THE SYNTHESIS, ASSEMBLY, AND SECRETION OF GAMMA GLOBULIN BY MOUSE MYELOMA CELLS : VI. ASSEMBLY OF IGM PROTEINS

The study of the synthesis, assembly, and secretion of IgM by seven murine myeloma tumors has revealed that free mu chain can be detected intracellularly after release from the ribosome. It combines with light chains to form µL. The major intracellular protein in six of the seven tumors was the 8S subunit. One tumor contained considerable amounts of 19S material intracellularly. Those tumors that did not contain 19S IgM intracellulariy appeared to assemble the subunits outside the cell

Peripheral Blood Cell Gene Expression Diagnostic for Identifying Symptomatic Transthyretin Amyloidosis Patients: Male and Female Specific Signatures

BACKGROUND: Early diagnosis of familial transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease-modifying therapies. Endomyocardial biopsies are typically amyloid positive when cardiomyopathy is suspected, but this disease manifestation is generally diagnosed late. Early diagnosis is often difficult because patients exhibit apparent symptoms of polyneuropathy, but have a negative amyloid biopsy. Thus, there is a pressing need for an additional early diagnostic strategy for TTR-aggregation-associated polyneuropathy and cardiomyopathy. METHODS AND FINDINGS: Global peripheral blood cell mRNA expression profiles from 263 tafamidis-treated and untreated V30M Familiar Amyloid Neuropathy patients, asymptomatic V30M carriers, and healthy, age- and sex-matched controls without TTR mutations were used to differentiate symptomatic from asymptomatic patients. We demonstrate that blood cell gene expression patterns reveal sex-independent, as well as male- and female-specific inflammatory signatures in symptomatic FAP patients, but not in asymptomatic carriers. These signatures differentiated symptomatic patients from asymptomatic V30M carriers with >80% accuracy. There was a global downregulation of the eIF2 pathway and its associated genes in all symptomatic FAP patients. We also demonstrated that the molecular scores based on these signatures significantly trended toward normalized values in an independent cohort of 46 FAP patients after only 3 months of tafamidis treatment. CONCLUSIONS: This study identifies novel molecular signatures that differentiate symptomatic FAP patients from asymptomatic V30M carriers as well as affected males and females. We envision using this approach, initially in parallel with amyloid biopsies, to identify individuals who are asymptomatic gene carriers that may convert to FAP patients. Upon further validation, peripheral blood cell mRNA expression profiling could become an independent early diagnostic. This quantitative gene expression signature for symptomatic FAP could also become a biomarker to demonstrate significant disease-modifying effects of drugs and drug candidates. For example, when new disease modifiers are being evaluated in a FAP clinical trial, such surrogate biomarkers have the potential to provide an objective, quantitative and mechanistic molecular diagnostic of disease response to therapy.We acknowledge the following sources of research funding: NIH U19 A1063603 (DRS, SMK), NIH DK46335 (JWK) and NIH R01AG19259 (JNB)info:eu-repo/semantics/publishedVersio

De novo SCN2A splice site mutation in a boy with autism spectrum disorder

BACKGROUND: SCN2A is a gene that codes for the alpha subunit of voltage-gated, type II sodium channels, and is highly expressed in the brain. Sodium channel disruptions, such as mutations in SCN2A, may play an important role in psychiatric disorders. Recently, de novo SCN2A mutations in autism spectrum disorder (ASD) have been identified. The current study characterizes a de novo splice site mutation in SCN2A that alters mRNA and protein products. CASE PRESENTATION: We describe results from clinical and genetic characterizations of a seven-year-old boy with ASD. Psychiatric interview and gold standard autism diagnostic instruments (ADOS and ADI-R) were used to confirm ASD diagnosis, in addition to performing standardized cognitive and adaptive functioning assessments (Leiter-R and Vineland Adaptive Behavior Scale), and sensory reactivity assessments (Sensory Profile and Sensory Processing Scales). Genetic testing by whole exome sequencing revealed four de novo events, including a splice site mutation c.476 + 1G > A in SCN2A, a missense mutation (c.2263G > A) causing a p.V755I change in the TLE1 gene, and two synonymous mutations (c.2943A > G in the BUB1 gene, and c.1254 T > A in C10orf68 gene). The de novo SCN2A splice site mutation produced a stop codon 10 amino acids downstream, possibly resulting in a truncated protein and/or a nonsense-mediated mRNA decay. The participant met new DSM-5 criteria for ASD, presenting with social and communication impairment, repetitive behaviors, and sensory reactivity issues. The participant's adaptive and cognitive skills fell in the low range of functioning. CONCLUSION: This report indicates that a splice site mutation in SCN2A might be contributing to the risk of ASD. Describing the specific phenotype associated with SCN2A mutations might help to reduce heterogeneity seen in ASD

Challenges and support needs of parents and children when a parent is at end of life: A systematic review

Background: Preparing children for the death of a parent is challenging. Parents are often uncertain if and how to communicate and support their children. Many parents feel it is protecting their children by not telling them about the prognosis. Children less prepared for parental death from a terminal illness are more susceptive to later adversities. To facilitate coping and moderate for such adversities, there is a need to gain insight and understand the experience and challenges confronted by families. Aim: This review synthesised evidence on the experiences of parents and children when a parent is at end of life to discern their challenges, support needs and factors that facilitated good practice. Design: Mixed-methods systematic review. Data sources: Four electronic databases (CINAHL, PubMed, PsycINFO and Ovid MEDLINE) using MeSH terms and word searches in October 2018. Studies were not limited by year of publication, language or country. Grey literature searches were also completed on Google Scholar and OpenGrey. Results: In all, 7829 records were identified; 27 qualitative and 0 quantitative studies met the inclusion criteria. Eight descriptive themes were identified, further categorised into two broad themes: (1) barriers and facilitators in sharing the news that a parent is dying and (2) strategies to manage the changing situation. Conclusion: Lack of understanding in relation to the parent’s prognosis, denial and feeling ill-equipped were suggested as barriers for parents to share the news with their children. Engagement with social networks, including extended family relatives and peers, and maintaining routines such as attending school were suggested supportive by parents and children. Findings are limited primarily to White, middle-class two-parent families. A number of areas for future research are identified.</p

Phelan-McDermid syndrome: a review of the literature and practice parameters for medical assessment and monitoring

The purpose of this study is to contribute to a deeper understanding about how placement discontinuities of children in foster care affect their learning. The aim is to find out more about their learning and what role school plays in their life. A life-world perspective is used and theories mainly developed by Alfred Schütz (2002) build the theoretical framework. The empirical research is mainly based on narratives of a pair of twins at 19 years of age, who agreed to share their life stories and experiences of their time in school. Meetings were arranged separately with Alex, the boy, and Helena, the girl, both eager to participate. They felt that their stories could contribute to knowledge. The stories show that placement discontinuities in their early childhood made memories and their perspective of time blurry. They both suffered severe neglect in two of their foster care placements. School offered them a safe place throughout their adolescent years. However, despite this, they are critical to the teachers who saw that they suffered neglect at home but never acted upon that knowledge. Hence their first-hand experiences suggest that teachers, considered important in earlier research studies, are not as important as friend made or the daily routines that provide certain security in an otherwise uncertain life. The social services didn’t listen or support them. Alex and Helena felt that they had to take care of themselves. Their stories show that both of them are goal-oriented and that they highly value a good education. This is evident since they have always taken responsibility to complete set homework and to make school a functional place where they have also learned to know themselves. Furthermore, it is obvious that the twins have played a tremendous role for each other when their life-world time after time has changed. Alex and Helena’s stories and experiences can give the social services a deeper understanding of what lies behind the statistics. A teacher, who listens, shows support and has ambitious expectations regarding the children’s academic performance, has been confirmed in previous research to be of significant importance. In addition, the study shows that teachers should learn more about children in foster care. A life-world perspective and life-world theories can contribute to an alternative point of view regarding learning in life-world discontinuities. Learning can be reflected on by using Schütz theory about “strangers” as a way of understanding learning in a wider range, especially when there are discontinues in the life-world. The reflections made in this study point out the possibility that schools, as organizations, seem to have independent cultures that can be transferred between one another. In fact there seems to be certain variables that are the same for schools in general and hence it is of significant value to recognize school as a regional life-world. The expectations of how you act as a student and among friends are important for the sense of belonging. It is possible that Alex and Helena succeeded in school partly because some of the things they learned about the first school could be transferred to their new school. The study contributes with two new concepts; “livsvärldsbrott”- life-world-disruption and “livsvärldsbevarande”- life-world-preservation

Interaction of the Phosphotyrosine Interaction/Phosphotyrosine Binding-related Domains of Fe65 with Wild-type and Mutant Alzheimer's β-Amyloid Precursor Proteins

The two tandem phosphotyrosine interaction/phosphotyrosine binding (PID/PTB) domains of the Fe65 protein interact with the intracellular region of the Alzheimer's beta-amyloid precursor protein (APP). This interaction, previously demonstrated in vitro and in the yeast two hybrid system, also takes place in vivo in mammalian cells, as demonstrated here by anti-Fe65 co-immunoprecipitation experiments. This interaction differs from that occurring between other PID/PTB domain-containing proteins, such as Shc and insulin receptor substrate 1, and activated growth factor receptors as follows: (i) the Fe65-APP interaction is phosphorylation-independent; (ii) the region of the APP intracellular domain involved in the binding is larger than that of the growth factor receptor necessary for the formation of the complex with Shc; and (iii) despite a significant similarity the carboxyl-terminal regions of PID/PTB of Fe65 and of Shc are not functionally interchangeable in terms of binding cognate ligands. A role for Fe65 in the pathogenesis of familial Alzheimer's disease is suggested by the finding that mutant APP, responsible for some cases of familial Alzheimer's disease, shows an altered in vivo interaction with Fe65

Highly conserved molecular pathways, including Wnt signaling, promote functional recovery from spinal cord injury in lampreys

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Scientific Reports 8 (2018): 742, doi:10.1038/s41598-017-18757-1.In mammals, spinal cord injury (SCI) leads to dramatic losses in neurons and synaptic connections, and consequently function. Unlike mammals, lampreys are vertebrates that undergo spontaneous regeneration and achieve functional recovery after SCI. Therefore our goal was to determine the complete transcriptional responses that occur after SCI in lampreys and to identify deeply conserved pathways that promote regeneration. We performed RNA-Seq on lamprey spinal cord and brain throughout the course of functional recovery. We describe complex transcriptional responses in the injured spinal cord, and somewhat surprisingly, also in the brain. Transcriptional responses to SCI in lampreys included transcription factor networks that promote peripheral nerve regeneration in mammals such as Atf3 and Jun. Furthermore, a number of highly conserved axon guidance, extracellular matrix, and proliferation genes were also differentially expressed after SCI in lampreys. Strikingly, ~3% of differentially expressed transcripts belonged to the Wnt pathways. These included members of the Wnt and Frizzled gene families, and genes involved in downstream signaling. Pharmacological inhibition of Wnt signaling inhibited functional recovery, confirming a critical role for this pathway. These data indicate that molecular signals present in mammals are also involved in regeneration in lampreys, supporting translational relevance of the model.We gratefully acknowledge support from the National Institutes of Health (R03NS078519 to OB; R01GM104123 to JJS; R01NS078165 to JRM), The Feinstein Institute for Medical Research and The Marine Biological Laboratory, including the Charles Evans Foundation Research Award, the Albert and Ellen Grass Foundation Faculty Research Award, and The Eugene and Millicent Bell Fellowship Fund in Tissue Engineering