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There is a growing consensus that the various forms of cell death (necrosis, apoptosis and autophagy) are not separated by strict boundaries, but rather share molecular effectors and signaling routes. Among the latter, a clear role is played by calcium (Ca 2+ ), the ubiquitous second messenger involved in the control of a broad variety of physiological events. Fine tuning of intracellular Ca 2+ homeostasis by anti- and proapoptotic proteins shapes the Ca 2+ signal to which mitochondria and other cellular effectors are exposed, and hence the efficiency of various cell death inducers. Here, we will review: (i) the evidence linking calcium homeostasis to the regulation of apoptotic, and more recently autophagic cell death, (ii) the discussion of mitochondria as a critical, although not unique checkpoint and (iii) the molecular and functional elucidation of ER/mitochondria contacts, corresponding to the mitochondria-associated membrane (MAM) subfraction and proposed to be a specialized signaling microdomain.

Endoplasmic reticulum stress is emerging as an important modulator of different pathologies and as a mechanism contributing to cancer cell death in response to therapeutic agents. In several instances, oxidative stress and the onset of endoplasmic reticulum (ER) stress occur together; yet, the molecular events linking reactive oxygen species (ROS) to ER stress-mediated apoptosis are currently unknown. Here, we show that PERK (RNA-dependent protein kinase (PKR)-like ER kinase), a key ER stress sensor of the unfolded protein response, is uniquely enriched at the mitochondria-associated ER membranes (MAMs). PERK −/− cells display disturbed ER morphology and Ca 2+ signaling as well as significantly weaker ER-mitochondria contact sites. Re-expression of a kinase-dead PERK mutant but not the cytoplasmic deletion mutant of PERK in PERK −/− cells re-establishes ER-mitochondria juxtapositions and mitochondrial sensitization to ROS-mediated stress. In contrast to the canonical ER stressor thapsigargin, during ROS-mediated ER stress, PERK contributes to apoptosis twofold by sustaining the levels of pro-apoptotic C/EBP homologous protein (CHOP) and by facilitating the propagation of ROS signals between the ER and mitochondria through its tethering function. Hence, this study reveals an unprecedented role of PERK as a MAMs component required to maintain the ER-mitochondria juxtapositions and propel ROS-mediated mitochondrial apoptosis. Furthermore, it suggests that loss of PERK may cause defects in cell death sensitivity in pathological conditions linked to ROS-mediated ER stress.

Voltage-dependent anion channels (VDACs) are expressed in three isoforms, with common channeling properties and different roles in cell survival. We show that VDAC1 silencing potentiates apoptotic challenges, whereas VDAC2 has the opposite effect. Although all three VDAC isoforms are equivalent in allowing mitochondrial Ca 2+ loading upon agonist stimulation, VDAC1 silencing selectively impairs the transfer of the low-amplitude apoptotic Ca 2+ signals. Co-immunoprecipitation experiments show that VDAC1, but not VDAC2 and VDAC3, forms complexes with IP 3 receptors, an interaction that is further strengthened by apoptotic stimuli. These data highlight a non-redundant molecular route for transferring Ca 2+ signals to mitochondria in apoptosis.

To characterize the demographics and diagnoses of garden tool-related eye injuries presenting to United States emergency departments (EDs). Eye injuries associated with gardening tools from 2014 to 2023 were identified using the National Electronic Injury Surveillance System (NEISS). Cases involving the eyeball and relevant product codes were analyzed using descriptive statistics and linear regression. A total of 218 cases represented an estimated 9326 ED visits (95 % CI: 7001–11,652). Although injuries declined overall (Beta = −43.5), a 132.2 % increase occurred from 2020 to 2023, likely reflecting increased gardening post-pandemic. Adults (78.4 %) and males (61.0 %) were most affected. Common diagnoses included contusions/corneal abrasions (53.7 %), foreign bodies (13.3 %), and subconjunctival hemorrhage/hyphema (10.1 %). Environmental debris was the most frequent cause. Gardening tool-related eye injuries primarily affect adults and are often caused by debris, leading to largely preventable outcomes such as abrasions. Promoting protective eyewear and public education may help reduce these injuries.

Recent data have revealed an unexpected role of Bcl-2 in modulating the steady-state levels and agonist-dependent fluxes of Ca 2+ ions. Direct monitoring of endoplasmic reticulum (ER) Ca 2+ concentration with recombinant probes reveals a lower state of filling in Bcl-2-overexpressing cells and a higher leak rate from the organelle. The broader set of indirect data using cytosolic probes reveals a more complex scenario, as in many cases no difference was detected in the Ca 2+ content of the intracellular pools. At the same time, Ca 2+ signals have been shown to affect important checkpoints of the apoptotic process, such as mitochondria, thus tuning the sensitivity of cells to various challenges. In this contribution, we will review (i) the data on the effect of Bcl-2 on [Ca 2+ ] er , (ii) the functional significance of the Ca 2+ -signalling alteration and (iii) the current insight into the possible mechanisms of this effect.

Explicit rewards are commonly used to reinforce a behavior, a form of learning that engages the dopaminergic neuromodulatory system. In contrast, skill acquisition can display dramatic improvements from a social learning experience, even though the observer receives no explicit reward. Here, we test whether a dopaminergic signal contributes to social learning in naïve gerbils that are exposed to, and learn from, a skilled demonstrator performing an auditory discrimination task. Following five exposure sessions, naïve observer gerbils were allowed to practice the auditory task and their performance was assessed across days. We first tested the effect of an explicit food reward in the observer’s compartment that was yoked to the demonstrator’s performance during exposure sessions. Naïve observer gerbils with the yoked reward learned the discrimination task significantly faster, as compared to unrewarded observers. The effect of this explicit reward was abolished by administration of a D1/D5 dopamine receptor antagonist during the exposure sessions. Similarly, the D1/D5 antagonist reduced the rate of learning in unrewarded observers. To test whether a dopaminergic signal was sufficient to enhance social learning, we administered a D1/D5 receptor agonist during the exposure sessions in which no reward was present and found that the rate of learning occurred significantly faster. Finally, a quantitative analysis of vocalizations during the exposure sessions suggests one behavioral strategy that contributes to social learning. Together, these results are consistent with a dopamine-dependent reward signal during social learning.

To describe the demographics and diagnoses of swimming and water sports-related eye injuries (SWSEI) presenting to United States (US) emergency departments (EDs). The National Electronic Injury Surveillance System (NEISS) database was used to identify cases of eye injury related to swimming, pools, water sports, and associated equipment from 2013 to 2022. National injury rates were estimated using US Census data at the midpoint of the study (January 1, 2017). The NEISS query provided 1156 SWSEI for analysis. This resulted in an estimated 42,472 (95 % confidence interval, 24,508-60,438) injuries, representing a rate of 1.3 injuries per 10,000 US residents. Most patients were male (50.9 %) and children (72.9 %). Most injuries occurred during summer months (68.9 %) and at recreation or other public centers (80.8 %). Most reported cases (46.9 %) had ocular irritation or inflammation (conjunctivitis, iritis, iridocyclitis) across all ages. Most injuries were from swimming (51.5 %), followed by irritation due to chlorine or other chemicals (12.5 %); 2.5 % of cases resulted in hospital admission. This study suggests that most SWSEI occurred in the pediatric population during the summer at public venues and resulted in ocular irritation or inflammation. Future research should evaluate the effectives of prevention strategies for SWSEI.

The reduction of intracellular 1,4,5-inositol trisphosphate (IP 3 ) levels stimulates autophagy, whereas the enhancement of IP 3 levels inhibits autophagy induced by nutrient depletion. Here, we show that knockdown of the IP 3 receptor (IP 3 R) with small interfering RNAs and pharmacological IP 3 R blockade is a strong stimulus for the induction of autophagy. The IP 3 R is known to reside in the membranes of the endoplasmic reticulum (ER) as well as within ER–mitochondrial contact sites, and IP 3 R blockade triggered the autophagy of both ER and mitochondria, as exactly observed in starvation-induced autophagy. ER stressors such as tunicamycin and thapsigargin also induced autophagy of ER and, to less extent, of mitochondria. Autophagy triggered by starvation or IP 3 R blockade was inhibited by Bcl-2 and Bcl-X L specifically targeted to ER but not Bcl-2 or Bcl-X L proteins targeted to mitochondria. In contrast, ER stress-induced autophagy was not inhibited by Bcl-2 and Bcl-X L . Autophagy promoted by IP 3 R inhibition could not be attributed to a modulation of steady-state Ca 2+ levels in the ER or in the cytosol, yet involved the obligate contribution of Beclin-1, autophagy-related gene (Atg)5, Atg10, Atg12 and hVps34. Altogether, these results strongly suggest that IP 3 R exerts a major role in the physiological control of autophagy.

During ageing skeletal muscles undergo a process of structural and functional remodelling that leads to sarcopenia, a syndrome characterized by loss of muscle mass and force and a major cause of physical frailty. To determine the causes of sarcopenia and identify potential targets for interventions aimed at mitigating ageing-dependent muscle wasting, we focussed on the main signalling pathway known to control protein turnover in skeletal muscle, consisting of the insulin-like growth factor 1 (IGF1), the kinase Akt and its downstream effectors, the mammalian target of rapamycin (mTOR) and the transcription factor FoxO. Expression analyses at the transcript and protein level, carried out on well-characterized cohorts of young, old sedentary and old active individuals and on mice aged 200, 500 and 800 days, revealed only modest age-related differences in this pathway. Our findings suggest that during ageing there is no downregulation of IGF1/Akt pathway and that sarcopenia is not due to FoxO activation and upregulation of the proteolytic systems. A potentially interesting result was the increased phosphorylation of the ribosomal protein S6, indicative of increased activation of mTOR complex1 (mTORC1), in aged mice. This result may provide the rationale why rapamycin treatment and caloric restriction promote longevity, since both interventions blunt activation of mTORC1; however, this change was not statistically significant in humans. Finally, genetic perturbation of these pathways in old mice aimed at promoting muscle hypertrophy via Akt overexpression or preventing muscle loss through inactivation of the ubiquitin ligase atrogin1 were found to paradoxically cause muscle pathology and reduce lifespan, suggesting that drastic activation of the IGF1-Akt pathway may be counterproductive, and that sarcopenia is accelerated, not delayed, when protein degradation pathways are impaired.

Mitochondrial disorders are a group of pathologies characterized by impairment of mitochondrial function mainly due to defects of the respiratory chain and consequent organellar energetics. This affects organs and tissues that require an efficient energy supply, such as brain and skeletal muscle. They are caused by mutations in both nuclear- and mitochondrial DNA (mtDNA)-encoded genes and their clinical manifestations show a great heterogeneity in terms of age of onset and severity, suggesting that patient-specific features are key determinants of the pathogenic process. In order to correlate the genetic defect to the clinical phenotype, we used a cell culture model consisting of fibroblasts derived from patients with different mutations in the mtDNA-encoded ND5 complex I subunit and with different severities of the illness. Interestingly, we found that cells from patients with the 13514A>G mutation, who manifested a relatively late onset and slower progression of the disease, display an increased autophagic flux when compared with fibroblasts from other patients or healthy donors. We characterized their mitochondrial phenotype by investigating organelle turnover, morphology, membrane potential and Ca 2+ homeostasis, demonstrating that mitochondrial quality control through mitophagy is upregulated in 13514A>G cells. This is due to a specific downregulation of mitochondrial Ca 2+ uptake that causes the stimulation of the autophagic machinery through the AMPK signaling axis. Genetic and pharmacological manipulation of mitochondrial Ca 2+ homeostasis can revert this phenotype, but concurrently decreases cell viability. This indicates that the higher mitochondrial turnover in complex I deficient cells with this specific mutation is a pro-survival compensatory mechanism that could contribute to the mild clinical phenotype of this patient.