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The interplay between AMPA-type glutamate receptors (AMPARs) and major histocompatibility complex class I (MHC-I) proteins in regulating synaptic signaling is a crucial aspect of central nervous system (CNS) function. In this study, we investigate the significance of the cytoplasmic tail of MHC-I in synaptic signaling within the CNS and its impact on the modulation of synaptic glutamate receptor expression. Specifically, we focus on the Y321 to F substitution (Y321F) within the conserved cytoplasmic tyrosine YXXΦ motif, known for its dual role in endocytosis and cellular signaling of MHC-I. Our findings reveal that the Y321F substitution influences the expression of AMPAR subunits GluA2/3 and leads to alterations in the phosphorylation of key kinases, including Fyn, Lyn, p38, ERK1/2, JNK1/2/3, and p70 S6 kinase. These data illuminate the crucial role of MHC-I in AMPAR function and present a novel mechanism by which MHC-I integrates extracellular cues to modulate synaptic plasticity in neurons, which ultimately underpins learning and memory. [ABSTRACT FROM AUTHOR]

Major histocompatibility complex class I (MHC-I) proteins are expressed in neurons, where they regulate synaptic plasticity. However, the mechanisms by which MHC-I functions in the CNS remains unknown. Here we describe the first structural analysis of a MHC-I protein, to resolve underlying mechanisms that explains its function in the brain. We demonstrate that Y321F mutation of the conserved cytoplasmic tyrosine-based endocytosis motif YXXΦ in MHC-I affects spine density and synaptic structure without affecting neuronal complexity in the hippocampus, a region of the brain intimately involved in learning and memory. Furthermore, the impact of the Y321F substitution phenocopies MHC-I knock-out (null) animals, demonstrating that reverse, outside-in signalling events sensing the external environment is the major mechanism that conveys this information to the neuron and this has a previously undescribed yet essential role in the regulation of synaptic plasticity. [ABSTRACT FROM AUTHOR]

Purpose of Review: Rectal cancers are treated with chemotherapy, radiotherapy, and surgery. While trials have illustrated the benefits of radiotherapy for locoregional control, recent investigations have questioned the need in select cases. This review seeks to understand why, how, and when radiation can be omitted from rectal cancer management. Recent Findings: Absolute contraindications of radiation include pregnancy, and relative contraindications include fertility concerns, sexual outcomes, autoimmune conditions, and prior radiation. Low-risk features of rectal cancer might warrant the omission of neoadjuvant radiation. MRI-directed therapy, chemotherapy alone, and immunotherapy may offer future ways to omit radiation. Summary: While radiation continues to be an essential component for rectal cancer treatment, there may be circumstances that it can be omitted. It is important to educate patients that not receiving radiation is a deviation from standard of care. In the future, we may see developments and changes in the treatment paradigm for rectal cancer. [ABSTRACT FROM AUTHOR]