bluuebunny/crossref_metadata_2025_split huggingface dataset:
Language and Social Regions Are Affected in Toddlers with Autism and Predict Later Language Outcome
Authors: Duan Kuaikuai , Eyler Lisa , Pierce Karen , Lombardo Michael V. , Datko Michael , Hagler Donald , Taluja Vani , Zahiri Javad , Campbell Kathleen , Barnes Cynthia Carter , Arias Steven , Nalabolu Srinivasa , Troxel Jaden , Dale Anders M. , Courchesne Eric 
Published: October 2022

ABSTRACTAutism spectrum disorder is a heterogeneous neurodevelopmental disorder. Early brain overgrowth yet reduced cerebellar size is well recognized for autism, but cortical regions involved show inconsistent patterns of alteration. No complete and replicable map of early regional brain size alterations has been charted. It is also not clear whether individual differences in brain size relate to autism symptom severity and cognitive deficits and predict later language outcomes. We leveraged structural MRI data from 166 autistic and 109 typical developing toddlers to comprehensively and systematically investigate regional gray matter volume alterations and cortical surface area and thickness perturbations in autism compared to typical developing toddlers using linear mixed-effect models. We then examined their replicability in an independent cohort of 38 autistic and 37 typical developing toddlers. We further investigated associations between regional brain size and symptom severity, Mullen and Vineland cognitive performance using linear regression models. Lastly, we investigated whether early brain size (at intake mean age of 2.5 years) can improve support vector machine prediction of language outcome at 3-4 years of age when added to a model containing intake clinical and behavioral measures. Compared to typical developing toddlers, autistic toddlers presented larger or thicker lateral temporal regions, smaller or thinner frontal lobe and midline structures, larger callosal subregion volume, and smaller cerebellum. Most of these differences were replicated in an independent toddler cohort. Moreover, the identified gray matter alterations were related to autism symptom severity and cognitive impairments at intake, and, remarkably, they improved the accuracy for predicting later language outcome beyond intake clinical and demographic variables. Gray matter volume, thickness, and surface area in regions involved in language, social, and face processing were altered in autistic toddlers. Alterations in these regions are major early-age developmental attributes of autism. The early-age alterations in these cortical attributes in different regions may be the result of dysregulation in multiple neural processes and stages, consistent with prenatal multi-process, multi-stage models of autism. Here we also show these gray matter alterations are promising prognostic biomarkers for language outcome prediction.
CAR-T Cells with Phytohemagglutinin (PHA) Provide Anti-Cancer Capacity with Better Proliferation, Rejuvenated Effector Memory, and Reduced Exhausted T Cell Frequencies
Authors: Gulden Gamze , Sert Berranur , Teymur Tarik , Ay Yasin , Tiryaki Nulifer Neslihan , Ovalı Ercüment , Tarhan Nevzat , Tastan Cihan 
Published: October 2022

ABSTRACTThe development of genetic modification techniques has led to the opening of a new era in cancer treatments that have been limited to conventional treatments such as chemotherapy. Since not only cancerous cells but also healthy cells are damaged by the drugs, intensive efforts are made to develop cancer-targeted techniques. The most promising approach is genetically modified CAR-T cell therapy. The high central memory T cell (Tcm) and stem cell-like memory T cell (Tscm) ratios in the CAR-T cell population increase the effectiveness of immunotherapy. Therefore, it is important to increase the populations of CAR-expressing Tcm and Tscm cells to ensure that CAR-T cells remain long-term and have cytotoxic (anti-tumor) efficacy. In this study, we aimed to improve CAR-T cell therapy’s time-dependent efficacy and stability, increasing the survival time and reducing the probability of cancer cell growth. To increase the subpopulation of Tcm and Tscm in CAR-T cells, we investigated to produce a long-term stable and cytotoxic efficient CAR-T cell by modifications in the cell activation-dependent production method using Phytohemagglutinin. Phytohemagglutinin (PHA), a lectin that binds to the membranes of T cells and increases metabolic activity and cell division, is studied to increase the Tcm and Tscm population. Although it is known that PHA significantly increases Tcm cells, B-lymphocyte antigen CD19 specific CAR-T cell expansion, its anti-cancer and memory capacity has not yet been tested compared to aCD3/aCD28. Two different types of CAR (aCD19 scFv CD8- (CD28 or 41BB)-CD3z-EGFRt) expressing T cells were generated and their immunogenic phenotype, exhausted phenotype, Tcm-Tscm populations, and cytotoxic activities were determined in this study. The proportion of T cell memory phenotype in the CAR-T cell populations generated by PHA was observed to be higher than that of aCD3/aCD28-amplified CAR-T cells with similar cytotoxic (anti-tumor) and higher proliferation capacity. Here, we show that PHA provides long-term and efficient CAR-T cell production, suggesting a potential alternative to aCD3/aCD28-amplified CAR-T cells.
Chinese fir genome and the evolution of gymnosperms
Authors: Lin Si-Zu , Chen Yu , Wu Chao , Sun Wei-Hong , Li Zhen , Chen Hengchi , Wang Jieyu , Ji Changmian , Li Shu-Bin , Wang Zhiwen , Tsai Wen-Chieh , Ma Xiang-Qing , Lan Si-Ren , Zhang Fei-Ping , Xie Ya-Cong , Yao Lei , Zhang Yan , Lü Meng-Meng , Zhang Jia-Jun , Zhang Di-Yang , Ye Yi-Quan , Yu Xia , Xu Shan-Shan , Ma Zhi-Hui , Ding Guo-Chang , Cao Guang-Qiu , He Zong-Ming , Wu Peng-Fei , Lin Kai-Min , Liu Ai-Qin , Lin Yan-Qing , Ruan Shao-Ning , Liu Bao , Cao Shi-Jiang , Zhou Li-Li , Li Ming , Shuai Peng , Hou Xiao-Long , Wu Yi-Han , Li Nuo , Xiong Sheng , Hao Yang , Zhou Zhuang , Liu Xue-Die , Zuo Dan-Dan , Li Jia , Wang Pei , Zhang Jian , Liu Ding-Kun , Chen Gui-Zhen , Huang Jie , Huang Ming-Zhong , Li Yuanyuan , Zheng Qinyao , Zhao Xiang , Zhong Wen-Ying , Wang Feng-Ling , Cheng Xin-Chao , Yu Yin , Liu Zhi-Wei , Zheng Hongkun , Ming Ray , Van de Peer Yves , Liu Zhong-Jian 
Published: October 2022

AbstractSeed plants comprise angiosperms and gymnosperms. The latter includes gnetophytes, cycads, Ginkgo, and conifers. Conifers are distributed worldwide, with 630 species distributed across eight families and 70 genera. Their distinctiveness has triggered much debate on their origin, evolution, and phylogenetic placement among seed plants. To better understand the evolution of gymnosperms and their relation to other seed plants, we report here a high-quality genome sequence for a tree species, Chinese fir (Cunninghamia lanceolata), which has excellent timber quality and high aluminum adaptability and is a member of Cupressaceae with high levels of heterozygosity. We assembled an 11.24 Gb genome with a contig N50 value of 2.15 Mb and anchored the 10.89 Gb sequence to 11 chromosomes. Phylogenomic analyses showed that cycads sister to Ginkgo, which place to sister in all gymnosperm lineages, and Gnetales within conifers sister to Pinaceae. Whole-genome duplication (WGD) analysis showed that the ancestor of seed plants has differentiated into angiosperms and gymnosperms after having experienced a WGD event. The ancestor of extant gymnosperm has experienced a gymnosperm-specific WGD event and the extant angiosperms do not share a common WGD before their most recent common ancestor diverged into existing angiosperms lineages. Analysis of the MADS-box gene family ofC. lanceolatarevealed the developmental mechanism of the reproductive organs inC. lanceolata, which supported the (A)B(C) model of the development of gymnosperms reproductive organs. In addition, astringent seeds and shedding of whole branches (with withered leaves) might be a strategy ofC. lanceolatathat evolved during long-term adaptation to an aluminum-rich environment. The findings also reveal the molecular regulation mechanism of shade tolerance inC. lanceolataseedlings. Our results improve the resolution of ancestral genomic features within seed plants and the knowledge of genome evolution and diversification of gymnosperms.
AdultDrosophilalegs do not regenerate after amputation
Authors: Sustar Anne , Tuthill John C. 
Published: October 2022

AbstractA recent paper by Abramset al. (2021) claimed that a simple dietary supplement is sufficient to induce appendage regeneration in jellyfish, flies, and mice. This would be remarkable, if true, because it was previously thought that flies and mice lack the capacity for regeneration after injury. We therefore sought to replicate their provocative results. We amputated one tibia of over 1000 fruit flies, fed them control or supplemented diets, and carefully examined their legs three weeks post-injury. We did not, however, observe any instances of leg regeneration. We conducted additional experiments that confirmed the complete absence of neurons, muscles, or other living cells in amputated tibias. Abramset al. also reported the formation of a white blob at the amputation site, which they interpreted as an intermediate regeneration morphology. We tested this hypothesis more rigorously and conclude that the white blob consists of bacteria. Overall, we failed to find any evidence for leg regeneration inDrosophila, even when flies were fed the supplemented diet. Our results therefore contradict the overarching conclusion of Abramset al. that dietary supplements are sufficient to unlock an ancestral mechanism that induces appendage regeneration.
A fungal lytic polysaccharide monooxygenase is required for cell wall integrity, thermotolerance, and virulence of the fungal human pathogenCryptococcus neoformans
Authors: Probst Corinna , Hallas-Møller Magnus , Ipsen Johan Ø. , Brooks Jacob T. , Andersen Karsten , Haon Mireille , Berrin Jean-Guy , Martens Helle J. , Nichols Connie B. , Johansen Katja S. , Alspaugh J. Andrew 
Published: October 2022

AbstractFungi often adapt to environmental stress by altering their size, shape, or rate of cell division. These morphological changes require reorganization of the cell wall, a structural feature external to the cell membrane composed of highly interconnected polysaccharides and glycoproteins. Lytic polysaccharide monooxygenases (LPMOs) are copper-dependent enzymes that are typically secreted into the extracellular space to catalyze initial oxidative steps in the degradation of complex biopolymers such as chitin and cellulose. However, their roles in modifying endogenous microbial carbohydrates are poorly characterized. TheCEL1gene in the human fungal pathogenCryptococcus neoformans(Cn) is predicted by sequence homology to encode an LPMO of the AA9 enzyme family. TheCEL1gene is induced by host physiological pH and temperature, and it is primarily localized to the fungal cell wall. Targeted mutation of theCEL1gene revealed that it is required for the expression of stress response phenotypes, including thermotolerance, cell wall integrity, and efficient cell cycle progression. Accordingly, acel1Δdeletion mutant was avirulent in two models ofC. neoformansinfection. Therefore, in contrast to LPMO activity in other microorganisms that primarily targets exogenous polysaccharides, these data suggest thatCnCel1 promotes intrinsic fungal cell wall remodeling events required for efficient adaptation to the host environment.Author summaryFungi need to adapt quickly to environmental stresses to thrive. The fungal cell wall, which supplies support and integrity to the cell, is an essential compartment to react and interact with the surrounding environment. Rapid changes within the carbohydrate composition and architecture occur in response to environmental stresses. Lytic polysaccharide monooxygenases (LPMOs) are mononuclear copper-enzymes, secreted by microbes to assist in the first steps of remodeling and degrading complex and recalcitrant carbohydrates. In this study we explore the role of the putative AA9 family LPMOCnCel1 for growth and virulence of the fungal human pathogenCryptococcus neoformans. TheCEL1gene is highly up-regulated in presence of host stresses and acel1Δmutant strain is avirulent in a murine model of infection. Downstream analysis of virulence-associated phenotypes identified theCEL1gene to be required for thermotolerance as well as cell wall integrity, and efficient cell cycle progression in presence of host-mimicking stresses. Based upon those findings we propose thatCnCel1 likely promotes intrinsic fungal cell wall remodeling events essential for adaptation to the host environment.
The effects of drought and inter-plant competition on the ectomycorrhizal interaction between fungi and Aleppo pine seedlings
Authors: Herol Lior , Shemesh Hagai , Avidar Mor , Yirmiahu Shahar , Zach Yair , Klein Tamir , Livne-Luzon Stav 
Published: October 2022

AbstractAn increase in tree mortality is currently evident in forests around the world. Such mortality could be counterbalanced by the native regeneration of seedlings. Seedling establishment under natural conditions is often limited by inter-plant competition and drought conditions. Many forest ecosystems rely on ectomycorrhizal relationships which could be affected by competition and drought, altering forest resilience.We carried out an experiment testing the combined effects of drought, herbaceous competition, and ectomycorrhizal fungi (EMF) on the growth and shape of Aleppo pine seedlings and the EMF community composition.Pines that germinated in the presence of the EMF spores were taller, had greater biomass, and more side branches. However, under conditions of either competition or drought, the effect of EMF on seedling biomass and height was greatly reduced, while the effect on shoot branching was maintained. Under a combination of drought and competition, EMF had no influence on plant growth and shape. The EMF community was strongly dominated byGeoporaspecies, and its structure was not affected by the treatments. Plants experiencing competition were nitrogen poor but presented the highest levels of EMF sequence abundance.Stressful conditions seem to alter the relationship between EMF and seedling growth. Specifically, under drought, both colonization and seedling response to EMF was small. However, under competition, colonization was maintained while no growth enhancement was evident. This discrepancy highlights the complexity of the benefits provided to seedlings by EMF under ecologically relevant conditions.
Design and performance of a long-read sequencing panel for pharmacogenomics
Authors: van der Lee Maaike , Busscher Loes , Menafra Roberta , Zhai Qinglian , van den Berg Redmar R. , Kingan Sarah B , Gonzaludo Nina , Hon Ting , Han Ting , Arbiza Leonardo , Numanagić Ibrahim , Kloet Susan L. , Swen Jesse J. 
Published: October 2022

AbstractPharmacogenomics (PGx)-guided drug treatment is one of the cornerstones of personalized medicine. However, the genes involved in drug response are highly complex and known to carry many (rare) variants. Current technologies (short-read sequencing and SNP panels) are limited in their ability to resolve these genes and characterize all variants. Moreover, these technologies cannot always phase variants to their allele of origin. Recent advance in long-read sequencing technologies have shown promise in resolving these problems. Here we present a long-read sequencing panel-based approach for PGx using PacBio HiFi sequencing.A capture based approach was developed using a custom panel of clinically-relevant pharmacogenes including up- and downstream regions. A total of 27 samples were sequenced and panel accuracy was determined using benchmarking variant calls for 3 Genome in a Bottle samples and GeT-RM star(*)-allele calls for 21 samples..The coverage was uniform for all samples with an average of 94% of bases covered at >30×. When compared to benchmarking results, accuracy was high with an average F1 score of 0.89 for INDELs and 0.98 for SNPs. Phasing was good with an average of 68% the target region phased (compared to ~20% for short-reads) and an average phased haploblock size of 6.6kbp. Using Aldy 4, we compared our variant calls to GeT-RM data for 8 genes (CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, SLCO1B1, TPMT), and observed highly accurate star(*)-allele calling with 98.2% concordance (165/168 calls), with only one discordance inCYP2C9leading to a different predicted phenotype.We have shown that our long-read panel-based approach results in high accuracy and target phasing for SNVs as well as for clinical star(*)-alleles.
A SNP affects Wnt4 expression in endometrial stroma, with antagonistic implications for pregnancy, endometriosis and reproductive cancers
Authors: Pavlicev Mihaela , McDonough-Goldstein Caitlin E. , Zupan Andreja Moset , Muglia Lisa , Hu Yueh-Chiang , Kong Fansheng , Monangi Nagendra , Dagdas Gülay , Zupancic Nina , Marziaz Jamie , Sinner Debora , Zhang Ge , Wagner Günter , Muglia Louis 
Published: October 2022

AbstractThe common human single nucleotide polymorphism rs3820282 is associated with multiple phenotypes ranging from gestational length to likelihood of endometriosis and ovarian cancer and can thus serve as a paradigm for a highly pleiotropic genetic variant. Pleiotropy makes it challenging to assign specific causal roles to particular genetic variants. Deleterious mutations in multifunctional genes may cause either the co-occurrence of multiple disorders in the same individuals (i.e., syndromes), or be repeatedly associated with a variety of disorders in a population. Moreover, the adverse effects can occur in combination with advantages in other traits, maintaining high frequencies of deleterious alleles in the population. To reveal the causal role of this specific SNP, we investigated the molecular mechanisms affected by rs3820282 in mice. We have shown previously that rs3820282 introduces a high affinity estrogen receptor 1 binding site at theWnt4locus. Having introduced this nucleotide substitution into the homologous site of the mouse genome by CRISPR/Cas 9 we show that this change causes a specific upregulation ofWnt4transcription in the endometrial stromal cells during the preovulatory estrogen peak in late proestrus. Transcriptomic analysis of the whole uterus reveals broad systemic effects on uterine gene expression, including downregulation of proliferation and induction of many progesterone-regulated pro-implantation genes. The effect on proliferation is limited to the luminal epithelium, whereas other effects involve the uterine stromal compartment. We suggest that in the uterus, these changes could contribute to increased permissiveness to embryo invasion. Yet in other estrogen-responsive tissues, the same changes potentially lead to decreased resistance to invasion by cancer cells and endometriotic foci. A single molecular effect of rs3820282 onWnt4expression may thus underlie the various associated phenotypic effects.
Extreme genome diversity and cryptic speciation in a harmful algal bloom forming eukaryote
Authors: Wisecaver Jennifer H. , Auber Robert P. , Pendleton Amanda L. , Watervoort Nathan F. , Fallon Timothy R. , Riedling Olivia L. , Manning Schonna R. , Moore Bradley S. , Driscoll William W. 
Published: October 2022

ABSTRACTHarmful algal blooms (HABs) of the toxic haptophytePrymnesium parvumare a recurrent problem in many inland and estuarine waters around the world. Strains ofP. parvumvary in the toxins they produce and in other physiological traits associated with HABs, but the genetic basis for this variation is unknown. To investigate genome diversity in this morphospecies, we generated genome assemblies for fifteen phylogenetically and geographically diverse strains ofP. parvumincluding Hi-C guided, near-chromosome level assemblies for two strains. Comparative analysis revealed considerable DNA content variation between strains, ranging from 115 Mbp to 845 Mbp. Strains included haploids, diploids, and polyploids, but not all differences in DNA content were due to variation in genome copy number. Haploid genome size between strains of different chemotypes differed by as much as 243 Mbp. Syntenic and phylogenetic analyses indicate that UTEX 2797, a common laboratory strain from Texas, is a hybrid that retains two phylogenetically distinct haplotypes. Investigation of gene families variably present across strains identified several functional categories associated with metabolism, including candidates for the biosynthesis of toxic metabolites, as well as genome size variation, including recent proliferations of transposable elements. Together, our results indicate thatP. parvumis comprised of multiple cryptic species. These genomes provide a robust phylogenetic and genomic framework for investigations into the eco-physiological consequences of the intra- and inter-specific genetic variation present inP. parvumand demonstrate the need for similar resources for other HAB-forming morphospecies.SIGNIFICANCE STATEMENTHarmful algal blooms (HABs) are a global concern. Efforts to understand the genetic basis of traits associated with the success of HAB-forming species are limited by a dearth of genomic resources. In this paper we present genomes for fifteen strains ofPrymnesium parvum, a toxic alga that causes ecosystem and societally disruptive HABs around the world. We uncover an unprecedented amount of sequence-level, gene family, and genome architecture evolution inP. parvumand provide evidence for both cryptic speciation and hybridization. These results illustrate how both inter- and intraspecific genetic variation can be dramatically underestimated in a protist morphospecies. More work is needed to understand the eco-physiological consequences of hidden genetic diversity inP. parvumand HAB-forming species more generally.
DRAM1 promotes antibacterial autophagy and lysosomal delivery of Mycobacterium marinum in macrophages
Authors: Banducci-Karp Adrianna , Xie Jiajun , Engels Sem A. G. , Sarantaris Christos , Varela Monica , Meijer Annemarie H. , van der Vaart Michiel 
Published: October 2022

AbstractDamage-Regulated Autophagy Modulator 1 (DRAM1) is an infection-inducible membrane protein, whose function in the immune response is incompletely understood. Based on previous results in a zebrafish infection model, we have proposed that DRAM1 is a host resistance factor against intracellular mycobacterial infection. To gain insight into the cellular processes underlying DRAM1-mediated host defence, here we studied the interaction of DRAM1 with Mycobacterium marinum in murine RAW264.7 macrophages. We found that shortly after phagocytosis, DRAM1 localised in a punctate pattern to mycobacteria, which gradually progressed to full DRAM1 envelopment of the bacteria. Within the same time frame, DRAM1-positive mycobacteria colocalised with the LC3 marker for autophagosomes and LysoTracker and LAMP1 markers for (endo)lysosomes. Knockdown analysis revealed that DRAM1 is required for recruitment of LC3 and for acidification of mycobacteria-containing vesicles. A reduction in the presence of LAMP1 further suggested reduced fusion of lysosomes with mycobacteria-containing vesicles. Finally, we show that DRAM1 knockdown impairs the ability of macrophages to control mycobacterial infection. Together, these results support that DRAM1 promotes the trafficking of mycobacteria through the degradative (auto)phagolysosomal pathway. Considering its prominent effect on host resistance to intracellular infection, DRAM1 is a promising target for therapeutic modulation of the microbicidal capacity of macrophages.