Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, tau and alpha-synuclein.

PURPOSE: There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils. METHODS: SPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (Aß)42, K18-tau, full-length 2N4R-tau and αSyn fibrils. In silico modeling was performed to examine the binding pockets of ligands on αSyn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson's disease patients and mouse models was performed with fluorescence ligands and specific antibodies. RESULTS: We optimized the protocol for the immobilization of Aß42, K18-tau, full-length 2N4R-tau and αSyn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for αSyn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-αSyn positivity in the brains of Parkinson's disease patients and αSyn preformed-fibril injected mice, 6E10-positive Aß in arcAß mice, and AT-8/AT-100-positivity in pR5 mice. CONCLUSION: SPR measurements of small molecules binding to Aß42, K18/full-length 2N4R-tau and αSyn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies.

Evolving Arctic maritime hazards: Declining sea ice and rising waves in the Northwest Passage.

The ongoing and projected retreat of Arctic sea ice has garnered international interest toward the utilization of Arctic maritime corridors for shipping, tourism, and development. Yet, with potential for increasing traffic in Arctic regions, it's important to consider additional environmental variables affected by climate change which may threaten maritime operations. Here, we use four climate model projections to produce ocean wave simulations and investigate the future magnitude and seasonality of sea ice risk coupled with wave hazards. Analyzing the potential 5 mo shipping season spanning July to November along the Northwest Passage maritime route between 2020 and 2070, our results show a substantial decline in sea ice risk over the analysis time period, resulting in near open-water conditions along the route for a 5 mo period by 2070. However, as seasonal ice coverage retreats, there is a significant upward trend in wave heights along the route during July and November, with the timing of the greatest wave height shifting away from September toward later in the season. This result is pertinent as the possibility of seasonally unprecedented extreme waves coupled with subfreezing late fall temperatures makes for an especially hazardous environment, thus emphasizing the importance of considering the interaction between evolving sea ice and interdependent hazards when predicting the risks and challenges faced by Arctic maritime operations.

Symmetry, separation, and stability: Physical properties for effective dosimetric space with a stabilized hyaluronic acid spacer.

BACKGROUND: The proximity of the rectum to the prostate in radiation therapy (RT) for prostate cancer presents a significant dosimetric challenge, leading to high rectal doses and resulting in detrimental side effects. Perirectal tissue spacing reduces rectal dose and gastrointestinal toxicities by mechanically separating these organs. A variety of materials have been explored for use as rectal spacers, most recently, a stabilized hyaluronic acid (HA) gel, which can be formed into deliberate a shape, and retains the definition of that shape, while remaining flexible, unlike polyethylene glycol (PEG) hydrogels. PURPOSE: This study evaluates the dosimetric impact of the spacer, including shape symmetry, the degree of separation at different locations, and the temporal stability of the space. Our goal is to provide physics-informed guidance on the optimal use of this sculptable spacer. METHODS: A secondary analysis was performed on data from a 13-center prospective randomized trial (NCT04189913), involving 136 patients with centrally-reviewed treatment plans conducted on CT/MR simulation scans before and after receiving HA spacer implants. Patients were treated with 60 Gy in 20 fractions to the prostate. For this study, python software was utilized for automated processing of DICOM RTstruct and RTdose files, facilitating detailed analysis of the spacer's impact on anatomical displacement and dosimetric outcomes. Complete dose-volume histograms (DVHs) were reconstructed, and combined into composite population DVHs before and after implant, verified against trial-reported dose points. Patients were divided into similar groups of separation and symmetry, and differences in their composite DVHs were tested for significance. Stability of the spacer was studied by comparing serial MRI images and by computing the distance between contours at four axial planes, at simulation and 3-month follow-up, post RT. RESULTS: The introduction of the HA spacer significantly enhanced rectal sparing, as evidenced by a reduction in the mean rectal integral dose by over 6 Gy. High rates of implant symmetry (>95%) were observed, indicating nearly optimal lateral spacer placement. In superior-inferior coverage, this study like many others, saw the spacing largest at the superior extent but becoming more variable inferiorly at the level of the prostate apex. This allowed study of the apex as a specific area for dosimetric concern. Stability assessments confirmed that the spacer maintained its position and dimensions between the simulation and the 3-month post-RT, implying stable geometry during treatment, with only minimal separation changes observed. Statistical analysis using the Kruskal-Wallis test revealed significant correlations of larger separations at the inferior and apical planes with improved dosimetric outcomes, including rV30Gy. CONCLUSION: The use of a stabilized HA spacer in prostate RT effectively enhances prostate-rectum separation, leading to significant rectal sparing without undesirable dose compromises. This study underscores the role of strategic placement and shape, specifically including > 1 cm separation from the base down to the prostate apex. When combined with the treatment planning techniques used in the trial to create a steep dosimetric gradient across the spacer, these findings elucidate the dosimetric outcomes that can be expected in the clinical implementation of HA spacer. This is particularly relevant in the evolution of hypofractionated treatment regimens for prostate cancer therapy.

e3SIM: epidemiological-ecological-evolutionary simulation framework for genomic epidemiology.

Infectious disease dynamics are driven by the complex interplay of epidemiological, ecological, and evolutionary processes. Accurately modeling these interactions is crucial for understanding pathogen spread and informing public health strategies. However, existing simulators often fail to capture the dynamic interplay between these processes, resulting in oversimplified models that do not fully reflect real-world complexities in which the pathogen's genetic evolution dynamically influences disease transmission. We introduce the epidemiological-ecological-evolutionary simulator (e3SIM), an open-source framework that concurrently models the transmission dynamics and molecular evolution of pathogens within a host population while integrating environmental factors. Using an agent-based, discrete-generation, forward-in-time approach, e3SIM incorporates compartmental models, host-population contact networks, and quantitative-trait models for pathogens. This integration allows for realistic simulations of disease spread and pathogen evolution. Key features include a modular and scalable design, flexibility in modeling various epidemiological and population-genetic complexities, incorporation of time-varying environmental factors, and a user-friendly graphical interface. We demonstrate e3SIM's capabilities through simulations of realistic outbreak scenarios with SARS-CoV-2 and Mycobacterium tuberculosis, illustrating its flexibility for studying the genomic epidemiology of diverse pathogen types.

Growth promotion in wheat seedlings altered by conditions in the culture medium of Azospirillum brasilense.

Agricultural management using technologies that help farmers increase productivity and reduce production costs must be promoted to ensure agricultural sustainability. The objective of the study was to achieve the pH effect of growth solution, chemical treatment, use of osmoprotector additive and mineral nitrate presence, on the activity of growth promoting bacteria, Azospirillum brasilense, and its effects on the physiological quality of seeds and wheat seedling growth. The first experiment evaluated the physiological quality of seeds and the second experiment was divided into four, evaluating the growth of wheat seedling in a hydroponic system. The experiments were prolonged in a very randomized design, with four replications. The physiological quality of the seeds was evaluated by germination tests, first germination count, length of the shoot and root and dry mass of the shoot and root. Initial growth was evaluated by quantifying the dry mass of the leaf shoot and root and the root system intervals. The pH of the solution and the presence of nitrogen did not influence the effects of inoculation of the A. brasilense bacteria. With the use of chemical treatment and osmoprotective additive, A. brasilense had no effect on the growth of wheat seedlings.

The impact of landing forces on repeated jumping performance.

BACKGROUND: High-velocity concentric actions can be negatively impacted by cumulative fatigue during plyometric training. Reducing vertical ground reaction forces (GRF) upon landing could decrease eccentric demands, potentially minimizing fatigue, maintaining concentric performance, and benefiting concentric training adaptations. Therefore, this study examined the effect of intentionally higher and lower landing vertical GRF on the ability to sustain concentric jumping performance. METHODS: Twenty men (25.2±3.5 years) performed 30 maximal effort jumps over a 50 cm hurdle (high-landing GRF) and onto a 50 cm box (low-landing GRF), on two separate occasions in a counter-balanced order. Jumps were measured using two force platforms (one for takeoff and one for landing) and a linear position transducer. The 30 jumps were divided into 5 groups of 6 repetitions, and the mean value for each group was analyzed. RESULTS: There was no significant condition × repetition group interaction for any parameters, indicating that the greater landing GRF during hurdle jumps did not negatively affect concentric jump performance throughout the 30 jumps. Concentric velocities and jump height were significantly greater during box jumps compared to hurdle jumps. CONCLUSIONS: Thirty maximal-effort jumps did not cause fatigue-related decrease of performance, independent of jump type (i.e., the magnitude of landing GRF). Although, reduced vertical GRF upon landing appears to have a neutral-to-positive effect on concentric jumping performance. Therefore, reducing landing GRF, such as by using BJs, could acutely augment jumping performance and help to reduce cumulative training load.

Rhodium-Catalyzed Enantioselective Intramolecular Hydroalkoxylation of Allenes and Application in the Total Synthesis of (R,R,R)-α-Tocopherol.

We report herein of a novel, enantioselective and rhodium- catalyzed cyclisation of allenyl alcohols towards chiral α-vinylic, cyclic ethers employing a rhodium/(R,R)-Me-ferrocelane catalyst. The corresponding chiral cyclic products were obtained in general high yield and enantioselectivities. The synthetic value of our obtained products was further exemplified by transformations of the allylic ether function. Furthermore, applying our newly developed method in our previously reported route towards the total synthesis of (R,R,R)-α-tocopherol, we were able to devise a significantly improved 2nd generation total synthesis with 12 steps in the longest linear sequence and an overall total yield of 24%.

Finite Width of Anyons Changes Their Braiding Signature.

Anyons are particles intermediate between fermions and bosons, characterized by a nontrivial exchange phase, yielding remarkable braiding statistics. Recent experiments have shown that anyonic braiding has observable consequences on edge transport in the fractional quantum Hall effect (FQHE). Here, we study transport signatures of anyonic braiding when the anyons have a finite width. We show that the width of the anyons, even when extremely small, can have a tremendous impact on transport properties and braiding signatures. In particular, we find that taking the finite width into account allows us to explain recent experimental results on the FQHE at filling factor 2/5 [M. Ruelle et al., Phys. Rev. X 13, 011031 (2023)PRXHAE2160-330810.1103/PhysRevX.13.011031]. Our work shows that the finite width of anyons crucially influences setups involving anyonic braiding, especially when the exchange phase is larger than π/2.

Sarbecovirus disease susceptibility is conserved across viral and host models.

Coronaviruses have caused three severe epidemics since the start of the 21st century: SARS, MERS and COVID-19. The severity of the ongoing COVID-19 pandemic and increasing likelihood of future coronavirus outbreaks motivates greater understanding of factors leading to severe coronavirus disease. We screened ten strains from the Collaborative Cross mouse genetic reference panel and identified strains CC006/TauUnc (CC006) and CC044/Unc (CC044) as coronavirus-susceptible and resistant, respectively, as indicated by variable weight loss and lung congestion scores four days post-infection. We generated a genetic mapping population of 755 CC006xCC044 F2 mice and exposed the mice to one of three genetically distinct mouse-adapted coronaviruses: clade 1a SARS-CoV MA15 (n=391), clade 1b SARS-CoV-2 MA10 (n=274), and clade 2 HKU3-CoV MA (n=90). Quantitative trait loci (QTL) mapping in SARS-CoV MA15- and SARS-CoV-2 MA10-infected F2 mice identified genetic loci associated with disease severity. Specifically, we identified seven loci associated with variation in outcome following infection with either virus, including one, HrS43, that is present in both groups. Three of these QTL, including HrS43, were also associated with HKU3-CoV MA outcome. HrS43 overlaps with a QTL previously reported by our lab that is associated with SARS-CoV MA15 outcome in CC011xCC074 F2 mice and is also syntenic with a human chromosomal region associated with severe COVID-19 outcomes in humans GWAS. The results reported here provide: (a) additional support for the involvement of this locus in SARS-CoV MA15 infection, (b) the first conclusive evidence that this locus is associated with susceptibility across the Sarbecovirus subgenus, and (c) demonstration of the relevance of mouse models in the study of coronavirus disease susceptibility in humans.

Probing the basis of disease heterogeneity in multiple sclerosis using genetically diverse mice.

Multiple sclerosis (MS) is a complex disease with significant heterogeneity in disease course and progression. Genetic studies have identified numerous loci associated with MS risk, but the genetic basis of disease progression remains elusive. To address this, we leveraged the Collaborative Cross (CC), a genetically diverse mouse strain panel, and experimental autoimmune encephalomyelitis (EAE). The thirty-two CC strains studied captured a wide spectrum of EAE severity, trajectory, and presentation, including severe-progressive, monophasic, relapsing remitting, and axial rotary (AR)-EAE, accompanied by distinct immunopathology. Sex differences in EAE severity were observed in six strains. Quantitative trait locus analysis revealed distinct genetic linkage patterns for different EAE phenotypes, including EAE severity and incidence of AR-EAE. Machine learning-based approaches prioritized candidate genes for loci underlying EAE severity ( Abcc4 and Gpc6 ) and AR-EAE ( Yap1 and Dync2h1 ). This work expands the EAE phenotypic repertoire and identifies novel loci controlling unique EAE phenotypes, supporting the hypothesis that heterogeneity in MS disease course is driven by genetic variation. Summary: The genetic basis of disease heterogeneity in multiple sclerosis (MS) remains elusive. We leveraged the Collaborative Cross to expand the phenotypic repertoire of the experimental autoimmune encephalomyelitis (EAE) model of MS and identify loci controlling EAE severity, trajectory, and presentation.

A series of pyrimidine-based antifungals with anti-mold activity disrupt ER function in Aspergillus fumigatus.

Fungal infections are a major contributor to morbidity and mortality among immunocompromised populations. Moreover, fungal disease caused by molds are difficult to treat and are associated with particularly high mortality. To address the need for new mold-active antifungal drugs, we performed a high-throughput screen with Aspergillus fumigatus, the most common pathogenic mold. We identified a novel, pyrimidine-based chemical scaffold with broad-spectrum antifungal activity including activity against several difficult-to-treat molds. A chemical genetics screen of Saccharomyces cerevisiae suggested that this compound may target the endoplasmic reticulum (ER) and perturb ER function and/or homeostasis. Consistent with this model, this compound induces the unfolded protein response and inhibits secretion of A. fumigatus collagenases. Initial cytotoxicity and pharmacokinetic studies show favorable features including limited mammalian cell toxicity and bioavailability in vivo. Together, these data support the further medicinal chemistry and pre-clinical development of this pyrimidine scaffold toward more effective treatments for life-threatening invasive mold infections.IMPORTANCEInvasive fungal diseases are life-threatening infections caused by fungi in immunocompromised individuals. Currently, there are only three major classes of antifungal drugs available to treat fungal infections; however, these options are becoming even more limited with the global emergence of antifungal drug resistance. To address the need for new antifungal therapies, we performed a screen of chemical compounds and identified a novel molecule with antifungal activity. Initial characterization of this compound shows drug-like features and broad-spectrum activity against medically important fungi. Together, our results support the continued development of this compound as a potential future therapy for these devastating fungal infections.

Atp1a2 and Kcnj9 are candidate genes underlying oxycodone behavioral sensitivity and withdrawal in C57BL/6 substrains.

Opioid use disorder is heritable, yet its genetic etiology is largely unknown. Analysis of addiction model traits in rodents (e.g., opioid behavioral sensitivity and withdrawal) can facilitate genetic and mechanistic discovery. C57BL/6J and C57BL/6NJ substrains have extremely limited genetic diversity, yet can show reliable phenotypic diversity which together, can facilitate gene discovery. The C57BL/6NJ substrain was less sensitive to oxycodone (OXY)-induced locomotor activity compared to the C57BL/6J substrain. Quantitative trait locus (QTL) mapping in an F2 cross identified a distal chromosome 1 QTL explaining 7-12% of the variance in OXY locomotor sensitivity and anxiety-like withdrawal in the elevated plus maze. We identified a second QTL for withdrawal on chromosome 5 near the candidate gene Gabra2 (alpha-2 subunit of GABA-A receptor) explaining 9% of the variance. Next, we generated recombinant lines from an F2 founder spanning the distal chromosome 1 locus (163-181 Mb), captured the QTL for OXY sensitivity and withdrawal, and fine-mapped a 2.45-Mb region (170.16-172.61 Mb). There were five striatal cis-eQTL transcripts in this region (Pcp4l1, Ncstn, Atp1a2, Kcnj9, Igsf9), two of which were confirmed at the protein level (KCNJ9, ATP1A2). Kcnj9, a.k.a., GIRK3, codes for a potassium channel that is a major effector of mu opioid receptor signaling. Atp1a2 codes for a subunit of a Na+/K+ ATPase enzyme that regulates neuronal excitability and shows adaptations following chronic opioid administration. To summarize, we identified genetic sources of opioid behavioral differences in C57BL/6 substrains, two of the most widely and often interchangeably used substrains in opioid addiction research.

United States Provider Experiences with Telemedicine for Hepatitis C Treatment: A Nationwide Survey.

Background: Hepatitis C virus (HCV) elimination requires treatment access expansion, especially for underserved populations. Telehealth has the potential to improve HCV treatment access, although data are limited on its incorporation into standard clinical practice. Methods: We conducted a cross-sectional, e-mail survey of 598 US HCV treatment providers who had valid email addresses and 1) were located in urban areas and had written ≥20 prescriptions for HCV treatment to US Medicare beneficiaries in 2019-20 or 2) were located in non-urban areas and wrote any HCV prescriptions in 2019-20. Through email, we notified providers of a self-administered electronic 28-item survey of clinical strategies and attitudes about telemedicine for HCV. Results: We received 86 responses (14% response rate), of which 75 used telemedicine for HCV in 2022. Of those 75, 24% were gastroenterologists/hepatologists, 23% general medicine, 17% infectious diseases, and 32% non-physicians. Most (82%) referred patients to commercial laboratories, and 85% had medications delivered directly to patients. Overwhelmingly, respondents (92%) felt that telehealth increases healthcare access, and 76% reported that it promotes or is neutral for treatment completion. Factors believed to be "extremely" or "very" important for telehealth use included patient access to technology (86%); patients' internet access (74%); laboratory access (76%); reimbursement for video visits (74%) and audio-only visits (66%). Non-physician licensing and liability statutes were rated "extremely" or "very" important by 43% and 44%, respectively. Conclusions: Providers felt that telehealth increases HCV treatment access. Major limitations were technological requirements, reimbursement, and access to ancillary services. These findings support the importance of digital equity and literacy to achieve HCV elimination goals.

Determining Excited-State Absorption Properties of a Quinoid Flavin by Polarization-Resolved Transient Spectroscopy.

As important naturally occurring chromophores, photophysical/chemical properties of quinoid flavins have been extensively studied both experimentally and theoretically. However, little is known about the transition dipole moment (TDM) orientation of excited-state absorption transitions of these important compounds. This aspect is of high interest in the fields of photocatalysis and quantum control studies. In this work, we employ polarization-associated spectra (PAS) to study the excited-state absorption transitions and the underlying TDM directions of a standard quinoid flavin compound. As compared to transient absorption anisotropy (TAA), an analysis based on PAS not only avoids diverging signals but also retrieves the relative angle for ESA transitions with respect to known TDM directions. Quantum chemical calculations of excited-state properties lead to good agreement with TA signals measured in magic angle configuration. Only when comparing experiment and theory for TAA spectra and PAS, do we find deviations when and only when the S0 → S1 of flavin is used as a reference. We attribute this to the vibronic coupling of this transition to a dark state. This effect is only observed in the employed polarization-controlled spectroscopy and would have gone unnoticed in conventional TA.

Adjuvant-dependent impact of inactivated SARS-CoV-2 vaccines during heterologous infection by a SARS-related coronavirus.

Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection.

Primary Mucinous Carcinoma of the Thyroid: A Case Report, Literature Review, and Immunohistochemistry Summary.

Introduction: Primary mucinous carcinoma of the thyroid is an exceedingly rare malignancy that is histologically similar to mucinous carcinoma of other sites. Accurate diagnosis is a challenging yet crucial component of clinical management for both patients and our understanding of this rare disease. Case Presentation: We report the case of a 69-year-old male patient with primary mucinous carcinoma of the thyroid. Microscopic examination of a biopsy specimen showed fibrous tissue, which was extensively and irregularly infiltrated by a cytologically malignant epithelial neoplasm showing glandular differentiation with mucin production. Immunohistochemistry demonstrated that tumor cells were positive for TTF1, thyroglobulin, CK7, and PAX8. Co-expression of TTF1 and PAX8 is most commonly seen in thyroid tumors. These findings support our diagnosis of mucinous carcinoma of thyroid origin, which is rare and highly aggressive. Conclusion: In this report, we present the only documented case of primary mucinous carcinoma of the thyroid reported in the United States in the last decade. The diagnosis of primary mucinous carcinoma of the thyroid can be challenging. Therefore, we discuss and detail the clinicopathologic tumor profile and provide more current, detailed histological criteria to assist in the diagnosis of this rare disease.

Levitons in correlated nano-scale systems.

In this short review (written to celebrate David Campbell's 80th birthday), we provide a theoretical description of quantum transport in nanoscale systems in the presence of single-electron excitations generated by Lorentzian voltage drives, termed Levitons. These excitations allow us to realize the analog of quantum optics experiments using electrons instead of photons. Importantly, electrons in condensed matter systems are strongly affected by the presence of different types of non-trivial correlations, with no counterpart in the domain of photonic quantum optics. After providing a short introduction about Levitons in non-interacting systems, we focus on how they operate in the presence of two types of strong electronic correlations in nanoscale systems, such as those arising in the fractional quantum Hall effect or in superconducting systems. Specifically, we consider Levitons in a quantum Hall bar of the fractional quantum Hall effect, pinched by a quantum point contact, where anyons with fractional charge and statistics tunnel between opposite edges. In this case, a Leviton-Leviton interaction can be induced by the strongly correlated background. Concerning the effect of superconducting correlations on Levitons, we show that, in a normal metal system coupled to BCS superconductors, half-integer Levitons minimize the excess noise in the Andreev regime. Interestingly, energy-entangled electron states can be realized on-demand in this type of hybrid setup by exploiting crossed Andreev reflection. The results exposed in this review have potential applications in the context of quantum information and computation with single-electron flying qubits.

Host cell-specific metabolism of linoleic acid controls Toxoplasma gondii growth in cell culture.

The obligate intracellular parasite Toxoplasma gondii can infect and replicate in any warm-blooded cell tested to date, but much of our knowledge about T. gondii cell biology comes from just one host cell type: human foreskin fibroblasts (HFFs). To expand our knowledge of host-parasite lipid interactions, we studied T. gondii in intestinal epithelial cells, the first site of host-parasite contact following oral infection and the exclusive site of parasite sexual development in feline hosts. We found that highly metabolic Caco-2 cells are permissive to T. gondii growth even when treated with high levels of linoleic acid (LA), a polyunsaturated fatty acid (PUFA) that kills parasites in HFFs. Caco-2 cells appear to sequester LA away from the parasite, preventing membrane disruptions and lipotoxicity that characterize LA-induced parasite death in HFFs. Our work is an important step toward understanding host-parasite interactions in feline intestinal epithelial cells, an understudied but important cell type in the T. gondii life cycle.

A mutation in Themis contributes to anaphylaxis severity following oral peanut challenge in CC027 mice.

BACKGROUND: The development of peanut allergy is due to a combination of genetic and environmental factors, although specific genes have proven difficult to identify. Previously, we reported that peanut-sensitized Collaborative Cross strain CC027/GeniUnc (CC027) mice develop anaphylaxis upon oral challenge to peanut, in contrast to C3H/HeJ (C3H) mice. OBJECTIVE: This study aimed to determine the genetic basis of orally induced anaphylaxis to peanut in CC027 mice. METHODS: A genetic mapping population between CC027 and C3H mice was designed to identify the genetic factors that drive oral anaphylaxis. A total of 356 CC027xC3H backcrossed mice were generated, sensitized to peanut, then challenged to peanut by oral gavage. Anaphylaxis and peanut-specific IgE were quantified for all mice. T-cell phenotyping was conducted on CC027 mice and 5 additional Collaborative Cross strains. RESULTS: Anaphylaxis to peanut was absent in 77% of backcrossed mice, with 19% showing moderate anaphylaxis and 4% having severe anaphylaxis. There were 8 genetic loci associated with variation in response to peanut challenge-6 associated with anaphylaxis (temperature decrease) and 2 associated with peanut-specific IgE levels. There were 2 major loci that impacted multiple aspects of the severity of acute anaphylaxis, at which the CC027 allele was associated with worse outcome. At one of these loci, CC027 has a private genetic variant in the Themis gene. Consistent with described functions of Themis, we found that CC027 mice have more immature T cells with fewer CD8+, CD4+, and CD4+CD25+CD127- regulatory T cells. CONCLUSIONS: Our results demonstrate a key role for Themis in the orally reactive CC027 mouse model of peanut allergy.

Multidisciplinary analysis of cancer-related fatigue at the time of diagnosis: preliminary results of the BIOCARE FActory cohort.

PURPOSE: Cancer-related fatigue (CRF) is a common side effect of cancer and cancer treatment that significantly impairs the quality of life and can persist for years after treatment completion. Although fatigue is often associated with cancer treatment, it is also a result of the disease itself, even before intervention. CRF at the time of diagnosis may affect treatment timing or completion and is a consistent predictor of post-treatment fatigue at any time. The mechanisms underlying CRF are multidimensional and not well understood, particularly at the time of diagnosis. METHODS: Sixty-five breast cancer patients at the time of diagnosis were included. The participants completed self-assessment questionnaires about CRF, sleep disturbances, and emotional symptoms and wore an accelerometer to assess levels of spontaneous physical activity and sleep quality. During the experimental session, the participants underwent cognitive, neuromuscular, and exercise metabolism evaluations. RESULTS: Using augmented backward elimination regression, this study found that emotional symptoms and perceived sleep disturbances were the strongest predictors of CRF (adjusted r2 = 0.51). Neuromuscular fatigability and sleep disturbance were also associated with physical dimensions, whereas cognitive performance was associated with cognitive dimensions. CONCLUSION: At the time of diagnosis, emotional and cognitive dimensions are over-represented compared to the general population, and specific subdimensions have specific predictors that support the idea of distinct mechanisms. Evaluating CRF subdimensions and their potential mechanisms at the time of diagnosis would be particularly relevant for identifying high-risk patients and offering them appropriate interventions. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov (NCT04391543) in May, 2020.