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The cell type-specific expression of key transcription factors is central to development and disease. Brachyury/T/TBXT is a major transcription factor for gastrulation, tailbud patterning, and notochord formation; however, how its expression is controlled in the mammalian notochord has remained elusive. Here, we identify the complement of notochord-specific enhancers in the mammalian Brachyury/T/TBXT gene. Using transgenic assays in zebrafish, axolotl, and mouse, we discover three conserved Brachyury-controlling notochord enhancers, T3, C, and I, in human, mouse, and marsupial genomes. Acting as Brachyury-responsive, auto-regulatory shadow enhancers, in cis deletion of all three enhancers in mouse abolishes Brachyury/T/Tbxt expression selectively in the notochord, causing specific trunk and neural tube defects without gastrulation or tailbud defects. The three Brachyury-driving notochord enhancers are conserved beyond mammals in the brachyury/tbxtb loci of fishes, dating their origin to the last common ancestor of jawed vertebrates. Our data define the vertebrate enhancers for Brachyury/T/TBXTB notochord expression through an auto-regulatory mechanism that conveys robustness and adaptability as ancient basis for axis development.

The cell type-specific expression of key transcription factors is central to development. Brachyury/T/TBXT is a major transcription factor for gastrulation, tailbud patterning, and notochord formation; however, how its expression is controlled in the mammalian notochord has remained elusive. Here, we identify the complement of notochord-specific enhancers in the mammalian Brachyury/T/TBXT gene. Using transgenic assays in zebrafish, axolotl, and mouse, we discover three Brachyury -controlling notochord enhancers T3, C , and I in human, mouse, and marsupial genomes. Acting as Brachyury-responsive, auto-regulatory shadow enhancers, deletion of all three enhancers in mouse abolishes Brachyury/T expression selectively in the notochord, causing specific trunk and neural tube defects without gastrulation or tailbud defects. Sequence and functional conservation of Brachyury -driving notochord enhancers with the brachyury/tbxtb loci from diverse lineages of fishes dates their origin to the last common ancestor of jawed vertebrates. Our data define the enhancers for Brachyury/T/TBXTB notochord expression as ancient mechanism in axis development.

Abstract Using connected sensing devices to remotely monitor health is a promising way to help transition healthcare from a rather reactive to a more precision medicine oriented proactive approach, which could be particularly relevant in the face of rapid population ageing and the challenges it poses to healthcare systems. Sensor derived digital measures of health, such as digital biomarkers or digital clinical outcome assessments, may be used to monitor health status or the risk of adverse events like falls. Current research around such digital measures has largely focused on exploring the use of few individual measures obtained through mobile devices. However, especially for long-term applications in older adults, this choice of technology may not be ideal and could further add to the digital divide. Moreover, large-scale systems biology approaches, like genomics, have already proven beneficial in precision medicine, making it plausible that the same could also hold for remote-health monitoring. In this context, we introduce and describe a zero-interaction digital exhaust: a set of 1268 digital measures that cover large parts of a person’s activity, behavior and physiology. Making this approach more inclusive of older adults, we base this set entirely on contactless, zero-interaction sensing technologies. Applying the resulting digital exhaust to real-world data, we then demonstrate the possibility to create multiple ageing relevant digital clinical outcome assessments. Paired with modern machine learning, we find these assessments to be surprisingly powerful and often on-par with mobile approaches. Lastly, we highlight the possibility to discover novel digital biomarkers based on this large-scale approach.

Background: Transverse sinus stenting (TSS) is an increasingly common treatment for patients with idiopathic intracranial hypertension (IIH). However, detailed neuro-ophthalmic evidence on visual and pharmacotherapy outcomes after TSS is scarce and heterogeneous. This study aimed to describe the visual outcomes of patients undergoing TSS for IIH and to ascertain the proportion of patients who could be weaned off intracranial pressure (ICP)-lowering medication postoperatively. Methods: A retrospective chart review of all patients with IIH from 2 tertiary academic neuro-ophthalmology practices who underwent TSS between 2016 and 2022 was performed. Indications for stenting included failure of pharmacotherapy, intolerance of pharmacotherapy, and acute vision loss from severe papilledema. Data on demographics, symptoms, visual function, pharmacotherapy, and TSS were collected. The paired Wilcoxon rank sum test was used to compare changes in visual acuity (VA) and visual field mean deviation (VFMD) between the baseline and most recent visits. Results: Of the 435 patients with IIH, 15 (13 women) met inclusion criteria. After TSS, ICP-lowering pharmacotherapy was discontinued in 10 patients and decreased in 4; 1 patient was not on ICP-lowering medication before TSS. All patients experienced resolution or improvement of symptoms (10 resolution, 4 improved, 1 asymptomatic before TSS) and papilledema (11 resolution, 4 improved) after stenting. Papilledema resolution was confirmed with optical coherence tomography–measured peripapillary nerve fiber layer thickness (median decrease 147 µm, interquartile range 41.8–242.8 µm, P < 0.001). Change in VA between the baseline and most recent visit was not significant, but VFMD improved significantly after stenting (median increase 3.0, IQR 2.0–4.2, P < 0.001). No patient developed transverse sinus restenosis nor in-stent thrombosis postoperatively across a median venogram follow-up of 20.8 (11.3–49.8) weeks. In addition, no patient required subsequent surgical intervention for IIH. Conclusions: In this cohort of patients with IIH and fulminant presentation, medication resistance, or medication intolerance, TSS was an effective and safe treatment modality. Most patients were able to stop ICP-lowering medications while demonstrating striking improvement in symptomatology and visual function. [ABSTRACT FROM AUTHOR]

Haematopoietic stem cells (HSCs) arise in the developing aorta during embryogenesis. The number of HSC clones born has been estimated through transplantation, but experimental approaches to assess the absolute number of forming HSCs in a native setting have remained challenging. Here, we applied single-cell and clonal analysis of HSCs in zebrafish to quantify developing HSCs. Targeting creERT2 in developing cd41:eGFP+ HSCs enabled long-term assessment of their blood contribution. We also applied the Brainbow-based multicolour Zebrabow system with drl:creERT2 that is active in early haematopoiesis to induce heritable colour barcoding unique to each HSC and its progeny. Our findings reveal that approximately 21 HSC clones exist prior to HSC emergence and 30 clones are present during peak production from aortic endothelium. Our methods further reveal that stress haematopoiesis, including sublethal irradiation and transplantation, reduces clonal diversity. Our findings provide quantitative insights into the early clonal events that regulate haematopoietic development.

In healthy individuals, increasing cognitive load induces an asymmetric deployment of visuospatial attention, which favors the right visual space. To date, the neural mechanisms of this left/right attentional asymmetry are poorly understood. The aim of the present study was thus to investigate whether a left/right asymmetry under high cognitive load is due to a shift in the interhemispheric balance between the left and right posterior parietal cortices (PPCs), favoring the left PPC. To this end, healthy participants completed a visuospatial attention detection task under low and high cognitive load, whilst undergoing biparietal transcranial direct current stimulation (tDCS). Three different tDCS conditions were applied in a within-subjects design: sham, anodal left/cathodal right, and cathodal left/anodal right stimulation. The results revealed a left/right attentional asymmetry under high cognitive load in the sham condition. This asymmetry disappeared during cathodal left/anodal right tDCS, yet was not influenced by anodal left/cathodal right tDCS. There were no left/right asymmetries under low cognitive load in any of the conditions. Overall, these findings demonstrate that attentional asymmetries under high cognitive load can be modulated in a polarity-specific fashion by means of tDCS. They thus support the assumption that load-related asymmetries in visuospatial attention are influenced by interhemispheric balance mechanisms between the left and right PPCs.

Background: Newly acquired long-term cognitive impairments are common among survivors of critical illness. They have been linked to the stressful situation that patients experience in the intensive care unit (ICU). In this paper we use virtual reality (VR) technology to comfort critically ill patients and reduce stress during their ICU stay. We investigate the acceptance, comfort, recollection, and visual perception of VR stimulation and how it affects physiological parameters.Methods: A VR head-mounted display was used to present immersive nature scenes to 33 critically ill cardiac surgery patients [mean age 63 years (range 32–83)]. Data was collected with an eye tracker fitted inside the VR head-mounted display to measure eye movements (250 Hz) and sensors to record physiological parameters (240 Hz). Patients received VR stimulation (for 5 min.) prior to ICU admission, during ICU stay, and 3 months after discharge. Acceptance, recollection and comfort were assessed with validated questionnaires.Results: The number of gazed meaningful objects per minute was significantly lower during the ICU session compared to pre- and follow-up sessions, whereas mean duration of fixation on meaningful moving objects did not differ between the sessions. While respiratory rate decreased significantly during VR stimulation, heart rate and blood pressure remained constant. Post-ICU rating of VR acceptance during ICU stay was moderate to high and discomfort low. Recollection of VR was high [28/33 patients (84.8%)], while recollection of ICU stay was low [10/33 patients (30.3%)].Conclusion: Eye movements indicate that patients were able to perceive and process cognitive stimulation during their ICU stay. VR was recalled better than the rest of the ICU stay and well accepted. Decreased respiratory rate during stimulation indicate a relaxing effect of VR.

Cross-modal spatial cueing can affect performance in a visual search task. For example, search performance improves if a visual target and an auditory cue originate from the same spatial location, and it deteriorates if they originate from different locations. Moreover, it has recently been postulated that multisensory settings, i.e., experimental settings, in which critical stimuli are concurrently presented in different sensory modalities (e.g., visual and auditory), may trigger asymmetries in visuospatial attention. Thereby, a facilitation has been observed for visual stimuli presented in the right compared to the left visual space. However, it remains unclear whether auditory cueing of attention differentially affects search performance in the left and the right hemifields in audio-visual search tasks. The present study investigated whether spatial asymmetries would occur in a search task with cross-modal spatial cueing. Participants completed a visual search task that contained no auditory cues (i.e., unimodal visual condition), spatially congruent, spatially incongruent, and spatially non-informative auditory cues. To further assess participants' accuracy in localising the auditory cues, a unimodal auditory spatial localisation task was also administered. The results demonstrated no left/right asymmetries in the unimodal visual search condition. Both an additional incongruent, as well as a spatially non-informative, auditory cue resulted in lateral asymmetries. Thereby, search times were increased for targets presented in the left compared to the right hemifield. No such spatial asymmetry was observed in the congruent condition. However, participants' performance in the congruent condition was modulated by their tone localisation accuracy. The findings of the present study demonstrate that spatial asymmetries in multisensory processing depend on the validity of the cross-modal cues, and occur under specific attentional conditions, i.e., when visual attention has to be reoriented towards the left hemifield.