bluuebunny/crossref_metadata_2025 huggingface dataset:
Pelvic Ring Fractures: Does Spinopelvic Alignment Affect Sacral and Lumbopelvic Fixation Stability?
Authors: Tripathi Sudharshan , Kumaran Yogesh , Soehnlen Sophia M. , Kelkar Amey , Seki Toshihiro , Sakai Takashi , Goel Vijay , Quatman Carmen E. , Nishida Norihiro
Published: October 2024

Background Context

Pelvic ring is a complex boney and ligamentous complex and its structural integrity is paramount to be able to withstand the high forces. Pelvic ring fractures, which can result from low-energy impacts or high-velocity injuries and falls from great heights, can severely impair the structural integrity of the pelvic ring. These injuries can be fatal, especially in geriatric patients, with mortality rates ranging between 10% and 16%. Pelvic ring injuries require immediate stabilization, typically performed through internal fixation, to maintain circulatory balance and achieve anatomical restoration of the pelvis.

Methods

A previously validated FE model of the spine, pelvis, and femur model was used to evaluate how different fixation techniques for pelvic ring injury affect spinopelvic biomechanics. The SS, PI, PT and LL of the normal, intact model was modified to generate two more SS models for this study. One modified model with an SS of 20º was considered the low SS model (SSD), while the second modified model with an SS of 32º was termed the high SS model (SSI). A unilateral pelvic ring fracture was simulated by resecting the left side of the sacrum and pelvis. The fractures were stabilized using two different posterior stabilization techniques 1) The fractures were stabilized using two different posterior stabilization techniques, and 2) L5-Ilium posterior screw fixation without cross connector (L5_PF_WO_CC).

Results

SSI demonstrated the higher range of motion, followed by Normal model and least by SSD model at right Sacroiliac Joint. No differences were seen between with and without cross connector model for range of motion at right SIJ. For L5-S1 motion models treated with cross connectors demonstrated the least motion compared to those treated without cross connectors for all configurations and loading conditions. For the sacrum fracture, models with high sacral slopes recorded the least horizontal displacement, followed by decreased sacral slope models for both configurations and loading conditions.
ProtNote: a multimodal method for protein-function annotation
Authors: Char Samir , Corley Nathaniel , Alamdari Sarah , Yang Kevin K. , Amini Ava P.
Published: October 2024

Understanding the protein sequence-function relationship is essential for advancing protein biology and engineering. However, fewer than 1% of known protein sequences have human-verified functions. While deep learning methods have demonstrated promise for protein function prediction, current models are limited to predicting only those functions on which they were trained. Here, we introduce ProtNote, a multimodal deep learning model that leverages free-form text to enable both supervised and zero-shot protein function prediction. ProtNote not only maintains near state-of-the-art performance for annotations in its train set, but also generalizes to unseen and novel functions in zero-shot test settings. We envision that ProtNote will enhance protein function discovery by enabling scientists to use free text inputs, without restriction to predefined labels – a necessary capability for navigating the dynamic landscape of protein biology.
Protein catabolites as blood-based biomarkers of aging physiology: Findings from the Dog Aging Project
Authors: Harrison Benjamin R. , Partida-Aguilar Maria , Marye Abbey , Djukovic Danijel , Kauffman Mandy , Dunbar Matthew D. , Mariner Blaise L. , McCoy Brianah M. , Algavi Yadid M. , Muller Efrat , Baum Shiri , Bamberger Tal , Raftery Dan , Creevy Kate E. ,   Dog Aging Project Consortium, Avery Anne , Borenstein Elhanan , Snyder-Mackler Noah , Promislow Daniel E.
Published: October 2024

Our understanding of age-related physiology and metabolism has grown through the study of systems biology, including transcriptomics, single-cell analysis, proteomics and metabolomics. Studies in lab organisms in controlled environments, while powerful and complex, fall short of capturing the breadth of genetic and environmental variation in nature. Thus, there is now a major effort in geroscience to identify aging biomarkers and to develop aging interventions that might be applied across the diversity of humans and other free-living species. To meet this challenge, the Dog Aging Project (DAP) is designed to identify cross-sectional and longitudinal patterns of aging in complex systems, and how these are shaped by the diversity of genetic and environmental variation among companion dogs. Here we surveyed the plasma metabolome from the first year of sampling of the Precision Cohort of the DAP. By incorporating extensive metadata and whole genome sequencing information, we were able to overcome the limitations inherent in breed-based estimates of genetic and physiological effects, and to probe the physiological and dietary basis of the age-related metabolome. We identified a significant effect of age on approximately 40% of measured metabolites. Among other insights, we discovered a potentially novel biomarker of age in the post-translationally modified amino acids (ptmAAs). The ptmAAs, which can only be generated by protein hydrolysis, covaried both with age and with other biomarkers of amino acid metabolism, and in a way that was robust to diet. Clinical measures of kidney function mediated about half of the higher ptmAA levels in older dogs. This work identifies ptmAAs as robust indicators of age in dogs, and points to kidney function as a physiological mediator of age-associated variation in the plasma metabolome.
Self-pruning in tree crowns is influenced by functional strategies and neighborhood interactions
Authors: Kothari Shan , Urgoiti Jon , Messier Christian , Keeton William S. , Paquette Alain
Published: October 2024

As canopy closure causes forest stands to face increasing light limitation, trees’ lower branches begin to die back. This process, called self-pruning, defines a crown’s base and depth and shapes the structure of entire stands. Self-pruning is often thought to occur after shading causes individual branches to transition from net carbon sources to sinks. Under this explanation, we would expect resource-conservative and shade-tolerant species to initiate self-pruning under deeper shade because their branches need less light to maintain a positive carbon balance. However, the notion that branches are fully autonomous may be complicated by ‘correlative inhibition,’ in which plants preferentially allocate resources towards sunlit branches. Consistent with this idea, we predicted that within species, trees with sunlit tops would initiate self-pruning at a higher light threshold. Lastly, we predicted that plot-level diversity in self-pruning strategies would correlate with productivity and total crown volume. We tested these predictions in an experiment where 12 temperate tree species were planted in plots of varying diversity and composition. We measured characteristics of crown size and position as well as the light level at the crown base (denotedLbase), which we took as an estimate of the light threshold of self-pruning. As we predicted, more shade-tolerant and resource-conservative species self-pruned at a deeper level of shade (lowerLbase). In addition, most species had higherLbasewhen they had more light at the crown top, suggestive of correlative inhibition. With respect to their neighbors’ traits, though, conservative and acquisitive species showed contrary patterns of plasticity: conservative species had lowerLbasearound conservative neighbors, while acquisitive species had lowerLbasearound acquisitive neighbors. However, all species declined in crown depth when they grew alongside larger, more acquisitive neighbors. As predicted, plots with a greater interspecific diversity ofLbasehad greater basal area and crown volume. Using simulations, we showed that plasticity in crown depth between monocultures and mixtures strengthened the relationship with crown volume, primarily due to competitive release experienced by acquisitive species. By placing shade-induced self-pruning in a comparative context, we clarify how forest function emerges from competition for light between individual trees.
Loss of virulence ofBotrytis cinereamutants defective in phytotoxin production is restored by modifying inoculation medium
Authors: Qin Si , Shi-Kunne Xiaoqian , Chen Jie , Beenen Henriek G. , You Yaohua , van Kan Jan A. L.
Published: October 2024

Botrydial, botcinic acid and their derivatives are major phytotoxic metabolites produced by the necrotrophic fungal pathogenBotrytis cinerea. These phytotoxins are able to induce programmed cell death in the host and thereby promote plant susceptibility toB. cinerea.We observed that aΔbot2Δboa6double mutant strain, which synthesizes neither botrydial nor botcinic acid, was almost avirulent on tomato leaves when the disease assay was performed using synthetic minimal Gamborg B5 medium. However, virulence of this mutant was restored when the inoculation medium was supplemented with yeast extract. Further virulence assays which compared the double mutant with other multiple mutants using both inoculation media, revealed a prominent contribution of botrydial and botcinic acid to the full virulence ofB. cinerea. Therefore, we performed an RNA-sequencing experiment to identifyB. cinereagenes that contribute to the phenotypic switch from an “incompatible” to a “compatible” interaction between tomato and theΔbot2Δboa6double mutant. Four genes encoding cell death-inducing effector proteins were upregulated inB. cinereaby the addition of yeast extract, and their transcript profiles grouped within a co-expression module that was positively correlated with the compatible interaction. Functional analyses of these effector genes were performed by overexpressing them individually in theΔbot2Δboa6background, followed by disease assays with the Gamborg B5 medium without yeast extract.

Importance

The grey mould fungusBotrytis cinereais a model for necrotrophic plant pathogens due to its wide host range, economic impact, well-assembled genome, and versatile mechanisms for inducing host cell death during colonization. Botrydial and botcinic acid have previously been characterized as major phytotoxins produced byB. cinerea. However, studies from different groups reported variable results regarding the contributions of these phytotoxins to fungal virulence. Here we demonstrate that botrydial and botcinic acid make a prominent contribution to the full virulence ofB. cinerea, by performing infection assays with mutants that are defective in phytotoxin production and/or multiple cell death-inducing proteins using different inoculation media. This work highlights the pivotal roles of these phytotoxins as compared to other virulence factors, as well as the significant impact of inoculation conditions on compatible and incompatible interactions between the fungus and its hosts.
Validation of a Novel Smartphone Pupillometer Application Compared to a Dedicated Clinical Pupillometer in the Measurement of the Pupillary Light Reflex of Healthy Volunteers
Authors: Middleton PM , Davies W , Buzytsky I
Published: October 2024

Aim

This study aimed to assess the correlation between the PLR curves of 25 healthy volunteers, generated with the MindMirror mobile telephone application, with PLR data from a dedicated clinical pupillometer.

Materials & methods

Paired pupillary light reflex curves were recorded from 25 healthy volunteers using the MindMirror mobile telephone application, and a Neuroptics NPi 200 clinical pupillometer. The curves were analysed for correlation using a Pearson correlation coefficient across both curve sets.

Results

Close correlation was demonstrated between all parameters except maximum and mean pupillary constriction velocity. These values were consistently lower in the MindMirror derived curves and may be explained by the intensity of the light stimulus available from a mobile telephone being significantly less that that used by the clinical pupillometer.

Conclusion

A mobile telephone equipped with a MindMirror mobile phone application may provide a reliable, low cost and widely available alternative to a clinical pupillometer in the assessment of the pupillary light reflex.

Plain language summary

Clinical pupillometry allows objective measurement of Pupillary Light Reflex (PLR) parameters, giving reproducible measurements shown to be independent predictors of adverse outcomes in patients with various neurological insults, and is increasingly being used as a clinical assessment tool among ambulatory patients outside of the hospital setting, particularly for concussion assessment in sports medicine. The MindMirror™ smartphone application uses artificial intelligence to identify and measure changes in important PLR components, and was shown to deliver variables with high levels of correlation and agreement with existing measurement tools such as the Neuroptics NPi-200TM Automated Pupillometer.

Tweetable abstract

A novel smartphone-based AI tool identifies potential predictors of neurological insults such as concussion with similar performance to dedicated tools.
Reversal of vein of Galen aneurysmal malformation by stimulation of flow-mediated vessel fusion
Authors: Martin-Valiente Edwige , Du Yao , Goemans Chloé , Zindy Egor , Adam Myckel , Scheid Benoît , Vikkula Miikka , Lubicz Boris , Vanhollebeke Benoit , Baeyens Nicolas
Published: October 2024

Congenital vascular malformations arise from defective homeostatic development of the vascular tree1. The aneurysmal malformation of the Vein of Galen (VGAM) is the most frequent neurovascular malformation in neonates, with limited therapeutic options and poor outcomes in the most severe cases2. This congenital disease is consecutive to germline genetic mutation ofRASA1orEPHB43,4, but little is known about the mechanisms leading to its development. We generated mutantrasa1aandephb4adeficiency models in zebrafish reproducing the genetic and structural characteristics of the VGAM in the dorsal longitudinal vein of the cerebral vasculature. We link the development of the malformation to a failure of the fusion of precursor blood vessels into a draining vessel for the choroidal type malformations and to a failure to constrict for the mural type malformations. The fusion process is driven by blood flow, sensed and integrated by endothelial cells. RASA1 deficiency destabilizes the homeostatic response to blood flow and contributes to impaired flow-mediated activation of MAPK and PI3K signaling. We targeted these defective mechanotransduction mechanisms pharmacologically in bothrasa1aandephb4amutant models, successfully reestablishing the fusion and constriction processes in preexisting malformations. This work identifies molecular actors of the flow-mediated blood vessel fusion mechanism, a specific angiogenetic program, and provides ground for treating VGAM and other vascular remodeling disorders.
The effect of surfactants and film-forming polymers on pulmonary surfactant function measuredin vitrois dose-rate dependent
Authors: Sengupta Sreyoshee , Barlow Hugh J. , Baltazar Maria T. , Sørli Jorid B.
Published: October 2024

Surfactants and film-forming polymers are common ingredients in consumer spray products such as cleaning products, hair care products, and anti-perspirants. Spraying eases application by creating aerosolised droplets of the product that can distribute evenly over the treated surface. However, these aerosols can potentially be inhaled during their normal application. Droplets that reach the alveoli can interact with the pulmonary surfactant; a complex mixture of phospholipids and proteins that regulates the surface tension at the air-liquid interface. This interaction could elevate the minimum surface tension at maximum compression and change the surface rheology of the pulmonary surfactant at the interface. We tested four surfactants and seven polymers for their ability to inhibit pulmonary surfactant functionin vitroand investigated if the inhibition is dose-rate dependent i.e., the product of the concentration (mg/mL) and aerosolisation rate (mL/min). We found that independent of chemical class (surfactant or polymer) there was a clear dose-rate dependent inhibition of pulmonary surfactant function and that different chemicals inhibited function at different dose-rates. We compared the points of departure of inhibitory chemicals to a polymer with known dose-rate dependent lung toxicity. When assessing the risk of chemicals that might be inhaled, it is essential to ensure normal use would not inhibit pulmonary surfactant function leading to immediate effects on the lungs.

Lay summary

Spray products create a cloud of tiny droplets in the air when they are used. This cloud can be inhaled, and if it reaches the deepest parts of the lungs, it can interact with the thin layer of liquid, called pulmonary surfactant, that covers the cells. It protects the lung tissue during the constant movement of breathing. Droplets can sometimes disrupt the pulmonary surfactant function, making breathing difficult. Chemicals that are used in spray products must be tested to assess if they are harmful if inhaled. In this project we studied the effect of chemicals that are commonly found in spray products on the functioning of the pulmonary surfactantin vitro. The results can be combined with otherin vitromethods to test if chemicals are harmful to inhale without testing on animals.
Modelling human social vision with cinematic stimuli
Authors: Santavirta Severi , Paranko Birgitta , Seppälä Kerttu , Hyönä Jukka , Nummenmaa Lauri
Published: October 2024

Sociability is central for humans. Visual information ranging from low-level physical features (e.g. luminance) to semantic information (e.g. face recognition) and high-level social inference (e.g. emotional valence of social interactions) is constantly sampled for navigating the social world. Here we utilize large-scale eye tracking during natural vision for mapping how different levels of visual information guide the perception of social scenes. In three experiments, participants (N = 166) watched full-length films and short movie clips with varying social content (total duration: 193 minutes) during eye tracking. To model the association between the perceptual features and spatiotemporal eye movement parameters (gaze position, gaze synchronization, pupil size and blinking), we extracted 39 stimulus features from the movies including low-level audiovisual features (e.g. luminance, motion), presence and location of mid-level semantic categories (e.g. faces, objects) and high-level social information (e.g. body movements, pleasantness). Pupil size was modulated by luminance, scene cuts and emotional arousal while gaze position was most accurately predicted by a combination of the presence of human faces, local motion and entropy. Faces and eyes were prioritized over other semantic categories and blinking rate decreased during periods of attentional engagement. Altogether the results show that human social vision is primarily guided by low-level physical features and mid-level semantic categories, while high-level social features such as emotional arousal primarily modulate pupillary responses.
A body detection inversion effect revealed by a large-scale inattentional blindness experiment
Authors: Gandolfo Marco , Peelen Marius V.
Published: October 2024

As a social species, humans preferentially attend to the faces and bodies of other people. Previous research revealed specialized cognitive mechanisms for processing human faces and bodies. For example, upright person silhouettes are more readily found than inverted silhouettes in visual search tasks. It is unclear, however, whether these findings reflect a top-down attentional bias to social stimuli or bottom-up sensitivity to visual cues signaling the presence of other people. Here, we tested whether the upright human form is preferentially detected in the absence of attention. To rule out influences of top-down attention and expectation, we conducted a large-scale single-trial inattentional blindness experiment on a diverse sample of naive participants (N=13.539). While participants were engaged in judging the length of a cross at fixation, we briefly presented an unexpected silhouette of a person or a plant next to the cross. Subsequently, we asked whether participants noticed anything other than the cross. Results showed that silhouettes of people were more often noticed than silhouettes of plants. Crucially, upright person silhouettes were also more often detected than inverted person silhouettes, despite these stimuli being identical in their low-level visual features. These results were replicated in a second experiment involving headless person silhouettes. Finally, capitalizing on the exceptionally large and diverse sample, further analyses revealed strong detection differences across age and gender. These results indicate that the visual system is tuned to the form of the upright human body, allowing for the quick detection of other people even in the absence of attention.
Helminthic parasite infections of endangered western hoolock gibbons (Hoolock hoolock) in degraded habitats of Bangladesh
Authors: Kabir M Tarik , Lappan Susan , Acharjee Rajib , Pomy Jesmin Sultana , Sah Shahrul Anuar Mohd , Ruppert Nadine
Published: October 2024

Although habitat degradation and anthropogenic disturbance can increase the risk of parasitic infections for many animals, including primates, little information about parasitism in wild gibbons is available, and almost nothing is known about the prevalence of helminth infection in wild populations. Globally threatened western hoolock gibbons (Hoolock hoolock, Harlan 1834) are exposed to significant anthropogenic disturbances across their range. We examined faecal samples from wild gibbons in three highly degraded and fragmented forests in Bangladesh: Lawachara National Park, Saltila forest, and Sheikh Jamal Inani National Park, for helminths, and identified two helminthic parasites,Bunostomumsp., andEnterobiussp. Overall helminthic parasite prevalence (percentage of samples containing parasites) and intensity (mean number of parasites individuals per sample) in faecal samples from wild gibbons were 82% and 12.1, respectively. This is the first report ofBunostomumsp. andEnterobiussp. infections in wild individuals of western hoolock gibbons or any other small ape. Habitat fragmentation, degradation, human encroachment, and other anthropogenic disturbances in Bangladesh may contribute to higher infection risk and transmission of zoonotic diseases in this highly arboreal gibbon species, with unknown consequences for their health and long-term survival. As parasitic infections can be transmitted within and across species, affecting humans, other primates, and other wild and domesticated animals, habitat protection and restoration and public awareness campaigns applying the One Health approach should be used to mitigate the spread of zoonotic disease in shared landscapes.

HIGHLIGHTS

First reported helminthic parasite infections withBunostomumsp. andEnterobiussp. in wild gibbons

Out of 50 collected fecal samples from the endangered Western hoolock gibbon in three degraded forests in Bangladesh, 41 (82%) tested positive for helminthic infections

Parasite intensity ranged from 1 to 45 individuals per gram, with a median intensity of 9

Lower parasite intensity (≤5) was more common in winter than in the monsoon season indicating seasonal variations

GRAPHICAL ABSTRACT
Polymorphisms in rs2069845 are associated with IL-6 and soluble IL-6 receptor levels during total joint replacement
Authors: Anderson Kyle D. , Dulion Bryan , Wong John , Patel Niyati , Debenedetti Anne , Della Valle Craig J. , Ross Ryan D.
Published: October 2024

As the number of patients undergoing total joint replacement (TJR) surgery increases, so does the number of revision surgeries. One driver of implant failure and subsequent revision surgery is peri-implant osteolysis, which is driven by inflammation-mediated bone loss. IL-6 is an inflammatory marker that is elevated during the peri-operative period. Early elevations in IL-6 levels have been linked to osteolysis development. The current study asked whether there is genetic contribution to the IL-6-related peri-operative inflammatory reaction to TJR surgery. Patients undergoing primary TJR (total hip or total knee) provided pre-operative and post-operative blood samples for measurement of the circulating levels of IL-6 and the soluble IL-6 receptor (sIL-6r) and evaluation of allele status of three single nucleotide polymorphisms (SNPs) linked to IL-6 or sIL-6r levels - rs2069845, rs228145, and rs4537545. Circulating sIL-6r levels were associated with allele status in the rs2228145 SNP. More interestingly, allele status in the rs2069845 SNP was associated with the change in circulating IL-6 levels following TJR surgery. Specifically, patients with the A,A allele had increasing levels of IL-6, while those harboring the G,A allele had decreasing levels of IL-6. Although the study was not designed to follow implant survival, due to the critical role of IL-6 in driving peri-implant osteolysis development, the results may suggest that the rs2069845 allele has a role in the success of orthopedic implants. rs2069845 polymorphisms may be a useful patient-specific marker of inflammatory response to TJR surgery.
A genome-to-proteome atlas charts natural variants controlling proteome diversity and forecasts their fitness effects
Authors: Jakobson Christopher M. , Hartl Johannes , Trébulle Pauline , Mülleder Michael , Jarosz Daniel F. , Ralser Markus
Published: October 2024

Despite abundant genomic and phenotypic data across individuals and environments, the functional impact of most mutations on phenotype remains unclear. Here, we bridge this gap by linking genome to proteome in 800 meiotic progeny from an intercross between two closely relatedSaccharomyces cerevisiaeisolates adapted to distinct niches. Modest genetic distance between the parents generated remarkable proteomic diversity that was amplified in the progeny and captured by 6,476 genotype-protein associations, over 1,600 of which we resolved to single variants. Proteomic adaptation emerged through the combined action of numerouscis- andtrans-regulatory mutations, a regulatory architecture that was conserved across the species. Notably,trans-regulatory variants often arose in proteins not traditionally associated with gene regulation, such as enzymes. Moreover, the proteomic consequences of mutations predicted fitness under various stresses. Our study demonstrates that the collective action of natural genetic variants drives dramatic proteome diversification, with molecular consequences that forecast phenotypic outcomes.

Highlights

- Proteome diversity arises from natural genetic variants, with divergent proteomes in closely related parents and progeny.

-Cis-regulatory elements had strong individual impacts, but coherenttranseffects combined to dominate protein expression.

- Directional selection and frequent transgression suggest much of the proteome is under selective pressure.

- Manytrans-regulators are enzymes or transporters, with fewer than 4% of pQTLs linking known interactors.

- Genome-to-proteome connections predicted the fitness impact of mutations under various stresses, including a strong but hidden causal variant inIRA2/NF1.
Comparative Genome Study of Multidrug-resistantSerratia marcescensstrain IU-BTGE-M-3 Isolated from a Diarrheal Patient Reveals Antibiotic Resistance Profile
Authors: Hossain Md. Shohorab , Mamun Md. Abdullah Al , Alshaya Dalal Sulaiman , Attia KOTB A , Han Changhee , Haque AKM Ariful , Rahman Md Mafizur
Published: October 2024

Serratia marcescensis a notable pathogen known for its intrinsic and acquired antimicrobial resistance, posing challenges in healthcare. The study investigates the multidrug-resistant (MDR)Serratia marcescensstrain BTGE-M-3, focusing on its genomic features and antibiotic resistance. The strain was identified using both morphological and molecular approaches, and its genome, which measured 4.97 Mbp and exhibited a GC content of 59.7%, was sequenced. The genome has 4,827 genes, including essential antibiotic resistance genes, such astet(41) for tetracyclines,aac(6′)-Icfor aminoglycosides,OqxBfor fluoroquinolones, andblaSST-1 beta-lactam, alongside various virulence determinants. Comparative genomics revealed high similarity (98.06% ANI) toS. marcescensstrain KS10, supporting its classification within the same species. Additionally, the genome analysis showed thatS. marcescensstrain IU-BTGE-M-3 comprises of 4390 gene clusters, 4564 genes, and 244 unique singleton genes. To summarize, the results showed thatS. marcescensstrain IU-BTGE-M-3 exhibited a high level of genomic diversity as well as diverse metabolic, cellular, and biological functions, and it is hypothesized that frequent strain exchanges resulted in the horizontal transfer of drug resistance genes. This study underscores the importance of genomic surveillance in understanding and combating antibiotic resistance in therapeutic settings.
From Eggs to Guts: Symbiotic Association ofSodalis nezaraesp. nov. with the Southern Green Shield BugNezara viridula
Authors: Rogowska-van der Molen Magda A. , Manzano-Marín Alejandro , Postma Jelle L. , Coolen Silvia , van Alen Theo , Jansen Robert S. , Welte Cornelia U.
Published: October 2024

Phytophagous insects engage in symbiotic relationships with bacteria that contribute to digestion, nutrient supplementation, and development of the host. The analysis of shield bug microbiomes has been mainly focused on the gut intestinal tract predominantly colonized byPantoeasymbionts, and other microbial community members in the gut or other organs have hardly been investigated. In this study, we reveal that the Southern green shield bugNezara viridulaharbours aSodalissymbiont in several organs, with a notable prevalence in salivary glands, and anterior regions of the midgut. Removing external egg microbiota via sterilization profoundly impacted insect viability but did not disrupt the vertical transmission ofSodalisandPantoeasymbionts. Based on the dominance ofSodalisin testes, we deduce thatN. viridulamales could be involved in symbiont vertical transmission. Genomic analyses comparingSodalisspecies revealed thatSodalissp. Nvir shares characteristics with both free- living and obligate insect-associatedSodalisspp.Sodalissp. Nvir also displays genome instability typical of endosymbiont lineages, which suggests ongoing speciation to an obligate endosymbiont. Together, our study reveals that shield bugs harbour unrecognized symbionts that might be paternally transmitted.
ACSS2 regulates ferroptosis in an E2F1-dependent manner in breast cancer brain metastatic cells
Authors: Esquea Emily M. , Young Riley G. , Ciraku Lorela , Merzy Jessica , Ahmed Nusaiba N. , Talarico Alexandra N. , Karuppiah Mangalam , Gocal Wiktoria , Simone Nicole L. , Dick Alexej , Reginato Mauricio J.
Published: October 2024

Brain metastasis diagnosis in breast cancer patients is considered an end-stage event. The median survival after diagnosis is measured in months, thus there is an urgent need to develop novel treatment strategies. Breast cancers that metastasize to the brain must adapt to the unique brain environment and are highly dependent on acetate metabolism for growth and survival. However, the signaling pathways that regulate survival in breast cancer brain metastatic (BCBM) tumors are not known. Primary brain tumor cells can convert acetate to acetyl-CoA via phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by the cyclin-dependent kinase-5 (CDK5) regulated by the nutrient sensor O-GlcNAc transferase (OGT). Here, we show that breast cancer cells selected to metastasize to the brain contain increased levels of O-GlcNAc, OGT and ACSS2-Ser267 phosphorylation compared to parental breast cancer cells. Moreover, OGT and CDK5 are required for breast cancer cell growth in the brain parenchymain vivo.Importantly, ACSS2 and ACSS2-S267D phospho-mimetic mutant are critical forin vivobreast cancer growth in the brain but not in the mammary fat pad. Mechanistically, we show that ACSS2 regulates BCBM cell survival by suppressing ferroptosis via regulation of E2F1-mediated expression of anti-ferroptotic proteins SLC7A11 and GPX4. Lastly, we show treatment with a novel brain-permeable small molecule ACSS2 inhibitor induced ferroptosis and reduced BCBM growthex vivoandin vivo. These results suggest a crucial role for ACSS2 in protecting from ferroptosis in breast cancer brain metastatic cells and suggests that breast cancer brain metastatic cells may be susceptible to ferroptotic inducers.
NUDIX Hydrolases Target Specific Inositol Pyrophosphates and Regulate Phosphate and Iron Homeostasis, and the Expression of Defense Genes in Arabidopsis
Authors: Schneider Robin , Lami Klea , Prucker Isabel , Stolze Sara Christina , Strauß Annett , Langenbach Kevin , Kamleitner Marília , Belay Yemisrach Zewdu , Ritter Kevin , Furkert David , Gaugler Philipp , Lange Esther , Faiß Natalie , Schmidt Julie Marie , Harings Michael , Krusenbaum Lukas , Wege Stefanie , Kriescher Simon ,   The Jeremy, Schoof Heiko , Fiedler Dorothea , Nakagami Hirofumi , Giehl Ricardo F. H. , Lahaye Thomas , Jessen Henning J. , Gaugler Verena , Schaaf Gabriel
Published: October 2024

Inositol pyrophosphates (PP-InsPs) are important signaling molecules that regulate diverse cellular processes in eukaryotes, including energy homeostasis and phosphate (Pi) signaling. However, the enzymes responsible for their turnover in plants remain largely unknown. Using a non-hydrolysable PP-InsP analog in a pull-down approach, we identified a family of Arabidopsis Nudix hydrolases (NUDTs) that group into two closely related subclades. Throughin vitroassays, heterologous expression systems, and higher-order gene-edited mutants, we explored the substrate specificities and physiological roles of these hydrolases. Using a combination of strong anion exchange (SAX)-HPLC, PAGE, and capillary electrophoresis electrospray ionization mass spectrometry (CE-ESI-MS), we found that their PP-InsP pyrophosphatase activity is enantiomer-selective and Mg2+-dependent. Specifically, subclade I NUDTs preferentially hydrolyze 4-InsP7, while subclade II NUDTs target 3-InsP7, with minor activity against other PP-InsPs, including 5-InsP7. In higher-order mutants of subclade II NUDTs, we observed defects in both Piand iron homeostasis, accompanied by increased levels of 1/3-InsP7and 5-InsP7, with a markedly larger increase in 1/3-InsP7. Furthermore, ectopic expression of NUDTs from both subclades induced local Pistarvation responses (PSRs). However, RNA-seq analysis of WT andnudt12/13/16plants suggests that these NUDTs have PSR-independent roles, potentially involving 1/3-InsP7in the regulation of plant defense. Expanding beyond subclade II NUDTs, we demonstrated susceptibility of the 3PP-position of PP-InsPs to enzymatic activities unrelated to NUDTs, and found that such activities are conserved across plants and humans. Additionally, we found that NUDT effectors from pathogenic ascomycete fungi exhibit a substrate specificity similar to subclade I NUDTs. Collectively, our study provides new insights into the roles of NUDTs in regulating PP-InsP signaling pathways in plants and highlights cross-kingdom conservation of enzymes involved in PP-InsP metabolism.
Conserved principles of spatial biology define tumor heterogeneity and response to immunotherapy
Authors: Behera Vivek , Giba Hannah , Pen Ue-Yu , Di Lello Anna , Doran Benjamin A. , Esposito Alessandra , Pezeshk Apameh , Bestvina Christine M. , Kline Justin , Garassino Marina C. , Raman Arjun S.
Published: October 2024

The tumor microenvironment (TME) is an immensely complex ecosystem1,2. This complexity underlies difficulties in elucidating principles of spatial organization and using molecular profiling of the TME for clinical use3. Through statistical analysis of 96 spatial transcriptomic (ST-seq) datasets spanning twelve diverse tumor types, we found a conserved distribution of multicellular, transcriptionally covarying units termed ‘Spatial Groups’ (SGs). SGs were either dependent on a hierarchical local spatial context – enriched for cell-extrinsic processes such as immune regulation and signal transduction – or independent from local spatial context – enriched for cell-intrinsic processes such as protein and RNA metabolism, DNA repair, and cell cycle regulation. We used SGs to define a measure of gene spatial heterogeneity – ‘spatial lability’ – and categorized all 96 tumors by their TME spatial lability profiles. The resulting classification captured spatial variation in cell-extrinsic versus cell-intrinsic biology and motivated class-specific strategies for therapeutic intervention. Using this classification to characterize pre-treatment biopsy samples of 16 non-small cell lung cancer (NSCLC) patients outside our database distinguished responders and non-responders to immune checkpoint blockade while programmed death-ligand 1 (PD-L1) status and spatially unaware bulk transcriptional markers did not. Our findings show conserved principles of TME spatial biology that are both biologically and clinically significant.
Computational design of bifaceted protein nanomaterials
Authors: Rankovic Sanela , Carr Kenneth D. , Decarreau Justin , Skotheim Rebecca , Kibler Ryan D. , Ols Sebastian , Lee Sangmin , Chun Jung-Ho , Tooley Marti R. , Dauparas Justas , Eisenach Helen E. , Glögl Matthias , Weidle Connor , Borst Andrew J. , Baker David , King Neil P.
Published: October 2024

Recent advances in computational methods have led to considerable progress in the design of self-assembling protein nanoparticles. However, nearly all nanoparticles designed to date exhibit strict point group symmetry, with each subunit occupying an identical, symmetrically related environment. This limits the structural diversity that can be achieved and precludes anisotropic functionalization. Here, we describe a general computational strategy for designing multi-component bifaceted protein nanomaterials with two distinctly addressable sides. The method centers on docking pseudosymmetric heterooligomeric building blocks in architectures with dihedral symmetry and designing an asymmetric protein-protein interface between them. We used this approach to obtain an initial 30-subunit assembly with pseudo-D5 symmetry, and then generated an additional 15 variants in which we controllably altered the size and morphology of the bifaceted nanoparticles by designingde novoextensions to one of the subunits. Functionalization of the two distinct faces of the nanoparticles withde novoprotein minibinders enabled specific colocalization of two populations of polystyrene microparticles coated with target protein receptors. The ability to accurately design anisotropic protein nanomaterials with precisely tunable structures and functions could be broadly useful in applications that require colocalizing two or more distinct target moieties.
Rapid Hippocampal Synaptic Potentiation Induced by Ketamine Metabolite (2R,6R)-Hydroxynorketamine Persistently Primes Synaptic Plasticity
Authors: Brown Kyle A. , Ajibola Musa I. , Gould Todd D.
Published: October 2024

The pharmacologically active (R,S)-ketamine (ketamine) metabolite (2R,6R)-hydroxynorketamine (HNK) maintains ketamine’s preclinical antidepressant profile without adverse effects. While hypotheses have been proposed to explain how ketamine and its metabolites initiate their antidepressant-relevant effects, it remains unclear how sustained therapeutic actions arise following drug elimination. To distinguish the physiological mechanisms involved in the rapid from sustained actions of HNK, we utilized extracellular electrophysiology combined with pharmacology to develop anin vitrohippocampal slice incubation model that exhibited pharmacological fidelity to the 1) rapid synaptic potentiation induced by HNK at the Schaffer collateral-CA1 (SC-CA1) synapse during bath-application to slices collected from mice, and 2) maintenance of metaplastic (priming) activity that lowered the threshold forN-methyl-D-aspartate receptor (NMDAR) activation-dependent long-term potentiation (LTP) hours afterin vivodosing. We then used this model to reveal novel druggable mechanisms engaged in HNK’s temporally-sensitive antidepressant synaptic actions, finding that the induction of synaptic potentiation by HNK did not require NMDAR activity, but NMDAR activity was necessary to maintain synaptic priming. HNK required protein kinase A (PKA) activity to rapidly potentiate SC-CA1 neurotransmission to facilitate synaptic priming that persistently promoted LTP formation. HNK’s rapid actions were blocked by inhibitors of adenylyl cyclase 1 (AC1), but not an AC5 inhibitor. We conclude that HNK rapidly potentiates SC-CA1 synaptic efficacy, which then stimulates priming mechanisms that persistently favor antidepressant-relevant plasticity. Targeting such priming mechanisms may be an effective antidepressant strategy, and using approaches such as our incubation model may aid in revealing novel pharmacological targets.
Effects of Martian magnetic and gravitational fields across multiple generations of the nematode C. elegans
Authors: Akinosho Aalimah , Benefield Zachary , Fritz Allison , Stein Wolfgang , Vidal-Gadea Andres G
Published: October 2024

Life on Earth evolved under a specific set of environmental conditions, including consistent gravitational and magnetic fields. However, planned human missions to Mars in the coming decades will expose terrestrial organisms to radically different conditions, with Martian gravity being approximately 38% of Earth's and a significantly reduced magnetic field. Understanding the combined effects of these factors is crucial, as they may impact biological systems that evolved under different conditions. In this study, we investigated the effects of simulated Martian gravity and hypomagnetic fields on the nematode Caenorhabditis elegans across six generations. We used an integrated experimental setup consisting of clinostats to mimic the reduced Martian gravity, and Merritt coil magnetic cages to model the decreased Martian magnetic fields. We assessed behavioral, morphological, and physiological responses of C. elegans. High-throughput automated assays revealed significant reductions in motor output and morphological dimensions for animals in the Mars treatment compared to matched earth-like controls. We assessed neurological function by means of chemotaxis assays and found a progressive decline in performance for worms raised under the Martian paradigm compared to Earth controls. Our results show that worms grown under Martian-like conditions exhibit progressive physiological alterations across generations, suggesting that the unique environment of Mars might pose challenges to biological function and adaptation. These findings contribute to understanding how living organisms may respond to the combined effects of reduced gravity and hypomagnetic fields, providing insights relevant for future human exploration and potential colonization of Mars.
Mitochondrial small RNA alterations associated with increased lysosome activity in an Alzheimer’s Disease Mouse Model uncovered by PANDORA-seq
Authors: Zhang Xudong , Shi Junchao , Thakore Pratish , Gonzales Albert L. , Earley Scott , Chen Qi , Zhou Tong , Earley Yumei Feng
Published: October 2024

Emerging small noncoding RNAs (sncRNAs), including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), are critical in various biological processes, such as neurological diseases. Traditional sncRNA-sequencing (seq) protocols often miss these sncRNAs due to their modifications, such as internal and terminal modifications, that can interfere with sequencing. We recently developed panoramic RNA display by overcoming RNA modification aborted sequencing (PANDORA-seq), a method enabling comprehensive detection of modified sncRNAs by overcoming the RNA modifications. Using PANDORA-seq, we revealed a novel sncRNA profile enriched by tsRNAs/rsRNAs in the mouse prefrontal cortex and found a significant downregulation of mitochondrial tsRNAs and rsRNAs in an Alzheimer’s disease (AD) mouse model compared to wild-type controls, while this pattern is not present in the genomic tsRNAs and rsRNAs. Moreover, our integrated analysis of gene expression and sncRNA profiles reveals that those downregulated mitochondrial sncRNAs negatively correlate with enhanced lysosomal activity, suggesting a crucial interplay between mitochondrial RNA dynamics and lysosomal function in AD. Given the versatile tsRNA/tsRNA molecular actions in cellular regulation, our data provide insights for future mechanistic study of AD with potential therapeutic strategies.

Graphical Abstract
Early life factors and dementia risk: A study of adverse childhood experiences and later-life cognition and behaviour
Authors: Mudalige Dinithi , Guan Dylan X. , Ballard Clive , Creese Byron , Corbett Anne , Pickering Ellie , Hampshire Adam , Roach Pamela , Smith Eric E. , Ismail Zahinoor
Published: October 2024

Introduction

Adverse childhood experiences (ACEs) are associated with brain alterations and cognitive decline. In later life, cognitive impairment and mild behavioural impairment (MBI) are associated with greater dementia risk.

Objective & Study Design

We investigated whether more severe ACEs are cross-sectionally associated with worse later-life cognitive and behavioural symptoms.

Method

Data are from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging (CAN-PROTECT). Measures included the Childhood Trauma Screener (CTS-5), neuropsychological testing, Everyday Cognition (ECog)-II scale, and MBI Checklist (MBI-C). Linear regressions modelled associations between ACEs severity and neuropsychological test scores. Multivariable negative binomial regressions (zero-inflated, if appropriate) modelled associations between ACEs severity and ECog-II and MBI-C scores. All models controlled for age, sex, education, and ethnocultural origin. Clinical diagnoses of depression and/or anxiety were explored as covariates or mediators.

Results

In adjusted analyses, higher ACEs scores were associated with worse performance on Trail-Making B (standardized b=0.10, q=0.003), Switching Stroop (b=-0.08, q=0.027), Paired Associates Learning (b=-0.08, q=0.049), and Digit Span (b=-0.08, q=0.029). Higher ACEs scores were also associated with higher ECog-II (b=1.08, q=0.029) and MBI-C (b=1.20, q<0.001) scores; these associations were neither mediated by affective symptoms (ECog p=0.16; MBI p=0.13) nor moderated by sex (ECog p=0.09; MBI p=0.46).

Conclusion

Older adults with a history of more severe ACEs show greater cognitive and behavioural risk markers for dementia that cannot be explained by previous psychiatric history. Further research into ACEs as an early modifiable risk factor for dementia is warranted.