Between Slit and Repulsion: Cell and Molecular Mechanisms Underlying Robo-Mediated Midline Guidance

Understanding how axon guidance receptors are activated by their extracellular ligands to regulate growth cone motility is critical to learning how proper wiring is established during development. Roundabout (Robo) is one such guidance receptor that mediates repulsion from its ligand Slit in both invertebrates and vertebrates. Here we show that endocytic trafficking of the Robo receptor in response to Slit-binding is necessary for its repulsive signaling output. Dose-dependent genetic interactions and in vitro Robo activation assays support a role for Clathrin-dependent endocytosis, and entry into both the early and late endosomes as positive regulators of Slit-Robo signaling. We identify two conserved motifs in Robo\u27s cytoplasmic domain that are required for its Clathrin-dependent endocytosis and activation in vitro, and gain of function and genetic rescue experiments provide strong evidence that these trafficking events are required for Robo repulsive guidance activity in vivo. Our data support a model in which Robo\u27s ligand-dependent internalization from the cell surface to the late endosome is essential for receptor activation and proper repulsive guidance at the midline by allowing recruitment of the downstream effector Son of Sevenless in a spatially constrained endocytic trafficking compartment. We then go on to provide evidence for the placement of Robo endocytosis after the previously reported kuzbanian-mediated juxtamembrane activating cleavage and before a newly reported inactivating presenilin-mediated transmembrane cleavage that serves to curtail the timecourse of signaling from activated Robo

Reducing Intubation Time in Adult Cardiothoracic Surgery Patients: A Review of Data under the Direction of a Board Certified Critical Care Intensivist

Background: Prolonged intubation after cardiac surgery increases the risk of morbidity and mortality and lengthens hospital stays. Factors that influence the ability to extubate patients with speed and efficiency include the type of operation, the patient’s baseline physiological condition, and provider practice patterns. The purpose of this research was to prove that the change of practice patterns that followed the addition of an intensivist lessened extubation times in cardiac surgery patients. It was hypothesized that the interventions brought on by the introduction of an intensivist would greatly reduce the amount of time a patient is intubated while in the intensive care unit. Problem: Prolonged intubation times contributed to increased length of stay in the intensive care unit, increased morbidity and mortality rates. Method: Barriers of extubation were identified and a protocol was agreed upon by advanced practice providers along with RN’s. A comprehensive unit based safety initiative was designed and put into practice. From April 2020 to April 2021 data was collected where the cardiac intensive care unit was without an intensivist. Data was then collected from April 2021 to April 2022 when there was an intensivist on site. The data analyzed included the number of patient’s extubated under six hours out of the total number of cases. Cases included in the study consisted of CABG’s and Valves. Cases excluded from the study were aneurysm repairs and minimally assisted CABG’s where the patients came out of the OR extubated. Considerations included the elimination of Morphine/Versed, the introduction of Precedex and Propofol and more attention to the last paralytic/reversal agent out of the operating room. Results: Extubation in under six hours on the unit without an intensivist occurred in 116/571 patients (20.3%). With the introduction of an intensivist on the unit there was a total of 181/531 patients extubated in under six hours (34%). Conclusion: The number of early extubations increased with an intensivist in the intensive care unit.https://scholar.rochesterregional.org/nursingresearchday/1012/thumbnail.jp

Leveraging Language Models to Detect Greenwashing

In recent years, climate change repercussions have increasingly captured public interest. Consequently, corporations are emphasizing their environmental efforts in sustainability reports to bolster their public image. Yet, the absence of stringent regulations in review of such reports allows potential greenwashing. In this study, we introduce a novel methodology to train a language model on generated labels for greenwashing risk. Our primary contributions encompass: developing a mathematical formulation to quantify greenwashing risk, a fine-tuned ClimateBERT model for this problem, and a comparative analysis of results. On a test set comprising of sustainability reports, our best model achieved an average accuracy score of 86.34% and F1 score of 0.67, demonstrating that our methods show a promising direction of exploration for this task

The cellular basis of distinct thirst modalities

Fluid intake is an essential innate behaviour that is mainly caused by two distinct types of thirst. Increased blood osmolality induces osmotic thirst that drives animals to consume pure water. Conversely, the loss of body fluid induces hypovolaemic thirst, in which animals seek both water and minerals (salts) to recover blood volume. Circumventricular organs in the lamina terminalis are critical sites for sensing both types of thirst-inducing stimulus. However, how different thirst modalities are encoded in the brain remains unknown. Here we employed stimulus-to-cell-type mapping using single-cell RNA sequencing to identify the cellular substrates that underlie distinct types of thirst. These studies revealed diverse types of excitatory and inhibitory neuron in each circumventricular organ structure. We show that unique combinations of these neuron types are activated under osmotic and hypovolaemic stresses. These results elucidate the cellular logic that underlies distinct thirst modalities. Furthermore, optogenetic gain of function in thirst-modality-specific cell types recapitulated water-specific and non-specific fluid appetite caused by the two distinct dipsogenic stimuli. Together, these results show that thirst is a multimodal physiological state, and that different thirst states are mediated by specific neuron types in the mammalian brain

Traversing digital-creative perspectives: preparing design and technology students for interdisciplinary work.

The project aim, as stated in the original proposal, was “‘to develop and evaluate a novel collaborative approach using inter-disciplinary curricula to enhance work-readiness of computing and creative advertising undergraduates. The project vehicle is a live brief for the university Computing and Art & Design departments to work with Wycombe District Council to develop a mobile and location-sensitive “Heritage Trail App” to interpret significant sites in High Wycombe”. The overall aim of the project has remained unchanged. However, as a result of the success of the first cycle of project work (undertaken in the 2016-17 academic year), the university was approached by Buckinghamshire County Council and offered an opportunity for a further client partnership to develop a ‘web-app’ to support the delivery of the ‘Safe Places Scheme’, an initiative to provide locations where vulnerable people may seek support when they are out and about in the community. This also allowed the project team to develop and validate the approach with a new student subject and a different year group during the second and final cycle of project work (undertaken in 2017-18). This time final year BSc Computing students worked in partnership with second year BA students reading Graphic Arts, Graphic Design and Illustration. The underpinning project objectives and their mapping to the original themes of ‘Call A’ are also unchanged and are as follows: (1) Align computing and design curricula to develop vocationally relevant collaborative skills. Maps to ‘develop[ing] curriculum innovations from interdisciplinary research, interdisciplinary professional practice …’ (2) Evaluate learning gain arising from an innovative approach to authentically represent interdisciplinary and collaborative digital-creative environments. Maps to ‘respond to employer demands for advanced skills or knowledge’. 5 (3) Analyse engagement metrics to: a) predict/reflect progress in learning and collaboration; b) flag need for supportive interventions; c) use for self-directed learning. Maps to ‘develop use of learner analytics for particular pedagogic purposes’

Complementary networks of cortical somatostatin interneurons enforce layer specific control

The neocortex is functionally organized into layers. Layer four receives the densest bottom up sensory inputs, while layers 2/3 and 5 receive top down inputs that may convey predictive information. A subset of cortical somatostatin (SST) neurons, the Martinotti cells, gate top down input by inhibiting the apical dendrites of pyramidal cells in layers 2/3 and 5, but it is unknown whether an analogous inhibitory mechanism controls activity in layer 4. Using high precision circuit mapping, in vivo optogenetic perturbations, and single cell transcriptional profiling, we reveal complementary circuits in the mouse barrel cortex involving genetically distinct SST subtypes that specifically and reciprocally interconnect with excitatory cells in different layers: Martinotti cells connect with layers 2/3 and 5, whereas non-Martinotti cells connect with layer 4. By enforcing layer-specific inhibition, these parallel SST subnetworks could independently regulate the balance between bottom up and top down input

Engineering Education Research: Reviewing Journal Manuscripts Fairly, Constructively, Effectively

Peer review is the mechanism for quality control in academic journals. When a manuscript is submitted to a journal, the editors invite other researchers – peers – to review it anonymously. The reviews should serve to support the journal editors in making decisions, and to support the authors in improving the manuscripts before publication. Therefore, reviews need to be fair and constructive. As reviewing can also take considerable effort, it is useful for the reviewer to consider how to do it effectively. Given the important role of peer review in a field, and the considerable effort it takes, it is valuable to jointly consider all these aspects of reviewing in a dialogue with reviewers, authors and editors. This paper presents the outcomes of such a dialogue with 49 participants in the field of engineering education research

Mapping multimorbidity in individuals with schizophrenia and bipolar disorders: evidence from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLAM BRC) case register

OBJECTIVES: The first aim of this study was to design and develop a valid and replicable strategy to extract physical health conditions from clinical notes which are common in mental health services. Then, we examined the prevalence of these conditions in individuals with severe mental illness (SMI) and compared their individual and combined prevalence in individuals with bipolar (BD) and schizophrenia spectrum disorders (SSD). DESIGN: Observational study. SETTING: Secondary mental healthcare services from South London PARTICIPANTS: Our maximal sample comprised 17 500 individuals aged 15 years or older who had received a primary or secondary SMI diagnosis (International Classification of Diseases, 10th edition, F20-31) between 2007 and 2018. MEASURES: We designed and implemented a data extraction strategy for 21 common physical comorbidities using a natural language processing pipeline, MedCAT. Associations were investigated with sex, age at SMI diagnosis, ethnicity and social deprivation for the whole cohort and the BD and SSD subgroups. Linear regression models were used to examine associations with disability measured by the Health of Nations Outcome Scale. RESULTS: Physical health data were extracted, achieving precision rates (F1) above 0.90 for all conditions. The 10 most prevalent conditions were diabetes, hypertension, asthma, arthritis, epilepsy, cerebrovascular accident, eczema, migraine, ischaemic heart disease and chronic obstructive pulmonary disease. The most prevalent combination in this population included diabetes, hypertension and asthma, regardless of their SMI diagnoses. CONCLUSIONS: Our data extraction strategy was found to be adequate to extract physical health data from clinical notes, which is essential for future multimorbidity research using text records. We found that around 40% of our cohort had multimorbidity from which 20% had complex multimorbidity (two or more physical conditions besides SMI). Sex, age, ethnicity and social deprivation were found to be key to understand their heterogeneity and their differential contribution to disability levels in this population. These outputs have direct implications for researchers and clinicians