Dectin-1 Mediated Regulation of Dendritic Cell Metabolism

Dendritic cells (DCs) are critical antigen presenting cells that link the innate and adaptive immune systems. DCs are activated through a variety of receptors and respond with a diverse array of metabolic changes that are not yet well understood. IL-1β is a key inflammatory cytokine produced by DCs when they are activated through both toll-like receptors and C-type lectin receptors. IL-1β is activated by the inflammasome signaling complex but how the inflammasome is controlled by glycolysis is not yet well understood. We demonstrate that DC activation through TLR or C-type lectin receptors induces a shift to aerobic glycolytic metabolism. We show that while the transcription of IL-1β in DCs activated through both these receptors is not under glycolytic control, whether or not translation of IL-1β is under glycolytic control remains unclear. These findings provide new information on Dectin-1 mediated metabolic reprogramming in DCs. Understanding the link between metabolic changes and Dectin-1-mediated DC activation has broad implications for improved vaccine design and clinical intervention to fungal infection

Understanding the Role of Runx2 in a Breast Cancer Progression Cell Model

Runx2 is a transcription factor required for bone formation and osteoblastic differentiation during normal development and is implicated in metastatic disease during breast cancer progression. Runx2 is highly expressed in many metastatic breast cancers and breast cancer cell lines Knockdown of Runx2 in various breast cancer cell lines restores epithelial characteristics and reduces proliferation, migration, and invasion. However, the role of Runx2 in breast cancer progression from early to late stages is not well understood. The MCF10A derived breast cancer progression model provides the opportunity to study the role of Runx2 in a series of cell lines that progress from nearly normal, with low Runx2 levels, to highly metastatic and aggressive, with much higher Runx2 levels. To address if removal of Runx2 affects gene expression and what pathways it may influence, specifically focused on breast cancer progression, we knocked down Runx2 using an shRNA lentivirus. Depletion of Runx2 inhibits the expression of mesenchymal markers including N-cadherin, Fibronectin, and Vimentin. Despite this finding, functional characteristics including proliferation, migration, and invasion were minimally affected. Possible reasons for the difference in results compared to other cell systems are discussed. As an alternative approach, we have generated stable, inducible cell lines using CRISPRi dCas9-KRAB to target Runx2 and in the future will investigate the effects of Runx2 knockdown in these cells

The Reading Difficulty of Parent Education Materials

It is not necessary to emphasize the fact that reading plays an important part in the education of parents. A more significant problem is that of discovering the characteristics of materials that fall at different levels of difficulty. A solution of this problem would make possible a more effective selection and preparation of materials suitable to the widely differing reading abilities that one finds among adults. The purpose of this investigation is to determine the factors that are associated with difficulty and to learn what the characteristics of materials are at the various levels. To carry out this study the reading difficulty of a series of sixteen selections was determined experimentally and the variation of numerous factors with difficulty was analyzed

Visualization-Based Mapping of Language Function in the Brain

Cortical language maps, obtained through intraoperative electrical stimulation studies, provide a rich source of information for research on language organization. Previous studies have shown interesting correlations between the distribution of essential language sites and such behavioral indicators as verbal IQ and have provided suggestive evidence for regarding human language cortex as an organization of multiple distributed systems. Noninvasive studies using ECoG, PET, and functional MR lend support to this model; however, there as yet are no studies that integrate these two forms of information. In this paper we describe a method for mapping the stimulation data onto a 3-D MRI-based neuroanatomic model of the individual patient. The mapping is done by comparing an intraoperative photograph of the exposed cortical surface with a computer-based MR visualization of the surface, interactively indicating corresponding stimulation sites, and recording 3-D MR machine coordinates of the indicated sites. Repeatability studies were performed to validate the accuracy of the mapping technique. Six observers—a neurosurgeon, a radiologist, and four computer scientists, independently mapped 218 stimulation sites from 12 patients. The mean distance of a mapping from the mean location of each site was 2.07 mm, with a standard deviation of 1.5 mm, or within 5.07 mm with 95% confidence. Since the surgical sites are accurate within approximately 1 cm, these results show that the visualization-based approach is accurate within the limits of the stimulation maps. When incorporated within the kind of information system envisioned by the Human Brain Project, this anatomically based method will not only provide a key link between noninvasive and invasive approaches to understanding language organization, but will also provide the basis for studying the relationship between language function and anatomical variability

Neuronal activity in the human lateral temporal lobe. II. Responses to the subjects own voice.

We have recorded neuronal responses in the lateral temporal lobe of man to overt speech during open brain surgery for epilepsy. Tests included overt naming of objects and reading words or short sentences shown on a projector screen, repetition of tape recorded words or sentences presented over a loudspeaker, and free conversation. Neuronal activity in the dominant and non-dominant temporal lobe were about equally affected by overt speech. As during listening to language (see Creutzfeldt et al. 1989), responses differed between recordings from sites in the superior and the middle or inferior temporal gyrus. In the superior temporal gyrus all neurons responded clearly and each in a characteristic manner. Activation could be related to phonemic aspects, to segmentation or to the length of spoken words or sentences. However, neurons were mostly differently affected by listening to words and language as compared to overt speaking. In neuronal populations recorded simultaneously with one or two microelectrodes, some neurons responded predominantly to one or the other type of speech. Excitatory responses during overt speaking were always auditory. In the middle temporal gyrus more neurons (about 2/3) responded to overt speaking than to listening alone. Activations elicited during overt speech were seen in about 1/3 of our sample, but they were more sluggish than those recorded in the superior gyrus. A prominent feature was suppression of on-going activity, which we found in about 1/3 of middle and in some superior temporal gyrus neurons. This suppression could preced vocalization by up to a few hundred ms, and could outlast it by up to 1 s. Evoked ECoG-potentials to words heard or spoken were different, and those to overt speech were more widespread

Unsupervised decoding of long-term, naturalistic human neural recordings with automated video and audio annotations

Fully automated decoding of human activities and intentions from direct neural recordings is a tantalizing challenge in brain-computer interfacing. Most ongoing efforts have focused on training decoders on specific, stereotyped tasks in laboratory settings. Implementing brain-computer interfaces (BCIs) in natural settings requires adaptive strategies and scalable algorithms that require minimal supervision. Here we propose an unsupervised approach to decoding neural states from human brain recordings acquired in a naturalistic context. We demonstrate our approach on continuous long-term electrocorticographic (ECoG) data recorded over many days from the brain surface of subjects in a hospital room, with simultaneous audio and video recordings. We first discovered clusters in high-dimensional ECoG recordings and then annotated coherent clusters using speech and movement labels extracted automatically from audio and video recordings. To our knowledge, this represents the first time techniques from computer vision and speech processing have been used for natural ECoG decoding. Our results show that our unsupervised approach can discover distinct behaviors from ECoG data, including moving, speaking and resting. We verify the accuracy of our approach by comparing to manual annotations. Projecting the discovered cluster centers back onto the brain, this technique opens the door to automated functional brain mapping in natural settings

Anatomical Parcellation of Cortical Language Sites

Anatomical labeling of cerebral cortical stimulation (CSM) sites is necessary for intelligent computer querying of a rich and unique experimental database examining neural substrates underlying human language production. To this end, we have developed a parcellation scheme for the lateral surface of the human cerebral cortex. We then compared results generated utilizing this approach to those generated using an alternative method implemented in the Talairach Daemon

Neuronal activity in the human lateral temporal lobe. I. Responses to speech.

Single and multiple unit neuronal activity was recorded from the cortex of the lateral temporal lobe in conscious humans during open brain surgery for the treatment of epilepsy. Recordings were obtained from the right and left superior, middle and inferior temporal gyrus of 34 patients (41 recording sites). Recordings were restricted to regions to be resected during subsequent surgery. This excluded recordings from language areas proper. Neuronal responses to words and sentences presented over a loudspeaker and during free conversation were recorded. No significant differences between the right and left hemisphere were obvious. All neurons in the superior temporal gyrus responded to various aspects of spoken language with temporally well defined activation/inhibition patterns, but not or only little to non-linguistic noises or tones. Excitatory responses were typically short or prolonged (up to several hundred ms) bursts of discharges at rates above 20/sec, reaching peak rates of 50–100/s. Such responses could be specifically related to certain combinations of consonants suggesting a function in categorization, they could depend on word length, could differentiate between polysyllabic and compound words of the same length or could be unspecifically related to language as such. No formant specific responses were found, but the prolonged excitations across syllables suggest that consonant/vowel combinations may play a role for some activation patterns. Responses of some neurons (or neuronal populations) depended on the attention paid to the words and sentences, or the task connected with them (repeat words, speech addressed to the patient demanding something). Neurons in the middle and inferior temporal gyrus were only little affected by listening to single words or sentences, but some were unspecifically activated by words or while listening to sentences. Excitatory responses varied within a limited range of discharge rates usually below 5–10/s. Phonetic distortion of spoken language could reduce responses in superior temporal gyrus neurons, but also the slight changes in discharge rate of middle temporal neurons could be absent during distorted and uncomprehensible speech sounds. We conclude that superior temporal gyrus neuron responses reflect some general phonetic but not semantic aspects of spoken language. Middle and inferior temporal gyrus neurons do not signal phonetic aspects of language, but may be involved in understanding language under certain conditions