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Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have clinical, pathological and genetic overlapping. Lipid pathways are implicated in ALS. This study examined the effect of blood lipid levels on ALS, FTD risk, and survival in ALS. Methods: A systematic review and meta-analysis of high and low-density lipoprotein cholesterol (HDL-c and LDL-c), total cholesterol, triglycerides, apolipoproteins B and A1 levels with ALS was performed. Two-sample Mendelian randomisation (MR) analysis sought the causal effects of these exposures on ALS, FTD, and survival in ALS. The effect of lipid-lowering drugs was also examined using genetic proxies for targets of lipid-lowering medications. Results: Three cohort studies met the inclusion criteria for meta-analysis. Meta-analysis indicated an association between higher LDL-c (HRper mmol/L = 1.07, 95%CI:1.02–1.12; I 2 =18%) and lower HDL-c (HRper mmol/L = 0.83, 95%CI:0.74–0.94; I 2 =0%) with an increased risk of ALS. MR suggested causal effects of higher LDL-c (ORIVW = 1.085, 95%:CI 1.008–1.168, pFDR = 0.0406), total cholesterol (ORIVW = 1.081, 95%:CI 1.013–1.154, pFDR = 0.0458) and apolipoprotein B (ORIVW = 1.104, 95%:CI 1.041–1.171, pFDR = 0.0061) increasing ALS risk, and higher apolipoprotein B level increasing FTD risk (ORIVW = 1.424, 95%CI 1.072–1.829, pFDR = 0.0382). Reducing LDL-c through APOB inhibition was associated with lower ALS (ORIVW = 0.84, 95%CI 0.759–0.929, pFDR = 0.00275) and FTD risk (ORIVW = 0.581, 95%CI 0.387–0.874, pFDR = 0.0362). Conclusion: These data support the influence of LDL-c and total cholesterol on ALS risk and apolipoprotein B on the risk of ALS and FTD. Potential APOB inhibition might decrease the risk of sporadic ALS and FTD. Further work in monogenic forms of ALS and FTD is necessary to determine whether blood lipids influence penetrance and phenotype. [ABSTRACT FROM AUTHOR]

During B cell maturation, transitional and mature B cells acquire cell-intrinsic features that determine their ability to exit quiescence and mount effective immune responses. Here we use label-free proteomics to quantify the proteome of B cell subsets from the mouse spleen and map the differential expression of environmental sensing, transcription, and translation initiation factors that define cellular identity and function. Cross-examination of the full-length transcriptome and proteome identifies mRNAs related to B cell activation and antibody secretion that are not accompanied by detection of the encoded proteins. In addition, proteomic data further suggests that the translational repressor PDCD4 restrains B cell responses, in particular those from marginal zone B cells, to a T-cell independent antigen. In summary, our molecular characterization of B cell maturation presents a valuable resource to further explore the mechanisms underpinning the specialized functions of B cell subsets, and suggest the presence of 'poised' mRNAs that enable expedited B cell responses. B cells pursue specific genetic programs to facilitate downstream cellular functions. Here the authors identify, using a combination of proteomic, transcriptomic and functional analyses, a group of mRNAs related to early activation and antibody production that are expressed in B cells without corresponding proteins, hinting a 'poised' state of B cells. [ABSTRACT FROM AUTHOR]

In this brief article, the editorial team for the special issue "The Application of REBT Theory and Practice to High-Performance Settings" offer an introduction to the topic. Herein, we introduce the area of Rational Emotive Behavior Therapy (REBT) within performance settings and give a brief overview of the papers included in the special issue. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop a Rational Emotive Behaviour Therapy (REBT) based group counselling program for athletes, and then to experimentally test the effects of the program on the competitive anxiety and irrational beliefs of non-western student-athletes. The effects of the REBT based program was examined using a 2 × 2 controlled quasi-experimental group design. 22 student-athletes participated in the study (11 in the experimental group and 11 in the control group). The Sport Anxiety Scale-2 was used to assess athlete competitive anxiety. To test the effects of program, descriptive statistics were calculated, and Bayesian repeated-measures ANOVA were conducted. Thematic analysis is used to analyse qualitative data. Data revealed significant decreases from pre- to post- in irrational beliefs and competitive anxiety in the REBT group compared to the control group. The findings indicated a positive effect of the REBT based program on the student-athletes' competitive anxiety levels. [ABSTRACT FROM AUTHOR]

Researchers are beginning to explore the antecedents to anxiety symptomology. Such antecedents to anxiety symptomology may be that of irrational beliefs and motivation regulation. It has been intimated that both irrational beliefs and motivation regulation can be risk factors for increased anxiety in athletes. Research is yet to explore the association between these two antecedents, and how and whether they interact in predicting anxiety symptomology. The present paper investigates such associations within two phases. In phase one, we identify the predictive capacity of irrational beliefs and motivation regulation on anxiety symptomology in 61 elite ultra-marathon runners. Results support intimated associations between irrational beliefs and motivation regulation, evidencing that irrational performance beliefs negatively associated with relative autonomous motivation. In addition, it was found that irrational performance beliefs positively associated with anxiety symptomology, whilst autonomous motivation negatively associated with anxiety symptomology in elite ultra-marathon runners. In phase two, we use a narrative approach to understand seven elite athletes' stories surrounding their performance beliefs, motivation, and anxiety symptomology. Phase two supports findings in phase one, evidencing that the co-existence of both irrational performance beliefs and controlled motivation is an antecedent to anxiety symptomology and dysfunctional behaviours in ultra-marathon runners. The findings of both phase one and phase two are discussed in relation to the theoretical and practical implications for elite athletes. [ABSTRACT FROM AUTHOR]

There has been a scarcity of research regarding the unique mental health risk factors that adolescent athletes face. The recently proposed Rational Emotive Self Determination Scale for Adolescents (RESD-A) has been suggested to understand some of the antecedent and associative factors of adolescent athlete mental health. The principal aim of this study is to examine the structural and criterion validity of the RESD-A in an athlete sample for the first time. To achieve this aim, two hundred and forty-two club level soccer athletes participated in the study. Confirmatory factor analysis (CFA) was conducted to test the validity of the RESD-A's factor structure. Partial correlation analyses with the subscales of RESD-A, emotional intelligence, and mental health scores were used to examine criterion validity. Initial results for the structural and criterion validity of the RESD-A with an athlete population are promising. The potential importance, limitations and directions for future research are discussed. [ABSTRACT FROM AUTHOR]

According to Rational Emotive Behaviour Therapy (REBT), humans have a strong biological tendency to adopt self-defeating irrational beliefs which are subsequently driven by the socio-cultural environment one lives in Ellis (J Individ Psychol 32:145–168, 1976). Sport of all levels presents a unique environment which may serve to explain sport-related irrationalities harboured by athletes given that sport seems to endorse irrationality evident by the language used by key personnel and outlets (e.g., coaches and the media; (Turner in Front Psychol 7(9):1–16, 2016. https://doi.org/10.3389/fpsyg.2016.01423). An athlete's beliefs and philosophies are shaped by a myriad of people within and outside of sport with whom they look to for guidance, such as coaches, medical professionals, parents, and the media. These key social agents within an athlete's micro- and macro-environment harbour and model irrationality through their behaviour, language and processes. These irrationalities may then be internalized, giving rise to the development and maintenance of irrational beliefs in athletes. Research has consistently demonstrated the association between irrational beliefs and deleterious mental health outcomes in athletes, such as psychological distress (e.g., Turner in Bernard and Dryden (eds.) REBT: advances in theory, research, prevention, promotion, Springer Press, pp. 307–335, 2019). Therefore, the aim of our commentary is twofold: (1) to critically explore how key stakeholders within an athlete's micro- and macro- environment contribute to the development, maintenance, and strengthening of irrational beliefs in athletes and, (2) to provide guidance to key stakeholders on weakening irrational beliefs and strengthening rational beliefs, thereby promoting a healthy and successful sport environment and positive mental health outcomes in athletes. [ABSTRACT FROM AUTHOR]

The reported usage of rational emotive behaviour therapy (REBT) in high performance sport is becoming more common in research literature. This research indicates that REBT is a useful and effective approach to performance psychology. However, applied professional practice reflections and insights remain sparse. The current paper brings together REBT practitioners who work predominantly in performance settings (i.e., sport) to answer three questions pertaining to their application of REBT. Practitioners were asked to respond to the following questions: (1) What do you consider to be among the main irrational beliefs that interfere with performance? (2) In your experience, which irrational beliefs impair one's ability to recover from a significant injury or major setback? (3) Can you describe the role of cognitive restructuring/change/reappraisal/disputation in applied work as it relates to performance? In the present paper, the practitioners' responses are collected and presented, following which common themes are drawn from the responses to form guidance for practitioners wishing to apply REBT in performance settings. It is hoped that the experiences of the included practitioners will be useful for those wishing to take an REBT approach to their performance psychology consultancy. [ABSTRACT FROM AUTHOR]

Successful vaccines rely on activating a functional humoral immune response through the generation of class-switched high affinity immunoglobulins (Igs). The germinal center (GC) reaction is crucial for this process, in which B cells are selected in their search for antigen and T cell help. A major hurdle to understand the mechanisms of B cell:T cell cooperation has been the lack of an antigen-specific in vitro GC system. Here we report the generation of antigen-specific, high-affinity, class-switched Igs in simple 2-cell type cultures of naive B and T cells. B cell antigen uptake by phagocytosis is key to generate these Igs. We have used the method to interrogate if T cells confer directional help to cognate B cells that present antigen and to bystander B cells. We find that bystander B cells do not generate class-switched antibodies due to a defective formation of T-B conjugates and an early conversion into memory B cells. An antigen-specific in vitro germinal center system based on the use of just two cell types, B cells and CD4+ T cells, is developed to study antigen-specific germinal center reactions and T cell help to cognate versus bystander B cells. [ABSTRACT FROM AUTHOR]

The ZFP36 family of RNA-binding proteins acts post-transcriptionally to repress translation and promote RNA decay. Studies of genes and pathways regulated by the ZFP36 family in CD4+ T cells have focussed largely on cytokines, but their impact on metabolic reprogramming and differentiation is unclear. Using CD4+ T cells lacking Zfp36 and Zfp36l1, we combined the quantification of mRNA transcription, stability, abundance and translation with crosslinking immunoprecipitation and metabolic profiling to determine how they regulate T cell metabolism and differentiation. Our results suggest that ZFP36 and ZFP36L1 act directly to limit the expression of genes driving anabolic processes by two distinct routes: by targeting transcription factors and by targeting transcripts encoding rate-limiting enzymes. These enzymes span numerous metabolic pathways including glycolysis, one-carbon metabolism and glutaminolysis. Direct binding and repression of transcripts encoding glutamine transporter SLC38A2 correlated with increased cellular glutamine content in ZFP36/ZFP36L1-deficient T cells. Increased conversion of glutamine to α-ketoglutarate in these cells was consistent with direct binding of ZFP36/ZFP36L1 to Gls (encoding glutaminase) and Glud1 (encoding glutamate dehydrogenase). We propose that ZFP36 and ZFP36L1 as well as glutamine and α-ketoglutarate are limiting factors for the acquisition of the cytotoxic CD4+ T cell fate. Our data implicate ZFP36 and ZFP36L1 in limiting glutamine anaplerosis and differentiation of activated CD4+ T cells, likely mediated by direct binding to transcripts of critical genes that drive these processes. [ABSTRACT FROM AUTHOR]

Motor neuron diseases such as amyotrophic lateral sclerosis are primarily characterized by motor neuron degeneration with additional involvement of non-neuronal cells, in particular, microglia. In previous work, we have established protocols for the differentiation of iPSC-derived spinal motor neurons and microglia. Here, we combine both cell lineages and establish a novel co-culture of iPSC-derived spinal motor neurons and microglia, which is compatible with motor neuron identity and function. Co-cultured microglia express key identity markers and transcriptomically resemble primary human microglia, have highly dynamic ramifications, are phagocytically competent, release relevant cytokines and respond to stimulation. Further, they express key amyotrophic lateral sclerosis-associated genes and release disease-relevant biomarkers. This novel and authentic human model system facilitates the study of physiological motor neuron-microglia crosstalk and will allow the investigation of non-cell-autonomous phenotypes in motor neuron diseases such as amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]

This paper reports the development and initial validation of the Persian language Irrational Performance Beliefs Inventory (iPBI-Persian). The original iPBI was developed to provide a validated measure of the four core irrational beliefs of rational emotive behavior therapy (REBT) within performance-based samples, such as athletes. Data retrieved from 334 athletes (169 men, 165 women, Mage = 21.52 ± 4.00 years) were analyses using SPSS and LISREL software packages. After the linguistic and cross-cultural adaptation processes, confirmatory factor analysis (CFA) results showed that six items did not have acceptable factor loadings. After removal of problem items, a 22-item version was developed (CFI = 0.96). The iPBI-Persian demonstrated excellent levels of reliability, with internal consistency and test–retest reliability, as well as construct validity. This paper indicates that the 22-item iPBI-Persian can be used as a self-assessment instrument to evaluate irrational performance beliefs in Iranian athlete samples. [ABSTRACT FROM AUTHOR]

CD8+ T cell differentiation into effector cells is initiated early after antigen encounter by signals from the T cell antigen receptor and costimulatory molecules. The molecular mechanisms that establish the timing and rate of differentiation however are not defined. Here we show that the RNA binding proteins (RBP) ZFP36 and ZFP36L1 limit the rate of differentiation of activated naïve CD8+ T cells and the potency of the resulting cytotoxic lymphocytes. The RBP function in an early and short temporal window to enforce dependency on costimulation via CD28 for full T cell activation and effector differentiation by directly binding mRNA of NF-κB, Irf8 and Notch1 transcription factors and cytokines, including Il2. Their absence in T cells, or the adoptive transfer of small numbers of CD8+ T cells lacking the RBP, promotes resilience to influenza A virus infection without immunopathology. These findings highlight ZFP36 and ZFP36L1 as nodes for the integration of the early T cell activation signals controlling the speed and quality of the CD8+ T cell response. RNA binding proteins (RBP) have a function in T cell activation and differentiation. Here the authors show that in the absence of two RBPs, ZFP36 and ZFP36L1, T cells acquire more rapidly superior effector capabilities, showing a limiting function for RBP in T cell activation and differentiation. [ABSTRACT FROM AUTHOR]

The germinal centre (GC) is required for the generation of high affinity antibodies and immunological memory. Here we show that the RNA binding protein HuR has an essential function in GC B cells to sustain the GC response. In its absence, the GC reaction and production of high-affinity antibody is severely impaired. Mechanistically, HuR affects the transcriptome qualitatively and quantitatively. The expression and splicing patterns of hundreds of genes are altered in the absence of HuR. Among these genes, HuR is required for the expression of Myc and a Myc-dependent transcriptional program that controls GC B cell proliferation and Ig somatic hypermutation. Additionally, HuR regulates the splicing and abundance of mRNAs required for entry into and transition through the S phase of the cell cycle, and it modulates a gene signature associated with DNA deamination protecting GC B cells from DNA damage and cell death. Germinal centre (GC) responses may require RNA binding proteins (RBP) for post-transcriptional gene regulation. Here the authors show the RBP HuR supports GCs by promoting Myc and Myc-dependent transcription to enhance antigen-specific GC B cell selection and production of high affinity antibodies. [ABSTRACT FROM AUTHOR]

The present case study puts forth the first idiographic application of a one to one Rational Emotive Behavior Therapy (REBT; Ellis in J Individ Psychol 13:38–44, 1957) intervention integrated with Motivational Interviewing (MI; Miller and Rollnick in Motivational interviewing: helping people change, Guilford Press, London, 2013) with a client (elite athlete) on irrational beliefs, self-determined motivation, and sporting performance. Building and maintaining a strong working alliance with a client is considered central to both MI and REBT, and psychological interventions generally. Whilst there are widespread recognition and recommendations of the importance of working alliance, the guidance on how to explicitly cultivate this beyond broad descriptions is relatively scant. Using the present case of 'Theo', MI was used as an identifiable and measurable framework to foster a strong working alliance between the practitioner and client, to increase Theo's readiness and enhance the effects of the REBT intervention. After receiving eight one-to-one REBT sessions, data indicated acute and maintained reductions in Theo's endorsement of irrational beliefs, increases in self-determined motivation, and marked increases in sporting performance. In addition, measures of treatment fidelity showed the effective and maintained inclusion of core MI principles through the REBT intervention. Ultimately, the case supports the effective application of REBT in addition to MI, whilst providing guidelines by which practitioners can actively facilitate a working alliance when applying REBT. Further, the case contributes to the emerging literature that links reductions in irrational beliefs with enhanced self-determined motivation and its potential value on wellbeing and/or performance. [ABSTRACT FROM AUTHOR]

TDP-43 accumulates in nerve cells of nearly all cases of amyotrophic lateral sclerosis (ALS; the commonest form of motor neuron disease) and in the majority of Tau-negative frontotemporal lobar degeneration (FTLD). There is currently no biochemical test or marker of disease activity for ALS or FTLD, and the clinical diagnosis depends on the opinion of an experienced neurologist. TDP-43 has a key role in the pathogenesis of ALS/FTLD. Measuring TDP-43 in easily accessible biofluids, such as blood or cerebrospinal fluid, might reduce diagnostic delay and offer a readout for use in future drug trials. However, attempts at measuring disease-specific forms of TDP-43 in peripheral biofluids of ALS and FTLD patients have not yielded consistent results, and only some of the pathological biochemical features of TDP-43 found in human brain tissue have been detected in clinical biofluids to date. Reflecting on the molecular pathology of TDP-43, this review provides a critical overview on biofluid studies and future directions to develop a TDP-43-based clinical biomarker for ALS and FTLD. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the corticomotorneuronal network responsible for voluntary movement. There are well-established clinical, genetic and pathological overlaps between ALS and frontotemporal dementia (FTD), which together constitute the ‘TDP-43 proteinopathies’. An ever-expanding list of genes in which mutation leads to typical ALS have implicated abnormalities in RNA processing, protein homoeostasis and axonal transport. How these apparently distinct pathways converge to cause the characteristic clinical syndrome of ALS remains unclear. Although there are major gaps in our understanding of the essential nature of ALS pathophysiology, the identification of genetic causes in up to 15% of ALS patients, coupled with advances in biotechnology and biomarker research provide a foundation for approaches to treatment based on ‘precision medicine’, and even prevention of the disease in pre-symptomatic mutation carriers in the future. Currently, multidisciplinary care remains the bedrock of management and this is increasingly being put onto an evidence-based footing. [ABSTRACT FROM AUTHOR]

Abstract: Successful vaccines rely on activating a functional humoral response that results from promoting a proper germinal center (GC) reaction. Key in this process is the activation of follicular B cells that need to acquire antigens and to present them to cognate CD4 T cells. Here, we report that follicular B cells can phagocytose large antigen‐coated particles, a process thought to be exclusive of specialized antigen‐presenting cells such as macrophages and dendritic cells. We show that antigen phagocytosis by B cells is BCR‐driven and mechanistically dependent on the GTPase RhoG. Using Rhog−/− mice, we show that phagocytosis of antigen by B cells is important for the development of a strong GC response and the generation of high‐affinity class‐switched antibodies. Importantly, we show that the potentiation effect of alum, a common vaccine adjuvant, requires direct phagocytosis of alum–antigen complexes by B cells. These data suggest a new avenue for vaccination approaches by aiming to deliver 1–3 μm size antigen particles to follicular B cells. [ABSTRACT FROM AUTHOR]

Post-transcriptional regulation of cellular mRNA is essential for protein synthesis. Here we describe the importance of mRNA translational repression and mRNA subcellular location for protein expression during B lymphocyte activation and the DNA damage response. Cytoplasmic RNA granules are formed upon cell activation with mitogens, including stress granules that contain the RNA binding protein Tia1. Tia1 binds to a subset of transcripts involved in cell stress, including p53 mRNA, and controls translational silencing and RNA granule localization. DNA damage promotes mRNA relocation and translation in part due to dissociation of Tia1 from its mRNA targets. Upon DNA damage, p53 mRNA is released from stress granules and associates with polyribosomes to increase protein synthesis in a CAPindependent manner. Global analysis of cellular mRNA abundance and translation indicates that this is an extended ATM-dependent mechanism to increase protein expression of key modulators of the DNA damage response. [ABSTRACT FROM AUTHOR]

The reported application of rational emotive behavior therapy (REBT) with athletes is growing but remains scarce within sport psychology literature. This study used a single-case multiple-baseline across participants design to investigate the effects of REBT on irrational self-depreciation beliefs and unconditional self-acceptance (USA) with three male mixed martial arts (MMA) athletes. Visual and statistical analyses indicate a reduction in total irrationality and self-depreciation and an increase in USA, which was maintained at 6 months post-REBT for two of the three athletes. Social validation data revealed positive changes in emotion management and performance in all athletes. The mechanisms by which REBT promoted changes in self-depreciation and USA are discussed as are recommendations regarding the future implementation of REBT with athletes. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is now recognised to be a heterogeneous neurodegenerative syndrome of the motor system and its frontotemporal cortical connections. The development and application of structural and functional imaging over the last three decades, in particular magnetic resonance imaging (MRI), has allowed traditional post mortem histopathological and emerging molecular findings in ALS to be placed in a clinical context. Cerebral grey and white matter structural MRI changes are increasingly being understood in terms of brain connectivity, providing insights into the advancing degenerative process and producing candidate biomarkers. Such markers may refine the prognostic stratification of patients and the diagnostic pathway, as well as providing an objective assessment of changes in disease activity in response to future therapeutic agents. Studies are being extended to the spinal cord, and the application of neuroimaging to unaffected carriers of highly penetrant genetic mutations linked to the development of ALS offers a unique window to the pre-symptomatic landscape. [ABSTRACT FROM AUTHOR]

Post-transcriptional regulation of mRNA by the RNA-binding protein HuR (encoded by Elavl1) is required in B cells for the germinal center reaction and for the production of class-switched antibodies in response to thymus-independent antigens. Transcriptome-wide examination of RNA isoforms and their abundance and translation in HuR-deficient B cells, together with direct measurements of HuR-RNA interactions, revealed that HuR-dependent splicing of mRNA affected hundreds of transcripts, including that encoding dihydrolipoamide S-succinyltransferase (Dlst), a subunit of the 2-oxoglutarate dehydrogenase (α-KGDH) complex. In the absence of HuR, defective mitochondrial metabolism resulted in large amounts of reactive oxygen species and B cell death. Our study shows how post-transcriptional processes control the balance of energy metabolism required for the proliferation and differentiation of B cells. [ABSTRACT FROM AUTHOR]

The extant literature reveals a scarcity of research applying rational emotive behavior therapy (REBT) in business settings. Against the backdrop of severe market conditions and inevitable involuntary job loss, the application of psychological interventions to reduce mental and physical health issues is highly pertinent and potentially valuable. This paper reports the effects of an intensive REBT programme on the irrational beliefs of staff undergoing redundancy from a Blue-Chip organisation. A repeated-measures single-group intervention design was adopted so that changes in irrational beliefs could be assessed over the course of the REBT programme. Results indicated significant reductions in total irrational beliefs, other-depreciation, need for achievement, and demand for fairness from pretest to posttest phases. Social validation data indicated perceived psychological and performance benefits. Results are discussed with reference to mechanisms of change, study limitations, and applied research issues. [ABSTRACT FROM AUTHOR]

Inhibitors against the p110? isoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias. As p110? is primarily expressed in leukocytes, drugs against p110? have not been considered for the treatment of solid tumours. Here we report that p110? inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110? inactivation in regulatory T?cells unleashes CD8+ cytotoxic T?cells and induces tumour regression. Thus, p110? inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology. [ABSTRACT FROM AUTHOR]

The rapid changes in gene expression that accompany developmental transitions, stress responses and proliferation are controlled by signal-mediated coordination of transcriptional and post-transcriptional mechanisms. In recent years, understanding of the mechanics of these processes and the contexts in which they are employed during hematopoiesis and immune challenge has increased. An important aspect of this progress is recognition of the importance of RNA-binding proteins and noncoding RNAs. These have roles in the development and function of the immune system and in pathogen life cycles, and they represent an important aspect of intracellular immunity. [ABSTRACT FROM AUTHOR]

We found upregulation of expression of the microRNA miR-155 in primary effector and effector memory CD8+ T cells, but low miR-155 expression in naive and central memory cells. Antiviral CD8+ T cell responses and viral clearance were impaired in miR-155-deficient mice, and this defect was intrinsic to CD8+ T cells, as miR-155-deficient CD8+ T cells mounted greatly diminished primary and memory responses. Conversely, miR-155 overexpression augmented antiviral CD8+ T cell responses in vivo. Gene-expression profiling showed that miR-155-deficient CD8+ T cells had enhanced type I interferon signaling and were more susceptible to interferon's antiproliferative effect. Inhibition of the type I interferon-associated transcription factors STAT1 or IRF7 resulted in enhanced responses of miR-155-deficient CD8+ T cells in vivo. We have thus identified a previously unknown role for miR-155 in regulating responsiveness to interferon and CD8+ T cell responses to pathogens in vivo. [ABSTRACT FROM AUTHOR]

Insights into the mechanisms of amyotrophic lateral sclerosis (ALS) have relied predominantly on the study of postmortem tissue. Modern technology has improved the ability of scientists to probe effectively the underlying biology of ALS by examination of genomic, proteomic and physiological changes in patients, as well as to monitor functional and structural changes in patients over the course of disease. While effective treatments for ALS are lacking, the discovery of biomarkers for this disease offers clinicians tools for rapid diagnosis, improved ways to monitor disease progression, and insights into the pathophysiology of sporadic ALS. The ultimate aim is to broaden the therapeutic options for patients with this disease. [ABSTRACT FROM AUTHOR]

ZFP36L1 and ZFP36L2 are RNA-binding proteins (RBPs) that interact with AU-rich elements in the 3′ untranslated region of mRNA, which leads to mRNA degradation and translational repression. Here we show that mice that lacked ZFP36L1 and ZFP36L2 during thymopoiesis developed a T cell acute lymphoblastic leukemia (T-ALL) dependent on the oncogenic transcription factor Notch1. Before the onset of T-ALL, thymic development was perturbed, with accumulation of cells that had passed through the β-selection checkpoint without first expressing the T cell antigen receptor β-chain (TCRβ). Notch1 expression was higher in untransformed thymocytes in the absence of ZFP36L1 and ZFP36L2. Both RBPs interacted with evolutionarily conserved AU-rich elements in the 3′ untranslated region of Notch1 and suppressed its expression. Our data establish a role for ZFP36L1 and ZFP36L2 during thymocyte development and in the prevention of malignant transformation. [ABSTRACT FROM AUTHOR]

The objective of this study is to report trends in mortality, as certified on death certificates, from multiple sclerosis (MS), motor neuron disease (MND), primary Parkinson’s disease (PD), and epilepsy, analysing not only the underlying cause of death but also all certified causes for each disease. Death records in the Oxford region, 1979–2006, and England, 1996–2006, were analysed for ascertaining the trends in mortality. The percentage of deaths coded as the underlying cause changed over time, coinciding with changes to the rules for selecting the underlying cause of death. Changes over time to coding rules had a large impact on apparent trends in death rates for PD when studied by underlying cause alone. They also had significant, though smaller, effects on trends in death rates for MS, MND and epilepsy. Nationally, in the last period of the study, underlying cause mortality identified 64% of deaths with a mention of MS, 88% of MND, 56% of PD, and 48% of epilepsy. In the longstanding Oxford data from 1979 to 2006, death rates based on all certified causes of death showed no significant change for MS; an upward trend for MND (notably in women over 75), though only in the last few years of the study; a significant but small decline for PD; and no significant change for epilepsy. When mortality statistics are analysed by underlying cause only, their value is reduced. A substantial percentage of neurological deaths are missed. Time trends may be misleading. All certified causes for each disease, as well as the underlying cause, should be analysed. [ABSTRACT FROM AUTHOR]

Background A 44-year-old male presented to a general neurology clinic with a 6-month history of progressive right-sided spastic hemiparesis without sensory symptoms or signs. The thigh muscle in the affected leg showed signs of wasting. The patient had a remote family history of celiac disease. Investigations Neurological examination, neurophysiological studies, brain MRI scan, routine blood tests, duodenal biopsy, cerebrospinal fluid analysis including polymerase chain reaction test for JC virus DNA, serological testing for HIV and for the presence of serum antibodies to endomysium, gliadin and tissue transglutaminase. Diagnosis Celiac disease with neurological involvement, mimicking amyotrophic lateral sclerosis. Management Strict gluten-free diet. [ABSTRACT FROM AUTHOR]

Four PLS patients underwent cerebral [11C]-flumazenil PET. They were compared firstly with a group of controls, then later directly with a group of sporadic ALS patients and a familial ALS group homozygous for the ‘D90A’ SOD1 gene mutation. There was a similar pattern of decreased binding in PLS patients when compared to controls as that seen in a previous study of sporadic ALS patients, supporting the concept that PLS is part of the same overall spectrum of MND. However, in direct group comparisons, both sporadic and homD90A ALS patients demonstrated relative decreases in anterior and orbito-frontal binding compared to PLS patients, suggesting that there may be differences in cortical vulnerability between phenotypic groups. [ABSTRACT FROM AUTHOR]

Through their ability to regulate production of the key lipid messenger PtdIns(3,4,5)P3, the class I phosphatidylinositol-3-OH kinases (PI(3)Ks) support many critical cell responses. They, in turn, can be regulated by cell-surface receptors through signals acting on either their adaptor subunits (for example, through phosphotyrosine or Gβγs) or their catalytic subunits (for example, through GTP-Ras). The relative significance of these controlling inputs is undefined in vivo. Here, we have studied the roles of Gβγs, the adaptor p101, Ras and the Ras binding domain (RBD) in the control of the class I PI(3)K, PI(3)Kγ, in mouse neutrophils. Loss of p101 leads to major reductions in the accumulation of PtdIns(3,4,5)P3, activation of protein kinase B (PKB) and in migration towards G-protein activating ligands in vitro, and to an aseptically inflamed peritoneum in vivo. Loss of sensitivity of PI(3)Kγ to Ras unexpectedly caused similar reductions, but additionally caused a substantial loss in production of reactive oxygen species (ROS). We conclude that Gβγs, p101 and the Ras–RBD interaction all have important roles in the regulation of PI(3)Kγ in vivo and that they can simultaneously, but differentially, control distinct PI(3)Kγ effectors. [ABSTRACT FROM AUTHOR]

Genomic imprinting results in allele-specific silencing according to parental origin. Silencing is brought about by imprinting control regions (ICRs) that are differentially marked in gametogenesis. The group of imprinted transcripts in the mouse Gnas cluster (Nesp, Nespas, Gnasxl, Exon 1A and Gnas) provides a model for analyzing the mechanisms of imprint regulation. We previously identified an ICR that specifically regulates the tissue-specific imprinted expression of the Gnas gene. Here we identify a second ICR at the Gnas cluster. We show that a paternally derived targeted deletion of the germline differentially methylated region (DMR) associated with the antisense Nespas transcript unexpectedly affects both the expression of all transcripts in the cluster and methylation of two DMRs. Our results establish that the Nespas DMR is the principal ICR at the Gnas cluster and functions bidirectionally as a switch for modulating expression of the antagonistically acting genes Gnasxl and Gnas. Uniquely, the Nespas DMR acts on the downstream ICR at exon 1A to regulate tissue-specific imprinting of the Gnas gene. [ABSTRACT FROM AUTHOR]

Genomic imprinting brings about allele-specific silencing according to parental origin. Silencing is controlled by cis-acting regulatory regions that are differentially marked during gametogenesis and can act over hundreds of kilobases to silence many genes. Two candidate imprinting control regions (ICRs) have been identified at the compact imprinted Gnas cluster on distal mouse chromosome 2, one at exon 1A upstream of Gnas itself and one covering the promoters for Gnasxl and the antisense Nespas (ref. 8). This imprinted cluster is complex, containing biallelic, maternally and paternally expressed transcripts that share exons. Gnas itself is mainly biallelically expressed but is weakly paternally repressed in specific tissues. Here we show that a paternally derived targeted deletion of the germline differentially methylated region at exon 1A abolishes tissue-specific imprinting of Gnas. This rescues the abnormal phenotype of mice with a maternally derived Gnas mutation. Imprinting of alternative transcripts, Nesp, Gnasxl and Nespas (ref. 13), in the cluster is unaffected. The results establish that the differentially methylated region at exon 1A contains an imprinting control element that specifically regulates Gnas and comprises a characterized ICR for a gene that is only weakly imprinted in a minority of tissues. There must be a second ICR regulating the alternative transcripts. [ABSTRACT FROM AUTHOR]