THE SYNTHESIS, ASSEMBLY, AND SECRETION OF GAMMA GLOBULIN BY MOUSE MYELOMA CELLS : VI. ASSEMBLY OF IGM PROTEINS

The study of the synthesis, assembly, and secretion of IgM by seven murine myeloma tumors has revealed that free mu chain can be detected intracellularly after release from the ribosome. It combines with light chains to form µL. The major intracellular protein in six of the seven tumors was the 8S subunit. One tumor contained considerable amounts of 19S material intracellularly. Those tumors that did not contain 19S IgM intracellulariy appeared to assemble the subunits outside the cell

IgM-producing tumors in the BALB/c mouse: a model for B-cell maturation

Five adjuvant induced BALB/c tumors producing IgM—McPc 1748, W 3469, TEPC 183, McPc 774, and Y 5781—were characterized morphologically by electron microscopy, analysis of the distribution of surface-bound and intracytoplasmic IgM using immunofluorescence, and by biochemical study of IgM synthesis, turnover, and secretion. The cells of different tumors appear to represent different stages in B-cell maturation when compared to normal, lipopolysaccharide-stimulated B cells. Thus, McPc 1748 tumor cells resemble 10–25-h stimulated normal B cells, 3469 cells resemble 20–35-h stimulated B cells, TEPC 183 cells resemble 45–65-h stimulated B cells, Y 5781 cells resemble 80–110-h stimulated B cells, and McPc 774 cells resemble 100–130-h stimulated B cells

The Impact of Left Hemisphere Stroke on Force Control with Familiar and Novel Objects: Neuroanatomic Substrates and Relationship to Apraxia

Fingertip force scaling for lifting objects frequently occurs in anticipation of finger contact. An ongoing question concerns the types of memories that are used to inform predictive control. Object-specific information such as weight may be stored and retrieved when previously encountered objects are lifted again. Alternatively, visual size and shape cues may provide estimates of object density each time objects are encountered. We reasoned that differences in performance with familiar versus novel objects would provide support for the former possibility. Anticipatory force production with both familiar and novel objects was assessed in six left hemisphere stroke patients, two of whom exhibited deficient actions with familiar objects (ideomotor apraxia; IMA), along with five control subjects. In contrast to healthy controls and stroke participants without IMA, participants with IMA displayed poor anticipatory scaling with familiar objects. However, like the other groups, IMA participants learned to differentiate fingertip forces with repeated lifts of both familiar and novel objects. Finally, there was a significant correlation between damage to the inferior parietal and superior and middle temporal lobes and impaired anticipatory control for familiar objects. These data support the hypotheses that anticipatory control during lifts of familiar objects in IMA patients are based on object-specific memories and that the ventro-dorsal stream is involved in the long-term storage of internal models used for anticipatory scaling during object manipulation

A Combination of Thematic and Similarity-Based Semantic Processes Confers Resistance to Deficit Following Left Hemisphere Stroke

Semantic knowledge may be organized in terms of similarity relations based on shared features and/or complementary relations based on co-occurrence in events. Thus, relationships between manipulable objects such as tools may be defined by their functional properties (what the objects are used for) or thematic properties (e.g., what the objects are used with or on). A recent study from our laboratory used eye-tracking to examine incidental activation of semantic relations in a word–picture matching task and found relatively early activation of thematic relations (e.g., broom–dustpan), later activation of general functional relations (e.g., broom–sponge), and an intermediate pattern for specific functional relations (e.g., broom–vacuum cleaner). Combined with other recent studies, these results suggest that there are distinct semantic systems for thematic and similarity-based knowledge and that the “specific function” condition drew on both systems. This predicts that left hemisphere stroke that damages either system (but not both) may spare specific function processing. The present experiment tested these hypotheses using the same experimental paradigm with participants with left hemisphere lesions (N = 17). The results revealed that, compared to neurologically intact controls (N = 12), stroke participants showed later activation of thematic and general function relations, but activation of specific function relations was spared and was significantly earlier for stroke participants than controls. Across the stroke participants, activation of thematic and general function relations was negatively correlated, further suggesting that damage tended to affect either one semantic system or the other. These results support the distinction between similarity-based and complementarity-based semantic relations and suggest that relations that draw on both systems are relatively more robust to damage

Spatially Distributed Tactile Feedback for Kinesthetic Motion Guidance

Apraxic stroke patients need to perform repetitive arm movements to regain motor functionality, but they struggle to process the visual feedback provided by typical virtual rehabilitation systems. Instead, we imagine a low cost sleeve that can measure the movement of the upper limb and provide tactile feedback at key locations. The feedback provided by the tactors should guide the patient through a series of desired movements by allowing him or her to feel limb configuration errors at each instant in time. After discussing the relevant motion capture and actuator options, this paper describes the design and programming of our current prototype, a wearable tactile interface that uses magnetic motion tracking and shaftless eccentric mass motors. The sensors and actuators are attached to the sleeve of an athletic shirt with novel plastic caps, which also help focus the vibration on the user\u27s skin. We connect the motors in current drive for improved performance, and we present a full parametric model for their in situ dynamic response (acceleration output given current input)

Transcriptomic changes in the frontal cortex associated with paternal age

Advanced paternal age is robustly associated with several human neuropsychiatric disorders, particularly autism. The precise mechanism(s) mediating the paternal age effect are not known, but they are thought to involve the accumulation of de novo (epi)genomic alterations. In this study we investigate differences in the frontal cortex transcriptome in a mouse model of advanced paternal age

Lack of class I H-2 antigens in cells transformed by radiation leukemia virus is associated with methylation and rearrangement of H-2 DNA

Transformation of murine thymocytes by radiation leukemia virus is associated with reduced expression of the class I antigens encoded in the major histocompatibility complex (MHC) and increased methylation and altered restriction enzyme patterns of MHC DNA. These changes may play a role in host susceptibility to virus-induced leukemogenesis and accord with the notion that viral genomes play a regulatory function when they integrate adjacent to histocompatibiity genes

The role of action representations in thematic object relations

A number of studies have explored the role of associative/event-based (thematic) and categorical (taxonomic) relations in the organization of object representations. Recent evidence suggests that thematic information may be particularly important in determining relationships between manipulable artifacts. However, although sensorimotor information is on many accounts an important component of manipulable artifact representations, little is known about the role that action may play during the processing of semantic relationships (particularly thematic relationships) between multiple objects. In this study, we assessed healthy and left hemisphere stroke participants to explore three questions relevant to object relationship processing. First, we assessed whether participants tended to favor thematic relations including action (Th+A, e.g., wine bottle—corkscrew), thematic relationships without action (Th-A, e.g., wine bottle—cheese), or taxonomic relationships (Tax, e.g., wine bottle—water bottle) when choosing between them in an association judgment task with manipulable artifacts. Second, we assessed whether the underlying constructs of event relatedness, action relatedness, and categorical relatedness determined the choices that participants made. Third, we assessed the hypothesis that degraded action knowledge and/or damage to temporo-parietal cortex, a region of the brain associated with the representation of action knowledge, would reduce the influence of action on the choice task. Experiment 1 showed that explicit ratings of event, action, and categorical relatedness were differentially predictive of healthy participants' choices, with action relatedness determining choices between Th+A and Th-A associations above and beyond event and categorical ratings. Experiment 2 focused more specifically on these Th+A vs. Th-A choices and demonstrated that participants with left temporo-parietal lesions, a brain region known to be involved in sensorimotor processing, were less likely than controls and tended to be less likely than patients with lesions sparing that region to use action relatedness in determining their choices. These data indicate that action knowledge plays a critical role in processing of thematic relations for manipulable artifacts

Peripheral Blood Cell Gene Expression Diagnostic for Identifying Symptomatic Transthyretin Amyloidosis Patients: Male and Female Specific Signatures

BACKGROUND: Early diagnosis of familial transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease-modifying therapies. Endomyocardial biopsies are typically amyloid positive when cardiomyopathy is suspected, but this disease manifestation is generally diagnosed late. Early diagnosis is often difficult because patients exhibit apparent symptoms of polyneuropathy, but have a negative amyloid biopsy. Thus, there is a pressing need for an additional early diagnostic strategy for TTR-aggregation-associated polyneuropathy and cardiomyopathy. METHODS AND FINDINGS: Global peripheral blood cell mRNA expression profiles from 263 tafamidis-treated and untreated V30M Familiar Amyloid Neuropathy patients, asymptomatic V30M carriers, and healthy, age- and sex-matched controls without TTR mutations were used to differentiate symptomatic from asymptomatic patients. We demonstrate that blood cell gene expression patterns reveal sex-independent, as well as male- and female-specific inflammatory signatures in symptomatic FAP patients, but not in asymptomatic carriers. These signatures differentiated symptomatic patients from asymptomatic V30M carriers with >80% accuracy. There was a global downregulation of the eIF2 pathway and its associated genes in all symptomatic FAP patients. We also demonstrated that the molecular scores based on these signatures significantly trended toward normalized values in an independent cohort of 46 FAP patients after only 3 months of tafamidis treatment. CONCLUSIONS: This study identifies novel molecular signatures that differentiate symptomatic FAP patients from asymptomatic V30M carriers as well as affected males and females. We envision using this approach, initially in parallel with amyloid biopsies, to identify individuals who are asymptomatic gene carriers that may convert to FAP patients. Upon further validation, peripheral blood cell mRNA expression profiling could become an independent early diagnostic. This quantitative gene expression signature for symptomatic FAP could also become a biomarker to demonstrate significant disease-modifying effects of drugs and drug candidates. For example, when new disease modifiers are being evaluated in a FAP clinical trial, such surrogate biomarkers have the potential to provide an objective, quantitative and mechanistic molecular diagnostic of disease response to therapy.We acknowledge the following sources of research funding: NIH U19 A1063603 (DRS, SMK), NIH DK46335 (JWK) and NIH R01AG19259 (JNB)info:eu-repo/semantics/publishedVersio