Faculty Bibliography

Follicular helper T cells (T_FH) mediate B cell selection and clonal expansion in germinal centers (GCs), and follicular regulatory T cells (T_FR) prevent the emergence of self-reactive B cells and help to extinguish the reaction. Here we show that GC reactions continually recruit T cells from both the naïve conventional and naive thymic regulatory T cell (Treg) repertoires. In the early GC, newly recruited T cells develop into T_FH, whereas cells entering during the contraction phase develop into T_FR cells that contribute to GC dissolution. The T_FR fate decision is associated with decreased antigen availability and is modulated by slow antigen delivery or mRNA vaccination. Thus, invasion of ongoing GCs by newly developing T_FH and T_FR helps remodel the GC based on antigen availability.

Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.

The 2030 Agenda for Sustainable Development sets out, through 17 Sustainable Development Goals (SDGs), a path for the prosperity of people and the planet. SDG 3 in particular aims to ensure healthy lives and promote well-being for all at all ages and includes several targets to enhance health. This review presents a "headache-tailored" perspective on how to achieve SDG 3 by focusing on six specific actions: targeting chronic headaches; reducing the overuse of acute pain-relieving medications; promoting the education of healthcare professionals; granting access to medication in low- and middle-income countries (LMIC); implementing training and educational opportunities for healthcare professionals in low and middle income countries; building a global alliance against headache disorders. Addressing the burden of headache disorders directly impacts on populations' health, as well as on the possibility to improve the productivity of people aged below 50, women in particular. Our analysis pointed out several elements, and included: moving forward from frequency-based parameters to define headache severity; recognizing and managing comorbid diseases and risk factors; implementing a disease management multi-modal management model that incorporates pharmacological and non-pharmacological treatments; early recognizing and managing the overuse of acute pain-relieving medications; promoting undergraduate, postgraduate, and continuing medical education of healthcare professionals with specific training on headache; and promoting a culture that favors the recognition of headaches as diseases with a neurobiological basis, where this is not yet recognized. Making headache care more sustainable is an achievable objective, which will require multi-stakeholder collaborations across all sectors of society, both health-related and not health-related. Robust investments will be needed; however, considering the high prevalence of headache disorders and the associated disability, these investments will surely improve multiple health outcomes and lift development and well-being globally.

The necroptosis pathway is a lytic, pro-inflammatory mode of cell death that is widely implicated in human disease, including renal, pulmonary, gut and skin inflammatory pathologies. The precise mechanism of the terminal steps in the pathway, where the RIPK3 kinase phosphorylates and triggers a conformation change and oligomerization of the terminal pathway effector, MLKL, are only emerging. Here, we structurally identify RIPK3-mediated phosphorylation of the human MLKL activation loop as a cue for MLKL pseudokinase domain dimerization. MLKL pseudokinase domain dimerization subsequently drives formation of elongated homotetramers. Negative stain electron microscopy and modelling support nucleation of the MLKL tetramer assembly by a central coiled coil formed by the extended, ~80 Å brace helix that connects the pseudokinase and executioner four-helix bundle domains. Mutational data assert MLKL tetramerization as an essential prerequisite step to enable the release and reorganization of four-helix bundle domains for membrane permeabilization and cell death.

BACKGROUND:At the beginning of the COVID-19 pandemic in the United States in the spring of 2020, many Americans avoided the healthcare system, while those with COVID-19 symptoms were faced with decisions about seeking healthcare services for this novel virus. METHODS:Using a probability sample (n = 1088) from the Michigan adult population of PCR-confirmed COVID-19 cases who were diagnosed prior to July 31, 2020, we used logistic regression to examine sociodemographic and symptom severity predictors of care-seeking behaviors. The analyses examined three different outcomes: (1) whether respondents sought care and, among those who sought care, whether they sought care from (2) a primary care provider or (3) an emergency room. Final models were adjusted for sex, age, race and ethnicity, income, education, marital status, living arrangement, health insurance, and self-reported symptom severity. RESULTS:We found that participants ages 65 and older had 4.00 times higher odds of seeking care than 18-34-year-olds (95% CI: 2.21, 7.24), while adults reporting very severe symptoms had roughly 15 times higher odds of seeking care than those with mild symptoms (95% CI: 7.73, 27.01). Adults who were non-Hispanic Black or were uninsured had lower odds of seeking care from a primary care physician versus seeking care from other locations in comparison to adults who were non-Hispanic White or were privately insured, respectively (non-Hispanic Black: aOR = 0.27, 95% CI: 0.16, 0.44; Uninsured: aOR = 0.19, 95% CI: 0.09, 0.42). Conversely, adults who were older or reported more severe symptoms had higher odds of seeking care from an emergency room versus other locations in comparison to adults who were younger or reported less severe symptoms (Age 65+: aOR = 2.96, 95% CI: 1.40, 6.28; Very Severe Symptoms: aOR = 6.63, 95% CI: 3.33, 13.20). CONCLUSIONS:Our results suggest differential utilization of healthcare services early in the COVID-19 pandemic. Further analyses are needed to examine the reasons for these differences.

INTRODUCTION/BACKGROUND:Appendicolithiasis is a risk factor for perforated acute appendicitis. There is limited inpatient data on predictors of progression in appendicolithiasis-associated non-perforated acute appendicitis. METHODS:We identified adults presenting with appendicolithiasis-associated non-perforated acute appendicitis (on computed tomography) who underwent appendectomy. Logistic regression was used to investigate predictors of in-hospital perforation (on histopathology). RESULTS:296 patients with appendicolithiasis-associated non-perforated acute appendicitis were identified; 48 (16.2%) had perforation on histopathology. Mean (standard deviation [SD]) age was 39 (14.9) years. The mean (SD) length of stay (LOS) was 1.5 (1.8) days. LOS was significantly longer with perforated (mean [SD]: 3.0 [3.1] days) vs. non-perforated (mean [SD]: 1.2 [1.2] days) appendicitis (p < 0.001). On multivariate analysis, in-hospital perforation was associated with age > 65 years (OR 5.4, 95% CI: 1.4- 22.2; p = 0.015), BMI > 30 kg/m2 (OR 3.5, 95% CI: 1.3-8.9; p = 0.011), hyponatremia (OR 3.6, 95% CI: 1.3-9.8; p = 0.012). There was no significant association with age 25-65 years, gender, race, steroids, time-to- surgery, neutrophil percentage, or leukocyte count. CONCLUSION/CONCLUSIONS:Geriatric age, obesity, and hyponatremia are associated with progression to perforation in appendicolithiasis-associated non-perforated acute appendicitis.

BACKGROUND:Exposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-β (Aβ) plaque formation and increases the risk for Alzheimer's disease (AD). Although the Aβ neuritic plaques characteristic of AD are observed in a minority of later-stage CTE cases, diffuse plaques are more common. This study examined whether former professional and college American football players, including those with cognitive impairment and dementia, have elevated neuritic Aβ plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected. METHODS:We examined 237 men ages 45-74, including 119 former professional (PRO) and 60 former college (COL) football players, with and without cognitive impairment and dementia, and 58 same-age men without a history of contact sports or TBI (unexposed; UE) and who denied cognitive or behavioral symptoms at telephone screening. Former players were categorized into four diagnostic groups: normal cognition, subjective memory impairment, mild cognitive impairment, and dementia. Positive florbetapir PET was defined by cortical-cerebellar average SUVR of ≥ 1.10. Multivariable linear regression and analysis of covariance (ANCOVA) compared florbetapir average SUVR across diagnostic and exposure groups. Multivariable logistic regression compared florbetapir positivity. Race, education, age, and APOE4 were covariates. RESULTS:There were no diagnostic group differences either in florbetapir average SUVR or the proportion of elevated florbetapir uptake. Average SUVR means also did not differ between exposure groups: PRO-COL (p = 0.94, 95% C.I. = [- 0.033, 0.025]), PRO-UE (p = 0.40, 95% C.I. = [- 0.010, 0.029]), COL-UE (p = 0.36, 95% CI = [0.0004, 0.039]). Florbetapir was not significantly associated with years of football exposure, cognition, or daily functioning. CONCLUSIONS:Cognitive impairment in former American football players is not associated with PET imaging of neuritic Aβ plaque deposition. These findings are inconsistent with a neuropathological diagnosis of AD in individuals with substantial RHI exposure and have both clinical and medico-legal implications. TRIAL REGISTRATION/BACKGROUND:NCT02798185.

The pathogenetic mechanism of persistent post-concussive symptoms (PCS) following concussion remains unclear. Thalamic damage is known to play a role in PCS prolongation while the evidence and biomarkers that trigger persistent PCS have never been elucidated. We collected longitudinal neuroimaging and behavior data from patients and rodents after concussion, complemented with rodents' histological staining data, to unravel the early biomarkers of persistent PCS. Diffusion tensor imaging (DTI) were acquired to investigated the thalamic damage, while quantitative thalamocortical coherence was derived through resting-state functional MRI for evaluating thalamocortical functioning and predicting long-term behavioral outcome. Patients with prolonged symptoms showed abnormal DTI-derived indices at the boundaries of bilateral thalami (peri-thalamic regions). Both patients and rats with persistent symptoms demonstrated enhanced thalamocortical coherence between different thalamocortical circuits, which disrupted thalamocortical multifunctionality. In rodents, the persistent DTI abnormalities were validated in thalamic reticular nucleus (TRN) through immunohistochemistry, and correlated with enhanced thalamocortical coherence. Strong predictive power of these coherence biomarkers for long-term PCS was also validated using another patient cohort. Postconcussive events may begin with persistent TRN injury, followed by disrupted thalamocortical coherence and prolonged PCS. Functional MRI-based coherence measures can be surrogate biomarkers for early prediction of long-term PCS.