Nano-Organization at the Synapse: Segregation of Distinct Forms of Neurotransmission

Synapses maintain synchronous, asynchronous, and spontaneous modes of neurotransmission through distinct molecular and biochemical pathways. Traditionally a single synapse was assumed to have a homogeneous organization of molecular components both at the active zone and post-synaptically. However, recent advancements in experimental tools and the further elucidation of the physiological significance of distinct forms of release have challenged this notion. In comparison to rapid evoked release, the physiological significance of both spontaneous and asynchronous neurotransmission has only recently been considered in parallel with synaptic structural organization. Active zone nanostructure aligns with postsynaptic nanostructure creating a precise trans-synaptic alignment of release sites and receptors shaping synaptic efficacy, determining neurotransmission reliability, and tuning plasticity. This review will discuss how studies delineating synaptic nanostructure create a picture of a molecularly heterogeneous active zone tuned to distinct forms of release that may dictate diverse synaptic functional outputs.

Physiological roles of short-chain and long-chain menaquinones (vitamin K2) in Lactococcus cremoris

Lactococcus cremoris and L. lactis are well-known for their occurrence and applications in dairy fermentations, but their niche extends to a range of natural and food production environments. L. cremoris and L. lactis produce MKs (vitamin K2), mainly as the long-chain forms represented by MK-9 and MK-8, and a detectable amount of short-chain forms represented by MK-3. The physiological significance of the different MK forms in the lifestyle of these bacterial species has not been investigated extensively. In this study, we used L. cremoris MG1363 to construct mutants producing different MK profiles by deletion of genes encoding (i) a menaquinone-specific isochorismate synthase, (ii) a geranyltranstransferase and (iii) a prenyl diphosphate synthase. These gene deletions resulted in (i) a non-MK producer (ΔmenF), (ii) a presumed MK-1 producer (ΔispA) and (iii) a MK-3 producer (Δllmg_0196), respectively. By examining the phenotypes of the MG1363 wildtype strain and respective mutants, including biomass accumulation, stationary phase survival, oxygen consumption, primary metabolites, azo dye/copper reduction, and proteomes, under aerobic, anaerobic and respiration-permissive conditions, we could infer that short-chain MKs like MK-1 and MK-3 are preferred to mediate extracellular electron transfer and reaction with extracellular oxygen, while the long-chain MKs like MK-9 and MK-8 are more efficient in aerobic respiratory electron transport chain. The different electron transfer routes mediated by short-chain and long-chain MKs likely support growth and survival of L. cremoris in a range of (transiently) anaerobic and aerobic niches including food fermentations, highlighting the physiological significance of diverse MKs in L. cremoris.

Physiological significance of pericoronary inflammation in epicardial functional stenosis and global coronary flow reserve

Both fractional flow reserve (FFR) and global coronary flow reserve (g-CFR) provide prognostic information in patients with stable coronary artery disease (CAD). Inflammation plays a vital role in impaired endothelial dysfunction and atherosclerotic progression, potentially predicting cardiovascular mortality. This study aimed to evaluate the physiological significance of pericoronary adipose tissue inflammation assessed by CT attenuation (PCATA) in epicardial functional stenosis severity and g-CFR in patients with CAD. A total of 131 CAD patients with a single de novo epicardial coronary stenosis who underwent coronary CT-angiography (CCTA), phase-contrast cine-magnetic resonance imaging (PC-CMR) and FFR measurement were studied. PCATA was assessed using the mean CT attenuation value. G-CFR was obtained by quantifying absolute coronary sinus flow (ml/min/g) by PC-CMR at rest and during maximum hyperemia. Median FFR, g-CFR, and PCATA values were 0.75, 2.59, and − 71.3, respectively. Serum creatinine, NT-proBNP, left ventricular end-diastolic volume, and PCATA were independently associated with g-CFR. PCATA showed a significant incremental predictive efficacy for impaired g-CFR (< 2.0) when added to the clinical risk model. PCATA was significantly associated with g-CFR, independent of FFR. Our results suggest the pathophysiological mechanisms linking perivascular inflammation with g-CFR in CAD patients.

Bacterial Epigenomics: Coming of Age

Epigenetic DNA methylation in bacteria has been traditionally studied in the context of antiparasitic defense and as part of the innate immune discrimination between self and nonself DNA. However, sequencing advances that allow genome-wide analysis of DNA methylation at the single-base resolution are nowadays expanding and have propelled a modern epigenomic revolution in our understanding of the extent, evolution, and physiological significance of methylation.

Bio-physiological significance of light, natural and artificial

The bio-physiological significance of light, natural and artificial, continues to be of great interest to many physiologists and physicians.

VCP maintains nuclear size by regulating the DNA damage-associated MDC1–p53–autophagy axis in Drosophila

The maintenance of constant karyoplasmic ratios suggests that nuclear size has physiological significance. Nuclear size anomalies have been linked to malignant transformation, although the mechanism remains unclear. By expressing dominant-negative TER94 mutants in Drosophila photoreceptors, here we show disruption of VCP (valosin-containing protein, human TER94 ortholog), a ubiquitin-dependent segregase, causes progressive nuclear size increase. Loss of VCP function leads to accumulations of MDC1 (mediator of DNA damage checkpoint protein 1), connecting DNA damage or associated responses to enlarged nuclei. TER94 can interact with MDC1 and decreases MDC1 levels, suggesting that MDC1 is a VCP substrate. Our evidence indicates that MDC1 accumulation stabilizes p53A, leading to TER94K2A-associated nuclear size increase. Together with a previous report that p53A disrupts autophagic flux, we propose that the stabilization of p53A in TER94K2A-expressing cells likely hinders the removal of nuclear content, resulting in aberrant nuclear size increase.