Coordinating brain-distributed network activities in memory resistant to extinction.

Certain memories resist extinction to continue invigorating maladaptive actions. The robustness of these memories could depend on their widely distributed implementation across populations of neurons in multiple brain regions. However, how dispersed neuronal activities are collectively organized to underpin a persistent memory-guided behavior remains unknown. To investigate this, we simultaneously monitored the prefrontal cortex, nucleus accumbens, amygdala, hippocampus, and ventral tegmental area (VTA) of the mouse brain from initial recall to post-extinction renewal of a memory involving cocaine experience. We uncover a higher-order pattern of short-lived beta-frequency (15-25 Hz) activities that are transiently coordinated across these networks during memory retrieval. The output of a divergent pathway from upstream VTA glutamatergic neurons, paced by a slower (4-Hz) oscillation, actuates this multi-network beta-band coactivation; its closed-loop phase-informed suppression prevents renewal of cocaine-biased behavior. Binding brain-distributed neural activities in this temporally structured manner may constitute an organizational principle of robust memory expression.

Finding the right candidate: Developing hiring guidelines for screening applicants for clinical research coordinator positions.

Impact: The success of any clinical research team is dependent on hiring individuals with the experience and skill set needed for a specific research project. Strategies to improve the ability of human resource (HR) recruiters to screen and advance qualified candidates for a project will result in improved initiation and execution of the project. Objective/Goals: HR recruiters play a critical role in matching research applicants to the posted job descriptions and presenting a list of top candidates to the PI/hiring manager for interview and hiring consideration. Methods/Study Population: Creating guidelines to screen for applicant qualification based on resumes when clinical research positions have multiple levels of expertise required is a complex process of discovery, moving from subjective rationale for rating individual resumes to a more structured less biased evaluation process. To improve the hiring process of the research workforce, we successfully developed guidelines for categorizing research coordinator applications by level from beginner to advanced. Results/Anticipated Results: Through guideline development, we provide a framework to reduce bias and improve the matching of applicant resumes to job levels for improved selection of top candidates to advance for interviewing. Improved applicant to job matching offers an advantage to reduce hiring time, anticipate training needs, and shorten the timeline to active project engagement. These guidelines can form the basis for initial screening and ultimately matching individual qualities to project-specific needs.

Chronic hepatitis B in remote, tropical Australia; successes and challenges.

INTRODUCTION: Aboriginal and Torres Strait Islander Australians living in remote locations suffer disproportionately from chronic hepatitis B (CHB). Defining the temporospatial epidemiology of the disease-and assessing the ability of local clinicians to deliver optimal care-is crucial to improving patient outcomes in these settings. METHODS: The demographic, laboratory and radiology findings in all patients diagnosed with CHB after 1990, and presently residing in remote Far North Queensland (FNQ), tropical Australia, were correlated with their management and clinical course. RESULTS: Of the 602 patients, 514 (85%) identified as Aboriginal and Torres Strait Islander Australians, 417 (69%) of whom had Torres Strait Islander heritage. Among the 514 Aboriginal and Torres Strait Islander Australians, there were only 61 (12%) born after universal postnatal vaccination was introduced in 1985. Community CHB prevalence varied significantly across the region from 7/1707 (0.4%) in western Cape York to 55/806 (6.8%) in the Eastern Torres Strait Islands. Although 240/602 (40%) are engaged in care, with 65 (27%) meeting criteria for antiviral therapy, only 43 (66%) were receiving this treatment. Among 537 with complete data, 32 (6%) were cirrhotic, of whom 15 (47%) were engaged in care and 10 (33%) were receiving antiviral therapy. Only 64/251 (26%) in whom national guidelines would recommend hepatocellular carcinoma (HCC) surveillance are receiving screening, however, only 20 patients have been diagnosed with HCC since 1999. CONCLUSION: Vaccination has had a dramatic effect on CHB prevalence in FNQ in only a generation. However, although engagement in care is the highest in Australia, this is not translating into initiation of antiviral therapy in all those that should be receiving it, increasing their risk of developing cirrhosis and HCC. New strategies are necessary to improve the care of Indigenous Australians living with CHB to reduce the morbidity and mortality of this preventable disease.

Public psychology and the Cold War brainwashing scare.

In 1950, a new word 'brainwashing' entered the English language. Though its meaning was always ambiguous and continuously evolving, it captured various concerns about the future uses of psychology in warfare and domestic life and the potential for new technologies to control and manipulate human minds. Recent scholarship on what historians have called the 'Cold War brainwashing scare' has tended to treat brainwashing as a Cold War paranoia or fantasy that not only was never to be, but was never really supported by scientific research. Drawing on recent scholarship and my own research, this paper examines some of the interactions between experts and popular discourses on brainwashing. For many experts, the Cold War brainwashing scare offered an opportunity to engage the public with contemporary psychological theory and research. But it was by no means a discussion over which they had complete control. It will be argued that the popular debate about brainwashing was not only a question of dealing with scientific 'facts', but existed in a more diverse imaginary concerned as much with present realities, as it was with future possibilities. Much in the same way that stories about artificial intelligence are reported today, discussions of techniques of brainwashing were often accompanied by speculation both wild and grounded about how new technology may be used in the future and by whom. This paper covers three examples: Korean War military psychiatrists, the popular theories of William Sargant and the field of experimental research known broadly as sensory deprivation. It concludes with some observations about current concerns about psychological manipulation in the digital age and the role psychology expertise plays in navigating these concerns.

On 'modified human agents': John Lilly and the paranoid style in American neuroscience.

The personal papers of the neurophysiologist John C. Lilly at Stanford University hold a classified paper he wrote in the late 1950s on the behavioural modification and control of 'human agents'. The paper provides an unnerving prognosis of the future application of Lilly's research, then being carried out at the National Institute of Mental Health. Lilly claimed that the use of sensory isolation, electrostimulation of the brain, and the recording and mapping of brain activity could be used to gain 'push-button' control over motivation and behaviour. This research, wrote Lilly, could eventually lead to 'master-slave controls directly of one brain over another'. The paper is an explicit example of Lilly's preparedness to align his research towards Cold War military aims. It is not, however, the research for which Lilly is best known. During the 1960s and 1970s, Lilly developed cult status as a far-out guru of consciousness exploration, promoting the use of psychedelics and sensory isolation tanks. Lilly argued that, rather than being used as tools of brainwashing, these techniques could be employed by the individual to regain control of their own mind and retain a sense of agency over their thoughts and actions. This article examines the scientific, intellectual, and cultural relationship between the sciences of brainwashing and psychedelic mind alteration. Through an analysis of Lilly's autobiographical writings, I also show how paranoid ideas about brainwashing and mind control provide an important lens for understanding the trajectory of Lilly's research.

Training in experimental design and statistics is essential: Response to Jordan.

This Formal Comment responds to Jordan et al., and stresses that if scientific findings are to be robust, training in experimental design and statistics is critical to ensure that research questions, design considerations, and analyses are aligned.

A phase I/randomized phase II study of GM.CD40L vaccine in combination with CCL21 in patients with advanced lung adenocarcinoma.

The GM.CD40L vaccine, which recruits and activates dendritic cells, migrates to lymph nodes, activating T cells and leading to systemic tumor cell killing. When combined with the CCL21 chemokine, which recruits T cells and enhances T-cell responses, additive effects have been demonstrated in non-small cell lung cancer mouse models. Here, we compared GM.CD40L versus GM.CD40L plus CCL21 (GM.CD40L.CCL21) in lung adenocarcinoma patients with ≥ 1 line of treatment. In this phase I/II randomized trial (NCT01433172), patients received intradermal vaccines every 14 days (3 doses) and then monthly (3 doses). A two-stage minimax design was used. During phase I, no dose-limiting toxicities were shown in three patients who received GM.CD40L.CCL21. During phase II, of evaluable patients, 5/33 patients (15.2%) randomized for GM.DCD40L (p = .023) and 3/32 patients (9.4%) randomized for GM.DCD40L.CCL21 (p = .20) showed 6-month progression-free survival. Median overall survival was 9.3 versus 9.5 months with GM.DCD40L versus GM.DCD40L.CCL21 (95% CI 0.70-2.25; p = .44). For GM.CD40L versus GM.CD40L.CCL21, the most common treatment-related adverse events (TRAEs) were grade 1/2 injection site reaction (51.4% versus 61.1%) and grade 1/2 fatigue (35.1% versus 47.2%). Grade 1 immune-mediated TRAEs were isolated to skin. No patients showed evidence of pseudo-progression or immune-related TRAEs of grade 1 or greater of pneumonitis, endocrinopathy, or colitis, and none discontinued treatment due to toxicity. Although we found no significant associations between vaccine immunogenicity and outcomes, in limited biopsies, one patient treated with GMCD40L.CCL21 displayed abundant tumor-infiltrating lymphocytes. This possible effectiveness warrants further investigation of GM.CD40L in combination approaches.

What exactly is 'N' in cell culture and animal experiments?

Biologists determine experimental effects by perturbing biological entities or units. When done appropriately, independent replication of the entity-intervention pair contributes to the sample size (N) and forms the basis of statistical inference. If the wrong entity-intervention pair is chosen, an experiment cannot address the question of interest. We surveyed a random sample of published animal experiments from 2011 to 2016 where interventions were applied to parents and effects examined in the offspring, as regulatory authorities provide clear guidelines on replication with such designs. We found that only 22% of studies (95% CI = 17%-29%) replicated the correct entity-intervention pair and thus made valid statistical inferences. Nearly half of the studies (46%, 95% CI = 38%-53%) had pseudoreplication while 32% (95% CI = 26%-39%) provided insufficient information to make a judgement. Pseudoreplication artificially inflates the sample size, and thus the evidence for a scientific claim, resulting in false positives. We argue that distinguishing between biological units, experimental units, and observational units clarifies where replication should occur, describe the criteria for genuine replication, and provide concrete examples of in vitro, ex vivo, and in vivo experimental designs.

ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons.

Miles-Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in ZC4H2, was identified in a XLID re-sequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three ZC4H2 mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features. In silico modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in zc4h2 were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specific markers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt ZC4H2 rescued the mutant phenotype. Mutant zebrafish injected with human p.L66H or p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support ZC4H2 as a novel XLID gene with a required function in interneuron development. Loss of function of ZC4H2 thus likely results in altered connectivity of many brain and spinal circuits.