bluuebunny/crossref_metadata_2025 huggingface dataset:
Anatomical Organization of the Amygdala: A Brief Visual Review
Authors: Dalla Corte Amauri , Pinzetta Giulia , Ruwel Andressa Goldman , Maia Taylor Felipe Alves , Leal Theonas , Frizon Leonardo Almeida , Isolan Gustavo Rassier
Published: December 2023

The amygdala consists of a collection of nuclei that are deep within the medial temporal lobe. Despite its small size, the amygdala is one of the most densely connected structures in the brain, and it plays a role in many superior neural functions, including neurovegetative control, motor control, memory processing, and neuromodulation. Advances in neuroimaging technology for examining brain activity have opened up new ways of understanding the functional contribution of this structure to emotions, learning, and related memories. Many studies have shown that the amygdala plays a key role in the pathophysiology of neuropsychiatric disorders, such as anxiety disorders, depression, aggression, and temporal epilepsy. This article reviews the anatomical structure of the amygdaloid complex and the connectivity among its subdivisions and with other brain structures, which will serve as a basis for understanding the clinical correlations.
Acute and sub-acute metabolic change in different brain regions induced by moderate blunt traumatic brain injury
Authors: Kumari Megha , Hasija Yasha , Trivedi Richa
Published: December 2023

The objective of the study was to observe the effect of moderate closed-head injury on hippocampal, thalamic, and striatal tissue metabolism with time. Closed head injury is responsible for metabolic changes. These changes can be permanent or temporary, depending on the injury’s impact. For the experiment, 20 rats were randomly divided into four groups, each containing five animals. Animals were subjected to injury using a modified Marmarou’s weight drop device; hippocampal, thalamic, and striatal tissue samples were collected after 1 day, 3 days, and 7 days of injury. NMR spectra were acquired following sample processing. Changes in myo-inositol, creatine, glutamate, succinate, lactate, and N-acetyl aspartic acid in hippocampal tissues were observed at day 3 PI. The tyrosine level in the hippocampus was altered at day 7 PI. While thalamic and striatal tissue samples showed altered levels of branched-chain amino acids and myo-inositol at day 1PI. Taurine, gamma amino butyric acid (GABA), choline, and alpha keto-glutarate levels were found to be significantly altered in striatal tissues at days 1 and 3PI. Acetate and GABA levels were altered in the thalamus on day 1 PI. The choline level in the thalamus was found to alter at all-time points after injury. The alteration in these metabolites may be due to the alteration in their respective pathways. Neurotransmitter and energy metabolism pathways were found to be altered in all three brain regions after TBI. This study may help better understand the effect of injury on the metabolic balance of a specific brain region and recovery.
Metagenome-assembled genomes of three Hepatoplasmataceae provide insights into isopod-mollicute symbiosis
Authors: Kawato Satoshi , Nozaki Reiko , Kondo Hidehiro , Hirono Ikuo
Published: December 2023

The digestive organs of terrestrial isopods harbor bacteria of the recently proposed mollicute family Hepatoplasmataceae. The only complete genome available so far for Hepatoplasmataceae is that of “Candidatus Hepatoplasma crinochetorum”. The scarcity of genome sequences has hampered our understanding of the symbiotic relationship between isopods and mollicutes. Here, we present four complete metagenome-assembled genomes (MAGs) of uncultured Hepatoplasmataceae members identified from shotgun sequencing data of isopods. We propose genomospecies names for three MAGs that show substantial sequence divergence from any previously known Hepoatoplamsataceae members: “Candidatus Tyloplasma littoralis” identified from the semiterrestrial isopod Tylos granuliferus, “Candidatus Hepatoplasma vulgare” identified from the common pill bug Armadillidium vulgare, and “Candidatus Hepatoplasma scaber” identified from the common rough woodlouse Porcellio scaber. Phylogenomic analysis of 155 mollicutes confirmed that Hepatoplasmataceae is a sister clade of Metamycoplasmataceae in the order Mycoplasmoidales. 16S ribosomal RNA gene sequences and phylogenomic analysis showed that “Candidatus Tyloplasma littoralis” and other semiterrestrial isopod-associated mollicutes represent the placeholder genus “g_Bg2” in the r214 release of the Genome Taxonomy Database, warranting their assignment to a novel genus. Our analysis also revealed that that Hepatoplasmataceae lack major metabolic pathways but has a likely intact type IIA CRISPR-Cas9 machinery. Although the localization of the Hepatoplasmatacae members have not been verified microscopically in this study, these genomic characteristics are compatible with the idea that these mollicutes have an ectosymbiotic lifestyle with high nutritional dependence on their host, as has been demonstrated for other members of the family. We could not find evidence that Hepatoplasmataceae encode polysaccharide-degrading enzymes that aid host digestion. If they are to provide nutritional benefits, it may be through extra-copy nucleases, peptidases, and a patatin-like lipase. Exploration of potential host-symbiont interaction-associated genes revealed large, repetitive open reading frames harboring beta-sandwich domains, possibly involved with host cell adhesion. Overall, genomic analyses suggest that isopod-mollicute symbiosis is not characterized by carbohydrate degradation, and we speculate on their potential role as defensive symbionts through spatial competition with pathogens to prevent infection.
Lactiplantibacillus brownii sp. nov., a novel psychrotolerant species isolated from sauerkraut
Authors: Heng Yu Chyuan , Silvaraju Shaktheeshwari , Lee Jolie Kar Yi , Kittelmann Sandra
Published: December 2023

A Gram-stain-positive, rod-shaped, facultatively anaerobic and homofermentative strain, named WILCCON 0030T, was isolated from sauerkraut (fermented cabbage) collected from a local market in the Moscow region of Russia. Comparative analyses based on 16S rRNA gene sequence similarity and whole genome relatedness indicated that strain WILCCON 0030T was most closely related to the type strains

Lactiplantibacillus nangangensis

NCIMB 15186T,

Lactiplantibacillus daoliensis

LMG 31171T and

Lactiplantibacillus pingfangensis

LMG 31176T. However, the average nucleotide identity and digital DNA–DNA hybridization prediction values with these closest relatives only ranged from 84.6 to 84.9 % and from 24.1 to 24.7 %, respectively, and were below the 95.0 and 70.0% thresholds for species delineation. Substantiated by further physiological and biochemical analyses, strain WILCCON 0030T represents a novel species within the genus

Lactiplantibacillus

for which we propose the name Lactiplantibacillus brownii sp. nov. (type strain WILCCON 0030T=DSM 116485T=LMG 33211T).
Dystrophin deficiency impairs cell junction formation during embryonic myogenesis
Authors: Mozin Elise , Massouridès Emmanuelle , Mournetas Virginie , Lièvre Clémence , Bourdon Audrey , Jackson Dana L , Packer Jonathan S , Seong Juyoung , Trapnell Cole , Le Guiner Caroline , Adjali Oumeya , Pinset Christian , Mack David L , Dupont Jean-Baptiste
Published: December 2023

Mutations in theDMDgene lead to Duchenne muscular dystrophy, a severe X-linked neuromuscular disorder that manifests itself as young boys acquire motor functions. DMD is typically diagnosed at 2 to 4 years of age, but the absence of dystrophin negatively impacts muscle structure and function before overt symptoms appear in patients, which poses a serious challenge in the optimization of standards of care. In this report, we investigated the early consequences of dystrophin deficiency during skeletal muscle development. We used single-cell transcriptome profiling to characterize the myogenic trajectory of human pluripotent stem cells and showed that DMD cells bifurcate to an alternative branch when they reach the somite stage. Here, dystrophin deficiency was linked to marked dysregulations of cell junction protein families involved in the cell state transitions characteristic of embryonic somitogenesis. Altogether, this work demonstrates thatin vitro, dystrophin deficiency has deleterious effects on cell-cell communication during myogenic development, which should be considered in future therapeutic strategies for DMD.
A comprehensive overview and benchmarking analysis of fast algorithms for genome-wide association studies
Authors: Liu Fang , Zhang Jie , Zhao Yusheng , Schmidt Renate H. , Mascher Martin , Reif Jochen C. , Jiang Yong
Published: December 2023

Genome-wide association studies (GWAS) are a ubiquitous tool for identifying genetic variants associated with complex traits in structured populations. During the past 15 years, many fast GWAS algorithms based on a state-of-the-art model, namely the linear mixed model, have been published to cope with the rapidly growing data size. In this study, we provide a comprehensive overview and benchmarking analysis of 33 commonly used GWAS algorithms. Key mathematical techniques implemented in different algorithms were summarized. Empirical data analysis with 12 selected algorithms showed differences regarding the identification of quantitative trait loci (QTL) in several plant species. The performance of these algorithms evaluated in 10,800 simulated data sets with distinct population size, heritability and genetic architecture revealed the impact of these parameters on the power of QTL identification and false positive rate. Based on these results, a general guide on the choice of algorithms for the research community is proposed.
Unlocking consumer coexistence: The role of self-organised spatial heterogeneity
Authors: Guill Christian , Nößler Felix , Klauschies Toni
Published: December 2023

In metacommunities, habitat heterogeneity facilitates species coexistence if superior competitors disperse maladaptively towards unfavourable habitats or if they hedge insufficiently against fluctuating environmental conditions. We show that similar mechanisms also operate in metacommunities with homogeneous habitat quality when heterogeneous biomass distributions emerge from self-organised pattern formation. Depending on whether the induced biomass patterns are static or fluctuating, either lower or higher dispersal rates can allow inferior competitors to coexist with their superior counterparts. Coexistence is further promoted when the inferiors can plastically reduce emigration from resource-rich patches. Furthermore, if the competitors differ in their abilities to induce pattern formation, a novel coexistence mechanism akin to relative non-linearity emerges, where the temporarily dominant competitor modifies the spatio-temporal variation in the biomass distributions such that it favours the recovery of the currently rare competitor. Self-organised pattern formation thus generically provides mechanisms for maintaining diversity in metacommunities without requiring a priori habitat heterogeneity.
HDAC10 blockade upregulates SPARC expression thereby repressing melanoma cell growth and BRAF inhibitor resistance
Authors: Ling Hongbo , Li Yixuan , Peng Changmin , Yang Shengyu , Seto Edward
Published: December 2023

Secreted Protein Acidic and Rich in Cysteine (SPARC), a highly conserved secreted glycoprotein, is crucial for various bioprocesses. Here we demonstrate that histone deacetylase 10 (HDAC10) is a key regulator ofSPARCexpression. HDAC10 depletion or inhibition upregulates, while overexpression of HDAC10 downregulates, SPARC expression. Mechanistically, HDAC10 coordinates with histone acetyltransferase p300 to modulate the acetylation state of histone H3 lysine 27 (H3K27ac) atSPARCregulatory elements and the recruitment of bromodomain-containing protein 4 (BRD4) to these regions, thereby tuningSPARCtranscription. HDAC10 depletion and resultant SPARC upregulation repress melanoma cell growth, primarily by induction of autophagy via activation of AMPK signaling. Moreover, SPARC upregulation due to HDAC10 depletion partly accounts for the resensitivity of resistant cells to a BRAF inhibitor. Our work reveals the role of HDAC10 in gene regulation through epigenetic modification and suggests a potential therapeutic strategy for melanoma or other cancers by targeting HDAC10 and SPARC.

Highlights

HDAC10 is the primary HDAC member that tightly controls SPARC expression.

HDAC10 coordinates with p300 in modulating the H3K27ac state atSPARCregulatory elements and the recruitment of BRD4 to these regions.

HDAC10 depletion and resultant SPARC upregulation inhibit melanoma cell growth by inducing autophagy via activation of AMPK signaling.

SPARC upregulation as a result of HDAC10 depletion resensitizes resistant cells to BRAF inhibitors.
From Viral Infections to Alzheimer’s Disease: Unveiling the Mechanistic Links Through Systems Bioinformatics
Authors: Onisiforou Anna , Zanos Panos
Published: December 2023

Background

Emerging evidence suggests that certain microorganisms, including viral infections, may contribute to the onset and/or progression of Alzheimer’s Disease (AD), a neurodegenerative condition characterized by memory impairment and cognitive decline. However, the precise extent of their involvement and the underlying mechanisms through which specific viruses increase AD susceptibility risk remain elusive.

Methods

We used an integrative systems bioinformatics approach to identity viral-mediated pathogenic mechanisms by which specific viral species, namely Herpes Simplex Virus 1 (HSV-1), Human Cytomegalovirus (HCMV), Epstein-Barr Virus (EBV), Kaposi Sarcoma-associated Herpesvirus (KSHV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Influenza A virus (IAV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), could facilitate the pathogenesis of AD via virus-host protein-protein interactions (PPIs). We also sought to uncover potential synergistic pathogenic effects resulting from the reactivation of specific herpesviruses (HSV-1, HCMV and EBV) during acute SARS-CoV-2 infection, potentially increasing AD susceptibility.

Results

Our findings show thatHerpesviridaeFamily members (HSV-1, EBV, KSHV, HCMV) impact AD-related processes like amyloid-beta formation, neuronal death, and autophagy. Hepatitis viruses (HBV, HCV) influence processes crucial for cellular homeostasis and dysfunction. Importantly, hepatitis viruses affect microglia activation via virus-host PPIs. Reactivation of HCMV during SARS-CoV-2 infection could potentially foster a lethal interplay of neurodegeneration, via synergistic pathogenic effects on AD-related processes like response to unfolded protein, regulation of autophagy, response to oxidative stress and amyloid-beta formation.

Conclusions

Collectively, these findings underscore the complex link between viral infections and AD development. Perturbations in AD-related processes by viruses can arise from both shared and distinct mechanisms among viral species in different categories, potentially influencing variations in AD susceptibility.
Identification of candidate biomarkers and pathways associated with multiple sclerosis using bioinformatics and next generation sequencing data analysis
Authors: Vastrad Basavaraj , Vastrad Chanabasayya
Published: December 2023

Multiple sclerosis (MS) is the main reason for disability caused by autoimmunity. However, effective biomarkers for MS have not been identified. This study explored the molecular mechanisms and potential therapeutic targets for MS occurrence and progression using bioinformatics and next generation sequencing (NGS) data analysis. NGS data GSE138614, including patients with MS and 25 normal control samples, were obtained from Gene Expression Omnibus (GEO) database Differentially expressed genes (DEGs) were filtered and subjected to gene ontology (GO) and pathway enrichment analyses. Protein–protein interaction (PPI) network and module analyses were performed based on the DEGs. MiRNA-hub gene regulatory network and TF-hub gene regulatory network analysis were built by Cytoscape to predict the underlying microRNAs (miRNAs) and transcription factors (TFs) associated with hub genes. We also validated the identified hub genes via receiver operating characteristic (ROC) curve analysis. A total of 959 DEGs (479 up regulated genes and 480 down regulated genes) were detected. The GO terms and pathways of DEGs involve immune system process, developmental process, immune system and regulation of cholesterol biosynthesis by SREBP (SREBF). The network analysis revealed that hub genes include LCK, PYHIN1, SLAMF1, DOK2, TAB2, CFTR, RHOB, LMNA, EGLN3 and ERBB3 might be involved in the development of MS. The present investigation illustrates a characteristic gene profile in MS, which might contribute to the interpretation of the progression of MS and provide novel biomarkers and therapeutic targets for MS.
Artificial Intelligence and Machine Learning in Cancer Related Pain: A Systematic Review
Authors: Salama Vivian , Godinich Brandon , Geng Yimin , Humbert-Vidan Laia , Maule Laura , Wahid Kareem A. , Naser Mohamed A. , He Renjie , Mohamed Abdallah S.R. , Fuller Clifton D. , Moreno Amy C.
Published: December 2023

Background/objective

Pain is a challenging multifaceted symptom reported by most cancer patients, resulting in a substantial burden on both patients and healthcare systems. This systematic review aims to explore applications of artificial intelligence/machine learning (AI/ML) in predicting pain-related outcomes and supporting decision-making processes in pain management in cancer.

Methods

A comprehensive search of Ovid MEDLINE, EMBASE and Web of Science databases was conducted using terms including “Cancer”, “Pain”, “Pain Management”, “Analgesics”, “Opioids”, “Artificial Intelligence”, “Machine Learning”, “Deep Learning”, and “Neural Networks” published up to September 7, 2023. The screening process was performed using the Covidence screening tool. Only original studies conducted in human cohorts were included. AI/ML models, their validation and performance and adherence to TRIPOD guidelines were summarized from the final included studies.

Results

This systematic review included 44 studies from 2006-2023. Most studies were prospective and uni-institutional. There was an increase in the trend of AI/ML studies in cancer pain in the last 4 years. Nineteen studies used AI/ML for classifying cancer patients’ pain development after cancer therapy, with median AUC 0.80 (range 0.76-0.94). Eighteen studies focused on cancer pain research with median AUC 0.86 (range 0.50-0.99), and 7 focused on applying AI/ML for cancer pain management decisions with median AUC 0.71 (range 0.47-0.89). Multiple ML models were investigated with. median AUC across all models in all studies (0.77). Random forest models demonstrated the highest performance (median AUC 0.81), lasso models had the highest median sensitivity (1), while Support Vector Machine had the highest median specificity (0.74). Overall adherence of included studies to TRIPOD guidelines was 70.7%. Lack of external validation (14%) and clinical application (23%) of most included studies was detected. Reporting of model calibration was also missing in the majority of studies (5%).

Conclusion

Implementation of various novel AI/ML tools promises significant advances in the classification, risk stratification, and management decisions for cancer pain. These advanced tools will integrate big health-related data for personalized pain management in cancer patients. Further research focusing on model calibration and rigorous external clinical validation in real healthcare settings is imperative for ensuring its practical and reliable application in clinical practice.
NF1 modulates microtubule repair and sensitivity to antibody-drug conjugates
Authors: Achutti Duso Bruno , Messuti Eleonora , Tini Giulia , Bonetti Emanuele , Castiglioni Alessia , Frigè Gianmaria , Ciossani Giuseppe , Monzani Silvia , Soriani Chiara , Khuntsariya Daria , Roda Nicolò , Polazzi Andrea , Ippolito Marica R. , Doronzoro Elena G. , Mane Eltjona , Milani Martina , Bottosso Michele , Pagliuca Martina , Farfalla Alessia , Dondi Ambra , Nicolo’ Eleonora , Reduzzi Carolina , Jemos Costantino , Guerini-Rocco Elena , Rodighiero Simona , Tosoni Daniela , Medford Arielle , Davis Andrew , D’amico Paolo , Santaguida Stefano , Cristofanill Massimo , Braun Marcus , Lansky Zdenek , Scietti Luigi , Pelicci Pier Giuseppe , Mazzarella Luca
Published: December 2023

Antibody-Drug Conjugates (ADC) have revolutionized the treatment of several tumors, and extensive research is being devoted to the identification of predictive biomarkers. These are particularly sought after in fields, like breast cancer, in which multiple ADCs with identical target but different payloads have been approved. NF1 is a tumor suppressor widely mutated across several cancers, best characterized as an inhibitor of RAS signaling. Additional functions have been proposed but not deeply investigated, due to its large size and complex domain structure. Whether somatic NF1 mutations can be used to guide clinical decisions is not known.

Here, combining patient data,in vitro/in vivomodels and protein biochemistry, we show that NF1 loss sensitizes cancer cells to T-DM1, the first approved ADC in breast cancer, through a novel, RAS-independent function on microtubular dynamics and repair. NF1 exhibits all biochemical properties of a bona fide Microtubule-Associated Protein (MAP) and specifically enhances intratubular repair, a recently discovered phenomenon whose regulation remains poorly characterized. NF1 loss results in mitotic defects and low-grade aneuploidy in cell lines and patients. Increased sensitivity to T-DM1 upon NF1 loss is confirmed in breast cancer patients analysed across institutions in Europe and USA.

Our results define NF1 as a key regulatory factor for microtubular repair and the first ADC payload-associated predictive biomarker identified to date.
Development of pre-clinical murine models for fibrolamellar hepatocellular carcinoma
Authors: He Andy , Coles Garry L. , Hartmann Griffin G. , Arand Julia , Le Vicky , Mauch Brandon , Xu Lei , Nguyen Thuyen , Hazard Florette K. , Sage Julien
Published: December 2023

Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of cancer that affects primarily adolescents and young adults. FLC tumors are typically associated with an intrachromosomal deletion resulting in expression of a fusion protein between the chaperone DNAJ1B and the protein kinase PKA. FLC is challenging to study because of its rarity and limited pre-clinical models. Here we developed a novel transgenic mouse model of FLC. In this model, DNAJ1B-PKA expression in the liver of mouse embryos results in perinatal lethality associated with liver developmental defects, while DNAJ1B-PKA expression in the liver of adult mice initiates tumors resembling FLC at low penetrance. We sought to developex vivocell models from these tumors but failed to establish long-term cell lines. New pre-clinical models of FLC will provide novel insights into the biology of this rare cancer and may help identify novel therapeutic strategies.
SOLUBILIZER OF BACTERIAL ORIGIN SURFACTIN INCREASES THE BIOLOGICAL ACTIVITY OF C60 FULLERENE
Authors: Emelyantsev Sergey , Prazdnova Evgeniya , Chistyakov Vladimir
Published: December 2023

Currently, there exists conflicting data regarding the biological activity of unmodified fullerene C60. Various sources report its toxicity, geroprotective activity, and potential interaction with DNA. Contradictory findings regarding the toxicity of C60may arise from the use of toxic solvents, as well as the influence of bioavailability and bioactivity on the preparation conditions of C60 suspensions. Furthermore, the microbiota of experimental animals can impact geroprotective activity results by releasing surfactants that facilitate substance penetration through the cell membrane.

In this study, we selected conditions for solubilizing fullerene C60in a solution of surfactin, a surfactant of bacterial origin, as well as in a 2% aqueous solution of TWEEN 80, employing ultrasound. Through bioluminescent analysis using lux biosensors in E. coli MG1655, we observed that C60in surfactin reduced induced genotoxic and oxidative stress. Given that surfactin enhances membrane permeability to fullerene C60, suspensions of fullerene in designated concentrations of surfactin can be regarded as a DNA protector and antioxidant, warranting further investigation as a promising component of novel drugs.
Definition of the effector landscape across 13 Phytoplasma proteomes with LEAPH and EffectorComb
Authors: Calia Giulia , Cestaro Alessandro , Schuler Hannes , Janik Katrin , Donati Claudio , Moser Mirko , Bottini Silvia
Published: December 2023

Background

Crop pathogens are a major threat to plants’ health, reducing the yield and quality of agricultural production. Among them, theCandidatusPhytoplasma genus, a group of fastidious phloem-restricted bacteria, can parasite a wide variety of both ornamental and agro-economically important plants. Several aspects of the interaction with the plant host are still unclear but it was discovered that phytoplasmas secrete certain proteins (effectors) responsible for the symptoms associated with the disease. Identifying and characterizing these proteins is of prime importance for globally improving plant health in an environmentally friendly context.

Results

We challenged the identification of phytoplasma’s effectors by developing LEAPH, a novel machine-learning ensemble predictor for phytoplasmas pathogenicity proteins. The prediction core is composed of four models: Random Forest, XGBoost, Gaussian, and Multinomial Naive Bayes. The consensus prediction is achieved by a novel consensus prediction score. LEAPH was trained on 479 proteins from 53 phytoplasmas species, described by 30 features accounting for the biological complexity of these protein sequences. LEAPH achieved 97.49% accuracy, 95.26% precision, and 98.37% recall, ensuring a low false-positive rate and outperforming available state-of-the-art methods for putative effector prediction. The application of LEAPH to 13 phytoplasma proteomes yields a comprehensive landscape of 2089 putative pathogenicity proteins. We identified three classes of these proteins according to different secretion models: “classical”, presenting a signal peptide, “classically-like” and “non-classical”, lacking the canonical secretion signal. Importantly, LEAPH was able to identify 15 out of 17 known experimentally validated effectors belonging to the three classes. Furthermore, to help the selection of novel candidates for biological validation, we applied the Self-Organizing Maps algorithm and developed a shiny app called EffectorComb. Both tools would be a valuable resource to improve our understanding of effectors in plant–phytoplasmas interactions.

Conclusions

LEAPH and EffectorComb app can be used to boost the characterization of putative effectors at both computational and experimental levels and can be employed in other phytopathological models. Both tools are available athttps://github.com/Plant-Net/LEAPH-EffectorComb.git.
Volumetric studies of phenylalanine in the pre micellar regions of Cetyl trimethyl ammonium bromide (CTAB) in aqueous solution
Authors: Ansari Nizamul Haque
Published: December 2023

Interactions between amino acid (dl-phenylalanine) and surfactant (cetyltrimethyl ammonium bromide) was investigated using density and density data was utilized to calculate apparent molar volume, and partial molar volume also known as limiting molar volumeto find out solute-solvent interactions between amino acid and surfactant.
Machine-learning-based Structural Analysis of Interactions between Antibodies and Antigens
Authors: Zhang Grace , Su Zhaoqian , Zhang Tom , Wu Yinghao
Published: December 2023

Computational analysis of paratope-epitope interactions between antibodies and their corresponding antigens can facilitate our understanding of the molecular mechanism underlying humoral immunity and boost the design of new therapeutics for many diseases. The recent breakthrough in artificial intelligence has made it possible to predict protein-protein interactions and model their structures. Unfortunately, detecting antigen-binding sites associated with a specific antibody is still a challenging problem. To tackle this challenge, we implemented a deep learning model to characterize interaction patterns between antibodies and their corresponding antigens. With high accuracy, our model can distinguish between antibody-antigen complexes and other types of protein-protein complexes. More intriguingly, we can identify antigens from other common protein binding regions with an accuracy of higher than 70% even if we only have the epitope information. This indicates that antigens have distinct features on their surface that antibodies can recognize. Additionally, our model was unable to predict the partnerships between antibodies and their particular antigens. This result suggests that one antigen may be targeted by more than one antibody and that antibodies may bind to previously unidentified proteins. Taken together, our results support the precision of antibody-antigen interactions while also suggesting positive future progress in the prediction of specific pairing.
Regulation of transcription patterns, poly-ADP-ribose, and RNA-DNA hybrids by the ATM protein kinase
Authors: Woolley Phillip R. , Wen Xuemei , Conway Olivia M. , Ender Nicolette A. , Lee Ji-Hoon , Paull Tanya T.
Published: December 2023

The ATM protein kinase is a master regulator of the DNA damage response and also an important sensor of oxidative stress. Analysis of gene expression in Ataxia-telangiectasia patient brain tissue shows that large-scale transcriptional changes occur in patient cerebellum that correlate with expression level and GC content of transcribed genes. In human neuron-like cells in culture we map locations of poly-ADP-ribose and RNA-DNA hybrid accumulation genome-wide with ATM inhibition and find that these marks also coincide with high transcription levels, active transcription histone marks, and high GC content. Antioxidant treatment reverses the accumulation of R-loops in transcribed regions, consistent with the central role of ROS in promoting these lesions. Based on these results we postulate that transcription-associated lesions accumulate in ATM-deficient cells and that the single-strand breaks and PARylation at these sites ultimately generate changes in transcription that compromise cerebellum function and lead to neurodegeneration over time in A-T patients.
CD20 expression regulates CD37 levels in B-cell lymphoma – implications for immunotherapies
Authors: Bobrowicz Malgorzata , Kusowska Aleksandra , Krawczyk Marta , Slusarczyk Aleksander , Barankiewicz Joanna , Domagala Joanna , Kubacz Matylda , Šmída Michal , Dostalova Lenka , Marhelava Katsiaryna , Fidyt Klaudyna , Forcados Christopher , Pepek Monika , Baranowska Iwona , Szumera-Cieckiewicz Anna , Inderberg Else Marit , Wälchli Sébastien , Graczyk-Jarzynka Agnieszka , Gehlert Carina Lynn , Peipp Matthias , Firczuk Malgorzata , Prochorec-Sobieszek Monika , Winiarska Magdalena
Published: December 2023

Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of patients. Therefore, novel approaches to treat aggressive lymphomas are being intensively investigated. Several RTX-resistant (RR) cell lines have been established as surrogate models to study resistance to R-CHOP. Our study reveals that RR cells are characterized with a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate for the first time that CD20 and CD37 form a complex and the presence of CD20 stabilizes CD37 in the cell membrane. Consequently, we observe a diminished cytotoxicity of anti-CD37 monoclonal antibody (mAb) in complement-dependent cytotoxicity in both RR and CD20 KO cells that can be partially restored upon lysosome inhibition. On the other hand, the internalization rate of anti-CD37 mAb in CD20 KO cells is increased when compared to controls, suggesting unhampered efficacy of antibody drug conjugates. Importantly, even a major downregulation in CD37 levels does not hamper the efficacy of CD37-directed chimeric antigen receptor (CAR) T cells. In summary, we present here a novel mechanism of CD37 regulation with further implications for the use of anti-CD37 immunotherapies.
Histone Deacetylase Inhibitors Prevent Cytokine-Induced β Cell Dysfunction Through Restoration of Stromal Interaction Molecule 1 Expression and Activation of Store-Operated Calcium Entry
Authors: Lee Chih-Chun , Kono Tatsuyoshi , Syed Farooq , Weaver Staci A. , Sohn Paul , Wu Wenting , Chang Garrick , Liu Jing , Rupnik Marjan Slak , Evans-Molina Carmella
Published: December 2023

Histone deacetylase inhibitors (HDIs) modulate β cell function in preclinical models of diabetes; however, the mechanisms underlying these beneficial effects have not been determined. In this study, we investigated the impact of the HDI sodium butyrate (NaB) on β cell function and calcium (Ca2+) signaling using ex vivo and in vitro models of diabetes. Our results show that NaB significantly improved glucose-stimulated insulin secretion in islets from human organ donors with type 2 diabetes and in cytokine-treated INS-1 β cells. Consistently, NaB partially rescued glucose-stimulated Ca2+oscillations in mouse islets treated with proinflammatory cytokines. Because the oscillatory phenotype of Ca2+in the β cell is governed by changes in endoplasmic reticulum (ER) Ca2+levels, next we explored the relationship between NaB and store-operated calcium entry (SOCE), a rescue mechanism that acts to refill ER Ca2+levels through STIM1-mediated gating of plasmalemmal Orai channels. We found that NaB treatment preserved basal ER Ca2+levels and restored SOCE in IL-1β-treated INS-1 cells. Furthermore, we linked these changes with the restoration of STIM1 levels in cytokine-treated INS-1 cells and mouse islets, and we found that NaB treatment was sufficient to prevent β cell death in response to IL-1β treatment. Mechanistically, NaB counteracted cytokine-mediated reductions in phosphorylation levels of key signaling molecules, including AKT, ERK1/2, glycogen synthase kinase-3α (GSK-3α), and GSK-3β. Taken together, these data support a model whereby HDI treatment promotes β cell function and Ca2+homeostasis under proinflammatory conditions through STIM1-mediated control of SOCE and AKT-mediated inhibition of GSK-3.
Breast cancer cells promote osteoclast differentiation in an MRTF-dependent paracrine manner
Authors: Chawla Pooja , Sharma Ishani , Gau David , Eder Ian , Chen Fangyuan , Yu Virginia , Welling Niharika , Boone David , Taboas Juan , Lee Adrian V. , Larregina Adriana , Galson Deborah L. , Roy Partha
Published: December 2023

Bone is a frequent site for breast cancer metastasis. The vast majority of breast cancer-associated metastasis is osteolytic in nature, and RANKL (receptor activator for nuclear factor κB)-induced differentiation of bone marrow-derived macrophages (BMDMs) to osteoclasts (OCLs) is a key requirement for osteolytic metastatic growth of cancer cells. In this study, we demonstrate that Myocardin-related transcription factor (MRTF) in breast cancer cells plays an important role in paracrine modulation of RANKL-induced osteoclast differentiation. This is partly attributed to MRTF’s critical role in maintaining the basal cellular expression of connective tissue growth factor (CTGF), findings that align with a strong positive correlation between CTGF expression and MRTF-A gene signature in the human disease context. Luminex analyses reveal that MRTF depletion in breast cancer cells has a broad impact on OCL-regulatory cell-secreted factors that extend beyond CTGF. Experimental metastasis studies demonstrate that MRTF depletion diminishes OCL abundance and bone colonization breast cancer cellsin vivo, suggesting that MRTF inhibition could be an effective strategy to diminish OCL formation and skeletal involvement in breast cancer. In summary, this study highlights a novel tumor-extrinsic function of MRTF relevant to breast cancer metastasis.

SIGNIFICANCE STATEMENT

MRTF, a transcriptional coactivator of SRF, is known to promote breast cancer progression through its tumor-cell-intrinsic function. Whether and how MRTF activity in tumor cells modulates other types of cells in the tumor microenvironment are not clearly understood.

This study uncovers a novel tumor-cell-extrinsic function of MRTF in breast cancer cells in promoting osteoclast differentiation partly through CTGF regulation, and further demonstrates MRTF’s requirement for bone colonization of breast cancer cells in vivo.

Our studies suggest that MRTF inhibition could be an effective strategy to diminish osteoclast formation and skeletal involvement in metastatic breast cancer.
Multi-Level Contrastive Learning for Protein-Ligand Binding Residue Prediction
Authors: Zhang Jiashuo , Wang Ruheng , Wei Leyi
Published: December 2023

Protein-ligand interactions play a crucial role in various biological functions, with their accurate prediction being pivotal for drug discovery and design processes. Traditional methods for predicting protein-ligand interactions are limited. Some can only predict interactions with a specific molecule, restricting their applicability, while others aim for multiple types but fail to effectively utilize information across different interactions, leading to increased complexity and inefficiency. This study presents a novel deep learning model named MucLiPred and a dual contrastive learning mechanism aimed at improving the prediction of multiple ligand-protein interactions and the identification of potential ligand-binding residues. We proposed two novel contrastive learning paradigms at residue and type levels, training the discriminative representation of samples. The residue-level contrastive learning hones in on distinguishing binding from non-binding residues with precision, shedding light on nuanced local interactions. In contrast, the type-level contrastive learning delves into the overarching context of ligand types, ensuring that representations of identical ligand types gravitate closer in the representational space and bolstering the model’s proficiency in discerning interaction motifs, enhancing the model’s ability to recognize global interaction patterns. This approach culminates in nuanced multi-ligand predictions, unraveling relationships between various ligand types, and fortifying the potential for precise protein-ligand interaction predictions. Empirical findings underscore MucLiPred’s dominance over existing models, highlighting its robustness and unparalleled prediction accuracy. The integration of dual contrastive learning techniques amplifies its capability to detect potential ligand-binding residues with precision. By optimizing the model’s structure, we discovered that separating representation and classification tasks, leads to improved performance. Consequently, MucLiPred stands out as a groundbreaking tool in protein-ligand interaction prediction, laying the groundwork for future endeavors in this complex arena.
Clinical evaluation of a low-coverage whole-genome test for detecting homologous recombination deficiency in ovarian cancer
Authors: Boidot Romain , Blum Michael G.B. , Wissler Marie-Pierre , Gottin Céline , Ruzicka Jiri , Chevrier Sandy , Delhomme Tiffany M. , Audoux Jérome , Jeanniard Adrien , Just Pierre-Alexandre , Harter Philipp , Pignata Sandro , González-Martin Antonio , Marth Christian , Mäenpää Johanna , Colombo Nicoletta , Vergote Ignace , Fujiwara Keiichi , Duforet-Frebourg Nicolas , Bertrand Denis , Philippe Nicolas , Ray-Coquard Isabelle , Pujade-Lauraine Eric
Published: December 2023

Background

The PAOLA-1/ENGOT-ov25 trial showed that maintenance olaparib plus bevacizumab increases survival of advanced ovarian cancer patients with homologous recombination deficiency (HRD). However, decentralized solutions to test for HRD in clinical routine are scarce. The goal of this study was to retrospectively validate on tumor samples from the PAOLA-1 trial, a decentralized HRD test based on low coverage shallow Whole Genome Sequencing (sWGS).

Methods

The study comprised 368 patients from the PAOLA-1 trial. The sWGS test was compared to the Myriad MyChoice HRD test (Myriad Genetics), and results were analyzed with respect to Progression-Free Survival (PFS).

Results

We found a 95% concordance between the HRD status of the two tests (95% Confidence Interval (CI) 92%-97%). The Positive Percentage Agreement (PPA) of the sWGS test was 95% (95% CI; 90%-97%) like its Negative Percentage Agreement (NPA) (95% CI; 89%-98%). Only 1% (95% CI; 0-3%) of its results were inconclusive. In patients with HRD-positive tumors treated with olaparib plus bevacizumab, the PFS Hazard Ratio (HR) was 0.38 (95% CI; 0.26-0.54) with sWGS and 0.32 (95% CI; 0.22-0.45) with the Myriad assay. In patients with HRD-negative tumors, HR was 0.98 (95% CI; 0.68-1.41) and 1.05 (95% CI; 0.70-1.57) with sWGS and Myriad tests. Among patients with BRCA-wildtype tumors, those with HRD-positive tumors, benefited from olaparib plus bevacizumab maintenance, with HR of 0.48 (95% CI: 0.29-0.79) and of 0.38 (95% CI: 0.23 to 0.63) with sWGS and Myriad test.

Conclusion

The SeqOne sWGS assay offers a clinically validated approach to detect HRD.
Telemedicine Perspectives of Patients with Non-Dialysis Kidney Disease and Kidney Transplant – A Qualitative Meta-Analysis
Authors: Manko Christopher D. , Apple Benjamin J. , Chang Alexander R. , Johannes Bobbie L.
Published: December 2023

Rationale & Objective

While the use of telemedicine has increased dramatically across disciplines, patient perspectives on telemedicine related to chronic kidney disease are not well understood. We systematically reviewed qualitative studies on patients with chronic kidney disease to better understand these patients’ perspectives related to telemedicine.

Study Design

Qualitative Meta-Analysis

Setting & Study Populations

Pre-dialysis chronic kidney disease and kidney transplant patients that used telemedicine.

Selection Criteria for Studies

English language studies published in the year 2000 and beyond that investigated patient perspectives in a qualitative manner. Works that were not qualitative or did not focus on provider-patient interactive modes of telemedicine were excluded.

Data Extraction

375 papers were pulled from PubMed, Embase, and Academic Science Premier. After filtering, 8 final papers were selected. These papers were critically appraised for quality and were used in the final analysis.

Analytical Approach

We developed a codebook to systematically review each of the selected papers through qualitative meta-analysis.

Results

Four primary themes were identified (autonomy, logistics, privacy/confidentiality, and trust) with additional subthemes and further subdivisions to signify positive versus negative experiences. The majority of subthemes and subdivisions (n=9) identified were positively attributed by patients compared to negative attributes (n=6). The subtheme most commonly found was avoiding travel to the hospital, which was identified in all 8 papers. There was substantial variability in the number of papers demonstrating the other subthemes and subdivisions.

Limitations

Lack of provider perspectives, non-English studies, and studies published before the year 2000. Papers published after the start of data extraction were also not included.

Conclusions

Telemedicine should continue to be offered to patients with kidney disease and kidney transplant patients to facilitate access. Additional research should focus on ways to decrease negative factors experienced by some patients such as difficulty with using the technology.
Perspectives on using a celebrity narrative to teach the psychiatric formulation to final year medical students
Authors: Hickey David , McFarland John
Published: December 2023

Objectives

The proficiency of an accomplished psychiatrist encompasses the development, adaptation, and refinement of a biopsychosocial formulation. A formulation aids clinical decision-making by organizing information and furnishes a documented rationale for decisions. Despite its significance, psychiatric trainees often perceive the formulation as arduous and time-intensive, leading to avoidance. Educational shortcomings are pervasive. Addressing this calls for low-cost, novel solutions. Undergraduate medical education possesses aspiring psychiatrists and provides a platform to develop a foundational understanding of formulation. This study aims to explore the viability of a novel, resource-efficient approach employing a celebrity case narrative to attain a fundamental understanding of the psychiatric formulation while concurrently elucidating activated pedagogical cognitions by using such methodology from the student’s perspective.

Methods

A psychiatric formulation tutorial was conducted across five distinct final-year medical student cohorts during one academic year. A standardized tutorial structure was devised, incorporating interchangeable case studies. Following the tutorial, a post-tutorial survey was administered, followed by interviews that underwent qualitative analysis.

Results

Seventy-seven participants responded to the survey, expressing favourable views. Twenty students consented to interviews. They were distributed across five sessions with an average of four participants per group. Interviews yielded five key themes: Understanding of formulation, cognitive engagement, emotional salience and ethical considerations with twelve corresponding subthemes. The results suggested viability in using this methodology to teach formulation to foster a basic understanding and elicited a range of pedagogical phenomenon that may have contributed to this understanding.

Conclusion

This study indicates that integrating a celebrity narrative into psychiatric formulation teaching intervention bears potential for enhancing engagement concurrently mitigating negative attitudes towards the formulation. The approach reveals latent learning outcomes suggesting a profound pedagogical impact. The range of pedagogical process elucidated lays a foundational research base for future instructional design and research.

Declaration of interest

None