Phase 1 study of latozinemab in progranulin-associated frontotemporal dementia.

INTRODUCTION: Heterozygous mutations in the GRN gene lead to reduced progranulin (PGRN) levels in plasma and cerebrospinal fluid (CSF) and are causative of frontotemporal dementia (FTD) with > 90% penetrance. Latozinemab is a human monoclonal immunoglobulin G1 antibody that is being developed to increase PGRN levels in individuals with FTD caused by heterozygous loss-of-function GRN mutations. METHODS: A first-in-human phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple-dose intravenous administration of latozinemab in eight symptomatic participants with FTD caused by a heterozygous loss-of-function GRN mutation (FTD-GRN). RESULTS: Latozinemab demonstrated favorable safety and PK/PD profiles. Multiple-dose administration of latozinemab increased plasma and CSF PGRN levels in participants with FTD-GRN to levels that approximated those seen in healthy volunteers. DISCUSSION: Data from the first-in-human phase 1 study support further development of latozinemab for the treatment of FTD-GRN. Highlights: GRN mutations decrease progranulin (PGRN) and cause frontotemporal dementia (FTD).Latozinemab is being developed as a PGRN-elevating therapy.Latozinemab demonstrated a favorable safety profile in a phase 1 clinical trial.Latozinemab increased PGRN levels in the CNS of symptomatic FTD-GRN participants.

STARTRAC analyses of scRNAseq data from tumor models reveal T cell dynamics and therapeutic targets.

Single-cell RNA sequencing is a powerful tool to examine cellular heterogeneity, novel markers and target genes, and therapeutic mechanisms in human cancers and animal models. Here, we analyzed single-cell RNA sequencing data of T cells obtained from multiple mouse tumor models by PCA-based subclustering coupled with TCR tracking using the STARTRAC algorithm. This approach revealed various differentiated T cell subsets and activation states, and a correspondence of T cell subsets between human and mouse tumors. STARTRAC analyses demonstrated peripheral T cell subsets that were developmentally connected with tumor-infiltrating CD8+ cells, CD4+ Th1 cells, and T reg cells. In addition, large amounts of paired TCRα/ß sequences enabled us to identify a specific enrichment of paired public TCR clones in tumor. Finally, we identified CCR8 as a tumor-associated T reg cell marker that could preferentially deplete tumor-associated T reg cells. We showed that CCR8-depleting antibody treatment provided therapeutic benefit in CT26 tumors and synergized with anti-PD-1 treatment in MC38 and B16F10 tumor models.

Risk Overgeneralization in Times of a Contagious Disease Threat.

People's assessment of risks is swayed by their current feelings. COVID-19 invokes powerful feelings because it is (i) a salient, enormous threat, (ii) unfamiliar, and (iii) intertwined with xenophobia. These three factors are known to exert predictable influence on people's risk overgeneralization, policy preference, and sociopolitical attitudes. We provide a succinct, illustrative review of empirical work on these dynamics in times of a disease outbreak (e.g., the 2009 H1N1 swine flu, the 2014 Ebola). Theoretical and applied implications for the present COVID-19 pandemic include the value of salience in motivating public opinion change, the importance of reducing unfamiliarity for curbing risk-averse tendencies, and the need for policies that guard against xenophobia-driven racism in collaborative efforts.

Lineage tracking reveals dynamic relationships of T cells in colorectal cancer.

T cells are key elements of cancer immunotherapy1 but certain fundamental properties, such as the development and migration of T cells within tumours, remain unknown. The enormous T cell receptor (TCR) repertoire, which is required for the recognition of foreign and self-antigens2, could serve as lineage tags to track these T cells in tumours3. Here we obtained transcriptomes of 11,138 single T cells from 12 patients with colorectal cancer, and developed single T cell analysis by RNA sequencing and TCR tracking (STARTRAC) indices to quantitatively analyse the dynamic relationships among 20 identified T cell subsets with distinct functions and clonalities. Although both CD8+ effector and 'exhausted' T cells exhibited high clonal expansion, they were independently connected with tumour-resident CD8+ effector memory cells, implicating a TCR-based fate decision. Of the CD4+ T cells, most tumour-infiltrating T regulatory (Treg) cells showed clonal exclusivity, whereas certain Treg cell clones were developmentally linked to several T helper (TH) cell clones. Notably, we identified two IFNG+ TH1-like cell clusters in tumours that were associated with distinct IFNγ-regulating transcription factors -the GZMK+ effector memory T cells, which were associated with EOMES and RUNX3, and CXCL13+BHLHE40+ TH1-like cell clusters, which were associated with BHLHE40. Only CXCL13+BHLHE40+ TH1-like cells were preferentially enriched in patients with microsatellite-instable tumours, and this might explain their favourable responses to immune-checkpoint blockade. Furthermore, IGFLR1 was highly expressed in both CXCL13+BHLHE40+ TH1-like cells and CD8+ exhausted T cells and possessed co-stimulatory functions. Our integrated STARTRAC analyses provide a powerful approach to dissect the T cell properties in colorectal cancer comprehensively, and could provide insights into the dynamic relationships of T cells in other cancers.

Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing.

Systematic interrogation of tumor-infiltrating lymphocytes is key to the development of immunotherapies and the prediction of their clinical responses in cancers. Here, we perform deep single-cell RNA sequencing on 5,063 single T cells isolated from peripheral blood, tumor, and adjacent normal tissues from six hepatocellular carcinoma patients. The transcriptional profiles of these individual cells, coupled with assembled T cell receptor (TCR) sequences, enable us to identify 11 T cell subsets based on their molecular and functional properties and delineate their developmental trajectory. Specific subsets such as exhausted CD8+ T cells and Tregs are preferentially enriched and potentially clonally expanded in hepatocellular carcinoma (HCC), and we identified signature genes for each subset. One of the genes, layilin, is upregulated on activated CD8+ T cells and Tregs and represses the CD8+ T cell functions in vitro. This compendium of transcriptome data provides valuable insights and a rich resource for understanding the immune landscape in cancers.

Two faces of social-psychological realism.

This commentary places Jussim (2012) in dialogue with sociological perspectives on social reality and the political-academic nature of scientific paradigms. Specifically, we highlight how institutions, observers, and what is being observed intersect, and discuss the implications of this intersection on measurement within the social world. We then identify similarities between Jussim's specific narrative regarding social perception research, with noted patterns of scientific change.

Multiple Acid Sensors Control Helicobacter pylori Colonization of the Stomach.

Helicobacter pylori's ability to respond to environmental cues in the stomach is integral to its survival. By directly visualizing H. pylori swimming behavior when encountering a microscopic gradient consisting of the repellent acid and attractant urea, we found that H. pylori is able to simultaneously detect both signals, and its response depends on the magnitudes of the individual signals. By testing for the bacteria's response to a pure acid gradient, we discovered that the chemoreceptors TlpA and TlpD are each independent acid sensors. They enable H. pylori to respond to and escape from increases in hydrogen ion concentration near 100 nanomolar. TlpD also mediates attraction to basic pH, a response dampened by another chemoreceptor TlpB. H. pylori mutants lacking both TlpA and TlpD (ΔtlpAD) are unable to sense acid and are defective in establishing colonization in the murine stomach. However, blocking acid production in the stomach with omeprazole rescues ΔtlpAD's colonization defect. We used 3D confocal microscopy to determine how acid blockade affects the distribution of H. pylori in the stomach. We found that stomach acid controls not only the overall bacterial density, but also the microscopic distribution of bacteria that colonize the epithelium deep in the gastric glands. In omeprazole treated animals, bacterial abundance is increased in the antral glands, and gland colonization range is extended to the corpus. Our findings indicate that H. pylori has evolved at least two independent receptors capable of detecting acid gradients, allowing not only survival in the stomach, but also controlling the interaction of the bacteria with the epithelium.

Chemodetection and Destruction of Host Urea Allows Helicobacter pylori to Locate the Epithelium.

The gastric pathogen Helicobacter pylori interacts intimately with the gastric mucosa to avoid the microbicidal acid in the stomach lumen. The cues H. pylori senses to locate and colonize the gastric epithelium have not been well defined. We show that metabolites emanating from human gastric organoids rapidly attract H. pylori. This response is largely controlled by the bacterial chemoreceptor TlpB, and the main attractant emanating from epithelia is urea. Our previous structural analyses show that TlpB binds urea with high affinity. Here we demonstrate that this tight binding controls highly sensitive responses, allowing detection of urea concentrations as low as 50 nM. Attraction to urea requires that H. pylori urease simultaneously destroys the signal. We propose that H. pylori has evolved a sensitive urea chemodetection and destruction system that allows the bacterium to dynamically and locally modify the host environment to locate the epithelium.

Chemorepulsion from the Quorum Signal Autoinducer-2 Promotes Helicobacter pylori Biofilm Dispersal.

UNLABELLED: The gastric pathogen Helicobacter pylori forms biofilms on abiotic and biotic surfaces. We have shown previously that H. pylori perceives the quorum signal autoinducer-2 (AI-2) as a chemorepellent. We report here that H. pylori chemorepulsion from endogenous AI-2 influences the proportions and spatial organization of cells within biofilms. Strains that fail to produce AI-2 (∆luxS strains) or are defective for chemotaxis (∆cheA strains) formed more spatially homogenous biofilms with a greater proportion of adherent versus planktonic cells than wild-type biofilms. Reciprocally, a strain that overproduced AI-2 (luxS(OP)) formed biofilms with proportionally fewer adherent cells. Along with the known AI-2 chemoreceptor, TlpB, we identified AibA and AibB, two novel periplasmic binding proteins that are required for the AI-2 chemorepulsion response. Disruptions in any of the proteins required for AI-2 chemotaxis recapitulated the biofilm adherence and spatial organization phenotype of the ∆luxS mutant. Furthermore, exogenous administration of AI-2 was sufficient to decrease the proportion of adherent cells in biofilms and promote dispersal of cells from biofilms in a chemotaxis-dependent manner. Finally, we found that disruption of AI-2 production or AI-2 chemotaxis resulted in increased clustering of cells in microcolonies on cultured epithelial cells. We conclude that chemotaxis from AI-2 is a determinant of H. pylori biofilm spatial organization and dispersal. IMPORTANCE: Bacterial biofilms are ubiquitous in nature, but the mechanisms governing their assembly and spatial organization are not fully understood. Bacterial communication through quorum sensing has been shown to influence biofilm growth through the regulation of biofilm genes. Our study revealed a new role for quorum sensing in biofilms through rapid chemotactic responses to quorum signals. Specifically, we studied how chemorepulsion of Helicobacter pylori from the universal quorum signal autoinducer-2 (AI-2) shapes the spatial organization of its biofilms. We demonstrate that the chemorepulsive response of H. pylori to AI-2 is necessary to promote its dispersal from biofilms grown on both abiotic and biotic surfaces and is sufficient to promote dispersal in a chemotaxis-dependent manner. This work has broad implications for understanding the mechanisms by which endogenously produced microbial compounds shape the assembly and spatial organization of microbial communities in their environments.

Authors' response: multitudes of perspectives: integrating the Selfish Goal model with views on scientific metaphors, goal systems, and society.

In our response, we address commentators' feedback regarding the contributions and limitations of the Selfish Goal model. We first clarify potential misunderstandings regarding the model's contributions and the role of consciousness. Second, we situate evaluations of the selfish metaphor within the similarities and differences inherent to the goal-gene comparison. We then respond to commentators' insights regarding future directions and implications of our model, particularly with respect to the broader organizational systems in which goals may operate. Finally, we reiterate important considerations for goal research moving forward.

The Selfish Goal: autonomously operating motivational structures as the proximate cause of human judgment and behavior.

We propose the Selfish Goal model, which holds that a person's behavior is driven by psychological processes called goals that guide his or her behavior, at times in contradictory directions. Goals can operate both consciously and unconsciously, and when activated they can trigger downstream effects on a person's information processing and behavioral possibilities that promote only the attainment of goal end-states (and not necessarily the overall interests of the individual). Hence, goals influence a person as if the goals themselves were selfish and interested only in their own completion. We argue that there is an evolutionary basis to believe that conscious goals evolved from unconscious and selfish forms of pursuit. This theoretical framework predicts the existence of unconscious goal processes capable of guiding behavior in the absence of conscious awareness and control (the automaticity principle), the ability of the most motivating or active goal to constrain a person's information processing and behavior toward successful completion of that goal (the reconfiguration principle), structural similarities between conscious and unconscious goal pursuit (the similarity principle), and goal influences that produce apparent inconsistencies or counterintuitive behaviors in a person's behavior extended over time (the inconsistency principle). Thus, we argue that a person's behaviors are indirectly selected at the goal level but expressed (and comprehended) at the individual level.

Superman to the rescue: Simulating physical invulnerability attenuates exclusion-related interpersonal biases.

People cope with social exclusion both by seeking reconnection with familiar individuals and by denigrating unfamiliar and disliked others. These reactions can be seen as adaptive responses in ancestral environments where ostracism exposed people to physical dangers and even death. To the extent that reactions to ostracism evolved to minimize exposure to danger, alleviating these foundational concerns with danger may lessen people's need to cope with exclusion. Three studies demonstrate how a novel physical invulnerability simulation lessens both positive and negative reactions to social exclusion. Study 1 found that simulating physical invulnerability lessened exclusion-triggered negative attitudes toward stigmatized groups, and demonstrated that perceived invulnerability to injury (vs. imperviousness to pain) accounted for this effect. Studies 2 and 3 focused on another facet of social bias by revealing that simulating physical invulnerability lessened the desire for social connection.

Shift from widespread symbiont infection of host tissues to specific colonization of gills in juvenile deep-sea mussels.

The deep-sea mussel Bathymodiolus harbors chemosynthetic bacteria in its gills that provide it with nutrition. Symbiont colonization is assumed to occur in early life stages by uptake from the environment, but little is known about this process. In this study, we used fluorescence in situ hybridization to examine symbiont distribution and the specificity of the infection process in juvenile B. azoricus and B. puteoserpentis (4-21 mm). In the smallest juveniles, we observed symbionts, but no other bacteria, in a wide range of epithelial tissues. This suggests that despite the widespread distribution of symbionts in many different juvenile organs, the infection process is highly specific and limited to the symbiotic bacteria. Juveniles ≥ 9 mm only had symbionts in their gills, indicating an ontogenetic shift in symbiont colonization from indiscriminate infection of almost all epithelia in early life stages to spatially restricted colonization of gills in later developmental stages.

Immunizing against prejudice: effects of disease protection on attitudes toward out-groups.

Contemporary interpersonal biases are partially derived from psychological mechanisms that evolved to protect people against the threat of contagious disease. This behavioral immune system effectively promotes disease avoidance but also results in an overgeneralized prejudice toward people who are not legitimate carriers of disease. In three studies, we tested whether experiences with two modern forms of disease protection (vaccination and hand washing) attenuate the relationship between concerns about disease and prejudice against out-groups. Study 1 demonstrated that when threatened with disease, vaccinated participants exhibited less prejudice toward immigrants than unvaccinated participants did. In Study 2, we found that framing vaccination messages in terms of immunity eliminated the relationship between chronic germ aversion and prejudice. In Study 3, we directly manipulated participants' protection from disease by having some participants wash their hands and found that this intervention significantly influenced participants' perceptions of out-group members. Our research suggests that public-health interventions can benefit society in areas beyond immediate health-related domains by informing novel, modern remedies for prejudice.

The human commensal Bacteroides fragilis binds intestinal mucin.

The mammalian gastrointestinal tract harbors a vast microbial ecosystem, known as the microbiota, which benefits host biology. Bacteroides fragilis is an important anaerobic gut commensal of humans that prevents and cures intestinal inflammation. We wished to elucidate aspects of gut colonization employed by B. fragilis. Fluorescence in situ hybridization was performed on colonic tissue sections from B. fragilis and Escherichia coli dual-colonized gnotobiotic mice. Epifluorescence imaging reveals that both E. coli and B. fragilis are found in the lumen of the colon, but only B. fragilis is found in the mucosal layer. This observation suggests that physical association with intestinal mucus could be a possible mechanism of gut colonization by B. fragilis. We investigated this potential interaction using an in vitro mucus binding assay and show here that B. fragilis binds to murine colonic mucus. We further demonstrate that B. fragilis specifically and quantitatively binds to highly purified mucins (the major constituent in intestinal mucus) using flow cytometry analysis of fluorescently labeled purified murine and porcine mucins. These results suggest that interactions between B. fragilis and intestinal mucin may play a critical role during host-bacterial symbiosis.

Smooth Trajectories Travel Farther into the Future: Perceptual Fluency Effects on Prediction of Trend Continuation.

This research examines how processing fluency influences people's perceptions of whether a trend will continue into the future. Specifically, three studies hypothesized that people who read descriptions of increasing or decreasing trends in easy-to-read font would be more likely to predict that the trend would continue into the future, compared to people exposed to difficult-to-read font. Studies 1 and 2 establish this effect for an increasing trend, whereas Study 3 replicates the findings with a decreasing trend. Taken together, these results suggest processing fluency as a factor that affects assessment of future potential.

The Scaffolded Mind: Higher mental processes are grounded in early experience of the physical world.

It has long been a staple of psychological theory that early life experiences significantly shape the adult's understanding of and reactions to the social world. Here we consider how early concept development along with evolved motives operating early in life can come to exert a passive, unconscious influence on the human adult's higher-order goal pursuits, judgments, and actions. In particular, we focus on concepts and goal structures specialized for interacting with the physical environment (e.g., distance cues, temperature, cleanliness, and self-protection), which emerge early and automatically as a natural part of human development and evolution. It is proposed that via the process of scaffolding, these early sensorimotor experiences serve as the foundation for the later development of more abstract concepts and goals. Experiments using priming methodologies reveal the extent to which these early concepts serve as the analogical basis for more abstract psychological concepts, such that we come easily and naturally to speak of close relationships, warm personalities, moral purity, and psychological pain. Taken together, this research demonstrates the extent to which such foundational concepts are capable of influencing people's information processing, affective judgments, and goal pursuit, oftentimes outside of their intention or awareness.

Peak of desire: activating the mating goal changes life-stage preferences across living kinds.

In three studies, we explored the existence of an evolved sensitivity to the peak that would be consistent with the evolutionary origins of many basic human preferences. Activating the evolved motive of mating activates related adaptive mechanisms, including a general sensitivity to cues of growth and decay associated with determining mate value in human courtship. These studies show that priming the mating goal also activates an evaluative bias that influences how people evaluate cues of growth. Specifically, living kinds that are immature or past their prime are devalued, whereas living kinds that are at their peak become increasingly valued. Study 1 establishes this goal-driven effect for human stimuli indirectly related to the mating goal. Studies 2 and 3 establish that the evaluative bias produced by the activated mating goal extends to living kinds, but not artifacts.

The positives of negative emotions: willingness to express negative emotions promotes relationships.

Four studies support the hypothesis that expressing negative emotion is associated with positive relationship outcomes, including elicitation of support, building of new close relationships, and heightening of intimacy in the closest of those relationships. In Study 1, participants read vignettes in which another person was experiencing a negative emotion. Participants reported they would provide more help when the person chose to express the negative emotion. In Study 2, participants watched a confederate preparing for a speech. Participants provided more help to her when she expressed nervousness. In Study 3, self-reports of willingness to express negative emotions predicted having more friends, controlling for demographic variables and extraversion. In Study 4, self-reports of willingness to express negative emotion measured prior to arrival at college predicted formation of more relationships, greater intimacy in the closest of those relationships, and greater received support from roommates across participants' first semester of college.