bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systematic mapping of antibiotic cross-resistance and collateral sensitivity with chemical genetics
Authors: Sakenova Nazgul , Cacace Elisabetta , Orakov Askarbek , Huber Florian , Varik Vallo , Kritikos George , Michiels Jan , Bork Peer , Cossart Pascale , Goemans Camille , Typas Athanasios 
Published: January 2024

AbstractBy acquiring or evolving resistance to one antibiotic, bacteria can become resistant to a second one, due to shared underlying mechanisms. This is called cross-resistance (XR) and further limits therapeutic choices. The opposite scenario, in which initial resistance leads to sensitivity to a second antibiotic, is termed collateral sensitivity (CS) and can inform cycling or combinatorial treatments. Despite their clinical relevance, our current knowledge of such interactions is limited, mostly due to experimental constraints in their assessment and lack of understanding of the underlying mechanisms. To fill this gap, we used published chemical genetic data on the impact of allEscherichia colinon-essential genes on resistance/sensitivity to 40 antibiotics, and devised a metric that robustly discriminates between known XR and CS antibiotic interactions. This metric, based on chemical genetic profile (dis)similarity between two drugs, allowed us to infer 404 XR and 267 CS interactions, thereby expanding the number of known interactions by more than 3-fold – including reclassifying 116 previously reported interactions. We benchmarked our results by validating 55 out of 59 inferred interactions via experimental evolution. By identifying mutants driving XR and CS interactions in chemical genetics, we recapitulated known and uncovered previously unknown mechanisms, and demonstrated that a given drug pair can exhibit both interactions depending on the resistance mechanism. Finally, we applied CS drug pairs in combination to reduce antibiotic resistance development in vitro. Altogether, our approach provides a systematic framework to map XR/CS interactions and their mechanisms, paving the way for the development of rationally-designed antibiotic combination treatments.
Unification of cell-scale metabolic activity with biofilm behavior by integration of advanced flow and reactive-transport modeling and microfluidic experiments
Authors: Zhao Jiao , Zarabadi Mir Pouyan , Hall Derek M. , Dahal Sanjeev , Greener Jesse , Yang Laurence 
Published: January 2024

AbstractThe bacteriaGeobacter sulfurreducens(GS) is a promising candidate for broad applications involving bioelectrochemical systems (BES), such as environmental bioremediation and energy production. To date, most GS studies have reported biofilm-scale metrics, which fail to capture the interactions between cells and their local environments via the complex metabolism at the cellular level. Moreover, the dominance of studies considering diffusion-only molecular mass transport models within the biofilm has ignored the role of internal advection though the biofilm in flow BES. Among other things, this incomplete picture of anode-adhered GS biofilms has led to missed opportunities in optimizing the operational parameters for BES. To address these gaps, we have modernized a GS genome-scale metabolic model (GEM) and complemented it with local flow and reactive-transport models (FRTM). We tuned certain interactions within the model that were critical to reproducing the experimental results from a pure-culture GS biofilm in a microfluidic bioelectrochemical cell under precisely controlled conditions. The model provided insights into the role of mass transport in determining the spatial availability of nutrient molecules within the biofilm. Thus, we verified that fluid advection within biofilms was significantly more important and complex than previously thought. Coupling these new transport mechanisms to GEM revealed adjustments in intracellular metabolisms based on cellular position within the biofilm. Three findings require immediate dissemination to the BES community: (i) Michaelis-Menten kinetics overestimate acetate conversion in biofilm positions where acetate concentration is high, whereas Coulombic efficiencies should be nearly 10% lower than is assumed by most authors; (ii) unification of the empirically observed flow sensitivity of biofilm-scale kinetic parameters and cell-scale values are finally achieved; and (iii) accounting for advection leads to estimations of diffusion coefficients which are much lower than proposed elsewhere in the literature. In conclusion, in-depth spatiotemporal understanding of mechanisms within GS biofilm across relevant size scales opens the door to new avenues for BES optimization, from fine-scale processes to large-scale applications, including improved techno-economic analyses.
Partial rejuvenation of the spermatogonial stem cell niche after gender-affirming hormone therapy in trans women
Authors: Delgouffe Emily , Silva Samuel Madureira , Chalmel Frédéric , Cools Wilfried , Raets Camille , Tilleman Kelly , T’Sjoen Guy , Baert Yoni , Goossens Ellen 
Published: January 2024

ABSTRACTAlthough the impact of gender-affirming hormone therapy (GAHT) on spermatogenesis in trans women has already been studied, data on its precise effects on the testicular environment is poor. Therefore, this study aimed to characterize, through histological and transcriptomic analysis, the spermatogonial stem cell niche of 106 trans women who underwent standardized GAHT, comprising estrogens and cyproterone acetate. A partial dedifferentiation of Sertoli cells was observed, marked by the co-expression of androgen receptor and anti-Müllerian hormone which mirrors the situation in peripubertal boys. The Leydig cells also exhibited a distribution analogous to peripubertal tissue, accompanied by a reduced insulin-like factor 3 expression. Although most peritubular myoid cells expressed alpha-smooth muscle actin 2, the expression pattern was disturbed. Besides this, fibrosis was particularly evident in the tubular wall and the lumen was collapsing in most participants. A spermatogenic arrest was also observed in all participants. The transcriptomic profile of transgender tissue confirmed a loss of mature characteristics - a partial rejuvenation - of the spermatogonial stem cell niche and, in addition, detected inflammation processes occurring in the samples. The present study shows that GAHT changes the spermatogonial stem cell niche by partially rejuvenating the somatic cells and inducing fibrotic processes. These findings are important to further understand how estrogens and testosterone suppression affect the testis environment, and in the case of orchidectomized testes as medical waste material, their potential use in research.
Patient derived model ofUBA5-associated encephalopathy identifies defects in neurodevelopment and highlights potential therapies
Authors: Chen Helen , Wang Yong-Dong , Blan Aidan W. , Almanza-Fuerte Edith P. , Bonkowski Emily S. , Bajpai Richa , Pruett-Miller Shondra M. , Mefford Heather C. 
Published: January 2024

AbstractUBA5encodes for the E1 enzyme of the UFMylation cascade, which plays an essential role in ER homeostasis. The clinical phenotypes of UBA5-associated encephalopathy include developmental delays, epilepsy and intellectual disability. To date, there is no humanized neuronal model to study the cellular and molecular consequences ofUBA5pathogenic variants. We developed and characterized patient-derived cortical organoid cultures and identified defects in GABAergic interneuron development. We demonstrated aberrant neuronal firing and microcephaly phenotypes in patient-derived organoids. Mechanistically, we show that ER homeostasis is perturbed along with exacerbated unfolded protein response pathway in cells and organoids expressingUBA5pathogenic variants. We also assessed two gene expression modalities that augmentedUBA5expression to rescue aberrant molecular and cellular phenotypes. Our study provides a novel humanized model that allows further investigations ofUBA5variants in the brain and highlights novel systemic approaches to alleviate cellular aberrations for this rare, developmental disorder.One-sentence summaryPatient derived model of UBA5-assoicated DEE recapitulated disease phenotype, revealed defects in neurodevelopment, and highlighted potential therapies.
Phosphate overplus response inChlamydomonas reinhardtii: polyphosphate dynamics to monitor phosphate uptake and turnover
Authors: Zúñiga-Burgos Tatiana , Saiardi Adolfo , Camargo-Valero Miller Alonso , Baker Alison 
Published: January 2024

AbstractMany micro-organisms store inorganic phosphate (Pi) in the form of polyphosphate (polyP) and exhibit in-cell polyP accumulation, a phenomenon known as ‘phosphate overplus response’, when resupplied with Pi after a period of deprivation. Quantitative and qualitative methods were used to follow the dynamics of polyP synthesis and turnover in four strains ofChlamydomonas reinhardtiiduring Pi deprivation followed by nutrient resupply. The lowest level of in-cell polyP during Pi deprivation, which also correlates with the cessation of growth, is the key parameter for the timing of Pi resupply to maximise the Pi overplus response Additional nutrients do not affect the size of the overplus response, but they are important for continued growth and maximal Pi removal from the media. Tracking polyP allows the correct time for nutrient resupply to be determined and therefore a reproducible Pi overplus response to be achieved. Depending on whether maximum cellular phosphorus (P) content or maximum Pi removal is desired different strategies may be required – e,g., Pi deprivation until growth cessation then resupplying complete nutrients gives the best trade-off between high in-cell P accumulation, high Pi uptake and algal biomass growth. Although polyP levels are maintained after Pi resupply, the polymer is dynamically remodelled. IP6increases during this time. This increase does not precede polyP synthesis as predicted by a model where inositol phosphates switch on polyP synthesis. One strain tested, CC-5325, shows enhanced Pi uptake and levels of polyP and total in-cell P, suggesting that strain selection is also important.ImportanceThere is strong interest in using microalgae to sustainably control and recover nutrients, especially P, from wastewater. This would help to meet environmental discharge consents and recycle nutrients into agriculture or other applications. Like bacteria and yeasts, microalgae exhibit a Pi overplus phenomenon when Pi-deprived cells are resupplied with P, but microalgae do not require an additional carbon source and can simultaneously uptake nitrogen as well. Use of microalgae in wastewater treatment is limited by the unpredictability of their response and sensitivity to environmental factors, but engineered systems can greatly benefit from better understanding Pi dynamics and polyP accumulation. In the literature there is a lack of consensus regarding protocols to maximise the Pi overplus. In this work we provide robust measurements of quantitative physiological parameters, which should allow reproducibility in laboratory studies and provide design parameters for algal-based nutrient recovery systems from waste waters.
LncRNA-CIR6 Mediates Repair of Infarcted Hearts by Inducing MSCs Differentiation into Cardiogenic Cells through CDK1
Authors: Cui Xiaotian , Dong Hui , Luo Shenghe , Zhuang Bingqi , Li Yansheng , Zhong Chongning , Ma Yuting , Cheng Xianwu , Hong Lan 
Published: January 2024

AbstractPurposeThis study aims to investigate the induction effect of LncRNA-CIR6 on MSCs differentiation into Cardiogenic Cellsin vitroandin vivo.MethodsIn addition to pretreatment with the Ro-3306 (CDK1 inhibitor), LncRNA-CIR6 was transfected into BMSCs and hUCMSCs using jetPRIME. LncRNA-CIR6 was transfected into C57BL/6 mice heart by 100 μL of AAV9-cTnT-LncRNA-CIR6-ZsGreen i.v. After 3 weeks of transfection followed by AMI surgery, hUCMSCs (5×105/100 μL) were injected by i.v 1 week later. Cardiac function was evaluated using VEVO 2100 and electric mapping 9 days after cell injection. IF, Evans blue-TTC, Masson staining, FACS, and WB were used to determine relevant indicators.ResultsLncRNA-CIR6 induced a significant percentage of differentiation in BMSCs (83.00±0.58)% and hUCMSCs (95.43±2.13)% into cardiogenic cells, as determined by the expression of cTnT. Compared with MI group, cardiac contraction and conduction function in MI heart treated by LncRNA-CIR6 or combined with MSCs injection groups were significantly increased as well as the area of MI and fibrosis were significantly lower. The transcriptional expression region of LncRNA-CIR6 was in Chr17 from 80209290 to 80209536. The functional region of LncRNA-CIR6 was located at nucleotides 0-50/190-255 in the sequence. CDK1 is a protein found to be related to the proliferation and differentiation of cardiomyocytes is which located in the functional region of LncRNA-CIR6 secondary structure (from 0 to 17). Ro-3306 impeded the differentiation of MSCs into cardiogenic cells, while MSCs transfected with LncRNA-CIR6 showed high expression of CDK1. LncRNA-CIR6 mediates repair of infarcted hearts by inducing MSCs differentiation into cardiogenic cells through CDK1.ConclusionsLncRNA-CIR6 mediates repair of infarcted hearts by inducing MSCs differentiation into cardiogenic cells through CDK1.
Bending the course of evolution: how mutualistic interactions affect macroevolutionary dynamics of diversification in mimetic butterflies
Authors: Chazot N. , Pires Braga M. , Aubier T.G. , Llaurens V. , Willmott K. R. , Elias M. 
Published: January 2024

AbstractEvidence that species interactions can affect macroevolutionary dynamics of trait and species diversification is scarce. Mutualistic Müllerian mimicry is a compelling example of example of ecological interactions that has been shown to drive evolutionary convergence, Here, we test how mutualistic Müllerian mimicry shapes macroevolutionary patterns of diversification in the Ithomiini butterflies. We show that the age of color patterns is the primary determinant of species richness within mimicry rings but not phylogenetic diversity. We find pervasive phylogenetic signal in mimicry rings and in color patterns associated within polymorphic species. Only a small set of mimicry rings show high phylogenetic diversity. We identify patterns of saturation in the accumulation of new mimicry rings and in the number of evolutionary convergences towards the most species-rich mimicry rings. Those saturation patterns are likely caused by niche filling along various ecological dimensions, within and among the mimetic communities living in sympatry. The time-dependent effects detected in our study illustrate how neutral processes and ecological interactions interact and shape species and phenotypic diversification.
Experimental evidence that investment into ejaculation and mating effort impose different life history trade-offs
Authors: Chung Meng-Han Joseph , Fox Rebecca J. , Jennions Michael D. 
Published: January 2024

AbstractWhen males compete, sexual selection favors reproductive traits that increase their mating or fertilization success (pre- and post-copulatory sexual selection). It is assumed that males face a trade-off between these two types of sexual traits because they both draw on investment from the same pool of resources. Consequently, investment into mate acquisition or ejaculation should create similar trade-offs with other key life history traits. Tests of these assumptions are exceedingly rare. Males only ejaculate after they mate, and investment into ejaculation is therefore highly correlated with mating effort. Consequently, little is known about how each component of reproductive investment affects a male’s future performance. Here, we ran an experiment using a novel technique to distinguish the life history costs of mating effort and ejaculation for mosquitofish (Gambusia holbrooki). We compared manipulated males (mate without ejaculation), control males (mate and ejaculate) and naïve males (neither mate nor ejaculate) continuously housed with a female and two rival males. We assessed their growth, somatic maintenance, mating and fighting behavior, and sperm traits after 8 and 16 weeks. Past mating effort significantly lowered a male’s future mating effort and growth, but not his sperm production; while past sperm release significantly lowered a male’s future ejaculate quantity, but not his mating effort. These findings challenge the assumption that male reproductive investment draws from a common pool of resources such that, all else being equal, greater mating effort reduces ejaculate investment, andvice versa. Instead, we provide clear evidence that investment in traits under pre- and post-copulatory sexual selection have different trait-specific effects on subsequent male reproductive performance that occur both early and late in life.
Dual-targeting CRISPR-CasRx reducesC9orf72ALS/FTD sense and antisense repeat RNAs in vitro and in vivo
Authors: Kempthorne Liam , Vaizoglu Deniz , Cammack Alexander J. , Carcolé Mireia , Suklai Pacharaporn , Muralidharan Bhavana , Kroll François , Moens Thomas G. , Yshii Lidia , Verschoren Stijn , Hölbling Benedikt V. , Katona Eszter , Mikheenko Alla , Coneys Rachel , de Oliveira Paula , Zhang Yong-Jie , Jansen Karen , Daughrity Lillian M , McGown Alexander , Ramesh Tennore M. , Van Den Bosch Ludo , Rahim Ahad A. , Petrucelli Leonard , Rihel Jason , Isaacs Adrian M. 
Published: January 2024

AbstractThe most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a G4C2repeat expansion in intron 1 of theC9orf72gene. This repeat expansion undergoes bidirectional transcription to produce sense and antisense repeat RNA species. Both sense and antisense-derived repeat RNAs undergo repeat-associated non-AUG translation in all reading frames to generate five distinct dipeptide repeat proteins (DPRs). Importantly, toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs. This suggests targeting both sense and antisense repeat RNA may provide the most effective therapeutic strategy. The RNA-targeting CRISPR-Cas13 systems offer a promising avenue for simultaneous targeting of multiple RNA transcripts, as they mature their own guide arrays, thus allowing targeting of more than one RNA species from a single construct. We show that CRISPR-Cas13d originating fromRuminococcus flavefaciens(CasRx) can successfully reduceC9orf72sense and antisense repeat transcripts and DPRs to background levels in HEK cells overexpressingC9orf72repeats. CRISPR-CasRx also markedly reduced the endogenous sense and antisense repeat RNAs and DPRs in three independentC9orf72patient-derived iPSC-neuron lines, without detectable off-target effects. To determine whether CRISPR-CasRx is effectivein vivo, we treated two distinctC9orf72repeat mouse models using AAV delivery and observed a significant reduction in both sense and antisense repeat-containing transcripts. Taken together this work highlights the potential for RNA-targeting CRISPR systems as therapeutics forC9orf72ALS/FTD.
Revealing the atomic and electronic mechanism of human manganese superoxide dismutase product inhibition
Authors: Azadmanesh Jahaun , Slobodnik Katelyn , Struble Lucas R. , Lutz William E. , Coates Leighton , Weiss Kevin L. , Myles Dean A. A. , Kroll Thomas , Borgstahl Gloria E. O. 
Published: January 2024

ABSTRACTHuman manganese superoxide dismutase (MnSOD) is a crucial oxidoreductase that maintains the vitality of mitochondria by converting O2●-to O2and H2O2with proton-coupled electron transfers (PCETs). Since changes in mitochondrial H2O2concentrations are capable of stimulating apoptotic signaling pathways, human MnSOD has evolutionarily gained the ability to be highly inhibited by its own product, H2O2. A separate set of PCETs is thought to regulate product inhibition, though mechanisms of PCETs are typically unknown due to difficulties in detecting the protonation states of specific residues that coincide with the electronic state of the redox center. To shed light on the underlying mechanism, we combined neutron diffraction and X-ray absorption spectroscopy of the product-bound, trivalent, and divalent states to reveal the all-atom structures and electronic configuration of the metal. The data identifies the product-inhibited complex for the first time and a PCET mechanism of inhibition is constructed.
Oligomeric HIV-1 Integrase Structures Reveal Functional Plasticity for Intasome Assembly and RNA Binding
Authors: Jing Tao , Shan Zelin , Dinh Tung , Biswas Avik , Jang Sooin , Greenwood Juliet , Li Min , Zhang Zeyuan , Gray Gennavieve , Shin Hye Jeong , Zhou Bo , Passos Dario , Aiyer Sriram , Li Zhen , Craigie Robert , Engelman Alan N. , Kvaratskhelia Mamuka , Lyumkis Dmitry 
Published: January 2024

AbstractIntegrase (IN) performs dual essential roles during HIV-1 replication. During ingress, IN functions within an oligomeric “intasome” assembly to catalyze viral DNA integration into host chromatin. During late stages of infection, tetrameric IN binds viral RNA and orchestrates the condensation of ribonucleoprotein complexes into the capsid core. The molecular architectures of HIV-1 IN assemblies that mediate these distinct events remain unknown. Furthermore, the tetramer is an important antiviral target for allosteric IN inhibitors. Here, we determined cryo-EM structures of wildtype HIV-1 IN tetramers and intasome hexadecamers. Our structures unveil a remarkable plasticity that leverages IN C-terminal domains and abutting linkers to assemble functionally distinct oligomeric forms. Alteration of a newly recognized conserved interface revealed that both IN functions track with tetramerizationin vitroand during HIV-1 infection. Collectively, our findings reveal how IN plasticity orchestrates its diverse molecular functions, suggest a working model for IN-viral RNA binding, and provide atomic blueprints for allosteric IN inhibitor development.
Structure of the extracellular region of the adhesion GPCR CELSR1 reveals a compact module which regulates G protein-coupling
Authors: Bandekar Sumit J. , Garbett Krassimira , Kordon Szymon P. , Dintzner Ethan , Shearer Tanner , Sando Richard C. , Araç Demet 
Published: January 2024

AbstractCadherin EGF Laminin G seven-pass G-type receptors (CELSRs or ADGRCs) are conserved adhesion G protein-coupled receptors which are essential for animal development. CELSRs have extracellular regions (ECRs) containing 23 adhesion domains which couple adhesion to intracellular signaling. However, molecular-level insight into CELSR function is sparsely available. We report the 4.3 Å cryo-EM reconstruction of the mCELSR1 ECR with 13 domains resolved in the structure. These domains form a compact module mediated by interdomain interactions with contact between the N- and C-terminal domains. We show the mCELSR1 ECR forms an extended species in the presence of Ca2+, which we propose represents the antiparallel cadherin repeat dimer. Using assays for adhesion and G protein-coupling, we assign the N-terminal CADH1-8 module as necessary for cell adhesion and we show the C-terminal CAHD9-GAIN module regulates signaling. Our work provides important molecular context to the literature on CELSR function and opens the door towards further mechanistic studies.