Cell Rep Methods. 2023 Oct 17:100621. doi: 10.1016/j.crmeth.2023.100621. Online ahead of print.

ABSTRACT

Molecular representation learning plays an important role in molecular property prediction. Existing molecular property prediction models rely on the de facto standard of covalent-bond-based molecular graphs for representing molecular topology at the atomic level and totally ignore the non-covalent interactions within the molecule. In this study, we propose a molecular geometric deep learning model to predict the properties of molecules that aims to comprehensively consider the information of covalent and non-covalent interactions of molecules. The essential idea is to incorporate a more general molecular representation into geometric deep learning (GDL) models. We systematically test molecular GDL (Mol-GDL) on fourteen commonly used benchmark datasets. The results show that Mol-GDL can achieve a better performance than state-of-the-art (SOTA) methods. Extensive tests have demonstrated the important role of non-covalent interactions in molecular property prediction and the effectiveness of Mol-GDL models.

PMID:37875121 | DOI:10.1016/j.crmeth.2023.100621

Dev Cell. 2023 Oct 20:S1534-5807(23)00519-1. doi: 10.1016/j.devcel.2023.09.013. Online ahead of print.

ABSTRACT

Generating cells with the molecular and functional properties of embryo cells and with full developmental potential is an aim with fundamental biological significance. Here we report the in vitro generation of mouse transient morula-like cells (MLCs) via the manipulation of signaling pathways. MLCs are molecularly distinct from embryonic stem cells (ESCs) and cluster instead with embryo 8- to 16-cell stage cells. A single MLC can generate a blastoid, and the efficiency increases to 80% when 8-10 MLCs are used. MLCs make embryoids directly, efficiently, and within 4 days. Transcriptomic analysis shows that day 4-5 MLC-derived embryoids contain the cell types found in natural embryos at early gastrulation. Furthermore, MLCs introduced into morulae segregate into epiblast (EPI), primitive endoderm (PrE), and trophectoderm (TE) fates in blastocyst chimeras and have a molecular signature indistinguishable from that of host embryo cells. These findings represent the generation of cells that are molecularly and functionally similar to the precursors of the first three cell lineages of the embryo.

PMID:37875119 | DOI:10.1016/j.devcel.2023.09.013

Sci Rep. 2023 Oct 24;13(1):18185. doi: 10.1038/s41598-023-45183-3.

ABSTRACT

Osteoporosis is a bone condition characterized by reduced bone mineral density (BMD), poor bone microarchitecture/mineralization, and/or diminished bone strength. This asymptomatic disorder typically goes untreated until it presents as a low-trauma fracture of the hip, spine, proximal humerus, pelvis, and/or wrist, requiring surgery. Utilizing RNA interference (RNAi) may be accomplished in a number of ways, one of which is by the use of very tiny RNA molecules called microRNAs (miRNAs) and small interfering RNAs (siRNAs). Several kinds of antagomirs and siRNAs are now being developed to prevent the detrimental effects of miRNAs. The goal of this study is to find new antagonists for miRNAs and siRNAs that target multiple genes in order to reduce osteoporosis and promote bone repair. Also, choosing the optimum nanocarriers to deliver these RNAis appropriately to the body could lighten up the research road. In this context, we employed gene ontology analysis to search across multiple datasets. Following data analysis, a systems biology approach was used to process it. A molecular dynamics (MD) simulation was used to explore the possibility of incorporating the suggested siRNAs and miRNA antagonists into polymeric bioresponsive nanocarriers for delivery purposes. Among the three nanocarriers tested [polyethylene glycol (PEG), polyethylenimine (PEI), and PEG-PEI copolymer], MD simulations show that the integration of PEG-PEI with has-mIR-146a-5p is the most stable (total energy = -372.84 kJ/mol, Gyration radius = 2.1084 nm), whereas PEI is an appropriate delivery carrier for has-mIR-7155. The findings of the systems biology and MD simulations indicate that the proposed RNAis might be given through bioresponsive nanocarriers to accelerate bone repair and osteoporosis treatment.

PMID:37875547 | DOI:10.1038/s41598-023-45183-3

Sci Rep. 2023 Oct 24;13(1):18139. doi: 10.1038/s41598-023-44938-2.

ABSTRACT

Plants protect their tissues from insect herbivory with specialized structures and chemicals, such as cuticles, trichomes, and metabolites contained therein. Bacteria inside the insect gut are also exposed to plant defences and can potentially modify the outcome of plant-insect interactions. To disentangle this complex multi-organism system, we used tomato mutants impaired in the production of plant defences (odorless-2 and jasmonic acid-insensitive1) and two cultivars (Ailsa Craig and Castlemart), exposed them to herbivory by the cabbage looper (Trichoplusia ni H.) and collected the insect frass for bacterial community analysis. While the epicuticular wax and terpene profiles were variable, the leaf fatty acid composition remained consistent among genotypes. Moreover, larval weight confirmed the negative association between plant defences and insect performance. The distinctive frass fatty acid profiles indicated that plant genotype also influences the lipid digestive metabolism of insects. Additionally, comparisons of leaf and insect-gut bacterial communities revealed a limited overlap in bacterial species between the two sample types. Insect bacterial community abundance and diversity were notably reduced in insects fed on the mutants, with Enterobacteriaceae being the predominant group, whereas putatively pathogenic taxa were found in wildtype genotypes. Altogether, these results indicate that plant defences can modulate insect-associated bacterial community composition.

PMID:37875520 | DOI:10.1038/s41598-023-44938-2

Adv Sci (Weinh). 2023 Oct 24:e2300123. doi: 10.1002/advs.202300123. Online ahead of print.

ABSTRACT

Systemic Lupus Erythematosus (SLE) etiopathogenesis highlights the contributions of overproduction of CD4+ T cells and loss of immune tolerance. However, the involvement of CD8+ T cells in SLE pathology and disease progression remains unclear. Here, the comprehensive immune cell dysregulation in total 263 clinical peripheral blood samples composed of active SLE (aSLE), remission SLE (rSLE) and healthy controls (HCs) is investigated via mass cytometry, flow cytometry and single-cell RNA sequencing. This is observed that CD8+ CD27+ CXCR3- T cells are increased in rSLE compare to aSLE. Meanwhile, the effector function of CD8+ CD27+ CXCR3- T cells are overactive in aSLE compare to HCs and rSLE, and are positively associated with clinical SLE activity. In addition, the response of peripheral blood mononuclear cells (PBMCs) is monitored to interleukin-2 stimulation in aSLE and rSLE to construct dynamic network biomarker (DNB) model. It is demonstrated that DNB score-related parameters can faithfully predict the remission of aSLE and the flares of rSLE. The abundance and functional dysregulation of CD8+ CD27+ CXCR3- T cells can be potential biomarkers for SLE prognosis and concomitant diagnosis. The DNB score with accurate prediction to SLE disease progression can provide clinical treatment suggestions especially for drug dosage determination.

PMID:37875396 | DOI:10.1002/advs.202300123

Talanta. 2023 Oct 17;268(Pt 1):125318. doi: 10.1016/j.talanta.2023.125318. Online ahead of print.

ABSTRACT

Consistent retention time (tR) of metabolites is vital for identification in metabolomic analysis with ultrahigh-performance liquid-chromatography (UPLC). To minimize inter-experimental tR variations from the reversed-phase UPLC-MS, we developed an endogenous retention-index (endoRI) using in-sample straight-chain acylcarnitines with different chain-length (LC, C0-C26) without additives. The endoRI-corrections reduced the tR variations caused by the combined changes of mobile phases, gradients, flow-rates, elution time, columns and temperature from up to 5.1 min-0.2 min for most metabolites in a model metabolome consisting of 91 metabolites and multiple biological matrices including human serum, plasma, fecal, urine, A549 cells and rabbit liver extracts. The endoRI-corrections also reduced the inter-batch and inter-platform tR variations from 1.5 min to 0.15 min for 95 % of detected features in the above biological samples. We further established a quantitative model between tR and LC for predicting tR values of acylcarnitines when absent in samples. This makes it possible to compare metabolites' tR from different tR databases and the UPLC-based metabolomic data from different batches.

PMID:37875029 | DOI:10.1016/j.talanta.2023.125318

PLoS One. 2023 Oct 24;18(10):e0290371. doi: 10.1371/journal.pone.0290371. eCollection 2023.

ABSTRACT

Parkinson's disease (PD) is a common neurodegenerative disease (NDD) characterized by the loss of dopaminergic neurons in the substantia nigra. Similar to other NDDs, the buildup of toxic protein aggregates in PD leads to progressive neuronal loss, culminating in neurodegeneration. Accumulating evidence indicates that alterations in subcellular organelles, particularly the endoplasmic reticulum (ER), are critically involved in pathological neurodegenerative events in NDDs, including PD. Mutations in the F-box only protein 7 (FBXO7 or PARK15) gene have been found to cause early onset autosomal recessive familiar PD. FBXO7 functions as an adaptor protein in the Skp1-Cullin1-F-box protein (SCF) E3 ubiquitin ligase complex, which promotes substrate ubiquitination. Although FBXO7 is involved in the ubiquitination of various target proteins, little is known about the upstream regulatory mechanism of FBXO7 and/or its modulator(s). Ubiquitin specific protease 7 (USP7) is a deubiquitinating enzyme that regulates the balance between protein synthesis and degradation by removing ubiquitin from target substrates. The role of USP7 in various types of cancer is well-established; however, its role in NDDs has not been elucidated to date. In this study, we identified that USP7 acts as a novel regulator of FBXO7, positively regulating the stability of FBXO7 through Lys48-linked deubiquitination. Moreover, USP7 was found to mitigate ER stress-induced cytotoxicity and apoptosis by preventing the proteasomal degradation of FBXO7. Taken together, our study suggests that the functional relationship between FBXO7 and USP7 may play a crucial role in ER stress-induced apoptosis and the pathogenesis of PD.

PMID:37874827 | DOI:10.1371/journal.pone.0290371

Br J Dermatol. 2023 Oct 24:ljad410. doi: 10.1093/bjd/ljad410. Online ahead of print.

ABSTRACT

BACKGROUND: Co-existing long-term conditions (LTC) in psoriasis and their potential causal associations with the disease are not well-established.

OBJECTIVES: This study aims to determine distinct clusters of LTC in people with psoriasis and the potential bi-directional causal association between these LTC and psoriasis.

METHODS: Using latent class analysis, cross-sectional data of people with psoriasis from the UK Biobank were analysed to identify distinct psoriasis-related co-morbidity profiles. Linkage disequilibrium score regression (LDSR) was applied to compute the genetic correlation between psoriasis and LTC. Two-sample bidirectional Mendelian randomisation (MR) analysis assessed potential causal direction using independent genetic variants that reached genome-wide significance (P < 5 × 10-8).

RESULTS: Five co-morbidity clusters were identified in a population of 10,873 people with psoriasis. LDSR revealed that psoriasis was positively genetically correlated with heart failure (rg = 0.23, p = 8.8 × 10-8), depression (rg = 0.12, p = 2.7 × 10-5), coronary artery disease (CAD) (rg = 0.15, p = 2 × 10-4), and type 2 diabetes (rg = 0.19, p = 3 × 10-3). Genetic liability to CAD was associated with an increased risk of psoriasis (ORIVW = 1.159; 95%CI 1.055-1.274; p = 2 × 10-3). The MR-PRESSO (ORMR-PRESSO = 1.13; 95%CI 1.042-1.228; p = 6 × 10-3) and the MR-RAPS (ORMR-RAPS = 1.149; 95%CI 1.062-1.242; p = 5 × 10-4) approaches corroborate the IVW findings. The weighted median generated similar and consistent effect estimates but was not statistically significant (ORWM = 1.076; 95%CI 0.949-1.221; p = 0.251). Evidence for a suggestive increased risk was detected for CAD (ORIVW = 1.031; 95%CI 1.003-1.059; p = 0.032) and heart failure (ORIVW = 1.019; 95%CI 1.005-1.033; p = 9 × 10-3) in those with genetic liability to psoriasis; however, MR sensitivity analyses did not reach statistical significance.

CONCLUSIONS: Five distinct clusters of psoriasis co-morbidities were observed with these findings to offer opportunities for an integrated approach to comorbidity prevention and treatment. Co-existing LTC share with psoriasis common genetic and non-genetic risk factors, and aggressive lifestyle modification in these people is anticipated to have an impact beyond psoriasis risk. Genetically predicted coronary artery disease is possibly associated with an increased risk of psoriasis, altering our prior knowledge.

PMID:37874776 | DOI:10.1093/bjd/ljad410

Microbiol Resour Announc. 2023 Oct 24:e0065123. doi: 10.1128/MRA.00651-23. Online ahead of print.

ABSTRACT

We report the draft genome sequence of Pseudomonas sp. ER28, capable of utilizing the model naphthenic acid, cyclohexane pentanoic acid, as its sole carbon source. It was recovered from oil sands process-affected water containing cyclic and acyclic naphthenic acids. The genome size is 5.7 Mbp, and the G + C content is 60%.

PMID:37874142 | DOI:10.1128/MRA.00651-23

Orphanet J Rare Dis. 2023 Oct 24;18(1):335. doi: 10.1186/s13023-023-02953-6.

ABSTRACT

BACKGROUND: 22q11.2 Deletion Syndrome (22q11DS) is a genetic disorder characterized by the deletion of adjacent genes at a location specified as q11.2 of chromosome 22, resulting in an array of clinical phenotypes including autistic spectrum disorder, schizophrenia, congenital heart defects, and immune deficiency. Many characteristics of the disorder are known, such as the phenotypic variability of the disease and the biological processes associated with it; however, the exact and systemic molecular mechanisms between the deleted area and its resulting clinical phenotypic expression, for example that of neuropsychiatric diseases, are not yet fully understood.

RESULTS: Using previously published transcriptomics data (GEO:GSE59216), we constructed two datasets: one set compares 22q11DS patients experiencing neuropsychiatric diseases versus healthy controls, and the other set 22q11DS patients without neuropsychiatric diseases versus healthy controls. We modified and applied the pathway interaction method, originally proposed by Kelder et al. (2011), on a network created using the WikiPathways pathway repository and the STRING protein-protein interaction database. We identified genes and biological processes that were exclusively associated with the development of neuropsychiatric diseases among the 22q11DS patients. Compared with the 22q11DS patients without neuropsychiatric diseases, patients experiencing neuropsychiatric diseases showed significant overrepresentation of regulated genes involving the natural killer cell function and the PI3K/Akt signalling pathway, with affected genes being closely associated with downregulation of CRK like proto-oncogene adaptor protein. Both the pathway interaction and the pathway overrepresentation analysis observed the disruption of the same biological processes, even though the exact lists of genes collected by the two methods were different.

CONCLUSIONS: Using the pathway interaction method, we were able to detect a molecular network that could possibly explain the development of neuropsychiatric diseases among the 22q11DS patients. This way, our method was able to complement the pathway overrepresentation analysis, by filling the knowledge gaps on how the affected pathways are linked to the original deletion on chromosome 22. We expect our pathway interaction method could be used for problems with similar contexts, where complex genetic mechanisms need to be identified to explain the resulting phenotypic plasticity.

PMID:37872602 | DOI:10.1186/s13023-023-02953-6

BMC Med Imaging. 2023 Oct 23;23(1):165. doi: 10.1186/s12880-023-01114-2.

ABSTRACT

OBJECTIVE: Diagnosis of small airway disease on computed tomography (CT) scans is challenging in patients with a history of chemical warfare exposure. We developed a software package based on different methodologies to identify and quantify small airway disease in CT images. The primary aim was to identify the best automatic methodology for detecting small airway disease in CT scans of Iran-Iraq War victims of chemical warfare.

METHODS: This retrospective case-control study enrolled 46 patients with a history of chemical warfare exposure and 27 controls with inspiratory/expiratory (I/E) CT scans and spirometry tests. Image data were automatically segmented, and inspiratory images were registered into the expiratory images' frame using the locally developed software. Parametric response mapping (PRM) and air trapping index (ATI) mapping were performed on the CT images. Conventional QCT methods, including expiratory/inspiratory mean lung attenuation (E/I MLA) ratio, normal density E/I (ND E/I) MLA ratio, attenuation volume Index (AVI), %low attenuation areas (LAA) < -856 in exhale scans, and %LAA < -950 in inhale scans were also computed. QCT measurements were correlated with spirometry results and compared across the two study groups.

RESULTS: The correlation analysis showed a significant negative relationship between three air trapping (AT) measurements (PRM, ATI, and %LAAExp < -856) and spirometry parameters (Fev1, Fvc, Fev1/Fvc, and MMEF). Moreover, %LAAExp < -856 had the highest significant negative correlation with Fev1/Fvc (r = -0.643, P-value < 0.001). Three AT measurements demonstrated a significant difference between the study groups. The E/I ratio was also significantly different between the two groups (P-value < 0.001). Binary logistic regression models showed PRMFsad, %LAAExp < -856, and ATI as significant and strong predictors of the study outcome. Optimal cut-points for PRMFsad = 19%, %LAAExp < -856 = 23%, and ATI = 27% were identified to classify the participants into two groups with high accuracy.

CONCLUSION: QCT methods, including PRM, ATI, and %LAAExp < -856 can greatly advance the identification and quantification of SAD in chemical warfare victims. The results should be verified in well-designed prospective studies involving a large population.

PMID:37872482 | DOI:10.1186/s12880-023-01114-2

Nat Biotechnol. 2023 Oct 23. doi: 10.1038/s41587-023-01964-9. Online ahead of print.

ABSTRACT

Pooled CRISPR screens with single-cell RNA sequencing readout (Perturb-seq) have emerged as a key technique in functional genomics, but they are limited in scale by cost and combinatorial complexity. In this study, we modified the design of Perturb-seq by incorporating algorithms applied to random, low-dimensional observations. Compressed Perturb-seq measures multiple random perturbations per cell or multiple cells per droplet and computationally decompresses these measurements by leveraging the sparse structure of regulatory circuits. Applied to 598 genes in the immune response to bacterial lipopolysaccharide, compressed Perturb-seq achieves the same accuracy as conventional Perturb-seq with an order of magnitude cost reduction and greater power to learn genetic interactions. We identified known and novel regulators of immune responses and uncovered evolutionarily constrained genes with downstream targets enriched for immune disease heritability, including many missed by existing genome-wide association studies. Our framework enables new scales of interrogation for a foundational method in functional genomics.

PMID:37872410 | DOI:10.1038/s41587-023-01964-9

Nat Cancer. 2023 Oct 23. doi: 10.1038/s43018-023-00656-2. Online ahead of print.

ABSTRACT

Despite recent advances in the treatment of acute myeloid leukemia (AML), there has been limited success in targeting surface antigens in AML, in part due to shared expression across malignant and normal cells. Here, high-density immunophenotyping of AML coupled with proteogenomics identified unique expression of a variety of antigens, including the RNA helicase U5 snRNP200, on the surface of AML cells but not on normal hematopoietic precursors and skewed Fc receptor distribution in the AML immune microenvironment. Cell membrane localization of U5 snRNP200 was linked to surface expression of the Fcγ receptor IIIA (FcγIIIA, also known as CD32A) and correlated with expression of interferon-regulated immune response genes. Anti-U5 snRNP200 antibodies engaging activating Fcγ receptors were efficacious across immunocompetent AML models and were augmented by combination with azacitidine. These data provide a roadmap of AML-associated antigens with Fc receptor distribution in AML and highlight the potential for targeting the AML cell surface using Fc-optimized therapeutics.

PMID:37872381 | DOI:10.1038/s43018-023-00656-2

Nat Commun. 2023 Oct 23;14(1):6693. doi: 10.1038/s41467-023-42572-0.

ABSTRACT

Group A streptococcus (GAS) is a major bacterial pathogen responsible for both local and systemic infections in humans. The molecular mechanisms that contribute to disease heterogeneity remain poorly understood. Here we show that the transition from a local to a systemic GAS infection is paralleled by pathogen-driven alterations in IgG homeostasis. Using animal models and a combination of sensitive proteomics and glycoproteomics readouts, we documented the progressive accumulation of IgG cleavage products in plasma, due to extensive enzymatic degradation triggered by GAS infection in vivo. The level of IgG degradation was modulated by the route of pathogen inoculation, and mechanistically linked to the combined activities of the bacterial protease IdeS and the endoglycosidase EndoS, upregulated during infection. Importantly, we show that these virulence factors can alter the structure and function of exogenous therapeutic IgG in vivo. These results shed light on the role of bacterial virulence factors in shaping GAS pathogenesis, and potentially blunting the efficacy of antimicrobial therapies.

PMID:37872209 | DOI:10.1038/s41467-023-42572-0

Nat Commun. 2023 Oct 23;14(1):6692. doi: 10.1038/s41467-023-42402-3.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) tumours carry multiple gene mutations and respond poorly to treatments. There is currently an unmet need for drug carriers that can deliver multiple gene cargoes to target high solid tumour burden like PDAC. Here, we report a dual targeted extracellular vesicle (dtEV) carrying high loads of therapeutic RNA that effectively suppresses large PDAC tumours in mice. The EV surface contains a CD64 protein that has a tissue targeting peptide and a humanized monoclonal antibody. Cells sequentially transfected with plasmid DNAs encoding for the RNA and protein of interest by Transwell®-based asymmetric cell electroporation release abundant targeted EVs with high RNA loading. Together with a low dose chemotherapy drug, Gemcitabine, dtEVs suppress large orthotopic PANC-1 and patient derived xenograft tumours and metastasis in mice and extended animal survival. Our work presents a clinically accessible and scalable way to produce abundant EVs for delivering multiple gene cargoes to large solid tumours.

PMID:37872156 | DOI:10.1038/s41467-023-42402-3

Nature. 2023 Oct 23. doi: 10.1038/s41586-023-06750-w. Online ahead of print.

ABSTRACT

A SARS-CoV-2 Omicron subvariant, BA.2.86, has emerged and spread to numerous countries worldwide, raising alarm because its spike protein contains 34 additional mutations compared to its BA.2 predecessor1. We examined its antigenicity using human sera and monoclonal antibodies (mAbs). Reassuringly, BA.2.86 was not more resistant to human sera than the currently dominant XBB.1.5 and EG.5.1, indicating that the new subvariant would not have a growth advantage in this regard. Importantly, sera from patients who had XBB breakthrough infection exhibited robust neutralizing activity against all viruses tested, suggesting that upcoming XBB.1.5 monovalent vaccines could confer added protection. While BA.2.86 showed greater resistance to mAbs to subdomain 1 (SD1) and receptor-binding domain (RBD) class 2 and 3 epitopes, it was more sensitive to mAbs to class 1 and 4/1 epitopes in the "inner face" of RBD that is exposed only when this domain is in the "up" position. We also identified six new spike mutations that mediate antibody resistance, including E554K that threatens SD1 mAbs in clinical development. The BA.2.86 spike also had a remarkably high receptor affinity. The ultimate trajectory of this new SARS-CoV-2 variant will soon be revealed by continuing surveillance, but its worldwide spread is worrisome.

PMID:37871613 | DOI:10.1038/s41586-023-06750-w

Biomed Pharmacother. 2023 Oct 20;168:115755. doi: 10.1016/j.biopha.2023.115755. Online ahead of print.

ABSTRACT

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D) share common features, including insulin resistance. Brain insulin resistance has been implicated as a key factor in the pathogenesis of AD. Recent studies have demonstrated that anti-diabetic drugs sodium-glucose cotransporter-2 inhibitor (SGLT2-i) and dipeptidyl peptidase-4 inhibitor (DPP4-i) improve insulin sensitivity and provide neuroprotection. However, the effects of these two inhibitors on the brain metabolism and insulin resistance remain uninvestigated. We developed a T2D-AD mouse model using a high-fat diet (HFD) for 19 weeks along with a single dose of streptozotocin (100 mg/kg, intraperitoneally) at the fourth week of HFD initiation. Subsequently, the animals were treated with SGLT2-i (empagliflozin, 25 mg/kg/day orally [p.o.]) and DPP4-i (sitagliptin, 100 mg/kg/day p.o.) for 7 weeks. Subsequently, behavioral tests were performed, and the expression of insulin signaling, AD-related, and other signaling pathway proteins in the brain were examined. T2D-AD mice not only showed increased blood glucose levels and body weight but also insulin resistance. SGLT2-i and DPP4-i effectively ameliorated insulin sensitivity and reduced body weight in these mice. Furthermore, SGLT2-i and DPP4-i significantly improved hippocampal-dependent learning, memory, and cognitive functions in the T2D-AD mouse model. Interestingly, SGLT2-i and DPP4-i reduced the hyperphosphorylated tau (pTau) levels and amyloid β (Aβ) accumulation and enhanced brain insulin signaling. SGLT2-i reduced pTau accumulation through the angiotensin converting enzyme-2/angiotensin (1-7)/ mitochondrial assembly receptor axis, whereas DPP4-i reduced Aβ accumulation by increasing insulin-degrading enzyme levels. These findings suggest that SGLT2-i and DPP4-i prevent AD-like pathology and cognitive dysfunction in T2D mice potentially through affecting brain insulin signaling via different mechanisms.

PMID:37871560 | DOI:10.1016/j.biopha.2023.115755

PLoS Comput Biol. 2023 Oct 23;19(10):e1011379. doi: 10.1371/journal.pcbi.1011379. Online ahead of print.

ABSTRACT

Most computational methods that infer somatic copy number alterations (SCNAs) from bulk sequencing of DNA analyse tumour samples individually. However, the sequencing of multiple tumour samples from a patient's disease is an increasingly common practice. We introduce Refphase, an algorithm that leverages this multi-sampling approach to infer haplotype-specific copy numbers through multi-sample phasing. We demonstrate Refphase's ability to infer haplotype-specific SCNAs and characterise their intra-tumour heterogeneity, to uncover previously undetected allelic imbalance in low purity samples, and to identify parallel evolution in the context of whole genome doubling in a pan-cancer cohort of 336 samples from 99 tumours.

PMID:37871126 | DOI:10.1371/journal.pcbi.1011379

IEEE Trans Vis Comput Graph. 2023 Oct 23;PP. doi: 10.1109/TVCG.2023.3326582. Online ahead of print.

ABSTRACT

Exploration and analysis of high-dimensional data are important tasks in many felds that produce large and complex data, like the fnancial sector, systems biology, or cultural heritage. Tailor-made visual analytics software is developed for each specifc application, limiting their applicability in other felds. However, as diverse as these felds are, their characteristics and requirements for data analysis are conceptually similar. Many applications share abstract tasks and data types and are often constructed with similar building blocks. Developing such applications, even when based mostly on existing building blocks, requires signifcant engineering efforts. We developed ManiVault, a fexible and extensible open-source visual analytics framework for analyzing high-dimensional data. The primary objective of ManiVault is to facilitate rapid prototyping of visual analytics workfows for visualization software developers and practitioners alike. ManiVault is built using a plugin-based architecture that offers easy extensibility. While our architecture deliberately keeps plugins self-contained, to guarantee maximum fexibility and re-usability, we have designed and implemented a messaging API for tight integration and linking of modules to support common visual analytics design patterns. We provide several visualization and analytics plugins, and ManiVault's API makes the integration of new plugins easy for developers. ManiVault facilitates the distribution of visualization and analysis pipelines and results for practitioners through saving and reproducing complete application states. As such, ManiVault can be used as a communication tool among researchers to discuss workfows and results. A copy of this paper and all supplemental material is available at osf.io/9k6jw, and source code at github.com/ManiVaultStudio.

PMID:37871056 | DOI:10.1109/TVCG.2023.3326582

Nucleic Acids Res. 2023 Oct 23:gkad910. doi: 10.1093/nar/gkad910. Online ahead of print.

ABSTRACT

In various autoimmune diseases, dysfunctional TREX1 (Three prime Repair Exonuclease 1) leads to accumulation of endogenous single-stranded DNA (ssDNA), double-stranded DNA (dsDNA) and DNA/RNA hybrids in the cytoplasm and triggers immune activation through the cGAS-STING pathway. Although inhibition of TREX1 could be a useful strategy for cancer immunotherapy, profiling cellular functions in terms of its potential substrates is a key step. Particularly important is the functionality of processing DNA/RNA hybrids and RNA substrates. The exonuclease activity measurements conducted here establish that TREX1 can digest both ssRNA and DNA/RNA hybrids but not dsRNA. The newly solved structures of TREX1-RNA product and TREX1-nucleotide complexes show that 2'-OH does not impose steric hindrance or specific interactions for the recognition of RNA. Through all-atom molecular dynamics simulations, we illustrate that the 2'-OH-mediated intra-chain hydrogen bonding in RNA would affect the binding with TREX1 and thereby reduce the exonuclease activity. This notion of higher conformational rigidity in RNA leading TREX1 to exhibit weaker catalytic cleavage is further validated by the binding affinity measurements with various synthetic DNA-RNA junctions. The results of this work thus provide new insights into the mechanism by which TREX1 processes RNA and DNA/RNA hybrids and contribute to the molecular-level understanding of the complex cellular functions of TREX1 as an exonuclease.

PMID:37870446 | DOI:10.1093/nar/gkad910