Attentional Orienting and Disfluency-Related Memory Boost Are Intact in Adults With Moderate-Severe Traumatic Brain Injury.

PURPOSE: Traumatic brain injury (TBI) is associated with a range of cognitive-communicative deficits that interfere with everyday communication and social interaction. Considerable effort has been directed at characterizing the nature and scope of cognitive-communication disorders in TBI, yet the underlying mechanisms of impairment are largely unspecified. The present research examines sensitivity to a common communicative cue, disfluency, and its impact on memory for spoken language in TBI. METHOD: Fifty-three participants with moderate-severe TBI and 53 noninjured comparison participants listened to a series of sentences, some of which contained disfluencies. A subsequent memory test probed memory for critical words in the sentences. RESULTS: Participants with TBI successfully remembered the spoken words (b = 1.57, p < .0001) at a similar level to noninjured comparison participants. Critically, participants with TBI also exhibited better recognition memory for words preceded by disfluency compared to words from fluent sentences (b = 0.57, p = .02). CONCLUSIONS: These findings advance mechanistic accounts of cognitive-communication disorder by revealing that, when isolated for experimental study, individuals with moderate-severe TBI are sensitive to attentional orienting cues in speech and exhibit enhanced recognition of individual words preceded by disfluency. These results suggest that some aspects of cognitive-communication disorders may not emerge from an inability to perceive and use individual communication cues, but rather from disruptions in managing (i.e., attending, weighting, integrating) multiple cognitive, communicative, and social cues in complex and dynamic interactions. This hypothesis warrants further investigation.

CCR3-dependent eosinophil recruitment is regulated by sialyltransferase ST3Gal-IV.

Eosinophil recruitment is a pathological hallmark of many allergic and helminthic diseases. Here, we investigated chemokine receptor CCR3-induced eosinophil recruitment in sialyltransferase St3gal4-/- mice. We found a marked decrease in eosinophil extravasation into CCL11-stimulated cremaster muscles and into the inflamed peritoneal cavity of St3gal4-/- mice. Ex vivo flow chamber assays uncovered reduced adhesion of St3gal4-/- compared to wild type eosinophils. Using flow cytometry, we show reduced binding of CCL11 to St3gal4-/- eosinophils. Further, we noted reduced binding of CCL11 to its chemokine receptor CCR3 isolated from St3gal4-/- eosinophils. This was accompanied by almost absent CCR3 internalization of CCL11-stimulated St3gal4-/- eosinophils. Applying an ovalbumin-induced allergic airway disease model, we found a dramatic reduction in eosinophil numbers in bronchoalveolar lavage fluid following intratracheal challenge with ovalbumin in St3gal4-deficient mice. Finally, we also investigated tissue-resident eosinophils under homeostatic conditions and found reduced resident eosinophil numbers in the thymus and adipose tissue in the absence of ST3Gal-IV. Taken together, our results demonstrate an important role of ST3Gal-IV in CCR3-induced eosinophil recruitment in vivo rendering this enzyme an attractive target in reducing unwanted eosinophil infiltration in various disorders including allergic diseases.

Preclinical evaluation of two phylogenetically distant arenavirus vectors for the development of novel immunotherapeutic combination strategies for cancer treatment.

BACKGROUND: Engineered arenavirus vectors have recently been developed to leverage the body's immune system in the fight against chronic viral infections and cancer. Vectors based on Pichinde virus (artPICV) and lymphocytic choriomeningitis virus (artLCMV) encoding a non-oncogenic fusion protein of human papillomavirus (HPV)16 E6 and E7 are currently being tested in patients with HPV16+ cancer, showing a favorable safety and tolerability profile and unprecedented expansion of tumor-specific CD8+ T cells. Although the strong antigen-specific immune response elicited by artLCMV vectors has been demonstrated in several preclinical models, PICV-based vectors are much less characterized. METHODS: To advance our understanding of the immunobiology of these two vectors, we analyzed and compared their individual properties in preclinical in vivo and in vitro systems. Immunogenicity and antitumor effect of intratumoral or intravenous administration of both vectors, as well as combination with NKG2A blockade, were evaluated in naïve or TC-1 mouse tumor models. Flow cytometry, Nanostring, and histology analysis were performed to characterize the tumor microenvironment (TME) and T-cell infiltrate following treatment. RESULTS: Despite being phylogenetically distant, both vectors shared many properties, including preferential infection and activation of professional antigen-presenting cells, and induction of potent tumor-specific CD8+ T-cell responses. Systemic as well as localized treatment induced a proinflammatory shift in the TME, promoting the infiltration of inducible T cell costimulator (ICOS)+CD8+ T cells capable of mediating tumor regression and prolonging survival in a TC-1 mouse tumor model. Still, there was evidence of immunosuppression built-up over time, and increased expression of H2-T23 (ligand for NKG2A T cell inhibitory receptor) following treatment was identified as a potential contributing factor. NKG2A blockade improved the antitumor efficacy of artARENA vectors, suggesting a promising new combination approach. This demonstrates how detailed characterization of arenavirus vector-induced immune responses and TME modulation can inform novel combination therapies. CONCLUSIONS: The artARENA platform represents a strong therapeutic vaccine approach for the treatment of cancer. The induced antitumor immune response builds the backbone for novel combination therapies, which warrant further investigation.

Benign synthesis of terpene-based 1,4-p-menthane diamine.

Terpenes represent a promising renewable feedstock for the substitution of fossil resources in the synthesis of renewable platform chemicals, like diamines. This work describes the synthesis and full characterization of 1,4-p-menthane diamine (1,4-PMD) obtained from α-terpinene (1). A two-step procedure using dibenzyl azodicarboxylate (DBAD) and H2 as rather benign reagents was employed under comparatively mild conditions. Both C-N bonds were formed simultaneously during a visible-light mediated Diels-Alder reaction, which was investigated in batch or flow, avoiding regioselectivity issues during the amination steps that are otherwise typical for terpene chemistry. Heterogeneously catalyzed quadruple hydrogenation of the cycloadduct (2a) yielded 1,4­PMD (3). While the intermediate cycloadduct was shown to be distillable, the target diamine can be sublimed, offering sustainable purification methods.

Teletherapy Used to Breakdown Access Barriers.

The studies presented in this literature review reveal the numerous ways that teletherapy can be used to treat patients with mental health issues. The literature includes six research articles from published scientific journals that span from 2005 to 2020. The three types of telehealth therapy reviewed include mobile telehealth, telephone, and video technology. The six research articles focus on the ways that telehealth can reach communities of lower socioeconomic status (SES) and those suffering from access barriers. The benefits of teletherapy include cost savings, time efficiency, easier access, and a reduction in recidivism. Challenges include access barriers, financial difficulties, anxiety, and fear of stigmatization. Limitations of the studies presented include a lack of accessibility to internet and technology, privacy issues, and insurance coverage. Overall, results show that teletherapy provides an affordable, accessible alternative to traditional in-person mental health therapy, especially in reaching lower SES groups, Veterans, and patients with access restrictions.

Linguistic features of spontaneous speech predict conversational recall.

Empirical studies of conversational recall show that the amount of conversation that can be recalled after a delay is limited and biased in favor of one's own contributions. What aspects of a conversational interaction shape what will and will not be recalled? This study aims to predict the contents of conversation that will be recalled based on linguistic features of what was said. Across 59 conversational dyads, we observed that two linguistic features that are hallmarks of interactive language use-disfluency (um/uh) and backchannelling (ok, yeah)-promoted recall. Two other features-disagreements between the interlocutors and use of "like"-were not predictive of recall. While self-generated material was better remembered overall, both hearing and producing disfluency and backchannels improved memory for the associated utterances. Finally, the disfluency-related memory boost was similar regardless of the number of disfluencies in the utterance. Overall, we conclude that interactional linguistic features of conversation are predictive of what is and is not recalled following conversation.

Alcohol and common ground: The effects of intoxication on linguistic markers of shared understanding during social exchange.

OBJECTIVE: Most alcohol consumption takes place in social contexts, and the belief that alcohol enhances social interactions has been identified as among the more robust predictors of alcohol use disorder (AUD) development. Yet, we know little of how alcohol affects mental representations of others-what we share and do not share-nor the extent to which intoxication might impact the development of shared understanding (i.e., common ground) between interaction partners. Employing a randomized experimental design and objective linguistic outcome measures, we present two studies examining the impact of alcohol consumption on the development and use of common ground. METHOD: In Study 1, groups of strangers or friends were administered either alcohol (target Breath Alcohol Content = .08%) or a control beverage, following which they completed a task requiring them to develop a shared language to describe ambiguous images and then describe those images to either a knowledgeable or a naïve partner. The same procedures were completed in Study 2 using a within-subjects alcohol administration design and all-stranger groups. RESULTS: Study 1 findings did not reach significance but suggested that alcohol may facilitate common ground development selectively among stranger groups. This effect emerged as significant in the context of the within-subjects design of Study 2, b = -0.19, p = .007, with participants demonstrating greater facility in establishing common ground during alcohol versus control sessions. CONCLUSIONS: Results suggest that alcohol facilitates the development of shared linguistic understanding in novel social spaces, indicating common ground as one potential mechanism to consider in our broader examination of alcohol reinforcement and AUD etiology. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A replicating LCMV-based vaccine for the treatment of solid tumors.

Harnessing the immune system to eradicate tumors requires identification and targeting of tumor antigens, including tumor-specific neoantigens and tumor-associated self-antigens. Tumor-associated antigens are subject to existing immune tolerance, which must be overcome by immunotherapies. Despite many novel immunotherapies reaching clinical trials, inducing self-antigen-specific immune responses remains challenging. Here, we systematically investigate viral-vector-based cancer vaccines encoding a tumor-associated self-antigen (TRP2) for the treatment of established melanomas in preclinical mouse models, alone or in combination with adoptive T cell therapy. We reveal that, unlike foreign antigens, tumor-associated antigens require replication of lymphocytic choriomeningitis virus (LCMV)-based vectors to break tolerance and induce effective antigen-specific CD8+ T cell responses. Immunization with a replicating LCMV vector leads to complete tumor rejection when combined with adoptive TRP2-specific T cell transfer. Importantly, immunization with replicating vectors leads to extended antigen persistence in secondary lymphoid organs, resulting in efficient T cell priming, which renders previously "cold" tumors open to immune infiltration and reprograms the tumor microenvironment to "hot." Our findings have important implications for the design of next-generation immunotherapies targeting solid cancers utilizing viral vectors and adoptive cell transfer.

Alternating Arenavirus Vector Immunization Generates Robust Polyfunctional Genotype Cross-Reactive Hepatitis B Virus-Specific CD8 T-Cell Responses and High Anti-Hepatitis B Surface Antigen Titers.

Hepatitis B Virus (HBV) is a major driver of infectious disease mortality. Curative therapies are needed and ideally should induce CD8 T cell-mediated clearance of infected hepatocytes plus anti-hepatitis B surface antigen (HBsAg) antibodies (anti-HBs) to neutralize residual virus. We developed a novel therapeutic vaccine using non-replicating arenavirus vectors. Antigens were screened for genotype conservation and magnitude and genotype reactivity of T cell response, then cloned into Pichinde virus (PICV) vectors (recombinant PICV, GS-2829) and lymphocytic choriomeningitis virus (LCMV) vectors (replication-incompetent, GS-6779). Alternating immunizations with GS-2829 and GS-6779 induced high-magnitude HBV T cell responses, and high anti-HBs titers. Dose schedule optimization in macaques achieved strong polyfunctional CD8 T cell responses against core, HBsAg, and polymerase and high titer anti-HBs. In AAV-HBV mice, GS-2829 and GS-6779 were efficacious in animals with low pre-treatment serum HBsAg. Based on these results, GS-2829 and GS-6779 could become a central component of cure regimens.

PhenoID, a language model normalizer of physical examinations from genetics clinical notes.

Background: Phenotypes identified during dysmorphology physical examinations are critical to genetic diagnosis and nearly universally documented as free-text in the electronic health record (EHR). Variation in how phenotypes are recorded in free-text makes large-scale computational analysis extremely challenging. Existing natural language processing (NLP) approaches to address phenotype extraction are trained largely on the biomedical literature or on case vignettes rather than actual EHR data. Methods: We implemented a tailored system at the Children's Hospital of Philadelpia that allows clinicians to document dysmorphology physical exam findings. From the underlying data, we manually annotated a corpus of 3136 organ system observations using the Human Phenotype Ontology (HPO). We provide this corpus publicly. We trained a transformer based NLP system to identify HPO terms from exam observations. The pipeline includes an extractor, which identifies tokens in the sentence expected to contain an HPO term, and a normalizer, which uses those tokens together with the original observation to determine the specific term mentioned. Findings: We find that our labeler and normalizer NLP pipeline, which we call PhenoID, achieves state-of-the-art performance for the dysmorphology physical exam phenotype extraction task. PhenoID's performance on the test set was 0.717, compared to the nearest baseline system (Pheno-Tagger) performance of 0.633. An analysis of our system's normalization errors shows possible imperfections in the HPO terminology itself but also reveals a lack of semantic understanding by our transformer models. Interpretation: Transformers-based NLP models are a promising approach to genetic phenotype extraction and, with recent development of larger pre-trained causal language models, may improve semantic understanding in the future. We believe our results also have direct applicability to more general extraction of medical signs and symptoms. Funding: US National Institutes of Health.

Keeping track of who knows what in multiparty conversation despite severe memory impairment.

Language use has long been understood to be tailored to the intended addressee, a process termed audience design. Audience design is reflected in multiple aspects of language use, including adjustments based on the addressee's knowledge about the topic at hand. In group settings, audience design depends on representations of multiple individuals, each of whom may have different knowledge about the conversational topic. A central question, then, concerns how these representations are encoded and retrieved in multiparty conversation where successful conversation requires keeping track of who knows what. In the present research, we probe the biological memory systems that are involved in this process of multiparty audience design. We present the results of two experiments that compare language use in persons with bilateral hippocampal damage and severe declarative memory impairment (amnesia), and demographically matched neurotypical comparison participants. Participants played a game in which they discussed abstract images with one partner in conversation, and then discussed the images again with the same partner or with a new partner in a three-party conversation. Neurotypical participants' language use reflected newly formed representations of which partner was familiar with which images. Participants with amnesia showed evidence of partner-specific audience design in multiparty conversation but it was attenuated, especially when success required rapid alternations between representations of common ground. The findings suggest partial independence of the formation and use of partner-specific representations from the hippocampal-dependent declarative memory system and highlight the unique contributions of the declarative memory system to flexible and dynamic language use.

Immunogenic arenavirus vector SIV vaccine reduces setpoint viral load in SIV-challenged rhesus monkeys.

HIV affects more than 38 million people worldwide. Although HIV can be effectively treated by lifelong combination antiretroviral therapy, only a handful of patients have been cured. Therapeutic vaccines that induce robust de novo immune responses targeting HIV proteins and latent reservoirs will likely be integral for functional HIV cure. Our study shows that immunization of naïve rhesus macaques with arenavirus-derived vaccine vectors encoding simian immunodeficiency virus (SIVSME543 Gag, Env, and Pol) immunogens is safe, immunogenic, and efficacious. Immunization induced robust SIV-specific CD8+ and CD4+ T-cell responses with expanded cellular breadth, polyfunctionality, and Env-binding antibodies with antibody-dependent cellular cytotoxicity. Vaccinated animals had significant reductions in median SIV viral load (1.45-log10 copies/mL) after SIVMAC251 challenge compared with placebo. Peak viral control correlated with the breadth of Gag-specific T cells and tier 1 neutralizing antibodies. These results support clinical investigation of arenavirus-based vectors as a central component of therapeutic vaccination for HIV cure.

Memory for social media images following traumatic brain injury.

PRIMARY OBJECTIVE: An emerging body of research examines the role of computer-mediated communication in supporting social connection in persons with traumatic brain injury (TBI). We examine the cognitive impacts of engaging with images posted to social media for persons with moderate-severe TBI. RESEARCH DESIGN: Prior work shows that after viewing social media posts, adults have better memory for posts when they generate a comment about the post. We examined if persons with TBI experience a memory benefit for commented-upon social media images similar to non-injured comparison participants. METHODS AND PROCEDURES: 53 persons with moderate-to-severe TBI and 52 non-injured comparison participants viewed arrays of real social media images and were prompted to comment on some of them. After a brief delay, a surprise two-alternative forced choice recognition memory test measured memory for these images. MAIN OUTCOMES AND RESULTS: Persons with TBI remembered social media images at above-chance levels and experienced a commenting-related memory boost much like non-injured comparison participants. CONCLUSIONS: These findings add to a growing literature on the potential benefits of social media use in individuals with TBI and point to the benefits of active engagement for memory in social media contexts in TBI.

On the reproducibility of extrusion-based bioprinting: round robin study on standardization in the field.

The outcome of three-dimensional (3D) bioprinting heavily depends, amongst others, on the interaction between the developed bioink, the printing process, and the printing equipment. However, if this interplay is ensured, bioprinting promises unmatched possibilities in the health care area. To pave the way for comparing newly developed biomaterials, clinical studies, and medical applications (i.e. printed organs, patient-specific tissues), there is a great need for standardization of manufacturing methods in order to enable technology transfers. Despite the importance of such standardization, there is currently a tremendous lack of empirical data that examines the reproducibility and robustness of production in more than one location at a time. In this work, we present data derived from a round robin test for extrusion-based 3D printing performance comprising 12 different academic laboratories throughout Germany and analyze the respective prints using automated image analysis (IA) in three independent academic groups. The fabrication of objects from polymer solutions was standardized as much as currently possible to allow studying the comparability of results from different laboratories. This study has led to the conclusion that current standardization conditions still leave room for the intervention of operators due to missing automation of the equipment. This affects significantly the reproducibility and comparability of bioprinting experiments in multiple laboratories. Nevertheless, automated IA proved to be a suitable methodology for quality assurance as three independently developed workflows achieved similar results. Moreover, the extracted data describing geometric features showed how the function of printers affects the quality of the printed object. A significant step toward standardization of the process was made as an infrastructure for distribution of material and methods, as well as for data transfer and storage was successfully established.

Items Outperform Adjectives in a Computational Model of Binary Semantic Classification.

Semantic memory encompasses one's knowledge about the world. Distributional semantic models, which construct vector spaces with embedded words, are a proposed framework for understanding the representational structure of human semantic knowledge. Unlike some classic semantic models, distributional semantic models lack a mechanism for specifying the properties of concepts, which raises questions regarding their utility for a general theory of semantic knowledge. Here, we develop a computational model of a binary semantic classification task, in which participants judged target words for the referent's size or animacy. We created a family of models, evaluating multiple distributional semantic models, and mechanisms for performing the classification. The most successful model constructed two composite representations for each extreme of the decision axis (e.g., one averaging together representations of characteristically big things and another of characteristically small things). Next, the target item was compared to each composite representation, allowing the model to classify more than 1,500 words with human-range performance and to predict response times. We propose that when making a decision on a binary semantic classification task, humans use task prompts to retrieve instances representative of the extremes on that semantic dimension and compare the probe to those instances. This proposal is consistent with the principles of the instance theory of semantic memory.

Intact speech-gesture integration in narrative recall by adults with moderate-severe traumatic brain injury.

PURPOSE: Real-world communication is situated in rich multimodal contexts, containing speech and gesture. Speakers often convey unique information in gesture that is not present in the speech signal (e.g., saying "He searched for a new recipe" while making a typing gesture). We examine the narrative retellings of participants with and without moderate-severe traumatic brain injury across three timepoints over two online Zoom sessions to investigate whether people with TBI can integrate information from co-occurring speech and gesture and if information from gesture persists across delays. METHODS: 60 participants with TBI and 60 non-injured peers watched videos of a narrator telling four short stories. On key details, the narrator produced complementary gestures that conveyed unique information. Participants retold the stories at three timepoints: immediately after, 20-min later, and one-week later. We examined the words participants used when retelling these key details, coding them as a Speech Match (e.g., "He searched for a new recipe"), a Gesture Match (e.g., "He searched for a new recipe online), or Other ("He looked for a new recipe"). We also examined whether participants produced representative gestures themselves when retelling these details. RESULTS: Despite recalling fewer story details, participants with TBI were as likely as non-injured peers to report information from gesture in their narrative retellings. All participants were more likely to report information from gesture and produce representative gestures themselves one-week later compared to immediately after hearing the story. CONCLUSION: We demonstrated that speech-gesture integration is intact after TBI in narrative retellings. This finding has exciting implications for the utility of gesture to support comprehension and memory after TBI and expands our understanding of naturalistic multimodal language processing in this population.

Antioxidants stimulate BACH1-dependent tumor angiogenesis.

Lung cancer progression relies on angiogenesis, which is a response to hypoxia typically coordinated by hypoxia-inducible transcription factors (HIFs), but growing evidence indicates that transcriptional programs beyond HIFs control tumor angiogenesis. Here, we show that the redox-sensitive transcription factor BTB and CNC homology 1 (BACH1) controls the transcription of a broad range of angiogenesis genes. BACH1 is stabilized by lowering ROS levels; consequently, angiogenesis gene expression in lung cancer cells, tumor organoids, and xenograft tumors increased substantially following administration of vitamins C and E and N-acetylcysteine in a BACH1-dependent fashion under normoxia. Moreover, angiogenesis gene expression increased in endogenous BACH1-overexpressing cells and decreased in BACH1-knockout cells in the absence of antioxidants. BACH1 levels also increased upon hypoxia and following administration of prolyl hydroxylase inhibitors in both HIF1A-knockout and WT cells. BACH1 was found to be a transcriptional target of HIF1α, but BACH1's ability to stimulate angiogenesis gene expression was HIF1α independent. Antioxidants increased tumor vascularity in vivo in a BACH1-dependent fashion, and overexpressing BACH1 rendered tumors sensitive to antiangiogenesis therapy. BACH1 expression in tumor sections from patients with lung cancer correlated with angiogenesis gene and protein expression. We conclude that BACH1 is an oxygen- and redox-sensitive angiogenesis transcription factor.

Milling Medium-Free Suzuki Coupling by Direct Mechanocatalysis: From Mixer Mills to Resonant Acoustic Mixers.

Here we describe the development of a sustainable and cost-effective approach for catalytic cross-coupling reactions in mechanochemistry. It is found that the substrate's impact with the vessel wall alone is sufficient to initiate the reaction, thus indicating that milling balls function primarily as a mixing agent for direct mechanocatalytic Suzuki coupling. The absence of milling balls can be offset by adjusting the rheology using liquid-assisted grinding (LAG). The LAG sweet spot of 0.25 µL mg-1 is confirmed for both resonance acoustic mixers (RAMs) and ball-free mixer mills, and is higher than in the presence of milling balls. RAMs exhibit excellent performance in the Suzuki reaction, achieving yields of 90 % after 60 min and complete conversion after 90 min. The longevity of the milling vessel is significantly improved in a RAM, allowing for at least 20 reactions without deterioration.

The Multiple Perspectives Theory of Mental States in Communication.

Inspired by early proposals in philosophy, dominant accounts of language posit a central role for mutual knowledge, either encoded directly in common ground, or approximated through other cognitive mechanisms. Using existing empirical evidence from language and memory, we challenge this tradition, arguing that mutual knowledge captures only a subset of the mental states needed to support communication. In a novel theoretical proposal, we argue for a cognitive architecture that includes separate, distinct representations of the self and other, and a cognitive process that compares these representations continuously during conversation, outputting both similarities and differences in perspective. Our theory accounts for existing data, interfaces with findings from other cognitive domains, and makes novel predictions about the role of perspective in language use. We term this new account the Multiple Perspectives Theory of mental states in communication.