bluuebunny/crossref_metadata_2025 huggingface dataset:
A Statistical Model for Inference of Recent and Incident HIV Infection Using Surveillance Data on Individuals Newly Diagnosed With HIV Infection in Scotland
Authors: McDonald Scott A. , Yeung Alan , Nandwani Rak , Clutterbuck Daniel , Wallace Lesley A. , Cullen Beth L. , Shepherd Samantha J. , Roy Kirsty , Marsh Kimberly , Gunson Rory , Hutchinson Sharon J.
Published: June 2024

Background:

To inform global ambitions to end AIDS, evaluation of progress toward HIV incidence reduction requires robust methods to measure incidence. Although HIV diagnosis date in routine HIV/AIDS surveillance systems are often used as a surrogate marker for incidence, it can be misleading if acquisition of transmission occurred years before testing. Other information present in data such as antibody testing dates, avidity testing result, and CD4 counts can assist, but the degree of missing data is often prohibitive.

Methods:

We constructed a Bayesian statistical model to estimate the annual proportion of first ever HIV diagnoses in Scotland (period 2015–2019) that represent recent HIV infection (ie, occurring within the previous 3–4 months) and incident HIV infection (ie, infection within the previous 12 months), by synthesizing avidity testing results and surveillance data on the interval since last negative HIV test.

Results:

Over the 5-year analysis period, the model-estimated proportion of incident infection was 43.9% (95% CI: 40.9 to 47.0), and the proportion of recent HIV infection was 21.6% (95% CI: 19.1 to 24.1). Among the mode of HIV acquisition categories, the highest proportion of recent infection was estimated for people who inject drugs: 27.4% (95% CI: 20.4 to 34.4).

Conclusions:

The Bayesian approach is appropriate for the high prevalence of missing data that can occur in routine surveillance data sets. The proposed model will aid countries in improving their understanding of the number of people who have recently acquired their infection, which is needed to progress toward the goal of HIV transmission elimination.
The Value of Metabolites and Vitamins for the Assessment of Nutritional Status in Hospitalized Patients
Authors: Verheul Esmee A. H. , Ouwerkerk Joep J. J. , Dijkink Suzan , Krijnen Pieta , Verhoeven Aswin , Giera Martin , Yeh Daniel D. , Schipper Inger B.
Published: June 2024

This systematic review aims to summarize the currently available literature regarding the association of plasma metabolites and vitamins with the nutritional status in adult hospitalized patients. A systematic literature search was performed in PubMed and EMBASE, and all studies comparing metabolite or vitamin levels in malnourished versus well-nourished hospitalized patients were included. Twenty-three studies were eligible for inclusion, representing 3803 hospitalized patients. Several metabolites involved in the metabolism of methionine, purine, glutathione, carnitine, phenylalanine, and tryptophan, as well as some vitamins, seem to be associated with malnutrition in hospitalized patients. These compounds can potentially be used to assess nutritional status.
Randomized Controlled Trial of Enhanced Recovery After Surgery Protocols in Live Kidney Donors: ERASKT Study
Authors: Saks Jacob , Yoon Uzung , Neiswinter Natalie , Schwenk Eric S. , Goldberg Stephen , Nguyen Linh , Torjman Marc C. , Elia Elia , Shah Ashesh
Published: June 2024

Background:

Enhanced recovery after surgery (ERAS) pathways represent a comprehensive approach to optimizing perioperative management and reducing hospital stay and cost. In living donor kidney transplantation, key impediments to postoperative discharge include pain, and opioid associated complications such as nausea, vomiting, and the return of gastrointestinal function.

Methods:

In this randomized controlled trial, living kidney transplantation donors were assigned to either the ERAS or control group. The ERAS group patients received 15 preoperative, 17 intraoperative, 19 postoperative element intervention. The control group received standard care. The ERAS group received a multimodal opioid sparing pain management including an intraoperative transverse abdominis plane block. Our primary outcome measure was postoperative opioid consumption. The secondary outcome measures were postoperative pain scores, first oral intake, and hospital length of stay.

Results:

There were no significant differences in demographics between the 2 groups. The ERAS group had a statistically significant reduction in total postoperative opioid consumption calculated in intravenous morphine equivalents (24.2 ± 20.2 versus 71 ± 39.5 mg, P < 0.01). Postoperative pain scores were significantly lower (P < 0.001) from 1 h postoperatively to 48 h. Surgical time was 45 min shorter (P = 0.037). Intraoperative PlasmaLyte administration was lower (PlasmaLyte: 1444 ± 907 versus 2168 ± 1347 mL, P = 0.049). Time to tolerating regular diet was shorter by 2 h (P < 0.008), and length of hospital stay was decreased by 10.1 h.

Conclusions:

The ERAS group experienced superior postoperative analgesia and a shorter length of hospital stay compared with controls.
Near-field scattering by the method of locally subsonic waves
Authors: Chapman C. J. , Hawkins S. C.
Published: June 2024

A technique is developed for determining the sound field scattered by a compact body when it is close enough to an acoustic source to be in its near field. Our approach is based on the fact that large regions of many near fields may be well approximated at each point in space by a
subsonic
plane wave (also called an inhomogeneous plane wave, or an evanescent wave). Such a wave is defined by the property that in one direction it propagates with subsonic phase speed, while in a perpendicular direction it has exponential amplitude variation. Hence by defining a canonical problem, compact scattering of a subsonic plane wave, and solving it, we are able to give a unified analytical treatment of many near-field scattering problems. Our approach draws on the formulae of Rayleigh scattering (as applied to an incident field with complex wavenumber) and the asymptotic theory of the wave equation. For an arbitrary three-dimensional multipole, we determine in full detail how its subsonic wave structure depends on the spherical harmonic parameters

(
m
,
n
)

, and show that our approach has a very large region of validity.
Uncovering wall-shear stress dynamics from neural-network enhanced fluid flow measurements
Authors: Lagemann Esther , Brunton Steven L. , Lagemann Christian
Published: June 2024

Accurate prediction and measurement of wall-shear stress dynamics in fluid flows is crucial in domains as diverse as transportation, public utility infrastructure, energy technology and human health. However, we still lack adequate experimental methods that simultaneously capture the temporal and the spatial behaviour of the wall-shear stress. In this contribution, we present a holistic approach that derives these dynamics from particle-image velocimetry (PIV) measurements using a deep optical flow estimator with physical knowledge. While the experimental measurements resemble state-of-the-art PIV set-ups, the established particle image processing is replaced by a deep neural network specifically tailored to extract velocity and wall-shear stress information. Since this
WSSflow
framework operates at the original image resolution, it provides the respective flow field information at a much higher spatial resolution compared with state-of-the-art PIV processing. The results show that this per-pixel approach is essential for an accurate wall-shear stress estimation. The validity and physical correctness of the derived flow quantities are demonstrated with synthetic and real-world experimental data of a turbulent channel flow, a wavy turbulent channel flow and an elastic blood vessel flow. Where baseline data are available for comparison, the instantaneous and time-averaged wall-shear stress predictions accurately follow the ground truth data.
Colony pattern development of a synthetic bistable switch
Authors: Chu Pan , Zhu Jingwen , Ma Zhixin , Fu Xiongfei
Published: June 2024

Microbial colony development hinges upon a myriad of factors, including mechanical, biochemical, and environmental niches, which collectively shape spatial patterns governed by intricate gene regulatory networks. The inherent complexity of this phenomenon necessitates innovative approaches to comprehend and compare the mechanisms driving pattern formation. Here, we unveil the multistability of bacterial colony patterns orchestrated by a simple synthetic bistable switch. Utilizing quantitative imaging and spatially resolved transcriptome approaches, we explore the deterministic process of a ring-like colony pattern formation from a single cell. This process is primarily driven by bifurcation events programmed by the gene regulatory network and microenvironmental cues. Additionally, we observe a noise-induced process amplified by the founder effect, leading to patterns of symmetry-break during range expansion. The degrees of asymmetry are profoundly influenced by the initial conditions of single progenitor cells during the nascent stages of colony development. These findings underscore how the process of range expansion enables individual cells, exposed to a uniform growth-promoting environment, to exhibit inherent capabilities in generating emergent, self-organized behaviour.
Head dopaminergic and serotonergic neurons monitor alterations in gut bacterial activity through a gut-brain-gut axis
Authors: Li Guanqun , Wu Yangyang , Huang Xiaowen , Du Minghui , Tang Hongyun
Published: June 2024

The brain is suggested to monitor gut microbial changes to critically maintain health, whereas the particular bacterial alterations and the mechanisms involved are largely unclear. Here, through a genome-wide screen, we identified 29E. coligenes whose inactivation can be surveilled byC. eleganshead dopaminergic and serotonergic neurons through increasing host neuronal dopamine and serotonin biosynthesis. Mechanistically, we found that these head neurons respond to theE. colilack of respiratory chain genes by detecting the bacteria-caused reductions in host labile iron levels that impair intestinal mitochondria, and the intestine-expressed mitochondrial stress sensor ATFS-1 is critically involved. Furthermore, this neuronal response in turn promotes intestinal ferritin-1 expression to counteract bacteria-caused labile iron reduction and thereby maintaining mitochondrial function. Our findings systematically identify bacterial activity changes that elevate brain dopamine and serotonin levels and unveil an unexpected gut-brain-gut axis in which the head neurons inspect bacterial activity-mediated changes in host iron metabolism and mitochondrial function, enlightening crucial roles and mechanisms of brain in surveilling microbial activity alterations.
Transcriptome analysis ofDrosophila suzukiireveals molecular mechanisms conferring pyrethroid and spinosad resistance
Authors: Tabuloc Christine A. , Carlson Curtis R. , Ganjisaffar Fatemeh , Truong Cindy C. , Chen Ching-Hsuan , Lewald Kyle M. , Hidalgo Sergio , Nicola Nicole L. , Jones Cera E. , Sial Ashfaq A. , Zalom Frank G. , Chiu Joanna C.
Published: June 2024

Drosophila suzukiilay eggs in soft-skinned, ripening fruits, making this insect a serious threat to berry production. Since its 2008 introduction into North America, growers have used insecticides, such as pyrethroids and spinosads, as the primary approach forD. suzukiimanagement, resulting in detections of insecticide resistance in this pest. This study sought to identify the molecular mechanisms conferring insecticide resistance in these populations. We sequenced the transcriptomes of two pyrethroid- and two spinosad-resistant isofemale lines. In both pyrethroid-resistant lines and one spinosad-resistant line, we identified overexpression of metabolic genes that are implicated in resistance in other insect pests. In the other spinosad-resistant line, we observed an overexpression of cuticular genes that have been linked to resistance. Our findings enabled the development of molecular diagnostics that we used to confirm persistence of insecticide resistance in California, U.S.A. To validate these findings, we leveragedD. melanogastermutants with reduced expression of metabolic or cuticular genes that were found to be upregulated in resistantD. suzukiito demonstrate that these genes are involved in promoting resistance. This study is the first to characterize the molecular mechanisms of insecticide resistance inD. suzukiiand provides insights into how current management practices can be optimized.
Spatial Transcriptomics Prediction from Histology Images at Single-cell Resolution using RedeHist
Authors: Zhong Yunshan , Zhang Jiaxiang , Ren Xianwen
Published: June 2024

Spatial transcriptomics (ST) offers substantial promise in elucidating the tissue architecture of biological systems. However, its utility is frequently hindered by constraints such as high costs, time-intensive procedures, and incomplete gene readout. Here we introduce RedeHist, a novel deep learning approach integrating scRNA-seq data to predict ST from histology images at single-cell resolution. Application of RedeHist to both sequencing-based and imaging-based ST data demonstrated its outperformance in high-resolution and accurate prediction, whole-transcriptome gene imputation, and fine-grained cell annotation compared with the state-of-the-art algorithms.
Common and unique neurophysiological signatures for the stopping and revising of actions reveal the temporal dynamics of inhibitory control
Authors: Hervault Mario , Wessel Jan R.
Published: June 2024

Inhibitory control is a crucial cognitive-control ability for behavioral flexibility that has been extensively investigated through action-stopping tasks. Multiple neurophysiological features have been proposed to represent ‘signatures’ of inhibitory control during action-stopping, though the processes signified by these signatures are still controversially discussed. The present study aimed to disentangle these processes by comparing simple stopping situations with those in which additional action revisions were needed. Three experiments in female and male humans were performed to characterize the neurophysiological dynamics involved in action-stopping and - changing, with hypotheses derived from recently developed two-stage ‘pause-then-cancel’ models of inhibitory control. Both stopping and revising an action triggered an early broad ‘pause’-process, marked by frontal EEG β-bursts and non-selective suppression of corticospinal excitability. However, partial-EMG responses showed that motor activity was only partially inhibited by this ‘pause’, and that this activity can be further modulated during action-revision. In line with two-stage models of inhibitory control, subsequent frontocentral EEG activity after this initial ‘pause’ selectively scaled depending on the required action revisions, with more activity observed for more complex revisions. This demonstrates the presence of a selective, effector-specific ‘retune’ phase as the second process involved in action-stopping and -revision. Together, these findings show that inhibitory control is implemented over an extended period of time and in at least two phases. We are further able to align the most commonly proposed neurophysiological signatures to these phases and show that they are differentially modulated by the complexity of action-revision.

Significance Statement

Inhibitory control is one of the most important control processes by which humans can regulate their behavior. Multiple neurophysiological signatures have been proposed to reflect inhibitory control. However, these play out on different time scales and appear to reflect different aspects of cognitive control, which are controversially debated.

Recent two-stage models of inhibitory control have proposed that two phases implement the revisions of actions: ‘pause’ and ‘retune’. Here, we provide the first empirical evidence for this proposition: Action revisions engendered a common initial low-latency ‘pause’, during which motor activity is broadly suppressed. Later activity, however, distinguishes between simple stopping of actions and more complex action revisions. These findings provide novel insights into the sequential dynamics of human action control.
Methylation and Transcriptomic Profiling Reveals Short Term and Long Term Regulatory Responses in Polarized Macrophages
Authors: Migliaccio Giorgia , Morikka Jack , del Giudice Giusy , Vaani Maaret , Möbus Lena , Serra Angela , Federico Antonio , Greco Dario
Published: June 2024

Macrophage plasticity allows the adoption of distinct functional states in response to environmental cues. While unique transcriptomic profiles define these states, focusing solely on transcription neglects potential long-term effects. The investigation of epigenetic changes can be used to understand how temporary stimuli can result in lasting effects. Moreover, epigenetic alterations play an important role in the pathophysiology of macrophages, including phenomena related to the trained innate immunity, which allow faster and more efficient inflammatory responses upon subsequent encounters with the same pathogen. In this study, we used a multi-omics approach to elucidate the interplay between gene expression and DNA-methylation, unravelling the long-term effects of diverse polarizing environments on macrophage activity. We identified a common core set of genes that are differentially methylated regardless of exposure suggesting a potential mechanism for rapid adaptation to various stimuli. These conserved epigenetic modifications might represent a fundamental state that allows for flexible responses to various environmental cues. Functional analysis revealed that processes requiring rapid responses displayed transcriptomic regulation, whereas functions critical for long-term adaptations exhibited co-regulation at both transcriptomic and epigenetic levels. Our study unveils a novel set of genes critically linked to the long-term effects of macrophage polarization. This discovery underscores the potential of epigenetics in elucidating how macrophages establish long-term memory and influence health outcomes.

Highlights:

- Environmental signals trigger gene changes in macrophages, leaving a long-lasting epigenetic reprogramming

- Epigenetic changes and metabolic shifts in polarized macrophages suggest training mechanisms

- Common gene set epigenetically altered across different cues, suggest common adaptation to various stimuli

Graphical Abstract
CRISPRware: an efficient method for contextual gRNA library design
Authors: Malekos Eric , Montano Christy , Carpenter Susan
Published: June 2024

We present CRISPRware, an efficient method for generating guide RNA (gRNA) libraries against transcribed, translated, and noncoding regions. CRISPRware leverages next-generation sequencing data to design context-specific gRNAs and accounts for genetic variation, which allows allele-specific guide design on a genome-wide scale. The latter ability holds promise for the development of gene therapy in the context of gene dosing and dominant negative mutations.
Pharmacologic Inhibition of Ferroptosis Attenuates Experimental Abdominal Aortic Aneurysm Formation
Authors: Krebs Jonathan R. , Bellotti Paolo , Valisno Jeff Arni C. , Su Gang , Sharma Shiven , Kollareth Denny Joseph Manual , Hartman Joseph B. , Adithan Aravinthan , Spinosa Michael , Kamat Manasi , Garrett Timothy , Cai Guoshuai , Sharma Ashish K. , Upchurch Gilbert R.
Published: June 2024

The pathogenesis of abdominal aortic aneurysm (AAA) formation involves vascular inflammation, thrombosis formation and programmed cell death leading to aortic remodeling. Recent studies have suggested that ferroptosis, an excessive iron-mediated cell death, can regulate cardiovascular diseases, including AAAs. However, the role of ferroptosis in immune cells, like macrophages, and ferroptosis-related genes in AAA formation remains to be deciphered. Single cell-RNA sequencing of human aortic tissue from AAA patients demonstrates significant differences in ferroptosis-related genes compared to control aortic tissue. Using two established murine models of AAA and aortic rupture in C57BL/6 (WT) mice, we observed that treatment with liproxstatin-1, a specific ferroptosis inhibitor, significantly attenuated aortic diameter, pro-inflammatory cytokine production, immune cell infiltration (neutrophils and macrophages), increased smooth muscle cell α-actin expression and elastic fiber disruption compared to mice treated with inactivated elastase in both pre-treatment and treatment after a small AAA had already formed. Lipidomic analysis using mass spectrometry shows a significant increase in ceramides and a decrease in intact lipid species levels in murine tissue compared to controls in the chronic AAA model on day 28. Mechanistically,in vitrostudies demonstrate that liproxstatin-1 treatment of macrophages mitigated the crosstalk with aortic smooth muscle cells (SMCs) by downregulating MMP2 secretion. Taken together, this study demonstrates that pharmacological inhibition by liproxstatin-1 mitigates macrophage-dependent ferroptosis contributing to inhibition of aortic inflammation and remodeling during AAA formation.
A potent agonist-based PROTAC targeting Pregnane X Receptor that delays colon cancer relapse
Authors: Bansard Lucile , Laconde Guillaume , Delfosse Vanessa , Huet Tiphaine , Ayeul Margaux , Rigal Emilie , Donati Quentin , Gerbal-Chaloin Sabine , Daujat-Chavanieu Martine , Legrand Baptiste , Chavanieu Alain , Martin Anthony R. , Pannequin Julie , Bourguet William , Amblard Muriel , Pascussi Jean Marc
Published: June 2024

Tumor recurrence is often attributed to drug-tolerant cancer stem cells. We previously demonstrated that down regulation of the Pregnane X Receptor (PXR, NR1I2) decreases chemoresistance of cancer stem cells and prevents colorectal cancer recurrence in xenograft mouse models. These is a lack of PXR antagonists that are appropriate for clinical use. In this study, we report the design and synthesis of a novel PXR agonist-based PROTAC (JMV7048) that induces polyubiquitination and degradation of human PXR protein in an E3 CRBN ubiquitin ligase- and the 26S proteasome-dependent manner. This molecule specifically degrades PXR in colon carcinoma, hepatoma, and pancreatic cancer cell lines, but not in primary cultures of human hepatocytes. Crucially, JMV7048 decreased PXR protein expression in colon cancer stem cells and sensitized them to chemotherapy significantly delaying cancer relapsein vivo.PROTACs targeting PXR protein could thus become novel therapeutic agents to enhance cancer cell sensitivity to chemotherapy.
Spatial domain analysis to estimate spatiotemporal pathological mechanisms in microenvironment with single-cell spatial omics data
Authors: Sakai Shunsuke A. , Nomura Ryosuke , Nagasawa Satoi , Chi SungGi , Suzuki Ayako , Suzuki Yutaka , Ishikawa Shumpei , Tsuchihara Katsuya , Kageyama Shun-Ichiro , Yamashita Riu
Published: June 2024

Single-cell spatial omics analysis requires consideration of biological functions and mechanisms in a microenvironment. However, microenvironment analysis using bioinformatic methods is limited by the need to detect histological morphology. In this study, we developed SpatialKNife (SKNY), an image-processing-based toolkit that detects spatial domains that potentially reflect histology and extends these domains to the microenvironment. The SKNY algorithm identified tumour spatial domains from spatial transcriptomic data of breast cancer, followed by clustering of these domains, trajectory estimation, and spatial extension to the tumour microenvironment (TME). The results of the trajectory estimation were consistent with the known mechanisms of cancer progression. We observed endothelial cell and macrophage infiltration into the TME at mid-stage progression. Our results suggest that analysis using the spatial domain as a unit reflects pathological mechanisms in the TME. This approach may be applicable to the biological estimation of diverse microenvironments.
Consolidated Calcium kinetic rates in a Caucasian population as a function of age and sex
Authors: Hartung Niklas , A Abrams Steven , Huisinga Wilhelm , Weisser Karin
Published: June 2024

Calcium plays an important role in bone physiology and its kinetics change over lifetime. The analysis of calcium deposition and resorption through stable isotope techniques has guided recommendations on nutritional uptake for overall health. In addition, calcium kinetics have great relevance for toxicokinetic studies of bone-seeking elements (e.g, aluminium and lead) since these elements use common uptake and release pathways. While the impact of many factors on calcium kinetics have been investigated individually, a consolidated age- and sex-dependent kinetic description amenable for toxicokinetic modeling, however, is still lacking. Motivated by this need, we systematically reviewed the existing literature on calcium kinetics and assembled a large and consistent dataset. Then, building on the work of O’Flaherty in the 1990s, we formulated age- and sex-dependent functions describing calcium deposition, resorption, net retention, and mass. This description represents the current knowledge on calcium kinetics in a reference individual of Caucasians as most data was from this population.
RNAfold: RNA tertiary structure prediction using variational autoencoder
Authors: Kazanskii M.A. , Uroshlev L. , Zatylkin F. , Pospelova I. , Kantidze O. , Gankin Y.
Published: June 2024

Understanding the RNA tertiary structure is crucial for advancing therapeutic development and vaccine design. Previous methods, such as dynamic simulations, have been used to study RNA structure. However, these methods often struggle to capture the complex non-linear relationships in RNA sequences. Other approaches focused on simple models, resulting in lower performance. Indeed, one of the main challenges in predicting RNA tertiary structure is the lack of data, and using complicated algorithms is limited. In this paper, we introduce the Variational Autoencoder (VAE). In this paper, we introduce the Variational Autoencoder (VAE) for the problem of RNA folding and demonstrate that the Variational Autoencoder could yield promising results. Our model achieves a Root Mean Square Error (RMSE) of approximately 3.3Å in predicting nucleotide positions, significantly outperforming existing approaches.
UltraCortex: Submillimeter Ultra-High Field 9.4 T Brain MR Image Collection and Manual Cortical Segmentations
Authors: Mahler Lucas , Steiglechner Julius , Bender Benjamin , Lindig Tobias , Ramadan Dana , Bause Jonas , Birk Florian , Heule Rahel , Charyasz Edyta , Erb Michael , Jangir Kumar Vinod , E Hagberg Gisela , Martin Pascal , Lohmann Gabriele , Scheffler Klaus
Published: June 2024

TheUltraCortexrepository (https://www.ultracortex.org) houses magnetic resonance imaging data of the human brain obtained at an ultra-high field strength of 9.4 T. It contains 86 structural MR images with spatial resolutions ranging from 0.6 to 0.8 mm. Additionally, the repository includes segmentations of 12 brains into gray and white matter compartments. These segmentations have been independently validated by two expert neuroradiologists, thus establishing them as a reliable gold standard. This resource provides researchers with access to high-quality brain imaging data and validated segmentations, facilitating neuroimaging studies and advancing our understanding of brain structure and function. Existing repositories do not accommodate field strengths beyond 7 T, nor do they offer validated segmentations, underscoring the significance of this new resource.
An improved method for sampling and quantitative protein analytics of cerebrospinal fluid of single mice
Authors: Lourbopoulos Athanasios , Müller Stephan A. , Jocher Georg , Wick Manfred , Plesnila Nikolaus , Lichtenthaler Stefan F.
Published: June 2024

Mice are the most commonly used preclinical animal model, but protein analytics of murine cerebrospinal fluid (CSF) remains challenging because of low CSF volume (often <10 µl) and frequent blood contaminations. We developed an improved CSF sampling method that allows routine collection of increased volumes (20-30 µl) of pure CSF from individual mice, enabling multiple protein analytical assays from a single sample. Based on cell counts and hemoglobin ELISAs, we provide an easy quality control workflow for obtaining cell- and blood-free murine CSF. Through mass spectrometry-based proteomics using an absolutely quantified external standard, we estimated concentrations for hundreds of mouse CSF proteins. While repeated CSF sampling from the same mouse was possible, it induced CSF proteome changes. Applying the improved method, we found that the mouse CSF proteome remains largely stable over time in wild-type mice, but that amyloid pathology in the 5xFAD mouse model of Alzheimer’s disease massively changes the CSF proteome. Neurofilament light chain and TREM2, markers of neurodegeneration and activated microglia, respectively, were strongly upregulated and validated using immunoassays. In conclusion, our refined murine CSF collection method overcomes previous limitations, allowing multiple quantitative protein analyses for applications in biomedicine.
Transcriptomic Insights into the Epigenetic Modulation of Turnip Mosaic Virus Evolution inArabidopsis thaliana
Authors: Olmo-Uceda María J. , Ambrós Silvia , Corrêa Régis L. , Elena Santiago F.
Published: June 2024

Plant-virus interaction models propose that a virus’s ability to infect a host genotype depends on the compatibility between virulence and resistance genes. Recently, we conducted an evolution experiment in which lineages of turnip mosaic virus (TuMV) were passaged inArabidopsis thalianagenotypes carrying mutations in components of the DNA methylation and the histone demethylation epigenetic pathways. All evolved lineages increased infectivity, virulence and viral load in a host genotype-dependent manner. To better understand the underlying reasons for these evolved relationships, we delved into the transcriptomic responses of mutant and WT plant genotypes in mock conditions and infected with either the ancestral or evolved viruses. Such a comparison allowed us to classify every gene into nine basic expression profiles. Regarding the targets of viral adaptation, our analyses allowed the identification of common viral targets as well as host genotype-specific genes and categories of biological processes. As expected, immune response-related genes were found to be altered upon infection. However, we also noticed the pervasive over-representation of other functional groups, suggesting that viral adaptation was not solely driven by the level of expression of plant resistance genes. In addition, a significant association between the presence of transposable elements within or upstream the differentially expressed genes was observed. Finally, integration of transcriptomic data into a virus-host protein-protein interaction network highlighted the most impactful interactions. These findings shed extra light on the complex dynamics between plants and viruses, indicating that viral infectivity depends on various factors beyond just the plant’s resistance genes.
Vaccine-elicited and naturally elicited antibodies differ in their recognition of the HIV-1 fusion peptide
Authors: Reveiz Mateo , Xu Kai , Lee Myungjin , Wang Shuishu , Olia Adam S. , Harris Darcy R. , Liu Kevin , Liu Tracy , Schaub Andrew J. , Stephens Tyler , Wang Yiran , Zhang Baoshan , Huang Rick , Tsybovsky Yaroslav , Kwong Peter D. , Rawi Reda
Published: June 2024

Broadly neutralizing antibodies have been proposed as templates for HIV-vaccine design, but it has been unclear how similar vaccine-elicited antibodies are to their naturally elicited templates. To provide insight, here we compare the recognition of naturally elicited and vaccine-elicited antibodies targeting the HIV-1-fusion peptide, which comprises envelope (Env) residues 512-526, with the most common sequence being AVGIGAVFLGFLGAA. Naturally elicited antibodies bound peptides with negative-charge substitutions around residues 517-520 substantially better than the most common sequence, despite these substitutions rarely appearing in HIV; by contrast, vaccine-elicited antibodies were less tolerant of sequence variation, with no substitution of residues 512-516 showing increased binding. Molecular dynamics analysis and cryo-EM structure of the naturally elicited ACS202 antibody in complex with HIV-Env trimer with A517E suggested enhanced binding to result from electrostatic interactions with positively charged antibody residues. Overall, vaccine-elicited antibodies appeared to be more fully optimized to bind the most common fusion peptide sequence.

HIGHLIGHTS

Peptide substitution scan reveals naturally elicited antibodies against fusion peptide (FP) can bind select non-canonical FP sequences with high affinity.

Peptide substitution scan data for FP antibodies correlates significantly with their differential selection indicating variation in binding relates to neutralization tolerance.

Structure and energetic analysis of naturally elicited ACS202 with HIV-Env trimer reveals basis for improved recognition of A517E mutant.

Atomic level interactions from MD simulation analysis corroborate trends observed with peptide substitutions.

verall, peptide substitution scans reveal vaccine-elicited antibodies against FP to be less permissive to FP-sequence variability than naturally elicited antibodies.
Noradrenergic tuning of arousal is coupled to coordinated movements
Authors: Li Li , Rana Akshay N. , Li Esther M. , Travis Myesa O. , Bruchas Michael R.
Published: June 2024

Matching arousal level to the motor activity of an animal is important for efficiently allocating cognitive resources and metabolic supply in response to behavioral demands, but how the brain coordinates changes in arousal and wakefulness in response to motor activity remains an unclear phenomenon. We hypothesized that the locus coeruleus (LC), as the primary source of cortical norepinephrine (NE) and promoter of cortical and sympathetic arousal, is well-positioned to mediate movement-arousal coupling. Here, using a combination of physiological recordings, fiber photometry, optogenetics, and behavioral tracking, we show that the LCNEactivation is tightly coupled to the return of organized movements during waking from an anesthetized state. Moreover, in an awake animal, movement initiations are coupled to LCNEactivation, while movement arrests, to LCNEdeactivation. We also report that LCNEactivity covaries with the depth of anesthesia and that LCNEphotoactivation leads to sympathetic activation, consistent with its role in mediating increased arousal. Together, these studies reveal a more nuanced, modulatory role that LCNEplays in coordinating movement and arousal.
3D in-situ characterization reveals the instability-induced auxetic behavior of collagen scaffolds for tissue engineering
Authors: Chen Enze , Kim Byumsu , Bouklas Nikolaos , J. Bonassar Lawrence , Gaitanaros Stavros
Published: June 2024

Collagen scaffolds seeded with human chondrocytes have shown great potential for cartilage repair and regeneration. However, these porous scaffolds buckle under low compressive forces, creating regions of highly localized deformations that can cause cell death and deteriorate the integrity of the engineered tissue. We perform three-dimensional (3D) tomography-based characterization to track the evolution of collagen scaffolds’ microstructure under large deformation. The results illustrate how instabilities produce a spatially varying compaction across the specimens, with more pronounced collapse near the free boundaries. We discover that, independent of differences in pore-size distributions, all collagen scaffolds examined displayed strong auxetic behavior i.e., their transverse area contracts under compression, as a result of the instability cascade. This feature, typically characteristic of engineered metamaterials, is of critical importance for the performance of collagen scaffolds in tissue engineering, especially regarding the persistent challenge of lateral integration in cartilage constructs.
Dissociation of novel open loop from ventral putamen to motor areas from classic closed loop in humans II: task-based function
Authors: Dundon Neil M. , Rizor Elizabeth , Stasiak Joanne , Wang Jingyi , Sabugo Kiana , Villaneuva Christina , Barandon Parker , Bostan Andreea C. , Lapate Regina C. , Grafton Scott T.
Published: June 2024

Humans ubiquitously increase the speed of their movements when motivated by incentives (i.e., capturing reward or avoiding loss). The complex interplay between incentivization and motor output is pertinent for unpacking the functional profiles of different circuits that link the basal ganglia with motor cortical areas. Here, we analyzed the functional profile of nodes forming two circuits involving putamen and motor cortical areas: the traditional “closed-loop circuit” (CLC) from sensorimotor dorsal putamen (PUTd) and a putative “open-loop circuit” (OLC) from ventral putamen (PUTv). Establishing differential function between CLC and OLC is particularly relevant for therapeutic approaches to Parkinson’s disease, where OLC function is hypothesized to be relatively spared by the disease process. In a large sample fMRI study, 68 healthy controls executed speeded reaches with a joystick under different levels of incentivization to accurately hit precision targets. We dissociated effects of “incentive per se” (i.e., changes in brain activity when an upcoming movement obtains a reward or avoids a loss) from “RT effects” (i.e., brain activity that directly scales with adjustments to movement initiation time). Incentive per se was observed across sites in both CLC and OLC. However, RT effects were primarily in nodes of the OLC and motor sites, consistent with the hypothesized anatomy and function of OLC. Our findings additionally suggest valence might mediate when incentives recruit OLC to more prominent control of motor behavior.
Sliding window functional connectivity inference with nonstationary autocorrelations and cross-correlations
Authors: Zhang Jing , Posse Stefan , Tatsuoka Curtis
Published: June 2024

Functional connectivity (FC) is the degree of synchrony of time series between distinct, spatially separated brain regions. While traditional FC analysis assumes the temporal stationarity throughout a brain scan, there is growing recognition that connectivity can change over time and is not stationary, leading to the concept of dynamic FC (dFC). Resting-state functional magnetic resonance imaging (fMRI) can assess dFC using the sliding window method with the correlation analysis of fMRI signals. Accurate statistical inference of sliding window correlation must consider the autocorrelated nature of the time series. Currently, the dynamic consideration is mainly confined to the point estimation of sliding window correlations. Using in vivo resting-state fMRI data, we first demonstrate the non-stationarity in both the cross-correlation function (XCF) and the autocorrelation function (ACF). Then, we propose the variance estimation of the sliding window correlation considering the nonstationary of XCF and ACF. This approach provides a means to dynamically estimate confidence intervals in assessing dynamic connectivity. Using simulations, we compare the performance of the proposed method with other methods, showing the impact of dynamic ACF and XCF on connectivity inference. Accurate variance estimation can help in addressing the critical issue of false positivity and negativity.
Increased Netrin downstream of overactive Hedgehog signaling disrupts optic fissure formation
Authors: Lusk Sarah , LaPotin Sarah , Presnell Jason S. , Kwan Kristen M.
Published: June 2024

Background

Uveal coloboma, a developmental eye defect, is caused by failed development of the optic fissure, a ventral structure in the optic stalk and cup where axons exit the eye and vasculature enters. The Hedgehog (Hh) signaling pathway regulates optic fissure development: loss-of-function mutations in the Hh receptorptch2produce overactive Hh signaling and can result in coloboma. We previously proposed a model where overactive Hh signaling disrupts optic fissure formation by upregulating transcriptional targets acting both cell- and non-cell-autonomously. Here, we examine the Netrin family of secreted ligands as candidate Hh target genes.

Results

We find multiple Netrin ligands upregulated in the zebrafishptch2mutant during optic fissure development. Using a gain-of-function approach to overexpress Netrin in a spatiotemporally specific manner, we find thatnetrin1aornetrin1boverexpression is sufficient to cause coloboma and disrupt wild-type optic fissure formation. We used loss-of-function alleles, CRISPR/Cas9 mutagenesis, and morpholino knockdown to test if loss of Netrin can rescue coloboma in theptch2mutant: loss ofnetringenes does not rescue theptch2mutant phenotype.

Conclusion

These results suggest that Netrin is sufficient but not required to disrupt optic fissure formation downstream of overactive Hh signaling in theptch2mutant.

Key Findings

Overactive Hedgehog signaling in theptch2mutant causes increased netrin expression

Spatiotemporally specific overexpression of netrin1a and netrin1b can cause coloboma

Spatiotemporally specific overexpression of netrin1a can disrupt optic fissure and stalk formation as well as optic stalk cell morphology, similar to theptch2mutant

Loss of netrin ligands in theptch2mutant does not rescue the phenotype
TransfoRNA: Navigating the Uncertainties of Small RNA Annotation with an Adaptive Machine Learning Strategy
Authors: Taha Yasser , Jehn Julia , Kahraman Mustafa , Frank Maurice , Heuvelman Marco , Horos Rastislav , Yau Christopher , Steinkraus Bruno , Sikosek Tobias
Published: June 2024

Small RNAs hold crucial biological information and have immense diagnostic and therapeutic value. While many established annotation tools focus on microRNAs, there are myriads of other small RNAs that are currently underutilized. These small RNAs can be difficult to annotate, as ground truth is limited and well-established mapping and mismatch rules are lacking.

TransfoRNA is a machine learning framework based on Transformers that explores an alternative strategy. It uses common annotation tools to generate a small seed of high-confidence training labels, while then expanding upon those labels iteratively. TransfoRNA learns sequence-specific representations of all RNAs to construct a similarity network which can be interrogated as new RNAs are annotated, allowing to rank RNAs based on their familiarity. While models can be flexibly trained on any RNA dataset, we here present a version trained on TCGA (The Cancer Genome Atlas) small RNA sequences and demonstrate its ability to add annotation confidence to an unrelated dataset, where 21% of previously unannotated RNAs could be annotated. Relative to its training data, TransfoRNA could boost high-confidence annotations in TCGA by ∼50% while providing transparent explanations even for low-confidence ones. It could learn to annotate 97% of isomiRs from just single examples and confidently identify new members of other familiar classes with high accuracy, while reliably rejecting false RNAs.

All source code is available athttps://github.com/gitHBDX/TransfoRNAand can be executed at Code Ocean (https://codeocean.com/capsule/5415298/). An interactive website is available atwww.transforna.com.

GRAPHICAL ABSTRACT
The Proton Resonance Enhancement for CEST imaging and Shift Exchange (PRECISE) family of RF pulse shapes for Chemical Exchange Saturation Transfer MRI
Authors: Mohanta Zinia , Stabinska Julia , Gilad Assaf A. , Barker Peter B. , McMahon Michael T.
Published: June 2024

Purpose

To optimize a 100 msec pulse for producing CEST MRI contrast and evaluate in mice.

Methods

A gradient ascent algorithm was employed to generate a family of 100 point, 100 msec pulses for use in CEST pulse trains (‘PRECISE’). Gradient ascent optimizations were performed for exchange rates (kca) = 500 s−1, 1,500 s−1, 2,500 s−1, 3,500 s−1and 4,500 s−1and offsets (Δω) = 9.6, 7.8, 4.2 and 2.0 ppm. 7 PRECISE pulse shapes were tested on an 11.7 T scanner using a phantom containing three representative CEST agents with peak saturation B1= 4 μT. The pulse producing the most contrast in phantoms was then evaluated for CEST MRI pH mapping of the kidneys in healthy mice after iopamidol administration.

Results

The most promising pulse in terms of contrast performance across all three phantoms was the 9.6 ppm, 2500 s−1optimized pulse with ∼2.7 x improvement over Gaussian and ∼1.3x’s over Fermi pulses. This pulse also displayed a large improvement in contrast over the Gaussian pulse after administration of iopamidol in live mice.

Conclusion

A new 100 msec pulse was developed based on gradient ascent optimizations which produced better contrast compared to standard Gaussian and Fermi pulses in phantoms. This shape also showed a substantial improvement for CEST MRI pH mapping in live mice over the Gaussian shape and appears promising for a wide range of CEST applications.
Changes in miRNA secondary structure can predict mutations associated with cancer and other diseases
Authors: Novev Javor K. , E. Ahnert Sebastian
Published: June 2024

MicroRNAs (miRNAs) are ubiquitous short RNAs regulating gene expression in many organisms, including humans. How the secondary structure (SS) of a mature miRNA affects its regulatory function remains an open question. Here we investigate this question through computational SS predictions of miRNA point mutants. We explore the mutational neighborhoods of miRNAs with association to human diseases, including cancer. We focus on possible SS changes independent of target-site complementarity, by leaving the seed region unchanged. We formulate metrics of the SS differences between such mutants and their wild types (WTs), and test whether these metrics predict disease association by comparing our results with the miRNASNP-v3 database. We find that disease-related mutants tend to have a higher probability of being fully unfolded than their WT; this and other SS-related measures are statistically significant at the database level. With the same approach, we identify a subset of individual miRNAs for which SS changes are most likely to predict disease-related mutations. These are hsa-miR-1269b, hsa-miR-4537, hsa-miR-4477b, hsa-miR-4641, and hsa-miR-6821-3p. In addition, we show that there are pairs of known miRNA WTs differing only by disease-related point mutations outside the seed region and exhibit very different SS. These pairs include hsa-miR-1269a—hsa-miR-1269b, and hsa-miR-3689a-3p—hsa-miR-3689b-3p.