bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atm loss does not radiosensitize a primary mouse model of Pten-deleted brainstem glioma
Authors: Stewart Connor E. , Guerra Garcia Maria E. , Luo Lixia , Williams Nerissa T. , Ma Yan , Regal Joshua A. , Ghosh Debosir , Sansone Patrick , Oldham Mark , Deland Katherine , Becher Oren J. , Kirsch David G. , Reitman Zachary J. 
Published: August 2022

AbstractDiffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase ataxia telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if Atm inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by Atm deletion, which may guide the design of future clinical trials.Brief SummaryWe develop a mouse model of PTEN-mutated brainstem glioma and find that perturbation of the ATM does not enhance radiation efficacy in this model.
MAPK13 stabilization via m6A modification limits anti-cancer efficacy of rapamycin
Authors: Kim Joohwan , Chun Yujin , Ramirez Cuauhtemoc B. , Hoffner Lauren A. , Jung Sunhee , Jang Ki-Hong , Rubtsova Varvara I. , Jang Cholsoon , Lee Gina 
Published: August 2022

AbstractN6-adenosine methylation (m6A) is the most abundant mRNA modification that controls gene expression through diverse mechanisms. m6A-dependent regulation of oncogenes and tumor suppressors indeed contribute to tumor development. However, the role of m6A-mediated gene regulation after drug treatment or resistance is poorly understood. Here, we report that m6A modification ofmitogen-activated protein kinase 13(MAPK13) determines the sensitivity of cancer cells to the mechanistic target of rapamycin complex 1 (mTORC1)- targeting chemotherapeutic agent rapamycin. mTORC1 induces m6A modification ofMAPK13mRNA at its 3’ untranslated region (3’UTR) through methyltransferase-like 3 (METTL3)-METTL14-Wilms’ tumor 1-associating protein (WTAP) methyltransferase complex, thereby stimulating its mRNA degradation via an m6A reader protein YTH domain family protein 2 (YTHDF2). Rapamycin blunts this process and stabilizesMAPK13. Unexpectedly,MAPK13silencing suppresses cell growth and enhances rapamycin’s anti-cancer effects, suggesting thatMAPK13is an oncogenic gene activated by rapamycin via a feedback regulation. Together, our data indicate that rapamycin-mediatedMAPK13mRNA stabilization may confer drug resistance, and it can thus be a therapeutic target to sensitize cancer cells to rapamycin.
ALT in Pediatric High-Grade Gliomas Can Occur withoutATRXMutation and is Enriched in Patients with Pathogenic Germline MMR Variants
Authors: Stundon Jennifer L. , Ijaz Heba , Gaonkar Krutika S. , Kaufman Rebecca S. , Jin Run , Karras Anastasios , Vaksman Zalman , Kim Jung , Corbett Ryan J. , Lueder Matthew R. , Miller Daniel P. , Guo Yiran , Santi Mariarita , Li Marilyn , Lopez Gonzalo , Storm Phillip B. , Resnick Adam C. , Waanders Angela J. , MacFarland Suzanne P. , Stewart Douglas R. , Diskin Sharon J. , Rokita Jo Lynne , Cole Kristina A. 
Published: August 2022

ABSTRACTBackgroundTo achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available.MethodsWe performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n=40/579) of these tumors and completed additional validation by ultrabright telomeric fociin situon a subset of these tumors. We used CCA to validateTelomereHunterfor computational prediction of ALT status and focus subsequent analyses on pediatric high-grade glioma (pHGG) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations.ResultsALT is common in pHGG (n=24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). SomaticATRXmutations occur in 50% of ALT+ pHGG and in 30% of ALT-pHGG. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT. Conclusions: We demonstrate thatATRXis mutated in only a subset of ALT+ pHGG, suggesting other mechanisms ofATRXloss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with development of ALT in patients with pHGG.Key PointsATRX alterations are frequent, but not required, for an ALT phenotype in pHGGspHGG patients with germline mismatch repair variants have higher rate of ALT + tumorsTelomereHunteris validated to predict ALT in pHGGsImportance of the StudyWe performed orthogonal molecular and computational analyses to detect the presence of alternative lengthening of telomeres in a highly characterized cohort of pediatric brain tumors. We demonstrate that many pHGG utilize ALT without a mutation in ATRX, suggesting either loss of function of ATRX via an alternative mechanism or an alternate means of development of ALT. We show that germline variants in MMR genes are significantly associated with ALT in pHGG. Our work adds to the biological understanding of the development of ALT and provides an approach to stratify patients who may benefit from future ALT-directed therapies in this patient population.
Plant species within Streptanthoid Complex associate with distinct microbial communities that shift to be more similar under drought
Authors: Igwe Allie N. , Pearse Ian S. , Aguilar Jessica M. , Strauss Sharon Y. , Vannette Rachel L. 
Published: August 2022

ABSTRACTProlonged water stress can reduce plant growth and fitness and may shift rhizoplane microbial communities. Although drought affects microbial structure of many plant species, it is still poorly understood whether closely related plant species host distinct microbial communities or respond similarly to drought. To explore this question, eight members of the Streptanthus clade with varying affinity to serpentine were subjected to three watering regimes. Rhizoplane bacterial communities were described using 16S rRNA gene amplicon sequencing and we explored the impact of watering treatment and plant species on alpha diversity, differential abundance, and beta diversity of soil bacterial communities. Among most plant species, reduced watering also reduced alpha diversity, but plant species did not strongly impact alpha diversity. Drought treatment reduced microbial community dissimilarity among samples: bacterial communities were more similar when plants received less water. Watering altered the relative abundance of bacterial genera within Proteobacteria, Firmicutes, Bacteroidetes, Planctomycetes, and Acidobacteria, which responded similarly in the rhizoplane of most plant species. These results suggest that prolonged water stress in Streptanthus spp. can result in convergent microbial communities among plant species. We suggest the functional consequences of these shifts be examined to assess effects on plant and microbial fitness under drought conditions.
Selection on sperm size in response to promiscuity and variation in female sperm storage organs
Authors: Cramer Emily R. A. , Yilma Zelealem B. , Lifjeld Jan T. 
Published: August 2022

AbstractSperm cells are exceptionally morphologically diverse across taxa. However, morphology can be quite uniform within species, particularly for species where females copulate with many males per reproductive bout. Strong sexual selection in these promiscuous species is widely hypothesized to reduce intraspecific sperm variation. Conversely, we hypothesize that intraspecific sperm size variation may be maintained by high among-female variation in the size of sperm storage organs, assuming that paternity success improves when sperm are compatible in size with the sperm storage organ. We use individual-based simulations and an analytical model to evaluate how selection on sperm size depends on promiscuity level and variation in sperm storage organ size (hereafter, female preference variation). Simulated species with high promiscuity showed stabilizing selection on sperm when female preference variation was low, and disruptive selection when female preference variation was high, consistent with the analytical model results. With low promiscuity (2-3 mates per female), selection on sperm was stabilizing for all levels of female preference variation in the simulations, contrasting with the analytical model. Promiscuity level, or mate sampling, thus has a strong impact on the selection resulting from female preferences. Further, for species with low promiscuity, disruptive selection on male traits will occur under more limited circumstances than many previous models suggest. Variation in female sperm storage organs likely has strong implications for intraspecific sperm variation in highly promiscuous species, but likely does not explain differences in intraspecific sperm variation for less promiscuous taxa.
N-terminal region of Drosophila melanogaster Argonaute2 forms amyloid-like aggregates
Authors: Narita Haruka , Shima Tomohiro , Iizuka Ryo , Uemura Sotaro 
Published: August 2022

AbstractArgonaute proteins play a central role in RNA silencing by forming protein-small RNA complexes responsible for the silencing process. While most Argonaute proteins have a short N-terminal region, Argonaute2 in Drosophila melanogaster (DmAgo2) harbors a long and unique N-terminal region. Previous in vitro biochemical studies have shown that the loss of this region does not impair the RNA silencing activity of the complex. However, an N-terminal mutant of Drosophila melanogaster has demonstrated abnormal RNA silencing activity. To explore the causes of this discrepancy between in vitro and in vivo studies, we investigated the biophysical properties of the region. Because the N-terminal region is highly rich in glutamine and glycine residues, which is a well-known property for prion-like domains (PrLD), the possibility of the N-terminal region functioning as a PrLD was tested. Our biochemical assays demonstrated that the N-terminal region can form aggregates that are not dissociated even in the presence of SDS. Also, the aggregates enhanced the fluorescence intensity of thioflavin-T, an amyloid detection reagent. The kinetics of the aggregation followed that of typical amyloid formation exhibiting the self-propagating activity. Further, we directly visualized the aggregation process of the N-terminal region under fluorescence microscopy and found that the aggregations took fractal or fibril shapes. Together, the results indicate that the N-terminal region is a PrLD. Many other PrLDs have been reported to modulate the function of proteins through their aggregation. Therefore, our results raise the possibility that aggregation of the N-terminal region regulates the RNA silencing activity of DmAgo2.
The evolution and spread of sulfur-cycling enzymes reflect the redox state of the early Earth
Authors: Mateos Katherine , Chappell Garrett , Klos Aya , Le Bryan , Boden Joanne , Stüeken Eva , Anderson Rika 
Published: August 2022

AbstractThe biogeochemical sulfur cycle plays a central role in fueling microbial metabolisms, regulating the Earth’s redox state, and impacting climate. However, geochemical reconstructions of the ancient sulfur cycle are confounded by ambiguous isotopic signals. Here, we use phylogenetic reconciliation to ascertain the timing of ancient sulfur cycling gene events across the tree of life. Our results suggest that metabolisms using sulfide oxidation emerged in the Archean, but those involving thiosulfate emerged only after the Great Oxidation Event. Our data reveal that observed geochemical signatures resulted not from the expansion of a single type of organism, but were instead associated with genomic innovation across the biosphere. Moreover, our results provide the first indication of organic sulfur cycling from the mid-Proterozoic onwards, with implications for climate regulation and atmospheric biosignatures. Overall, our results provide insights into how the biological sulfur cycle evolved in tandem with the redox state of the early Earth.Teaser:Phylogenomics analyses reveal that the evolution of microbial sulfur metabolisms co-evolved with the redox state of the early Earth.
Synonymous codon substitutions regulate transcription and translation of an upstream gene
Authors: Rodriguez Anabel , Wright Gabriel S. , Lundgren Taylor J. , Moss McKenze J. , Li Jun , Milenkovic Tijana , Huber Paul W. , Champion Matthew M. , Emrich Scott J. , Clark Patricia L. 
Published: August 2022

ABSTRACTSynonymous codons were originally viewed as interchangeable with no phenotypic consequences. However, over the years a substantial body of evidence has demonstrated that some synonymous substitutions can perturb a variety of gene expression and protein homeostasis mechanisms, including translational efficiency, translational fidelity and co-translational folding of the encoded protein. To date, synonymous codon-derived perturbations have largely focused on effects within a single gene. Here we show that synonymous codon substitutions made far within an E. coli plasmid-encoded protein coding sequence frequently led to significant upregulation of a neighboring, upstream gene. Notably, in four out of nine synonymously recoded sequences, significant upregulation of the upstream gene arose due to cryptic transcription of the anti-sense strand. Surprisingly, cryptic transcription of the upstream gene readily bypassed its native transcriptional repression mechanism. Even more surprisingly, translation of this upstream gene correlates closely with the subset of its mRNA transcribed from the cryptic internal promoter, rather than its total mRNA level. These results suggest that synonymous codons in bacteria may be under selection to both preserve the amino acid sequence of the encoded gene while also avoiding internal sequence elements that significantly perturb transcriptional and translational regulation of neighboring genes.
A host E3 ubiquitin ligase regulatesSalmonellavirulence by targeting an SPI-2 effector involved in SIF biogenesis
Authors: Meng Kun , Yang Jin , Xue Juan , Lv Jun , Zhu Ping , Shi Liuliu , Li Shan 
Published: August 2022

AbstractSalmonellaTyphimurium creates an intracellular niche for its replication by utilizing a large cohort of effectors, including several that function to interfere with host ubiquitin signaling. Although the mechanism of action of many such effectors has been elucidated, how the interplay between the host ubiquitin network and bacterial virulence factors dictates the outcome of infection largely remains undefined. Here we found that the SPI-2 effector SseK3 inhibits SNARE pairing to promote the formation ofSalmonella-induced filament by Arg-GlcNAcylation of SNARE proteins, including SNAP25, VAMP8, and Syntaxin. Further study reveals that host cells counteract the activity of SseK3 by inducing the expression of the ubiquitin E3 ligase TRIM32, which catalyzes K48-linked ubiquitination on SseK3 and targets its membrane-associated portion for degradation. Hence, TRIM32 antagonizes SNAP25 Arg-GlcNAcylation induced by SseK3 to restrict SIF biogenesis andSalmonellareplication. Our study reveals a mechanism by which host cells inhibit bacterial replication by eliminating specific virulence factor.
Molecular characterization of the type VI secretion system effector Tlde1a reveals a structurally altered LD-transpeptidase fold
Authors: Cobo Neil Lorente , Sibinelli-Sousa Stephanie , Biboy Jacob , Vollmer Waldemar , Bayer-Santos Ethel , Prehna Gerd 
Published: August 2022

ABSTRACTThe type VI secretion system (T6SS) is a molecular machine that Gram-negative bacteria have adapted for multiple functions, including interbacterial competition. Bacteria use the T6SS to deliver protein effectors into adjacent cells to kill rivals and establish niche dominance. Central to T6SS mediated bacterial competition is an arms race to acquire diverse effectors to attack and neutralize target cells. The peptidoglycan has a central role in bacterial cell physiology, and effectors that biochemically modify peptidoglycan structure effectively induce cell death. One such T6SS effector is Tlde1a fromSalmonellaTyphimurium. Tlde1a functions as an LD-carboxypeptidase to cleave tetrapeptide stems and as an LD-transpeptidase to exchange the terminal D-alanine of a tetrapeptide stem with a noncanonical D-amino acid. To understand how Tlde1a exhibits toxicity at the molecular level, we determined the X-ray crystal structure of Tlde1a alone and in complex with D-amino acids. Our structural data revealed that Tlde1a possesses a unique LD-transpeptidase fold consisting of a dual pocket active site with a capping subdomain. This includes an exchange pocket to bind a D-amino acid for exchange and a catalytic pocket to position the D-alanine of a tetrapeptide stem for cleavage. Toxicity assays inEscherichia coliandin vitropeptidoglycan biochemical assays with Tlde1a variants, correlate Tlde1a molecular features directly to its biochemical functions. We observe that the LD-carboxypeptidase and LD-transpeptidase activities of Tlde1a are both structural and functionally linked. Overall, our data highlights how an LD-transpeptidase fold has been structurally altered to create a toxic effector in the T6SS arms race.
Bernstein polynomial approximation of fixation probability in finite population evolutionary games
Authors: Park Jiyeon , Newton Paul K. 
Published: August 2022

AbstractWe use the Bernstein polynomials of degree d as the basis for constructing a uniform approximation to the rate of evolution (related to the fixation probability) of a species in a two-component finite-population frequency-dependent evolutionary game setting. The approximation is valid over the full range 0 ≤ w ≤ 1, where w is the selection pressure parameter, and converges uniformly to the exact solution as d → ∞. We compare it to a widely used non-uniform approximation formula in the weak-selection limit (w ∼ 0) as well as numerically computed values of the exact solution. Because of a boundary layer that occurs in the weak-selection limit, the Bernstein polynomial method is more efficient at approximating the rate of evolution in the strong selection region (w ∼ 1) (requiring the use of fewer modes to obtain the same level of accuracy) than in the weak selection regime.
Genetic disruption of isocitrate dehydrogenase arrests the full development of sexual stage parasites in Plasmodium falciparum
Authors: Yang Ming , Ke Hangjun , Morrisey Joanne M. , Mather Michael W. , Vaidya Akhil B. 
Published: August 2022

AbstractThe malaria parasites encode all eight mitochondrial enzymes that can constitute the classical tricarboxylic acid (TCA) cycle. We previously reported that genetic ablation of six out of eight TCA enzymes had no significant impact on the parasite survival and growth in asexual blood stage; aconitase knockout (ΔACO) parasites were, however, arrested as late-stage gametocytes. Herein, we describe a defective gametocyte development phenotype resulting from the knockout of another TCA enzyme, isocitrate dehydrogenase (IDH). Similar to the ΔACO gametocytes, ΔIDH gametocytes stall at stage III/IV and cannot form mature gametocytes or undergo exflagellation. Both ACO and IDH KO gametocytes exhibit fragmented mitochondrial morphology. Knockout of IDH also exerts a fitness cost, leading to a decrease in growth rate in erythrocytic stages. We examined two possible causes for the phenotype in the ΔIDH gametocytes: 1. Accumulation of reactive oxygen species (ROS) within the parasite mitochondrion due to diminished production of mitochondrial NADPH during the 10-14 days of gametocyte development; or 2. Cytotoxicity of built-up citrate upstream of IDH. We found that antioxidant agents such as N-acetylcysteine and MitoQ did not rescue the phenotype of ΔACO or ΔIDH gametocytes. Large amounts of citrate in the medium also had no significant effect on the gametocyte development or gamete formation of wildtype parasites. Our results demonstrate the importance of IDH in gametocytogenesis, providing evidence that IDH as well as aconitase could be further explored as targets for gametocidal agents and malaria transmission blockers.
A key regulator with a MIF-like domain orchestrates cellular differentiation and virulence in the fungal pathogen Magnaporthe oryzae
Authors: Galli Matteo , Jacob Stefan , Zheng Ying , Ghezellou Parviz , Gand Martin , Albuquerque Wendell , Imani Jafargholi , Allasia Valérie , Coustau Christine , Keller Harald , Spengler Bernhard , Thines Eckhard , Kogel Karl-Heinz 
Published: August 2022

SummaryMACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) is a pleiotropic protein with chemotactic, pro-inflammatory, and growth-promoting activities first discovered in mammals. In parasites, MIF homologs are involved in immune evasion and pathogenesis. Here, we present the first comprehensive analysis of a MIF protein from the devastating plant pathogen Magnaporthe oryzae (Mo). The fungal genome encodes a single MIF protein (MoMIF1) that, unlike the human homolog, harbors multiple low-complexity regions (LCRs) and is unique to Ascomycota. Following infection, MoMIF1 is expressed in the biotrophic phase of the fungus, and is strongly down-regulated during subsequent necrotrophic growth in leaves and roots. We show that MoMIF1 is secreted during plant infection, affects the production of the mycotoxin tenuazonic acid and inhibits plant cell death. Our results show that MoMIF1 is a novel key regulator of fungal virulence that maintains the balance between biotrophy and necrotrophy during the different phases of fungal infection.