Evidence for shallow cognitive maps in schizophrenia.

Individuals with schizophrenia can have marked deficits in goal-directed decision making. Prominent theories differ in whether schizophrenia (SZ) affects the ability to exert cognitive control, or the motivation to exert control. An alternative explanation is that schizophrenia negatively impacts the formation of cognitive maps, the internal representations of the way the world is structured, necessary for the formation of effective action plans. That is, deficits in decision-making could also arise when goal-directed control and motivation are intact, but used to plan over ill-formed maps. Here, we test the hypothesis that individuals with SZ are impaired in the construction of cognitive maps. We combine a behavioral representational similarity analysis technique with a sequential decision-making task. This enables us to examine how relationships between choice options change when individuals with SZ and healthy age-matched controls build a cognitive map of the task structure. Our results indicate that SZ affects how people represent the structure of the task, focusing more on simpler visual features and less on abstract, higher-order, planning-relevant features. At the same time, we find that SZ were able to display similar performance on this task compared to controls, emphasizing the need for a distinction between cognitive map formation and changes in goal-directed control in understanding cognitive deficits in schizophrenia.

The construction and use of cognitive maps in model-based control.

When making decisions, we sometimes rely on habit and at other times plan toward goals. Planning requires the construction and use of an internal representation of the environment, a cognitive map. How are these maps constructed, and how do they guide goal-directed decisions? We coupled a sequential decision-making task with a behavioral representational similarity analysis approach to examine how relationships between choice options change when people build a cognitive map of the task structure. We found that participants who encoded stronger higher-order relationships among choice options showed increased planning and better performance. These higher-order relationships were more strongly encoded among objects encountered in high-reward contexts, indicating a role for motivation during cognitive map construction. In contrast, lower-order relationships such as simple visual co-occurrence of objects did not predict goal-directed planning. These results show that the construction of cognitive maps is an active process, with motivation dictating the degree to which higher-order relationships are encoded and used for planning. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Cortico-hippocampal networks carry information about characters and their relationships in an extended narrative.

Social information is a centerpiece of human experience. Despite a wealth of research into the way we understand social relationships and how aspects of social life might be supported by the brain, relatively little is known about how the brain represents individual people and their relationships with others. How do intrinsic networks in the brain track people and their connections in complex situations? Here, we sought to understand this issue using an open neuroimaging dataset in which people freely viewed "The Grand Budapest Hotel." Using support vector machine classification of fMRI activity patterns, we found that character identity could be decoded throughout subsystems of the brain's "Default Mode" Network, especially in regions of an Anterior Temporal and a Medial Prefrontal subsystem, as well as a Medial Temporal Network (MTN). We tested character relationships in two ways - onscreen co-occurrence and shared semantic information from an independent sample of character descriptions - and found evidence for these representations throughout the "Default Mode" Network, and the MTN. The extent to which each variant of character relationships fit neural patterns differed across networks, with abstract semantic relatedness being especially prominent in regions of Anterior Temporal and Medial Prefrontal Networks. These data show that subsystems of the brain's "Default Mode" Network and MTN carry information about individual people as well as their connections, and highlight a particularly strong role for the Anterior Temporal network in representing this information.

Transventricular Cardioscopic Release of a Trapped Prosthetic Mitral Valve Leaflet.

Trapped prosthetic valve leaflets are a rare but challenging complication. A 68-year-old male patient had previously undergone redo aortic valve replacement. Postoperatively, he decompensated with severe mitral regurgitation, requiring extracorporeal membrane oxygenation and a salvage mitral valve replacement via right thoracotomy with very difficult access. This procedure was complicated by a trapped valve leaflet. He recovered well initially but presented 2 years later with worsening heart failure due to mitral stenosis and rising pulmonary artery pressures. Due to the high risk of sternotomy and right thoracotomy, a transventricular cardioscopic release of the trapped mitral valve leaflet was undertaken by left minithoracotomy. The procedure was successful, and the patient was discharged home on day 12. This novel minimally invasive approach, which does not require myocardial preservation, is ideal for high-risk patients with this rare complication and has not previously been described. We hope that by sharing our experience, others will consider this innovative approach.

Aging impacts memory for perceptual, but not narrative, event details.

Memory is well known to decline over the course of healthy aging. However, memory is not a monolith and draws from different kinds of representations. Historically, much of our understanding of age-related memory decline stems from recognition of isolated studied items. In contrast, real-life events are often remembered as narratives, and this kind of information is generally missed in typical recognition memory studies. Here, we designed a task to tax mnemonic discrimination of event details, directly contrasting perceptual and narrative memory. Older and younger adults watched an episode of a television show and later completed an old/new recognition test featuring targets, novel foils, and similar lures in narrative and perceptual domains. While we observed no age-related differences on basic recognition of repeated targets and novel foils, older adults showed a deficit in correctly rejecting perceptual, but not narrative, lures. These findings provide insight into the vulnerability of different memory domains in aging and may be useful in characterizing individuals at risk for pathological cognitive decline.

Implementation and results of a standardized process for identifying ambulatory pharmacy clinical outcome measures.

PURPOSE: Given the variation in clinical practice, a clinician-centric, standardized process to implement and validate clinical pharmacy outcome measures was developed. SUMMARY: Four specialty clinics with embedded clinic-based pharmacists underwent an iterative process to define, refine, and implement the build of electronic health record functionality for outcome measure data collection and reporting. Starting with a list of identified measures, clinic workgroups met to discuss each measure and identify gaps in measure implementation. Information technology experts created electronic documentation forms with discrete data and reports based on criteria specified by the clinic workgroups. Of 32 outcome measures identified as priorities for demonstrating pharmacists' impact in previous research, 29 were implemented for routine monitoring through this project. Implementation strategies included identification through existing reporting, development of discrete documentation tools within the electronic health record, and development of new reporting tools from available discrete data fields. Time to implementation decreased from the first to the last pilot clinic implementation, as demonstrated through a 9-day reduction in electronic documentation form development and 31-day reduction in report development turnaround time. CONCLUSION: A standardized and reproducible process was developed for the implementation of clinical pharmacy outcomes measures for 4 specialty clinics. The process was successfully utilized to develop measurable outputs for a variety of oncology and nononcology specialty disease states based upon multidisciplinary stakeholder input.

Flexible reuse of cortico-hippocampal representations during encoding and recall of naturalistic events.

Although every life event is unique, there are considerable commonalities across events. However, little is known about whether or how the brain flexibly represents information about different event components at encoding and during remembering. Here, we show that different cortico-hippocampal networks systematically represent specific components of events depicted in videos, both during online experience and during episodic memory retrieval. Regions of an Anterior Temporal Network represented information about people, generalizing across contexts, whereas regions of a Posterior Medial Network represented context information, generalizing across people. Medial prefrontal cortex generalized across videos depicting the same event schema, whereas the hippocampus maintained event-specific representations. Similar effects were seen in real-time and recall, suggesting reuse of event components across overlapping episodic memories. These representational profiles together provide a computationally optimal strategy to scaffold memory for different high-level event components, allowing efficient reuse for event comprehension, recollection, and imagination.

Silent recognition of flagellins from human gut commensal bacteria by Toll-like receptor 5.

Flagellin, the protein subunit of the bacterial flagellum, stimulates the innate immune receptor Toll-like receptor 5 (TLR5) after pattern recognition or evades TLR5 through lack of recognition. This binary response fails to explain the weak agonism of flagellins from commensal bacteria, raising the question of how TLR5 response is tuned. Here, we screened abundant flagellins present in metagenomes from human gut for both TLR5 recognition and activation and uncovered a class of flagellin-TLR5 interaction termed silent recognition. Silent flagellins were weak TLR5 agonists despite pattern recognition. Receptor activity was tuned by a TLR5-flagellin interaction distal to the site of pattern recognition that was present in Salmonella flagellin but absent in silent flagellins. This interaction enabled flagellin binding to preformed TLR5 dimers and increased TLR5 signaling by several orders of magnitude. Silent recognition by TLR5 occurred in human organoids and mice, and silent flagellin proteins were present in human stool. These flagellins were produced primarily by the abundant gut bacteria Lachnospiraceae and were enriched in nonindustrialized populations. Our findings provide a mechanism for the innate immune system to tolerate commensal-derived flagellins while remaining vigilant to the presence of flagellins produced by pathogens.

Development and implementation of a standardized process for identifying ambulatory pharmacy clinical outcomes measures.

PURPOSE: There is minimal available guidance on the process for selection of clinical outcomes measures to demonstrate the impact of clinic-based pharmacists (CBPs) despite an increased need and desire for outcomes data. The overall aims of this project were to (1) develop a standardized process for identifying clinical outcomes measures impacted by CBPs and (2) identify and prioritize potential clinical outcomes measures to track for CBPs within 4 specialty clinic pilot sites. METHODS: To develop a standardized process for identification and prioritization of measures, 4 consecutive Plan-Do-Study-Act (PDSA) cycles were performed with 4 different specialty clinics serving as pilot sites. Following each pilot cycle, rapid cycle improvements were implemented. A modified Delphi methodology served as the framework for measure selection and included gathering expert stakeholder insights regarding importance, feasibility, and validity of potential measures. Measures were identified via environmental scan of existing validated quality metrics, clinical guidelines, and other relevant literature. RESULTS: The primary outcome for this project was the development and refinement of a standardized process for measure identification and prioritization. The secondary outcome was narrowed and ranked lists of stakeholder-prioritized measures for 4 CBP-embedded pilot specialty clinics. These lists included 12 cardiothoracic transplant, 6 breast oncology, 9 neurology, and 7 gynecologic oncology measures. CONCLUSION: The measure identification and prioritization process developed was successfully utilized to identify and prioritize outcomes measures to track for 4 CBP-embedded specialty clinics. Due to the successful use of the process in a variety of specialty clinics, the standardized process has significant potential for expansion.

Representations of Complex Contexts: A Role for Hippocampus.

The hippocampus plays a critical role in supporting episodic memory, in large part by binding together experiences and items with surrounding contextual information. At present, however, little is known about the roles of different hippocampal subfields in supporting this item-context binding. To address this question, we constructed a task in which items were affiliated with differing types of context-cognitive associations that vary at the local, item level and membership in temporally organized lists that linked items together at a global level. Participants made item recognition judgments while undergoing high-resolution fMRI. We performed voxel pattern similarity analyses to answer the question of how human hippocampal subfields represent retrieved information about cognitive states and the time at which a past event took place. As participants recollected previously presented items, activity patterns in the CA23DG subregion carried information about prior cognitive states associated with these items. We found no evidence to suggest reinstatement of information about temporal context at the level of list membership, but exploratory analyses revealed representations of temporal context at a coarse level in conjunction with representations of cognitive contexts. Results are consistent with characterizations of CA23DG as a critical site for binding together items and contexts in the service of memory retrieval.

Endothelin-1 receptor blockade does not alter the sympathetic and hemodynamic response to acute intermittent hypoxia in men.

Repeat exposures to low oxygen (intermittent hypoxia, IH), like that observed in sleep apnea, elicit increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in men. Endothelin (ET) receptor antagonists can attenuate the sympathetic and BP response to IH in rodents; whether these data translate to humans are unclear. We hypothesized that ET-receptor antagonism would ameliorate any rise in MSNA and BP following acute IH in humans. Twelve healthy men (31 ± 1 yr) completed two visits (control, bosentan) separated by at least 1 wk. MSNA, BP, and baroreflex sensitivity (modified Oxford) were assessed during normoxic rest before and following 30 min of IH. The midpoint (T50) for each individual's baroreflex curve was calculated. Acute IH increased plasma ET-1 (P < 0.01), MSNA burst frequency (P = 0.03), and mean BP (P < 0.01). There was no effect of IH on baroreflex sensitivity (P = 0.46), although an increase in T50 was observed (P < 0.01). MSNA burst frequency was higher (P = 0.04) and mean BP (P < 0.01) was lower following bosentan treatment compared with control. There was no effect of bosentan on baroreflex sensitivity (P = 0.53), although a lower T50 was observed on the bosentan visit (P < 0.01). There was no effect of bosentan on increases in MSNA (P = 0.81) or mean BP (P = 0.12) following acute IH. Acute IH results in an increase in ET-1, MSNA, and BP in healthy young men. The effect of IH on MSNA and BP is not attenuated following ET-receptor inhibition. Present data suggest that acute IH does not increase MSNA or BP through activation of ET-receptors in healthy young men.NEW & NOTEWORTHY Repeat exposures to low oxygen (intermittent hypoxia, IH) elicit increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in men. Endothelin (ET) receptor antagonists can attenuate the sympathetic and BP response to IH in rodents; whether these data translate to humans were unclear. We show acute IH results in an increase in ET-1, MSNA, and BP in healthy young men; however, the effect of IH on MSNA and BP does not occur through activation of ET-receptors in healthy young men.

Utilization of BODIPY-based redox events to manipulate the Lewis acidity of fluorescent boranes.

This report describes the implementation of a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dye into the ligand framework of a borane. The redox-active nature of the BODIPY dye is utilized to generate a family of molecular boranes that are capable of exhibiting tunable Lewis acidities through BODIPY-based redox events.

Narratives bridge the divide between distant events in episodic memory.

Many studies suggest that information about past experience, or episodic memory, is divided into discrete units called "events." Yet we can often remember experiences that span multiple events. Events that occur in close succession might simply be linked because of their proximity to one another, but we can also build links between events that occur farther apart in time. Intuitively, some kind of organizing principle should enable temporally distant events to become bridged in memory. We tested the hypothesis that episodic memory exhibits a narrative-level organization, enabling temporally distant events to be better remembered if they form a coherent narrative. Furthermore, we tested whether post-encoding memory consolidation is necessary to integrate temporally distant events. In three experiments, participants learned and subsequently recalled events from fictional stories, in which pairs of temporally distant events involving side characters ("sideplots") either formed one coherent narrative or two unrelated narratives. Across participants, we varied whether recall was assessed immediately after learning, or after a delay: 24 hours, 12 hours between morning and evening ("wake"), or 12 hours between evening and morning ("sleep"). Participants recalled more information about coherent than unrelated narrative events, in most delay conditions, including immediate recall and wake conditions, suggesting that post-encoding consolidation was not necessary to integrate temporally distant events into a larger narrative. Furthermore, post hoc modeling across experiments suggested that narrative coherence facilitated recall over and above any effects of sentence-level semantic similarity. This reliable memory benefit for coherent narrative events supports theoretical accounts which propose that narratives provide a high-level architecture for episodic memory.

Intrinsic functional connectivity in the default mode network predicts mnemonic discrimination: A connectome-based modeling approach.

The ability to distinguish existing memories from similar perceptual experiences is a core feature of episodic memory. This ability is often examined using the mnemonic similarity task in which people discriminate memories of studied objects from perceptually similar lures. Studies of the neural basis of such mnemonic discrimination have mostly focused on hippocampal function and connectivity. However, default mode network (DMN) connectivity may also support such discrimination, given that the DMN includes the hippocampus, and its connectivity supports many aspects of episodic memory. Here, we used connectome-based predictive modeling to identify associations between intrinsic DMN connectivity and mnemonic discrimination. We leveraged a wide range of abilities across healthy younger and older adults to facilitate this predictive approach. Resting-state functional connectivity in the DMN predicted mnemonic discrimination outside the MRI scanner, especially among prefrontal and temporal regions and including several hippocampal regions. This predictive relationship was stronger for younger than older adults, primarily for temporal-prefrontal connectivity. The novel associations established here are consistent with mounting evidence that broader cortical networks including the hippocampus support mnemonic discrimination. They also suggest that age-related network disruptions undermine the extent that the DMN supports this ability. This study provides the first indication of how intrinsic functional properties of the DMN support mnemonic discrimination.

Multi-start Evolutionary Nonlinear OpTimizeR (MENOTR): A hybrid parameter optimization toolbox.

Parameter optimization or "data fitting" is a computational process that identifies a set of parameter values that best describe an experimental data set. Parameter optimization is commonly carried out using a computer program utilizing a non-linear least squares (NLLS) algorithm. These algorithms work by continuously refining a user supplied initial guess resulting in a systematic increase in the goodness of fit. A well-understood problem with this class of algorithms is that in the case of models with correlated parameters the optimized output parameters are initial guess dependent. This dependency can potentially introduce user bias into the resultant analysis. While many optimization programs exist, few address this dilemma. Here we present a data analysis tool, MENOTR, that is capable of overcoming the initial guess dependence in parameter optimization. Several case studies with published experimental data are presented to demonstrate the capabilities of this tool. The results presented here demonstrate how to effectively overcome the initial guess dependence of NLLS leading to greater confidence that the resultant optimized parameters are the best possible set of parameters to describe an experimental data set. While the optimization strategies implemented within MENOTR are not entirely novel, the application of these strategies to optimize parameters in kinetic and thermodynamic biochemical models is uncommon. MENOTR was designed to require minimal modification to accommodate a new model making it immediately accessible to researchers with a limited programming background. We anticipate that this toolbox can be used in a wide variety of data analysis applications. Prototype versions of this toolbox have been used in a number of published investigations already, as well as ongoing work with chemical-quenched flow, stopped-flow, and molecular tweezers data sets. STATEMENT OF SIGNIFICANCE: Non-linear least squares (NLLS) is a common form of parameter optimization in biochemistry kinetic and thermodynamic investigations These algorithms are used to fit experimental data sets and report corresponding parameter values. The algorithms are fast and able to provide good quality solutions for models involving few parameters. However, initial guess dependence is a well-known drawback of this optimization strategy that can introduce user bias. An alternative method of parameter optimization are genetic algorithms (GA). Genetic algorithms do not have an initial guess dependence but are slow at arriving at the best set of fit parameters. Here, we present MENOTR, a parameter optimization toolbox utilizing a hybrid GA/NLLS algorithm. The toolbox maximizes the strength of each strategy while minimizing the inherent drawbacks.

The hippocampus constructs narrative memories across distant events.

Life's events are scattered throughout time, yet we often recall different events in the context of an integrated narrative. Prior research suggests that the hippocampus, which supports memory for past events, can support the integration of overlapping associations or separate events in memory. However, the conditions that lead to hippocampus-dependent memory integration are unclear. We used functional brain imaging to test whether the opportunity to form a larger narrative (narrative coherence) drives hippocampal memory integration. During encoding of fictional stories, patterns of hippocampal activity, including activity at boundaries between events, were more similar between distant events that formed one coherent narrative, compared with overlapping events taken from unrelated narratives. One day later, the hippocampus preferentially supported detailed recall of coherent narrative events, through reinstatement of hippocampal activity patterns from encoding. These findings demonstrate a key function of the hippocampus: the integration of events into a narrative structure for memory.

Transient-state kinetic analysis of multi-nucleotide addition catalyzed by RNA polymerase I.

RNA polymerases execute the first step in gene expression: transcription of DNA into RNA. Eukaryotes, unlike prokaryotes, express at least three specialized nuclear multisubunit RNA polymerases (Pol I, Pol II, and Pol III). RNA polymerase I (Pol I) synthesizes the most abundant RNA, ribosomal RNA. Nearly 60% of total transcription is devoted to ribosomal RNA synthesis, making it one of the cell's most energy consuming tasks. While a kinetic mechanism for nucleotide addition catalyzed by Pol I has been reported, it remains unclear to what degree different nucleotide sequences impact the incorporation rate constants. Furthermore, it is currently unknown if the previous investigation of a single-nucleotide incorporation was sensitive to the translocation step. Here, we show that Pol I exhibits considerable variability in both kmax and K1/2values using an in vitro multi-NTP incorporation assay measuring AMP and GMP incorporations. We found the first two observed nucleotide incorporations exhibited faster kmax-values (∼200 s-1) compared with the remaining seven positions (∼60 s-1). Additionally, the average K1/2 for ATP incorporation was found to be approximately threefold higher compared with GTP, suggesting Pol I has a tighter affinity for GTP compared with ATP. Our results demonstrate that Pol I exhibits significant variability in the observed rate constant describing each nucleotide incorporation. Understanding of the differences between the Pol enzymes will provide insight on the evolutionary pressures that led to their specialized roles. Therefore, the findings resulting from this work are critically important for comparisons with other polymerases across all domains of life.

Free-Living, Psychrotrophic Bacteria of the Genus Psychrobacter Are Descendants of Pathobionts.

Host-adapted microorganisms are generally assumed to have evolved from free-living, environmental microorganisms, as examples of the reverse process are rare. In the phylum Gammaproteobacteria, family Moraxellaceae, the genus Psychrobacter includes strains from a broad ecological distribution including animal bodies as well as sea ice and other nonhost environments. To elucidate the relationship between these ecological niches and Psychrobacter's evolutionary history, we performed tandem genomic analyses with phenotyping of 85 Psychrobacter accessions. Phylogenomic analysis of the family Moraxellaceae reveals that basal members of the Psychrobacter clade are Moraxella spp., a group of often-pathogenic organisms. Psychrobacter exhibited two broad growth patterns in our phenotypic screen: one group that we called the "flexible ecotype" (FE) had the ability to grow between 4 and 37°C, and the other, which we called the "restricted ecotype" (RE), could grow between 4 and 25°C. The FE group includes phylogenetically basal strains, and FE strains exhibit increased transposon copy numbers, smaller genomes, and a higher likelihood to be bile salt resistant. The RE group contains only phylogenetically derived strains and has increased proportions of lipid metabolism and biofilm formation genes, functions that are adaptive to cold stress. In a 16S rRNA gene survey of polar bear fecal samples, we detect both FE and RE strains, but in in vivo colonizations of gnotobiotic mice, only FE strains persist. Our results indicate the ability to grow at 37°C, seemingly necessary for mammalian gut colonization, is an ancestral trait for Psychrobacter, which likely evolved from a pathobiont.IMPORTANCE Host-associated microbes are generally assumed to have evolved from free-living ones. The evolutionary transition of microbes in the opposite direction, from host associated toward free living, has been predicted based on phylogenetic data but not studied in depth. Here, we provide evidence that the genus Psychrobacter, particularly well known for inhabiting low-temperature, high-salt environments such as sea ice, permafrost soils, and frozen foodstuffs, has evolved from a mammalian-associated ancestor. We show that some Psychrobacter strains retain seemingly ancestral genomic and phenotypic traits that correspond with host association while others have diverged to psychrotrophic or psychrophilic lifestyles.

Tuning the reduction potentials of benzoquinone through the coordination to Lewis acids.

Electron transfer promoted by the coordination of a substrate molecule to a Lewis acid or hydrogen bonding group is a critical step in many biological and catalytic transformations. This computational study investigates the nature of the interaction between benzoquinone and one and two Lewis acids by examining the influence of Lewis acid strength on the ability to alter the two reduction potentials of the coordinated benzoquinone molecule. To investigate this interaction, the coordination of the neutral (Q), singly reduced ([Q]˙-), and doubly reduced benzoquinone ([Q]2-) molecule to eight Lewis acids was analyzed. Coordination of benzoquinone to a Lewis acid became more favorable by 25 kcal mol-1 with each reduction of the benzoquinone fragment. Coordination of benzoquinone to a Lewis acid also shifted each of the reduction potentials of the coordinated benzoquinone anodically by 0.50 to 1.5 V, depending on the strength of the Lewis acid, with stronger Lewis acids exhibiting a larger effect on the reduction potential. Coordination of a second Lewis acid further altered each of the reduction potentials by an additional 0.70 to 1.6 V. Replacing one of the Lewis acids with a proton resulted in the ability to modify the pKa of the protonated Lewis acid-Q/[Q]˙-/[Q]2- adducts by about 10 pKa units, in addition to being able to alter the ability to transfer a hydrogen atom by 10 kcal mol-1, and the capacity to transfer a hydride by about 30 kcal mol-1.

Defining the divergent enzymatic properties of RNA polymerases I and II.

Eukaryotes express at least three nuclear DNA-dependent RNA polymerases (Pols) responsible for synthesizing all RNA required by the cell. Despite sharing structural homology, they have functionally diverged to suit their distinct cellular roles. Although the Pols have been studied extensively, direct comparison of their enzymatic properties is difficult because studies are often conducted under disparate experimental conditions and techniques. Here, we directly compare and reveal functional differences between Saccharomyces cerevisiae Pols I and II using a series of quantitative in vitro transcription assays. We find that Pol I single-nucleotide and multinucleotide addition rate constants are faster than those of Pol II. Pol I elongation complexes are less stable than Pol II elongation complexes, and Pol I is more error prone than Pol II. Collectively, these data show that the enzymatic properties of the Pols have diverged over the course of evolution, optimizing these enzymes for their unique cellular responsibilities.