Int J Endocrinol Metab. 2021 Jan 20;19(1):e104889. doi: 10.5812/ijem.104889. eCollection 2021 Jan.

ABSTRACT

BACKGROUND: Congenital hypothyroidism (CH), as one of the most common endocrine disorders, is a preventable cause of mental retardation.

OBJECTIVE: This study aimed to identify familial-related risk factors for CH in Iranian newborns.

METHODS: A population-based case-control study was performed on the National Registry System of patients with CH in Iran. In this study, 906 controls and 454 cases were studied for one year. Familial related factors were investigated using logistic regression models. Population attributable fraction (PAF) was also calculated for each significant risk factor.

RESULTS: Using multivariate analysis, an increased risk for CH was observed in patients with congenital anomalies (odds ratio (OR): 5.77, 95% confidence interval (CI): 2.37 - 14.01), history of mental retardation in family (OR:2.10, 95% CI: 1.15-3.83), mother's hypothyroidism during pregnancy (OR: 2.01, 95% CI: 1.33 - 3.03), intra-family marriage (OR:1.49, 95% CI: 1.18 - 1.89), gestational diabetes (OR: 1.69, 95% CI: 1.09 - 2.63), having a hypothyroid child in the family (OR: 2.48, 95% CI: 1.39 - 4.42), and twins or more (OR: 2.61, 95% CI: 1.31 - 5.21). The highest PAF among familial-related risk factors for CH is related to the intra-family marriage (14.9%).

CONCLUSIONS: This study revealed that familial-related risk factors and consanguine marriages play an essential role in the high incidence of CH in Iran. About 15% of CH in Iran could be attributed to intra-family marriage alone.

PMID:33815515 | PMC:PMC8010566 | DOI:10.5812/ijem.104889

Front Plant Sci. 2021 Mar 19;12:538580. doi: 10.3389/fpls.2021.538580. eCollection 2021.

ABSTRACT

Plant cells perceive and adapt to an ever-changing environment by modifying their plasma membrane (PM) proteome. Whereas secretion deposits new integral membrane proteins, internalization by endocytosis removes membrane proteins and associated ligands, largely with the aid of adaptor protein (AP) complexes and the scaffolding molecule clathrin. Two AP complexes function in clathrin-mediated endocytosis at the PM in plant cells, the heterotetrameric AP-2 complex and the hetero-octameric TPLATE complex (TPC). Whereas single subunit mutants in AP-2 develop into viable plants, genetic mutation of a single TPC subunit causes fully penetrant male sterility and silencing single subunits leads to seedling lethality. To address TPC function in somatic root cells, while minimizing indirect effects on plant growth, we employed nanobody-dependent delocalization of a functional, GFP-tagged TPC subunit, TML, in its respective homozygous genetic mutant background. In order to decrease the amount of functional TPC at the PM, we targeted our nanobody construct to the mitochondria and fused it to TagBFP2 to visualize it independently of its bait. We furthermore limited the effect of our delocalization to those tissues that are easily accessible for live-cell imaging by expressing it from the PIN2 promoter, which is active in root epidermal and cortex cells. With this approach, we successfully delocalized TML from the PM. Moreover, we also show co-recruitment of TML-GFP and AP2A1-TagRFP to the mitochondria, suggesting that our approach delocalized complexes, rather than individual adaptor complex subunits. In line with the specific expression domain, we only observed minor effects on root growth, yet realized a clear reduction of endocytic flux in epidermal root cells. Nanobody-dependent delocalization in plants, here exemplified using a TPC subunit, has the potential to be widely applicable to achieve specific loss-of-function analysis of otherwise lethal mutants.

PMID:33815429 | PMC:PMC8018273 | DOI:10.3389/fpls.2021.538580

Front Immunol. 2021 Mar 19;12:632512. doi: 10.3389/fimmu.2021.632512. eCollection 2021.

ABSTRACT

Visceral leishmaniasis (VL) is a fatal parasitic disease if untreated. Treatment options of VL diminish due to emerging drug resistance. Although the principal host cells for the multiplication of Leishmania are macrophages, neutrophils are the first cells infected with the parasites rapidly after parasite inoculation. Leishmania can survive in neutrophils despite the potent antimicrobial effector functions of neutrophils that can eliminate the parasites. Recently, the growing field of immunometabolism provided strong evidence for the therapeutic potential in targeting metabolic processes as a means of controlling immune effector functions. Therefore, the understanding of the immunometabolic profile of neutrophils during Leishmania infection could provide new promising targets for host-directed therapies against VL. To our knowledge, this is the first study addressing the bioenergetics profile of L. donovani-infected primary human neutrophils. Transcriptome analysis of L. donovani-infected neutrophils revealed an early significant upregulation of several glycolytic enzymes. Extracellular flux analysis showed that glycolysis and glycolytic capacity were upregulated in L. donovani-infected neutrophils at 6 h post infection. An increased glucose uptake and accumulation of glycolytic end products were further signs for an elevated glycolytic metabolism in L. donovani-infected neutrophils. At the same time point, oxidative phosphorylation provided NADPH for the oxidative burst but did not contribute to ATP production. Inhibition of glycolysis with 2-DG significantly reduced the survival of L. donovani promastigotes in neutrophils and in culture. However, this reduction was due to a direct antileishmanial effect of 2-DG and not a consequence of enhanced antileishmanial activity of neutrophils. To further address the impact of glucose metabolism during the first days of infection in vivo, we treated C57BL/6 mice with 2-DG prior to infection with L. donovani and assessed the parasite load one day and seven days post infection. Our results show, that seven days post-infection the parasite load of 2-DG treated animals was significantly higher than in mock treated animals. This data indicates that glycolysis serves as major energy source for antimicrobial effector functions against L. donovani. Inhibition of glycolysis abrogates important neutrophil effector functions that are necessary the initial control of Leishmania infection.

PMID:33815385 | PMC:PMC8017142 | DOI:10.3389/fimmu.2021.632512

Front Immunol. 2021 Mar 18;12:589786. doi: 10.3389/fimmu.2021.589786. eCollection 2021.

ABSTRACT

BANK1 transcript is upregulated in whole blood after kidney transplantation in tolerant patients. In comparison to patients with rejection, tolerant patients display higher level of regulatory B cells (Bregs) expressing granzyme B (GZMB+) that have the capability to prevent effector T cells proliferation. However, BANK1 was found to be decreased in these GZMB+ Bregs. In this article, we investigated seven different transcriptomic studies and mined the literature in order to make link between BANK1, tolerance and Bregs. As for GZMB+ Bregs, we found that BANK1 was decreased in other subtypes of Bregs, including IL10+ and CD24hiCD38hi transitional regulatory B cells, along with BANK1 was down-regulated in activated/differentiated B cells, as in CD40-activated B cells, in leukemia and plasma cells. Following a reductionist approach, biological concepts were extracted from BANK1 literature and allowed us to infer association between BANK1 and immune signaling pathways, as STAT1, FcγRIIB, TNFAIP3, TRAF6, and TLR7. Based on B cell signaling literature and expression data, we proposed a role of BANK1 in B cells of tolerant patients that involved BCR, IP3R, and PLCG2, and a link with the apoptosis pathways. We confronted these data with our experiments on apoptosis in total B cells and Bregs, and this suggests different involvement for BANK1 in these two cells. Finally, we put in perspective our own data with other published data to hypothesize two different roles for BANK1 in B cells and in Bregs.

PMID:33815360 | PMC:PMC8015775 | DOI:10.3389/fimmu.2021.589786

Front Microbiol. 2021 Mar 17;12:653107. doi: 10.3389/fmicb.2021.653107. eCollection 2021.

ABSTRACT

The misuse of antibiotics is leading to the emergence of multidrug-resistant (MDR) bacteria, and in the absence of available treatments, this has become a major global threat. In the middle of the recent severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic, which has challenged the whole world, the emergence of MDR bacteria is increasing due to prophylactic administration of antibiotics to intensive care unit patients to prevent secondary bacterial infections. This is just an example underscoring the need to seek alternative treatments against MDR bacteria. To this end, phage therapy has been proposed as a promising tool. However, further research in the field is mandatory to assure safety protocols and to develop appropriate regulations for its use in clinics. This requires investing more in such non-conventional or alternative therapeutic approaches, to develop new treatment regimens capable of reducing the emergence of MDR and preventing future global public health concerns that could lead to incalculable human and economic losses.

PMID:33815346 | PMC:PMC8010138 | DOI:10.3389/fmicb.2021.653107

Front Endocrinol (Lausanne). 2021 Mar 18;12:601160. doi: 10.3389/fendo.2021.601160. eCollection 2021.

ABSTRACT

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is characterised by dysfunctional lipid metabolism and cholesterol homeostasis, and a related chronic inflammatory response. NAFLD has become the most common cause of chronic liver disease in many countries, and its prevalence continues to rise in parallel with increasing rates of obesity. Here, we evaluated the putative NAFLD-attenuating effects of a multicomponent medicine consisting of 24 natural ingredients: Hepar compositum (HC-24).

METHODS: Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) with a macronutrient composition and cholesterol content comparable to human diets for 24 weeks to induce obesity-associated metabolic dysfunction, including hepatic steatosis and inflammation. HC-24 or vehicle control was administered intraperitoneally 3 times/week (1.5 ml/kg) for the last 18 weeks of the study. Histological analyses of liver and adipose tissue were combined with extensive hepatic transcriptomics analysis. Transcriptomics results were further substantiated with ELISA, immunohistochemical and liver lipid analyses.

RESULTS: HFD feeding induced obesity and metabolic dysfunction including adipose tissue inflammation and increased gut permeability. In the liver, HFD-feeding resulted in a disturbance of cholesterol homeostasis and an associated inflammatory response. HC-24 did not affect body weight, metabolic risk factors, adipose tissue inflammation or gut permeability. While HC-24 did not alter total liver steatosis, there was a pronounced reduction in lobular inflammation in HC-24-treated animals, which was associated with modulation of genes and proteins involved in inflammation (e.g., neutrophil chemokine Cxcl1) and cholesterol homeostasis (i.e., predicted effect on 'cholesterol' as an upstream regulator, based on gene expression changes associated with cholesterol handling). These effects were confirmed by CXCL1 ELISA, immunohistochemical staining of neutrophils and biochemical analysis of hepatic free cholesterol content. Intrahepatic free cholesterol levels were found to correlate significantly with the number of inflammatory aggregates in the liver, thereby providing a potential rationale for the observed anti-inflammatory effects of HC-24.

CONCLUSIONS: Free cholesterol accumulates in the liver of Ldlr-/-.Leiden mice under physiologically translational dietary conditions, and this is associated with the development of hepatic inflammation. The multicomponent medicine HC-24 reduces accumulation of free cholesterol and has molecular and cellular anti-inflammatory effects in the liver.

PMID:33815271 | PMC:PMC8014004 | DOI:10.3389/fendo.2021.601160

Rev Fish Biol Fish. 2021 Mar 29:1-21. doi: 10.1007/s11160-021-09641-3. Online ahead of print.

ABSTRACT

One of the most pronounced effects of climate change on the world's oceans is the (generally) poleward movement of species and fishery stocks in response to increasing water temperatures. In some regions, such redistributions are already causing dramatic shifts in marine socioecological systems, profoundly altering ecosystem structure and function, challenging domestic and international fisheries, and impacting on human communities. Such effects are expected to become increasingly widespread as waters continue to warm and species ranges continue to shift. Actions taken over the coming decade (2021-2030) can help us adapt to species redistributions and minimise negative impacts on ecosystems and human communities, achieving a more sustainable future in the face of ecosystem change. We describe key drivers related to climate-driven species redistributions that are likely to have a high impact and influence on whether a sustainable future is achievable by 2030. We posit two different futures-a 'business as usual' future and a technically achievable and more sustainable future, aligned with the Sustainable Development Goals. We then identify concrete actions that provide a pathway towards the more sustainable 2030 and that acknowledge and include Indigenous perspectives. Achieving this sustainable future will depend on improved monitoring and detection, and on adaptive, cooperative management to proactively respond to the challenge of species redistribution. We synthesise examples of such actions as the basis of a strategic approach to tackle this global-scale challenge for the benefit of humanity and ecosystems.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11160-021-09641-3.

PMID:33814734 | PMC:PMC8006506 | DOI:10.1007/s11160-021-09641-3

J Alzheimers Dis. 2021 Apr 1. doi: 10.3233/JAD-201347. Online ahead of print.

ABSTRACT

BACKGROUND: Lipid alterations contribute to Alzheimer's disease (AD) pathogenesis. Lipidomics studies could help systematically characterize such alterations and identify potential biomarkers.

OBJECTIVE: To identify lipids associated with mild cognitive impairment and amyloid-β deposition, and to examine lipid correlation patterns within phenotype groupsMethods:Eighty plasma lipids were measured using mass spectrometry for 1,255 non-demented participants enrolled in the Mayo Clinic Study of Aging. Individual lipids associated with mild cognitive impairment (MCI) were first identified. Correlation network analysis was then performed to identify lipid species with stable correlations across conditions. Finally, differential correlation network analysis was used to determine lipids with altered correlations between phenotype groups, specifically cognitively unimpaired versus MCI, and with elevated brain amyloid versus without.

RESULTS: Seven lipids were associated with MCI after adjustment for age, sex, and APOE4. Lipid correlation network analysis revealed that lipids from a few species correlated well with each other, demonstrated by subnetworks of these lipids. 177 lipid pairs differently correlated between cognitively unimpaired and MCI patients, whereas 337 pairs of lipids exhibited altered correlation between patients with and without elevated brain amyloid. In particular, 51 lipid pairs showed correlation alterations by both cognitive status and brain amyloid. Interestingly, the lipids central to the network of these 51 lipid pairs were not significantly associated with either MCI or amyloid, suggesting network-based approaches could provide biological insights complementary to traditional association analyses.

CONCLUSION: Our attempt to characterize the alterations of lipids at network-level provides additional insights beyond individual lipids, as shown by differential correlations in our study.

PMID:33814434 | DOI:10.3233/JAD-201347

J Alzheimers Dis. 2021 Mar 25. doi: 10.3233/JAD-200964. Online ahead of print.

ABSTRACT

BACKGROUND: Understanding how dysregulation in lipid metabolism relates to the severity of Alzheimer's disease (AD) pathology might be critical in developing effective treatments.

OBJECTIVE: To identify lipid species in cerebrospinal fluid (CSF) associated with signature AD pathology and to explore their relationships with measures reflecting AD-related processes (neurodegeneration, inflammation, deficits in verbal episodic memory) among subjects at the pre- and early symptomatic stages of dementia.

METHODS: A total of 60 subjects that had been referred to an Icelandic memory clinic cohort were classified as having CSF AD (n = 34) or non-AD (n = 26) pathology profiles. Untargeted CSF lipidomic analysis was performed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) for the detection of mass-to-charge ratio (m/z) features. CSF proteins reflecting neurodegeneration (neurofilament light [NFL]) and inflammation (chitinase-3-like protein 1 [YKL-40], S100 calcium-binding protein B [S100B], glial fibrillary acidic protein [GFAP]) were also measured. Rey Auditory Verbal Learning (RAVLT) and Story tests were used for the assessment of verbal episodic memory.

RESULTS: Eight out of 1008 features were identified as best distinguishing between the CSF profile groups. Of those, only the annotation of the m/z feature assigned to lipid species C18 ceramide was confirmed with a high confidence. Multiple regression analyses, adjusted for age, gender, and education, demonstrated significant associations of CSF core AD markers (Aβ 42: st.β= -0.36, p = 0.007; T-tau: st.β= 0.41, p = 0.005) and inflammatory marker S100B (st.β= 0.51, p = 0.001) with C18 ceramide levels.

CONCLUSION: Higher levels of C18 ceramide associated with increased AD pathology and inflammation, suggesting its potential value as a therapeutic target.

PMID:33814423 | DOI:10.3233/JAD-200964

Philos Trans R Soc Lond B Biol Sci. 2021 May 24;376(1825):20200159. doi: 10.1098/rstb.2020.0159. Epub 2021 Apr 5.

ABSTRACT

The first animal mitochondrial genomes to be sequenced were of several vertebrates and model organisms, and the consistency of genomic features found has led to a 'textbook description'. However, a more broad phylogenetic sampling of complete animal mitochondrial genomes has found many cases where these features do not exist, and the phylum Mollusca is especially replete with these exceptions. The characterization of full mollusc mitogenomes required considerable effort involving challenging molecular biology, but has created an enormous catalogue of surprising deviations from that textbook description, including wide variation in size, radical genome rearrangements, gene duplications and losses, the introduction of novel genes, and a complex system of inheritance dubbed 'doubly uniparental inheritance'. Here, we review the extraordinary variation in architecture, molecular functioning and intergenerational transmission of molluscan mitochondrial genomes. Such features represent a great potential for the discovery of biological history, processes and functions that are novel for animal mitochondrial genomes. This provides a model system for studying the evolution and the manifold roles that mitochondria play in organismal physiology, and many ways that the study of mitochondrial genomes are useful for phylogeny and population biology. This article is part of the Theo Murphy meeting issue 'Molluscan genomics: broad insights and future directions for a neglected phylum'.

PMID:33813887 | DOI:10.1098/rstb.2020.0159

Biochem Genet. 2021 Apr 3. doi: 10.1007/s10528-021-10062-x. Online ahead of print.

ABSTRACT

Although many genes and miRNAs have been reported for various cancers, pancreatic cancer's specific genes or miRNAs have not been studied precisely yet. Therefore, we have analyzed the gene and miRNA expression profile of pancreatic cancer data in the gene expression omnibus (GEO) database. The microarray-derived miRNAs and mRNAs were annotated by gene ontology (GO) and signaling pathway analysis. We also recognized mRNAs that were targeted by miRNA through the mirDIP database. An integrated analysis of the microarray revealed that only 6 out of 43 common miRNAs had significant differences in their expression profiles between the tumor and normal groups (P value < 0.05 and |log Fold Changes (logFC)|> 1). The hsa-miR-210 had upregulation, whereas hsa-miR-375, hsa-miR-216a, hsa-miR-217, hsa-miR-216b and hsa-miR-634 had downregulation in pancreatic cancer (PC). The analysis results also revealed 109 common mRNAs by microarray and mirDIP 4.1 databases. Pathway analysis showed that amoebiasis, axon guidance, PI3K-Akt signaling pathway, absorption and focal adhesion, adherens junction, platelet activation, protein digestion, human papillomavirus infection, extracellular matrix (ECM) receptor interaction, and riboflavin metabolism played important roles in pancreatic cancer. GO analysis revealed the significant enrichment in the three terms of biological process, cellular component, and molecular function, which were identified as the most important processes associated strongly with pancreatic cancer. In conclusion, DTL, CDH11, COL5A1, ITGA2, KIF14, SMC4, VCAN, hsa-mir-210, hsa-mir-217, hsa-mir-216a, hsa-mir-216b, hsa-mir-375 and hsa-mir-634 can be reported as the novel diagnostic or even therapeutic markers for the future studies. Also, the hsa-mir-107 and hsa-mir-125a-5p with COL5A1, CDH11 and TGFBR1 genes can be introduced as major miRNA and genes on the miRNA-drug-mRNA network. The new regulatory network created in our study could give a deeper knowledge of the pancreatic cancer.

PMID:33813720 | DOI:10.1007/s10528-021-10062-x

EBioMedicine. 2021 Apr 1;66:103314. doi: 10.1016/j.ebiom.2021.103314. Online ahead of print.

ABSTRACT

BACKGROUND: Nucleic acids are potent stimulators of type I interferon (IFN-I) and antiviral defense, but may also promote pathological inflammation. A range of diseases are characterized by elevated IFN-I, including systemic lupus erythematosus (lupus). The DNA-activated cGAS-STING pathway is a major IFN-I-inducing pathway, and activation of signaling is dependent on trafficking of STING from the ER to the Golgi.

METHODS: Here we used cell culture systems, a mouse lupus model, and material from lupus patients, to explore the mode of action of a STING antagonistic peptide, and its ability to modulate disease processes.

FINDINGS: We report that the peptide ISD017 selectively inhibits all known down-stream activities of STING, including IFN-I, inflammatory cytokines, autophagy, and apoptosis. ISD017 blocks the essential trafficking of STING from the ER to Golgi through a mechanism dependent on the STING ER retention factor STIM1. Importantly, ISD017 blocks STING activity in vivo and ameliorates disease development in a mouse model for lupus. Finally, ISD017 treatment blocks pathological cytokine responses in cells from lupus patients with elevated IFN-I levels.

INTERPRETATION: These data hold promise for beneficial use of STING-targeting therapy in lupus.

FUNDING: The Novo Nordisk Foundation, The European Research Council, The Lundbeck Foundation, European Union under the Horizon 2020 Research, Deutsche Forschungsgemeinschaft, Chulalongkorn University.

PMID:33813142 | DOI:10.1016/j.ebiom.2021.103314

Trends Microbiol. 2021 Mar 31:S0966-842X(21)00061-5. doi: 10.1016/j.tim.2021.03.002. Online ahead of print.

ABSTRACT

Environmental accumulation of anthropogenic pollutants is a pressing global issue. The biodegradation of these pollutants by microbes is an emerging field but is hampered by inefficient degradation rates and a limited knowledge of potential enzymes and pathways. Here, we advocate the view that significant progress can be achieved by harnessing artificial community selection for a desired biological process, an approach that makes use of eco-evolutionary principles. The selected communities can either be directly used in bioremediation applications or further be analyzed and modified, for instance through a combination of systems biology, synthetic biology, and genetic engineering. This knowledge can then inform machine learning and enhance the discovery of novel biodegradation pathways.

PMID:33812769 | DOI:10.1016/j.tim.2021.03.002

Mater Sci Eng C Mater Biol Appl. 2021 Apr;123:112017. doi: 10.1016/j.msec.2021.112017. Epub 2021 Mar 9.

ABSTRACT

The growth of bacteria and the formation of complex bacterial structures on biomedical devices is a major challenge in modern medicine. The aim of this study was to develop a biocompatible, conducting and antibacterial polymer coating applicable in biomedical engineering. Since conjugated polymers have recently aroused strong interest as controlled delivery systems for biologically active compounds, we decided to employ a poly(3,4-ethylenedioxythiophene) (PEDOT) matrix to immobilize a powerful, first-line antibiotic: tetracycline (Tc). Drug immobilization was carried out simultaneously with the electrochemical polymerization process, allowing to obtain a polymer coating with good electrochemical behaviour (charge storage capacity of 19.15 ± 6.09 mC/cm2) and high drug loading capacity (194.7 ± 56.2 μg/cm2). Biological activity of PEDOT/Tc matrix was compared with PEDOT matrix and a bare Pt surface against a model Gram-negative bacteria strain of Escherichia coli with the use of LIVE/DEAD assay and SEM microscopy. Finally, PEDOT/Tc was shown to serve as a robust electroactive coating exhibiting antibacterial activity.

PMID:33812635 | DOI:10.1016/j.msec.2021.112017

Methods. 2021 Mar 31:S1046-2023(21)00090-6. doi: 10.1016/j.ymeth.2021.03.016. Online ahead of print.

ABSTRACT

A candidate digital PCR (dPCR)-based reference measurement procedure for quantification of human cytomegalovirus (hCMV) was evaluated in 10 viral load comparison schemes (seven external quality assessment (EQA) and three additional training schemes) organized by INSTAND e.V. over four years (between September 2014 and March 2018). Four metrology institutes participated in these schemes using the same extraction method and dPCR measurement procedure for the hCMV specific target sequence of UL54 gene. The calibration independent reference measurement procedure results from the metrology institutes were compared to the results of the clinical diagnostic laboratories applying hCMV qPCR measurement procedures calibrated to reference materials. While the criteria for the acceptable deviation from the target value interval for INSTAND's EQA schemes is from -0.8 log10 to +0.8 log10, the majority of dPCR results were between -0.2 log10 to +0.2 log10. Only 4 out of 45 results exceeded this interval with the maximum deviation of -0.542 log10. In the training schemes containing samples with lower hCMV concentrations, more than half of the results deviated less than ± 0.2 log10 from the target value, while more than 95% deviated less than ± 0.4 log10 from the target value. Evaluation of intra-and inter-laboratory variation of dPCR results confirmed high reproducibility and trueness of the method. This work demonstrates that dPCR has the potential to act as a calibration independent reference measurement procedure for the value assignment of hCMV calibration and reference materials to support qPCR calibration as well as ultimately for routine hCMV load testing.

PMID:33812016 | DOI:10.1016/j.ymeth.2021.03.016

Plant J. 2021 Apr 2. doi: 10.1111/tpj.15259. Online ahead of print.

ABSTRACT

To examine the effect of mitochondrial function on photosynthesis, wild-type and transgenic Nicotiana tabacum with varying amounts of alternative oxidase (AOX) were treated with different respiratory inhibitors. Initially, each inhibitor increased the reduction state of the chloroplast electron transport chain (cETC), most severely in AOX knockdowns and least severely in AOX overexpressors. This indicated that the mitochondrion was a necessary sink for photo-generated reductant, contributing to the "P700 oxidation capacity" of photosystem I. Initially, the Complex III inhibitor myxothiazol (MYXO) and the mitochondrial ATP synthase inhibitor oligomycin (OLIGO) caused an increase in photosystem II regulated nonphotochemical quenching not evident with the Complex III inhibitor antimycin A (AA). This indicated that the increased quenching depended upon AA-sensitive cyclic electron transport (CET). Following 12 h with OLIGO, the reduction state of the cETC recovered in all plant lines. Recovery was associated with large increases in the protein amount of chloroplast ATP synthase and mitochondrial uncoupling protein. This increased the capacity for photophosphorylation in the absence of oxidative phosphorylation and enabled the mitochondrion to act again as sink for photo-generated reductant. Comparing the AA and MYXO treatments at 12 h showed that CET optimized photosystem I quantum yield, depending upon the P700 oxidation capacity. When this capacity was too high, CET drew electrons away from other sinks, moderating the P700+ amount. When P700 oxidation capacity was too low, CET acted as an electron overflow, moderating the amount of reduced P700. This study reveals flexible chloroplast-mitochondrion interactions able to overcome lesions in energy metabolism.

PMID:33811402 | DOI:10.1111/tpj.15259

Sci Immunol. 2021 Apr 2;6(58):eabc7302. doi: 10.1126/sciimmunol.abc7302.

ABSTRACT

Plasmacytoid dendritic cells (pDCs) can rapidly produce interferons and other soluble factors in response to extracellular viruses or virus mimics such as CpG-containing DNA. pDCs can also recognize live cells infected with certain RNA viruses, but the relevance and functional consequences of such recognition remain unclear. We studied the response of primary DCs to the prototypical persistent DNA virus, human cytomegalovirus (CMV). Human pDCs produced high amounts of type I interferon (IFN-I) when incubated with live CMV-infected fibroblasts but not with free CMV; the response involved integrin-mediated adhesion, transfer of DNA-containing virions to pDCs, and the recognition of DNA through TLR9. Compared with transient polyfunctional responses to CpG or free influenza virus, pDC response to CMV-infected cells was long-lasting, dominated by the production of IFN-I and IFN-III, and lacked diversification into functionally distinct populations. Similarly, pDC activation by influenza-infected lung epithelial cells was highly efficient, prolonged, and dominated by interferon production. Prolonged pDC activation by CMV-infected cells facilitated the activation of natural killer cells critical for CMV control. Last, patients with CMV viremia harbored phenotypically activated pDCs and increased circulating IFN-I and IFN-III. Thus, recognition of live infected cells is a mechanism of virus detection by pDCs that elicits a unique antiviral immune response.

PMID:33811059 | DOI:10.1126/sciimmunol.abc7302

Int J Mol Sci. 2021 Mar 26;22(7):3436. doi: 10.3390/ijms22073436.

ABSTRACT

Maize has played a key role in the sustenance and cultural traditions of the inhabitants of the southwestern USA for many centuries. Blue maize is an important component of the diverse landraces still cultivated in the region but the degree to which they are related is unknown. This research was designed to ascertain the genotypic, morphological, and phenotypic diversity of six representative southwestern blue maize landraces. Their genotypic diversity was examined using tunable genotyping-by-sequencing (tGBS™). A total of 81,038 high quality SNPs were identified and obtained through tGBS. A total of 45 morphological and biochemical traits were evaluated at two locations in New Mexico. The varieties Los Lunas High and Flor del Rio were genetically less related with other southwestern landraces whereas diffusion between Navajo Blue, Hopi Blue, Yoeme Blue, and Taos Blue demonstrated that these landraces were genetically related. Phenotypic variability was highest for kernel traits and least for plant traits. Plant, ear, and kernel traits were fairly consistent within and across locations. Principal component analysis and tGBS showed that Corn Belt variety 'Ohio Blue' was distinctly different from southwestern landraces. Genotypic analysis displayed that southwestern landraces are genetically closely related, but selection has resulted in differing phenotypes. This study has provided additional insight into the genetic relatedness of southwestern blue maize landraces.

PMID:33810494 | DOI:10.3390/ijms22073436

Antibiotics (Basel). 2021 Mar 22;10(3):337. doi: 10.3390/antibiotics10030337.

ABSTRACT

Marine natural products (MNPs) have been an important and rich source for antimicrobial drug discovery and an effective alternative to control drug resistant infections. Herein, we report bioassay guided fractionation of marine extracts from sponges Lendenfeldia, Ircinia and Dysidea that led us to identify novel compounds with antimicrobial properties. Tertiary amines or quaternary amine salts: aniline 1, benzylamine 2, tertiary amine 3 and 4, and quaternary amine salt 5, along with three known compounds (6-8) were isolated from a crude extract and MeOH eluent marine extracts. The antibiotic activities of the compounds, and their isolation as natural products have not been reported before. Using tandem mass spectrometry (MS) analysis, potential structures of the bioactive fractions were assigned, leading to the hit validation of potential compounds through synthesis, and commercially available compounds. This method is a novel strategy to overcome insufficient quantities of pure material (NPs) for drug discovery and development which is a big challenge for pharmaceutical companies. The antibacterial screening of the marine extracts has shown several of the compounds exhibited potent in-vitro antibacterial activity, especially against methicillin-resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentration (MIC) values between 15.6 to 62.5 microg mL-1. Herein, we also report structure activity relationships of a diverse range of commercial structurally similar compounds. The structure-activity relationships (SAR) results demonstrate that modification of the amines through linear chain length, and inclusion of aromatic rings, modifies the observed antimicrobial activity. Several commercially available compounds, which are structurally related to the discovered molecules, showed broad-spectrum antimicrobial activity against different test pathogens with a MIC range of 50 to 0.01 µM. The results of cross-referencing antimicrobial activity and cytotoxicity establish that these compounds are promising potential molecules, with a favourable therapeutic index for antimicrobial drug development. Additionally, the SAR studies show that simplified analogues of the isolated compounds have increased bioactivity.

PMID:33810102 | DOI:10.3390/antibiotics10030337

Int J Mol Sci. 2021 Mar 12;22(6):2902. doi: 10.3390/ijms22062902.

ABSTRACT

In response to cardiac ischemia/reperfusion, proteolysis mediated by extracellular matrix metalloproteinase inducer (EMMPRIN) and its secreted ligand cyclophilin-A (CyPA) significantly contributes to cardiac injury and necrosis. Here, we aimed to investigate if, in addition to the effect on the funny current (I(f)), Ivabradine may also play a role against cardiac necrosis by reducing EMMPRIN/CyPA-mediated cardiac inflammation. In a porcine model of cardiac ischemia/reperfusion (IR), we found that administration of 0.3 mg/kg Ivabradine significantly improved cardiac function and reduced cardiac necrosis by day 7 after IR, detecting a significant increase in cardiac CyPA in the necrotic compared to the risk areas, which was inversely correlated with the levels of circulating CyPA detected in plasma samples from the same subjects. In testing whether Ivabradine may regulate the levels of CyPA, no changes in tissue CyPA were found in healthy pigs treated with 0.3 mg/kg Ivabradine, but interestingly, when analyzing the complex EMMPRIN/CyPA, rather high glycosylated EMMPRIN, which is required for EMMPRIN-mediated matrix metalloproteinase (MMP) activation and increased CyPA bonding to low-glycosylated forms of EMMPRIN were detected by day 7 after IR in pigs treated with Ivabradine. To study the mechanism by which Ivabradine may prevent secretion of CyPA, we first found that Ivabradine was time-dependent in inhibiting co-localization of CyPA with the granule exocytosis marker vesicle-associated membrane protein 1 (VAMP1). However, Ivabradine had no effect on mRNA expression nor in the proteasome and lysosome degradation of CyPA. In conclusion, our results point toward CyPA, its ligand EMMPRIN, and the complex CyPA/EMMPRIN as important targets of Ivabradine in cardiac protection against IR.

PMID:33809359 | DOI:10.3390/ijms22062902