B cell–intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans

Engagement of cytokine receptors by specific ligands activate Janus kinase–signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21–induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients

The role of physiological afferent nerve activity during in vivo maturation of the calyx of held synapse

We studied how afferent nerve activity affects the in vivo maturation of a fast glutamatergic CNS synapse, the calyx of Held. To address this question, we exploited the distinct presynaptic Ca2+ channel subtypes governing transmitter release at the cochlear inner hair cell (IHC)-spiral neuron synaptic junction compared with those at higher synapses along the auditory pathways. We characterized the functional properties of calyx synapses in wild type (wt) compared with those developing in Ca(V)1.3 subunit-deficient (Ca(V)1.3-/-) mice. Ca(V)1.3-/- mice are deaf because of an absence of glutamate release from IHC, which results in a complete lack of cochlea-driven nerve activity. Presynaptic Ca2+ channel properties, Ca2+ dependence of exocytosis, number of readily releasable quanta, and AMPA mEPSCs were unchanged in postnatal day 14 (P14) to P17 calyx synapses of Ca(V)1.3-/- mice. However, synaptic strength was augmented because presynaptic action potentials were broader, leading to increased quantal release, consistent with lower paired-pulse ratios and stronger depression during repetitive synaptic stimulation. Furthermore, asynchronous release after trains was elevated presumably because of higher residual Ca2+ accumulating in the presynaptic terminals. Finally, we measured larger NMDA EPSCs with higher sensitivity to the NR2B subunit-specific antagonist ifenprodil in P14-P17 synapses of Ca(V)1.3-/- compared with wt mice. These results suggest that auditory activity is required for the adjustment of synaptic strength as well as for the downregulation of synaptic NMDA receptors during postnatal development of the calyx of Held. In contrast, properties of the presynaptic release machinery and postsynaptic AMPA receptors are unaffected by chronic changes in the level of afferent activity at this synapse

Kinetics of both synchronous and asynchronous quantal release during trains of action potential-evoked EPSCs at the rat calyx of Held

We studied the kinetics of transmitter release during trains of action potential (AP)-evoked excitatory postsynaptic currents (EPSCs) at the calyx of Held synapse of juvenile rats. Using a new quantitative method based on a combination of ensemble fluctuation analysis and deconvolution, we were able to analyse mean quantal size (q) and release rate (ξ) continuously in a time-resolved manner. Estimates derived this way agreed well with values of q and quantal content (M) calculated for each EPSC within the train from ensemble means of peak amplitudes and their variances. Separate analysis of synchronous and asynchronous quantal release during long stimulus trains (200 ms, 100 Hz) revealed that the latter component was highly variable among different synapses but it was unequivocally identified in 18 out of 37 synapses analysed. Peak rates of asynchronous release ranged from 0.2 to 15.2 vesicles ms−1 (ves ms−1) with a mean of 2.3 ± 0.6 ves ms−1. On average, asynchronous release accounted for less than 14% of the total number of about 3670 ± 350 vesicles released during 200 ms trains. Following such trains, asynchronous release decayed with several time constants, the fastest one being in the order of 15 ms. The short duration of asynchronous release at the calyx of Held synapse may aid in generating brief postsynaptic depolarizations, avoiding temporal summation and preserving action potential timing during high frequency bursts

StEER-EERI: 2023 Mw 7.8 Kahramanmaras, Türkiye earthquake sequence joint Preliminary Virtual Reconnaissance Report (PVRR)

An Mw 7.8 earthquake occurred at a depth of 17.9 km and with epicenter coordinates 37.174°N 37.032°E near the city of Nurdağı in the Gaziantep province of Türkiye at about 4:17 AM local time on February 6, 2023. As a result of this sequence of earthquakes and aftershocks, around 28,500 buildings partially or completely collapsed, while another 66,000 buildings were severely damaged in Türkiye. In Syria, more than 22,000 buildings were affected by the earthquakes, with 2,850 partially/completely collapsed or severely damaged. As of March 8, the total official death toll due to these earthquakes was reported to be 45,968 confirmed deaths in Türkiye and 7,259 in Syria. In Türkiye alone, more than 100,000 people were reported as injured. The province of Hatay in Türkiye was severely impacted by this sequence of ground shaking, including an Mw 6.4 earthquake that occurred on February 20, two weeks after the main event. Around half of the buildings in the affected regions of Türkiye were constructed before 2000, i.e., before modern principles of earthquake design were implemented in the Turkish Seismic Code. Fragility functions developed for the building stock in the area showed that collapse under large shaking was possible for these relatively older buildings. However, several collapses of buildings constructed after 2000 were also observed. The performance of infrastructures was generally acceptable, with most bridges, roads, and tunnels remaining operational and no significant issues with the power grid and water supply infrastructure. In terms of good performance, the 12 seismically isolated hospitals in the earthquake-impacted region were operational after the earthquakes and, more importantly, allowed these healthcare facilities to serve their emergency response functions in the aftermath of the extraordinary destruction. Their operational performance greatly contrasted with the observed collapses of some hospitals that were not seismically isolated. This project encompasses the joint products of the StEER and EERI LFE program's response to this event: Preliminary Virtual Reconnaissance Report (PVRR)

ATP-induced morphological changes in supporting cells of the developing cochlea

The developing cochlea of mammals contains a large group of columnar-shaped cells, which together form a structure known as Kölliker’s organ. Prior to the onset of hearing, these inner supporting cells periodically release adenosine 5′-triphosphate (ATP), which activates purinergic receptors in surrounding supporting cells, inner hair cells and the dendrites of primary auditory neurons. Recent studies indicate that purinergic signaling between inner supporting cells and inner hair cells initiates bursts of action potentials in auditory nerve fibers before the onset of hearing. ATP also induces prominent effects in inner supporting cells, including an increase in membrane conductance, a rise in intracellular Ca2+, and dramatic changes in cell shape, although the importance of ATP signaling in non-sensory cells of the developing cochlea remains unknown. Here, we review current knowledge pertaining to purinergic signaling in supporting cells of Kölliker’s organ and focus on the mechanisms by which ATP induces changes in their morphology. We show that these changes in cell shape are preceded by increases in cytoplasmic Ca2+, and provide new evidence indicating that elevation of intracellular Ca2+ and IP3 are sufficient to initiate shape changes. In addition, we discuss the possibility that these ATP-mediated morphological changes reflect crenation following the activation of Ca2+-activated Cl− channels, and speculate about the possible functions of these changes in cell morphology for maturation of the cochlea