Initial Stimulus Research Articles

An Ergogenic Medical Education: Building Curricula to Optimize Performance and Decrease Burnout.

One of the most pervasive myths in our culture today is the belief that training increases performance. When, in fact, training decreases performance. The current structure of training programs and educational curriculums provide the evidence regarding the acceptance of this belief. Intense focus is placed on the quantity of training time with little regard for additional factors. In pursuit of excellence, maximizing training opportunity and learning exposure insists upon the sacrifice of recovery time. However, recovery is the necessary training period to increase performance. In athletics, training without recovery leads to overtraining syndrome. Burnout is the non-athletic equivalency seen in under-recovered learners and workers. As demonstrated by the climbing burnout rates, the current structure of educational programs, epitomized by medical residency, perpetuates the myth that more training equals better performance. The purpose of the article does not revolve around the presentation of novel research discoveries, but it insists upon the implementation of previously established performance data in curricula development beyond athletics. The inflection and deflection points along the growth and adaptation curves can be explicitly utilized to meet the educational and professional standards set forth by educational institutions. When tracking performance as the metric, initial training stimuli creates a descending slope, e.g., “training decreases performance.” The concept that training creates a negative deflection is a neglected concept in academics. By incorporating this feature into learning environments, training can transition from surviving training redundancy to thriving with an optimal work:recovery ratio.

Computational Analysis of Bone Remodeling in the Proximal Tibia Under Electrical Stimulation Considering the Piezoelectric Properties.

The piezoelectricity of bone is known to play a crucial role in bone adaptation and remodeling. The application of an external stimulus such as mechanical strain or electric field has the potential to enhance bone formation and implant osseointegration. Therefore, in the present study, the objective is to investigate bone remodeling under electromechanical stimulation as a step towards establishing therapeutic strategies. For the first time, piezoelectric bone remodeling in the human proximal tibia under electro-mechanical loads was analyzed using the finite element method in an open-source framework. The predicted bone density distributions were qualitatively and quantitatively assessed by comparing with the computed tomography (CT) scan and the bone mineral density (BMD) calculated from the CT, respectively. The effect of model parameters such as uniform initial bone density and reference stimulus on the final density distribution was investigated. Results of the parametric study showed that for different values of initial bone density the model predicted similar but not identical final density distribution. It was also shown that higher reference stimulus value yielded lower average bone density at the final time. The present study demonstrates an increase in bone density as a result of electrical stimulation. Thus, to minimize bone loss, for example, due to physical impairment or osteoporosis, mechanical loads during daily physical activities could be partially replaced by therapeutic electrical stimulation.

NKT and NKT-like Cells in Autoimmune Neuroinflammatory Diseases-Multiple Sclerosis, Myasthenia Gravis and Guillain-Barre Syndrome.

NKT cells comprise three subsets—type I (invariant, iNKT), type II, and NKT-like cells, of which iNKT cells are the most studied subset. They are capable of rapid cytokine production after the initial stimulus, thus they may be important for polarisation of Th cells. Due to this, they may be an important cell subset in autoimmune diseases. In the current review, we are summarising results of NKT-oriented studies in major neurological autoimmune diseases—multiple sclerosis, myasthenia gravis, and Guillain-Barre syndrome and their corresponding animal models.

NETosis and the Immune System in COVID-19: Mechanisms and Potential Treatments.

NETosis is a form of neutrophil death leading to the release of extracellular chromatin and the assembling of proteins, including antiviral proteins, primed by an initial pathogenic stimulus. Under certain specific conditions, neutrophils can exhibit a double-edged activity. This event has been implicated in COVID-19 among other conditions. Neutrophil extracellular traps (NETs) are involved in the pathogenesis of COVID-19 by promoting a pro-inflammatory and a procoagulant state leading to multiorgan failure. This particular form of host defense promoted by neutrophils is closely related to the well-known cytokine storm observed in severe COVID-19 patients. These two elements therefore represent possible targets for treatment of severe SARS-CoV-2 infections.

The Evaluation of Postural Stability and Fall Risk in Patients with Primary Hip Osteoarthritis.

The hip is a significant weight-bearing joint and hip osteoarthritis (HOA) is one of the common musculoskeletal disorders. HOA may affect postural stability and fall risk by disrupting joint biomechanics. Fourty patients with unilateral primary HOA and a control group consisting of 41 healthy subjects were included in the study. HOA wasradiographicallygraded byKellgren Lawrence (KL) HOA classification. There were 26 patients with mild HOA (KL grade ≤ 2) and 14 patients with moderate-severe HOA (KL grade ≥ 3). The falls efficacy scale-international was used to assess fear of falling. Postural stability and the fall risk were evaluated by using the Biodex Stability System. The postural stability and the fall risk indices were statistically significantly higher in the study group. Also, there was a positive correlation between the number of falls in the last 1year, weight, and body mass index; and these correlations were statistically significant (r 0.686, p 0.003; r 0.477, p 0.002; r 0.444, p 0.004). There was no statistically significant difference in fall risk by the HOA was mild or moderate-severe. Determining the deterioration in postural stability and the fall risk in patients with both mild and moderate-severe HOA may be a stimulus for early initiation of postural stability exercises in HOA.

Carbamazepine/oxcarbazepine and valproate have different effects on the electroconvulsive therapy seizure threshold

Patients receiving mood stabilizers such as valproate (VAL) and carbamazepine (CMZP)/Oxcarbazepine (OX) may be referred for electroconvulsive therapy (ECT). The relative effects of these anticonvulsants on seizure threshold and seizure duration are unknown. We extracted data for a 20-month period from the medical records of patients who received bilateral ECT while on treatment with VAL (n=102) or CMZP/OX (n=31; 20 on CMZP, 11 on oxcarbazepine). Age-matched ECT-treated anticonvulsant-free patients (n=133) formed the control group. Seizure threshold in these patients had been determined by stimulus dose titration. The effect of VAL vs CMZP/OX on seizure threshold was examined using multivariable regression with adjustment for confounders. The mean (standard deviation) seizure threshold at the first ECT was highest in the CMZP/OX group (243.9 [106.1] mC), intermediate in the VAL group (177.7 [97.0] mC), and lowest in the control group (138.7 [86.0 Mc]). The regression model explained 37.5% of the variance in seizure threshold at the first ECT. Age, use of CMZP/OX, and anticonvulsant dose were each significantly associated with higher seizure threshold. CMZP/OX was associated with a higher initial ECT seizure threshold than VAL. ECT practitioners may prefer to start with a higher initial stimulus dose in patients receiving CMZP/OX or VAL, and more so for CMZP/OX than VAL, to avoid repeated sub-convulsive stimuli being administered.

Mutual Gains from Eurasian Railway Connectivity

This paper analyzes the relationship between Eurasian rail services (especially the China–EU services that have flourished since 2011) and the overland “Belt” part of the Belt and Road Initiative (BRI). The initial market-driven stimulus was from car and electronics firms linking their East Asian and European production networks, and the establishment of Eurasian value chains remains an important theme. As regular rail freight services between China and Europe became more frequent, between more termini and offering more ancillary services, trade costs were reduced along the BRI Belt with mutual benefits for Asian and European countries. The paper first documents the growth and current status of the overland rail freight services; the sound economic foundation for the rail services and the continued growth of traffic during the COVID-19 pandemic indicate the sustainability of this part of the BRI. It then discusses the relationship of the Eurasian rail services to the wider BRI, emphasizing the importance of multiple routes and of connections to ports. Finally, the paper reviews the literature on the economic gains from improved rail connectivity and on the relationship between hard and soft infrastructure. The principal conclusion is that market-driven commercial incentives, public policies and the BRI have contributed to the success of the Belt mainlines and links to Indian Ocean ports are expected to integrate the currently separate Belt and Road.

Wavelike propagation of quorum activation through a spatially distributed bacterial population under natural regulation

Many bacteria communicate using diffusible pheromone signals known as autoinducers. When the autoinducer concentration reaches a threshold, which requires a minimum population density or ‘quorum’, the bacteria activate specific gene regulatory pathways. Simple diffusion of autoinducer can activate quorum-dependent pathways in cells that are located at substantial distances from the secreting source. However, modeling has predicted that autoinducer diffusion, coupled with positive feedback regulation in autoinducer synthesis, could also allow a quorum-regulated behavior to spread more rapidly through a population by moving as a self-sustaining front at constant speed. Here we show that such propagation can occur in a population of bacteria whose quorum pathway operates under its own natural regulation. We find that in unstirred populations of Vibrio fischeri, introduction of autoinducer at one location triggers a wavelike traveling front of natural bioluminescence. The front moves with a well-defined speed ∼2.5 mm h−1, eventually outrunning the slower diffusional spreading of the initial stimulus. Consistent with predictions from modeling, the wave travels until late in growth, when population-wide activation occurs due to basal autoinducer production. Subsequent rounds of waves, including waves propagating in the reverse direction, can also be observed late in the growth of V. fischeri under natural regulation. Using an engineered, lac-dependent strain, we show that local stimuli other than autoinducers can also elicit a self-sustaining, propagating response. Our data show that the wavelike dynamics predicted by simple mathematical models of quorum signaling are readily detected in bacterial populations functioning under their own natural regulation, and that other, more complex traveling phenomena are also present. Because a traveling wave can substantially increase the efficiency of intercellular communication over macroscopic distances, our data indicate that very efficient modes of communication over distance are available to unmixed populations of V. fischeri and other microbes.

Jasmonic acid priming of potato uses hypersensitive response-dependent defense and delays necrotrophic phase change against Phytophthora infestans

One of the most important diseases affecting potato is late blight, caused by the oomycete Phtytophthora infestans. The use of jasmonic acid has been reported to reduce the progression of the disease in potato, but the defense mechanisms involved in this response are unknown. In this study we described the effect of jasmonic acid as a priming agent over time in the defense response of potato against the invasion of P. infestans. We observed that the initial stimulus generated by the exogenous application of jasmonic acid had an effect on the stomatal conductance of the treated tissue and activated StMYC2 expression. Results reveal a priming effect in plants inoculated 11 days after treatment with jasmonic acid, evidenced by an increased transcriptional induction of defense-associated genes, decrease in the number of necrotic lesions and an evident reduction of lesion area (72.23%). Furthermore, in this study, we show that the tested concentration of jasmonic acid does not have an adverse effect at the physiological level in plants, since variation in stomatal conductance was transient, no change in chlorophyll a fluorescence and no early senescence in leaves was observed.

Setting a prioritized agenda to drive speech-language therapy research in health.

Prioritized research agendas are viewed internationally as an important method for ensuring that health research meets actual areas of clinical need. There is growing evidence for speech-language therapy-prioritized research agendas, particularly in disorder-specific areas. However, there are few general research priority agendas to guide speech-language therapy research. To collaboratively develop a prioritized research agenda for an Australian public health context with clinical speech-language therapists (SLTs), academic SLTs and consumers of speech-language therapy services. An initial stimulus list of potential research areas for prioritization was collected from SLTs via an online survey. Two categories (service delivery and expanded scope of practice) were selected from this list for prioritization due to their relevance across multiple health services. The Nominal Group Technique (NGT) was used to develop a prioritized research agenda for each of the two categories. One NGT session was conducted with each of the three participant groups (clinical SLTs, academic SLTs, consumers) for each category (total NGT sessions = six). The prioritization data for each group within each category were summed to give a single, ranked prioritized research agenda for each category. Two prioritized research agendas were developed. Within each agenda, SLTs and consumers prioritized a need for more research in areas related to specific practice areas (e.g., Alternative and Augmentative Communication, Communication Partner Training), as well as broader professional issues (e.g., telehealth, working with culturally and linguistically diverse families). The current findings support the need for funding proposals and targeted projects that address these identified areas of need. What is already known on this subject Evidence-based practice is a critical component of SLT practice. There is often a disconnect between the research evidence generated and areas of clinical need, and in some areas a lack of evidence. Prioritized research agendas can help drive research in areas of clinical need. What this paper adds to existing knowledge A collaborative, prioritized SLT research agenda was developed using the NGT according to the views of clinical SLTs, academic SLTs and consumers of speech-language therapy services in a conglomerate of public health services. SLTs and consumers identified a need for further research in specific areas of SLT practice as well as broader emerging professional issues What are the potential or actual clinical implications of this work? Targeted research projects funded on a large scale are required to address these identified areas of need. Other health services around the world could replicate this prioritization process to drive research in areas of clinical need.

Consolidation of memory traces in cultured cortical networks requires low cholinergic tone, synchronized activity and high network excitability

In systems consolidation, encoded memories are replayed by the hippocampus during slow-wave sleep (SWS), and permanently stored in the neocortex. Declarative memory consolidation is believed to benefit from the oscillatory rhythms and low cholinergic tone observed in this sleep stage, but underlying mechanisms remain unclear. To clarify the role of cholinergic modulation and synchronized activity in memory consolidation, we applied repeated electrical stimulation in mature cultures of dissociated rat cortical neurons with high or low cholinergic tone, mimicking the cue replay observed during systems consolidation under distinct cholinergic concentrations. In the absence of cholinergic input, these cultures display activity patterns hallmarked by network bursts, synchronized events reminiscent of the low frequency oscillations observed during SWS. They display stable activity and connectivity, which mutually interact and achieve an equilibrium. Electrical stimulation reforms the equilibrium to include the stimulus response, a phenomenon interpreted as memory trace formation. Without cholinergic input, activity was burst-dominated. First application of a stimulus induced significant connectivity changes, while subsequent repetition no longer affected connectivity. Presenting a second stimulus at a different electrode had the same effect, whereas returning to the initial stimuli did not induce further connectivity alterations, indicating that the second stimulus did not erase the ‘memory trace’ of the first. Distinctively, cultures with high cholinergic tone displayed reduced network excitability and dispersed firing, and electrical stimulation did not induce significant connectivity changes. We conclude that low cholinergic tone facilitates memory formation and consolidation, possibly through enhanced network excitability. Network bursts or SWS oscillations may merely reflect high network excitability.

Congenital Disruption of Glycinergic Signaling Results in Fewer Phrenic Motor Neurons and Impaired Diaphragm Neuromotor Control

Glycine (Gly) is a key inhibitory neurotransmitter at phrenic motor neurons (PhMN). In development, Gly is excitatory, transitioning to inhibitory action in the postnatal period. In adult conditions such as amyotrophic lateral sclerosis (ALS), excessive excitatory signaling onto motor neurons results in excitotoxic motor neuron death. However, it is not known how an imbalance of neurotransmission early in development impacts PhMNs at maturity. This is a knowledge gap, as some congenital hypertonia conditions exhibit an imbalance in neurotransmitter signaling, with these individuals suffering significant morbidity and mortality from respiratory disorders. Using an animal model of congenital hypertonia (spa mouse [B6.Cg-Glrbspa/J] with a Gly receptor mutation), we evaluated PhMN and motor unit physiology. Similar to previous work in other Gly mutants, we hypothesized that spa mice will have excessive developmental PhMN loss with preserved PhMNs having a smaller somal size compared to wildtype (WT) mice. We also hypothesized that fewer PhMNs in spa mice will result in an increased diaphragm (DIAm) innervation ratio (number of DIAm fibers innervated by a PhMN) and increased DIAm neuromuscular transmission failure (NMTF). Spa and WT mice from our colony, ages 6 to 16 weeks, underwent unilateral retrograde labeling of PhMNs via rhodamine phrenic nerve dip. After three days, mice were euthanized, perfused with 4% paraformaldehyde, cervical spinal cord excised and processed for longitudinal cryosectioning (70 µm) and prepared for confocal imaging. Absolute PhMN counts were obtained using mosaic images of adjacent serial sections. Somal size measurements (i.e. surface area) were obtained using ImageJ. DIAm force was determined from DIAm strip preparations stretched to optimal length, and force was evoked by phrenic nerve stimulation at 40 Hz in 330 ms duration trains repeated each s (33% duty cycle) for 120 s. To assess NMTF, force evoked by phrenic nerve stimulation was compared to force evoked by direct DIAm stimulation superimposed every 15 s. Total DIAm fiber number was estimated in H&E stained cross-sections. Spa mice had 30% fewer PhMNs compared to WT (P=0.005) with somal size being 22% smaller in spa mice (P=0.019). Spa mice had 20% NMTF during the initial stimulus train compared to 8% in WT mice with spa mice having 82% NMTF and WT having 40% NMTF at end of stimulation. Spa mice had a 39% greater innervation ratio of DIAm motor units compared to WT. Developmental PhMN loss and somal size is significantly disrupted in congenital hypertonia due to impaired Gly signaling and may impact performance of high-force expulsive DIAm activities. In addition, the increased innervation ratio of DIAm motor units in spa mice, likely contributes to the NMTF due to branch point failure. Overall, this results in less effective airway defense and straining behaviors in congenital hypertonia. Our next step is to identify crucial developmental milestones when excessive PhMN loss occurs and the impact on large versus small PhMNs.

Role of A1/A2 Neurons in the Dysregulation of Vasopressin Release and Dilutional Hyponatremia in Liver Disease

Purpose Inappropriate release of arginine vasopressin (AVP) has been linked to dilutional hyponatremia in patients with liver disease. Plasma AVP remains elevated leading to water retention, hypoosmolality, ascites formation, and a perceived decrease in plasma volume. The perceived decrease in plasma volume is sensed by the A1/A2 norepinephrine neurons in the caudal ventrolateral medulla (CVLM) and the nucleus tractus solitarius (NTS) respectively. We propose that these neurons provide the initial stimuli that activates AVP-secreting neurons in the supraoptic nucleus (SON) leading to increased plasma AVP and dilutional hyponatremia. Method We used the Bile duct ligation (BDL) rat model of liver failure for our experiments. Selective lesioning of the SON-projecting A1/A2 norepinephrine neurons was achieved using anti-DβH-Saporin [IT-03] (Advanced Targeting Systems). Plasma copeptin concentration was measured as a surrogate marker for plasma AVP using ELISA. Plasma osmolality and hematocrit measurements were also taken. Immunohistochemistry for delta fosB and dopamine beta-hydroxylase (DβH) was performed on brain tissue slices. The slices were viewed using an Olympus microscope (BX41) equipped for epifluorescence and images were taken using Olympus DP70 digital camera with DP manager software (version 2.2.1). The number of immunoreactive cells to ΔFosB and DβH were counted using Image J. Results We found that lesioning of the A1/A2 neurons in the Saporin/BDL group (n=9) caused a decrease in the plasma AVP concentration versus the Vehicle/BDL control group (n=6), p<0.05. However, the number of delta fosB immunoreactive A1/A2 cells was not significantly different. Lesioning of the A1/A2 neurons seemed to normalize osmolality and hematocrit in the BDL group. Although the difference was not statistically significant. Conclusion Our experiments suggests that A1/A2 neurons could be involved in the increased plasma AVP seen in male BDL rats as well as the decreased plasma osmolality.

Congenital, acquired, or both? The only two congenitally based, acquired heart diseases.

Discrete subaortic stenosis (DSS) is a type of left ventricular outflow tract obstruction whereas double-chambered right ventricle is a form of right ventricular outflow tract obstruction. Both of these cardiac malformations share lots of similar characteristics which classify them as acquired developmental heart diseases despite their congenital anatomical substrate. Both of them are frequently associated to ventricular septal defects. The initial stimulus in their pathogenetic process is anatomical abnormalities or variations. Subsequently, a hemodynamic process is triggered finally leading to an abnormal subaortic fibroproliferative process with regard to DSS or to hypertrophy of ectopic muscles as far as double-chambered right ventricle is concerned. In many cases, these pathologies are developed secondarily to surgical management of other congenital or acquired heart defects. Moreover, high recurrence rates after initial successful surgical therapy, particularly regarding DSS, have been described. Finally, an interesting coexistence of DSS and double-chambered aortic ventricle has also been reported in some cases.

Erratum: Fairhall, "Cross Recruitment of Domain-Selective Cortical Representations Enables Flexible Semantic Knowledge".

In the article, “Cross Recruitment of Domain-Selective Cortical Representations Enables Flexible Semantic Knowledge,” by Scott L. Fairhall, which appeared on pages [3096–3103][1] of the April 8, 2020 issue, errors were published. The description of the initial stimulus selection includes

Active maintenance of musical and linguistic information as a function of musical experience

Recent research suggests that linguistic and musical information are processed by shared working memory resources in non-musicians. However, it is still unclear how musical information is actively maintained by those with extensive musical experience. Some evidence suggests that those with musical experience may utilize distinct processing systems for the active maintenance of linguistic and musical information. To explore this possibility, a cross-modal interference paradigm was used in which those with and without musical experience were presented with an initial stimulus (word or chord), followed by intervening stimuli (words, chords, or silence), and then a comparison stimulus (word or chord). The participants’ task was to indicate whether the comparison stimulus was the same or different from the initial stimulus. Results revealed a pattern of data that would be expected if the active maintenance of linguistic and musical information was accomplished by distinct systems in those with musical experience and a unitary system in non-musicians.

Breakdown in hepatic tolerance and its relation to autoimmune liver diseases.

The liver is a complex immunological organ. It has both immunogenic and tolerogenic capacity. Tolerogenic potential of human liver with its protective firewalls is required to guard the body against the continuous influx of microbial product from the gut via the sinusoids and biliary tree. Immunotolerance and anergic state is maintained by a combined effort of both immune cells, parenchyma cells, epithelial and endothelial cells. Despite this, an unknown trigger can ignite the pathway towards breakdown in hepatic tolerance leading to autoimmune liver diseases. Understanding the initial stimulus which causes the hepatic immune system to switch from the regulatory arm towards self-reactive effector arm remains challenging. Dissecting this pathology using the current technological advances is crucial to develop curative immune based therapy in autoimmune liver diseases. We discuss the hepatic immune cells and non-immune cells which maintain liver tolerance and the evidence of immune system barrier breach which leads to autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis.

Apoptosis mapping in space and time of 3D tumor ecosystems reveals transmissibility of cytotoxic cancer death.

The emerging tumor-on-chip (ToC) approaches allow to address biomedical questions out of reach with classical cell culture techniques: in biomimetic 3D hydrogels they partially reconstitute ex vivo the complexity of the tumor microenvironment and the cellular dynamics involving multiple cell types (cancer cells, immune cells, fibroblasts, etc.). However, a clear bottleneck is the extraction and interpretation of the rich biological information contained, sometime hidden, in the cell co-culture videos. In this work, we develop and apply novel video analysis algorithms to automatically measure the cytotoxic effects on human cancer cells (lung and breast) induced either by doxorubicin chemotherapy drug or by autologous tumor-infiltrating cytotoxic T lymphocytes (CTL). A live fluorescent dye (red) is used to selectively pre-stain the cancer cells before co-cultures and a live fluorescent reporter for caspase activity (green) is used to monitor apoptotic cell death. The here described open-source computational method, named STAMP (spatiotemporal apoptosis mapper), extracts the temporal kinetics and the spatial maps of cancer death, by localizing and tracking cancer cells in the red channel, and by counting the red to green transition signals, over 2-3 days. The robustness and versatility of the method is demonstrated by its application to different cell models and co-culture combinations. Noteworthy, this approach reveals the strong contribution of primary cancer-associated fibroblasts (CAFs) to breast cancer chemo-resistance, proving to be a powerful strategy to investigate intercellular cross-talks and drug resistance mechanisms. Moreover, we defined a new parameter, the 'potential of death induction', which is computed in time and in space to quantify the impact of dying cells on neighbor cells. We found that, contrary to natural death, cancer death induced by chemotherapy or by CTL is transmissible, in that it promotes the death of nearby cancer cells, suggesting the release of diffusible factors which amplify the initial cytotoxic stimulus.

Aberrant regulation of retinoic acid signaling genes in cerebral arterio venous malformation nidus and neighboring astrocytes

BackgroundCerebral arterio venous malformations (AVM) are a major causal factor for intracranial hemorrhage, which result in permanent disability or death. The molecular mechanisms of AVM are complex, and their pathogenesis remains an enigma. Current research on cerebral AVM is focused on characterizing the molecular features of AVM nidus to elucidate the aberrant signaling pathways. The initial stimuli that lead to the development of AVM nidus structures between a dilated artery and a vein are however not known.MethodsIn order to understand the molecular basis of development of cerebral AVM, we used in-depth RNA sequencing with the total RNA isolated from cerebral AVM nidus. Immunoblot and qRT-PCR assays were used to study the differential gene expression in AVM nidus, and immunofluorescence staining was used to study the expression pattern of aberrant proteins in AVM nidus and control tissues. Immunohistochemistry was used to study the expression pattern of aberrant proteins in AVM nidus and control tissues.ResultsThe transcriptome study has identified 38 differentially expressed genes in cerebral AVM nidus, of which 35 genes were upregulated and 3 genes were downregulated. A final modular analysis identified an upregulation of ALDH1A2, a key rate-limiting enzyme of retinoic acid signaling pathway. Further analysis revealed that CYR61, a regulator of angiogenesis, and the target gene for retinoic acid signaling is upregulated in AVM nidus. We observed that astrocytes associated with AVM nidus are abnormal with increased expression of GFAP and Vimentin. Triple immunofluorescence staining of the AVM nidus revealed that CYR61 was also overexpressed in the abnormal astrocytes associated with AVM tissue.ConclusionUsing high-throughput RNA sequencing analysis and immunostaining, we report deregulated expression of retinoic acid signaling genes in AVM nidus and its associated astrocytes and speculate that this might trigger the abnormal angiogenesis and the development of cerebral AVM in humans.

Effects of Noise and Serial Position on Free Recall of Spoken Words and Pupil Dilation during Encoding in Normal-Hearing Adults.

This preliminary study assessed the effects of noise and stimulus presentation order on recall of spoken words and recorded pupil sizes while normal-hearing listeners were trying to encode a series of words for a subsequent recall task. In three listening conditions (stationary noise in Experiment 1; quiet versus four-talker babble in Experiment 2), participants were assigned to remember as many words as possible to recall them in any order after each list of seven sentences. In the two noise conditions, lists of sentences fixed at 65 dB SPL were presented at an easily audible level via a loudspeaker. Reading span (RS) scores were used as a grouping variable, based on a median split. The primacy effect was present apart from the noise interference, and the high-RS group significantly outperformed the low-RS group at free recall measured in the quiet and four-talker babble noise conditions. RS scores were positively correlated with free-recall scores. In both quiet and four-talker babble noise conditions, sentence baselines after correction to the initial stimulus baseline increased significantly with increasing memory load. Larger sentence baselines but smaller peak pupil dilations seemed to be associated with noise interruption. The analysis method of pupil dilation used in this study is likely to provide a more thorough understanding of how listeners respond to a later recall task in comparison with previously used methods. Further studies are needed to confirm the applicability of our method in people with impaired hearing using multiple repetitions to estimate the allocation of relevant cognitive resources.