Response control networks are selectively modulated by attention to rare events and memory load regardless of the need for inhibition.

Recent evidence has sparked debate about the neural bases of response selection and inhibition. In the current study, we employed two reactive inhibition tasks, the Go/Nogo (GnG) and Simon tasks, to examine questions central to these debates. First, we investigated whether a fronto-cortical-striatal system was sensitive to the need for inhibition per se or the presentation of infrequent stimuli, by manipulating the proportion of trials that do not require inhibition (Go/Compatible trials) relative to trials that require inhibition (Nogo/Incompatible trials). A cortico-subcortical network composed of insula, putamen, and thalamus showed greater activation on salient and infrequent events, regardless of the need for inhibition. Thus, consistent with recent findings, key parts of the fronto-cortical-striatal system are engaged by salient events and do not appear to play a selective role in response inhibition. Second, we examined how the fronto-cortical-striatal system is modulated by working memory demands by varying the number of stimulus-response (SR) mappings. Right inferior parietal lobule showed decreasing activation as the number of SR mappings increased, suggesting that a form of associative memory - rather than working memory - might underlie performance in these tasks. A broad motor planning and control network showed similar trends that were also modulated by the number of motor responses required in each task. Finally, bilateral lingual gyri were more robustly engaged in the Simon task, consistent with the role of this area in shifts of visuo-spatial attention. The current study sheds light on how the fronto-cortical-striatal network is selectively engaged in reactive control tasks and how control is modulated by manipulations of attention and memory load.

Adipose-Tumor Crosstalk contributes to CXCL5 Mediated Immune Evasion in PDAC.

Background: CXCR1/2 inhibitors are being implemented with immunotherapies in PDAC clinical trials. Cytokines responsible for stimulating these receptors include CXCL ligands, typically secreted by activated immune cells, fibroblasts, and even adipocytes. Obesity has been linked to poor patient outcome and altered anti-tumor immunity. Adipose-derived cytokines and chemokines have been implicated as potential drivers of tumor cell immune evasion, suggesting a possibility of susceptibility to targeting specifically in the context of obesity. Methods: RNA-sequencing of human PDAC cell lines was used to assess differential influences on the cancer cell transcriptome after treatment with conditioned media from peri-pancreatic adipose tissue of lean and obese PDAC patients. The adipose-induced secretome of PDAC cells was then assessed by cytokine arrays and ELISAs. Lentiviral transduction and CRISPR-Cas9 was used to knock out CXCL5 from a murine PDAC cell line for orthotopic tumor studies in diet-induced obese, syngeneic mice. Flow cytometry was used to define the immune profiles of tumors. Anti-PD-1 immune checkpoint blockade therapy was administered to alleviate T cell exhaustion and invoke an immune response, while the mice were monitored at endpoint for differences in tumor size. Results: The chemokine CXCL5 was secreted in response to stimulation of PDAC cells with human adipose conditioned media (hAT-CM). PDAC CXCL5 secretion was induced by either IL-1ß or TNF, but neutralization of both was required to limit secretion. Ablation of CXCL5 from tumors promoted an immune phenotype susceptible to PD-1 inhibitor therapy. While application of anti-PD-1 treatment to control tumors failed to alter tumor growth, knockout CXCL5 tumors were diminished. Conclusions: In summary, our findings show that known adipokines TNF and IL-1ß can stimulate CXCL5 release from PDAC cells in vitro. In vivo , CXCL5 depletion alone is sufficient to promote T cell infiltration into tumors in an obese setting, but requires checkpoint blockade inhibition to alleviate tumor burden. DATA AVAILABILITY STATEMENT: Raw and processed RNAseq data will be further described in the GEO accession database ( awaiting approval from GEO for PRJ number ). Additional raw data is included in the supplemental material and available upon reasonable request. WHAT IS ALREADY KNOWN ON THIS TOPIC: Obesity is linked to a worsened patient outcome and immunogenic tumor profile in PDAC. CXCR1/2 inhibitors have begun to be implemented in combination with immune checkpoint blockade therapies to promote T cell infiltration under the premise of targeting the myeloid rich TME. WHAT THIS STUDY ADDS: Using in vitro/ex vivo cell and tissue culture-based assays with in vivo mouse models we have identified that adipose derived IL-1ß and TNF can promote tumor secretion of CXCL5 which acts as a critical deterrent to CD8 T cell tumor infiltration, but loss of CXCL5 also leads to a more immune suppressive myeloid profile. HOW THIS STUDY MIGHT AFFECT RESEARCH PRACTICE OR POLICY: This study highlights a mechanism and emphasizes the efficacy of single CXCR1/2 ligand targeting that could be beneficial to overcoming tumor immune-evasion even in the obese PDAC patient population.

Model-based functional neuroimaging using dynamic neural fields: An integrative cognitive neuroscience approach.

A fundamental challenge in cognitive neuroscience is to develop theoretical frameworks that effectively span the gap between brain and behavior, between neuroscience and psychology. Here, we attempt to bridge this divide by formalizing an integrative cognitive neuroscience approach using dynamic field theory (DFT). We begin by providing an overview of how DFT seeks to understand the neural population dynamics that underlie cognitive processes through previous applications and comparisons to other modeling approaches. We then use previously published behavioral and neural data from a response selection Go/Nogo task as a case study for model simulations. Results from this study served as the 'standard' for comparisons with a model-based fMRI approach using dynamic neural fields (DNF). The tutorial explains the rationale and hypotheses involved in the process of creating the DNF architecture and fitting model parameters. Two DNF models, with similar structure and parameter sets, are then compared. Both models effectively simulated reaction times from the task as we varied the number of stimulus-response mappings and the proportion of Go trials. Next, we directly simulated hemodynamic predictions from the neural activation patterns from each model. These predictions were tested using general linear models (GLMs). Results showed that the DNF model that was created by tuning parameters to capture simultaneously trends in neural activation and behavioral data quantitatively outperformed a Standard GLM analysis of the same dataset. Further, by using the GLM results to assign functional roles to particular clusters in the brain, we illustrate how DNF models shed new light on the neural populations' dynamics within particular brain regions. Thus, the present study illustrates how an interactive cognitive neuroscience model can be used in practice to bridge the gap between brain and behavior.

Melanoma cells undergo aggressive coalescence in a 3D Matrigel model that is repressed by anti-CD44.

Using unique computer-assisted 3D reconstruction software, it was previously demonstrated that tumorigenic cell lines derived from breast tumors, when seeded in a 3D Matrigel model, grew as clonal aggregates which, after approximately 100 hours, underwent coalescence mediated by specialized cells, eventually forming a highly structured large spheroid. Non-tumorigenic cells did not undergo coalescence. Because histological sections of melanomas forming in patients suggest that melanoma cells migrate and coalesce to form tumors, we tested whether they also underwent coalescence in a 3D Matrigel model. Melanoma cells exiting fragments of three independent melanomas or from secondary cultures derived from them, and cells from the melanoma line HTB-66, all underwent coalescence mediated by specialized cells in the 3D model. Normal melanocytes did not. However, coalescence of melanoma cells differed from that of breast-derived tumorigenic cell lines in that they 1) coalesced immediately, 2) underwent coalescence as individual cells as well as aggregates, 3) underwent coalescence far faster and 4) ultimately formed long, flat, fenestrated aggregates that were extremely dynamic. A screen of 51 purified monoclonal antibodies (mAbs) targeting cell surface-associated molecules revealed that two mAbs, anti-beta 1 integrin/(CD29) and anti-CD44, blocked melanoma cell coalescence. They also blocked coalescence of tumorigenic cells derived from a breast tumor. These results add weight to the commonality of coalescence as a characteristic of tumorigenic cells, as well as the usefulness of the 3D Matrigel model and software for both investigating the mechanisms regulating tumorigenesis and screening for potential anti-tumorigenesis mAbs.

Feature-Based Change Detection Reveals Inconsistent Individual Differences in Visual Working Memory Capacity.

Visual working memory (VWM) is a key cognitive system that enables people to hold visual information in mind after a stimulus has been removed and compare past and present to detect changes that have occurred. VWM is severely capacity limited to around 3-4 items, although there are robust individual differences in this limit. Importantly, these individual differences are evident in neural measures of VWM capacity. Here, we capitalized on recent work showing that capacity is lower for more complex stimulus dimension. In particular, we asked whether individual differences in capacity remain consistent if capacity is shifted by a more demanding task, and, further, whether the correspondence between behavioral and neural measures holds across a shift in VWM capacity. Participants completed a change detection (CD) task with simple colors and complex shapes in an fMRI experiment. As expected, capacity was significantly lower for the shape dimension. Moreover, there were robust individual differences in behavioral estimates of VWM capacity across dimensions. Similarly, participants with a stronger BOLD response for color also showed a strong neural response for shape within the lateral occipital cortex, intraparietal sulcus (IPS), and superior IPS. Although there were robust individual differences in the behavioral and neural measures, we found little evidence of systematic brain-behavior correlations across feature dimensions. This suggests that behavioral and neural measures of capacity provide different views onto the processes that underlie VWM and CD. Recent theoretical approaches that attempt to bridge between behavioral and neural measures are well positioned to address these findings in future work.

Mediated coalescence: a possible mechanism for tumor cellular heterogeneity.

Recently, we demonstrated that tumorigenic cell lines and fresh tumor cells seeded in a 3D Matrigel model, first grow as clonal islands (primary aggregates), then coalesce through the formation and contraction of cellular cables. Non-tumorigenic cell lines and cells from normal tissue form clonal islands, but do not form cables or coalesce. Here we show that as little as 5% tumorigenic cells will actively mediate coalescence between primary aggregates of majority non-tumorigenic or non-cancerous cells, by forming cellular cables between them. We suggest that this newly discovered, specialized characteristic of tumorigenic cells may explain, at least in part, why tumors contain primarily non-tumorigenic cells.

A computer-assisted 3D model for analyzing the aggregation of tumorigenic cells reveals specialized behaviors and unique cell types that facilitate aggregate coalescence.

We have developed a 4D computer-assisted reconstruction and motion analysis system, J3D-DIAS 4.1, and applied it to the reconstruction and motion analysis of tumorigenic cells in a 3D matrix. The system is unique in that it is fast, high-resolution, acquires optical sections using DIC microscopy (hence there is no associated photoxicity), and is capable of long-term 4D reconstruction. Specifically, a z-series at 5 µm increments can be acquired in less than a minute on tissue samples embedded in a 1.5 mm thick 3D Matrigel matrix. Reconstruction can be repeated at intervals as short as every minute and continued for 30 days or longer. Images are converted to mathematical representations from which quantitative parameters can be derived. Application of this system to cancer cells from established lines and fresh tumor tissue has revealed unique behaviors and cell types not present in non-tumorigenic lines. We report here that cells from tumorigenic lines and tumors undergo rapid coalescence in 3D, mediated by specific cell types that we have named "facilitators" and "probes." A third cell type, the "dervish", is capable of rapid movement through the gel and does not adhere to it. These cell types have never before been described. Our data suggest that tumorigenesis in vitro is a developmental process involving coalescence facilitated by specialized cells that culminates in large hollow spheres with complex architecture. The unique effects of select monoclonal antibodies on these processes demonstrate the usefulness of the model for analyzing the mechanisms of anti-cancer drugs.

Diagnosis of calcium pyrophosphate dihydrate deposition disease by fine needle aspiration biopsy: a case report.

BACKGROUND: Calcium pyrophosphate dihydrate deposition disease is a relatively rare disease with variable clinical presentations. CASE: A 73-year-old man presented with worsening lower back pain and fever. Fine needle aspiration biopsy of the lumbar vertebral bodies (L3-L4) revealed abundant neutrophils admixed with small, birefringent, rhomboid crystals in Diff-Quik-stained smears. These crystals were confirmed as calcium pyrophosphate dihydrate on cell block sections. A diagnosis of osteomyelitis and calcium pyrophosphate dihydrate deposition disease was rendered. The patient was treated with antibiotics and responded well. CONCLUSION: Calcium pyrophosphate dihydrate deposition disease can be diagnosed by fine needle aspiration biopsy, and an accurate diagnosis can be greatly facilitated by cell block sections. However, such a diagnosis may be neglected if the specimen is not carefully inspected.