Search

The hyper-targeted advertising that emerged on digital platforms over the past two decades is now more productively understood as tuned advertising, a dynamic and unfolding process where ads are continuously algorithmically “optimised” to users in real time. Following Rieder and Hofmann (2020), we aim to develop a framework for the “conditions for the practice of observing” algorithmically-tuned digital advertising. We draw on our research across the Australian Ad Observatory and a multi-year research project on digital alcohol advertising. Across these projects we build customised tools to collect ads from platform ad libraries and through data donation from citizen scientists. We argue that the power of digital advertising is increasingly located in its capacity to tune. Platforms’ ad transparency tools draw our attention to ads, but we need to develop the capacity to observe the dynamic socio-technical process of tuning. We conceptualise and present visualisations of “tuned sequences” of ads, as an alternative to “libraries” of ads. We argue that developing the capacity to observe these tuned sequences better articulates the mode of observation required to develop the forms of public understanding and accountability both civil society organisations and researchers are looking for.

Digital advertising’s cultural surround is algorithmically tuned. The popular narrative about digital advertising is that it is hyper-targeted and customized. In this article, we argue that digital platforms’ targeted advertising is more productively understood as tuned advertising, where algorithmic models optimize the resonance between ads and consumers in a continuous rhythmic flow of images, videos, and text. We develop the concept of tuned advertising by drawing on a study conducted with 204 young people from the Australian state of Victoria, where they sent us over 5,169 screenshots of alcohol, gambling, and unhealthy food ads they saw in their digital feeds. We identify five different “vibes” in the collections of ads they sent us that reflect different subjectivities and practices of consumption. We argue that digital platforms create a mode of advertising organized around tuning the vibe between ads, content, and users.

The policy orientations of advanced neoliberal democracies situate young people as rational actors who are responsible for their own career outcomes. While career scholars have been critical of how this routinely ignores the unequal effects of structural constraints on personal agency, they have long suggested that young people should have access to the best available ‘roadmaps’ and advice to navigate the uncertainties baked into the contemporary economic landscape. Complementing the significant attention that is given to the (potentially emancipatory) experience of formal careers guidance, we present findings from a multi-method study. We explore young Australians’ (aged 15–24) navigation of careers information through a nationally representative survey (n = 1103), focus groups with 90 participants and an analysis of 15,227 social media comments. We suggest that the variety of formal and informal sources pursued and accessed by young people forms a relational ‘ecology’. This relationality is twofold. First, information is often sequential, and engagements with one source can inform the experience or pursuit of another. Second, navigation of the ecology is marked by a high level of intersubjectivity through interpersonal support networks including peers, family and formal service provision. These insights trouble a widespread, but perhaps simplistic, reading of young people having largely internalised a neoliberal sensibility of ‘entrepreneurial selfhood’ in their active pursuit of a range of career advice. Throughout our analysis, we attend to the ways that engagement in the career information ecology is shaped by social inequalities, further underscoring challenges facing careers guidance and social justice goals.

Social media posts and profiles have become a key part of hiring and firing processes, producing a “hidden curriculum of surveillance.” When hiring, employers routinely engage in “cybervetting” job candidates, making judgments based on their social media presence (or absence), and so too can social media disclosures impact (positively and negatively) employment progression and even result in termination. Where is the line between personal social media use and professional identities? What is the difference between holding people in positions of power to account and invading the privacy of everyday people? What kinds of social media posts get people fired? In this article, we report on a study of 312 news media articles that document stories of people being fired because of a social media post. We divide the corpus into posts made by the individuals who are fired (“self-posts,” n = 264) and posts made by others that resulted in the subject of those posts losing their job (“third party,” n = 48). Racism was the most common reason people were fired in these news stories, followed by other forms of discriminatory behavior (such as queerphobia), offensive content, workplace conflict, political content, acts of violence, and abuse. We examine these narratives through the lens of what van Dijck describes as “professional value,” and ultimately seek to question how these stories normalize the “hidden curriculum of surveillance,” putting additional pressure on employees and young people who are called to act on social media through the prism of future employment.

Fabry disease, OMIM 301500, is a progressive multisystem storage disorder due to the deficiency of alpha-galactosidase A (GALA). Neurological and vascular manifestations of this disorder with regard to hearing loss have not been analysed quantitatively in large cohorts. We conducted a retrospective cross sectional analysis of hearing loss in 109 male and female patients with Fabry disease who were referred to and seen at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA on natural history and enzyme replacement study protocols. There were 85 males aged 6-58 years (mean 31 years, SD 13) and 24 females aged 22-72 years (mean 42 years, SD 12). All patients underwent a comprehensive audiological evaluation. In addition, cerebral white matter lesions, peripheral neuropathy, and kidney function were quantitatively assessed. HL(95), defined as a hearing threshold above the 95th percentile for age and gender matched normal controls, was present in 56% [95% CI (42.2-67.2)] of the males. Prevalence of HL(95) was lower in the group of patients with residual GALA enzyme activity compared with those without detectable activity (33% versus 63%) HL(95) was present in the low-, mid- and high-frequency ranges for all ages. Male patients with HL(95) had a higher microvascular cerebral white matter lesion load [1.4, interquartile range (IQR) 0-30.1 +/- versus 0, IQR 0-0], more pronounced cold perception deficit [19.4 +/- 5.5 versus 13.5 +/- 5.5 of just noticeable difference (JND) units] and lower kidney function [creatinine: 1.6 +/- 1.2 versus 0.77 +/- 0.2 mg/dl; blood urea nitrogen (BUN): 20.1 +/- 14.1 versus 10.3 +/- 3.28 mg/dl] than those without HL(95) (P < 0.001). Of the females, 38% had HL(95). There was no significant association with cold perception deficit, creatinine or BUN in the females. Word recognition and acoustic reflexes analyses suggested a predominant cochlear involvement. We conclude that hearing loss involving all frequency regions significantly contributes to morbidity in patients with Fabry disease. Our quantitative analysis suggests a correlation of neuropathic and vascular damage with hearing loss in the males. Residual GALA activity appears to have a protective effect against hearing loss. [ABSTRACT FROM AUTHOR]

For the past 12 years, Facebook has played a significant role in mediating the lives of its users. Disclosures on the site go on to serve as intimate, co-constructed life records, albeit with unique and always-evolving affordances. The ways in which romantic relationships are mediated on the site are complex and contested: “What is the significance of articulating a romantic relationship on Facebook?” “Why do some choose to make socially and culturally critical moments like the beginning and ends of relationships visible on Facebook, whereas others (perhaps within the same relationship) do not?” “How do these practices change over time?” and “When is it time to go “Facebook official”?” In this article, we draw on qualitative research with Facebook users in their 20s in Australia and the United Kingdom who have been using the site for 5 years or more. Interviews with participants revealed that romantic relationships were central to many of their growing up narratives, and in this article, we draw out examples to discuss four kinds of (non-exclusive) practices: (1) overt relationship status disclosures, mediated through the “relationship status” affordance of the site, (2) implied relationship disclosures, mediated through an increase in images and tags featuring romantic partners, (3) the intended absence of relationship visibility, and (4) later-erased or revised relationship disclosures. We also critique the ways in which Facebook might work to produce normative “relationship traces,” privileging neat linearity, monogamy, and obfuscating (perhaps usefully, perhaps not) the messy complexity of romantic relationships.

Se utilizó la técnica de ADN Polimórfico Amplificado al Azar (RAPD) para analizar muestras de ADN de 70 individuos de C. acutus provenientes de los ríos Jesús María, Tárcoles y Tusubres en el Pacífico Central de Costa Rica para estimar la diversidad genética, la diferenciación entre poblaciones, el flujo genético y la distancia genética. La diversidad genética fue baja en los tres ríos H = 0.2201 en el río Jesús María, 0.2358 en el río Tárcoles y 0.2589 en el río Tusubres. La diversidad genética para el total de los individuos también fue baja, H = 0.2452. Entre las tres poblaciones hay una dinámica metapoblacional (G ST = 0.0367) principalmente en las poblaciones de los ríos Jesús María y Tárcoles. El valor de flujo genético (Nm = 13.1361) y el número de individuos registrado para cada río por Porras (2004) sugieren que la población del río Tárcoles está cumpliendo el papel de fuente y las de Jesús María y Tusubres constituyen los sumideros. Hubo relación directa entre la distancia genética y la distancia geográfica (z = 1.1449, r = 0.9731, p< 0.0010). Estos resultados indican la necesidad de diseñar una estrategia para la conservación de estos cocodrilos que considere la existencia de la metapoblación entre los tres ríos y también es importante realizar un estudio genético en el resto de la costa Pacífica del Costa Rica y en todo el ámbito de distribución de esta especie.The crocodylid Crocodylus acutus is found in the Central Pacific of Costa Rica only in small populations, and the species is protected by law. RAPD was used to analyze 70 DNA samples of Crocodylus acutus from the rivers Jesus Maria, Tarcoles and Tusubres in the Central Pacific of Costa Rica in order to estimate genetic diversity, differentiation among populations, gene flow and genetic distance between them. Genetic diversity was low in the three rivers, H = 0.2201 in the Jesus Maria river, 0.2358 in the Tarcoles river and 0.2589 in the Tusubres river. Among the three populations there is a metapopulational dynamic (GST = 0.0367), mainly between the populations of the Jesus Maria and Tarcoles rivers. The value of gene flow (Nm = 13.1361) and the number of individuals reported for each river in 2004 suggests that the population of the Tarcoles river is the source and those from Jesus Maria and Tusubres are the drains. There was a direct relationship between the genetic distance and the geographical distance (z =1.1449, r =0.9731, p< 0.0010). A conservation strategy for these crocodiles must consider the existence of the metapopulation between the three rivers and the importance of studying the genetics of the American Crocodile in the rest of the Pacific coast of Costa Rica, as well as over the entire distribution range of this species. Rev. Biol. Trop. 56 (3): 1471-1480. Epub 2008 September 30.

Abstract Background We previously demonstrated improved sweating after enzyme replacement therapy (ERT) in Fabry disease using the thermo-regularity sweat and quantitative sudomotor axon reflex tests. Skin-impedance, a measure skin-moisture (sweating), has been used in the clinical evaluation of burns and pressure ulcers using the portable dynamic dermal impedance monitor (DDIM) system. Methods We compared skin impedance measurements in hemizygous patients with Fabry disease (22 post 3-years of bi-weekly ERT and 5 ERT naive) and 22 healthy controls. Force compensated skin-moisture values were used for statistical analysis. Outcome measures included 1) moisture reading of the 100th repetitive reading, 2) rate of change, 3) average of 60–110th reading and 4) overall average of all readings. Results All outcome measures showed a significant difference in skin-moisture between Fabry patients and control subjects (p < 0.0001). There was no difference between Fabry patients on ERT and patients naïve to ERT. Increased skin-impedance values for the four skin-impedance outcome measures were found in a small number of dermatome test-sites two days post-enzyme infusions. Conclusion The instrument portability, ease of its use, a relatively short time required for the assessment, and the fact that DDIM system was able to detect the difference in skin-moisture renders the instrument a useful clinical tool.

Background: Negative symptom severity predicts functional outcome and quality life in people with psychosis. However, negative symptoms are poorly responsive to antipsychotic medication and existing literature has not converged on their neurobiological basis. Previous work in small schizophrenia samples has observed that lower cerebellar-prefrontal connectivity is associated with higher negative symptom severity and demonstrated in a separate neuromodulation experiment that increasing cerebellar-prefrontal connectivity reduced negative symptom severity. We sought to expand this finding to test associations between cerebellar-prefrontal connectivity with negative symptom severity and cognitive performance in a large, transdiagnostic sample of individuals with psychotic disorders., Methods: In this study, 260 individuals with psychotic disorders underwent resting-state MRI and clinical characterization. Negative symptom severity was measured using the Positive and Negative Symptoms Scale, and cognitive performance was assessed with the Screen for Cognitive Impairment in Psychiatry. Using a previously identified cerebellar region as a seed, we performed seed to whole brain analyses and regressed connectivity against negative symptom severity, using age and sex as covariates., Results: Consistent with prior work, we identified relationships between higher cerebellar-prefrontal connectivity and lower negative symptom severity (r=-0.17, p=.007). Higher cerebellar-prefrontal connectivity was also associated with better delayed verbal learning (r=.13, p=.034)., Conclusions: Our results provide further evidence supporting the relationship between cerebellar-prefrontal connectivity and negative symptom severity and cognitive performance. Larger, randomized, sham-controlled neuromodulation studies should test if increasing cerebellar-prefrontal connectivity leads to reductions in negative symptoms in psychosis.

Background and Hypothesis: Current treatments for schizophrenia are only partially effective, and there are no medications for negative symptoms or cognitive impairment. Neuromodulation, such as repetitive transcranial magnetic stimulation (rTMS), has potential as a novel intervention for schizophrenia. Prior to clinical use, rTMS should have demonstrated safety in a large schizophrenia population. However, the safety profile of rTMS in schizophrenia is not well characterized, and regulatory agencies have expressed concern about safety in this population., Study Design: We conducted a systematic review with meta-analysis of rTMS studies in schizophrenia. We searched PubMed, the Cochrane Library, PsycINFO, and Science Citation Index Expanded for rTMS studies in schizophrenia that reported adverse effects. We extracted the number of participants who experienced an adverse effect and calculated the prevalence of each adverse effect for active or sham rTMS. We tested the difference between the prevalence of events in the active and sham conditions. We assessed risk of bias using the Cochrane Handbook., Study Results: The initial search identified 1472 studies. After screening, 261 full-text studies were assessed, and 126 met inclusion criteria (N = 4122 total subjects). The prevalence of headache or scalp pain, dizziness or syncope, facial twitching, and nausea was higher for active rTMS compared to sham (P < .05). The prevalence of all other adverse effects, including seizure, was not different between active and sham rTMS., Conclusions: rTMS is safe and well tolerated for people with schizophrenia. Individuals with schizophrenia are not at increased risk for adverse effects, including seizure, compared to the general population., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Decades of psychosis research highlight the prevalence and the clinical significance of negative emotions, such as fear and anxiety. Translational evidence demonstrates the pivotal role of the amygdala in fear and anxiety. However, most of these approaches have used hypothesis-driven analyses with predefined regions of interest. A data-driven analysis may provide a complimentary, unbiased approach to identifying brain correlates of fear and anxiety. The aim of the current study was to identify the brain basis of fear and anxiety in early psychosis and controls using a data-driven approach. We analyzed data from the Human Connectome Project for Early Psychosis, a multi-site study of 125 people with psychosis and 58 controls with resting-state fMRI and clinical characterization. Multivariate pattern analysis of whole-connectome data was used to identify shared and psychosis-specific brain correlates of fear and anxiety using the NIH Toolbox Fear-Affect and Fear-Somatic Arousal scales. We then examined clinical correlations of Fear-Affect scores and connectivity patterns. Individuals with psychosis had higher levels of Fear-Affect scores than controls (p < 0.05). The data-driven analysis identified a cluster encompassing the amygdala and hippocampus where connectivity was correlated with Fear-Affect score (p < 0.005) in the entire sample. The strongest correlate of Fear-Affect was between this cluster and the anterior insula and stronger connectivity was associated with higher Fear-Affect scores (r = 0.31, p = 0.0003). The multivariate pattern analysis also identified a psychosis-specific correlate of Fear-Affect score between the amygdala/hippocampus cluster and a cluster in the ventromedial prefrontal cortex (VMPFC). Higher Fear-Affect scores were correlated with stronger amygdala/hippocampal-VMPFC connectivity in the early psychosis group (r = 0.33, p = 0.002), but not in controls (r = -0.15, p = 0.28). The current study provides evidence for the transdiagnostic role of the amygdala, hippocampus, and anterior insula in the neural basis of fear and anxiety and suggests a psychosis-specific relationship between fear and anxiety symptoms and amygdala/hippocampal-VMPFC connectivity. Our novel data-driven approach identifies novel, psychosis-specific treatment targets for fear and anxiety symptoms and provides complimentary evidence to decades of hypothesis-driven approaches examining the brain basis of threat processing., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Psychomotor disturbances are observed across psychiatric disorders and often manifest as psychomotor slowing, agitation, disorganized behavior, or catatonia. Psychomotor function includes both cognitive and motor components, but the neural circuits driving these subprocesses and how they relate to symptoms have remained elusive for centuries., Methods: We analyzed data from the HCP-EP (Human Connectome Project for Early Psychosis), a multisite study of 125 participants with early psychosis and 58 healthy participants with resting-state functional magnetic resonance imaging and clinical characterization. Psychomotor function was assessed using the 9-hole pegboard task, a timed motor task that engages mechanical and psychomotor components of action, and tasks assessing processing speed and task switching. We used multivariate pattern analysis of whole-connectome data to identify brain correlates of psychomotor function., Results: We identified discrete brain circuits driving the cognitive and motor components of psychomotor function. In our combined sample of participants with psychosis (n = 89) and healthy control participants (n = 52), the strongest correlates of psychomotor function (pegboard performance) (p < .005) were between a midline cerebellar region and left frontal region and presupplementary motor area. Psychomotor function was correlated with both cerebellar-frontal connectivity (r = 0.33) and cerebellar-presupplementary motor area connectivity (r = 0.27). However, the cognitive component of psychomotor performance (task switching) was correlated only with cerebellar-frontal connectivity (r = 0.19), whereas the motor component (processing speed) was correlated only with cerebellar-presupplementary motor area connectivity (r = 0.15), suggesting distinct circuits driving unique subprocesses of psychomotor function., Conclusions: We identified cerebellar-cortical circuits that drive distinct subprocesses of psychomotor function. Future studies should probe relationships between cerebellar connectivity and psychomotor performance using neuromodulation., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Neurocognitive impairment is a well-known phenomenon in schizophrenia that begins prior to psychosis onset. Connectome-wide association studies have inconsistently linked cognitive performance to resting-state fMRI. We hypothesized a carefully selected cognitive instrument and refined population would allow identification of reliable brain-behavior associations with connectome-wide association studies. To test this hypothesis, we first identified brain-cognition correlations via a connectome-wide association study in early psychosis. We then asked, in an independent dataset, if these brain-cognition relationships would generalize to individuals who develop psychosis in the future., Methods: The Seidman Auditory Continuous Performance Task (ACPT) effectively differentiates healthy participants from those with psychosis. Our connectome-wide association study used the Human Connectome Project for Early Psychosis (n=183) to identify links between connectivity and ACPT performance. We then analyzed the North American Prodrome Longitudinal Study 2 (n=345), a multi-site prospective study of individuals at risk for psychosis. We tested the connectome-wide association study-identified cognition-connectivity relationship in both individuals at risk for psychosis and controls., Results: Our connectome-wide association study in early-course psychosis identified robust associations between better ACPT performance and higher prefrontal-somatomotor connectivity (p<.005). Prefrontal-somatomotor connectivity was also related to ACPT performance in at-risk individuals who would develop psychosis (n=17). This finding was not observed in nonconverters (n=196) or controls (n=132)., Conclusions: This connectome-wide association study identified reproducible links between connectivity and cognition in separate samples of psychosis and at-risk individuals who would later develop psychosis. A carefully selected task and population improves the ability of connectome-wide association studies to identify reliable brain-phenotype relationships., (Copyright © 2024. Published by Elsevier Inc.)

Individuals with schizophrenia are 10 times more likely to have a tobacco use disorder than the general population. Up to 80% of those with schizophrenia smoke tobacco regularly, a prevalence three-times that of the general population. Despite the striking prevalence of tobacco use in schizophrenia, current treatments are not tailored to the pathophysiology of this population. There is growing support for use of noninvasive brain stimulation (NIBS) to treat substance use disorders (SUDs), particularly for tobacco use in neurotypical smokers. NIBS interventions targeting the dorsolateral prefrontal cortex have been effective for nicotine dependence in control populations-so much so that transcranial magnetic stimulation is now FDA-approved for smoking cessation. However, this has not borne out in the studies using this approach in schizophrenia. We performed a literature search to identify articles using NIBS for the treatment of nicotine dependence in people with schizophrenia, which identified six studies. These studies yielded mixed results. Is it possible that nicotine has a unique effect in schizophrenia that is different than its effect in neurotypical smokers? Individuals with schizophrenia may receive additional benefit from nicotine's pro-cognitive effects than control populations and may use nicotine to improve brain network abnormalities from their illness. Therefore, clinical trials of NIBS interventions should test a schizophrenia-specific target for smoking cessation. We propose a generalized approach whereby schizophrenia-specific brain circuitry related to SUDs is be identified and then targeted with NIBS interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ward, Brady, Halko and Lizano.)

The early stage of psychosis (ESP) is a critical period where effective intervention has the most favorable impact on outcomes. Thalamic connectivity abnormalities have been consistently found in psychosis, and are associated with clinical symptoms and cognitive deficits. However, most studies consider ESP patients as a homogeneous population and fail to take the duration of illness into account. In this study, we aimed to capture the progression of thalamic connectivity changes over the first five years of psychosis. Resting-state functional MRI scans were collected from 156 ESP patients (44 with longitudinal data) and 82 healthy controls (24 with longitudinal data). We first performed a case-control analysis comparing thalamic connectivity with 13 networks in the cortex and cerebellum. Next, we modelled the shape (flat, linear, curvilinear) of thalamic connectivity trajectories by comparing flexible non-linear versus linear models. We then tested the significance of the duration of illness and diagnosis in trajectories that changed over time. Connectivity changed over the ESP period between the thalamus and default mode network (DMN) and fronto-parietal network (FPN) nodes in both the cortex and cerebellum. Three models followed a curvilinear trajectory (early increase followed by a subsequent decrease), while thalamo-cerebellar FPN connectivity followed a linear trajectory of steady reductions over time, indicating different rates of change. Finally, diagnosis significantly predicted thalamic connectivity. Thalamo-cortical and thalamo-cerebellar connectivity change in a dynamic fashion during the ESP period. A better understanding of these changes may provide insights into the compensatory and progressive changes in functional connectivity in the early stages of illness., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Tobacco use is the top preventable cause of early mortality in schizophrenia. Over 60% of people with schizophrenia smoke, three times the general prevalence. The biological basis of this increased risk is not understood, and existing interventions do not target schizophrenia-specific pathology. We therefore used a connectome-wide analysis to identify schizophrenia-specific circuits of nicotine addiction. We reanalyzed data from two studies: In Cohort 1, 35 smokers (18 schizophrenia, 17 control) underwent resting-state fMRI and clinical characterization. A multivariate pattern analysis of whole-connectome data was used to identify the strongest links between cigarette use and functional connectivity. In Cohort 2, 12 schizophrenia participants and 12 controls were enrolled in a randomized, controlled crossover study of nicotine patch with resting-state fMRI. We correlated change in network functional connectivity with nicotine dose. In Cohort 1, the strongest ( p < 0.001) correlate between connectivity and cigarette use was driven by individual variation in default mode network (DMN) topography. In individuals with greater daily cigarette consumption, we observed a pathological expansion of the DMN territory into the identified parieto-occipital region, while in individuals with lower daily cigarette consumption, this region was external to the DMN. This effect was entirely driven by schizophrenia participants. Given the relationship between DMN topography and nicotine use we observed in Cohort 1, we sought to directly test the impact of nicotine on this network using an independent second cohort. In Cohort 2, nicotine reduced DMN connectivity in a dose-dependent manner ( R = -0.50; 95% CI -0.75 to -0.12, p < 0.05). In the placebo condition, schizophrenia subjects had hyperconnectivity compared to controls ( p < 0.05). Nicotine administration normalized DMN hyperconnectivity in schizophrenia. We here provide direct evidence that the biological basis of nicotine dependence is different in schizophrenia and in non-schizophrenia populations. Our results suggest the high prevalence of nicotine use in schizophrenia may be an attempt to correct a network deficit known to interfere with cognition., Competing Interests: AJ is a consultant for Axial Biotherapeutics for activities unrelated to this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ward, Beermann, Nawaz, Halko, Janes, Moran and Brady.)

Objective: Negative symptoms of schizophrenia are substantially disabling and treatment resistant. Novel treatments like repetitive transcranial magnetic stimulation (TMS) need to be examined for the same using the experimental medicine approach that incorporates tests of mechanism of action in addition to clinical efficacy in trials., Methods: Study was a double-blind, parallel, randomized, sham-controlled trial recruiting schizophrenia with at least a moderate severity of negative symptoms. Participants were randomized to real or sham intermittent theta burst stimulation (iTBS) under MRI-guided neuro-navigation, targeting the cerebellar vermis area VII-B, at a stimulus intensity of 100% active motor threshold, two sessions/day for five days (total = 6000 pulses). Assessments were conducted at baseline (T0), day-6 (T1) and week-6 (T2) after initiation of intervention. Main outcomes were, a) Scale for the Assessment of Negative Symptoms (SANS) score (T0, T1, T2), b) fronto-cerebellar resting state functional connectivity (RSFC) (T0, T1)., Results: Thirty participants were recruited in each arm. Negative symptoms improved in both arms (p < 0.001) but was not significantly different between the two arms (p = 0.602). RSFC significantly increased between the cerebellar vermis and the right inferior frontal gyrus (p cluster-FWER  = 0.033), right pallidum (p cluster-FWER  = 0.042) and right frontal pole (p cluster-FWER  = 0.047) in the real arm with no change in the sham arm., Conclusion: Cerebellar vermal iTBS engaged a target belonging to the class of cerebello-subcortical-cortical networks, implicated in negative symptoms of schizophrenia. However, this did not translate to a superior clinical efficacy. Future trials should employ enhanced midline cerebellar TMS stimulation parameters for longer durations that can potentiate and translate biological changes into clinical effects., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The brain is the seat of body weight homeostasis. However, our inability to control the increasing prevalence of obesity highlights a need to look beyond canonical feeding pathways to broaden our understanding of body weight control 1-3 . Here we used a reverse-translational approach to identify and anatomically, molecularly and functionally characterize a neural ensemble that promotes satiation. Unbiased, task-based functional magnetic resonance imaging revealed marked differences in cerebellar responses to food in people with a genetic disorder characterized by insatiable appetite. Transcriptomic analyses in mice revealed molecularly and topographically -distinct neurons in the anterior deep cerebellar nuclei (aDCN) that are activated by feeding or nutrient infusion in the gut. Selective activation of aDCN neurons substantially decreased food intake by reducing meal size without compensatory changes to metabolic rate. We found that aDCN activity terminates food intake by increasing striatal dopamine levels and attenuating the phasic dopamine response to subsequent food consumption. Our study defines a conserved satiation centre that may represent a novel therapeutic target for the management of excessive eating, and underscores the utility of a 'bedside-to-bench' approach for the identification of neural circuits that influence behaviour., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Colorectal cancer (CRC) tumor microenvironment (TME) characteristics, such as tumor infiltrating lymphocyte (TIL) densities and PD-L1 status, are predictive of recurrence, disease-free survival, and overall survival. In many malignancies, TME characteristics are also predictive of response to immunotherapy. As window of opportunity studies using neoadjuvant immunotherapy become more common and treatment guidelines incorporate TME features, accurate assessment of the pre-treatment TME using the biopsy specimen is critical. However, no study has thoroughly evaluated the correlation between the TMEs of the biopsy and resection specimens., Methods: We conducted a retrospective analysis of patients with stage I-III CRC with matched biopsy and resection specimens. CD3+, CD4+, CD8+, and FoxP3+ lymphocyte populations at the center of tumor (CT) and invasive margin (IM) and tumor PD-L1 status in the biopsy and resection specimens were evaluated. TIL populations were compared using Mann-Whitney U tests or Student's t tests and correlated using Pearson r., Results: CD3+ and CD4+ densities were significantly higher in the CT of the biopsy relative to the resection specimen Comparing biopsy and resection specimens, no TIL population at either the CT or IM had a correlation coefficient > 0.5. Determining PD-L1 status based on biopsy tissue resulted in a sensitivity of 37.1%, specificity of 81.4%, and accuracy of 61.5%., Conclusions: These findings demonstrate significant discordance between the TME of the biopsy and resection specimens. Caution should be used when basing treatment decisions on pre-treatment endoscopic biopsy findings and when interpreting changes in the TME between pre-treatment biopsy and resection specimens after neoadjuvant therapy.

Background: Auditory hallucinations (AH) are typically associated with schizophrenia (SZ), but they are also prevalent in bipolar disorder (BD). Despite the large body of research on the neural correlates of AH in SZ, the pathophysiology underlying AH remains unclear. Few studies have examined the neural substrates associated with propensity for AH in BD. Investigating AH across the psychosis spectrum has the potential to inform about the neural signature associated with the trait of AH, irrespective of psychiatric diagnosis., Methods: We compared resting state functional magnetic resonance imaging data in psychosis patients with (n = 90 AH; 68 SZ, 22 BD) and without (n = 55 NAH; 16 SZ, 39 BD) lifetime AH. We performed region of interest (ROI)-to-ROI functional connectivity (FC) analysis using 91 cortical, 15 subcortical, and 26 cerebellar atlas-defined regions. The primary aim was to identify FC differences between patients with and without lifetime AH. We secondarily examined differences between AH and NAH within each diagnosis., Results: Compared to the NAH group, patients with AH showed higher FC between cerebellum and frontal (left precentral gyrus), temporal [right middle temporal gyrus (MTG), left inferior temporal gyrus (ITG), left temporal fusiform gyrus)], parietal (bilateral superior parietal lobules), and subcortical (left accumbens, left palldium) brain areas. AH also showed lower FC between temporal lobe regions (between right ITG and right MTG and bilateral superior temporal gyri) relative to NAH., Conclusions: Our findings suggest that dysconnectivity involving the cerebellum and temporal lobe regions may be common neurofunctional elements associated with AH propensity across the psychosis spectrum. We also found dysconnectivity patterns that were unique to lifetime AH within SZ or bipolar psychosis, suggesting both common and distinct mechanisms underlying AH pathophysiology in these disorders., (Copyright © 2021. Published by Elsevier Inc.)

Background: Psychotic disorders are characterized by impairment in social cognitive processing, which is associated with poorer community functioning. However, the neural mechanisms of social impairment in psychosis remain unclear. Social impairment is a hallmark of other psychiatric illnesses as well, including autism spectrum disorders (ASD), and the nature and degree of social cognitive impairments across psychotic disorders and ASD are similar, suggesting that mechanisms that are known to underpin social impairments in ASD may also play a role in the impairments seen in psychosis. Specifically, in both humans and animal models of ASD, a cerebellar-parietal network has been identified that is directly related to social cognition and social functioning. In this study we examined social cognition and resting-state brain connectivity in people with psychosis and in neurotypical adults. We hypothesized that social cognition would be most strongly associated with cerebellar-parietal connectivity, even when using a whole-brain data driven approach. Methods: We examined associations between brain connectivity and social cognition in a trans-diagnostic sample of people with psychosis ( n = 81) and neurotypical controls ( n = 45). Social cognition was assessed using the social cognition domain score of the MATRICS Consensus Cognitive Battery. We used a multivariate pattern analysis to correlate social cognition with resting-state functional connectivity at the individual voxel level. Results: This approach identified a circuit between right cerebellar Crus I, II and left parietal cortex as the strongest correlate of social cognitive performance. This connectivity-cognition result was observed in both people with psychotic disorders and in neurotypical adults. Conclusions: Using a data-driven whole brain approach we identified a cerebellar-parietal circuit that was robustly associated with social cognitive ability, consistent with findings from people with ASD and animal models. These findings suggest that this circuit may be marker of social cognitive impairment trans-diagnostically and support cerebellar-parietal connectivity as a potential therapeutic target for enhancing social cognition., (Copyright © 2020 Brady, Beermann, Nye, Eack, Mesholam-Gately, Keshavan and Lewandowski.)

Objective: Low-dose testosterone has been shown to improve depression symptom severity, fatigue, and sexual function in small studies in women not formally diagnosed with major depressive disorder. The authors sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with antidepressant-resistant major depression. A functional MRI (fMRI) substudy examined effects on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation., Methods: The authors conducted an 8-week randomized double-blind placebo-controlled trial of adjunctive testosterone cream in 101 women, ages 21-70, with antidepressant-resistant major depression. The primary outcome measure was depression symptom severity as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. The primary outcome of the fMRI substudy (N=20) was change in ACC activity., Results: The participants' mean age was 47 years (SD=14) and their mean baseline MADRS score was 26.6 (SD=5.9). Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS scores decreased in both study arms from baseline to week 8 (testosterone arm: from 26.8 [SD=6.3] to 15.3 [SD=9.6]; placebo arm: from 26.3 [SD=5.4] to 14.4 [SD=9.3]), with no significant difference between groups. Improvement in fatigue and sexual function did not differ between groups, nor did side effects. fMRI results showed a relationship between ACC activation and androgen levels before treatment but no difference in ACC activation with testosterone compared with placebo., Conclusions: Adjunctive transdermal testosterone, although well tolerated, was not more effective than placebo in improving symptoms of depression, fatigue, or sexual dysfunction. Imaging in a subset of participants demonstrated that testosterone did not result in greater activation of the ACC.

Neuroimaging studies of psychotic disorders have demonstrated abnormalities in structural and functional connectivity involving widespread brain networks. However, these group-level observations have failed to yield any biomarkers that can provide confirmatory evidence of a patient's current symptoms, predict future symptoms, or predict a treatment response. Lack of precision in both neuroanatomical and clinical boundaries have likely contributed to the inability of even well-powered studies to resolve these key relationships. Here, we employed a novel approach to defining individual-specific functional connectivity in 158 patients diagnosed with schizophrenia (n = 49), schizoaffective disorder (n = 37), or bipolar disorder with psychosis (n = 72), and identified neuroimaging features that track psychotic symptoms in a dimension- or disorder-specific fashion. Using individually specified functional connectivity, we were able to estimate positive, negative, and manic symptoms that showed correlations ranging from r = 0.35 to r = 0.51 with the observed symptom scores. Comparing optimized estimation models among schizophrenia spectrum patients, positive and negative symptoms were associated with largely non-overlapping sets of cortical connections. Comparing between schizophrenia spectrum and bipolar disorder patients, the models for positive symptoms were largely non-overlapping between the two disorder classes. Finally, models derived using conventional region definition strategies performed at chance levels for most symptom domains. Individual-specific functional connectivity analyses revealed important new distinctions among cortical circuits responsible for the positive and negative symptoms, as well as key new information about how circuits underlying symptom expressions may vary depending on the underlying etiology and illness syndrome from which they manifest.

Objective: The interpretability of results in psychiatric neuroimaging is significantly limited by an overreliance on correlational relationships. Purely correlational studies cannot alone determine whether behavior-imaging relationships are causal to illness, functionally compensatory processes, or purely epiphenomena. Negative symptoms (e.g., anhedonia, amotivation, and expressive deficits) are refractory to current medications and are among the foremost causes of disability in schizophrenia. The authors used a two-step approach in identifying and then empirically testing a brain network model of schizophrenia symptoms., Methods: In the first cohort (N=44), a data-driven resting-state functional connectivity analysis was used to identify a network with connectivity that corresponds to negative symptom severity. In the second cohort (N=11), this network connectivity was modulated with 5 days of twice-daily transcranial magnetic stimulation (TMS) to the cerebellar midline., Results: A breakdown of connectivity in a specific dorsolateral prefrontal cortex-to-cerebellum network directly corresponded to negative symptom severity. Restoration of network connectivity with TMS corresponded to amelioration of negative symptoms, showing a statistically significant strong relationship of negative symptom change in response to functional connectivity change., Conclusions: These results demonstrate that a connectivity breakdown between the cerebellum and the right dorsolateral prefrontal cortex is associated with negative symptom severity and that correction of this breakdown ameliorates negative symptom severity, supporting a novel network hypothesis for medication-refractory negative symptoms and suggesting that network manipulation may establish causal relationships between network markers and clinical phenomena.

Converging evidence indicates that groups of patients with nominally distinct psychiatric diagnoses are not separated by sharp or discontinuous neurobiological boundaries. In healthy populations, individual differences in behavior are reflected in variability across the collective set of functional brain connections (functional connectome). These data suggest that the spectra of transdiagnostic symptom profiles observed in psychiatric patients may map onto detectable patterns of network function. To examine the manner through which neurobiological variation might underlie clinical presentation, we obtained fMRI data from over 1,000 individuals, including 210 diagnosed with a primary psychotic disorder or affective psychosis (bipolar disorder with psychosis and schizophrenia or schizoaffective disorder), 192 presenting with a primary affective disorder without psychosis (unipolar depression, bipolar disorder without psychosis), and 608 demographically matched healthy comparison participants recruited through a large-scale study of brain imaging and genetics. Here, we examine variation in functional connectomes across psychiatric diagnoses, finding striking evidence for disease connectomic "fingerprints" that are commonly disrupted across distinct forms of pathology and appear to scale as a function of illness severity. The presence of affective and psychotic illnesses was associated with graded disruptions in frontoparietal network connectivity (encompassing aspects of dorsolateral prefrontal, dorsomedial prefrontal, lateral parietal, and posterior temporal cortices). Conversely, other properties of network connectivity, including default network integrity, were preferentially disrupted in patients with psychotic illness, but not patients without psychotic symptoms. This work allows us to establish key biological and clinical features of the functional connectomes of severe mental disease., Competing Interests: Conflict of interest statement: Over the past 3 years, D.A.P. has received consulting fees from Akili Interactive Labs, BlackThorn Therapeutics, Boehringer Ingelheim, Compass, Posit Science, and Takeda Pharmaceuticals and honoraria from Alkermes for activities unrelated to the current review. J.T.B. has received consulting fees from Pear Therapeutics and Niraxx Therapeutics. J.L.R. has received investigator-initiated funding from Pamlab. D.Ö. served on an Advisory Board for Neurocrine Inc. in December 2016, unrelated to the current work. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors., (Copyright © 2019 the Author(s). Published by PNAS.)

Purpose: Rosenblat and McIntyre (Acta Psychiatr Scand. 2015;132: 180-191) propose that immune disorders are important mediators between bipolar disorders and medical comorbidities. Rosenblat et al (Bipolar Disord. 2016;18:89-101) present a meta-analysis showing that adjunctive anti-inflammatory agents could evoke moderate antidepressant responses in bipolar disorders. We propose using the anti-inflammatory drug colchicine to improve the long-term safety and efficacy of lithium treatment for bipolar disorders., Methods: This report is based on searches of the PubMed and Web of Science databases., Results: Bipolar disorders are associated with significant medical comorbidities such as hypertension, overweight/obesity, diabetes mellitus, metabolic syndrome, and arteriosclerosis, accompanied by enhanced release of pro-inflammatory markers during changes in mood state. During lithium therapy, granulocyte-colony stimulating factor, CD34+ hematopoietic stem/progenitor cells, and neutrophil elastase enter the circulation with activated neutrophils to promote the extravascular migration of activated neutrophils and enhance tissue inflammation. Concurrent treatment with lithium and low-dose colchicine could facilitate the responsiveness of bipolar patients to lithium by reducing leukocyte tissue emigration, the release of neutrophil elastase, and the release of leukocyte pro-inflammatory cytokines such as IL-1β that are regulated by the NLRP3 inflammasome assembly complex., Conclusions: Concurrent therapy with lithium and low-dose colchicine could reduce complications involving leukocyte-mediated inflammatory states in bipolar patients and promote patient acceptance and responsiveness to lithium therapy.

Editor's Note.-RadioGraphics continues to publish radiologic-pathologic case material selected from the American Institute for Radiologic Pathology (AIRP) "best case" presentations. The AIRP conducts a 4-week Radiologic Pathology Correlation Course, which is offered five times per year. On the penultimate day of the course, the best case presentation is held at the American Film Institute Silver Theater and Cultural Center in Silver Spring, Md. The AIRP faculty identifies the best cases, from each organ system, brought by the resident attendees. One or more of the best cases from each of the five courses are then solicited for publication in RadioGraphics. These cases emphasize the importance of radiologic-pathologic correlation in the imaging evaluation and diagnosis of diseases encountered at the institute and its predecessor, the Armed Forces Institute of Pathology (AFIP).

Background: Using resting-state functional magnetic resonance imaging (rsfMRI), we previously compared cohorts of bipolar I subjects in a manic state to those in a euthymic state to identify mood state-specific patterns of cortico-amygdala connectivity. Our results suggested that mania is reflected in the disruption of emotion regulation circuits. We sought to replicate this finding in a group of subjects with bipolar disorder imaged longitudinally across states of mania and euthymia METHODS: We divided our subjects into three groups: 26 subjects imaged in a manic state, 21 subjects imaged in a euthymic state, and 10 subjects imaged longitudinally across both mood states. We measured differences in amygdala connectivity between the mania and euthymia cohorts. We then used these regions of altered connectivity to examine connectivity in the longitudinal bipolar group using a within-subjects design., Results: Our findings in the mania vs euthymia cohort comparison were replicated in the longitudinal analysis. Bipolar mania was differentiated from euthymia by decreased connectivity between the amygdala and pre-genual anterior cingulate cortex. Mania was also characterized by increased connectivity between amygdala and the supplemental motor area, a region normally anti-correlated to the amygdala in emotion regulation tasks., Limitations: Stringent controls for movement effects limited the number of subjects in the longitudinal sample., Conclusions: In this first report of rsfMRI conducted longitudinally across mood states, we find that previously observed between-group differences in amygdala connectivity are also found longitudinally within subjects. These results suggest resting state cortico-amygdala connectivity is a biomarker of mood state in bipolar disorder., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Histone deacetylase inhibitors (HDACis) are a potent class of tumor-suppressive agents traditionally believed to exert their effects through loosening tightly-wound chromatin resulting in de-inhibition of various tumor suppressive genes. Recent literature however has shown altered intratumoral hypoxia signaling with HDACi administration not attributable to changes in chromatin structure. We sought to determine the precise mechanism of HDACi-mediated hypoxia signaling attenuation using vorinostat (SAHA), an FDA-approved class I/IIb/IV HDACi. Through an in-vitro and in-vivo approach utilizing cell lines for hepatocellular carcinoma (HCC), osteosarcoma (OS), and glioblastoma (GBM), we demonstrate that SAHA potently inhibits HIF-a nuclear translocation via direct acetylation of its associated chaperone, heat shock protein 90 (Hsp90). In the presence of SAHA we found elevated levels of acetyl-Hsp90, decreased interaction between acetyl-Hsp90 and HIF-a, decreased nuclear/cytoplasmic HIF-α expression, absent HIF-α association with its nuclear karyopharyin Importin, and markedly decreased HIF-a transcriptional activity. These changes were associated with downregulation of downstream hypoxia molecules such as endothelin 1, erythropoietin, glucose transporter 1, and vascular endothelial growth factor. Findings were replicated in an in-vivo Hep3B HRE-Luc expressing xenograft, and were associated with significant decreases in xenograft tumor size. Altogether, this study highlights a novel mechanism of action of an important class of chemotherapeutic., Competing Interests: CONFLICTS OF INTEREST The authors disclose no potential conflicts of interest.

Background: This study aimed to identify how the activity of large-scale brain networks differs between mood states in bipolar disorder. The authors measured spontaneous brain activity in subjects with bipolar disorder in mania and euthymia and compared these states to a healthy comparison population., Methods: 23 subjects with bipolar disorder type I in a manic episode, 24 euthymic bipolar I subjects, and 23 matched healthy comparison (HC) subjects underwent resting state fMRI scans. Using an existing parcellation of the whole brain, we measured functional connectivity between brain regions and identified significant differences between groups., Results: In unbiased whole-brain analyses, functional connectivity between parietal, occipital, and frontal nodes within the dorsal attention network (DAN) were significantly greater in mania than euthymia or HC subjects. In the default mode network (DMN), connectivity between dorsal frontal nodes and the rest of the DMN differentiated both mood state and diagnosis., Limitations: The bipolar groups were separate cohorts rather than subjects imaged longitudinally across mood states., Conclusions: Bipolar mood states are associated with highly significant alterations in connectivity in two large-scale brain networks. These same networks also differentiate bipolar mania and euthymia from a HC population. State related changes in DAN and DMN connectivity suggest a circuit based pathology underlying cognitive dysfunction as well as activity/reactivity in bipolar mania. Altered activities in neural networks may be biomarkers of bipolar disorder diagnosis and mood state that are accessible to neuromodulation and are promising novel targets for scientific investigation and possible clinical intervention., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Existing models of the pathophysiology of bipolar disorder posit disruption in neural circuits of emotion regulation and reward processing. However, few fMRI studies have compared regional brain activity and connectivity in different mood states in bipolar disorder to determine if manic symptomatology is reflected in specific circuit abnormalities. The purpose of this study was to test the hypothesis that bipolar mania is associated with altered connectivity between cortical regions thought to regulate subcortical structures such as the amygdala and striatum., Methods: 28 subjects with bipolar disorder in a manic state, 24 different bipolar subjects in a euthymic state, and 23 matched healthy comparison subjects underwent resting state fMRI scans. Several cortical and sub-cortical structures implicated in the pathogenesis of bipolar disorder were selected for study. We conducted a whole-brain analysis of functional connectivity of these regions., Results: Bipolar mania was differentiated from euthymia by decreased functional connectivity between the amygdala and anterior cingulate cortex (ACC). Mania was also characterized by increased connectivity between amygdala and dorsal frontal cortical structures that are normally anti-correlated in emotion regulation tasks., Limitations: Both groups of bipolar subjects were prescribed medications. The study was not longitudinal in design., Conclusions: Compared to bipolar subjects in a euthymic state, subjects in the manic state demonstrate disrupted functional connectivity between brain regions involved in the regulation of emotion and the amygdala. This disruption of activity in neural circuits involved in emotion may underlie the emotional dysregulation inherent to a bipolar manic episode., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Fabry disease is a glycosphingolipid storage disorder that is caused by a genetic deficiency of the enzyme alpha-galactosidase A (AGA, EC 3.2.1.22). It is a multisystem disease that affects the vascular, cardiac, renal, and nervous systems. One of the hallmarks of this disorder is neuropathic pain and sympathetic and parasympathetic nervous dysfunction. The exact mechanism by which changes in AGA activity result in change in neuronal function is not clear, partly due to of a lack of relevant model systems. In this study, we report the development of an in vitro model system to study neuronal dysfunction in Fabry disease by using short-hairpin RNA to create a stable knock-down of AGA in the human cholinergic neuronal cell line, LA-N-2. We show that gene-silenced cells show specifically reduced AGA activity and store globotriaosylceramide. In gene-silenced cells, release of the neurotransmitter acetylcholine is significantly reduced, demonstrating that this model may be used to study specific neuronal functions such as neurotransmitter release in Fabry disease., (Published by Elsevier Inc.)

Bipolar disorder is a chronic psychiatric disorder that is a cause of significant symptomatology even in the setting of optimal treatment. Most current treatments are developed from serendipity, and not based on known pathophysiology. In this review we examine a number of somatic and pharmacologic therapies that are poised to become part of the armamentarium of interventions to treat bipolar illness. As a group, these interventions are derived from a growing understanding of the biological underpinnings of bipolar disorders. We will look at emergent treatments based on our understanding of the molecular biology, neuroanatomy, and the genetics of bipolar disorder., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), can attenuate tumor-associated edema and improve patient symptoms but based on magnetic resonance imaging, is associated with non-enhancing tumor progression and possibly gliosarcoma differentiation. To gain insight into these findings, we investigated the role of hypoxia and epithelial-mesenchymal transition (EMT)-associated proteins in GBM. Tumor markers of hypoxia and EMT were upregulated in bevacizumab-treated tumors from GBM patients compared to untreated counterparts. Exposure of glioma cells to 1% oxygen tension increased cell proliferation, expression of EMT-associated proteins and enhanced cell migration in vitro. These phenotypic changes were significantly attenuated by pharmacologic knockdown of hypoxia-inducible Factor 1α (HIF1α) or HIF2α, indicating that HIFs represent a therapeutic target for mesenchymal GBM cells. These findings provide insights into potential development of novel therapeutic targeting of angiogenesis-specific pathways in GBM.

Gaucher disease is caused by mutations of the GBA1 gene, which encodes the lysosomal anchored gluococerebrosidase (GCase). GBA1 mutations commonly result in protein misfolding, abnormal chaperone recognition, and premature degradation, but are less likely to affect catalytic activity. In the present study, we demonstrate that the Hsp90/HOP/Cdc37 complex recruits Hsp27 after recognition of GCase mutants with subsequent targeting of GCase mutant peptides to degradation mechanisms such as VCP and the 26S proteasome. Inhibition of Hsp27 not only increased the quantity of enzyme but also enhanced GCase activity in fibroblasts derived from patients with Gaucher disease. These findings provide insight into a possible therapeutic strategy for protein misfolding diseases by correcting chaperone binding and altering subsequent downstream patterns of protein degradation.

Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disorder with systemic and central nervous system (CNS) involvement due to deficiency of α-L-iduronidase (IDUA). We previously identified a receptor-binding peptide from apolipoprotein E (e) that facilitated a widespread delivery of IDUAe fusion protein into CNS. In this study, we evaluated the long-term CNS biodistribution, dose-correlation, and therapeutic benefits of IDUAe after systemic, sustained delivery via hematopoietic stem cell (HSC)-mediated gene therapy with expression restricted to erythroid/megakaryocyte lineages. Compared to the highest dosage group treated by nontargeted control IDUAc (165 U/ml), physiological levels of IDUAe in the circulation (12 U/ml) led to better CNS benefits in MPS I mice as demonstrated in glycosaminoglycan accumulation, histopathology analysis, and neurological behavior. Long-term brain metabolic correction and normalization of exploratory behavior deficits in MPS I mice were observed by peripheral enzyme therapy with physiological levels of IDUAe derived from clinically attainable levels of HSC transduction efficiency (0.1). Importantly, these levels of IDUAe proved to be more beneficial on correction of cerebrum pathology and behavioral deficits in MPS I mice than wild-type HSCs fully engrafted in MPS I chimeras. These results provide compelling evidence for CNS efficacy of IDUAe and its prospective translation to clinical application.