Chronic kidney disease (CKD/uremia) remains vexing because it increases the risk of atherothrombosis and is also associated with bleeding complications on standard antithrombotic/antiplatelet therapies. Although the associations of indolic uremic solutes and vascular wall proteins [such as tissue factor (TF) and aryl hydrocarbon receptor (AHR)] are being defined, the specific mechanisms that drive the thrombotic and bleeding risks are not fully understood. We now present an indolic solute–specific animal model, which focuses on solute-protein interactions and shows that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in an AHR- and TF-dependent manner. We further demonstrate that AHR regulates TF through STIP1 homology and U-box–containing protein 1 (STUB1). As a ubiquitin ligase, STUB1 dynamically interacts with and degrades TF through ubiquitination in the uremic milieu. TF regulation by STUB1 is supported in humans by an inverse relationship of STUB1 and TF expression and reduced STUB1-TF interaction in uremic vessels. Genetic or pharmacological manipulation of STUB1 in vascular smooth muscle cells inhibited thrombosis in flow loops. STUB1 perturbations reverted the uremic hyperthrombotic phenotype without prolonging the bleeding time, in contrast to heparin, the standard-of-care antithrombotic in CKD patients. Our work refines the thrombosis axis (STUB1 is a mediator of indolic solute–AHR-TF axis) and expands the understanding of the interconnected relationships driving the fragile thrombotic state in CKD. It also establishes a means of minimizing the uremic hyperthrombotic phenotype without altering the hemostatic balance, a long-sought-after combination in CKD patients.

A single session of repetitive transcranial magnetic stimulation (rTMS) can induce behavioural effects that outlast the duration of the stimulation train itself (off-line effects). Series of rTMS sessions on consecutive days are being used for therapeutic applications in a variety of disorders and are assumed to lead to the build-up of cumulative effects. However, no studies have carefully assessed this notion. In the present study we applied 30 daily sessions of 1 Hz rTMS (continuous train of 20 min) to repeatedly modulate activity in the posterior parietal cortex and associated neural systems in two intact cats. We assessed the effect on visuospatial orientation before and after each stimulation session. Cumulative sessions of rTMS progressively induced visuospatial neglect-like 'after-effects' of greater magnitude (from 5-10% to 40-50% error levels) and increasing spatial extent (from 90-75 degrees to 45-30 degrees eccentricity locations), affecting the visual hemifield contralateral to the stimulated hemisphere. Nonetheless, 60 min after each TMS session, visual detection-localization abilities repeatedly returned to baseline levels. Furthermore, no lasting behavioural effect could be demonstrated at any time across the study, when subjects were tested 1 or 24 h post-rTMS. We conclude that the past history of periodically cumulative rTMS sessions builds up a lasting 'memory', resulting in increased facilitation to subsequent TMS-induced disruptions. Such a phenomenon allows a behavioural effect of progressively higher magnitude, but equal duration, in response to individual TMS interventions.

Globally, over 25% of all children under the age of 5 years experience malnutrition leading to cognitive and emotional impairments that can persist into adulthood and beyond. We use a rodent model to determine the impact of prenatal protein malnutrition on executive functions in an attentional set-shifting task and metabolic activity in prefrontal cortex (PFC) subregions critical to these behaviors. Long-Evans dams were provided with a low (6% casein) or adequate (25% casein) protein diet 5 weeks before mating and during pregnancy. At birth, the litters were culled to 8 pups and fostered to control dams on the 25% casein diet. At postnatal day 90, prenatally malnourished rats were less able to shift attentional set and reverse reward contingencies than controls, demonstrating cognitive rigidity. Naive same-sexed littermates were assessed for regional brain activity using the metabolic marker ¹⁴C-2-deoxyglucose (2DG). The prenatally malnourished rats had lower metabolic activity than controls in prelimbic, infralimbic, anterior cingulate, and orbitofrontal cortices, but had comparable activity in the nearby piriform cortex and superior colliculus. This study demonstrates that prenatal protein malnutrition in a well-described animal model produces cognitive deficits in tests of attentional set shifting and reversal learning, similar to findings of cognitive inflexibility reported in humans exposed to early childhood malnutrition.

Transcranial direct current stimulation (tDCS) has recently undergone a resurgence in popularity as a powerful tool to non-invasively manipulate brain activity. While tDCS has been used to alter functions tied to primary motor and visual cortices, its impact on extrastriate visual areas involved in visuo-spatial processing has not yet been examined. In the current study, we applied tDCS to the cat visuoparietal (VP) cortex and assayed performance in a paradigm designed to assess the capacity to detect, localize and orient to static targets appearing at different spatial eccentricities within the visual field. Real or sham cathodal tDCS was unilaterally applied to the VP cortex, and orienting performance was assessed during (online), immediately after (offline; Experiments 1 and 2), and 1 or 24 h after the end of the tDCS stimulation (Experiment 2). Performance was compared to baseline data collected immediately prior to stimulation. Real, but not sham, tDCS induced significant decreases in performance for static visual targets presented in the contrastimulated visual hemifield. The behavioral impact of tDCS was most apparent during the online and immediate offline periods. The tDCS effect decayed progressively over time and performance returned to baseline levels approximately 60 min after stimulation. These results are consistent with the effects of both invasive and non-invasive deactivation methods applied to the same brain region, and indicate that tDCS has the potential to modify neuronal activity in extrastriate visual regions and to sculpt brain activity and behavior in normal and neurologically impaired subjects.