bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mesenchymal stem cell suppresses the efficacy of CAR-T toward killing lymphoma cells by modulating the microenvironment through stanniocalcin-1
Authors: Zhang Rui , Liu Qingxi , Zhou Sa , He Hongpeng , Zhao Mingfeng , Ma Wenjian 
Published: September 2022

AbstractStem cells play critical roles both in the development of cancer and therapy resistance. Although mesenchymal stem cells (MSCs) can actively migrate to tumor sites, their impact on CAR-T immunotherapy has been little addressed. Using an in vitro cell co-culture model including lymphoma cells and macrophages, here we report that the CAR-T cell mediated cytotoxicity was significantly inhibited in the presence of MSCs. MSC caused an increase of CD4+ T cells and Treg cells but decrease of CD8+ T cells. In addition, MSCs stimulated the expression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death-ligand 1 (PD-L1) that contribute to the immune-suppressive function of tumor. Moreover, MSCs suppressed key components of NLRP3 inflammasome by modulating mitochondrial ROS release. Interestingly, all these suppressive events hindering CAR-T efficacy could be abrogated if the STC1 gene, which encodes the glycoprotein hormone staniocalcin-1, was knockdown in MSC. Using xenograft mice, we confirmed that CAR-T function could also be inhibited by MSC in vivo and STC1 played a critical role. These data revealed a novel function of MSC and staniocalcin-1 in suppressing CAR-T efficacy, which should be considered in cancer therapy and may also have potential applications in controlling the toxicity arising from excessive immune response.
Alternative proteoforms and proteoform-dependent assemblies in humans and plants
Authors: McWhite Claire D. , Sae-Lee Wisath , Yuan Yaning , Mallam Anna L. , Gort-Freitas Nicolas A. , Ramundo Silvia , Onishi Masayuki , Marcotte Edward M. 
Published: September 2022

ABSTRACTVariability of proteins at the sequence level creates an enormous potential for proteome complexity. Exploring the depths and limits of this complexity is an ongoing goal in biology. Here, we systematically survey human and plant high-throughput bottom-up native proteomics data for protein truncation variants, where substantial regions of the full-length protein are missing from an observed protein product. In humans, Arabidopsis, and the green alga Chlamydomonas, approximately one percent of observed proteins show a short form, which we can assign by comparison to RNA isoforms as either likely deriving from transcript-directed processes or limited proteolysis. While some detected protein fragments align with known splice forms and protein cleavage events, multiple examples are previously undescribed, such as our observation of fibrocystin proteolysis and nuclear translocation in a green alga. We find that truncations occur almost entirely between structured protein domains, even when short forms are derived from transcript variants. Intriguingly, multiple endogenous protein truncations of phase-separating translational proteins resemble cleaved proteoforms produced by enteroviruses during infection. Some truncated proteins are also observed in both humans and plants, suggesting that they date to the last eukaryotic common ancestor. Finally, we describe novel proteoform-specific protein complexes, where loss of a domain may accompany complex formation.
Assembly mechanism of the AIM2 inflammasome sensor revealed by single-molecule analysis
Authors: Sharma Meenakshi , de Alba Eva 
Published: September 2022

ABSTRACTPathogenic dsDNA prompts AIM2 (Absent In Melanoma 2) assembly leading to the formation of the inflammasome, a multimeric complex that triggers the inflammatory response. The recognition of foreign dsDNA involves AIM2 self-assembly concomitant with dsDNA binding. However, we lack mechanistic and kinetic information on the formation and propagation of the assembly, which can shed light on innate immunity’s time response and specificity. Using correlative optical traps and fluorescence microscopy, we determine here the association and dissociation rates of the AIM2-DNA complex at the single-molecule level. We identify distinct mechanisms for oligomer growth via the binding of incoming AIM2 molecules to adjacent dsDNA or direct interaction with bound AIM2 assemblies, thus resembling primary and secondary nucleation processes. Through these mechanisms, AIM2 oligomers increase at least fourfold their size in seconds. Finally, our data indicate that single AIM2 molecules do not diffuse/scan along the DNA, suggesting that oligomerization depends on stochastic encounters with DNA and/or DNA-bound AIM2 molecules.
Transcription factor TFII-I fine tunes innate properties of B lymphocytes
Authors: Singh Amit , Kaileh Mary , De Supriyo , Mazan-Mamczarz Krystyna , Bayarsaihan Dashzeveg , Sen Ranjan , Roy Ananda L 
Published: September 2022

AbstractThe ubiquitously expressed transcription factor TFII-I is a multifunctional protein with pleiotropic roles in gene regulation. TFII-I associated polymorphisms are implicated in Sjögren’s syndrome and Lupus in humans and, germline deletion of the Gtf2i gene in mice leads to embryonic lethality. Here we report a unique role for TFII-I in homeostasis of innate properties of B lymphocytes. Loss of Gtf2i in murine B lineage cells leads to a change in transcriptome and chromatin landscape, which resembles myeloid-like features and coincides with enhanced sensitivity to LPS induced transcription. TFII-I deficient B cells also show increased switching to IgG3, a phenotype associated with inflammation. These results demonstrate a role for TFII-I in maintaining immune homeostasis and provide clues for GTF2I polymorphisms associated with B cell dominated autoimmune diseases in humans.
Multi-modal brain magnetic resonance imaging database covering marmosets with a wide age range
Authors: Hata Junichi , Nakae Ken , Tsukada Hiromichi , Woodward Alexander , Haga Yawara , Iida Mayu , Uematsu Akiko , Seki Fumiko , Ichinohe Noritaka , Gong Rui , Kaneko Takaaki , Yoshimaru Daisuke , Watakabe Akiya , Abe Hiroshi , Tani Toshiki , Skibbe Henrik , Maeda Masahide , Papazian Frederic , Hagiya Kei , Kishi Noriyuki , Shimogori Tomomi , Yamamori Tetsuo , Okano Hirotaka James , Okano Hideyuki 
Published: September 2022

AbstractMagnetic resonance imaging (MRI) is a noninvasive neuroimaging method beneficial for the identification of normal developmental and aging processes and data sharing. Marmosets have a relatively shorter life expectancy (approximately 10 years) than other primates, including, humans because they grow and age faster. Hence, the common marmoset model is effective in aging research. The current study investigated the aging process of the marmoset brain and provided an open MRI database on marmosets with a wide age range. The Brain/MINDS Marmoset Brain MRI Dataset contains brain MRI information on 216 marmosets aged between 1 and 10 years. During its release date, it is the largest public dataset worldwide. Further, it comprises multi contrast MRI images. In addition, 91 of 216 animals have corresponding ex vivo high-resolution MRI datasets. Our MRI database, which is available at the Brain/MINDS Data portal might help understand the effects of different factors, such as age, sex, body size, and fixation, on the brain. Moreover, it can contribute to and accelerate brain science studies worldwide.
Profiling Dynamic Patterns of Single-cell Motility
Authors: Maity Debonil , Sivakumar Nikita , Kamat Pratik , Zamponi Nahuel , Min Chanhong , Du Wenxuan , Jayatilaka Hasini , Johnston Adrian , Starich Bartholomew , Agrawal Anshika , Riley Deanna , Venturutti Leandro , Melnick Ari , Cerchietti Leandro , Walston Jeremy , Phillip Jude M. 
Published: September 2022

ABSTRACTCell motility plays an essential role in many biological processes as cells move and interact within their local microenvironments. Current methods for quantifying cell motility typically involve tracking individual cells over time, but the results are often presented as averaged values across cell populations. While informative, these ensemble approaches have limitations in assessing cellular heterogeneity and identifying generalizable patterns of single-cell behaviors, at baseline and in response to perturbations. In this study, we introduce CaMI, a computational framework designed to leverage the single-cell nature of motility data. CaMI identifies and classifies distinct spatio-temporal behaviors of individual cells, enabling robust classification of single-cell motility patterns in a large dataset (n=74,253 cells). This framework allows quantification of spatial and temporal heterogeneities, determination of single-cell motility behaviors across various biological conditions, and provides a visualization scheme for direct interpretation of dynamic cell behaviors. Importantly, CaMI reveals insights that conventional cell motility analyses may overlook, showcasing its utility in uncovering robust biological insights. Together, we present a multivariate framework to classify emergent patterns of single-cell motility, emphasizing the critical role of cellular heterogeneity in shaping cell behaviors across populations.TeaserA computational framework to identify and classify single-cell motility patterns and phenotypic heterogeneity across biological conditions.
Classification of patients with osteoarthritis through clusters of comorbidities using 633,330 individuals from Spain
Authors: Pineda-Moncusí Marta , Dernie Francesco , Dell’Isola Andrea , Kamps Anne , Runhaar Jos , Swain Subhashisa , Zhang Weiya , Englund Martin , Pitsillidou Irene , Strauss Victoria Y , Robinson Danielle E , Prieto-Alhambra Daniel , Khalid Sara 
Published: September 2022

AbstractObjectivesTo explore clustering of comorbidities among patients with a new diagnosis of osteoarthritis (OA) and estimate the 10-year mortality risk for each identified cluster.MethodsThis is a population-based cohort study of individuals with first incident diagnosis of OA of the hip, knee, ankle/foot, wrist/hand, or ‘unspecified’ site between 2006 and 2020, using SIDIAP (a primary care database representative from Catalonia, Spain). At the time of OA diagnosis, conditions associated with OA in the literature that were found in ≥1% of the individuals (n=35) were fitted into two cluster algorithms, K-means and latent class analysis (LCA). Models were assessed using a range of internal and external evaluation procedures. Mortality risk of the obtained clusters was assessed by survival analysis using Cox proportional hazards.ResultsWe identified 633,330 patients with a diagnosis of OA. Our proposed best solution used LCA to identify four clusters: ‘Low-morbidity (relatively low number of comorbidities), ‘Back/neck pain plus mental health’, ‘Metabolic syndrome’ and ‘Multimorbidity’ (higher prevalence of all study comorbidities). Compared to the ‘Low-morbidity, the ‘Multimorbidity’ cluster had the highest risk of 10-year mortality (adjusted HR: 2.19 [95%CI: 2.15-2.23]), followed by ‘Metabolic syndrome’ (adjusted HR: 1.24 [95%CI: 1.22-1.27]]) and ‘Back/neck pain plus mental health’ (adjusted HR: 1.12 [95%CI: 1.09-1.15]).ConclusionPatients with a new diagnosis of OA can be clustered into groups based on their comorbidity profile, with significant differences in 10-year mortality risk. Further research is required to understand the interplay between OA and particular comorbidity groups, and the clinical significance of such results.Key MessagesPatients with newly diagnosed osteoarthritis can by classified into different clusters by their comorbidity patterns.Such classification can help identify ‘high-risk’ patients who require more intense attention from healthcare providers.The main patient sub-groups were ‘Low-morbidity’, ‘Back/neck pain plus mental health’, ‘Metabolic syndrome’ and ‘Multimorbidity’.
Deep phylotaxonogenomic revision of the genus Xanthomonas within family Xanthomonadaceae and proposal of novel family Frateuriaceae within order Xanthomonadales
Authors: Bansal Kanika , Kumar Sanjeet , Singh Anu , Chaudhary Arushi , Patil Prabhu B. 
Published: September 2022

AbstractGenus Xanthomonas is primarily comprise phytopathogenic species. In a recent study by carrying out deep phyto-taxonogenomics, we reported that even the genera Xylella, Stenotrophomonas and Pseudoxanthomonas are miss-classified and belong to genus Xanthomonas. Hence to understand the breadth of the genus, we carried out deep phylo-taxonogenomics of the order Xanthomonadales. Such investigation revealed that at least four more genera belong to genus Xanthomonas with prominent being Lysobacter. Further order level deep phylo-taxonogenomics revealed two major families. One being the original family Xanthomonadaceae and other is proposed as Frateuriaceae fam. nov. as synonym of family Rhodanobacteraceae with novel genus Frateuria gen. nov.
The cell envelope of Thermotogae suggests a mechanism for outer membrane biogenesis
Authors: Sexton Danielle L. , Hashimi Ameena , Sibanda Lloyd , Beskrovnaya Polina , Huan Tao , Tocheva Elitza I. 
Published: September 2022

AbstractThe presence of a cell membrane is one of the major structural components defining life. Recent phylogenomic analyses have supported the hypothesis that the last bacterial common ancestor was likely a diderm. Yet, the mechanisms that guided outer membrane (OM) biogenesis remain unknown. Thermotogae is an early-branching phylum with a unique OM, the toga, previously shown to form 2-dimensional arrays of β-barrel trimers. Here we use cryo-electron tomography to characterize the in situ cell envelope architecture of Thermotoga maritima, proteomics and lipidomics to identify the protein and lipid composition of the toga, and bioinformatics to assess the distribution of the major toga components across the phylum. We show that the toga is composed of multiple Ompα and β-barrel homologs that represent a highly diverse bipartite OM-tethering system. We further reveal the presence of membrane microdomains (∼200nm) in the toga that are enriched in phosphatidylethanolamine (PE) lipids required to support the type 4 pilus and the BamA transmembrane complexes. Together, our results highlight a toga-like structure as a possible intermediate between monoderm and diderm cell envelope transitions.
PbAP2-FG2 and AP2R-2 function together as a transcriptional repressor complex essential for Plasmodium female development
Authors: Nishi Tsubasa , Kaneko Izumi , Iwanaga Shiroh , Yuda Masao 
Published: September 2022

AbstractGametocyte development is a critical step in the life cycle of Plasmodium. Despite that numbers of studies in the gametocyte development have been conducted, the molecular mechanisms regulating this process remains to be fully understood. This study investigates the functional roles of two female-specific transcriptional regulators, PbAP2-FG2 and AP2R-2, in P. berghei. Knockout of pbp2-fg2 or ap2r-2 impairs female gametocyte development, resulting in developmental arrest during ookinete development. ChIP-seq analyses of these two factors indicated their colocalization on the genome, suggesting they function as a complex. These analyses also revealed that their target genes contained a variety of genes, including both male and female-enriched genes. Moreover, differential expression analyses showed that these target genes were upregulated through the disruption of pbp2-fg2 or ap2r-2, indicating that these two factors function as a transcriptional repressor complex in female gametocytes. Further target analysis demonstrated a significant overlap between the target genes of PbAP2-FG2 and AP2-G, suggesting that repression of early gametocyte genes activated by AP2-G is one of the key roles for this female transcriptional repressor complex. Our results indicate that the PbAP2-FG2-AP2-R2 complex-mediated repression of the target genes supports the female differentiation from early gametocytes.Author SummaryGametocyte development in Plasmodium parasites, a causative agent of malaria, is an essential step for their transmission from vertebrate hosts to mosquitoes. Gametocytes are sexual precursor cells produced from a subpopulation of asexual blood-stage parasites. Upon uptake by mosquitoes through blood feeding, the male and female gametocytes become microgametes and macrogametes, respectively, and then they fertilize and develop into the mosquito midgut invasive stage, called ookinete. Therefore, it is crucial to understand the underlying mechanisms regulating this developmental process. This study revealed that the two female transcriptional regulators, PbAP2-FG2 and AP2R-2, function together as an essential transcriptional repressor complex in P. berghei, the target genes of which include male, female, and early gametocyte genes activated by AP2-G. Our findings suggest that PbAP2-FG2 and AP2R-2 play multiple roles in supporting the development of female gametocytes from early gametocytes.
USP7 inactivation suppresses APC-mutant intestinal hyperproliferation and tumor development
Authors: Novellasdemunt Laura , Kucharska Anna , Baulies Anna , Vlachogiannis Georgios , Repana Dimitra , Rowan Andrew , Suárez-Bonnet A , Ciccarelli Francesca , Valeri Nicola , Li Vivian S. W. 
Published: September 2022

AbstractTruncating mutation of the tumor suppressor gene adenomatous polyposis coli (APC) is the hallmark of colorectal cancer (CRC), resulting in constitutive WNT activation. Despite decades of research, targeting WNT signaling in cancer remains challenging due to its essential role in normal stem cell maintenance. We have previously shown that the deubiquitinating enzyme USP7 is a tumor-specific WNT activator in APC-truncated cells by deubiquitinating and stabilizing β-catenin, but its role in gut tumorigenesis is unknown. Here we show in vivo that deletion of Usp7 in Apc-truncated mice inhibits crypt hyperproliferation and intestinal tumor development. Importantly, intestine-specific Usp7 mutation does not yield any phenotype in wildtype animals, indicating that its loss is well tolerated. Unexpectedly, prolonged deletion of Usp7 in Apc+/− intestine induces varying degrees of colitis. Treatment with a USP7 inhibitor suppresses growth of patient-derived cancer organoids in vitro and of xenografts carrying APC truncations. We propose that USP7 inhibition may be efficacious for tumor-specific therapy of sporadic APC-mutated CRC, while patients with germline APC mutations should not receive such treatment.HighlightsUsp7 deletion in Apc-truncated mice reduces intestinal tumor development.Intestine-specific Usp7 mutation mutation has no phenotype in wildtype animals.Treatment with Usp7 inhibitor suppresses growth of patient-derived cancer organoids carrying Apc truncations in vitro and of xenografts.
UBA52 attunes VDAC1-mediated mitochondrial dysfunction and dopaminergic neuronal death
Authors: Tiwari Shubhangini , Singh Abhishek , Gupta Parul , K Amrutha , Singh Sarika 
Published: September 2022

AbstractMitochondrial homeostasis regulates energy metabolism, calcium buffering, cell function and apoptosis. The present study has been conducted to investigate the implications of ubiquitin-encoding gene UBA52 in mitochondrial physiology. Transient expression of Myc-UBA52 in neurons significantly inhibited the rotenone-induced increase in reactive oxygen species generation, nitrite level and depleted glutathione level. Mass spectrometric and co-immunoprecipitation data suggested the profound interaction of UBA52 with mitochondrial outer membrane channel protein, VDAC1 in both the wild-type and Myc-α-synuclein overexpressed neuronal cells and in the Parkinson’s disease (PD)-specific substantia nigra and striatal region of the rat brain. In vitro ubiquitylation assay revealed that UBA52 participates in the ubiquitylation of VDAC1 through E3 ligase CHIP. Myc-UBA52 overexpression in neurons further improved the mitochondrial functionality and cell viability by preventing the alteration in mitochondrial membrane potential, mitochondrial complex-I activity, translocation of cytochrome-c and p-Nrf2 along with effect on intracellular calcium uptake, thus collectively inhibiting the opening of mitochondrial permeability transition pore. Additionally, Myc-UBA52 expression in neuronal cells offered protection against apoptotic and autophagic cell death. Altogether, our findings delineate functional association between UBA52 and mitochondrial homeostasis, providing new insights into the deterrence of dopaminergic cell death during acute PD pathogenesis.
Strand-biased circularizing integrative elements spread tmexCD-toprJ gene clusters encoding RND-type multidrug efflux pumps by repeated transpositions
Authors: Dao Trung Duc , Yano Hirokazu , Takemura Taichiro , Hirabayashi Aki , Trang Le Thi , Tran Hoang Huy , Shibayama Keigo , Hasebe Futoshi , Kasuga Ikuro , Suzuki Masato 
Published: September 2022

AbstractAntimicrobial resistance genes (ARGs) are associated with mobile genetic elements (MGEs) that conscript useful genes into the human–microbe and microbe–microbe battlefields. Thus, under intense selective pressure, ARGs have been constantly adapting and evolving, spreading among microbes. tmexCD-toprJ gene clusters, which encode resistance–nodulation–cell division (RND)-type efflux pumps, confer multidrug-resistance to clinically important antimicrobials, including tigecycline. Noteworthily, these gene clusters have emerged in gram-negative bacteria in humans, animals, and the environment worldwide by MGE-mediated transfer. Here we show a hidden MGE, strand-biased circularizing integrative element (SE), that is recently recognized to mediate transpositions of ARGs, associated with the spread of tmexCD-toprJ gene clusters. We identified multidrug-resistant isolates of Aeromonas species in a water environment in Vietnam that harbored multiple copies of tmexCD-toprJ in their chromosomes that were associated with SEs. In particular, Aeromonas hydrophila NUITM-VA1 was found to harbor two copies of a novel variant of tmexC3.3D3.3-topJ1 within cognate SEs, whereas Aeromonas caviae NUITM-VA2 harbored four copies of a novel variant of tmexC2D2.3-topJ2 within cognate SEs. Based on the nature of SE to incorporate a neighboring sequence into the circular form and reinsert it into target sites during transposition, we identified the order of intragenomic movements of tmexCD-toprJ gene clusters. Altogether, our findings suggest that most known subgroups of tmexCD-toprJ and their subvariants underwent transpositions among bacterial chromosomes and plasmids via SEs. Hence, a tmexCD-toprJ gene cluster ancestor may have been initially mobilized via SE, subsequently spreading among bacteria and evolving in new hosts.