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The article seeks to explore a number of ‘double binds' in the theory and practice of Catholic religious education. There is a disparity between the goal of education, as a universal practice of hu...

This chapter will consider challenges to the Catholic educational vision, through the work of two twentieth-century Jesuit theologians; each highly influential, though neither an educational theorist as such. The Uruguayan Juan Luis Segundo (1925–1996) was a distinctive but contrarian voice among Latin American liberationists. Karl Rahner (1904–1984), from Germany, taught for many years at the Jesuit faculty in Innsbruck, and is unmistakeably one of the most influential Catholic theologians of the twentieth century.

Biallelic variants in the ERCC excision repair 6 like 2 gene (ERCC6L2) are known to cause bone marrow failure (BMF) due to defects in DNA repair and mitochondrial function. Here, we report on eight cases of BMF from five families harboring biallelic variants in ERCC6L2, two of whom present with myelodysplasia. We confirm that ERCC6L2 patients' lymphoblastoid cell lines (LCLs) are hypersensitive to DNA-damaging agents that specifically activate the transcription coupled nucleotide excision repair (TCNER) pathway. Interestingly, patients' LCLs are also hypersensitive to transcription inhibitors that interfere with RNA polymerase II (RNA Pol II) and display an abnormal delay in transcription recovery. Using affinity-based mass spectrometry we found that ERCC6L2 interacts with DNA-dependent protein kinase (DNA-PK), a regulatory component of the RNA Pol II transcription complex. Chromatin immunoprecipitation PCR studies revealed ERCC6L2 occupancy on gene bodies along with RNA Pol II and DNA-PK. Patients' LCLs fail to terminate transcript elongation accurately upon DNA damage and display a significant increase in nuclear DNA-RNA hybrids (R loops). Collectively, we conclude that ERCC6L2 is involved in regulating RNA Pol II-mediated transcription via its interaction with DNA-PK to resolve R loops and minimize transcription-associated genome instability. The inherited BMF syndrome caused by biallelic variants in ERCC6L2 can be considered as a primary transcription deficiency rather than a DNA repair defect.

The opening chapter of the volume sets the context by describing Rene Girard’s Mimetic Theory as a ‘new optic’ on religion in general and on the question of religion and violence in particular. The specific issue which concerns this volume, and the conferences from which it arose, is whether Girard’s insights can be extended or applied to include the wisdom of non-Christian religious traditions, notably Islam. The framework for this investigation is the notion of an ‘Abrahamic revolution’. This is the claim that Judaism, Christianity, and Islam share a distinctive ethical breakthrough: a rupture with ‘archaic’ sacrificial practices and a partisanship for the innocent victim. Such a breakthrough is attested in key scriptural traditions common to the three faiths, especially the Akedah (sacrifice of Abraham’s son), and the story of Joseph. The chapter includes an initial exegesis of Girard’s ambivalent pronouncements on Islam, to see how far these are compatible with the thesis of an Abrahamic revolution, and concludes with an overview of the contributions in the rest of the volume.

The concluding chapter of the volume does not seek to provide a synthesis of the conversation between ‘Mimetic Theory and Islam, which would be premature. On the contrary, lacunae are identified where further work is needed. Nevertheless, a possible common trajectory is identified, which arises from the peculiar theoretical status of Mimetic Theory, which occupies a space between the science of religion and theology/spirituality. Both Girard and Muslim interlocutors are convinced of the limitations of an ‘outsider’, social-scientific approach to faith. True insight comes from submission to a revelation from ‘beyond’ and is inseparable from personal and group conversion and asceticism. The chapter also includes a summary of contributions from authors who have been a part of this dialogue but whose contributions are not included as chapters in the present volume.

Telomeric dysfunction is linked to colorectal cancer (CRC) initiation. However, the relationship of normal tissue and tumor telomere lengths with CRC progression, molecular features and prognosis is unclear. Here, we measured relative telomere length (RTL) by real-time quantitative PCR in 90 adenomas (aRTL), 419 stage I-IV CRCs (cRTL) and adjacent normal mucosa (nRTL). Age-adjusted RTL was analyzed against germline variants in telomere biology genes, chromosome instability (CIN), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), TP53, KRAS, BRAF mutations and clinical outcomes. In 509 adenoma or CRC patients, nRTL decreased with advancing age. Female gender, proximal location and the TERT rs2736100 G allele were independently associated with longer age-adjusted nRTL. Adenomas and carcinomas exhibited telomere shortening in 79% and 67% and lengthening in 7% and 15% of cases. Age-adjusted nRTL and cRTL were independently associated with tumor stage, decreasing from adenoma to stage III and leveling out or increasing from stage III to IV, respectively. Cancer MSI, CIMP, TP53, KRAS and BRAF status were not related to nRTL or cRTL. Near-tetraploid CRCs exhibited significantly longer cRTLs than CIN- and aneuploidy CRCs, while cRTL was significantly shorter in CRCs with larger numbers of chromosome breaks. Age-adjusted nRTL, cRTL or cRTL:nRTL ratios were not associated with disease-free or overall survival in stage II/III CRC. Taken together, our data show that both normal mucosa and tumor RTL are independently associated with CRC progression, and highlight divergent associations of CRC telomere length with tumor CIN profiles.

Significance Bone marrow failure (BMF) is an inherited life-threatening condition characterized by defective hematopoiesis, developmental abnormalities, and predisposition to cancer. BMF caused by ERCC6L2 mutations is considered to be a genome instability syndrome, because DNA repair is compromised in patient cells. In this study, we report BMF cases with biallelic disease-causing variants and provide evidence from patients’ cells that transcription deficiency can explain the genome instability. Specifically, we demonstrate that ERCC6L2 participates in RNA polymerase II-mediated transcription via interaction with DNA-dependent protein kinase (DNA-PK) and resolves DNA–RNA hybrids (R loops). Collectively, our data point to a causal mechanism in BMF in which patients with ERCC6L2 mutations are defective in the repair of transcription-associated DNA damage., Biallelic variants in the ERCC excision repair 6 like 2 gene (ERCC6L2) are known to cause bone marrow failure (BMF) due to defects in DNA repair and mitochondrial function. Here, we report on eight cases of BMF from five families harboring biallelic variants in ERCC6L2, two of whom present with myelodysplasia. We confirm that ERCC6L2 patients’ lymphoblastoid cell lines (LCLs) are hypersensitive to DNA-damaging agents that specifically activate the transcription coupled nucleotide excision repair (TCNER) pathway. Interestingly, patients’ LCLs are also hypersensitive to transcription inhibitors that interfere with RNA polymerase II (RNA Pol II) and display an abnormal delay in transcription recovery. Using affinity-based mass spectrometry we found that ERCC6L2 interacts with DNA-dependent protein kinase (DNA-PK), a regulatory component of the RNA Pol II transcription complex. Chromatin immunoprecipitation PCR studies revealed ERCC6L2 occupancy on gene bodies along with RNA Pol II and DNA-PK. Patients’ LCLs fail to terminate transcript elongation accurately upon DNA damage and display a significant increase in nuclear DNA–RNA hybrids (R loops). Collectively, we conclude that ERCC6L2 is involved in regulating RNA Pol II-mediated transcription via its interaction with DNA-PK to resolve R loops and minimize transcription-associated genome instability. The inherited BMF syndrome caused by biallelic variants in ERCC6L2 can be considered as a primary transcription deficiency rather than a DNA repair defect.

This chapter sets the contemporary debates about Catholic Education within the frame of political theology. Various themes and motifs from current political theology are offered as useful lenses which might be able to guide us through perplexing times. The chapter is structured around a discussion of four questions: What message does the 2016 world crisis hold? How can political theology help us to understand where we are now? What religious wisdom can the Church offer to her children and to the world? Is the Catholic education system in Britain ready to face a post-2016 world? In an extended conclusion, the chapter ponders on how to move beyond the default position of perpetual readiness to repel assaults from aggressive secularists. It is suggested that the time has come to at least entertain the possibility, offered to us by a variety of political theologians, that our age is in fact post-secular; and that these groups are so aggressive and resolute, precisely because they intuit their own soullness vulnerability; and the fact that they may, after all, be losing the battle. There might be fresh hope for reframing discussions about the nature and aims of Catholic Education.

This article, “reflects back and works forwards”, by thinking together the three “sorrowful mysteries” of the last one hundred years; three marked and irrevocable steps of escalation and complexity in the history of international conflict. Along with so many others in this centenary year, we commemorate: its causes, and the lessons to be learned. What are the continuities between the Great War, 1914–18, and the second “sorrowful mystery”, the advent of nuclear weapons? This brings us to the specific challenges that face us in the present: globalized violence in the name of religion, the reactive “war on terror” and the development of “smart” technology, remind us that our context too is unprecedented and uniquely dangerous. Explanatory avenues opened up include discussion of the moral and political implications of unmanned weapons, or drones. Here is an example of the crisis of sacrifice associated with Rene Girard, while Girard's own recasting of Clausewitz's notion of the “escalation to extremes”, and the humanism in Edward Schillebeeckx are also examined.

This article explores the resonance of the concept of the katēchon in apocalyptic political thought and in relation to Rene Girard’s mimetic theory. The katēchon has played a significant role in contemporary political theology. Like the scapegoat, the katēchon is a disturbing concept. An erroneous conflation of katēchein (to seize, to possess, to hold fast) and kōlyein (to hold off, to defer, to restrain) has allowed mainstream Christian thinking to be infiltrated by extra-biblical sources. Girardian mimetic theory makes senses of this problematic concept, in precisely the way that the author of John’s gospel allows us to make sense of the double-edged prophecy of Caiaphas (John 11:50). Just as Jesus is, and is not, a “scapegoat” (in the sense intended by Caiaphas), so Christianity has performed a katēchontic role while being, ultimately, the destroyer of all katēchontic principles.

This article examines the argument of William T. Cavanaugh’s The Myth of Religious Violence in the light of the mimetic theory of the French-American cultural theorist Rene Girard. Though the two projects are significantly different I argue for their mutual compatibility. Each author is “apologetic” for the Christian revelation, though the presence of theology in “The Myth . . .” is muted or implicit, as in Walter Benjamin’s parable of the puppet and the dwarf. I argue for four areas of specific convergence between Cavanaugh and Girard, arising from a shared Augustinian, “two Cities” suspicion of the state, and their resistance to the secularising marginalisation of the Judeo-Christian tradition. The notion of martyrdom as a “dramatic” performance is a further shared dimension. Finally, I argue that the apparent divergence of their approaches, between an anthropological thesis (Girard’s) and a historical one (Cavanaugh’s) is narrowed when we consider the later work of Girard and its examination of...

Exome sequencing was performed in three index cases with bone marrow failure and neurological dysfunction and whose parents are first-degree cousins. Homozygous truncating mutations were identified in ERCC6L2 in two of the individuals. Both of these mutations affect the subcellular localization and stability of ERCC6L2. We show here that knockdown of ERCC6L2 in human A549 cells significantly reduced their viability upon exposure to the DNA-damaging agents mitomycin C and Irofulven, but not etoposide and camptothecin, suggesting a role in nucleotide excision repair. ERCC6L2-knockdown cells also displayed H2AX phosphorylation, which significantly increased upon genotoxic stress, suggesting an early DNA-damage response. Intriguingly, ERCC6L2 was seen to translocate to the mitochondria and the nucleus in response to DNA damage, and ERCC6L2 knockdown induced intracellular reactive oxygen species (ROS). Treatment with the ROS scavenger N-acetyl cysteine attenuated the Irofulven-induced cytotoxicity in ERCC6L2-knockdown cells and abolished ERCCGL2 traffic to the mitochondria and nucleus in response to this DNA-damaging agent. Collectively, these observations identify a distinct bone-marrow-failure syndrome due to mutations in ERCC6L2, a gene implicated in DNA repair and mitochondrial function.

The recessive disorder poikiloderma with neutropenia (PN) is caused by mutations in the C16orf57 gene that encodes the highly conserved USB1 protein. Here, we present the 1.1 Å resolution crystal structure of human USB1, defining it as a member of the LigT-like superfamily of 2H phosphoesterases. We show that human USB1 is a distributive 3'-5' exoribonuclease that posttranscriptionally removes uridine and adenosine nucleosides from the 3' end of spliceosomal U6 small nuclear RNA (snRNA), directly catalyzing terminal 2', 3' cyclic phosphate formation. USB1 measures the appropriate length of the U6 oligo(U) tail by reading the position of a key adenine nucleotide (A102) and pausing 5 uridine residues downstream.We show that the 3' ends of U6 snRNA in PN patient lymphoblasts are elongated and unexpectedly carry nontemplated 3' oligo(A) tails that are characteristic of nuclear RNA surveillance targets. Thus, our study reveals a novel quality control pathway in which posttranscriptional 3'-end processing by USB1 protects U6 snRNA from targeting and destruction by the nuclear exosome. Our data implicate aberrant oligoadenylation of U6 snRNA in the pathogenesis of the leukemia predisposition disorder PN.

Dyskeratosis congenita and its variants have overlapping phenotypes with many disorders including Coats plus, and their underlying pathology is thought to be one of defective telomere maintenance. Recently, biallelic CTC1 mutations have been described in patients with syndromes overlapping Coats plus. CTC1, STN1 and TEN1 are part of the telomere-capping complex involved in maintaining telomeric structural integrity. Based on phenotypic overlap we screened 73 genetically uncharacterized patients with dyskeratosis congenita and related bone marrow failure syndromes for mutations in this complex. Biallelic CTC1 mutations were identified in 6 patients but none in either STN1 or TEN1. We have expanded the phenotypic spectrum associated with CTC1 mutations and report that intracranial and retinal abnormalities are not a defining feature, as well as showing that the effect of these mutations on telomere length is variable. The study also demonstrates the lack of disease-causing mutations in other components of the telomere-capping complex.

Aplastic anemia (AA) and myelodysplasia (MDS) are forms of bone marrow failure that are often part of the same progressive underlying disorder. While most cases are simplex and idiopathic, some show a clear pattern of inheritance; therefore, elucidating the underlying genetic cause could lead to a greater understanding of this spectrum of disorders. We used a combination of exome sequencing and SNP haplotype analysis to identify causative mutations in a family with a history of autosomal-dominant AA/MDS. We identified a heterozygous mutation in SRP72, a component of the signal recognition particle (SRP) that is responsible for the translocation of nascent membrane-bound and excreted proteins to the endoplasmic reticulum. A subsequent screen revealed another autosomal-dominant family with an inherited heterozygous SRP72 mutation. Transfection of these sequences into mammalian cells suggested that these proteins localize incorrectly within the cell. Furthermore, coimmunoprecipitation of epitope-tagged SRP72 indicated that the essential RNA component of the SRP did not fully associate with one of the SRP72 variants. These results suggest that inherited mutations in a component of the SRP have a role in the pathophysiology of AA/MDS, identifying a third pathway for developing these disorders alongside transcription factor and telomerase mutations.

The myelodysplastic syndromes (MDS) are heterogeneous and can evolve into acute myeloid leukaemia (AML). Rare familial cases are reported in which five disease genes have been identified to date (RUNX1, CEBPA, TERC, TERT and GATA2). Here we report the genetic categorization of 27 families with familial MDS/AML. All of these families were screened for RUNX1, CEBPA, TERC, TERT and GATA2 as well as TET2 and NPM1. Five of the 27 families had telomerase mutations; one had a RUNX1 mutation, while none were found to have TET2, CEBPA or NPM1 mutations. We identified four families with heterozygous GATA2 mutations, each associated with a different phenotype. While one of these mutations is novel, three have been previously reported: one has been described in dendritic cell, monocyte, B and NK lymphoid (DCML) deficiency and one is in a family that has been reported in a series with primary lymphoedema with a predisposition to AML (Emberger syndrome). In summary, genetic characterization was shown in 10 (four GATA2, three TERT, two TERC, one RUNX1) of these families; however 17 remain uncharacterized, highlighting marked genetic heterogeneity in familial MDS/AML and the scope for further functional pathways that could give rise to this group of disorders.

The affinities as well as the distinguishing features of two accounts of the socio-poliitcal dimensions of the gospel are here examined, in the light of the apparent marginalisation of the 'social question' in the post-conciliar Church. How can these two discourses re-engage with contemporary debate? The concern of philosophers such as Giorgio Agamben with the notion of a 'state of exception', and the idea of a 'realistic utopia' being propounded by post-Rawlsian theorists of economic and social justice, offer two opportunities for this.

Dyskeratosis congenita (DC) is a heterogeneous disorder, both genetically and phenotypically (1). Clinical presentation is classically defined by a triad of mucocutaneous features: abnormal reticulate skin pigmentation, nail dystrophy and leukoplakia. Bone marrow failure and a spectrum of other somatic abnormalities are also commonly observed (2). In its severe form, DC overlaps with the Hoyeraal–Hreidarsson (HH) syndrome, characterized by immunodeficiency, cerebellar hypoplasia, microcephaly and growth retardation as well as aplastic anaemia (AA). Because of this wide range of phenotypes, a clinical diagnosis of DC can often be quite difficult, although we would usually define a DC patient as having at least two of the three mucocutaneous features with either evidence of bone marrow failure or two or more other somatic abnormalities (3). In some cases a genetic diagnosis can be made, based on the identification of a mutation in one of the seven genes (DKC1, TERC, TERT, NOP10, NHP2, TINF2 and C16orf57). Through genome-wide linkage analysis and candidate gene sequencing, the TINF2 gene was initially identified as the cause of DC in one family showing autosomal dominant inheritance of the disease (4). It has subsequently become clear that mutations in this gene usually arise de novo in sporadic cases, causing a relatively severe form of DC (4, 5). The gene encodes a core component of the shelterin complex – a group of proteins that interact to protect telomeres. This protein is called TIN2, the telomeric repeat binding factor 1 (TRF1)-interacting nuclear factor 2; it is an essential mediator of TRF1 function and acts as an important regulator of telomere length (6, 7). TIN2 acts as the central component of the shelterin complex, binding not only TRF1 but also TRF2, a second telomere DNA-binding protein (8) and TPP1, the TIN2-interacting protein (9). TIN2-anchored TPP1 plays a major role in the recruitment of telomerase to telomeres in human cells (10). TPP1 is also important for recruiting POT1 (protection of telomeres), which is the third DNA-binding protein of the shelterin complex. POT1 binds to telomeric single-stranded DNA, protecting chromosome ends from the DNA-damage response (11). A second larger isoform of TIN2 has recently been identified, and this appears to have a role in tethering telomeres to the nuclear matrix (12). Since our previous report in 2008 (5), we have been screening for TINF2 mutations in all patients referred to our DC registry with various forms of bone marrow failure. This has led to the identification of 16 new families with eight previously unreported variants. They show that the phenotype associated with TINF2 mutation is broader than previously thought, but also raise the question as to whether all of these novel variants are pathogenic.

Dyskeratosis congenita (DC) is an inherited poikiloderma which in addition to the skin abnormalities is typically associated with nail dystrophy, leucoplakia, bone marrow failure, cancer predisposition and other features. Approximately 50% of DC patients remain genetically uncharacterized. All the DC genes identified to date are important in telomere maintenance. To determine the genetic basis of the remaining cases of DC, we undertook linkage analysis in 20 families and identified a common candidate gene region on chromosome 16 in a subset of these. This region included the C16orf57 gene recently identified to be mutated in poikiloderma with neutropenia (PN), an inherited poikiloderma displaying significant clinical overlap with DC. Analysis of the C16orf57 gene in our uncharacterized DC patients revealed homozygous mutations in 6 of 132 families. In addition, three of six families previously classified as Rothmund-Thomson syndrome (RTS-a poikiloderma that is sometimes confused with PN) were also found to have homozygous C16orf57 mutations. Given the role of the previous DC genes in telomere maintenance, telomere length was analysed in these patients and found to be comparable to age-matched controls. These findings suggest that mutations in C16orf57 unify a distinct set of families which clinically can be categorized as DC, PN or RTS. This study also highlights the multi-system nature (wider than just poikiloderma and neutropenia) of the clinical features of affected individuals (and therefore house-keeping function of C16orf57), a possible role for C16orf57 in apoptosis, as well as a distinct difference from previously characterized DC patients because telomere length was normal.

The primary pathology in many cases of myelodysplasia (MDS) and acute myeloid leukemia (AML) remains unknown. In some cases, two or more affected members have been identified in the same family. To date, mutations in two genes have been directly implicated: the hematopoietic transcription factors RUNX1 (runt-related transcription factor 1) and CEBPA (CCATT-box enhancer binding protein alpha). However, there are also other familial cases of MDS/AML where the genetic basis remains unknown. Both MDS, and to a lesser extent AML, have been observed in cases of the bone marrow failure syndrome dyskeratosis congenita, in which telomerase mutations have been identified. Recently, an increased incidence of telomerase reverse transcriptase mutations has been reported in a series of de novo AML. We have now identified novel mutations in the telomerase RNA (TERC) or telomerase reverse transcriptase component (TERT) within 4 of 20 families presenting with familial MDS/AML. Functional analysis has demonstrated that all mutations adversely impact on telomerase activity in vitro, and affected individuals have short telomeres. These families, in conjunction with a review of previously published cases, help to further define the pathological role of telomerase mutations in MDS/AML and have implications for the biology, treatment and screening regimen of de novo cases.

Dyskeratosis congenita (DC) is a multi-system disorder which in its classical form is characterised by abnormalities of the skin, nails and mucous membranes. In approximately 80% of cases, it is associated with bone marrow dysfunction. A variety of other abnormalities (including bone, brain, cancer, dental, eye, gastrointestinal, immunological and lung) have also been reported. Although first described almost a century ago it is the last 10 years, following the identification of the first DC gene (DKC1) in 1998, in which there has been rapid progress in its understanding. Six genes have been identified, defects in which cause different genetic subtypes (X-linked recessive, autosomal dominant, autosomal recessive) of DC. The products of these genes encode components that are critical for telomere maintenance; either because they are core constituents of telomerase (dyskerin, TERC, TERT, NOP10 and NHP2) or are part of the shelterin complex that protects the telomeric end (TIN2). These advances have also highlighted the connection between the more “cryptic/atypical” forms of the disease including aplastic anaemia and idiopathic pulmonary fibrosis. Equally, studies on this disease have demonstrated the critical importance of telomeres in human cells (including stem cells) and the severe consequences of their dysfunction. In this context DC and related diseases can now be regarded as disorders of “telomere and stem cell dysfunction”.

Dyskeratosis congenita (DC) is an inherited multi-system disorder characterised by muco-cutaneous abnormalities, bone marrow failure and a predisposition to malignancy. Bone marrow failure is the principal cause of mortality and is thought to be the result of premature cell death in the haematopoietic compartment because DC cells age prematurely and tend to have short telomeres. DC is genetically heterogeneous and patients have mutations in genes that encode components of the telomerase complex (DKC1, TERC, TERT, NOP10 and NHP2), and telomere shelterin complex (TINF2), both important in telomere maintenance. Here, we transduced primary T lymphocytes and B lymphocyte lines established from patients with TERC and DKC1 mutations with wild type TERC-bearing lentiviral vectors. We found that transduction with exogenous TERC alone was capable of increasing telomerase activity in mutant T lymphocytes and B lymphocyte lines and improved the survival and thus overall growth of B-lymphocyte lines over a prolonged period, regardless of their disease mutation. Telomeres in TERC-treated lines were longer than in the untreated cultures. This is the first study of its kind in DC lymphocytes and the first to demonstrate that transduction with TERC alone can improve cell survival and telomere length without the need for exogenous TERT.

This report highlights another differentiating factor among the various subtypes of DC, demonstrating a new link between genotype and phenotype in the disease and has implications for the diagnosis and treatment of DC patients dependent upon the causative mutation in each case.

Dyskeratosis congenita (DC) is a multisystem bone marrow failure syndrome characterized by a triad of mucocutaneous abnormalities and a predisposition to cancer. The genetic basis of DC remains unknown in more than 60% of patients. Mutations have been identified in components of the telomerase complex (dyskerin, TERC, TERT, NOP10, and NHP2), and recently in one component of the shelterin complex TIN2 (gene TINF2). To establish the role of TINF2 mutations, we screened DNA from 175 uncharacterised patients with DC as well as 244 patients with other bone marrow failure disorders. Heterozygous coding mutations were found in 33 of 175 previously uncharacterized DC index patients and 3 of 244 other patients. A total of 21 of the mutations affected amino acid 282, changing arginine to histidine (n = 14) or cysteine (n = 7). A total of 32 of 33 patients with DC with TINF2 mutations have severe disease, with most developing aplastic anaemia by the age of 10 years. Telomere lengths in patients with TINF2 mutations were the shortest compared with other DC subtypes, but TERC levels were normal. In this large series, TINF2 mutations account for approximately 11% of all DC, but they do not play a significant role in patients with related disorders. This study emphasises the role of defective telomere maintenance on human disease.

Dyskeratosis congenita (DC) is a multisystem bone marrow failure syndrome characterized by a triad of mucocutaneous abnormalities and an increased predisposition to malignancy. X-linked DC is due to mutations in DKC1, while heterozygous mutations in TERC (telomerase RNA component) and TERT (telomerase reverse transcriptase) have been found in autosomal dominant DC. Many patients with DC remain uncharacterized, particularly families displaying autosomal recessive (AR) inheritance. We have now identified novel homozygous TERT mutations in 2 unrelated consanguineous families, where the index cases presented with classical DC or the more severe variant, Hoyeraal-Hreidarsson (HH) syndrome. These TERT mutations resulted in reduced telomerase activity and extremely short telomeres. As these mutations are homozygous, these patients are predicted to have significantly reduced telomerase activity in vivo. Interestingly, in contrast to patients with heterozygous TERT mutations or hemizygous DKC1 mutations, these 2 homozygous TERT patients were observed to have higher-than-expected TERC levels compared with controls. Collectively, the findings from this study demonstrate that homozygous TERT mutations, resulting in a pure but severe telomerase deficiency, produce a phenotype of classical AR-DC and its severe variant, the HH syndrome.

An exploration of different understandings of 'sacrifice' by Christian theologians, and how these affect our understanding of the eucharist, especially in the light of the mimetic of Rene Girard.

Background Lentiviral vectors may be vectors of choice for transducing liver cells; they mediate integration in quiescent cells and offer potential for long-term expression. In adult liver, hepatocytes are generally mitotically quiescent. There has been controversy as to the necessity for lentiviral vector target cells to be in the cell cycle; currently, there is consensus that effective transduction can be achieved in quiescent hepatocytes, by using virus at high titre. However, transduction approaches which reduce the multiplicities of infection (MOIs) required provide potential benefit of cost and safety for therapeutic use.Methods We used two late-generation HIV-based lentiviral vector systems (pHR-SIN-cppT SGW and pRRLSIN.cPPT.PGK.WPRE) encoding LacZ/GFP reporter genes to transduce adult and fetal human hepatocytes in vitro +/- growth factors, hepatocyte growth factor (HGF) and epidermal growth Green fluorescent protein (GFP) expression was observed factor (EGF). and quantified by fluorescence spectrometry for protein microscopically, expression, fluorescence-activated cell sorting (FACS) analysis to identify the proportion of cells expressing GFP, and real-time quantitative polymerase chain reaction (PCR) for number of integrations.Results Gene expression following lentiviral transduction of human liver cells in vitro was markedly enhanced by the growth factors HGF and EGF. in adult cells growth factors led to a greater proportion of cells expressing more GFP per cell, from more integration events. In human fetal cells, the proportion of transduced hepatocytes remained identical, but cells expressed more GFP protein.Conclusions This has implications for the design of regimes for liver cell gene therapy, allowing marked reduction of MOIs, and reducing both cost and risk of viral-mediated toxicity. Copyright (c) 2007 John Wiley & Sons, Ltd.

The mechanisms by which steatosis renders hepatocytes susceptible to damage in non-alcoholic steatohepatitis (NASH) are unclear although fat accumulation is believed to increase hepatocyte susceptibility to inflammatory cytokines and oxidative stress. We therefore investigated the susceptibility of steatotic, hepatocyte-derived cells to TNF alpha and the pro-oxidant, t-butylhydroperoxide (TBH). HepG2 spheroids rendered steatotic by fat-loading with 0.15 mM oleic or palmitic acid for 48 h and treated with TNF alpha or TBH for 18 h exhibited surprisingly lower levels of cytotoxicity, and increased anti-oxidant activity (superoxide dismutase (SOD)) compared with non fat-loaded controls. The protective effect of steatosis was significantly reversed by the inhibition of AMP-activated kinase (AMPK) since spheroids transfected with a kinase-dead AMPK alpha 2 subunit, exhibited a significant increase in TBH-induced cytotoxicity when fat-loaded. In conclusion, our findings suggest that fat-loaded hepatocyte-clerived cells are surprisingly less Susceptible to cytokine and pro-oxidant induced damage via an adaptive mechanism dependent, in part, on AMPK activity.

Dyskeratosis congenita (DC) and its phenotypically severe variant, Hoyeraal-Hreidarsson syndrome (HHS), are multisystem bone-marrow-failure syndromes in which the principal pathology is defective telomere maintenance. The genetic basis of many cases of DC and HHS remains unknown. Using whole-exome sequencing, we identified biallelic mutations in RTEL1, encoding a helicase essential for telomere maintenance and regulation of homologous recombination, in an individual with familial HHS. Additional screening of RTEL1 identified biallelic mutations in 6/23 index cases with HHS but none in 102 DC or DC-like cases. All 11 mutations in ten HHS individuals from seven families segregated in an autosomal-recessive manner, and telomere lengths were significantly shorter in cases than in controls (p = 0.0003). This group had significantly higher levels of telomeric circles, produced as a consequence of incorrect processing of telomere ends, than did controls (p = 0.0148). These biallelic RTEL1 mutations are responsible for a major subgroup (∼29%) of HHS. Our studies show that cells harboring these mutations have significant defects in telomere maintenance, but not in homologous recombination, and that incorrect resolution of T-loops is a mechanism for telomere shortening and disease causation in humans. They also demonstrate the severe multisystem consequences of its dysfunction.

On the 18th January 2000 a broken pipeline owned and operated by the oil company Petrobras spilt some 1300 tonne of bunker fuel into Guanabara Bay, Rio de Janeiro. The wildlife response was divided amongst 2 operational strategies and included – avian fauna and cetaceans. This paper deals with the cetacean response only. Cetaceans are generally not considered as an important feature of an oil spill response. Contingency planning for cetaceans in oil spills is now becoming an important element for preparedness for some countries. The cetacean response in Guanabara Bay specifically targeted a pod of about 70 members of the species Sotalia fluviatilis, a small dolphin that inhabits the bay. The response included the development of a plan that included a response system, a monitoring program and action plans. The response system detailed the mechanism for the plan to work and adopted the incident control management system. The monitoring program related to the study of any short term or long term deleterious effects resulting from the spill and consisted of basic spatial, temporal and behavioural studies. Action plans were developed specific to the character of Guanabara Bay and included the rescue and rehabilitation strategies necessary to respond to oil affected cetaceans. A training program was then developed and implemented to personnel who were to enact the cetacean response.