Notes

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This technical note describes two devices to enable accurate irradiation of mice on clinical linac-based systems. To study the effects of radiation in murine, preclinical animal models, controlled and accurate dosing is important. This is not only important when specific volumes need to be irradiated, but also when the whole animal body is irradiated. To enable both purposes, we designed two devices. Olaparib concentration One device to administer Total Body Irradiation (TBI) simultaneously to six, free walking mice, and a second device, denoted as target box, in which we irradiate specific parts of the mice whilst organs-at-risk (OAR) are protected. In this latter device, we can position the mice in multiple ways. One configuration allows to sedate twelve mice simultaneously by isoflurane inhalation anesthesia and protect the body by lead shielding to allow radiation of the head only. Alternatively, the target box can be used to sedate maximal 4 mice simultaneously to irradiate the flank or paws only. All these setups allow high experimental throughput and thus a minimal occupation of the clinical equipment. As measured, the delivered radiation dosages in the regions of interest were accurate for both devices. In this technical note, we describe the design and build of these devices.Mutations in the voltage-gated potassium channel Kv7.4 (encoded as KCNQ4) lead to the early onset of non-syndromic hearing loss, which is significant during language acquisition. The deletion of the S269 pore residue (genetic Δ mutation) in Kv7.4 has been reported to be associated with hearing loss. So far, there is no mechanistic understanding of how this mutation modulates channel function. To understand the role of S269 in ion conduction, we performed molecular dynamics simulations for both wild type and ΔS269 mutant channels. Simulations indicate that the ΔS269 mutation suppresses the fluctuations in the neighboring Y269 residue and thereby consolidates the ring formed by I307 and F310 residues in the adjacent S6 helixes in the cavity region. We show that the long side chains of I307 near the entrance to the cavity form a hydrophobic gate. Comparison of the free energy profiles of a cavity ion in Kv7.4 and Kv7.4[ΔS269] channels reveals a sizable energy barrier in the latter case, which suppresses ion conduction. Thus the simulation studies reveal that the hydrophobic gate resulting from the ΔS269 mutation appears to be responsible for sensorineural hearing loss.Human prostaglandin E2 receptor 4 (EP4) is one of the four subtypes of prostaglandin E2 (PGE2) receptors and belongs to the rhodopsin-type G protein-coupled receptor (GPCR) family. Particularly, EP4 is expressed in various cancer cells and is involved in cancer-cell proliferation by a G protein signaling cascade. To prepare an active form of EP4 for biochemical characterization and pharmaceutical application, this study designed a recombinant protein comprising human EP4 fused to the P9 protein (a major envelope protein of phi6 phage) and overexpressed the P9-EP4 fusion protein in the membrane fraction of E. coli. The solubilized P9-EP4 with sarkosyl (a strong anionic detergent) was purified by affinity chromatography. The purified protein was stabilized with amphiphilic polymers derived from poly-γ-glutamate. The polymer-stabilized P9-EP4 showed specific interaction with the alpha subunits of Gs or Gi proteins, and a high content of α-helical structure by a circular dichroism spectroscopy. Furthermore, the polymer-stabilized P9-EP4 showed strong heat resistance compared with P9-EP4 in detergents. The functional preparation of EP4 and its stabilization with amphiphilic polymers could facilitate both the biochemical characterization and pharmacological applications targeting EP4.Receptor Expressed in Lymphoid Tissues (RELT) is a human tumor necrosis factor receptor superfamily member (TNFRSF) that is expressed most prominently in cells and tissues of the hematopoietic system. RELL1 and RELL2 are two homologs that physically interact with RELT and co-localize with RELT at the plasma membrane. This study sought to further elucidate the function of RELT by identifying novel protein interactions with RELT family members. The transcription factor MyoD family inhibitor domain-containing (MDFIC) was identified in a yeast two-hybrid genetic screen using RELL1 as bait. MDFIC co-localizes with RELT family members at the plasma membrane; this co-localization was most prominently observed with RELL1 and RELL2. In vitro co-immunoprecipitation (Co-IP) was utilized to demonstrate that MDFIC physically interacts with RELT, RELL1, and RELL2. Co-IP using deletion mutants of MDFIC and RELT identified regions important for physical association between MDFIC and RELT family members and a computational analysis revealed that RELT family members are highly disordered proteins. Immunohistochemistry of normal human lymph nodes revealed RELT staining that was most prominent in macrophages. Interestingly, the level of RELT staining significantly increased progressively in low and high-grade B-cell lymphomas versus normal lymph nodes. RELT co-staining with CD20 was observed in B-cell lymphomas, indicating that RELT is expressed in malignant B cells. Collectively, these results further our understanding of RELT-associated signaling pathways, the protein structure of RELT family members, and provide preliminary evidence indicating an association of RELT with B-cell lymphomas.
In the absence of effective pharmacotherapy, there is an urgent need to test evidence-based dementia care interventions using pragmatic trial approaches. We present results from a study in which an evidence-based, nonpharmacologic intervention for persons living with Alzheimer's disease and related dementia (ADRD) and their informal caregivers, Care of Persons with Dementia in their Environments (COPE), was tested in a Medicaid and state revenue-funded home and community-based service (HCBS) program.

Using pragmatic trial design strategies, persons living with ADRD and their caregivers were randomly assigned as dyads to receive COPE plus usual HCBS (COPE;
= 145 dyads) or usual HCBS only (Usual Care or UC;
= 146 dyads). Outcomes were measured prerandomization, and 4 and 12 months postrandomization. Outcomes for persons living with ADRD included functional independence, activity engagement, self-reported quality of life, and behavioral and psychological symptoms. Caregiver outcomes included perceived well-being, confidence using dementia management strategies, and degree of distress caused by behavioral and psychological symptoms.
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