Aire in Autoimmunity.

The role of the autoimmune regulator (Aire) in central immune tolerance and thymic self-representation was first described more than 20 years ago, but fascinating new insights into its biology continue to emerge, particularly in the era of advanced single-cell genomics. We briefly describe the role of human genetics in the discovery of Aire, as well as insights into its function gained from genotype-phenotype correlations and the spectrum of Aire-associated autoimmunity-including insights from patients with Aire mutations with broad and diverse implications for human health. We then highlight emerging trends in Aire biology, focusing on three topic areas. First, we discuss medullary thymic epithelial diversity and the role of Aire in thymic epithelial development. Second, we highlight recent developments regarding the molecular mechanisms of Aire and its binding partners. Finally, we describe the rapidly evolving biology of the identity and function of extrathymic Aire-expressing cells (eTACs), and a novel eTAC subset called Janus cells, as well as their potential roles in immune homeostasis.

Dynamic encounters with red blood cells trigger splenic marginal zone B cell retention and function.

Spleen marginal zone (MZ) B cells are important for antibody responses against blood-borne antigens. The signals they use to detect exposure to blood are not well defined. Here, using intravital two-photon microscopy in mice, we observe transient contacts between MZ B cells and red blood cells that are in flow. We show that MZ B cells use adhesion G-protein-coupled receptor ADGRE5 (CD97) for retention in the spleen. CD97 function in MZ B cells depends on its ability to undergo autoproteolytic cleavage and signaling via Gα13 and ARHGEF1. Red blood cell expression of the CD97 ligand CD55 is required for MZ B cell homeostasis. Applying a pulling force on CD97-transfected cells using an optical C-trap and CD55+ beads leads to accumulation of active RhoA and membrane retraction. Finally, we show that CD97 deficiency leads to a reduced T cell-independent IgM response. Thus, our studies provide evidence that MZ B cells use mechanosensing to position in a manner that enhances antibody responses against blood-borne antigens.

A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation.

The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment1,2. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn's disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacter species induce T regulatory (Treg) and T follicular helper (TFH) cells under homeostatic conditions, but induce inflammatory T helper 17 (TH17) cells when induced Treg (iTreg) cells are compromised3,4. How Helicobacter and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iTreg cell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of Treg cells. These RORγt+ cells-probably type 3 innate lymphoid cells and/or Janus cells5-require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFß activator αv integrin. In the absence of any of these factors, there was expansion of pathogenic TH17 cells instead of iTreg cells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions.

Thymic and extrathymic Aire-expressing cells in maternal-fetal tolerance.

Healthy pregnancy requires maternal immune tolerance to both fetal and placental tissues which contain a range of self- and non-self-antigens. While many of the components and mechanisms of maternal-fetal tolerance have been investigated in detail and previously and thoroughly reviewed (Erlebacher A. Annu Rev Immunol. 2013;31:387-411), the role of autoimmune regulator (Aire), a critical regulator of central tolerance expressed by medullary thymic epithelial cells (mTECs), has been less explored. Aire is known to facilitate the expression of a range of otherwise tissue-specific antigens (TSAs) in mTECs, and here we highlight recent work showing a role for mTEC-mediated thymic selection in maintaining maternal-fetal tolerance. Recently, however, our group and others have identified additional populations of extrathymic Aire-expressing cells (eTACs) in the secondary lymphoid organs. These hematopoietic antigen-presenting cells possess the ability to induce functional inactivation and/or deletion of cognate T cells, and deletion of maternal eTACs during pregnancy increases T-cell activation in the lymph nodes and lymphocytic infiltration of the uterus, leading to pregnancy complications including intrauterine growth restriction (IUGR) and fetal resorption. In this review, we briefly summarize findings related to essential Aire biology, discuss the known roles of Aire-deficiency related to pregnancy complications and infertility, review the newly discovered role for eTACs in the maintenance of maternal-fetal tolerance-as well as recent work defining eTACs at the single-cell level-and postulate potential mechanisms by which eTACs may regulate this process.

First-Principles Nonadiabatic Dynamics of Molecules at Metal Surfaces with Vibrationally Coupled Electron Transfer.

Accurate description of nonadiabatic dynamics of molecules at metal surfaces involving electron transfer has been a long-standing challenge for theory. Here, we tackle this problem by first constructing high-dimensional neural network diabatic potentials including state crossings determined by constrained density functional theory, then applying mixed quantum-classical surface hopping simulations to evolve coupled electron-nuclear motion. Our approach accurately describes the nonadiabatic effects in CO scattering from Au(111) without empirical parameters and yields results agreeing well with experiments under various conditions for this benchmark system. We find that both adiabatic and nonadiabatic energy loss channels have important contributions to the vibrational relaxation of highly vibrationally excited CO(v_{i}=17), whereas relaxation of low vibrationally excited states of CO(v_{i}=2) is weak and dominated by nonadiabatic energy loss. The presented approach paves the way for accurate first-principles simulations of electron transfer mediated nonadiabatic dynamics at metal surfaces.

Achieving the Fundamental Quantum Limit of Linear Waveform Estimation.

Sensing a classical signal using a linear quantum device is a pervasive application of quantum-enhanced measurement. The fundamental precision limits of linear waveform estimation, however, are not fully understood. In certain cases, there is an unexplained gap between the known waveform-estimation quantum Cramér-Rao bound and the optimal sensitivity from quadrature measurement of the outgoing mode from the device. We resolve this gap by establishing the fundamental precision limit, the waveform-estimation Holevo Cramér-Rao bound, and how to achieve it using a nonstationary measurement. We apply our results to detuned gravitational-wave interferometry to accelerate the search for postmerger remnants from binary neutron-star mergers. If we have an unequal weighting between estimating the signal's power and phase, then we propose how to further improve the signal-to-noise ratio by a factor of sqrt[2] using this nonstationary measurement.

Corn stover variability drives differences in bisabolene production by engineered Rhodotorula toruloides.

Microbial conversion of lignocellulosic biomass represents an alternative route for production of biofuels and bioproducts. While researchers have mostly focused on engineering strains such as Rhodotorula toruloides for better bisabolene production as a sustainable aviation fuel, less is known about the impact of the feedstock heterogeneity on bisabolene production. Critical material attributes like feedstock composition, nutritional content, and inhibitory compounds can all influence bioconversion. Further, the given feedstocks can have a marked influence on selection of suitable pretreatment and hydrolysis technologies, optimizing the fermentation conditions, and possibly even modifying the microorganism's metabolic pathways, to better utilize the available feedstock. This work aimed to examine and understand how variations in corn stover batches, anatomical fractions, and storage conditions impact the efficiency of bisabolene production by R. toruloides. All of these represent different facets of feedstock heterogeneity. Deacetylation, mechanical refining, and enzymatic hydrolysis of these variable feedstocks served as the basis of this research. The resulting hydrolysates were converted to bisabolene via fermentation, a sustainable aviation fuel precursor, using an engineered R. toruloides strain. This study showed that different sources of feedstock heterogeneity can influence microbial growth and product titer in counterintuitive ways, as revealed through global analysis of protein expression. The maximum bisabolene produced by R. toruloides was on the stalk fraction of corn stover hydrolysate (8.89 ± 0.47 g/L). Further, proteomics analysis comparing the protein expression between the anatomic fractions showed that proteins relating to carbohydrate metabolism, energy production, and conversion as well as inorganic ion transport metabolism were either significantly upregulated or downregulated. Specifically, downregulation of proteins related to the iron-sulfur cluster in stalk fraction suggests a coordinated response by R. toruloides to maintain overall metabolic balance, and this was corroborated by the concentration of iron in the feedstocks. ONE-SENTENCE SUMMARY: This study elucidates the effects of different sources of corn stover on bisabolene production by engineered Rhodotorula toruloides, highlighting the importance of understanding feedstock variability to enhance bioprocess efficiency and economic outcomes.

Correlating area deprivation index with initial stage at presentation and with follow up and recurrence within an advanced practice provider-led survivorship clinic.

INTRODUCTION: Living in disadvantaged neighborhoods has been shown to result in worse healthcare outcomes. The Area Deprivation Index (ADI) is a metric that ranks neighborhoods by socioeconomic disadvantage utilizing numerous factors including income, education, employment, and housing quality. METHODS: A retrospective review of all patients who underwent surveillance in an APP-led head and neck cancer survivorship clinic from Dec 2016 to Oct 2020 at an academic tertiary care center were included. Tumor characteristics, visit frequency, recurrence, number of missed appointments, loss of follow up, and ADI scores were collected. RESULTS: 543 patients were included in the study. A majority were male (69.9 %) and white race (84.9 %) with an average age of 64.6 years old. Average ADI national percentile score was 71.6(range: 17 to 100). ADI national percentile score was not predictive of tumor characteristics at initial presentation: lymphovascular invasion (p = 0.940; OR 1.0 [95 % CI: 0.9 to 1.1]), extranodal extension (p = 0.576; OR 1.0 [95 % CI: 0.9 to 1.2]), positive margins (p = 0.069; OR 0.9 [95 % CI: 0.9 to 1.0]). ADI national percentile score was not significantly correlated with loss to follow up (p = 0.153; OR 1.2 [95 % CI: 0.9 to 1.7] or cancer recurrence (p = 0.594; OR 1.0 [95 % CI: 0.9 to 1.1]). Missing one or more clinic visits was correlated with loss to follow up (p = 0.029; OR 13.1 [95 % CI: 1.3 to 131.7]. CONCLUSION: Living in a disadvantaged neighborhood did not correlate with negative tumor characteristics, loss to follow up, or recurrence within an APP-led survivorship head and neck cancer clinic.

Association between blood transfusion and outcomes of free flap head and neck cancer surgery.

OBJECTIVE: Investigate the impact of patient risk factors and blood transfusions in Head and Neck free flap surgeries. STUDY DESIGN: Retrospective chart review. SETTING: Single tertiary referral center. METHODS: 400 patients were included undergoing free flap reconstruction from 2014 to 2020. The primary outcome measures were red blood cell transfusion and volume transfused. Race, sex, flap location and tissue type, pathology, dependent functional status, length of stay, and cancer recurrence were evaluated for association with red blood cell transfusion intraoperatively and/or postoperatively. Transfusions were indicated on patients with Hemoglobin <7-8 and/or symptomatic anemia. ANOVA and Chi2 statistical analysis were performed. The significance was set at p ≤0.05. RESULTS: Of the 400 patients included, 58 required red blood cell transfusion. Of these 67.8 % were males, racial demographics included 9.00 % African American, 1.30 % Asian, 1.00 % Hispanic/Latino, 87.8 % White, 1.00 % other. African American patients received a higher volume of transfused red blood cells versus white patients (855.00 mL vs. 437.07 mL, p = 0.005). Length of stay was significantly associated with red blood cell transfusion (5.95 days vs. 7.22 days, p ≤0.001). Dependent functional status and need for red blood cell transfusion were associated (p = 0.002). Type of free flap was associated with need for red blood cell transfusion (p ≤0.001) with anterolateral thigh flaps being the most common resulting in transfusion (34/58). CONCLUSION: Red blood cell transfusion was significantly associated with race, dependent functional status and length of stay. Certain free flaps have a higher risk of blood transfusion.

Copper(I) Iodide Thin Films: Deposition Methods and Hole-Transporting Performance.

The pursuit of p-type semiconductors has garnered considerable attention in academia and industry. Among the potential candidates, copper iodide (CuI) stands out as a highly promising p-type material due to its conductivity, cost-effectiveness, and low environmental impact. CuI can be employed to create thin films with >80% transparency within the visible range (400-750 nm) and utilizing various low-temperature, scalable deposition techniques. This review summarizes the deposition techniques for CuI as a hole-transport material and their performance in perovskite solar cells, thin-film transistors, and light-emitting diodes using diverse processing methods. The preparation methods of making thin films are divided into two categories: wet and neat methods. The advancements in CuI as a hole-transporting material and interface engineering techniques hold promising implications for the continued development of such devices.

A Multi-Modal Approach to Islet and Pancreas Transplantation With Calcineurin-Sparing Immunosuppression Maintains Long-Term Insulin Independence in Patients With Type I Diabetes.

Long-term success in beta-cell replacement remains limited by the toxic effects of calcineurin inhibitors (CNI) on beta-cells and renal function. We report a multi-modal approach including islet and pancreas-after-islet (PAI) transplant utilizing calcineurin-sparing immunosuppression. Ten consecutive non-uremic patients with Type 1 diabetes underwent islet transplant with immunosuppression based on belatacept (BELA; n = 5) or efalizumab (EFA; n = 5). Following islet failure, patients were considered for repeat islet infusion and/or PAI transplant. 70% of patients (four EFA, three BELA) maintained insulin independence at 10 years post-islet transplant, including four patients receiving a single islet infusion and three patients undergoing PAI transplant. 60% remain insulin independent at mean follow-up of 13.3 ± 1.1 years, including one patient 9 years after discontinuing all immunosuppression for adverse events, suggesting operational tolerance. All patients who underwent repeat islet transplant experienced graft failure. Overall, patients demonstrated preserved renal function, with a mild decrease in GFR from 76.5 ± 23.1 mL/min to 50.2 ± 27.1 mL/min (p = 0.192). Patients undergoing PAI showed the greatest degree of renal impairment following initiation of CNI (56% ± 18.7% decrease in GFR). In our series, repeat islet transplant is ineffective at maintaining long-term insulin independence. PAI results in durable insulin independence but is associated with impaired renal function secondary to CNI dependence.

Efficient implementation and performance analysis of the independent electron surface hopping method for dynamics at metal surfaces.

Independent electron surface hopping (IESH) is a computational algorithm for simulating the mixed quantum-classical molecular dynamics of adsorbate atoms and molecules interacting with metal surfaces. It is capable of modeling the nonadiabatic effects of electron-hole pair excitations on molecular dynamics. Here, we present a transparent, reliable, and efficient implementation of IESH, demonstrating its ability to predict scattering and desorption probabilities across a variety of systems, ranging from model Hamiltonians to full dimensional atomistic systems. We further show how the algorithm can be modified to account for the application of an external bias potential, comparing its accuracy to results obtained using the hierarchical quantum master equation. Our results show that IESH is a practical method for modeling coupled electron-nuclear dynamics at metal surfaces, especially for highly energetic scattering events.

Differentials and predictors of food insecurity among Federally Qualified Health Center target populations in Philadelphia: a cross-sectional study.

BACKGROUND: Over the past decade, the prevalence of food insecurity declined in the United States but curiously climbed in Philadelphia, Pennsylvania, a sizable metropolitan area where many households experience food insecurity and are dependent on programs like SNAP. Therefore, we aimed to determine the burden of food insecurity among populations near Philadelphia Federally Qualified Health Center (FQHC) clinic sites. METHODS: This cross-sectional study was conducted in North Philadelphia, a populous and impoverished section of Philadelphia with many zip codes reporting 30-45% or more of the population below the federal poverty line. Students and clinicians affiliated with a local FQHC conducted surveys on residents (n = 379) within 1-mile radiuses of three FQHC sites, using the Hunger Vital Sign™, a validated food security tool. Survey data were collected through door-to-door visits in the summer of 2019. We used simple, age-adjusted bivariable, and multivariable logistic regression models to predict food insecurity with independent variables, including age, sex, language preference, and BMI category. RESULTS: Food insecurity in North Philadelphia was much higher (36.9%) than previously reported in Philadelphia and nationwide. Food insecurity was inversely associated with age (AOR = 0.98, 95% CI: 0.97, 1.00), overweight (AOR = 0.58, 95% CI: 0.32, 1.06), and obesity (AOR = 0.60, 95% CI: 0.33, 1.09). CONCLUSION: In North Philadelphia, the burden of food insecurity is higher than in the greater Philadelphia area, Pennsylvania state, and the rest of the nation and is predicted by age and BMI of residents. These findings demonstrate a need for more locally targeted research and interventions on food insecurity in impoverished urban settings.

Sinus culture differences in patients with radiographic evidence of odontogenic disease.

PURPOSE: Odontogenic sinusitis is a well-known entity with a different pathogenesis than chronic rhinosinusitis. Nonspecific symptoms can make diagnosis difficult. This study aims to compare culture results between patients with and without computed tomography findings indicative of possible odontogenic disease. MATERIALS AND METHODS: This was a retrospective cohort study in which patients undergoing endoscopic sinus surgery for chronic sinusitis over a three-year period at a single institution were reviewed. CT imaging was reviewed for evidence of dental disease, specifically periapical lucency, dehiscence of the floor of the maxillary sinus, oroantral fistula, or foreign body. Culture results were then assessed and compared between groups with CT evidence of a possible odontogenic source to those without. RESULTS: Overall, 231 patients were evaluated. 92 patients (39.8 %) were found to have evidence of a likely odontogenic source on CT. Cultures were available for 118 of 231 patients (51.1 %). Patients with CT signs of odontogenic disease were significantly more likely to grow Proteus mirabilis (p = 0.018) and Klebsiella pneumoniae (p = 0.037) on culture. Patients without CT signs of odontogenic sources were significantly more likely to grow Pseudomonas aeruginosa (p = 0.009). Of note, patients with CT findings concerning for an odontogenic source were also more likely to grow fungi other than Aspergillus and Mucor species on culture (p = 0.004). CONCLUSION: Patients with CT findings concerning for an odontogenic source of sinus disease showed differences in culture results that could be important in differentiating pathogenesis of sinus disease.

Comparing donor site morbidity in osteocutaneous radial forearm versus fibula free flap for mandibular reconstruction.

PURPOSE: The osteocutaneous radial forearm free flap has gained popularity as a less morbid option for oromandibular reconstruction compared to the fibular free flap. However, there is a paucity of data regarding direct outcome comparison between these techniques. METHODS: Retrospective chart review of 94 patients who underwent maxillomandibular reconstruction intervened from July 2012-October 2020 at the University of Arkansas for Medical Sciences. All other bony free flaps were excluded. Endpoints retrieved encompassed demographics, surgical outcomes, perioperative data, and donor site morbidity. Continuous data points were analyzed using independent sample t-Tests. Qualitative data was analyzed using Chi-Square tests to determine significance. Ordinal variables were tested using the Mann-Whitney U test. RESULTS: The cohort was equally male and female, with a mean age of 62.6 years. There were 21 and 73 patients in the osteocutaneous radial forearm free flap and fibular free flap cohorts, respectively. Excluding age, the groups were otherwise comparable, including tobacco use, and ASA classification. Bony defect (OC-RFFF = 7.9 cm, FFF = 9.4 cm, p = 0.021) and skin paddle (OC-RFFF = 54.6 cm2, FFF = 72.21 cm2, p = 0.045) size were larger in the fibular free flap group. However, no significant difference was found between cohorts with respect to skin graft. There was no statistically significant difference between cohorts regarding the rate of donor site infection, tourniquet time, ischemia time, total operative time, blood transfusion, or length of hospital stay. CONCLUSIONS: No significant difference in perioperative donor site morbidity was found between patients undergoing fibular forearm free flap and osteocutaneous radial forearm flap for maxillomandibular reconstruction. Osteocutaneous radial forearm flap performance was associated with significantly older age, which may represent a selection bias.

A novel microsurgical reconstruction technique in a living-related liver donor hepatic artery dissection using the native hepatic artery.

In living donor liver transplantation, hepatic artery intimal dissection is a rare but devastating complication often resulting in the inability to utilize the graft. We detail the salvage of a dissected donor right hepatic artery utilizing the recipient hepatic artery. After removal of the right lobe, the donor artery was found to have an intimal dissection extending to multiple branches. The liver transplant surgeons requested their plastic microsurgeon colleague to assist with reconstruction. Ultimately, the native recipient hepatic artery was used as a branch graft as the caliber and branching pattern was appropriate. Back table microvascular reconstruction was performed using the explanted recipient hepatic artery branches as a graft to the four donor artery branches. Every anastomosis was assessed with intraoperative doppler; all were patent with acceptable flow characteristics. The patient did well post-operatively with post-operative ultrasounds demonstrating patency of the graft. Four months post-transplantation the patient developed two polymicrobial abscesses that were drained and resolved with normalization of liver function tests. This case highlights how collaboration with a microvascular surgeon enabled the salvage of a living donor graft when faced with a complex arterial dissection.

Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4⁺ T cells.

The autoimmune regulator (Aire) is essential for prevention of autoimmunity; its role is best understood in the thymus, where it promotes self-tolerance through tissue-specific antigen (TSA) expression. Recently, extrathymic Aire-expressing cells (eTACs) have been described in murine secondary lymphoid organs, but the identity of such cells and their role in immune tolerance remains unclear. Here we have shown that eTACs are a discrete major histocompatibility complex class II (MHC II)(hi), CD80(lo), CD86(lo), epithelial cell adhesion molecule (EpCAM)(hi), CD45(lo) bone marrow-derived peripheral antigen-presenting cell (APC) population. We also have demonstrated that eTACs can functionally inactivate CD4⁺ T cells through a mechanism that does not require regulatory T cells (Treg) and is resistant to innate inflammatory stimuli. Together, these findings further define eTACs as a distinct tolerogenic cell population in secondary lymphoid organs.

Examining Associations between Adverse Childhood Experiences and Posttraumatic Stress Disorder Symptoms among Young Survivors of Urban Violence.

Our study examines the association between Adverse Childhood Experience (ACE) exposure and posttraumatic stress disorder (PTSD) symptoms among survivors of violence. In this cross-sectional study, an ACE questionnaire and PTSD Checklist for DSM-5 (PCL-5) were completed by 147 participants ≤ 3 months after presenting to a Philadelphia, PA emergency department between 2014 and 2019 with a violent injury. This study treated ACEs, both separate and cumulative, as exposures and PTSD symptom severity as the outcome. Most participants (63.3%) met criteria for provisional PTSD, 90% reported experiencing ≥ 1 ACE, and 39% reported experiencing ≥ 6 ACEs. Specific ACEs were associated with increasing PCL-5 scores and increased risk for provisional PTSD. Additionally, as participants' cumulative ACE scores increased, their PCL-5 scores worsened (b = 0.16; p < 0.05), and incremental ACE score increases predicted increased odds for a positive provisional PTSD screen. Results provide further evidence that ACEs exacerbate the development of PTSD in young survivors of violence. Future research should explore targeted interventions to treat PTSD among survivors of interpersonal violence.

Electrochemical impedance and X-ray absorption spectroscopy analyses of degradation in dye-sensitized solar cells containing cobalt tris(bipyridine) redox shuttles.

Electrochemical impedance spectroscopy (EIS) is a commonly used steady-state technique to examine the internal resistance of electron-transfer processes in solar cell devices, and the results are directly related to the photovoltaic performance. In this study, EIS was performed to study the effects of accelerated ageing, aiming for insights into the degradation mechanisms of dye-sensitized solar cells (DSSCs) containing cobalt tris(bipyridine) complexes as redox mediators. Control experiments based on aged electrolytes differing in concentrations of the redox couple components and cation co-additives were conducted to reveal the correlation of the cell degradation with external and internal properties. The failure modes of the cells emerged as changes in the kinetics of charge- and ion-transfer processes. An insufficient concentration of the redox complexes, in particular Co(III), was found to be the main reason for the inferior performance after ageing. The related characterization of electrolytes aged outside the solar cell devices confirms the loss of active Co(III) complexes in the device electrolytes. A new EIS feature at low frequencies emerged during ageing and was analysed. The new EIS feature demonstrates the presence of an unexpected rate-limiting, charge-transfer process in aged devices, which can be attributed to the TiO2/electrolyte interface. High-resolution fluorescence detected X-ray absorption spectroscopy (HERFD-XAS) was performed to identify the reduction of a part of Co(III) to Co(II) after ageing, by investigating the Co K absorption edge. The HERFD-XAS data suggested a partial reduction of Co(III) to Co(II), accompanied by a difference in symmetry of the reduced species.