The RNA-binding protein PTBP1 is necessary for B cell selection in germinal centers.

Antibody affinity maturation occurs in germinal centers (GCs), where B cells cycle between the light zone (LZ) and the dark zone. In the LZ, GC B cells bearing immunoglobulins with the highest affinity for antigen receive positive selection signals from helper T cells, which promotes their rapid proliferation. Here we found that the RNA-binding protein PTBP1 was needed for the progression of GC B cells through late S phase of the cell cycle and for affinity maturation. PTBP1 was required for proper expression of the c-MYC-dependent gene program induced in GC B cells receiving T cell help and directly regulated the alternative splicing and abundance of transcripts that are increased during positive selection to promote proliferation

For whom is a health-promoting intervention effective? Predictive factors for performing activities of daily living independently

BACKGROUND: Health-promoting interventions tailored to support older persons to remain in their homes, so-called "ageing in place" is important for supporting or improving their health. The health-promoting programme "Elderly Persons in the Risk Zone," (EPRZ) was set up for this purpose and has shown positive results for maintaining independence in activities of daily living for older persons 80 years and above at 1- and 2 year follow-ups. The aim of this study was to explore factors for maintaining independence in the EPRZ health-promoting programme.METHODS: Total of 459 participants in the original trial was included in the analysis; 345 in the programme arm and 114 in the control arm. Thirteen variables, including demographic, health, and programme-specific indicators, were chosen as predictors for independence of activities of daily living. Logistic regression was performed separately for participants in the health promotion programme and in the control arm.RESULTS: In the programme arm, being younger, living alone and self-rated lack of tiredness in performing mobility activities predicted a positive effect of independence in activities of daily living at 1-year follow-up (odds ratio [OR] 1.18, 1.73, 3.02) and 2-year, (OR 1.13, 2.01, 2.02). In the control arm, being less frail was the only predictor at 1-year follow up (OR 1.6 1.09, 2.4); no variables predicted the outcome at the 2-year follow-up.CONCLUSIONS: Older persons living alone - as a risk of ill health - should be especially recognized and offered an opportunity to participate in health-promoting programmes such as "Elderly Persons in the Risk Zone". Further, screening for subjective frailty could form an advantageous guiding principle to target the right population when deciding to whom health-promoting intervention should be offered.TRIAL REGISTRATION: The original clinical trial was registered at ClinicalTrials.gov. Identifier: NCT00877058 , April 6, 2009

Germinal center B cells recognize antigen through a specialized immune synapse architecture

B cell activation is regulated by B cell antigen receptor (BCR) signaling and antigen internalization in immune synapses. Using large-scale imaging across B cell subsets, we show that in contrast to naive and memory B cells, which gathered antigen towards the synapse center before internalization, germinal center (GC) B cells extracted antigen by a distinct pathway using small peripheral clusters. Both naive and GC B cell synapses required proximal BCR signaling, but GC cells signaled less through the protein kinase C-β (PKC-β)–NF-κB pathway and produced stronger tugging forces on the BCR, thereby more stringently regulating antigen binding. Consequently, GC B cells extracted antigen with better affinity discrimination than naive B cells, suggesting that specialized biomechanical patterns in B cell synapses regulate T-cell dependent selection of high-affinity B cells in GCs

Relationship between home care service use and changes in the care needs level of Japanese elderly

<p>Abstract</p> <p>Background</p> <p>With the introduction of long-term care insurance (LTCI) in Japan, more home care services are available for the community-dwelling elderly. To deliver effective home care services, it is important to know the effects of service use. In this study, as the first step to determine this, we sought to describe different home service use in the sustained/improved group and deteriorated group in their care needs levels, and to report the relationship between the use of home care services and changes in care needs levels.</p> <p>Methods</p> <p>The participants included 624 of a total of 1,474 users of LTCI services in one city in Japan. Home care service users were stratified into a 'lower care needs level subgroup' and a 'higher care needs level subgroup' based on the baseline care needs level. Simple statistical comparison and multiple logistic regression analyses in which the change in care needs level was set as a dependent variable were performed. Gender, age, and baseline care needs level were designated as control variables. Home based services were treated as independent variables. In this study, home care services consisted of home help, home bathing services, a visiting nurse, home rehabilitation, nursing home daycare, health daycare, loan of medical devices, respite stay in a nursing home, respite stay in a health care facility, respite stay in a sanatorium-type medical care facility, and medical management by a physician.</p> <p>Results</p> <p>In the lower care needs level subgroup, age (OR = 1.04, CI, 1.01-1.08), use of respite stay in a nursing home (OR = 2.55; CI, 1.43-4.56), and the number of types of long-term care services (OR = 1.33; CI, 1.02-1.74) used during an 11 month period were significantly related to a deterioration of the user's care needs level. In the higher care needs level subgroup, use of medical management by a physician (OR = 6.99; CI, 1.42-41.25) was significantly related to a deterioration of the user's care needs level. There were no home based services significantly related to sustaining or improving the user's care needs level.</p> <p>Conclusion</p> <p>There were different home service use in two groups (the sustained/improved group and the deteriorated group). Respite stay in a nursing home service use and more types of service use were related to experiencing a deterioration of care needs level in lower care needs level community-dwelling elderly persons in Japan. Further, medical management by a physician service was related to experiencing a deterioration of care needs level in higher care needs level community-dwelling elderly persons.</p

Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

Contains fulltext : 169681.pdf (publisher's version ) (Open Access)Heterozygous mutations or deletions of the human Euchromatin Histone Methyltransferase 1 (EHMT1) gene are the main causes of Kleefstra syndrome, a neurodevelopmental disorder that is characterized by impaired memory, autistic features and mostly severe intellectual disability. Previously, Ehmt1+/- heterozygous knockout mice were found to exhibit cranial abnormalities and decreased sociability, phenotypes similar to those observed in Kleefstra syndrome patients. In addition, Ehmt1+/- knockout mice were impaired at fear extinction and novel- and spatial object recognition. In this study, Ehmt1+/- and wild-type mice were tested on several cognitive tests in a touchscreen-equipped operant chamber to further investigate the nature of learning and memory changes. Performance of Ehmt1+/- mice in the Visual Discrimination &Reversal learning, object-location Paired-Associates learning- and Extinction learning tasks was found to be unimpaired. Remarkably, Ehmt1+/- mice showed enhanced performance on the Location Discrimination test of pattern separation. In line with improved Location Discrimination ability, an increase in BrdU-labelled cells in the subgranular zone of the dentate gyrus was observed. In conclusion, reduced levels of EHMT1 protein in Ehmt1+/- mice does not result in general learning deficits in a touchscreen-based battery, but leads to increased adult cell proliferation in the hippocampus and enhanced pattern separation ability

Induction of GADD34 Is Necessary for dsRNA-Dependent Interferon-β Production and Participates in the Control of Chikungunya Virus Infection

Nucleic acid sensing by cells is a key feature of antiviral responses, which generally result in type-I Interferon production and tissue protection. However, detection of double-stranded RNAs in virus-infected cells promotes two concomitant and apparently conflicting events. The dsRNA-dependent protein kinase (PKR) phosphorylates translation initiation factor 2-alpha (eIF2α) and inhibits protein synthesis, whereas cytosolic DExD/H box RNA helicases induce expression of type I-IFN and other cytokines. We demonstrate that the phosphatase-1 cofactor, growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), an important component of the unfolded protein response (UPR), is absolutely required for type I-IFN and IL-6 production by mouse embryonic fibroblasts (MEFs) in response to dsRNA. GADD34 expression in MEFs is dependent on PKR activation, linking cytosolic microbial sensing with the ATF4 branch of the UPR. The importance of this link for anti-viral immunity is underlined by the extreme susceptibility of GADD34-deficient fibroblasts and neonate mice to Chikungunya virus infection

Sequencing HIV-neutralizing antibody exons and introns reveals detailed aspects of lineage maturation.

CAPRISA, 2018.Abstract available in pdf