bluuebunny/crossref_metadata_2025 huggingface dataset:
Modifying Tacrolimus-related Toxicity After Liver Transplantation Comparing Life Cycle Pharma Tacrolimus Versus Extended-released Tacrolimus: A Multicenter, Randomized Controlled Trial
Authors: Mulder Midas B. , van Hoek Bart , Polak Wojtek G. , Alwayn Ian P.J. , de Winter Brenda C.M. , Darwish Murad Sarwa , Verhey-Hart Elke , Elshove Lara , Erler Nicole S. , Hesselink Dennis A. , den Hoed Caroline M. , Metselaar Herold J.
Published: March 2024

Background.

The aim of this open-label, multicenter, randomized controlled study was to investigate whether the life cycle pharma (LCP)-tacrolimus compared with the extended-release (ER)-tacrolimus formulation results in a difference in the prevalence of posttransplant diabetes, hypertension and chronic kidney disease (CKD) at 12 mo after liver transplantation.

Methods.

Patients were 1:1 randomized to either of the 2 tacrolimus formulations. The primary endpoint was defined as a composite endpoint of any of 3 events: sustained (>3 mo postrandomization) posttransplant diabetes, new-onset hypertension, and/or CKD, defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 for >3 m during the follow-up.

Results.

In total, 105 patients were included. In the intention-to-treat analysis, a statistically significant lower proportion of liver transplant recipients in the LCP-tacrolimus group reached the composite primary endpoint at 12 mo compared with the ER-tacrolimus group (50.9% [27/53], 95% confidence interval [CI], 37.9%-63.9% versus 71.2% [37/52], 95% CI, 57.7%-81.7%; risk difference: 0.202; 95% CI, 0.002-0.382; P = 0.046). No significant difference was found in the per protocol analysis. In the intention-to-treat and per protocol population, fewer liver transplant recipients in the LCP-tacrolimus group developed CKD and new-onset hypertension compared with the ER-tacrolimus group. No differences in rejection rate, graft and patient survival were found.

Conclusions.

A statistically significant and clinically relevant reduction in the prevalence of the composite primary endpoint was found in the LCP-tacrolimus group compared with the ER-tacrolimus group in the first year after liver transplantation with comparable efficacy.
Incidence of Endoscopic Retrograde Cholangiography after Subtotal Fenestrating and Reconstituting Cholecystectomy
Authors: Nordness Mina F , Smith Michael C , Fogel Jessa , Guillamondegui Oscar D , Dennis Bradley M , Gunter Oliver L
Published: March 2024

BACKGROUND:

Laparoscopic subtotal cholecystectomy (SC) is used for the difficult cholecystectomy, but published experience with resource use for SC is limited. We hypothesized that the need for advanced resources are common after SC.

STUDY DESIGN:

This was a retrospective review of laparoscopic cholecystectomies between 2017 and 2021 at a large center. SC cases were identified using a medical record tool. Baseline characteristics were assessed with Student’s t-test and chi-square test. Primary outcome was endoscopic retrograde cholangiography (ERC) within 60 days. Secondary outcomes were reconstituted SC on postoperative ERC and length of stay (LOS). Uni- and multivariable logistic regression were used for binary outcomes. Multiple linear regression was used for LOS. Covariates included were age, sex, BMI, and American Society of Anesthesiology class.

RESULTS:

A total of 1,222 laparoscopic cholecystectomies were performed between 2017 and 2021. Of these, 87 (7%) were SC. Male (p < 0.001) and older (p < 0.001) patients were more likely to undergo SC. Odds of postoperative ERC were higher in the SC group (odds ratio 9.79, 95% CI 5.90 to16.23, p < 0.001). There was no difference in preoperative ERC (17% vs 21%, p = 0.38). Reconstituting SC had lower odds of postoperative ERC (odds ratio 0.12, 95% CI 0.023 to 0.58, p = 0.009). LOS was 1.81 times higher in the SC group (p ≤ 0.001). Postoperative ERC was not associated with LOS (p = 0.24).

CONCLUSIONS:

We present one of the largest single-center series of SC. Patients who underwent SC are more likely to be male, older, have higher American Society of Anesthesiology class, and have increased LOS. SC should be performed when access to ERC and interventional radiology is available. In the absence of these adjuncts, reconstituting SC decreases the need for early ERC, but long-term outcomes are unknown.
Size dependent antipredator responses in a fish–shrimp mutualism
Authors: Polverino Giovanni , Lehtonen Topi K. , Geschke Andrew , Callahan Tara , Urbancic Jessica , Wong Bob B. M.
Published: March 2024

For prey, taking refuge from predators has obvious fitness benefits but may also be costly by impinging on time and effort available for feeding or attracting mates. The antipredator responses of refuge-seeking animals are therefore predicted to vary strategically depending on how threatening they perceive the risk. To test this, we studied the impacts of a simulated predatory threat on the antipredator responses of wild sandy prawn-gobies (Ctenogobiops feroculus) that co-inhabit burrows withAlpheusshrimp (family Alpheidae) in a mutualistic relationship. We exposed goby–shrimp pairs, repeatedly on three separate occasions, to an approaching threat and measured the antipredator behaviours of both partners. We found that re-emerging from the burrow took longer in large compared to small fish. Moreover, quicker re-emergence by small—but not medium or large-sized gobies—was associated with an earlier flight from the approaching threat (i.e. when the threat was still further away). Finally, the goby and shrimp sharing a burrow were matched in body size and their risk-taking behaviour was highly dependent on one another. The findings contribute to our understanding of how an individual's phenotype and perception of danger relates to its risk-taking strategy, and how mutualistic partners can have similar risk sensitivities.
Backspin inRuellia ciliatifloradoes not maximize seed dispersal range, but provides moderate dispersal range that is robust to launch conditions
Authors: Hesse-Withbroe Joseph L. , Whitaker Dwight L.
Published: March 2024

Ruellia ciliatiflorais a perennial herb whose fruits explosively dehisce, launching their thin disc-like seeds over 6 m with a backspin up to 1660 Hz. While it has been previously shown that the backspin launch orientation minimizes the aerodynamic drag experienced by the seeds, it is not immediately obvious whether backspin is also the range-maximizing launch orientation. Here the three-dimensional equation of motion of a thin, spinning disc flying through a fluid medium was derived and solved numerically to simulate the flight of seeds ofR. ciliatifloraunder different launch conditions. Simulations of seed flights reveal that the range-maximizing launch orientation lies between sidespin and topspin, far from the backspin that is observed in nature. While this range-maximizing orientation results in dispersal ranges of nearly 10 m, the precise orientation is highly sensitive to other launch parameters, chiefly spin rate and launch angle. By contrast, backspin, which yields moderate dispersal ranges about 60% of the range-maximizing orientation, is robust to perturbations in launch parameters that the plant cannot precisely control.
The Microbiome of C. elegans Enhances Growth of S. aureus During Infection
Authors: Rossi Sydney G , Fisher Michael L
Published: March 2024

Staphylococcus aureus is a significant human pathogen associated with a wide range of infections. The microbiome, consisting of diverse microbial communities, has been recognized as a critical factor in modulating host-pathogen interactions. This study aimed to investigate the role of the Caenorhabditis elegans microbiome in Staphylococcus aureus infection by transferring worms from the standard laboratory food source (OP50) or a microbiome sample to S. aureus cultures.  Our findings revealed that the C. elegans microbiome paradoxically enhanced Staphylococcus aureus colonization, resulting in increased pathogen burden compared to worms transferred from E.coli OP50. These results underscore the importance of the microbiome in modulating host susceptibility.
Methylomarinovum tepidoasis sp. nov., a moderately thermophilic methanotroph of the family Methylothermaceae isolated from a deep-sea hydrothermal field
Authors: Hirayama Hisako , Takaki Yoshihiro , Abe Mariko , Miyazaki Masayuki , Uematsu Katsuyuki , Matsui Yohei , Takai Ken
Published: March 2024

A novel aerobic methanotrophic bacterium, designated as strain IN45T, was isolated from in situ colonisation systems deployed at the Iheya North deep-sea hydrothermal field in the mid-Okinawa Trough. IN45T was a moderately thermophilic obligate methanotroph that grew only on methane or methanol at temperatures between 25 and 56 °C (optimum 45–50 °C). It was an oval-shaped, Gram-reaction-negative, motile bacterium with a single polar flagellum and an intracytoplasmic membrane system. It required 1.5–4.0 % (w/v) NaCl (optimum 2–3 %) for growth. The major phospholipid fatty acids were C16 : 1ω7c, C16 : 0 and C18 : 1ω7c. The major isoprenoid quinone was Q-8. The 16S rRNA gene sequence comparison revealed 99.1 % sequence identity with Methylomarinovum caldicuralii IT-9T, the only species of the genus Methylomarinovum with a validly published name within the family Methylothermaceae. The complete genome sequence of IN45T consisted of a 2.42-Mbp chromosome (DNA G+C content, 64.1 mol%) and a 20.5-kbp plasmid. The genome encodes genes for particulate methane monooxygenase and two types of methanol dehydrogenase (mxaFI and xoxF). Genes involved in the ribulose monophosphate pathway for carbon assimilation are encoded, but the transaldolase gene was not found. The genome indicated that IN45T performs partial denitrification of nitrate to N2O, and its occurrence was indirectly confirmed by N2O production in cultures grown with nitrate. Genomic relatedness indices between the complete genome sequences of IN45T and M. caldicuralii IT-9T, such as digital DNA–DNA hybridisation (51.2 %), average nucleotide identity (92.94 %) and average amino acid identity (93.21 %), indicated that these two methanotrophs should be separated at the species level. On the basis of these results, strain IN45T represents a novel species, for which we propose the name Methylomarinovum tepidoasis sp. nov. with IN45T (=JCM 35101T =DSM 113422T) as the type strain.
Dynamin-2 Mutations Linked to Neonatal-onset Centronuclear Myopathy impair exocytosis and endocytosis in adrenal chromaffin cells
Authors: Bayonés Lucas , Guerra-Fernández María José , Figueroa-Cares Cindel , Gallo Luciana I. , Alfonso-Bueno Samuel , Báez-Matus Ximena , González-Jamett Arlek , Cárdenas Ana M. , Marengo Fernando D.
Published: March 2024

ABSTRACT

Dynamins are large GTPases whose primary function is to catalyze membrane scission during endocytosis, but also modulate other cellular processes, such as actin polymerization and vesicle trafficking. Recently, we reported that centronuclear myopathy associated dynamin-2 mutations, p.A618T and p.S619L, impair Ca2+-induced exocytosis of GLUT4 containing vesicles in immortalized human myoblasts. As exocytosis and endocytosis occur within rapid timescales, here we applied high-temporal resolution techniques, such as patch-clamp capacitance measurements and carbon-fiber amperometry to assess the effects of these mutations on these two cellular processes using bovine chromaffin cells as a study model. We found that the expression of any of these dynamin-2 mutants inhibits a dynamin and F-actin dependent form of fast endocytosis triggered by single action potential stimulus, as well as inhibits a slow compensatory endocytosis induced by 500 ms square depolarization. Both dynamin-2 mutants further reduced the exocytosis induced by 500 ms depolarizations, and the frequency of release events and the recruitment of NPY-labelled vesicles to the cell cortex after stimulation of nicotinic acetylcholine receptors with DMPP. They also provoked a significant decrease in the Ca2+-induced formation of new actin filaments in permeabilized chromaffin cells. In summary, our results indicate that the CNM- linked p.A618T and p.S619L mutations in dynamin-2 affect exocytosis and endocytosis, being the disruption of F-actin a possible explanation for these results. These impaired cellular processes might underlie the pathogenic mechanisms associated with these mutations.
Circadian dynamics of the Zbtb14 protein in the ventral hippocampus are disrupted in epileptic mice
Authors: Güntan İlke , Ghestem Antoine , Nazaruk Kinga , Nizińska Karolina , Olszewski Maciej , Nowicka Dorota , Bernard Christophe , Łukasiuk Katarzyna
Published: March 2024

Our previousin silicodata indicated an overrepresentation of the ZF5 motif in the promoters of genes in which circadian oscillations are altered in the ventral hippocampus in the pilocarpine model of temporal lobe epilepsy in mice. In this study, we test the hypothesis that the Zbtb14 protein oscillates in the hippocampus in a circadian manner and that this oscillation is disrupted by epilepsy.

We found that Zbtb14 immunostaining is present in the cytoplasm and cell nuclei. Western blot data indicate that the cytoplasmic and nuclear levels of Zbtb14 protein oscillate, but the phase is shifted. The densities of the Zbtb14-immunopositive express circadian dynamics in the ventral hilus and Ca3 but not in the dorsal hilus, Ca3, or the somatosensory cortex. In the pilocarpine model of epilepsy increase in the level of Zbtb14 protein was found at 11 PM, but not at 3 PM compared to controls. Finally,in silicoanalysis revealed the presence of the ZF5 motif in the promoters of 21 out of 24 genes down-regulated by epileptiform dischargesin vitro, many of which are involved in neuronal plasticity. Our data suggest that Zbtb14 may be involved in the circadian dynamic of seizure regulation or brain response to seizure rhythmicity.

Highlights

the Zbtb14 protein is expressed in neurons in the mouse brain;

Zbtb14 protein levels oscillate through the circadian cycle in the ventral hippocampus but not in the dorsal hippocampus;

the oscillations of the Zbtb14 protein occur in both the cytoplasm and nucleus but in a different temporal pattern;

the circadian dynamics of the Zbtb14 protein are perturbed in epilepsy in anin vivomodel of epilepsy;

numerous genes that are downregulated in thein vitromodel of epileptiform discharges have a ZF5 motif in their promoters
HyperTraPS-CT: Inference and prediction for accumulation pathways with flexible data and model structures
Authors: Aga Olav N. L. , Brun Morten , Dauda Kazeem A. , Diaz-Uriarte Ramon , Giannakis Konstantinos , Johnston Iain G.
Published: March 2024

Accumulation processes, where many potentially coupled features are acquired over time, occur throughout the sciences, from evolutionary biology to disease progression, and particularly in the study of cancer progression. Existing methods for learning the dynamics of such systems typically assume limited (often pairwise) relationships between feature subsets, cross-sectional or untimed observations, small feature sets, or discrete orderings of events. Here we introduce HyperTraPS-CT (Hypercubic Transition Path Sampling in Continuous Time) to compute posterior distributions on continuous-time dynamics of many, arbitrarily coupled, traits in unrestricted state spaces, accounting for uncertainty in observations and their timings. We demonstrate the capacity of HyperTraPS-CT to deal with cross-sectional, longitudinal, and phylogenetic data, which may have no, uncertain, or precisely specified sampling times. HyperTraPS-CT allows positive and negative interactions between arbitrary subsets of features (not limited to pairwise interactions), supporting Bayesian and maximum-likelihood inference approaches to identify these interactions, consequent pathways, and predictions of future and unobserved features. We also introduce a range of visualisations for the inferred outputs of these processes and demonstrate model selection and regularisation for feature interactions. We apply this approach to case studies on the accumulation of mutations in cancer progression and the acquisition of anti-microbial resistance genes in tuberculosis, demonstrating its flexibility and capacity to produce predictions aligned with applied priorities.
Hemozoin induces Malaria via activation of DNA damage, p38 MAPK and Neurodegenerative Pathways in Human iPSC-derived Neuronal Model of Cerebral Malaria
Authors: Pranty Abida lslam , Szepanowski Leon-Phillip , Wruck Wasco , Karikari Akua Afriyie , Adjaye James
Published: March 2024

Malaria caused byPlasmodium falciparuminfection results in severe complications including cerebral malaria (CM), in which approximately 30% of patients end up with neurological sequelae. Sparse in vitro cell culture-based experimental models which recapitulate the molecular basis of CM in humans has impeded progress in our understanding of its etiology. This study employed healthy human induced pluripotent stem cells (iPSCs) derived neuronal cultures stimulated with hemozoin (HMZ)-the malarial toxin as a model for CM. Secretome, qRT-PCR, Metascape, and KEGG pathway analyses were conducted to assess elevated proteins, genes, and pathways. Neuronal cultures treated with HMZ showed enhanced secretion of interferon-gamma (IFN-γ), interleukin (IL)1-beta (IL-1β), IL-8 and IL-16. Enrichment analysis revealed malaria, positive regulation of cytokine production and positive regulation of mitogen-activated protein kinase (MAPK) cascade which confirm inflammatory response to HMZ exposure. KEGG assessment revealed up-regulation of malaria, MAPK and neurodegenerative diseases-associated pathways which corroborates findings from previous studies. Additionally, HMZ induced DNA damage in neurons. This study has unveiled that exposure of neuronal cultures to HMZ, activates molecules and pathways similar to that observed in CM and neurodegenerative diseases. Furthermore, our model is an alternative to rodent experimental models of CM.
A high resolution model of the grapevine leaf morphospace predicts synthetic leaves
Authors: Chitwood Daniel H. , Torres-Lomas Efrain , Hadi Ebi S. , Peterson Wolfgang L. G. , Fischer Mirjam F. , Rogers Sydney E. , He Chuan , Acierno Michael G. F. , Azumaya Shintaro , Benjamin Seth Wayne , Chalise Devendra Prasad , Chess Ellice E. , Engelsma Alex J. , Fu Qiuyi , Jaikham Jirapa , Knight Bridget M. , Kodjak Nikita S. , Lengyel Adazsofia , Muñoz Brenda L. , Patterson Justin T. , Rincon Sundara I. , Schumann Francis L. , Shi Yujie , Smith Charlie C. , Clair Mallory K. St. , Sweeney Carly S. , Whitaker Patrick , Wu James , Diaz-Garcia Luis
Published: March 2024

Grapevine leaves are a model morphometric system. Sampling over ten thousand leaves using dozens of landmarks, the genetic, developmental, and environmental basis of leaf shape has been studied and a morphospace for the genusVitispredicted. Yet, these representations of leaf shape fail to capture the exquisite features of leaves at high resolution.

We measure the shapes of 139 grapevine leaves using 1672 pseudo-landmarks derived from 90 homologous landmarks with Procrustean approaches. From hand traces of the vasculature and blade, we have derived a method to automatically detect landmarks and place pseudo-landmarks that results in a high-resolution representation of grapevine leaf shape. Using polynomial models, we create continuous representations of leaf development in 10Vitisspp.

We visualize a high-resolution morphospace in which genetic and developmental sources of leaf shape variance are orthogonal to each other. Using classifiers,V. vinifera, Vitisspp., rootstock and dissected leaf varieties as well as developmental stages are accurately predicted. Theoretical eigenleaf representations sampled from across the morphospace that we call synthetic leaves can be classified using models.

By predicting a high-resolution morphospace and delimiting the boundaries of leaf shapes that can plausibly be produced within the genusVitis, we can sample synthetic leaves with realistic qualities. From an ampelographic perspective, larger numbers of leaves sampled at lower resolution can be projected onto this high-resolution space; or, synthetic leaves can be used to increase the robustness and accuracy of machine learning classifiers.

Societal Impact Statement

Grapevine leaves are emblematic of the strong visual associations people make with plants. At a glance, leaf shape is immediately recognizable, and it is because of this reason it is used to distinguish grape varieties. In an era of computationally-enabled, machine learning-derived representations of reality, we can revisit how we view and use the shapes and forms that plants display to understand our relationship with them. Using computational approaches combined with time-honored methods, we can predict theoretical leaves that are possible to understand the genetics, development, and environmental responses of plants in new ways.
Requirement of a Wnt5A-Microbiota Axis in the Maintenance of Gut B Cell Repertoire and Protection from Infection
Authors: Sengupta Soham , Sen Malini
Published: March 2024

We investigated the influence of a Wnt5A-gut microbiota axis on gut B cell repertoire and protection from infection, having previously demonstrated that Wnt5A in association with gut commensals help shape gut T cell repertoire. Accordingly, Wnt5A heterozygous mice, which express less than wild type level of Wnt5A, and their isolated Peyer’s patches (PP), were studied in comparison with the wild type counterparts. The percentages of IgM and IgA expressing B cells were quite similar in the PP of both sets of mice. However, the PP of the Wnt5A heterozygous mice harbored significantly higher than wild type levels of microbiota bound B cell secreted IgA (sIgA), indicating the prevalence of a microbial population therein, that is significantly altered from that of wild type. Additionally, the percentage of PP IgG1 expressing B cells was appreciably depressed in the Wnt5A heterozygous mice in comparison to wild type. Wnt5A heterozygous mice, furthermore, exhibited notably higher than the wild type levels of morbidity and mortality following infection withSalmonella enterica, a common gut pathogen. Difference in morbidity/mortality correlated with considerable disparity between the PP-B cell repertoires of theSalmonellainfected Wnt5A heterozygous and wild type mice, the percentage of IgG1 expressing B1b cells in the PP of heterozygous mice remaining significantly low as compared to wild type. Overall, these results suggest that a gut Wnt5A-microbiota axis is intrinsically associated with the maintenance of gut B cell repertoire and protection from infection.

Importance

Although it is well accepted that B cells and microbiota are required for protection from infection and preservation of gut health, a lot remains unknown about how the optimum B cell repertoire and microbiota are maintained in the gut. The importance of this study lies in the fact that it unveils a potential role of a growth factor termed Wnt5A in the safeguarding of the gut B cell population and microbiota, thereby protecting the gut from the deleterious effect of infections by common pathogens. Documentation of the involvement of a Wnt5A-microbiota axis in the shaping of a protective gut B cell repertoire, furthermore, opens up new avenues of investigations for understanding gut disorders related to microbial dysbiosis and B cell homeostasis that till date, are considered incurable.
Interspecific trait differences drive plant community responses on serpentine soils
Authors: Delhaye Guillaume , Dimitrakopoulos Panayiotis G. , Adamidis George C.
Published: March 2024

Serpentine ecosystems are characterized by multiple environmental stressors such as high levels of trace metals such as nickel (Ni), low availability of macronutrients and low water retention. These harsh environmental conditions exert a strong selective force on the vegetation, but their effect on the functional trait composition of the communities remains unknown.

In 26 plots on four serpentine sites on Lesbos Island (Greece), we measured six leaf functional traits related to resource acquisition and stress resistance on the 20 most abundant plant species. We quantified the proportion of variance explained by inter- and intraspecific traits difference and tested if individual species show changes in trait values explained by soil Ni content. We investigated the selective value and the community level changes for each trait along the natural soil Ni gradient using a species multilevel model approach and functional diversity analyses. We also tested the role of the abundant serpentine endemicOdontarrhena lesbiacain driving these patterns.

Intraspecific variation explained by soil Ni content is smaller than 2%, with most of the variance being explained by interspecific differences in trait values and most species do not show significant changes in trait values. At the community level, leaf thickness is the only trait driving an increase in species abundance along the gradient. Functional diversity analyses suggest a shift towards a stress tolerance syndrome (thick leaves with low SLA values) on Ni rich soils, but an increase in the diversity of these traits. However, these patterns are driven by the increasing abundance ofO. lesbiaca. When this species is excluded, there is an increase in the community mean leaf area and SLA, suggesting that the community does not respond to metallic stress with classical stress syndromes.

Synthesis.Intraspecific variation in leaf trait responds little to soil metal toxicity. Endemic species harbour original trait values compared to species with broad distribution which should justify their conservation as a priority.
Repeatability of an extended phenotype: potential causes and consequences of nest variation in the Northern House Wren (Troglodytes aedon aedon)
Authors: Carr Chandler E. G. , Swanson Zoë M. , Reichard Dustin G.
Published: March 2024

LAY SUMMARY

Repeatability of construction behaviors in the wild is understudied

House Wrens are a cavity-nesting songbird

House Wren nests are highly variable in their morphology

Female House Wrens are repeatable in cup composition, but not nest dimensions

The dimensions of the nest are built to match the dimensions of the cavity

House Wren nests are unrelated to nestling survival or female condition

Female preferences for nest building may explain nest variation

Construction behavior is an aspect of the extended phenotype that allows organisms to build structures that alter their environments in potentially beneficial ways. Although individuals vary in the expression of this extended phenotype (e.g., structure morphology), the repeatability of construction behaviors remain understudied, especially among free-living populations. Many oviparous taxa construct nests, making them of particular interest because variation in nest architecture may directly affect fitness. Using a free-living, cavity-nesting songbird, the Northern House Wren (Troglodytes aedon aedon), as our model, we estimated the contribution of the primary builder (the female) to nest variability by measuring the repeatability of nest morphology between successive clutches. We further examined whether nest morphology was related to the dimensions of the nesting cavity, breeding date, or nest success. We found the composition of the cup lining to be a highly repeatable behavior for the nesting female, although the size and composition of the structural platform appeared more related to the dimensions of the cavity. Nest morphology remained variable throughout the breeding season, showing no significant correlations with breeding date, and it was unrelated to clutch size or offspring survival. Our study suggests that variation in construction behavior is likely the product of multiple factors including the preferences of the builder and physical constraints. The absence of any clear links between construction behavior and fitness indicates that nest morphology is not under strong selection. As a result, diverse female building preferences may explain the extreme among-individual variation in nest structure in this species.
Local FK506 delivery induces osteogenesis inin vivorat bone defect and rabbit spine fusion models
Authors: Harrer Julia Andraca , Fulton Travis M. , Sangadala Sreedhara , Kaiser Jarred , Devereaux Emily J. , Oliver Colleen , Presciutti Steven M. , Boden Scott D. , Willett Nick J.
Published: March 2024

Bone grafting procedures are commonly used for the repair, regeneration, and fusion of bones in in a wide range of orthopaedic surgeries, including large bone defects and spine fusion procedures. Autografts are the clinical gold standard, though recombinant human bone morphogenetic proteins (rhBMPs) are often used, particularly in difficult clinical situations. However, treatment with rhBMPs can have off-target effects and significantly increase surgical costs, adding to patients’ already high economic and mental burden. Recent studies have identified that FDA-approved immunosuppressant drug, FK506 (Tacrolimus), can also activate the BMP pathway by binding to its inhibitors. This study tested the hypothesis that FK506, as a standalone treatment, could induce osteogenic differentiation of human mesenchymal stromal cells (hMSCs), as well as functional bone formation in a rat segmental bone defect model and rabbit spinal fusion model. FK506 potentiated the effect of low dose BMP-2 to enhance osteogenic differentiation and mineralization of hMSCsin vitro. Standalone treatment with FK506 delivered on a collagen sponge, produced consistent bone bridging of a rat critically-sized femoral defect with functional mechanical properties comparable to naïve bone. In a rabbit single level posterolateral spine fusion model, treatment with FK506 delivered on a collagen sponge successfully fused the L5-L6 vertebrae at rates comparable to rhBMP-2 treatment. These data demonstrate the ability of FK506 to induce bone formation in human cells and two challengingin vivomodels, and indicate FK506 can be utilized either as a standalone treatment or in conjunction with rhBMP to treat a variety of spine disorders.

Graphical Abstract
Bayesian Optimization of Neurostimulation (BOONStim)
Authors: Oliver Lindsay D. , Jeyachandra Jerrold , Dickie Erin W. , Hawco Colin , Mansour Salim , Hare Stephanie M. , Buchanan Robert W. , Malhotra Anil K. , Blumberger Daniel M. , Deng Zhi-De , Voineskos Aristotle N.
Published: March 2024

Background

Transcranial magnetic stimulation (TMS) treatment response is influenced by individual variability in brain structure and function. Sophisticated, user-friendly approaches, incorporating both established functional magnetic resonance imaging (fMRI) and TMS simulation tools, to identify TMS targets are needed.

Objective

The current study presents the development and validation of the Bayesian Optimization of Neuro-Stimulation (BOONStim) pipeline.

Methods

BOONStim uses Bayesian optimization for individualized TMS targeting, automating interoperability between surface-based fMRI analytic tools and TMS electric field modeling. BOONStim’s Bayesian optimization performance was evaluated in a sample dataset (N=10) using standard circular and functional connectivity-defined targets, and compared to densely sampled grid optimization.

Results

Bayesian optimization converged to similar levels of total electric field stimulation across targets in under 30 iterations, converging within 5% error of the maxima detected by grid optimization, and requiring less time.

Conclusions

BOONStim is a scalable and configurable user-friendly pipeline for individualized TMS targeting with quick turnaround.
Tumor microenvironment immunomodulation by nanoformulated TLR 7/8 agonist and PI3k delta inhibitor enhances therapeutic benefits of radiotherapy
Authors: Yazdimamaghani Mostafa , Kolupaev Oleg V. , Lim Chaemin , Hwang Duhyeong , Laurie Sonia J. , Perou Charles M. , Kabanov Alexander V. , Serody Jonathan S.
Published: March 2024

Infiltration of immunosuppressive cells into the breast tumor microenvironment (TME) is associated with suppressed effector T cell (Teff) responses, accelerated tumor growth, and poor clinical outcomes. Previous studies from our group and others identified infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as critical contributors to immune dysfunction in the orthotopic triple-negative breast cancer (TNBC) tumor model limiting the efficacy of adoptive cellular therapy. However, approaches to target these cells specifically in the TME are currently lacking. To overcome this barrier, polymeric micelles nanoparticles (PMNPs) were used for co-delivery of small molecule drugs activating Toll-like receptors 7 and 8 (TLR7/8) and inhibiting PI3K delta. The immunomodulation of the TME by TLR7/8 agonist and PI3K inhibitor altered macrophage polarization, reduced MDSC accumulation and selectively decreased tissue-resident Tregs in the TME, while enhancing the T and B cell adaptive immune response. PMNPs significantly enhanced the anti-tumor activity of local radiation therapy (RT) in mice bearing orthotopic TNBC tumors compared to RT alone. Taken together, these data demonstrate that RT combined with a nanoformulated immunostimulant restructured the TME and has promising potential for future translation combined with RT for patients with TNBC.
Effective connectivity predicts distributed neural coding of perceptual decision confidence, uncertainty and speed
Authors: Asadpour Abdoreza , Wong-Lin KongFatt
Published: March 2024

Decision-making is often accompanied by a level of confidence regarding the accuracy of one’s decision. Previous studies have indicated neural activity associated with perceptual decision confidence during sensory stimulus presentation. Choice-based reaction time (RT) has been suggested as an indirect but more objective measure of decision confidence – generally faster RT for higher confidence. However, it is unclear whether choice confidence and RT are mediated by distinct neural pathways, and whether their neural correlates are encoded nonlinearly. Within a perceptual decision-making task, we applied fMRI-informed EEG-based effective connectivity analysis via dynamic causal modelling (DCM) on event-related potentials and found the frontoparietal network for fast-vs-slow RT condition to be different from that of high-vs-low confidence rating condition. Furthermore, trial-by-trial DCM analysis predicted cortical layer-based, distributed and nonlinear coding of RT, confidence or uncertainty. Collectively, our study suggests that decision confidence and speed are instantiated by different dynamical networks distributed across cortical layers.
Male reproductive phenotype and coercive mating performance in the guppyPoecilia reticulata
Authors: Glavaschi Alexandra , Morbiato Elisa , Pilastro Andrea
Published: March 2024

In species with fixed alternative male mating tactics, differences between male phenotypes associated with each tactic are well understood. By contrast, in species with fully interchangeable male mating strategies, associations between male phenotypes and fitness when adopting different tactics have received much less attention. One such species is the Trinidad guppyPoecilia reticulata,where males perform high rates of coercive mating attempts (gonopodial thrusts, GTs hereafter) but also switch between GTs and courtship with great flexibility. Male phenotypes favored by females have been described in detail and consist of complex, nonlinear combinations of traits. Coercive tactics also contribute towards male fitness, but no study to date has provided a multivariate description of guppy phenotypes able to obtain fertilizations via GTs, despite evidence suggesting they should be different from phenotypes successful in cooperative mating scenarios. Here we observe male mating behavior in freely interacting mixed-sex groups and compute a GT performance variable based on the closest distance the male approaches the female before abandoning the thrust. We use multivariate selection techniques to relate GT performance to traits and combinations of traits known to contribute towards male fitness. Guppy males that perform best in GTs are small, bold, with large areas of iridescent coloration and fast-swimming sperm, as well as intermediate orange coloration and sperm count. This phenotype only partly confirms our expectation, as it comprises traits advantageous in cooperative mating scenarios. Our study highlights the importance of using multivariate approaches when investigating sexual selection in the context of coercive mating strategies.
Human monocyte subtype expression of neuroinflammation and regeneration-related genes is linked to age and sex
Authors: Tampé Juliane F. , Monni Emanuela , Palma-Tortosa Sara , Brogårdh Emil , Böiers Charlotta , Lindgren Arne G. , Kokaia Zaal
Published: March 2024

Stroke is a leading cause of disability and the third cause of death. The immune system plays an essential role in post-stroke recovery. After an ischemic stroke, monocytes infiltrate the injured brain tissue and can exacerbate or mitigate the damage. Ischemic stroke is more prevalent in the aged population, and the aging brain exhibits an altered immune response. There are also sex disparities in ischemic stroke incidence, outcomes, and recovery, and these differences may be hormone-driven and determined by genetic and epigenetic factors. Here, we studied whether human peripheral blood monocyte subtype (classical, intermediate, and non-classical) expression of neuronal inflammation- and regeneration-related genes depends on age and sex. A FACS analysis of blood samples from 44 volunteers (male and female, aged 28 to 98) showed that in contrast to other immune cells, the proportion of natural killer cells increased in females. The proportion of B-cells decreased in both sexes with age, and subtypes of monocytes were not linked to age or sex. Gene expression analysis by qPCR identified several genes differentially correlating with age and sex within different monocyte subtypes. Interestingly,ANXA1andCD36showed a consistent increase with aging in all monocytes, specifically in intermediate (CD36) and intermediate and non-classical (ANXA1) subtypes. Other genes (IL-1β, S100A8, TNFα, CD64, CD33, TGFβ1, TLR8, CD91) were differentially changed in monocyte subtypes with increased aging. Most age-dependent gene changes were differentially expressed in female monocytes. Our data shed light on the nuanced interplay of age and sex in shaping the expression of inflammation- and regeneration-related genes within distinct monocyte subtypes. Understanding these dynamics could pave the way for targeted interventions and personalized approaches in post-stroke care, particularly for the aging population and individuals of different sexes.
NOVEL SOLUTION BASED ON DETECTION OF MIRS-410-3P AND 141-5P FOR DIAGNOSTIC OF PROSTATE CANCER EVOLUTION
Authors: Carbache M.F , Nuñez E.R , Ouahid Y , Sainz E , Montoya J.J , Molera A , Soouto A , Vazquez D , Castan P , Carballido J
Published: March 2024

To date, prostate cancer (PCa) is both the most common tumour diagnosed in males and the second most common cause of cancer-related mortality(1,). Prevention programs and screening protocols have proven useful to detect the disease at population level, but they lack sensitivity and specificity in comparison to the molecular tests routinely available for screening of other types of cancer, leading to unnecessary biopsies and overtreatment in many cases. In this context, a new set of small RNA biomarkers are surfacing with promising results to predict tumour progression, risk reclassification and treatment response(2)such as miR-410-3p -3p and miR-141-5p. Former studies where these biomarkers were examined in prostate cancer tissues and cell lines by qRT-PCR have shown that high expression of miR-410-3p -3p correlates to both a) accurate diagnosis in certain groups where the PSA levels do not match results from biopsy, surgery and/or digital rectal examination and b) poor prognosis of prostate cancer patients(3). Likewise, miR-141-5p shows a parallel behaviour suggesting a potential combo for fine molecular analysis of the ratios. In this sense, recent studies have demonstrated that miR-410-3p -3p exert oncogenic functions through downregulating PTEN, proving that miR-410-3p -3p inhibits prostate cancer progression via downregulating PTEN/AKT/mTOR signalling pathway. Curiously enough, different behaviour has been reported for the biomarker in both, peripheral blood from patients and cancer-cell line(s)(34.5.6)models further pointing at the advantages of a dual gauging made possible by parallel semi-quantitation of miR-141-5p. In this sense, miR-141-5p has been clearly identified as to be upregulated in large cohorts (n over 500) of prostate cancer patients confirming overexpression in multivariate analysis in tumour epithelium and tumour stroma. This overexpression taken into the context of a peripheral blood reduction of miR-410-3p appears to be associated with increased risk of biochemical cancer recurrence in an independent study over 500 patients(7). Here we present the design, molecular set up and preclinical assessment of a novel system that uses the discarded volume from PSA blood tests to predict prostate cancer progression and biochemical cancer recurrence via detection of the biomarkers. The method described could potentially eliminate the need of invasive means such as biopsy, surgery and digital rectal examination.
Piloting wastewater-based surveillance of norovirus in England
Authors: Walker David I. , Witt Jessica , Rostant Wayne , Burton Robert , Davison Vicki , Ditchburn Jackie , Evens Nicholas , Godwin Reg , Heywood Jane , Lowther James , Peters Nancy , Porter Jonathan , Posen Paulette , Wickens Tyler , Wade Matthew J.
Published: March 2024

Wastewater-based epidemiology (WBE) gained widespread use as a tool for supporting clinical disease surveillance during the COVID-19 pandemic. There is now significant interest in the continued development of WBE for other pathogens of clinical significance. In this study, approximately 3,200 samples of wastewater from across England, previously collected for quantification of SARS-CoV-2, were re-analysed for the quantification of norovirus genogroup I (GI) and II (GII). Overall, GI and GII were detected in 93% and 98% of samples respectively, and at least one of the genogroups was detected in 99% of samples. GI was found at significantly lower concentrations than GII, but the proportion of each genogroup varied over time, with GI becoming more prevalent than GII in some areas towards the end of the study period (May 2021 – March 2022). Using relative strength indices (RSI), it was possible to study the trends of each genogroup, and total norovirus over time. Increases in norovirus levels appeared to coincide with the removal of COVID-19 related lockdown restrictions within England. Local Moran’s I analyses indicated several localised outbreaks of both GI and GII across England, notably the possible GI outbreak in the north of England in early 2022. Comparisons of national average norovirus concentrations in wastewater against concomitant norovirus reported case numbers showed a significant linear relationship. This highlights the potential for wastewater-based monitoring of norovirus as a valuable approach to support surveillance of norovirus in communities.
Copy number variants underlie the major selective sweeps in insecticide resistance genes inAnopheles arabiensisfrom Tanzania
Authors: Lucas Eric R. , Nagi Sanjay C. , Kabula Bilali , Batengana Bernard , Kisinza William , Egyir-Yawson Alexander , Essandoh John , Dadzie Sam , Chabi Joseph , Van’t Hof Arjen E. , Rippon Emily J. , Pipini Dimitra , Harding Nicholas J. , Dyer Naomi A. , Clarkson Chris S. , Miles Alistair , Weetman David , Donnelly Martin J.
Published: March 2024

To keep ahead of the evolution of resistance to insecticides in mosquitoes, national malaria control programmes must make use of a range of insecticides, both old and new, while monitoring resistance mechanisms. Knowledge of the mechanisms of resistance remains limited inAnopheles arabiensis, which in many parts of Africa is of increasing importance because it is apparently less susceptible to many indoor control interventions. Furthermore, comparatively little is known in general about resistance to non-pyrethroid insecticides such as pirimiphos-methyl (PM), which are crucial for effective control in the context of resistance to pyrethroids. We performed a genome-wide association study to determine the molecular mechanisms of resistance to deltamethrin (commonly used in bednets) and PM, inAn. arabiensisfrom two regions in Tanzania. Genomic regions of positive selection in these populations were largely driven by copy number variants (CNVs) in gene families involved in resistance to these two insecticides. We found evidence of a new gene cluster involved in resistance to PM, identifying a strong selective sweep tied to a CNV in theCoeae2g-Coeae6gcluster of carboxylesterase genes. Using complementary data fromAn. coluzziiin Ghana, we show that copy number at this locus is significantly associated with PM resistance. Similarly, for deltamethrin, resistance was strongly associated with a novel CNV allele in theCyp6aa/Cyp6pcluster. Against this background of metabolic resistance, target site resistance was very rare or absent for both insecticides. Mutations in the pyrethroid target siteVgscwere at very low frequency in Tanzania, yet combining these samples with threeAn. arabiensisindividuals from West Africa revealed a startling diversity of evolutionary origins of target site resistance, with up to 5 independent origins ofVgsc-995 mutations found within just 8 haplotypes. Thus, despite having been first recorded over 10 years ago,Vgscresistance mutations in TanzanianAn. arabiensishave remained at stable low frequencies. Overall, our results provide a new copy number marker for monitoring resistance to PM in malaria mosquitoes, and reveal the complex picture of resistance patterns inAn. arabiensis.
Genome-Wide Identification of G-Quadruplex forming regions in Arabidopsis: Unraveling the Role of Pif like Helicase (AtPLH1) in Gene Regulation and Stress Response
Authors: Singh Surabhi , Singh Shubhangi , Gupta Khushboo , Sharma Himanshi , Bady Shivsam , Sondhi Manushka , Garg Rohini
Published: March 2024

G-quadruplexes (GQSes) are highly stable DNA secondary structures, which exist as knots in the genome during different cellular processes like replication, transcription and translation. Although several studies have shown the role of GQS-helicases regulating several cellular processes in yeast and human, their detailed characterization in plants is still lacking. In this study, we identified GQS-enriched regions by DNA affinity purification followed by sequencing from Arabidopsis Pif-like helicase 1 (Atplh1) mutant. Differentially enriched peaks (DEPs) in the mutant showed preferential distribution in the exonic and promoter regions. The genes involved in various processes like transcriptional regulation, UDP- glucosylation, response to abiotic stress, ethylene biosynthesis and response to carbohydrate stimulus, were found to be differentially regulated between control and mutant plants. The differentially expressed genes (DEGs) showed enrichment of binding sites of ERF, WRKY, BBM and BIM transcription factors. Further, the DEGs harboring DEPs were found associated with response to wounding and salt stress, response to unfolded protein, heat stress response and UDP-glycosyl transferase activity. In addition, the mutants exhibited lesser growth inhibition under cold stress. Overall, our study identified genome-wide GQSes inArabidopsisand altered gene expression regulated by AtPLH1.