bluuebunny/crossref_metadata_2025 huggingface dataset:
First record of Ixodes keiransi (Acari: Ixodidae) in New Jersey, USA
Authors: Narvaez Zoe E , Egizi Andrea M , Price Dana C
Published: March 2024

The hard tick, Ixodes keiransi Beati, Nava, Venzal, & Guglielmone, formerly the North American lineage of Ixodes affinis Neumann, is expanding its range northward along the US East Coast. In July 2023, we collected I. keiransi adult female and nymph in a single sampling event, suggesting its range now includes southern New Jersey. In this area, I. keiransi is sympatric with northern populations of Ixodes scapularis Say (Acari: Ixodidae), the primary vector of Lyme disease. Given its status as an enzootic vector of spirochaetes in the Borrelia burgdorferi sensu lato complex, proper differentiation of these 2 species will be critical for accurate estimates of entomological risk. Targeted surveillance should be implemented to monitor further I. keiransi expansion and to elucidate the phenology and enzootic role of this and other understudied Ixodes spp. in the northeastern United States.
Forensic investigation of carcass decomposition and dipteran fly composition over the summer and winter: a comparative analysis of indoor versus outdoor at a multi-story building
Authors: Almutawa Masha’el Y , Al-Khalifa Mohamed S , Al-Dhafer Hathal M , Abdel-Dayem Mahmoud S , Ebaid Hossam , Ahmed Ashraf M
Published: March 2024

This study aimed to explore the rate of decomposition of rabbit carcasses and the succession pattern of the associated dipteran flies outdoor, indoor, and on the roof of a 4-story building during the summer and winter. A total of 6,069 flies were recorded, with 30.91% reported as 2 waves outdoor and on the roof in the summer and 69.09% as 4 waves outdoor in the winter. The roof showed the most flies in the summer but the least in the winter, whereas the outdoor showed the most in the winter but the least in the summer. The ground and first floors showed the most indoor flies, while the second and third floors showed the least in both seasons. Indoor carcasses decomposed slower than those outdoor, and those on the second and third floors decomposed slower than those on the ground and first floors. Ten fly species from 8 families were identified in the winter, compared to 6 from 5 families in the summer. The most abundant species was Musca domestica Linnaeus (Muscidae) on the roof in the summer, while it was Chrysomya albiceps (Wiedemannn) (Calliphoridae) outdoor in the winter. The rare species (singletons) were Musca sp. (Muscidae) and Megaselia scalaris (Loew) (Phoridae) on the first floor in both seasons, Scaptomyza pallida (Zetterstedt) (Drosophilidae) on the ground floor in the summer, and Atherigona orientalis Schiner (Muscidae) outdoor in the winter. These data highlight the variance in carcass decomposition and fly composition across outdoor, indoor, and the roof of human dwellings, which could be of forensic importance.
NR3C2 microdeletions—an underrecognized cause of pseudohypoaldosteronism type 1A: a case report and literature review
Authors: Boyanton Bobby L , Zarate Yuri A , Broadfoot Brannon G , Kelly Thomas , Crawford Brendan D
Published: March 2024

Objectives

Pseudohypoaldosteronism type 1A (PHA1A) is caused by haploinsufficiency of the mineralocorticoid receptor (MR). Heterozygous small insertions/deletions, transitions, and/or transversions within NR3C2 comprise the majority (85%-90%) of pathogenic copy number variants. Structural chromosomal abnormalities, contiguous gene deletion syndromes, and microdeletions are infrequent. We describe a neonate with PHA1A due to a novel NR3C2 microdeletion involving exons 1-2.

Methods

Literature review identified 39 individuals with PHA1A due to NR3C2 microdeletions. Transmission modality, variant description(s), testing method(s), exon(s) deleted, and affected functional domain(s) were characterized.

Results

In total, 40 individuals with NR3C2 microdeletions were described: 19 involved contiguous exons encoding a single MR domain; 21 involved contiguous exons encoding multiple MR domains. Transmission modality frequency was familial (65%), de novo (20%), or unknown (15%). Sequencing (Sanger or short-read next-generation) failed to detect microdeletions in 100% of tested individuals (n = 38). All were detected using deletion/duplication testing modalities. In 2 individuals, only microarray-based testing was performed; microdeletions were detected in both cases.

Conclusion

Initial testing for PHA1A should rely on sequencing to detect the most common genetic alterations. Deletion/duplication analysis should be performed when initial testing is nondiagnostic. Most NR3C2 microdeletions are parentally transmitted, thus highlighting the importance of familial genetic testing and counseling.
Darwin3: a large-scale neuromorphic chip with a novel ISA and on-chip learning
Authors: Ma De , Jin Xiaofei , Sun Shichun , Li Yitao , Wu Xundong , Hu Youneng , Yang Fangchao , Tang Huajin , Zhu Xiaolei , Lin Peng , Pan Gang
Published: March 2024

Spiking neural networks (SNNs) are gaining increasing attention for their biological plausibility and potential for improved computational efficiency. To match the high spatial-temporal dynamics in SNNs, neuromorphic chips are highly desired to execute SNNs in hardware-based neuron and synapse circuits directly. This paper presents a large-scale neuromorphic chip named Darwin3 with a novel instruction set architecture, which comprises 10 primary instructions and a few extended instructions. It supports flexible neuron model programming and local learning rule designs. The Darwin3 chip architecture is designed in a mesh of computing nodes with an innovative routing algorithm. We used a compression mechanism to represent synaptic connections, significantly reducing memory usage. The Darwin3 chip supports up to 2.35 million neurons, making it the largest of its kind on the neuron scale. The experimental results showed that the code density was improved by up to 28.3× in Darwin3, and that the neuron core fan-in and fan-out were improved by up to 4096× and 3072× by connection compression compared to the physical memory depth. Our Darwin3 chip also provided memory saving between 6.8× and 200.8× when mapping convolutional spiking neural networks onto the chip, demonstrating state-of-the-art performance in accuracy and latency compared to other neuromorphic chips.
Crosstalk between COVID-19 and the gut-brain axis: a gut feeling
Authors: Kalam Nida , Balasubramaniam Vinod R M T
Published: March 2024

The microbes in the gut are crucial for maintaining the body’s immune system and overall gut health. However, it is not fully understood how an unstable gut environment can lead to more severe cases of SARS-CoV-2 infection. The gut microbiota also plays a role in the gut-brain axis and interacts with the central nervous system through metabolic and neuroendocrine pathways. The interaction between the microbiota and the host’s body involves hormonal, immune, and neural pathways, and any disruption in the balance of gut bacteria can lead to dysbiosis, which contributes to pathogen growth. In this context, we discuss how dysbiosis could contribute to comorbidities that increase susceptibility to SARS-CoV-2. Probiotics and fecal microbiota transplantation have successfully treated infectious and non-infectious inflammatory-related diseases, the most common comorbidities. These treatments could be adjuvant therapies for COVID-19 infection by restoring gut homeostasis and balancing the gut microbiota.
Grape seed proanthocyanins protect fluoride-induced hepatotoxicity via the Nrf2 signaling pathway in male rats
Authors: Wei Ran , Ping Guan Fang , Lang Zhe Tao , Wang Er Hui
Published: March 2024

Background

Fluoride is a necessary element for human health, but excessive fluoride intake is found toxic to the liver. Previous studies confirmed that Grape seed procyanidin extract (GSPE) protects against fluoride-induced hepatic injury. However, the mechanism underlying this protective effect remains obscure. To evaluate the protective effect of GSPE against fluoride-induced hepatic injury and explore the possible hepatoprotective role of the Nrf2 signaling pathway to find effective strategies for the treatment and prevention of fluoride-induced hepatotoxicity. This study aims to explore the mechanisms by which GSPE attenuates fluoride-induced hepatotoxicity through a rat drinking water poisoning model.

Methods

Hepatic injury was determined by serum biochemical parameters, oxidative parameters, HE, and TUNEL analysis. The protein expression levels of apoptosis-related proteins like Bax, B-cell lymphoma-2 (Bcl-2), and Caspase-3 and the nuclear factor, erythroid 2 like 2 (Nrf2) were analyzed by Western blot.

Resluts

Our results showed that GSPE administration reduced fluoride-induced elevated serum ALT and AST and enhanced the antioxidant capacity of the liver. In addition, GSPE mitigated fluoride-induced histopathological damage and reduced the liver cell apoptosis rate. Furthermore, GSPE significantly up-regulated the expression and nuclear translocation of the Nrf2 and decreased apoptosis-related proteins like Bax and caspase-3 in the hepatic.

Conclusion

Taken together, GSPE exerts protective effects on the oxidative damage and apoptosis of fluoride-induced hepatic injury via the activation of the Nrf2 signaling pathway. This study provides a new perspective for the mechanism study and scientific prevention and treatment of liver injury induced by endemic fluorosis.
Mechanism of miR-98-5p in gastric cancer cell proliferation, migration, and invasion through the USP44/CTCFL axis
Authors: Zhang Kangkang , Zhao Jinjiang , Bi Zhibin , Feng Yafei , Zhang Huipeng , Zhang Jinjie , Qin Xiaowei , Zhao Yanbo , Niu Ruilong , Mei Xianghuang , He Zhipeng , Yang Jingcheng , Lv Jiake , Guo Wei
Published: March 2024

Objectives

Gastric cancer (GC) is the leading digestive malignancy with high incidence and mortality rate. microRNAs (miRs) play an important role in GC progresssion. This study aimed to investigate the effect of miR-98-5p on proliferation, migration, and invasion of GC cells.

Methods

The expression levels of miR-98-5p, ubiquitin specific peptidase 44 (USP44), and CCCTCbinding factor-like (CTCFL) in GC tissues and cells were identified using reversetranscription quantitative polymerase chain reaction and Western blot assay. The relationship between miR-98-5p expression/USP44 and the clinicopathological features in GC patients was analyzed. GC cell proliferation, invasion, and migration were evaluated by cell counting kit-8 and clone formation assays and Transwell assays. The bindings of miR-98-5p to USP44 and USP44 to CTCFL were examined using dualluciferase assay and co-immunoprecipitation. GC cells were treated with MG132 and the ubiquitination level of CTCFL was examined using ubiquitination assay. Rescue experiments were performed to verify the roles of USP44 and CTCFL in GC cells.

Results

miR-98-5p was downregulated in GC. miR-98-5p overexpression inhibited the proliferation, migration, and invasion of GC cells. miR-98-5p inhibited USP44 expression. USP44 bound to CTCFL and limited ubiquitination degradation of CTCFL. Overexpression of USP44 and CTCFL attenuated the inhibitory effects of miR-98-5p overexpression on GC cell progression.

Conclusion

miR-98-5p overexpression limited USP44-mediated CTCFL deubiquitination, and suppressed CTCFL expression, mitigating GC cell proliferation, migration, and invasion.
Understanding the Utility of Endocardial Electrocardiographic Imaging in Epi-Endocardial Mapping of 3D Reentrant Circuits
Authors: Toloubidokhti Maryam , Gharbia Omar A , Parkosa Adityo , Trayanova Natalia , Hadjis Alexios , Tung Roderick , Nazarian Saman , Sapp John L. , Wang Linwei
Published: March 2024

Background

Studies of VT mechanisms are largely based on a 2D portrait of reentrant circuits on one surface of the heart. This oversimplifies the 3D circuit that involves the depth of the myocardium. Simultaneous epicardial and endocardial (epi-endo) mapping was shown to facilitate a 3D delineation of VT circuits, which is however difficult via invasive mapping.

Objective

This study investigates the capability of noninvasive epicardial-endocardial electrocardiographic imaging (ECGI) to elucidate the 3D construct of VT circuits, emphasizing the differentiation of epicardial, endocardial, and intramural circuits and to determine the proximity of mid-wall exits to the epicardial or endocardial surfaces.

Methods

120-lead ECGs of VT in combination with subject-specific heart-torso geometry are used to compute unipolar electrograms (CEGM) on ventricular epicardium and endocardia. Activation isochrones are constructed, and the percentage of activation within VT cycle length is calculated on each surface. This classifies VT circuits into 2D (surface only), uniform transmural, nonuniform transmural, and mid-myocardial (focal on surfaces). Furthermore, the endocardial breakthrough time was accurately measured using Laplacian eigenmaps, and by correlating the delay time of the epi-endo breakthroughs, the relative distance of a mid-wall exit to the epicardium or the endocardium surfaces was identified.

Results

We analyzed 23 simulated and in-vivo VT circuits on post-infarction porcine hearts. In simulated circuits, ECGI classified 21% as 2D and 78% as 3D: 82.6% of these were correctly classified. The relative timing between epicardial and endocardial breakthroughs was correctly captured across all cases. In in-vivo circuits, ECGI classified 25% as 2D and 75% as 3D: in all cases, circuit exits and entrances were consistent with potential critical isthmus delineated from combined LGE-MRI and catheter mapping data.

Conclusions

ECGI epi-endo mapping has the potential for fast delineation of 3D VT circuits, which may augment detailed catheter mapping for VT ablation.
Post-GWAS functional analyses ofCNTNAP5suggests its role in glaucomatous neurodegeneration
Authors: Chakraborty Sudipta , Sarma Jyotishman , Roy Shantanu Saha , Mitra Sukanya , Bagchi Sayani , Das Sankhadip , Saha Sreemoyee , Mahapatra Surajit , Bhattacharjee Samsiddhi , Maulik Mahua , Acharya Moulinath
Published: March 2024

Primary angle closure glaucoma (PACG) affects more than 20 million people worldwide, with an increased prevalence in south-east Asia. In a prior haplotype-based GWAS, we identified a novelCNTNAP5genic region, significantly associated with PACG. In the current study, we have extended our perception ofCNTNAP5involvement in glaucomatous neurodegeneration in a zebrafish model, through investigating phenotypic consequences pertinent to retinal degeneration upon knockdown of cntnap5 by translation-blocking morpholinos. While cntnap5 knockdown was successfully validated using an antibody, immunofluorescence followed by western blot analyses in cntnap5-morphant (MO) zebrafish revealed increased expression of acetylated tubulin indicative of perturbed cytoarchitecture of retinal layers. Moreover, significant loss of Nissl substance is observed in the neuro-retinal layers of cntnap5-MO zebrafish eye, indicating neurodegeneration. Additionally, in spontaneous movement behavioural analysis, cntnap5-MO zebrafish have a significantly lower average distance traversed in light phase compared to mismatch-controls, whereas no significant difference was observed in the dark phase, corroborating with vision loss in the cntnap5-MO zebrafish. This study provides the first direct functional evidence of a putative role ofCNTNAP5in visual neurodegeneration.
CD40 is an immune checkpoint regulator that potentiates myocardial inflammation through activation and expansion of CCR2+macrophages and CD8 T-cells
Authors: Jimenez Jesus , Amrute Junedh , Ma Pan , Wang Xiaoran , Dai Raymond , Lavine Kory J.
Published: March 2024

Novel immune checkpoint therapeutics including CD40 agonists have tremendous promise to elicit antitumor responses in patients resistant to current therapies. Conventional immune checkpoint inhibitors (PD-1/PD-L1, CTLA-4 antagonists) are associated with serious adverse cardiac events including life-threatening myocarditis. However, little is known regarding the potential for CD40 agonists to trigger myocardial inflammation or myocarditis. Here, we leveraged genetic mouse models, single cell sequencing, and cell depletion studies to demonstrate that an anti-CD40 agonist antibody reshapes the cardiac immune landscape through activation of CCR2+macrophages and subsequent recruitment of effector memory CD8 T-cells. We identify a positive feedback loop between CCR2+macrophages and CD8 T-cells driven by IL12b, TNF, and IFN-γ signaling that promotes myocardial inflammation and show that prior exposure to CD40 agonists sensitizes the heart to secondary insults and accelerates LV remodeling. Collectively, these findings highlight the potential for CD40 agonists to promote myocardial inflammation and potentiate heart failure pathogenesis.
A new framework for evaluating model out-of-distribution for the biochemical domain
Authors: Fernández-Díaz Raúl , Hoang Thanh Lam , Lopez Vanessa , Shields Denis C.
Published: March 2024

Quantifying model generalization to out-of-distribution data has been a longstanding challenge in machine learning. Addressing this issue is crucial for leveraging machine learning in scientific discovery, where models must generalize to new molecules or materials. Current methods typically split data into train and test sets using various criteria — temporal, sequence identity, scaffold, or random cross-validation — before evaluating model performance. However, with so many splitting criteria available, existing approaches offer limited guidance on selecting the most appropriate one, and they do not provide mechanisms for incorporating prior knowledge about the target deployment distribution(s).

To tackle this problem, we have developed a novel metric, AU-GOOD, which quantifies expected model performance under conditions of increasing dissimilarity between train and test sets, while also accounting for prior knowledge about the target deployment distribution(s), when available. This metric is broadly applicable to biochemical entities, including proteins, small molecules, nucleic acids, or cells; as long as a relevant similarity function is defined for them. Recognizing the wide range of similarity functions used in biochemistry, we propose criteria to guide the selection of the most appropriate metric for partitioning. We also introduce a new partitioning algorithm that generates more challenging test sets, and we propose statistical methods for comparing models based on AU-GOOD.

Finally, we demonstrate the insights that can be gained from this framework by applying it to two different use cases: developing predictors for pharmaceutical properties of small molecules, and using protein language models as embeddings to build biophysical property predictors.
Sparse Testing Designs for Optimizing Predictive Ability in Sugarcane Populations
Authors: Garcia-Abadillo Julian , Adunola Paul , Aguilar Fernando S. , Trujillo-Montenegro Jhon Henry , Riascos John Jaime , Persa Reyna , Isidro y Sanchez Julio , Jarquín Diego
Published: March 2024

Sugarcane is a crucial crop for sugar and bioenergy production. Saccharose content and total weight are the two main key commercial traits that compose sugarcane’s yield. These traits are under complex genetic control and their response patterns are influenced by the genotype-by-environment (G×E) interaction. An efficient breeding of sugarcane demands an accurate assessment of the genotype stability through multi-environment trials (METs), where genotypes are tested/evaluated across different environments. However, phenotyping all genotype-in-environment combinations is often impractical due to cost and limited availability of propagation-materials. This study introduces the sparse testing designs as a viable alternative, leveraging genomic information to predict unobserved combinations through genomic prediction models. This approach was applied to a dataset comprising 186 genotypes across six environments (6 × 186 = 1,116 phenotypes). Our study employed three predictive models, including environment and genotype as main effects, as well as the G×E interaction to predict saccharose accumulation (SA) and tons of cane per hectare (TCH). Calibration sets sizes varying between 72 (6.5%) to 186 (16.7%) of the total number of phenotypes were composed to predict the remaining 930 (83.3%). Additionally, we explored the optimal number of common genotypes across environments for G×E pattern prediction. Results demonstrate that maximum accuracy for SA (ρ= 0.611) and for TCH (ρ= 0.341) was achieved using in training sets few (3) to no common (0) genotype across environments maximizing the number of different genotypes that were tested only once. Significantly, we show that reducing phenotypic records for model calibration has minimal impact on predictive ability, with sets of 12 non-overlapped genotypes per environment (72 = 12 × 6) being the most convenient cost-benefit combination.
The transcription factor ATML1 maintains giant cell identity by inducing synthesis of its own long-chain fatty acid-containing ligands
Authors: Vadde Batthula Vijaya Lakshmi , Russell Nicholas J. , Bagde Saket Rahul , Askey Bryce , Saint-Antoine Michael , Brownfield Bryce , Mughal Salaiha , Apprill Lauren E. , Khosla Aashima , Clark Frances K. , Schwarz Erich M. , Alseekh Saleh , Fernie Alisdair R. , Singh Abhyudai , Schrick Kathrin , Fromme J. Christopher , Skirycz Aleksandra , Formosa-Jordan Pau , Roeder Adrienne H. K.
Published: March 2024

During development, cells not only adopt specialized identities but also maintain those identities. Endoreduplication is thought to maintain cell identity. High concentrations of ARABIDOPSIS THALIANA MERISTEM LAYER1 (ATML1) specify giant cell identity and induce endoreduplication in sepals. How different concentrations of ATML1 can specify different identities remains unclear. Here, we show that high concentrations of ATML1 induce the biosynthesis of both long-chain and very long-chain fatty acids (LCFAs/VLCFAs), and these fatty acids are required for the maintenance of giant cell identity. Inhibition of VLCFA biosynthesis causes endoreduplicated giant cells to resume division and lose their identity, indicating that endoreduplication is not sufficient to maintain cell identity. Structural predictions suggest that LCFA-containing lipids bind to the START domain 2 of ATML1, causing ATML1 dimerization and its auto-activation. Our data and modeling imply that ATML1 induces biosynthesis of its own lipid ligands in a positive feedback loop, shedding light on the intricate network dynamics that specify and maintain giant cell identity.

Teaser:Endoreduplicated cells inArabidopsis thalianasepals divide and de-differentiate in the absence of VLCFA biosynthesis.
EHMT2 Inactivation in Pancreatic Epithelial Cells Shapes the Transcriptional Landscape and Inflammation Response of the Whole Pancreas
Authors: Pollin Gareth , Mathison Angela J. , de Assuncao Thiago M. , Thomas Anju , Zeighami Lida , Salmonson Ann , Liu Hongfei , Urrutia Guillermo , Vankayala Pallavi , Pandol Stephen J , Zimmermann Michael T. , Iovanna Juan , Jin Victor X. , Urrutia Raul , Lomberk Gwen
Published: March 2024

The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the maturation and homeostasis of multiple organs. Recently, we have shown that EHMT2 inactivation alters growth and immune gene expression networks, antagonizing KRAS-mediated pancreatic cancer initiation and promotion. Here, we elucidate the essential role of EHMT2 in maintaining a transcriptional landscape that protects organs from inflammation. Comparative RNA-seq studies between normal postnatal and young adult pancreatic tissue fromEHMT2conditional knockout animals (EHMT2fl/fl) targeted to the exocrine pancreatic epithelial cells (Pdx1-CreandP48Cre/+), reveal alterations in gene expression networks in the whole organ related to injury-inflammation-repair, suggesting an increased predisposition to damage. Thus, we induced an inflammation repair response in theEHMT2fl/flpancreas and used a data science-based approach to integrate RNA-seq-derived pathways and networks, deconvolution digital cytology, and spatial transcriptomics. We also analyzed the tissue response to damage at the morphological, biochemical, and molecular pathology levels. TheEHMT2fl/flpancreas displays an enhanced injury-inflammation-repair response, offering insights into fundamental molecular and cellular mechanisms involved in this process. More importantly, these data show that conditional EHMT2 inactivation in exocrine cells reprograms the local environment to recruit mesenchymal and immunological cells needed to mount an increased inflammatory response. Mechanistically, this response is an enhanced injury-inflammation-repair reaction with a small contribution of specific EHMT2-regulated transcripts. Thus, this new knowledge extends the mechanisms underlying the role of the EHMT2-mediated pathway in suppressing pancreatic cancer initiation and modulating inflammatory pancreatic diseases.
Development of the 12-Base Short Dimeric Myogenetic Oli-godeoxynucleotide That Induces Myogenic Differentiation
Authors: Umezawa Koji , Ikeda Rena , Sakamoto Taiichi , Enomoto Yuya , Nihashi Yuma , Shinji Sayaka , Shimosato Takeshi , Kagami Hiroshi , Takaya Tomohide
Published: March 2024

A myogenetic oligodeoxynucleotide (myoDN), iSN04 (5’-AGA TTA GGG TGA GGG TGA-3’), is a single-stranded 18-base telomeric DNA that serves as an anti-nucleolin aptamer and induces myogenic differentiation, which is expected to be a nucleic acid drug for the prevention of disease-associated muscle wasting. To improve the drug efficacy and synthesis cost of myoDN, shortening the sequence while maintaining its structure-based function is a major challenge. Here, we report the novel 12-base non-telomeric myoDN, iMyo01 (5’-TTG GGT GGG GAA-3’), which has comparable myogenic activity to iSN04. iMyo01 as well as iSN04 promoted myotube formation of primary-cultured human myoblasts with upregulation of myogenic gene expression. Both iMyo01 and iSN04 interacted with nucleolin, but iMyo01 did not bind to berberine, the isoquinoline alkaloid that stabilizes iSN04. Nuclear magnetic resonance revealed that iMyo01 forms a G-quadruplex structure despite its short sequence. Native polyacrylamide gel electrophoresis and computational molecular dynamics simulation indicated that iMyo01 forms a homodimer to generate a G-quadru-plex. These results provide new insights into the aptamer truncation technology that preserves aptamer conformation and bioactivity for the development of efficient nucleic acid drugs.

Key Contribution

This study reports the structure-based shortening of a myogenetic oligodeox-ynucleotide, iSN04, as an anti-nucleolin aptamer that induces myogenesis. The shortening technology of aptamers while maintaining their conformation and activity improves their potency of drug function and synthesis cost.
Exploring the probiotic potential, antioxidant capacity, and healthy aging based on whole genome analysis of Lactiplantibacillus plantarum LPJBC5 isolated from fermented milk product
Authors: Bhattacharya Anupam , Joishy Tulsi K. , Khan Mojibur R.
Published: March 2024

Lactiplantibacillus plantarum is a beneficial bacterium commonly found in fermented foods, including fermented milk products. In the present study, we reported the whole genome sequence of L. plantarum LPJBC5. The complete genome sequence of LPJBC5 was 3.23Mb, and the average GC% was found to be 44.55% encoding a total of 3016 genes. A comprehensive analysis of the LPJBC5 genome detected major carbohydrate-active enzymes, exopolysaccharide synthesis genes (eps), and the presence of genes related to stress response and antioxidant activity. Longevity regulating genes including katE, CAT (chloramphenicol acetyltransferase), catB and their regulating pathways (MAPK signaling pathway) were detected in the LPJBC5 genome. The genome was found to contain plantaracin (pln) operon for the production of antimicrobial bacteriocin and various regions of secondary metabolite biosynthetic gene clusters, including the type III polyketide synthases (T3PKS), Ribosomally synthesized and post-translationally modified peptide product (Ripp-Like), which exhibit specific antimicrobial activity. A comparative pangenome analysis was performed to further evaluate the metabolic framework of L. plantarum JBC5, including the complete L. plantarum genome (N=30) retrieved from publicly available repositories. The core/soft-core genome was found to harbor probiotic associated marker genes. Functional analysis revealed the presence of genes majorly enriched in cell wall/membrane/envelop biogenesis, carbohydrate metabolism and transport, amino acid metabolism and transport, translational mechanism, and transcription processes. Identification of probiotic and longevity associated genes suggests that LPJBC5 holds potential as a probiotic candidate with multifaceted applications in the food industries.
Comprehensive detection and characterization of human druggable pockets through novel binding site descriptors
Authors: Comajuncosa-Creus Arnau , Jorba Guillem , Barril Xavier , Aloy Patrick
Published: March 2024

Druggable pockets are protein regions that have the ability to bind organic small molecules, and their characterization is essential in target-based drug discovery. However, strategies to derive pocket descriptors are scarce and usually exhibit limited applicability. Here, we present PocketVec, a novel approach to generate pocket descriptors for any protein binding site of interest through the inverse virtual screening of lead-like molecules. We assess the performance of our descriptors in a variety of scenarios, showing that it is on par with the best available methodologies, while overcoming some important limitations. In parallel, we systematically search for druggable pockets in the folded human proteome, using experimentally determined protein structures and AlphaFold2 models, identifying over 32,000 binding sites in more than 20,000 protein domains. Finally, we derive PocketVec descriptors for each small molecule binding site and run an all-against-all similarity search, exploring over 1.2 billion pairwise comparisons. We show how PocketVec descriptors facilitate the identification of druggable pocket similarities not revealed by structure- or sequence-based comparisons. Indeed, our analyses unveil dense clusters of similar pockets in distinct proteins for which no inhibitor has yet been crystalized, opening the door to strategies to prioritize the development of chemical probes to cover the druggable space.
Machine learning-based prediction of fish acute mortality: Implementation, interpretation, and regulatory relevance
Authors: Gasser Lilian , Schür Christoph , Perez-Cruz Fernando , Schirmer Kristin , Baity-Jesi Marco
Published: March 2024

Regulation of chemicals requires knowledge of their toxicological effects on a large number of species, which has traditionally been acquired throughin vivotesting. The recent effort to find alternatives based on machine learning, however, has not focused on guaranteeing transparency, comparability and reproducibility, which makes it difficult to assess advantages and disadvantages of these methods. Also, comparable baseline performances are needed. In this study, we trained regression models on the ADORE “t-F2F” challenge proposed in [Schüret al.,Nature Scientific data, 2023] to predict acute mortality, measured as LC50 (lethal concentration 50), of organic compounds on fishes. We trained LASSO, random forest (RF), XGBoost, Gaussian process (GP) regression models, and found a series of aspects that are stable across models: (i) using mass or molar concentrations does not affect performances; (ii) the performances are only weakly dependent on the molecular representations of the chemicals, but (iii) strongly on how the data is split. Overall, the tree-based models RF and XGBoost performed best and we were able to predict the log10-transformed LC50 with a root mean square error of 0.90, which corresponds to an order of magnitude on the original LC50 scale. On a local level, on the other hand, the models are not able to consistently predict the toxicity of individual chemicals accurately enough. Predictions for single chemicals are mostly influenced by a few chemical properties while taxonomic traits are not captured sufficiently by the models. We discuss technical and conceptual improvements for these challenges to enhance the suitability ofin silicomethods to environmental hazard assessment. Accordingly, this work showcases state-of-the-art models and contributes to the ongoing discussion on regulatory integration.

Environmental significance

Conventional environmental hazard assessment in its current form will not be able to adapt to the growing need for toxicity testing. Alternative methods, such as toxicity prediction through machine learning, could fulfill that need in an economically and ethically sound manner. Proper implementation, documentation, and the integration into the regulatory process are prerequisites for the usability and acceptance of these models.
Abnormal global longitudinal strain and reduced serum inflammatory markers in cardiac AL amyloidosis patients without significant amyloid fibril deposition
Authors: Edwards Camille V. , Ferri Grace M. , Villegas-Galaviz Josue , Ghosh Sabrina , Bawa Pushpinder Singh , Wang Feiya , Klimtchuk Elena , Ajayi Tinuola B. , Morgan Gareth J. , Prokaeva Tatiana , Staron Andrew , Ruberg Frederick L. , Sanchorawala Vaishali , Giadone Richard M. , Murphy George J.
Published: March 2024

Background

Cardiac dysfunction in AL amyloidosis is thought to be partly related to the direct impact of AL LCs on cardiomyocyte function, with the degree of dysfunction at diagnosis as a major determinant of clinical outcomes. Nonetheless, mechanisms underlying LC-induced myocardial toxicity are not well understood.

Methods

We identified gene expression changes correlating with human cardiac cells exposed to a cardiomyopathy-associated κAL LC. We then sought to confirm these findings in a clinical dataset by focusing on clinical parameters associated with the pathways dysregulated at the gene expression level.

Results

Upon exposure to a cardiomyopathy-associated κAL LC, cardiac cells exhibited gene expression changes related to myocardial contractile function and inflammation, leading us to hypothesize that there could be clinically detectable changes in GLS on echocardiogram and serum inflammatory markers in patients. Thus, we identified 29 patients with normal IVSd but abnormal cardiac biomarkers suggestive of LC-induced cardiac dysfunction. These patients display early cardiac biomarker staging, abnormal GLS, and significantly reduced serum inflammatory markers compared to patients with clinically evident amyloid fibril deposition.

Conclusion

Collectively, our findings highlight early molecular and functional signatures of cardiac AL amyloidosis, with potential impact for developing improved patient biomarkers and novel therapeutics.
Pivotal role of biallelic frequency analysis in identifying copy number alterations using genome-wide methods in tumors with a high level of aneuploidy
Authors: Rymuza Julia , Woroniecka Renata , Grygalewicz Beata , Bujko Mateusz
Published: March 2024

Chromosome number abnormalities is one of the hallmarks of cancer. DNA copy number alterations (CNA) are studied using various genome-wide methods. In our study we investigated CNA in human pituitary tumors using three platforms CytoSNP-850K microarrays, low-pass whole-genome sequencing (average x7 coverage, LPWGS), and Infinium Methylation EPIC array. Virtual karyotypes based on each dataset were generated using open-source software packages for each sample. Concordant CNA profiles were found for most of tumor. Surprisingly, substantial discrepancies between results from SNP arrays and LPWGS/EPIC arrays were identified in 20% of tumors, for which discrimination of true karyotype was required. B-allelic frequency data from SNP arrays was crucial to adjust normal ploidy level as ultimately verified with FISH. The discrepancy between virtual karyotypes was more pronounced the more CNAs were found. When CNAs covered more than half of genome the level of normal/diploid copy number was incorrectly set with methods, based solely on signal intensity/read-counts coverage. To conclude, CNA analysis with methods such as LPWGS and methylation arrays in highly aneuploid tumors are prone to a bias from improper normal ploidy level setting. These methods are commonly used therefore we aimed to aware the scientific community about this underestimated methodological problem.
An optimized somatic embryo transformation system assisted homozygous edited rubber tree generation method mediated by CRISPR/Cas9
Authors: Yang Xianfeng , Lin Qiufei , Udayabhanu Jinu , Hua Yuwei , Dai Xuemei , Xin Shichao , Wang Xiaoyi , Huang Huasun , Huang Tiandai
Published: March 2024

Previously, we have realized the CRISPR/Cas9-RNP and plasmid mediated protoplast transient transformation genome editing in the rubber tree (Hevea brasiliensis), but no gene editing plants were acquired due to the bottleneck of genetic transformation. In present study, antibiotic sensitivity tests against kanamycin, hygromycin and basta were analyzed for embryo screening, the results demonstrated that 10 mg/L hygromycin is the best for transformation. ThenAgrobacteriummediated transformation ofH. brasiliensisembryos was carried out using a pCAMBIA1300-based CRISPR/Cas9 vector targeting Phytoene desaturase gene (HbPDS). High-throughput sequencing of T0 generation positive embryos which were used as regeneration materials in typical transformation procedure showed that more than 90% T0 edited embryos are chimeric with a 3.2% editing efficiency. A T0 embryo with 9.8% edited cells was sliced into small pieces for one more cycle embryogenesis to produce T1 generation embryos in order to improve the ratio of homozygous embryos. Subsequently, next-generation sequencing (NGS) demonstrated that 29 out of 33 T1 embryos were edited, nearly 50% of which were found homozygous. At last, besides four chimeric plantlets with partial albino leaves, four plantlets with complete albino phenotype were regenerated from the 29 T1 generation edited embryos, among which one is a homozygous mono-allelic mutant and the other three are homozygous bi-allelic mutants. NGS demonstrated that the threshold for the proportion of edited cells with expected albino phenotype is between 70-85%. Additionally, Tail-PCR indicate that the T-DNA was inserted into different genome positions in the four homozygous edited plantlets, combined with the different genotypes are considered, the four homozygous plantlets can be confirmed as independently derived from single transformed cells. Overall, this is the first edited rubber trees with expected phenotype reported publicly, which shows the potential in genetic improvement ofH. brasiliensisby CRISPR/Cas9 gene editing, and subculture of T0 positive transformed somatic embryos into T1 generation is proved to be an effective and necessary procedure to produce homozygous transgenic plantlets. This study presents a significant advancement in transgenic and gene editing for rubber tree.
Lack of dominant-negative activity for tumor-associated ZNRF3 missense mutations at endogenous expression levels
Authors: Li Shanshan , Niu Jiahui , Zhang Ruyi , Massaar Sanne , Merode Jenna van , Schipper Nicky de , Kamp Lisa van de , Peppelenbosch Maikel P. , Smits Ron
Published: March 2024

ZNRF3, a negative regulator of β-catenin signaling, removes Wnt receptors from the membrane. Currently, it is unknown which tumor-associated variants can be considered driver mutations and through which mechanisms they contribute to cancer. Here we show that all truncating mutations analyzed at endogenous levels exhibit loss-of-function, with longer variants retaining partial activity. Regarding missense mutations, we show that 27/82 ZNRF3 variants in the RING and R-Spondin domain structures, lead to (partial) loss-of-function/hyperactivation. Mechanistically, defective R-spondin domain variants appear to undergo endoplasmic-reticulum-associated degradation due to protein misfolding. They show reduced stability and fail to reach the membrane correctly, which can be partially restored for several variants by culturing cells at 27°C. Although RING and R-spondin domain mutations in RNF43/ZNRF3 are often considered to possess dominant-negative oncogene-like activity in cancers, our findings challenge this notion. When representative variants are heterozygously introduced into endogenous ZNRF3, their impact on β-catenin signaling mirrors that of heterozygous knockout, suggesting that the supposed dominant-negative effect is non-existent. In other words, so-called “hyperactivating” ZNRF3/RNF43 mutations behave as classical loss-of-function mutations at endogenous levels. Taken together, our findings provide valuable information on ZNRF3 mutation impact in tumorigenesis and clarify their mechanism of action.
Integration of molecular coarse-grained model into geometric representation learning framework for protein-protein complex property prediction
Authors: Yue Yang , Li Shu , Cheng Yihua , Zhu Zexuan , Wang Lie , Hou Tingjun , He Shan
Published: March 2024

Structure-based machine learning algorithms have been utilized to predict the properties of protein-protein interaction (PPI) complexes, such as binding affinity, which is critical for understanding biological mechanisms and disease treatments. While most existing algorithms represent PPI complex graph structures at the atom-scale or residue-scale, these representations can be computationally expensive or may not sufficiently integrate finer chemical-plausible interaction details for improving predictions. Here, we introduce MCGLPPI, a novel geometric representation learning framework that combines graph neural networks (GNNs) with the MARTINI molecular coarse-grained (CG) model to predict overall PPI properties accurately and efficiently. This framework maps proteins onto a concise CG-scale complex graph, where nodes represent CG beads and edges encode chemically plausible interactions. The GNN-based encoder is tailored to extract high-quality representations from this graph, efficiently capturing the overall properties of the protein complex structure. Extensive experiments on three different downstream PPI property prediction tasks demonstrate that MCGLPPI achieves competitive performance compared with the counterparts at the atom- and residue-scale, but with only a third of the computational resource consumption. Furthermore, the CG-scale pre-training on protein domain-domain interaction structures enhances its predictive capabilities for PPI tasks. MCGLPPI offers an effective and efficient solution for PPI overall property predictions, serving as a promising tool for the large-scale analysis of biomolecular interactions.
The molecular impact of cigarette smoking resembles aging across tissues
Authors: Ramirez Jose Miguel , Ribeiro Rogério , Soldatkina Oleksandra , Moraes Athos , García-Pérez Raquel , Ferreira Pedro G. , Melé Marta
Published: March 2024

Tobacco smoke is the main cause of preventable mortality worldwide. Smoking increases the risk of developing many diseases and has been proposed as an aging accelerator. Yet, the molecular mechanisms driving smoking-related health decline and aging acceleration in most tissues remain unexplored. Here, we characterize gene expression, alternative splicing, DNA methylation and histological alterations induced by cigarette smoking across human tissues. We show that smoking impacts tissue architecture and triggers systemic inflammation. We find that in many tissues, the effects of smoking significantly overlap those of aging in the same direction. Specifically, both age and smoking upregulate inflammatory genes and drive hypomethylation at enhancers. In addition, we observe widespread smoking-driven hypermethylation at target regions of the Polycomb repressive complex, which is a well-known aging effect. Smoking-induced epigenetic changes overlap causal aging CpGs, suggesting that these methylation changes may directly mediate aging acceleration observed in smokers. Finally, we find that smoking effects that are shared with aging are more persistent over time. Overall, our multi-tissue and multi-omic analysis of the effects of cigarette smoking provides an extensive characterization of the impact of tobacco smoke across tissues and unravels the molecular mechanisms driving smoking-induced tissue homeostasis decline and aging acceleration.
ArtiDock: fast and accurate machine learning approach to protein-ligand docking based on multimodal data augmentation
Authors: Voitsitskyi Taras , Yesylevskyy Semen , Bdzhola Volodymyr , Stratiichuk Roman , Koleiev Ihor , Ostrovsky Zakhar , Vozniak Volodymyr , Khropachov Ivan , Henitsoi Pavlo , Popryho Leonid , Zhytar Roman , Nafiiev Alan , Starosyla Serhii
Published: March 2024

We present ArtiDock - the deep learning technique for predicting ligand poses in the protein binding pockets (aka “AI docking”), which is based on augmenting inherently limited training data with algorithmically generated artificial binding pockets and the ensembles of representative conformations of the ligand-protein complexes obtained from MD simulations. Performance of ArtiDock is compared systematically with other AI docking techniques and conventional docking programs on the PoseBusters dataset, which is dedicated for benchmarking the AI pose prediction algorithms. ArtiDock outperforms the best AI docking techniques and the major conventional docking programs, being at least an order of magnitude faster while providing superior accuracy in terms of RMSD and additional ligand pose correctness metrics. The influence of data augmentation on the model performance is evaluated and the perspectives of further development are discussed.
Extreme temperatures impede the release success of captive-bred avian scavengers
Authors: Anglister Nili , Acácio Marta , Vaadia Gideon , Arnon Eitam , Bruer Michael , Hatzofe Ohad , Miller Ygal , King Roni , Pinter-Wollman Noa , Spiegel Orr
Published: March 2024

Conservation translocations (reinforcements and reintroductions) are central for managing various endangered species, yet, their implementation is logistically and financially challenging. Because many translocations fail due to the mortality of released individuals, identifying and preventing these factors is crucial. Here we examine risk factors affecting the post-release survival of the Griffon vulture (Gyps fulvus). The Israeli population is facing extinction, and the recovery efforts by the local Nature and Parks Authority include supplemental releases of individuals from captive-breeding or rehabilitated birds (mostly imported from Spain). We use GPS tracking and thermometers to compare movement, behavior, and weather conditions experienced by released and wild-born individuals active in the same area and time. Our results show that the Judean Desert release site had a significantly lower survival rate than other release sites included in the program. After excluding several possible factors (e.g. known pathogens) with pathological examinations, we found that released individuals at this area were exposed to higher temperatures preceding their death (compared to wild-born griffons nearby), suggesting heat stress as the cause of death. Arguably, they failed to avoid the harsh environmental conditions, resulting in overheating due to their inexperience and undeveloped flight ability, as reflected by their lower probabilities of flying and shorter travel distances per day compared to wild-born vultures. These findings have led to adjustments of the local release protocol, (namely winter releases) resulting in a significant improvement in the early survival of translocated Griffons in the Judean Desert. Accounting for the harmful effects of extreme weather conditions is particularly important in a world facing climate change. More broadly, this sequence of scientific investigation with data integration from ecological, clinical, and biotelemetry sources, leading to improvement in translocation success demonstrates how conservation practices can be optimized by supporting studies to ensure the survival of endangered species in the wild.