bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of pretreating wheat middlings and sunflower meal with fiber degrading enzymes on components solubilization and utilization in broiler chickens
Authors: Njeri Felix M , Patterson Robert , Gachuiri Charles K , Kiarie Elijah G
Published: September 2023

Pretreating fibrous feedstuffs with exogenous enzymes may improve their utilization in broiler chickens. Pretreatment of wheat middlings (WM) and sunflower meal (SM) with fiber degrading enzymes (FDE) was investigated for 1) in vitro solubilization of crude protein (CP) and fiber-degrading (experiment 1), and 2) apparent retention (AR) of CP, neutral detergent fiber (NDF), nitrogen corrected apparent metabolizable energy (AMEn), as well as the concentration of ceca digesta metabolites in broiler chickens (experiment 2). In experiment 1, WM was pretreated with FDE and SM with FDE ± protease and incubated in a shaker for 24 or 48 h at 40°C and 200 rpm. Samples were centrifuged, and the supernatant used for assay of sugars and organic acids and pellet processed for determination of apparent disappearance (AD) of dry matter (DM), fiber, and CP solubilization. In experiment 2, WM and SM were pretreated with FDE for 24 h, oven-dried, and incorporated in iso-caloric and iso-nitrogenous experimental diets. Diets were: 1) a corn–soybean meal positive control (PC); 2) PC plus untreated WM and SM (negative control, NC), and diets 3, 4, 5, and 6 test diets, in which the untreated WM and SM in NC were replaced with pretreated WM and SM at 25% (N25), 50% (N50), 75% (N75), and 100% (N100), respectively. Diets were prepared in mash form in two phases (starter, days 0 to 21 and finisher, days 22 to 42) and had TiO2 (0.3%) as an indigestible marker. A total of 288 Ross708 d-old male broiler chicks were placed in cages based on body weights (6 birds/cage) and allocated diets (n = 8). Birds had free access to feed and water. Samples of excreta for AR and AMEn, and of ceca digesta for the concentration of short-chain fatty acids (SCFA) were collected at the end of each phase. Pretreatment with FDE increased (P < 0.001) solubilization of CP, AD of NDF, and release of sugars and organic acids in the supernatant. The mixture of FDE and protease further increased (P < 0.001) CP solubilization in SM. Feeding pretreated WM and SM had a linear response (P ≤ 0.038) on AMEn, and gross energy (GE) (day 21) and a quadratic response (P < 0.05) on AR of components and AMEn (day 42) and concentration of total SCFA on day 42. On day 42, N25 and N50 had higher AR of DM, CP, NDF, and GE than N75 and N100. In conclusion, pretreatment of WM and SM with enzymes increased CP and fiber degradation. Incorporating moderate amounts (N25 and N50) of pretreated WM and SM in a corn–soybean meal diet fed to broiler chickens improved nutrient and energy utilization.
Triglyceride-glucose index as a biomarker to differentiate stroke subtypes: A hospital-based cross-sectional study
Authors: Daoussi Nizar , Zemni Imen , Saad Yasmin , Abbes Amal , Ben Dhia Rihab , Mhiri Mariem , Belghith-Sriha Asma , Frih-Ayed Mahbouba
Published: September 2023

Background

A growing body of literature suggests that the triglyceride-glucose (TyG) index is linked to ischemic stroke in several ways. The usefulness of this biomarker to differentiate etiologic stroke subtypes has not been thoroughly studied. We aimed to figure out whether the TyG index differentiates cardioembolic (CE) from non-cardioembolic (NCE) strokes.

Methods

A cross-sectional hospital-based study of consecutive stroke cases admitted to the University Hospital of Monastir in Tunisia from January 2018 to December 2022. The TyG index was calculated through the natural logarithm (Ln) of the product of triglyceride and glucose fasting levels. A binary logistic regression was performed to analyze the association between the TyG index and the studied stroke subtypes. We plotted the receiver operating characteristic curve (ROC curve) to determine the best cutoff point for the TyG index in differentiating between CE and NCE stroke subtypes.

Results

We included 320 patients (mean age: 64.2 ±11.1 years; 65.3% males). The TyG index values were independently associated with the NCE subtype (OR=2.38; 95% CI=1.52-3.73; p<0.001) when analyzed as a continuous data variable. Logistic regression of quartile distribution showed that the probability of developing a NCE stroke increased proportionally with the TyG index quartiles. The ROC curve showed an area under the curve of 0.636 (95% CI=0.565-0.707; p<0.001) with a cutoff of 8.8 (sensitivity = 68.8%, specificity = 57%).

Conclusion

High levels of the TyG index are associated with a higher prevalence of NCE stroke while low values are associated with CE strokes. Thus, the TyG index can be a useful biomarker in the differentiation between CE and NCE stroke subtypes.
A proposed grading system for spinal cord arteriovenous shunts
Authors: Yu Jia-Xing , Lu Hao-Han , Bian Li-Song , Feng Yue-Shan , Li Jing-Wei , Yang Fan , Li Gui-Lin , He Chuan , Ye Ming , Hu Peng , Sun Li-Yong , Ma Yong-Jie , Ren Jian , Ling Feng , Hong Tao , Zhang Hong-Qi
Published: September 2023

Background

The clinical outcomes of microsurgery for spinal cord arteriovenous shunts (SCAVSs) exhibit fluctuations due to varying patient selection criteria, underscoring the importance of a standardized surgical grading system that can effectively stratify the feasibility of SCAVSs resection.

Methods

A cohort of 308 consecutive patients with surgically treated SCAVSs was randomly divided into a modeling group and a validation group. The surgical grading system was developed based on the independent risk factors of incomplete resection identified in the modeling group and subsequently verified in the validation group. The system’s specificity and sensitivity were tested through Receiver Operating Characteristic (ROC) analyses.

Results

Multivariate analysis indicated that metameric AVSs (p=0.007), AVSs with maximum length ≥3 cm (p=0.017), embedded AVSs (p=0.032) and anterior sulcal artery supply (p=0.013) were independent risk factors of incomplete resection. Subsequently, each of the four parameters is assigned one point, and the SCAVSs grade is calculated by aggregating all parameter scores. The area under ROC curve (AUC) of modeling group and validation group was 0.856 (95% confidence interval [95% CI], 0.794-0.919) and 0.819 (95% CI, 0.747-0.892) respectively. Across the entire cohort, patients with scores ranging from 0 to 4 exhibited complete resection rates of 88.7%, 66.7%, 30.6%, 4.5% and 6.3%. The corresponding rates of severe treatment-related deterioration were found to be at levels of 6.0%, 12.0%, 12.9%, 31.8% and 25.0 %, respectively. Conclusion: The proposed grading system effectively stratifies the surgical feasibility of SCAVSs based on both the probability of achieving complete resection and the treatment risk. Its simplicity renders it a valuable tool for clinical decision-making, as well as a reference point for evaluating treatment outcomes across different centers and surgical techniques.
Large-scale annotated dataset for cochlear hair cell detection and classification
Authors: Buswinka Christopher J. , Rosenberg David B. , Simikyan Rubina G. , Osgood Richard T. , Fernandez Katharine , Nitta Hidetomi , Hayashi Yushi , Liberman Leslie W. , Nguyen Emily , Yildiz Erdem , Kim Jinkyung , Jarysta Amandine , Renauld Justine , Wesson Ella , Thapa Punam , Bordiga Pierrick , McMurtry Noah , Llamas Juan , Kitcher Siân R. , López-Porras Ana I. , Cui Runjia , Behnammanesh Ghazaleh , Bird Jonathan E. , Ballesteros Angela , Vélez-Ortega A. Catalina , Edge Albert SB , Deans Michael R. , Gnedeva Ksenia , Shrestha Brikha R. , Manor Uri , Zhao Bo , Ricci Anthony J. , Tarchini Basile , Basch Martin , Stepanyan Ruben S. , Landegger Lukas D. , Rutherford Mark , Liberman M. Charles , Walters Bradley J. , Kros Corné J. , Richardson Guy P. , Cunningham Lisa L. , Indzhykulian Artur A.
Published: September 2023

Our sense of hearing is mediated by cochlear hair cells, localized within the sensory epithelium called the organ of Corti. There are two types of hair cells in the cochlea, which are organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains a few thousands of hair cells, and their survival is essential for our perception of sound because they are terminally differentiated and do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. However, the sheer number of cells along the cochlea makes manual quantification impractical. Machine learning can be used to overcome this challenge by automating the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, human, pig and guinea pig cochlear tissue, from normal conditions and followingin-vivoandin-vitroototoxic drug application. The dataset includes over 90,000 hair cells, all of which have been manually identified and annotated as one of two cell types: inner hair cells and outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to supply other groups within the hearing research community with the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.
Adrenergic and mesenchymal signatures are identifiable in cell-free DNA and correlate with metastatic disease burden in children with neuroblastoma
Authors: Vayani Omar R. , Kaufman Maria E. , Moore Kelley , Chennakesavalu Mohansrinivas , TerHaar Rachel , Chaves Gepoliano , Chlenski Alexandre , He Chuan , Cohn Susan L. , Applebaum Mark A.
Published: September 2023

Background

Cell free DNA (cfDNA) profiles of 5-hydroxymethylcytosine (5-hmC), an epigenetic marker of open chromatin and active gene expression, are correlated with metastatic disease burden in patients with neuroblastoma. Neuroblastoma tumors are comprised of adrenergic (ADRN) and mesenchymal (MES) cells, and the relative abundance of each in tumor biopsies has prognostic implications. We hypothesized that ADRN and MES specific signatures could be quantified in cfDNA 5-hmC profiles and would augment the detection of metastatic burden in patients with neuroblastoma.

Methods

We previously performed an integrative analysis to identify ADRN and MES specific genes (n=373 and n=159, respectively). Purified DNA from cell lines was serial diluted with healthy donor cfDNA. Using Gene Set Variation Analysis (GSVA), ADRN and MES signatures were optimized. We then quantified signature scores, and our prior neuroblastoma signature, in cfDNA from 84 samples from 46 high-risk patients including 21 patients with serial samples.

Results

Samples from patients with higher metastatic burden had increased GSVA scores for both ADRN and MES gene signatures (p < 0.001). While ADRN and MES signature scores tracked together in serially collected samples, we identified instances of patients with increases in either MES or ADRN score at relapse.

Conclusions

While it is feasible to identify ADRN and MES signatures using 5-hmC profiles of cfDNA from neuroblastoma patients and correlate these signatures to metastatic burden, additional data are needed to determine the optimal strategies for clinical implementation. Prospective evaluation in larger cohorts is ongoing.
White spot syndrome virus endogenous viral elements (EVE) revealed by circular viral copy DNA (cvcDNA) in shrimp
Authors: Taengchaiyaphum Suparat , Srisala Jiraporn , Wongkhaluang Prapatsorn , Sukthaworn Suchitraporn , Macias Joaquin , Udin Iman Ihsan , Chokkara Madhu Babu , Athikkavil Mohammed Musthafa , Alday-Sanz Victoria , Flegel Timothy W. , Sritunyalucksana Kallaya
Published: September 2023

Circular, viral copy DNA (cvcDNA) can reveal the existence of endogenous viral elements (EVE) in shrimp genomic DNA. Here we describe isolation and sequencing of cvcDNA from a breeding stock of the whiteleg shrimpPenaeus vannamei. The stock was developed by onward breeding and selection for white spot syndrome virus (WSSV)-free individual survivors of white spot disease outbreaks. The stock exhibits high tolerance to WSSV. A pool of DNA extracted from 10 shrimp from this stock was subjected to cvcDNA isolation and amplification followed by high throughput sequencing. This revealed DNA fragments corresponding to locations covering much of the 300,000 bp WSSV genome. However, high frequency-read-fragments (HFRF) mapped to a surprisingly small region of approximately 1,400 bp. We hypothesized that the HFRF reflected their selection due to provision of tolerance to WSSV. Four PCR primer sets were designed to cover the 1,365 bp mapped region. One pair (Set 1) targeted the whole 1,365 bp mapped region, while another 3 primer sets (Set 2-4), targeted regions within the 1,365 bp target. All 4 primer sets were used with DNA samples from each of 36 shrimp from the same breeding stock (including the 10 used for cvcDNA preparation). Individual positive PCR results varied widely from shrimp to shrimp, ranging from only 1 primer set up to 4 primer sets. Only 1 specimen gave an amplicon of 1,365 bp, while others gave single to multiple positive amplicons in both continuous and discontinuous regions. This indicated that the amplicons did not arise from contiguous targets and might vary in insertion length. The results also confirmed that none of the shrimp were infected with WSSV. Sequencing of the PCR amplicons of expected sizes revealed sequence identity to extant WSSV genomes. This data will be used to screen the breeding stock for EVE that provide WSSV tolerance.
Benchmarking of PROTAC docking and virtual screening tools
Authors: Rovers Evianne , Schapira Matthieu
Published: September 2023

Proteolysis targeting chimeras (PROTACs) are bifunctional compounds that recruit an E3 ligase to a target protein to induce ubiquitination and degradation of the target and are pioneer molecules in the field of proximity pharmacology. Rational PROTAC design is a challenging process and novel computational tools have emerged that attempt to predict the ternary complexes created by PROTACs and identify PROTAC candidates. To compare the performance of recent PROTAC design and screening methods, a benchmark was developed to test the ability of these tools to 1) predict the ternary complexes observed in crystal structures and 2) dissociate active from inactive PROTACs. Unlike traditional protein-protein complex prediction software, the PROTAC virtual screening methods often generate successfully PROTAC-induced protein complex structures observed crystallographically, but these experimentally validated predictions are not dissociated from dozens or more of other predicted structures. PROTAC virtual screening efficiency is unclear and highly variable, in part due to the limited size of experimental datasets and the low number of negative controls. Defining ubiquitination zones within cullin-RING complexes does not improve predictions, but conformational arrangements can sometimes be found that are exclusively associated with active PROTACs. Computer assisted PROTAC design is still in its infancy. Pioneering tools highlight the promises and challenges in the field and may be more valuable when guided by clear structural and biophysical data and validated on specific chemical series.
Remote homolog detection places insect chemoreceptors in a cryptic protein superfamily spanning the tree of life
Authors: Himmel Nathaniel J. , Moi David , Benton Richard
Published: September 2023

Many proteins exist in the so-called “twilight zone” of sequence alignment, where low pairwise sequence identity makes it difficult to determine homology and phylogeny1, 2. As protein tertiary structure is often more conserved3, recent advances inab initioprotein folding have made structure-based identification of putative homologs feasible4–6. However, structural screening and phylogenetics are in their infancy, particularly for twilight zone proteins. We present a pipeline for the identification and characterization of distant homologs, and apply it to 7-transmembrane domain ion channels (7TMICs), a protein group founded by insect Odorant and Gustatory receptors. Previous sequence and limited structure-based searches identified putatively-related proteins, mainly in other animals and plants7–10. However, very few 7TMICs have been identified in non-animal, non-plant taxa. Moreover, these proteins’ remarkable sequence dissimilarity made it uncertain if disparate 7TMIC types (Gr/Or, Grl, GRL, DUF3537, PHTF and GrlHz) are homologous or convergent, leaving their evolutionary history unresolved. Our pipeline identified thousands of new 7TMICs in archaea, bacteria and unicellular eukaryotes. Using graph-based analyses and protein language models to extract family-wide signatures, we demonstrate that 7TMICs have structure and sequence similarity, supporting homology. Through sequence and structure-based phylogenetics, we classify eukaryotic 7TMICs into two families (Class-A and Class-B), which are the result of a gene duplication predating the split(s) leading to Amorphea (animals, fungi and allies) and Diaphoretickes (plants and allies). Our work reveals 7TMICs as a cryptic superfamily with origins close to the evolution of cellular life. More generally, this study serves as a methodological proof of principle for the identification of extremely distant protein homologs.
Stimulation of median raphe terminals in dorsal CA2 reduces social investigation in male mice specifically investigating social stimulus of ovariectomized female mice
Authors: Lee Su Hyun , Cilz Nicholas I. , Avram Sarah K. Williams , Cymerblit-Sabba Adi , Song June , Courey Karis , Howley Austin , Cooke Michaela E. , Young W. Scott
Published: September 2023

The cornu ammonis area 2 (CA2) region is essential for social behaviors, especially in social aggression and social memory. Recently, we showed that targeted CA2 stimulation of vasopressin presynaptic fibers from the paraventricular nuclei of hypothalamus strongly enhances social memory in mice. In addition, the CA2 area of the mouse hippocampus receives neuronal inputs from other regions including the septal nuclei, the diagonal bands of Broca, supramammillary nuclei, and median raphe nucleus. However, the functions of these projections have been scarcely investigated. A functional role of median raphe (MR) – CA2 projection is supported by the MR to CA2 projections and 82% reduction of hippocampal serotonin (5-HT) levels following MR lesions. Thus, we investigated the behavioral role of presynaptic fibers from the median raphe nucleus projecting to the dorsal CA2 (dCA2). Here, we demonstrate the optogenetic stimulation of 5-HT projections to dCA2 from the MR do not alter social memory, but instead reduce social interaction. We show that optical stimulation of MR fibers excites interneurons in the stratum radiatum (SR) and stratum lacunosum moleculare (SLM) of CA2 region. Consistent with these observations, we show that bath application of 5-HT increases spontaneous GABA release onto CA2 pyramidal neurons and excites presumed interneurons located in the SR/SLM. This is the first study, to our knowledge, which investigates the direct effect of 5-HT release from terminals onto dCA2 neurons on social behaviors. This highlights the different roles for these inputs (i.e., vasopressin inputs regulating social memory versus serotonin inputs regulating social interaction).
Natural gene variation inCannabis sativaunveils a key region of cannabinoid synthase enzymes
Authors: Villard Cloé , Bayer Christian , Medici Nora Pasquali , van de Peppel Arjen C. , Cankar Katarina , Verstappen Francel , Kappers Iris F. , Schranz M. Eric , Daniel Bastian , van Velzen Robin
Published: September 2023

Cannabinoids are well-known specialised metabolites from the plantCannabis sativaL. (cannabis). They exhibit various therapeutical to intoxicating psychoactive effects and have potential for medicinal applications. Among the enzymes involved in cannabinoid biosynthesis, cannabinoid oxidocyclases such as the tetrahydrocannabinolic acid (THCA) synthase play a key role in determining cannabis chemotype. To improve our understanding of cannabinoid oxidocyclase structure-function relationship, we proposed a new approach to targeted mutagenesis. By reviewing cannabis natural variation, three cannabinoid oxidocyclase mutations (S355N, CONF, G376R) associated to atypical plant chemotypes were selected.In-vitrocharacterization of THCA synthase mutants demonstrated these mutations significantly impact enzyme activity, correlating with the associated chemotype: S355N nearly inactivated the THCA synthase, CONF impaired CBGA metabolization and altered product specificity, while G376R drastically reduced enzyme activity and altered product specificity.In-silicodocking experiments permitted to model the successive steps of THCA synthase substrate metabolization, revealing that the three mutations hamper substrate binding. Collectively, our results demonstrated how plant diversity can be leveraged to guide enzyme targeted mutagenesis, highlighted a key region of cannabinoid oxidocyclases, and permitted the establishment of a new model of the THCA synthase catalytic mechanism. This provides new insights into enzyme function, which can ultimately help developing medicinal cannabis cultivars and cannabinoid biotechnological production.
Role of IL-6 and IL10 immune response genes against nematodeHaemonchus contortusin ovis aries- a novel report
Authors: Rawat Kavita , Pal Aruna , Banerjee Samiddha , Pal Abantika , Chatterjee Paresh Nath , Batabyal Subhasis
Published: September 2023

Haemonchus contortusis one of the most deadly parasites affecting sheep industry causing heavy economic loss. In our earlier study, we have reported RIGI, an earlier established antiviral molecule and CD14 (an earlier established antibacterial molecule) to have potential role in antiparasitic immunity for the first time. In this current study, we aim to clone and sequence the IL-6 and IL10 genes in sheep (Ovis aries) and utilized bioinformatics methods to analyze and compare the functional and structural domains of peptides produced from IL6 and IL10. Furthermore, the study explored these domains in three-dimensional structures. The findings of this study provide molecular characterization of IL-6 and IL10 in sheep, which is essential for advancing our understanding of functional immune responses in this animal. We report IL6 and IL10 to have potential antiparasitic role against H. contortus for first time. The production of these molecules opens up possibilities for its potential use as recombinant proteins to manipulate the immune response. Evaluating its value in vaccine research and gaining a broader understanding of its role in immune responses becomes feasible with the availability of IL-6 and IL10. Moreover, the differential mRNA expression levels of IL-6, IL10 between healthy and diseased sheep indicate its crucial role in maintaining homeostasis and mounting immune responses. IL10 acts as receptor for H. contortus. The identification of this immune-responsive gene also offers new avenues for investigating long-term resistance to H. contortus infection in sheep.
Logistic tumor-population growth and ghost-points symmetry
Authors: Pasetto Stefano , Harshe Isha , Brady-Nicholls Renee , Gatenby Robert. A. , Enderling Heiko
Published: September 2023

The observed time evolution of a population is well approximated by a logistic function in many research fields, including oncology, ecology, chemistry, demography, economy, linguistics, and artificial neural networks. Initial growth is exponential at a constant rate and capped at a limit size, i.e., the carrying capacity. In mathematical oncology, the carrying capacity has been postulated to be co-evolving and thus patient-specific. As the relative tumor-over-carrying capacity ratio may be predictive and prognostic for tumor growth and treatment response dynamics, it is paramount to estimate it from limited clinical data.

We show that exploiting the logistic function’s rotation symmetry can help estimate the population’s growth rate and carry capacity from fewer data points than conventional regression approaches. We test this novel approach against a classic oncology database of logistic tumor growth, achieving a 30% to 40% reduction in the time necessary to correctly estimate the logistic growth rate and carrying capacity. Our results will improve tumor dynamics forecasting and augment the clinical decision-making process.
Predicting RNA-seq coverage from DNA sequence as a unifying model of gene regulation
Authors: Linder Johannes , Srivastava Divyanshi , Yuan Han , Agarwal Vikram , Kelley David R.
Published: September 2023

Sequence-based machine learning models trained on genome-scale biochemical assays improve our ability to interpret genetic variants by providing functional predictions describing their impact on the cis-regulatory code. Here, we introduce a new model, Borzoi, which learns to predict cell- and tissue-specific RNA-seq coverage from DNA sequence. Using statistics derived from Borzoi’s predicted coverage, we isolate and accurately score variant effects across multiple layers of regulation, including transcription, splicing, and polyadenylation. Evaluated on QTLs, Borzoi is competitive with, and often outperforms, state-of-the-art models trained on individual regulatory functions. By applying attribution methods to the derived statistics, we extract cis-regulatory patterns driving RNA expression and post-transcriptional regulation in normal tissues. The wide availability of RNA-seq data across species, conditions, and assays profiling specific aspects of regulation emphasizes the potential of this approach to decipher the mapping from DNA sequence to regulatory function.
Navigating Pubertal Goldilocks: The Optimal Pace for Hierarchical Brain Organization
Authors: Szakács Hanna , Mutlu Murat Can , Balestrieri Giulio , Gombos Ferenc , Braun Jochen , Kringelbach Morten L. , Deco Gustavo , Kovács Ilona
Published: September 2023

Adolescence is a timed process with an onset, tempo, and duration. Nevertheless, the temporal dimension, especially the pace of maturation, remains an insufficiently studied aspect of developmental progression. This study focuses on the modifications due to the different timings of developmental shifts during adolescence and addresses the impact of adolescent maturation on brain development. To reveal potential relationships between pubertal pace and the advancement of brain organisation, we analyse the connection between skeletal age-based maturation stages and hierarchical organisation in the temporal dynamics of resting-state EEG recordings (alpha frequency range). By adopting skeletal maturity as a proxy for pubertal progress and employing entropy production to measure hierarchical brain organisation, our findings indicate that an average maturational trajectory optimally aligns with cerebral hierarchical order. Adaptive developmental plasticity may not fully compensate for accelerated or decelerated timelines, potentially increasing the risk of behavioural problems and psychiatric disorders consequent to such alterations.
CHARMM-GUI Multicomponent Assembler for Modeling and Simulation of Complex Multicomponent Systems
Authors: Kern Nathan R. , Lee Jumin , Choi Yeol Kyo , Im Wonpil
Published: September 2023

Atomic-scale molecular modeling and simulation are powerful tools for computational biology. However, constructing models with large, densely packed molecules, non-water solvents, or with combinations of multiple biomembranes, polymers, and nanomaterials remains challenging and requires significant time and expertise. Furthermore, existing tools do not support such assemblies under the periodic boundary conditions (PBC) necessary for molecular simulation. Here, we describeMulticomponent Assemblerin CHARMM-GUI that automates complex molecular assembly and simulation input preparation under the PBC. We demonstrate its versatility by preparing 6 challenging systems with varying density of large components: (1) solvated proteins, (2) solvated proteins with a pre-equilibrated membrane, (3) solvated proteins with a sheet-like nanomaterial, (4) solvated proteins with a sheet-like polymer, (5) a mixed membrane-nanomaterial system, and (6) a sheet-like polymer with gaseous solvent.Multicomponent Assembleris expected to be a unique cyberinfrastructure to facilitate innovative studies of complex interactions between small (organic and inorganic) molecules, biomacromolecules, polymers, and nanomaterials.
Hybrid Amyloid Quantum Dot Nanoassemblies to Probe Neuroinflammatory Damage
Authors: Chiang Wesley , Urban Jennifer M. , Yanchik-Slade Francine , Stout Angela , Nilsson Bradley L. , Gelbard Harris A. , Krauss Todd D.
Published: September 2023

Various oligomeric species of amyloid-beta have been proposed to play different immunogenic roles in the cellular pathology of Alzheimer’s Disease. However, investigating the role of a homogenous single oligomeric species has been difficult due to highly dynamic oligomerization and fibril formation kinetics that convert between many species. Here we report the design and construction of a quantum dot mimetic for larger spherical oligomeric amyloid species as an “endogenously” fluorescent proxy for this cytotoxic species to investigate its role in inducing inflammatory and stress response states in neuronal and glial cell types.
Myostatin is a major endocrine driver of follicle-stimulating hormone synthesis
Authors: Ongaro Luisina , Zhou Xiang , Wang Ying , Zhou Ziyue , Schultz Hailey , Buddle Evan R.S. , Brûlé Emilie , Lin Yeu-Farn , Schang Gauthier , Castonguay Roselyne , Liu Yewei , Su Gloria H. , Seidah Nabil , Ray Kevin C. , Karp Seth J. , Boehm Ulrich , Lee Se-Jin , Bernard Daniel J.
Published: September 2023

Myostatin is a paracrine myokine that regulates muscle mass in a variety of species, including humans. Here, we report a functional role for myostatin as an endocrine hormone directly promoting pituitary follicle-stimulating hormone (FSH) synthesis and thereby ovarian function. Previously, this FSH-stimulating role was attributed to other members of the transforming growth factor β family, the activins. The results both challenge activin’s eponymous role in FSH synthesis and establish an endocrine axis between skeletal muscle and the pituitary gland. The data also suggest that efforts to antagonize myostatin to treat muscle wasting disorders may have unintended consequences on fertility.

One-Sentence Summary

Hormone synthesis and reproduction depend on crosstalk between skeletal muscle and the pituitary gland.
Chromatographic, Immuno-inflammatory, and nephrotoxic Assessment of selected culinary oils in Experimental Models
Authors: Okoye Jude Ogechukwu , Delu-Mozie Chiagoziem Moral , Nwachioma Maureen Ugochukwu , Modozie Uchenna Benjamin
Published: September 2023

Background

Dietary oils are crucial for everyday human nutrition. They contain essential fatty acids and support a range of physiological functions. However, concerns regarding their possible toxicity have been expressed, particularly concerning the elevation of cholesterol levels, particularly Low-Density Lipoprotein (LDL). This study investigated the composition of selected dietary oils and determined their physiologic effects and the micro-architectural integrity of the kidney.

Methods

In this experimental study, 30 Albino rats were used in this study. The animals were divided into 5 groups: Groups A, B, C, D, and E (n=6 each). Group A (control) received normal rat pellets only while Groups B, C, D, and E received rat pellets mixed with Avocado oil, Coconut oil, Palm oil, and Peanut oil. Blood samples were drawn, and kidneys were excised. Data generated from biochemical, haematological, and histological investigations were analyzed using ANOVA, Pearson’s correlation, andPost hoctest. Significance was set at p< 0.05.

Results

The results indicated significant differences in fatty acid levels between oils (p< 0.05). Higher levels of oleic acid, lauric acid, palmitic acid, and oleic acid were found in coconut oil, Palm oil, Avocado oil, and Peanut oil, respectively. Significant differences in urea levels were observed between the control group and other treatment groups (p= 0.001). Group B had lower levels of triglyceride while groups C and D had higher levels of LDL and organ weight, respectively compared with the control group (p= 0.035, 0.042, and 0.008, respectively). Group E had a higher neutrophil-lymphocyte ratio, mean corpuscular haemoglobin concentration, lower lymphocyte-monocyte ratio, and red cell distribution width (p= 0.325, 0.025, 0.068, and 0.053, respectively). Kidney sections revealed varying degrees of necrosis and inflammation,

Conclusion

The study provides valuable insights indicating potential oil-induced effects on health. It advises caution during the application of the oils in culinary activities.
Scoring alignments by embedding vector similarity
Authors: Ashrafzadeh Sepehr , Golding G. Brian , Ilie Silvana , Ilie Lucian
Published: September 2023

Sequence similarity is of paramount importance in biology, as similar sequences tend to have similar function and share common ancestry. Scoring matrices, such as PAM or BLO-SUM, play a crucial role in all bioinformatics algorithms for identifying similarities, but have the drawback that they are fixed, independent of context. We propose a new scoring method for amino acid similarity that remedies this weakness, being contextually dependent. It relies on recent advances in deep learning architectures that employ self-supervised learning in order to leverage the power of enormous amounts of unlabelled data to generate contextual embeddings, which are vector representations for words. These ideas have been applied to protein sequences, producing embedding vectors for protein residues. We propose theE-scorebetween two residues as the cosine similarity between their embedding vector representations. Thorough testing on a wide variety of reference multiple sequence alignments indicate that the alignments produced using the newE-score method, especially ProtT5-score, are significantly better than those obtained using BLOSUM matrices. The new method proposes to change the way alignments are computed, with far reaching implications in all areas of textual data that use sequence similarity. The program to compute alignments based on variousE-scores is available as a web server ate-score.csd.uwo.ca. The source code is freely available for download fromgithub.com/lucian-ilie/E-score.
Foodscapes for Salmon and Other Mobile Consumers in River Networks
Authors: Rossi Gabriel J. , Bellmore J. Ryan , Armstrong Jonathan B. , Jeffres Carson , Naman Sean M. , Carlson Stephanie M. , Grantham Theodore E. , Kaylor Matthew J. , White Seth , Katz Jacob , Power Mary E.
Published: September 2023

Mobile consumers track fluctuating resources across heterogeneous landscapes to grow and survive. In river networks, the abundance and accessibility of food and the costs of foraging vary between habitats and through time, providing a shifting mosaic of growth opportunities for mobile consumers. However, a framework integrating the spatiotemporal dynamics of growth potential within riverscapes has been lacking. Here we present the concept of “foodscapes” to depict the dynamic changes in food abundance, food accessibility, and foraging costs that contribute to spatial and temporal variation of fish growth in rivers. Drawing on case studies of salmonid fishes from Alaska to California, we illustrate that “healthy” foodscapes provide a plethora of foraging opportunities—promoting diverse life history strategies that potentially enhance population stability. We identify knowledge gaps in understanding foodscapes, and approaches for management that focus on restoring trophic pathways which support diverse foraging and growth opportunities for fish in river networks.
Differential reaction norms to ocean acidification in two oyster species from contrasting habitats
Authors: Caillon Coline , Pernet Fabrice , Lutier Mathieu , Poi Carole Di
Published: September 2023

Ocean acidification (OA), a consequence of the increase in anthropogenic emissions of carbon dioxide, causes major changes in the chemistry of carbonates in the ocean with deleterious effects on calcifying organisms. The pH/pCO2range to which species are exposed in nature is important to consider when interpreting the response of coastal organisms to OA. In this context, emerging approaches, which assess the reaction norms of organisms to a wide pH gradient, are improving our understanding of tolerance thresholds and acclimation potential to OA. In this study, we decipher the reaction norms of two oyster species living in contrasting habitats: the intertidal oysterCrassostrea gigasand the subtidal flat oysterOstrea edulis, which are two economically and ecologically valuable species in temperate ecosystems. Six-month-old oysters of each species were exposed in common garden for 48 days to a pH gradient ranging from 7.7 to 6.4 (total scale). Both species are tolerant down to a pH of 6.6 with high plasticity in fitness-related traits such as survival and growth. However, oysters undergo remodelling of membrane fatty acids to cope with decreasing pH along with shell bleaching impairing shell integrity and consequently animal fitness. Finally, our work reveals species-specific physiological responses and highlights that intertidalC. gigasseems to have a better acclimation potential to rapid and extreme OA changes thanO. edulis. Overall, our study provides important data about the phenotypic plasticity and its limits in two oyster species, which is essential for assessing the challenges posed to marine organisms by OA.
Spatial behaviors and seasonal habitat use of the increasingly endangered thick-billed parrot (Rhynchopsitta pachyrhyncha)
Authors: Sheppard James K , Cruz Javier , Torres González Luz Francelia , Cruz Nieto Miguel Ángel , Swaisgood Ronald R. , Lamberski Nadine
Published: September 2023

The thick-billed parrot (Rhynchopsitta pachyrhyncha) inhabits highland pine forests in the Sierra Madre Occidental ranges of northwestern Mexico. Their populations have declined significantly to <2000 individuals due to habitat loss, illegal hunting and increasing predation. Despite their ecological and cultural importance and increasingly endangered status, the species is data deficient. Our study aimed to inform and enhance conservation management strategies for thick-billed parrots with information on their spatial ecology, habitat use, migratory behaviors and social associations. We deployed biotelemetry devices to conduct the first tracking study of wild thick-billed parrots. Our study revealed that thick-billed parrots are seasonal migrators, departing their breeding habitats around October and returning from southern habitats around April. Our research also identified previously unknown overwintering sites and migratory stopover locations, as well as a new nesting site. The parrots exhibited high spatial variability in range shifting behavior, but all tracked parrots exhibited range shifts during migration, with durations of 3 to 181 days and distances of 173 to 765 km. They traveled in close social groups and migratory routes primarily followed high-elevation forests along the Sierra Madre Occidental ranges. Home range analysis indicated smaller breeding site ranges and larger overwintering ranges, possibly reflecting nesting constraints and winter food resource dispersion. Parrot spatial associations favored high-elevation forest landscapes with tall and wide-trunked trees, underscoring the importance of preserving old-growth forests for nesting and foraging. Less than 20 % of parrot habitats have formal regulatory protections. Conservation management efforts must focus on increasing protections for nesting areas, overwintering habitats, and key migratory stopover sites. As climate change exacerbates regional threats, integrated management plans involving local stakeholders and communities are essential for the parrots’ long-term survival and the preservation of their old-growth forest habitats.
Exploring “dark matter” protein folds using deep learning
Authors: Harteveld Zander , Van Hall-Beauvais Alexandra , Morozova Irina , Southern Joshua , Goverde Casper , Georgeon Sandrine , Rosset Stéphane , Defferrard Michëal , Loukas Andreas , Vandergheynst Pierre , Bronstein Michael M. , Correia Bruno E.
Published: September 2023

De novoprotein design aims to explore uncharted sequence-and structure areas to generate novel proteins that have not been sampled by evolution. One of the main challenges inde novodesign involves crafting “designable” structural templates that can guide the sequence search towards adopting the target structures. Here, we present an approach to learn patterns of protein structure based on a convolutional variational autoencoder, dubbed Genesis. We coupled Genesis with trRosetta to design sequences for a set of protein folds and found that Genesis is capable of reconstructing native-like distance-and angle distributions for five native folds and three novel, so-called “dark-matter” folds as a demonstration of generalizability. We used a high-throughput assay to characterize protease resistance of the designs, obtaining encouraging success rates for folded proteins and further biochemically characterized folded designs. The Genesis framework enables the exploration of the protein sequence and fold space within minutes and is not bound to specific protein topologies. Our approach addresses the backbone designability problem, showing that structural patterns in proteins can be efficiently learned by small neural networks and could ultimately contribute to thede novodesign of proteins with new functions.
Human Ageing Genomic Resources: updates on key databases in ageing research
Authors: de Magalhães João Pedro , Abidi Zoya , Arantes dos Santos Gabriel , Avelar Roberto A. , Barardo Diogo , Chatsirisupachai Kasit , Clark Peter , De-Souza Evandro A. , Johnson Emily J. , Lopes Inês , Novoa Guy , Senez Ludovic , Talay Angelo , Thornton Daniel , To Paul Ka Po
Published: September 2023

Ageing is a complex and multifactorial process. For two decades, the Human Ageing Genomic Resources (HAGR) have aided researchers in the study of various aspects of ageing and its manipulation. Here we present the key features and recent enhancements of these resources, focusing on its six main databases. One database, GenAge, focuses on genes related to ageing, featuring 307 genes linked to human ageing and 2205 genes associated with longevity and ageing in model organisms. AnAge focuses on ageing, longevity, and life-history across animal species, containing data on 4645 species. DrugAge includes information about 1097 longevity drugs and compounds in model organisms such as mice, rats, flies, worms, and yeast. GenDR provides a list of 214 genes associated with the life-extending benefits of dietary restriction in model organisms. CellAge contains a catalogue of 866 genes associated with cellular senescence. The LongevityMap serves as a repository for genetic variants associated with human longevity, encompassing 3144 variants pertaining to 884 genes. Additionally, HAGR provides various tools as well as gene expression signatures of ageing, dietary restriction, and replicative senescence based on meta-analyses. Our databases are integrated, regularly updated, and manually curated by experts. HAGR is freely available online (https://genomics.senescence.info/).
Gene count normalization in single-cell imaging-based spatially resolved transcriptomics
Authors: Atta Lyla , Clifton Kalen , Anant Manjari , Aihara Gohta , Fan Jean
Published: September 2023

Recent advances in imaging-based spatially resolved transcriptomics (im-SRT) technologies now enable high-throughput profiling of targeted genes and their locations in fixed tissues. Normalization of gene expression data is often needed to account for technical factors that may confound underlying biological signals. Here, we investigate the potential impact of different gene count normalization methods with different targeted gene panels in the analysis and interpretation of im-SRT data. Using different simulated gene panels that overrepresent genes expressed in specific tissue regions or cell types, we demonstrate how normalization methods based on detected gene counts per cell differentially impact normalized gene expression magnitudes in a region- or cell type-specific manner. We show that these normalization-induced effects may reduce the reliability of downstream analyses including differential gene expression, gene fold change, and spatially variable gene analysis, introducing false positive and false negative results when compared to results obtained from gene panels that are more representative of the gene expression of the tissue’s component cell types. These effects are not observed with normalization approaches that do not use detected gene counts for gene expression magnitude adjustment, such as with cell volume or cell area normalization. We recommend using non-gene count-based normalization approaches when feasible and evaluating gene panel representativeness before using gene count-based normalization methods if necessary. Overall, we caution that the choice of normalization method and gene panel may impact the biological interpretation of the im-SRT data.
Translocation of gut commensal bacteria to the brain
Authors: Thapa Manoj , Kumari Anuradha , Chin Chui-Yoke , Choby Jacob E. , Jin Fengzhi , Bogati Bikash , Chopyk Daniel M. , Koduri Nitya , Pahnke Andrew , Elrod Elizabeth J. , Burd Eileen M. , Weiss David S. , Grakoui Arash
Published: September 2023

The gut-brain axis, a bidirectional signaling network between the intestine and the central nervous system, is crucial to the regulation of host physiology and inflammation. Recent advances suggest a strong correlation between gut dysbiosis and neurological diseases, however, relatively little is known about how gut bacteria impact the brain. Here, we reveal that gut commensal bacteria can translocate directly to the brain when mice are fed an altered diet that causes dysbiosis and intestinal permeability, and that this also occurs without diet alteration in distinct murine models of neurological disease. The bacteria were not found in other systemic sites or the blood, but were detected in the vagus nerve. Unilateral cervical vagotomy significantly reduced the number of bacteria in the brain, implicating the vagus nerve as a conduit for translocation. The presence of bacteria in the brain correlated with microglial activation, a marker of neuroinflammation, and with neural protein aggregation, a hallmark of several neurodegenerative diseases. In at least one model, the presence of bacteria in the brain was reversible as a switch from high-fat to standard diet resulted in amelioration of intestinal permeability, led to a gradual loss of detectable bacteria in the brain, and reduced the number of neural protein aggregates. Further, in murine models of Alzheimer’s disease, Parkinson’s disease, and autism spectrum disorder, we observed gut dysbiosis, gut leakiness, bacterial translocation to the brain, and microglial activation. These data reveal a commensal bacterial translocation axis to the brain in models of diverse neurological diseases.