bluuebunny/crossref_metadata_2025_split huggingface dataset:
Learning the functional landscape of microbial communities
Authors: Skwara Abigail , Gowda Karna , Yousef Mahmoud , Diaz-Colunga Juan , Raman Arjun S. , Sanchez Alvaro , Tikhonov Mikhail , Kuehn Seppe 
Published: March 2023

AbstractMicrobial consortia exhibit complex functional properties in contexts ranging from soils to bioreactors to human hosts. Understanding how community composition determines emergent function is a major goal of microbial ecology. Here we address this challenge using the concept of community-function landscapes – analogs to fitness landscapes – that capture how changes in community composition alter collective function. Using datasets that represent a broad set of community functions, from production/degradation of specific compounds to biomass generation, we show that statistically-inferred landscapes quantitatively predict community functions from knowledge of strain presence or absence. Crucially, community-function landscapes allow prediction without explicit knowledge of abundance dynamics or interactions between species, and can be accurately trained using measurements from a small subset of all possible community compositions. The success of our approach arises from the fact that empirical community-function landscapes are typically not rugged, meaning that they largely lack high-order epistatic contributions that would be difficult to fit with limited data. Finally, we show this observation is generic across many ecological models, suggesting community-function landscapes can be applied broadly across many contexts. Our results open the door to the rational design of consortia without detailed knowledge of abundance dynamics or interactions.
A lipopeptidomimetic of transcriptional activation domains selectively disrupts Med25 PPIs
Authors: Pattelli Olivia N. , Valdivia Estefanía Martínez , Beyersdorf Matthew S. , Regan Clint S. , Rivas Mónica , Merajver Sofia D. , Cierpicki Tomasz , Mapp Anna K. 
Published: March 2023

AbstractShort amphipathic peptides are capable of binding to transcriptional coactivators, often targeting the same binding surfaces as native transcriptional activation domains. However, they do so with modest affinity and generally poor selectivity, limiting their utility as synthetic modulators. Here we show that incorporation of a medium-chain, branched fatty acid to the N-terminus of one such heptameric lipopeptidomimetic (34913-8) increases the affinity for the coactivator Med25 >10-fold (Ki>>100 μM to 10 μM). Importantly, the selectivity of 34913-8 for Med25 compared to other coactivators is excellent. 34913-8 engages Med25 through interaction with the H2 face of itsActivatorInteractionDomain and in doing so stabilizes full-length protein in the cellular proteome. Further, genes regulated by Med25-activator PPIs are inhibited in a cell model of triple-negative breast cancer. Thus, 34913-8 is a useful tool for studying Med25 and the Mediator complex biology and the results indicate that lipopeptidomimetics may be a robust source of inhibitors for activator-coactivator complexes.
Modification of DNA by a viral enzyme and charged tRNA
Authors: Silva Rebekah M. B. , Slyvka Anton , Lee Yan-Jiun , Guan Chudi , Lund Sean R. , Raleigh Elisabeth A. , Skowronek Krzysztof , Bochtler Matthias , Weigele Peter R. 
Published: March 2023

AbstractBacteriophage enzymes synthesize varied and complex DNA hypermodifications. The enzyme encoded by the phage Mu genemomis necessary for post-replicative carbamoylmethyl addition to the exocyclic amine of deoxyadenosine in DNA during the lytic phase of the viral life-cycle. The molecular details of this modification reaction, including the molecular origins of the modification itself, have long eluded understanding. Here, we demonstrate that Mom co-opts the translational machinery of the host by harvesting activated glycine from charged tRNAGlyto hypermodify adenine. Based on this insight, we report the firstin vitroreconstitution of the Mu hypermodification from purified components. Using isotope labeling, we demonstrate that the carbamoyl nitrogen of the Mom modification is derived from theN6 of adenine, indicating an on-base rearrangement of theN6 aminoacylation product, possibly via a cyclic intermediate. Informed by the X-ray crystal structure of Mom, we have probed the location of the active site, identified a novel insertion, and established substrate specificities of the Mom enzyme.
Allosterically coupled conformational dynamics in solution prepare the sterol transfer protein StarD4 to release its cargo upon interaction with target membranes
Authors: Xie Hengyi , Weinstein Harel 
Published: March 2023

ABSTRACTComplex mechanisms regulate the cellular distribution of cholesterol, a critical component of eukaryote membranes involved in regulation of membrane protein functions directly and through the physiochemical properties of membranes. StarD4, a member of the steroidogenic acute regulator-related lipid-transfer (StART) domain (StARD)-containing protein family, is a highly efficient sterol-specific transfer protein involved in cholesterol homeostasis. Its mechanism of cargo loading and release remains unknown despite recent insights into the key role of phosphatidylinositol phosphates in modulating its interactions with target membranes. We have used large-scale atomistic Molecular dynamics (MD) simulations to study how the dynamics of cholesterol bound to the StarD4 protein can affect interaction with target membranes, and cargo delivery. We identify the two major cholesterol (CHL) binding modes in the hydrophobic pocket of StarD4, one near S136&S147 (the Ser-mode), and another closer to the putative release gate located near W171, R92&Y117 (the Trp-mode). We show that conformational changes of StarD4 associated directly with the transition between these binding modes facilitate the opening of the gate. To understand the dynamics of this connection we apply a machine-learning algorithm for the detection of rare events in MD trajectories (RED), which reveals the structural motifs involved in the opening of a front gate and a back corridor in the StarD4 structure occurring together with the spontaneous transition of CHL from the Ser-mode of binding to the Trp-mode. Further analysis of MD trajectory data with the information-theory based NbIT method reveals the allosteric network connecting the CHL binding site to the functionally important structural components of the gate and corridor. Mutations of residues in the allosteric network are shown to affect the performance of the allosteric connection. These findings outline an allosteric mechanism which prepares the CHL-bound StarD4 to release and deliver the cargo when it is bound to the target membrane.
Genome-wide characterization of T cell responses toBordetella pertussisreveals broad reactivity and similar polarization irrespective of childhood vaccination profiles
Authors: Antunes Ricardo da Silva , Garrigan Emily , Quiambao Lorenzo G , Dhanda Sandeep Kumar , Marrama Daniel , Westernberg Luise , Wang Eric , Sutherland Aaron , Armstrong Sandra K , Brickman Timothy J , Sidney John , Frazier April , Merkel Tod , Peters Bjoern , Sette Alessandro 
Published: March 2023

ABSTRACTThe incidence of whooping cough (pertussis), the respiratory disease caused byBordetella pertussis(BP) has increased in recent years, and it is suspected that the switch from whole-cell pertussis (wP) to acellular pertussis (aP) vaccines may be a contributing factor to the rise in morbidity. While a growing body of evidence indicates that T cells play a role in the control and prevention of symptomatic disease, nearly all data on human BP-specific T cells is related to the four antigens contained in the aP vaccines, and data detailing T cell responses to additional non-aP antigens, are lacking. Here, we derived a full-genome map of human BP-specific CD4+ T cell responses using a high-throughputex vivoActivation Induced Marker (AIM) assay, to screen a peptide library spanning over 3000 different BP ORFs. First, our data show that BP specific-CD4+ T cells are associated with a large and previously unrecognized breadth of responses, including hundreds of targets. Notably, fifteen distinct non-aP vaccine antigens were associated with reactivity comparable to that of the aP vaccine antigens. Second, the overall pattern and magnitude of CD4+ T cell reactivity to aP and non-aP vaccine antigens was similar regardless of aP vs wP childhood vaccination history, suggesting that the profile of T cell reactivity in adults is not driven by vaccination, but rather is likely driven by subsequent asymptomatic or sub-clinical infections. Finally, while aP vaccine responses were Th1/Th2 polarized as a function of childhood vaccination, CD4+ T cell responses to non-aP BP antigens vaccine responses were not, suggesting that these antigens could be used to avoid the Th2 bias associated with aP vaccination. Overall, these findings enhance our understanding of human T cell responses against BP and suggest potential targets for designing next-generation pertussis vaccines.
A metagenomic library cloning strategy that promotes high-level expression of captured genes to enable efficient functional screening
Authors: Rich Michelle H , Sharrock Abigail V , Mulligan Timothy S , Matthews Frazer , Brown Alistair S , Lee-Harwood Hannah R , Williams Elsie M , Copp Janine N , Little Rory F , Francis Jenni JB , Horvat Claire N , Stevenson Luke J , Owen Jeremy G , Saxena Meera T , Mumm Jeff S , Ackerley David F 
Published: March 2023

SummaryFunctional screening of environmental DNA (eDNA) libraries is a potentially powerful approach to discover enzymatic “unknown unknowns”, but is usually heavily biased toward the tiny subset of genes preferentially transcribed and translated by the screening strain. We have overcome this by preparing an eDNA library via partial digest with restriction enzyme Fatl (cuts CATG), causing a substantial proportion of ATG start codons to be precisely aligned with strong plasmid-encoded promoter and ribosome-binding sequences. Whereas we were unable to select nitroreductases from standard metagenome libraries, our Fatl strategy yielded 21 nitroreductases spanning eight different enzyme families, each conferring resistance to the nitro-antibiotic niclosamide and sensitivity to the nitro-prodrug metronidazole. We showed expression could be improved by co-expressing rare tRNAs and encoded proteins purified directly using an embedded Hisg-tag. In a transgenic zebrafish model of metronidazole-mediated targeted cell ablation, our lead MhqN-family nitroreductase proved ∼5- fold more effective than the canonical nitroreductase NfsB.
Clots reveal anomalous elastic behavior of fiber networks
Authors: Zakharov Andrei , Awan Myra , Cheng Terrence , Gopinath Arvind , Lee Sang-Joon John , Ramasubramanian Anand K. , Dasbiswas Kinjal 
Published: March 2023

AbstractThe mechanical properties of many soft natural and synthetic biological materials are relevant to their function. The emergence of these properties from the collective response of the structural components of the material to external stress as well as to intrinsic cell traction, remains poorly understood. Here, we examine the nonlinear elastic behavior of blood clots by combining microscopy and rheological measurements with an elastic network model that accounts for the stretching, bending, and buckling of constituent fibrin fibers. We show that the inhibition of fibrin crosslinking reduces fiber bending stiffness and introduces an atypical fiber buckling-induced softening regime at intermediate shear, before the well-characterized stiffening regime. We also show that crosslinking and platelet contraction significantly alter force propagation in the network in a strain-dependent manner. Our mechanics-based model, supported by experiments, provides a framework to understand the origins of characteristic and anomalous regimes of non-linear elastic response not only in blood clots, but also more generally in active biopolymer networks.
Evidence for ancient selective sweeps followed by differentiation among three species ofSphyrapicussapsuckers
Authors: Natola Libby , Irwin Darren 
Published: March 2023

AbstractSpeciation occurs when gene pools differentiate between populations, but that differentiation is heterogeneous across the genome. Understanding what parts of the genome are more prone to differentiation is a key mission in evolutionary biology because it can identify genomic regions and evolutionary processes central to the speciation process. Here, we study genomic variation among three closely related species of North American woodpecker: red-breasted, red-naped, and yellow-bellied sapsuckers. We construct a new sapsucker reference genome and use whole genome resequencing to measure genetic variation among these species and to quantify how the level of differentiation between these forms varies across the genome. We find that regions of high relative differentiation between species (FST) tend to have low absolute differentiation between species (πB), indicating that regions of high relative differentiation often have more recent between-population coalescence times than regions of low relative differentiation do. Most of the high-FSTgenomic windows are found on the Z chromosome, indicating this sex chromosome is particularly important in sapsucker speciation. We show that LD is high across the Z chromosome and that each species tends to have a unique Z haploblock, a pattern suggestive of chromosomal inversions. These results are consistent with a model of speciation in which selective sweeps of globally advantageous variants spread among partly differentiated populations, followed by differential local adaptation of those same genomic regions. We propose that sapsucker speciation may occur primarily via this process occurring on the Z chromosomes, followed by epistatic interactions between Z haploblocks.
Performance of ChatGPT as an AI-assisted decision support tool in medicine: a proof-of-concept study for interpreting symptoms and management of common cardiac conditions (AMSTELHEART-2)
Authors: Harskamp Ralf E. , De Clercq Lukas 
Published: March 2023

ABSTRACTBackgroundIt is thought that ChatGPT, an advanced language model developed by OpenAI, may in the future serve as an AI-assisted decision support tool in medicine.ObjectiveTo evaluate the accuracy of ChatGPT’s recommendations on medical questions related to common cardiac symptoms or conditions.MethodsWe tested ChatGPT’s ability to address medical questions in two ways. First, we assessed its accuracy in correctly answering cardiovascular trivia questions (n=50), based on quizzes for medical professionals. Second, we entered 20 clinical case vignettes on the ChatGPT platform and evaluated its accuracy compared to expert opinion and clinical course.ResultsWe found that ChatGPT correctly answered 74% of the trivia questions, with slight variation in accuracy in the domains coronary artery disease (80%), pulmonary and venous thrombotic embolism (80%), atrial fibrillation (70%), heart failure (80%) and cardiovascular risk management (60%). In the case vignettes, ChatGPT’s response matched in 90% of the cases with the actual advice given. In more complex cases, where physicians (general practitioners) asked other physicians (cardiologists) for assistance or decision support, ChatGPT was correct in 50% of cases, and often provided incomplete or inappropriate recommendations when compared with expert consultation.ConclusionsOur study suggests that ChatGPT has potential as an AI-assisted decision support tool in medicine, particularly for straightforward, low-complex medical questions, but further research is needed to fully evaluate its potential.
Diagnostic criteria for patellofemoral pain syndrome: a scoping review protocol
Authors: Casalini Alberto , Morganti Davide , Salvemini Angela M.R 
Published: March 2023

ABSTRACTBackgroundKnee pain is a frequent cause of mobility limitation and worsening quality of life. There are several atraumatic musculoskeletal disorders clinically presenting with knee pain and among them, there is patellofemoral pain syndrome (PFPS). According to the biopsychosocial approach, it is important to consider other factors and the whole person besides the anatomical structure. A specific diagnosis is important when a macroscopic damage is present and can be investigated with accurate test and diagnostic imaging. This scoping review aims to provide an overview of clinical tests and imaging commonly used in clinical practice to identify the aforementioned atraumatic knee pathology.Inclusion criteriaStudies considering patients with patellofemoral pain syndrome (PFPS) diagnosis and, in particular, studies concerning the diagnosis of this disorder in a rehabilitation and medical setting, will be included.MethodsThis review will follow the Joanna Briggs Institute (JBI) methodology. Medline, Scopus, Pedro will be searched. In addition, other records will be identified searching grey literature. Limits regarding year of publication will not applied. Secondary research studies will be excluded and only English studies will be included. Two reviewers will independently screen all studies for inclusion and disagreements will be resolved by a third author. A data collection table will be developed by the researchers and a narrative and graphical synthesis of the results will be presented.ConclusionThis scoping review will be the first presenting an overview of criteria used for the diagnosis of the PFPS. The results will help clinicians to consider the role of clinical tests and imaging in the framing of patients with patellofemoral pain syndrome (PFPS).
The spatial arrangement of laminar thickness profiles in the human cortex scaffolds processing hierarchy
Authors: Saberi Amin , Paquola Casey , Wagstyl Konrad , Hettwer Meike D. , Bernhardt Boris C. , Eickhoff Simon B. , Valk Sofie L. 
Published: March 2023

AbstractThe human neocortex consists of tangentially organized layers with unique cytoarchitectural properties. These layers show spatial variations in thickness and cytoarchitecture across the neocortex, which is thought to support brain function through enabling targeted corticocortical connections. Here, leveraging maps of the six cortical layers in 3D human brain histology, we aimed to quantitatively characterize the systematic covariation of laminar structure in the cortex and its functional consequences. After correcting for the effect of cortical curvature, we identified a spatial pattern of changes in laminar thickness covariance from lateral frontal to posterior occipital regions, which differentiated the dominance of infra- versus supragranular layer thickness. Corresponding to the laminar regularities of cortical connections along cortical hierarchy, the infragranular-dominant pattern of laminar thickness was associated with higher hierarchical positions of regions, mapped based on resting-state effective connectivity in humans and tract-tracing of structural connections in macaques. Moreover, we show that regions with comparable laminar thickness patterns correspond to inter-regional structural covariance, maturational coupling, and transcriptomic patterning, indicating developmental relevance. In sum, here we characterize the association between organization of laminar thickness and processing hierarchy, anchored in ontogeny. As such, we illustrate how laminar organization may provide a foundational principle ultimately supporting human cognitive functioning.
RB loss sensitizes cells to replication-associated DNA damage by PARP inhibition
Authors: Zamalloa L Gregory , Pruitt Margaret M , Hermance Nicole M , Gali Himabindu , Flynn Rachel L , Manning Amity L 
Published: March 2023

ABSTRACTThe retinoblastoma tumor suppressor protein (RB) interacts physically and functionally with a number of epigenetic modifying enzymes to control transcriptional regulation, respond to replication stress, promote DNA damage response and repair pathways, and regulate genome stability. To better understand how disruption of RB function impacts epigenetic regulation of genome stability and determine whether such changes may represent exploitable weaknesses of RB-deficient cancer cells, we performed an imaging-based screen to identify epigenetic inhibitors that promote DNA damage and compromise viability of RB-deficient cells. We found that loss of RB alone leads to high levels of replication-dependent poly-ADP ribosylation (PARylation) and that preventing PARylation through inhibition of PARP enzymes enables RB-deficient cells to progress to mitosis with unresolved replication stress and under-replicated DNA. These defects contribute to high levels of DNA damage, decreased proliferation, and compromised cell viability. We demonstrate this sensitivity is conserved across a panel of inhibitors that target both PARP1 and PARP2 and can be suppressed by re-expression of the RB protein. Together, these data indicate that inhibitors of PARP1 and PARP2 may be clinically relevant for RB-deficient cancers.
Antibiotics promote intestinal growth of carbapenem-resistantEnterobacteriaceaeby enriching nutrients and depleting microbial metabolites
Authors: Yip Alexander Y. G. , King Olivia G. , Omelchenko Oleksii , Kurkimat Sanjana , Horrocks Victoria , Mostyn Phoebe , Danckert Nathan , Ghani Rohma , Satta Giovanni , Jauneikaite Elita , Davies Frances J. , Clarke Thomas B. , Mullish Benjamin H. , Marchesi Julian R. , McDonald Julie A. K. 
Published: March 2023

ABSTRACTThe intestine is the primary colonisation site for carbapenem-resistantEnterobacteriaceae(CRE) and serves as a reservoir of CRE that cause invasive infections (e.g. bloodstream infections). Antibiotics disrupt colonisation resistance mediated by the gut microbiota, promoting the expansion of CRE within the intestine. We usedex vivofaecal cultures to measure the impact of antibiotics (that promote CRE intestinal colonisation) on the faecal microbiota from healthy human donors. We demonstrated that antibiotics decreased the abundance of gut commensals (includingBifidobacteriaceaeandBacteroidales) in human faecal microbiota, resulting in an enrichment of nutrients and a depletion of microbial metabolites. We measured the nutrient utilisation abilities, nutrient preferences, and metabolite inhibition susceptibilities of several carbapenem-resistantEnterobacteriaceaestrains, includingEscherichia coli,Klebsiella pneumoniae, andEnterobacter hormaechei. Nutrients (which were elevated with antibiotics) acted as carbon and nitrogen sources to support CRE growth, where CRE strains showed an ordered preference for specific nutrients. These nutrients were also increased in faeces from antibiotic-treated mice but decreased following intestinal colonisation with carbapenem-resistantE. coli. Microbial metabolites (which decreased with antibiotics) were inhibitory towards CRE growthin vitro. Carbapenem-resistantE. coligrowth was decreased in faecal samples from mice treated with a mixture of inhibitory metabolites compared with PBS-treated mice. These findings demonstrated that killing gut commensals with antibiotics disrupts colonisation resistance by enriching nutrients that support CRE growth and depleting metabolites that inhibit CRE growth. These results support the development of new microbiome therapeutics to prevent CRE intestinal colonisation, which would also prevent the subsequent development of invasive CRE infections.