Germinal Centers without T Cells

Germinal centers are critical for affinity maturation of antibody (Ab) responses. This process allows the production of high-efficiency neutralizing Ab that protects against virus infection and bacterial exotoxins. In germinal centers, responding B cells selectively mutate the genes that encode their receptors for antigen. This process can change Ab affinity and specificity. The mutated cells that produce high-affinity Ab are selected to become Ab-forming or memory B cells, whereas cells that have lost affinity or acquired autoreactivity are eliminated. Normally, T cells are critical for germinal center formation and subsequent B cell selection. Both processes involve engagement of CD40 on B cells by T cells. This report describes how high-affinity B cells can be induced to form large germinal centers in response to (4-hydroxy-3-nitrophenyl) acetyl (NP)-Ficoll in the absence of T cells or signaling through CD40 or CD28. This requires extensive cross-linking of the B cell receptors, and a frequency of antigen-specific B cells of at least 1 in 1,000. These germinal centers abort dramatically at the time when mutated high-affinity B cells are normally selected by T cells. Thus, there is a fail-safe mechanism against autoreactivity, even in the event of thymus-independent germinal center formation

Correction: Protocol of the Healthy Brain Study:An accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context

[This corrects the article DOI: 10.1371/journal.pone.0260952.]

Synaptic Transmission from Horizontal Cells to Cones Is Impaired by Loss of Connexin Hemichannels

In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast-sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina

Nonapical symmetric divisions underlie horizontal cell layer formation in the developing retina in vivo

Symmetric cell divisions have been proposed to rapidly increase neuronal number late in neurogenesis, but how critical this mode of division is to establishing a specific neuronal layer is unknown. Using in vivo time-lapse imaging methods, we discovered that in the laminated zebrafish retina, the horizontal cell (HC) layer forms quickly during embryonic development upon division of a precursor cell population. The precursor cells morphologically resemble immature, postmitotic HCs and express HC markers such as ptf1a and Prox1 prior to division. These precursors undergo nonapical symmetric division at the laminar location where mature HCs contact photoreceptors. Strikingly, the precursor cell type we observed generates exclusively HCs. We have thus identified a dedicated HC precursor, and our findings suggest a mechanism of neuronal layer formation whereby the location of mitosis could facilitate rapid contact between synaptic partner

Runners' experience of implicit coaching through music

In this paper we evaluate a music-based coaching system for runners, the SportsCoach. It measures the runner’s heart rate and increases music tempo when, for an optimal workout, the runner should speed up. Coaching is implicit, since the runner only needs to keep in sync with the music and no explicit instructions are given. We performed 2 experiments to evaluate how this implicit coaching was experienced in the actual context of running. The first experiment investigated how natural it is to keep running in sync with the music when the music tempo changes. We find that although runners are not naturally inclined to do so, a band of 10% below one’s natural tempo is mostly easily followed, especially by dancers. The second experiment evaluated the SportsCoach and contrasted its implicit form of coaching and synchronized music to explicit and absent forms of coaching and fixed tempo music. We find that the SportCoach concept scores well on most aspects, especially because of the synchronicity of music and running tempos

Impaired systolic blood pressure recovery directly after standing predicts mortality in older falls clinic patients

Normally, standing up causes a blood pressure (BP) drop within 15 seconds, followed by recovery to baseline driven by BP control mechanisms. The prognostic value of this initial BP drop, but also of the recovery hereafter, is unknown. The aim of this study was to examine the prognostic value of these BP characteristics in response to standing. In a retrospective cohort study of 238 consecutive patients visiting our falls outpatient clinic, we examined the relation between all-cause mortality and BP decline and recovery directly after active standing up with Cox proportional hazards analyses. Of 238 patients (mean age 78.4 ± 7.8 years), during a median follow-up of 21.0 months, 36 (15%) patients died. Neither absolute nor relative (%) initial BP drop after standing predicted mortality. In contrast, the magnitude of BP recovery 40-60 seconds after standing was associated with mortality, even after adjustment for age, comorbidity, and other baseline characteristics. When systolic BP had recovered to less than 80% of prestanding baseline after 60 seconds of standing, this was a powerful independent predictor of mortality (hazard ratio: 3.00; 95% confidence interval 1.17-7.68). Failure to recover from BP decline in the first minute after active standing up is associated with excess mortality in falls clinic patients. A recovery of systolic BP to less than 80% of baseline after 60 seconds may be used as an easily available cardiovascular marker for increased mortality risk in older falls clinic patient

Venn diagram showing the distribution of head turning-induced hypotension across the different head movements.

<p>Venn diagram showing the distribution of head turning-induced hypotension across the different head movements.</p