Initial Stimulus Research Articles

Joseph Charles Stoddart

Joseph Stoddart (“Joe”), who has died aged 87, was in the 1960s one of the pioneers of the specialty of intensive care. Today there are around 200 intensive care units...

Distinct regulatory ribosomal ubiquitylation events are reversible and hierarchically organized.

Activation of the integrated stress response (ISR) or the ribosome-associated quality control (RQC) pathway stimulates regulatory ribosomal ubiquitylation (RRub) on distinct 40S ribosomal proteins, yet the cellular role and fate of ubiquitylated proteins remain unclear. We demonstrate that uS10 and uS5 ubiquitylation are dependent upon eS10 or uS3 ubiquitylation, respectively, suggesting that a hierarchical relationship exists among RRub events establishing a ubiquitin code on ribosomes. We show that stress dependent RRub events diminish after initial stimuli and that demodification by deubiquitylating enzymes contributes to reduced RRub levels during stress recovery. Utilizing an optical RQC reporter we identify OTUD3 and USP21 as deubiquitylating enzymes that antagonize ZNF598-mediated 40S ubiquitylation and can limit RQC activation. Critically, cells lacking USP21 or OTUD3 have altered RQC activity and delayed eS10 deubiquitylation indicating a functional role for deubiquitylating enzymes within the RQC pathway.

The simultaneous oddball: Oddball presentation does not affect simultaneity judgments.

The oddball duration illusion describes how a rare or nonrepeated stimulus is perceived as lasting longer than a common or repeated stimulus. It has been argued that the oddball duration illusion could emerge because of an earlier perceived onset of an oddball stimulus. However, most methods used to assess the perceived duration of an oddball stimulus are ill suited to detect onset effects. Therefore, in the current article, I tested the perceived onset of oddball and standard stimuli using a simultaneity judgment task. In Experiments 1 and 2, repetition and rarity of the target stimulus were varied, and participants were required to judge whether the target stimulus and another stimulus were concurrent. In Experiment 3, I tested whether a brief initial stimulus could act as a conditioning stimulus in the oddball duration illusion. This was to ensure an oddball duration illusion could have occurred given the short duration of stimuli in the first two experiments. In both the first two experiments, I found moderate support for no onset-based difference between oddball and nonoddball stimuli. In Experiment 3, I found that a short conditioning stimulus could still lead to the oddball duration illusion occurring, removing this possible explanation for the null result. Experiment 4 showed that an oddball duration illusion could emerge given the rarity of the stimulus and a concurrent sound. In sum, the current article found evidence against an onset-based explanation of the oddball duration illusion.

A single reaction-diffusion equation for the multifarious eruptions of urticaria.

Urticaria is a common skin disorder characterized by the rapid appearance and disappearance of local skin edema and flares with itching. It is characterized by various macroscopic skin eruptions unique to patients and/or subtypes of urticaria with respect to shape, size, color, and/or duration of eruptions. Nevertheless, the mechanism underlying multifarious eruptions in urticaria is largely unknown. The eruptions are believed to be evoked by histamine release from mast cells in the skin. However, the majority of visible characteristics of urticaria cannot be explained by a simple injection of histamine to the skin. To explain the multifarious eruptions of urticaria, we developed a single reaction-diffusion model suggesting the self-activation and self-inhibition regulation of histamine release from mast cells. Using the model, we found that various geometrical shapes of eruptions typically observed in patients can be explained by the model parameters and randomness or strength of the initial stimuli to mast cells. Furthermore, we verified that the wheal-expanding speed of urticaria, which is shown to be much smaller than that of the intradermal injection experimental system may be explained by our model and a simple diffusion equation. Our study suggests that the simple reaction-diffusion dynamics, including the independent self-activating and -inhibitory regulation of histamine release, may account for the essential mechanism underlying the formation of multifarious eruptions in urticaria.

Metabolic Remodeling as a Way of Adapting to Tumor Microenvironment (TME), a Job of Several Holders.

The microenvironment depends and generates dependence on all the cells and structures that share the same niche, the biotope. The contemporaneous view of the tumor microenvironment (TME) agrees with this idea. The cells that make up the tumor, whether malignant or not, behave similarly to classes of elements within a living community. These elements inhabit, modify and benefit from all the facilities the microenvironment has to offer and that will contribute to the survival and growth of the tumor and the progression of the disease.The metabolic adaptation to microenvironment is a crucial process conducting to an established tumor able to grow locally, invade and metastasized. The metastatic cancer cells are reasonable more plastic than non-metastatic cancer cells, because the previous ones must survive in the microenvironment where the primary tumor develops and in addition, they must prosper in the microenvironment in the metastasized organ.The metabolic remodeling requires not only the adjustment of metabolic pathways per se but also the readjustment of signaling pathways that will receive and obey to the extracellular instructions, commanding the metabolic adaptation. Many diverse players are pivotal in cancer metabolic fitness from the initial signaling stimuli, going through the activation or repression of genes, until the phenotype display. The new phenotype will permit the import and consumption of organic compounds, useful for energy and biomass production, and the export of metabolic products that are useless or must be secreted for a further recycling or controlled uptake. In the metabolic network, three subsets of players are pivotal: (1) the organic compounds; (2) the transmembrane transporters, and (3) the enzymes.This chapter will present the "Pharaonic" intent of diagraming the interplay between these three elements in an attempt of simplifying and, at the same time, of showing the complex sight of cancer metabolism, addressing the orchestrating role of microenvironment and highlighting the influence of non-cancerous cells.

Decomposition Analysis for the Comparison and the Comprehension of Conventional Input-Output Impacts’ Indicators: An Empirical Paradigm

Sometimes, the priorities in the growing patterns create dubiousness, surprises and are proved unsuitable to re-form and redress the distortions of economy, magnifying them or even emerging news. When the external or the individual interferences are remained out of the planning, then the knowledge of why the various indices yield conflicting sectoral rankings can help the policy-makers to plan ameliorated strategies. In this paper a decomposition analysis for the components of conventional backward linkages’ (BLs’) indices and the corresponding type I multipliers (t.I-Ms’) has been taken place, in order to support the comparison and the comprehension of conflictions that are recorded on their derived sectoral rankings. For the empirical paradigm, data from the Greek economy have been used. The indicators’ appropriateness for the developmental planning has been scrutinized giving an emphasis on the model’s causality, the initial exogenous stimuli and the “intrasectoral initial trends for impacts’ generation”. The analysis provides a proof that the BL’s indices are strongly tendentious and the t.I-Ms’ are preferable for the medium-to-long run growing planning.

Neural Dynamics of Serial Dependence in Numerosity Perception.

Serial dependence-an attractive perceptual bias whereby a current stimulus is perceived to be similar to previously seen ones-is thought to represent the process that facilitates the stability and continuity of visual perception. Recent results demonstrate a neural signature of serial dependence in numerosity perception, emerging very early in the time course during perceptual processing. However, whether such a perceptual signature is retained after the initial processing remains unknown. Here, we address this question by investigating the neural dynamics of serial dependence using a recently developed technique that allowed a reactivation of hidden memory states. Participants performed a numerosity discrimination task during EEG recording, with task-relevant dot array stimuli preceded by a task-irrelevant stimulus inducing serial dependence. Importantly, the neural network storing the representation of the numerosity stimulus was perturbed (or pinged) so that the hidden states of that representation can be explicitly quantified. The results first show that a neural signature of serial dependence emerges early in the brain signals, starting soon after stimulus onset. Critical to the central question, the pings at a later latency could successfully reactivate the biased representation of the initial stimulus carrying the signature of serial dependence. These results provide one of the first pieces of empirical evidence that the biased neural representation of a stimulus initially induced by serial dependence is preserved throughout a relatively long period.

Should we administer rectal anti-inflammatory drugs in all ERCPs in order to prevent pancreatitis? At least, it does not harm!

Acute pancreatitis is the most common complication of endoscopic retrograde cholangio-pancreatography (ERCP). The sensitivity of the pancreas, which may respond with such violence to the slightest pressure exerted at the entrance to its main duct in the papilla of Vater, is even philosophically surprising. In fact, each touch on the papilla increases the potential for pancreatitis development. The initial stimulus resulting in obstruction of pancreatic secretion may be the edema caused by the catheter's physical contact, the thermal effect of sphincterotomy, or the overdistension induced by the injected contrast. The triggering fact is followed by a release of inflammatory cytokines, which induce changes in pancreatic microcirculation.

Altered neural oscillations and connectivity in the beta band underlie detail-oriented visual processing in autism

Sensory and perceptual anomalies may have a major impact on basic cognitive and social skills in humans. Autism Spectrum Disorder (ASD) represents a special perspective to explore this relationship, being characterized by both these features. The present study employed electroencephalography (EEG) to test whether detail-oriented visual perception, a recognized hallmark of ASD, is associated with altered neural oscillations and functional connectivity in the beta frequency band, considering its role in feedback and top-down reentrant signalling in the typical population. Using a visual crowding task, where participants had to discriminate a peripheral target letter surrounded by flankers at different distances, we found that detail-oriented processing in children with ASD, as compared to typically developing peers, could be attributed to anomalous oscillatory activity in the beta band (15–30 Hz), while no differences emerged in the alpha band (8–12 Hz). Altered beta oscillatory response reflected in turn atypical functional connectivity between occipital areas, where the initial stimulus analysis is accomplished, and infero-temporal regions, where objects identity is extracted. Such atypical beta connectivity predicted both ASD symptomatology and their detail-oriented processing. Overall, these results might be explained by an altered feedback connectivity within the visual system, with potential cascade effects in visual scene parsing and higher order functions.

Acoustic\u2013phonetic and auditory mechanisms of adaptation in the perception of sibilant fricatives

Listeners are highly proficient at adapting to contextual variation when perceiving speech. In the present study, we examined the effects of brief speech and nonspeech contexts on the perception of sibilant fricatives. We explored three theoretically motivated accounts of contextual adaptation, based on phonetic cue calibration, phonetic covariation, and auditory contrast. Under the cue calibration account, listeners adapt by estimating a talker-specific average for each phonetic cue or dimension; under the cue covariation account, listeners adapt by exploiting consistencies in how the realization of speech sounds varies across talkers; under the auditory contrast account, adaptation results from (partial) masking of spectral components that are shared by adjacent stimuli. The spectral center of gravity, a phonetic cue to fricative identity, was manipulated for several types of context sound: /z/-initial syllables, /v/-initial syllables, and white noise matched in long-term average spectrum (LTAS) to the /z/-initial stimuli. Listeners’ perception of the /s/–/ʃ/ contrast was significantly influenced by /z/-initial syllables and LTAS-matched white noise stimuli, but not by /v/-initial syllables. No significant difference in adaptation was observed between exposure to /z/-initial syllables and matched white noise stimuli, and speech did not have a considerable advantage over noise when the two were presented consecutively within a context. The pattern of findings is most consistent with the auditory contrast account of short-term perceptual adaptation. The cue covariation account makes accurate predictions for speech contexts, but not for nonspeech contexts or for the absence of a speech-versus-nonspeech difference.

A System of Interacting Neurons with Short Term Synaptic Facilitation

In this paper we present a simple microscopic stochastic model describing short term plasticity within a large homogeneous network of interacting neurons. Each neuron is represented by its membrane potential and by the residual calcium concentration within the cell at a given time. Neurons spike at a rate depending on their membrane potential. When spiking, the residual calcium concentration of the spiking neuron increases by one unit. Moreover, an additional amount of potential is given to all other neurons in the system. This amount depends linearly on the current residual calcium concentration within the cell of the spiking neuron. In between successive spikes, the potentials and the residual calcium concentrations of each neuron decrease at a constant rate. We show that in this framework, short time memory can be described as the tendency of the system to keep track of an initial stimulus by staying within a certain region of the space of configurations during a short but macroscopic amount of time before finally being kicked out of this region and relaxing to equilibrium. The main technical tool is a rigorous justification of the passage to a large population limit system and a thorough study of the limit equation.

Abstract A12: The establishment, maintenance, and maladaptive role of epigenetic memory in mediating pancreatic tumorigenesis

Abstract Cellular decision-making is highly dependent on cues present in the environment. As such, biologic systems have evolved efficient ways to respond to salient and often transient stimuli by encoding and transducing relevant extracellular information to chromatin. Additionally, accumulating evidence suggests that cells are capable of remembering previously experienced stimuli, allowing them to adjust their behaviors appropriately when confronted in the future with a similar or different stimulus. However, the ability of cells to respond to a transient stimulus and to encode a persistent record of that experience following its resolution has yet to be explored comprehensively in a preneoplastic context. Here we determine the lasting effect in the pancreas of an acinar-to-ductal metaplasia (ADM) event, to elucidate the impact of prior inflammation on tissue function and subsequent tumorigenesis. In a lineage-traced model of acinar cell dedifferentiation, we demonstrate that following ADM, histologically normal acinar cells exhibit broad gains in chromatin accessibility that persist well after exposure to the initial ADM-inducing stimulus. We show that the effect on chromatin is not reflected in the transcriptional state of acinar cells. Moreover, we employ extensive flow-cytometry based analysis of immune cell and niche acinar populations to show there is no long-term cell-extrinsic population, nor a significant expansion of either the Dclk1+ or Nk1r+ acinar populations. Finally, we employ single-cell RNA-seq analyses to define the alterations to epithelial cells and the associated microenvironment long after regeneration following an episode of pancreatitis. These data suggest that inflammation-exposed acinar cells are capable of establishing an altered, persistently accessible chromatin state that lasts long after the initial lineage destabilizing event. Currently we are defining if, following resolution of pancreatitis, activation of mutant Kras will be sufficient to induce premalignant transformation within the acinar compartment that manifests as pancreatic intraepithelial neoplasia (PanIN)—the most common precursor lesion to pancreatic ductal adenocarcinoma (PDAC). Understanding how this postinflammatory chromatin state synergizes with oncogenic stress will further explain why inflammation is a hallmark risk factor for cancer development. Together, our studies will characterize the establishment, maintenance, and maladaptive role of epigenetic memory in the development of pancreatic cancer. Citation Format: David J. Falvo, Rohit Chandwani. The establishment, maintenance, and maladaptive role of epigenetic memory in mediating pancreatic tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A12.

Patterns of electrical brain activation in response to socially-disputed perceptual judgments.

In recent years, neuroscience has begun to investigate brain responses to social stimuli. To date, however, the effects of social feedback on attentional and perceptual processes remain unclear. In this study, participants were asked to judge the hues of distinct, or ambiguously coloured stimuli, and to indicate their confidence ratings. Alleged social feedback was then provided, either endorsing or disputing the participants' responses. Participants were then presented the stimulus a second time and given the option to reconsider their decision. Behavioural findings showed that confidence levels decreased both with task difficulty and with conflicting social feedback. Event-related potential data showed greater P2 and N2 amplitudes for ambiguous squares compared to distinct squares upon initial stimulus presentations, compatible with heightened attention. Moreover, a decreased P300 was found for ambiguous stimuli, consistent with an increase in metacognitive activity. After social feedback, an early-late positive potential between 270 and 370 ms continued to distinguish ambiguous from distinct stimuli. More importantly, after 400 ms, the late positive potential distinguished endorsed from disputed stimuli. These results reveal that social feedback, while decreasing effects linked to uncertainty, gives rise to later processes associated with enhanced motivational significance of the stimulus following divergence from social approval.

The microbiota-gut-brain axis: An emerging role for the epigenome.

Through the gut-brain axis, the microorganisms that reside in the gut are able to exert an important influence on the central nervous system. Preclinical and clinical evidence suggests that alterations in the composition of the gut microbiota are involved in gastrointestinal and neurological disorders. During critical neurodevelopmental time periods, such as the early life, changes in gut microbial composition may detrimentally impact neurodevelopment, and subsequently lead to neurological disorders in later life. The finding that neurological disorders persist suggests that epigenetic modifications may be involved in response to disruption of the microbiota-gut-brain axis. Through establishing epigenetic modifications, environmental (microbial) signals can interfere with the cellular gene expression patterns. These long-lasting modifications exert their effects even when the initial stimulus is removed. In this review, we discuss the pathways that provide bidirectional communication between the microbiota and the central and peripheral nervous systems. Furthermore, we summarize how these microorganisms in the gut exert their influence through changing the epigenome in the brain-gut axis.Impact statementAlterations in the composition of gut microbiota may influence the etiology of gastrointestinal and neurological disorders by disturbing the communication in the gut-brain axis. Epigenetic changes in the gut-brain axis may perpetuate these phenotypes even when the gut microbiota has been restored. The studies reviewed in this article provide an overview of the influence the microbiota exerts onto its host’s epigenome. First, we summarize the bidirectional pathways through which the microbiota and the gut-brain axis communicate. Second, we provide evidence for the epigenome-altering capacity of the gut microbiota. Finally, we address the existing knowledge gaps and highlight the potential role of the epigenome in the microbiota-gut-brain axis.

Current Understanding of the Acute Exacerbation of Chronic Rhinosinusitis.

Background: Acute exacerbations of chronic rhinosinusitis (CRS) have been increasingly recognized as an important disease entity with a significant impact on the quality of life. There is a growing amount of research on the etiopathogenesis and management of acute exacerbations of CRS. This review aims to summarize the current literature and provide an overall understanding of acute CRS exacerbations.Methods: A related literature review with the key terms of “chronic rhinosinusitis” and “exacerbation” was performed using PubMed.Results: There is no consensus definition of the acute exacerbation of CRS. Impaired mucociliary clearance, atrophic rhinitis, and immunologic changes are important predisposing factors for acute CRS exacerbations. Current evidence supports the role of the transient viral infection as the initial inflammatory stimulus in the pathogenesis of acute CRS exacerbations. Secondary bacterial infection or microbial community dysbiosis within the sinonasal cavity is the main event during the acute exacerbation of CRS. Distinct changes in local and systemic immune responses during exacerbation provide new insights into the pathophysiology of CRS exacerbation. Although current guidelines suggest the use of short-term antibiotics in patients with acute CRS exacerbation for symptomatic relief, evidence-based treatment recommendations for acute CRS exacerbation are still lacking, and large-high-quality RCTs are required.Conclusion: There have been significant advances in understanding the etiology and immunological feathers of acute CRS exacerbation. Nevertheless, consensus definition, diagnostic criterion, biomarkers to differentiate acute CRS exacerbation from CRS, assessment of disease severity, and evidence-based treatment options for acute CRS exacerbation are still lacking.

Information preferences across species: Pigeons, rats, and dogs

We tested the information preferences of three different species; pigeons, rats and dogs. Eight animals of each species received forced trials that produced one of two stimulus sequences. In the first sequence, response to an initial stimulus led to one of two other stimuli, one of which guaranteed a food reward was coming and the other of which guaranteed no food reward was coming. In the second sequence, response to an initial stimulus led to one of two other stimuli, both of which predicted food reward on 50 % of the trials. The net reinforcement rate for both of the sequences was 50 %. On probe test trials, both initial stimuli were presented, and the subject chose between the informative and the non-informative cue, and the percent choice of the information sequence, in which stimuli predicted food or no food reliably, was recorded for each species across 10 sessions. Statistical tests showed that although pigeons showed a preference for the information sequence, neither rats nor dogs showed this preference. Experimental and ecological explanations are discussed.

Towards multi-dynamic mechano-biological optimization of 3D-printed scaffolds to foster bone regeneration

Substantial tissue loss, such as in large bone defects, represents a clinical challenge for which regenerative therapies and tissue engineering strategies aim at offering treatment alternatives to conventional replacement approaches by metallic implants. 3D printing technologies provide endless opportunities to shape scaffold structures that could support endogenous regeneration. However, it remains unclear which of the numerous parameters at hand eventually enhance tissue regeneration. In the last decades, a significant effort has been made in the development of computer tools to optimize scaffold designs. Here, we aim at giving a more comprehensive overview summarizing current computer optimization framework technologies. We confront these with the most recent advances in scaffold mechano-biological optimization, discuss their limitations and provide suggestions for future development. We conclude that the field needs to move forward to not only optimize scaffolds to avoid implant failures but to improve their mechano-biological behaviour: providing an initial stimulus for fast tissue organisation and healing and accounting for remodelling, scaffold degradation and consecutive filling with host tissue. So far, modelling approaches fall short in including the various scales of tissue dynamics. With this review, we wish to stimulate a move towards multi-dynamic mechano-biological optimization of 3D-printed scaffolds. Statement of significanceLarge bone defects represent a clinical challenge for which tissue engineering strategies aim at offering alternatives to conventional treatment strategies. 3D printing technologies provide endless opportunities to shape scaffold structures that could support endogenous regeneration. However, it remains unclear which of the numerous parameters at hand eventually enhance tissue regeneration. In the last decades, a significant effort has been made in the development of computer tools to optimize scaffold designs. This review summarizes current computer optimization frameworks and most recent advances in mechano-biological optimization of bone scaffolds to better stimulate bone regeneration. We wish to stimulate a move towards multi-dynamic mechano-biological optimization of 3D-printed scaffolds.

Preferential activation of spinal sensorimotor networks via lateralized transcutaneous spinal stimulation in neurologically intact humans.

Transcutaneous spinal stimulation (TSS), a noninvasive technique to modulate sensorimotor circuitry within the spinal cord, has been shown to enable a wide range of functions that were thought to be permanently impaired in humans with spinal cord injury. However, the extent to which TSS can be used to target specific mediolateral spinal cord circuitry remains undefined. We tested the hypothesis that TSS applied unilaterally to the skin ~2 cm lateral to the midline of the lumbosacral spine selectively activates ipsilateral spinal sensorimotor circuitry, resulting in ipsilateral activation of downstream lower extremity neuromusculature. TSS cathodes and anodes were positioned lateral from the midline of the spine in 15 healthy subjects while supine, and the timing of TSS pulses was synchronized to recordings of lower extremity muscle activity and force. At motor threshold, left and right TSS-evoked muscle activity was significantly higher in the ipsilateral leg compared with contralateral recordings from the same muscles. Similarly, we observed a significant increase in force production in the ipsilateral leg compared with the contralateral leg. Delivery of paired TSS pulses, during which an initial stimulus was applied to one side of the spinal cord and 50 ms later a second stimulus was applied to the contralateral side, revealed that ipsilateral leg muscle responses decreased following the initial stimulus, whereas contralateral muscle responses did not decrease, indicating side-specific activation of lateral spinal sensorimotor circuitry. Our results indicate TSS can selectively engage ipsilateral neuromusculature via lumbosacral sensorimotor networks responsible for lower extremity function in healthy humans.NEW & NOTEWORTHY We demonstrate the selectivity of transcutaneous spinal stimulation (TSS), which has been shown to enable function in humans with chronic paralysis. Specifically, we demonstrate that TSS applied to locations lateral to the spinal cord can selectively activate ipsilateral spinal sensorimotor networks. We quantified lumbosacral spinal network activity by recording lower extremity muscle electromyography and force. Our results suggest lumbosacral TSS engages side-specific spinal sensorimotor networks associated with ipsilateral lower extremity function in humans.

Transition from Acute to Chronic Pain: Evaluating Risk for Chronic Postsurgical Pain

Background: The pathophysiology of pain involves complex nervous system interactions after initial noxious stimuli. When stimuli persist, biochemical and structural changes occur in the nociceptive pathways of the central and peripheral nervous systems, leading to pain sensitization. Peripheral and central sensitization are key in the transition from acute to chronic pain. This development of chronic pain is particularly common following various surgical procedures, with many postsurgical patients experiencing persistent pain for significant periods. Chronic pain is a common and severe complication of surgery, and preventing its development is tantamount in improving patient outcomes. Objectives: To understand underlying pathophysiology of chronic postsurgical pain (CPSP) and the underlying risk factors predisposing the transition from acute to CPSP. To review our ability to identify patients at highest risk for the development CPSP. To identify evidence-based multimodal approaches that can aid in the prevention of CPSP. Study Design: Narrative review of peer-reviewed literature. Setting: Inpatient surgical centers. Methods: Medline and Cochrane databases were reviewed to identify publications relevant to CPSP pathophysiology, risk factors, predictive models, and prevention. Publications were selected based on author expertise to summarize our current understanding of CPSP. Results: This review presents our current understanding of CPSP in the following domains: underlying pathophysiology, predisposing risk factors, predictive models of CPSP, and preventative strategies. Each section provides a structured review of key evidence base to understand the complex topic of CPSP. Limitations: This narrative review is a nonsystematic review of relevant publications aimed at presenting succinct overview of CPSP. Conclusions: The incidence of CPSP can potentially be reduced through early identification of perioperative, genetic, physiologic, and psychologic factors. Models predicting the development of CPSP continue to improve and may help focus preventative efforts in patients at highest risk. There is a growing body of evidence supporting the use of multimodal analgesia and anesthetic techniques in the reducing rates of CPSP development. Key words: Acute pain, chronic postsurgical pain, pain sensitization, chronic pain prevention, regional anesthesia, pain adjuncts, neuraxial anesthesia, chronic pain risk factors

ALG-2/AGO-Dependent mir-35 Family Regulates DNA Damage-Induced Apoptosis Through MPK-1/ERK MAPK Signaling Downstream of the Core Apoptotic Machinery in Caenorhabditis elegans.

MicroRNAs (miRNAs) associate with argonaute (AGO) proteins to post-transcriptionally modulate the expression of genes involved in various cellular processes. Herein, we show that loss of the Caenorhabditis elegans AGO gene alg-2 results in rapid and significantly increased germ cell apoptosis in response to DNA damage inflicted by ionizing radiation (IR). We demonstrate that the abnormal apoptosis phenotype in alg-2 mutant animals can be explained by reduced expression of mir-35 miRNA family members. We show that the increased apoptosis levels in IR-treated alg-2 or mir-35 family mutants depend on a transient hyperactivation of the C. elegans ERK1/2 MAPK ortholog MPK-1 in dying germ cells. Unexpectedly, MPK-1 phosphorylation occurs downstream of caspase activation and depends at least in part on a functional cell corpse-engulfment machinery. Therefore, we propose a refined mechanism, in which an initial proapoptotic stimulus by the core apoptotic machinery initiates the engulfment process, which in turn activates MAPK signaling to facilitate the demise of genomically compromised germ cells.