Antiviral Res. 2023 Jun 13:105653. doi: 10.1016/j.antiviral.2023.105653. Online ahead of print.

ABSTRACT

The main protease (Mpro) of SARS-CoV-2 is essential for viral replication, which suggests that the Mpro is a critical target in the development of small molecules to treat COVID-19. This study used an in-silico prediction approach to investigate the complex structure of SARS-CoV-2 Mpro in compounds from the United States National Cancer Institute (NCI) database, then validate potential inhibitory compounds against the SARS-CoV-2 Mpro in cis- and trans-cleavage proteolytic assays. Virtual screening of ∼280,000 compounds from the NCI database identified 10 compounds with highest site-moiety map scores. Compound NSC89640 (coded C1) showed marked inhibitory activity against the SARS-CoV-2 Mpro in cis-/trans-cleavage assays. C1 strongly inhibited SARS-CoV-2 Mpro enzymatic activity, with a half maximal inhibitory concentration (IC50) of 2.69 μM and a selectivity index (SI) of >74.35. The C1 structure served as a template to identify structural analogs based on AtomPair fingerprints to refine and verify structure-function associations. Mpro-mediated cis-/trans-cleavage assays conducted with the structural analogs revealed that compound NSC89641 (coded D2) exhibited the highest inhibitory potency against SARS-CoV-2 Mpro enzymatic activity, with an IC50 of 3.05 μM and a SI of >65.57. Compounds C1 and D2 also displayed inhibitory activity against MERS-CoV-2 with an IC50 of <3.5 μM. Thus, C1 shows potential as an effective Mpro inhibitor of SARS-CoV-2 and MERS-CoV. Our rigorous study framework efficiently identified lead compounds targeting the SARS-CoV-2 Mpro and MERS-CoV Mpro.

PMID:37321487 | DOI:10.1016/j.antiviral.2023.105653

Lancet. 2023 Jun 12:S0140-6736(23)00810-3. doi: 10.1016/S0140-6736(23)00810-3. Online ahead of print.

ABSTRACT

BACKGROUND: The long-term health consequences of COVID-19 remain largely unclear. The aim of this study was to describe the long-term health consequences of patients with COVID-19 who have been discharged from hospital and investigate the associated risk factors, in particular disease severity.

METHODS: We did an ambidirectional cohort study of patients with confirmed COVID-19 who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7 and May 29, 2020. Patients who died before follow-up; patients for whom follow-up would be difficult because of psychotic disorders, dementia, or readmission to hospital; those who were unable to move freely due to concomitant osteoarthropathy or immobile before or after discharge due to diseases such as stroke or pulmonary embolism; those who declined to participate; those who could not be contacted; and those living outside of Wuhan or in nursing or welfare homes were all excluded. All patients were interviewed with a series of questionnaires for evaluation of symptoms and health-related quality of life, underwent physical examinations and a 6-min walking test, and received blood tests. A stratified sampling procedure was used to sample patients according to their highest seven-category scale during their hospital stay as 3, 4, and 5-6, to receive pulmonary function test, high resolution CT of the chest, and ultrasonography. Enrolled patients who had participated in the Lopinavir Trial for Suppression of SARS-CoV-2 in China received SARS-CoV-2 antibody tests. Multivariable adjusted linear or logistic regression models were used to evaluate the association between disease severity and long-term health consequences.

FINDINGS: In total, 1733 of 2469 discharged patients with COVID-19 were enrolled after 736 were excluded. Patients had a median age of 57·0 years (IQR 47·0-65·0) and 897 (52%) were male and 836 (48%) were female. The follow-up study was done from June 16 to Sept 3, 2020, and the median follow-up time after symptom onset was 186·0 days (175·0-199·0). Fatigue or muscle weakness (52%, 855 of 1654) and sleep difficulties (26%, 437 of 1655) were the most common symptoms. Anxiety or depression was reported among 23% (367 of 1616) of patients. The proportions of 6-min walking distance less than the lower limit of the normal range were 17% for those at severity scale 3, 13% for severity scale 4, and 28% for severity scale 5-6. The corresponding proportions of patients with diffusion impairment were 22% for severity scale 3, 29% for scale 4, and 56% for scale 5-6, and median CT scores were 3·0 (IQR 2·0-5·0) for severity scale 3, 4·0 (3·0-5·0) for scale 4, and 5·0 (4·0-6·0) for scale 5-6. After multivariable adjustment, patients showed an odds ratio (OR) of 1·61 (95% CI 0·80-3·25) for scale 4 versus scale 3 and 4·60 (1·85-11·48) for scale 5-6 versus scale 3 for diffusion impairment; OR 0·88 (0·66-1·17) for scale 4 versus scale 3 and OR 1·76 (1·05-2·96) for scale 5-6 versus scale 3 for anxiety or depression, and OR 0·87 (0·68-1·11) for scale 4 versus scale 3 and 2·75 (1·61-4·69) for scale 5-6 versus scale 3 for fatigue or muscle weakness. Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with an estimated glomerular filtration rate (eGFR) of 90 mL/min per 1·73 m2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m2 at follow-up.

INTERPRETATION: At 6 months after acute infection, COVID-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression. Patients who were more severely ill during their hospital stay had more severe impaired pulmonary diffusion capacities and abnormal chest imaging manifestations, and are the main target population for intervention of long-term recovery.

FUNDING: National Natural Science Foundation of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Key Research and Development Program of China, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, and Peking Union Medical College Foundation.

PMID:37321233 | DOI:10.1016/S0140-6736(23)00810-3

Environ Int. 2023 Jun 10;177:108027. doi: 10.1016/j.envint.2023.108027. Online ahead of print.

ABSTRACT

Over 400,000 people are estimated to have been exposed to World Trade Center particulate matter (WTCPM) since the attack on the Twin Towers in Lower Manhattan on September 11, 2001. Epidemiological studies have found that exposure to dust may cause respiratory ailments and cardiovascular diseases. However, limited studies have performed a systematic analysis of transcriptomic data to elucidate the biological responses to WTCPM exposure and the therapeutic options. Here, we developed an in vivo mouse exposure model of WTCPM and administered two drugs (i.e., rosoxacin and dexamethasone) to generate transcriptomic data from lung samples. WTCPM exposure increased the inflammation index, and this index was significantly reduced by both drugs. We analyzed the transcriptomics derived omics data using a hierarchical systems biology model (HiSBiM) with four levels, including system, subsystem, pathway, and gene analyses. Based on the selected differentially expressed genes (DEGs) from each group, WTCPM and the two drugs commonly affected the inflammatory responses, consistent with the inflammation index. Among these DEGs, the expression of 31 genes was affected by WTCPM exposure and consistently reversed by the two drugs, and these genes included Psme2, Cldn18, and Prkcd, which are involved in immune- and endocrine-related subsystems and pathways such as thyroid hormone synthesis, antigen processing and presentation, and leukocyte transendothelial migration. Furthermore, the two drugs reduced the inflammatory effects of WTCPM through distinct pathways, e.g., vascular-associated signaling by rosoxacin, whereas mTOR-dependent inflammatory signaling was found to be regulated by dexamethasone. To the best of our knowledge, this study constitutes the first investigation of transcriptomics data of WTCPM and an exploration of potential therapies. We believe that these findings provide strategies for the development of promising optional interventions and therapies for airborne particle exposure.

PMID:37321070 | DOI:10.1016/j.envint.2023.108027

New Phytol. 2023 Jun 15. doi: 10.1111/nph.19022. Online ahead of print.

ABSTRACT

Increasing drought phenomena pose a serious threat to agricultural productivity. Although plants have multiple ways to respond to the complexity of drought stress, the underlying mechanisms of stress sensing and signaling remain unclear. The role of the vasculature, in particular the phloem, in facilitating inter-organ communication is critical and poorly understood. Combining genetic, proteomic and physiological approaches, we investigated the role of AtMC3, a phloem-specific member of the metacaspase family, in osmotic stress responses in Arabidopsis thaliana. Analyses of the proteome in plants with altered AtMC3 levels revealed differential abundance of proteins related to osmotic stress pointing into a role of the protein in water-stress-related responses. Overexpression of AtMC3 conferred drought tolerance by enhancing the differentiation of specific vascular tissues and maintaining higher levels of vascular-mediated transportation, while plants lacking the protein showed an impaired response to drought and inability to respond effectively to the hormone abscisic acid. Overall, our data highlight the importance of AtMC3 and vascular plasticity in fine-tuning early drought responses at the whole plant level without affecting growth or yield.

PMID:37320971 | DOI:10.1111/nph.19022

BMC Bioinformatics. 2023 Jun 15;24(1):252. doi: 10.1186/s12859-023-05355-4.

ABSTRACT

BACKGROUND: Bioinformatics capability to analyze spatio-temporal dynamics of gene expression is essential in understanding animal development. Animal cells are spatially organized as functional tissues where cellular gene expression data contain information that governs morphogenesis during the developmental process. Although several computational tissue reconstruction methods using transcriptomics data have been proposed, those methods have been ineffective in arranging cells in their correct positions in tissues or organs unless spatial information is explicitly provided.

RESULTS: This study demonstrates stochastic self-organizing map clustering with Markov chain Monte Carlo calculations for optimizing informative genes effectively reconstruct any spatio-temporal topology of cells from their transcriptome profiles with only a coarse topological guideline. The method, eSPRESSO (enhanced SPatial REconstruction by Stochastic Self-Organizing Map), provides a powerful in silico spatio-temporal tissue reconstruction capability, as confirmed by using human embryonic heart and mouse embryo, brain, embryonic heart, and liver lobule with generally high reproducibility (average max. accuracy = 92.0%), while revealing topologically informative genes, or spatial discriminator genes. Furthermore, eSPRESSO was used for temporal analysis of human pancreatic organoids to infer rational developmental trajectories with several candidate 'temporal' discriminator genes responsible for various cell type differentiations.

CONCLUSIONS: eSPRESSO provides a novel strategy for analyzing mechanisms underlying the spatio-temporal formation of cellular organizations.

PMID:37322439 | DOI:10.1186/s12859-023-05355-4

ISME J. 2023 Jun 15. doi: 10.1038/s41396-023-01442-9. Online ahead of print.

NO ABSTRACT

PMID:37322286 | DOI:10.1038/s41396-023-01442-9

Nat Med. 2023 Jun 15. doi: 10.1038/s41591-023-02372-x. Online ahead of print.

ABSTRACT

Primary sclerosing cholangitis (PSC) is an immune-mediated disease of the bile ducts that co-occurs with inflammatory bowel disease (IBD) in almost 90% of cases. Colorectal cancer is a major complication of patients with PSC and IBD, and these patients are at a much greater risk compared to patients with IBD without concomitant PSC. Combining flow cytometry, bulk and single-cell transcriptomics, and T and B cell receptor repertoire analysis of right colon tissue from 65 patients with PSC, 108 patients with IBD and 48 healthy individuals we identified a unique adaptive inflammatory transcriptional signature associated with greater risk and shorter time to dysplasia in patients with PSC. This inflammatory signature is characterized by antigen-driven interleukin-17A (IL-17A)+ forkhead box P3 (FOXP3)+ CD4 T cells that express a pathogenic IL-17 signature, as well as an expansion of IgG-secreting plasma cells. These results suggest that the mechanisms that drive the emergence of dysplasia in PSC and IBD are distinct and provide molecular insights that could guide prevention of colorectal cancer in individuals with PSC.

PMID:37322120 | DOI:10.1038/s41591-023-02372-x

Commun Biol. 2023 Jun 15;6(1):642. doi: 10.1038/s42003-023-05008-5.

ABSTRACT

Ectopic ATP synthase on the plasma membrane (eATP synthase) has been found in various cancer types and is a potential target for cancer therapy. However, whether it provides a functional role in tumor progression remains unclear. Here, quantitative proteomics reveals that cancer cells under starvation stress express higher eATP synthase and enhance the production of extracellular vesicles (EVs), which are vital regulators within the tumor microenvironment. Further results show that eATP synthase generates extracellular ATP to stimulate EV secretion by enhancing P2X7 receptor-triggered Ca2+ influx. Surprisingly, eATP synthase is also located on the surface of tumor-secreted EVs. The EVs-surface eATP synthase increases the uptake of tumor-secreted EVs in Jurkat T-cells via association with Fyn, a plasma membrane protein found in immune cells. The eATP synthase-coated EVs uptake subsequently represses the proliferation and cytokine secretion of Jurkat T-cells. This study clarifies the role of eATP synthase on EV secretion and its influence on immune cells.

PMID:37322056 | DOI:10.1038/s42003-023-05008-5

Nat Commun. 2023 Jun 15;14(1):3565. doi: 10.1038/s41467-023-39373-w.

NO ABSTRACT

PMID:37322005 | DOI:10.1038/s41467-023-39373-w

JCI Insight. 2023 Jun 15:e167310. doi: 10.1172/jci.insight.167310. Online ahead of print.

ABSTRACT

The RNA-binding protein LIN28B is overexpressed in over 30% of patients with colorectal cancer (CRC) and is associated with poor prognosis. In the present study, we unravel a novel mechanism by which LIN28B regulates colonic epithelial cell-cell junctions and CRC metastasis. Using human CRC cells (DLD-1, Caco-2 and LoVo) with either knockdown or overexpression of LIN28B, we identified Claudin 1 (CLDN1) tight junction protein as a direct downstream target and effector of LIN28B. RNA immunoprecipitation revealed that LIN28B directly binds to and post-transcriptionally regulates CLDN1 mRNA. Furthermore, using in vitro assays and a novel murine model of metastatic CRC, we show that LIN28B-mediated CLDN1 expression enhances collective invasion, cell migration, and metastatic liver tumor formation. Bulk RNA-sequencing of the metastatic liver tumors identified NOTCH3 as a downstream effector of the LIN28B-CLDN1 axis. Additionally, genetic and pharmacologic manipulation of NOTCH3 signaling revealed that NOTCH3 was necessary for invasion and metastatic liver tumor formation. In summary, our results suggest that LIN28B promotes invasion and liver metastasis of CRC by post-transcriptionally regulating CLDN1 and activating NOTCH3 signaling. This discovery offers a promising new therapeutic option for metastatic CRC to the liver, an area where therapeutic advancements have been relatively scarce.

PMID:37318881 | DOI:10.1172/jci.insight.167310

Mol Syst Biol. 2023 Jun 15:e11799. doi: 10.15252/msb.202311799. Online ahead of print.

NO ABSTRACT

PMID:37318792 | DOI:10.15252/msb.202311799

Appl Environ Microbiol. 2023 Jun 15:e0023823. doi: 10.1128/aem.00238-23. Online ahead of print.

ABSTRACT

Metabolic degeneracy describes the phenomenon that cells can use one substrate through different metabolic routes, while metabolic plasticity, refers to the ability of an organism to dynamically rewire its metabolism in response to changing physiological needs. A prime example for both phenomena is the dynamic switch between two alternative and seemingly degenerate acetyl-CoA assimilation routes in the alphaproteobacterium Paracoccus denitrificans Pd1222: the ethylmalonyl-CoA pathway (EMCP) and the glyoxylate cycle (GC). The EMCP and the GC each tightly control the balance between catabolism and anabolism by shifting flux away from the oxidation of acetyl-CoA in the tricarboxylic acid (TCA) cycle toward biomass formation. However, the simultaneous presence of both the EMCP and GC in P. denitrificans Pd1222 raises the question of how this apparent functional degeneracy is globally coordinated during growth. Here, we show that RamB, a transcription factor of the ScfR family, controls expression of the GC in P. denitrificans Pd1222. Combining genetic, molecular biological and biochemical approaches, we identify the binding motif of RamB and demonstrate that CoA-thioester intermediates of the EMCP directly bind to the protein. Overall, our study shows that the EMCP and the GC are metabolically and genetically linked with each other, demonstrating a thus far undescribed bacterial strategy to achieve metabolic plasticity, in which one seemingly degenerate metabolic pathway directly drives expression of the other. IMPORTANCE Carbon metabolism provides organisms with energy and building blocks for cellular functions and growth. The tight regulation between degradation and assimilation of carbon substrates is central for optimal growth. Understanding the underlying mechanisms of metabolic control in bacteria is of importance for applications in health (e.g., targeting of metabolic pathways with new antibiotics, development of resistances) and biotechnology (e.g., metabolic engineering, introduction of new-to-nature pathways). In this study, we use the alphaproteobacterium P. denitrificans as model organism to study functional degeneracy, a well-known phenomenon of bacteria to use the same carbon source through two different (competing) metabolic routes. We demonstrate that two seemingly degenerate central carbon metabolic pathways are metabolically and genetically linked with each other, which allows the organism to control the switch between them in a coordinated manner during growth. Our study elucidates the molecular basis of metabolic plasticity in central carbon metabolism, which improves our understanding of how bacterial metabolism is able to partition fluxes between anabolism and catabolism.

PMID:37318336 | DOI:10.1128/aem.00238-23

J Vis Exp. 2023 May 16;(195). doi: 10.3791/65287.

ABSTRACT

Xenopus have been powerful model organisms for understanding vertebrate development and disease for over 100 years. Here, a rapid blood perfusion protocol in Xenopus, aimed at a consistent and drastic reduction of blood within all tissues, is defined. Perfusion is carried out by inserting a needle directly into the ventricle of the heart and pumping heparinized phosphate-buffered saline (PBS) through the vascular system. The procedure can be completed in approximately 10 min per animal. The blood is dominated by a few highly abundant proteins and cell types, creating numerous issues as these proteins mask most other molecules and cell types of interest. The reproducible characterization of adult Xenopus tissues with quantitative proteomics and single-cell transcriptomics will benefit from applying this protocol prior to organ sampling. The protocols for tissue sampling are defined in companion papers. These procedures are aimed at the standardization of practices across Xenopus of different sex, age, and health status, specifically X. laevis and X. tropicalis.

PMID:37318240 | DOI:10.3791/65287

J Agric Food Chem. 2023 Jun 15. doi: 10.1021/acs.jafc.3c01377. Online ahead of print.

ABSTRACT

Herbicide-resistant soybeans are among the most widely planted transgenic crops. The in situ evaluation of spatial lipidomics in transgenic and non-transgenic soybeans is important for directly assessing the unintended effects of exogenous gene introduction. In this study, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI)-based non-targeted analytical strategies were used for the first time for in situ detection and imaging of endogenous lipid distributions in transgenic (EPSPS and PAT genes) herbicide-resistant soybean (Glycine max Merrill) (S4003.14) and non-transgenic soybean (JACK) seeds. Statistical analysis revealed significant differences in lipids between S4003.14 and JACK seeds. The variable importance of projection analysis further revealed that 18 identified lipids, including six phosphatidylcholines (PCs), four phosphatidylethanolamines (PEs), five triacylglycerols (TAGs), and three cytidine diphosphate-diacylglycerols (CDP-DAGs), had the strongest differential expression between S4003.14 and JACK seeds. Among those, the upregulated expressions of PC(P-36:1), PC(36:2), PC(P-36:0), PC(37:5), PE(40:2), TAG(52:1), TAG(55:5), and CDP-DAG(37:2) and the downregulated expressions of PC (36:1), TAG(43:0), and three PEs (i.e., PE(P-38:1), PE(P-38:0), and PE(P-40:3)) were successfully found in the S4003.14 seeds, compared to these lipids detected in the JACK seeds. Meanwhile, the lipids of PC (44:8), CDP-DAG(38:0), and CDP-DAG(42:0) were uniquely detected in the S4003.14 soybean seeds, and TAG(45:2) and TAG(57:10) were detected as the unique lipids in the JACK seeds. The heterogeneous distribution of these lipids in the soybean seeds was also clearly visualized using MALDI-MSI. MSI results showed that lipid expression was significantly up/downregulated in S4003.14 seeds, compared to that in JACK seeds. This study improves our understanding of the unintended effects of herbicide-resistant EPSPS and PAT gene transfers on spatial lipidomes in soybean seeds and enables the continued progression of MALDI-MSI as an emerging, reliable, and rapid molecular imaging tool for evaluating unintended effects in transgenic plants.

PMID:37318082 | DOI:10.1021/acs.jafc.3c01377

Eur J Prev Cardiol. 2023 Jun 15:zwad204. doi: 10.1093/eurjpc/zwad204. Online ahead of print.

ABSTRACT

AIMS: To assess whether overweight and obesity are independently associated with cardiometabolic health (as categorized based on the presence/absence of cardiovascular disease [CVD] risk factors [diabetes, hypercholesterolemia, or hypertension]), and the role of lifestyle on this association.

METHODS: A nationwide cohort of Spanish adults (18-64 years) was studied using a cross-sectional and prospective observational design. Lifestyle-related factors (physical activity, sleeping characteristics, alcohol drinking, and smoking) were registered and participants were classified as having an 'unhealthy' or 'healthy' cardiometabolic status attending to the presence or absence, respectively, of ≥1 CVD risk factor.

RESULTS: 596,111 participants (44 ± 9 years, 67% male) were studied at baseline, with prospective analyses in a subcohort (N = 302,061; median follow-up, 2 years [range, 2 to 5]). Compared to normal weight, overweight and obesity were associated with a higher prevalence (odds ratio, 1.67 [95% confidence interval, 1.61-1.67]) and 2.70 [2.69-2.78], respectively) and incidence (1.62 [1.59-1.67] and 2.70 [2.63-2.78]) of an unhealthy cardiometabolic status. Meeting physical activity guidelines reduced the odds of an unhealthy cardiometabolic status at baseline (0.87 [0.85-0.88]) among individuals with overweight/obesity, as well as of transitioning from a healthy to an unhealthy status during the follow-up (0.87 [0.84-0.94]). No significant associations were found for the remainder of lifestyle factors.

CONCLUSION: Overweight and obesity are independently associated with an unhealthy cardiometabolic status. Regular physical activity attenuates not only the prevalence, but also the incidence of CVD risk factors.

PMID:37317985 | DOI:10.1093/eurjpc/zwad204

G3 (Bethesda). 2023 Jun 15:jkad133. doi: 10.1093/g3journal/jkad133. Online ahead of print.

ABSTRACT

Herbivorous insects are exceptionally diverse, accounting for a quarter of all known eukaryotic species, but the genomic basis of adaptations that enabled this dietary transition remains poorly understood. Many studies have suggested that expansions and contractions of chemosensory and detoxification gene families - genes directly mediating interactions with plant chemical defenses - underlie successful plant colonization. However, this hypothesis has been challenging to test because the origins of herbivory in many insect lineages are ancient (>150 million years ago [mya]), obscuring genomic evolutionary patterns. Here, we characterized chemosensory and detoxification gene family evolution across Scaptomyza, a genus nested within Drosophila that includes a recently derived (<15 mya) herbivore lineage of mustard (Brassicales) specialists and carnation (Caryophyllaceae) specialists, and several non-herbivorous species. Comparative genomic analyses revealed that herbivorous Scaptomyza have among the smallest chemosensory and detoxification gene repertoires across 12 drosophilid species surveyed. Rates of gene turnover averaged across the herbivore clade were significantly higher than background rates in over half of the surveyed gene families. However, gene turnover was more limited along the ancestral herbivore branch, with only gustatory receptors and odorant binding proteins experiencing strong losses. The genes most significantly impacted by gene loss, duplication, or changes in selective constraint were those involved in detecting compounds associated with feeding on living plants (bitter or electrophilic phytotoxins) or their ancestral diet (fermenting plant volatiles). These results provide insight into the molecular and evolutionary mechanisms of plant-feeding adaptations and highlight gene candidates that have also been linked to other dietary transitions in Drosophila.

PMID:37317982 | DOI:10.1093/g3journal/jkad133

J Clin Pharmacol. 2023 Jun;63 Suppl 1:S96-S105. doi: 10.1002/jcph.2265.

ABSTRACT

Pregnant women are still viewed as therapeutic orphans to the extent that they are avoided as participants in mainstream clinical trials and not considered a priority for targeted drug research despite the fact that many clinical conditions exist during pregnancy for which pharmacotherapy is warranted. Part of the challenge is the uncertain risk potential that pregnant women represent in the absence of timely and costly toxicology and developmental pharmacology studies, which only partly mitigate such risks. Even when clinical trials are conducted in pregnant women, they are often underpowered and absent biomarkers and exclude evaluation across multiple stages of pregnancy where relevant development risk could have been assessed. Quantitative systems pharmacology model development has been proposed as one solution to fill knowledge gaps, make earlier and perhaps more informed risk assessment, and design more informative trials with better recommendations for biomarker and end point selection including design and sample size optimality. Funding for translational research in pregnancy is limited but will fill some of these gaps, especially when joined with ongoing clinical trials in pregnancy that also fill certain knowledge gaps, especially biomarker and end point evaluation across pregnancy states linked to clinical outcomes. Opportunities exist for further advances in quantitative systems pharmacology model development with the inclusion of real-world data sources and complimentary artificial intelligence/machine learning approaches. The successful coordination of the approach reliant on these new data sources will require commitments to share data and a diverse multidisciplinary group that seeks to develop open science models that benefit the entire research community, ensuring that such models can be used with high fidelity. New data opportunities and computational resources are highlighted in an effort to project how these efforts can move forward.

PMID:37317502 | DOI:10.1002/jcph.2265

Microorganisms. 2023 May 4;11(5):1201. doi: 10.3390/microorganisms11051201.

ABSTRACT

Various organisms, including bacteria, protists, fungi, plants, and animals, secrete proteins and peptides that self-assemble into ordered amyloid fibrils that perform different physiological functions [...].

PMID:37317177 | DOI:10.3390/microorganisms11051201

Cancer Sci. 2023 Jun 14. doi: 10.1111/cas.15870. Online ahead of print.

ABSTRACT

Transformer 2 alpha homolog (TRA2A), a member of the serine/arginine-rich splicing factor family, has been shown to control mRNA splicing in development and cancers. However, it remains unclear whether TRA2A is involved in lncRNA regulation. In the present study, we found that TRA2A was upregulated and correlated with poor prognosis in esophageal cancer. Downregulation of TRA2A suppressed the tumor growth in xenograft nude mice. Epitranscriptomic microarray showed that depletion of TRA2A affected global lncRNA methylation similarly to the key m6 A methyltransferase, METTL3, by silencing. MeRIP-qPCR, RNA pull-down, CLIP analyses, and stability assays indicated that ablation of TRA2A reduced m6 A-modification of the oncogenic lncRNA MALAT1, thus inducing structural alterations and reduced stability. Furthermore, Co-IP experiments showed TRA2A directly interacted with METTL3 and RBMX, which also affected the writer KIAA1429 expression. Knockdown of TRA2A inhibited cell proliferation in a manner restored by RBMX/KIAA1429 overexpression. Clinically, MALAT1, RBMX, and KIAA1429 were prognostic factors of worse survival in ESCA patients. Structural similarity-based virtual screening in FDA-approved drugs repurposed nebivolol, a β1 -adrenergic receptor antagonist, as a potent compound to suppress the proliferation of esophageal cancer cells. Cellular thermal shift and RIP assay indicated that nebivolol may compete with MALAT1 to bind TRA2A. In conclusion, our study revealed the noncanonical function of TRA2A, which coordinates with multiple methylation proteins to promote oncogenic MALAT1 during ESCA carcinogenesis.

PMID:37317053 | DOI:10.1111/cas.15870

Adv Nutr. 2023 Jun 12:S2161-8313(23)01326-1. doi: 10.1016/j.advnut.2023.06.005. Online ahead of print.

ABSTRACT

Human milk (HM) provides a plethora of nutritional and non-nutritional compounds that support infant development. For many compounds, concentrations vary substantially among mothers and across lactation, and their impact on infant growth is poorly understood. We systematically searched Medline, EMBASE, the Cochrane Library, Scopus, and Web of Science to synthesize evidence published between 1980-2022 on HM components and anthropometry through 2 years of age among term-born infants. Outcomes included weight-for-length, length-for-age, weight-for-age, BMI-for-age, and growth velocity. From 9,992 abstracts screened, 144 articles were included and categorized based on their reporting of HM micronutrients, macronutrients, or bioactive components. Micronutrients (vitamins and minerals) are reported here, based on 28 articles involving 2,526 mother-infant dyads. Studies varied markedly in their designs, sampling times, geographic and socioeconomic settings, reporting practices, and in the HM analytes and infant anthropometrics measured. Meta-analysis was not possible because data were sparse for most micronutrients. The most-studied minerals were zinc (15 articles, 1,423 dyads) and calcium (7 articles, 714 dyads). HM iodine, manganese, calcium, and zinc concentrations were positively associated with several outcomes (each in at least 2 studies), while magnesium (in a single study) was negatively associated with linear growth during early lactation. However, few studies measured HM intake, adjusted for confounders, provided adequate information about complementary and formula feeding, or adequately described HM collection protocols. Only 4 studies (17%) had high overall quality scores. The biological functions of individual HM micronutrients are likely influenced by other HM components; yet only one study analyzed data from multiple micronutrients simultaneously and few addressed other HM components. Thus, available evidence on this topic is largely inconclusive and fails to address the complex composition of HM. High-quality research employing chronobiology and systems biology approaches is required to understand how HM components work independently and together to influence infant growth, and to identify new avenues for future maternal, newborn, or infant nutritional interventions.

PMID:37315898 | DOI:10.1016/j.advnut.2023.06.005