Senescent Changes in Orientation, Frequency, and 3-D Slant and Shape Perception

The ability to perceive the 3-Dimensional world is effortless despite the fact that the input to the visual system is 2-Dimensional. Attempts to derive biologically plausible models of shape from texture have focused on how changes in orientation and spatial frequency information are processed based on the response properties of primary visual cortex (V1) neurons. However, the relative contributions of orientation and spatial frequency information in detecting slant and shape from 3-D surfaces are not well understood. Additionally, in senescence, changes in optical components of the eye result in reduced frequency sensitivity, but whether concurrent neurophysiological changes affect the ability to discriminate orientation, and whether there is a resulting effect on form processing with age have remained unclear. An initial set of psychophysical experiments administered to younger adults showed that changes in orientation (or orientation modulations, OMs) dictated 3-D slant perception at shallow and steep slants, while changes in frequency (or frequency modulations, FMs) were only effective at steeper slants. This effect of OMs dictating slant and shape percept remained present even if a surface contained a texture with OM and FM components specifying inconsistent degrees of surface slant or curvature. Three additional psychophysical experiments were conducted to assess age-related changes in orientation and shape discrimination between younger and older observers. Consistent with previous findings in the literature, the older observers had significantly higher contrast thresholds than the younger group. Orientation discrimination thresholds were significantly higher for older observers when stimulus contrast was expressed as absolute values. However, when thresholds were evaluated in terms of multiples of detection threshold (to normalize stimuli for visibility across observers), age-related differences in orientation discrimination were not observed. Similarly, when observers performed a shape detection task, no significant difference was observed in shape detection thresholds across different spatial frequencies when age-related differences in contrast sensitivity were taken into account. However, when observers were given a shape discrimination task, older observers showed a significantly higher discrimination threshold at the highest spatial frequency even when thresholds were normalized for visibility. These findings suggest that while contrast detection thresholds increase with age, orientation and shape processing remain largely preserved. This suggests that in the context of degradations in optical and neural inputs, the overall percept of orientation and shape remains preserved with age, consistent with findings in several other areas in the visual system (e.g., color vision, perceived contrast). Our results suggest that the preservation of orientation and frequency perception with age at least partially contribute to the stability of 3-D shape perception, for stimuli in which orientation and frequency changes are cues for 3-D shape

Dominance of Orientation over Frequency in the Perception of 3-D Slant and Shape

In images of textured three-dimensional surfaces, pattern changes can be characterized as changes in orientation and spatial frequency, features for which neurons in primary visual cortex are classically selective. Previously, we have demonstrated that correct 3-D shape perception is contingent on the visibility of orientation flows that run parallel to the surface curvature. We sought to determine the relative contributions of orientation modulations (OMs) and frequency modulations (FMs) for the detection of slant and shape from 3-D surfaces. Results show that 1) when OM and FM indicate inconsistent degrees of surface slant or curvature, observer responses were consistent with the slant or curvature specified by OM even if the FM indicated a slant or curvature in the opposite direction to the same degree. 2) For slanted surfaces, OM information dictates slant perception at both shallow and steep slants while FM information is effective only for steep slants. Together these results point to a dominant role of OM information in the perception of 3-D slant and shape

Outcomes of concomitant aortic valve replacement and coronary artery bypass grafting at teaching hospitals versus nonteaching hospitals

ObjectiveHospitals with a high volume and academic status produce better patient outcomes than other hospitals after complex surgical procedures. Risk models show that concomitant aortic valve replacement and coronary artery bypass grafting pose a greater risk than isolated coronary artery bypass grafting or aortic valve replacement. We examined the relationship of hospital teaching status and the presence of a thoracic surgery residency program with aortic valve replacement/coronary artery bypass grafting outcomes.MethodsBy using the Nationwide Inpatient Sample database, we identified patients who underwent concomitant aortic valve replacement/coronary artery bypass grafting from 1998 to 2007 at nonteaching hospitals, teaching hospitals without a thoracic surgery residency program, and teaching hospitals with a thoracic surgery residency program. Multivariate analysis was performed to identify intergroup differences. Risk-adjusted multivariable logistic regression analysis was used to assess independent predictors of in-hospital mortality and complication rates.ResultsThe 3 groups of patients did not differ significantly in their baseline characteristics. Patients who underwent aortic valve replacement/coronary artery bypass grafting had higher overall risk-adjusted complication rates in nonteaching hospitals (odds ratio 1.58; 95% confidence interval, 1.39–1.80; P < .0001) and teaching hospitals without a thoracic surgery residency program (odds ratio 1.42; 95% confidence interval, 1.26–1.60; P < .0001) than in thoracic surgery residency program hospitals. However, no difference was observed in the adjusted mortality rate for nonteaching hospitals (odds ratio 0.95; 95% confidence interval, 0.87–1.04; P = .25) or teaching hospitals without a thoracic surgery residency program (odds ratio 1.00; 95% confidence interval, 0.92–1.08; P = .98) when compared with thoracic surgery residency program hospitals. Robust statistical models were used for analysis, with c-statistics of 0.98 (complications) and 0.82 (mortality).ConclusionPatients who require complex cardiac operations may have better outcomes when treated at teaching hospitals with a thoracic surgery residency program

Remote Diagnostic System

The Canadian health care system is a publically funded service for all residents in Canada. While most medical services are covered by the plan, there are few others along with drug prescriptions that are billed at the patient\u27s expense. In general, Canadians are in support of the current health care system provided by the government. However, inefficiency in the current health care system poses a major problem. Our proposed solution to the inefficiency in the ER is to engage remote diagnosis before the patient arrives at the hospital. In conjunction, timely and easily accessible patient data will aim to decrease the patient\u27s length of stay, and to reduce the wait time for other patients in the ER. The solution consists of three components: remote diagnosis tool, central server, and a data display client. The combination of components create what we call the Remote Diagnostic System. Paramedics will be able to assess the patient\u27s condition and digitally transfer the assessment data to the hospital. ER doctors will review the data on a data display client, and can contact the paramedics for additional assessment if needed. Otherwise, they can simply prepare treatments and wait for the patient’s arrival so it can be done immediately, depending on the severity of the injur

Prolonged and tunable residence time using reversible covalent kinase inhibitors.

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo

Peptide Location Fingerprinting Reveals Tissue Region-Specific Differences in Protein Structures in an Ageing Human Organ

From MDPI via Jisc Publications RouterHistory: accepted 2021-09-14, pub-electronic 2021-09-27Publication status: PublishedFunder: Manchester Institute for Collaborative Research on Ageing; Grant(s): n/aFunder: Walgreens Boots Alliance; Grant(s): n/aIn ageing tissues, long-lived extracellular matrix (ECM) proteins are susceptible to the accumulation of structural damage due to diverse mechanisms including glycation, oxidation and protease cleavage. Peptide location fingerprinting (PLF) is a new mass spectrometry (MS) analysis technique capable of identifying proteins exhibiting structural differences in complex proteomes. PLF applied to published young and aged intervertebral disc (IVD) MS datasets (posterior, lateral and anterior regions of the annulus fibrosus) identified 268 proteins with age-associated structural differences. For several ECM assemblies (collagens I, II and V and aggrecan), these differences were markedly conserved between degeneration-prone (posterior and lateral) and -resistant (anterior) regions. Significant differences in peptide yields, observed within collagen I α2, collagen II α1 and collagen V α1, were located within their triple-helical regions and/or cleaved C-terminal propeptides, indicating potential accumulation of damage and impaired maintenance. Several proteins (collagen V α1, collagen II α1 and aggrecan) also exhibited tissue region (lateral)-specific differences in structure between aged and young samples, suggesting that some ageing mechanisms may act locally within tissues. This study not only reveals possible age-associated differences in ECM protein structures which are tissue-region specific, but also highlights the ability of PLF as a proteomic tool to aid in biomarker discovery

Development of a standardized histopathology scoring system using machine learning algorithms for intervertebral disc degeneration in the mouse model—An ORS spine section initiative

Mice have been increasingly used as preclinical model to elucidate mechanisms and test therapeutics for treating intervertebral disc degeneration (IDD). Several intervertebral disc (IVD) histological scoring systems have been proposed, but none exists that reliably quantitate mouse disc pathologies. Here, we report a new robust quantitative mouse IVD histopathological scoring system developed by building consensus from the spine community analyses of previous scoring systems and features noted on different mouse models of IDD. The new scoring system analyzes 14 key histopathological features from nucleus pulposus (NP), annulus fibrosus (AF), endplate (EP), and AF/NP/EP interface regions. Each feature is categorized and scored; hence, the weight for quantifying the disc histopathology is equally distributed and not driven by only a few features. We tested the new histopathological scoring criteria using images of lumbar and coccygeal discs from different IDD models of both sexes, including genetic, needle-punctured, static compressive models, and natural aging mice spanning neonatal to old age stages. Moreover, disc sections from common histological preparation techniques and stains including H&E, SafraninO/Fast green, and FAST were analyzed to enable better cross-study comparisons. Fleiss\u27s multi-rater agreement test shows significant agreement by both experienced and novice multiple raters for all 14 features on several mouse models and sections prepared using various histological techniques. The sensitivity and specificity of the new scoring system was validated using artificial intelligence and supervised and unsupervised machine learning algorithms, including artificial neural networks, k-means clustering, and principal component analysis. Finally, we applied the new scoring system on established disc degeneration models and demonstrated high sensitivity and specificity of histopathological scoring changes. Overall, the new histopathological scoring system offers the ability to quantify histological changes in mouse models of disc degeneration and regeneration with high sensitivity and specificity

Edgetic perturbation models of human inherited disorders

Cellular functions are mediated through complex systems of macromolecules and metabolites linked through biochemical and physical interactions, represented in interactome models as ‘nodes' and ‘edges', respectively. Better understanding of genotype-to-phenotype relationships in human disease will require modeling of how disease-causing mutations affect systems or interactome properties. Here we investigate how perturbations of interactome networks may differ between complete loss of gene products (‘node removal') and interaction-specific or edge-specific (‘edgetic') alterations. Global computational analyses of ∼50 000 known causative mutations in human Mendelian disorders revealed clear separations of mutations probably corresponding to those of node removal versus edgetic perturbations. Experimental characterization of mutant alleles in various disorders identified diverse edgetic interaction profiles of mutant proteins, which correlated with distinct structural properties of disease proteins and disease mechanisms. Edgetic perturbations seem to confer distinct functional consequences from node removal because a large fraction of cases in which a single gene is linked to multiple disorders can be modeled by distinguishing edgetic network perturbations. Edgetic network perturbation models might improve both the understanding of dissemination of disease alleles in human populations and the development of molecular therapeutic strategies

Manuscript Architect: a Web application for scientific writing in virtual interdisciplinary groups

BACKGROUND: Although scientific writing plays a central role in the communication of clinical research findings and consumes a significant amount of time from clinical researchers, few Web applications have been designed to systematically improve the writing process. This application had as its main objective the separation of the multiple tasks associated with scientific writing into smaller components. It was also aimed at providing a mechanism where sections of the manuscript (text blocks) could be assigned to different specialists. Manuscript Architect was built using Java language in conjunction with the classic lifecycle development method. The interface was designed for simplicity and economy of movements. Manuscripts are divided into multiple text blocks that can be assigned to different co-authors by the first author. Each text block contains notes to guide co-authors regarding the central focus of each text block, previous examples, and an additional field for translation when the initial text is written in a language different from the one used by the target journal. Usability was evaluated using formal usability tests and field observations. RESULTS: The application presented excellent usability and integration with the regular writing habits of experienced researchers. Workshops were developed to train novice researchers, presenting an accelerated learning curve. The application has been used in over 20 different scientific articles and grant proposals. CONCLUSION: The current version of Manuscript Architect has proven to be very useful in the writing of multiple scientific texts, suggesting that virtual writing by interdisciplinary groups is an effective manner of scientific writing when interdisciplinary work is required