Accumulation and local proliferation of antigen-specific CD4+ T cells in antigen-bearing tissue

Although activation and subsequent expansion of naive CD4(+) T cells within lymph nodes is well characterized, the fate of T effector cells activated within peripheral tissues during secondary reactions is poorly defined. Therefore, we studied the recruitment, proliferation and egress of antigen-specific Th1 effector cells in comparison with nonspecific Th1 cells throughout a delayed-type hypersensitivity reaction (DTH). Although we observed a high turnover of Th1 effector cells with unspecific high-rate recruitment and CCR7-dependent egress from the inflamed tissue in the early, acute DTH phase, a strong, selective accumulation of antigen-specific T cells occurred during the chronic, late DTH phase. This was mainly based on local proliferation of CD4(+) effector cells within the DTH tissue and concomitant retention. Considering the strong CCR7-dependent Th cell egress found in this model, the reduced CCR7 expression on antigen-specific T cells isolated from late-phase DTH tissue most likely contributes to the retention of these cells within the tissue. Thus, peripheral tissues can support not only the proliferation of CD8(+) T cells, as recently shown, but also that of CD4(+) T effector cells, forming a pool of tissue-resident T cells.     

Design, synthesis and structure-activity relationships of (indo-3-yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate

We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.     

Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease

Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD-rs6812193 near SCARB2 (p = 7.6 × 10(-10), OR = 0.84) and rs11868035 near SREBF1/RAI1 (p = 5.6 × 10(-8), OR = 0.85)-both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%-7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered.     

High blood pressure,antihypertensive medication and lung function in a general adult population

Background

Several studies showed that blood pressure and lung function are associated. Additionally, a potential effect of antihypertensive medication, especially beta-blockers, on lung function has been discussed. However, side effects of beta-blockers have been investigated mainly in patients with already reduced lung function. Thus, aim of this analysis is to determine whether hypertension and antihypertensive medication have an adverse effect on lung function in a general adult population.

Methods

Within the population-based KORA F4 study 1319 adults aged 40-65 years performed lung function tests and blood pressure measurements. Additionally, information on anthropometric measurements, medical history and use of antihypertensive medication was available. Multivariable regression models were applied to study the association between blood pressure, antihypertensive medication and lung function.

Results

High blood pressure as well as antihypertensive medication were associated with lower forced expiratory volume in one second (p = 0.02 respectively p = 0.05; R²: 0.65) and forced vital capacity values (p = 0.01 respectively p = 0.05, R²: 0.73). Furthermore, a detailed analysis of antihypertensive medication pointed out that only the use of beta-blockers was associated with reduced lung function, whereas other antihypertensive medication had no effect on lung function. The adverse effect of beta-blockers was significant for forced vital capacity (p = 0.04; R²: 0.65), while the association with forced expiratory volume in one second showed a trend toward significance (p = 0.07; R²: 0.73). In the same model high blood pressure was associated with reduced forced vital capacity (p = 0.01) and forced expiratory volume in one second (p = 0.03) values, too.

Conclusion

Our analysis indicates that both high blood pressure and the use of beta-blockers, but not the use of other antihypertensive medication, are associated with reduced lung function in a general adult population.     

The filopodium: A stable structure with highly regulated repetitive cycles of elongation and persistence depending on the actin cross-linker fascin

The ability of mammalian cells to adhere and to migrate is an essential prerequisite to form higher organisms. Early migratory events include substrate sensing, adhesion formation, actin bundle assembly and force generation. Latest research revealed that filopodia are important not only for sensing the substrate but for all of the aforementioned highly regulated processes. However, the exact regulatory mechanisms are still barely understood. Here, we demonstrate that filopodia of human keratinocytes exhibit distinct cycles of repetitive elongation and persistence. A single filopodium thereby is able to initiate the formation of several stable adhesions. Every single filopodial cycle is characterized by an elongation phase, followed by a stabilization time and in many cases a persistence phase. The whole process is strongly connected to the velocity of the lamellipodial leading edge, characterized by a similar phase behavior with a slight time shift compared with filopodia and a different velocity. Most importantly, re-growth of existing filopodia is induced at a sharply defined distance between the filopodial tip and the lamellipodial leading edge. On the molecular level this regrowth is preceded by a strong filopodial reduction of the actin bundling protein fascin. This reduction is achieved by a switch to actin polymerization without fascin incorporation at the filopodial tip and therefore subsequent out-transport of the cross-linker by actin retrograde flow.Key words: filopodia, lamellipodia, cell migration, fascin, adhesion, retrograde flow, actin polymerization     

Communicable diseases prioritized for surveillance and epidemiological research: results of a standardized prioritization procedure in Germany, 2011

Introduction

To establish strategic priorities for the German national public health institute (RKI) and guide the institute''s mid-term strategic decisions, we prioritized infectious pathogens in accordance with their importance for national surveillance and epidemiological research.

Methods

We used the Delphi process with internal (RKI) and external experts and a metric-consensus approach to score pathogens according to ten three-tiered criteria. Additional experts were invited to weight each criterion, leading to the calculation of a median weight by which each score was multiplied. We ranked the pathogens according to the total weighted score and divided them into four priority groups.

Results

127 pathogens were scored. Eighty-six experts participated in the weighting; “Case fatality rate” was rated as the most important criterion. Twenty-six pathogens were ranked in the highest priority group; among those were pathogens with internationally recognised importance (e.g., Human Immunodeficiency Virus, Mycobacterium tuberculosis, Influenza virus, Hepatitis C virus, Neisseria meningitides), pathogens frequently causing large outbreaks (e.g., Campylobacter spp.), and nosocomial pathogens associated with antimicrobial resistance. Other pathogens in the highest priority group included Helicobacter pylori, Respiratory Syncytial Virus, Varicella zoster virus and Hantavirus.

Discussion

While several pathogens from the highest priority group already have a high profile in national and international health policy documents, high scores for other pathogens (e.g., Helicobacter pylori, Respiratory syncytial virus or Hantavirus) indicate a possible under-recognised importance within the current German public health framework. A process to strengthen respective surveillance systems and research has been started. The prioritization methodology has worked well; its modular structure makes it potentially useful for other settings.     

A new thermosensitive smc-3 allele reveals involvement of cohesin in homologous recombination in C. elegans

The cohesin complex is required for the cohesion of sister chromatids and for correct segregation during mitosis and meiosis. Crossover recombination, together with cohesion, is essential for the disjunction of homologous chromosomes during the first meiotic division. Cohesin has been implicated in facilitating recombinational repair of DNA lesions via the sister chromatid. Here, we made use of a new temperature-sensitive mutation in the Caenorhabditis elegans SMC-3 protein to study the role of cohesin in the repair of DNA double-strand breaks (DSBs) and hence in meiotic crossing over. We report that attenuation of cohesin was associated with extensive SPO-11-dependent chromosome fragmentation, which is representative of unrepaired DSBs. We also found that attenuated cohesin likely increased the number of DSBs and eliminated the need of MRE-11 and RAD-50 for DSB formation in C. elegans, which suggests a role for the MRN complex in making cohesin-loaded chromatin susceptible to meiotic DSBs. Notably, in spite of largely intact sister chromatid cohesion, backup DSB repair via the sister chromatid was mostly impaired. We also found that weakened cohesins affected mitotic repair of DSBs by homologous recombination, whereas NHEJ repair was not affected. Our data suggest that recombinational DNA repair makes higher demands on cohesins than does chromosome segregation.     

The Biological Significance of the Pair-bond in the Shrimp Hymenocera picta

The painted shrimp exhibits a social system of “relative monogamy”. The selective consequences of mate attachment for the individuals have been studied by long term observations and experiments.