Structure of the interleukin-5 receptor complex exemplifies the organizing principle of common beta cytokine signaling.

Cytokines regulate immune responses by binding to cell surface receptors, including the common subunit beta (ßc), which mediates signaling for GM-CSF, IL-3, and IL-5. Despite known roles in inflammation, the structural basis of IL-5 receptor activation remains unclear. We present the cryo-EM structure of the human IL-5 ternary receptor complex, revealing architectural principles for IL-5, GM-CSF, and IL-3. In mammalian cell culture, single-molecule imaging confirms hexameric IL-5 complex formation on cell surfaces. Engineered chimeric receptors show that IL-5 signaling, as well as IL-3 and GM-CSF, can occur through receptor heterodimerization, obviating the need for higher-order assemblies of ßc dimers. These findings provide insights into IL-5 and ßc receptor family signaling mechanisms, aiding in the development of therapies for diseases involving deranged ßc signaling.

Long-Term Oral Tamoxifen Administration Decreases Brain-Derived Neurotrophic Factor in the Hippocampus of Female Long-Evans Rats.

Tamoxifen, a selective estrogen receptor modulator (SERM), is commonly used as an adjuvant drug therapy for estrogen-receptor-positive breast cancers. Though effective at reducing the rate of cancer recurrence, patients often report unwanted cognitive and affective side effects. Despite this, the impacts of chronic tamoxifen exposure on the brain are poorly understood, and rodent models of tamoxifen exposure do not replicate the chronic oral administration seen in patients. We, therefore, used long-term ad lib consumption of medicated food pellets to model chronic tamoxifen exposure in a clinically relevant way. Adult female Long-Evans Hooded rats consumed tamoxifen-medicated food pellets for approximately 12 weeks, while control animals received standard chow. At the conclusion of the experiment, blood and brain samples were collected for analyses. Blood tamoxifen levels were measured using a novel ultra-performance liquid chromatography-tandem mass spectrometry assay, which found that this administration paradigm produced serum levels of tamoxifen similar to those in human patients. In the brain, brain-derived neurotrophic factor (BDNF) was visualized in the hippocampus using immunohistochemistry. Chronic oral tamoxifen treatment resulted in a decrease in BDNF expression across several regions of the hippocampus. These findings provide a novel method of modeling and measuring chronic oral tamoxifen exposure and suggest a putative mechanism by which tamoxifen may cause cognitive and behavioral changes reported by patients.

Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function.

Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed on activated T cells and an emerging immunotherapy target. Domain 1 (D1) of LAG-3, which has been purported to directly interact with major histocompatibility complex class II (MHCII) and fibrinogen-like protein 1 (FGL1), has been the major focus for the development of therapeutic antibodies that inhibit LAG-3 receptor-ligand interactions and restore T cell function. Here, we present a high-resolution structure of glycosylated mouse LAG-3 ectodomain, identifying that cis-homodimerization, mediated through a network of hydrophobic residues within domain 2 (D2), is critically required for LAG-3 function. Additionally, we found a previously unidentified key protein-glycan interaction in the dimer interface that affects the spatial orientation of the neighboring D1 domain. Mutation of LAG-3 D2 residues reduced dimer formation, dramatically abolished LAG-3 binding to both MHCII and FGL1 ligands, and consequentially inhibited the role of LAG-3 in suppressing T cell responses. Intriguingly, we showed that antibodies directed against D1, D2, and D3 domains are all capable of blocking LAG-3 dimer formation and MHCII and FGL-1 ligand binding, suggesting a potential allosteric model of LAG-3 function tightly regulated by dimerization. Furthermore, our work reveals unique epitopes, in addition to D1, that can be targeted for immunotherapy of cancer and other human diseases.

Self-Reported Accommodation Needs for Patients with Disabilities in Primary Care.

BACKGROUND: People with disabilities experience barriers to engaging with health care due to inaccessible social and physical environments at primary care clinics. Despite legal mandates, identification and provision of necessary accommodations for this population at primary care clinics are poor. The objective of this cross-sectional study was to assess patient-reported disability status and accommodation needs among patients at a primary care clinic. METHODS: An electronic health record-based Disability and Accommodations Questionnaire assessing disability status, types, and accommodation needs was developed by subject matter experts at Michigan Medicine and the University of Michigan Council for Disability Concerns. The questionnaire underwent multiple rounds of reviews and revisions before its use in clinical settings. A paper-based questionnaire was administered to all patients presenting for a wellness-based visit at an academic health system primary care clinic in southeast Michigan. Data were collected between March 2022 and August 2022. RESULTS: Approximately 13% of the 541 patients self-reported a disability, with 54.2% indicating at least one needed accommodation. The most commonly reported disabilities were mental health and hearing-related disabilities, by 4.8% and 4.6% of patients, respectively. The most frequently requested accommodations were communication- or language-based (for example, presence of an American Sign Language interpreter, assistive listening devices), cognitive-based (for example, inclusion of a support person with care decisions), and mobility-based (for example, assistance with transfers). CONCLUSION: The Disability and Accommodations Questionnaire helped identify the presence of a disability, its types, and any requested accommodations requested at a primary care health center.

Structural insights into the mechanism of leptin receptor activation.

Leptin is an adipocyte-derived protein hormone that promotes satiety and energy homeostasis by activating the leptin receptor (LepR)-STAT3 signaling axis in a subset of hypothalamic neurons. Leptin signaling is dysregulated in obesity, however, where appetite remains elevated despite high levels of circulating leptin. To gain insight into the mechanism of leptin receptor activation, here we determine the structure of a stabilized leptin-bound LepR signaling complex using single particle cryo-EM. The structure reveals an asymmetric architecture in which a single leptin induces LepR dimerization via two distinct receptor-binding sites. Analysis of the leptin-LepR binding interfaces reveals the molecular basis for human obesity-associated mutations. Structure-based design of leptin variants that destabilize the asymmetric LepR dimer yield both partial and biased agonists that partially suppress STAT3 activation in the presence of wild-type leptin and decouple activation of STAT3 from LepR negative regulators. Together, these results reveal the structural basis for LepR activation and provide insights into the differential plasticity of signaling pathways downstream of LepR.

A 360° electronic device for recording high-resolution intraoperative electrocorticography of the brain during awake craniotomy.

OBJECTIVE: Epilepsy is common among patients with supratentorial brain tumors; approximately 40%-70% of patients with glioma develop brain tumor-related epilepsy (BTRE). Intraoperative localization of the epileptogenic zone during surgical tumor resection (real-time data) may improve intervention techniques in patients with lesional epilepsy, including BTRE. Accurate localization of the epileptogenic signals requires electrodes with high-density spatial organization that must be placed on the cortical surface during surgery. The authors investigated a 360° high-density ring-shaped cortical electrode assembly device, called the "circular grid," that allows for simultaneous tumor resection and real-time electrophysiology data recording from the brain surface. METHODS: The authors collected data from 99 patients who underwent awake craniotomy from January 2008 to December 2018 (29 patients with the circular grid and 70 patients with strip electrodes), of whom 50 patients were matched-pair analyzed (25 patients with the circular grid and 25 patients with strip electrodes). Multiple variables were then retrospectively assessed to determine if utilization of this device provides more accurate real-time data and improves patient outcomes. RESULTS: Matched-pair analysis showed higher extent of resection (p = 0.03) and a shorter transient motor recovery period during the hospitalization course (by approximately 6.6 days, p ≤ 0.05) in the circular grid patients. Postoperative versus preoperative Karnofsky Performance Scale (KPS) score difference/drop was greater for the strip electrode patients (p = 0.007). No significant difference in postoperative seizures between the 2 groups was present (p = 0.80). CONCLUSIONS: The circular grid is a safe, feasible tool that grants direct access to the cortical surgical surface for tissue resection while simultaneously monitoring electrical activity. Application of the circular grid to different brain pathologies may improve intraoperative epileptogenic detection accuracy and functional outcomes, while decreasing postoperative complications.

Biochemical and Functional Evaluation of the Intramolecular Disulfide Bonds in the Zinc-Chelating Antimicrobial Protein Human S100A7 (Psoriasin).

Human S100A7 (psoriasin) is a metal-chelating protein expressed by epithelial cells. It is a 22-kDa homodimer with two EF-hand domains per subunit and two transition-metal-binding His3Asp sites at the dimer interface. Each subunit contains two cysteine residues that can exist as free thiols (S100A7red) or as an intramolecular disulfide bond (S100A7ox). Herein, we examine the disulfide bond redox behavior, the Zn(II) binding properties, and the antibacterial activity of S100A7, as well as the effect of Ca(II) ions on these properties. In agreement with prior work [Hein, K. Z., et al. (2013) Proc. Natl. Acad. Sci. U. S. A. 112, 13039-13044], we show that apo S100A7ox is a substrate for the mammalian thioredoxin system; however, negligible reduction of the disulfide bond is observed for Ca(II)- and Zn(II)-bound S100A7ox. Furthermore, metal binding depresses the midpoint potential of the disulfide bond. S100A7ox and S100A7red each coordinate 2 equiv of Zn(II) with subnanomolar affinity in the absence and presence of Ca(II) ions, and the cysteine thiolates in S100A7red do not form a third high-affinity Zn(II) site. These results refute a prior model implicating the Cys thiolates of S100A7red in high-affinity Zn(II) binding [Hein, K. Z., et al. (2013) Proc. Natl. Acad. Sci. U. S. A. 112, 13039-13044]. S100A7ox and the disulfide-null variants show comparable Zn(II)-depletion profiles; however, only S100A7ox exhibits antibacterial activity against select bacterial species. Metal substitution experiments suggest that the disulfide bonds in S100A7 may enhance metal sequestration by the His3Asp sites and thereby confer growth inhibitory properties to S100A7ox.

Comparison of the elastic and yield properties of human femoral trabecular and cortical bone tissue.

The ability to determine trabecular bone tissue elastic and failure properties has biological and clinical importance. To date, trabecular tissue yield strains remain unknown due to experimental difficulties, and elastic moduli studies have reported controversial results. We hypothesized that the elastic and tensile and compressive yield properties of trabecular tissue are similar to those of cortical tissue. Effective tissue modulus and yield strains were calibrated for cadaveric human femoral neck specimens taken from 11 donors, using a combination of apparent-level mechanical testing and specimen-specific, high-resolution, nonlinear finite element modeling. The trabecular tissue properties were then compared to measured elastic modulus and tensile yield strain of human femoral diaphyseal cortical bone specimens obtained from a similar cohort of 34 donors. Cortical tissue properties were obtained by statistically eliminating the effects of vascular porosity. Results indicated that mean elastic modulus was 10% lower (p<0.05) for the trabecular tissue (18.0+/-2.8 GPa) than for the cortical tissue (19.9+/-1.8 GPa), and the 0.2% offset tensile yield strain was 15% lower for the trabecular tissue (0.62+/-0.04% vs. 0.73+/-0.05%, p<0.001). The tensile-compressive yield strength asymmetry for the trabecular tissue, 0.62 on average, was similar to values reported in the literature for cortical bone. We conclude that while the elastic modulus and yield strains for trabecular tissue are just slightly lower than those of cortical tissue, because of the cumulative effect of these differences, tissue strength is about 25% greater for cortical bone.

Early intervention in a case of jargon aphasia: efficacy of language comprehension therapy.

A client with dysphasia was treated during the first six months following onset. A cognitive neuropsychological model of language processing was used to establish the levels of impairment in auditory comprehension. Three separate phases of therapy were administered: a semantic therapy; a period of therapy where both semantics and auditory processing were treated; and therapy designed to enhance the processing of words in a sentence. Four assessments were used to measure changes between each therapy phase and the results demonstrate that improvement occurred in a pattern which suggests specific effects of treatment.

Simulated disability exercises and their impact on attitudes toward persons with disabilities.

Two separate graduate rehabilitation counselling groups from a mid-south university either did or did not take part in a wheelchair sensitivity training pilot study designed to enhance their understanding as to what life might be like for persons who use a wheelchair. Twenty students were individually accompanied on a designated route across campus by a non-disabled graduate researcher. Eighteen other graduate students formed a control group and did not participate. Both groups completed a contextually different 14-item Likert type questionnaire designed to assess their perceptions of persons with physical disabilities based on either the sensitivity exercise or their experience in the rehabilitation programme. Results from this quasi-experimental study suggested that regardless of whether they participated in the sensitivity training, both groups perceived they would become better counsellors. t-Tests revealed significant differences in the two groups' responses to questions pertaining to daily frustrations experienced by persons with physical disabilities and a pre-occupation with how accessible places are. Other differences noted were that persons with physical disabilities must feel different from being stared at and must have a harder time in society. Implications of the utility and misuses of these one-time experiences are explored.

Radiotherapeutic applications of pelvic computed tomography.

One hundred and four computed tomography (CT) examinations were performed on 72 consecutive radiotherapy patients with pelvic malignancies. Prostate, bladder, rectosigmoid, gynecologic, and lymphomatous primaries were studied. Computed tomography demonstrated tumor volumes larger than clinically expected in 40% and tumor extension into unsuspected tissues in 43%. Based on CT, staging was revised upward in 25%. Computed tomography aided initial treatment planning in 61%. In 27 patients having post-therapy scans, changes in tumor volume were demonstrated in 59%. Modifications in therapy were made for 30% of the follow-up group. Computed tomography is recommended as an important adjunct in the workup and management of radiotherapy patients with pelvic malignancies.