bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endoplasmic reticulum associated degradation adaptor Sel1L regulates T cell survival and homeostasis
Authors: Dils Alexander Thomas , Correa Luis O. , Gronevelt Jessica Paige , Liu Lu , Kadiyala Padma , Li Qing , Carty Shannon A. 
Published: February 2023

Abstract
Suppressor/Enhancer of Lin-12-like (Sel1L) acts as a critical adaptor in endoplasmic reticulum-associated degradation (ERAD), a process that maintains cellular protein quality control through the degradation of misfolded proteins. Here, we investigate the role of Sel1L in mature T cells. CD4Cre-driven deletion of Sel1L in murine models resulted in a slight decrease in the frequency and absolute number of CD4 and CD8 single-positive thymocytes with a profound reduction in peripheral T cells. Using mixed bone marrow chimeras, Sel1L regulates peripheral T cell survival in a cell-intrinsic manner. Sel1L-deficient T cells have increased AnnexinV staining suggesting Sel1L deletion promotes apoptosis. Furthermore, the Sel1L conditional knockout mice have a marked defect in the naïve CD8+ T cell compartment, which also occurs in a cell-intrinsic manner. These data suggest that Sel1L is critical for the maintenance of naïve CD8+ T cell homeostasis. Sel1L-deficient T cells exhibit enhanced mTORC1 activation with increased cellular phosphorylated S6 ribosomal protein and phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (4-EBP1), as well as altered cellular metabolism. These results identify a novel role for Sel1L in T cell survival and homeostasis.
Differential response of young and aged Virtual Memory CD8 T (TVM) cells to helminth-induced Th-2 cytokines
Authors: Hussain Tabinda , Nguyen Angela , Daunt Carmel , Thiele Daniel , Smith Tiffany , Harris Nicola , Quinn Kylie , La Gruta Nicole 
Published: February 2023

Abstract
TVM cells are antigen-naïve, semi-differentiated CD8 T cells that develop in response to common γ (γc) chain cytokines, like IL-15 and IL-4. TVM cells respond more rapidly than conventional naïve CD8 T cells to antigen stimulation, thereby providing early control of viral and bacterial infections. TVM cells comprise 20% of the naive CD8 T cell pool in young mice but are selectively retained and make up to 50% of all antigenically naïve CD8 T cells in aged mice. In addition, aged TVM cells exhibit markers of senescence and lose proliferative capacity compared to young TVM cells. Recently, it was shown that IL-4 generated during helminth infection drove TVM cell expansion and improved pathogen clearance in subsequent infections. However, it is not known if the expanded subset is maintained with age or whether helminth infections similarly expand or improve the function of aged TVM cells. To evaluate this, we infected young mice with the helminth, Heligmosomoides polygyrus, and aged them to over 18 months. There was no difference in number or function of TVM cells in previously infected as compared to naïve aged mice. We then infected aged mice with helminths and observed no increase in TVM cell numbers, but there was a reduction in IFN-γ production by aged TVM cells. When naïve TVM cells were transferred to a young helminth infected host, proliferation of aged TVM cells was markedly reduced as compared to young TVM cells. Collectively these data suggest that, the protective effect of helminth infection in young mice, mediated by TVM cell expansion, is firstly not maintained into advanced age. Secondly, this effect cannot be generated in aged mice due to aged TVM cells being intrinsically less responsive to the helminth-induced cytokine environment.
Adaptive γδ T cell function is directly subverted by the Yersinia pseudotuberculosis outer protein YopJ
Authors: Chu Timothy H , Khairallah Camille , Shieh Jason , Cho Rhea , Qiu Zhijuan , Zhang Yue , Jayatilaka Indralatha , Thanassi David , Beyaz Semir , Yang Vincent , Bliska James , Sheridan Brian S 
Published: February 2023

Abstract
Vγ4 T cells are an unconventional subset of T cells that protect the intestinal mucosa from pathogen invasion and capable of anamnestic responses. Yersinia pseudotuberculosis (Yptb) is a foodborne pathogen that invades through the intestinal mucosa and subverts immune function by translocation of Yersiniaouter protein (Yop) effectors into target cells. In this study, we evaluated the response of adaptive Vγ4 T cells to Yptb to determine if adaptive γδ T cells are a target of immune subversion. Tracking Yptb translocation of Yop effectors through a FRET-based reporter assay revealed targeted and preferential delivery of Yop effectors directly into adaptive γδ T cells inhibited anti-microbial IFNγ production. Using a series of recombinant Yptb deficient or defective in numerous pathogenicity genes revealed that direct subversion of the adaptive γδ T cell IFNγ response was mediated by the adhesion molecule YadA, the injectosome component YopB, and the YopJ effector. Thus, Yptb attachment and translocation of YopJ directly into adaptive γδ T cells is a major mechanism of γδ T cell subversion. RNA-Seq of adaptive γδ T cells revealed that a broad anti-pathogen gene signature was inhibited by translocation of YopJ and suggested a role of the STAT4 pathway in this process. Indeed, IL-12p40 promoted the adaptive γδ T cell IFNγ response and YopJ limited STAT4 phosphorylation levels. Importantly, circulating human Vδ2+T cells were similarly targeted and inhibited by the YopJ effector, highlighting a novel and conserved Yptb pathway that subverts adaptive γδ T cell function.
M. tuberculosis resides in permissive, lysosome-poor recruited macrophages during chronic infection
Authors: Zheng Weihao , Chang I-Chang , Limberis Jason , Ning Fei , Ernst Joel 
Published: February 2023

Abstract
M. tuberculosis (Mtb) infects lung phagocytes including alveolar macrophages (AM) and recruited/monocyte-derived macrophages (RM). However, little is known about the distinct roles of different cell subsets in Mtb persistence, and how they differ in controlling Mtb during chronic infection. Using fluorescent reporter strains and quantitation of live bacteria by cfu plating of sorted cell subsets, we found that AM are superior to RM in restricting and killing Mtb during chronic infection (4 wk PI). Subsequent bulk RNA-Seq of live-sorted cells from infected mice reveal that genes of the lysosome pathway are under-expressed in RM compared with AM. Using functional assays, we show here that RM have poorer lysosome function than AM. Specifically, AM not only have more lysosome content, more abundant lysosomal enzyme content and activities, but also have higher expression of proteins for lysosome acidification and more acidic lysosomes. Moreover, immunofluorescence data reveal that AM have more nuclear TFEB than RM. Nuclear translocation activates TFEB, which serves as a master regulator of lysosome biogenesis. We also found that TFEB overexpressing bone marrow-derived macrophages have enhanced abilities to kill virulent Mtb. Together, these results imply that TFEB may drive the difference of lysosome functions between AM and RM, leading to the difference in killing Mtb, and that Mtb takes advantage of intrinsically lysosome-poor RM for persistence.
Microtubules and dynein regulate human neutrophil nuclear volume and hypersegmentation during H. pylori infection
Authors: Toro Stephanie L Silva-Del , Allen Lee-Ann H 
Published: February 2023

Abstract
Neutrophils (polymorphonuclear leukocytes, PMNs) are heterogeneous and can exhibit considerable phenotypic and functional plasticity. In keeping with this, we discovered previously that Helicobacter pylori infection induces N1-like subtype differentiation of human PMNs that is notable for profound nuclear hypersegmentation. Herein, we utilized biochemical approaches and confocal and super-resolution microscopy to gain insight into the underlying molecular mechanisms. Sensitivity to inhibition by nocodazole and taxol indicated that microtubule dynamics were required to induce and sustain hypersegmentation, and super-resolution STED imaging demonstrated that microtubules were significantly more abundant and longer in hypersegmented cells. Dynein activity was also required and enrichment of this motor protein at the nuclear periphery was enhanced following H. pylori infection. In contrast, centrosome splitting did not occur, and lamin B receptor abundance and ER morphology were unchanged. Finally, analysis of STED image stacks using Imaris software revealed that nuclear volume increased markedly prior to the onset of hypersegmentation and that nuclear size was differentially modulated by nocodazole and taxol in the presence and absence of infection. Taken together, our data define a new mechanism of hypersegmentation that is mediated by microtubules and dynein and as such advance understanding of processes that regulate nuclear morphology.
A systemic inflammatory response primes blood monocytes in cutaneous leishmaniasis
Authors: Amorim Camila Farias , Goshu Brukawit A , Lombana Cláudia , Novais Fernanda O , Nguyen Ba T. , Carvalho Lucas P. , Carvalho Edgar M. , Beiting Daniel P. , Scott Phillip 
Published: February 2023

Abstract
Cutaneous leishmaniasis is a localized infection controlled by CD4+ T cells that produce IFN-y within lesions. Phagocytic cells recruited to lesions are exposed to IFN-y which triggers their ability to kill the intracellular parasites. To determine what systemic responses are occurring that might influence the disease, we performed RNA sequencing (RNA-seq) on the blood of 50 L. braziliensis-infected patients, as well as 14 healthy controls. Genes reflecting Interferon downstream activation such as GBP1-6, STAT1, IDO1, AIM2, BATF2, SOCS1 and FCGR-related genes, were upregulated in patients and functional enrichment analysis identified a transcriptional type II Interferon-stimulated gene (ISG) signature as the dominant response. An increase in monocytes and macrophages in the blood, estimated from our RNA-seq dataset, was positively correlated with this type II ISG signature. Consistent with this result, patients had circulating IFN-y in their serum. Monocytes in the bone marrow and circulating in the blood of mice infected with leishmania exhibited increased expression of Class II, further supporting the premise that there is a systemic response to infection. Together, these results suggest that there is a mechanism to limit systemic spread of the parasites, as well as enhance parasite control by pre-activating cells prior to lesion entry.
Early Th2 response to Plasmodium yoelii infection is associated with intestinal mastocytosis, bacteremia and elevated intestinal permeability.
Authors: Donnelly Erinn L. , Céspedes Nora , Garrison Sarah , Haapanen Lori , Van de Water Judy , Luckhart Shirley 
Published: February 2023

Abstract
The presence of bacteria in the blood or bacteremia is complication of malaria that occurs across a broad range of ages and clinical manifestations and is associated with increased morbidity and mortality, but the factors that predispose patients to developing this “leaky gut” phenotype are poorly understood. Enteric bacteria are thought to translocate from the intestinal lumen into circulation via damaged tight and adherens junctions. Mast cell (MC) activation in both humans and mice is known to disrupt epithelial junction integrity and increase intestinal permeability. Increases in intestinal MCs have been noted in both mouse and primate models of malaria. Activated MCs are potent sources of Th2 cytokines, histamine, and other factors that can influence both the innate and adaptive immune response. To better understand the temporal patterns of both the circulating and intestinal immune response to non-lethal infection, we infected C57BL/6J mice with Plasmodium yoelii yoelii 17XNL and analyzed circulating white blood cell counts, bacteria levels, cytokines, intestinal permeability to dextran and ileal MC numbers 1, 2, 4, 6, 8 and 10 days post infection. We observed an early elevation (day 4) in Th2 cytokines interleukin (IL)-4, IL-6 and IL-10. Interestingly, we also observed an early elevation in basophils and eosinophils, granulocytes associated with allergic inflammation. These findings coincided with the first appearance of MCs in the ileum and preceded the development of bacteremia (day 6) and elevations in intestinal permeability to dextran (day 8), suggesting the early Th2 response to infection is a potential driver of mastocytosis and increased permeability.
Expression of CCR2 and VEGFR1 is required for monocyte migration into Mycobacterium tuberculosis-induced lung granulomas.
Authors: Herbath Melinda , Harding Jeffrey S , Fabry Zsuzsanna , Sandor Matyas 
Published: February 2023

Abstract
Granulomas provide protection against Mycobacterium tuberculosis (Mtb) infection and dissemination but also contribute to long term pathogen survival in the host. Macrophages are the dominant cell type in mycobacterial granulomas, playing a central role in bacterial control. Most macrophages recruited to the lung during infection are derived from monocytes in the blood. Our lab has previously shown that continuous cell replacement is important in mycobacterial lesions and CCL2 and granuloma macrophage-produced VEGF-A are required for granuloma maintenance as blocking the action of these chemokines results in the reduction of granuloma size and number in BCG and Mtb infection.
Here we show that expression of CCR2 and VEGFR1 by monocytes is required for the migration of these cells into Mtb-induced lung granulomas. Blockade of CCR2 and VEGFR1 with Propagermanium or SU5416, respectively, reduced monocyte migration toward granuloma cells in vitro or in vivo. A 1:1:1 mixture of color-coded WT, Flt1 fl/fl x LyzMCre and CCR2−/− BM-derived monocytes was adoptively transferred into C57BL/6J recipient mice. The ratio of transferred cells in the lungs, spleen, blood, and BM was measured 1 day and 10 days after transfer. By day 10, most of the transferred cells were present in the lung parenchyma. Loss of VEGFR1 on the transferred monocytes decreased monocyte migration to the lung parenchyma dramatically while homing of CCR2−/− cells was inhibited to every tested site.
In the granulomatous lung the main source of VEGF-A is the macrophage. We are developing macrophage-targeted blockade of VEGF-A to reduce granulomatous pathology with the reduction of off-target effects.
CXCR3 gene deletion in murine cryptococcal meningoencephalitis leads to a shift in CD4-T Cell transcriptional profile away from hyperactive/cytotoxic phenotype.
Authors: Martens Jacob William Shelton , Xu Jintao , Goughenour Kristie D , Subbiah Harini , Kwak Doyun L. , Parkin Brian L. , Olszewski Michal A 
Published: February 2023

Abstract
Cryptococcal meningoencephalitis (CM) is the major cause of infectious neurological death worldwide, mainly affecting immunocompromised patients. CNS damage is often linked to aberrant inflammatory responses following infection. Deletion of CXCR3 in murine CM leads to improved mouse survival and diminished neuroinflammation and damage while maintaining fungal clearance. To establish how CXCR3-deletion suppressed pathological CD4 T cell responses without limiting protective responses, we analyzed transcriptional profiles of brain leukocytes isolated from WT and CXCR3KO with CM using single-cell RNA seq. Distinct clusters of CNS CD4 T-cells were found in CM mice: naïve, effector memory, activated, and exhausted T cells, as well as Th1 and Th2 clusters. The activated T cell clusters (CD69, ICOS, and 4-1BB high) exhibited a Th1-skewed phenotype (T-bet and IFN-γ high). CXCR3KO mice exhibited a marked shift away from these effector T cell clusters, with observed decreases in both memory and activated CD4 T cell phenotypes. In contrast, the naive T cell clusters were maintained in the CXCR3KO mice. The activated CD4 T cell clusters showed significant increase in expression of cytotoxic NKG7 in the WT mice compared to CXCR3KO mice. Interestingly, an IL-17A-expressing γδ-T cell cluster largely absent in the WT was increased in CXCR3KO mice.
In conclusion, CXCR3 deletion resulted in a pronounced shift away from highly activated Th1 profile toward a more moderate activated phenotype with a decrease in cytotoxicity, supporting the role of the CXCR3 axis in inducing pathological T cell phenotypes in the brain. The emergence of IL-17A-producing γδ-T cells is unexpected and deserves future studies in the context of protection versus pathology.
Identification of unique memory T cell populations associated with protection against Chlamydia trachomatis reinfection in the peripheral blood of highly exposed women
Authors: Poston Taylor , Kollipara Avinash , O’Connell Catherine , Zheng Xiaojing , Darville Toni 
Published: February 2023

Abstract
Chlamydia trachomatis (Ct) is an obligate intracellular bacterium that annually infects 100 million people globally and leaves 1 million women infertile, making vaccine development a priority. While repeated infections are common, they can elicit partial protective immunity. To better determine protective T cell responses elicited by natural infection to guide rational vaccine design, we performed single-cell RNA sequencing (scRNA-seq) on sorted CD3+ T cells from PBMC samples of two uninfected and four infected women, two who remained uninfected (F/U−; n=2) and two who became reinfected (F/U+; n=2) when tested at intervals over a year. We detected enrichment of two CD4 and two CD8 subpopulations in the F/U− subgroup, compared to F/U+ or uninfected controls. The CD4 T cell populations were characterized by differential expression of genes involved in cell activation, tissue homing, memory, and Th1/17 differentiation (LMNA, S100A11/10/4, ANXA1/2, LGALS1/3, TIMP1, CD29, CD161, IL7R), and the CD8 T cell populations differentially expressed markers of cell growth, activation, cytokine signaling, and cytotoxicity (CCL4/5, GRZMA/K, NKG7, CST7, HLA-DRA/B1, CD74). Both CD8 subsets expressed fewer markers of terminal differentiation, suggestive of memory and/or transitional effector phenotypes. These pilot data demonstrate that, even though Ct is mucosally restricted, differential T cell responses are detectable in peripheral blood by scRNA-seq and can improve understanding of T cell heterogeneity, activation, differentiation, and functional responses that promote protection.
Primary biodiversity data on zooplankton, macroinvertebrates, and fish from freshwater ecosystems of Uganda
Authors: Musinguzi Laban , Olokotum Mark , Nakiyende Herbert , Egessa Robert , Kiggundu Vicent , Pabire Ghandi Willy , Bassa Samuel , Nsega Monic , Kamya AshIraf , Rwezawula Philip , Lugya Jessy , Magezi Godfrey , Naluwayiro Janet , Natugonza Vianny 
Published: February 2023

Effective conservation requires reliable data and information on the status of biodiversity. The conservation of freshwater biodiversity lags behind terrestrial and marine biodiversity because data and information limitations are greatest in freshwater ecosystems. Given that freshwater ecosystems are inhabited by disproportionately more species than other ecosystems, paucity of data and information threatens many species and dependent ecosystem services. Data and information on freshwater biodiversity is limited mainly because few freshwater ecosystems are considered for regular monitoring. However, even existing data is scattered and in non-user-friendly formats, limiting accessibility and use. It is desirable to make freshwater biodiversity data and information accessible everywhere so that it attains its full potential in guiding conservation. To increase accessibility to freshwater biodiversity data in Uganda, we present 34 datasets covering three major freshwater taxa: zooplankton, macroinvertebrates, and fish within freshwater ecosystems in the country. The datasets provide occurrence records and corresponding abundance data where applicable for the three major groups. The datasets which are available through the Global Biodiversity Information Facility (GBIF) cover a long period from 1971-2021 and have a total of 56,104 occurrence records. Of these records, 8,674 records were published in 2022. The data were mobilized from primary biodiversity surveys conducted by scientists at the National Fisheries Resources Research Institute (NaFIRRI) in Uganda. The surveys covered most of the water bodies in the country. The datasets are envisaged to increase accessibility to data for freshwater conservation research, decision making and capacity building. The data has already found use in development of conservation tools and conservation status assessments.
Medicus invidiae
Authors: Preložnik Andrej 
Published: February 2023

Fascinum, magični falus, ni le najpogostejše sredstvo za odvračanje zlonosnega pogleda in zavisti, ampak se tudi pojavlja v najrazličnejših oblikah. Tako je tudi na Ptuju, kjer ga srečujemo v raznih izvedbah in kombinacijah - od amuletov in nakita, do upodobitev na uporabnih predmetih in kipih. Falusi so na naštetih predmetih varovali zelo različne osebe, stvari in prostore: otroke, konje in prevozna sredstva, pečat ali zapečateno vsebino, uporabne predmete, bivališča in njihove prebivalce, delavnice in njihove izdelke, prostor in skupnost. Kot osebo varovalo se pojavljajo v obliki različnih amuletov, ki so lahko bili samostojni obeski, lik znotraj enega predmeta ali za predmet znotraj niza večih (crepundia). Med materiali, iz katerih so izdelani, so na Ptuju zaenkrat zastopani takšni, ki jim je bila zanesljivo (zlato, jantar) oziroma verjetno (fajansa) pripisana posebna moč. Po grobnih kontekstih sodeč so jih v Petovijoni nosili predvsem otroci. Iz brona so preostali ptujski amuleti različnih oblik, ki jih lahko verjetno povezujemo z zaščito konja, voza ali prostora. S falusom sta okrašena tudi dva bronasta predmeta, namenjena praktični uporabi. V tem primeru predstavlja falus dodatno varovalo. Na kamnitih spomenikih s falusom gre za sinkretizem Terminusa in Priapa. Herma ter oba reliefa so slogovno sicer različni, falus na njih pa predstavlja tako življenjsko energijo in rodovitnost kot obrambno silo, ki varuje mejo/območje in preganja škodljivce vseh vrst, vključno z zavistneži. Keramični kipec sodi med podobe, ki so z grotesknostjo in faličnostjo ščitile posebej ranljive stanove in obrti. Podobnemu kipcu je lahko pripadal tudi odlomljen keramični falus. Oba predmeta sta bila odkrita na območju lončarske delavnice. Za posodico s falusom zaenkrat ne moremo reči ničesar določenega, razen da je verjetno tudi pri tej falus vsaj deloma apotropejske narave.
Poreklo teh predmetov je podobno raznoliko kot predmeti sami. Gotovo so nekatere izdelali domači obrtniki, opazno eksotični izdelki pa so prihajali iz Italije in Akvileje (jantarni amuleti, krilati obesek), iz vzhodnega Sredozemlja (fajansni), iz zahodnih provinc (pečatna škatlica). Datiramo jih lahko med prvo in tretje stoletje. Dokaj jasno zamejeni so amuleti v nizih, ki so značilni za prvo ali začetek drugega stoletja, podobno velja za obeske s konjske oprave in krilati tintinabulum.