bluuebunny/crossref_metadata_2025_split huggingface dataset:
A mitochondrial SET domain protein is essential inT. bruceiand required for mitochondrial morphology and function
Authors: Knight Emily W. , Ventura Rebeca Aquino , Mukala Niharikha , Morris Meredith T. 
Published: February 2024

AbstractProtein lysine methylation is a ubiquitous post-translational modification. First identified in histone tails, many non-histone proteins are methylated at lysine residues. SET domain proteins catalyze the transfer of a methyl group from a donor such as S-adenosyl-L-methionine (SAM) to lysine residues. In this work, we identify a novel SET domain protein, TbSETD, in the African trypanosome,Trypanosoma brucei, and demonstrate that it is essential in both insect stage procyclic form and bloodstream form parasites. Epitope-tagged TbSETD localizes to the mitochondrion and TbSETD-deficient parasites exhibit growth defects, altered mitochondrial morphology, increased ROS levels, and increased sensitivity to apoptotic triggers. TbSETD binding proteins identified in immunoprecipitation experiments were enriched in mitoribosomal proteins. We also demonstrate that TbSETD immunoprecipitated from parasites has methyltransferase activityin vitroand methyllysine western blots reveal that TbSETD-deficient parasites have reduced levels of a 37 kDa mitochondrial protein. OrthoMCL DB indicates TbSETD is conserved only in kinetoplastids, suggesting a unique role in the biology of these parasites, and highlighting its potential as a drug target.SignificanceKinetoplastid parasites include several medically important organisms for which current treatments are insufficient. SET domain protein lysine methyltransferases (PKMTs) are highly druggable and have predominately been studied in the context of chromatin remodeling and gene expression. This work provides the first example of a SET domain PKMT that localizes to the mitochondria in any protozoan parasite and the first implication that protein lysine methylation may be important to mitoribosomal biogenesis.
ErbB inhibition rescues nigral dopamine neuron hyperactivity and repetitive behaviors in a mouse model of fragile X syndrome
Authors: D’Addario Sebastian Luca , Rosina Eleonora , Massaro Cenere Mariangela , Bagni Claudia , Mercuri Nicola Biagio , Ledonne Ada 
Published: February 2024

AbstractRepetitive behaviors are core symptoms of autism spectrum disorders (ASD) and fragile X syndrome (FXS), the prevalent genetic cause of intellectual disability and autism. The nigrostriatal dopamine (DA) circuit rules movement and habit formation; therefore, its dysregulation stands as a leading substrate for repetitive behaviors. However, beyond indirect evidence, specific assessment of nigral DA neuron activity in ASD and FXS models is lacking. Here, we show that hyperactivity of substantia nigra pars compacta (SNpc) DA neurons is an early feature of FXS. The underlying mechanisms rely on mGluR1 and ErbB receptors. Up-regulation of ErbB4 and ErbB2 in nigral DA neurons drives neuronal hyperactivity and repetitive behaviors of the FXS mouse, simultaneously rescued by ErbB inhibition. In conclusion, beyond providing the first evidence of dysregulation of the SNpc DA nucleus in FXS, we identify novel targets - ErbB receptors - whose inhibition proficiently attenuates repetitive behaviors, thus opening an avenue toward innovative therapies for ASD and FXS.
FLIPs: Novel Genetically Encoded Biosensors for Functional Imaging of Cell Signaling by Polarization Microscopy
Authors: Miclea Paul , Nagy-Marková Vendula , Van den Eynde Robin , Vandenberg Wim , Sakhi Alina , Bondar Alexey , Myšková Jitka , Dedecker Peter , Lazar Josef 
Published: February 2024

AbstractGenetically encoded fluorescent biosensors convert specific biomolecular events into optically detectable signals. By revealing biochemical processesin situ, they have revolutionized cell biology. However, imaging molecular processes often requires modifying the proteins involved, and many molecular processes are still to be imaged. Here we present a novel, widely applicable design of genetically encoded biosensors that notably expand the observation possibilities, by taking advantage of a hitherto overlooked detection principle: directionality of optical properties of fluorescent proteins. The probes, which we term FLIPs, offer an extremely simple design, high sensitivity, multiplexing capability, ratiometric readout and resilience to bleaching artifacts, without requiring any modifications to the probe targets. We demonstrate their performance on real-time single-cell imaging of activation of G protein-coupled receptors (GPCRs), G proteins, arrestins, small GTPases, as well as receptor tyrosine kinases, even at endogenous expression levels. We also identify a new, pronounced, endocytosis-associated conformational change in a GPCR–β-arrestin complex. By demonstrating a novel detection principle and allowing many more cellular processes to be visualized, FLIPs are likely to inspire numerous future developments and insights.
An age-specific platelet differentiation path from hematopoietic stem cells contributes to exacerbated thrombosis
Authors: Poscablo DM , Worthington AK , Smith-Berdan S , Manso BA , Adili R , Cool T , Reggiardo RE , Dahmen S , Beaudin AE , Boyer SW , Holinstat M , Forsberg EC 
Published: February 2024

SUMMARYPlatelet dysregulation is drastically increased with advanced age and contributes to making cardiovascular disorders the leading cause of death of elderly humans. Hematopoietic stem and progenitor cells continuously give rise to platelets, but their contributions to variable platelet production and activity throughout life remain unclear. Here we reveal a direct differentiation pathway from hematopoietic stem cells into platelets that is unique to aging. An unequivocal genetic lineage tracing mouse model demonstrated that this age-specific pathway is progressively propagated over time. Remarkably, the age-specific platelet path is decoupled from all other hematopoietic lineages, including erythropoiesis, and operates as an additional layer in parallel with canonical platelet production. This results in two molecularly and functionally distinct populations of megakaryocyte progenitor cells that that operate in parallel. The age-specific megakaryocyte progenitor population has profoundly enhanced capacity to engraft, expand, and reconstitute platelets, and produces an additional platelet population that exists only in old mice. Consistent with increased thrombotic incidence upon aging, the two pools of co-existing platelets contribute to age-related thrombocytosis and dramatically increased thrombosisin vivo. Upon acute, platelet-specific stress, the age-specific MkPs endowed old mice with superior capacity to rapidly restore platelet counts. These findings reveal stem cell-based aging as a mechanism for platelet dysregulation and identify an aging-induced population of functionally enhanced MkPs as a unique source of age-specific platelets.>HIGHLIGHTSAging leads to two parallel platelet specification paths from HSCsThe shortcut platelet pathway is perpetuated by highly expansive MkPs unique to agingThe age-specific differentiation path contributes to thrombosis and platelet hyperreactivityAge-specific MkPs serve as potent first responders to acute platelet loss
Synergistic and antagonistic drug interactions are prevalent but not conserved across acute myeloid leukemia cell lines
Authors: Kalkan Fatma Neslihan , Yildiz Muhammed Sadik , Wood N. Ezgi , Farid Michael , McCoy Melissa , Zhang Chengcheng , Lin Milo , Posner Bruce , Chung Stephen S. , Toprak Erdal 
Published: February 2024

AbstractAcute myeloid leukemia (AML) is the most prevalent type of leukemia in adults. Despite advancements in medicine, the standard treatment that utilizes a combination of cytarabine and daunorubicin for AML has remained the same for decades. Combination drug therapies are proven to be an effective way to achieve targeted efficacy while minimizing drug dosage along with the unintended side effects. However, a systematic survey of synergistic potential of drug-drug interactions in the context of AML pathology is currently lacking. Here we examine the interactions between 15 frequently used cancer drugs across distinct AML cell lines and demonstrate that synergistic and antagonistic drug-drug interactions are widespread but not conserved across these cell lines. Notably, enasidenib (AG-221) and venetoclax (ABT-199), recently approved anticancer agents, exhibited the highest counts of synergistic interactions and the fewest antagonistic ones. In contrast, 6-Thioguanine (6-TG), a purine analog, was involved in the highest number of antagonistic interactions. The interactions we report here cannot be attributed solely to the inherent synergistic or antagonistic natures of these three drugs, as each drug we examined was involved in several synergistic or antagonistic interactions in the cell lines we tested. Moreover, we observed that these drug-drug interactions are not conserved across cell lines, suggesting that the success of combination therapies might vary depending on AML genotypes. For instance, we found that a single mutation in the TF1 cell line could dramatically alter drug-drug interactions, even turning synergistic interactions into antagonistic ones, as seen with AG-221 and cladribine A (2CdA). Our findings provide a preclinical survey of the potential synergistic effects revealing the complexity of the problemin vitro. However, the exploitable synergistic regimes in clinical scenarios remain to be explored. We anticipate these results to be an insightful guideline for future clinical studies, aiming to refine chemotherapy regimens and ultimately enhance patient outcomes.
Functional marker CAPS-799 of theTaPHT1;9-4Bgene is useful for screening phosphorus-efficient wheat cultivars
Authors: Wang Jinfeng , Chen Zedong , Shi Huanting , Lou Chuang , Fu Kaixia , Wang Yaxin , Yu Bo , Guo Tiancai , Wang Yonghua , Wang Pengfei , Kang Guozhang 
Published: February 2024

AbstractContextIn our previous study,TaPHT1;9-4B, one key high-affinity Pi transporter, was found to greatly contribute to Pi acquisition and transportation, and its functional marker CAPS-799 was subsequently developed to identify its Pi-efficient elite haplotype.ObjectiveThe study aimed to screen a varieties of wheat cultivars by using the above CAPS-799, identify its Pi-efficient elite haplotype cultivars, and reveal its physiological mechanism.MethodsSuccessive two-year field experiments without Pi fertilizer supply, and hydroponic experiment with low Pi (10 μM) were performed. P concentrations, biomasses, grain yields, yield components, root growth parameters, andTaPHT1;9-4Btranscript levels were measured. Total P accumulation and transport efficiency, and the relative growth rates were calculated.ResultsEight Pi-efficient wheat cultivars (Hap3haplotype) were screened out by using the CAPS-799 from 80 modern major cultivars, and in successive two-year field experiments, their grain yields, spike numbers, P absorption and transport efficiencies were significantly higher than those ofNon-Hap3haplotypes (Hap1, 2and4) under no Pi fertilizer supply condition, and therefore, these eight cultivars belonged to Pi-efficient elite haplotype.TaPHT1;9-4Btranscript levels in roots at the early stage of grain filling period in field experiment, and the relative growth rates of total root surface areas, volumes and mean root diameters ofHap3cultivars in hydroponic experiment, were markedly higher than other haplotypes.ConclusionsCAPS-799 was a useful functional marker for screening Pi-efficient wheat cultivars, and its Pi-efficient wheat cultivars were characterized with higherTaPHT1;9-4Btranscript levels and more roots.ImplicationsCAPS-799 will be used to screen or develop Pi-efficient wheat cultivars.
Short communications of a new circulating Dengue genotype III American II lineage in Mexico: outbreak 2022-2023
Authors: Madera-Sandoval RL , Rodríguez-Maldonado AP , Rivero-Arredondo SV , Quiroz-Mercado J , Molina-Gomez IE , Hernandez-Rivas L , Lopez-Martinez I , Vazquez-Pichardo M , Correa-Morales F , Wong-Arámbula C 
Published: February 2024

AbstractWe report for the first time the circulation of American II lineage of Dengue virus serotype 3 genotype III in Mexico uncovered by the genomic surveillance in charge of the Instituto de Diagnóstico y Referencia Epidemiológicos through sequencing the whole genome using Illumina platform. The importance of the characterization of a new lineage circulating in Mexico impacts public health and the actions to be taken to mitigate new outbreaks and in the future associate them with clinical responses that the new lineage may cause.
Syndemic Geographic Patterns of Cancer Types in a Health Deprived Area of England: a new Paradigm for Public Health Cancer Interventions?
Authors: Jones Catherine , Keegan Tom , Knox Andy , Birtle Alison , Mendes Jessica A. , Heys Kelly , Atkinson Peter , Sedda Luigi 
Published: February 2024

AbstractCancer poses a significant public health challenge, and accurate tools are crucial for effective intervention, especially in high-risk areas. The North West of England, historically identified as a region with high cancer incidence, has become a focus for public health initiatives. This study aims to analyse cancer risk factors, demographic trends and spatial patterns in this region by employing a novel spatial joint modelling framework designed to account for large frequencies of left-censored data.Cancer diagnoses were collected at the postcode sector level. The dataset was left-censored due to confidentiality issues, and categorised as interval censored. Demographic and behavioural factors, alongside socio-economic variables, both at individual and geographic unit levels, were obtained from the linkage of primary and secondary health data and various open source datasets. An ecological investigation was conducted using joint spatial modelling on nine cancer types (breast, colorectal, gynaecology, haematology, head and neck, lung, skin, upper GI, urology), for which explanatory factors were selected by employing an accelerated failure model with lognormal distribution. Post-processing included principal components analysis and hierarchical clustering to delineate geographic areas with similar spatial patterns of different cancer types.The study included 15,506 cancer diagnoses from 2017 to 2022, with the highest incidence in skin, breast and urology cancers. Preliminary censoring adjustments reduced censored records from 86% to 60%. Factors such as age, ethnicity, frailty and comorbidities were associated with cancer risk. The analysis identified 22 relevant variables, with comorbidities and ethnicity being prominent. The spatial distribution of the risk and cumulative risk of the cancer types revealed regional variations, with five clusters identified. Rural areas were the least affected by cancer and Barrow-in-Furness was the area with the highest cancer risk.This study emphasizes the need for targeted interventions addressing health inequalities in different geographical regions. The findings suggest the need for tailored public health interventions, considering specific risk factors and socio-economic disparities. Policymakers can utilize the spatial patterns identified to allocate resources effectively and implement targeted cancer prevention programmes.
A missense mutation in theXan-hgene encoding the Mg-chelatase subunit I leads to a viable pale green line with phenotypic features of potential interest for barley breeding programs
Authors: Persello Andrea , Tadini Luca , Rotasperti Lisa , Ballabio Federico , Tagliani Andrea , Torricella Viola , Jahns Peter , Dalal Ahan , Moshelion Menachem , Camilloni Carlo , Rosignoli Serena , Hansson Mats , Cattivelli Luigi , Horner David , Rossini Laura , Tondelli Alessandro , Salvi Silvio , Pesaresi Paolo 
Published: February 2024

AbstractThe pale green trait, i.e. reduced chlorophyll content, has been shown to increase the efficiency of photosynthesis and biomass accumulation when photosynthetic microorganisms and tobacco plants are cultivated at high densities. Thus, thehus1barley mutant is defective in photosystem antenna biogenesis, and exhibits a 50% reduction in leaf chlorophyll content. Nevertheless, its agronomical performance under standard field conditions is comparable to that of the wild-type. This supports the notion that crops can decrease their investment in antenna proteins and chlorophyll biosynthesis without detrimental effects on productivity. Here, we assess the effects of reducing leaf chlorophyll content in barley by altering the chlorophyll biosynthesis pathway (CBP). To this end, we have isolated and characterised the pale green barley mutantxan-h.chli-1, which carries a missense mutation in theXan-hgene for subunit I of Mg-chelatase (HvCHLI), the first enzyme in the CBP. Intriguingly,xan-h.chli-1is the only known viable homozygous mutant at theXan-hlocus in barley. The Arg298Lys amino-acid substitution in the ATP-binding cleft causes a slight decrease inHvCHLI protein abundance, and a marked reduction in Mg-chelatase activity. Under controlled growth conditions, mutant plants display reduced accumulation of antenna and photosystem core subunits, together with reduced photosystem II yield relative to wild type under moderate illumination, and consistently higher than wild-type levels at high light intensities. Moreover, the reduced content of leaf chlorophyll is associated with a stable reduction in daily transpiration rate, and slight decreases in total biomass accumulation and water-use efficiency. These traits are reminiscent of phenotypic features of wild barley accessions and landraces that thrive under arid climatic conditions. Overall, our findings make thexan-h.chli-1allelic variant of potential interest for tailoring barley, and other crop plants, for growth in harsh environments.
Boosting the Sensitivity of Quantitative Single-Cell Proteomics with Activated lon-Tandem Mass Tags (AI-TMT)
Authors: Peters-Clarke Trenton M. , Liang Yiran , Mertz Keaton L. , Lee Kenneth W. , Westphall Michael S. , Hinkle Joshua D. , McAlister Graeme C. , Syka John E. P. , Kelly Ryan T. , Coon Joshua J. 
Published: February 2024

ABSTRACTSingle-cell proteomics is a powerful approach to precisely profile protein landscapes within individual cells toward a comprehensive understanding of proteomic functions and tissue and cellular states. The inherent challenges associated with limited starting material in single-cell analyses demands heightened analytical sensitivity. Just as advances in sample preparation maximize the amount of material that makes it from the cell to the mass spectrometer, we strive to maximize the number of ions that make it from ion source to the detector. In isobaric tagging experiments, limited reporter ion generation limits quantitative accuracy and precision. The combination of infrared photoactivation and ion parking circumvents them/zdependence inherent in HCD, maximizing reporter generation and avoiding unintended degradation of TMT reporter molecules in a method we term activated ion-tandem mass tags (AI-TMT). The method was applied to single-cell human proteomes using 18-plex TMTpro, resulting in a 4-5-fold increase in reporter ion signal on average compared to conventional SPS-MS3approaches. AI-TMT enables faster duty cycles, higher throughput, and increased peptide identification and quantification. Comparative experiments showcase 4-5-fold lower injection times for AI-TMT, providing superior sensitivity without compromising accuracy. In all, AI-TMT enhances the sensitivity and dynamic range of proteomic experiments and is compatible with other techniques, including gas-phase fractionation and real-time searching, promising increased gains in the study of cellular heterogeneity and disease mechanisms.
Stress pathway outputs are encoded by pH-dependent phase separation of its components
Authors: Didan Yuliia , Ghomlaghi Milad , Nguyen Lan K. , Ng Dominic C. H. 
Published: February 2024

AbstractSignal processing by intracellular kinases control near all biological processes but how precise functions of signal pathways evolve with changed cellular contexts is poorly understood. Functional specificity of c-Jun N-terminal Kinases (JNK) activated in response to a broad range of pathological and physiological stimuli are partly encoded by signal strength. Here we reveal that intracellular pH (pHi) is a significant component of the JNK regulatory network and defines JNK signal response to precise stimuli. We showed that nuanced fluctuations in physiological pHi regulates JNK activity in response to cell stress. Interestingly, the relationship between pHi and JNK activity was dependent on specific stimuli and upstream kinases involved in pathway activation. Cytosolic alkalinisation promoted phase transition of upstream ASK1 to augment JNK activation. While increased pHi similarly induced JNK2 to form condensates, this led to attenuated JNK activity. Mathematical modelling of feedback signalling incorporating pHi and differential contribution by JNK2 and ASK1 condensates was sufficient to delineate the strength of JNK signal response to specific stimuli. This new knowledge of pHi regulation with consideration of JNK2 and ASK1 contribution to signal transduction may delineate oncogenic versus tumour suppressive functions of the JNK pathway and cancer cell drug responses.
Mechanistic dissection of theCHD4enhancers reveals cooperative functions among the homotypic ZNF410 clustered motifs
Authors: Xu Siyuan , Ren Ren , Peng Chuxuan , Lu Haowen , Ly Lana C. , Crossley Merlin , Xu Bin , Cheng Xiaodong , Blobel Gerd A. , Lan Xianjiang 
Published: February 2024

SUMMARYTranscription factors often regulate numerous target genes. However, ZNF410 controls only a single gene,CHD4,in human erythroid cells by its highly restricted chromatin occupancy to theCHD4locus via two clusters of ZNF410 binding motifs. Here, we uncover that ZNF410 controls chromatin accessibility and activity of the twoCHD4enhancer regions. Combining CRISPR/Cas9 genomic deletion with CRISPRi approaches, we demonstrate that both enhancer regions additively contribute toCHD4gene expression. Mutations of the di-adenine nucleotides within the ZNF410 binding motif fully disrupt ZNF410-DNA interaction. Luciferase assays, ChIP-seq, and ATAC-seq studies reveal that the homotypic clustered motifs within theCHD4enhancers are recognized by ZNF410 in a collaborative fashion. Especially, the three ZNF410 motifs located in the 3’ end of the distal enhancer act as “switch motifs” to control the chromatin accessibility and activity of the whole distal enhancer region. Together, our findings expose a complex functional hierarchy of motifs, where clustered motifs bound by the same transcription factor cooperate to fine-tune the expression of target gene.HighlightsZNF410 maintains the accessibility of theCHD4enhancer regionsThe two enhancer elements additively modulateCHD4gene expressionThe dinucleotide “AA” is the key bases within ZNF410 binding motifZNF410 binds to homotypic clustered motifs in a cooperative manner