Otolith sectioning reveals higher maximum age in greater weever (Trachinus draco).

Growth and maximum age are two key parameters that inform resilience of fish populations to exploitation. Existing information on those for greater weever inhabiting the eastern North Sea is based on the analysis of whole otoliths. Here, we present a reanalysis using sectioned otoliths. The results reveal a different growth pattern and a higher maximum age than that previously reported. The higher maximum age makes greater weever populations more vulnerable to exploitation. Such information can serve as a basis for the estimation of the growth curve that can be used for future assessment of the species.

Gene's expression underpinning the divergent predictive value of [18F]F-fluorodeoxyglucose and prostate-specific membrane antigen positron emission tomography in primary prostate cancer: a bioinformatic and experimental study.

BACKGROUND: Positron Emission Tomography (PET) imaging with Prostate-Specific Membrane Antigen (PSMA) and Fluorodeoxyglucose (FDG) represent promising biomarkers for risk-stratification of Prostate Cancer (PCa). We verified whether the expression of genes encoding for PSMA and enzymes regulating FDG cellular uptake are independent and additive prognosticators in PCa. METHODS: mRNA expression of genes involved in glucose metabolism and PSMA regulation obtained from primary PCa specimens were retrieved from open-source databases and analyzed using an integrative bioinformatics approach. Machine Learning (ML) techniques were used to create predictive Progression-Free Survival (PFS) models. Cellular models of primary PCa with different aggressiveness were used to compare [18F]F-PSMA-1007 and [18F]F-FDG uptake kinetics in vitro. Confocal microscopy, immunofluorescence staining, and quantification analyses were performed to assess the intracellular and cellular membrane PSMA expression. RESULTS: ML analyses identified a predictive functional network involving four glucose metabolism-related genes: ALDOB, CTH, PARP2, and SLC2A4. By contrast, FOLH1 expression (encoding for PSMA) did not provide any additive predictive value to the model. At a cellular level, the increase in proliferation rate and migratory potential by primary PCa cells was associated with enhanced FDG uptake and decreased PSMA retention (paralleled by the preferential intracellular localization). CONCLUSIONS: The overexpression of a functional network involving four glucose metabolism-related genes identifies a higher risk of disease progression since the earliest phases of PCa, in agreement with the acknowledged prognostic value of FDG PET imaging. By contrast, the prognostic value of PSMA PET imaging is independent of the expression of its encoding gene FOLH1. Instead, it is influenced by the protein docking to the cell membrane, regulating its accessibility to tracer binding.

Mandatory role of endoplasmic reticulum and its pentose phosphate shunt in the myocardial defense mechanisms against the redox stress induced by anthracyclines.

Anthracyclines' cardiotoxicity involves an accelerated generation of reactive oxygen species. This oxidative damage has been found to accelerate the expression of hexose-6P-dehydrogenase (H6PD), that channels glucose-6-phosphate (G6P) through the pentose phosphate pathway (PPP) confined within the endoplasmic/sarcoplasmic reticulum (SR). To verify the role of SR-PPP in the defense mechanisms activated by doxorubicin (DXR) in cardiomyocytes, we tested the effect of this drug in H6PD knockout mice (H6PD-/-). Twenty-eight wildtype (WT) and 32 H6PD-/- mice were divided into four groups to be treated with intraperitoneal administration of saline (untreated) or DXR (8 mg/Kg once a week for 3 weeks). One week thereafter, survivors underwent imaging of 18F-deoxyglucose (FDG) uptake and were sacrificed to evaluate the levels of H6PD, glucose-6P-dehydrogenase (G6PD), G6P transporter (G6PT), and malondialdehyde. The mRNA levels of SR Ca2+-ATPase 2 (Serca2) and ryanodine receptors 2 (RyR2) were evaluated and complemented with Hematoxylin/Eosin staining and transmission electron microscopy. During the treatment period, 1/14 DXR-WT and 12/18 DXR-H6PD-/- died. At microPET, DXR-H6PD-/- survivors displayed an increase in left ventricular size (p < 0.001) coupled with a decreased urinary output, suggesting a severe hemodynamic impairment. At ex vivo analysis, H6PD-/- condition was associated with an oxidative damage independent of treatment type. DXR increased H6PD expression only in WT mice, while G6PT abundance increased in both groups, mismatching a generalized decrease of G6PD levels. Switching-off SR-PPP impaired reticular accumulation of Ca2+ decelerating Serca2 expression and upregulating RyR2 mRNA level. It thus altered mitochondrial ultrastructure eventually resulting in a cardiomyocyte loss. The recognized vulnerability of SR to the anthracycline oxidative damage is counterbalanced by an acceleration of G6P flux through a PPP confined within the reticular lumen. The interplay of SR-PPP with the intracellular Ca2+ exchanges regulators in cardiomyocytes configure the reticular PPP as a potential new target for strategies aimed to decrease anthracycline toxicity.

Enhancing Motor Brain Activity Improves Memory for Action Language: A tDCS Study.

The embodied cognition approach to linguistic meaning posits that action language understanding is grounded in sensory-motor systems. However, evidence that the human motor cortex is necessary for action language memory is meager. To address this issue, in two groups of healthy individuals, we perturbed the left primary motor cortex (M1) by means of either anodal or cathodal transcranial direct current stimulation (tDCS), before participants had to memorize lists of manual action and attentional sentences. In each group, participants received sham and active tDCS in two separate sessions. Following anodal tDCS (a-tDCS), participants improved the recall of action sentences compared with sham tDCS. No similar effects were detected following cathodal tDCS (c-tDCS). Both a-tDCS and c-tDCS induced variable changes in motor excitability, as measured by motor-evoked potentials induced by transcranial magnetic stimulation. Remarkably, across groups, action-specific memory improvements were positively predicted by changes in motor excitability. We provide evidence that excitatory modulation of the motor cortex selectively improves performance in a task requiring comprehension and memory of action sentences. These findings indicate that M1 is necessary for accurate processing of linguistic meanings and thus provide causal evidence that high-order cognitive functions are grounded in the human motor system.

Efficacy and Safety of Dexmedetomidine for Prolonged Sedation in the PICU: A Prospective Multicenter Study (PROSDEX).

OBJECTIVES: We sought to evaluate dexmedetomidine efficacy in assuring comfort and sparing conventional drugs when used for prolonged sedation (≥24 hr) in critically ill patients, by using validated clinical scores while systematically collecting drug dosages. We also evaluated the safety profile of dexmedetomidine and the risk factors associated with adverse events. DESIGN: Observational prospective study. SETTING: Nine tertiary-care PICUs. PATIENTS: Patients less than 18 years who received dexmedetomidine for greater than or equal to 24 hours between January 2016 and December 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One-hundred sixty-three patients (median age, 13 mo; interquartile range, 4-71 mo) were enrolled. The main indication for dexmedetomidine use was as an adjuvant for drug-sparing (42%). Twenty-three patients (14%) received dexmedetomidine as monotherapy. Seven percent of patients received a loading dose. The median infusion duration was 108 hours (interquartile range, 60-168 hr), with dosages between 0.4 (interquartile range, 0.3-0.5) and 0.8 µg/kg/hr (interquartile range, 0.6-1.2 µg/kg/hr). At 24 hours of dexmedetomidine infusion, values of COMFORT-B Scale (n = 114), Withdrawal Assessment Tool-1 (n = 43) and Cornell Assessment of Pediatric Delirum (n = 6) were significantly decreased compared with values registered immediately pre dexmedetomidine (p < 0.001, p < 0.001, p = 0.027). Dosages/kg/hr of benzodiazepines, opioids, propofol, and ketamine were also significantly decreased (p < 0.001, p < 0.001, p = 0.001, p = 0.027). The infusion was weaned off in 85% of patients, over a median time of 36 hours (interquartile range, 12-48 hr), and abruptly discontinued in 15% of them. Thirty-seven percent of patients showed hemodynamic changes, and 9% displayed hemodynamic adverse events that required intervention (dose reduction in 79% of cases). A multivariate logistic regression model showed that a loading dose (odds ratio, 4.8; CI, 1.2-18.7) and dosages greater than 1.2 µg/kg/hr (odds ratio, 5.4; CI, 1.9-15.2) increased the odds of hemodynamic changes. CONCLUSIONS: Dexmedetomidine used for prolonged sedation assures comfort, spares use of other sedation drugs, and helps to attenuate withdrawal syndrome and delirium symptoms. Adverse events are mainly hemodynamic and are reversible following dose reduction. A loading dose and higher infusion dosages are independent risk factors for hemodynamic adverse events.

Withdrawal Assessment Tool-1 Monitoring in PICU: A Multicenter Study on Iatrogenic Withdrawal Syndrome.

OBJECTIVES: Withdrawal syndrome is an adverse reaction of analgesic and sedative therapy, with a reported occurrence rate between 17% and 57% in critically ill children. Although some factors related to the development of withdrawal syndrome have been identified, there is weak evidence for the effectiveness of preventive and therapeutic strategies. The main aim of this study was to evaluate the frequency of withdrawal syndrome in Italian PICUs, using a validated instrument. We also analyzed differences in patient characteristics, analgesic and sedative treatment, and patients' outcome between patients with and without withdrawal syndrome. DESIGN: Observational multicenter prospective study. SETTING: Eight Italian PICUs belonging to the national PICU network Italian PICU network. PATIENTS: One hundred thirteen patients, less than 18 years old, mechanically ventilated and treated with analgesic and sedative therapy for five or more days. They were admitted in PICU from November 2012 to May 2014. INTERVENTIONS: Symptoms of withdrawal syndrome were monitored with Withdrawal Assessment Tool-1 scale. MEASUREMENTS AND MAIN RESULTS: The occurrence rate of withdrawal syndrome was 64.6%. The following variables were significantly different between the patients who developed withdrawal syndrome and those who did not: type, duration, and cumulative dose of analgesic therapy; duration and cumulative dose of sedative therapy; clinical team judgment about analgesia and sedation's difficulty; and duration of analgesic weaning, mechanical ventilation, and PICU stay. Multivariate logistic regression analysis revealed that patients receiving morphine as their primary analgesic were 83% less likely to develop withdrawal syndrome than those receiving fentanyl or remifentanil. CONCLUSIONS: Withdrawal syndrome was frequent in PICU patients, and patients with withdrawal syndrome had prolonged hospital treatment. We suggest adopting the lowest effective dose of analgesic and sedative drugs and frequent reevaluation of the need for continued use. Further studies are necessary to define common preventive and therapeutic strategies.

Task-related modulation of motor response to emotional bodies: A TMS motor-evoked potential study.

Exposure to emotional body postures during perceptual decision-making tasks has been linked to transient suppression of motor reactivity, supporting the monitoring of emotionally relevant information. However, it remains unclear whether this effect occurs implicitly, i.e., when emotional information is irrelevant to the task. To investigate this issue, we used single-pulse transcranial magnetic stimulation (TMS) to assess motor excitability while healthy participants were asked to categorize pictures of body expressions as emotional or neutral (emotion recognition task) or as belonging to a male or a female actor (gender recognition task) while receiving TMS over the motor cortex at 100 and 125 ms after picture onset. Results demonstrated that motor-evoked potentials (MEPs) were reduced for emotional body postures relative to neutral postures during the emotion recognition task. Conversely, MEPs increased for emotional body postures relative to neutral postures during the gender recognition task. These findings indicate that motor inhibition, contingent upon observing emotional body postures, is selectively associated with actively monitoring emotional features. In contrast, observing emotional body postures prompts motor facilitation when task-relevant features are non-emotional. These findings contribute to embodied cognition models that link emotion perception and action tendencies.

Predators with multiple ontogenetic niche shifts have limited potential for population growth and top-down control of their prey.

Catastrophic collapses of top predators have revealed trophic cascades and community structuring by top-down control. When populations fail to recover after a collapse, this may indicate alternative stable states in the system. Overfishing has caused several of the most compelling cases of these dynamics, and in particular Atlantic cod stocks exemplify such lack of recovery. Often, competition between prey species and juvenile predators is hypothesized to explain the lack of recovery of predator populations. The predator is then considered to compete with its prey for one resource when small and to subsequently shift to piscivory. Yet predator life history is often more complex than that, including multiple ontogenetic diet shifts. Here we show that no alternative stable states occur when predators in an intermediate life stage feed on an additional resource (exclusive to the predator) before switching to piscivory, because predation and competition between prey and predator do not simultaneously structure community dynamics. We find top-down control by the predator only when there is no feedback from predator foraging on the additional resource. Otherwise, the predator population dynamics are governed by a bottleneck in individual growth occurring in the intermediate life stage. Therefore, additional resources for predators may be beneficial or detrimental for predator population growth and strongly influence the potential for top-down community control.

Prediction of poor graft function by means of gastric tonometry in patients undergoing liver transplantation.

UNLABELLED: INTRODUCTION. Splanchnic hypoperfusion appears to play a key role in the failure of functional recovery of the graft after orthotopic liver transplantation (LT). The aim of this study was to determine if alterations of tonometric parameters, which are related to splanchnic perfusion, could predict poor graft function in patients undergoing LT. MATERIALS AND METHODS: After Ethics Committee approval, 68 patients undergoing LT were enrolled. In all the patients, regional-arterial CO2 gradient (Pr-aCO2) was recorded; in addition, the difference between Pr-aCO2 recorded at anhepatic phase (T1) and at the end of surgery (T2) (T2- T1 = ΔPr-aCO2) was calculated. Poor graft function was determined on the basis of Toronto's classification 72 hours after LT. Student t-test and logistic regression analysis were used for statistical purpose. Results. ΔPr-aCO2 was significantly greater in patients with poor graft function (3.5 ± 13.2) compared to patients with good graft function (-5.8 ± 12.3) (p = 0.014). The logistic regression analysis showed that the ΔPr-aCO2 was able to predict the onset of poor graft function (p = 0.037). A value of ΔPr-aCO2 ≥ -4 was associated with poor graft function with a sensibility of 93.3% and a specificity of 42.3%. CONCLUSION. Our study suggests that the change of Pr-aCO2 may be a valuable index of graft dysfunction. Gastric tonometry might give early prognostic information on the graft outcome, and it may aid clinicians in planning a more strict follow-up and proper interventions in order to improve graft survival.

Disturbing the activity of the primary motor cortex by means of transcranial magnetic stimulation affects long term memory of sentences referred to manipulable objects.

Introduction: Previous studies on embodied meaning suggest that simulations in the motor cortex play a crucial role in the processing of action sentences. However, there is little evidence that embodied meaning have functional impact beyond working memory. This study examines how the neuromodulation of the motor cortex (M1) could affect the processing of action-related language, measuring participants' performance in a long-term memory task. Method: Participants were submitted to two sessions in separate days, one with low-frequency repetitive transcranial magnetic stimulation (rTMS) and the other with sham rTMS. The pulses were delivered for 15 minutes over M1 or over V1, used as a control area. After each stimulation or sham period, the participants were asked to memorize a list of simple sentences, with a manual action verb or an attentional verb, followed in both cases by a noun referred to a manipulable object (e.g., to hang a cane vs. to observe a cane). Finally, they received the verbs as cues with instructions to recall the nouns. Results: The results showed that low frequency rTMS on M1, compared to sham stimulation, significantly improved the performance in the memory task, for both types of sentences. No change in performance was found after the rTMS stimulation of V1. Discussion: These results confirm that the perturbation on the motor system, affect the memory of manipulable object names in the context of sentences, providing further evidence of the role played by the sensorimotor system in the encoding and recall of concrete sentences of action.

You are fired! Exclusion words induce corticospinal modulations associated with vicarious pain.

Self- and vicarious experience of physical pain induces inhibition of the motor cortex (M1). Experience of social rejections recruits the same neural network as physical pain; however, whether social pain modulates M1 corticospinal excitability remains unclear. This study examines for the first time whether social exclusion words, rather than simulated social exclusion tasks, modulate embodied sensorimotor networks during the vicarious experience of others' pain. Participants observed visual sequences of painful and functional events ending with a superimposed word with social exclusion, social inclusion or non-social meaning. Motor-evoked potentials (MEPs) to single-pulse transcranial magnetic stimulation of the left M1 were recorded at 400 or 550 ms from word onset. MEPs tended to inhibit during the observation of pain, relative to functional events. Moreover, MEPs recorded at 400 ms from word onset, during pain movies, decreased following the presentation of exclusion, relative to inclusion/neutral words. The magnitude of these two modulations marginally correlated with participants' interindividual differences in personal distress and self-esteem. These findings provide evidence of vicarious responses to others' pain in the M1 corticospinal system and enhancement of such vicarious response in the earlier phases of semantic processing of exclusion words-supporting activation of social pain-embodied representations.

Divergent Oxidative Stress in Normal Tissues and Inflammatory Cells in Hodgkin and Non-Hodgkin Lymphoma.

BACKGROUND: Previous studies reported mitochondrial and endoplasmic reticulum redox stress in peripheral blood mononucleated cells (PBMCs) of treatment-naïve Hodgkin lymphoma (HL) patients. Here, we assessed whether this response also applies to non-HL (NHL) patients, and whether the oxidative damage is a selective feature of PBMCs or, rather, also affects tissues not directly involved in the inflammatory response. METHODS: Isolated PBMCs of 28 HL, 9 diffuse large B cell lymphoma, 8 less aggressive-NHL, and 45 controls underwent flow cytometry to evaluate redox stress and uptake of the glucose analogue 2-NBDG. This analysis was complemented with the assay of malondialdehyde (MDA) levels and enzymatic activity of glucose-6P-dehydrogenase and hexose-6P-dehydrogenase (H6PD). In all lymphoma patients, 18F-fluoro-deoxyglucose uptake was estimated in the myocardium and skeletal muscles. RESULTS: Mitochondrial reactive oxygen species generation and MDA levels were increased only in HL patients as well as H6PD activity and 2-NBDG uptake. Similarly, myocardial FDG retention was higher in HL than in other groups as opposed to a similar tracer uptake in the skeletal muscle. CONCLUSIONS: Redox stress of PBMCs is more pronounced in HL with respect to both NHL groups. This phenomenon is coherent with an increased activity of H6PD that also extends to the myocardium.

Rescue hypothermia for refractory hypercapnia.

Hypothermia may reduce the CO(2) production by decreasing the metabolism of the cooled tissue. We describe the first clinical use of hypothermia to lower hypercarbia in a case of bronchiolitis related respiratory failure unresponsive to maximal respiratory support. In this case, hypothermia allowed sparing the use of extracorporeal life support. Conclusion Hypothermia might be useful for severe acute respiratory failure unresponsive to aggressive respiratory support.

The neural inhibition network is causally involved in the disembodiment effect of linguistic negation.

Negation applied to action contexts reduces the activation of the motor system. According to the Reusing Inhibition for Negation (RIN) hypothesis, such "disembodiment" effect occurs because understanding negations engages the reuse of inhibitory control mechanisms. Here, we investigated whether the right inferior frontal gyrus (rIFG) - a key area of the inhibitory control system - contributes to primary motor cortex (M1) processing of negated action-sentences. Using a perturb-and-measure paradigm, we applied off-line low-frequency repetitive TMS (rTMS) over the rIFG, before performing a reading task involving action and attentional sentences presented in both affirmative or negative form. During the reading task, motor excitability was assessed by recording motor-evoked potentials (MEPs) induced by single-pulse TMS (spTMS) over the left M1, at two loci in the sentence: the verb or the object. Results show that after sham stimulation (baseline), motor excitability measured on the verb, was reduced for negative, compared to affirmative action sentences. Crucially, neuromodulation of rIFG suppressed this inhibitory effect of negation, since motor excitability was equaled for negative and affirmative action sentences. As expected, no effect of negation was observed for attentional sentences or when the pulse was delivered over the object. Our study confirms that understanding negative action sentences inhibits M1. This effect took place at an early stage of semantic processing (i.e., while processing the verb in our task), and faded at a later time-point. Critically, by highlighting a causal role of rIFG in this motor inhibition, we provide direct neurophysiological support to the RIN hypothesis.

Fundamental Role of Pentose Phosphate Pathway within the Endoplasmic Reticulum in Glutamine Addiction of Triple-Negative Breast Cancer Cells.

Cancer utilization of large glutamine equivalents contributes to diverging glucose-6-P flux toward the pentose phosphate shunt (PPP) to feed the building blocks and the antioxidant responses of rapidly proliferating cells. In addition to the well-acknowledged cytosolic pathway, cancer cells also run a largely independent PPP, triggered by hexose-6P-dehydrogenase within the endoplasmic reticulum (ER), whose activity is mandatory for the integrity of ER-mitochondria networking. To verify whether this reticular metabolism is dependent on glutamine levels, we complemented the metabolomic characterization of intermediates of the glucose metabolism and tricarboxylic acid cycle with the estimation of proliferating activity, energy metabolism, redox damage, and mitochondrial function in two breast cancer cell lines. ER-PPP activity and its determinants were estimated by the ER accumulation of glucose analogs. Glutamine shortage decreased the proliferation rate despite increased ATP and NADH levels. It depleted NADPH reductive power and increased malondialdehyde content despite a marked increase in glucose-6P-dehydrogenase. This paradox was explained by the deceleration of ER-PPP favored by the decrease in hexose-6P-dehydrogenase expression coupled with the opposite response of its competitor enzyme glucose-6P-phosphatase. The decreased ER-PPP activity eventually hampered mitochondrial function and calcium exchanges. These data configure the ER-PPP as a powerful, unrecognized regulator of cancer cell metabolism and proliferation.

Recommendations for analgesia and sedation in critically ill children admitted to intensive care unit.

We aim to develop evidence-based recommendations for intensivists caring for children admitted to intensive care units and requiring analgesia and sedation. A panel of national paediatric intensivists expert in the field of analgesia and sedation and other specialists (a paediatrician, a neuropsychiatrist, a psychologist, a neurologist, a pharmacologist, an anaesthesiologist, two critical care nurses, a methodologist) started in 2018, a 2-year process. Three meetings and one electronic-based discussion were dedicated to the development of the recommendations (presentation of the project, selection of research questions, overview of text related to the research questions, discussion of recommendations). A telematic anonymous consultation was adopted to reach the final agreement on recommendations. A formal conflict-of-interest declaration was obtained from all the authors. Eight areas of direct interest and one additional topic were considered to identify the best available evidence and to develop the recommendations using the Evidence-to-Decision framework according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. For each recommendation, the level of evidence, the strength of the recommendation, the benefits, the harms and the risks, the benefit/harm balance, the intentional vagueness, the values judgement, the exclusions, the difference of the opinions, the knowledge gaps, and the research opportunities were reported. The panel produced 17 recommendations. Nine were evaluated as strong, 3 as moderate, and 5 as weak. Conclusion: a panel of national experts achieved consensus regarding recommendations for the best care in terms of analgesia and sedation in critically ill children.

Early Right Motor Cortex Response to Happy and Fearful Facial Expressions: A TMS Motor-Evoked Potential Study.

The ability to rapidly process others' emotional signals is crucial for adaptive social interactions. However, to date it is still unclear how observing emotional facial expressions affects the reactivity of the human motor cortex. To provide insights on this issue, we employed single-pulse transcranial magnetic stimulation (TMS) to investigate corticospinal motor excitability. Healthy participants observed happy, fearful and neutral pictures of facial expressions while receiving TMS over the left or right motor cortex at 150 and 300 ms after picture onset. In the early phase (150 ms), we observed an enhancement of corticospinal excitability for the observation of happy and fearful emotional faces compared to neutral expressions specifically in the right hemisphere. Interindividual differences in the disposition to experience aversive feelings (personal distress) in interpersonal emotional contexts predicted the early increase in corticospinal excitability for emotional faces. No differences in corticospinal excitability were observed at the later time (300 ms) or in the left M1. These findings support the notion that emotion perception primes the body for action and highlights the role of the right hemisphere in implementing a rapid and transient facilitatory response to emotional arousing stimuli, such as emotional facial expressions.

Early motor reactivity to observed human body postures is affected by body expression, not gender.

The early response to emotional stimuli involves a transient suppression of motor reactivity to favor monitoring of emotionally relevant information. Using transcranial magnetic stimulation (TMS), we have previously shown that viewing emotional body postures induces an early and transient reduction in motor excitability. Yet, it remains unclear whether early motor responses to emotional bodies are automatic or influenced by top-down factors such as task- or gender-related effects. To address these issue, we administered TMS over the right motor cortex (M1) during observation of still pictures of fearful expressions, happy expressions, neutral movements and neutral static body postures, and recorded motor-evoked potentials (MEPs) at an early phase of processing (i.e., at 100-125 ms from stimulus onset). To test gender-related effects, we presented male and female models to male and female participants. To test task-related effects, we asked participants to categorize the different body postures into either four (4AFC: fearful, happy, neutral movements, or static postures) or two distinct categories (2AFC: emotional or neutral postures). Results showed a reduction of MEPs for fearful and happy body postures relative to neutral movements and static postures. This motor suppression was not influenced by the gender of the actor, the gender of the observer, or the task performed. These findings indicate that early motor responses to observed human body postures are affected by the type of expression displayed by the observed model more than by task- or gender-related effects, suggesting these responses may be relatively automatic.

Intramuscular injection of vectorized-scFvMC1 reduces pathological tau in two different tau transgenic models.

With evidence supporting the prion-like spreading of extracellular tau as a mechanism for the initiation and progression of Alzheimer's disease (AD), immunotherapy has emerged as a potential disease-modifying strategy to target tau. Many studies have proven effective to clear pathological tau species in animal models of AD, and several clinical trials using conventional immunotherapy with anti-tau native antibodies are currently active. We have previously generated a vectorized scFv derived from the conformation-dependent anti-tau antibody MC1, scFvMC1, and demonstrated that its intracranial injection was able to prevent tau pathology in adult tau mice. Here, we show that, in a prevention paradigm and in two different tau transgenic models (JNPL3 and P301S), a one-time intramuscular injection of AAV1-scFvMC1 generated a long-lasting peripheral source of anti-tau scFvMC1 and significantly reduced insoluble and soluble tau species in the brain. Moreover, our data showed that scFvMC1 was internalized by the microglia, in the absence of overt inflammation. This study demonstrates the efficacy of intramuscular delivery of vectorized scFv to target tau, and suggests a new potential application to treat AD and the other tauopathies.

Electrifying discourse: Anodal tDCS of the primary motor cortex selectively reduces action appraisal in naturalistic narratives.

Non-invasive stimulation of the primary motor cortex (M1) modulates processing of decontextualized action words and sentences (i.e., verbal units denoting bodily motion). This suggests that language comprehension hinges on brain circuits mediating the bodily experiences evoked by verbal material. Yet, despite its relevance to constrain mechanistic language models, such a finding fails to reveal whether and how relevant circuits operate in the face of full-blown, everyday texts. Using a novel naturalistic discourse paradigm, we examined whether direct modulation of M1 excitability influences the grasping of narrated actions. Following random group assignment, participants received anodal transcranial direct current stimulation over the left M1, or sham stimulation of the same area, or anodal stimulation of the left ventrolateral prefrontal cortex. Immediately afterwards, they listened to action-laden and neutral stories and answered questions on information realized by verbs (denoting action and non-action processes) and circumstances (conveying locative or temporal details). Anodal stimulation of the left M1 selectively decreased outcomes on action-relative to non-action information -a pattern that discriminated between stimulated and sham participants with 74% accuracy. This result was particular to M1 and held irrespective of the subjects' working memory and vocabulary skills, further attesting to its specificity. Our findings suggest that offline modulation of motor-network excitability might lead to transient unavailability of putative resources needed to evoke actions in naturalistic texts, opening promising avenues for the language embodiment framework.