The Received Method for Ruling Out Brain Areas from Being NCC Undermines Itself

Research into the neural correlates of consciousness (NCC) aims to identify not just those brain areas that are NCC, but also those that are not. In the received method for ruling out a brain area from being an NCC, this is accomplished by showing a brain area’s content to be consistently absent from subjects’ reports about what they are experiencing. This paper points out how this same absence can be used to infer that the brain area’s content is cognitively inaccessible, in which case we would expect its content to be absent from subjects’ reports whether its content is (phenomenally) conscious or not. If so, such reports cannot count as evidence against that brain area being an NCC, and the received method fails. An alternative method (one suggested in Block, 2007) is considered

Clostridium septicum aortitis with synchronous ascending colon and rectal adenocarcinoma.

Clostridium septicum (C. septicum) aortitis is a rare condition frequently associated with colon adenocarcinoma and carries a poor prognosis. We report the case of a 66-year-old man who presented with abdominal pain, blood in the stool, fever and chills. Laboratory tests were significant for leukocytosis and microcytic anemia. Abdominal imaging revealed a right colon mass and aortitis. Colonoscopy confirmed the right colon mass and also discovered a rectal mass, both adenocarcinomas. Treatment consisted of antibiotics, aortic repair, right hemi-colectomy and later trans-anal excision of the rectal mass. Blood cultures and the aortic specimen grew C. septicum. The patient improved and was doing well in follow up

Ceramic Shell Cup Effigies from Illinois and their Implications

Ceramic effigies ofmarine shell cups have long been known from Mississippian sites in Illinois and elsewhere in the Southeast, and have been included in studies of other ceramic effigies, such as animal figures and head pots (Holmes 1886). This paper focuses on 31 known Illinois specimens. I will show that, in Illinois, the geographic range of these effigies is primarily restricted to the American Bottom around Cahokia, and their occurrence is largely limited to Late Mississippian Moorehead and Sand Prairie phases (A.D. 1200 to 1400). I also explore possible meanings of shell cups and, by extension, ceramic effigies of shell cups. Ethnohistoric as well as archaeological evidence show that lightning whelk cups and, by analogy, shell cup effigies functioned in contexts of uncertainty and conflict, consistent with their context in Illinois.Ope

Dislocation, Not Dissociation: The Neuroanatomical Argument Against Visual Experience Driving Motor Action

Common sense suggests that visual consciousness is essential to skilled motor action, but Andy Clark—inspired by Milner and Goodale's dual visual systems theory—has appealed to a wide range of experimental dissociations to argue that such an assumption is false. Critics of Clark's argument contend that the content driving motor action is actually within subjects' experience, just not easily discovered. In this article, I argue that even if such content exists, it cannot be guiding motor action, since a review of current visual neuroscience indicates that the visual brain areas producing conscious representations are distinct from those driving motor actio

Fluorescently Labeled siRNAs and their Theranostic Applications in Cancer Gene Therapy

Gene therapy has emerged as a promising precision nano-medicine strategy in the treatment of numerous diseases including cancer. At the forefront of its utility are the applications of short-interfering RNA (siRNA), that silence oncogenic mRNA expression leading to cancer cell death through the RNA interference (RNAi) pathway. Despite the therapeutic potential, siRNAs are limited by poor pharmacological properties, which has hindered their translation into the clinic. Recent studies, however, have highlighted the applications of modified siRNAs, including the use of fluorescent probes and siRNA nanostructures in cancer detection and treatment. The siRNAs reported in this thesis are designed to target and silence the overexpression of the Glucose Regulated Proteins (GRPs) in cancer. The GRPs are a class of chaperone proteins involved in protein folding events within the endoplasmic reticulum. Under physiological or pathological stress, some GRPs translocate to the cell surface where they function as signaling receptors for oncogenic activity. Therefore, cancer cell surface GRPs have been classified as clinically proven biomarkers. Chapter 2 outlines the design, synthesis and characterization of linear as well as novel V- and Y-shape RNA templates with the use of a ribouridine branchpoint synthon. The RNA templates self-assembled into spheres, triangles, squares, pentagons and hexagons of discrete sizes and shapes, confirmed by native PAGE while TEM imaging validated the sizes and shapes of the siRNA nanostructures. Moreover, thermal denaturation and CD spectroscopy were used to ascertain the prerequisite siRNA hybrids for their RNAi applications. Of interest from this initial study, the self-assembled siRNA hybrids (5 nM) that targeted GRP-75, 78 and 95 elicited a synergistic effect, which resulted in potent gene knockdown as well as cancer cell death. The simultaneous integration of therapy and diagnostics (“theranostics”) has been utilized to diagnose and treat cancers at their earliest stages, when they are most likely curable or at least treatable. Building on the work described in Chapter 2, the covalently attachment of fluorescein isothiocyanate (FITC) allowed for monitoring cell uptake and biological activity of a wide range of siRNA motifs. Incorporation of FITC had negligible influence on the A-type helix of the siRNAs, while maintaining good hybrid thermal stability. The FL-siRNAs showed some degree of fluorescence quenching relative to the unlabeled siRNAs. However, the higher-order V- and Y-shape siRNA structures enabled the incorporation of multiple fluorescent reporters, which increased siRNA fluorescence but failed to overcome the quenching effects. Upon transfection within the PC-3 prostate cancer cells, the FL-siRNA hybrids (50 nM) exhibited less mRNA knockdown (~10-30%) when compared to their non-labeled counterparts (~40-80%). Conjugation of the FITC probe to the sense strand of the siRNAs re-established mRNA knockdown (~50

Impact of KRAS Mutations on Management of Colorectal Carcinoma

The epidermal growth factor receptor (EGFR) pathway is a therapeutic target in the management of colorectal cancer (CRC). EGFR antagonists are active in this disease; however, only a subset of patients respond to such therapy. A Kirsten ras sarcoma viral oncogene (KRAS) wild-type (WT) status of the tumor is necessary, but possibly not sufficient, for a response to anti-EGFR monoclonal antibody therapy. Mechanisms of primary resistance to such therapy in patients harboring KRAS WT tumors are discussed. Strategies to overcome resistance to anti-EGFR monoclonal antibody therapy, including novel agents and combinations of novel therapies, are explored. Also, the use of anti-EGFR monoclonal antibodies in the adjuvant and neoadjuvant setting is reviewed

The Interplay of Electrostatics and Chemical Positioning in the Evolution of Antibiotic Resistance in TEM β-Lactamases

The interplay of enzyme active site electrostatics and chemical positioning is important for understanding the origin(s) of enzyme catalysis and the design of novel catalysts. We reconstruct the evolutionary trajectory of TEM-1 β-lactamase to TEM-52 toward extended-spectrum activity to better understand the emergence of antibiotic resistance and to provide insights into the structure–function paradigm and noncovalent interactions involved in catalysis. Utilizing a detailed kinetic analysis and the vibrational Stark effect, we quantify the changes in rates and electric fields in the Michaelis and acyl-enzyme complexes for penicillin G and cefotaxime to ascertain the evolutionary role of electric fields to modulate function. These data are combined with MD simulations to interpret and quantify the substrate-dependent structural changes during evolution. We observe that this evolutionary trajectory utilizes a large preorganized electric field and substrate-dependent chemical positioning to facilitate catalysis. This governs the evolvability, substrate promiscuity, and protein fitness landscape in TEM β-lactamase antibiotic resistance

Underwhelming force: Evaluating the neuropsychological evidence for higher-order theories of consciousness

Proponents of the higher-order (HO) theory of consciousness (e.g., Lau and Rosenthal) have recently appealed to brain lesion evidence to support their thesis that mental states are conscious when and only when represented by other mental states. This article argues that this evidence fails to support HO theory, doing this by first determining what kinds of conscious deficit should result when HO state-producing areas are damaged, then arguing that these kinds of deficit do not occur in the studies to which HO theorists appeal. The article also develops an apparatus that can be used to evaluate whether other lesion evidence con- firms or disconfirms HO theory