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Abstract. Background:. Lumbar facet joint arthropathy (LFJA) is a major cause of low back pain (LBP), with current treatments offering limited long-term benefits. Bone marrow–derived mesenchymal stem cells (BM-MSCs) show promise due to their immunomodulatory and trophic effects, potentially addressing underlying degenerative processes in LFJA. Objectives:. This initial report describes the outcomes of the first treated patient in an ongoing mutidisciplinary phase 1 clinical trial evaluating the safety and feasibility of intra-articular allogeneic BM-MSCs for painful LFJA. Methods:. Following enrollment in our IRB-approved protocol, symptomatic LFJA was confirmed through double blocks on L4 and L5 medial branches. Two 1-mL syringes, each containing 10 million BM-MSCs, were prepared in the cGMP facility and administered bilaterally to the patient’s L4-L5 lumbar facet joints. The patient underwent standardized follow-ups, including clinical examinations and functional and imaging assessments for 2 years, utilizing patient-reported outcomes measurement information system—computer adaptive tests (PROMIS CATs), visual analogue scale, Oswestry disability index, work functional status and opioid pain medication use, and MR imaging Fenton–Czervionke score. Results:. The patient tolerated the procedure well, with no drug-related adverse events during the study period. Pain, spine function, and work functional status improved at multiple follow-ups. This patient also reported improvements in mental and social health, along with a notable improvement in the grade of facet synovitis observed at the one-year follow-up MRI evaluation. Conclusions:. This case report suggests the safety and feasibility of administering intra-articular allogeneic BM-MSCs, offering therapeutic benefits for pain management and functional activities.

IntroductionThis is a prospective, rigorous inquiry into the systemic immune effects of standard adjuvant chemoradiotherapy, for WHO grade 4, glioblastoma. The purpose is to identify peripheral immunologic effects never yet reported in key immune populations, including myeloid-derived suppressor cells, which are critical to the immune suppressive environment of glioblastoma. We hypothesize that harmful immune-supportive white blood cells, myeloid derived suppressor cells, expand in response to conventionally fractionated radiotherapy with concurrent temozolomide, essentially promoting systemic immunity similar what is seen in chronic diseases like diabetes and heart disease.Methods16 patients were enrolled in a single-institution, observational, immune surveillance study where peripheral blood was collected and interrogated by flow cytometry and RNAseq. Tumor tissue from baseline assessment was analyzed with spatial proteomics to link peripheral blood findings to baseline tissue characteristics.ResultsWe identified an increase in myeloid-derived suppressor cells during the final week of a six-week treatment of chemoradiotherapy in peripheral blood of patients that were not alive at two years after diagnosis compared to those who were living. This was also associated with a decrease in CD8+ T lymphocytes that produced IFNγ, the potent anti-tumor cytokine.DiscussionThese data suggest that, as in chronic inflammatory disease, systemic immunity is impaired following delivery of adjuvant chemoradiotherapy. Finally, baseline investigation of myeloid cells within tumor tissue did not differ between survival groups, indicating immune surveillance of peripheral blood during adjuvant therapy may be a critical missing link to educate our understanding of the immune effects of standard of care therapy for glioblastoma.

Abstract Background Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity. Methods Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens. Results While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient. Conclusions This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.

ABSTRACTThere is a previously unrecognized coupling which underlies the Western evaluation of aesthetic experiences. By and large, we are taught that for our aesthetic pleasures to have any “value” (i.e. to be good) they must do more than merely entertain, distract, or delight. Instead, they should confront us with some “truth” about the nature of our existence and/or guide us to some “reality” concerning the state of our world. This paper asks: 1) whence this prejudice concerning the value of our aesthetic experiences? 2) What metaphysical and ethical assumptions underlie this epistemological standard? And, finally, 3) how might our expectations concerning the nature and value of aesthetic experiences alter if these assumptions are called into question, as they are, for example, by contemporary metaphysical pessimism? This paper uses the concept of “guilty pleasures” as a site to expose the history of our Western assumptions concerning the evaluation of aesthetic experiences and to explore how a pessimistic revaluation of reality might change our analysis of what comprises “good” art. To this end, this paper traces the origins of our aesthetic assumptions in the West, shows how these assumptions continue to influence our aesthetic expectations today, exposes the hidden metaphysical premises, which underly those expectations, and explores why and how we might call these premises into question through a pessimistic revaluation of existence. All of these supports, in the end, a critical reassessment of the status and value our so-called “guilty pleasures.”

ABSTRACTImmunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients.

ABSTRACTActivins, members of the TGF-beta superfamily, have been isolated and identified in the endocrine system, but have not been substantially investigated in the context of the immune system and endocrine-unrelated cancers. Here, we demonstrated that tumor-bearing mice had elevated systemic activin levels, which correlated directly with tumor burden. Likewise, cancer patients have elevated plasma activin levels compared to healthy controls. We observed that both tumor and immune cells could be sources of activins. Importantly, our in vitro studies suggest that activins promote differentiation of naïve CD4+ cells into Foxp3-expressing induced regulatory T cells (Tregs), particularly when TGF-beta was limited in the culture medium. Database and qRT-PCR analysis of sorted major immune cell subsets in mice revealed that activin receptor 1c (ActRIC) was uniquely expressed on Tregs and that both ActRIC and ActRIIB (activin receptor 2b) were highly upregulated during iTreg differentiation. ActRIC-deficient naïve CD4+ cells were found to be defective in iTreg generation both in vitro and in vivo. Treg suppression assays were also performed, and ActRIC deficiency did not change the function or stability of iTregs. Mice lacking ActRIC or mice treated with monoclonal anti-ActRIC antibody were more resistant to tumor progression than wild-type controls. This phenotype was correlated with reduced expression of Foxp3 in CD4+ cells in the tumor microenvironment. In light of the information presented above, blocking activin-ActRIC signaling is a promising and disease-specific strategy to impede the accumulation of immunosuppressive iTregs in cancer. Therefore, it is a potential candidate for cancer immunotherapy.

Field level data from a voluntary water use reporting program in the Delta region of Mississippi (MS), USA, provides empirical evidence that crop growers increase the amount of groundwater pumped for irrigation during periods of high temperature (degree days above 32 C). Regression analysis reveals that growers apply excess irrigation to cope with high temperature conditions while growing season evapotranspiration and precipitation are not significant factors in their decision of how much irrigation to apply. The existing literature indicates that excess water does not alleviate the harmful effect of extreme heat, making the excess irrigation wasteful and costly. Additional degree days above 32 C are associated with a 4.6 mm increase in irrigation depth (46 m3ha−1). This result may be partially explained by the fact that most farmers use visual cues (such as leaf folding which correlate with air temperature) to initiate irrigation events regardless of soil moisture contents. To quantify the impact of this mismatch, we estimate that shifting the underlying sensitivity in the farmers’ minds by 1 C would reduce groundwater pumpage by 800862 mega liters across the Delta region of Mississippi, USA. The monetary cost of mismanaging heat stress with excessive irrigation is estimated at a minimum of over US$33 million per year. We further identify two additional possible distortions affecting the demand for irrigation groundwater: (i) overestimated benefits from irrigation; and (ii) underestimated groundwater pumping cost. The policy implication is that more efforts and incentives should be placed for programs that affect the producers’ water management mindset, such as ''Master Irrigator'' programs that will reduce or eliminate the identified groundwater distortions and optimize benefits from irrigation.

Using 15 years of student enrollment histories from administrative data spanning the 2004-05 through 2018-19 school years at all public colleges, universities, and technical/trade schools in the state of Ohio, we examine rates of re-enrollment in postsecondary education for individuals pursuing additional credentials following the receipt of a sub-baccalaureate certificate. We find that the majority of certificate recipients re-enroll to continue their progression toward stacking credentials. The likelihood of re-enrollment diminishes for certificate earners as they get further out from the term when their initial certificate was completed. Certificate earners re-enroll at an accelerated rate if they acquired their initial certificate at a community college, if they currently have low wages at their jobs, and following increases in local unemployment rates. Our findings lend support to sociological ideas about the role of institutional contexts, opportunity costs, and labor market opportunities in shaping non-traditional postsecondary pathways across the life course.

Low-dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokine's preferential expansion of immunosuppressive regulatory T cells (Tregs). However, off-target immune cell activation and short serum half-life limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating Tregs over immune effector cells. Although promising, therapeutic translation of this approach is complicated by the need to optimize dosing ratios and by the instability of the cytokine/antibody complex. We leverage structural insights to engineer a single-chain hIL-2/F5111 antibody fusion protein, termed F5111 immunocytokine (IC), which potently and selectively activates and expands Tregs. F5111 IC confers protection in mouse models of colitis and checkpoint inhibitor-induced diabetes mellitus. These results provide a roadmap for IC design and establish a Treg-biased immunotherapy that could be clinically translated for autoimmune disease treatment.

"Stackable" credentials offer opportunities for college students to start by earning short-term credentials in vocational and technical fields, then stack additional credentials as they progress in careers, building skills in the classroom and in the workforce. Stackable credentials come at a cost: colleges expend resources in developing and offering stackable credential programs, students pay to enroll, and government aid programs support colleges and students. Given these investments, it is important to know whether stackable programs generate value for students and local economies. This study analyzes the introduction of new certificate or associate degree program options at Ohio community colleges during school years 2004-2005 to 2016-2017. Comparing among students who had just completed a credential, the students whose college had an additional program within their field of study were more likely to re-enroll and earn additional credentials within two years. The additional short-term enrollment did not significantly decrease students' participation in employment or transfers to a university, indicating that stackable credentials fit with their career and educational progression.

Increasing the number of science, technology, engineering, and mathematics (STEM) degrees is a national priority and one way to promote the socioeconomic mobility of students from low-income families. Prior research examining why students do not complete STEM majors often points to students' lack of academic preparation, preferences for non-STEM majors, or lack of information about the value of STEM. This paper uses a randomized experiment to investigate an alternative explanation, that some students lack the financial resources to succeed in demanding majors. In a control group of university students from low-income families, 18.6% of students had declared a STEM major by their third year of college. In a treatment group who were offered additional need-based grant aid upon entering college, 26.5% of students declared a STEM major. Among students who had graduated within six years after entering college, 12.2% of control group graduates had earned a STEM degree compared to 20.2% of treatment group students. Need-based grants thus appear to have the potential to increase the share of low-income students studying and earning degrees in STEM.

Abstract Crop yields are adversely affected by nitrogen (N) losses in humid subtropical regions. This study was conducted to determine whether N dynamics could be manipulated through planting geometry and fertilizer placement. The effects of irrigation (irrigated and rainfed), row pattern (single‐ and twin‐row), and N placement (surface dribble, one knife, two knives, and control) on corn (Zea mays L.) productivity and N use efficiency were investigated at Leland, Mississippi, on a Bosket very fine sandy loam. The total N rate was split into two equal halves of 128 kg N ha−1 at V2 and V6 growth stages. The effects of row pattern and N placement were consistent between irrigated and rainfed environments. There was no interaction between row pattern and N placement nor did row pattern affect corn productivity or N use efficiency parameters. In 2020, when less than 30 mm of rainfall occurred from the first N application through 2 weeks after the last N application, corn grain yield and agronomic N efficiency were not different among placement methods and averaged 11.1 Mg ha−1 and 20.3 kg grain kg−1 fertilizer N, respectively. However, in 2021, applying N with one knife increased corn grain yield by 7% to 14% compared to the two knives and surface dribble application methods; in that year, 235 mm of rainfall occurred from the first N application through 2 weeks after the last N application. Applying N with one knife appears to consistently improve crop productivity and N use efficiency parameters for both irrigated and rainfed environments.

Background: Lower childhood intelligence test scores are reported in some studies to be associated with higher risk of depression in adulthood. The reasons for the association are unclear. This longitudinal data-linkage study explored the relationship between childhood intelligence (at age ∼11) and risk of depression in later-life (up to age ∼85), and whether childhood family structure and adulthood socio-economic and geographical factors accounted for some of this association. Methods: Intelligence test scores collected in the Scottish Mental Survey 1947 were linked to electronic health records (hospital admissions and prescribing data) between 1980 and 2020 (n = 53,037), to identify diagnoses of depression. Mixed-effect Cox regression models were used to explore the relationship between childhood intelligence test scores and risk of depression in later-life. Analyses were also adjusted for childhood family structure (size of family) and adulthood socio-economic and geographical factors (Carstairs index, urban/rural). Results: Twenty-seven percent of participants were diagnosed with depression during follow-up (n = 14,063/53,037). Greater childhood intelligence test scores were associated with a reduced risk of depression in an unadjusted analysis (HR = 0.95, 95% CI = 0.93 to 0.97, P

Abstract Specificity remains a major challenge to current therapeutic strategies for cancer. Mutation associated neoantigens (MANAs) are products of genetic alterations, making them highly specific therapeutic targets. MANAs are HLA-presented (pHLA) peptides derived from intracellular mutant proteins that are otherwise inaccessible to antibody-based therapeutics. Here, we describe the cryo-EM structure of an antibody-MANA pHLA complex. Specifically, we determine a TCR mimic (TCRm) antibody bound to its MANA target, the KRASG12V peptide presented by HLA-A*03:01. Hydrophobic residues appear to account for the specificity of the mutant G12V residue. We also determine the structure of the wild-type G12 peptide bound to HLA-A*03:01, using X-ray crystallography. Based on these structures, we perform screens to validate the key residues required for peptide specificity. These experiments led us to a model for discrimination between the mutant and the wild-type peptides presented on HLA-A*03:01 based exclusively on hydrophobic interactions.

This article discusses dominance personality dimensions found in primates, particularly in the great apes, and how they compare to dominance in humans. Dominance traits are seen in virtually all primate species, and these dimensions reflect how adept an individual is at ascending within a social hierarchy. Among great apes, dominance is one of the most prominent personality factors but, in humans, dominance is usually modeled as a facet of extraversion. Social, cultural, and cognitive differences between humans and our closest ape relatives are explored, alongside humanity’s hierarchical and egalitarian heritage. The basic characteristics of dominance in humans and nonhuman great apes are then described, alongside the similarities and differences between great apes. African apes live in societies each with its own hierarchical organization. Humans were a possible exception for some of our history, but more recently, hierarchies have dominated. The general characteristics of high-dominance humans, particularly those living in industrialized nations, are described. Dominance itself can be subdivided into correlated subfactors: domineering, prestige, and leadership. Various explanations have been posed for why dominance has declined in prominence within human personality factor structures, and several possibilities are evaluated. The value of dominance in personality research is discussed: dominance has links to, for instance, age, sex, aggression, self-esteem, locus of control, stress, health, and multiple socioeconomic status indicators. The piece concludes with recommendations for researchers who wish to assess dominance in personality.

Like the Copernican revolution which initiated the Modern project, there has been a thermodynamic revolution in the empirical sciences in the last two centuries. The aim of this paper is to show how we might draw from this revolution to make new and startling metaphysical and ethical claims concerning the nature and value of reality. To this end, this paper employs Aristotle’s account of the relation of the various philosophies and sciences to one another to show how we might assert a new theory of being, moral value, and practical action from the primacy of entropic decay asserted in the contemporary mathematical sciences. This paper proceeds to show how, from what the contemporary sciences have concluded concerning the primacy of entropic decay within reality, unbecoming might be forwarded as a new account of the essence of existence: i.e., the first cause and motivating principle of reality’s formal, material, efficient, and final nature. The paper concludes by arguing that a new and surprising account of universal ethical value and normative duty can be deduced from such a metaphysics of decay.

Drought can have complex effects on plants due to different responses of photosynthesis, growth and carbon storage. Here, the authors show that tree growth does not always stop before photosynthesis and non-structural carbohydrate may not accumulate.