The number of nicotinic acetylcholine receptors (AChRs) present in the plasma membrane of muscle and neuronal cells is limited by the assembly of individual subunits into mature pentameric receptors. ...This process is usually inefficient, and a large number of the synthesized subunits are degraded by endoplasmic reticulum (ER)-associated degradation. To identify cellular factors required for the synthesis of AChRs, we performed a genetic screen in the nematode Caenorhabditis elegans for mutants with decreased sensitivity to the cholinergic agonist levamisole. We isolated a partial loss-of-function allele of ER membrane protein complex-6 (emc-6) , a previously uncharacterized gene in C. elegans . emc-6 encodes an evolutionarily conserved 111-aa protein with two predicted transmembrane domains. EMC-6 is ubiquitously expressed and localizes to the ER. Partial inhibition of EMC-6 caused decreased expression of heteromeric levamisole-sensitive AChRs by destabilizing unassembled subunits in the ER. Inhibition of emc-6 also reduced the expression of homomeric nicotine-sensitive AChRs and GABA A receptors in C. elegans muscle cells. emc-6 is orthologous to the yeast and human EMC6 genes that code for a component of the recently identified ER membrane complex (EMC). Our data suggest this complex is required for protein folding and is connected to ER-associated degradation. We demonstrated that inactivation of additional EMC members in C. elegans also impaired AChR synthesis and induced the unfolded protein response. These results suggest that the EMC is a component of the ER folding machinery. AChRs might provide a valuable proxy to decipher the function of the EMC further.
Methylation of histone H3 lysine 4 (H3K4me), a mark associated with gene activation, is mediated by SET1 and the related mixed lineage leukemia (MLL) histone methyltransferases (HMTs) across species. ...Mammals contain seven H3K4 HMTs, Set1A, Set1B, and MLL1-MLL5. The activity of SET1 and MLL proteins relies on protein-protein interactions within large multisubunit complexes that include three core components: RbBP5, Ash2L, and WDR5. It remains unclear how the composition and specificity of these complexes varies between cell types and during development. Caenorhabditis elegans contains one SET1 protein, SET-2, one MLL-like protein, SET-16, and single homologs of RbBP5, Ash2L, and WDR5. Here we show that SET-2 is responsible for the majority of bulk H3K4 methylation at all developmental stages. However, SET-2 and absent, small, or homeotic discs 2 (ASH-2) are differentially required for tri- and dimethylation of H3K4 (H3K4me3 and -me2) in embryos and adult germ cells. In embryos, whereas efficient H3K4me3 requires both SET-2 and ASH-2, H3K4me2 relies mostly on ASH-2. In adult germ cells by contrast, SET-2 serves a major role whereas ASH-2 is dispensable for H3K4me3 and most H3K4me2. Loss of SET-2 results in progressive sterility over several generations, suggesting an important function in the maintenance of a functional germ line. This study demonstrates that individual subunits of SET1-related complexes can show tissue specificity and developmental regulation and establishes C. elegans as a model to study SET1-related complexes in a multicellular organism.
Introduction
Since the approval by the EMA of emicizumab for the care of severe haemophilia A without inhibitor, most of the patients of our haemophilia treatment centre started this new treatment. ...Thanks to the setting of a therapeutic patient education program including three pharmaceutical consultations (PC), we could follow patients’ lifestyle evolution.
Aim
The study aimed to assess the perceived clinical evolution, quality of life and treatment satisfaction of patients after 1 year of emicizumab therapy in real‐life settings.
Methods
The study was observational, retrospective and monocentric. Every patient over 18 years old receiving emicizumab from June 2020 and who underwent the 3 PC until March 2022 were included. The clinical evolution was self‐estimated by patients with zero‐to‐six scales before versus 1 year after emicizumab, according to the following parameters: general health state, pain and bleedings (spontaneous or post‐traumatic, and patients’ identification ability). Patients’ quality of life was also estimated with the EQ‐5D‐3L survey. Their satisfaction, graduated with a zero‐to‐ten scale, and treatment management were reported during the third PC.
Results
Thirty‐eight patients were enrolled. Their general health state improved significantly (p = .0023) with an EQ‐5D‐3L score at 69.6 (±19.4) out of 100. Although chronic pains remained a persistent issue for 33 (86.8%) patients, their intensity was significantly decreasing after 1 year. Perceived frequency of bleedings was significantly reduced too. On average, the satisfaction of emicizumab therapy was 9.1 (± 1.02) out of 10.
Conclusion
After 1 year of emicizumab therapy, the general health state estimated by patients improved, the pain and the perceived frequency of bleedings diminished. Overall, this treatment received a high patients’ satisfaction rate.
Repression of somatic cell fate in the germline Robert, Valérie J; Garvis, Steve; Palladino, Francesca
Cellular and Molecular Life Sciences,
10/2015, Letnik:
72, Številka:
19
Journal Article, Book Review
Recenzirano
Germ cells must transmit genetic information across generations, and produce gametes while also maintaining the potential to form all cell types after fertilization. Preventing the activation of ...somatic programs is, therefore, crucial to the maintenance of germ cell identity. Studies in Caenorhabditis elegans, Drosophila melanogaster, and mouse have revealed both similarities and differences in how somatic gene expression is repressed in germ cells, thereby preventing their conversion into somatic tissues. This review will focus on recent developments in our understanding of how global or gene-specific transcriptional repression, chromatin regulation, and translational repression operate in the germline to maintain germ cell identity and repress somatic differentiation programs.
We consider the simultaneous clustering of rows and columns of a matrix and more particularly the ability to measure the agreement between two co-clustering partitions. The new criterion we developed ...is based on the Adjusted Rand Index and is called the Co-clustering Adjusted Rand Index named CARI. We also suggest new improvements to existing criteria such as the classification error which counts the proportion of misclassified cells and the Extended Normalized Mutual Information criterion which is a generalization of the criterion based on mutual information in the case of classic classifications. We study these criteria with regard to some desired properties deriving from the co-clustering context. Experiments on simulated and real observed data are proposed to compare the behavior of these criteria.
Histone H3 Lys 4 methylation (H3K4me) is deposited by the conserved SET1/MLL methyltransferases acting in multiprotein complexes, including Ash2 and Wdr5. Although individual subunits contribute to ...complex activity, how they influence gene expression in specific tissues remains largely unknown. In Caenorhabditis elegans, SET-2/SET1, WDR-5.1, and ASH-2 are differentially required for germline H3K4 methylation. Using expression profiling on germlines from animals lacking set-2, ash-2, or wdr-5.1, we show that these subunits play unique as well as redundant functions in order to promote expression of germline genes and repress somatic genes. Furthermore, we show that in set-2- and wdr-5.1-deficient germlines, somatic gene misexpression is associated with conversion of germ cells into somatic cells and that nuclear RNAi acts in parallel with SET-2 and WDR-5.1 to maintain germline identity. These findings uncover a unique role for SET-2 and WDR-5.1 in preserving germline pluripotency and underline the complexity of the cellular network regulating this process.
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•H3K4 methylation represses expression of somatic genes in the C. elegans germline•Loss of H3K4 methylation results in germline transdifferentiation•Transdifferentiation increases across generations•The nuclear RNAi pathway contributes to the maintenance of germ cell identity
Germ cells are totipotent, meaning that they can give rise to all cells of an organism. Robert et al. identify a function for H3K4 methylation, a histone modification mediated by the SET-2/SET1 methyltransferase, in repressing somatic gene expression in the C. elegans germline. In the absence of SET-2/SET1 and H3K4 methylation, germ cells differentiate into somatic cells, indicating that H3K4 methylation helps preserve germ cell identity.
Here we report a case of Epstein–Barr virus (EBV)‐associated smooth muscle tumor (SMT) of the peripheral nerve in a young man seropositive for human immunodeficiency virus (HIV). Initially, the ...lesion was clinically and radiologically confused with a schwannoma of the forearm's posterior interosseous nerve. The diagnosis was corrected by histological examination, which revealed a well‐defined tumor consisting of eosinophilic spindle cells, positive for α‐smooth muscle actin on immunohistochemistry and positive for EBV‐encoded early RNA (EBER) on in situ hybridization. EBV‐associated SMTs are well described in the literature; they are frequently multiple and arise in many organs. They occur preferentially in young adults with poorly controlled and chronic HIV infection. The prognosis is influenced by the complications of immunodeficiency. To our knowledge, this is the first description of a peripheral nerve location. Because EBV‐associated SMT should be considered in the differential diagnosis of a tumor in the peripheral or central nervous systems in immunocompromised patients, EBV should be tested in these locations. Thus, a cause of immunodeficiency should be identified when the diagnosis of EBV‐associated SMT is made.
Six recombinant factor VIII (rFVIII) products have been marketed worldwide. In 2013, the Research of Determinants of Inhibitor Development (RODIN) study group reported an unexpectedly high risk of ...inhibitor development with a second-generation full-length rFVIII (Product D) in previously untreated patients (PUPs) with severe hemophilia A (HA). In 1994, French public health authorities established a prospective cohort to monitor hemophilia treatment safety. A PUP subgroup was designed to investigate inhibitor risk factors. We analyzed this subcohort in view of the RODIN findings. After excluding 50 patients who participated in the RODIN study, the primary analysis focused on 303 boys with severe HA first treated with a rFVIII product. A clinically significant inhibitor was detected in 114 boys (37.6%). The inhibitor incidence was higher with Product D vs the most widely used rFVIII product (adjusted hazard ratio aHR, 1.55; 95% confidence interval CI, 0.97-2.49). Similar results were found for high-titer inhibitors and in 10 sensitivity analyses. No heterogeneity was observed between RODIN and our results. Combined aHRs were 1.58 (95% CI, 1.17-2.14) for all inhibitors and 1.70 (95% CI, 1.15-2.52) for high-titer inhibitors. Our results confirm the higher immunogenicity of Product D vs other rFVIII products in PUPs with severe HA.
•A currently marketed rFVIII product is associated with a higher risk of inhibitor development in boys with severe hemophilia A.•This result, validated by extensive sensitivity analyses, confirms a recently published study and cannot be explained by identified biases.
The Drosophila element Mos1 is a class II transposon, which moves by a ‘cut‐and‐paste’ mechanism and can be experimentally mobilized in the Caenorhabditis elegans germ line. Here, we triggered the ...excision of identified Mos1 insertions to create chromosomal breaks at given sites and further manipulate the broken loci. Double‐strand break (DSB) repair could be achieved by gene conversion using a transgene containing sequences homologous to the broken chromosomal region as a repair template. Consequently, mutations engineered in the transgene could be copied to a specific locus at high frequency. This pathway was further characterized to develop an efficient tool—called MosTIC—to manipulate the C. elegans genome. Analysis of DSB repair during MosTIC experiments demonstrated that DSBs could also be sealed by end‐joining in the germ line, independently from the evolutionarily conserved Ku80 and ligase IV factors. In conjunction with a publicly available Mos1 insertion library currently being generated, MosTIC will provide a general tool to customize the C. elegans genome.
Life expectancy for patients with haemophilia (PWH) has significantly increased in the last decades, due to improvement of clotting factor replacement therapy. However, despite a lower cardiovascular ...mortality rate and contrasting prevalence for non‐fatal ischaemic heart disease (IHD), cardiovascular diseases are increasing in PWH. The prevalence of cardiovascular risk factors in PWH is as prevalent as in the general population, whereas an increased risk of hypertension has been observed in some studies. Furthermore, PWH are not protected against atherosclerosis. Coronary artery disease treatment is extremely challenging in PWH. Two ‘institutional’ guidelines for the management of IHD in PWH have been published. Since these recommendations, the use of new drugs such as prasugrel, ticagrelor, bivalirudin, new oral anticoagulants and new drug‐eluting stents have been recommended in the general population but should be evaluated in PWH. Some questions arise: which trough level during long‐term single or dual antiplatelet treatment (DAT) is really needed? The clinical role of platelet testing remains ill defined but may be considered in selected patients. A multidisciplinary approach is necessary for the management of IHD in PWH in order to treat the patient as any patient according to the cardiological guidelines during the acute phase, and long‐term management should be discussed.
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