Network Reconstruction as a Novel High-Level Marker of Functional Neuronal Viability.

Neuronal viability is essential for the maintenance of neuronal networks. Already slight noxious modifications, for example, the selective interruption of interneurons' function, which enhances the excitatory drive inside a network, may already be harmful for the overall network. To monitor neuronal viability on the network level, we implemented a network reconstruction approach that infers the effective connectivity of cultured neurons from live-cell fluorescence microscopy recordings.

Modulation of GCN2/eIF2α/ATF4 Pathway in the Liver and Induction of FGF21 in Young Goats Fed a Protein- and/or Phosphorus-Reduced Diet.

Mammals respond to amino acid (AA) deficiency by initiating an AA response pathway (AAR) that involves the activation of general control nonderepressible 2 (GCN2), phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), and activation of transcription factor 4 (ATF4). In this study, the effects of protein (N) and/or phosphorus (P) restriction on the GCN2/eIF2α/ATF4 pathway in the liver and the induction of fibroblast growth factor 21 (FGF21) in young goats were investigated. An N-reduced diet resulted in a decrease in circulating essential AA (EAA) and an increase in non-essential AA (NEAA), as well as an increase in hepatic mRNA expression of and and protein expression of GCN2.

Distension evoked mucosal secretion in human and porcine colon in vitro.

It was suggested that intestinal mucosal secretion is enhanced during muscle relaxation and contraction. Mechanisms of mechanically induced secretion have been studied in rodent species. We used voltage clamp Ussing technique to investigate, in human and porcine colonic tissue, secretion evoked by serosal (Pser) or mucosal (Pmuc) pressure application (2-60 mmHg) to induce distension into the mucosal or serosal compartment, respectively.

The Expression of Insulin in the Central Nervous System: What Have We Learned So Far?

After being discovered over a century ago, insulin was long considered to be a hormone exclusively produced by the pancreas. Insulin presence was later discovered in the brain, which was originally accounted for by its transport across the blood-brain barrier. Considering that both insulin mRNA and insulin were detected in the central nervous system (CNS), it is now known that this hormone is also synthesized in several brain regions, including the hypothalamus, hippocampus, cerebral and cerebellar cortex, and olfactory bulb.

Spontaneous activity of specific C-nociceptor subtypes from diabetic patients and mice: Involvement of reactive dicarbonyl compounds and (sensitized) transient receptor potential channel A1.

Background: Diabetic metabolism causes changes of the chemical milieu including accumulation of reactive carbonyl species, for example, methylglyoxal (MGO). MGO activates chemosensitive TRPA1 on nociceptors, but the contribution to neuronal pathophysiology causing pain and hyperalgesia in diabetic neuropathy is not fully understood.

Methods: We employed single-nerve-fiber recordings in type 2 diabetes patients with (spDN) and without cutaneous pain (DN) and in streptozotocin-diabetic and healthy mice.

Resolving the prefrontal mechanisms of adaptive cognitive behaviors: A cross-species perspective.

The prefrontal cortex (PFC) enables a staggering variety of complex behaviors, such as planning actions, solving problems, and adapting to new situations according to external information and internal states. These higher-order abilities, collectively defined as adaptive cognitive behavior, require cellular ensembles that coordinate the tradeoff between the stability and flexibility of neural representations. While the mechanisms underlying the function of cellular ensembles are still unclear, recent experimental and theoretical studies suggest that temporal coordination dynamically binds prefrontal neurons into functional ensembles.

B4GALNT3 regulates glycosylation of sclerostin and bone mass.

Background: Global sclerostin inhibition reduces fracture risk efficiently but has been associated with cardiovascular side effects. The strongest genetic signal for circulating sclerostin is in the B4GALNT3 gene region, but the causal gene is unknown. B4GALNT3 expresses the enzyme beta-1,4-N-acetylgalactosaminyltransferase 3 that transfers N-acetylgalactosamine onto N-acetylglucosaminebeta-benzyl on protein epitopes (LDN-glycosylation).

Glial Glutamate Transporter-Mediated Plasticity: System x/xCT/SLC7A11 and EAAT1/2 in Brain Diseases.

Glial cells play an essential role in the complex function of the nervous system. In particular, astrocytes provide nutritive support for neuronal cells and are involved in regulating synaptic transmission. Oligodendrocytes ensheath axons and support information transfer over long distances.

Boosting neuregulin 1 type-III expression hastens SMA motor axon maturation.

Intercellular communication between axons and Schwann cells is critical for attaining the complex morphological steps necessary for axon maturation. In the early onset motor neuron disease spinal muscular atrophy (SMA), many motor axons are not ensheathed by Schwann cells nor grow sufficiently in radial diameter to become myelinated. These developmentally arrested motor axons are dysfunctional and vulnerable to rapid degeneration, limiting efficacy of current SMA therapeutics.

Dexmedetomidine Has Differential Effects on the Contractility of Equine Jejunal Smooth Muscle Layers In Vitro.

α2 agonists are frequently used in horses with colic, even though they have been shown to inhibit gastrointestinal motility. The aim of this study was to determine the effect of dexmedetomidine on small intestinal in vitro contractility during different phases of ischaemia. Experimental segmental jejunal ischaemia was induced in 12 horses under general anaesthesia, and intestinal samples were taken pre-ischaemia and following ischaemia and reperfusion.

Endocannabinoid administration affects taste preference and the expression of cannabinoid and opioid receptors in the amygdala of early lactating cows.

The aim of the study was to investigate the influence of intraperitoneal N-arachidonoylethanolamide (AEA) on taste preference for feed and water, tongue taste receptor signalling (TAS1R2, GNAT3), and endocannabinoid (CNR1, CNR2, GPR55) and opioid (OPRD1, OPRK1, OPRM1, OPRL1) receptors in the amygdala and nucleus accumbens in periparturient cows. We conducted taste preference tests using unaltered, umami-tasting, and sweet-tasting water and feed, before and after calving. After calving, eight cows received AEA injections (3 µg/(kg bodyweight × day), 25 days), whereas eight control (CON) cows received saline injections.

Deep Isoflurane Anesthesia Is Associated with Alterations in Ion Homeostasis and Specific Na+/K+-ATPase Impairment in the Rat Brain.

Background: Maintenance of ion homeostasis is essential for normal brain function. Inhalational anesthetics are known to act on various receptors, but their effects on ion homeostatic systems, such as sodium/potassium-adenosine triphosphatase (Na+/K+-ATPase), remain largely unexplored. Based on reports demonstrating global network activity and wakefulness modulation by interstitial ions, the hypothesis was that deep isoflurane anesthesia affects ion homeostasis and the key mechanism for clearing extracellular potassium, Na+/K+-ATPase.

The protection quest is a primary key to sharing the neutralizing antibody response to cover against all emerging VOCs based on BIV1-CovIran studies.

Over time, the antigenic evolution of emerging variants of SARS-CoV-2 has demanded the development of potential protective vaccines. Administration of additional doses of current vaccines based on the WT spike protein may boost immunity, but their effectiveness has dwindled for patients with more recent variants. Here, we studied the neutralization activity of post-WT strain-based vaccination and a structural simulation based on the interactions of the RBD-hACE2 as the key to initiating infection among the VOCs of SARS-CoV-2.

Validation of a SARS-CoV-2 Surrogate Virus Neutralization Test in Recovered and Vaccinated Healthcare Workers.

Vaccination against COVID-19 is the main public health approach to fight against the pandemic. The Spike (S) glycoprotein of SARS-CoV-2 is the principal target of the neutralizing humoral response. We evaluated the analytical and clinical performances of a surrogate virus neutralization test (sVNT) compared to conventional neutralization tests (cVNTs) and anti-S eCLIA assays in recovered and/or vaccinated healthcare workers.

Synthetic Small Molecule Modulators of Hsp70 and Hsp40 Chaperones as Promising Anticancer Agents.

A class of chaperones dubbed heat shock protein 70 (Hsp70) possesses high relevance in cancer diseases due to its cooperative activity with the well-established anticancer target Hsp90. However, Hsp70 is closely connected with a smaller heat shock protein, Hsp40, forming a formidable Hsp70-Hsp40 axis in various cancers, which serves as a suitable target for anticancer drug design. This review summarizes the current state and the recent developments in the field of (semi-)synthetic small molecule inhibitors directed against Hsp70 and Hsp40.

Short- and Long-Term Effects of Cocaine on Enteric Neuronal Functions.

Cocaine is one of the most consumed illegal drugs among (young) adults in the European Union and it exerts various acute and chronic negative effects on psychical and physical health. The central mechanism through which cocaine initially leads to improved performance, followed by addictive behavior, has already been intensively studied and includes effects on the homeostasis of the neurotransmitters dopamine, partly mediated via nicotinic acetylcholine receptors, and serotonin. However, effects on the peripheral nervous system, including the enteric nervous system, are much less understood, though a correlation between cocaine consumption and gastrointestinal symptoms has been reported.

Transgenic HPV11-E2 protein modulates URR activity in vivo.

In vitro experiments have shown that the E2 protein of human papillomaviruses (HPV) binds to the upstream regulatory region (URR) of the viral genome and modulates transcription. Additionally, it seems to be a necessary component for viral DNA replication together with E1. We have developed a transgenic mouse model containing the URR region of the low-risk virus HPV11 that regulates the expression of the lacZ reporter gene.

Single-Molecule Localization Microscopy of Presynaptic Active Zones in after Rapid Cryofixation.

Single-molecule localization microscopy (SMLM) greatly advances structural studies of diverse biological tissues. For example, presynaptic active zone (AZ) nanotopology is resolved in increasing detail. Immunofluorescence imaging of AZ proteins usually relies on epitope preservation using aldehyde-based immunocompetent fixation.

Myristoylated Neuronal Calcium Sensor-1 captures the ciliary vesicle at distal appendages.

The primary cilium is a microtubule-based organelle that cycles through assembly and disassembly. In many cell types, formation of the cilium is initiated by recruitment of ciliary vesicles to the distal appendage of the mother centriole. However, the distal appendage mechanism that directly captures ciliary vesicles is yet to be identified.