Biol Psychiatry. 2024 Nov 28:S0006-3223(24)01781-5. doi: 10.1016/j.biopsych.2024.11.013. Online ahead of print.

ABSTRACT

BACKGROUND: Opioid addiction is a worldwide public health crisis. In the United States, for example, opioids cause more drug overdose deaths than any other substance. Yet, opioid addiction treatments have limited efficacy, meaning that additional treatments are needed.

METHODS: To help address this problem, we used network-based machine learning techniques to integrate results from genome-wide association studies (GWAS) of opioid use disorder (OUD) and problematic prescription opioid misuse with transcriptomic, proteomic, and epigenetic data from the dorsolateral prefrontal cortex (dlPFC) of opioid overdose victims and controls.

RESULTS: We identified 211 highly interrelated genes identified by GWAS or dysregulation in the dlPFC of opioid overdose victims that implicated the Akt, BDNF, and ERK pathways, identifying 414 drugs targeting 48 of these opioid addiction-associated genes. Some of the identified drugs are approved to treat other substance use disorders (SUDs) or depression.

CONCLUSIONS: Our synthesis of multi-omics using a systems biology approach revealed key gene targets that could contribute to drug repurposing, genetics-informed addiction treatment, and future discovery.

PMID:39615775 | DOI:10.1016/j.biopsych.2024.11.013

Cell Syst. 2024 Nov 26:S2405-4712(24)00310-7. doi: 10.1016/j.cels.2024.11.001. Online ahead of print.

ABSTRACT

T cells develop from hematopoietic progenitors in the thymus and protect against pathogens and cancer. However, the emergence of human T cell-competent blood progenitors and their subsequent specification to the T lineage have been challenging to capture in real time. Here, we leveraged a pluripotent stem cell differentiation system to understand the transcriptional dynamics and cell fate restriction events that underlie this critical developmental process. Time-resolved single-cell RNA sequencing revealed that downregulation of the multipotent hematopoietic program, upregulation of >90 lineage-associated transcription factors, and cell-cycle exit all occur within a highly coordinated developmental window. Gene-regulatory network inference uncovered a role for YBX1 in T lineage specification. We mapped the differentiation cell fate hierarchy using transcribed lineage barcoding and discovered that mast and myeloid potential bifurcate from each other early in hematopoiesis, upstream of T lineage restriction. Our systems-level analyses provide a quantitative, time-resolved model of human T cell fate specification. A record of this paper's transparent peer review process is included in the supplemental information.

PMID:39615483 | DOI:10.1016/j.cels.2024.11.001

Plant Biotechnol J. 2024 Nov 30. doi: 10.1111/pbi.14527. Online ahead of print.

ABSTRACT

Biomass crops engineered to accumulate energy-dense triacylglycerols (TAG or 'vegetable oils') in their vegetative tissues have emerged as potential feedstocks to meet the growing demand for renewable diesel and sustainable aviation fuel (SAF). Unlike oil palm and oilseed crops, the current commercial sources of TAG, vegetative tissues, such as leaves and stems, only transiently accumulate TAG. In this report, we used grain (Texas430 or TX430) and sugar-accumulating 'sweet' (Ramada) genotypes of sorghum, a high-yielding, environmentally resilient biomass crop, to accumulate TAG in leaves and stems. We initially tested several gene combinations for a 'push-pull-protect' strategy. The top TAG-yielding constructs contained five oil transgenes for a sorghum WRINKLED1 transcription factor ('push'), a Cuphea viscosissima diacylglycerol acyltransferase (DGAT; 'pull'), a modified sesame oleosin ('protect') and two combinations of specialized Cuphea lysophosphatidic acid acyltransferases and medium-chain acyl-acyl carrier protein thioesterases. Though intended to generate oils with medium-chain fatty acids, engineered lines accumulated oleic acid-rich oil to amounts of up to 2.5% DW in leaves and 2.0% DW in stems in the greenhouse, 36-fold and 49-fold increases relative to wild-type (WT) plants, respectively. Under field conditions, the top-performing event accumulated TAG to amount to 5.5% DW in leaves and 3.5% DW in stems, 78-fold and 58-fold increases, respectively, relative to WT TX430. Transcriptomic and fluxomic analyses revealed potential bottlenecks for increased TAG accumulation. Overall, our studies highlight the utility of a lab-to-field pipeline coupled with systems biology studies to deliver high vegetative oil sorghum for SAF and renewable diesel production.

PMID:39615039 | DOI:10.1111/pbi.14527

Nat Plants. 2024 Nov 29. doi: 10.1038/s41477-024-01859-w. Online ahead of print.

ABSTRACT

Plants continuously respond to changing environmental conditions to prevent damage and maintain optimal performance. To regulate gas exchange with the environment and to control abiotic stress relief, plants have pores in their leaf epidermis, called stomata. Multiple environmental signals affect the opening and closing of these stomata. High temperatures promote stomatal opening (to cool down), and drought induces stomatal closing (to prevent water loss). Coinciding stress conditions may evoke conflicting stomatal responses, but the cellular mechanisms to resolve these conflicts are unknown. Here we demonstrate that the high-temperature-associated kinase TARGET OF TEMPERATURE 3 directly controls the activity of plasma membrane H+-ATPases to induce stomatal opening. OPEN STOMATA 1, which regulates stomatal closure to prevent water loss during drought stress, directly inactivates TARGET OF TEMPERATURE 3 through phosphorylation. Taken together, this signalling axis harmonizes stomatal opening and closing under high temperatures and/or drought. In the context of global climate change, understanding how different stress signals converge on stomatal regulation allows the development of climate-change-ready crops.

PMID:39613896 | DOI:10.1038/s41477-024-01859-w

Sci Rep. 2024 Nov 29;14(1):29721. doi: 10.1038/s41598-024-80768-6.

ABSTRACT

Clinical trials are costly and time-intensive endeavors, with a high rate of drug candidate failures. Moreover, the standard approaches often evaluate drugs under a limited number of protocols. In oncology, where multiple treatment protocols can yield divergent outcomes, addressing this issue is crucial. Here, we present a computational framework that simulates clinical trials through a combination of mathematical and statistical models. This approach offers a means to explore diverse treatment protocols efficiently and identify optimal strategies for oncological drug administration. We developed a computational framework with a stochastic mathematical model as its core, capable of simulating virtual clinical trials closely recapitulating the clinical scenarios. Testing our framework on the landmark SOLO-1 clinical trial investigating Poly-ADP-Ribose Polymerase maintenance treatment in high-grade serous ovarian cancer, we demonstrate that managing toxicity through treatment interruptions or dose reductions does not compromise treatment's clinical benefits. Additionally, we provide evidence suggesting that further reduction of hematological toxicity could significantly improve the clinical outcomes. The value of this computational framework lies in its ability to expedite the exploration of new treatment protocols, delivering critical insights pivotal to shaping the landscape of upcoming clinical trials.

PMID:39613825 | DOI:10.1038/s41598-024-80768-6

Nat Commun. 2024 Nov 29;15(1):10393. doi: 10.1038/s41467-024-54741-w.

ABSTRACT

Infectious disease is the result of interactions between host and pathogen and can depend on genetic variations in both. We conduct a genome-to-genome study of paired human and Mycobacterium tuberculosis genomes from a cohort of 1556 tuberculosis patients in Lima, Peru. We identify an association between a human intronic variant (rs3130660, OR = 10.06, 95%CI: 4.87 - 20.77, P = 7.92 × 10-8) in the FLOT1 gene and a subclavaluee of Mtb Lineage 2. In a human macrophage infection model, we observe hosts with the rs3130660-A allele exhibited stronger interferon gene signatures. The interacting strains have altered redox states due to a thioredoxin reductase mutation. We investigate this association in a 2020 cohort of 699 patients recruited during the COVID-19 pandemic. While the prevalence of the interacting strain almost doubled between 2010 and 2020, its infection is not associated with rs3130660 in this recent cohort. These findings suggest a complex interplay among host, pathogen, and environmental factors in tuberculosis dynamics.

PMID:39613754 | DOI:10.1038/s41467-024-54741-w

Nat Commun. 2024 Nov 29;15(1):10396. doi: 10.1038/s41467-024-54543-0.

ABSTRACT

The long-term consequences of cancer and its therapy on the patients' immune system years after cancer-free survival remain poorly understood. Here, we present an in-depth characterization of the bone marrow immune ecosystem of multiple myeloma long-term survivors, from initial diagnosis up to 17 years following a single therapy line and cancer-free survival. Using comparative single-cell analyses combined with molecular, genomic, and functional approaches, we demonstrate that multiple myeloma long-term survivors exhibit pronounced alterations in their bone marrow microenvironment associated with impaired immunity. These immunological alterations were frequently linked to an inflammatory immune circuit fueled by the long-term persistence or resurgence of residual myeloma cells. Notably, even in the complete absence of any detectable residual disease for decades, sustained changes in the immune system were observed, suggesting an irreversible 'immunological scarring' caused by the initial exposure to the cancer and therapy. Collectively, our study provides key insights into the molecular and cellular bone marrow ecosystem of long-term survivors of multiple myeloma, revealing both reversible and irreversible alterations in the immune compartment.

PMID:39613747 | DOI:10.1038/s41467-024-54543-0

Oral Oncol. 2024 Nov 28;160:107111. doi: 10.1016/j.oraloncology.2024.107111. Online ahead of print.

ABSTRACT

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is characterized by significant genetic intra-tumor heterogeneity (ITH), which may hinder precision medicine strategies that depend on results from single tumor-biopsy specimens. Treatment response assessment relies on radiologic imaging, which cannot detect minimal residual disease (MRD). We assessed the relevance of circulating tumor DNA (ctDNA) as a biomarker for ITH and MRD in HNSCC.

MATERIALS AND METHODS: We recruited 41 non-metastatic resectable HNSCC patients treated with upfront curative-intent surgery in the prospective biobanking SCANDARE study (NCT03017573). Thirty-one patients (76 %) showed recurrent disease at a median follow-up of 41 months. Targeted next-generation sequencing was performed on resected tumor tissues, as well as on serial blood samples obtained at surgery, within 14 weeks after surgery, at six months and at recurrence.

RESULTS: ctDNA was detected in 21/41 patients at surgery (sensitivity: 51 %; 95 % CI, 35-67 %) and 15/22 patients at recurrence (sensitivity: 68 %; 95 % confidence interval [CI], 45-86 %). Among patients with mutations identified in longitudinal plasma samples, additional mutations missed in tumor tissues were reported in 3/21 patients (14 %), while emerging mutations were reported in 9/21 patients (43 %). In the postoperative surveillance setting, ctDNA-based MRD detection anticipated clinical recurrence with a median lead-time of 9.9 months (interquartile range, 8.0-14.5 months) in 17/27 patients (63 %). When detected within 14 weeks after surgery, MRD correlated with disease recurrence after adjusting for classical prognostic variables (HR = 3.0; 95 % CI, 1.1-7.9; p = 0.03).

CONCLUSIONS: ctDNA detection is a useful biomarker for ITH and MRD in resectable HNSCC patients.

PMID:39612700 | DOI:10.1016/j.oraloncology.2024.107111

Development. 2024 Dec 1;151(23):dev202781. doi: 10.1242/dev.202781. Epub 2024 Nov 29.

ABSTRACT

It has been shown that 5-methylcytosine (m5C), one of the most abundant modifications on RNA, regulates various biological processes. However, the function of m5C modification in the nervous system is still largely unknown. Here, we show that the m5C reader Ybx1 is highly expressed in the developing mouse hippocampus in the central nervous system (CNS). Conditional knockout of Ybx1 in the dentate gyrus (DG) decreases mossy fiber growth and affects short-term memory. In the peripheral nervous system (PNS), the mRNA of Ybx1 is enriched in the axons of dorsal root ganglion (DRG) neurons and can be locally translated. Inhibition of local translation of Ybx1 results in a decrease in axon growth. We further identify 28 target mRNAs of Ybx1 in DRG neurons, including Ttl and Mmp24. Axon-specific knockdown of Ttl and Mmp24 decreases axon growth rate both in DRG and DG. It could be a general mechanism that locally translated Ybx1 regulates axon growth by controlling local translation in both CNS and PNS.

PMID:39611865 | DOI:10.1242/dev.202781

J Am Chem Soc. 2024 Nov 29. doi: 10.1021/jacs.4c11809. Online ahead of print.

ABSTRACT

Fatty acid de novo synthesis (FADNS) is a critical process in lipogenesis that is characteristically altered in clear cell renal cell carcinoma (ccRCC), which is the major type of kidney cancer. An important challenge in studying the FADNS process has been the accurate measurement of cytosolic lipogenic acetyl-CoA (AcCoA), the precursor in FADNS, due to its compartmentalization within cells. Here, we describe a novel NMR-based method to decode the isotopic enrichment of lipogenic AcCoA, which, as we demonstrated, is encoded in the simple signal ratios of the geminal methyl groups of lanosterol during its biosynthesis. The approach was validated based on the independence of the tracer enrichment and species along with the expected FADNS modulation using differentially enriched tracers and a well-studied drug. Application of this technique to 786-O ccRCC cells showed that glucose may serve as a major carbon source for lipogenic AcCoA in FADNS at physiological nutrient concentrations, at odds with previous studies that indicated glutamine's dominant role through reductive carboxylation under higher nutrient conditions. Further investigation into glutamine's alternative roles in ccRCC cells suggested its major involvement in the bioenergetic TCA cycle, pyrimidine synthesis, and glutathione synthesis, which is also critical in ccRCC growth. The glutamine-dependent glutathione synthesis was also suggested as a possible metabolic vulnerability compared to normal kidney cells using a glutathione synthesis inhibitor. The current study provides a simple tool for studying an important aspect of lipid metabolism and suggests translational implications for targeting glucose-driven lipogenesis and glutamine-supported glutathione synthesis in ccRCC.

PMID:39611721 | DOI:10.1021/jacs.4c11809

New Phytol. 2024 Nov 29. doi: 10.1111/nph.20304. Online ahead of print.

ABSTRACT

The response of arbuscular mycorrhizal (AM) symbiosis to environmental fluctuations involves resource exchange between host plants and fungal partners, associations between different AM fungal taxa, and biomass allocation between AM fungal spore and hyphal structures; yet a systematic understanding of these responses to meadow degradation remains relatively unknown, particularly in Xizang alpine meadow. Here, we approached this knowledge gap by labeling dual isotopes of air 13CO2 and soil 15NH4Cl, computing ecological networks of AM fungal communities, and quantifying AM fungal biomass allocation among spores, intra- and extraradical hyphae. We found that the exchange ratio of photosynthate and nitrogen between plants and AM fungi increased with the increasing severity of meadow degradation, indicating greater dependence of host plants on this symbiosis for resource acquisition. Additionally, using 18S rRNA gene metabarcoding, we found that AM fungal co-occurrence networks were more complex in more degraded meadows, supporting the stress gradient hypothesis. Meadow degradation also increased AM fungal biomass allocation toward traits associated with intra- and extraradical hyphae at the expense of spores. Our findings suggest that an integrated consideration of resource exchange, ecological networks, and biomass allocation may be important for the restoration of degraded ecosystems.

PMID:39611464 | DOI:10.1111/nph.20304

Front Immunol. 2024 Nov 14;15:1484029. doi: 10.3389/fimmu.2024.1484029. eCollection 2024.

ABSTRACT

Broadly neutralizing antibodies have been proposed as templates for HIV-1 vaccine design, but it has been unclear how similar vaccine-elicited antibodies are to their naturally elicited templates. To provide insight, here we compare the recognition of naturally elicited and vaccine-elicited antibodies targeting the HIV-1 fusion peptide, which comprises envelope (Env) residues 512-526, with the most common sequence being AVGIGAVFLGFLGAA. Naturally elicited antibodies bound peptides with substitutions to negatively charged amino acids at residue positions 517-520 substantially better than the most common sequence, despite these substitutions rarely appearing in HIV-1; by contrast, vaccine-elicited antibodies were less tolerant of sequence variation, with no substitution of residues 512-516 showing increased binding. Molecular dynamics analysis and cryo-EM structural analysis of the naturally elicited ACS202 antibody in complex with the HIV-1 Env trimer with an alanine 517 to glutamine substitution suggested enhanced binding to result from electrostatic interactions with positively charged antibody residues. Overall, vaccine-elicited antibodies appeared to be more fully optimized to bind the most common fusion peptide sequence, perhaps reflecting the immunization with fusion peptide of the vaccine-elicited antibodies.

PMID:39611147 | PMC:PMC11602501 | DOI:10.3389/fimmu.2024.1484029

In Silico Plants. 2024 Aug 30;6(2):diae015. doi: 10.1093/insilicoplants/diae015. eCollection 2024.

ABSTRACT

Guard cell movements depend, in part, on the remodelling of vacuoles from a highly fragmented state to a fused morphology during stomata opening. Indeed, full opening of plant stomata requires vacuole fusion to occur. Fusion of vacuole membranes is a highly conserved process in eukaryotes, with key roles played by two multi-subunit complexes: HOPS (homotypic fusion and vacuolar protein sorting) and SNARE (soluble NSF attachment protein receptor). HOPS is a vacuole tethering factor that is thought to chaperone SNAREs from apposing vacuole membranes into a fusion-competent complex capable of rearranging membranes. In plants, recruitment of HOPS subunits to the tonoplast has been shown to require the presence of the phosphoinositide phosphatidylinositol 3-phosphate. However, chemically depleting this lipid induces vacuole fusion. To resolve this counter-intuitive observation regarding the role of HOPS in regulating plant vacuole morphology, we defined a quantitative model of vacuole fusion dynamics and used it to generate testable predictions about HOPS-SNARE interactions. We derived our model by using simulation-based inference to integrate prior knowledge about molecular interactions with limited, qualitative observations of emergent vacuole phenotypes. By constraining the model parameters to yield the emergent outcomes observed for stoma opening-as induced by two distinct chemical treatments-we predicted a dual role for HOPS and identified a stalled form of the SNARE complex that differs from phenomena reported in yeast. We predict that HOPS has contradictory actions at different points in the fusion signalling pathway, promoting the formation of SNARE complexes, but limiting their activity.

PMID:39611053 | PMC:PMC11599693 | DOI:10.1093/insilicoplants/diae015

Front Plant Sci. 2024 Nov 14;15:1427578. doi: 10.3389/fpls.2024.1427578. eCollection 2024.

ABSTRACT

Deep space flight imposes higher levels of damage on biological organisms; however, its specific effects on rice remain unclear. To investigate the variations in DNA methylation under deep space flight conditions, this study examined rice seeds carried by Chang'e-5. After 23 days of lunar orbital flight, the samples were planted in an artificial climate chamber and subjected to transcriptome and DNA methylation sequencing during the tillering and heading stages. The methylation patterns in the rice genome exhibited variability in response to lunar orbital stressors. DNA methylation alters the expression and interaction patterns of functional genes, involving biological processes such as metabolism and defense. Furthermore, we employed single-sample analysis methods to assess the gene expression and interaction patterns of different rice individuals. The genes exhibiting changes at the transcriptional and methylation levels varied among the different plants; however, these genes regulate consistent biological functions, primarily emphasizing metabolic processes. Finally, through single-sample analysis, we identified a set of miRNAs induced by lunar orbital stressors that potentially target DNA methylation regulatory factors. The findings of this study broaden the understanding of space biological effects and lay a foundation for further exploration of the mechanisms by which deep space flight impacts plants.

PMID:39610890 | PMC:PMC11603183 | DOI:10.3389/fpls.2024.1427578

Dev Cell. 2024 Nov 19:S1534-5807(24)00668-3. doi: 10.1016/j.devcel.2024.11.003. Online ahead of print.

ABSTRACT

Pulsatile activity of the extracellular signal-regulated kinase (ERK) controls several cellular, developmental, and regenerative programs. Sequential segmentation of somites along the vertebrate body axis, a key developmental program, is also controlled by ERK activity oscillation. The oscillatory expression of Her/Hes family transcription factors constitutes the segmentation clock, setting the period of segmentation. Although oscillation of ERK activity depends on Her/Hes proteins, the underlying molecular mechanism remained mysterious. Here, we show that Her/Hes proteins physically interact with and stabilize dual-specificity phosphatases (Dusp) of ERK, resulting in oscillations of Dusp4 and Dusp6 proteins. Pharmaceutical and genetic inhibition of Dusp activity disrupt ERK activity oscillation and somite segmentation in zebrafish. Our results demonstrate that post-translational interactions of Her/Hes transcription factors with Dusp phosphatases establish the fundamental vertebrate body plan. We anticipate that future studies will identify currently unnoticed post-translational control of ERK pulses in other systems.

PMID:39610242 | DOI:10.1016/j.devcel.2024.11.003

Clin Proteomics. 2024 Nov 28;21(1):64. doi: 10.1186/s12014-024-09516-2.

ABSTRACT

BACKGROUND: Alternative N-glycosylation of serum proteins has been observed in colorectal cancer (CRC), esophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), while comparative study among those three cancers has not been reported before. We aimed to identify serum N-glycans signatures and introduce a discriminative model across the gastrointestinal cancers.

METHODS: The study population was initially screened according to the exclusion criteria process. Serum N-glycans profiling was characterized by a high-throughput assay based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Diagnostic model was built by random forest, and unsupervised machine learning was performed to illustrate the differentiation between the three major gastrointestinal (GI) cancers.

RESULTS: We have found that three major gastrointestinal cancers strongly associated with significantly decreased mannosylation and mono-galactosylation, as well as increased sialylation of serum glycoproteins. A highly accurate discriminative power (> 0.90) for those gastrointestinal cancers was obtained with serum N-glycome based predictive model. Additionally, serum N-glycome profile exhibited distinct distributions across GI cancers, and several altered N-glycans were hyper-regulated in each specific disease.

CONCLUSIONS: Serum N-glycome profile was differentially expressed in three major gastrointestinal cancers, providing a new clinical tool for cancer diagnosis and throwing a light upon the disease-specific molecular signatures.

PMID:39609732 | DOI:10.1186/s12014-024-09516-2

Nat Biomed Eng. 2024 Nov 28. doi: 10.1038/s41551-024-01259-7. Online ahead of print.

ABSTRACT

Optimization of oncolytic viruses for therapeutic applications requires the strategic removal or mutagenesis of virulence genes alongside the insertion of transgenes that enhance viral replication, spread and immunogenicity. However, the complexity of many viral genomes and the labour-intensive nature of methods for the generation and isolation of recombinant viruses have hindered the development of therapeutic oncolytic viruses. Here we report an iterative strategy that exploits the preferential susceptibility of viruses to certain antibiotics to accelerate the engineering of the genomes of oncolytic viruses for the insertion of immunomodulatory cytokine transgenes, and the identification of dispensable genes with regard to replication of the recombinant oncolytic viruses in tumour cells. We applied the strategy by leveraging insertional mutagenesis via the Sleeping Beauty transposon system, combined with long-read nanopore sequencing, to generate libraries of herpes simplex virus type 1 and vaccinia virus, identifying stable transgene insertion sites and gene deletions that enhance the safety and efficacy of the viruses.

PMID:39609558 | DOI:10.1038/s41551-024-01259-7

Nat Commun. 2024 Nov 28;15(1):10316. doi: 10.1038/s41467-024-54734-9.

ABSTRACT

Next-generation T-cell-directed vaccines for COVID-19 focus on establishing lasting T-cell immunity against current and emerging SARS-CoV-2 variants. Precise identification of conserved T-cell epitopes is critical for designing effective vaccines. Here we introduce a comprehensive computational framework incorporating a machine learning algorithm-MHCvalidator-to enhance mass spectrometry-based immunopeptidomics sensitivity. MHCvalidator identifies unique T-cell epitopes presented by the B7 supertype, including an epitope from a + 1-frameshift in a truncated Spike antigen, supported by ribosome profiling. Analysis of 100,512 COVID-19 patient proteomes shows Spike antigen truncation in 0.85% of cases, revealing frameshifted viral antigens at the population level. Our EpiTrack pipeline tracks global mutations of MHCvalidator-identified CD8 + T-cell epitopes from the BNT162b4 vaccine. While most vaccine epitopes remain globally conserved, an immunodominant A*01-associated epitope mutates in Delta and Omicron variants. This work highlights SARS-CoV-2 antigenic features and emphasizes the importance of continuous adaptation in T-cell vaccine development.

PMID:39609459 | DOI:10.1038/s41467-024-54734-9

NPJ Syst Biol Appl. 2024 Nov 29;10(1):139. doi: 10.1038/s41540-024-00460-3.

ABSTRACT

Parameter estimation is one of the central challenges in computational biology. In this paper, we present an approach to estimate model parameters and assess their identifiability in cases where only partial knowledge of the system structure is available. The partially known model is embedded into a system of hybrid neural ordinary differential equations, with neural networks capturing unknown system components. Integrating neural networks into the model presents two main challenges: global exploration of the mechanistic parameter space during optimization and potential loss of parameter identifiability due to the neural network flexibility. To tackle these challenges, we treat biological parameters as hyperparameters, allowing for global search during hyperparameter tuning. We then conduct a posteriori identifiability analysis, extending a well-established method for mechanistic models. The pipeline performance is evaluated on three test cases designed to replicate real-world conditions, including noisy data and limited system observability.

PMID:39609454 | DOI:10.1038/s41540-024-00460-3

Cell Death Dis. 2024 Nov 28;15(11):863. doi: 10.1038/s41419-024-07247-8.

ABSTRACT

Recent developments have broadened our perception of SARS-CoV-2, indicating its capability to affect the body systemically beyond its initial recognition as a mere respiratory pathogen. However, the pathways of its widespread are not well understood. Employing a dual-modality approach, we integrated findings from a Murine Hepatitis Virus (MHV) infection model with corroborative clinical data to investigate the pervasive reach of Coronaviruses. The novel presence of viral particles within red blood cells (RBCs) was demonstrated via high-resolution transmission electron microscopy, with computational modeling elucidating a potential heme-mediated viral entry mechanism via Spike protein affinity. Our data affirm viral localization in RBCs, suggesting heme moieties as facilitators for cellular invasion. Exacerbation of MHV pathology upon hemin administration, contrasted with chloroquine-mediated amelioration, underscoring a heme-centric pathway in disease progression. These observations extend the paradigm of Coronavirus pathogenicity to include hemoprotein interactions. This study casts new light on the systemic invasion capabilities of Coronaviruses, linking RBC hemoproteins with viral virulence. The modulation of disease severity through heme-interacting agents heralds a promising avenue for COVID-19 therapeutics. Our findings propose a paradigm shift in the treatment approach, leveraging the virus-heme interplay as a strategic hinge for intervention.

PMID:39609423 | DOI:10.1038/s41419-024-07247-8