Diagnostic overshadowing: self-injurious behaviour as a manifestation of pain in the head and neck.

In the healthcare domain, diagnostic overshadowing is a concerning issue involving the erroneous attribution of physical symptoms to a patient's mental health, behavioural intricacies, or pre-existing disabilities. Individuals facing learning and communication challenges are particularly susceptible to this phenomenon, struggling to articulate or comprehend their experienced symptoms. Likewise, patients with autism spectrum disorder can have an escalated risk due to possible challenges in interpreting bodily cues. This article delves into the specialised care required for individuals with learning disabilities and/or autism, highlighting the pervasive risk of diagnostic overshadowing and the potential manifestation of pain as self-injurious behaviour in these patient groups. By underscoring the need to mitigate diagnostic overshadowing within dental practice, we advocate for reasonable adjustments in care delivery and comprehensive education of the dental team. Proficient tools for pain assessment and effective communication are emphasised to collectively improve the healthcare experience for these vulnerable patient cohorts.

Controlling DNA replication origins in response to DNA damage - inhibit globally, activate locally.

DNA replication in eukaryotic cells initiates from multiple replication origins that are distributed throughout the genome. Coordinating the usage of these origins is crucial to ensure complete and timely replication of the entire genome precisely once in each cell cycle. Replication origins fire according to a cell-type-specific temporal programme, which is established in the G1 phase of each cell cycle. In response to conditions causing the slowing or stalling of DNA replication forks, the programme of origin firing is altered in two contrasting ways, depending on chromosomal context. First, inactive or 'dormant' replication origins in the vicinity of the stalled replication fork become activated and, second, the S phase checkpoint induces a global shutdown of further origin firing throughout the genome. Here, we review our current understanding on the role of dormant origins and the S phase checkpoint in the rescue of stalled forks and the completion of DNA replication in the presence of replicative stress.

Identification of a heteromeric complex that promotes DNA replication origin firing in human cells.

Treslin/TICRR (TopBP1-interacting, replication stimulating protein/TopBP1-interacting, checkpoint, and replication regulator), the human ortholog of the yeast Sld3 protein, is an essential DNA replication factor that is regulated by cyclin-dependent kinases and the DNA damage checkpoint. We identified MDM two binding protein (MTBP) as a factor that interacts with Treslin/TICRR throughout the cell cycle. We show that MTBP depletion by means of small interfering RNA inhibits DNA replication by preventing assembly of the CMG (Cdc45-MCM-GINS) holohelicase during origin firing. Although MTBP has been implicated in the function of the p53 tumor suppressor, we found MTBP is required for DNA replication irrespective of a cell's p53 status. We propose that MTBP acts with Treslin/TICRR to integrate signals from cell cycle and DNA damage response pathways to control the initiation of DNA replication in human cells.

Spred2 interaction with the late endosomal protein NBR1 down-regulates fibroblast growth factor receptor signaling.

The potential for modulation of growth factor signaling by endocytic trafficking of receptors is well recognized, but the underlying mechanisms are poorly understood. We examined the regulation of fibroblast growth factor (FGF) signaling by Sprouty related with EVH1 (Ena/VASP homology 1) domain (Spred), a family of signaling inhibitors with proposed tumor-suppressive functions. The inhibitory activity of Spreds has been linked to their N-terminal EVH1 domain, but the molecular mechanism is unknown. In this study, we identify a novel late endosomal protein that directly binds to the EVH1 domain of Spred2. Neighbor of BRCA1 (NBR1) is a highly conserved multidomain protein that interacts and colocalizes with Spred2 in vivo. Attenuation of FGF signaling by Spred2 is dependent on the interaction with NBR1 and is achieved by redirecting the trafficking of activated receptors to the lysosomal degradation pathway. Our findings suggest a critical function for NBR1 in the regulation of receptor trafficking and provide a mechanism for down-regulation of signaling by Spred2 via NBR1.

The APC/C maintains the spindle assembly checkpoint by targeting Cdc20 for destruction.

The spindle assembly checkpoint (SAC) is required to block sister chromatid separation until all chromosomes are properly attached to the mitotic apparatus. The SAC prevents cells from entering anaphase by inhibiting the ubiquitylation of cyclin B1 and securin by the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase. The target of the SAC is the essential APC/C activator Cdc20. It is unclear how the SAC inactivates Cdc20 but most current models suggest that Cdc20 forms a stable complex with the Mad2 checkpoint protein. Here we show that most Cdc20 is not in a complex with Mad2; instead Mad2 is required for Cdc20 to form a complex with another checkpoint protein, BubR1. We further show that during the SAC, the APC/C ubiquitylates Cdc20 to target it for degradation. Thus, ubiquitylation of human Cdc20 is not required to release it from the checkpoint complex, but to degrade it to maintain mitotic arrest.

Cdc20 and Cks direct the spindle checkpoint-independent destruction of cyclin A.

Successful mitosis requires the right protein be degraded at the right time. Central to this is the spindle checkpoint that prevents the destruction of securin and cyclin B1 when there are improperly attached chromosomes. The principal target of the checkpoint is Cdc20, which activates the anaphase-promoting complex/cyclosome (APC/C). A Drosophila Cdc20/fizzy mutant arrests in mitosis with high levels of cyclins A and B, but paradoxically the spindle checkpoint does not stabilize cyclin A. Here, we investigated this paradox and found that Cdc20 is rate limiting for cyclin A destruction. Indeed, Cdc20 binds efficiently to cyclin A before and in mitosis, and this complex has little associated Mad2. Furthermore, the cyclin A complex must bind to a Cks protein to be degraded independently of the checkpoint. Thus, we identify a crucial role for the Cks proteins in mitosis and one mechanism by which the APC/C can target substrates independently of the spindle checkpoint.