bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small RNA regulation of an essential process induces bacterial resistance to aminoglycosides during oxidative stress
Authors: Baussier Corentin , Oriol Charlotte , Durand Sylvain , Py Beatrice , Mandin Pierre 
Published: October 2023

AbstractFe-S clusters are essential cofactors involved in many reactions across all domains of life. InEscherichia coliand other enterobacteria, Fe-S cluster synthesis involves two machineries: Isc and Suf. While Isc functions as a housekeeping system, Suf is activated under stress conditions such as iron starvation or oxidative stress. Interestingly, cells functioning under Suf show reduced entry of aminoglycosides, leading to resistance to these antibiotics. The transcriptional regulator IscR, itself an Fe-S cluster containing protein, controls the transition between Isc and Suf machineries. Noteworthy, IscR has a critical impact on the virulence of various bacterial pathogens by regulating both Fe-S biogenesis and other pathways directly linked to host adaptation. Here, we discovered that two small regulatory RNAs (sRNAs), FnrS and OxyS, controliscRexpression by base-pairing to the 5’ UTR of theiscRmRNA. Remarkably, these sRNAs act in opposite ways and in opposite conditions: FnrS, expressed in anaerobiosis, represses the expression ofiscRwhile OxyS, expressed during oxidative stress, activates it. Using anE. colistrain experiencing protracted oxidative stress, we further demonstrate thatiscRexpression is rapidly and significantly enhanced in the presence of OxyS. Strikingly, we further show that OxyS induces resistance to aminoglycosides during oxidative stress through this unexpected regulation of Fe-S clusters biogenesis, revealing a new role for this sRNA.Significance StatementThis study sheds light on the regulatory mechanisms controlling the synthesis of essential Fe-S clusters in bacteria, revealing unexpected roles for two small RNAs (FnrS and OxyS) in modulating the expression of the transcriptional regulator IscR. The findings suggest that this regulatory network could lead bacterial resistance to aminoglycoside antibiotics during oxidative stress, a condition associated with chronic infections. Ultimately, this work highlights the importance of understanding the intricate regulatory networks controlling bacterial metabolism and adaptation to stress, which could have significant implications for public health.
FibrilPaint to determine the length of Tau amyloids in fluids
Authors: Aragonès Pedrola Júlia , Dekker Françoise A. , Garfagnini Tommaso , Mayer Guy , Koopman Margreet B. , Bergmeijer Menno , Förster Friedrich , Hoozemans Jeroen J. M. , Jensen Henrik , Friedler Assaf , Rüdiger Stefan G. D. 
Published: October 2023

AbstractTau aggregation into amyloid fibrils is linked to the development of neurodegenerative diseases, including Alzheimer’s Disease. The molecular processes underlying aggregation in disease are poorly understood. Here, we introduce FibrilPaint1 as a tool to measure the size of Tau amyloid fibrils in fluids, from early aggregation stages to mature fibrils. FibrilPaint1 is a 22mer peptide with many exciting properties, which makes it a tool for diagnostics and an attractive start point for developing a class of effective fibril targeting degraders: (i) FibrilPaint1 binds fibrils with nanomolar affinity; (ii) it does also bind to oligomeric precursors, down to a size of only 4 layers; (iii) it does not bind to monomers (KD > 100 µM); (iv) it is fluorescently labelled, which allows monitoring and localising interactions. (v) FibrilPaint1 recognises various Tau fibrils, including patient derived fibrils from Alzheimer, Corticobasal degeneration and Frontotemporal dementia; (vi) FibrilPaint1 is selective for the amyloid state and does not have background binding to amorphous aggregates, blood serum or cell lysate. In combination with Flow Induced Dispersion Analysis (FIDA), a microfluidics technology, we determined the molecular size of amyloid fibrils with sub-microliter sample volumes. This set-up acts as a molecular ruler at layer resolution - we determined Tau fibril length from 4 to 1100 layers in solution. This is an interesting parameter that can be used for diagnostic applications and biochemical research in dementia.
RBM39 shapes innate immunity through transcriptional and splicing control of key factors of the interferon response
Authors: Li Teng-Feng , Rothhaar Paul , Lang Arthur , Grünvogel Oliver , Colasanti Ombretta , Olivera Ugarte Santa Mariela , Traut Jannik , Piras Antonio , Acosta-Rivero Nelson , Gonçalves Magalhães Vladimir , Springer Emely , Betz Andreas , Huang Hao-En , Park Jeongbin , Qiu Ruiyue , Gnouamozi Gnimah Eva , Mehnert Ann-Kathrin , Dao Thi Viet Loan , Urban Stephan , Muckenthaler Martina , Schlesner Matthias , Wohlleber Dirk , Binder Marco , Bartenschlager Ralf , Pichlmair Andreas , Lohmann Volker 
Published: October 2023

AbstractRNA-binding motif protein 39 (RBM39) is an RNA-binding protein involved in tumorigenesis, cell metabolism, and development. Here, we performed a genome-wide CRISPR/Cas9 screen in two liver-derived cell lines and identified RBM39 as a regulator of cell intrinsic innate immune responses. The knockdown ofRBM39or the treatment with Indisulam, an aryl sulfonamide drug targeting RBM39 for proteasomal degradation, strongly reduced the induction of interferon-stimulated genes (ISGs) in response to double-stranded RNA (dsRNA) or viral infections upon sensing by toll-like receptor 3 (TLR3) or cytosolic RIG-I-like receptors. RNA sequencing (seq) and mass spectrometry identified that transcription and/or splicing of the key pathway components IRF3, RIG-I, and MDA5 were affected by RBM39 depletion.RBM39knockdown further restrained type I and type III IFN pathways, by reducing expression of the type I IFN receptor subunit interferon alpha and beta receptor subunit 2 (IFNAR2), type III IFN receptor subunit interleukin 10 receptor subunit beta (IL-10RB) and transcription factor signal transducer and activator of transcription (STAT) 1 and 2. RBM39 overall orchestrates innate immunity by regulating basal expression of key factors of the interferon response via transcription and/or alternative splicing.SignificanceThe function of RBM39 in tumorigenesis has been investigated intensively in the last decade, but its immunological role is still largely unknown. In our study, we identified RBM39 as a regulatory factor of cell intrinsic signaling via a CRISPR/Cas9 screen. Depletion of RBM39 impairs TLR3, RIG-I/MDA5, and IFN pathways, and thus attenuates innate immune responses. Our omics analysis revealed that RBM39 governs the basal expression of several key factors within these pathways, such as RNA sensors RIG-I and MDA5, type I/III receptors, transcription factors IRF3, STAT1 and STAT2, via its transcriptional and splicing function. Therefore, RBM39 might be a therapeutic target to modulate innate immunity, e.g. in the context of autoimmune disorders.
Disrupting the interaction between AMBRA1 and DLC1 is a promising therapeutic strategy for neurodegeneration that prevents apoptosis while enhancing autophagy and mitophagy
Authors: Hawkins Kate , Watt Meg , Gillotin Sébastien , Hanspal Maya , Helley Martin , Richardson Jill , Corbett Nicola , Brownlees Janet 
Published: October 2023

AbstractActivating molecule in Beclin1-regulated autophagy (AMBRA1) has critical roles in autophagy, mitophagy, cell cycle regulation, neurogenesis and apoptosis. Dysregulation of these processes are hallmarks of various neurodegenerative diseases and therefore AMBRA1 represents a potential therapeutic target. The flexibility of its intrinsically disordered regions allows AMBRA1 to undergo conformational changes and thus perform its function as an adaptor protein for various different complexes. Understanding the relevance of these multiple protein-protein interactions will allow us to gain information about which to target pharmacologically. To compare potential AMBRA1 activation strategies we have designed and validated several mutant constructs (ACTA, TAT, WD40 and S1014) in addition to characterising their effects on proliferation, apoptosis, autophagy and mitophagy in SHSY5Y cells. AMBRA1TAT, which is a mutant form of AMBRA1 that can’t interact with dynein light chain (DLC)1 at the microtubules, produced the most promising results. Indeed, overexpression of this mutant protected cells against apoptosis and induced autophagy and mitophagy in SHSY5Y cells in addition to enhancing the switch from quiescence to proliferation in mouse neural stem cells. Future studies should focus on designing compounds that inhibit the protein-protein interaction between AMBRA1 and DLC1 and thus have potential to be used as a drug strategy to treat neurodegeneration.
Explainable protein function annotation using local structure embeddings
Authors: Derry Alexander , Altman Russ B. 
Published: October 2023

AbstractThe rapid expansion of protein sequence and structure databases has resulted in a significant number of proteins with ambiguous or unknown function. While advances in machine learning techniques hold great potential to fill this annotation gap, current methods for function prediction are unable to associate global function reliably to the specific residues responsible for that function. We address this issue by introducing PARSE (Protein Annotation by Residue-Specific Enrichment), a knowledge-based method which combines pre-trained embeddings of local structural environments with traditional statistical techniques to identify enriched functions with residue-level explainability. For the task of predicting the catalytic function of enzymes, PARSE achieves comparable or superior global performance to state-of-the-art machine learning methods (F1 score > 85%) while simultaneously annotating the specific residues involved in each function with much greater precision. Since it does not require supervised training, our method can make one-shot predictions for very rare functions and is not limited to a particular type of functional label (e.g. Enzyme Commission numbers or Gene Ontology codes). Finally, we leverage the AlphaFold Structure Database to perform functional annotation at a proteome scale. By applying PARSE to the dark proteome—predicted structures which cannot be classified into known structural families—we predict several novel bacterial metalloproteases. Each of these proteins shares a strongly conserved catalytic site despite highly divergent sequences and global folds, illustrating the value of local structure representations for new function discovery.
Facilitating clinically relevant skin tumor diagnostics with spectroscopy-driven machine learning
Authors: Andersson Emil , Hult Jenny , Troein Carl , Stridh Magne , Sjögren Benjamin , Pekar-Lukacs Agnes , Hernandez-Palacios Julio , Edén Patrik , Persson Bertil , Olariu Victor , Malmsjö Malin , Merdasa Aboma 
Published: October 2023

AbstractIn the dawning era of artificial intelligence (AI), health care stands to undergo a significant transformation with the increasing digitalization of patient data. Digital imaging, in particular, will serve as an important platform for AI to be implemented to aid decision making and diagnostics. A growing number of studies demonstrate the potential of AI for automatic pre-surgical skin tumor delineation, which could have tremendous impact on clinical practice. However, current methods have the drawback of relying on a ground truth image in which the tumor borders are already identified, which is not clinically possible. We report a novel approach where hyperspectral images provides spectra from small regions representing healthy tissue and tumor, which are used to generate prediction maps using artificial neural networks. Thereafter, a segmentation algorithm automatically manages to determine the skin tumor borders. Our approach therefore circumvents the need for a complete ground truth image, where the training data is contained within each individual patient. This links to an important strength of our approach as we develop individual network models for each patient. Our approach is therefore not only more clinically relevant, but it also interesting for emerging precision skin tumor diagnostics where adaptability toward the individual is key.
Influence of myosin regulatory light chain and myosin light chain kinase on hair cells of the inner ear
Authors: Oya Ryohei , Woo Kwang Min , Fabella Brian , Alonso R. G. , Hudspeth A. J. 
Published: October 2023

AbstractIn the receptor organs of the inner ear and lateral line, sensory hair cells detect mechanical stimuli such as sounds, accelerations, and water movements. In each instance a stimulus deflects the hair bundle, a hair cell’s mechanically sensitive organelle. The bundle pivots upon the cell’s apical surface, which includes an actin meshwork called the cuticular plate and is surrounded by a ring of filamentous actin and non-muscle myosin II (NM2). Myosin regulatory light chain (RLC) is expressed at the apical surfaces of hair cells and RLC is additionally found in hair bundles. NM2 and the phosphorylation of RLC by myosin light chain kinase (MLCK) have earlier been shown to regulate the sizes and shapes of hair cells’ apical surfaces. We have found that inhibitors of NM2 and MLCK reduce the stiffness of hair bundles from the bullfrog’s sacculus. Moreover, MLCK inhibition inhibits the spontaneous oscillation of hair bundles and increases the resting open probability of transduction channels. In addition, MLCK inhibition elevates hearing thresholds in mice. We conclude that NM2 and the phosphorylation of RLC modulate slow adaptation and thereby help to set the normal operating conditions of hair bundles.Statement of significanceSensory hair cells play a key role in mechanoelectrical transduction by the inner ear and lateral-line system. To detect stimuli such as sounds and accelerations, hair cells use an active process to amplify their mechanical inputs. Although amplification is accomplished in part by the activity of the mechanosensitive hair bundles, the molecular mechanism of the active process remains uncertain. The present study shows that non-muscle myosin II (NM2) and the phosphorylation of myosin regulatory right chains (RLC) by myosin light chain kinase (MLCK) regulate the stiffness and spontaneous oscillation of hair bundles as well as the resting open probability of mechanotransduction channels. The results implicate myosin motors in the control of the active process of hair cells.
Pharmacogenetics of efavirenz exposure in cervicovaginal fluid during pregnancy and postpartum
Authors: Eniayewu Oluwasegun , Azuka Uche , Ogah Jonah , Adejuyigbe Ebunoluwa , Bolaji Oluseye , Olagunju Adeniyi 
Published: October 2023

AbstractObjectivesAdequate antiretroviral drug distribution into the female genital tract (FGT) could play an important role in reducing the risk of heterosexual and mother-to-child transmission of HIV. In this study, we investigated the combined influence of pregnancy and genetic polymorphisms on efavirenz pharmacokinetics in cervicovaginal fluid (CVF) of women receiving antiretroviral therapy.MethodsA total of 159 women (147 pregnant and 12 postpartum) living with HIV and receiving efavirenz-containing antiretroviral therapy were recruited across two sites in Nigeria (Federal Medical Centre, and Bishop Murray Medical Centre, Makurdi) between 2017-2020. In stage 1, sparse CVF and dried blood spot (DBS) samples were obtained from each participant during pregnancy to assess possible association between drug concentration andCYP2B6polymorphisms (516G>T and 983 T>C). In the second stage, participants were stratified into three genotype groups (extensive, intermediate and low metabolisers) and re-enrolled for intensive pharmacokinetic sampling.ResultsIn stage 1 (88 CVF, 81 plasma and 73 paired samples),CYP2B6 516G>Twas independently associated with both CVF (β = 997 ng/mL (90% CI: 598, 1357),p =5.7 x 10-5) and plasma (β = 1400 ng/mL (90% CI: 1051, 1748),p =5.7 x 10-9) efavirenz concentration during pregnancy. In the second stage (12 pregnant, 12 postpartum), median (IQR) efavirenz Cminin CVF during pregnancy versus postpartum was 243 ng/ml (168-402) vs 447 ng/ml (159-974), Cmaxwas 1031 ng/ml (595-1771) vs 1618 ng/ml (675-2695), and AUC0-24was 16465 ng.h/ml (9356-30417) vs 30715 ng.h/ml (10980-43714). Overall, median CVF-to-plasma AUC ratio was 0.34 during pregnancy and 0.46 postpartum. When patients were stratified usingCYP2B6 516G>T, efavirenz median clearance increased by 57.9% during pregnancy compared with postpartum control (p= 0.232) in patients with theCYP2B6516GT genotype. The AUC0-24h, Cmaxand Cminreduced by 33.8% ((p=0.182), 8.6% (0.175) and 59.5% (0.171) during pregnancy, with values of 20671 ng.h/ml (15993-28712), 1550 ng/ml (1090-2090) and 330 ng/ml (250-440), respectively, compared with 31229 ng.h/ml (27660-41873), 1695 ng/ml (1540-3003) and 814 ng/ml (486-981) during postpartum in this genotype.Median efavirenz Cminin CVF was 1.93 and 3.55 times higher than the PBIC90of 126 ng/ml in the pregnant and postpartum cohorts, respectively.ConclusionsEfavirenz is well distributed into the CVF, and both pregnancy and polymorphisms in its disposition genes affect CVF exposure.
Growth retardation in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1
Authors: Gao Christine W , Lin Wan-Ying , Riddle Ryan C , Chopra Sheetal , Boukas Leandros , Hansen Kasper D , Björnsson Hans T , Fahrner Jill A 
Published: October 2023

ABSTRACTGrowth retardation is a characteristic feature of both Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), Mendelian disorders of the epigenetic machinery with similar phenotypes but distinct genetic etiologies. We previously described skeletal growth retardation in a mouse model of KS1 and further established that aKmt2d−/−chondrocyte model of KS1 exhibits precocious differentiation. Here we characterized growth retardation in a mouse model of KS2,Kdm6atm1d/+. We show thatKdm6atm1d/+mice have decreased femur and tibia length compared to controls and exhibit abnormalities in cortical and trabecular bone structure.Kdm6atm1d/+growth plates are also shorter, due to decreases in hypertrophic chondrocyte size and hypertrophic zone height. Given these disturbances in the growth plate, we generatedKdm6a−/−chondrogenic cell lines. Similar to our priorin vitromodel of KS1, we found thatKdm6a−/−cells undergo premature, enhanced differentiation towards chondrocytes compared toKdm6a+/+controls. RNA-seq showed thatKdm6a−/−cells have a distinct transcriptomic profile that indicates dysregulation of cartilage development. Finally, we performed RNA-seq simultaneously onKmt2d−/−,Kdm6a−/−, and control lines at Days 7 and 14 of differentiation. This revealed surprising resemblance in gene expression betweenKmt2d−/−andKdm6a−/−at both time points and indicates that the similarity in phenotype between KS1 and KS2 also exists at the transcriptional level.
Cytoophidia influence cell cycle and size inSchizosaccharomyces pombe
Authors: Deng Ruolan , Li Yi-Lan , Liu Ji-Long 
Published: October 2023

AbstractCTP synthase (CTPS) forms cytoophidia in all three domains of life. Here we focus on the function of cytoophidia in cell proliferation usingSchizosaccharomyces pombeas a model system. We find that converting His359of CTPS into Ala359leads to cytoophidium disassembly. By reducing the level of CTPS protein or specific point mutations, the loss of cytoophidia prolongs the G2 phase and expands cell size. In addition, the loss-filament mutant of CTPS leads to a decrease in the expression of genes related to G2/M transition and cell growth, includingslm9. The overexpression ofslm9alleviates the G2 phase elongation and cell size enlargement induced by CTPS loss-filament mutant. Overall, our results connect cytoophidia with cell cycle and cell size control inSchizosaccharomyces pombe.
Cortical and behavioural tracking of rhythm in music: Effects of pitch predictability, enjoyment, and expertise
Authors: Keitel Anne , Pelofi Claire , Guan Xinyi , Watson Emily , Wight Lucy , Allen Sarah , Mencke Iris , Keitel Christian , Rimmele Johanna 
Published: October 2023

AbstractThe cortical tracking of stimulus features (such as the sound envelope) is a crucial neural requisite of how we process continuous music. We here tested whether cortical tracking of the beat, typically related to rhythm processing, is modulated by pitch predictability and other top-down factors. Participants listened to tonal (high pitch predictability) and atonal (low pitch predictability) music while undergoing EEG, and we analysed their cortical tracking of the acoustic envelope. Interestingly, cortical envelope tracking was stronger while listening to atonal than tonal music, likely reflecting listeners’ violated pitch expectations. Envelope tracking was also stronger with more expertise and enjoyment. Furthermore, we analysed cortical tracking of pitch surprisal (using IDyOM) and show that listeners’ expectations for tonal and atonal music match those computed by the IDyOM model, with higher surprisal (prediction errors) for atonal than tonal music. Behaviourally, we measured participants’ ability to tap along to the beat of tonal and atonal sequences in two experiments. In both experiments, finger-tapping performance was better in the tonal than the atonal condition, indicating a positive effect of pitch predictability on behavioural rhythm processing. Cortical envelope tracking predicted tapping performance for tonal music, as did pitch surprisal tracking for atonal music, indicating that conditions of high and low predictability might impose different processing regimes. We show that cortical envelope tracking, beyond reflecting musical rhythm processing, is modulated by pitch predictability, as well as musical expertise and enjoyment. Taken together, our results show various ways in which those top-down factors impact musical rhythm processing.
Long-term dynamics of the “Serratia marcescenscomplex” in the hospital-built environment
Authors: Aracil-Gisbert Sonia , Fernández-De-Bobadilla Miguel D. , Guerra-Pinto Natalia , Serrano-Calleja Silvia , Pérez-Cobas Ana Elena , Soriano Cruz , de Pablo Raúl , Lanza Val F. , Pérez-Viso Blanca , Reuters Sandra , Hasman Henrik , Cantón Rafael , Baquero Fernando , Coque Teresa M. 
Published: October 2023

ABSTRACTSerratia marcescensis an opportunistic pathogen historically associated with abrupt, unpredictable, and severe outbreaks in hospital intensive care units (ICUs) and, more recently, with the spread of acquired genes encoding carbapenem resistance. However, the population biology and ecology ofS. marcescensin the hospital ecosystem is still poorly understood. Here, we combine epidemiological information of 1417Serratiaisolates collected from the sinks of a large ICU ward that underwent significant demographic and operational changes (2019-2020) and 99 non-redundant outbreak/non-outbreak isolates from the same hospital (2003-2019), with genomic data of 165 isolates. We first report hospital sinks as reservoirs of heterogeneous and coexistent populations of theS. marcescenscomplex (SMC). A novel SMC clade congruent with the recently describedSerratia neveispecies is predominant, exhibiting chromosomal AmpC β-lactamase with an unusual basal expression in contrast to one of the major features ofS. marcescens. PersistentSerratiasink strains are identical to those involved in clonal and polyclonal outbreaks of VIM-1 and OXA-48 producers since at least 2017. The “source-sink” dynamics of SMC populations able to acquire the highly conserved plasmids such as IncL carryingblaVIM-1orblaOXA-48offer novel insights that might improve interventions to control outbreaks and treat Serratia infections in high-risk hospital areas.