J Multidiscip Healthc. 2023 May 1;16:1215-1229. doi: 10.2147/JMDH.S403700. eCollection 2023.

ABSTRACT

INTRODUCTION: The lack of feasible therapies and comorbidities aggravate the COVID-19 case-fatality rate (CFR). However, reports examining CFR associations with diabetes, concomitant cardiovascular diseases, chronic kidney disease, and chronic liver disease (CLD) are limited. More studies assessing hydroxychloroquine (Hcq) and antivirals are needed.

PURPOSE: To examine associations of COVID-19 CFR in comorbid patient groups each with single comorbidities and after treatment with Hcq, favipiravir, and dexamethasone (Dex), either alone or in combination versus standard care.

METHODS: Using statistical analysis, we descriptively determined these associations among 750 COVID-19 patient groups during the last quarter of 2021.

RESULTS: A diabetes comorbidity (40%, n=299) showed twice the fatality (CFR 14%) of the others (CFR 7%; P=0.001). Hypertension (Htn) was the second-commonest comorbidity (29.5%, n=221), with similar CFR to diabetes (15% and 7% for Htn and non-Htn, respectively), but with higher significance (P=0.0006167). Although only 4% (n=30) heart failure (HF) was reported, the CFR (40%) was much higher than in those without it (8%). A similar rate (4%) for chronic kidney disease was reported, with CFRs of 33% and 9% among those with and without it, respectively (P=0.00048). Ischemic heart disease was 11% (n=74), followed by chronic liver disease (0.4%) and history of smoking (1%); however, these were not significant due to the sample sizes. Treatment indicated standard care and Hcq alone or in combination were superior (CFR of 4% and 0.5%, respectively) compared to favipiravir (25%) or Dex (38.5%) independently or in combination (35.4%). Furthermore, Hcq performed well (CFR 9%) when combined with Dex (9%; P=4.28-26).

CONCLUSION: The dominance of diabetes and other comorbidities with significant association with CFR implied existence of a common virulence mechanism. The superiority of low-dose Hcq and standard care over antivirals warrants further studies.

PMID:37153358 | PMC:PMC10162097 | DOI:10.2147/JMDH.S403700

Ecol Evol. 2023 May 2;13(5):e10030. doi: 10.1002/ece3.10030. eCollection 2023 May.

ABSTRACT

Basic information on the ecology of species is key for their conservation. Here we study the ecology of the little-known yellow-throated bunting Emberiza elegans based on a multi-year study on its breeding grounds in the Russian Far East. For the first time in this species, we quantified breeding habitat parameters, calculated sex-specific apparent survival, and determined individual nonbreeding locations using light-level geolocation. We found that the habitat around song posts of male yellow-throated buntings is characterized by tree and shrub layers on richly littered moist ground. Habitat use overlaps with co-occurring Tristram's Buntings Emberiza tristrami and Black-faced Buntings E. spodocephala, but territories differ especially in tree cover and litter cover. Based on 4 years of color-ringing data of 72 individuals, we calculated an apparent survival rate of 36%, with higher survival estimates for male than for female yellow-throated buntings. We found no effect of carrying a geolocator on survival. We retrieved six geolocators from males. All birds migrated south-westward during autumn and spent the nonbreeding season at locations in China 700-1700 km away from their breeding sites. At least two individuals spent the boreal winter outside of the known range in northern or central China. Birds left the breeding area between early October and early November and returned between mid-March and mid-April. Our data on habitat use, survival rate, and migratory connectivity will help to assess threats to the populations of this enigmatic species, which might include habitat loss due to forest fires on the breeding grounds, and unsustainable harvest for consumption during the nonbreeding season.

PMID:37153014 | PMC:PMC10154376 | DOI:10.1002/ece3.10030

Front Endocrinol (Lausanne). 2023 Apr 21;14:1189508. doi: 10.3389/fendo.2023.1189508. eCollection 2023.

NO ABSTRACT

PMID:37152971 | PMC:PMC10161729 | DOI:10.3389/fendo.2023.1189508

Front Mol Biosci. 2023 Apr 21;10:1113249. doi: 10.3389/fmolb.2023.1113249. eCollection 2023.

ABSTRACT

Autophagy is a contentious issue in leishmaniasis and is emerging as a promising therapeutic regimen. Published research on the impact of autophagic regulation on Leishmania survival is inconclusive, despite numerous pieces of evidence that Leishmania spp. triggers autophagy in a variety of cell types. The mechanistic approach is poorly understood in the Leishmania parasite as autophagy is significant in both Leishmania and the host. Herein, this review discusses the autophagy proteins that are being investigated as potential therapeutic targets, the connection between autophagy and lipid metabolism, and microRNAs that regulate autophagy and lipid metabolism. It also highlights the use of systems biology to develop novel autophagy-dependent therapeutics for leishmaniasis by utilizing artificial intelligence (AI), machine learning (ML), mathematical modeling, network analysis, and other computational methods. Additionally, we have shown many databases for autophagy and metabolism in Leishmania parasites that suggest potential therapeutic targets for intricate signaling in the autophagy system. In a nutshell, the detailed understanding of the dynamics of autophagy in conjunction with lipids and miRNAs unfolds larger dimensions for future research.

PMID:37152895 | PMC:PMC10160387 | DOI:10.3389/fmolb.2023.1113249

Front Bioeng Biotechnol. 2023 Apr 20;11:1176445. doi: 10.3389/fbioe.2023.1176445. eCollection 2023.

ABSTRACT

Replacing traditional substrates in industrial bioprocesses to advance the sustainable production of chemicals is an urgent need in the context of the circular economy. However, since the limited degradability of non-conventional carbon sources often returns lower yields, effective exploitation of such substrates requires a multi-layer optimization which includes not only the provision of a suitable feedstock but the use of highly robust and metabolically versatile microbial biocatalysts. We tackled this challenge by means of systems metabolic engineering and validated Escherichia coli W as a promising cell factory for the production of the key building block chemical 2-ketoisovalerate (2-KIV) using whey as carbon source, a widely available and low-cost agro-industrial waste. First, we assessed the growth performance of Escherichia coli W on mono and disaccharides and demonstrated that using whey as carbon source enhances it significantly. Second, we searched the available literature and used metabolic modeling approaches to scrutinize the metabolic space of E. coli and explore its potential for overproduction of 2-KIV identifying as basic strategies the block of pyruvate depletion and the modulation of NAD/NADP ratio. We then used our model predictions to construct a suitable microbial chassis capable of overproducing 2-KIV with minimal genetic perturbations, i.e., deleting the pyruvate dehydrogenase and malate dehydrogenase. Finally, we used modular cloning to construct a synthetic 2-KIV pathway that was not sensitive to negative feedback, which effectively resulted in a rerouting of pyruvate towards 2-KIV. The resulting strain shows titers of up to 3.22 ± 0.07 g/L of 2-KIV and 1.40 ± 0.04 g/L of L-valine in 24 h using whey in batch cultures. Additionally, we obtained yields of up to 0.81 g 2-KIV/g substrate. The optimal microbial chassis we present here has minimal genetic modifications and is free of nutritional autotrophies to deliver high 2-KIV production rates using whey as a non-conventional substrate.

PMID:37152640 | PMC:PMC10158823 | DOI:10.3389/fbioe.2023.1176445

Front Syst Neurosci. 2023 Apr 20;17:1193488. doi: 10.3389/fnsys.2023.1193488. eCollection 2023.

NO ABSTRACT

PMID:37152611 | PMC:PMC10157151 | DOI:10.3389/fnsys.2023.1193488

Front Plant Sci. 2023 Apr 19;14:1191677. doi: 10.3389/fpls.2023.1191677. eCollection 2023.

NO ABSTRACT

PMID:37152183 | PMC:PMC10154671 | DOI:10.3389/fpls.2023.1191677

Front Plant Sci. 2023 Apr 21;14:1158288. doi: 10.3389/fpls.2023.1158288. eCollection 2023.

ABSTRACT

The shade avoidance syndrome (SAS) is a collective adaptive response of plants under shade highlighted by characteristic phenotypes such as hypocotyl elongation, which is largely mediated by concerted actions of auxin and GA. We identified ATHB2, a homeodomain-leucine zipper (HD-Zip) domain transcription factor known to be rapidly induced under shade condition, as a positive regulator of GA biosynthesis necessary for the SAS by transactivating the expression of GA20ox2, a key gene in the GA biosynthesis pathway. Based on promoter deletion analysis, EMSA and ChIP assay, ATHB2 appears to regulate the GA20ox2 expression as a direct binding target. We also found that the GA20ox2 expression is under negative control by TCP13, the effect of which can be suppressed by presence of ATHB2. Considering a rapid induction kinetics of ATHB2, this relationship between ATHB2 and TCP13 may allow ATHB2 to play a shade-specific activator for GA20ox by derepressing a pre-existing activity of TCP13.

PMID:37152153 | PMC:PMC10160606 | DOI:10.3389/fpls.2023.1158288

Front Plant Sci. 2023 Apr 21;14:1172228. doi: 10.3389/fpls.2023.1172228. eCollection 2023.

NO ABSTRACT

PMID:37152147 | PMC:PMC10161898 | DOI:10.3389/fpls.2023.1172228

Front Plant Sci. 2023 Apr 20;14:1197058. doi: 10.3389/fpls.2023.1197058. eCollection 2023.

NO ABSTRACT

PMID:37152140 | PMC:PMC10158978 | DOI:10.3389/fpls.2023.1197058

Front Oncol. 2023 Apr 21;13:1171003. doi: 10.3389/fonc.2023.1171003. eCollection 2023.

ABSTRACT

Helicobacter pylori (H. pylori) are Gram-negative bacteria that cause chronic gastritis and are considered the main risk factor for the development of gastric cancer. H. pylori have evolved to survive the harsh luminal environment of the stomach and are known to cause damage and signaling aberrations in gastric epithelial cells, which can result in premalignant and malignant pathology. As well as colonizing the gastric mucus and surface epithelial cells, a subpopulation of H. pylori can invade deep into the gastric glands and directly interact with progenitor and stem cells. Gland colonization therefore bears the potential to cause direct injury to long-lived cells. Moreover, this bacterial subpopulation triggers a series of host responses that cause an enhanced proliferation of stem cells. Here, we review recent insights into how gastric gland colonization by H. pylori is established, the resulting pro-carcinogenic epithelial signaling alterations, as well as new insights into stem cell responses to infection. Together these point towards a critical role of gland-associated H. pylori in the development of gastric cancer.

PMID:37152042 | PMC:PMC10160455 | DOI:10.3389/fonc.2023.1171003

Innovation (Camb). 2023 Apr 11;4(3):100422. doi: 10.1016/j.xinn.2023.100422. eCollection 2023 May 15.

NO ABSTRACT

PMID:37151909 | PMC:PMC10160585 | DOI:10.1016/j.xinn.2023.100422

Plant J. 2023 May 7. doi: 10.1111/tpj.16268. Online ahead of print.

ABSTRACT

Tomato is a prominent fruit and vegetable with rich genetic resources for the improvement of the crop. By using a phenotype-guided screen of an excess of 7900 tomato accessions from around the world we identified new associations for complex traits such as fruit weight and total soluble solids (Brix). Here, we present the phenotypic data on several years of trials. To illustrate the power of this dataset we use two case studies. First, evaluation of colour revealed allelic variation in phytoene synthase 1 that resulted in differently coloured or even bi-coloured fruit. Secondly, in view of the negative relationship between fruit weight and Brix we preselected a subset of the collection that includes high and low Brix values in each category of fruit sizes. Genome wide association analysis allowed us to detect novel loci associated with total soluble solid content and fruit weight. In addition, we developed eight F2 biparental intraspecific populations. Furthermore, by taking a phenotype guided approach we were able to isolate individuals with high Brix that were not compromised in terms of yield. In addition, the demonstration of novel results despite the high number of previous genome wide association studies of these traits in tomato suggests that adoption of a phenotype-guided pre-selection of germplasm may represent a general strategy for finding target genes for breeding.

PMID:37150955 | DOI:10.1111/tpj.16268

Cell Rep. 2023 May 6;42(5):112477. doi: 10.1016/j.celrep.2023.112477. Online ahead of print.

ABSTRACT

Signaling via N-methyl-d-aspartate receptors (NMDARs) is critical for the maturation of glutamatergic synapses, partly through a developmental switch from immature synapses expressing primarily GluN2B- and GluN3A-containing subtypes to GluN2A-rich mature ones. This subunit switch is thought to underlie the synaptic stabilization of NMDARs necessary for neural network consolidation. However, the cellular mechanisms controlling the NMDAR exchange remain unclear. Using a combination of single-molecule and confocal imaging and biochemical and electrophysiological approaches, we show that surface GluN3A-NMDARs form a highly diffusive receptor pool that is loosely anchored to synapses. Remarkably, changes in GluN3A subunit expression selectively alter the surface diffusion and synaptic anchoring of GluN2A- but not GluN2B-NMDARs, possibly through altered interactions with cell surface receptors. The effects of GluN3A on NMDAR surface diffusion are restricted to an early time window of postnatal development in rodents, allowing GluN3A subunits to control the timing of NMDAR signaling maturation and neuronal network refinements.

PMID:37149869 | DOI:10.1016/j.celrep.2023.112477

Sci Total Environ. 2023 May 4:163908. doi: 10.1016/j.scitotenv.2023.163908. Online ahead of print.

ABSTRACT

With the benefits of coming at low-cost, being light-weight and having a high formability and durability, conventional plastics are widely used in both industry and daily life. However, because of their durability and extensive half-life with poor degradability and the low recycling rate, large amounts of plastic waste are accumulated in various environments, posing a significant threat to organisms and ecosystems. Compared to conventional physical and chemical degradation, biodegradation of plastic might become a promising and environmentally friendly solution for this problem. One of the aims of this review is to briefly describe the impact of plastics (especially microplastics). To facilitate rapid advancements in the area of plastic biodegradation, this paper provides a comprehensive review of the candidate organisms capable of biodegrading plastics and originating from four categories including natural microorganisms, artificially derived microorganisms, algae and animal organisms. In addition, the potential mechanism during plastic biodegradation and associated driving factors are summarized and discussed. Furthermore, the recent biotechnological progress (e.g. synthetic biology, systems biology, etc.) is highlighted as being key for future research. Finally, innovative research avenues for future studies are proposed. Concluding, our review is addressing the practical application of plastic biodegradation and the plastic pollution, thus necessitating more sustainable developments.

PMID:37149171 | DOI:10.1016/j.scitotenv.2023.163908

Phytochemistry. 2023 May 4:113707. doi: 10.1016/j.phytochem.2023.113707. Online ahead of print.

ABSTRACT

Grayanotoxin I (GTX I) is a major toxin in leaves of Rhododendron species, where it provides a defence against insect and vertebrate herbivores. Surprisingly, it is also present in R. ponticum nectar, and this can hold important implications for plant-pollinator mutualisms. However, knowledge of GTX I distributions across the genus Rhododendron and in different plant materials is currently limited, despite the important ecological function of this toxin. Here we characterise GTX I expression in the leaves, petals, and nectar of seven Rhododendron species. Our results indicated interspecific variation in GTX I concentration across all species. GTX I concentrations were consistently higher in leaves compared to petals and nectar. Our findings provide preliminary evidence for phenotypic correlation between GTX I concentrations in defensive tissues (leaves and petals) and floral rewards (nectar), suggesting that Rhododendron species may commonly experience functional trade-offs between herbivore defence and pollinator attraction.

PMID:37149121 | DOI:10.1016/j.phytochem.2023.113707

Dev Cell. 2023 May 3:S1534-5807(23)00180-6. doi: 10.1016/j.devcel.2023.04.010. Online ahead of print.

ABSTRACT

Understanding the role of the immune microenvironment in modulating intratumor heterogeneity is essential for effective cancer therapies. Using multicolor lineage tracing in genetically engineered mouse models and single-cell transcriptomics, we show that slowly progressing tumors contain a multiclonal landscape of relatively homogeneous subpopulations within a well-organized tumor microenvironment. In more advanced and aggressive tumors, however, the multiclonal landscape develops into competing dominant and minor clones accompanied by a disordered microenvironment. We demonstrate that this dominant/minor landscape is associated with differential immunoediting, in which minor clones are marked by an increased expression of IFNγ-response genes and the T cell-activating chemokines Cxcl9 and Cxcl11. Furthermore, immunomodulation of the IFNγ pathway can rescue minor clones from elimination. Notably, the immune-specific gene signature of minor clones exhibits a prognostic value for biochemical recurrence-free survival in human prostate cancer. These findings suggest new immunotherapy approaches for modulating clonal fitness and tumor progression in prostate cancer.

PMID:37148881 | DOI:10.1016/j.devcel.2023.04.010

Curr Opin Plant Biol. 2023 May 4;74:102371. doi: 10.1016/j.pbi.2023.102371. Online ahead of print.

ABSTRACT

Metabolic enzymes tend to evolve towards catalytic efficacy, precision and speed. This seems particularly true for ancient and conserved enzymes involved in fundamental cellular processes that are present virtually in every cell and organism and converting and producing relatively limited metabolite numbers. Nevertheless, sessile organisms like plants have an astonishing repertoire of specific (specialized) metabolites that, by numbers and chemical complexity, by far exceed primary metabolites. Most theories agree that early gene duplication, subsequent positive selection and diversifying evolution have allowed relaxed selection of duplicated metabolic genes, thus facilitating the accumulation of mutations that could broaden substrate/product specificity and lower activation barriers and kinetics. Here, we use oxylipins, oxygenated fatty acids of plastidial origin to which the phytohormone jasmonate belongs, and triterpenes, a large group of specialized metabolites whose biosynthesis is often elicited by jasmonates, to showcase the structural and functional diversity of chemical signals and products in plant metabolism.

PMID:37148672 | DOI:10.1016/j.pbi.2023.102371

EBioMedicine. 2023 May 4;92:104602. doi: 10.1016/j.ebiom.2023.104602. Online ahead of print.

ABSTRACT

BACKGROUND: Systems biology leveraging multi-OMICs technologies, is rapidly advancing development of precision therapies and matching patients to targeted therapies, leading to improved responses. A new pillar of precision oncology lies in the power of chemogenomics to discover drugs that sensitizes malignant cells to other therapies. Here, we test a chemogenomic approach using epigenomic inhibitors (epidrugs) to reset patterns of gene expression driving the malignant behavior of pancreatic tumors.

METHODS: We tested a targeted library of ten epidrugs targeting regulators of enhancers and super-enhancers on reprogramming gene expression networks in seventeen patient-derived primary pancreatic cancer cell cultures (PDPCCs), of both basal and classical subtypes. We subsequently evaluated the ability of these epidrugs to sensitize pancreatic cancer cells to five chemotherapeutic drugs that are clinically used for this malignancy.

FINDINGS: To comprehend the impact of epidrug priming at the molecular level, we evaluated the effect of each epidrugs at the transcriptomic level of PDPCCs. The activating epidrugs showed a higher number of upregulated genes than the repressive epidrugs (χ2 test p-value <0.01). Furthermore, we developed a classifier using the baseline transcriptome of epidrug-primed-chemosensitized PDPCCs to predict the best epidrug-priming regime to a given chemotherapy. Six signatures with a significant association with the chemosensitization centroid (R ≤ -0.80; p-value < 0.01) were identified and validated in a subset of PDPCCs.

INTERPRETATION: We conclude that targeting enhancer-initiated pathways in patient-derived primary cells, represents a promising approach for developing new therapies for human pancreatic cancer.

FUNDING: This work was supported by INCa (Grants number 2018-078 to ND and 2018- 079 to JI), Canceropole PACA (ND), Amidex Foundation (ND), and INSERM (JI).

PMID:37148583 | DOI:10.1016/j.ebiom.2023.104602

Biotechnol Bioeng. 2023 May 6. doi: 10.1002/bit.28417. Online ahead of print.

ABSTRACT

Chinese hamster ovary (CHO) cells, predominant hosts for recombinant biotherapeutics production, generate lactate as a major glycolysis by-product. High lactate levels adversely impact cell growth and productivity. The goal of this study was to reduce lactate in CHO cell cultures by adding chemical inhibitors to hexokinase-2 (HK2), the enzyme catalyzing the conversion of glucose to glucose 6-phosphate, and examine their impact on lactate accumulation, cell growth, protein titers, and N-glycosylation. Five inhibitors of HK2 enzyme at different concentrations were evaluated, of which 2-deoxy- d-glucose (2DG) and 5-thio- d-glucose (5TG) successfully reduced lactate accumulation with only limited impacts on CHO cell growth. Individual 2DG and 5TG supplementation led to a 35%-45% decrease in peak lactate, while their combined supplementation resulted in a 60% decrease in peak lactate. Inhibitor supplementation led to at least 50% decrease in moles of lactate produced per mol of glucose consumed. Recombinant EPO-Fc titers peaked earlier relative to the end of culture duration in supplemented cultures leading to at least 11% and as high as 32% increase in final EPO-Fc titers. Asparagine, pyruvate, and serine consumption rates also increased in the exponential growth phase in 2DG and 5TG treated cultures, thus, rewiring central carbon metabolism due to low glycolytic fluxes. N-glycan analysis of EPO-Fc revealed an increase in high mannose glycans from 5% in control cultures to 25% and 37% in 2DG and 5TG-supplemented cultures, respectively. Inhibitor supplementation also led to a decrease in bi-, tri-, and tetra-antennary structures and up to 50% lower EPO-Fc sialylation. Interestingly, addition of 2DG led to the incorporation of 2-deoxy-hexose (2DH) on EPO-Fc N-glycans and addition of 5TG resulted in the first-ever observed N-glycan incorporation of 5-thio-hexose (5TH). Six percent to 23% of N-glycans included 5TH moieties, most likely 5-thio-mannose and/or 5-thio-galactose and/or possibly 5-thio-N-acetylglucosamine, and 14%-33% of N-glycans included 2DH moieties, most likely 2-deoxy-mannose and/or 2-deoxy-galactose, for cultures treated with different concentrations of 5TG and 2DG, respectively. Our study is the first to evaluate the impact of these glucose analogs on CHO cell growth, protein production, cell metabolism, N-glycosylation processing, and formation of alternative glycoforms.

PMID:37148536 | DOI:10.1002/bit.28417