bluuebunny/crossref_metadata_2025 huggingface dataset:
Magnetic orientation in juvenile Atlantic herring (
Clupea harengus
) could involve cryptochrome 4 as a potential magnetoreceptor
Authors: Laurien Malien , Mende Lara , Luhrmann Lena , Frederiksen Anders , Aldag Mandus , Spiecker Lisa , Clemmesen Catriona , Solov’yov Ilia A. , Gerlach Gabriele
Published: June 2024

The Earth’s magnetic field can provide reliable directional information, allowing migrating animals to orient themselves using a magnetic compass or estimate their position relative to a target using map-based orientation. Here we show for the first time that young, inexperienced herring (
Clupea harengus
, Ch) have a magnetic compass when they migrate hundreds of kilometres to their feeding grounds. In birds, such as the European robin (
Erithacus rubecula
), radical pair-based magnetoreception involving cryptochrome 4 (ErCRY4) was demonstrated; the molecular basis of magnetoreception in fish is still elusive. We show that
cry4
expression in the eye of herring is upregulated during the migratory season, but not before, indicating a possible use for migration. The amino acid structure of herring ChCRY4 shows four tryptophans and a flavin adenine dinucleotide-binding site, a prerequisite for a magnetic receptor. Using homology modelling, we successfully reconstructed ChCRY4 of herring, DrCRY4 of zebrafish (
Danio rerio
) and StCRY4 of brown trout (
Salmo trutta
) and showed that ChCRY4, DrCRY4 and ErCRY4a, but not StCRY4, exhibit very comparable dynamic behaviour. The electron transfer could take place in ChCRY4 in a similar way to ErCRY4a. The combined behavioural, transcriptomic and simulation experiments provide evidence that CRY4 could act as a magnetoreceptor in Atlantic herring.
A circle of life: platelet and megakaryocyte cytoskeleton dynamics in health and disease
Authors: Liu Haonan , Welburn Julie P. I.
Published: June 2024

Platelets are blood cells derived from megakaryocytes that play a central role in regulating haemostasis and vascular integrity. The microtubule cytoskeleton of megakaryocytes undergoes a critical dynamic reorganization during cycles of endomitosis and platelet biogenesis. Quiescent platelets have a discoid shape maintained by a marginal band composed of microtubule bundles, which undergoes remarkable remodelling during platelet activation, driving shape change and platelet function. Disrupting or enhancing this process can cause platelet dysfunction such as bleeding disorders or thrombosis. However, little is known about the molecular mechanisms underlying the reorganization of the cytoskeleton in the platelet lineage. Recent studies indicate that the emergence of a unique platelet tubulin code and specific pathogenic tubulin mutations cause platelet defects and bleeding disorders. Frequently, these mutations exhibit dominant negative effects, offering valuable insights into both platelet disease mechanisms and the functioning of tubulins. This review will highlight our current understanding of the role of the microtubule cytoskeleton in the life and death of platelets, along with its relevance to platelet disorders.
Correlated changes in stress resistance and biochemical parameters in response to long-term protein restriction in
Drosophila melanogaster
Authors: Krittika Sudhakar , Yadav Pankaj
Published: June 2024

Studies in fruit flies,
Drosophila melanogaster
, have observed considerable variation in the effect of dietary protein restriction (PR) on various fitness traits. In addition, not only are there inconsistent results relating lifespan to stress resistance, but also the long-term effects of PR are unexplored. We study PR implementation across generations (long term) hypothesizing that it will be beneficial for fitness traits, stress resistance and storage reserves due to nutritional plasticity transferred by parents to offspring in earlier
Drosophila
studies. By imposing two concentrations of PR diets (50% and 70% of control protein) from the pre-adult and adult (age 1 day) stages of the flies, we assessed the stage-specific and long-term effect of the imposed PR. All long-term PR flies showed increased resistance against the tested stressors (starvation, desiccation, H
2
O
2
-induced oxidative stress). In addition, we also found long-term PR-induced increased stress resistance across generations. The PR flies also possessed higher protein and triglyceride (TG) content, reduced glucose and unaffected glycogen levels. We also assayed the effect of returning the PR flies to control (AL) food for a single generation and assessed their biochemical parameters to witness the transient PR effect. It was seen that TG content upon reversal was similar to AL flies except for PRI70 males; however, the glucose levels of PR males increased, while they were consistently lower in females. Taken altogether, our study suggests that long-term PR implementation contributes to increased stress resistance and was found to influence storage reserves in
D. melanogaster
.
Brightness cues affect gap negotiation behaviours in zebra finches flying between perches
Authors: Borsier Emma , Sanders Helen , Taylor Graham K.
Published: June 2024

Flying animals have had to evolve robust and effective guidance strategies for dealing with habitat clutter. Birds and insects use optic flow expansion cues to sense and avoid obstacles, but orchid bees have also been shown to use brightness cues during gap negotiation. Such brightness cues might therefore be of general importance in structuring visually guided flight behaviours. To test the hypothesis that brightness cues also affect gap negotiation behaviours in birds, we presented captive zebra finches
Taeniopygia guttata
with a symmetric or asymmetric background brightness distribution on the other side of a tunnel. The background brightness conditions influenced both the birds’ decision to enter the tunnel aperture, and their flight direction upon exit. Zebra finches were more likely to initiate flight through the tunnel if they could see a bright background through it; they were also more likely to fly to the bright side upon exiting. We found no evidence of the centring response that would be expected if optic flow cues were balanced bilaterally during gap negotiation. Instead, the birds entered the tunnel by targeting a clearance of approximately one wing length from its near edge. Brightness cues therefore affect how zebra finches structure their flight when negotiating gaps in enclosed environments.
The diversity of social complexity in termites
Authors: Revely Lewis , Eggleton Paul , Clement Rebecca , Zhou Chuanyu , Bishop Tom R.
Published: June 2024

Sociality underpins major evolutionary transitions and significantly influences the structure and function of complex ecosystems. Social insects, seen as the pinnacle of sociality, have traits like obligate sterility that are considered ‘master traits’, used as single phenotypic measures of this complexity. However, evidence is mounting that completely aligning both phenotypic and evolutionary social complexity, and having obligate sterility central to both, is erroneous. We hypothesize that obligate and functional sterility are insufficient in explaining the diversity of phenotypic social complexity in social insects. To test this, we explore the relative importance of these sterility traits in an understudied but diverse taxon: the termites. We compile the largest termite social complexity dataset to date, using specimen and literature data. We find that although functional and obligate sterility explain a significant proportion of variance, neither trait is an adequate singular proxy for the phenotypic social complexity of termites. Further, we show both traits have only a weak association with the other social complexity traits within termites. These findings have ramifications for our general comprehension of the frameworks of phenotypic and evolutionary social complexity, and their relationship with sterility.
Pleiotropy alleviates the fitness costs associated with resource allocation trade-offs in immune signalling networks
Authors: Martin Reese A. , Tate Ann T.
Published: June 2024

Many genes and signalling pathways within plant and animal taxa drive the expression of multiple organismal traits. This form of genetic pleiotropy instigates trade-offs among life-history traits if a mutation in the pleiotropic gene improves the fitness contribution of one trait at the expense of another. Whether or not pleiotropy gives rise to conflict among traits, however, likely depends on the resource costs and timing of trait deployment during organismal development. To investigate factors that could influence the evolutionary maintenance of pleiotropy in gene networks, we developed an agent-based model of co-evolution between parasites and hosts. Hosts comprise signalling networks that must faithfully complete a developmental programme while also defending against parasites, and trait signalling networks could be independent or share a pleiotropic component as they evolved to improve host fitness. We found that hosts with independent developmental and immune networks were significantly more fit than hosts with pleiotropic networks when traits were deployed asynchronously during development. When host genotypes directly competed against each other, however, pleiotropic hosts were victorious regardless of trait synchrony because the pleiotropic networks were more robust to parasite manipulation, potentially explaining the abundance of pleiotropy in immune systems despite its contribution to life history trade-offs.
Impact of Cardiac Position, Morphology and Operative Technique on Long-Term Fontan Outcomes in Heterotaxy
Authors: Kadowaki Sachiko , uçar Zeynep , Fan Chun-Po Steve , Zahiri Yasmin , Yap Kok Hooi , Tocharoenchok Teerapong , Chen Weidan , Dipchand Anne I. , Honjo Osami , Barron David J.
Published: June 2024

Objectives

Heterotaxy is characterized by complex venous connections and cardiac position requiring individualized strategies for Fontan. This study aimed to assess 25-year outcomes of heterotaxy patients undergone Fontan operation, with particular focus on morphological features and surgical techniques.

Methods

82 consecutive heterotaxy patients who underwent Fontan operation from 1985 to 2021 were compared to 150 with tricuspid atresia (TA) and 144 with hypoplastic left heart syndrome (HLHS). Kaplan-Meier method and Cox proportional hazard model were used for transplant-free survival and predictor analysis.

Results

Right Atrial Isomerism (RAI) was present in 45 cases and Left Atrial Isomerism (LAI) in 37. The 20-year transplant-free survival was comparable between the groups (RAI vs. LAI, 76% [95% confidence interval, 57-87%] vs. 68% [47-82%], p=0.22). Techniques were extracardiac in 66%, intra-atrial conduit in 9%, lateral tunnel in 18%. More intervention on pulmonary veins occurred in the RAI group. Cardiac position and apicocaval juxtaposition did not influence outcome. The IVC-contralateral PA Fontan was associated with 100% survival, while the IVC-ipsilateral PA Fontan at the side of the cardiac apex showed 67% [34-87%] survival at 20 years. Moderate or severe ventricular dysfunction at 20 years was found in 15% (6-39%) and 0% of RAI and LAI patients among hospital survivors, respectively (p=0.09). In-hospital mortality was higher in heterotaxy (9.8% [5-19%]) compared to TA (1.3% [0.3-5.3%], p<.01) and HLHS (2.8% [1.1-7.3%], p=0.02). There was no in-hospital death after 2000 in any of groups. The 20-year transplant-free survival in heterotaxy (72% [59-82%]) was worse than that in TA (95% [89-97%], p<0.001) but was not significantly different from that in HLHS (80% [69-87%], p=0.11). Reintervention rate at 20 years was significantly higher in heterotaxy (18% [11-29%]) vs. HLHS (8% [4-16%]) (p=0.01). Ventricular dysfunction was a predictor for death (univariate p<0.001).

Conclusion

Various routing techniques can be successfully applied to overcome the anatomical challenges of heterotaxy. Although higher in-hospital mortality and reintervention rate were found in heterotaxy in the early era, overall survival post Fontan was similar to that in HLHS. RAI had comparable survival to LAI with greater proportion requiring pulmonary vein intervention at time of Fontan.
Rates of biome shift predict diversification dynamics in flowering plants
Authors: Boyko James D. , Vasconcelos Thais
Published: June 2024

The remarkable diversity of angiosperm species has prompted a search for universal drivers that modulate rates of speciation and extinction across this clade. To date, attempts to explain differences in species diversity have focused on the potential correlation of diversification rates with particular key traits.However, an often-overlooked explanation is that evolutionary lability, here defined as the rates of trait change, is a better predictor of the diversification dynamics than the observed traits themselves. This hypothesis, first proposed in the context of biome shifts 50 years ago, is based on the idea that the capacity to adapt to environmental changes is the key element defining angiosperm diversification dynamics. Using a phylogenetic dataset of 49 angiosperm clades including 18,617 species we demonstrate that the propensity of change between open and closed-canopy biomes is significantly correlated with lineage speciation and extinction rates across clades. Additionally, we find that transition rates tend to be faster from open to closed-canopy biomes. This results in ancestral state estimates that favor several deep time origins of open-canopy biomes, contrary to prevailing ideas that lineages occurring in open-canopy biomes tend to emerge from closed-canopy ones in angiosperms. We propose that a shift in focus from static traits to dynamic evolutionary processes may provide a more comprehensive understanding into how biodiversity is generated and maintained, in angiosperms and other organisms.
ULTRA-Effective Labeling of Repetitive Genomic Sequence
Authors: Olson Daniel R , Wheeler Travis J
Published: June 2024

In the age of long read sequencing, genomics researchers now have access to accurate repetitive DNA sequence (including satellites) that, due to the limitations of short read sequencing, could previously be observed only as unmappable fragments. Tools that annotate repetitive sequence are now more important than ever, so that we can better understand newly uncovered repetitive sequences, and also so that we can mitigate errors in bioinformatic software caused by those repetitive sequences. To that end, we introduce the 1.0 release of our tool for identifying and annotating locally-repetitive sequence, ULTRA (ULTRA Locates Tandemly Repetitive Areas). ULTRA is fast enough to use as part of an efficient annotation pipeline, produces state-of-the-art reliable coverage of repetitive regions containing many mutations, and provides interpretable statistics and labels for repetitive regions. It released under an open license, and available for download at https://github.com/TravisWheelerLab/ULTRA.
The Inner Ear and Aging Brain: A Cross-Sectional Study of Vestibular Function and Morphometric Variations in the Entorhinal and Trans-Entorhinal Cortex
Authors: Vania Claire , Padova Dominic , Ratnanather J. Tilak , Agrawal Yuri
Published: June 2024

While the vestibular system is widely known for helping to maintain balance, posture, and stable vision, mounting research has also demonstrated its importance in cognition and aging. Recent studies have found that peripheral vestibular loss is significantly associated with deficits in spatial cognitive function in older adults. However, the exact neural pathways through which vestibular loss affects spatial cognitive ability in older adults are unknown. Clinical and subclinical studies have shown that vestibular loss is associated with structural and functional alterations in the spatial cognitive network. Yet, studies on the entorhinal cortex (ERC) and trans-entorhinal cortex (TEC)—two key cortical regions in the vestibular spatial cognitive network—are scarce. This cross-sectional study examines the relationship between vestibular end-organ function and morphometric changes in the ERC and TEC. We used a subset of 103 patients from the Baltimore Longitudinal Study for Aging who had T1-weighted MRI and vestibular physiological data during the same visit to investigate the relationship between age-related vestibular function and the shape of the ERC and TEC. The vestibular end-organ function was evaluated through the cervical vestibular-evoked myogenic potential (cVEMP) test to assess saccular function, the ocular VEMP (oVEMP) test to evaluate the utricular function, and the video head-impulse test (vHIT) to assess semicircular canal function based on vestibular ocular reflex (VOR). Shape alterations were evaluated in terms of surface expansion/contraction relative to the average ERC or TEC shape. Reduced saccular function was associated with surface expansion in the pro-rhinal region of the left ERC, which is hypothesized to be involved in spatial cognitive function, in the intermediate caudal and intermediate superior regions of the right ERC, and the sulcal region of the right TEC. Reduced utricular function was associated with surface contraction in the left lateral TEC and the anterior sulcal and transentorhinal regions of the left ERC, and surface expansion in the lateral region of the left ERC. Reduced canal function is predominantly associated with surface contraction in the pro-rhinal and lateral regions of the right ERC and with posterior sulcal and transentorhinal regions of the right TEC. These end-organ-specific and differential findings highlight the complex relationship between vestibular function and the shapes of the ERC and TEC, key regions that subserve spatial cognitive ability and other crucial cognitive abilities. Future work will determine whether these structural alterations related to vestibular loss may underlie the observed deficits in spatial cognitive ability in older adults and Alzheimer’s disease.
Communicating cancer treatment with pictogram-based timeline visualizations
Authors: Jambor Helena Klara , Ketges Julian , Otto Anna Lea , von Bonin Malte , Trautmann-Grill Karolin , Teipel Raphael , Middeke Jan Moritz , Uhlig Maria , Eichler Martin , Pannasch Sebastian , Bornhäuser Martin
Published: June 2024

Objective

This study evaluated the legibility, comprehension, and clinical usability of visual timelines for communicating cancer treatment paths. We examined how these visual aids enhance participants and patient understanding of their treatment plans.

Materials and Methods

The study included two online surveys and one in-person survey with hematology cancer patients. The online surveys involved 306 and 160 participants respectively, while the clinical evaluation included 30 patients (11 re-surveyed) and 24 medical doctors. Participants were assessed on their ability to understand treatment paths provided with audio information alone or with visual aids. The study also evaluated the comprehension of key treatment terms and the ability of patients to recall their cancer treatment paths.

Results

Visual representations effectively communicated treatment terms, with 7 out of 8 terms achieving over 85% transparency as pictograms, compared to 5 out of 8 for comics and 4 out of 8 for photos. Visual treatment timelines improved response quality, increased confidence, and were rated higher in information quality than audio-only information. In the clinical evaluation, patients showed good comprehension (mean response quality: 0.82) and recall (mean response quality: 0.71 after several weeks), and both patients and physicians found the visual aids helpful.

Discussion

We discuss that visual timelines enhance patient comprehension and confidence in cancer communication. We also discuss limitations of the online surveys and clinical evaluation. The importance of accessible visual aids in patient consultations is emphasized, with potential benefits for diverse patient populations.

Conclusion

Visual aids in the form of treatment timelines improve the legibility and comprehension of cancer treatment paths. Both patients and physicians support integrating these tools into cancer treatment communication.
Exploring pathways to compulsory detention in psychiatric hospital and ways to prevent repeat detentions; Service user perspectives
Authors: Birken Mary , Kular Ariana , Nyikavaranda Patrick , Parkinson Jordan , Mitchell Lizzie , Fraser Kathleen Lindsay , White Valerie Christina , Seale Janet , Hardy Jackie , Stone Cady , Holden Mark Keith , Elliott Tyler , Li Zishi , Mbeah-Bankas Henrietta , Wood Lisa , Lobban Fiona , Lloyd-Evans Brynmor , Johnson Sonia
Published: June 2024

Purpose

This study, co-produced by a team of academics, lived experience researchers and clinicians, explores the views and experiences of people who have been compulsorily detained in hospital under the Mental Health Act (1983) (MHA) in England, to understand how and why, from their perspective, compulsory detentions occur, and what might help prevent them.

Methods

Semi-structured qualitative interviews were conducted with 20 people (55% male, 40% Black/Black British, 30% White British) who had been compulsory detained in hospital within the past 5 years. Lived experience researchers with relevant personal experience carried out interviews via telephone or videoconference and participated in analysis of data via a template approach.

Results

We derived three over-arching themes from interviews. The first theme “Individual factors increasing or reducing likelihood of being detained” encompassed factors related to people’s own lives and attitudes, including life stressors, not taking medication, the risk individuals may pose to themselves or others, and their attitude to and management of their mental health. The second theme “Family and Support Network” reflects how attitudes and support from family, friends and support network may contribute to compulsory detentions or support people to stay well. The third theme “Need for improvement in Service Responses” identified limitations of services that contribute to detention, including lack of collaborative care and choice, poor quality of professional support, and discriminatory attitudes from staff. Each theme also included potential approaches to addressing these limitations and reducing compulsory detentions.

Conclusion

Findings suggest multiple interacting factors may lead to people being detained in hospital under the MHA, and that improvements to services, such as increasing collaborative care and service user-led family involvement, could prevent further detentions.
Risk of Heart Failure among Individuals with Metabolic Syndrome Components
Authors: Lamichhane Rajan , Bharti Vijay , Lamichhane Aarshi R , Zaheer Kamran
Published: June 2024

Metabolic dysfunction of metabolic syndromes (MetS) has been widely reported to be a significant risk factor for heart failure (HF). While this interaction is well studied, what combinations of MetS factors pose the greatest risk for HF are not well defined. We hypothesize that some components of MetS are of higher risk of HF compared to others. We explored the relationship between the independent components of MetS and their combinatory effect on the risk of HF. All metabolic syndrome components except hypertriglyceridemia were significant individually (P-value<0.001), while hypertension (HTN) and diabetes or insulin resistance (IR) had the higher risk of developing heart failure when taken collectively. The odds of heart failure among the individuals who had HTN and IR was 7.7 times those who didn’t have any MetS components. We observed the additive effect of number of metabolic components on HF, for the individuals who had only one MetS symptom, the odd of HF was 5.4 time compared to those who didn’t have any of MetS symptoms. Similarly, these odds of HF were 6.4 and 7.4 times for those who had at least 2 or at least 3 symptoms respectively. Even though obesity is a significant risk factor for cardiovascular diseases, we found the protective effect of obesity on heart failure, which is an interesting result and needs further investigation.
Efficient generation of human dendritic cells from iPSC by introducing a feeder-free expansion step for hematopoietic progenitors
Authors: Elahi Zahra , Jameson Vanta , Sakkas Magdaline , Butcher Suzanne K , Mintern Justine D , Radford Kristen J , Wells Christine A
Published: June 2024

Dendritic cells (DCs) are rare innate immune cells that are essential regulators of anti-tumour, anti-viral and vaccine responses by the adaptive immune system. Conventional dendritic cells, particularly the cDC1 subset, are most desired for DC-based immunotherapies, however, it can be difficult to isolate sufficient numbers of primary cells from patients. The most common alternate sources of DC areex vivo, such as monocyte-derived or DC expanded from cord blood hematopoietic progenitors. Induced pluripotent stem cells (iPSC) offer a promising solution, providing an opportunity forin vitrogenerating DCs that are suitable for patient-derived or off-the-shelf batch-manufactured cells. Here, we developed anin vitroprotocol designed to maximise the yield of iPSC-derived DC progenitors, with the specific goal of generating DC1-like cells. The iPSC-DCs subsets generated by our method could be partitioned by cell surface phenotypes of cDC1, cDC2 and DC3, but they were most transcriptionally similar to monocyte-derived DC (MoDC). Stimulated iPSC-DCs generated pro-inflammatory cytokines, expressed migratory chemokine receptors including CCR7 which indicates capacity to traffic through lymphatic endothelium, and upregulated co-stimulatory molecules, indicating their potential for productive interactions with T-cells. This method offers a promising step towards an expandable source of allogeneic human dendritic cells for future applications.
Improved determination of protein turnover rate with heavy water labeling by mass isotopomer ratio selection
Authors: Currie Jordan , Ng Dominic C. M. , Pandi Boomathi , Black Alexander , Manda Vyshnavi , Pavelka Jay , Lam Maggie P. Y. , Lau Edward
Published: June 2024

The synthesis and degradation rates of proteins form an essential component of gene expression control. Heavy water labeling has been used in conjunction with mass spectrometry to measure protein turnover rates, but the optimal analytical approaches to derive turnover rates from the isotopomer patterns of deuterium labeled peptides continue to be a subject of research. Here we describe a method, which comprises a reverse lookup of numerically approximated peptide isotope envelopes, coupled to the selection of optimal isotopomer pairs based on peptide sequence, to calculate the molar fraction of new peptide synthesis in heavy water labeling mass spectrometry experiments. We validated this approach using an experimental calibration curve comprising mixtures of fully unlabeled and fully labeled proteomes. We then re-analyzed 17 proteome-wide turnover experiments from four mouse organs, and showed that the method increases the coverage of well-fitted peptides in protein turnover experiments by 25–82%. The method is implemented in the Riana software tool for protein turnover analysis, and may avail ongoing efforts to study the synthesis and degradation kinetics of proteins in animals on a proteome-wide scale.

What’s new

We describe a reverse lookup method to calculate the molar fraction of new synthesis from numerically approximated peptide isotopomer profiles in heavy water labeling mass spectrometry experiments. Using an experimental calibration curve comprising mixtures of fully unlabeled and fully labeled proteomes at various proportions, we show that this method provides a straightforward way to calculate the proportion of new proteins in a protein pool from arbitrarily chosen isotopomer ratios. We next analyzed which of the isotopomer pairs within the peptide isotope envelope yielded isotopomer time courses that fit most closely to kinetic models, and found that the identity of the isotopomer pair depends partially on the number of deuterium accessible labeling sites of the peptide. We next derived a strategy to automatically select the isotopomer pairs to calculate turnover rates based on peptide sequence, and showed that this increases the coverage of existing proteome-wide turnover experiments in multiple data sets of the mouse heart, liver, kidney, and skeletal muscle by up to 25–82%.
The node of Ranvier influences thein vivoaxonal transport of mitochondria and signalling endosomes
Authors: Tosolini Andrew P. , Abatecola Federico , Negro Samuele , Sleigh James N. , Schiavo Giampietro
Published: June 2024

Efficient long-range axonal transport is essential for maintaining neuronal function, and perturbations in this process underlie severe neurological diseases. We have previously demonstrated that signalling endosomes are transportedin vivoat comparable speeds across motor neurons (MNs) innervating different hindlimb muscles, as well as between forelimb and hindlimb peripheral nerves. In contrast, axonal transport is faster in MNs compared to sensory neurons innervating the same muscle. Found periodically across the myelin sheath, Nodes of Ranvier (NoR) are short uncovered axonal domains that facilitate action potential propagation. Currently, it remains unresolved how the distinct molecular structures of the NoR impact axonal transport dynamics. Here, using intravital time-lapse microscopy of sciatic nerves in live, anaesthetised mice, we assessed diverse organelle dynamics at the NoR. We first observed that axonal morphologies were similar between fast and slow MNs, and found that signalling endosomes and mitochondria accumulate on the distal side of the NoR in both motor neuron subtypes. Assessment of axonal transport of signalling endosomes and mitochondria revealed a decrease in velocity and increase in pausing as the organelles transit through the NoR, followed by an increase in speed in the adjacent intranodal region. Collectively, this study has established axonal transport dynamics of two independent organelles at the NoRin vivo, and has relevance for several pathologies affecting peripheral nerves and the NoR, such as peripheral neuropathy, motor neuron diseases, and/or multiple sclerosis.
The AID2 system offers a potent tool for rapid, reversible, or sustained degradation of essential proteins in live mice
Authors: Sladky Valentina C , Strong Margaret A , Tapias-Gomez Daniel , Jewett Cayla E , Drown Chelsea G , Scott Phillip M , Holland Andrew J
Published: June 2024

Studying essential genes required for dynamic processes in live mice is challenging as genetic perturbations are irreversible and limited by slow protein depletion kinetics. The first-generation auxin-inducible-degron (AID) system is a powerful tool for analyzing inducible protein loss in cultured cells. However, auxin administration is toxic to mice, preventing its long-term use in animals. Here, we use an optimized second-generation AID system to achieve the conditional and reversible loss of the essential centrosomal protein CEP192 in live mice. We show that the auxin derivative 5-Ph-IAA is well tolerated over two weeks and drives near-complete CEP192-mAID degradation in less than one hourin vivo. Prolonged CEP192 loss led to cell division failure and cell death in proliferative tissues. Thus, the second-generation AID system is well suited for rapid and/or sustained protein depletion in live mice, offering a valuable new tool for interrogating protein functionin vivo.
Diet predicts performance trade-offs along Atlantic salmon ontology
Authors: Aykanat Tutku , Jacobsen Jan Arge , Hindar Kjetil
Published: June 2024

Understanding the mechanistic basis of life history divergence is fundamental for predictive ecology. Variation in resource use impacts life history divergence and provides a framework for studying life history trade-offs. Contrary to the theory, empirical evidence does not support that resource allocation alone mediates life history divergence in the wild, which subsequently suggests a pivotal role for resource acquisition, but this has not been empirically demonstrated in free-living populations. Here, we sampled wild Atlantic salmon (Salmo salar) from different age groups during their marine feeding stage and hypothesized that prey taxa (consumption of crustaceansversusfish) has an age-dependent effect on the condition factor. We found salmon in their first year at sea had a higher condition factor when foraging on larger numbers of crustaceans and a lower condition factor when foraging on larger numbers of fish, andvice versain older sea age groups, a result that supported our hypothesis. Provided that condition factor is a predictor of age-at-maturity, our results show that resource acquisition may be an important process shaping life history variation in Atlantic salmon via modulating age-dependent performance trade-offs. Our results also emphasize the importance of bottom-up trophic cascades for maturation age and help to better predict the maturation dynamics of wild populations in the marine environment.
Trigeminal ganglion and tooth innervation modifications following genetic and pharmacological Nogo-A inhibition
Authors: Pirenne Laurence , Balic Anamaria , Santis Ilaria De , Bevilacqua Alessandro , Lai Chai Foong , Pagella Pierfrancesco , Schwab Martin E. , Mitsiadis Thimios A.
Published: June 2024

Nogo-A is a major regulator of neural development and regeneration, but its role in tooth innervation remains largely unknown. Neurons from trigeminal ganglia support teeth homeostasis and regeneration, and disorders of their function could have significant pathophysiological consequences. In this study, we show that Nogo-A is expressed in the trigeminal ganglia and in the neurons innervating the teeth, and that its deletion affects both the number and patterning of neurons in teeth. In organotypic cultures, Nogo-A blocking antibodies affect the trigeminal ganglia-derived neuronal outgrowths and allow premature innervation of tooth germs. RNA sequencing analysis revealed that Nogo-A deletion induces alterations linked to functions at synapses and interference with neurotrophin signalling during the differentiation and maturation of trigeminal neurons. Taken together, these results reveal for the first time the importance of Nogo-A as a major regulator of tooth innervation and point to its potential as a clinical therapeutic target.
Discovery and mechanistic characterization of a probiotic-origin 3β-OH-Δ5-6-cholesterol-5β-reductase directly converting cholesterol to coprostanol
Authors: Netter Urmila , Bisht Vishakha , Gaurav Amit , Sharma Rekha , Ghosh Avik , Bisht Vinod Singh , Ambatipudi Kiran , Sharma Hanuman Prasad , Mohanty Sujata , Loat Shubham , Sarkar Mihir , Tahlan Kapil , Navani Naveen K
Published: June 2024

On the one hand, cholesterol is a foundational molecule for various structural and biochemical pathways, while elevated cholesterol levels are associated with cardiovascular diseases. Some selected strains of Lactobacilli are also known for modulating cholesterol levels. However, the molecular mechanism of cholesterol transformation by lactobacilli has remained challenging to reveal. This study reports the discovery and role of a microbial 3β-OH-Δ5-6-cholesterol-5β-reductase fromLimosilactobacillus fermentumNKN51, which directly converts cholesterol to coprostanol, thereby resolving the enigma. Protein engineering of the reductase enzyme identified the cholesterol and NADP+interacting amino acids, detailing the catalytic mechanism of 5βChR. Phylogenetic studies emphasize the abundance of 5βChRs in gut commensal lactobacilli, which shares a common ancestor with plant 5β reductases. Meta-analysis results of healthy participant microbiomes underline the significance of 5βChR homologs, while a cohort study reveals an association between higher 5βChR abundance and diabetes. The discovery of the 5βChR enzyme and its molecular mechanism in cholesterol metabolism pave the way for a better understanding of the gut-associated microbiome and the design of practical applications to ameliorate dyslipidemia.
OSBA: An open neonatal neuroimaging atlas and template for spina bifida aperta
Authors: Speckert Anna , Ji Hui , Payette Kelly , Grehten Patrice , Kottke Raimund , Ackermann Samuel , Padden Beth , Mazzone Luca , Moehrlen Ueli ,   SPINA BIFIDA STUDY GROUP ZURICH, Jakab Andras
Published: June 2024

We present the Open Spina Bifida Aperta (OSBA) atlas, an open atlas and set of neuroimaging templates for spina bifida aperta (SBA). Traditional brain atlases may not adequately capture anatomical variations present in pediatric or disease-specific cohorts. The OSBA atlas fills in this gap by representing the computationally averaged anatomy of the neonatal brain with SBA after fetal surgical repair. The OSBA atlas was constructed using structural T2-weighted and diffusion tensor MRI of 28 newborns with SBA who underwent prenatal surgical correction. The corrected gestational age at MRI was 38.1 ± 1.1 weeks (mean ± SD). The OSBA atlas consists of T2-weighted and fractional anisotropy templates, along with 9 tissue prior maps and region of interest (ROI) delineations. The OSBA atlas offers a standardized reference space for spatial normalization and anatomical ROI definition. Our image segmentation and cortical ribbon definition is based on a human-in-the-loop approach including manual segmentation. The precise alignment of the ROIs was achieved by a combination of manual image alignment and automated, non-linear image registration. By providing a dedicated neonatal atlas for SBA, we enable more accurate spatial standardization and support advanced analyses such as diffusion tractography and connectomic studies in newborns affected by this condition.
A history-dependent integrase recorder of plant gene expression with single cell resolution
Authors: Maranas Cassandra J. , George Wesley , Scallon Sarah K. , VanGilder Sydney , Nemhauser Jennifer L. , Guiziou Sarah
Published: June 2024

During development, most cells experience a progressive restriction of fate that ultimately results in a fully differentiated mature state. Understanding more about the gene expression patterns that underlie developmental programs can inform engineering efforts for new or optimized forms. Here, we present a four-state integrase-based recorder of gene expression history and demonstrate its use in tracking gene expression events in Arabidopsis thaliana in two developmental contexts: lateral root initiation and stomatal differentiation. The recorder uses two serine integrases to mediate sequential DNA recombination events, resulting in step-wise, history-dependent switching between expression of fluorescent reporters. By using promoters that express at different times along each of the two differentiation pathways to drive integrase expression, we successfully tied fluorescent status to an ordered progression of gene expression along the developmental trajectory. In one snapshot of a mature tissue, our recorder was able to reveal past gene expression with single cell resolution. In this way, we were able to capture heterogeneity in stomatal development, confirming the existence of two alternate paths of differentiation.
LCN2 promotes focal adhesion formation and invasion by stimulating Src activation
Authors: Choudhary Bhagya Shree , Chaudhary Nazia , Vijan Aditi , Mandal Dibita , Pilankar Leena , Gawand Shubham , Khan Bushra K. , Shivashankar Anusha , Doloi Rinki , Joshi Neha , Das Manjula , Dalal Sorab N.
Published: June 2024

Previous work has demonstrated that Lipocalin2 (LCN2) expression promotes invasion and migration in multiple tumor types. The mechanisms by which LCN2 promotes invasion and migration remain unclear. Previous work from our laboratory demonstrated that LCN2 promotes actin filament formation by inhibiting actin glutathionylation. In this report, we demonstrate that in addition to inhibiting actin glutathionylation, LCN2 stimulates invasion by promoting the formation of focal adhesions, which is independent of the ability of LCN2 to bind iron. LCN2 promotes focal adhesion formation by promoting the activation of c-Src by stimulating the expression of the transcription factor ETS1. ETS1 activates the expression of the protein phosphatase, PTP1B, resulting in the auto-activation of c-Src and increased paxillin phosphorylation leading to focal adhesion formation. These results demonstrate that LCN2 has iron-dependent and independent functions in promoting invasion and highlight the multiple mechanisms by which LCN2 promotes invasion and suggest that c-Src inhibitors could be used to treat invasive colorectal cancer.

Expression of LCN2 is elevated in invasive colorectal cancer. We demonstrate that LCN2 promotes invasion by stimulating the formation of focal adhesions by promoting Src activation.
Conformational dynamics of electrostatically charged Intrinsically Disordered Proteins
Authors: Schwarz Simon , Sarkar Subhartha , Sakhapov Damir , Enderlein Jörg , Sturm Anja , Wardetzky Max
Published: June 2024

We experimentally and computationally study the dynamics of homogeneously electrically charged intrinsically disordered proteins (IDPs) in ionic solutions (aqueous solutions containing salt). Computationally, this is achieved by extending a recently introduced discrete elastic rod (DER) model to include electrostatic interactions. The respective model includes only three free parameters: bending stiffness, bond length, and hydrodynamic radius. These parameters were obtained by fitting the measured conformational dynamics of uncharged polypeptides as reported in a previous publication [8]. We compare our computational results with photo-electron transfer fluorescence correlation spectroscopy (PET-FCS) measurements of the conformational dynamics of the highly charged (-44 e−) intrinsically disordered protein Prothymosin α. We here report on an agreement between the loop-closing rates obtained from our computational model and the respective experimental measurements, with rate values significantly slower than those observed for uncharged IDPs.
Deep long-read metagenomic sequencing reveals niche differentiation in carbon cycling potential between benthic and planktonic microbial populations
Authors: Viver Tomeu , Knittel Katrin , Amann Rudolf , Orellana Luis H.
Published: June 2024

Coastal marine sediments function as large-scale natural biocatalytic filters, remineralizing and transforming organic matter. Benthic microbiomes exhibit remarkable temporal stability, contrasting with the dynamic, substrate-driven successions of bacterioplankton. Nonetheless, understanding their role in carbon cycling and interactions between these microbial groups is limited due to the complexity of benthic microbiomes. Here, we used a seasonally resolved, deep short- and long-read metagenomic approach to examine distinctive genomic features of microbiomes recovered from sediment, the overlaying water column, and particle-attached bacteria and archaea in the North Sea. We recovered 115 benthic metagenome-assembled genomes (MAGs) that belonged toWoeseiales,Rhizobiales,Planctomycetia,Gemmatimonadota, andDesulfobacterotaspecies. WhileProteobacteriaandActinobacteriotawere characteristic phyla of sediments,AcidimicrobiiaandDesulfocapsaceaespecies were shared between sediments and particle-attached fractions of the water column, indicative of significant bentho-pelagic coupling. Predominant members of the familyWoeseiaceaecarried polysaccharide utilization loci (PULs) predicted to target laminarin, alginate, and α-glucan in sediments. In contrast, water column species lacked PULs and encoded a significantly higher fraction of sulfatases and peptidases, indicating a role in the degradation of protein-rich and sulfated organic matter. Our findings disentangle family-level adaptations and niche differentiation between globally significant benthic and water column populations involved in marine organic matter degradation and carbon storage.
Arid1bhaploinsufficiency in pyramidal neurons causes cellular and circuit changes in neocortex but is not sufficient to produce behavioral or seizure phenotypes
Authors: Marshall Alec H. , Hanson Meretta A. , Boyle Danielle J. , Nagarajan Devipriyanka , Bibi Noor , Fitzgerald Julie , Gaitten Emilee , Kokiko-Cochran Olga N. , Gu Bin , Wester Jason C.
Published: June 2024

Arid1bis a high confidence risk gene for autism spectrum disorder that encodes a subunit of a chromatin remodeling complex expressed in neuronal progenitors. Haploinsufficiency causes a broad range of social, behavioral, and intellectual disability phenotypes, including Coffin-Siris syndrome. Recent work using transgenic mouse models suggests pathology is due to deficits in proliferation, survival, and synaptic development of cortical neurons. However, there is conflicting evidence regarding the relative roles of excitatory projection neurons and inhibitory interneurons in generating abnormal cognitive and behavioral phenotypes. Here, we conditionally knocked out either one or both copies ofArid1bfrom excitatory projection neuron progenitors and systematically investigated the effects on intrinsic membrane properties, synaptic physiology, social behavior, and seizure susceptibility. We found that disruptingArid1bexpression in excitatory neurons alters their membrane properties, including hyperpolarizing action potential threshold; however, these changes depend on neuronal subtype. Using paired whole-cell recordings, we found increased synaptic connectivity rate between projection neurons. Furthermore, we found reduced strength of excitatory synapses to parvalbumin (PV)-expression inhibitory interneurons. These data suggest an increase in the ratio of excitation to inhibition. However, the strength of inhibitory synapses from PV interneurons to excitatory neurons was enhanced, which may rebalance this ratio. Indeed,Arid1bhaploinsufficiency in projection neurons was insufficient to cause social deficits and seizure phenotypes observed in a preclinical germline haploinsufficient mouse model. Our data suggest that while excitatory projection neurons likely contribute to autistic phenotypes, pathology in these cells is not the primary cause.
The protamines of the noble false widow spiderSteatoda nobilisprovide an example of liquid-liquid phase separation chromatin transitions during spermiogenesis
Authors: Leyden Melissa R. , Michalik Peter , Baruffaldi Luciana , Mahmood Susheen , Kalani Ladan , Hunt Donald F. , Eirin-Lopez Jose Maria , Andrade Maydianne C.B. , Shabanowitz Jeffrey , Ausió Juan
Published: June 2024

While there is extensive information about sperm nuclear basic proteins (SNBP) in vertebrates, there is very little information about Arthropoda by comparison. This paper aims to contribute to filling this gap by analyzing these proteins in the sperm of the noble false widow spiderSteatoda nobilis(Order Araneae, Family Theridiidae). To this end, we have developed a protein extraction method that allows the extraction of cysteine-containing protamines suitable for the preparation and analysis of SNBPs from samples where the amount of starting tissue material is limited. We carried out top-down mass spectrometry sequencing and molecular phylogenetic analyses to characterize the protamines ofS. nobilisand other spiders. We also used electron microscopy to analyze the chromatin organization of the sperm, and we found it to exhibit liquid-liquid phase spinodal decomposition during the late stages of spermiogenesis. These studies further our knowledge of the distribution of SNBPs within the animal kingdom and provide additional support for a proposed evolutionary origin of many protamines from a histone H1 (H5) replication-independent precursor.