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Background: The mechanisms underlying generalized forms of dissociative ('psychogenic') amnesia are poorly understood. One theory suggests that memory retrieval is inhibited via prefrontal control. Findings from cognitive neuroscience offer a candidate mechanism for this proposed retrieval inhibition. By applying predictions based on these experimental findings, we examined the putative role of retrieval suppression in dissociative amnesia., Methods: We analyzed fMRI data from two previously reported cases of dissociative amnesia. Patients had been shown reminders from forgotten and remembered time periods (colleagues and school friends). We examined the neuroanatomical overlap between regions engaged in the unrecognized compared to the recognized condition, and the regions engaged during retrieval suppression in laboratory-based tasks. Effective connectivity analyses were performed to test the hypothesized modulatory relationship between the right anterior dorsolateral prefrontal cortex (raDLPFC) and the hippocampus. Both patients were scanned again following treatment, and analyses were repeated., Results: We observed substantial functional alignment between the inhibitory regions engaged during laboratory-based retrieval suppression tasks, and those engaged when patients failed to recognize their current colleagues. This included significant activation in the raDLPFC and right ventrolateral prefrontal cortex, and a corresponding deactivation across autobiographical memory regions (hippocampus, medial PFC). Dynamic causal modeling confirmed the hypothesized modulatory relationship between the raDLPFC and the hippocampus. This pattern was no longer evident following memory recovery in the first patient, but persisted in the second patient who remained amnesic., Conclusions: Findings are consistent with an inhibitory mechanism driving down activity across core memory regions to prevent the recognition of personally relevant stimuli.

Individuals with depression typically remember their past in a generalised manner, at the cost of retrieving specific event memories. This may impair engagement with cognitive behavioural therapy (CBT) tasks that use concrete episodic information to challenge maladaptive beliefs, potentially limiting their therapeutic benefit. Study 1 demonstrated that an episodic specificity induction increased detail and specificity of autobiographical memory in people with major depression, relative to control conditions (N = 88). We therefore examined whether the induction enhanced the efficacy of CBT tasks that depend on episodic memory - cognitive reappraisal (Study 2, N = 30), evidence gathering (Study 2, N = 30), and planning behavioural experiments (Study 3a, N = 30). Across all three tasks, there were no significant differences in emotion- or belief-change between the specificity and control conditions. Although the induction temporarily enhanced specificity in depressed individuals, it did not significantly augment the efficacy of CBT tasks theorised to benefit from the use of specific mnemonic information., Competing Interests: Declaration of competing interest The authors declare that there were no conflicts of interest with respect to the authorship or the publication of this article., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cognitive dysfunction is often reported in patients who have experienced acute respiratory distress syndrome (ARDS). Extra Corporeal Membrane Oxygenation (ECMO) therapy is increasingly used to manage ARDS patients in ICU, transforming survival rates. However, few studies have examined cognitive outcomes., Methods: We examined self-reported cognitive complaints, psychiatric outcomes and neuropsychological test performance in survivors of severe hypoxaemia managed with VV-ECMO, at 18-24 month follow-up, compared with a group of healthy controls., Results: Over 70% of ECMO-treated patients (N = 46) complained of difficulty in at least one aspect of cognition on self-report measures (study 1). However, a much lower frequency of cognitive impairment was found on formal neuropsychological testing (study 2). Mean neuropsychological test scores of the ECMO group (N = 24) did not significantly differ from healthy controls (N = 23) after controlling for depression. Less than 30% of ECMO-treated patients showed impairments in anterograde memory, and deficits on general IQ or executive function were seen in <17% of patients. However, we observed high levels of self-reported anxiety and depression in the ECMO-treated patients., Conclusions: Cognitive outcomes in ECMO-treated patients were generally good, with preserved neuropsychological function in the majority of patients, despite severe hypoxaemia and high rates of self-reported difficulties. However, we saw high levels of mental health symptoms in these patients, highlighting a need for psychological support., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Adoptive cell therapy with chimeric antigen receptor T cells (CAR-T) has become a standard treatment for patients with certain aggressive B cell malignancies and holds promise to improve the care of patients suffering from numerous other cancers in the future. However, the high manufacturing cost of CAR-T cell therapies poses a major barrier to their broader clinical application. Among the key cost drivers of CAR-T production are single-use reagents for T cell activation and clinical-grade viral vector. The presence of variable amounts of contaminating monocytes in the starting material poses an additional challenge to CAR-T manufacturing, since they can impede T cell stimulation and transduction, resulting in manufacturing failure., Methods: We created K562-based artificial antigen-presenting cells (aAPC) with genetically encoded T cell stimulation and costimulation that represent an inexhaustible source for T cell activation. We additionally disrupted endogenous expression of the low-density lipoprotein receptor (LDLR) on these aAPC (aAPC-ΔLDLR) using CRISPR-Cas9 gene editing nucleases to prevent inadvertent lentiviral transduction and avoid the sink effect on viral vector during transduction. Using various T cell sources, we produced CD19-directed CAR-T cells via aAPC-ΔLDLR-based activation and tested their in vitro and in vivo antitumor potency against B cell malignancies., Results: We found that lack of LDLR expression on our aAPC-ΔLDLR conferred resistance to lentiviral transduction during CAR-T production. Using aAPC-ΔLDLR, we achieved efficient expansion of CAR-T cells even from unpurified starting material like peripheral blood mononuclear cells or unmanipulated leukapheresis product, containing substantial proportions of monocytes. CD19-directed CAR-T cells that we produced via aAPC-ΔLDLR-based expansion demonstrated potent antitumor responses in preclinical models of acute lymphoblastic leukemia and B-cell lymphoma., Conclusions: Our aAPC-ΔLDLR represent an attractive approach for manufacturing of lentivirally transduced T cells that may be simpler and more cost efficient than currently available methods., Competing Interests: Competing interests: Some of the authors have filed provisional patent applications related to the use of the aAPC’s described herein. BPK is an inventor on various patents and patent applications that describe gene editing and epigenetic editing technologies. BPK is a consultant for Avectas and an advisor for Acrigen Biosciences. JKJ has financial interests in Beam Therapeutics, Editas Medicine, Excelsior Genomics, Pairwise Plants, Poseida Therapeutics, Transposagen Biopharmaceuticals, and Verve Therapeutics (f/k/a Endcadia). JKJ’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. JKJ is a member of the Board of Directors of the American Society of Gene and Cell Therapy. JKJ is a coinventor on various patents and patent applications that describe gene editing and epigenetic editing technologies., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Borohydride reduction of the imine groups in a pyruvate-derived cobalt(III) complex, (OC-6-33')-[Co(Aim(2)trien)](2)[ZnCl(4)], occurs with high diastereoselectivity. The major diastereoisomeric product, (OC-6-33'-ARSSR,CSRRS)-[Co(A(2)trien)]Cl has been isolated and crystallographically characterised. The results from base-induced isomerisation of the major isomer allow us to conclude that most of the remaining material from the reduction reactions (consisting of minor diastereoisomers) differs from the major isomer only in the relative configuration of the coordinated amines. Therefore the initial borohydride attack on the imine groups must have occurred predominantly on the same face of each imine as that which produces the major isomer. The diastereoselectivity of the reaction can be rationalised by proposing hydrogen bonding interactions between the incoming hydride reagent and other donor groups in the complex.

In survey sampling, information about the prevalence of a health outcome Y for a defined target population is frequently obtained using a two-stage data collection process. In the first stage, households that have members of the target population are identified and socio-demographic data that are believed to be associated with Y are collected. At the end of the first stage of data collection, permission is requested to contact the member's health providers so that accurate information about Y can be obtained. When permission is obtained, a second phase of data collection is conducted in which those health providers are contacted and Y is obtained. A 'complete response' results when data are obtained from both the first and the second phases of the survey. A 'partial response' results when data are collected from the first phase, but Y is not obtained in the second phase. To adjust for selection bias in estimating the prevalence of Y caused by partial responders' missing Y values, potential differences between complete and partial responders are typically taken into account by using weighting class methods. These methods assume that missing Y values are missing at random (MAR). This paper describes statistical tests for evaluating whether missing data are missing completely at random or MAR., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

SLIDE software, which models the flexibility of protein and ligand side chains while docking, was used to screen several large databases to identify inhibitors of Brugia malayi asparaginyl-tRNA synthetase (AsnRS), a target for anti-parasitic drug design. Seven classes of compounds identified by SLIDE were confirmed as micromolar inhibitors of the enzyme. Analogs of one of these classes of inhibitors, the long side-chain variolins, cannot bind to the adenosyl pocket of the closed conformation of AsnRS due to steric clashes, though the short side-chain variolins identified by SLIDE apparently bind isosterically with adenosine. We hypothesized that an open conformation of the motif 2 loop also permits the long side-chain variolins to bind in the adenosine pocket and that their selectivity for Brugia relative to human AsnRS can be explained by differences in the sequence and conformation of this loop. Loop flexibility sampling using Rigidity Optimized Conformational Kinetics (ROCK) confirms this possibility, while scoring of the relative affinities of the different ligands by SLIDE correlates well with the compounds' ranks in inhibition assays. Combining ROCK and SLIDE provides a promising approach for exploiting conformational flexibility in structure-based screening and design of species selective inhibitors.

Aims: We review literature and present new observations on the differences among three general patterns of aerenchyma origin and their systematic distributions among the flowering plants, and we clarify terminology on root aerenchyma., Scope: From our own previous works and some new observations, we have analysed the root cortex in 85 species of 41 families in 21 orders of flowering plants that typically grow in wetlands to determine the characteristic patterns of aerenchyma., Findings: A developmental and structural pattern that we term expansigeny, as manifested by honeycomb aerenchyma, is characteristic of all aquatic basal angiosperms (the Nymphaeales) and basal monocots (the Acorales). Expansigenous aerenchyma develops by expansion of intercellular spaces into lacunae by cell division and cell expansion. Schizogeny and lysigeny, so often characterized in recent reviews as the only patterns of root cortex lacunar formation, are present in most wetland plants, but are clearly not present in the most basal flowering plants., Conclusion: We conclude that expansigeny is the basic type of aerenchyma development in roots of flowering plants and that the presence of expansigenous honeycomb aerenchyma in root cortices was fundamental to the success of the earliest flowering plants found in wetland environments.

Uncertainties associated with the effects from chronic low-level exposures to radiation prompted us to construct a Low Dose Rate Irradiation Facility (LoDIF). The facility was designed specifically to test the appropriateness of the 10 mGy d(-1) guideline often espoused as acceptable for protection of aquatic biota from ionizing radiation. Scientists at the 0.4 ha facility use 40 outdoor mesocosms and 137Cs irradiators of three different source strengths to research the effects of chronic low-level irradiation at different levels of biological organization. A description of the facility is included along with results from a pilot study in which Japanese medaka (a small fish native to Asia) were chronically irradiated at the highest dose rate possible within the facility (350+/-150 mGy d(-1)). Irradiated fish produced fewer eggs per day (p=0.03); had a lower percentage of viable eggs (p=0.04), and produced a lower percentage of hatchlings (p=0.05). Although these data are not surprising based on the relatively high dose rates, they are important to future work at the LoDIF because they confirm the utility of our chosen model organism for detecting population-level responses, and they illustrate the statistical power achieved from using replicated mesocosms, in that statistical significance was achieved with few replicates per treatment. Future directions for the LoDIF are presented, as well as an invitation for interested researchers to participate in our studies.

Using epifluorescent and histochemical techniques, we examined anatomical differences in the shoot organs of Typha latifolia, T. angustifolia and T. glauca. The leaf lamina of T. latifolia and T. glauca had enlarged epidermal cells and a thickened cuticle above the subepidermal vascular bundles; that of T. angustifolia lacked these characteristics. Leaf sheaths were similar among the species and all lacked the epidermal thickenings found in the lamina. The fertile stems had typical scattered vascular bundles with a band of fibres that was most prominent in T. glauca. The sterile stems were only 1 cm in length and contained a multiseriate hypodermis and a uniseriate endodermis over part of their length. The rhizomes were similar except for a pronounced band of fibres surrounding the central core in T. angustifolia. The rhizome was also characterized by an outer cortical region with a large multiseriate hypodermis/exodermis and a uniseriate endodermis with Casparian bands, suberin lamellae and secondarily thickened walls.

Pichinde virus infection of inbred guinea-pigs is a model for arenaviral infections in humans. Infected animals experience reduced levels of multiple coagulation factors caused by either consumption coagulopathy or impaired factor synthesis. A radioimmunoassay (RIA) of guinea-pig fibrinopeptide A (gFPA) has been developed to measure the degree of thrombin action in vivo. gFPA was synthesized via the solid-phase method and conjugated to bovine serum albumin (BSA). A double antibody RIA was established employing goat anti-rabbit IgG to precipitate the primary complex composed of either 125I-5-Tyr-gFPA or 125I-12-Tyr-gFPA and rabbit anti-gFPA-BSA. The cross-reaching material was removed by mixing the plasma with 3 vol of ethanol. The supernatant was filtered through a hollow fibre apparatus by centrifugation. Plasma gFPA immunoreactivities of outbred guinea-pigs averaged 6.56 ng/ml. The gFPA-RIA was validated by determining the quantity of gFPA released from thrombin-degraded fibrinogen. A transient elevation of gFPA levels was detected in Pichinde-infected animals by the gFPA-RIA using 125I-12-Tyr-gFPA as a tracer. The pathogenic mechanism by which the increased gFPA levels may lead to the lethality of Pichinde virus infection remains to be elucidated. It is possible that the coagulopathy triggers changes in immune and inflammatory pathways that induces high cytokine concentrations, with deleterious effects on organs such as the heart and lungs.