bluuebunny/crossref_metadata_2025_split huggingface dataset:
CFI-1/ARID3 functions unilaterally to restrict gap junction formation inC. elegans
Authors: Wu Zan , Pang Lin , Ding Mei 
Published: April 2024

AbstractElectrical coupling is vital to neural communication, facilitating synchronized activity among neurons. Despite its significance, the precise mechanisms governing the establishment of gap junction connections between specific neurons remain elusive. Here, we identified that the PVC interneuron inCaenorhabditis elegansforms gap junction connections with the PVR interneuron. The transcriptional regulator CFI-1/ARID3 is specifically expressed in the PVC but not PVR interneuron. Reducingcfi-1expression in the PVC interneuron leads to enhanced gap junction formation in the PVR neuron, while ectopic expression ofcfi-1in the PVR neuron restores the proper level of gap junction connections in the PVC neuron, along with the normal touch response. These findings unveil the pivotal role of CFI-1/ARID3 in bidirectionally regulating the formation of gap junctions within a specific neuronal pair, shedding light on the intricate molecular mechanisms governing neuronal connectivityin vivo.SUMMARY STATEMENTProper electrical coupling could be achieved by either of the partner cells; however distinctive influence on neuron circuits maybe achieved.
Physical determinants of daily physical activity in older men and women
Authors: Karavirta Laura , Aittokoski Timo , Pynnönen Katja , Rantalainen Timo , Westgate Kate , Gonzales Tomas , Palmberg Lotta , Neuvonen Joona , Lipponen Jukka A. , Turunen Katri , Nikander Riku , Portegijs Erja , Rantanen Taina , Brage Søren 
Published: April 2024

AbstractIntroductionThe ability to perform bodily movement varies in ageing men and women. We investigated whether physical fitness may explain sex differences in daily physical activity energy expenditure (PAEE) among older people.MethodsA population-based cohort of 75, 80, and 85-year-old men and women (n=409, 62 % women) underwent laboratory-based assessment of walking speed, maximal knee extension strength, and body fat percentage. Free-living physical activity was assessed as total PAEE, and light (LPA) and moderate-to-vigorous physical activity (MVPA) using individually calibrated combined accelerometry and heart rate sensing. Path modelling was used to examine indirect associations between sex, physical fitness, and physical activity.ResultsMen had a more favourable physical fitness profile and higher overall PAEE (mean 34.0 (SD 10.8) kJ/kg/day) than women (28.3 (8.4) kJ/kg/day, p<0.001). The path model for PAEE explained 33 % of the variance. The direct association of sex on PAEE was non-significant, whereas the association between sex and PAEE through body fat (β=0.20, p<0.001) and walking speed (β=0.05, p=0.001) were statistically significant. Similarly, the associations between sex and MVPA through body fat (β=0.11, p=0.002) and walking speed (β=0.05, p=0.001) were significant, as were the associations between sex and LPA through body fat (β=0.24, p<0.001) and walking speed (β=0.03, p=0.019).ConclusionDifferences in physical activity between men and women may reflect underlying differences in cardiorespiratory fitness and adiposity. These results highlight the importance of maintaining physical fitness to support active living in older adults.
Ultrafast metaproteomics for quantitative assessment of strain isolates and microbiomes
Authors: Kazakova Elizaveta , Ivanov Mark , Kusainova Tomiris , Bubis Julia , Polivtseva Valentina , Petrikov Kirill , Gorshkov Vladimir , Kjeldsen Frank , Gorshkov Mikhail , Delegan Yanina , Solyanikova Inna , Tarasova Irina 
Published: April 2024

ABSTRACTBACKGROUNDMicrobial communities play a crucial role in human health and environmental regulation, but present an especial challenge for the analytical science due to their diversity and dynamic range. Tandem mass spectrometry provides functional insights on microorganisms life cycle, but still lacks throughput and sensitivity. MALDI TOF is widely used for ultrafast identification of species, but does not assess their functional activity. Development of ultrafast mass spectrometry methods and bioinformatic approaches applicable for both accurate identification and functional assessment of microbial communities based on their protein content is of high interest.RESULTSWe show for the first time that both identity and functional activity of microorganisms and their communities can be accurately determined in experiments as short as 7 minutes per sample, using the basic Orbitrap MS configuration without peptide fragmentation. The approach was validated using strain isolates, mock microbiomes composed of bacteria spiked at known concentrations and human fecal microbiomes. Our new bioinformatic algorithm identifies the bacterial species with an accuracy of 95 %, when no prior information on the sample is available. Microbiome composition was resolved at the genus level with the mean difference between the actual and identified components of 12 %. For mock microbiomes, Pearson coefficient of up to 0.97 was achieved in estimates of strain biomass change. By the example ofRhodococcusbiodegradation ofn-alkanes, phenols and its derivatives, we showed the accurate assessment of functional activity of strain isolates, compared with the standard label-free and label-based approaches.SIGNIFICANCEOur approach makes microbial proteomics fast, functional and insightful using the Orbitrap instruments even without employing peptide fragmentation technology. The approach can be applied to any microorganisms and can take a niche in routine functional assessment of microbial pathogens and consortiums in clinical diagnostics together with MALDI TOF MS and 16S rRNA gene sequencing.
Conditional protein splicing of theMycobacterium tuberculosisRecA intein in its native host
Authors: Schneider Ryan F. , Hallstrom Kelly , DeMott Christopher , McDonough Kathleen A. 
Published: April 2024

Abstract/summaryTherecAgene, encoding Recombinase A (RecA) is one of threeMycobacterium tuberculosis(Mtb) genes encoding an in-frameintervening proteinsequence (intein) that must splice out of precursor host protein to produce functional protein. Ongoing debate about whether inteins function solely as selfish genetic elements or benefit their host cells requires understanding of interplay between inteins and their hosts. We measured environmental effects on native RecA intein splicing within Mtb using a combination of western blots and promoter reporter assays. RecA splicing was stimulated in bacteria exposed to DNA damaging agents or by treatment with copper in hypoxic, but not normoxic, conditions. Spliced RecA was processed by the Mtb proteasome, while free intein was degraded efficiently by other unknown mechanisms. Unspliced precursor protein was not observed within Mtb despite its accumulation during ectopic expression of MtbrecAwithinE. coli. Surprisingly, Mtb produced free N-extein in some conditions, and ectopic expression of Mtb N-extein activated LexA inE. coli.These results demonstrate that the bacterial environment greatly impacts RecA splicing in Mtb, underscoring the importance of studying intein splicing in native host environments and raising the exciting possibility of intein splicing as a novel regulatory mechanism in Mtb.Significance StatementGene regulation and DNA repair are critical to the success ofMycobacterium tuberculosis, a major bacterial pathogen. The present study found significant interplay between the Mtb host environment and splicing behavior of an integrative intein element within the Mtb RecA protein, which is involved in DNA repair. These findings challenge the concept of inteins as strictly selfish genetic elements by showing that activity of the RecA intein in Mtb is finely tuned to its host and raising the possibility that intein exaptation provides Mtb with additional ways to selectively modulate RecA function.
Engineering sequestration-based biomolecular classifiers with shared resources
Authors: Moghimianavval Hossein , Gispert Ignacio , Castillo Santiago R. , Corning Olaf B. W. H. , Liu Allen P. , Samaniego Christian Cuba 
Published: April 2024

AbstractConstructing molecular classifiers that enable cells to recognize linear and non-linear input patterns would expand the biocomputational capabilities of engineered cells, thereby unlocking their potential in diagnostics and therapeutic applications. While several biomolecular classifier schemes have been designed, the effect of biological constraints such as resource limitation and competitive binding on the function of those classifiers has been left unexplored. Here, we first demonstrate the design of a sigma factor-based perceptron as a molecular classifier working on the principles of molecular sequestration between the sigma factor and its anti-sigma molecule. We then investigate how the output of the biomolecular perceptron,i.e., its response pattern or decision boundary, is affected by the competitive binding of sigma factors to a pool of shared and limited resources of core RNA polymerase. Finally, we reveal the influence of sharing limited resources on multi-layer perceptron neural networks and outline design principles that enable the construction of non-linear classifiers using sigma-based biomolecular neural networks in the presence of competitive resource-sharing effects.
Urine microbiome changes during and after radiotherapy for prostate cancer
Authors: Złoch Michał , Sibińska Ewelina , Monedeiro Fernanda , Miśta Wioletta , Arendowski Adrian , Fijałkowski Piotr , Pietrowska Monika , Mrochem-Kwarciak Jolanta , Jędrzejewska Anna , Telka Ewa , Karoń Kinga , Rabsztyn Małgorzata , Pomastowski Paweł , Gabryś Dorota 
Published: April 2024

ABSTRACTBackgroundThe urinary microbiome may play a new important role in the development of complications, but still, there is no information about their changes during and after radiotherapy (RT). This study aimed to use the matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) technique to identify the microbiome and assess its changes in urine samples of 88 patients irradiated for prostate cancer.Material and methodsBlood for biochemical analysis and urine samples for MALDI were collected at various time points before gold fiducial implantation (t1) at the beginning (t2) and end of radiotherapy (t3); during follow-up, 1 (t4), 4 (t5), 7 (t6) months after the end of treatment.ResultsWe identified 1801 different microbial isolates, in 89% (470/528) samples revealed the presence of at least one microbial species among which 79% (373/470) were polymicrobial. Species level: 136 G+, 29 G-, 2Candidahave been noted. The far most abundant group of the identified microorganisms wasStaphylococcusmembers −51.6% of all isolates followed byMicrococcus(9.1%),Enterococcus(7.6%),Kocuria(5.6%),Corynebacterium(5.4%), andStreptococcus(2.2%). A lower variety of microorganisms incident was observed at the end of RT. The total number of species (TNS) was 50 at t1, increased up to 61 at t2, and then fell to the initial value of 52 at t3. The increase in biodiversity was noted after radiotherapy t4-68, t5-86, and t6-75 (p<0.05). Changes in the biodiversity of the urinary microbiota were also reflected in the differences in the total number of isolates (TNI) – 261, 281, and 273 for time points t1-t3 compared to the 292, 362, and 332 for time points t4-t6 as well as in the total number of detected genera (TNG) – 25, 29, 23 (t1-t3) and 28, 38, 31 (t4-t6).Actinomyces,Corynebacterium,Staphylococcus,Streptococcus, demonstrated significant correlation with the RT stages. Concerning individual species, onlyK. rhizophilaabundance significantly increased with time (p=0.045). Bacteria incidence was strongly correlated with glucose levels in urine. The same correlation was observed for glucose levels in blood, but in a weak manner. Staphylococcus presence was related to higher tPSA.ConclusionRT for prostate cancer induces a dynamic response in the urinary microbiome, characterized by an initial reduction in diversity post-RT followed by a subsequent increase. Our findings highlight the significant influence of glucose levels in both urine and blood on the urinary microbiota. These insights contribute to the evolving understanding of the interplay between RT, the urinary microbiome, and patient health, paving the way for more targeted interventions and personalized approaches in prostate cancer treatment.
Structural basis of iron piracy by a prominent human gut symbiont
Authors: Silale Augustinas , Soo Yung Li , Mark Hannah , Basle Arnaud , van den Berg Bert 
Published: April 2024

AbstractIron is an essential element that can be growth-limiting in microbial communities, particularly those present within host organisms. To acquire iron, many bacteria secrete siderophores, secondary metabolites that chelate ferric iron. These iron chelates can be transported back into the cell via TonB-dependent transporters in the outer membrane, followed by intracellular liberation of the iron.Salmonellaproduces siderophores during gut infection. In response to iron starvation, the human gut symbiontBacteroides thetaiotaomicronupregulates an iron piracy system, XusABC, which steals iron-bound siderophores from the invadingSalmonella. Here, we investigated the molecular details of ferric enterobactin uptake by the XusAB complex. Our crystal and cryogenic electron microscopy structures explain how the XusB lipoprotein recognises iron-bound siderophores and passes them on to the XusA TonB-dependent transporter for translocation across the outer membrane. Moreover, our results suggest that XusABC and homologous systems can transport a variety of siderophores with different iron-chelating functional groups.
Alternate recognition by dengue protease: Proteolytic and binding assays provide functional evidence beyond an induced-fit
Authors: Behnam Mira A. M. , Klein Christian D. 
Published: April 2024

ABSTRACTProteases are key enzymes in viral replication, and interfering with these targets is the basis for therapeutic interventions. We previously introduced a hypothesis about conformational selection in the protease of dengue virus and related flaviviruses, based on conformational plasticity noted in X-ray structures. The present work presents the first functional evidence for alternate recognition by the dengue protease, in a mechanism based primarily on conformational selection rather than induced-fit. Recognition of distinct substrates and inhibitors in proteolytic and binding assays varies to a different extent, depending on factors known to influence the dengue protease structure such as pH and salinity. Furthermore, the buffer type and temperature cause a change in binding, proteolysis, or inhibition behavior. Using representative inhibitors with distinct structural scaffolds, we identify two contrasting binding profiles to dengue protease. Noticeable effects are observed in the binding assay upon inclusion of a non-ionic detergent in comparison to the proteolytic assay. The findings highlight the impact of the selection of testing conditions on the observed ligand affinity or inhibitory potency. From a broader scope, the dengue protease presents an example, where the induced-fit paradigm appears insufficient to explain binding events with the biological target. Furthermore, this protein reveals the complexity of comparing or combining biochemical assay data obtained under different conditions. This can be particularly critical for artificial intelligence (AI) approaches in drug discovery that rely on large datasets compiled from different sources.HIGHLIGHTS- Buffer type, pH, salt, and temperature influence ligand recognition.- Experimental conditions in binding and proteolytic assays affect the obtained data.- Ligand recognition in DENV protease involves mainly conformational selection.Graphic for table of contents
Single-nuclei histone modification profiling of the adult human central nervous system unveils epigenetic memory of developmental programs
Authors: Kabbe Mukund , Agirre Eneritz , Carlström Karl E. , Baldivia Pohl Fabio , Ruffin Nicolas , van Bruggen David , Meijer Mandy , Seeker Luise A. , Bestard-Cuche Nadine , Lederer Alex R. , Zhang Jilin , Ahola Virpi , Goldman Steven A. , Bartosovic Marek , Jagodic Maja , Williams Anna , Castelo-Branco Gonçalo 
Published: April 2024

AbstractThe adult human central nervous system (CNS) is remarkably complex, with neural cells displaying extensive transcriptional heterogeneity. However, how different layers of epigenetic regulation underpin this heterogeneity is poorly understood. Here, we profile the adult human CNS from distinct regions, for chromatin accessibility at the single-nuclei level. In addition, we simultaneously co-profiled the histone modifications H3K27me3 and H3K27ac at the single nuclei-level, providing their first map in all major human CNS cell types. We unveil primed chromatin signatures at HOX loci in spinal cord-derived human oligodendroglia (OLG) but not microglia. These signatures were reminiscent of developmental OLG but were decoupled from robust gene expression. Moreover, using high-resolution Micro-C, we show that induced pluripotent stem cell (iPS) derived human OLGs exhibit a HOX chromatin architecture compatible with the primed chromatin in adult OLGs, and bears a strong resemblance not only to OLG developmental architecture, but also high-grade pontine gliomas. Thus, adult OLG retain epigenetic memory from developmental states, which might enable them to promptly transcribe Hox genes, in contexts of regeneration, but also make them susceptible to gliomagenesis.
Cryo-EM analysis of complement C3 reveals a reversible major opening of the macroglobulin ring
Authors: Gadeberg Trine Amalie Fogh , Jørgensen Martin Høgholm , Olesen Heidi Gytz , Lorentzen Josefine , Harwood Seandean Lykke , Almeida Ana Viana , Fruergaard Marlene Uglebjerg , Jensen Rasmus Kjeldsen , Kanis Philipp , Pedersen Henrik , Tranchant Emil , Petersen Steen Vang , Thøgersen Ida Buch , Kragelund Birthe Brandt , Lyons Joseph Anthony , Enghild Jan Johannes , Andersen Gregers Rom 
Published: April 2024

AbstractThe C3 protein is the central molecule within the complement system and undergoes pattern-recognition-dependent proteolytic activation to C3b in the presence of pathogens and damage-associated patterns. Spontaneous pattern-independent activation of C3 occurs via hydrolysis, resulting in C3(H2O). However, the structural details of C3 hydrolysis remain elusive. Here, we show that the conformation of the C3(H2O) analog, C3MA, in which the C3 thioester is broken by aminolysis is indistinguishable from C3b except for the 77-residue anaphylatoxin (ANA) domain. In contrast, the reaction intermediate C3* formed during C3 adopts a dynamic conformation dramatically different from both C3 and C3MA/C3b. In C3*, unlocking of the macroglobulin (MG) 3 domain creates a large opening in the MG-ring through which the ANA domain translocates. In support of this mechanism, C3MA formation is inhibited by an MG3/MG4-interface-specific nanobody and prevented by linking the ANA domain to the C3 β-chain. Our study reveals an unexpected dynamic behavior of C3 where an exceptional conformational change allows the translocation of an entire domain through a large dynamic opening. These results form the basis for elucidation of thein vivocontribution of C3 hydrolysis to complement activation and offer a rational approach for modulation of C3(H2O) with the potential for preventing complement activation caused by intravascular hemolysis and surface contacts.
Depth-dependent magnetic crossover in a room-temperature skyrmion-hosting multilayer
Authors: Hicken T. J. , Wilson M. N. , Salman Z. , Zhang S. L. , Holt S. J. R. , Prokscha T. , Suter A. , Pratt F. L. , van der Laan G. , Hesjedal T. , Lancaster T. 
Published: April 2024

Skyrmion-hosting multilayer stacks are promising avenues for applications, although little is known about the depth dependence of the magnetism. We address this by reporting the results of circular dichroic resonant elastic x-ray scattering (CD-REXS), micromagnetic simulations, and low-energy muon-spin rotation (LE-μ+SR) measurements on a stack comprising [Ta/CoFeB/MgO]16/Ta on a Si substrate. Energy-dependent CD-REXS shows a continuous, monotonic evolution of the domain-wall helicity angle with incident energy, consistent with a three-dimensional hybrid domain-wall-like structure that changes from Néel-like near the surface to Bloch-like deeper within the sample. LE-μ+SR reveals that the magnetic field distribution in the trilayers near the surface of the stack is distinct from that in trilayers deeper within the sample. Our micromagnetic simulations support a quantitative analysis of the μ+SR results. By increasing the applied magnetic field, we find a reduction in the volume occupied by domain walls at all depths, consistent with a crossover into a region dominated by skyrmions above approximately 180 mT.

Published by the American Physical Society
2024
Improved analysis of isovector nucleon matrix elements with
Nf=2+1
flavors of
O(a)
improved Wilson fermions
Authors: Djukanovic Dalibor , von Hippel Georg , Meyer Harvey B. , Ottnad Konstantin , Wittig Hartmut 
Published: April 2024

We present an update of our determination of the isovector charges gAu−d, gSu−d and gTu−d, and the isovector twist-2 forward matrix elements ⟨x⟩u−d, ⟨x⟩Δu−Δd and ⟨x⟩δu−δd on the Nf=2+1 gauge ensembles generated by the Coordinated Lattice Simulations (CLS) effort. We have significantly extended our coverage of the parameter space by adding ensembles at the physical pion mass and fine lattice spacing, at nearly physical pion masses and very fine lattice spacings, and at very large physical lattice volumes, enabling a well-controlled extrapolation to the physical point. Another major improvement is achieved owing to the extended range of source-sink separations, which allows us to perform two-state fits to summed correlator ratios, leading to a much higher level of control over excited-state effects. Systematic uncertainties from the chiral, continuum and infinite-volume extrapolations are incorporated via model averages based on the Akaike information criterion. Our final results at the physical point are gAu−d=1.254(19)stat(15)sys[24]total, gSu−d=1.203(77)stat(81)sys[112]total, gTu−d=0.993(15)stat(05)sys[16]total, ⟨x⟩u−d=0.153(15)stat(10)sys[17]total, ⟨x⟩Δu−Δd=0.207(15)stat(06)sys[16]total, and ⟨x⟩δu−δd=0.195(17)stat(15)sys[23]total. While our results for the isovector charges are in excellent agreement with the FLAG 21 averages, we note that our error for the tensor charge gTu−d is considerably smaller.

Published by the American Physical Society
2024
Fully heavy tetraquark states and their evidences in LHC observations
Authors: Liu Ming-Sheng , Liu Feng-Xiao , Zhong Xian-Hui , Zhao Qiang 
Published: April 2024

Stimulated by the exciting progress on the observations of the fully charmed tetraquarks at LHC, we carry out a combined analysis of the mass spectra and fall-apart decays of the 1S-, 2S-, and 1P-wave ccc¯c¯ states in a nonrelativistic quark model. It is found that the X(6600) structure observed in the di-J/ψ invariant mass spectrum can be explained by the 1S-wave state T(4c)0++(6550). This structure may also bear some feed-down effects from the higher 2S and/or 1P tetraquark states. The X(6900) structure observed in both the di-J/ψ and J/ψψ(2S) channels can be naturally explained by the 2S-wave state T(4c)0++(6957). The small shoulder structure around 6.2–6.4 GeV observed at CMS and ATLAS may be due to the feed-down effects from some 1P-wave states with C=−1 and/or some 2S-wave states with JPC=0++. Other decay channels are implied in such a scenario and they can be investigated by future experimental analyses. Considering the large discovery potential at LHC, we also present predictions for the bbb¯b¯ states which can be searched for in the future.

Published by the American Physical Society
2024