bluuebunny/crossref_metadata_2025 huggingface dataset:
The use of ultrasonic radiation to suppress foaming in fermenters
Authors: Freeman G J , Reid A I , Martfnez C Valdecantos , Lynch F J , Juárez J A Gallego
Published: November 2023

The geometry of cylindroconical fermenters causes foam formation to reduce maximum wort fill level significantly. Accordingly a technology which removes foam without risk to beer quality would increase fermenter room capacity. Patented power ultrasound equipment has been shown to break beer foam. Pilot trials demonstrated that the ultrasound was able to break older foam much more effectively than freshly formed foam. There was a beneficial effect of reverberation around the vessel headspace. The technology showed enough potential for scale-up to full-size fermenters to be considered.
Innovation in yeast cell filtration: cost saving technology with high flux membranes
Authors: Rijn C J M van , Nijdam W , Stappen L A V G van der , Raspe OJ A , Broens L , Hoof S van
Published: November 2023

Common yeast cell filtration systems are based on diatomaceous earth. An alternative yeast cell filtration system has been tested using high flux microsieves made with silicon micromachining. The microsieves have been tested in a cross-flow filtration system with back-pulse techniques. The flux observed during the filtration of beer after maturation was at least 12,000 Vm%ar/hour without significant fiux decline. For cost saving high volume filtration a number of microsieves can be stacked to a compact micro filtration system. The developed system is chemical inert to most cleaning agents and therefore suitable for in-line cleaning.
Hydroxyl radical footprinting
Authors: Kolb Annie
Published: November 2023

Hydroxyl radicals have now been used for more than 15years to probe the structure of various macromolecules. They have also been widely used to footprint DNA-protein and RNA-protein complexes (1, 2). Hydroxyl radicals are w1y small, comparable in size to a water molecule, are most commonly generated from FeEDTA in solution by an innocuous and inexpensive procedure (see Protocols 2 and 3) <md are capable of cutting the DNA or RNA backbone at eve1y accessible nucleotide without sequence specificity (3-5). A footprinting reagent in which the .EDTA moiety is coupled to an intercalator can also be used to generate hydroxyl radicals (6). This reactant. methidium-propyl Fe-EDTA, binds to some preferred positions along the DNA, and consequently the pattern of DNA backbone cleavage is much less random than with Fee-EDTA alone.
Biochemistry of C. elegans
Authors: Mains Paule E , McGhee James D
Published: November 2023

Notwithstanding the virtues of C. elegans as an experimental system and extolled in the earlier chapters of this book, it is probably only fair to say that C. elegans is not an ideal organism in which to study biochemistry. It is tedious to grow and disrupt worms in the large quantities that are the usual starting point for conventional biochemistry, at least for the isolation of rare molecules. It is also difficult to produce tightly synchronized populations on a large scale eggshells and cuticles present impressive barriers and it is essentially impossible to produce biochemically useful quantities of pure tissues. There are two exceptions to this last statement, i.e. the production of sperm (1) and the production of oocytes (2, 3; and see below).
Comparison of protein three-dimensional structures
Authors: Johnson Mark S , Lehtonen Jukka V
Published: November 2023

In this chapter we define the different types of questions that may be asked through the comparison of the three-dimensional (3-D) structures of proteins, how to make the comparisons necessary to answer each question, and how to interpret them. We shall focus on the different strategies used, and the assumptions made within typical computer programs that are available.
Cell line preservation and authentication
Authors: Hay R J , Miranda-Cleland M , Durkin S , Miranda-Cleland M , Reid Y A
Published: November 2023

Literally thousands of different cell lines have been derived from human and other metazoan tissues. Many of these originate from normal tissues and exhibit a definable, limited doubling potential. Other cell lines may be propagated continuously, either having gone through an engineered or spontaneous genetic change from the normal primary population. or having been developed initially from turn over our tissue. Both finite lines of sufficient doubling potential and continuous lines can be expanded to produce a large number of aliquots, frozen, and authenticated for widespread use in research. Note: use of the terms cell line and cell strain is as recommended by The Tissue Culture Association committee on nomenclature (1).
Mindfulness and Social Work: Paying Attention to Ourselves, Our Clients, and Society
Authors: Hick Steven F
Published: November 2023

What is mindfulness? What are its foundations, and how can it help social workers in their practice? Mindfulness is an orientation to our everyday experiences that can be cultivated by means of various exercises and practices. By opening up in a particular way to their internal and external experiences, social workers and clients are better able to understand what is happening to them in both a psychological and sociological sense. With this understanding, people are better able to see the variety of ways in which they can respond. Habitual reactions are more easily avoided, and inner peace and balance are developed. Social workers are increasingly using aspects of mindfulness in three ways: (1) as a means of self-care, looking inward, and cultivating mindfulness within themselves; (2) directly in their practice as an intervention within micro-practice (direct intervention with individuals, families, and groups) and in mezzo- and macro-practice (community work and policy); and (3) as a means to positively affect the helping or therapeutic relationship between social worker and client.
Transvenous Embolization of Cerebrospinal Fluid-Venous Fistulas: Pearls, Pitfalls, and Lessons Learned
Authors: Naylor Ryan M. , Madhavan Ajay A. , Cutsforth-Gregory Jeremy K. , Lanzino Giuseppe , Brinjikji Waleed
Published: November 2023

Cerebrospinal fluid-venous fistulas (CSFVFs) are increasingly recognized as a cause of spontaneous intracranial hypotension (SIH), a debilitating neurologic condition that may present with postural headaches, hearing loss, and/or cognitive impairment. Curative treatment is available for patients whose fistulas are localized with myelography. Transvenous endovascular embolization has emerged in recent years as a safe, effective, and durable treatment option for patients with CSFVF. Here, we briefly review the clinical presentation of SIH, present diagnostic algorithm by which CSFVFs are identified, and discuss a stepwise treatment paradigm. We then detail endovascular treatment strategies of CSFVF with particular emphasis on direct versus indirect approaches to the fistula, embolization principles, and techniques to minimize complications. With increasing awareness of SIH and enhanced detection of CSFVF, it is important for endovascular neurosurgeons and neurointerventionalists to be familiar with transvenous CSFVF embolization strategies to meet the needs of this patient population.
Nonoperative treatment of multiple rib fractures, the results to beat: International multicenter prospective cohort study among 845 patients
Authors: Peuker Felix , Hoepelman Ruben J. , Beeres Frank J.P. , Balogh Zsolt J. , Beks Reinier B. , Sweet Arthur A.R. , IJpma Frank F.A. , Lansink Koen W.W. , van Wageningen Bas , Tromp Tjarda N. , Minervini Fabrizio , van Veelen Nicole M. , Hoogendoorn Jochem M. , de Jong Mirjam B. , van Baal Mark C.P.M. , Leenen Luke P.H. , Groenwold Rolf H.H. , Houwert R. Marijn
Published: November 2023

BACKGROUND

Optimal treatment (i.e., nonoperative or operative) for patients with multiple rib fractures remains debated. Studies that compare treatments are rationalized by the alleged poor outcomes of nonoperative treatment.

METHODS

The aim of this prospective international multicenter cohort study (between January 2018 and March 2021) with 1-year follow-up, was to report contemporary outcomes of nonoperatively treated patients with multiple rib fractures. Including 845 patients with three or more rib fractures. Primary outcome was in-hospital mortality. Secondary outcomes included hospital length of stay (HLOS), (pulmonary) complications, and quality of life.

RESULTS

Mean age was 57.7 ± 17.0 years, median Injury Severity Score was 17 (13–22) and the median number of rib fractures was 6 (4–8). In-hospital mortality rate was 1.5% (n = 13), 112 (13.3%) patients had pneumonia and four (0.5%) patients developed a symptomatic nonunion. The median HLOS was 7 days (4–13 days), and median intensive care unit length of stay was 2 days (1–5 days). Mean 5-Level Quality of Life Questionnaire index value was 0.83 ± 0.18 1 year after trauma. Polytrauma patients had a median HLOS of 10 days (6–18 days), a pneumonia rate of 17.6% (n = 77) and mortality rate of 1.7% (n = 7). Elderly patients (≥65 years) had a median HLOS of 9 days (5–15 days), a pneumonia rate of 19.7% (n = 57) and mortality rate of 4.1% (n = 12).

CONCLUSION

Overall, nonoperative treatment of patients with multiple rib fractures shows low mortality and morbidity rate and good quality of life after 1 year. Future studies evaluating the benefit of operative stabilization should use contemporary outcomes to establish the therapeutic margin of rib fixation.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level III.
Automated single-cell omics end-to-end framework with data-driven batch inference
Authors: Wang Yuan , Thistlethwaite William , Tadych Alicja , Ruf-Zamojski Frederique , Bernard Daniel J , Cappuccio Antonio , Zaslavsky Elena , Chen Xi , Sealfon Stuart C. , Troyanskaya Olga G.
Published: November 2023

To facilitate single-cell multi-omics analysis and improve reproducibility, we present SPEEDI (Single-cell Pipeline for End to End Data Integration), a fully automated end-to-end framework for batch inference, data integration, and cell type labeling. SPEEDI introduces data-driven batch inference and transforms the often heterogeneous data matrices obtained from different samples into a uniformly annotated and integrated dataset. Without requiring user input, it automatically selects parameters and executes pre-processing, sample integration, and cell type mapping. It can also perform downstream analyses of differential signals between treatment conditions and gene functional modules. SPEEDI’s data-driven batch inference method works with widely used integration and cell-typing tools. By developing data-driven batch inference, providing full end-to-end automation, and eliminating parameter selection, SPEEDI improves reproducibility and lowers the barrier to obtaining biological insight from these valuable single-cell datasets. The SPEEDI interactive web application can be accessed athttps://speedi.princeton.edu/.
ModrRNA1: A tool for possible RNA modification site identification with associated putative enzymes in bacterial rRNA
Authors: Thilanka Uvindu , Warushavithana Paaramitha Sithumini
Published: November 2023

Ribosomal RNA modifications play a crucial role in bacteria, impacting function, ribosome formation, and antibiotic resistance. ModrRNA1 replaces manual methods and introduces a user-friendly, streamlined bioinformatics tool for the identification of potential rRNA modification sites and associated enzymes, across various bacteria.

This tool utilizes a curated database of known bacterial rRNA modifications and enzymes, employing sequence alignment with a customized scoring system for precise site identification. High-confidence alignments generate annotated RNA sequence plots. Subsequently, enzyme detection is facilitated through structural comparisons, phylogenetics, and BLAST.

ModrRNA1 boasts a user-friendly web interface hosted athttps://modrrna.biotechie.orgwith the open-source code for customization available athttps://github.com/sciguysl/ModrRNA1. The results demonstrate ModrRNA1’s efficacy in identifying potential non-species-specific bacterial rRNA modification sites and species-specific associated enzymes.
Human neural stem cells restore spatial memory in a transgenic Alzheimer’s disease mouse model by an immunomodulating mechanism
Authors: Chen Kevin S. , Noureldein Mohamed H. , McGinley Lisa M. , Hayes John M. , Rigan Diana M. , Kwentus Jacquelin F. , Mason Shayna N. , Mendelson Faye E. , Savelieffd Masha G. , Feldman Eva L.
Published: November 2023

INTRODUCTION

Stem cells are a promising therapeutic in Alzheimer’s disease (AD) given the complex pathophysiologic pathways involved. However, the therapeutic mechanisms of stem cells remain unclear. Here, we used spatial transcriptomics to elucidate therapeutic mechanisms of human neural stem cells (hNSCs) in an animal model of AD.

METHODS

hNSCs were transplanted into the fimbria fornix of the hippocampus using the 5XFAD mouse model. Spatial memory was assessed by Morris water maze. Amyloid plaque burden was quantified. Spatial transcriptomics was performed and differentially expressed genes (DEGs) identified both globally and within the hippocampus. Subsequent pathway enrichment and ligand-receptor network analysis was performed.

RESULTS

hNSC transplantation restored learning curves of 5XFAD mice. However, there were no changes in amyloid plaque burden. Spatial transcriptomics showed 1061 DEGs normalized in hippocampal subregions. Plaque induced genes in microglia, along with populations of stage 1 and stage 2 disease associated microglia (DAM), were normalized upon hNSC transplantation. Pathologic signaling between hippocampus and DAM was also restored.

DISCUSSION

hNSCs normalized many dysregulated genes, although this was not mediated by a change in amyloid plaque levels. Rather, hNSCs appear to exert beneficial effects in part by modulating microglia-mediated neuroinflammation and signaling in AD.
Regional interneuron transcriptional changes reveal pathologic markers of disease progression in a mouse model of Alzheimer’s disease
Authors: Chen Kevin S. , Noureldein Mohamed H. , Rigan Diana M. , Hayes John M. , Savelieff Masha G. , Feldman Eva L.
Published: November 2023

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and leading cause of dementia, characterized by neuronal and synapse loss, amyloid-β and tau protein aggregates, and a multifactorial pathology involving neuroinflammation, vascular dysfunction, and disrupted metabolism. Additionally, there is growing evidence of imbalance between neuronal excitation and inhibition in the AD brain secondary to dysfunction of parvalbumin (PV)- and somatostatin (SST)-positive interneurons, which differentially modulate neuronal activity. Importantly, impaired interneuron activity in AD may occur upstream of amyloid-β pathology rendering it a potential therapeutic target. To determine the underlying pathologic processes involved in interneuron dysfunction, we spatially profiled the brain transcriptome of the 5XFAD AD mouse model versus controls, across four brain regions, dentate gyrus, hippocampal CA1 and CA3, and cortex, at early-stage (12 weeks-of-age) and late-stage (30 weeks-of-age) disease. Global comparison of differentially expressed genes (DEGs) followed by enrichment analysis of 5XFAD versus control highlighted various biological pathways related to RNA and protein processing, transport, and clearance in early-stage disease and neurodegeneration pathways at late-stage disease. Early-stage DEGs examination found shared,e.g., RNA and protein biology, and distinct,e.g., N-glycan biosynthesis, pathways enriched in PV-versus somatostatin SST-positive interneurons and in excitatory neurons, which expressed neurodegenerative and axon- and synapse-related pathways. At late-stage disease, PV-positive interneurons featured cancer and cancer signaling pathways along with neuronal and synapse pathways, whereas SST-positive interneurons showcased glycan biosynthesis and various infection pathways. Late-state excitatory neurons were primarily characterized by neurodegenerative pathways. These fine-grained transcriptomic profiles for PV- and SST-positive interneurons in a time- and spatial-dependent manner offer new insight into potential AD pathophysiology and therapeutic targets.
The L27 Domain of MPP7 enhances TAZ-YY1 Cooperation to Renew Muscle Stem Cells
Authors: Shao Anwen , Kissil Joseph L. , Fan Chen-Ming
Published: November 2023

Stem cells regenerate differentiated cells to maintain and repair tissues and organs. They also replenish themselves, i.e. self-renewal, for the regenerative process to last a lifetime. How stem cells renew is of critical biological and medical significance. Here we use the skeletal muscle stem cell (MuSC) to study this process. Using a combination of genetic, molecular, and biochemical approaches, we show that MPP7, AMOT, and TAZ/YAP form a complex that activates a common set of target genes. Among these targets,Carm1can direct MuSC renewal. In the absence of MPP7, TAZ can support regenerative progenitors and activateCarm1expression, but not to a level needed for self-renewal. Facilitated by the actin polymerization-responsive AMOT, TAZ recruits the L27 domain of MPP7 to up-regulateCarm1to the level necessary to drive MuSC renewal. The promoter ofCarm1, and those of other common downstream genes, also contain binding site(s) for YY1. We further demonstrate that the L27 domain of MPP7 enhances the interaction between TAZ and YY1 to activateCarm1. Our results define a renewal transcriptional program embedded within the progenitor program, by selectively up-regulating key gene(s) within the latter, through the combination of protein interactions and in a manner dependent on the promoter context.
Indistinguishable network dynamics can emerge from unalike plasticity rules
Authors: Ramesh Poornima , Confavreux Basile , Gonçalves Pedro J. , Vogels Tim P. , Macke Jakob H.
Published: November 2023

Synaptic plasticity is thought to be critical for building and maintaining brain circuits. Models of plasticity, or plasticity rules, are typically designed by hand, and evaluated based on their ability to elicit similar neuron or circuit properties to ground truth. While this approach has provided crucial insights into plasticity mechanisms, it is limited in its scope by human intuition and cannot identifyallplasticity mechanisms that are consistent with the empirical data of interest. In other words, focusing on individual hand-crafted rules ignores the potential degeneracy of plasticity mechanisms that explain the same empirical data, and may thus lead to inaccurate experimental predictions. Here, we use an unsupervised, adversarial approach to infer plasticity rules directly from neural activity recordings. We show that even in a simple, idealised network model, many mechanistically different plasticity rules are equally compatible with empirical data. Our results suggest the need for a shift in the study of plasticity rules, considering as many degenerate plasticity mechanisms consistent with data as possible, before formulating experimental predictions.
Sexual dimorphism in head size in wild burying beetles (Nicrophorus vespilloides)
Authors: Smith Jack M.L. , Catherall-Ostler Andrew M. , Mashoodh Rahia , Kilner Rebecca M.
Published: November 2023

Male burying beetles (Nicrophorus vespilloides) carry an additional abdominal segment and produce pheromones but otherwise the species is thought to be sexually monomorphic. Both sexes bear bright orange bands on their black elytra, which probably function as part of a warning display rather than in mate choice.

Although larger individuals are more likely to win contests to secure the small carrion required for reproduction, both sexes compete for this vital breeding resource. In wild populations, the sexes are alike in the mean and distribution in their body size.

Here we describe a form of sexual size dimorphism in wild populations that has previously been overlooked. We show that males have wider heads than females, for any given body size, and that the scaling relationship with body size is hyperallometric in males, but isometric in females. We also show how absolute head width, and the extent of sexual dimorphism in head width differs among wild populations which are within c.10km of each other.

We suggest that head size dimorphism could be adaptive, and could be due to divergent selection arising from task specialisation during biparental care, since the duties of care favoured by males are likely to require a greater bite force.
Ecological diversification in an adaptive radiation of plants: the role of de novo mutation and introgression
Authors: Stone Benjamin W. , Wessinger Carolyn A.
Published: November 2023

Adaptive radiations are characterized by rapid ecological diversification and speciation events, leading to fuzzy species boundaries between ecologically differentiated species. Adaptive radiations are therefore key systems for understanding how species are formed and maintained, including the role of de novo mutations vs. pre-existing variation in ecological adaptation and the genome-wide consequences of hybridization events. For example, adaptive introgression, where beneficial alleles are transferred between lineages through hybridization, may fuel diversification in adaptive radiations and facilitate adaptation to new environments. In this study, we employed whole-genome resequencing data to investigate the evolutionary origin of hummingbird-pollinated flowers and to characterize genome-wide patterns of phylogenetic discordance and introgression inPenstemonsubgenusDasanthera, a small and diverse adaptive radiation of plants. We found that magenta hummingbird-adapted flowers have apparently evolved twice from ancestral blue-violet bee-pollinated flowers within this radiation. These shifts in flower color are accompanied by a variety of inactivating mutations to a key anthocyanin pathway enzyme, suggesting that independent de novo loss-of-function mutations underlie parallel evolution of this trait. Although patterns of introgression and phylogenetic discordance were heterogenous across the genome, a strong effect of gene density suggests that, in general, natural selection opposes introgression and maintains genetic differentiation in gene-rich genomic regions. Our results highlight the importance of both de novo mutation and introgression as sources of evolutionary change and indicate a role for de novo mutation in driving parallel evolution in adaptive radiations.
Somatic structural variants driving distinct modes of oncogenesis in melanoma
Authors: Conway Jake R. , Gillani Riaz , Crowdis Jett , Reardon Brendan , Park Jihye , Han Seunghun , Titchen Breanna , Benamar Mouadh , Haq Rizwan , Van Allen Eliezer M.
Published: November 2023

The diversity of structural variants (SVs) in melanoma and how they impact oncogenesis are incompletely known. We performed harmonized analysis of SVs across melanoma histological and genomic subtypes, and we identified distinct global properties between subtypes. These included the frequency and size of SVs and SV classes, their relation to chromothripsis events, and the role of topologically associated domain (TAD) boundary altering SVs on cancer-related genes. Following our prior identification of double-stranded break repair deficiency in a subset of triple wild-type cutaneous melanoma, we identifiedMRE11andNBNloss-of-function SVs in melanomas with this mutational signature. Experimental knockouts ofMRE11andNBN, followed by olaparib cell viability assays in melanoma cells, indicated that dysregulation of each of these genes may cause sensitivity to PARPi in cutaneous melanomas. Broadly, harmonized analysis of melanoma SVs revealed distinct global genomic properties and molecular drivers, which may have biological and therapeutic impact.

Statement of Significance

The diversity of SVs in melanoma, and how they directly or indirectly impact oncogenesis, are incompletely known. Here we present analysis of melanoma SVs that reveal distinct global genomic properties and molecular drivers, some of which point to opportunities for further biological and therapeutic investigation.
GIN-TONIC: Non-hierarchical full-text indexing for graph-genomes
Authors: Öztürk Ünsal , Mattavelli Marco , Ribeca Paolo
Published: November 2023

This paper presents a new data structure, GIN-TONIC, designed to index arbitrary string-labelled directed graphs representing, for instance, pangenomes or transcriptomes. GIN-TONIC provides several capabilities not offered by other graph-indexing methods based on the FM-index. It is non-hierarchical, handling a graph as a single monolithic object; it indexes at nucleotide resolution all possible walks in the graph without the need to explicitly store them; it supports exact substring queries in polynomial time and space for all possible walk roots in the graph, even if there are exponentially many walks corresponding to such roots. Specific ad-hoc optimisations, such as a precomputed cache, allow GIN-TONIC to achieve excellent performance for input graphs of various topologies and sizes. Robust scalability capabilities and a querying performance close to that of a linear FM-Index are demonstrated for two real-world applications, a human pangenome and transcriptome. Source code and associated benchmarks are available on GitHub.

Availability and implementation

GIN-TONIC and all related programs are available athttps://github.com/uensalo/gin.
Phylogenetic diversity and regionalization in the temperate arid zone
Authors: Folk Ryan A. , Maassoumi Aliasghar A. , Siniscalchi Carolina M. , Kates Heather R. , Soltis Douglas E. , Soltis Pamela S. , Belitz Michael B. , Guralnick Robert P.
Published: November 2023

Astragalus(Fabaceae) is astoundingly diverse in temperate, cold arid regions of Earth, positioning this group as a model clade for investigating the distribution of plant diversity in the face of climatic challenge. Here we identify the spatial distribution of diversity and endemism inAstragalus, using species distribution models for 752 species and a phylogenetic tree comprising 847 species. We integrated these to map centers of species richness (SR) and relative phylogenetic diversity (RPD), and used grid cell randomizations to investigate centers of endemism. We also used clustering methods to identify phylogenetic regionalizations. We then assembled predictor variables of current climate conditions to test environmental factors predicting these phylogenetic diversity results, especially temperature and precipitation seasonality.

We find that SR centers are distributed globally at temperate middle latitudes in arid regions, but the Mediterranean Basin is the most important center of RPD. Endemism centers also occur globally, but Iran represents a key endemic area with a concentration of both paleo- and neoendemism. Phylogenetic regionalization recovered an east-west gradient in Eurasia and an amphitropical disjunction across North and South America; American phyloregions are overall most closely related to east and central Asia. SR, RPD, and lineage turnover are driven mostly by precipitation and seasonality, but endemism is driven primarily by diurnal temperature variation. Endemism and regionalization results point to western Asia and especially Iran as a biogeographic gateway between Europe and Asia. RPD and endemism highlight the importance of temperature and drought stress in determining plant diversity and endemism centers.
Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma
Authors: Yang Jiawen , Lim James T. , Victor Paul , Corona Marcelo G. , Chen Chen , Khawaja Hunain , Pan Qiong , Paine-Murrieta Gillian D. , Schnellmann Rick G. , Roe Denise J. , Gokhale Prafulla C. , DeCaprio James A. , Padi Megha
Published: November 2023

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA sequencing. Our data uncovered changes in expression and regulation of Wnt signaling pathway members. Building on this observation, we bioinformatically evaluated various Wnt pathway perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor activity in other cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium targets multiple MCC vulnerabilities. Pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical Wnt signaling but also inhibits cancer cell growth by activating p53-mediated apoptosis, disrupting mitochondrial function, and inducing endoplasmic reticulum stress. Finally, we demonstrated that pyrvinium reduces tumor growth in an MCC mouse xenograft model. These findings offer a new understanding of the role of Wnt signaling in MCC and highlight the utility of pyrvinium as a potential treatment for MCC.
NAD+controls circadian rhythmicity during cardiac aging
Authors: Carpenter Bryce J. , Lecacheur Margaux , Mangold Yannick N. , Cui Kai , Günther Stefan , Dierickx Pieterjan
Published: November 2023

Disruption of the circadian clock as well as reduced NAD+levels are both hallmarks of aging. While circadian rhythms and NAD+metabolism have been linked in heart disease, their relationship during cardiac aging is less clear. Here, we show that aging leads to disruption of diurnal gene expression in the heart. Long-term supplementation with the NAD+precursor nicotinamide riboside (NR) boosts NAD+levels, reprograms the diurnal transcriptome and reverses naturally occurring cardiac enlargement in aged female mice. In addition, complete abolishment of NAD+levels in CMs impairs PER2::luc oscillations, which is rescued by NR supplementation. These findings reveal an essential role for NAD+in regulation of the cardiac circadian clock upon aging, which opens up new avenues to counteract age-related cardiac disorders.
Non-Poissonian bursts in the arrival of phenotypic variation can strongly affect the dynamics of adaptation
Authors: Martin Nora S. , Schaper Steffen , Camargo Chico Q. , Louis Ard A.
Published: November 2023

The introduction of novel phenotypic variation in a population through random mutations plays a crucial role in evolutionary dynamics. Here we show that, when the probability that a sequence has a particular phenotype in its 1-mutational neighbourhood is low, statistical fluctuations imply that in the weak-mutation or monomorphic regime, novel phenotypic variation is not introduced at a constant rate, but rather in non-Poissonian “bursts”. In other words, a novel phenotype appears multiple times in quick succession, or not at all for many generations. We use the RNA secondary-structure genotype-phenotype map to explore how increasing levels of heterogeneity in mutational neighbourhoods strengthen the bursts. Similar results are obtained for the HP model for protein tertiary structure and the Biomorphs model for morphological development. Burst can profoundly affect adaptive dynamics. Most notably, they imply that differences in arrival rates of novel variation can influence fixation rates more than fitness differences do.
Reconstructing prevalence dynamics of wildlife pathogens from pooled and individual samples
Authors: Borremans Benny , Falvo Caylee A. , Crowley Daniel E. , Hoegh Andrew , Lloyd-Smith James O. , Peel Alison J. , Restif Olivier , Ruiz-Aravena Manuel , Plowright Raina K.
Published: November 2023

Pathogen transmission studies require sample collection over extended periods, which can be challenging and costly, especially in the case of wildlife. A useful strategy can be to collect pooled samples, but this presents challenges when the goal is to estimate prevalence. This is because pooling can introduce a dilution effect where pathogen concentration is lowered by the inclusion of negative or lower-concentration samples, while at the same time a pooled sample can test positive even when some of the contributing samples are negative. If these biases are taken into account, the concentration of a pooled sample can be leveraged to infer the most likely proportion of positive individuals, and thus improve overall prevalence reconstruction, but few methods exist that account for the sample mixing process.

We present a Bayesian multilevel model that estimates prevalence dynamics over time using pooled and individual samples in a wildlife setting. The model explicitly accounts for the complete mixing process that determines pooled sample concentration, thus enabling accurate prevalence estimation even from pooled samples only. As it is challenging to link individual-level metrics such as age, sex, or immune markers to infection status when using pooled samples, the model also allows the incorporation of individual-level samples. Crucially, when individual samples can test false negative, a potentially strong bias is introduced that results in incorrect estimates of regression coefficients. The model, however, can account for this by leveraging the combination of pooled and individual samples. Last, the model en- ables estimation of extrinsic environmental effects on prevalence dynamics.

Using a simulated dataset inspired by virus transmission in flying foxes, we show that the model is able to accurately estimate prevalence dynamics, false negative rate, and covariate effects. We test model performance for a range of realistic sampling scenarios and find that while it is generally robust, there are a number of factors that should be considered in order to maximize performance.

The model presents an important advance in the use of pooled samples for estimating prevalence dynamics in a wildlife setting, can be used with any biomarker of infection (Ct values, antibody levels, other infection biomarkers) and can be applied to a wide range of host-pathogen systems.
Brain Charts for People Living with Multiple Sclerosis
Authors: Keshavan A. , Peterson D. , Alexander-Bloch A. , Leyden K.M.
Published: November 2023

Multiple sclerosis (MS) is associated with brain volume loss throughout the disease course. Currently available automated segmentation methods can measure total brain volume as well as ventricular volume, which has been advocated as a robust surrogate for brain volume based on clinically acquired magnetic resonance imaging (MRI). However, brain and ventricle volumes change naturally with age and may be susceptible to biases from differences in acquisition hardware, imaging protocol, and image quality, in addition to statistical biases such as regression to the mean. In this work, brain charts for people living with MS were established that account for patient biological sex, age, and differences in acquisition and image quality. 379 subjects were imaged longitudinally at 5 MS centers using 13 MRI scanner models from 2 scanner manufacturers employing a variety of protocols that included T1-weighted and T2-weighted FLAIR imaging. Generalized Additive Models for Location Scale and Shape (GAMLSS) were employed, and scanner metadata as well as automated assessments of image quality were modeled. Cross-sectional brain charts and conditional, longitudinal brain charts were estimated separately in female and male participants resulting in interpretable and intuitive centile estimates. These findings indicate that brain charts for people living with MS are a promising method for turning quantitative volumetrics into actionable knowledge about a patient’s disease.

Highlights

Interpreting observed changes in brain volume can be challenging due to statistical biases including regression to the mean.

Brain size changes naturally with age and may be susceptible to biases associated with acquisition hardware, imaging protocol, and image quality.

Brain charts for people living with MS are a promising method for translating quantitative volumetrics into interpretable knowledge about a patient’s disease.
Temporal modulation of tactile perception during balance control
Authors: Wachsmann Fabian Dominik , Fiehler Katja , Voudouris Dimitris
Published: November 2023

Somatosensory feedback is essential for motor control, yet sensations from one’s own movements are often suppressed. Despite extensive research on movement-induced tactile suppression, its mechanisms remain unclear. Most studies focus on simple upper-limb movements, leaving the generalization to other body parts unexplored. This study examines tactile processing on the lower limb during balance control by varying feedback processing demands. Participants experienced visual perturbations in a virtual room challenging their posture. Tactile sensitivity was assessed using vibrotactile stimuli to the lower leg at different times around the perturbation. We found that postural behavior is both predictively tuned before and reactively adjusted to expected perturbations. Our results provide evidence that tactile sensitivity changes according to feedback processing demands on the lower limb. Such dynamic sensory modulation could reflect the continuous up- and down-regulation of feedback signals to accomplish the task at hand.
LEAFY and WAPO1 jointly regulate spikelet number per spike and floret development in wheat
Authors: Paraiso Francine , Lin Huiqiong , Li Chengxia , Woods Daniel P. , Lan Tianyu , Tumelty Connor , Debernardi Juan M. , Joe Anna , Dubcovsky Jorge
Published: November 2023

In wheat, the transition of the inflorescence meristem to a terminal spikelet (IM→TS) determines the spikelet number per spike (SNS), an important yield component. In this study, we demonstrate that the plant-specific transcription factor LEAFY (LFY) physically and genetically interacts with WHEAT ORTHOLOG OF APO1 (WAPO1) to regulate SNS and floret development. Loss-of-function mutations in either or both genes result in significant and similar reductions in SNS, as a result of a reduction in the rate of spikelet meristems formation per day. SNS is also modulated by significant genetic interactions betweenLFYandSQUAMOSAMADS-box genesVRN1andFUL2, which promote the IM→TS transition. Single-molecule fluorescencein-situhybridization revealed a down-regulation ofLFYand up-regulation of theSQUAMOSAMADS-box genes in the distal part of the developing spike during the IM→TS transition, supporting their opposite roles in the regulation of SNS in wheat. Concurrently, the overlap ofLFYandWAPO1transcription domains in the developing spikelets contributes to normal floret development. Understanding the genetic network regulating SNS is a necessary first step to engineer this important agronomic trait.

SUMMARY STATEMENT

The plant specific transcription factorLEAFYplays an important role in the regulation of the number of spikelets per spike in wheat.
Dextrin conjugation to colistin inhibits its toxicity, cellular uptake and acute kidney injuryin vivo
Authors: Varache Mathieu , Rizzo Siân , Sayers Edward J. , Newbury Lucy , Mason Anna , Liao Chia-Te , Chiron Emilie , Bourdiec Nathan , Jones Adam , Fraser Donald J. , Taylor Philip R. , Jones Arwyn T. , Thomas David W. , Ferguson Elaine L.
Published: November 2023

The acute kidney injury (AKI) and dose-limiting nephrotoxicity, which occurs in 20-60% of patients following systemic administration of colistin, represents a challenge in the effective treatment of multi-drug resistant gram-negative infections. To reduce clinical toxicity of colistin and improve targeting to infected /inflamed tissues, we previously developed dextrin-colistin conjugates, whereby colistin is designed to be released by amylase-triggered degradation of dextrin in infected and inflamed tissues, after passive targeting by the enhanced permeability and retention effect. Whilst it was evidentin vitrothat polymer conjugation can reduce toxicity and prolong plasma half-life, without significant reduction in antimicrobial activity of colistin, it was unclear how dextrin conjugation would alter cellular uptake and localisation of colistin in renal tubular cellsin vivo. We discovered that dextrin conjugation effectively reduced colistin’s toxicity towards human kidney proximal tubular epithelial cells (HK-2)in vitro, which was mirrored by significantly less cellular uptake of Oregon Green (OG)-labelled dextrin-colistin conjugate, when compared to colistin. Using live-cell confocal imaging, we revealed localisation of both, free and dextrin-bound colistin in endolysosome compartments of HK-2 and NRK-52E cells. Using a murine AKI model, we demonstrated dextrin-colistin conjugation dramatically diminishes both proximal tubular injury and renal accumulation of colistin. These findings reveal new insight into the mechanism by which dextrin conjugation can overcome colistin’s renal toxicity and show the potential of polymer conjugation to improve the side effect profile of nephrotoxic drugs.

Graphical abstract
A computational approach for deciphering the interactions between proximal and distal regulators in B cell differentiation
Authors: Park Sung-Joon , Nakai Kenta
Published: November 2023

Delineating the intricate interplay between promoter-proximal and -distal regulators is crucial for understanding the function of transcriptional mediator complexes implicated in the regulation of gene expression. The aim of the present study was to develop a computational method for accurately modeling the spatial proximal and distal regulatory interactions. Our method combined regression-based models to identify key regulators through gene expression prediction and a graph- embedding approach to detect coregulated genes. This approach enabled a detailed investigation of the gene regulatory mechanisms underlying peripheral B cell differentiation, accompanied by dramatic rearrangements of the genome structure. We found that while the promoter-proximal elements were the principal regulators of gene expression, the distal regulators fine-tuned transcription. Moreover, our approach unveiled the presence of modular regulators, such as structural cofactors and proximal/distal transcriptional factors, which were co-expressed with their target genes. These findings imply that the dysregulation of interactions between transcriptional and structural factors is associated with chromatin reorganization failure and ultimately an increased risk of malignancy. We envisage that our computational approach will help crack the transcriptionalcis-regulatory code of the three-dimensional network regulating gene expression.
Short-term Pre-operative Methionine Restriction Induces Browning of Perivascular Adipose Tissue and Improves Vein Graft Remodeling in Mice
Authors: Kip Peter , Sluiter Thijs J. , MacArthur Michael R. , Tao Ming , Jung Jonathan , Mitchell Sarah J. , Kooijman Sander , Kruit Nicky , Gorham Josh , Seidman Jonathan G. , Quax Paul H.A. , Aikawa Masanori , Ozaki C. Keith , Mitchell James R , de Vries Margreet R.
Published: November 2023

Short-term preoperative methionine restriction (MetR) shows promise as a translatable strategy to modulate the body’s response to surgical injury. Its application, however, to improve post-interventional vascular remodeling remains underexplored. Here, we find that MetR protects from arterial intimal hyperplasia in a focal stenosis model and adverse vascular remodeling after vein graft surgery. RNA sequencing reveals that MetR enhances the brown adipose tissue phenotype in arterial perivascular adipose tissue (PVAT) and induces it in venous PVAT. Specifically, PPAR-α was highly upregulated in PVAT-adipocytes. Furthermore, MetR dampens the post-operative pro-inflammatory response to surgery in PVAT-macrophagesin vivoandin vitro. This study shows for the first time that the detrimental effects of dysfunctional PVAT on vascular remodeling can be reversed by MetR, and identifies pathways involved in browning of PVAT. Furthermore, we demonstrate the potential of short-term pre-operative MetR as a simple intervention to ameliorate vascular remodeling after vascular surgery.

Graphical Abstract
LOSS OF CLDN5 -AND INCREASE IN IRF7- IN THE HIPPOCAMPUS AND CEREBRAL CORTEX OF DIABETIC MICE AT THE EARLY SYMPTOMATIC STAGE
Authors: Carús-Cadavieco Marta , González de la Fuente Sandra , Berenguer Inés , Serrano-Lope Miguel A. , Aguado Begoña , Palomer Ernest , Guix Francesc , Dotti Carlos G.
Published: November 2023

Analyzing changes in gene expression within specific brain regions of individuals with Type 2 Diabetes (T2DM) who do not exhibit significant cognitive deficits can yield valuable insights into the mechanisms that may underlie the progression toward a more severe phenotype, for example as when individuals age. Here, we present evidence that adult mice with long-term type 2 diabetes mellitus (T2DM) and minor cognitive deficits display alterations in the expression of 27 genes in the cerebral cortex and 16 genes in the hippocampus compared to non-T2DM mice. Only six of these genes undergo the same type of change both in the cortex and hippocampus: Interferon regulatory factor 7 (Irf7), Hypoxia-inducible factor 3 alpha (Hif-3α), period circadian clock 2 (Per2), xanthine dehydrogenase (Xdh), and Transforming growth factor β-stimulated clone 22/TSC22 (Tscd3) are all upregulated, while Claudin-5 (Cldn5) is downregulated. At the protein level, Claudin5 and IRF7 showed equivalente changes: downregulation of CLDN5 and upregulation of IRF7. These results suggest that cognitive deficits linked to chronic T2DM may stem from compromised blood-brain barrier integrity and an abnormal inflammatory response in the early stages of the disease. This underscores the potential for therapeutic interventions targeting CLDN5 and IRF7.
InSpectro-Gadget: A tool for estimating neurotransmitter and neuromodulator receptor distributions for MRS voxels
Authors: McManus Elizabeth , Muhlert Nils , Duncan Niall W.
Published: November 2023

Magnetic resonance spectroscopy (MRS) is widely used to estimate concentrations of glutamate and γ-aminobutyric acid (GABA) in specific regions of the living human brain. As cytoarchitectural properties differ across the brain, interpreting these measurements can be assisted by having knowledge of such properties for the MRS region(s) studied. In particular, some knowledge of likely local neurotransmitter receptor patterns can potentially give insights into the mechanistic environment GABAand glutamatergic neurons are functioning in. This may be of particular utility when comparing two or more regions, given that the receptor populations may differ substantially across them. At the same time, when studying MRS data from multiple participants or timepoints, the homogeneity of the sample becomes relevant, as measurements taken from areas with different cytoarchitecture may be difficult to compare. To provide insights into the likely cytoarchitectural environment of user-defined regions-of-interest, we produced an easy to use tool InSpectro-Gadget, that interfaces with receptor mRNA expression information from the Allen Human Brain Atlas. This Python tool allows users to input masks and automatically obtain a graphical overview of the receptor population likely to be found within. This includes comparison between multiple masks or participants where relevant. The receptors and receptor subunit genes featured include GABA- and glutamatergic classes, along with a wide range of neuromodulators. The functionality of the tool is explained here and its use demonstrated through a set of example analyses. The tool is available athttps://github.com/lizmcmanus/Inspectro-Gadget.