bluuebunny/crossref_metadata_2025_split huggingface dataset:
MADET: A Manually Curated Knowledgebase for Microbiomic Effects on Efficacy and Toxicity of Anticancer Treatments
Authors: Zhang Jie , Chen Xiqian , Zou Jiaxin , Li Chen , Kang Wanying , Guo Yang , Liu Sheng , Zhao Wenjing , Mou Xiangyu , Huang Jiayuan , Ke Jia 
Published: May 2022

AbstractA plethora of studies have reported the associations between microbiota and multiple diseases, leading to at least four databases to demonstrate microbiota-disease associations, i.e., gutMDisorder, mBodyMap, GMrepo and Amadis. Moreover, gut microbiota also mediates drug efficacy and toxicity, whereas a comprehensive database to elucidate the microbiota-drug associations is lacking. Here we report an open-access knowledgebase, MADET (Microbiomics of Anticancer Drug Efficacy and Toxicity), which harbors 453 manually annotated microbiota-drug associations from 24 papers. MADET provides user-friendly functions allowing users to freely browse, search, and download the data conveniently from the database. Users can customize their search filters in MADET using different types of keywords, including bacterial name (e.g., Akkermansia muciniphila), anticancer treatment (e.g., anti-PD-1 therapy) or cancer type (e.g., lung cancer) with different types of experimental evidence of microbiota-drug association and causation. We have also enabled user submission to further enrich the data document in MADET. The MADET database is freely available at https://www.madet.info. We anticipate that MADET will serve as a useful resource for a better understanding of the microbiota-drug associations and facilitate the future development of novel biomarkers and live biotherapeutic products for anticancer therapies.
Combined omic analyses reveal novel loss-of-function NLGN3 variants in GnRH deficiency and autism
Authors: Oleari Roberto , Lettieri Antonella , Manzini Stefano , Paganoni Alyssa , André Valentina , Grazioli Paolo , Busnelli Marco , Duminuco Paolo , Vitobello Antonio , Philippe Christophe , Bizaoui Varoona , Storr Helen L. , Amoruso Federica , Memi Fani , Vezzoli Valeria , Massa Valentina , Scheiffele Peter , Howard Sasha R. , Cariboni Anna 
Published: May 2022

AbstractGonadotropin releasing hormone (GnRH) deficiency is a disorder characterized by absent or delayed puberty, with largely unknown genetic causes. The purpose of this study was to obtain and exploit gene expression profiles of GnRH neurons during development to unveil novel biological mechanisms and genetic determinants underlying GnRH deficiency (GD). Here, we combined bioinformatic analyses of primary embryonic and immortalized GnRH neuron transcriptomes with exome sequencing from GD patients to identify candidate causative genes. Among differentially expressed and filtered transcripts, we found loss-of-function (LoF) variants of the autism-linked Neuroligin 3 (NLGN3) gene in two unrelated patients co- presenting with GD and neurodevelopmental traits. We demonstrated that NLGN3 is upregulated in maturing GnRH neurons and that NLGN3 wild type, but not mutant proteins, promotes neuritogenesis when overexpressed in developing GnRH cells. Our data represent proof-of-principle that this complementary approach can identify novel candidate GD genes and demonstrate that LoF NLGN3 variants may contribute to GD. This novel genotype- phenotype correlation implies common genetic mechanisms underlying neurodevelopmental disorders, such as GD and autistic spectrum disorder.
Single-cell profiling identifies a spectrum of human unconventional intraepithelial T lineage cells
Authors: Billiet Lore , De Cock Laurenz , Sanchez Guillem Sanchez , Mayer Rupert L. , Goetgeluk Glenn , De Munter Stijn , Pille Melissa , Ingels Joline , Jansen Hanne , Weening Karin , Pascal Eva , Raes Killian , Bonte Sarah , Kerre Tessa , Vandamme Niels , Seurinck Ruth , Roels Jana , Lavaert Marieke , Van Nieuwerburgh Filip , Leclercq Georges , Taghon Tom , Impens Francis , Menten Björn , Vermijlen David , Vandekerckhhove Bart 
Published: May 2022

AbstractIn the human thymus, a CD10+PD-1+TCRαβ+differentiation pathway diverges from the conventional single positive T cell lineages at the early double positive stage. These cells are phenotypically and functionally similar to murine unconventional intraepithelial lymphocyte (uIEL) precursors. Here, the progeny of the human uIEL lineage was identified in antigen-inexperienced blood. The uIELs in thymus and peripheral blood share a transcriptomic profile, characterized by hallmark transcription factors (i.e.ZNF683andIKZF2), and polyclonal TCR repertoire with autoreactive features, exhibiting a bias towards early TCR alpha chain rearrangements. Single-cell RNA sequencing confirmed a common developmental trajectory between the thymic and peripheral uIELs, and clearly delineated this unconventional lineage in peripheral blood. This population is phenotypically defined as CD3+TCRαβ+CD4-CCR7-CD26-. It contains CD10+recent thymic emigrants, Helios+KIR+CD8+Tregs and CD8αα+T cells. Thus, the uIEL lineage represents a well-defined but heterogeneous, unconventional TCRαβ+lineage mostly confined in human within the CD8 single positive T cells.SummaryBilliet et al. identify the postthymic progeny of the intraepithelial lymphocyte precursors in human based on shared characteristics of the T cell receptor repertoire and the transcriptome. This lineage represents a well-defined but heterogeneous, unconventional TCRαβ+lineage mostly confined within the CD8 single positive T cells.
Single-Cell RNA Sequencing Reveals the Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and its Tumor Microenvironment
Authors: Werba Gregor , Weissinger Daniel , Kawaler Emily A. , Zhao Ende , Kalfakakou Despoina , Dhara Surajit , Oh Grace , Jing Xiaohong , Beri Nina , Khanna Lauren , Gonda Tamas , Oberstein Paul , Hajdu Cristina , Loomis Cynthia , Heguy Adriana , Sherman Mara H. , Lund Amanda W. , Welling Theodore H. , Dolgalev Igor , Tsirigos Aristotelis , Simeone Diane M. 
Published: May 2022

AbstractThe tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. We performed single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we found a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibited similar transcriptional responses to chemotherapy, and did not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observed decreased ligand-receptor interactions in treated samples, particularly TIGIT on CD8+ T cells and its receptor on cancer cells, and identified TIGIT as the major inhibitory checkpoint molecule of CD8+ T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.
To β or not to β: Lack of correlation between APC mutation and β-catenin nuclear localization in colorectal cancer
Authors: Bala Pratyusha , Kavadipula Padmavathi , Sarkar Sanjana , Bashyam Murali Dharan 
Published: May 2022

AbstractColorectal cancer (CRC) appears to arise from sequential genetic lesions in tumor suppressor genes (APC, SMAD4 and TP53) and oncogenes (KRAS) leading to the classical adenoma to carcinoma progression. Biallelic APC inactivating genetic aberrations are detected in about 70% of early microadenomas implicating APC inactivation as the first genetic hit in CRC. APC is an essential protein of the Wnt ‘destruction complex’; APC inactivation is believed to cause disruption of the complex allowing stabilization and nuclear translocation of β-catenin, resulting in transcriptional activation of cancer-promoting genes. Here, we provide evidence for a surprising lack of correlation between APC mutation and β-catenin nuclear localization in early-onset sporadic rectal cancer samples. β-catenin nuclear localization and APC mutation were validated from serial FFPE sections representing same tumor regions. Several factors including status of KRAS mutation could not explain the absence of β-catenin nuclear localization in tumor samples harboring APC mutation. This lack of correlation was validated in CRC cell lines harboring various APC mutations. Our results provide evidence directly from tumor samples for possible non-canonical role(s) for mutant APC.
Peripheral membrane proteins modulate stress tolerance by safeguarding cellulose synthases
Authors: Kesten Christopher , García-Moreno Álvaro , Amorim-Silva Vítor , Menna Alexandra , Castillo Araceli G. , Percio Francisco , Armengot Laia , Ruiz-Lopez Noemi , Jaillais Yvon , Sánchez-Rodríguez Clara , Botella Miguel A 
Published: May 2022

AbstractControlled primary cell wall remodeling adapts plant growth under stressful conditions, but how these changes are conveyed to adjust cellulose synthesis is unknown. Here, we identify the Tetratricopeptide Thioredoxin-Like (TTL) proteins as new members of the cellulose synthase complex (CSC) and describe their unique and hitherto unknown dynamic association with the CSC under cellulose-deficient conditions. We find that TTLs are essential for maintaining cellulose synthesis under salinity stress, establishing a stress-resilient cortical microtubule array, and stabilizing CSCs at the plasma membrane. To fulfill these functions, TTLs interact with Cellulose Synthase1 (CESA1) and engage with cortical microtubules to promote their polymerization. We propose that TTLs function as bridges connecting stress perception with dynamic regulation of cellulose biosynthesis at the plasma membrane.One Sentence SummaryTTLs are peripheral membrane proteins that maintain the integrity of the cellulose synthase complex upon adverse conditions.
Neural signatures of auditory hypersensitivity following acoustic trauma
Authors: McGill Matthew , Hight Ariel E. , Watanabe Yurika L. , Parthasarathy Aravindakshan , Cai Dongqin , Clayton Kameron , Hancock Ken , Takesian Anne , Kujawa Sharon G. , Polley Daniel B. 
Published: May 2022

ABSTRACTThroughout the brain, neurons exhibit a remarkable capacity to maintain stable firing rates despite large perturbations in afferent activity levels. As an exception, homeostatic regulation of neural activity often fails in the adult auditory system after hearing loss. Cochlear deafferentation caused by aging or noise exposure triggers widespread neural hyperactivity, particularly in the auditory cortex (ACtx), which underlies perceptual disorders including tinnitus and hyperacusis. Here, we show that mice with noise-induced damage of the high-frequency cochlear base were behaviorally hypersensitive to spared mid-frequency tones and to direct optogenetic stimulation of auditory thalamocortical neurons. Chronic 2-photon calcium imaging from ACtx pyramidal neurons (PyrNs) revealed an initial stage of diffuse hyperactivity, hypercorrelation, and hyperresponsivity that consolidated around deafferented map regions three or more days after acoustic trauma.Deafferented PyrN ensembles displayed hypersensitive decoding of spared mid-frequency tones, mirroring behavioral hypersensitivity. At the level of individual PyrNs, some exhibited stable, homeostatic gain control after acoustic trauma, while others showed non-homeostatic excess gain. Interestingly, factors such as baseline spontaneous activity levels and sound level encoding could account for 40% of the variability in PyrN gain regulation after acoustic trauma. These findings suggest that non-homeostatic regulation of cortical sound intensity coding following sensorineural loss may underlie the well-established clinical phenomenon of loudness hypersensitivity. Further, while cortical gain changes are triggered by reduced bottom-up afferent input, their subsequent stabilization is also shaped by their local circuit milieu, where baseline response features can identify neurons with the greatest propensity for developing pathological hyperactivity following sensorineural hearing loss.
Telomerase-Dependent Ageing In The Zebrafish Brain
Authors: Martins Raquel R. , Besse Savandara , Ellis Pam S. , Hartopp Naomi , Mughal Nadiyah , Evans Owain , Wahib Mina HF , Yazigan Zerkif , Mortiboys Heather , Rera Michael , Henriques Catarina M. 
Published: May 2022

ABSTRACTDecreased telomerase expression, telomere shortening, senescence-associated markers and inflammation have all been independently observed in the ageing brain and associated with disease. However, causality between limited telomerase expression and brain senescence and neuro-inflammation in the natural ageing setting is yet to be established. Here, we address these questions using the zebrafish as an ageing model which, akin to humans, displays premature ageing and death in the absence of telomerase and where telomere shortening is a driver of cellular senescence.Our work shows for the first time that telomerase deficiency (tert-/-)accelerates key hallmarks of ageing identified in the Wild Type (WT) zebrafish brain at transcriptional, cellular, tissue and functional levels. We show that Tert-dependent transcriptomic changes associated with dysregulation of gene expression, stress response and dysregulation of immune genes are accompanied by accelerated accumulation of senescence-associated markers and inflammation in the aged brain. Importantly,In vivo, these changes correlate with increased blood-brain barrier permeability and altered cognitive behaviour. Of note, telomerase-dependent accumulation of senescence-associated markers in the brain occurs not only in the expected proliferative areas but also in non-proliferative ones, where it is unlikely due to telomere-dependent replicative exhaustion, suggesting that non-canonical roles of telomerase may be involved.Together, our work suggests that telomerase has a protective role in the zebrafish brain against the accumulation of senescence and neuro-inflammation and is required for blood brain barrier integrity.GRAPHICAL ABSTRACTGraphical Abstract: The zebrafish brain displays telomerase-dependent transcriptional hallmarks of ageing which associate with telomerase-dependent accumulation of senescence-associated markers and inflammation in the brain. Importantly,in vivo, telomerase deficiency accelerates dysfunction of the blood brain barrier and behavioural change with ageing.
Spinophilin limits metabotropic glutamate receptor 5 scaffolding to the postsynaptic density and cell type-specifically mediates excessive grooming
Authors: Morris Cameron W. , Watkins Darryl S. , Pennington Taylor , Doud Emma H. , Qi Guihong , Mosley Amber L. , Atwood Brady K. , Baucum Anthony J. 
Published: May 2022

AbstractBackgroundConstitutive knockout of the obsessive-compulsive disorder-associated protein, disks large associated protein 3 (SAPAP3), results in repetitive motor dysfunction, such as excessive grooming, caused by increased metabotropic glutamate receptor 5 (mGluR5) activity in striatal direct- and indirect pathway medium spiny neurons (dMSNs and iMSNs, respectively). However, MSN subtype-specific signaling mechanisms that mediate mGluR5-dependent adaptations underlying excessive grooming are not fully understood. Here, we investigate the MSN subtype-specific roles of the striatal signaling hub protein, spinophilin, in mediating repetitive motor dysfunction associated with mGluR5 function.MethodsQuantitative proteomics and immunoblotting were utilized to identify how spinophilin impacts mGluR5 phosphorylation and protein interaction changes. Plasticity and repetitive motor dysfunction associated with mGluR5 action was measured using our novel conditional spinophilin mouse model that had spinophilin knocked out from striatal dMSNs or/and iMSNs.ResultsLoss of spinophilin only in iMSNs decreased performance of a novel motor repertoire, but loss of spinophilin in either MSN subtype abrogated striatal plasticity associated with mGluR5 function and prevented excessive grooming caused by SAPAP3 knockout mice and treatment with the mGluR5-specific positive allosteric modulator (VU0360172) without impacting locomotion-relevant behavior. Biochemically, we determined spinophilin’s protein interaction correlates with grooming behavior and loss of spinophilin shifts mGluR5 interactions from lipid-raft associated proteins toward postsynaptic density (PSD) proteins implicated in psychiatric disorders.ConclusionsThese results identify spinophilin as a novel striatal signaling hub molecule in MSNs that cell subtype-specifically mediates behavioral, functional, and molecular adaptations associated with repetitive motor dysfunction in psychiatric disorders.
A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding
Authors: Wang Lei , Park Jun Young , Liu Fengming , Olesen Kris , Hou Shirui , Peng Jamy C. , Infield Jordan , Levesque Anna C. , Wang Yong-Dong , Jin Hongjian , Fan Yiping , Connelly Jon P. , Pruett-Miller Shondra M. , Hu Miaofen G. , Hinds Philip W. , Han Young-Goo 
Published: May 2022

AbstractThe neocortex, the center for higher brain function, first emerged in mammals and has become massively expanded and folded in humans, constituting almost half the volume of the human brain. Primary microcephaly, a developmental disorder in which the brain is smaller than normal at birth, mainly results from the number of neurons in the neocortex being reduced because of defects in neural progenitor cells (NPCs). Outer radial glia (oRGs), NPCs that are abundant in gyrencephalic species but rare in lisencephalic species, are thought to play key roles in the expansion and folding of the neocortex. However, how oRGs expand, whether they are necessary for neocortical folding, and whether defects in oRGs cause microcephaly remain important questions in the study of brain development, evolution, and disease. Here, we show that oRG expansion in mice, ferrets, and human cerebral organoids requires cyclin-dependent kinase 6 (CDK6), the mutation of which causes primary microcephaly via an unknown mechanism. In a mouse model in which increased Hedgehog signaling expands oRGs and intermediate progenitor cells and induces neocortical folding, CDK6 loss selectively decreased oRGs and abolished neocortical folding. Remarkably, this function of CDK6 in oRG expansion did not require its kinase activity, was not shared by the highly similar CDK4 and CDK2, and was disrupted by the mutation causing microcephaly. Therefore, our results indicate that CDK6 is conserved to promote oRG expansion; that oRGs are necessary for neocortical folding; and that defects in oRG expansion may cause primary microcephaly.Significance StatementPrimary microcephaly, a disorder in which the brain is smaller than normal at birth, disproportionately affects the neocortex. Although outer radial glia (oRGs) expansion is hypothesized to be important in neocortical expansion and folding, it remains unknown whether oRGs are necessary for neocortical folding and whether defective oRGs cause microcephaly. Moreover, how oRGs expand is not well understood. A mutation in CDK6 causes microcephaly via an unknown mechanism. Here, we show that CDK6 promotes oRG expansion and neocortical folding. This function of CDK6 does not require its kinase activity but is disrupted by a mutation that causes microcephaly. Our findings show that CDK6 is conserved to expand oRGs and provide evidence that oRG defects disrupt neocortical growth and folding.
Microparticle-delivered Cxcl9 prolongs Braf inhibitor efficacy in melanoma
Authors: Romano Gabriele , Paradiso Francesca , Li Peng , Shukla Pooja , Barger Lindsay N , El Naggar Olivia , Miller John P , Liang Roger J , Helms Timothy L , Lazar Alexander J , Wargo Jennifer A , Taraballi Francesca , Costello James C , Kwong Lawrence N 
Published: May 2022

ABSTRACTPatients with BRAF-mutant melanoma show significant responses to combined BRAF and MEK inhibition, but most relapse within 2 years. A major reservoir for drug resistance is minimal residual disease (MRD), comprised of drug-tolerant tumor cells laying in a dormant state. Towards exploiting potential therapeutic vulnerabilities of MRD, we established a genetically engineered mouse model of BrafV600E-driven melanoma MRD wherein genetic BrafV600Eextinction leads to strong but incomplete tumor regression. Transcriptional time-course analysis after BrafV600Eextinction revealed that after an initial surge of immune activation, tumors later became immunologically “cold” after MRD establishment. Computational analysis identified candidate T-cell recruiting chemokines that may be central players in the process, being strongly upregulated initially and steeply decreasing as the immune response faded. Therefore, we hypothesized that sustaining the chemokine signaling could impair MRD maintenance through increased recruitment of effector T-cells. We show that intratumoral administration of recombinant Cxcl9, either naked or loaded in microparticles, significantly impaired MRD relapse in BRAF-inhibited tumors, including several complete responses after microparticle-delivered rCxcl9 combined with BRAF and MEK-inhibition. Our experiments constitute a proof of concept that chemokine-based microparticle delivery systems are a potential strategy to forestall tumor relapse and thus improve the clinical success of frontline treatment methods.