bluuebunny/crossref_metadata_2025_split huggingface dataset:
In-vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma
Authors: Kaushik Akash K. , Burroughs Lindsey K. , Tarangelo Amy , Ragavan Mukundan , Wu Cheng-Yang , Li Xiangyi , Ahumada Kristen , Tcheuyap Vanina T. , Saatchi Faeze , Do Quyen N , Yong Cissy , Rosales Tracy , Stevens Christina , Rao Aparna , Faubert Brandon , Pachnis Panayotis , Zacharias Lauren G. , Vu Hieu , Cai Feng , Mathews Thomas P. , Slusher Barbara , Kapur Payal , Sun Xiankai , Merritt Matthew , Brugarolas James , DeBerardinis Ralph J. 
Published: November 2022

AbstractTargeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed metabolism in patient-derived xenografts (tumorgrafts) from diverse forms of RCC. Tumorgrafts fromVHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engage in oxidative and reductive glutamine metabolism. We used several approaches to suppress glutamine metabolism and test the effect on tumor growth. Genetic silencing of isocitrate dehydrogenase-1 or -2 impaired reductive labeling of TCA cycle intermediates and suppressed tumor growth. Glutaminase inhibition resulted in modest growth suppression and variable effects on glutamine metabolism in vivo. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase.TeaserGlutamine fuels the TCA cycle and amidotransferase pathways in clear cell renal cell carcinoma.
Schwann cells promote sensory neuron excitability during development
Authors: Kantarci Husniye , Elvira Pablo D. , Thottumkara Arun P. , Iyer Manasi , Donovan Lauren J. , Dugan Micaela Quinn , Ambiel Nicholas , O’Connell Emma M. , Granados Alejandro , Zeng Hong , Saw Nay L. , Lutz Amanda Brosius , Sloan Steven A. , Gray Erin E. , Tran Khanh V. , Vichare Aditi , Yeh Ashley K. , Münch Alexandra E. , Huber Max , Agrawal Aditi , Morri Maurizio , Shamloo Mehrdad , Anderson Thomas Anthony , Tawfik Vivianne L. , Du Bois J. , Bradley Zuchero J. 
Published: November 2022

SUMMARYExcitability—the ability to fire action potentials—is a signature feature of neurons. How neurons become excitable during development, and whether excitability is an intrinsic property of neurons or requires signaling from glial cells, remain unclear. Here we demonstrate that Schwann cells, the most abundant glia in the peripheral nervous system, promote somatosensory neuron excitability during development. We find that Schwann cells secrete prostaglandin E2, which is necessary and sufficient to induce developing somatosensory neurons to express normal levels of voltage-gated sodium channels and fire action potential trains. Inactivating this signaling pathway specifically in Schwann cells selectively impairs the maturation of nociceptor and proprioceptor somatosensory neuron subtypes, leading to corresponding sensory defects in thermoception, inflammatory pain, and proprioception. Our studies thus reveal a cell non-autonomous mechanism by which glia regulate neuronal excitability to enable the development of normal sensory functions.
Lomasomes and other fungal plasma membrane macroinvaginations have a tubular and lamellar genesis
Authors: Mazheika Igor S. , Kamzolkina Olga V. 
Published: November 2022

AbstractThe plasma membrane of filamentous fungi forms large invaginations (>100-200 nm in diameter or length), which are especially pronounced in xylotrophic basidiomycetes. Typically, such macroinvaginations are either tubules or parietal vesicles. Vesicular macroinvaginations at the electron microscopic level correspond to classical lomasomes. There is an assumption that vesicular macroinvaginations/lomasomes may be involved in macrovesicular endocytosis, i.e., be scissored from the plasma membrane and be transported to the cytoplasm. The original aim of this study was to test for the presence of macroendocytosis in xylotrophic fungi using a fluorescent styryl label and time-lapse and Z-stacks microscopic technologies. However, the results were unexpected. It was found that most of the membrane structures labeled in fungal cells by the styryl fluorophore (analogue of FM4-64) is various types of macroinvaginations of the plasma membrane. All of these macroinvaginations are or go through a tube or lamella stage. Moreover, under specific conditions of a microscopic preparation, different types of invaginations are formed at different times – the longer the sample observation time, the greater may be the diameter of the tubes that form macroinvaginations. In addition, the morphology and successive formation of macroinvaginations mimics the endocytic pathway: different types of the invaginations can easily be mistaken for primary endocytic vesicles, endosomes, and vacuole-lysosomes. The paper qualitatively and quantitatively analyzes various types of macroinvaginations of the plasma membrane, suggests their biological functions, and discusses the presence and features of classical and macrovesicular endocytosis in fungi. This study is another step towards understanding the complex physiology of filamentous fungi associated with changes in plasma membrane tension, rapid changes in hyphae size, and endocytosis. In addition, this work is a presentation of a new tubular system in wood-decaying fungi, which takes its place among the already described tubular systems: vacuolar, mitochondrial, and endoplasmic-reticular.
Modality Independent or Modality Specific? Common Computations Underlie Confidence Judgements in Visual and Auditory Decisions
Authors: West Rebecca K , Harrison William J , Matthews Natasha , Mattingley Jason B , Sewell David K 
Published: November 2022

AbstractHumans possess the ability to evaluate their confidence in a range of different decisions. In this study, we investigated the computational processes that underlie confidence judgements and the extent to which these computations are the same for perceptual decisions in the visual and auditory modalities. Participants completed two versions of a categorisation task with visual or auditory stimuli and made confidence judgements about their category decisions. In each modality, we varied both evidence strength, (i.e., the strength of the evidence for a particular category) and sensory uncertainty (i.e., the intensity of the sensory signal). We evaluated several classes of models which formalise the mapping of evidence strength and sensory uncertainty to confidence in different ways: 1) unscaled evidence strength models, 2) scaled evidence strength models, and 3) Bayesian models. Our model comparison results showed that across tasks and modalities, participants take evidence strength and sensory uncertainty into account in a way that is consistent with the scaled evidence strength class. Notably, the Bayesian class provided a relatively poor account of the data across modalities, particularly in the more complex categorisation task. Our findings suggest that a common process is used for evaluating confidence in perceptual decisions across domains, but that the parameter settings governing the process are tuned differently in each modality. Overall, our results highlight the impact of sensory uncertainty on confidence and the unity of metacognitive processing across sensory modalities.Author SummaryIn this study, we investigated the computational processes that describe how people derive a sense of confidence in their decisions. In particular, we determined whether the computations that underlie the evaluation of confidence for a visual decision are the same as those for an auditory decision. We tested a range of different models from 3 distinct classes which make different predictions about the computations that are used. We found that a single class of models provided the best account of confidence, suggesting a common process for evaluating confidence across sensory modalities. Even though these computations are governed by the same general process, our results suggest that the process is still fine-tuned within each modality.
More accurate analysis of maternal effect genes by siRNA electroporation into mouse oocytes
Authors: Yamamoto Takuto , Honda Shinnosuke , Ideguchi Issei , Suematsu Motoki , Ikeda Shuntaro , Minami Naojiro 
Published: November 2022

AbstractMaternal RNAs and proteins accumulate in mouse oocytes and control the initial stages of development. The DNA in sperm combines with protamine, which is exchanged after fertilization with maternal histones, including H3.3, but the effect of H3.3 on post-fertilization development has been unclear. In this study, we established an electroporation method to introduce H3.3 siRNA into germinal vesicle (GV)-stage oocytes without removing cumulus cells. In the traditional microinjection method, cumulus cells attached to oocytes must be removed; however, we confirmed that artificially removing cumulus cells from oocytes reduced fertilization rates, and oocytes originally free of cumulus cells had reduced developmental competence. When H3.3 siRNA was introduced at the GV stage, H3.3 was still present in the maternal pronucleus and second polar body, but not in the paternal pronucleus, resulting in embryonic lethality after fertilization. This indicates that the H3.3 protein was not incorporated into the paternal pronucleus because it was repeatedly translated and degraded in a relatively short time. On the other hand, H3.3 protein incorporated into the maternal genome in the GV stage escaped degradation and remained in the maternal pronucleus after fertilization. This new method of electroporation into GV-stage oocytes without removing cumulus cells is not skill intensive and is essential for the accurate analysis of maternal effect genes.In briefFor analysis of maternal factors contained in the oocyte, suppression of genes within the oocyte is necessary. In this paper, siRNA was introduced into oocytes by electroporation, showing that maternal mRNA was suppressed efficiently.
The molecular basis of phenotypic plasticity evolves in response to environmental predictability
Authors: Leung Christelle , Grulois Daphné , Quadrana Leandro , Chevin Luis-Miguel 
Published: November 2022

AbstractPhenotypic plasticity, the response of a given genotype to its environment of development, is a ubiquitous feature of life, enabling organisms to cope with variation in their environment. Theoretical studies predict that, under stationary environmental variation, the level of plasticity should evolve to match the predictability of selection at the timing of development. However, we still lack critical empirical evidence on the extent to which selection on phenotypic plasticity cascades down from higher phenotypic levels to their underlying molecular basis. Here, we used experimental evolution under controlled environmental fluctuations, to test whether the evolution of phenotypic plasticity in responses to environmental predictability (ρ2) occurred across biological levels, going from DNA methylation to gene expression to cell morphology. Transcriptomic results indicate clear effects of salinity andρ2×salinity interaction on gene expression, thus identifying sets of genes involved in plasticity and its evolution. These transcriptomic effects were independent of DNA methylation changes incis. However we did findρ2-specific responses of DNA methylation to salinity change, albeit weaker than for gene expression. Overall, we found consistent evolution of reduced plasticity in less predictable environments for DNA methylation, gene expression, and cell morphology. Our results provide the first clear empirical signature of plasticity evolution at multiple levels in response to environmental predictability, and highlight the importance of experimental evolution to address predictions from evolutionary theory, as well as investigate the molecular basis of plasticity evolution.
CRISPR/FnCas12a-mediated efficient multiplex and iterative genome editing in bacterial plant pathogens without donor DNA templates
Authors: Yan Fang , Wang Jingwen , Zhang Sujie , Lu Zhenwan , Li Shaofang , Ji Zhiyuan , Song Congfeng , Chen Gongyou , Xu Jin , Feng Jie , Zhou Xueping , Zhou Huanbin 
Published: November 2022

AbstractCRISPR-based genome editing technology is revolutionizing prokaryotic research, but it has been rarely studied in bacterial plant pathogens. Here, we have developed a targeted genome editing method with no requirement of donor templates for convenient and efficient gene knockout inXanthomonas oryzaepv.oryzae(Xoo), one of the most important bacterial pathogens on rice, by employing the heterogenous CRISPR/Cas12a fromFrancisella novicidaand NHEJ proteins fromMycobacterium tuberculosis.FnCas12a nuclease generated both small and large DNA deletions at the target sites as well as it enabled multiplex genome editing, gene cluster deletion and plasmid cure in theXooPXO99Astrain. Accordingly, a non-TAL effector-free polymutant strain PXO99AD25E, which lacks all 25Xopgenes involved inXoopathogenesis, has been engineered through iterative genome editing. Whole-genome sequencing analysis indicated that FnCas12a did not have a noticeable off-target effect. In addition, we revealed that these strategies are also suitable for targeted genome editing in another bacterial plant pathogenPseudomonas syringaepv.tomato(Pst). We believe that our bacterial genome editing method will greatly expand the CRISPR study on microorganisms and advance our understanding of the physiology and pathogenesis ofXoo.
Assessment of long-term trends in a threatened grassland bird community using daily bird lists
Authors: Bharadwaj Akshay , Mhamane Sarang , Bangal Priti , Menon Tarun , Isvaran Kavita , Quader Suhel 
Published: November 2022

AbstractOpen Natural Ecosystems (ONEs), such as tropical grasslands, are among the most threatened habitats on Earth today. The long-term monitoring of ONEs is an important research domain that is essential for understanding anthropogenic impacts and facilitating conservation action. Using a simple day-listing method over a 13-year period, we studied species trends in a central Indian grassland-agriculture mosaic experiencing several land-use changes. Our results indicate that some grassland species (such as the Great Indian BustardArdeotis nigriceps) show steep declines during the study period, while other generalist species (such as the Indian PeafowlPavo cristatus) show an increasing trend. Daily listing also reveals distinct seasonal patterns, and we discuss the Great Indian Bustard and Western Marsh HarrierCircus aeruginosusas examples. Our study highlights the utility of consistent checklist surveys to monitor population trends of bird communities within a changing landscape.
Programmed death-ligand 1 expression in human cancer three-dimensional cell culture models
Authors: Hudson K , Cross NA , Jordan-Mahy N , Leyland R 
Published: November 2022

AbstractProgrammed death-ligand 1 (PD-L1) expression is a survival mechanism employed by tumours to mediate immune evasion and tumour progression. PD-1/PD-L1-targeted therapies have revolutionised the cancer therapy landscape due to their ability to promote durable anti-tumour immune responses in select patients with advanced cancers. However, some patients are unresponsive, hyper-progressive or develop resistance. Better characterisation of the 3D architecture of solid tumours by utilising 3D cell culture could provide an environment that more closely recapitulatesin vivohuman tumours for investigating tumour-intrinsic PD-L1 signalling and immunotherapy responses. Here we investigated whether PD-L1 expression by human breast, prostate and colorectal cancer cell lines altered in 3D cell culture models compared to their 2D monolayer counterparts. We found that PD-L1 expression changed in 3D-cultured cancer cells when compared to 2D-cultured cells. Additionally, the expression of immunological markers, PD-1, PD-L2, CD44, DR4, DR5, Fas, and HLA-ABC were assessed in 3D cell culture and compared to their expression in 2D. These markers were also altered in 3D compared to 2D-cultured cells, highlighting the importance of utilising 3D models which may better able the investigation of tumour-intrinsic PD-L1 signalling, responses to PD-1/PD-L1-targeted therapy, and combination therapies.
Quantitative trait and transcriptome analysis of genetic complexity underpinning cardiac interatrial septation in mice using an advanced intercross line
Authors: Marjaneh Mahdi Moradi , Kirk Edwin P. , Patrick Ralph , Alankerage Dimuthu , Humphreys David T. , Del Monte-Nieto Gonzalo , Cornejo-Paramo Paola , Janbandhu Vaibhao , Doan Tram B. , Dunwoodie Sally L. , Wong Emily S. , Moran Chris , Martin Ian C.A. , Thomson Peter C. , Harvey Richard P. 
Published: November 2022

AbstractUnlike single-gene mutations leading to Mendelian conditions, common human diseases are likely emergent phenomena arising from multilayer, multiscale and highly interconnected interactions. Atrial and ventricular septal defects are the most common forms of cardiac congenital anomalies in humans. Atrial septal defects (ASD) show an open communication between left and right atria postnatally, potentially resulting in serious hemodynamic consequences if untreated. A milder form of atrial septal defect, patentforamen ovale(PFO), exists in about one quarter of the human population, strongly associated with ischaemic stroke and migraine. The anatomic liabilities and genetic and molecular basis of atrial septal defects remain unclear. Here, we advance our previous analysis of atrial septal variation through quantitative trait locus (QTL) mapping of an advanced intercross line (AIL) established between the inbred QSi5 and 129T2/SvEms mouse strains, that show extremes of septal phenotypes. Analysis resolved 37 unique septal QTL with high overlap between QTL for distinct septal traits. Whole genome sequencing of parental strains identified high confidence candidate deleterious variants, including in known human congenital heart disease genes, whereas transcriptome analysis of developing septa revealed networks involving ribosome, nucleosome, mitochondrial and extracellular matrix biosynthesis underlying septal variation. Analysis of variant architecture across different gene features, including enhancers and promoters, provided evidence for involvement of non-coding as well as protein coding variants. Our study provides the first high resolution picture of genetic complexity and network liability underlying common congenital heart disease, with relevance to human ASD and PFO.
Sphere-sequencing unveils local tissue microenvironments at single cell resolution
Authors: Handler Kristina , Bach Karsten , Borrelli Costanza , Ficht Xenia , Acar Ilhan E. , Moor Andreas E. 
Published: November 2022

AbstractThe spatial organization of cells within tissues is tightly linked to their biological function. Yet, methods to probe the entire transcriptome of multiple native tissue microenvironments at single cell resolution are lacking. Here, we introduce spheresequencing, a method that enables the transcriptomic characterization of single cells within spatially distinct tissue niches. Sphere-sequencing of the mouse metastatic liver revealed previously uncharacterized zonated genes and ligand-receptor interactions enriched in different hepatic microenvironments and the metastatic niche.
Spike-and-wave discharges of absence seizures in a sleep waves-constrained corticothalamic model
Authors: Dervinis Martynas , Crunelli Vincenzo 
Published: November 2022

ABSTRACTAimsRecurrent network activity in corticothalamic circuits generates physiological and pathological EEG waves. Many computer models have simulated spike-and-wave discharges (SWDs), the EEG hallmark of absence seizures (ASs). However, these models either provided detailed simulated activity only in a selected territory (i.e. cortical or thalamic) or did not test whether their corticothalamic networks could reproduce the physiological activities that are generated by these circuits.MethodsUsing a biophysical large-scale corticothalamic model that reproduces the full extent of EEG sleep waves, including sleep spindles, delta and slow (<0.1 Hz) waves, here we investigated how single abnormalities in voltage- or transmitter-gated channels in the neocortex or thalamus lead to SWDs.ResultsWe found that a selective increase in the tonic γ-aminobutyric acid type A receptor (GABA-A) inhibition of first order thalamocortical (TC) neurons or a selective decrease in cortical phasic GABA-A inhibition are sufficient to generate ∼4 Hz SWDs (as in humans) that invariably start in neocortical territories. Decreasing the leak conductance of higher order TC neurons leads to ∼7 Hz SWDs (as in rodent models) while maintaining sleep spindles at 7-14 Hz.ConclusionBy challenging key features of current mechanistic views, this simulated ictal corticothalamic activity provides novel understanding of ASs and makes key testable predictions.
ThePlasmodium falciparumapicoplast cysteine desulfurase provides sulfur for both iron sulfur cluster assembly and tRNA modification
Authors: Swift Russell P. , Elahi Rubayet , Rajaram Krithika , Liu Hans B. , Prigge Sean T. 
Published: November 2022

AbstractIron sulfur clusters (FeS) are ancient and ubiquitous protein cofactors that play fundamental roles in many aspects of cell biology. These cofactors cannot be scavenged or trafficked within a cell and thus must be synthesized in any subcellular compartment where they are required. We examined the FeS synthesis proteins found in the relict plastid organelle, called the apicoplast, of the human malaria parasitePlasmodium falciparum.Using a chemical bypass method, we deleted four of the FeS pathway proteins involved in sulfur acquisition and cluster assembly and demonstrated that they are all essential for parasite survival. However, the effect that these deletions had on the apicoplast organelle differed. Deletion of the cysteine desulfurase SufS led to disruption of the apicoplast organelle and loss of the organellar genome, whereas the other deletions did not affect organelle maintenance. Ultimately, we discovered that the requirement of SufS for organelle maintenance is not driven by its role in FeS biosynthesis, but rather, by its function in generating sulfur for use by MnmA, a tRNA modifying enzyme that we localized to the apicoplast. By complementing the activity of the parasite MnmA and SufS with a bacterial MnmA and its cognate cysteine desulfurase, we showed that the parasite SufS provides sulfur for both FeS biosynthesis and tRNA modification in the apicoplast. The dual role of parasite SufS is likely to be found in other plastid-containing organisms and highlights the central role of this enzyme in plastid biology.