bluuebunny/crossref_metadata_2025 huggingface dataset:
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

The 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

Functional 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

The 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

Speciation 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

Background

It 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.

Objective

To evaluate the accuracy of ChatGPT’s recommendations on medical questions related to common cardiac symptoms or conditions.

Methods

We 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.

Results

We 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.

Conclusions

Our 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

Background

Knee 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 criteria

Studies 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.

Methods

This 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.

Conclusion

This 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

The 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

The 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

The 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.
Unravelling individual rhythmic abilities using machine learning
Authors: Bella Simone Dalla , Janaqi Stefan , Benoit Charles-Etienne , Farrugia Nicolas , Bégel Valentin , Verga Laura , Harding Eleanor E. , Kotz Sonja A.
Published: March 2023

Humans can easily extract the rhythm of a complex sound, like music, and move to its regular beat, for example in dance. These abilities are modulated by musical training and vary significantly in untrained individuals. The causes of this variability are multidimensional and typically hard to grasp with single tasks. To date we lack a comprehensive model capturing the rhythmic fingerprints of both musicians and non-musicians. Here we harnessed machine learning to extract a parsimonious model of rhythmic abilities, based on the behavioral testing (with perceptual and motor tasks) of individuals with and without formal musical training (n= 79). We demonstrate that the variability of rhythmic abilities, and their link with formal and informal music experience, can be successfully captured by profiles including a minimal set of behavioral measures. These profiles can shed light on individual variability in healthy and clinical populations, and provide guidelines for personalizing rhythm-based interventions.
Lasiodiplodiaspecies associated with mango (Mangifera indicaL.) decline in Burkina Faso and influence of climatic factors on the disease distribution
Authors: Dianda Oumarou Zoéyandé , Wonni Issa , Ouédraogo Léonard , Sankara Philippe , Tollenaere Charlotte , Del Ponte Emerson M. , Fernandez Diana
Published: March 2023

Dieback or decline caused byLasiodiplodiaspp. is a major disease of mango trees (Mangifera indicaL.). The main objectives of this study were to identifyLasiodiplodiaspecies associated with mango decline in Burkina Faso, and to asses the climatic and edaphic factors affecting the geographic distribution of the disease in the country. The genetic diversity of 47Lasiodiplodiaisolates was studied based on sequence data of the translation elongation factor 1-alpha gene (tef1-a) and the rDNA internal transcribed spacer region (ITS). Phylogeny analyses grouped the isolates from Burkina Faso with 6 differentLasiodiplodiaspecies, includingL. euphorbicolathat accounted for 36 of the 47 isolates.Lasiodiplodiaisolates tested on mango seedlings induced the typical dieback symptoms. Disease incidence and severity were generally higher in the drier and warmer regions (eastern) of the country. This study provides the required information to establish control strategies against mango decline in Burkina Faso.
EphrinA5 regulates cell motility by modulating the targeting of DNMT1 to theNcam1promoter via lncRNA/DNA triplex formation
Authors: Yildiz Can Bora , Kundu Tathagata , Gehrmann Julia , Koesling Jannis , Ravaei Amin , Jakovcevski Mira , Pensold Daniel , Zimmermann Olav , Rossetti Giulia , Costa Ivan G. , Zimmer-Bensch Geraldine
Published: March 2023

Cell-cell communication is mediated by membrane receptors and their cognate ligands, such as the Eph/ephrin system, and dictates physiological processes, including cell proliferation and migration. However, whether and how Eph/ephrin signaling culminates in transcriptional regulation is largely unknown. Epigenetic mechanisms are key for integrating external “signals”, e.g., from neighboring cells, into the transcriptome. We have previously reported that ephrinA5 stimulation of immortalized cerebellar granule (CB) cells elicits transcriptional changes of lncRNAs and protein-coding genes. LncRNAs represent important adaptors for epigenetic writers through which they regulate gene expression. Here, we investigate the interaction of lncRNA with protein-coding genes by the combined power ofin silicomodeling of RNA/DNA interactions and respective wet lab approaches, in the context of ephrinA5-dependent regulation of cellular motility. We found thatSnhg15, a cancer-related lncRNA, forms a triplex structure with theNcam1promoter and interacts with DNMT1. EphrinA5 stimulation leads to reducedSnhg15expression, diminishedSnhg15/DNMT1 interaction and decreased DNMT1 association with theNcam1promoter. These findings can explain the attenuatedNcam1promoter methylation and elevatedNcam1expression that in turn elicits decreased cell motility of CB cells. Hence, we propose that ephrinA5 influences gene transcription via lncRNA-targeted DNA methylation underlying the regulation of cellular motility.
Evidence for adaptive evolution towards high magnetic sensitivity of potential magnetoreceptor in songbirds
Authors: Langebrake Corinna , Manthey Georg , Frederiksen Anders , Lugo Ramos Juan S. , Dutheil Julien Y. , Chetverikova Raisa , Solov’yov Ilia , Mouritsen Henrik , Liedvogel Miriam
Published: March 2023

Migratory birds possess remarkable accuracy in orientation and navigation, which involves various compass systems including the magnetic compass. Identifying the primary magnetosensor remains a fundamental open question. Cryptochromes (Cry) have been shown to be magnetically sensitive, specifically Cry4 shows enhanced magnetic sensitivity in migratory songbirds compared to resident species. Here, we investigate cryptochromes and their potential involvement in magnetoreception in a phylogenetic framework, integrating molecular evolutionary analyses with protein dynamics modeling. We base our analysis on 363 bird genomes and associate different selection regimes with migratory behaviour. We show that Cry4 is characterized by strong positive selection and high variability, typical characteristics of sensor proteins. We identify key sites that likely facilitated the evolution of a highly optimized sensory protein for night time compass orientation in songbirds and a potential functional shift or specialisation. Additionally, we show that Cry4 was lost in hummingbirds, parrots and Tyranni (Suboscines) and thus identified a natural comparative gene knockout, which can be used to test the function of Cry4 in birds. In contrast, the other two cryptochromes Cry1 and Cry2, were highly conserved in all species, indicating basal, non-sensory functions. Our results strengthen the hypothesised role of Cry4 as sensor protein in (night)-migratory songbirds.
Binding of the TRF2 iDDR motif to RAD50 highlights a convergent evolutionary strategy to inactivate MRN at telomeres
Authors: Khayat Freddy , Alshmery Majedh , Pal Mohinder , Oliver Antony W. , Bianchi Alessandro
Published: March 2023

Telomeres protect chromosome ends from unscheduled DNA repair, including from the MRN (MRE11, RAD50, NBS1) complex, which plays a critical role in the processing of double-stranded DNA breaks (DSBs). MRN orchestrates activation of the ATM kinase in the cellular DNA damage response (DDR), promotes DNA end-tethering aiding the nonhomologous end joining (NHEJ) pathway, and initiates DSB resection through the MRE11 nuclease. A previously identified protein motif (MIN, for MRN inhibitor) downregulates MRN activity via binding to RAD50 and has independently arisen at least twice, through convergent evolution of telomeric proteins Rif2 and Taz1, in budding and fission yeast respectively. We now provide a third example of convergent evolution for this binding mechanism for MRN at telomeres, by demonstrating that the iDDR motif of the human shelterin protein TRF2 binds to human RAD50 at the same site engaged by the MIN motif in the yeast proteins, despite lacking sequence homology. Modelling for the human CtIP interaction with RAD50 (necessary for activation of MRE11), and for the budding and fission yeast counterparts Sae2 and Ctp1, indicates that the interaction is mutually exclusive with binding of the iDDR/MIN motifs, pointing to a conserved mechanism for inhibition of MRN nuclease activity at telomeres.
Molecular mechanisms of inorganic-phosphate release from the core and barbed end of actin filaments
Authors: Oosterheert Wout , Blanc Florian E.C. , Roy Ankit , Belyy Alexander , Hofnagel Oliver , Hummer Gerhard , Bieling Peter , Raunser Stefan
Published: March 2023

The release of inorganic phosphate (Pi) from actin filaments constitutes a key step in their regulated turnover, which is fundamental to many cellular functions. However, the molecular mechanisms underlying Pirelease from both the core and barbed end of actin filaments remain unclear. Here, we combine cryo-EM with molecular dynamics simulations andin vitroreconstitution to demonstrate how actin releases Pithrough a ‘molecular backdoor’. While constantly open at the barbed end, the backdoor is predominantly closed in filament-core subunits and only opens transiently through concerted backbone movements and rotameric rearrangements of residues close to the nucleotide binding pocket. This mechanism explains why Piescapes rapidly from the filament end and yet slowly from internal actin subunits. In an actin variant associated with nemaline myopathy, the backdoor is predominantly open in filament-core subunits, resulting in greatly accelerated Pirelease after polymerization and filaments with drastically shortened ADP-Picaps. This demonstrates that the Pirelease rate from F-actin is controlled by steric hindrance through the backdoor rather than by the disruption of the ionic bond between Piand Mg2+at the nucleotide-binding site. Our results provide the molecular basis for Pirelease from actin and exemplify how a single, disease-linked point mutation distorts the nucleotide state distribution and atomic structure of the actin filament.
Inducible protein degradation as a strategy to identify Phosphoprotein Phosphatase 6 substrates in RAS-mutant colorectal cancer cells
Authors: Mariano Natasha C. , Rusin Scott F. , Nasa Isha , Kettenbach Arminja N.
Published: March 2023

Protein phosphorylation is an essential regulatory mechanism that controls most cellular processes, including cell cycle progression, cell division, and response to extracellular stimuli, among many others, and is deregulated in many diseases. Protein phosphorylation is coordinated by the opposing activities of protein kinases and protein phosphatases. In eukaryotic cells, most serine/threonine phosphorylation sites are dephosphorylated by members of the Phosphoprotein Phosphatase (PPP) family. However, we only know for a few phosphorylation sites which specific PPP dephosphorylates them. Although natural compounds such as calyculin A and okadaic acid inhibit PPPs at low nanomolar concentrations, no selective chemical PPP inhibitors exist. Here, we demonstrate the utility of endogenous tagging of genomic loci with an auxin-inducible degron (AID) as a strategy to investigate specific PPP signaling. Using Protein Phosphatase 6 (PP6) as an example, we demonstrate how rapidly inducible protein degradation can be employed to identify dephosphorylation SITES and elucidate PP6 biology. Using genome editing, we introduce AID-tags into each allele of the PP6 catalytic subunit (PP6c) in DLD-1 cells expressing the auxin receptor Tir1. Upon rapid auxin-induced degradation of PP6c, we perform quantitative mass spectrometry-based proteomics and phosphoproteomics to identify PP6 substrates in mitosis. PP6 is an essential enzyme with conserved roles in mitosis and growth signaling. Consistently, we identify candidate PP6c-dependent phosphorylation sites on proteins implicated in coordinating the mitotic cell cycle, cytoskeleton, gene expression, and mitogen-activated protein kinase (MAPK) and Hippo signaling. Finally, we demonstrate that PP6c opposes the activation of large tumor suppressor 1 (LATS1) by dephosphorylating Threonine 35 (T35) on Mps One Binder (MOB1), thereby blocking the interaction of MOB1 and LATS1. Our analyses highlight the utility of combining genome engineering, inducible degradation, and multiplexed phosphoproteomics to investigate signaling by individual PPPs on a global level, which is currently limited by the lack of tools for specific interrogation.
Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice
Authors: Mondal Samim Ali , Mann Shivani N. , van der Linden Carl , Sathiaseelan Roshini , Kamal Maria , Das Snehasis , Bubak Matthew P. , Logan Sreemathi , Miller Benjamin F. , Stout Michael B.
Published: March 2023

Metabolic dysfunction underlies several chronic diseases. Dietary interventions can reverse metabolic declines and slow aging but remaining compliant is difficult. 17α-estradiol (17α-E2) treatment improves metabolic parameters and slows aging in male mice without inducing significant feminization. We recently reported that estrogen receptor α is required for the majority of 17α-E2-mediated benefits in male mice, but that 17α-E2 also attenuates fibrogenesis in liver, which is regulated by estrogen receptor β (ERβ)-expressing hepatic stellate cells (HSC). The current studies sought to determine if 17α-E2-mediated benefits on systemic and hepatic metabolism are ERβ-dependent. We found that 17α-E2 treatment reversed obesity and related systemic metabolic sequela in both male and female mice, but this was partially blocked in female, but not male, ERβKO mice. ERβ ablation in male mice attenuated 17α-E2-mediated benefits on hepatic stearoyl-coenyzme A desaturase 1 (SCD1) and transforming growth factor β1 (TGF-β1) production, which play critical roles in HSC activation and liver fibrosis. We also found that 17α-E2 treatment suppresses SCD1 production in cultured hepatocytes and hepatic stellate cells, indicating that 17α-E2 directly signals in both cell-types to suppress drivers of steatosis and fibrosis. We conclude that ERβ partially controls 17α-E2-mediated benefits on systemic metabolic regulation in female, but not male, mice, and that 17α-E2 likely signals through ERβ in HSCs to attenuate pro-fibrotic mechanisms.
A highly conserved and globally prevalent cryptic plasmid is among the most numerous mobile genetic elements in the human gut
Authors: Fogarty Emily C , Schechter Matthew S , Lolans Karen , Sheahan Madeline L. , Veseli Iva , Moore Ryan , Kiefl Evan , Moody Thomas , Rice Phoebe A , Yu Michael K , Mimee Mark , Chang Eugene B , Mclellan Sandra L , Willis Amy D , Comstock Laurie E , Eren A Murat
Published: March 2023

Plasmids are extrachromosomal genetic elements that often encode fitness enhancing features. However, many bacteria carry ‘cryptic’ plasmids that do not confer clear beneficial functions. We identified one such cryptic plasmid, pBI143, which is ubiquitous across industrialized gut microbiomes, and is 14 times as numerous as crAssphage, currently established as the most abundant genetic element in the human gut. The majority of mutations in pBI143 accumulate in specific positions across thousands of metagenomes, indicating strong purifying selection. pBI143 is monoclonal in most individuals, likely due to the priority effect of the version first acquired, often from one’s mother. pBI143 can transfer between Bacteroidales and although it does not appear to impact bacterial host fitnessin vivo, can transiently acquire additional genetic content. We identified important practical applications of pBI143, including its use in identifying human fecal contamination and its potential as an inexpensive alternative for detecting human colonic inflammatory states.
Activity-dependent subcellular compartmentalization of dendritic mitochondria structure in CA1 pyramidal neurons
Authors: Virga Daniel M. , Hamilton Stevie , Osei Bertha , Morgan Abigail , Zamponi Emiliano , Park Natalie J. , Hewitt Victoria L. , Zhang David , Gonzalez Kevin C. , Bloss Erik , Polleux Franck , Lewis Tommy L.
Published: March 2023

Neuronal mitochondria play important roles beyond ATP generation, including Ca2+uptake, and therefore have instructive roles in synaptic function and neuronal response properties. Mitochondrial morphology differs significantly in the axon and dendrites of a given neuronal subtype, but in CA1 pyramidal neurons (PNs) of the hippocampus, mitochondria within the dendritic arbor also display a remarkable degree of subcellular, layer- specific compartmentalization. In the dendrites of these neurons, mitochondria morphology ranges from highly fused and elongated in the apical tuft, to more fragmented in the apical oblique and basal dendritic compartments, and thus occupy a smaller fraction of dendritic volume than in the apical tuft. However, the molecular mechanisms underlying this striking degree of subcellular compartmentalization of mitochondria morphology are unknown, precluding the assessment of its impact on neuronal function. Here, we demonstrate that this compartment-specific morphology of dendritic mitochondria requires activity-dependent, Camkk2- dependent activation of AMPK and its ability to phosphorylate two direct effectors: the pro-fission Drp1 receptor Mff and the recently identified anti-fusion, Opa1-inhibiting protein, Mtfr1l. Our study uncovers a new activity- dependent molecular mechanism underlying the extreme subcellular compartmentalization of mitochondrial morphology in dendrites of neuronsin vivothrough spatially precise regulation of mitochondria fission/fusion balance.
Dual roles for nucleus accumbens core dopamine D1-expressing neurons projecting to the substantia nigra pars reticulata in limbic and motor control
Authors: Attachaipanich Suthinee , Ozawa Takaaki , Macpherson Tom , Hikida Takatoshi
Published: March 2023

The nucleus accumbens (NAc) is a critical component of a limbic basal ganglia circuit that is thought to play an important role in decision-making and the processing of rewarding stimuli. As part of this circuit, dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) of the NAc core are known to send a major projection to the substantia nigra pars reticulata (SNr). However, the functional role of this SNr-projecting NAc D1-MSNs (NAcD1-MSN-SNr) pathway is still largely uncharacterized. Moreover, as the SNr is thought to belong to both limbic and motor information processing basal ganglia loops, it is possible that the NAcD1-MSN-SNr pathway may be able to influence both limbic and motor functions. In this study we investigated the effect of optogenetic activation of the NAcD1-MSN-SNr pathway on reward-learning and locomotor behavior. Stimulation of the axon terminals of NAc core D1-MSNs in the SNr induced a preference for a laser-paired location, self-stimulation via a laser-paired lever, and augmented instrumental responding for a liquid reward-paired lever. Additionally, stimulation was observed to increase locomotor behavior when delivered bilaterally and induced contralateral turning behavior when delivered unilaterally. These findings indicate that the NAcD1-MSN-SNr pathway is able to control both reward learning and motor behaviors.
A structural vista of phosducin-like PhLP2A-chaperonin TRiC cooperation during the ATP-driven folding cycle
Authors: Park Junsun , Kim Hyunmin , Gestaut Daniel , Lim Seyeon , Leitner Alexander , Frydman Judith , Roh Soung-Hun
Published: March 2023

Proper cellular proteostasis, essential for viability, requires a network of chaperones and cochaperones. ATP-dependent chaperonin TRiC/CCT partners with cochaperones prefoldin (PFD) and phosducin-like proteins (PhLPs) to facilitate the folding of essential eukaryotic proteins. Using cryoEM and biochemical analyses, we determine the ATP-driven cycle of TRiC-PFD-PhLP2A interaction. In the open TRiC state, PhLP2A binds to the chamber’s equator while its N-terminal H3-domain binds to the apical domains of CCT3/4, thereby displacing PFD from TRiC. ATP-induced TRiC closure rearranges the contacts of PhLP2A domains within the closed chamber. In the presence of substrate, actin and PhLP2A segregate into opposing chambers, each binding to the positively charged inner surfaces formed by CCT1/3/6/8. Notably, actin induces a conformational change in PhLP2A, causing its N-terminal helices to extend across the inter-ring interface to directly contact a hydrophobic groove in actin. Our findings reveal an ATP-driven PhLP2A structural rearrangement cycle within the TRiC chamber to facilitate folding.

Highlights

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Structural analysis of TRiC-mediated folding cycle with cochaperones PhLP2A and PFD.

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The interactions of PhLP2A and PFD with TRiC are mutually exclusive.

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PhLP2A domains interact in a subunit-specific manner with the TRiC chamber.

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PhLP2A domains are rearranged in ATP-closed TRiC to contact actin across the ring interface
Live-cell imaging provides direct evidence for a threshold in CDK activity at the G2/M transition
Authors: Sugiyama Hironori , Goto Yuhei , Kondo Yohei , Coudreuse Damien , Aoki Kazuhiro
Published: March 2023

Cyclin-dependent kinase (CDK) plays an essential role in determining the temporal ordering of the cell cycle phases. However, despite significant progress in studying regulators of CDK, it remains elusive how they coordinately affect CDK activity at the single-cell level and how CDK controls the temporal order of cell cycle events. This could be due to the lack of tools to monitor CDK activity in living cells. Here, we elucidate the dynamics of CDK activity in fission yeast and mammalian cells by using a newly developed CDK activity biosensor, Eevee-spCDK, based on Förster Resonance Energy Transfer (FRET). Taking advantage of this system, we unravel the profile of CDK activity in vegetatively growingS. pombecells. Thus, we detect a transient increase in S phase followed by a gradual increment during G2 phase. CDK activity then reaches its maximum in early M phase and rapidly decreases at mitotic exit. During G2 phase, CDK activity exhibits a biphasic pattern,i.e., an early slow increase and a late fast rise prior to the G2/M phase transition, as predicted from mathematical studies. Remarkably, although CDK activity does not necessarily correlate with cyclin levels, we find that it converges to the same level around mitotic onset in several mutant backgrounds, includingpom1Δcells andwee1orcdc25overexpressing cells. These data provide the first direct evidence that cells enter M phase when CDK activity reaches a high threshold, consistent with the quantitative model of cell cycle progression in fission yeast.
A reflection on contemporary myths of women's football: a historical analysis
Authors: Cooper Christine
Published: March 2023

Purpose

This study aims to provide a social accounting of early women's football as a form of consciousness raising, and to provide a platform to raise questions about the path of the future of the women's game.

Design/methodology/approach

Newspaper archival materials supplemented by books and journal articles.

Findings

British woman's football was repressed for 50 years by the football association.

Research limitations/implications

This is a discussion paper, rather than a full academic manuscript.

Practical implications

This paper is designed to enable questions to be raised about equality, and what that means in 2022.

Social implications

There is an opportunity to reconsider a “feminine” version of the field of football.

Originality/value

There is an opportunity to use feminist theories to consider the past and future of women's football.
Where was my cup of honey made? PDO honey and sub-regional ethnocentric consumer segments
Authors: Trentinaglia Maria Teresa , Cavicchioli Daniele , Pocol Cristina Bianca , Baldi Lucia
Published: March 2023

Purpose

The goal of this study is to understand if ethnocentrism exists at the sub-regional level among honey consumers living in the same production area as a protected designation of origin (PDO). Moreover, this analysis explores if ethnocentrism is influenced by individual economic conditions, among other socio-demographic characteristics.

Design/methodology/approach

A sample of 725 consumers was collected through the use of a questionnaire that was circulated in the province of Varese, one of the few honey PDO areas in Italy. The authors performed a principal component analysis and a two-step cluster analysis to identify different PDO honey consumer segments, focusing on their interest for PDO attributes.

Findings

The authors identified four consumer segments, depending on socio-demographic, consumption habits, frequencies, preferred attributes and preferences for the PDO product. One cluster exhibited strong preferences for the PDO honey, in the spirit of ethnocentrism, and was characterised by low-income levels; ethnocentric preferences were also observed in another cluster that had a different socio-economic profile.

Research limitations/implications

Honey is a niche product and not universally diffused among consumers: further analyses should investigate sub-national ethnocentrism for more universal food products. Yet, through the inspection of the different profiles found, it was possible to devise marketing strategies to boost PDO honey purchasing and to bring consumers closer to PDO products.

Originality/value

This analysis considers ethnocentrism as a segmentation criterion for PDO honey consumers that live in the very same PDO honey production area and enriches the existing literature on the relationship between ethnocentrism and individual economic status.
A genetic algorithm-based design model to provide reduced risk areas for housing interiors
Authors: Garip Seniye Banu , Güzelci Orkan Zeynel , Garip Ervin , Kocabay Serkan
Published: March 2023

Purpose

This study aims to present a novel Genetic Algorithm-Based Design Model (GABDM) to provide reduced-risk areas, namely, a “safe footprint,” in interior spaces during earthquakes. This study focuses on housing interiors as the space where inhabitants spend most of their daily lives.

Design/methodology/approach

The GABDM uses the genetic algorithm as a method, the Nondominated Sorting Genetic Algorithm II algorithm, and the Wallacei X evolutionary optimization engine. The model setup, including inputs, constraints, operations and fitness functions, is presented, as is the algorithmic model’s running procedure. Following the development phase, GABDM is tested with a sample housing interior designed by the authors based on the literature related to earthquake risk in interiors. The implementation section is organized to include two case studies.

Findings

The implementation of GABDM resulted in optimal “safe footprint” solutions for both case studies. However, the results show that the fitness functions achieved in Case Study 1 differed from those achieved in Case Study 2. Furthermore, Case Study 2 has generated more successful (higher ranking) “safe footprint” alternatives with its proposed furniture system.

Originality/value

This study presents an original approach to dealing with earthquake risks in the context of interior design, as well as the development of a design model (GABDM) that uses a generative design method to reduce earthquake risks in interior spaces. By introducing the concept of a “safe footprint,” GABDM contributes explicitly to the prevention of earthquake risk. GABDM is adaptable to other architectural typologies that involve footprint and furniture relationships.
Effect of public–private partnership features on contractual complexity: evidence from China
Authors: Zhang Lu , Shi Lei , Ma Li
Published: March 2023

Purpose

A public–private partnership (PPP) is an agreement between the government and private investors to deliver long-term public services. The efficiency of PPP projects depends on PPP contracts stipulating contractual parties' corresponding responsibilities and rights to deal with relational and performance risks. Although more complex contracts provide more remedies for mitigating ex-post transaction costs, they also result in the increased ex ante transaction costs associated with contract writing. Thus, contractual complexity is a design choice that can reduce the overall contract transaction costs.

Design/methodology/approach

Using 365 transportation PPP projects in China from 2010 to 2019, this study applies the Poisson regression model to examine the effects of payment mechanisms, ownership by investors and equity structure on contractual complexity.

Findings

PPP contracts have control and coordination functions with unique determinants. Parties in the government-pay mechanism are more likely to negotiate coordination provisions, which results in greater contractual complexity. PPP projects with state-owned enterprises (SOEs) have less contractual complexity in terms of both two functions of provisions, whereas the equity structure has no impact on contractual complexity.

Originality/value

These findings provide a nuanced understanding of how various contractual provisions are combined to perform control or coordination functions and make managerial recommendations to parties involved in PPP projects.
Exploring how different innovation ecosystems create shared value: insights from a multiple case study analysis
Authors: Piantoni Giulia , Arena Marika , Azzone Giovanni
Published: March 2023

Purpose

Innovation ecosystems (IEs) have attracted the attention of policymakers and researchers because of their potential to positively affect territories, creating shared value. However, due to the fragmentation of IEs, how this happens in different IEs has been explored only partially. This research aims to bridge this gap, aiming to support policymakers in understanding how to foster shared value in diverse IEs.

Design/methodology/approach

The paper identifies, based on the literature, two “drivers of aggregation” of IE's actors as key dimensions characterizing shared value in IEs, namely physical proximity and dominant issue. If these are combined, three archetypes emerge: Hub- and Chain-Driven, Place-Driven, Competence- and Issue-Driven IEs.Then, elements useful for understanding shared value creation in these archetypes are framed and studied in real cases.

Findings

Results reveal that aggregation drivers affect shared value creation, which differ among archetypes: in Competence- and Issue-Driven IEs alignment is challenged by the low physical proximity, which in Place-Driven IEs is high, but not enough to grant shared value; in Hub- and Chain-Driven IEs, the hub is the orchestrator, representing both a driver and a risk.

Originality/value

Differences in shared value creation processes relate to the set-up of the IE, which has relevant implications for policy definition. In Competence- and Issue-Driven IEs, policies at diverse levels align in funding and promoting the IE; in Place-Driven IEs, policies support anchors' development on-site; in Hub- and Chain-Driven IEs, policies, sometimes absent, should foster partnerships for projects for the territory, IE's enlargement and resilience.