Dynamic synchronization between hippocampal representations and stepping.

The hippocampus is a mammalian brain structure that expresses spatial representations1 and is crucial for navigation2,3. Navigation, in turn, intricately depends on locomotion; however, current accounts suggest a dissociation between hippocampal spatial representations and the details of locomotor processes. Specifically, the hippocampus is thought to represent mainly higher-order cognitive and locomotor variables such as position, speed and direction of movement4-7, whereas the limb movements that propel the animal can be computed and represented primarily in subcortical circuits, including the spinal cord, brainstem and cerebellum8-11. Whether hippocampal representations are actually decoupled from the detailed structure of locomotor processes remains unknown. To address this question, here we simultaneously monitored hippocampal spatial representations and ongoing limb movements underlying locomotion at fast timescales. We found that the forelimb stepping cycle in freely behaving rats is rhythmic and peaks at around 8 Hz during movement, matching the approximately 8 Hz modulation of hippocampal activity and spatial representations during locomotion12. We also discovered precisely timed coordination between the time at which the forelimbs touch the ground ('plant' times of the stepping cycle) and the hippocampal representation of space. Notably, plant times coincide with hippocampal representations that are closest to the actual position of the nose of the rat, whereas between these plant times, the hippocampal representation progresses towards possible future locations. This synchronization was specifically detectable when rats approached spatial decisions. Together, our results reveal a profound and dynamic coordination on a timescale of tens of milliseconds between central cognitive representations and peripheral motor processes. This coordination engages and disengages rapidly in association with cognitive demands and is well suited to support rapid information exchange between cognitive and sensory-motor circuits.

Estrogen Receptor Mutations as Novel Targets for Immunotherapy in Metastatic Estrogen Receptor-positive Breast Cancer.

Estrogen receptor-positive (ER+) breast cancer is not considered immunogenic and, to date, has been proven resistant to immunotherapy. Endocrine therapy remains the cornerstone of treatment for ER+ breast cancers. However, constitutively activating mutations in the estrogen receptor alpha (ESR1) gene can emerge during treatment, rendering tumors resistant to endocrine therapy. Although these mutations represent a pathway of resistance, they also represent a potential source of neoepitopes that can be targeted by immunotherapy. In this study, we investigated ESR1 mutations as novel targets for breast cancer immunotherapy. Using machine learning algorithms, we identified ESR1-derived peptides predicted to form stable complexes with HLA-A*0201. We then validated the binding affinity and stability of the top predicted peptides through in vitro binding and dissociation assays and showed that these peptides bind HLA-A*0201 with high affinity and stability. Using tetramer assays, we confirmed the presence and expansion potential of antigen-specific CTLs from healthy female donors. Finally, using in vitro cytotoxicity assays, we showed the lysis of peptide-pulsed targets and breast cancer cells expressing common ESR1 mutations by expanded antigen-specific CTLs. Ultimately, we identified five peptides derived from the three most common ESR1 mutations (D538G, Y537S, and E380Q) and their associated wild-type peptides, which were the most immunogenic. Overall, these data confirm the immunogenicity of epitopes derived from ESR1 and highlight the potential of these peptides to be targeted by novel immunotherapy strategies. SIGNIFICANCE: Estrogen receptor (ESR1) mutations have emerged as a key factor in endocrine therapy resistance. We identified and validated five novel, immunogenic ESR1-derived peptides that could be targeted through vaccine-based immunotherapy.

Impostor phenomenon and burnout syndrome among emergency physicians: a cross-sectional study.

INTRODUCTION: This study examined emergency physicians across the country in terms of Impostor Phenomenon (IP) and Burnout Syndrome (BoS). We aimed to evaluate the possible relationship between IP and BoS and determine which demographic characteristics pose a risk for IP and BoS. METHODS: This quantitative cross-sectional study consists of Clance Impostor Phenomenon Scale (CIPS) and Maslach Burnout Inventory (MBI) which were filled out online by the participants. A total of 389 volunteers participated in the study. RESULTS: The median age of participants was 30 years (Q1-Q3=27-35) and 57.3% (223) of them were male. The frequency of significant/intense IP was higher in women (28.9%) than in men (17%) (p=0.020). High emotional exhaustion and low personal accomplishment were more common in women than in men (71.7% vs 60.6% and 50% vs 31%, respectively). The median age of participants classified as none to mild IP was 34 years. It was 28 years in significant/intense IP. It was detected that the severity of IP increased as the participants got younger (p<0.001). Significant/intense IP was most common in residents (29%). The residents also had the highest frequency of depersonalization (73.5%). The frequency of moderate to intense IP was the least in participants who worked at a university hospital (74.6%). CONCLUSION: The results of this study indicated that IP and BoS are more common in residency. The increased frequency of IP and BoS in young female physicians may be attributed to hierarchical working arrangements and worry about academic performance. Experienced physicians with high levels of academic self-consciousness exhibited a low frequency of IP. Additionally, this study identified a moderate correlation between IP and BoS.