Reversible, Specific, Active Aggregates of Endogenous Proteins Assemble upon Heat Stress.

Heat causes protein misfolding and aggregation and, in eukaryotic cells, triggers aggregation of proteins and RNA into stress granules. We have carried out extensive proteomic studies to quantify heat-triggered aggregation and subsequent disaggregation in budding yeast, identifying >170 endogenous proteins aggregating within minutes of heat shock in multiple subcellular compartments. We demonstrate that these aggregated proteins are not misfolded and destined for degradation. Stable-isotope labeling reveals that even severely aggregated endogenous proteins are disaggregated without degradation during recovery from shock, contrasting with the rapid degradation observed for many exogenous thermolabile proteins. Although aggregation likely inactivates many cellular proteins, in the case of a heterotrimeric aminoacyl-tRNA synthetase complex, the aggregated proteins remain active with unaltered fidelity. We propose that most heat-induced aggregation of mature proteins reflects the operation of an adaptive, autoregulatory process of functionally significant aggregate assembly and disassembly that aids cellular adaptation to thermal stress.

Species-dependent posttranscriptional regulation of NOS1 by FMRP in the developing cerebral cortex.

Fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism, results from loss of function of the RNA-binding protein FMRP. Here, we show that FMRP regulates translation of neuronal nitric oxide synthase 1 (NOS1) in the developing human neocortex. Whereas NOS1 mRNA is widely expressed, NOS1 protein is transiently coexpressed with FMRP during early synaptogenesis in layer- and region-specific pyramidal neurons. These include midfetal layer 5 subcortically projecting neurons arranged into alternating columns in the prospective Broca's area and orofacial motor cortex. Human NOS1 translation is activated by FMRP via interactions with coding region binding motifs absent from mouse Nos1 mRNA, which is expressed in mouse pyramidal neurons, but not efficiently translated. Correspondingly, neocortical NOS1 protein levels are severely reduced in developing human FXS cases, but not FMRP-deficient mice. Thus, alterations in FMRP posttranscriptional regulation of NOS1 in developing neocortical circuits may contribute to cognitive dysfunction in FXS.

Central Nervous System Control of Glucose Homeostasis: A Therapeutic Target for Type 2 Diabetes?

Historically, pancreatic islet beta cells have been viewed as principal regulators of glycemia, with type 2 diabetes (T2D) resulting when insulin secretion fails to compensate for peripheral tissue insulin resistance. However, glycemia is also regulated by insulin-independent mechanisms that are dysregulated in T2D. Based on evidence supporting its role both in adaptive coupling of insulin secretion to changes in insulin sensitivity and in the regulation of insulin-independent glucose disposal, the central nervous system (CNS) has emerged as a fundamental player in glucose homeostasis. Here, we review and expand upon an integrative model wherein the CNS, together with the islet, establishes and maintains the defended level of glycemia. We discuss the implications of this model for understanding both normal glucose homeostasis and T2D pathogenesis and highlight centrally targeted therapeutic approaches with the potential to restore normoglycemia to patients with T2D.

Comparative neural correlates of DBS and MRgFUS lesioning for tremor control in essential tremor.

BACKGROUND: Given high rates of early complications and non-reversibility, refined targeting is necessitated for magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for essential tremor (ET). Selection of lesion location can be informed by considering optimal stimulation area from deep brain stimulation (DBS). METHODS: 118 patients with ET who received DBS (39) or MRgFUS (79) of the ventral intermediate nucleus (VIM) underwent stimulation/lesion mapping, probabilistic mapping of clinical efficacy and normative structural connectivity analysis. The efficacy maps were compared, which depict the relationship between stimulation/lesion location and clinical outcome. RESULTS: Efficacy maps overlap around the VIM ventral border and encompass the dentato-rubro-thalamic tract. While the MRgFUS map extends inferiorly into the posterior subthalamic area, the DBS map spreads inside the VIM antero-superiorly. CONCLUSION: Comparing the efficacy maps of DBS and MRgFUS suggests a potential alternative location for lesioning, more antero-superiorly. This may reduce complications, without sacrificing efficacy, and individualise targeting. TRIAL REGISTRATION NUMBER: NCT02252380.

Barriers Experienced by First Nations Deaf People in the Justice System.

Anecdotal evidence strongly suggests that members of the First Nations Deaf community experience more barriers when engaging with the criminal justice system than those who are not deaf. Therefore, our purpose for writing this article is to highlight legal and policy issues related to First Nations Deaf people, including perspectives of professionals working with these communities, living in Australia who have difficulty in accessing supports within the criminal justice system. In this article, we present data from semi-structured qualitative interviews focused on four key themes: (a) indefinite detention and unfit to plead, (b) a need for an intersectional approach to justice, (c) applying the maximum extent of the law while minimizing social services-related resources, and (d) the need for language access and qualified sign language interpreters. Through this article and the related larger sustaining project, we seek to center the experiences and needs of First Nations Deaf communities to render supports for fair, just, and equitable access in the Australian criminal justice system to this historically marginalized group.

Motor control complexity can be dynamically simplified during gait pattern exploration using motor control-based biofeedback.

Understanding how the central nervous system coordinates diverse motor outputs has been a topic of extensive investigation. Although it is generally accepted that a small set of synergies underlies many common activities, such as walking, whether synergies are equally robust across a broader array of gait patterns or can be flexibly modified remains unclear. Here, we evaluated the extent to which synergies changed as nondisabled adults (n = 14) explored gait patterns using custom biofeedback. Secondarily, we used Bayesian additive regression trees to identify factors that were associated with synergy modulation. Participants explored 41.1 ± 8.0 gait patterns using biofeedback, during which synergy recruitment changed depending on the type and magnitude of gait pattern modification. Specifically, a consistent set of synergies was recruited to accommodate small deviations from baseline, but additional synergies emerged for larger gait changes. Synergy complexity was similarly modulated; complexity decreased for 82.6% of the attempted gait patterns, but distal gait mechanics were strongly associated with these changes. In particular, greater ankle dorsiflexion moments and knee flexion through stance, as well as greater knee extension moments at initial contact, corresponded to a reduction in synergy complexity. Taken together, these results suggest that the central nervous system preferentially adopts a low-dimensional, largely invariant control strategy but can modify that strategy to produce diverse gait patterns. Beyond improving understanding of how synergies are recruited during gait, study outcomes may also help identify parameters that can be targeted with interventions to alter synergies and improve motor control after neurological injury.NEW & NOTEWORTHY We used a motor control-based biofeedback system and machine learning to characterize the extent to which nondisabled adults can modulate synergies during gait pattern exploration. Results revealed that a small library of synergies underlies an array of gait patterns but that recruitment from this library changes as a function of the imposed biomechanical constraints. Our findings enhance understanding of the neural control of gait and may inform biofeedback strategies to improve synergy recruitment after neurological injury.

A multidisciplinary approach to estimating wolf population size for long-term conservation.

The wolf (Canis lupus) is among the most controversial of wildlife species. Abundance estimates are required to inform public debate and policy decisions, but obtaining them at biologically relevant scales is challenging. We developed a system for comprehensive population estimation across the Italian alpine region (100,000 km2 ), involving 1513 trained operators representing 160 institutions. This extensive network allowed for coordinated genetic sample collection and landscape-level spatial capture-recapture analyses that transcended administrative boundaries to produce the first estimates of key parameters for wolf population status assessment. Wolf abundance was estimated at 952 individuals (95% credible interval 816-1120) and 135 reproductive units (i.e., packs) (95% credible interval 112-165). We also estimated that mature individuals accounted for 33-45% of the entire population. The monitoring effort was spatially estimated thereby overcoming an important limitation of citizen science data. This is an important approach for promoting wolf-human coexistence based on wolf abundance monitoring and an endorsement of large-scale harmonized conservation practices.

Una estrategia multidisciplinaria para la estimación del tamaño poblacional de los lobos para la conservación a largo plazo Resumen El lobo (Canis lupus) está entre las especies de fauna más controversiales. Se requieren estimaciones de abundancia para informar al debate público y las decisiones políticas, pero es un reto obtenerlos en escalas con relevancia biológica. Desarrollamos un sistema para la estimación completa de la población en la región alpina de Italia (100,000 km2 ), con la participación de 1,513 operadores entrenados que representan a 160 instituciones. Esta red extensa permitió una colecta coordinada de muestras genéticas y análisis de captura-recaptura espacial que trascendieron las fronteras administrativas para así producir las primeras estimaciones de los parámetros clave para la evaluación del estado de la población de los lobos. Se estimó la abundancia en 952 individuos (95% intervalo de confianza 816-1120) y 135 unidades reproductivas (es decir, manadas) (95% intervalo de confianza 112-165). También estimamos que los individuos maduros representaban el 33-45% de toda la población. El esfuerzo de monitoreo se estimó espacialmente, por lo que sobrepasó una limitación importante de la ciencia ciudadana. Esta estrategia es importante para promover la coexistencia entre lobos y humanos con base en el monitoreo de la abundancia y el apoyo a las prácticas armonizadas de conservación a gran escala.

An inside "beak": Molecular analysis of swab samples reveals the seabird diet of invasive Barn Owls in Hawai'i.

Predation is an important species interaction to monitor when assessing an invasive species' impact on a particular ecosystem, but it can be difficult to observe and thus, fully understand. On Kaua'i island, invasive Barn Owls (Tyto alba) predate native seabirds, but difficult terrain in this region and the cryptic nature of owl predation make traditional monitoring of predation quite challenging. Using Barn Owls collected as part of removal efforts on Kaua'i and Lehua islands, we conducted DNA metabarcoding of owl digestive tracts to detect and determine seabird species they predate. We used a seabird-targeted 12s marker to sequence 112 swabs from 55 owls and detected six seabird species, including two ESA-listed seabirds - Hawaiian Petrel (Pterodroma sandwichensis) and Newell's Shearwater (Puffinus newelli), in 12 swabs from 11 owls (20% of sampled owls). Corresponding morphological assessment of owl stomach contents detected seabird species as prey items in only 2% (1/55) of sampled owls, highlighting the utility of molecular approaches for detecting diet items, especially degraded or visually absent items. Additionally, this approach has proven very useful in revealing cryptic trophic interactions in inaccessible seabird populations. For the most comprehensive analysis of diet, the use of both esophageal and cloacal swabs for metabarcoding is recommended. Supplementing metabarcoding with other methods that can provide complementary prey information, such as stable isotope analysis, would help to characterize trophic interactions more fully. The method described here has proven to be a reliable tool for investigating diet in invasive owls and may be used to investigate cryptic predation in living birds as a minimally invasive technique, as well.

Anionic nanoparticle-induced perturbation to phospholipid membranes affects ion channel function.

Understanding the mechanisms of nanoparticle interaction with cell membranes is essential for designing materials for applications such as bioimaging and drug delivery, as well as for assessing engineered nanomaterial safety. Much attention has focused on nanoparticles that bind strongly to biological membranes or induce membrane damage, leading to adverse impacts on cells. More subtle effects on membrane function mediated via changes in biophysical properties of the phospholipid bilayer have received little study. Here, we combine electrophysiology measurements, infrared spectroscopy, and molecular dynamics simulations to obtain insight into a mode of nanoparticle-mediated modulation of membrane protein function that was previously only hinted at in prior work. Electrophysiology measurements on gramicidin A (gA) ion channels embedded in planar suspended lipid bilayers demonstrate that anionic gold nanoparticles (AuNPs) reduce channel activity and extend channel lifetimes without disrupting membrane integrity, in a manner consistent with changes in membrane mechanical properties. Vibrational spectroscopy indicates that AuNP interaction with the bilayer does not perturb the conformation of membrane-embedded gA. Molecular dynamics simulations reinforce the experimental findings, showing that anionic AuNPs do not directly interact with embedded gA channels but perturb the local properties of lipid bilayers. Our results are most consistent with a mechanism in which anionic AuNPs disrupt ion channel function in an indirect manner by altering the mechanical properties of the surrounding bilayer. Alteration of membrane mechanical properties represents a potentially important mechanism by which nanoparticles induce biological effects, as the function of many embedded membrane proteins depends on phospholipid bilayer biophysical properties.

Audiovisual biofeedback amplifies plantarflexor adaptation during walking among children with cerebral palsy.

BACKGROUND: Biofeedback is a promising noninvasive strategy to enhance gait training among individuals with cerebral palsy (CP). Commonly, biofeedback systems are designed to guide movement correction using audio, visual, or sensorimotor (i.e., tactile or proprioceptive) cues, each of which has demonstrated measurable success in CP. However, it is currently unclear how the modality of biofeedback may influence user response which has significant implications if systems are to be consistently adopted into clinical care. METHODS: In this study, we evaluated the extent to which adolescents with CP (7M/1F; 14 [12.5,15.5] years) adapted their gait patterns during treadmill walking (6 min/modality) with audiovisual (AV), sensorimotor (SM), and combined AV + SM biofeedback before and after four acclimation sessions (20 min/session) and at a two-week follow-up. Both biofeedback systems were designed to target plantarflexor activity on the more-affected limb, as these muscles are commonly impaired in CP and impact walking function. SM biofeedback was administered using a resistive ankle exoskeleton and AV biofeedback displayed soleus activity from electromyography recordings during gait. At every visit, we measured the time-course response to each biofeedback modality to understand how the rate and magnitude of gait adaptation differed between modalities and following acclimation. RESULTS: Participants significantly increased soleus activity from baseline using AV + SM (42.8% [15.1, 59.6]), AV (28.5% [19.2, 58.5]), and SM (10.3% [3.2, 15.2]) biofeedback, but the rate of soleus adaptation was faster using AV + SM biofeedback than either modality alone. Further, SM-only biofeedback produced small initial increases in plantarflexor activity, but these responses were transient within and across sessions (p > 0.11). Following multi-session acclimation and at the two-week follow-up, responses to AV and AV + SM biofeedback were maintained. CONCLUSIONS: This study demonstrated that AV biofeedback was critical to increase plantarflexor engagement during walking, but that combining AV and SM modalities further amplified the rate of gait adaptation. Beyond improving our understanding of how individuals may differentially prioritize distinct forms of afferent information, outcomes from this study may inform the design and selection of biofeedback systems for use in clinical care.

Ipsilateral and axial tremor response to focused ultrasound thalamotomy for essential tremor: clinical outcomes and probabilistic mapping.

BACKGROUND: MR-guided focused ultrasound (MRgFUS) thalamotomy has been shown to be a safe and effective treatment for essential tremor (ET). OBJECTIVE: To investigate the effects of MRgFUS in patients with ET with an emphasis on ipsilateral-hand and axial tremor subscores. METHODS: Tremor scores and adverse effects of 100 patients treated between 2012 and 2018 were assessed at 1 week, 3, 12, and 24 months. A subgroup analysis of ipsilateral-hand tremor responders (defined as patients with ≥30% improvement at any time point) and non-responders was performed. Correlations and predictive factors for improvement were analysed. Weighted probabilistic maps of improvement were generated. RESULTS: Significant improvement in axial, contralateral-hand and total tremor scores was observed at all study visits from baseline (p<0.0001). There was no significant improvement in ipsilateral subscores. A subset of patients (n=20) exhibited group-level ipsilateral-hand improvement that remained significant through all follow-ups (p<0.001). Multivariate regression analysis revealed that higher baseline scores predict better improvement in ipsilateral-hand and axial tremor. Probabilistic maps demonstrated that the lesion hotspot for axial improvement was situated more medially than that for contralateral improvement. CONCLUSION: MRgFUS significantly improved axial, contralateral-hand and total tremor scores. In a subset of patients, a consistent group-level treatment effect was observed for ipsilateral-hand tremor. While ipsilateral improvement seemed to be less directly related to lesion location, a spatial relationship between lesion location and axial and contralateral improvement was observed that proved consistent with the somatotopic organisation of the ventral intermediate nucleus. TRIAL REGISTRATION NUMBERS: NCT01932463, NCT01827904, and NCT02252380.

Interspecies chimeric conditions affect the developmental rate of human pluripotent stem cells.

Human pluripotent stem cells hold significant promise for regenerative medicine. However, long differentiation protocols and immature characteristics of stem cell-derived cell types remain challenges to the development of many therapeutic applications. In contrast to the slow differentiation of human stem cells in vitro that mirrors a nine-month gestation period, mouse stem cells develop according to a much faster three-week gestation timeline. Here, we tested if co-differentiation with mouse pluripotent stem cells could accelerate the differentiation speed of human embryonic stem cells. Following a six-week RNA-sequencing time course of neural differentiation, we identified 929 human genes that were upregulated earlier and 535 genes that exhibited earlier peaked expression profiles in chimeric cell cultures than in human cell cultures alone. Genes with accelerated upregulation were significantly enriched in Gene Ontology terms associated with neurogenesis, neuron differentiation and maturation, and synapse signaling. Moreover, chimeric mixed samples correlated with in utero human embryonic samples earlier than human cells alone, and acceleration was dose-dependent on human-mouse co-culture ratios. The altered gene expression patterns and developmental rates described in this report have implications for accelerating human stem cell differentiation and the use of interspecies chimeric embryos in developing human organs for transplantation.

Alternatives to whole gland treatment for localized prostate cancer: a review of novel focal therapies.

PURPOSE OF REVIEW: The mainstays of the management of clinically localized prostate cancer have historically rested upon active surveillance, radiation therapy, or radical prostatectomy. Although both radiation and surgical treatment of localized prostate cancer can achieve excellent oncologic outcomes, the subsequent potential adverse effects of urinary stress incontinence and erectile dysfunction are unappealing to patients. This has led to investigational studies centered upon focal treatment of the cancerous lesion, with the aim to improve quality-of-life outcomes. In this review, we describe numerous novel modalities, including nanoparticle ablation and irreversible electroporation, which are being utilized for the focal treatment of clinically localized prostate cancer. RECENT FINDINGS: Although many of these novel therapies are in their investigational infancy, several have revealed very promising results both in their post-treatment pathologic outcomes as well as objective quality-of-life measures. SUMMARY: Initial data regarding novel focal therapy for prostate cancer treatment show promising short-term outcomes in regards to oncologic and quality-of-life assessments. Further investigational studies are needed to determine inclusion criteria for the selection of optimal candidates.

Do metapopulations and management matter for relict headwater bull trout populations in a warming climate?

Mountain headwater streams have emerged as important climate refuges for native cold-water species due to their slow climate velocities and extreme physical conditions that inhibit non-native invasions. Species persisting in refuges often do so as fragmented, relict populations from broader historical distributions that are subject to ongoing habitat reductions and increasing isolation as climate change progresses. Key for conservation planning is determining where remaining populations will persist and how habitat restoration strategies can improve biological resilience to enhance the long-term prospects for species of concern. Studying bull trout, a headwater species in the northwestern USA, we developed habitat occupancy models using a data set of population occurrence in 991 natal habitat patches with a suite of novel geospatial covariates derived from high-resolution hydroclimatic scenarios and other sources representing watershed and instream habitat conditions, patch geometry, disturbance, and biological interactions. The best model correctly predicted bull trout occupancy status in 82.6% of the patches and included effects for: patch size estimated as habitat volume, extent of within-patch reaches <9°C mean August temperature, distance to nearest occupied patch, road density, invasive brook trout prevalence, patch slope, and frequency of high winter flows. The model was used to assess 16 scenarios of bull trout occurrence within the study streams that represented a range of restoration strategies under three climatic conditions (baseline, moderate change, and extreme change). Results suggested that regional improvements in bull trout status were difficult to achieve in realistic restoration strategies due to the pervasive nature of climate change and the limited extent of restoration actions given their high costs. However, occurrence probabilities in a subset of patches were highly responsive to restoration actions, suggesting that targeted investments to improve the resilience of some populations may be contextually beneficial. A possible strategy, therefore, is focusing effort on responsive populations near more robust population strongholds, thereby contributing to local enclaves where dispersal among populations further enhances resilience. Equally important, strongholds constituted a small numerical percentage of patches (5%-21%), yet encompassed the large majority of occupied habitat by volume (72%-89%) and their protection could have significant conservation benefits for bull trout.

Long-term effects of spasticity treatment, including selective dorsal rhizotomy, for individuals with cerebral palsy.

AIM: To understand the long-term effects of comprehensive spasticity treatment, including selective dorsal rhizotomy (SDR), on individuals with spastic cerebral palsy. METHOD: This was a pre-registered, multicenter, retrospectively matched cohort study. Children were matched on age range and spasticity at baseline. Children at one center underwent spasticity treatment including SDR (Yes-SDR, n=35) and antispastic injections. Children at two other centers had no SDR (No-SDR, n=40 total) and limited antispastic injections. All underwent subsequent orthopedic treatment. Participants returned for comprehensive long-term assessment (age ≥21y, follow-up ≥10y). Assessment included spasticity, contracture, bony alignment, strength, gait, walking energy, function, pain, stiffness, participation, and quality of life. RESULTS: Spasticity was effectively reduced at long-term assessment in the Yes-SDR group and was unchanged in the No-SDR group. There were no meaningful differences between the groups in any measure except the Gait Deviation Index (Yes-SDR + 11 vs No-SDR + 5) and walking speed (Yes-SDR unchanged, No-SDR declined 25%). The Yes-SDR group underwent more subsequent orthopedic surgery (11.9 vs 9.7 per individual) and antispastic injections to the lower limbs (14.4 vs <3, by design). INTERPRETATION: Untreated spasticity does not cause meaningful impairments in young adulthood at the level of pathophysiology, function, or quality of life.

Decoding perineuronal net glycan sulfation patterns in the Alzheimer's disease brain.

The extracellular matrix (ECM) of the brain comprises unique glycan "sulfation codes" that influence neurological function. Perineuronal nets (PNNs) are chondroitin sulfate-glycosaminoglycan (CS-GAG) containing matrices that enmesh neural networks involved in memory and cognition, and loss of PNN matrices is reported in patients with neurocognitive and neuropsychiatric disorders including Alzheimer's disease (AD). Using liquid chromatography tandem mass spectrometry (LC-MS/MS), we show that patients with a clinical diagnosis of AD-related dementia undergo a re-coding of their PNN-associated CS-GAGs that correlates to Braak stage progression, hyperphosphorylated tau (p-tau) accumulation, and cognitive impairment. As these CS-GAG sulfation changes are detectable prior to the regional onset of classical AD pathology, they may contribute to the initiation and/or progression of the underlying degenerative processes and implicate the brain matrix sulfation code as a key player in the development of AD clinicopathology.

Broad-scale eDNA sampling for describing aquatic species distributions in running waters: Pacific lamprey Entosphenus tridentatus in the upper Snake River, USA.

One of the most fundamental yet challenging tasks for aquatic ecologists is to precisely delineate the range of species, particularly those that are broadly distributed, require specialized sampling methods, and may be simultaneously declining and increasing in different portions of their range. An exemplar is the Pacific lamprey Entosphenus tridentatus, a jawless anadromous fish of conservation concern that is actively managed in many coastal basins in western North America. To efficiently determine its distribution across the accessible 56,168 km of the upper Snake River basin in the north-western United States, we first delimited potential habitat by using predictions from a species distribution model based on conventionally collected historical data and from the distribution of a potential surrogate, Chinook salmon Oncorhynchus tshawytscha, which yielded a potential habitat network of 10,615 km. Within this area, we conducted a two-stage environmental DNA survey involving 394 new samples and 187 archived samples collected by professional biologists and citizen scientists using a single, standardized method from 2015 to 2021. We estimated that Pacific lamprey occupied 1875 km of lotic habitat in this basin, of which 1444 km may have been influenced by recent translocation efforts. Pacific lamprey DNA was consistently present throughout most river main stems, although detections became weaker or less frequent in the largest and warmest downstream channels and near their headwater extent. Pacific lamprey were detected in nearly all stocked tributaries, but there was no evidence of indigenous populations in such habitats. There was evidence of post-stocking movement because detections were 1.8-36.0 km upstream from release sites. By crafting a model-driven spatial sampling template and executing an eDNA-based sampling campaign led by professionals and volunteers, supplemented by previously collected samples, we established a benchmark for understanding the current range of Pacific lamprey across a large portion of its range in the interior Columbia River basin. This approach could be tailored to refine range estimates for other wide-ranging aquatic species of conservation concern.

Two Cases of Severe Amanita Muscaria Poisoning Including a Fatality.

Ingestion of Amanita muscaria mushrooms results in transient central nervous system excitation and depression mediated by its components, ibotenic acid and muscimol. The mushroom is distributed worldwide and ingestions occur with some frequency. Although these ingestions have traditionally been considered benign, serious complications can occur. We present 2 cases of serious toxicity, including a fatality. The first case was a 44-y-old man who presented to the emergency department (ED) after cardiopulmonary arrest approximately 10 h after ingesting 4 to 5 dried A muscaria mushroom caps, which he used for their mind-altering effects. Despite successful resuscitation, he remained unresponsive and hypotensive and died 9 days later. The second case was a 75-y-old man who presented to the ED after accidentally consuming one large A muscaria mushroom cap he foraged in Eastern Turkey. The patient initially presented to the ED with hallucinations followed by lethargy, and he was intubated for airway protection. The patient's condition gradually improved, and he made a full recovery. A muscaria ingestion should not be considered benign as serious outcomes do occur. An understanding of how the main neuroactive chemicals, ibotenic acid and muscimol, affect the brain can help anticipate outcomes. Several high-risk features that portend a more serious course are identified.

Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes.

Despite a rapidly growing literature, the role played by the brain in both normal glucose homeostasis and in type 2 diabetes pathogenesis remains poorly understood. In this review, we introduce a framework for understanding the brain's essential role in these processes based on evidence that the brain, like the pancreas, is equipped to sense and respond to changes in the circulating glucose level. Further, we review evidence that glucose sensing by the brain plays a fundamental role in establishing the defended level of blood glucose, and that defects in this control system contribute to type 2 diabetes pathogenesis. We also consider the possibility that the close association between obesity and type 2 diabetes arises from a shared defect in the highly integrated neurocircuitry governing energy homeostasis and glucose homeostasis. Thus, whereas obesity is characterised by an increase in the defended level of the body's fuel stores (e.g. adipose mass), type 2 diabetes is characterised by an increase in the defended level of the body's available fuel (e.g. circulating glucose), with the underlying pathogenesis in each case involving impaired sensing of (or responsiveness to) relevant humoral negative feedback signals. This perspective is strengthened by growing preclinical evidence that in type 2 diabetes the defended level of blood glucose can be restored to normal by therapies that restore the brain's ability to properly sense the circulating glucose level. Graphical abstract.

Correction to: Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes.

The authors wish to point out a typographical error.