bluuebunny/crossref_metadata_2025 huggingface dataset:
MechanoProDB: A Web Based Database for Exploring the Mechanical Properties of Proteins
Authors: Mesbah Ismahene , Habermann Bianca , Rico Felix
Published: December 2023

The mechanical stability of proteins is crucial for biological processes. To understand the mechanical functions of proteins, it is important to know the protein structure and mechanical properties. Protein mechanics is usually investigated through force spectroscopy experiments and simulations that probe the forces required to unfold the protein of interest. While there is a wealth of data in the literature on force spectroscopy experiments and steered molecular dynamics simulations of forced protein unfolding, this information is spread and difficult to access by non-experts. Here we introduce MechanoProDB, a novel web-based database resource for collecting and mining data obtained from experimental and computational works. MechanoProDB provides a curated repository for a wide range of proteins, including muscle proteins, adhesion molecules and membrane proteins. The database incorporates relevant parameters that provide insights into the mechanical stability of proteins and their conformational stability such as the unfolding forces, energy landscape parameters and contour lengths of unfolding steps. Additionally, it provides intuitive annotations of the unfolding pathways of each protein, allowing users to explore the individual steps during mechanical unfolding. The user-friendly interface of MechanoProBD allows researchers to efficiently navigate, search and download data pertaining to specific protein folds or experimental conditions. Users can visualize protein structures using interactive tools integrated within the database, such as Mol*, and plot available data through integrated plotting tools. To ensure data quality and reliability, we have carefully manually verified and curated the data currently available on MechanoProDB. Furthermore, the database also features an interface that enables users to contribute new data and annotations, promoting community-driven comprehensiveness. The freely available MechanoProDB aims to streamline and accelerate research in the field of mechanobiology and biophysics by offering a unique platform for data sharing and analysis. MechanoProDB is freely available athttps://mechanoprodb.ibdm.univ-amu.fr.
Evolution of rhodopsin in flatfishes (Pleuronectiformes) is associated with depth and migratory behaviour
Authors: Macpherson Esme , Hauser Frances E , Van Nynatten Alexander , Chang Belinda SW , Lovejoy Nathan R
Published: December 2023

Visual signals are involved in many fitness-related tasks and are therefore essential for survival in many species. Aquatic organisms are ideal systems to study visual evolution, as the high diversity of spectral properties in aquatic environments generates great potential for adaptation to different light conditions. Flatfishes are an economically important group, with over 800 described species distributed globally, including halibut, flounder, sole and turbot. The diversity of flatfish species and wide array of environments they occupy provides an excellent opportunity to understand how this variation translates to molecular adaptation of vision genes. Using models of molecular evolution, we investigated how the light environments inhabited by different flatfish lineages have shaped evolution in the rhodopsin gene, which is responsible for mediating dim-light visual transduction. We found strong evidence for positive selection in rhodopsin, and this was correlated with both migratory behaviour and several fundamental aspects of habitat, including depth and freshwater/marine evolutionary transitions. We also identified several mutations that likely affect the wavelength of peak absorbance of rhodopsin, and outline how these shifts in absorbance correlate with response to the light spectrum present in different habitats. This is the first study of rhodopsin evolution in flatfishes that considers their extensive diversity, and our results highlight how ecologically-driven molecular adaptation has occurred across this group in response to transitions to novel light environments.
Microglial adipose triglyceride lipase regulates neuroinflammatory and behavioural responses to LPS
Authors: Robb Josephine Louise , Machuca-Parra Arturo Israel , Boisjoly Frédérick , Coursan Adeline , Manceau Romane , Majeur Danie , Rodaros Demetra , Bouyakdan Khalil , Greffard Karine , Bilodeau Jean-François , Forest Anik , Daneault Caroline , Ruiz Matthieu , Laurent Cyril , Arbour Nathalie , Layé Sophie , Fioramonti Xavier , Madore-Delpech Charlotte , Fulton Stephanie , Alquier Thierry ,   Representative of consortium
Published: December 2023

Adipose triglyceride lipase (ATGL), the enzyme that catalyses the rate-limiting step of triglyceride lipolysis, regulates inflammation in peripheral tissues. ATGL has been associated with both pro- and anti-inflammatory responses in different tissues suggesting its actions are dependent on cell type. Recent studies in microglia and macrophages suggest that lipid droplets (LD), a triglyceride storing organelle, and LD lipolysis via ATGL are important components of inflammatory responses. Here, we determined the impact of ATGL inhibition and microglia-specific ATGL loss-of-function on inflammatory and behavioural responses to acute pro-inflammatory insult. First, we evaluated the impact of lipolysis inhibition on lipopolysaccharide (LPS)-induced expression and secretion of cytokines in mouse primary microglia cultures. LPS led to LD accumulation in microglia and altered the expression of lipolysis regulators. The pan-lipase inhibitor ORlistat alleviated LPS-induced expression of IL-1β and IL-6. Specific inhibition of ATGL by ATGListatin had similar anti-inflammatory action on cytokines expression and secretion in both neonatal and adult microglia cultures. Second, targeted and untargeted lipidomic studies revealed that ATGL inhibition reduced LPS-induced generation of pro-inflammatory prostanoids and affected ceramide profile. Finally, the role of ATGL in neuroinflammation was assessed in a novel mouse model with inducible ATGL deletion specifically in microglia. Loss of microglial ATGL in adult male mice dampened LPS-induced expression of IL-6 and reduced LPS-induced sickness behaviour. Together, our results demonstrate that pharmacological inhibition or loss of ATGL-mediated triglyceride lipolysis reduces LPS-induced inflammation to suggest that inhibition of lipolysis plays a beneficial role in neuroinflammation.
A fast and flexible approximation of power-law adaptation for auditory computational models
Authors: Guest Daniel R. , Carney Laurel H.
Published: December 2023

1.

Power-law adaptation is a form of neural adaptation that has been shown to provide a better description of auditory-nerve adaptation dynamics as compared to simpler exponential-adaptation processes. However, the computational costs associated with power-law adaptation are high and, problematically, grow superlinearly with the number of samples in the simulation. This cost limits the applicability of power-law adaptation in simulations of responses to relatively long stimuli, such as speech, or in simulations for which high sampling rates are needed. Here, we present a simple approximation to power-law adaptation based on a parallel set of exponential-adaptation processes with different time constants, demonstrate that the approximation improves on an existing approximation provided in the literature, and provide updates to a popular phenomenological model of the auditory periphery that implements the new approximation.
Profile analysis in listeners with sensorineural hearing loss
Authors: Guest Daniel R. , Cameron David A. , Schwarz Douglas M. , Leong U-Cheng , Carney Laurel H.
Published: December 2023

Many sounds contain spectral modulations at multiple scales, but much is still unknown about how such spectral features are represented in the auditory system. One behavioral task that provides insight into this question is profile analysis. In a typical profile-analysis task, listeners are asked to discriminate between a complex tone with equal-amplitude components and a complex tone with a single incremented component. Because listeners can perform profile analysis even when the overall sound level of the stimuli is randomized from interval to interval, this task is thought to be a useful index of relative processing of spectral shape, rather than just sensitivity to absolute level changes. Here, we measured profile analysis across the frequency range in a group of listeners that varied widely in their hearing status. We then modeled the resulting behavioral data by decoding responses to the stimuli from computational models of the auditory nerve and inferior colliculus. We found that both hearing loss at the target frequency and increases in the target frequency were associated with poorer profile-analysis thresholds, and that these results could both be explained as the result of corresponding changes in sensitivity of temporal modulation-sensitive cells at the level of the inferior colliculus. These results suggest that key features of profile-analysis may reflect the limits of central neural tuning to temporal modulations.
Developmental remodeling repurposes larval neurons for sexual behaviors in adultDrosophila
Authors: Diamandi Julia A. , Duckhorn Julia C. , Miller Kara E. , Weinstock Mason , Leone Sofia , Murphy Micaela R. , Shirangi Troy R.
Published: December 2023

Most larval neurons inDrosophilaare repurposed during metamorphosis for functions in adult life, but their contribution to the neural circuits for sexually dimorphic behaviors is unknown. Here, we identify two interneurons in the nerve cord of adultDrosophilafemales that control ovipositor extrusion, a courtship rejection behavior performed by mated females. We show that these two neurons are present in the nerve cord of larvae as mature, sexually monomorphic interneurons. During pupal development, they acquire the expression of the sexual differentiation gene,doublesex, undergodoublesex-dependent programmed cell death in males, and are remodeled in females for functions in female mating behavior. Our results demonstrate that the neural circuits for courtship inDrosophilaare built in part using neurons that are sexually reprogrammed from former sex-shared activities in larval life.
Seasonally increasing parasite load is associated with microbiome dysbiosis in wild bumblebees
Authors: Young Mark G. , Just Josefine , Lee Ye Jin , McMahon Thomas , Gonzalez James , Noh Suegene , Angelini David R.
Published: December 2023

The microbiome is increasingly recognized for its complex relationship with host fitness. Bumblebees are host to a characteristic gut microbiome community that is derived and reinforced through social contact between individuals. The bumblebee microbiome is species-poor, and primarily composed from a small number of core taxa that are associated with the greater tribe of corbiculate bees. Experimental findings support a role for the core bumblebee microbiome in resistance to severe infections by a common trypanosomal parasite,Crithidia bombi. However, most studies have been small in scale, often considering just one or two bumblebee species, or making use of commercially-reared bees. To better understand the microbiome diversity of wild populations, we have deeply sampled field populations of ten sympatric species found throughout central and down east Maine in a three-year microbiome field survey. We have used 16S amplicon sequencing to produce microbiome community profiles, and qPCR to screen samples for infections byCrithidia bombi. The breadth of our dataset has enabled us to test for seasonal and interspecific trends in the microbiome community. Controlling for these external sources of variation, we have identified microbial factors associated with infection and parasite load that support the role of the core microbiome in resistance to severe infection.
Cyclase-associated protein is a pro-formin anti-capping processive depolymerase of actin barbed and pointed ends
Authors: Towsif Ekram M. , Shekhar Shashank
Published: December 2023

Cellular actin networks display distinct assembly and disassembly dynamics resulting from multicomponent reactions occurring primarily at the two ends and the sides of actin filaments [1–3]. While barbed ends are considered the hotspot of actin assembly [4], disassembly is thought to primarily occur via reactions on filament sides and pointed ends [3, 5–11]. Cyclase-associated protein (CAP) has emerged as the main protagonist of actin disassembly and remodeling – it collaborates with cofilin to increase pointed-end depolymerization by 300-fold [6, 7], promotes filament “coalescence” in presence of Abp1 [12], and accelerates nucleotide exchange to regenerate monomers for new rounds of assembly [13–15]. CAP has also been reported to enhance cofilin-mediated severing [16, 17], but these claims have since been challenged [7]. Using microfluidics-assisted three-color single-molecule imaging, we now reveal that CAP also has important functions at filament barbed ends. We reveal that CAP is a processive barbed-end depolymerase capable of tracking both ends of the filament. Each CAP binding event leads to removal of about 5,175 and 620 subunits from the barbed and pointed ends respectively. We find that the WH2 domain is essential, and the CARP domain is dispensable for barbed-end depolymerization. We show that CAP co-localizes with barbed-end bound formin and capping protein, in the process increasing residence time of formin by 10-fold and promoting dissociation of CP by 4-fold. Our barbed-end observations combined with previously reported activities of CAP at pointed ends and sides, firmly establish CAP as a key player in actin dynamics.
Simultaneous CRISPR screening and spatial transcriptomics reveals intracellular, intercellular, and functional transcriptional circuits
Authors: Binan Loϊc , Danquah Serwah , Valakh Vera , Simonton Brooke , Bezney Jon , Nehme Ralda , Cleary Brian , Farhi Samouil L
Published: December 2023

Pooled optical screens have enabled the study of cellular interactions, morphology, or dynamics at massive scale, but have not yet leveraged the power of highly-plexed single-cell resolved transcriptomic readouts to inform molecular pathways. Here, we present Perturb-FISH, which bridges these approaches by combining imaging spatial transcriptomics with parallel optical detection ofin situamplified guide RNAs. We show that Perturb-FISH recovers intracellular effects that are consistent with Perturb-seq results in a screen of lipopolysaccharide response in cultured monocytes, and uncover new intercellular and density-dependent regulation of the innate immune response. We further pair Perturb-FISH with a functional readout in a screen of autism spectrum disorder risk genes, showing common calcium activity phenotypes in induced pluripotent stem cell derived astrocytes and their associated genetic interactions and dysregulated molecular pathways. Perturb-FISH is thus a generally applicable method for studying the genetic and molecular associations of spatial and functional biology at single-cell resolution.
Safety and feasibility of a combined neuromodulation and yoga intervention for individuals with mild traumatic brain injury and chronic pain: a pilot study
Authors: Krese Kelly , Aaronson Alexandra , Donnelly Kyla Z , Shah Rachana , Chaudhuri Sarmistha , Bobra Sonia , Etingen Bella , Bedo Sabrina , Kale Ibuola , Billups Andrea , Colletta Kalea , Kletzel Sandra , Kemp Amy , Bender Pape Theresa L , Bhaumik Dulal , Herrold Amy A
Published: December 2023

The complex clinical presentation of patients with mild traumatic brain injury and chronic pain (mTBI+CP) often causes symptoms that are resistant to standard treatments. For the first time, our team combined intermittent theta burst stimulation and yoga (iTBS+LYB) to maximize treatment effect and promote functional recovery in a pilot open-label clinical trial among Veterans with mTBI+CP. A 3-minute iTBS protocol was delivered including 3 pulses of stimulation given at 50Hz, repeated every 200ms at 80% of the resting MT, with an inter-pulse-interval of 20ms. A 2s train of iTBS was repeated every 10s for a total of 190s, for a total of 600 pulses. After all participants received iTBS, a certified yoga instructor guided a 90-minute group LYB session. N=19 participants were enrolled; 71.4% (10/14) completed all 6 iTBS+LYB sessions. Three individuals experienced headaches, a known side effect of iTBS, which resulted in one participant self-withdrawing. iTBS+LYB for mTBI+CP is feasible and safe, with known side effects.
Dual T-cell constant β chain (TRBC)1 and TRBC2 staining for the identification of T-cell neoplasms by flow cytometry
Authors: Horna Pedro , Weybright Matthew J , Ferrari Mathieu , Jungherz Dennis , Peng YaYi , Akbar Zulaikha , Ilca F Tudor , Otteson Gregory E , Seheult Jansen N , Ortmann Janosch , Shi Min , Maciocia Paul M , Herling Marco , Pule Martin A , Olteanu Horatiu
Published: December 2023

The diagnosis of leukemic T-cell malignancies is often challenging, due to overlapping features with reactive T-cells and limitations of currently available T-cell clonality assays. Recently developed therapeutic antibodies specific for the mutually exclusive T-cell receptor constant β chain (TRBC)1 and TRBC2 isoforms provide a unique opportunity to assess for TRBC-restriction as a surrogate of clonality in the flow cytometric analysis of T-cell neoplasms. To demonstrate the diagnostic utility of this approach, we studied 135 clinical specimens with (50) or without (85) T-cell neoplasia, in addition to 29 blood samples from healthy donors. Dual TRBC1 and TRBC2 expression was studied within a comprehensive T-cell panel, in a fashion similar to the routine evaluation of kappa and lambda immunoglobulin light chains for the detection of clonal B-cells. Polytypic TRBC expression was demonstrated on total, CD4+and CD8+T-cells from all healthy donors; and by intracellular staining on benign T-cell precursors. All neoplastic T-cells were TRBC-restricted, except for 5 cases (10%) lacking TRBC expression. T-cell clones of uncertain significance were identified in 15 samples without T-cell malignancy (13%), and accounted for smaller subsets than neoplastic clones (median: 4.7% vs. 73% of lymphocytes, p<0.0001). Single staining for TRBC1 produced spurious TRBC1-dim subsets in 21 clinical specimens (16%), all of which resolved with dual TRBC1/2 staining. Assessment of TRBC restriction by flow cytometry provides a rapid diagnostic method to detect clonal T-cells, and to accurately determine the targetable TRBC isoform expressed by T-cell malignancies.
Prediction of Metastatic Site Based On Somatic Gene Mutations in Primary Tumors in Prostate Cancer
Authors: Gomez Paul
Published: December 2023

Objective

The goal of this research is to predict the most likely metastatic site(s) of a primary prostate cancer tumor that has been resected via radical prostatectomy; its genome has been sequenced to obtain a list of gene mutations; and after initial inspection of pelvic lymph nodes, there is no clinical evidence of metastasis. However, micrometastases might already be growing in distant organs and cannot be detected at the time of surgery.

Background

The most common metastatic targets in prostate cancer (PCa) are the pelvic lymph nodes (PLN) and bones. The PLNs are routinely dissected by a procedure called pelvic lymph node dissection (PLND) simultaneously with the surgical removal of the prostate to detect the presence of metastatic growths. Additionally, the prostate-specific antigen (PSA) level is used to assess the existence of a metastatic stage. However, micrometastases in other organs and tissues might be overlooked.

Methods

We downloaded publicly available prostate cancer tumor data from the websitewww.CbioPortal.org.

After choosing the 25 most commonly mutated genes by metastatic site (MS) and finding genes that are uniquely mutated on specific metastatic sites, we found that the mutational signature of a prostate cancer tumor is associated with its MS, and thus, we developed a method to numerically predict this association.

Results

After executing a computational algorithm on the data set of metastatic prostate tumors, it was found that we can predict metastatic sites with the following accuracies: bone (90.9%), retroperitoneum (87.5%), liver (83.0%), kidney (80.0%), pancreas (80.0%), adrenal glands (75.0%), lung (71.1%), and brain (72.5%).

Conclusions

We successfully developed a method and an algorithm that predict the most likely metastatic site of a primary prostate cancer tumor based on its genetic mutations. The accuracy of the predictions for eight metastatic sites ranges from 71.1% to 90.9%, with an average of 80.5%.
Small RNAs in plasma extracellular vesicles define biomarkers of premanifest changes in Huntington’s disease
Authors: Herrero-Lorenzo Marina , Pérez-Pérez Jesús , Escaramís Georgia , Martínez-Horta Saül , Pérez-González Rocío , Rivas-Asensio Elisa , Kulisevsky Jaime , Gámez-Valero Ana , Martí Eulàlia
Published: December 2023

Despite the advances in the understanding of Huntington’s disease (HD), there is the need for molecular biomarkers to categorize mutation-carriers during the preclinical stage of the disease preceding the functional decline. Small RNAs (sRNAs) are a promising source of biomarkers since their expression levels are highly sensitive to pathobiological processes. Here, using an optimized method for plasma extracellular vesicles (EVs) purification and an exhaustive analysis pipeline of sRNA sequencing data, we show that EV-sRNAs are early downregulated in mutation-carriers, and that this deregulation is associated with premanifest cognitive performance. Seven candidate sRNAs (tRF-Glu-CTC, tRF-Gly-GCC, miR-451a, miR-21-5p, miR-26a-5p, miR-27a-3p, and let7a-5p) were validated in additional subjects, showing a significant diagnostic accuracy at premanifest stages. Of these, miR – 21-5p was significantly decreased over time in a longitudinal study; and miR-21-5p and miR-26a-5p levels correlated with cognitive changes in the premanifest cohort. In summary, the present results suggest that deregulated plasma EV-sRNAs define an early biosignature in mutation carriers with specific species sensing the progression and cognitive changes occurring at the premanifest stage.
Brain network dynamics predict moments of surprise across contexts
Authors: Zhang Ziwei , Rosenberg Monica D.
Published: December 2023

We experience surprise when reality conflicts with our expectations. When we encounter such expectation violations in psychological tasks and daily life, are we experiencing completely different forms of surprise? Or is surprise a fundamental psychological process with shared neural bases across contexts? To address this question, we identified a brain network model, the surprise edge-fluctuation-based predictive model (EFPM), whose regional interaction dynamics measured with functional magnetic resonance imaging (fMRI) predicted surprise in an adaptive learning task. The same model generalized to predict surprise as a separate group of individuals watched suspenseful basketball games and as a third group watched videos violating psychological expectations. The surprise EFPM also uniquely predicts surprise, capturing expectation violations better than models built from other brain networks, fMRI measures, and behavioral metrics. These results suggest that shared neurocognitive processes underlie surprise across contexts and that distinct experiences can be translated into the common space of brain dynamics.
Non-coding rare variant associations with blood traits on 166 740 UK Biobank genomes
Authors: Ribeiro Diogo M. , Delaneau Olivier
Published: December 2023

Large biobanks with whole-genome sequencing now enable the association of non-coding rare variants with complex human traits. Given that >98% of the genome is available for exploration, the selection of non-coding variants remains a critical yet unresolved challenge in these analyses. Here, we leverage knowledge of blood gene regulation and deleteriousness scores to select non-coding variants pertinent for association with blood-related traits. We leverage whole genome sequencing and 59 blood cell count and biomarker measurements for 166 740 UK Biobank samples to perform variant collapsing tests. We identified hundreds of gene-trait associations involving non-coding variants across the 59 traits. However, we demonstrate that the majority of these non-coding rare variant associations (i) reproduce associations known from common variant studies and (ii) are driven by linkage disequilibrium between nearby common and rare variants. This study underscores the prevailing challenges in rare variant analysis and the need for caution when interpreting non-coding rare variant association results.
Humans progressively feel agency over events triggered before they act
Authors: Toma Marcus , Mattout Jérémie , Quentin Romain , Rassoulou Fayed , Gautier Alice , Maby Emmanuel , Vernet Marine
Published: December 2023

Artificial Intelligence (AI) has become increasingly efficient in anticipating our behavior. Will this impact, in the near future, how much we feel control over events generated with AI-assistance? This would in turn influence our decisions, actions, mental health and sense of responsibility. In everyday life, our sense of agency over events occurring at various delays after our actions has adapted to accommodate these delays. Here, we investigate whether our sense of agency can also adapt to an unusual situation where a consequence precedes an action. We used an online game in which players aimed to beat the computer at finding and clicking on a target to trigger an animation, while, in fact, an algorithm triggered the animation before the players’ click. The animation was not randomly controlled by the algorithm, but rather based on the history of the players’ past movements and on the beginning of their current movement. We used correlational, machine learning decoding, and modelling approaches to capture how players compute their reported sense of agency over the animation. We found evidence that, in less than an hour, players implicitly learned that the timing of the animation was related to their own actions, and adapted their sense of agency accordingly. Such findings may help us to anticipate how humans will integrate AI-assistance to guide their behavior.
Length–weight relationships of the French pikesEsoxspp (Teleostei, Esocidae)
Authors: Royer Lucas , Teletchea Fabrice , Delavergne Sophie , Lafitte Frédéric , Escarpit Marion , Molina Quentin , Breugnot Emilie , Cosson Eddy , L’Hostis Aurélia , Denys Gaël P.J.
Published: December 2023

Length–weight relationships for PikeEsox aquitanicusandEsox luciusfrom France are provided. A total of 9,070 specimens were collected, measured and weighted from 1981 to 2022 throughout France by Departmental Angling Federations and the French Biodiversity Agency during their survey by electrofishing. For all species, the values ofbare 2.960 forE. aquitanicusand 2.987 forEsox lucius. We hypothetize this difference by the poor environment where live the Aquitanian pike with no abundant available food and small prey fish species which do not contribute to good conditions for the growth. The study provides the first reference of length–weight relationships forE. aquitanicus.
Age-related changes in human skeletal muscle transcriptome and proteome are more affected by chronic inflammation and physical inactivity than primary aging
Authors: Kurochkina Nadia S. , Orlova Mira A. , Vigovskiy Maksim A. , Zgoda Viktor G. , Vepkhvadze Tatiana F. , Vavilov Nikita E. , Makhnovskii Pavel A. , Grigorieva Olga A. , Boroday Yakov R. , Philippov Vladislav V. , Lednev Egor M. , Efimenko Anastasia Yu. , Popov Daniil V.
Published: December 2023

Evaluation of the influence of primary and secondary aging on the manifestation of molecular and cellular hallmarks of aging is a challenging and currently unresolved issue. Our study represents the first demonstration of the distinct role of primary aging and chronic inflammation/physical inactivity – the most important drivers of secondary aging, in the regulation of transcriptomic and proteomic profiles in human skeletal muscle. To achieve this purpose, young healthy people (n=15), young (n=8) and older (n=37) patients with knee/hip osteoarthritis, a model to study the effect of long-term inactivity and chronic inflammation on the vastus lateralis muscle, were included in the study. It was revealed that widespread and substantial age-related changes in gene expression in older patients relative to young healthy people (∼4,000 genes regulating mitochondrial function, proteostasis, cell membrane, secretory and immune response) were related to the long-term physical inactivity and chronic inflammation rather than primary aging. Primary aging contributed mainly to the regulation of genes (∼200) encoding nuclear proteins (regulators of DNA repair, RNA processing, and transcription), mitochondrial proteins (genes encoding respiratory enzymes, mitochondrial complex assembly factors, regulators of cristae formation and mitochondrial reactive oxygen species production), as well as regulators of proteostasis. It was found that proteins associated with aging were regulated mainly at the post-transcriptional level. The set of putative primary aging genes and their potential transcriptional regulators can be used as a resource for further targeted studies investigating the role of individual genes and related transcription factors in the emergence of a senescent cell phenotype.
Do electromagnetic fields from subsea power cables effect elasmobranch behaviour? A risk-based approach for the Dutch Continental Shelf
Authors: Hermans Annemiek , Winter Hendrik V. , Gill Andrew B. , Murk Albertinka J.
Published: December 2023

Subsea power cables cause electromagnetic fields (EMFs) into the marine environment. Elasmobranchs (rays, skates, sharks) are particularly sensitive to EMFs as they use electromagnetic-receptive sensory systems for orientation, navigation and locating conspecifics or buried prey. Cables may intersect with egg laying sites, foraging habitat and migration routes of elasmobranchs and the effects of encountering EMFs on species of elasmobranchs are largely unknown. Demonstrated behavioural effects are attraction, disturbance and indifference, depending on EMF characteristics, exposed life stage, exposure level and duration. We estimated exposure levels of elasmobranchs to subsea cable EMFs, based on modelled magnetic fields in the Dutch Continental Shelf and compared these to reported elasmobranch sensory sensitivity ranges and experimental effect levels. We conclude that the risk from subsea power cables has a large uncertainty and varies per life stage and species ecology. Based on estimated no-observed effect levels (from 10-3to 10-1µT) we discuss what will probably be the most affected species and life stage for six common benthic elasmobranchs in the Southern North Sea. We identify critical knowledge gaps for reducing the uncertainty in the risk assessments for EMFs effects on elasmobranchs.
Neuro-Immune Communication at the Core of Craving-Associated Brain Structural Network Reconfiguration in Methamphetamine Users
Authors: Du Yanyao , Zhang Jiaqi , Cao Dan , Yang Wenhan , Li Jin , Li Deying , Song Ming , Yang Zhengyi , Zhang Jun , Jiang Tianzi , Liu Jun
Published: December 2023

Methamphetamine (MA) use disorder is a chronic neurotoxic brain disease characterized by a high risk of relapse driven by intense cravings. However, the neurobiological signatures of cravings remain unclear, limiting the effectiveness of various treatment methods. Diffusion MRI (dMRI) scans from 62 MA users and 57 healthy controls (HC) were used in this study. The MA users were longitudinally followed up during their period of long-term abstinence (duration of long-term abstinence: 347.52±99.25 days). We systematically quantified the control ability of each brain region for craving-associated state transitions using network control theory from a causal perspective. Craving-associated structural alterations (CSA) were investigated through multivariate group comparisons and biological relevance analysis. The neural mechanisms underlying CSA were elucidated using transcriptomic and neurochemical analyses. We observed that long-term abstinence-induced structural alterations significantly influenced the state transition energy involved in the cognitive control response to external information, which correlated with changes in craving scores (r∼ 0.35,P<0.01). Our causal network analysis further supported the crucial role of the prefrontal cortex (PFC) in craving mechanisms. Notably, while the PFC is central to the craving, the CSAs were distributed widely across multiple brain regions (PFDR<0.05), with strong alterations in somatomotor regions (PFDR<0.05) and moderate alterations in high-level association networks (PFDR<0.05). Additionally, transcriptomic, chemical compounds, cell-type analyses, and molecular imaging collectively highlight the influence of neuro-immune communication on human craving modulation. Our results offer an integrative, multi-scale perspective on unraveling the neural underpinnings of craving and suggest that neuro-immune signaling may be a promising target for future human addiction therapeutics.
Double-strand breaks in facultative heterochromatin require specific movements and chromatin changes for efficient repair
Authors: Wensveen Marieke R. , Dixit Aditya A. , Colmenares Serafin U. , Janssen Aniek
Published: December 2023

DNA double-strand breaks (DSBs) must be properly repaired within diverse chromatin domains to maintain genome stability. Whereas euchromatin has an open structure and is associated with active transcription, facultative heterochromatin is essential to silence developmental genes and forms compact nuclear condensates, called polycomb bodies. Whether the specific chromatin properties of facultative heterochromatin require distinct DSB repair mechanisms remains unknown. Here, we integrate single DSB systems in euchromatin and facultative heterochromatin inDrosophila melanogasterand find that facultative heterochromatic DSBs rapidly move outside polycomb bodies. These DSB movements coincide with a break-proximal reduction in the canonical heterochromatin mark histone H3 Lysine 27 trimethylation (H3K27me3). We demonstrate that DSB movement and loss of H3K27me3 at heterochromatic DSBs both depend on the histone demethylase dUtx. Moreover, loss of dUtx specifically disrupts completion of homologous recombination at heterochromatic DSBs. We conclude that DSBs in facultative heterochromatin require dUtx-mediated loss of H3K27me3 to promote DSB movement and repair.
Higher seed yield through selection for reduced seed shattering in Italian ryegrass (Lolium multiflorumLam.)
Authors: Kiesbauer Jenny , Kölliker Roland , Hug Maria , Sindelar Meril , Schlatter Linda Helene , Ohnmacht Jonathan , Studer Bruno , Grieder Christoph
Published: December 2023

Seed shattering, i.e., the loss of seeds at ripening stage shortly before or during seed harvest, is strongly reducing seed yield in Italian ryegrass (Lolium multiflorumLam.). The aim of this study was to evaluate the possibility to reduce seed shattering within breeding germplasm via recurrent phenotypic selection on spaced plants. Starting from a founder population of 300 plants serving as F0population, two cycles of phenotypic selection for high and low seed shattering were applied and compared to randomly selected individuals on spaced plant level and in plot trials. Comparison of the five resulting populations in a spaced plant trial revealed a significant effect of selection, with lowest seed shattering (15.3%) observed in the population selected twice for decreased shattering (15.3%) and highest seed shattering (47.9%) for the population selected twice for increased shattering. The same ranking of the five F2populations was observed in a subsequent trial with sown plots. Thus, using the method presented here, recurrent selection on single spaced plants allows to efficiently reduce seed shattering and, therefore, to increase seed yield in swards.
Testis organ culture system capable of evaluating testicular toxicity
Authors: Hashimoto Kiyoshi , Arakawa Hiroshi , Imamura Rikako , Nishimura Takuya , Kitajima Satoshi , Sato Takuya , Makiyama Kazuhide , Ogawa Takehiko , Yokota Satoshi
Published: December 2023

Successful treatment of pediatric cancers often results in long-term health complications, including potential effects on fertility. Therefore, assessing the male reproductive toxicity of anti-cancer drug treatments and the potential for recovery is of paramount importance. However,in vivoevaluations are time-intensive and require large numbers of animals. To overcome these constraints, we utilized an innovative organ culture system that supports long-term spermatogenesis by placing the testis tissue between a base agarose gel and a polydimethylsiloxane ceiling, effectively mirroring thein vivotesticular environment. The present study aimed to determine the efficacy of this organ culture system for accurately assessing testicular toxicity induced by cisplatin, using acrosin-green fluorescent protein (GFP) transgenic neonatal mouse testes. The testis fragments were treated with different concentrations of cisplatin-containing medium for 24 hours and incubated in fresh medium for up to 70 days. The changes in tissue volume and GFP fluorescence over time were evaluated to monitor the progression of spermatogenesis, in addition to the corresponding histopathology. Cisplatin treatment caused tissue volume shrinkage and reduced GFP fluorescence in a concentration-dependent manner. Recovery from testicular toxicity was also dependent on the concentration of cisplatin received. The results demonstrated that this novelin vitrosystem can be a faithful replacement for animal experiments to assess the testicular toxicity of anti-cancer drugs and their reversibility, providing a useful method for drug development.

Short Abstract

Assessing the male reproductive toxicity of anti-cancer drugs and the potential for recovery is of paramount importance, however,in vivoevaluations are time-intensive and require large numbers of animals. We utilized an innovative organ culture system that mirrors thein vivotesticular environment to determine its efficacy in accurately assessing testicular toxicity induced by cisplatin. The results demonstrate that this system can be a faithful replacement for animal experiments to assess the testicular toxicity of anti-cancer drugs and their reversibility.
Beyond BioID: Streptavidin outcompetes antibody fluorescence signals in protein localization and readily visualises targets evading immunofluorescence detection
Authors: Odenwald Johanna , Gabiatti Bernardo , Braune Silke , Shen Siqi , Zoltner Martin , Kramer Susanne
Published: December 2023

Immunofluorescence is a common method to localise proteins within their cellular context via fluorophore labelled antibodies and for some applications without alternative. However, some protein targets evade detection due to low protein abundance or accessibility issues. In addition, some imaging methods require a massive reduction in antigen density thus impeding detection of even medium-abundant proteins.

Here, we show that the fusion of the target protein to TurboID, a biotin ligase labelling lysine residues in close proximity, and subsequent detection of biotinylation by fluorescent streptavidin offers an “all in one” solution to the above-mentioned restrictions. For a wide range of target proteins tested, the streptavidin signal was significantly stronger than an antibody signal, markedly improving the imaging sensitivity in expansion microscopy and correlative light and electron microscopy, with no loss in resolution. Importantly, proteins within phase-separated regions, such as the central channel of the nuclear pores, the nucleolus or RNA granules, were readily detected with streptavidin, while most antibodies fail to label proteins in these environments. When TurboID is used in tandem with an HA epitope tag, co-probing with streptavidin and anti-HA can be used to map antibody- accessibility to certain cellular regions. As a proof of principle, we mapped antibody access to all trypanosome nuclear pore proteins (NUPs) and found restricted antibody labelling of all FG NUPs of the central channel that are known to be phase-separated, while most non-FG Nups could be labelled. Lastly, we show that streptavidin imaging can resolve dynamic, temporally and spatially distinct sub-complexes and, in specific cases, reveal a history of dynamic protein interaction.

In conclusion, streptavidin imaging has major advantages for the detection of lowly abundant or inaccessible proteins and in addition, can provide information on protein interactions and biophysical environment.
Metformin and guanylurea reduce survival, but have limited sublethal effects in larval zebrafish (Danio rerio)
Authors: Williams S. , Thompson W.A. , Masood N. , Birceanu O. , Easwaramoorthy M. , Qiu J. , Wilson J.Y.
Published: December 2023

Metformin is the most common first-line oral therapeutic agent used in the treatment of type-2 diabetes, one of the most prevalent chronic diseases in North America. Post excretion, the compound enters wastewater treatment plants where it is partially bio-transformed by bacteria into guanylurea. Both metformin and guanylurea enter freshwater environments in wastewater effluent where they are available for uptake by aquatic biota. However, our understanding of the effects of metformin and guanylurea on aquatic life is limited. We tested the hypothesis that metformin and guanylurea can influence the development of zebrafish (Danio rerio), by assessing morphometrics, cardiac development, energetic state, and behaviour of early larvae. Embryos were exposed to environmentally relevant (0.4, 4, 40 μg·L−1) and supra-environmental (400 and 4000 μg·L−1) concentrations of metformin and guanylurea from the 4-cell stage (3 hours post fertilization; hpf), until first feed (120 hpf). Exposures to 40 μg·L−1and higher of both metformin and guanylurea increased mortality. Metformin delayed hatching at the highest concentration tested (4000 μg·L−1). The incidence of spinal curvature increased with exposure to both chemicals at supra-environmental levels (400 and 4000 μg·L−1for metformin; 400 μg·L−1for guanylurea). Metformin and guanylurea exposure imposed slight bradycardia in early development, but did not alter oxygen consumption, ATP levels, carbohydrate levels, general swimming, light-dark movement, startle response, or thigmotaxis, irrespective of exposure concentration. The results suggest similar and low sensitivities of larval fish to both metformin and guanylurea. Apart from a small increase in mortality, these compounds impart a modest impact to the early-life stages of zebrafish that are largely limited to supra-environmental concentrations.
Neurodevelopmental timing and socio-cognitive development in a prosocial cooperatively breeding primate (Callithrix jacchus)
Authors: Cerrito Paola , Gascon Eduardo , Roberts Angela C. , Sawiak Stephen J. , Burkart Judith M.
Published: December 2023

Primate, and especially human, brain development is experience-dependent: it is shaped by the inputs received during critical periods. During early development, these inputs systematically differ between independently and cooperatively breeding species, because in cooperative breeders infants are interacting from birth with multiple caretakers and have to thrive in a richer and more challenging social environment. Here, we study the neurodevelopmental timing of the cooperatively breeding common marmoset and how it maps onto behavioral and developmental milestones. To obtain meaningful correlations of structure-function co-constructions, we combine behavioral, imaging (anatomical and functional) and neural tracing experiments. We focus on brain areas that are critically involved when observing conspecifics interacting with others and find that (i) these areas develop in clusters; (ii) these areas reach their maximum gray matter volume shortly after peak provisioning, when immatures are intensely provisioned by group members; (iii) the differentiation of these areas coincides with the period of intense negotiation between immatures and multiple adults over food, the birth of the next set of siblings, and the task of becoming a helper. Moreover, like in humans, differentiation is not fully completed at the age of first reproduction. In sum, we find that the developmental timing of social brain areas coincides with key social and developmental milestones in marmosets, and extends into early adulthood. This rich social input is likely critical for the emergence of the particularly strong prosociality and socio-cognitive skills of marmosets. Since humans are cooperative breeders too, these findings have strong implications for the evolution of human social cognition.
pan-MHC and cross-Species Prediction of T Cell Receptor-Antigen Binding
Authors: Han Yi , Yang Yuqiu , Tian Yanhua , Fattah Farjana J. , Itzstein Mitchell S. von , Hu Yifei , Zhang Minying , Kang Xiongbin , Yang Donghan M. , Liu Jialiang , Xue Yaming , Liang Chaoying , Raman Indu , Zhu Chengsong , Xiao Olivia , Dowell Jonathan E. , Homsi Jade , Rashdan Sawsan , Yang Shengjie , Gwin Mary E. , Hsiehchen David , Gloria-McCutchen Yvonne , Pan Ke , Wu Fangjiang , Gibbons Don , Wang Xinlei , Yee Cassian , Huang Junzhou , Reuben Alexandre , Cheng Chao , Zhang Jianjun , Gerber David E. , Wang Tao
Published: December 2023

Profiling the binding of T cell receptors (TCRs) of T cells to antigenic peptides presented by MHC proteins is one of the most important unsolved problems in modern immunology. Experimental methods to probe TCR-antigen interactions are slow, labor-intensive, costly, and yield moderate throughput. To address this problem, we developed pMTnet-omni, an Artificial Intelligence (AI) system based on hybrid protein sequence and structure information, to predict the pairing of TCRs of αβ T cells with peptide-MHC complexes (pMHCs). pMTnet-omni is capable of handling peptides presented by both class I and II pMHCs, and capable of handling both human and mouse TCR-pMHC pairs, through information sharing enabled this hybrid design. pMTnet-omni achieves a high overall Area Under the Curve of Receiver Operator Characteristics (AUROC) of 0.888, which surpasses competing tools by a large margin. We showed that pMTnet-omni can distinguish binding affinity of TCRs with similar sequences. Across a range of datasets from various biological contexts, pMTnet-omni characterized the longitudinal evolution and spatial heterogeneity of TCR-pMHC interactions and their functional impact. We successfully developed a biomarker based on pMTnet-omni for predicting immune-related adverse events of immune checkpoint inhibitor (ICI) treatment in a cohort of 57 ICI-treated patients. pMTnet-omni represents a major advance towards developing a clinically usable AI system for TCR-pMHC pairing prediction that can aid the design and implementation of TCR-based immunotherapeutics.