bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repurposing CD19-directed immunotherapies for pediatric t(8;21) acute myeloid leukemia
Authors: Barneh Farnaz , Koedijk Joost B. , Wijnen Noa E. , Meulendijks Tom , Ashtiani Minoo , Dunnebach Ester , Dautzenberg Noël , Cornel Annelisa M. , Krippner-Heidenreich Anja , Klein Kim , Zwaan C. Michel , Kuball Jürgen , Nierkens Stefan , Cloos Jacqueline , Kaspers Gertjan J.L. , Heidenreich Olaf 
Published: April 2024

AbstractIn contrast to patients with B cell precursor acute lymphoblastic leukemia (BCP-ALL), patients with acute myeloid leukemia (AML) have not yet benefited from recent advances in targeted immunotherapy. Repurposing immunotherapies that have been successfully used to target other hematological malignancies could, in case of a shared target antigen, represent a promising opportunity to expand the immunotherapeutic options for AML. Here, we evaluated the expression of CD19 in a large pediatric AML cohort, assessed theex vivoAML killing efficacy of CD19-directed immunotherapies, and characterized the bone marrow immune microenvironment in pediatric AML, BCP-ALL, and non-leukemic controls. Out of 167 newly diagnosedde novopediatric AML patients, 18 patients (11%) had CD19+AML, with 61% carrying the translocation t(8;21)(q22;q22). Among CD19+samples, we observed a continuum of CD19 expression levels on AML cells. In individuals exhibiting unimodal and high CD19 expression, the antigen was consistently present on nearly all CD34+CD38-and CD34+CD38+subpopulations. Inex vivoAML-T cell co-cultures, blinatumomab demonstrated substantial AML killing, with an efficacy similar to BCP-ALL. In addition, CAR T cells could effectively eliminate CD19+AML cellsex vivo. Furthermore, our immunogenomic assessment of the bone marrow immune microenvironment of newly diagnosed pediatric t(8;21) AML revealed that T- and NK cells had a less exhausted and senescent phenotype in comparison to pediatric BCP-ALL. Altogether, our study underscores the promise of CD19-directed immunotherapies for the treatment of pediatric CD19+AML.
The selective 5-HT2Areceptor agonist LPH-5 induces persistent and robust antidepressant-like effects in rodents
Authors: Jensen Anders A. , Cecchi Claudia R. , Hibicke Meghan , Bach Astrid H. , Kaadt Erik , Märcher-Rørsted Emil , Nichols Charles D. , Elfving Betina , Kristensen Jesper L. 
Published: April 2024

ABSTRACTPsychedelic-assisted psychotherapy has over the last decade emerged as a promising treatment strategy for mental health disease, and the therapeutic potential in classical psychedelics such as psilocybin, LSD and 5-MeO-DMT is presently being pursued in a plethora of clinical trials. However, the resurgent interest in the drugs as therapeutics has also prompted a search for novel agents with more specific pharmacological activities than the rather promiscuous classical psychedelics. Here we present the results of an elaborate preclinical characterization of one such compound, LPH-5 [(S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine]. LPH-5 was found to be a potent partial agonist at the 5-HT2Areceptor (5-HT2AR) and to exhibit pronounced selectivity for this receptor over the related 5-HT2Band 5-HT2Creceptors in a range of functional assays. LPH-5 (0.375 – 12.0 mg/kg,i.p.) dose-dependently induced head-twitch responses (HTR) in Sprague Dawley rats, with substantial 5-HT2AR engagement being observed at 0.5-1.0 mg/kg. Acute administration of LPH-5 (1.5 mg/kg,i.p.) induced robust antidepressant-like effects in Flinders Sensitive Line rats and adrenocorticotropic hormone-treated Sprague Dawley rats, and LPH-5 (0.3 and 1.5 mg/kg,i.p.) induced significant effects in a recently developed Wistar Kyoto rat model proposed to reflect the long-term antidepressant-like effects produced by psychedelics in humans. In conclusion, selective 5-HT2AR activation, as mediated here by LPH- 5, seems to hold antidepressant potential, suggesting that this activity component is key for the beneficial effects of classical psychedelics. Hence, we propose that LPH-5 and other 5-HT2AR- selective agonists could hold potential as therapeutics in psychiatric disease as a new generation of psychedelic-derived antidepressant.
Limnospira(Cyanobacteria) chemical fingerprint reveals local molecular adaptation
Authors: Roussel Théotime , Hubas Cédric , Halary Sébastien , Chynel Mathias , Duval Charlotte , Cadoret Jean-Paul , Meziane Tarik , Vernès Léa , Yéprémian Claude , Bernard Cécile , Marie Benjamin 
Published: April 2024

AbstractLimnospiracan colonize a wide variety of environments (e.g.,freshwater, brackish, alkaline or alkaline-saline water) and develop dominant and even permanent blooms that limit over-shadowed adjacent phototrophs diversity, especially in alkaline and saline environments. Previous phylogenomic analysis ofLimnospiraallowed us to distinguish two major phylogenetic clades (I and II) but failed to clearly segregate strains according to their respective habitats in terms of salinity or biogeography. In the present work, we attempt to determine whetherLimnospiradisplays metabolic signatures specific to its different habitats, particularly brackish or alkaline-saline ecosystems, and question the impact of accessory gene repertoires on respective chemical adaptations.The study of the metabolomic diversity of 93 strains ofLimnospirafrom the Paris Museum Collection, grown under standardized lab culture conditions, showed clearly distinct chemical fingerprints that were correlated with the respective biogeographic origins of the strains. The molecules that most distinguish the differentLimnospirageographic groups are sugars, lipids, peptides, photosynthetic pigments, and antioxidant molecules. Interestingly, these molecule enrichments might represent adaptation traits to the local conditions encountered in their respective sampling environments concerning salinity, light and oxidative stress. We hypothesize that within extreme environments, such as those colonized byLimnospira, a large set of flexible genes can provide remarkable adaptation to specific local environmental conditions (e.g.,salinity, light, and oxidative pressure). Thus, the occurrence withinLimnospirapopulation genomes of a specific set of flexible genes potentially involved in the production of certain metabolites may provide valuable adaptative traits that may support the bloom persistence beyond environmental condition variations.ImportanceLimnospiraare ubiquitous cyanobacteria able to colonize and dominate a wide range of alkaline-saline environments around the world according to remarkable adaptative strategies. Phylogenomic analysis ofLimnospira platensisallowed to distinguish two major phylogenetic clades (I and II) but failed to clearly segregate strains following their habitats in terms of salinity or biogeography. One can presume that the genes found within this variable portion of the genome of these clades could be involved inL. platensisadaptation to local environmental conditions. In the present paper, we attempt to determine whetherLimnospira platensisdisplays metabolic signatures specific to its different habitats, particularly brackish or alkalinesaline ecosystems, and question the impact of accessory gene repertoire on respective chemical adaptation.
Plant G x Microbial E: Plant genotype interaction with soil bacterial community shapes rhizosphere composition during invasion
Authors: Berlow Mae , Mesa Miles , Creek Mikayla , Duarte Jesse , Carpenter Elizabeth , Phinizy Brandon , Andonian Krikor , Dlugosch Katrina M 
Published: April 2024

ABSTRACTIt is increasingly recognized that different genetic variants can uniquely shape their microbiomes. Invasive species often evolve in their introduced ranges, but little is known about the potential for microbial associations to evolve during invasion as a result. We investigated invader genotype (G) and microbial environment (E) interactions inC. solstitialis(yellow starthistle), a Eurasian plant that is known to have evolved novel genotypes, and to have altered microbial interactions, in its severe invasion of California, USA. We conducted an experiment in which native and invading genotypes were inoculated with native and invaded range soil microbial communities. We used amplicon sequencing to characterize rhizosphere bacteria in both the experiment and the field soils from which they were derived. We found that bacterial diversity is higher in invaded soils, but that invading genotypes accumulated a lower diversity of bacteria and unique microbial composition in experimental inoculations, relative to native genotypes. Associations with potentially beneficial Streptomycetaceae were particularly interesting, as these were more abundant in the invaded range and accumulated on invading genotypes. Thus variation in microbial associations of invaders was driven by the interaction of G and E, and microbial communities appear to change in composition along with host evolution during invasion.
Identification of Glucosidase II that regulates STIM1 activation dynamics
Authors: Du Yangchun , Zheng Sisi , Wang Feifan , Li Jia , Yuan Xiaoman , Xi Chao , Zhou Yandong , Wang Youjun 
Published: April 2024

AbstractThe ubiquitous presence of stromal interaction molecule (STIM), endoplasmic reticulum (ER) Ca2+sensors, plays a crucial role for maintaining Ca2+homeostasis and signaling in mammalian cells by linking ER Ca2+depletion with extracellular Ca2+influx. Although recent advancements have shed light on glycosylation in STIM proteins, further exploration of deglycosylation enzyme modification and its role remains limited by methodological constraints. In this study, leveraging the miniTurbo-driven proximal biotinylation labeling method, we were able to screen for weak and transiently binding protein molecules within specific environments like ER lumina. Herein, we unveil glucosidase II, comprising GANAB and PRKCSH, as a novel partner of the STIM1 complex. Through investigations into Glucosidase II’s (Glu II) regulation of STIM1’s Ca2+affinities bothin celluloandin situ, alongside its impact on store-operated Ca2+entry (SOCE), we propose a novel mechanism wherein Glu II governs STIM1 activation by modulating Ca2+binding affinity, thereby adjusting the level of activated STIM1 in response to physiological stimulation.
Conserved Function of Drg GTPases in Promoting Protein Synthesis in Stalled Ribosomes
Authors: Hawk Christopher W. , Jin Hong 
Published: April 2024

AbstractMaintaining proper protein homeostasis is essential for cell physiology. The ribosome and GTPases, which are two of the most ancient and critical cellular molecules, are central players in protein synthesis and its regulation. Here we report the discovery of a new general translation factor that targets stalled ribosomes and promotes protein synthesis in an evolutionarily conserved manner. We show that the essential bacterial Obg GTPases are distant homologs of eukaryotic and archaeal Drg proteins and serve critical roles in promoting efficient protein translation in stalled ribosomes. Throughin vivocharacterization, including cross-species complementation of cells where ribosomes are induced to stall by addition of either the antibiotic anisomycin or exogenous mRNA harboring a long poly(A) sequence, we demonstrate that a conserved function of Drg proteins is to alleviate ribosomal stalling during translation. Our data show that bacterial Obg rescues stalled ribosomes in both Saccharomyces cerevisiae and human cells lacking endogenous Drgs, as does supplementation of the respective endogenous Drg proteins from yeast and human cells. Furthermore, the presence of ObgE and GTP stimulates peptidyl transfer, the key catalytic function of the ribosome, suggesting a possible molecular mechanism of this GTPase to enhance translation in stalled ribosomes. This discovery shows that the Drg protein is a new general translation factor that directly affords cells from the three domains of life a new form of translation regulation.
Plant Accessible Tissue Clearing Solvent System (PATCSOS) for 3-D Imaging of Whole Plants
Authors: Zhang Hantao , Zhu Lei , Zhao Hu , Li Zhen 
Published: April 2024

AbstractTissue clearing is a technique to make the inner structure of opaque tissue visible to achieve 3-dimensional (3-D) tissue imaging by unifying the refractive indexes of most of the cell components. Tissue clearing is widely used in animal tissue imaging, where whole body 3-D imaging has been realized. However, it has not been widely used in plant research. Most plant tissue clearing protocols have their disadvantages, including low efficiency, not being fluorescence-friendly and poor transparency on tissues with a high degree of lignification. In this work, we developed a new plant tissue clearing method for whole plant imaging, named Plant Accessible Tissue Clearing Solvent System (PATCSOS), which was based on the Polyethylene Glycol-associated Solvent System (PEGASOS). The PATCSOS method realized extensive transparency of plant tissues, including the flower, leaf, stem, root, and seed of Arabidopsis thaliana, with high efficiency. The PATCSOS method consists of four main steps: fixation, decolorization/delipidation, dehydration, and clearing. Subsequently a rapid and efficient clearing of mature plant tissue can be achieved. With PATCSOS, we can image Arabidopsis seedling in their entirety in 3-D using endogenous cellulose autofluorescence. What’s more, the PATCSOS method is compatible with fluorescence protein imaging and GUS staining, which greatly expands the applicability of this method. We also imaged intactNicotiana benthamianaleaf andZea maysembryos. Our results showed that the PATCSOS clearing method is an excellent tool to study plant development and cell biology.
Ribosomal, Satellite III (1q12) and Telomere Repeat Copy Number Variations in Cystic Fibrosis Patients Used as a Model of Permanent Stress and Survivability
Authors: Ershova E.S. , Kondratyeva E.I. , Porokhovnik L.N. , Voronkova A.Y. , Melyanovskaya Yu. L. , Krasovsky S.A. , Veiko R.V. , Zhekaite E.K. , Starinova M.A. , Veiko N.N. , Kostyuk S.V. 
Published: April 2024

ABSTRACTIntroductionRibosomal (rDNA), satellite III (f-SatIII) and telomere (TR) tandem repeats perform a variety of functions in the human cell. Copy number variations (CNVs) of these repeats contributes to the global chromatin architecture and genome expression changes in response to stress or pathology. An elevated rDNA abundance and lowered contents of f-SatIII and TR were found in blood leukocytes of patients with schizophrenia. The main question of the study was: are the CNVs of the three repeat types in blood leukocytes a universal phenomenon linked to a patho4logy associated with chronic oxidative stress? Cystic fibrosis (CF), a monogenic disease was chosen as an object of the study.Materials and MethodsWe determined the rDNA, f-SatIII and TR content in the blood leukocyte genomes of 545 subjects aged 0.2 to 50 years. The subjects were divided into three groups: Control (HC-group, N = 267), CF group (N= 186) and CF(d) group (severe patients, who died after some time upon sampling, aged 17 to 40 years, N = 92). For each patient, the type of the mutation inCFTRgene had been determined earlier. Non-radioactive quantitative hybridization technique was applied to quantify the repeats.Resultsthe rDNA abundance was elevated in the DNA of CF and CF(d) groups (565±105 copies per genome, N=278) compared to HC group (445±112 copies, N=267). A patient’s age 3 to 16 years was associated with “severe” mutations inCFTR(98% of cases), increased f-SatIII repeat counts and decreased telomere repeat (TR) contents in genome DNA compared to the age-matched controls. The genomes of deceased patients from CF(d) group also harbored increased numbers of f-SatIII and decreased numbers of TR. Patients above 16 years with a milder course of the disease and relatively low content of “severe”CFTRmutations contained less f-SatIII and more TR in their genomic DNA. A parameterrDNA·(f-SatIII/TR)showed a maximum difference between patients with relatively mild (age 17 to 40) and severe (age 17 to 40) forms of the pathology according to ROC analysis data (AUC = 0.86).ConclusionCystic fibrosis was associated with an increase in rDNA abundance and altered f-SatIII and TR contents in the DNA of cases compared to the controls. The severe course of the disease was characterized with high f-SatIII contents and shortened telomeres. Whereas mild CF cases were associated with low contents of f-SatIII and normal or slightly reduced telomere length. The indexrDNA· (f-SatIII/TR)might be a predictor of the patient’s life expectancy.
CRISPR-Cas9 knockout screen informs efficient reduction of theKomagataella phaffiisecretome
Authors: Dalvie Neil C. , Lorgeree Timothy R. , Yang Yuchen , Rodriguez-Aponte Sergio A. , Whittaker Charles A. , Hinckley Joshua A. , Clark John J. , Del Rosario Amanda M. , Love Kerry R. , Love J. Christopher 
Published: April 2024

AbstractThe yeastKomagataella phaffiiis widely used for manufacturing recombinant proteins, but secreted titers of recombinant proteins could be improved by genetic engineering. In this study, we hypothesized that cellular resources could be redirected from production of endogenous proteins to production of recombinant proteins be deletion of unneeded endogenous proteins. We identified a set of endogenous secreted proteins inK. phaffiiand attempted to disrupt these genes, but our efforts were hindered by limited annotation of genes, especially essential ones—this is a common problem for genetic engineering of non-model organisms. To predict essential genes, therefore, we designed, transformed, and sequenced a pooled library of guide RNAs for CRISPR-Cas9-mediated knockout of all endogenous secreted proteins. We then used predicted gene essentiality to guide iterative disruptions of up to 11 non-essential genes. Engineered strains exhibited a ∼20x increase in the production of human serum albumin and a twofold increase in the production of a monoclonal antibody. The pooled library of secretome-targeted guides for CRISPR-Cas9 and knowledge of gene essentiality reported here will facilitate future efforts to engineerK. phaffiifor production of other recombinant proteins and enzymes.
Spectrum of
S
- and
P
-wave
ccq¯q¯′

(q¯,q¯′=u¯,d¯,s¯)
systems in a chiral SU(3) quark model
Authors: Wang Du , Song Ke-Rang , Wang Wen-Ling , Huang Fei 
Published: April 2024

Inspired by the resonance Tcc+(3875) recently observed by the LHCb Collaboration, we systematically explore the S- and P-wave ccq¯q¯′ (q¯,q¯′=u¯,d¯,s¯) systems in a chiral SU(3) quark model. The Hamiltonian contains the kinetic energy, the one-gluon-exchange (OGE) potential, the confinement potential, and the one-boson-exchange (OBE) potential stemming from the coupling of quark and chiral fields. The Schrödinger equation is solved by use of the variational method with the spacial trial wave functions chosen as Gaussian functions. It is found that the lowest state has a mass 3879 MeV, isospin and spin-parity IJP=01+, and quark constituent ccu¯d¯, in agreement with the experimentally observed Tcc+(3875). This state is approximately at the calculated DD* threshold and has a root-mean-square radius of about 0.48 fm. These demonstrate that the Tcc+(3875) can be accommodated as a stable and compact tetraquark sate in the chiral SU(3) quark model. All the other S- and P-wave ccq¯q¯′ (q¯,q¯′=u¯,d¯,s¯) states lie about 100 to a few hundreds MeV higher than the corresponding meson-meson thresholds and thus are not suggested to be candidates of stable and compact tetraquark states due to their fall-apart decays to two mesons.

Published by the American Physical Society
2024
Electron
g−2
foreshadowing discoveries at FCC-ee
Authors: Davoudiasl Hooman , Giardino Pier Paolo 
Published: April 2024

A future e+e− circular collider (FCC-ee) may provide a unique probe of the electron Yukawa coupling through Higgs boson production on resonance. Motivated by this exciting possibility, we examine a simple model which can result in O(10) modifications of the Higgs coupling to electrons. The model can also lead to deviations in the electron anomalous magnetic moment, ge−2, which at present shows a +2.2σ or −3.7σ deviation, implied by differing precision determinations of the electromagnetic fine structure constant. The electron ge−2 can be a forerunner for FCC-ee discoveries which, as we elucidate, may not be accessible to the high-luminosity LHC measurements. A simple extension of our model can also account for the current deviation in the muon gμ−2.

Published by the American Physical Society
2024
Hadronic vacuum polarization: Comparing lattice QCD and data-driven results in systematically improvable ways
Authors: Davier Michel , Fodor Zoltán , Gérardin Antoine , Lellouch Laurent , Malaescu Bogdan , Stokes Finn M. , Szabó Kálmán K. , Toth Balint C. , Varnhorst Lukas , Zhang Zhiqing 
Published: April 2024

The precision with which hadronic vacuum polarization (HVP) is obtained determines how accurately important observables, such as the muon anomalous magnetic moment aμ or the low-energy running of the electromagnetic coupling α, are predicted. The two most precise approaches for determining HVP are dispersive relations combined with e+e−→hadrons cross section data and lattice QCD. However, the results obtained in these two approaches display significant tensions, whose origins are not understood. Here we present a framework that sheds light on this issue and—if the two approaches can be reconciled—allows them to be combined. Via this framework, we test the hypothesis that the tensions can be explained by modifying the R-ratio in different intervals of center-of-mass energy s. As ingredients, we consider observables that have been precisely determined in both approaches. These are the leading hadronic contributions to aμ, to the so-called intermediate window observable, and to the running of α between spacelike virtualities 1 and 10  GeV2 (for which only a preliminary lattice result exists). Our tests take into account all uncertainties and correlations, as well as uncertainties on uncertainties in the lattice results. For instance, using this framework we show that results obtained in the two approaches can be made to agree, for all three observables, by modifying the ρ peak in the experimental spectrum. More specifically, we show that this requires a common ∼5% increase in the contributions of the peak to each of the three observables. This result is robust against the presence or absence of the running of α in the comparison. However, such an increase is much larger than the uncertainties on the measured R-ratio. We also discuss a variety of generalizations of the methods used here, as well as the limits in the information that can be extracted from the R-ratio via a finite set of observables.

Published by the American Physical Society
2024