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In this study, the authors show that PTEN alters synaptic function after PDZ-dependent recruitment into spines induced by amyloid-β. This mechanism is crucial for pathogenesis, as preventing PTEN-PDZ interactions renders neurons resistant to amyloid-β and rescues cognitive function in Alzheimer's disease models. This suggests that PTEN is a critical effector of the synaptic pathology associated with Alzheimer's disease. Dyshomeostasis of amyloid-β peptide (Aβ) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. Aβ appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer's disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aβ-induced depression. Mechanistically, Aβ triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aβ-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aβ-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aβ signaling.

CRIPT, the cysteine-rich PDZ-binding protein, binds to the third PDZ domain of PSD-95 (postsynaptic density protein 95) family proteins and directly binds microtubules, linking PSD-95 family proteins to the neuronal cytoskeleton. Here, we show that overexpression of a full-length CRIPT leads to a modest decrease, and knockdown of CRIPT leads to an increase in dendritic branching in cultured rat hippocampal neurons. Overexpression of truncated CRIPT lacking the PDZ domain-binding motif, which does not bind to PSD-95, significantly decreases dendritic arborization. Conversely, overexpression of a full-length CRIPT significantly increases the number of immature and mature dendritic spines, and this effect is not observed when CRIPT∆PDZ is overexpressed. Competitive inhibition of CRIPT binding to the third PDZ domain of PSD-95 with PDZ3-binding peptides resulted in differential effects on dendritic arborization based on the origin of respective peptide sequence. These results highlight multifunctional roles of CRIPT during development and underscore the significance of the interaction between CRIPT and the third PDZ domain of PSD-95.

The idea that handedness indicates something about a person’s cognitive ability and personality is a perennial issue. A variety of models have been put forward to explain this relationship and predict a range of outcomes from higher levels of cognitive ability in left-handers or moderate right-handers to lower levels of achievement in left- or mixed-handers. We tested these models using a sample (n = 895) drawn from the BRAINnet database (www.brainnet.net). Participants completed a general cognitive ability (GCA) scale and a test of hand preference/performance. Moderate right-handers, as indexed by their performance measures, had higher GCA scores compared with strong left- or right-handers. The performance measure also showed lower levels of GCA for left-handers compared with right-handers. The hand preference data showed little or no association with cognitive ability—perhaps because this measure clusters individuals toward the extremes of the handedness distribution. While adding support to Annett’s heterozygous advantage model, which predicts a cognitive disadvantage for strong left- or right-handers, the data also confirm recent research showing a GCA disadvantage for left-handers. Although this study demonstrates that handedness is related to cognitive ability, the effects are subtle and might only be identified in large-scale studies with sensitive measures of hand performance. (JINS, 2010, 16, 585–592.)

T-cells specifically bind antigens to induce adaptive immune responses using highly specific molecular recognition, and a diverse T-cell repertoire with expansion of antigen-specific clones can indicate robust immune responses after infection or vaccination. For patients with inflammatory bowel disease (IBD), a spectrum of chronic intestinal inflammatory diseases usually requiring immunomodulatory treatment, the T-cell response has not been well characterized. Understanding the patient factors that result in strong vaccination responses is critical to guiding vaccination schedules and identifying mechanisms of T-cell responses in IBD and other immune-mediated conditions. Here we used T-cell receptor sequencing to show that T-cell responses in an IBD cohort were influenced by demographic and immune factors, relative to a control cohort of health care workers (HCWs). Subjects were sampled at the time of SARS-CoV-2 vaccination, and longitudinally afterwards; TCR Vβ gene repertoires were sequenced and analyzed for COVID-19-specific clones. We observed significant differences in the overall strength of the T-cell response by age and vaccine type. We further stratified the T-cell response into Class-I- and Class-II-specific responses, showing that Ad26.COV2.S vector vaccine induced Class-I-biased T-cell responses, whereas mRNA vaccine types led to different responses, with mRNA-1273 vaccine inducing a more Class-I-deficient T-cell response compared to BNT162b2. Finally, we showed that these T-cell patterns were consistent with antibody levels from the same patients. Our results account for the surprising success of vaccination in nominally immuno-compromised IBD patients, while suggesting that a subset of IBD patients prone to deficiencies in T-cell response may warrant enhanced booster protocols.

In contrast to the leftward inattention caused by right parietal damage, normal brain function shows a subtle neglect of the right and left sides in peripersonal and extrapersonal space, respectively. This study explored how these attentional biases cause healthy individuals to collide with objects on the right. In Experiment 1, participants navigated manual and electric wheelchairs through a narrow doorway. More rightward collisions were observed for the electric, but not the manual, wheelchair. Experiment 2 demonstrated that the rightward deviation for electric wheelchairs increased for wider doorways. Experiment 3 established that the rightward deviation is not the result of task-related vestibular input, using a remote control device to operate the wheelchair. The rightward deviation persisted in Experiment 4 when the doorway was removed, suggesting that the bias is the result of a mis-bisection of space. In Experiment 5, the rightward bias was replicated using an electric scooter, which is steered using handlebars. Finally, Experiment 6 required participants to point to the middle of the doorway, using a laser, before moving the scooter. Rightward mis-bisection was observed in both conditions. Rightward mis-bisection of lines in extrapersonal space provides the most parsimonious explanation of the rightward collisions and deviations.

Lay Summary T-cell and antibody responses to severe acute respiratory syndrome coronavirus 2 vaccination in inflammatory bowel disease patients are poorly correlated. T-cell responses are preserved by most biologic therapies, but augmented by anti-tumor necrosis factor (anti-TNF) treatment. While anti-TNF therapy blunts the antibody response, cellular immunity after vaccination is robust.

Cancer is an overwhelming concern with an estimated 1.7 million new cancer diagnoses expected in 2018 in the United States and over 600,000 predicted cancer-related deaths. Targeting the pathways that lead to tumor formation, disease progression, and cancer metastasis have been largely successful and this method has led to several breakthrough drugs. The therapies are often targeted towards key proteins that are overexpressed or mutated which results in pathway deregulation. We focused on two proteins that play a key role in cancer biology but have been notoriously difficult to target, IGF1R and Rac1. Traditional avenues for therapeutic development have failed for these two protein targets. We therefore have applied a number of biophysical techniques to develop novel and innovative approaches to IGF1R and Rac1 inhibition.

During the last decade, the object-oriented paradigm has been used increasingly to model advanced applications such as software-development environments (SDEs), CAD/CAM, and dynamic distributed decisionmaking (DDD). By offering data encapsulation, information hiding, and inheritance, the paradigm can model both the structure and behavior of complex applications [33] and also provide a robust design methodology that increases productivity and controls data consistency. When coupled with the availability of object-oriented database systems (c.g., Gemstone [38] - a Smalltalk extension [23], ORION [32], Cactis [28], ODE [4], and ONTOS [56] - C++ extensions [49], etc.), researchers can also explore the feasibility of the object-oriented paradigm for advanced applications that require persistent data storage and access.With the rising interest in the object-oriented paradigm, there has been a corresponding realization of some significant limitations to modeling the behavior 1 2 of an application using the paradigm. While most object-oriented models support behavior within types (intra-class behavior) through data encapsulation, interclass relationships and behavior are only minimally supported through ISA or inheritance hierarchies. Such limited support adversely affects the paradigm’s ability to model data in SDE and CAD/CAM applications. For example, in SDEs, complex inter-class relationships are vital when attempting to model incremental compilation, where the consistency of the parse tree, symbol table, call graphs, and other data representations must be maintained. We propose extending the object-oriented paradigm to include propagation actions in order to model these intricate inter-class relationships and behavior.The American Heritage Dictionary defines propagation as 1) Increase or spread, as by natural reproduction. 2) Dissemination, as of a belief [2],Propagation in databases may be thought of in a similar fashion. In a database, the act of propagation causes the effect of a change to data to be disseminated throughout the database. A simple example of propagation demonstrates that when a change occurs in the balance of a client’s bank account, a corresponding change in the bank’s total balance would also occur.The inclusion of propagation actions in the object-oriented paradigm would ensure that when an addition, modification, or deletion occurs to the database, automatic actions are taken to ensure that a consistent state of the database is maintained. These propagations actions would increase the modeling strength of the object-oriented paradigm by allowing the dynamic interactions between the 3 objects specified in a database application to be described at design time. In this manner, the object-oriented paradigm can be extended to model the complex behavior of a database application as well as the structure.During the last two years, we have been involved in a joint project researching the nature of propagation and its effects in an object-oriented environment. In [19], we have investigated the storage and maintenance of programs as objects in an object-oriented database in order to allow the designer to more easily conceptualize software throughout the development process. An early design attempt at incorporating propagation into an object-oriented model, namely ACM/PCM, is described in [15]. This effort outlines the characteristics of propagation, discusses the advantages of incorporating propagation into an object-oriented database, and describes a model developed by altering the ACM/PCM model [9] to include propagation. This work is extended in [20] which contains a further discussion of the benefits and nature of propagation in an object-oriented environment. Work done in [45] categorizes constraints and propagation rules in object-oriented schemas. The categorization allows for design-time analysis of database applications in order to determine the correctness of an application and provides a method for explicit specification of update actions during database design.As a result of this research, we present ADAM, an Active DAtabase Model that incorporates inter-class behavior into the object-oriented paradigm. ADAM is a database design tool and corresponding design methodology for the development of object-oriented applications that contain classes, inheritance, traditional 4 inter-class relationships, and complex inter-class relationships (propagation) between classes. The ADAM design tool allows the database designer to graphically supply application specifications and then generates a complete set of C++ classes that characterize the application. The designer uses three screens to specify the necessary object types and organize them into an inheritance hierarchy, define relationship types between object types, and describe inter-class propagation behavior. Each screen has a set of design options to support the creation of a portion of a graphical database application. When a design is complete, the designer then selects a Generate option which causes the ADAM tool to produce C+-|- classes corresponding to the object types, relationship types and behavior specified. To provide an overview into this work, the remainder of this chapter describes basic concepts and terminology relating to propagation, discusses the advantages of propagation and ADAM, outlines research goals, and lastly, reviews the organization of this thesis.