bluuebunny/crossref_metadata_2025 huggingface dataset:
CFU-S11 activity does not localize solely with the aorta in the aorta-gonad-mesonephros region
Authors: de Bruijn Marella F. T. R. , Peeters Marian C. E. , Luteijn Tanya , Visser Pim , Speck Nancy A. , Dzierzak Elaine
Published: October 2019

The aorta-gonad-mesonephros (AGM) region is a potent hematopoietic site in the midgestation mouse conceptus and first contains colony-forming units–spleen day 11 (CFU-S11) at embryonic day 10 (E10). Because CFU-S11 activity is present in the AGM region before the onset of hematopoietic stem cell (HSC) activity, CFU-S11 activity in the complex developing vascular and urogenital regions of the AGM was localized. From E10 onward, CFU-S11 activity is associated with the aortic vasculature, and is found also in the urogenital ridges (UGRs). Together with data obtained from organ explant cultures, in which up to a 16-fold increase in CFU-S11 activity was observed, it was determined that CFU-S11 can be increased autonomously both in vascular sites and in UGRs. Furthermore, CFU-S11 activity is present in vitelline and umbilical vessels. This, together with the presence of CFU-S11 in the UGRs 2 days before HSC activity, suggests both temporally and spatially distinct emergent sources of CFU-S11.
De novo factor VIII gene intron 22 inversion in a female carrier presents as a somatic mosaicism
Authors: Oldenburg Johannes , Rost Simone , El-Maarri Osman , Leuer Marco , Olek Klaus , Müller Clemens R. , Schwaab Rainer
Published: October 2019

The intron 22 inversion represents the most prevalentfactor VIII gene defect in severe hemophilia A, accounting for about 40% of all mutations. It is hypothesized that the inversion mutations occur almost exclusively in germ cells during meiotic cell division by intrachromosomal recombination between 1 of 2 telomeric copies of the Int22h region and its intragenic homologue. The majority of inversion mutations originate in male germ cells, where the lack of bivalent formation may facilitate flipping of the telomeric end of the single X chromosome. This is the first intron 22 inversion that presents as a somatic mosaicism in a female, affecting only about 50% of lymphocyte and fibroblast cells of the proposita. Supposing a post-zygotic de novo mutation as the usual cause of somatic mosaicism, the finding would imply that the intron 22 inversion mutation is not restricted to meiotic cell divisions but can also occur during mitotic cell divisions, either in germ cell precursors or in somatic cells.
Crystallographic structure and functional interpretation of the cytoplasmic domain of erythrocyte membrane band 3
Authors: Zhang Dachuan , Kiyatkin Anatoly , Bolin Jeffrey T. , Low Philip S.
Published: October 2019

The red blood cell membrane (RBCM) is a primary model for animal cell plasma membranes. One of its major organizing centers is the cytoplasmic domain of band 3 (cdb3), which links multiple proteins to the membrane. Included among its peripheral protein ligands are ankyrin (the major bridge to the spectrin-actin skeleton), protein 4.1, protein 4.2, aldolase, glyceraldehyde-3-phosphate dehydrogenase, phosphofructokinase, deoxyhemoglobin, p72syk protein tyrosine kinase, and hemichromes. The crystal structure of cdb3 is reported at 0.26 nm (2.6 Å) resolution. A tight symmetric dimer is formed by cdb3; it is stabilized by interlocked dimerization arms contributed by both monomers. Each subunit also includes a larger peripheral protein binding domain with an α+  β-fold. The binding sites of several peripheral proteins are localized in the structure, and the nature of the major conformational change that regulates membrane-skeletal interactions is evaluated. An improved structural definition of the protein network at the inner surface of the RBCM is now possible.
A phase I/II trial of iodine-131–tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas
Authors: Press Oliver W. , Eary Janet F. , Gooley Ted , Gopal Ajay K. , Liu Stephen , Rajendran Joseph G. , Maloney David G. , Petersdorf Stephen , Bush Sharon A. , Durack Lawrence D. , Martin Paul J. , Fisher Darrell R. , Wood Brent , Borrow James W. , Porter Bruce , Smith Justin P. , Matthews Dana C. , Appelbaum Frederick R. , Bernstein Irwin D.
Published: October 2019

Relapsed B-cell lymphomas are incurable with conventional chemotherapy and radiation therapy, although a fraction of patients can be cured with high-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT). We conducted a phase I/II trial to estimate the maximum tolerated dose (MTD) of iodine 131 (131I)–tositumomab (anti-CD20 antibody) that could be combined with etoposide and cyclophosphamide followed by ASCT in patients with relapsed B-cell lymphomas. Fifty-two patients received a trace-labeled infusion of 1.7 mg/kg 131I-tositumomab (185-370 MBq) followed by serial quantitative gamma-camera imaging and estimation of absorbed doses of radiation to tumor sites and normal organs. Ten days later, patients received a therapeutic infusion of 1.7 mg/kg tositumomab labeled with an amount of131I calculated to deliver the target dose of radiation (20-27 Gy) to critical normal organs (liver, kidneys, and lungs). Patients were maintained in radiation isolation until their total-body radioactivity was less than 0.07 mSv/h at 1 m. They were then given etoposide and cyclophosphamide followed by ASCT. The MTD of131I-tositumomab that could be safely combined with 60 mg/kg etoposide and 100 mg/kg cyclophosphamide delivered 25 Gy to critical normal organs. The estimated overall survival (OS) and progression-free survival (PFS) of all treated patients at 2 years was 83% and 68%, respectively. These findings compare favorably with those in a nonrandomized control group of patients who underwent transplantation, external-beam total-body irradiation, and etoposide and cyclophosphamide therapy during the same period (OS of 53% and PFS of 36% at 2 years), even after adjustment for confounding variables in a multivariable analysis.
T-lymphocyte production of macrophage inflammatory protein-1α is critical to the recruitment of CD8+ T cells to the liver, lung, and spleen during graft-versus-host disease
Authors: Serody Jonathan S. , Burkett Susan E. , Panoskaltsis-Mortari Angela , Ng-Cashin Judith , McMahon Eileen , Matsushima Glenn K. , Lira Sergio A. , Cook Donald N. , Blazar Bruce R.
Published: October 2019

To investigate the mechanism by which macrophage inflammatory protein-1α (MIP-1α) affects graft-versus-host disease (GVHD), the expression and function of MIP-1α in 2 murine models of GVHD were evaluated. In irradiated class I and class II disparate recipients, the expression of messenger RNA (mRNA) and protein for MIP-1α was significantly increased in GVHD target organs after transfer of allogeneic lymphocytes compared to syngeneic lymphocytes. When lymphocytes unable to make MIP-1α were transferred, there was a decrease in the production of MIP-1α in the liver, lung, and spleen of bm1 (B6.C-H2bm1/By) and bm12 (B6.C-H2bm12/KhEg) recipients compared to the transfer of wild-type splenocytes. At day 6 there was a 4-fold decrease in the number of transferred CD8+ T cells in the lung and approximately a 2-fold decrease in the number of CD8+ T cells in the liver and spleen in bm1 recipients after transfer of MIP-1α–deficient (MIP-1α−/−) splenocytes compared to wild-type (MIP-1α+/+) splenocytes. These differences persisted for 13 days after splenocyte transfer. In contrast, the number of donor CD4+ T cells found in the liver and lung was significantly increased after the transfer of MIP-1α−/− compared to wild-type splenocytes in bm12 recipients from day 6 through day 10. Thus, the transfer of allogeneic T cells was associated with the enhanced expression of MIP-1α in both a class I and class II mismatch setting. However, the increased expression only led to enhanced recruitment of CD8+, but not CD4+, donor T cells. Production of MIP-1α by donor T cells is important in the occurrence of GVHD and functions in a tissue-dependent fashion.
Dimerization of P-selectin in platelets and endothelial cells
Authors: Barkalow Fern J. , Barkalow Kurt L. , Mayadas Tanya N.
Published: October 2019

P-selectin is a leukocyte adhesion receptor stored in platelets and endothelial cells and is translocated to the surface upon cell activation. Purified P-selectin is oligomeric and has increased avidity for its ligand relative to the monomeric form, but whether P-selectin self-associates in the membrane of intact cells is not known. A chemical cross-linking approach was used to show that P-selectin is present as noncovalent dimers in resting platelets, human umbilical vein endothelial cells, and heterologous RIN5F cells expressing P-selectin. The results of 2-dimensional isoelectric focusing are consistent in showing P-selectin dimers as homodimers, but they are composed of a more basic subset of P-selectin than the monomers. This suggests that the dimers are a biochemically distinct subset of P-selectin. P-selectin dimers form in the endoplasmic reticulum and Golgi compartments of human umbilical vein endothelial cells only after synthesis of the mature P-selectin subunit, and are not preferentially stored in Weibel-Palade bodies as compared with the monomeric form. Platelet activation with thrombin receptor–activating peptide leads to the presence of P-selectin monomers and homodimers on the cell surface as well as P-selectin heterodimers, which are composed of P-selectin and an unidentified protein of approximately 81 kd molecular weight. In summary, these studies demonstrate that P-selectin is homodimeric in situ and that platelet activation leads to the formation of an additional activation-specific heterodimeric species. In addition, the homodimer has unique biochemical characteristics compared with the monomeric form, and dimerization occurs in the endoplasmic reticulum and Golgi compartments of endothelial cells.
The human antimicrobial and chemotactic peptides LL-37 and α-defensins are expressed by specific lymphocyte and monocyte populations
Authors: Agerberth Birgitta , Charo Jehad , Werr Joachim , Olsson Berit , Idali Farah , Lindbom Lennart , Kiessling Rolf , Jörnvall Hans , Wigzell Hans , Gudmundsson Gudmundur H.
Published: October 2019

We identified antibacterial components in human T and natural killer (NK) cells by using freshly isolated lymphocytes enriched for T and NK cells as starting material. After growing these lymphocytes for 5 days in the presence of interleukin (IL)–2, we isolated and characterized several antibacterial peptides/proteins from the supernatant—α-defensins (HNP 1-3), LL-37, lysozyme, and a fragment of histone H2B—although other active components were also present. We then used reverse transcriptase–polymerase chain reaction to search for expression of the gene coding for LL-37 in several B-cell lines, γδ T-cell lines, NK clones, and one monocytic cell line, with positive results, but found no expression in several αβ T-cell lines. The α-defensins (HNP 1-3) were also found to be expressed in several of these cell lines. To confirm the presence of these antibacterial peptides in lymphocytes, we localized them to NK, γδ T cells, B cells, and monocytes/macrophages by using double-staining immunohistochemical analysis of freshly isolated lymphocytes. We also found that primary cultures of lymphocytes transcribe and secrete LL-37 and that these processes are affected by IL-6 and interferon-γ. In addition, we demonstrated that LL-37 has chemotactic activity for polymorphonuclear leukocytes and CD4 T lymphocytes, whereas others have shown chemotactic activity for human α-defensins (HNP 1-2). These findings suggest that microbicidal peptides are effector molecules of lymphocytes and that antibacterial activity previously shown to be derived from T and NK cells may be partly mediated by the antibacterial peptides LL-37 and HNP 1-3.
Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells
Authors: Brossart Peter , Wirths Stefan , Stuhler Gernot , Reichardt Volker L. , Kanz Lothar , Brugger Wolfram
Published: October 2019

Vaccination of patients with cancer using dendritic cells (DCs) was shown to be effective for B-cell lymphoma and malignant melanoma. Here we provide evidence that patients with advanced breast and ovarian cancer can be efficiently vaccinated with autologous DCs pulsed with HER-2/neu– or MUC1-derived peptides. Ten patients were included in this pilot study. The DC vaccinations were well tolerated with no side effects. In 5 of 10 patients, peptide-specific cytotoxic T lymphocytes (CTLs) could be detected in the peripheral blood using both intracellular IFN-γ staining and 51Cr-release assays. The major CTL response in vivo was induced with the HER-2/neu–derived E75 and the MUC1-derived M1.2 peptide, which lasted for more than 6 months, suggesting that these peptides might be immunodominant. In addition, in one patient vaccinated with the MUC1-derived peptides, CEA- and MAGE-3 peptide-specific T-cell responses were detected after several vaccinations. In a second patient immunized with the HER-2/neu peptides, MUC1-specific T lymphocytes were induced after 7 immunizations, suggesting that antigen spreading in vivo might occur after successful immunization with a single tumor antigen. Our results show that vaccination of DCs pulsed with a single tumor antigen may induce immunologic responses in patients with breast and ovarian cancer. This study may be relevant to the design of future clinical trials of other peptide-based vaccines.
The Fanconi anemia proteins FANCA and FANCG stabilize each other and promote the nuclear accumulation of the Fanconi anemia complex
Authors: Garcia-Higuera Irene , Kuang Yanan , Denham Jessica , D'Andrea Alan D.
Published: October 2019

Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome with 8 complementation groups. Four of the FA genes have been cloned, and at least 3 of the encoded proteins, FANCA, FANCC, and FANCG/XRCC9, interact in a multisubunit protein complex. The FANCG protein binds directly to the amino terminal nuclear localization sequence (NLS) of FANCA, suggesting that FANCG plays a role in regulating FANCA nuclear accumulation. In the current study the functional consequences of FANCG/FANCA binding were examined. Correction of an FA-G cell line with the FANCG complementary DNA (cDNA) resulted in FANCA/FANCG binding, prolongation of the cellular half-life of FANCA, and an increase in the nuclear accumulation of the FA protein complex. Similar results were obtained upon correction of an FA-A cell line, with a reciprocal increase in the half-life of FANCG. Patient-derived mutant forms of FANCA, containing an intact NLS sequence but point mutations in the carboxy-terminal leucine zipper region, bound FANCG in the cytoplasm. The mutant forms failed to translocate to the nucleus of transduced cells, thereby suggesting a model of coordinated binding and nuclear translocation. These results demonstrate that the FANCA/FANCG interaction is required to maintain the cellular levels of both proteins. Moreover, at least one function of FANCG and FANCA is to regulate the nuclear accumulation of the FA protein complex. Failure to accumulate the nuclear FA protein complex results in the characteristic spectrum of clinical and cellular abnormalities observed in FA.
Apoptosis in megaloblastic anemia occurs during DNA synthesis by a p53-independent, nucleoside-reversible mechanism
Authors: Koury Mark J. , Price James O. , Hicks Geoffrey G.
Published: October 2019

Deficiency of folate or vitamin B12 (cobalamin) causes megaloblastic anemia, a disease characterized by pancytopenia due to the excessive apoptosis of hematopoietic progenitor cells. Clinical and experimental studies of megaloblastic anemia have demonstrated an impairment of DNA synthesis and repair in hematopoietic cells that is manifested by an increased percentage of cells in the DNA synthesis phase (S phase) of the cell cycle, compared with normal hematopoietic cells. Both folate and cobalamin are required for normal de novo synthesis of thymidylate and purines. However, previous studies of impaired DNA synthesis and repair in megaloblastic anemia have concerned mainly the decreased intracellular levels of thymidylate and its effects on nucleotide pools and misincorporation of uracil into DNA. An in vitro model of folate-deficient erythropoiesis was used to study the relationship between the S-phase accumulation and apoptosis in megaloblastic anemia. The results indicate that folate-deficient erythroblasts accumulate in and undergo apoptosis in the S phase when compared with control erythroblasts. Both the S-phase accumulation and the apoptosis were induced by folate deficiency in erythroblasts fromp53 null mice. The complete reversal of the S-phase accumulation and apoptosis in folate-deficient erythroblasts required the exogenous provision of specific purines or purine nucleosides as well as thymidine. These results indicate that decreased de novo synthesis of purines plays as important a role as decreased de novo synthesis of thymidylate in the pathogenesis of megaloblastic anemia.
Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation
Authors: Bekri Soumeya , Kispal Gyula , Lange Heike , Fitzsimons Edward , Tolmie John , Lill Roland , Bishop David F.
Published: October 2019

The human protein ABC7 belongs to the adenosine triphosphate-binding cassette transporter superfamily, and its yeast orthologue, Atm1p, plays a central role in the maturation of cytosolic iron-sulfur (Fe/S) cluster-containing proteins. Previously, a missense mutation in the human ABC7 gene was shown to be the defect in members of a family affected with X-linked sideroblastic anemia with cerebellar ataxia (XLSA/A). Here, the promoter region and the intron/exon structure of the human ABC7 gene were characterized, and the function of wild-type and mutant ABC7 in cytosolic Fe/S protein maturation was analyzed. The gene contains 16 exons, all with intron/exon boundaries following the AG/GT rule. A single missense mutation was found in exon 10 of the ABC7gene in 2 affected brothers with XLSA/A. The mutation was a G-to-A transition at nucleotide 1305 of the full-length cDNA, resulting in a charge inversion caused by the substitution of lysine for glutamate at residue 433 C-terminal to the putative sixth transmembrane domain of ABC7. Expression of normal ABC7 almost fully complemented the defect in the maturation of cytosolic Fe/S proteins in a yeast strain in which the ATM1 gene had been deleted (Δatm1 cells). Thus, ABC7 is a functional orthologue of Atm1p. In contrast, the expression of mutated ABC7 (E433K) or Atm1p (D398K) proteins in Δatm1 cells led to a low efficiency of cytosolic Fe/S protein maturation. These data demonstrate that both the molecular defect in XLSA/A and the impaired maturation of a cytosolic Fe/S protein result from an ABC7 mutation in the reported family.
The dynamics of hepatitis C virus binding to platelets and 2 mononuclear cell lines
Authors: Hamaia Samir , Li Chengyao , Allain Jean-Pierre
Published: October 2019

Hepatitis C virus (HCV) binds to platelets in chronically infected patients where free HCV constitutes only about 5% of total circulating virus. Free HCV preferentially binds to human mononuclear cell lines but free and complexed virus binds equally to platelets. The extent of free HCV binding to human Molt-4 T cells (which express CD81) and to human promonocytic U937 cells or to platelets (which do not express CD81) was similar. The binding of free HCV to the cell lines was saturated at a virus dose of 1 IU HCV RNA per cell but binding to platelets was not saturable. Human anti-HCV IgG, but not anti-CD81, markedly inhibited HCV binding to target cells in a dose-dependent manner. Human antibodies to HCV hypervariable region 1 of E2 glycoprotein partially inhibited viral binding to target cells. Recombinant E2 also inhibited viral binding to target cells in a dose-dependent manner, with the efficacy of this decreasing in the rank order of Molt-4 cells more than U937 cells more than platelets. In contrast to HCV, recombinant E2 bound to Molt-4 cells to an extent markedly greater than that apparent with U937 cells or platelets. These results suggest that the binding of HCV to blood cells is mediated by multiple cell surface receptors and that recombinant E2 binding may not be representative of the interaction of the intact virus with target cells.
Erythropoietin receptor-dependent erythroid colony-forming unit development: capacities of Y343 and phosphotyrosine-null receptor forms
Authors: Miller Chris P. , Heilman Destin W. , Wojchowski Don M.
Published: October 2019

Red cell development depends on the binding of erythropoietin (EPO) to receptors expressed by erythroid colony-forming units (CFUe) and the subsequent activation of receptor-bound Janus kinase (Jak2). Jak2 then mediates the phosphorylation of receptor tyrosine sites and the recruitment of 25 or more Src homology 2 domain-encoding proteins and associated factors. Previous studies have shown that an EPO receptor form containing Jak2-binding domains plus a single phosphotyrosine343 (PY343)–STAT5-binding site provides all signals needed for erythroid cell development. However, roles for PY343 and STAT5 remain controversial, and findings regarding PY-null receptor activities and erythropoiesis in STAT5-deficient mice are disparate. To study activities of a PY-null EPO receptor in primary cells while avoiding compensatory mechanisms, a form retaining domains for Jak2 binding and activation, but lacking all cytoplasmic tyrosine sites, was expressed in transgenic mice from aGATA1 gene-derived vector as a human epidermal growth factor receptor- murine EPO receptor chimera (EE-T-Y343F). The bio-signaling capacities of this receptor form were investigated in CFUe from thiamphenicol-treated mice. Interestingly, this PY-null EPO receptor form supported CFUe development (in the absence of detectable STAT5 activation) at efficiencies within 3-fold of those levels mediated by either an EE-T-Y343 form or the endogenous EPO receptor. However, EE-T-Y343F–dependent Ter119+ erythroblast maturation was attenuated. In tests of cosignaling with c-Kit, EE-T-Y343F nonetheless retained full capacity to synergize with c-Kit in promoting erythroid progenitor cell proliferation. Thus, EPO receptor PY-dependent events can assist late erythropoiesis but may be nonessential for EPO receptor–c-Kit synergy.
Cyclin A transcriptional suppression is the major mechanism mediating homocysteine-induced endothelial cell growth inhibition
Authors: Wang Hong , Jiang XiaoHua , Yang Fan , Chapman Gary B. , Durante William , Sibinga Nicholas E. S. , Schafer Andrew I.
Published: October 2019

Previously, it was reported that homocysteine (Hcy) specifically inhibits the growth of endothelial cells (ECs), suppresses Ras/mitogen-activated protein (MAP) signaling, and arrests cell growth at the G1/S transition of the cell cycle. The present study investigated the molecular mechanisms underlying this cell-cycle effect. Results showed that clinically relevant concentrations (50 μM) of Hcy significantly inhibited the expression of cyclin A messenger RNA (mRNA) in ECs in a dose- and time-dependent manner. G1/S-associated molecules that might account for this block were not changed, because Hcy did not affect mRNA and protein expression of cyclin D1 and cyclin E. Cyclin D1- and E-associated kinase activities were unchanged. In contrast, cyclin A–associated kinase activity and CDK2 kinase activity were markedly suppressed. Nuclear run-on assay demonstrated that Hcy decreased the transcription rate of the cyclin A gene but had no effect on the half-life of cyclin A mRNA. In transient transfection experiments, Hcy significantly inhibited cyclin A promoter activity in endothelial cells, but not in vascular smooth muscle cells. Finally, adenovirus-transduced cyclin A expression restored EC growth inhibition and overcame the S phase block imposed by Hcy. Taken together, these findings indicate that cyclin A is a critical functional target of Hcy-mediated EC growth inhibition.
Remote homology searches identify bacterial homologues of eukaryotic lipid transfer proteins, including Chorein-N domains in TamB and AsmA and Mdm31p
Authors: Levine Timothy P.
Published: October 2019

Background

All cells rely on lipids for key functions. Lipid transfer proteins allow lipids to exit the hydrophobic environment of bilayers, and cross aqueous spaces. One lipid transfer domain fold present in almost all eukaryotes is the TUbular LIPid binding (TULIP) domain. Three TULIP families have been identified in bacteria (P47, OrfX2 and YceB), but their homology to eukaryotic proteins is too low to specify a common origin. Another recently described eukaryotic lipid transfer domain in VPS13 and ATG2 is Chorein-N, which has no known bacterial homologues. There has been no systematic search for bacterial TULIPs or Chorein-N domains.

Results

Remote homology predictions for bacterial TULIP domains using HHsearch identified four new TULIP domains in three bacterial families. DUF4403 is a full length pseudo-dimeric TULIP with a 6 strand β-meander dimer interface like eukaryotic TULIPs. A similar sheet is also present in YceB, suggesting it homo-dimerizes. TULIP domains were also found in DUF2140 and in the C-terminus DUF2993. Remote homology predictions for bacterial Chorein-N domains identified strong hits in the N-termini of AsmA and TamB in diderm bacteria, which are related to Mdm31p in eukaryotic mitochondria. The N-terminus of DUF2993 has a Chorein-N domain adjacent to its TULIP domain.

Conclusions

TULIP lipid transfer domains are widespread in bacteria. Chorein-N domains are also found in bacteria, at the N-terminus of multiple proteins in the intermembrane space of diderms (AsmA, TamB and their relatives) and in Mdm31p, a protein that is likely to have evolved from an AsmA/TamB-like protein in the endosymbiotic mitochondrial ancestor. This indicates that both TULIP and Chorein-N lipid transfer domains may have originated in bacteria.
Cortical pencil lining on SWI MRI in NBIA and healthy aging
Authors: van der Weijden Marlous C. M. , van Laar Peter Jan , Lambrechts Roald A. , Verbeek Dineke S. , Tijssen Marina A. J.
Published: October 2019

Background

Neurodegeneration with brain iron accumulation (NBIA) is characterized by pathological iron accumulation in the subcortical nuclei and the cortex. As age-related iron accumulation studies in these structures are lacking in healthy aging, we aimed to characterize the dynamics of age-dependent iron accumulation in subcortical nuclei in healthy aging and selected NBIA cases. This is fundamental to understand the natural age-related iron deposition in the healthy brain prior to using this marker as a potential prognostic or diagnostic tool in neurodegenerative disorders.

Methods

Susceptibility-weighted imaging (SWI) scans from 81 healthy volunteers (0-79 years) and four genetically confirmed patients suffering from NBIA (2-14 years) were obtained. We scored the presence or absence of pencil lining of the motor cortex and putamen and analyzed the normalized SWI signal intensity ratio (NSIR) in five subcortical nuclei.

Results

In healthy subjects, an age-dependent increase of pencil lining occurred starting from the second decade of life and was present in all cases at the age of 50. In their first decade, NBIA patients showed no cortical pencil lining, but we did observe putaminal pencil lining at this stage. In healthy subjects, age and NSIR of all nuclei correlated positively and was particularly dynamic in early childhood until young adulthood in the globus pallidus, dentate nucleus and red nucleus, but not in the caudate nucleus and putamen. NBIA patients showed an increased NSIR in the globus pallidus only and not in the other subcortical nuclei compared to age-matched healthy subjects.

Conclusions

Cortical pencil lining is part of healthy aging. This should be considered when assessing this as a potential marker in NBIA diagnosis and prognosis. Putaminal pencil lining has the potential to become a specific marker for some subtypes of NBIA in the first decade of life, as it was only observed in NBIA and not in age-matched healthy subjects. NSIR in the subcortical nuclei during healthy aging was shown to be dynamic, accentuating the importance of having an age-dependent baseline.
Demyelinating syndrome in systemic sclerosis and neuromyelitis optica
Authors: Deeb Khaled , Eby Jessika , Labault-Santiago Jose
Published: October 2019

Background

This article reports a case diagnosis of a 44-year-old female who presented with intractable hiccups and vomit complicated with an acute onset of paraplegia. Transverse myelitis was evident on MRI and serological studies were consistent with Neuromyelitis Optica (NMO) based on NMO-IgG sero-positivity. Further studies revealed positive ANA, anti-RNA polymerase III autoantibodies, and Scl-70, leading to a concurrent diagnosis of systemic sclerosis (SSc). The coexistence of these two disease processes and their underlying clinical manifestations and therapeutic interventions are seldom reported in literature and are worth reporting.

Case presentation

The patient was treated with high dose steroids, and subsequently developed malignant hypertension and acute renal failure, later identified on biopsy as steroids-induced scleroderma renal crisis. Although Neuromyelitis Optica spectrum disorder (NMOSD) has often been associated with various collagen and autoimmune diseases, the coexistence of NMOSD and SSc presented a challenge where the patient underwent aggressive physical therapy and necessitated an intervention with Rituximab to achieve an appropriate clinical response.

We have received a written consent forms from the participant in our study, and we have them on file in case they are requested. We have also received the patient’s written consent for the data and images presented in this article.

Conclusion

This article expands on NMOSD associated autoimmune diseases. Systemic Sclerosis is an insidious disease that is often diagnosed late as not all patients often report skin manifestation. The finding suggests that patients presenting with acute neurological manifestations get tested for NMO-IgG/AQP-4 antibodies and other immunological studies based on clinical findings.
Identification of a novel splicing mutation in the SLC25A13 gene from a patient with NICCD: a case report
Authors: Zhang Linlin , Li Yingying , Shi Wenli , Gao Jinshuang , Tian Yuan , Li Ying , Guo Yaqing , Cui Shihong , Zhang Xiaoan
Published: October 2019

Background

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disorder and one of the most common inherent causes of cholestatic jaundice in Asian infants. Mutations in the SLC25A13 gene, which encodes citrin protein expressed in the liver, have been identified as the genetic cause for NICCD.

Case presentation

Here, we report a 4-month-old female with clinical features including jaundice, hyperbilirubinemia, hyperlactacidemia, and abnormal liver function. The patient was diagnosed with NICCD by differential diagnosis using genetic analysis. Mutations in 60 jaundice-related genes were tested by using amplicon sequencing, which was performed on an Ion S5XL genetic analyzer. A compound heterozygous mutation in the SLC25A13 gene was identified, consisting of a known deletion SLC25A13:c.852_855delTATG and a novel splicing mutation SLC25A13:c.1841 + 3_1841 + 4delAA. Sanger sequencing for the proband and her parents was performed to validate the result and reveal the source of mutations.

Conclusion

A compound heterozygous mutation in the SLC25A13 gene was identified in a 4-month-old female patient with NICCD. Our data suggest that amplicon sequencing is a helpful tool for the differential diagnosis of inherited diseases with similar symptoms. Further studies of the mutation spectrum of neonatal jaundice in China are warranted.
A systematic review of monitoring and evaluation indicators for sexual and reproductive health in humanitarian settings
Authors: Broaddus-Shea Elena T. , Kobeissi Loulou , Ummer Osama , Say Lale
Published: October 2019

Objective

To conduct a comprehensive mapping of published indicators for monitoring and evaluation (M&E) of sexual and reproductive health (SRH) services and outcomes in humanitarian settings.

Methods

A systematic search of the peer-reviewed and grey literature published between January 2008 and May 2018 was conducted to identify all references describing indicator sets for M&E of SRH services and outcomes in humanitarian settings. The databases MEDLINE, Web of Science, and Global Health, as well as 85 websites of relevant organizations involved in humanitarian response were searched. Characteristics of identified indicator sets and data from individual indicators was extracted.

Findings

Of 3278 records identified, 20 met the review’s inclusion criteria and 9 existing indicator sets were identified. A total of 179 relevant indicators were included in the mapping, and removal of duplicates yielded 132 unique indicators. Twenty-seven percent fell within the maternal health domain, followed by the HIV/AIDS domain (26%) and the gender-based violence domain (23%). The distribution of indicators by type (process/output, outcome, impact) was balanced overall but varied substantially across domains. The most commonly used data collection platforms were facility-based systems or population-based surveys. Domains covered and indicator definitions were inconsistent across indicator sets.

Conclusion

Results demonstrate the need to standardize data collection efforts for M&E of SRH services and outcomes in humanitarian settings and to critically appraise the extent to which different domains should be covered. A core list of indicators is essential for assessing response status over time as well as across countries.
A transcriptional response of Clostridium beijerinckii NRRL B-598 to a butanol shock
Authors: Sedlar Karel , Kolek Jan , Gruber Markus , Jureckova Katerina , Branska Barbora , Csaba Gergely , Vasylkivska Maryna , Zimmer Ralf , Patakova Petra , Provaznik Ivo
Published: October 2019

Background

One of the main obstacles preventing solventogenic clostridia from achieving higher yields in biofuel production is the toxicity of produced solvents. Unfortunately, regulatory mechanisms responsible for the shock response are poorly described on the transcriptomic level. Although the strainClostridium beijerinckiiNRRL B-598, a promising butanol producer, has been studied under different conditions in the past, its transcriptional response to a shock caused by butanol in the cultivation medium remains unknown.

Results

In this paper, we present a transcriptional response of the strain during a butanol challenge, caused by the addition of butanol to the cultivation medium at the very end of the acidogenic phase, using RNA-Seq. We resequenced and reassembled the genome sequence of the strain and prepared novel genome and gene ontology annotation to provide the most accurate results. When compared to samples under standard cultivation conditions, samples gathered during butanol shock represented a well-distinguished group. Using reference samples gathered directly before the addition of butanol, we identified genes that were differentially expressed in butanol challenge samples. We determined clusters of 293 down-regulated and 301 up-regulated genes whose expression was affected by the cultivation conditions. Enriched term “RNA binding” among down-regulated genes corresponded to the downturn of translation and the cluster contained a group of small acid-soluble spore proteins. This explained phenotype of the culture that had not sporulated. On the other hand, up-regulated genes were characterized by the term “protein binding” which corresponded to activation of heat-shock proteins that were identified within this cluster.

Conclusions

We provided an overall transcriptional response of the strainC. beijerinckiiNRRL B-598 to butanol shock, supplemented by auxiliary technologies, including high-pressure liquid chromatography and flow cytometry, to capture the corresponding phenotypic response. We identified genes whose regulation was affected by the addition of butanol to the cultivation medium and inferred related molecular functions that were significantly influenced. Additionally, using high-quality genome assembly and custom-made gene ontology annotation, we demonstrated that this settled terminology, widely used for the analysis of model organisms, could also be applied to non-model organisms and for research in the field of biofuels.
Use of literature mining for early identification of emerging contaminants in freshwater resources
Authors: Hartmann Julia , Wuijts Susanne , van der Hoek Jan Peter , de Roda Husman Ana Maria
Published: October 2019

Chemical and microbial contaminants in the aquatic environment pose a potential threat to humans and to ecosystems. Humans may be exposed to contaminants in water resources when used for drinking water production, agriculture, aquaculture or recreation. Climatological, social and demographic changes, as well as the increasing sensitivity of analytical techniques, may result in the augmented detection of contaminants. Recent research has shown that it takes about 15 years from the time of the first scientific study mentioning the presence of a contaminant in the environment for the issue to peak in scientific attention and regulatory action. One possible factor influencing this lengthy period is that the first article becomes lost in the vast number of publications. In this study, we therefore developed a methodology using literature mining to identify the first scientific study which reports the presence of a contaminant in the aquatic environment. The developed semi-automated methodology enables health and environment agencies to inform policy makers about contaminants in the aquatic environment that could be significant for public and environmental health in national, international and river basin settings. The methodology thereby assists the proactive governance of emerging contaminants in the aquatic environment. This was illustrated by a retrospective analysis of the period of emergence in the Netherlands of: (1) perfluorooctanoic acid in surface water, and (2) biological industrial wastewater treatment systems as potential infection sources for Legionnaires´ disease.
Shear Friction Characteristics and Modification Factor of Concrete Prepared Using Expanded Bottom Ash and Dredged Soil Granules
Authors: Yang Keun-Hyeok , Lee Kyung-Ho
Published: October 2019

The objective of this study is to assess the shear friction characteristics of lightweight aggregate concrete (LWAC) prepared using artificially expanded bottom ash and dredged soil granules. A total of 37 concrete mixtures were prepared under the classification of three series. In the first and second series, the natural sand content for replacing lightweight fine aggregates and the water-to-cement ratio varied to obtain different densities and compressive strengths of concrete. The third series was designed to estimate the effect of the maximum aggregate size on the friction resistance along the shear crack plane of the monolithic interfaces. The frictional angle of the LWAC tested was formulated as a function of the ratio of the effective tensile and compressive strengths of concrete through the expansion of the integrated mathematical models proposed by Kwon et al., based on the upper-bound theorem of concrete plasticity. When predicting the shear friction strength of LWAC, the present mathematical model exhibits relatively good accuracy, yielding the mean and standard deviation of the ratios between experiments and predictions of 1.06 and 0.14, respectively, whereas the empirical equations proposed by the AASHTO provision and Mattock underestimated the results. Ultimately, an advanced modification factor for shear design of LWAC is proposed as a function of the density and compressive strength of concrete and the maximum size of aggregates.
Toward a test of the “Law of Crime Concentration” in Japanese cities: a geographical crime analysis in Tokyo and Osaka
Authors: Amemiya Mamoru , Ohyama Tomoya
Published: October 2019

This brief report aims to reveal crime concentration at the district level in Tokyo and Osaka, Japan, two cities characterized by low crime rates. Eight types of property crimes that occurred between 2008 and 2017 in Tokyo and Osaka and had been aggregated by the census enumeration district were analyzed using the Gini coefficient based on the Poisson-Gamma method. The results indicated three patterns. First, crime concentration was identified. Second, the degree of concentration depended upon crime type. Commercial burglary was the most concentrated crime type, and theft from vehicle and theft from vending machine were the most dispersed. Third, crime concentration patterns either remained stable or became more concentrated over time. Additionally, while theft of bicycle was found to display stable concentration levels over time, the concentration level of purse snatching was fluid. On the basis of the results, this report discusses the possibility of establishing the “Law of Crime Concentration” (LCC) in two Japanese cities.
How do healthcare practitioners read electrocardiograms? A dual-process model of electrocardiogram interpretation
Authors: Davies Alan , Mueller Julia , Horseman Laura , Splendiani Bruno , Hill Elspeth , Vigo Markel , Harper Simon , Jay Caroline
Published: October 2019

Background/Aims: This article aims to improve the understanding of the applied cognitive processes when interpreting electrocardiograms in clinical practice. It will do this by examining the self-reported approach practitioners take to interpret any barriers they encounter.

Methods: This was a qualitative study in which medical practitioners, who routinely interpret electrocardiograms (n=31), were interviewed. The semi-structured interviews covered: their experience of interpretation; use of a system; pitfalls; changes to approach over time. An inductive thematic analysis was used to identify commonly occurring themes. A further set of practitioners (n=31), completed surveys that concerned their approach to an interpretation and use of interpretation frameworks/systems.

Results: Practitioners find it easier to interpret electrocardiograms as they gain experience, but the process remains difficult. Barriers to successful interpretation include artefacts altering the waveform, lack of familiarity with the presenting condition, stress/panic at the prospect of making an inaccurate judgement, and overconfidence in one's interpretation abilities.

Conclusions: The results support a dual-process system model that is developed with experience and enhances performance. Over time, experienced practitioners become able to move fluidly between a more formal systematic method and an experience-driven pattern recognition system. Potential errors that may arise from a reliance on pattern recognition (e.g. missing details) can be mitigated by using a systematic approach.
Loneliness, social isolation and cardiovascular risk
Authors: Alun Jackson , Murphy Barbara
Published: October 2019

Loneliness and social isolation are increasingly being acknowledged as risk factors for both physical and mental health problems. Recent statistics demonstrate that loneliness and isolation are on the rise internationally, to the point of being classed as an epidemic. In this paper, the authors outline some of the recent research linking loneliness and isolation to significant chronic diseases such as cardiovascular disease and type II diabetes; mental health disorders such as anxiety and depression; cognitive disorders and dementia. Isolation has also been shown to compromise recovery after acute cardiac events, being associated with increased hospital readmission and premature death. Indeed, isolation has now been identified as a risk factor equivalent in effect to traditional risk factors such as smoking, hypertension and obesity. While distinguishing between objective and subjective indicators of isolation, the authors highlight the complexity of this phenomenon, both in terms of definition and measurement, as well as the interplay between subjective and objective indicators. Important clinical implications for health professionals working with cardiac patients are also proposed, in terms of screening for isolation, and possible interventions to support patients at risk of isolation. The aim of the current article is to emphasise the importance of acknowledging loneliness and isolation as key risk factors requiring urgent attention, both in research and in clinical practice.
CQC Annual Report and Accounts 2018–19
Authors: Frankova Helena
Published: October 2019

Is the Care Quality Commission's annual expenditure – almost £228 million in 2018/19 – yielding results? This article looks for answers in their Annual Report and Accounts
The value of longitudinal data
Authors: Bradley Steve
Published: October 2019

Steve Bradley, Group Managing Director, Cegedim UK, outlines how data holds the key to better patient care
A guide to the CQC Annual Regulatory Review
Authors: McCutcheon Jonathan
Published: October 2019

In this article, Jonathan McCutcheon shares some lessons on the annual regulatory review carried out by the Care Quality Commission
Preparing for RSE
Authors: Cole Anna
Published: October 2019

The introduction of statutory relationships and sex education is drawing closer. Anna Cole looks at the aspects that might prove most controversial – or tricky – for school leaders
Classroom routines…
Authors: Bromley Matt
Published: October 2019

Establishing classroom rules and routines is a vital part of good teaching. Matt Bromley advises trainee teachers and NQTs on developing and building on effective practice
Self-harm: How teachers should respond
Authors: Waller Charlie
Published: October 2019

A guide from the University of Oxford and the Charlie Waller Memorial Trust offers practical ways in which schools and school staff can support young people at risk from self-harm
Feedback, metacognition and other interventions
Authors: Bromley Matt
Published: October 2019

The research reviews of the Teaching and Learning Toolkit show that metacognition and feedback are among the most effective strategies, especially for Pupil Premium students. Matt Bromley looks at what the evidence says about these and other promising approaches
Three tenets of effective Pupil Premium practice
Authors: Bromley Matt
Published: October 2019

For this Best Practice Focus, Matt Bromley describes three steps of Pupil Premium practice – touching upon identifying barriers, planning solutions, success criteria, evaluating impact, early intervention, language and literacy, cultural capital, literacy, numeracy, and transition
A case study of effective Pupil Premium practice
Authors: Everitt Helen , Sallows Ryan
Published: October 2019

Oriel High School has achieved some notable success with its Pupil Premium strategy. Helen Everitt and Ryan Sallows reflect on some of the key tenets of the school's work
Teaching by algorithm
Authors: Bromley Matt
Published: October 2019

How can algorithms, flowcharts and checklists be put to good use in education without us losing our sense of humanity, professional autonomy or creativity? Matt Bromley offers some practical ideas and reflections