bluuebunny/crossref_metadata_2025_split huggingface dataset:
Depressive-like behavior associated with colitis is altered after treatment with aryl hydrocarbon receptor ligand
Authors: Bogdon Raymond K , Roark Kasie , Saxena Archana , Mitchell Chandani , Hailey Michelle , Staley Shanieka Caroline , Busbee Phillip B 
Published: August 2023

Abstract
Colitis is a chronic inflammatory disease with no cure and an overall reduction in patient quality of life. Due to decreased mucous production and weakening of the colonic epithelial lining, gut -microbiota and their metabolites can invade the intestinal lamina propria and circulate systemically, a term known as “leaky gut”. Recent studies show a relationship exists between peripheral inflammation and depression. The gut-brain axis (GBA) acts as a bidirectional communication pathway between the enteric and central nervous system (CNS), and colitis patients are known to have increased incidence of depression. In the current study, we aimed to investigate the relationship between colitis, and its impact on depressive-like symptoms in mice. Colitis was chemically induced in mice and treated with indole-3-carbinol (I3C), a naturally-occurring aryl hydrocarbon receptor (AhR) our lab previously showed reduced colitis severity. Untargeted metabolomic profiles of over 200 metabolites revealed that during disease induction a potential neurotoxic and kynurenine pathway metabolite, quinolinic acid (QA), was upregulated in colitis models, but reduced after I3C treatment. As high QA levels are linked to depression, we performed tail suspension tests (TST) over the course of disease and treatment to assess depressive-like behavior in experimental mice. Our results show that colitis- induced mice had a higher immobility time as compared to healthy controls, but this was reversed upon treatment with I3C. These results suggest that colonic inflammation can lead to altered behavior and increased depressive-like symptoms through dysregulation of the gut metabolome, but restored after treatment with AhR ligand, I3C.
NIH P20GM103641
Oral CD8+ TRM surveil taste buds where their local reactivation drives papillary inflammation and bitter receptor expression
Authors: Stolley Michael , Masopust David 
Published: August 2023

Abstract
Resident memory T cells (TRM) expedite pathogen detection and clearance at typical portals of pathogen entry. While paradigms in TRM biology were largely established in a few select locations, comparatively little is known about how CD8+ TRM integrate within the oral cavity, which encompasses a functionally organized constellation of absorptive, secretory, and chemosensory tissues. To fill this knowledge gap, we developed a Viral-Prime, Epitope-Pull (VPEP) model for locally augmenting tractable populations of oral TRM to manipulate and study. Leveraging this approach, we document CD8+ TRM within and surrounding taste buds and papillae of the soft palate and tongue. Reactivation of oral T cells induced discernable inflammation within taste structures that was abrogated with prior in vivo CD103+ TRM depletion. Taste buds represent a collection of ~50–100 individual taste receptor cells (TRCs) which sense nutritive and potentially harmful dietary components. We hypothesized that reactivation of taste bud associated TRM would provoke TRC transcriptional changes including genes involved in gustation (taste). Bulk RNAseq was performed on TRM-reactivated circumvallate papillae and soft palate; primary taste-sensing locations in mice and enriched sources of TRCs relative to other oral tissues. Here we found the significant induction of several Tas2r (bitter receptor) genes not observed in control mice or TRM reactivated buccal mucosa. Teleologically, a heightened sensitivity to bitter compounds downstream of oral TRM reactivation may represent an evolved mechanism to protect against the accidental ingestion of noxious chemicals during oral or upper respiratory tract infections when other chemosensory modalities faulter.
T90 DE 022732 K99DE031014
Single-cell RNA sequencing reveals heterogeneous immune landscape of tumor infiltrated immune cell population in B cell deficiency against glioblastoma
Authors: Kim Yumin , Kim Chae Won 
Published: August 2023

Abstract
The distinct immune landscape of glioblastoma (GBM) from other cancer is an obstacle to GBM treatment. To overcome the limited efficacy of GBM therapy, identifying the interaction between the tumor and infiltrated immune cells is needed. The function of B cells against tumors is recently focused on to understand tumor microenvironments. However, there are still few studies on the function of B cells in glioblastoma. Here, we identify tumor infiltrated immune cell population in B cell deficient mouse GBM by landscape analysis against glioblastoma. Using single-cell transcriptome analysis, we find that the frequency of tumor infiltrated immune cells including T cells and monocyte/macrophage is changed by the absence of B cells in mouse GBM. The frequency of effector CD8 and CD4 T cells decreases in B cell deficient mice. Also, expression of the cytotoxic signature protein is downregulated in tumor infiltrated T cells which are known to play an important role in tumor cell killing. In the case of tumor infiltrated macrophage and microglia, expression of M2 signature increased in B cell deficient GBM which can lead immunosuppressive tumor microenvironment. This study reveals changes in the immune cell landscape according to the presence or absence of B cells and shows how B cells contribute to antitumor immunity through immune interaction.
Single-cell RNA sequencing reveals heterogeneous immune landscape of tumor-infiltrating lymphocytes in the glioblastoma tumor microenvironment in the absence of IFNAR
Authors: Lim Juhee , Lee Heung Kyu 
Published: August 2023

Abstract
Glioblastoma (GBM) is known to be the most common malignant brain cancer with a very poor prognosis. Despite standard conventional therapies patient survival rates still remain poor and reasons for this may be due to the extensive tumor cellular heterogeneity of the tumor microenvironment. Type I interferons (IFNs) are a family of cytokines produced by multiple cell types and are known to play a role in anticancer immunity through their signaling via the interferon alpha receptor (IFNAR). We find that absence of IFNAR compromises anti-tumor immunity against GBM. Single-cell RNA analysis of the immune landscape of GBM tumor-bearing IfnαR−/− mice reveals that there is an overall decrease in tumor-infiltrating lymphocytes into the brain along with overall decreased expression of IFNγ, TNFα, and Granzyme A. Analysis of lymphoid cells including T cells and NK cells shows substantial decreased infiltration in the presence of GBM in IFNαR deficient mice. Notably, CD4 and CD8 T cell infiltration is considerably reduced, although how the functions of these cells are affected is yet unknown. Analysis of tumor-infiltrating myeloid cells in the absence of interferon signaling reveals decreased infiltration of monocytes and tumor-associated macrophages as well. Thus, in this study, we are able to see that the absence of type I interferon signaling affects the overall recruitment of lymphoid and myeloid cells during the progression of GBM and likely contributes to the exacerbation of anti-tumor immunity.
Application of Next Generation Sequencing technology to determine breast cancer risk among Bangladeshi women
Authors: Rabbi Mohammad Fazle Alam , Pathan Kawsar Iqbal 
Published: August 2023

Abstract
Recent advancement in sequencing technology had led to the accurate and precise diagnosis of deadly diseases like breast cancer. Breast cancer is the second most common cancer in women, therefore, early diagnosis of this critical disease is important for prevention and therapeutic implications. BRCA1 and BRCA2 genes are significantly associated with breast cancer aetiology. Individuals carrying a germline mutation in BRCA genes increase their chance of developing breast or ovarian cancer in women and pancreatic cancer in both sexes. The purpose of this study was to determine the germline mutations of BRACA among the risk group of Bangladeshi women using Next Generation Sequencing (NGS). One hundred patients were selected randomly from the outdoor breast cancer clinic of DNA Solution Ltd. Using ‘Six-Point Scale’ twenty individuals were selected for BRCA gene mutation study. A clinical database was maintained to record personal and familial cancer history of the selected individuals. Personal identification was preserved according to Helsinki principals. Out of twenty enrolled individuals, seventeen individuals had a family history of cancer. However, upon sequencing data analysis, we observed only six patients carrying the pathogenic mutation of BRCA gene. This study only involved germline mutation and did not consider somatic mutation. Recent reports also suggest various genes other than BRCA are also associated with breast cancer occurrence. To our knowledge, this is the first time to use NGS technology to screen genetic mutations of breast cancer in Bangladesh. These data will help to develop early screening and possible prevention with better disease management in breast cancer.
No Funding Support
High-throughput Multidimensional Characterization of CD8 T cells in MOG Antibody-Associated Disease
Authors: Chizari Shahab , De Jager Philip L , Jiang Jenny 
Published: August 2023

Abstract
Inflammatory demyelinating diseases of the central nervous system (CNS) include clinically and pathologically distinct disorders. Myelin oligodendrocyte glycoprotein-associated disease (MOGAD) is a recently characterized antibody-mediated inflammatory demyelinating disorder of the CNS with clinical presentations which include optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis. The heterogenous clinical course of MOGAD along with unclear prognostic biomarkers makes treatment challenging, as some individuals have monophasic disease while others relapse. Recent work has attempted to identify biomarkers by performing scRNA-seq on the peripheral blood mononuclear cells (PBMC) of MOGAD patients and has highlighted an enrichment for a cytotoxic effector CD8 +T cell subset in MOGAD compared to healthy controls. However, this subset of cells remains under characterized, with questions regarding their antigen specificity, clonality, and overall involvement in MOGAD.
To further characterize this cell subset, we utilize a single cell technology, TetTCR-SeqHD, to evaluate the antigen-specificity, clonality, gene expression, and surface protein expression of CD8 +T cells isolated from the PBMC of MOGAD patients. In this approach, a large library of fluorescently labeled, DNA barcoded peptide-MHC tetramers are generated utilizing peptides derived from MOG or associated proteins such as myelin basic protein and proteolipid protein which are then used to isolate antigen specific CD8+ T cells for single cell analysis. Preliminary results show an enrichment of a distinct CD161 ++TRAV1–2 +MAIT cell population in MOGAD, which has been previously implicated in other chronic inflammatory diseases.
This work is supported by the Chan Zuckerberg Initiative Neurodegeneration Challenge Network Ben Barres Early Career Acceleration Award.
Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasis
Authors: Hao Jiaqing , Yu Jianyu , Yorek Matthew , Jabbari Ali , Li Bing 
Published: August 2023

Abstract
Psoriasis is a common chronic inflammatory skin disease. One of the hallmarks of psoriasis is the abundance of neutrophil infiltration in the skin lesions. However, the detailed molecular mechanisms of neutrophil chemotaxis and activation remains unclear. Here we demonstrated an upregulation of epidermal fatty acid binding protein (E-FABP, also known as FABP5) in skin tissue from both human psoriasis and imiquimod (IMQ)-induced psoriatic mouse model. Genetic deletion of FABP5 in global knockout mice and keratinocyte conditional (Krt6a-Cre) knockout mice, but not in myeloid cell conditional (Lysm-Cre) knockout mice, attenuated the skin erythema, thickness, and desquamation. Immunophenotypic analysis showed that FABP5 deficiency reduced the recruitment of Ly6G+ neutrophils in the dermis and ear of IMQ-treated mice. Mechanistically, activated keratinocytes in IMQ-treated mice produced chemokines and cytokines (e.g., CXCL8, IL-36γ) that triggered neutrophil chemotaxis and activation in a FABP5-dependent manner. Proteomic and IP analyses further identified that FABP5 interacted with a valosin-containing protein (VCP), a key player in NFκB signaling pathway in human keratinocytes. Silencing of FABP5 inhibited VCP-mediated IκBα phosphorylation and NFκB signaling activation. Collectively, these data suggest that FABP5 in keratinocytes interacts with VCP to activate NFκb signaling, thus playing an essential role in the neutrophil infiltration in psoriatic skin lesions.
R01AI137324, #LINK#R01CA180986#ENDLINK#
Spatial Transcriptomic Profiling Reveals the Pathophysiology of Early Stage Hidradenitis Suppurativa
Authors: Joh Christine , Jeong Soyoung , Lee Jung Ho , Lee Hee Jung , Kim Gwangil , Lee Cheol , Shin Jung U , Kim Hyun Je , Park Chung-Gyu , Jin Seon-Pil 
Published: August 2023

Abstract
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder that ranges from superficial nodules and deep abscesses to draining dermal tunnels in the intertriginous regions. It causes significant pain, scarring, and a poor quality of life, yet there are currently no effective treatment options. The role of tunnels or sinus tracts—a unique feature of moderate to severe HS—was reported that the epidermal tunnels are the source of inflammatory mediators in Hurley stages II and III. However, the pathophysiology of early stage HS needs further investigation. Here, we examined the intradermal epithelial cells surrounding these nodules in early HS in order to explore their features and function. Utilizing spatial transcriptomics, a cutting-edge technique that offers both spatial information of cells and their gene expression profiles, we compared the intradermal epithelial cell of HS patients in the early Hurley stage with the dermal wall of epidermal cysts in epidermal cyst patients. As expected, keratinocytes in the epidermis of individuals with HS were significantly activated, with increased levels of inflammatory cytokines, including IL-36G and CXCL8. In addition, the increase of IL-4R and IL-13RA1 suggests the increase of the sensitivity of Th2 cytokine on the epidermis and in dermal-infiltrating immune cells. Moreover, genes associated with B lymphocytes were highly expressed in the infiltrating immune cells of HS, implicating the importance of “epidermis-derived” inflammatory cytokines and the role of B cell infiltration in the pathomechanism of early HS.
Astrocytic expression of CD137 in the lumbar spinal cord following sciatic nerve crush model of neuropathic pain in mice
Authors: Cao Ling , Withers James , Bean Elizabeth N 
Published: August 2023

Abstract
Previously we have shown that CD137–CD137 ligand (CD137L) mediates pro-nociceptive behaviors in the sciatic nerve crush (SNC) model of neuropathic pain. Global CD137L knockout (KO) mice and wildtype (WT) mice intrathecally treated with neutralizing antibody against either CD137L or CD137 displayed significantly reduced neuropathic pain-like behaviors and faster functional recovery compared to WT mice following SNC. To identify the cellular sources of CD137 and CD137L in the spinal cord, a series of immunohistochemistry analyses was performed. While we could not detect significant expression of CD137L (in part due to both technical and biological issues), we observed CD137 expression exclusively co-localized with astrocytic marker glial fibrillary acidic filament (GFAP). We then conducted a time course study of CD137 expression in the lumbar spinal cord dorsal horn region, the region relevant to nociceptive behaviors, in B6-CD137L KO and B6 WT mice. Significant increases in CD137 expression (represented by integrated density) were observed in WT mice from days 7 to 28 following either SNC or sham surgery. The expression of CD137 in KO mice was slightly (however not statistically significantly) higher than that in WT mice at baseline, and did not change overtime post-either surgery. When RNA expression of CD137 was evaluated, although SNC induced significant upregulation of GFAP RNA expression in WT mice, no changes in CD137 RNA expression were detected in any treatment groups or any genotype of mice. Altogether, we report a novel expression of CD137 on murine spinal cord astrocytes. The underlying mechanism through which astrocytic CD137 mediates SNC-induced nociceptive behavior requires further investigation.
NIH/NINDS R01NS098426 (Cao) and Peter Caradonna from the COBRE Histology and Imaging Core funded by NIH/NIGMS P20GM103643 (Meng).
Elucidating Mycosis Fungoides Gene Expression in Skin of Color Patients from Howard University Dermatology
Authors: Nwade Nina , James Nia , Nagarkar Akanksha , Desse Sachi , Yildiz-Altay Ummugulsum , Okoye Ginette A , Byrd Angel S , Richmond Jillian M 
Published: August 2023

Abstract
Mycosis fungoides (MF) is the most common type of cutaneous T cell lymphoma.There are notable differences in MF presentation in Skin of Color (SOC) versus White skin, such as asymptomatic hyperpigmented and hypopigmented lesions resulting from malignant T-cell interaction from keratinocytes and melanocytes. Therefore, this work aims at elucidating MF immunopathogenesis and gene expression in SOC patients and determining whether clinical presentation differences are dependent on the cytokine type produced by the tumor. We used both hypopigmented and hyperpigmented MF biopsy samples from SOC patients with MF from Howard University Dermatology and compared their gene expression to that of biopsy samples from SOC healthy patients. Preliminary data showed an upregulation of genes such as PRDX1, HLA-DRA, CTNNB1, CSTB, and S100A4 in MF samples versus their healthy counterparts. The MF samples also exhibited downregulation of CCL3, CCRL2, PDGFB and HOXD4 genes when compared to their healthy counterparts. Lastly, the pathways ‘cell cycle and apoptosis’, ‘antigen presentation’, and ‘interferon signaling’ were increased in MF and decreased in the healthy samples. Overall, these data will elucidate MF gene expression in SOC patients as well as the immunopathogenesis that results in varying presentations. This may facilitate the development of more concise diagnostic criteria and personalized targeted immunotherapies to better health outcomes within a minority population.
Supported by grants from Dermatology Foundation DRSA (SD), the Skin of Color Society Research Grant (JMR), and the American Skin Association Milstein Research Scholar Award for Melanoma/Non-Melanoma Skin Cancer (ASB).
Treatment with doxorubicin and PD-1/CTLA-4 blockade improves T cell activation and anti-tumor efficacy in MCA-205 murine fibrosarcoma
Authors: Therrien Nicholas R , Tellez Cristiam Morreno , Kemp Lindsey E , Powers Kyle N , Levey Daniel , Chand Dhan , Wilkens Margaret , Grossman Joseph , Goodspeed Andrew , Davila Eduardo , Wilky Breelyn A 
Published: August 2023

Abstract
Immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 produce responses in about 20% of adult soft tissue sarcomas (STSs), however, most patients do not respond, potentially from poor T cell activation. Standard chemotherapy for STSs includes the anthracycline doxorubicin (DOX) which has been shown in preclinical cancer models to induce immunogenic cell death (ICD) via tumor production of type I interferons (IFN). We hypothesized that induction of ICD and IFN release by doxorubicin would enhance T cell activation, infiltration, and boost anti-tumor efficacy when combined with dual anti-PD-1/CTLA-4 blockade in the MCA-205 murine fibrosarcoma model. MCA-205 tumors were generated in C57BL/6 mice and were treated with DOX, anti-PD1 (RMP1–14), anti-CTLA4 (9D9 mouse IgG2b) or a mouse surrogate of botensilimab, an anti-CTLA4 (9D9 mouse IgG2b.DLE) antibody with enhanced binding to FcγR, or combination DOX plus anti-PD-1/CTLA-4. We found reduction of tumor growth and improved survival (median survival not reached) with DOX/PD-1/CTLA-4 compared to DOX (median survival 29.5 days). This correlated with a 2-fold increased influx of TILs as measured by flow cytometry and immunohistochemistry, with a marked increase in CD8:CD4 T cell ratio with increased expression of activation markers (PD-1, 4–1BB and TIM3). TCR Vβ clonotyping revealed a shift in clonotype frequency with DOX/PD-1/CTLA-4 relative to other treatment groups. Pathway analysis from bulk RNA sequencing demonstrated upregulation of T cell activation in DOX/PD-1/CTLA-4 tumors compared to control tumors. Further work will correlate these findings with human STS patients receiving DOX plus CTLA-4/PD-1 blockade in an ongoing clinical trial (NCT04028063).
This work was supported by grants from the University of Colorado Cancer Center (P30CA046934) and the University of Colorado School of Medicine.
Overlapping Mendelian disorders of immunity and metabolism shape CD4+ T cell immunometabolism
Authors: Patterson Andrew R , Chi Channing , Steiner KayLee K , Rathmell Jeffrey C 
Published: August 2023

Abstract
During the past decade it has become increasingly apparent that cellular metabolism plays a critical role in the function and regulation of the immune system. Immune cell utilization of specific metabolic pathways influences immune function and can be pharmacologically targeted to alter immune outcomes. The importance of immune cell metabolism and function is further demonstrated by the development of primary immunodeficiencies in patients deficient in certain metabolic pathways. To identify novel mechanisms governing the interplay between CD4+ T cell metabolism and function, we performed a series of CRISPR screens evaluating CD4+ T cell expansion, substrate uptake, and mitochondrial function. Specifically, we leveraged the Inborn Errors of Metabolism (IEM) and Immunity (IEI) to identify new immunometabolic regulators. Through these screens, I identified the transcription factor Bcl11b as a critical regulator in CD4+ effector T cell mitochondrial metabolism and function. Additional studies suggest Bcl11b plays a key role regulating mitochondria and metabolic stress in activated T cells. Conversely, screens of IEM genes for T cell functional defects showed that the N-linked glycosylation and the entry enzyme for de novohexosamine synthesis, Gfpt1, pathway were essential for CD4+ T cell expansion and survival. Notably, Gfpt1-deficient TH1 cells more affected than TH17 cells, which had greater capacity for salvage UDP-GlcNAc synthesis. This IEM and IEI-based CRISPR screening approach offers a unique opportunity to identify novel genes and regulatory pathways that are critical and sufficient for productive immune responses and to evaluate their effect on immunometabolism.
R01 DK105550