically proven advantages of intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP), utilisation has been low in many African countries. To increase uptake and achieve the desired effect, the World Health Organization revised the policy to a monthly administration. Assessing the coverage and impact of the revised policy on pregnancy and neonatal outcomes is, therefore, a necessity. A 2-parallel cross-sectional hospital-based study was carried out among pregnant women attending first antenatal care (ANC) and delivery. Maternal and cord blood samples were assayed for malaria parasites by quantitative PCR targeting both the 18S rDNA and the acidic terminal segment of Plasmodium falciparum var genes, and plasma SP levels were measured by liquid chromatography coupled to tandem mass spectrometry. Parasite prevalence was similar between the two study sites but decreased significantly between the first ANC (9% or 43%) and delivery (4% or 11%) based on the qPCR target. At delivery, 64.5% of women received ≥3 IPTp-SP dose, 15.5% received 2 doses and 6% had 1 dose. Taking ≥3 IPTp-SP doses was associated with an average birth weight increase of more than 0.165 kg. IPTp-SP uptake was associated with plasma SP level at delivery (OR = 32.3, p ≤ 0.005, 95% CI (13.3;78.4) for those that reported ≥3 IPTp-SP doses) while the same trend of improved birth weight was observed with high plasma SP levels. The new IPTp policy is well implemented and well utilised by women in the sites considered in this study and translates to the improved birth weight observed. This study confirms the interest and the clinical benefit expected from this policy change.

Abstract We report the observation of a coalescing compact binary with component masses 2.5–4.5 M ⊙ and 1.2–2.0 M ⊙ (all measurements quoted at the 90% credible level). The gravitational-wave signal GW230529_181500 was observed during the fourth observing run of the LIGO–Virgo–KAGRA detector network on 2023 May 29 by the LIGO Livingston observatory. The primary component of the source has a mass less than 5 M ⊙ at 99% credibility. We cannot definitively determine from gravitational-wave data alone whether either component of the source is a neutron star or a black hole. However, given existing estimates of the maximum neutron star mass, we find the most probable interpretation of the source to be the coalescence of a neutron star with a black hole that has a mass between the most massive neutron stars and the least massive black holes observed in the Galaxy. We provisionally estimate a merger rate density of <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:msubsup> <mml:mrow> <mml:mn>55</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>47</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>+</mml:mo> <mml:mn>127</mml:mn> </mml:mrow> </mml:msubsup> <mml:mspace width="0.25em"/> <mml:msup> <mml:mrow> <mml:mi>Gpc</mml:mi> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>3</mml:mn> </mml:mrow> </mml:msup> <mml:mspace width="0.25em"/> <mml:msup> <mml:mrow> <mml:mi>yr</mml:mi> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>1</mml:mn> </mml:mrow> </mml:msup> </mml:math> for compact binary coalescences with properties similar to the source of GW230529_181500; assuming that the source is a neutron star–black hole merger, GW230529_181500-like sources may make up the majority of neutron star–black hole coalescences. The discovery of this system implies an increase in the expected rate of neutron star–black hole mergers with electromagnetic counterparts and provides further evidence for compact objects existing within the purported lower mass gap.

Pigment epithelium-derived factor (PEDF) is a multifunctional protein with neurotrophic, anti-oxidative, and anti-inflammatory properties. It is also one of the most potent endogenous inhibitors of angiogenesis, playing an important role in restricting tumor growth, invasion, and metastasis. Studies show that PEDF binds to cell surface proteins, but little is known about how it exerts its effects. Recently, research identified phospholipase A2/nutrin/patatin-like phospholipase domain-containing 2 as one PEDF receptor. To identify other receptors, we performed yeast two-hybrid screening using PEDF as bait and discovered that the non-integrin 37/67-kDa laminin receptor (LR) is another PEDF receptor. Co-immunoprecipitation, His tag pulldown, and surface plasmon resonance assays confirmed the interaction between PEDF and LR. Using the yeast two-hybrid method, we further restricted the LR-interacting domain on PEDF to a 34-amino acid (aa) peptide (aa 44–77) and the PEDF-interacting domain on LR to a 91-aa fragment (aa 120–210). A 25-mer peptide named P46 (aa 46–70), derived from 34-mer, interacts with LR in surface plasmon resonance assays and binds to endothelial cell (EC) membranes. This peptide induces EC apoptosis and inhibits EC migration, tube-like network formation in vitro, and retinal angiogenesis ex vivo, like PEDF. Our results suggest that LR is a real PEDF receptor that mediates PEDF angiogenesis inhibition. Pigment epithelium-derived factor (PEDF) is a multifunctional protein with neurotrophic, anti-oxidative, and anti-inflammatory properties. It is also one of the most potent endogenous inhibitors of angiogenesis, playing an important role in restricting tumor growth, invasion, and metastasis. Studies show that PEDF binds to cell surface proteins, but little is known about how it exerts its effects. Recently, research identified phospholipase A2/nutrin/patatin-like phospholipase domain-containing 2 as one PEDF receptor. To identify other receptors, we performed yeast two-hybrid screening using PEDF as bait and discovered that the non-integrin 37/67-kDa laminin receptor (LR) is another PEDF receptor. Co-immunoprecipitation, His tag pulldown, and surface plasmon resonance assays confirmed the interaction between PEDF and LR. Using the yeast two-hybrid method, we further restricted the LR-interacting domain on PEDF to a 34-amino acid (aa) peptide (aa 44–77) and the PEDF-interacting domain on LR to a 91-aa fragment (aa 120–210). A 25-mer peptide named P46 (aa 46–70), derived from 34-mer, interacts with LR in surface plasmon resonance assays and binds to endothelial cell (EC) membranes. This peptide induces EC apoptosis and inhibits EC migration, tube-like network formation in vitro, and retinal angiogenesis ex vivo, like PEDF. Our results suggest that LR is a real PEDF receptor that mediates PEDF angiogenesis inhibition. Pigmented epithelium-derived factor (PEDF), 2The abbreviations used are: PEDF, pigment epithelium-derived factor; AD, activation domain; BD, binding domain; KAP, keratin-associated protein; LR laminin receptor; PNPLA2, PLA2/nutrin/patatin-like phospholipase domain-containing 2; RU, resonance unit; TUNEL, terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end labeling; Y2H, yeast two-hybrid; aa, amino acid(s); HuBMEC, human bone marrow endothelial cell; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; MAPK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; FBS, fetal bovine serum; Ni-NTA, nickel-nitrilotriacetic acid; PBS, phosphate-buffered saline; DAPI, 4′,6′-diamino-2-phenylindole; SPR, surface plasmon resonance; siRNA, small interfering RNA; HA, hemagglutinin; EC, endothelial cell; X-α-Gal, 5′-bromo-4-chloro-3′-indolyl-α-d-galactopyranoside. also known as SERPIN F1 and EPC1, is a 50-kDa serpin-like peptide. Although first identified in cultured pigment epithelial cells from fetal human retinas (1Tombran-Tink J. Chader G.G. Johnson L.V. Exp. Eye Res... 1991; 53: 411-414Google Scholar), we now know that liver, kidney, heart, testis, and lung tissues also express PEDF (2Tombran-Tink J. Mazuruk K. Rodriguez I.R. Chung D. Linker T. Englander E. Chader G.J. Mol. Vis... 1996; 2: 11Google Scholar). PEDF influences many biological processes. It is anti-angiogenic, anti-tumorigenic, anti-inflammatory, anti-oxidative, neurotrophic, and neuroprotective, and it exhibits anti-vasopermeability properties (3Bouck N. Trends Mol. Med... 2002; 8: 330-334Google Scholar, 4Tombran-Tink J. Barnstable C.J. Nat. Rev. Neurosci... 2003; 4: 628-636Google Scholar, 5Becerra S.P. Exp. Eye Res... 2006; 82: 739-740Google Scholar, 6Ek E.T. Dass C.R. Choong P.F. Trends Mol. Med... 2006; 12: 497-502Google Scholar, 7Zhang S.X. Wang J.J. Gao G. Shao C. Mott R. Ma J.X. FASEB J... 2006; 20: 323-325Google Scholar, 8Yamagishi S. Nakamura K. Ueda S. Kato S. Imaizumi T. Cell Tissue Res... 2005; 320: 437-445Google Scholar-9Liu H. Ren J.G. Cooper W.L. Hawkins C.E. Cowan M.R. Tong P.Y. Proc. Natl. Acad. Sci. U. S. A... 2004; 101: 6605-6610Google Scholar). These diverse actions affect many cell types, including retinal cells (10Yamagishi S. Inagaki Y. Amano S. Okamoto T. Takeuchi M. Makita Z. Biochem. Biophys. Res. Commun... 2002; 296: 877-882Google Scholar), neuronal cells (11Steele F.R. Chader G.J. Johnson L.V. Tombran-Tink J. Proc. Natl. Acad. Sci. U. S. A... 1993; 90: 1526-1530Google Scholar), endothelial cells (12Stellmach V. Crawford S.E. Zhou W. Bouck N. Proc. Natl. Acad. Sci. U. S. A... 2001; 98: 2593-2597Google Scholar), and hematopoietic stem cells (13Selleri C. Ragno P. Ricci P. Visconte V. Scarpato N. Carriero M.V. Rotoli B. Rossi G. Montuori N. Blood.. 2006; 108: 2476-2484Google Scholar). X-ray diffraction studies show that PEDF has an asymmetrical charge distribution (14Simonovic M. Gettins P.G. Volz K. Proc. Natl. Acad. Sci. U. S. A... 2001; 98: 11131-11135Google Scholar). A high density of basic residues on one side of the molecule (positive) interact with heparin and glycosaminoglycans, whereas acidic residues on the opposite side (negative) interact with type-1 collagen (15Alberdi E. Hyde C.C. Becerra S.P. Biochemistry.. 1998; 37: 10643-10652Google Scholar, 16Yasui N. Mori T. Morito D. Matsushita O. Kourai H. Nagata K. Koide T. Biochemistry.. 2003; 42: 3160-3167Google Scholar, 17Becerra S.P. Perez-Mediavilla L.A. Weldon J.E. Locatelli-Hoops S. deS Senanayake P. Notari L. Notario V. Hollyfield J.G. J. Biol. Chem... 2008; 283: 33310-33320Google Scholar, 18Meyer C. Notari L. Becerra S.P. J. Biol. Chem... 2002; 277: 45400-45407Google Scholar-19Hosomichi J. Yasui N. Koide T. Soma K. Morita I. Biochem. Biophys. Res. Commun... 2005; 335: 756-761Google Scholar). Yet the mechanisms explaining the diverse biological activities of PEDF remain unclear. A ligand/receptor interaction at the cell membrane seemed likely, in addition to interactions within extracellular matrices, because of the diverse effects and ubiquitous expression of PEDF and the fact that most PEDF deposits remain within extracellular matrices (20Alberdi E.M. Weldon J.E. Becerra S.P. BMC Biochem... 2003; 4: 1Google Scholar). We suspected that distinct PEDF receptors elicit divergent signals to cause different biological effects. Indeed, evidence shows that PEDF binds at least two receptors: a 60-kDa receptor in ECs and an 80-kDa receptor in neuronal cells (21Alberdi E. Aymerich M.S. Becerra S.P. J. Biol. Chem... 1999; 274: 31605-31612Google Scholar, 22Bilak M.M. Becerra S.P. Vincent A.M. Moss B.H. Aymerich M.S. Kuncl R.W. J. Neurosci... 2002; 22: 9378-9386Google Scholar, 23Aymerich M.S. Alberdi E.M. Martínez A. Becerra S.P. Investig. Ophthalmol. Vis. Sci... 2001; 42: S. Inagaki Y. Nakamura K. R. T. A. Imaizumi T. J. Mol. Cell 2004; 37: Scholar). has identified two on a peptide 44–77) and a peptide S. Volz K. T. Y. H. Aymerich M.S. Becerra S.P. R. D. Res... 2005; Scholar). peptide interacts with the 80-kDa receptor identified on cells and (21Alberdi E. Aymerich M.S. Becerra S.P. J. Biol. Chem... 1999; 274: 31605-31612Google Scholar, 22Bilak M.M. Becerra S.P. Vincent A.M. Moss B.H. Aymerich M.S. Kuncl R.W. J. Neurosci... 2002; 22: 9378-9386Google Scholar), and retinal M.S. Alberdi E.M. Martínez A. Becerra S.P. Investig. Ophthalmol. Vis. Sci... 2001; 42: to the and anti-vasopermeability properties of PEDF H. Ren J.G. Cooper W.L. Hawkins C.E. Cowan M.R. Tong P.Y. Proc. Natl. Acad. Sci. U. S. A... 2004; 101: 6605-6610Google Scholar, S. Volz K. T. Y. H. Aymerich M.S. Becerra S.P. R. D. Res... 2005; Scholar). Becerra and L. V. N. R. C. Notario S. J. J. Becerra S.P. J. Biol. Chem... 2006; identified 80-kDa PLA2/nutrin/patatin-like phospholipase domain-containing 2 as a PEDF receptor that binds the S. Volz K. T. Y. H. Aymerich M.S. Becerra S.P. R. D. Res... 2005; in that the in cell tumor density and peptide induces endothelial cell migration, and inhibits angiogenesis, a distinct EC receptor. We know the of the 60-kDa receptor. PEDF is one of the most potent endogenous inhibitors of angiogenesis, the of the vascular network from It inhibits endothelial cell in the of as vascular endothelial growth factor and fibroblast growth factor I. M. E. Mori K. M. L. K. K. S. Tong P. P. J. Investig. Ophthalmol. Vis. Sci... 2002; Scholar, H. M. Tombran-Tink J. J. Biochem. Biophys. Res. Commun... 2002; S. Y. Nakamura T. Y. T. H. J. Cell Sci... 2005; Scholar). show density in as the and that PEDF a role as a angiogenesis Bouck C. M.R. J. Crawford S.E. Nat. Med... 2003; Scholar). PEDF is It growth and It that the effects of PEDF endothelial cell the activation of the T. Zhou W. M. Bouck Nat. Med... 2002; 8: Scholar). and endothelial cell apoptosis in the of PEDF R. S. T. J. Exp. Med... 2004; Scholar, L. Barnstable C.J. Tombran-Tink J. Biochem. Biophys. Res. Commun... 2006; Scholar). Recently, J. M. J. Biol. Chem... 2006; that PEDF inhibits angiogenesis in retinal PEDF of the of This to receptors PEDF and to how We used a yeast two-hybrid to identify PEDF to that PEDF Our results that the non-integrin 37/67-kDa laminin receptor (LR) is a PEDF receptor. LR the 60-kDa receptor identified in ECs S. Inagaki Y. Nakamura K. R. T. A. Imaizumi T. J. Mol. Cell 2004; 37: Scholar). LR is a laminin receptor. It also mediates protein J. J. C. and S. J. and as a receptor as and S. J. Scholar, C. J. 2004; B. D. K. H. J. 2006; Scholar). LR is in and including cell growth, migration, and J. G. E. C. D. 2008; Scholar). Our research shows that LR PEDF We identified a 25-mer LR-interacting domain on PEDF and a PEDF-interacting domain on LR. 25-mer peptide exerts the and effects on ECs as PEDF. of PEDF used a two-hybrid of to a human with to the activation domain of the factor in a We used PEDF in a with the domain at We performed interaction on high in the to the We the in and with the using the to and PEDF different human PEDF amino and and the and of the we LR amino and with and and We the We the interaction between different of PEDF and LR the S. as performed as W.L. Moss J. M. J. Biol. Chem... with and protein as T. 2: and with and in Cell bone marrow endothelial cells P. C. D. A.M. M.M. in endothelial cell 2 We cultured cells in with at in a of We cells in with with and and Cell PEDF (aa and LR (aa in and to and expression We two cells that we at the using to the PEDF in and in used the and to human PEDF We fragment the and of the and LR and used to human LR We the and of the We PEDF from cells and laminin receptor from with to the cells with and we with and in We cells with We the cells with bovine with and and tag Cell in bovine We cells with and with in the We the cells in with We cells with a of the PEDF-interacting domain using We the a domain with the of a and a an interaction between the peptide and protein a with LR. 25-mer P46 (aa and We also peptide protein a we the interaction in real between PEDF peptide P46 and (aa (aa from E. and on a to a of between and resonance to the We a the To we also used PEDF protein and peptide P46 on with and binding We used PEDF protein and peptide P46 to We results with to to a with peptide at To the binding we used peptide at in the binding the first with LR LR at the at to with at We cells with and with with DAPI, and We with a We used a 25-mer peptide derived from keratin-associated protein S. N. E. A. C. A. J. Investig. 2008; as a peptide. using and a of inhibitors We protein using We of protein with and with We the to the We the with at We the at with the and in with a with We used to with with the protein at with 2 of on a We protein and the we the at We the a of We the with PBS, the We performed with as His PEDF binding to LR His tag of with as Notari L. V. N. R. C. Notario S. J. J. Becerra S.P. J. Biol. Chem... 2006; Scholar). PEDF protein with of (aa of (aa extracellular from E. in binding and at with We the in binding to the and at 2 with the and we with binding We the with of and with performed as M. A. G. J. D. E. Z. 2008; Scholar). in with of growth at We cultured cells in with FBS, and We the effects of PEDF, 25-mer peptide peptide on tube-like We from and the endothelial We performed distinct angiogenesis as C.C. E. J. Investig. Ophthalmol. Vis. Sci... 1996; 37: Scholar). PEDF, peptide P46 the of We used about of bFGF, of PEDF, and of to We used an to the of the and and the performed terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end using an Cell We at in in the cells in growth We cells with PEDF P46 in the of and We cells with with and to the We cell with We the of cells We the at and We a using a We cells with and in with and We the and LR in at We used to the human LR in and We used as a of the the and we used in We cells with to the We with We using in a We the using and the S.E. We to and with of 37/67-kDa LR as a PEDF the the expression and distinct biological of PEDF, we that peptide a of To we a screening a human using PEDF (aa as We the on high We and from the that with We the from with the that of membrane PEDF receptors, as and 37/67-kDa LR. Becerra and L. V. N. R. C. Notario S. J. J. Becerra S.P. J. Biol. Chem... 2006; identified as a PEDF one with potent phospholipase that We to on the membrane the LR. is a non-integrin laminin binding to PEDF (15Alberdi E. Hyde C.C. Becerra S.P. Biochemistry.. 1998; 37: 10643-10652Google Scholar, C. S. S. C. R. D. S. J... 2001; 20: Scholar). It is in the cell membrane and results from the of a known as receptor E. G. E. A. V. S. Mol. Biol. 1998; Scholar). an important role in cell and migration, angiogenesis, and tumor J. G. E. C. D. 2008; Scholar, E. B. L. M. C. E. S. Res... 2002; Scholar). and with the that the with PEDF the extracellular domain We to know the LR interact with PEDF in the and PEDF the of a 37/67-kDa LR-interacting on PEDF interact with in the This to protein membrane the of the domain in the LR. We performed in the yeast the and using and results that the two the the membrane of protein expression with a in the yeast the of we a using These results suggest that a the protein from LR. This the of interaction between LR with PEDF. of protein to protein the To identify the LR-interacting domain on PEDF, we PEDF from and and to of the We with (aa to of results a PEDF in N-terminal (aa 44–77) that interacts with This domain is also known as an the peptide S. Volz K. T. Y. H. Aymerich M.S. Becerra S.P. R. D. Res... 2005; Scholar). of PEDF-interacting on different from the extracellular domain of the LR and to of These with the PEDF PEDF peptide (aa 44–77) as We that the PEDF-interacting domain on restricted to fragment and the interaction between PEDF and because the interaction in with the and to an interaction between LR and the PEDF the interaction with PEDF to Indeed, and with PEDF 34-mer, fragment peptide to the peptide (aa known to interact with laminin and protein C. S. S. C. R. D. S. J... 2001; 20: Scholar). Although peptide is to PEDF it the interaction between LR and PEDF and peptide. This that with other LR PEDF PEDF and LR in LR interact with PEDF in the we cells with PEDF and LR using a to interaction between the LR and PEDF in We PEDF and LR expression with and in and and as and We the of and on in the cells of the results also that and with a at the cell This interaction of PEDF and LR at the membrane of To the PEDF and LR we performed a We LR proteins, in E. with PEDF from we to the protein using as a that PEDF with LR 2 and a interaction between PEDF and LR. with to LR and PEDF. This to the fact that a that with the PEDF binding on LR. To we performed a His tag using LR and LR extracellular domain We that PEDF with the binding LR We further confirmed interaction surface plasmon resonance shows PEDF binding to LR and on the shows that the signals PEDF binding to LR and is to to PEDF to the surface in the of LR 25-mer PEDF to Cell research has that PEDF binds to at least two cell membrane receptors, one 80-kDa receptor and one 60-kDa receptor (21Alberdi E. Aymerich M.S. Becerra S.P. J. Biol. Chem... 1999; 274: 31605-31612Google Scholar, 22Bilak M.M. Becerra S.P. Vincent A.M. Moss B.H. Aymerich M.S. Kuncl R.W. J. Neurosci... 2002; 22: 9378-9386Google Scholar, 23Aymerich M.S. Alberdi E.M. Martínez A. Becerra S.P. Investig. Ophthalmol. Vis. Sci... 2001; 42: S. Inagaki Y. Nakamura K. R. T. A. Imaizumi T. J. Mol. Cell 2004; 37: Scholar). 80-kDa receptor the L. V. N. R. C. Notario S. J. J. Becerra S.P. J. Biol. Chem... 2006; Scholar). We that the 60-kDa receptor LR. the interaction between PEDF and LR and identified a PEDF we the biological of to the peptide exhibits S. Volz K. T. Y. H. Aymerich M.S. Becerra S.P. R. D. Res... 2005; Scholar), and we a fragment elicit the effects. we used protein to the (aa 44–77) to and a 25-mer (aa as with a A and This peptide is on the surface of the of PEDF We used assays to the interaction between P46 and LR Our results show that P46 interacts with LR in an shows that the binding and that the to to with the P46 to the surface in the of LR We that peptide LR on cell membranes. We P46 peptide with at and a Our show binding to membrane binding cells also inhibits (13Selleri C. Ragno P. Ricci P. Visconte V. Scarpato N. Carriero M.V. Rotoli B. Rossi G. Montuori N. Blood.. 2006; 108: 2476-2484Google Scholar). also we used that with LR P46 at the and These results a 25-mer P46 the as know that PEDF has properties in and in (3Bouck N. Trends Mol. Med... 2002; 8: 330-334Google Scholar, 4Tombran-Tink J. Barnstable C.J. Nat. Rev. Neurosci... 2003; 4: 628-636Google Scholar, 5Becerra S.P. Exp. Eye Res... 2006; 82: 739-740Google E.T. Dass C.R. Choong P.F. Trends Mol. Med... 2006; 12: 497-502Google Scholar, S. Volz K. T. Y. H. Aymerich M.S. Becerra S.P. R. D. Res... 2005; Scholar). We performed a angiogenesis in in to peptide P46 also has properties. cells tube-like on using a and Our results show that P46 inhibits tube-like network formation in the as PEDF whereas peptide has We the effects of the peptide on angiogenesis in ex vivo, results show that P46 inhibits angiogenesis as as PEDF PEDF, P46 Cell and assays like PEDF, P46 cell A and It is that PEDF has a on ECs R. S. T. J. Exp. Med... 2004; Scholar). We P46 inhibits formation We apoptosis assays and assays in the of and the with and growth the of cells about We between PEDF, and P46 to the and the of cells to in the and in the P46 and PEDF, cells in P46 cells and in PEDF. To further activation on protein from cells and with PEDF and P46 We the PEDF and P46 and activation LR expression inhibition. This the between PEDF and the in apoptosis and apoptosis PEDF and P46 We with LR we cells with PEDF P46 We using and We a LR protein expression in LR We the expression and a in LR protein in the LR cells with the and show the with in the cells with LR and of with PEDF P46 at the in the cells with the cells in the of PEDF We the is important in as but it is also in as D. J. 1996; Scholar, W. P. 2005; Scholar). to angiogenesis has a in PEDF, a inhibits angiogenesis in and in in N. Trends Mol. Med... 2002; 8: 330-334Google Scholar, 4Tombran-Tink J. Barnstable C.J. Nat. Rev. Neurosci... 2003; 4: 628-636Google Scholar, 5Becerra S.P. Exp. Eye Res... 2006; 82: 739-740Google E.T. Dass C.R. Choong P.F. Trends Mol. Med... 2006; 12: 497-502Google Scholar). Our results a evidence that PEDF receptors in the of different cell types, distinct receptors to elicit divergent least two receptors one of in ECs and another of in neuronal cells (21Alberdi E. Aymerich M.S. Becerra S.P. J. Biol. Chem... 1999; 274: 31605-31612Google Scholar, 22Bilak M.M. Becerra S.P. Vincent A.M. Moss B.H. Aymerich M.S. Kuncl R.W. J. Neurosci... 2002; 22: 9378-9386Google Scholar, 23Aymerich M.S. Alberdi E.M. Martínez A. Becerra S.P. Investig. Ophthalmol. Vis. Sci... 2001; 42: S. Inagaki Y. Nakamura K. R. T. A. Imaizumi T. J. Mol. Cell 2004; 37: Scholar). Recently, has identified as a PEDF receptor L. V. N. R. C. Notario S. J. J. Becerra S.P. J. Biol. Chem... 2006; Scholar). its phospholipase the 80-kDa receptor identified in neuronal PEDF its and in and receptor L. V. N. R. C. Notario S. J. J. Becerra S.P. J. Biol. Chem... 2006; Scholar, C. C. M. P. Crawford S.E. J. 2008; Scholar). We identified a PEDF the LR. This to the 60-kDa receptor in ECs S. Inagaki Y. Nakamura K. R. T. A. Imaizumi T. J. Mol. Cell 2004; 37: Scholar). It has that the laminin receptor of two laminin receptor and that the S. E. E. A. C. V. S. J. Cell Biochem... 1998; Scholar). between and we identified LR as a PEDF receptor the first We that PEDF interacts with the extracellular of but with in as His tag and that PEDF interact with This in results to a domain in LR protein membrane shows that PEDF and 25-mer PEDF peptide with LR on the interaction of PEDF with LR 2 and We further identified a 25-mer derived from PEDF, as a interaction 25-mer interact with to cell EC EC migration, and angiogenesis in and ex vivo, like PEDF to the of PEDF, as EC the T. Zhou W. M. Bouck Nat. Med... 2002; 8: Scholar). PEDF inhibits in R. R. J. Investig. Ophthalmol. Vis. Sci... 2003; Scholar), that other that PEDF interactions to retinal other that and EC apoptosis R. S. T. J. Exp. Med... 2004; Scholar, L. Barnstable C.J. Tombran-Tink J. Biochem. Biophys. Res. Commun... 2006; Scholar). J. M. J. Biol. 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Multipartite entangled states are a fundamental resource for a wide range of quantum information processing tasks. In particular, in quantum networks, it is essential for the parties involved to be able to verify if entanglement is present before they carry out a given distributed task. Here we design and experimentally demonstrate a protocol that allows any party in a network to check if a source is distributing a genuinely multipartite entangled state, even in the presence of untrusted parties. The protocol remains secure against dishonest behaviour of the source and other parties, including the use of system imperfections to their advantage. We demonstrate the verification protocol in a three- and four-party setting using polarization-entangled photons, highlighting its potential for realistic photonic quantum communication and networking applications.

CBA/J female mice have a high rate of fetal resorption when mated with DBA/2J males. This fetal wastage can be dramatically reduced by immunizing the female with BALB/cJ but not DBA/2J spleen cells. We report here that immunization with BALB/cJ (but not DBA/2J) spleen cells leads to 1) anti-paternal MHC antibody that is predominantly of the IgG1 isotype, and which disappears from the serum during pregnancy; 2) increased active suppression in both the spleen and placenta; and 3) an ability to adoptively transfer the fetal protection and placental suppression with serum from the immunized mice. Congenic absorption studies before adoptive transfer indicate that the active component of the serum is also directed against the paternal MHC haplotype. These results indicate that maternal humoral immunity can lead to increased fetal protection in correlation with local active suppression in the placenta. They also suggest an expansion of the placental immunoabsorbent hypothesis to include the induction of active suppression against maternal cell-mediated immunity.

Software is now a key component present in all aspects of our society.Its preservation has attracted growing attention over the past years within the digital preservation community.We claim that source code-the only representation of software that contains human readable knowledge-is a precious digital object that needs special handling: it must be a first class citizen in the preservation landscape and we need to take action immediately, given the increasingly more frequent incidents that result in permanent losses of source code collections.In this paper we present Software Heritage, an ambitious initiative to collect, preserve, and share the entire corpus of publicly accessible software source code.We discuss the archival goals of the project, its use cases and role as a participant in the broader digital preservation ecosystem, and detail its key design decisions.We also report on the project road map and the current status of the Software Heritage archive that, as of early 2017, has collected more than 3 billion unique source code files and 700 million commits coming from more than 50 million software development projects.

These are lecture notes for a mini-course given at the St. Petersburg School in Probability and Statistical Physics in June 2012. Topics include integrable models of random growth, determinantal point processes, Schur processes and Markov dynamics on them, Macdonald processes and their application to asymptotics of directed polymers in random media.

Microbiome data predictive analysis within a machine learning (ML) workflow presents numerous domain-specific challenges involving preprocessing, feature selection, predictive modeling, performance estimation, model interpretation, and the extraction of biological information from the results. To assist decision-making, we offer a set of recommendations on algorithm selection, pipeline creation and evaluation, stemming from the COST Action ML4Microbiome. We compared the suggested approaches on a multi-cohort shotgun metagenomics dataset of colorectal cancer patients, focusing on their performance in disease diagnosis and biomarker discovery. It is demonstrated that the use of compositional transformations and filtering methods as part of data preprocessing does not always improve the predictive performance of a model. In contrast, the multivariate feature selection, such as the Statistically Equivalent Signatures algorithm, was effective in reducing the classification error. When validated on a separate test dataset, this algorithm in combination with random forest modeling, provided the most accurate performance estimates. Lastly, we showed how linear modeling by logistic regression coupled with visualization techniques such as Individual Conditional Expectation (ICE) plots can yield interpretable results and offer biological insights. These findings are significant for clinicians and non-experts alike in translational applications.

The concerted responses of eusocial insects to environmental stimuli are often referred to as collective cognition at the level of the colony. To achieve collective cognition, a group can draw on two different sources: individual cognition and the connectivity between individuals. Computation in neural networks, for example, is attributed more to sophisticated communication schemes than to the complexity of individual neurons. The case of social insects, however, can be expected to differ. This is because individual insects are cognitively capable units that are often able to process information that is directly relevant at the level of the colony. Furthermore, involved communication patterns seem difficult to implement in a group of insects as they lack a clear network structure. This review discusses links between the cognition of an individual insect and that of the colony. We provide examples for collective cognition whose sources span the full spectrum between amplification of individual insect cognition and emergent group-level processes.

A recent trend in programming language research is to use behavioral type theory to ensure various correctness properties of largescale, communication-intensive systems. Behavioral types encompass concepts such as interfaces, communication protocols, contracts, and choreography. The successful application of behavioral types requires a solid understanding of several practical aspects, from their representation in a concrete programming language, to their integration with other programming constructs such as methods and functions, to design and monitoring methodologies that take behaviors into account. This survey provides an overview of the state of the art of these aspects, which we summarize as the pragmatics of behavioral types.

We characterized CD8(+) T cells constitutively expressing CD25 in mice lacking the expression of MHC class II molecules. We showed that these cells are present not only in the periphery but also in the thymus. Like CD4(+)CD25(+) T cells, CD8(+)CD25(+) T cells appear late in the periphery during ontogeny. Peripheral CD8(+)CD25(+) T cells from MHC class II-deficient mice also share phenotypic and functional features with regulatory CD4(+)CD25(+) T cells: in particular, they strongly express glucocorticoid-induced TNFR family-related gene, CTLA-4 and Foxp3, produce IL-10, and inhibit CD25(-) T cell responses to anti-CD3 stimulation through cell contacts with similar efficiency to CD4(+)CD25(+) T cells. However, unlike CD4(+)CD25(+) T cells CD8(+)CD25(+) T cells from MHC class II-deficient mice strongly proliferate and produce IFN-gamma in vitro in response to stimulation in the absence of exogenous IL-2.

Quantum machine learning techniques have been proposed as a way to potentially enhance performance in machine learning applications. In this paper, we introduce two new quantum methods for neural networks. The first one is a quantum orthogonal neural network, which is based on a quantum pyramidal circuit as the building block for implementing orthogonal matrix multiplication. We provide an efficient way for training such orthogonal neural networks; novel algorithms are detailed for both classical and quantum hardware, where both are proven to scale asymptotically better than previously known training algorithms. The second method is quantum-assisted neural networks, where a quantum computer is used to perform inner product estimation for inference and training of classical neural networks. We then present extensive experiments applied to medical image classification tasks using current state of the art quantum hardware, where we compare different quantum methods with classical ones, on both real quantum hardware and simulators. Our results show that quantum and classical neural networks generates similar level of accuracy, supporting the promise that quantum methods can be useful in solving visual tasks, given the advent of better quantum hardware.

AIMS: A major breakthrough in the molecular genetics of hypertrophic cardiomyopathy (HCM) has made genetic testing now available in clinical practice, raising new questions about its implications, potential benefits, and the organisation of the procedure. The aim of this work was (1) to discuss the different questions related to genetic testing in HCM, and propose guidelines for the different situations, (2) to report our preliminary experience with a specific procedure. METHODS AND RESULTS: The main questions asked by patients and relatives concern presymptomatic diagnosis and prenatal counselling/diagnosis, while clinicians sometimes discuss diagnostic and prognostic testing. To take into account the complex medical and psychological implications of this new approach, we developed a specific, multidisciplinary, and multiple step procedure, including a cardiologist, a geneticist, and a psychologist. Seventy subjects were examined, including (1) 29 adults for presymptomatic diagnosis (of whom 10 left the procedure after the first visit and 19 continued, among whom six had a mutation and two experienced negative psychological impact, observed during follow up), (2) nine couples of parents for presymptomatic diagnosis in their children (the procedure was stopped after the first visit in eight and continued in one), (3) 22 couples for prenatal counselling (no prenatal genetic testing was asked for after the first visit), and (4) 10 subjects for diagnostic testing. We decided to perform no prognostic testing. CONCLUSION: Our preliminary experience confirms the complexity of the situation and suggests the necessity for a specific procedure to ensure good practice in genetic testing of HCM.

Continuous-time quantum walks provide a natural framework to tackle the fundamental problem of finding a node among a set of marked nodes in a graph, known as spatial search. Whether spatial search by continuous-time quantum walk provides a quadratic advantage over classical random walks has been an outstanding problem. Thus far, this advantage is obtained only for specific graphs or when a single node of the underlying graph is marked. In this Letter, we provide a new continuous-time quantum walk search algorithm that completely resolves this: our algorithm can find a marked node in any graph with any number of marked nodes, in a time that is quadratically faster than classical random walks. The overall algorithm is quite simple, requiring time evolution of the quantum walk Hamiltonian followed by a projective measurement. A key component of our algorithm is a purely analogue procedure to perform operations on a state of the form e^{-tH^{2}}|ψ⟩, which, for a given Hamiltonian H, only requires evolving H for time scaling as sqrt[t]. This allows us to quadratically fast-forward the dynamics of a continuous-time classical random walk. The applications of our Letter thus go beyond the realm of quantum walks and can lead to new analog quantum algorithms for preparing ground states of Hamiltonians or solving optimization problems.

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This article explores the use of non-idempotent intersection types in the framework of the λ-calculus. Different topics are presented in a uniform framework: head normalization, weak normalization, weak head normalization, strong normalization, inhabitation, exact bounds and principal typings. The reducibility technique, traditionally used when working with idempotent types, is replaced in this framework by trivial combinatorial arguments.

Abstract Wiesner’s unforgeable quantum money scheme is widely celebrated as the first quantum information application. Based on the no-cloning property of quantum mechanics, this scheme allows for the creation of credit cards used in authenticated transactions offering security guarantees impossible to achieve by classical means. However, despite its central role in quantum cryptography, its experimental implementation has remained elusive because of the lack of quantum memories and of practical verification techniques. Here, we experimentally implement a quantum money protocol relying on classical verification that rigorously satisfies the security condition for unforgeability. Our system exploits polarization encoding of weak coherent states of light and operates under conditions that ensure compatibility with state-of-the-art quantum memories. We derive working regimes for our system using a security analysis taking into account all practical imperfections. Our results constitute a major step towards a real-world realization of this milestone protocol.

Most post-quantum-cryptography schemes rely on the fact that learning noisy functions is hard, even for quantum computers. However, this task is easy if quantum data is provided, which poses interesting consequences in the area of cryptography.

We investigate different notions of recognizability for a free monoid morphism $\unicode[STIX]{x1D70E}:{\mathcal{A}}^{\ast }\rightarrow {\mathcal{B}}^{\ast }$ . Full recognizability occurs when each (aperiodic) point in ${\mathcal{B}}^{\mathbb{Z}}$ admits at most one tiling with words $\unicode[STIX]{x1D70E}(a)$ , $a\in {\mathcal{A}}$ . This is stronger than the classical notion of recognizability of a substitution $\unicode[STIX]{x1D70E}:{\mathcal{A}}^{\ast }\rightarrow {\mathcal{A}}^{\ast }$ , where the tiling must be compatible with the language of the substitution. We show that if $|{\mathcal{A}}|=2$ , or if $\unicode[STIX]{x1D70E}$ ’s incidence matrix has rank $|{\mathcal{A}}|$ , or if $\unicode[STIX]{x1D70E}$ is permutative, then $\unicode[STIX]{x1D70E}$ is fully recognizable. Next we investigate the classical notion of recognizability and improve earlier results of Mossé [Puissances de mots et reconnaissabilité des points fixes d’une substitution. Theoret. Comput. Sci. 99 (2) (1992), 327–334] and Bezuglyi et al [Aperiodic substitution systems and their Bratteli diagrams. Ergod. Th. &amp;amp; Dynam. Sys. 29 (1) (2009), 37–72], by showing that any substitution is recognizable for aperiodic points in its substitutive shift. Finally we define recognizability and also eventual recognizability for sequences of morphisms which define an $S$ -adic shift. We prove that a sequence of morphisms on alphabets of bounded size, such that compositions of consecutive morphisms are growing on all letters, is eventually recognizable for aperiodic points. We provide examples of eventually recognizable, but not recognizable, sequences of morphisms, and sequences of morphisms which are not eventually recognizable. As an application, for a recognizable sequence of morphisms, we obtain an almost everywhere bijective correspondence between the $S$ -adic shift it generates, and the measurable Bratteli–Vershik dynamical system that it defines.