Nat Commun. 2021 Mar 5;12(1):1428. doi: 10.1038/s41467-021-21702-6.

ABSTRACT

Since the beginning of the SARS-CoV-2 pandemic, COVID-19 appeared as a unique disease with unconventional tissue and systemic immune features. Here we show a COVID-19 immune signature associated with severity by integrating single-cell RNA-seq analysis from blood samples and broncho-alveolar lavage fluids with clinical, immunological and functional ex vivo data. This signature is characterized by lung accumulation of naïve lymphoid cells associated with a systemic expansion and activation of myeloid cells. Myeloid-driven immune suppression is a hallmark of COVID-19 evolution, highlighting arginase-1 expression with immune regulatory features of monocytes. Monocyte-dependent and neutrophil-dependent immune suppression loss is associated with fatal clinical outcome in severe patients. Additionally, our analysis shows a lung CXCR6+ effector memory T cell subset is associated with better prognosis in patients with severe COVID-19. In summary, COVID-19-induced myeloid dysregulation and lymphoid impairment establish a condition of 'immune silence' in patients with critical COVID-19.

PMID:33674591 | DOI:10.1038/s41467-021-21702-6

Proc Natl Acad Sci U S A. 2021 Mar 9;118(10):e2013056118. doi: 10.1073/pnas.2013056118.

ABSTRACT

The enormous cellular diversity in the mammalian brain, which is highly prototypical and organized in a hierarchical manner, is dictated by cell-type-specific gene-regulatory programs at the molecular level. Although prevalent in the brain, the contribution of alternative splicing (AS) to the molecular diversity across neuronal cell types is just starting to emerge. Here, we systematically investigated AS regulation across over 100 transcriptomically defined neuronal types of the adult mouse cortex using deep single-cell RNA-sequencing data. We found distinct splicing programs between glutamatergic and GABAergic neurons and between subclasses within each neuronal class. These programs consist of overlapping sets of alternative exons showing differential splicing at multiple hierarchical levels. Using an integrative approach, our analysis suggests that RNA-binding proteins (RBPs) Celf1/2, Mbnl2, and Khdrbs3 are preferentially expressed and more active in glutamatergic neurons, while Elavl2 and Qk are preferentially expressed and more active in GABAergic neurons. Importantly, these and additional RBPs also contribute to differential splicing between neuronal subclasses at multiple hierarchical levels, and some RBPs contribute to splicing dynamics that do not conform to the hierarchical structure defined by the transcriptional profiles. Thus, our results suggest graded regulation of AS across neuronal cell types, which may provide a molecular mechanism to specify neuronal identity and function that are orthogonal to established classifications based on transcriptional regulation.

PMID:33674385 | DOI:10.1073/pnas.2013056118

Cancer Immunol Res. 2021 Mar 5:canimm.0817.2020. doi: 10.1158/2326-6066.CIR-20-0817. Online ahead of print.

ABSTRACT

Merkel cell carcinomas (MCC) are immunogenic skin cancers associated with viral infection or UV-mutagenesis. To study T-cell infiltrates in MCC, we analyzed 58 MCC lesions from 39 patients using multiplex-immunohistochemistry/immunofluorescence (m-IHC/IF). CD4+ or CD8+ T cells comprised the majority of infiltrating T lymphocytes in most tumors. However, almost half of the tumors harbored prominent CD4/CD8 double negative (DN) T-cell infiltrates (>20% DN T cells) and in 12% of cases, DN T cells represented the majority of T cells. Flow cytometric analysis of single-cell suspensions from fresh tumors identified DN T cells as predominantly Vδ2- γδ T cells. In the context of γδ T-cell inflammation, these cells expressed PD1 and LAG3, which is consistent with a suppressed or exhausted phenotype, and CD103, which indicates tissue-residency. Furthermore, single-cell RNA sequencing (scRNA-seq) identified a transcriptional profile of γδ T cells suggestive of proinflammatory potential. T-cell receptor (TCR) analysis confirmed clonal expansion of Vδ1 and Vδ3 clonotypes and functional studies using cloned γδ TCRs demonstrated restriction of these for CD1c and MR1 antigen-presenting molecules. Based on a 13-gene γδ T cell-signature derived from scRNA-seq analysis, gene-set enrichment on bulk RNA-seq data showed a positive correlation between enrichment scores and DN T-cell infiltrates. An improved disease-specific survival was evident for patients with high enrichment scores and complete responses to anti-PD1/PD-L1 treatment were observed in three of four cases with high enrichment scores. Thus, γδ T-cell infiltration may serve as a prognostic biomarker and should be explored for therapeutic interventions.

PMID:33674358 | DOI:10.1158/2326-6066.CIR-20-0817

Clin Cancer Res. 2021 Mar 5:clincanres.3975.2019. doi: 10.1158/1078-0432.CCR-19-3975. Online ahead of print.

ABSTRACT

PURPOSE: Gemcitabine is most commonly used for pancreatic cancer (PC). However, the molecular features and mechanisms of the frequently occurred resistance remain unclear. This work aims at exploring the molecular features of gemcitabine resistance and identifying candidate biomarkers and combinatorial targets for the treatment.

EXPERIMENTAL DESIGN: In present study, we established 66 patient-derived xenografts (PDXs) based on clinical PC specimens and treated them with gemcitabine. We generated multi-omics data (including whole exome-seq, RNA-seq, miRNA-seq and DNA methylation array) of 15 drug sensitive and 13 resistant PDXs before and after the gemcitabine treatment. We performed integrative computational analysis to identify the molecular networks related to gemcitabine intrinsic and required resistance. Then, shRNA-based high-content screening was implemented to validate the function of the de-regulated genes.

RESULTS: The comprehensive multi-omics analysis and functional experiment revealed that MRPS5 and GSPT1 had strong effects on cell proliferation, and CD55 and DHTKD1 contributed to gemcitabine resistance in PC cells. Moreover, we found miR-135a-5p was significantly associated with the prognosis of PC patients and could be a candidate biomarker to predict gemcitabine response. Comparing the molecular features before and after the treatment, we found that PI3K-Akt, p53, HIF-1 pathways were significantly altered in multiple patients, providing candidate target pathways for reducing the acquired resistance.

CONCLUSIONS: This integrative genomic study systematically investigated the predictive markers and molecular mechanisms of chemoresistance in PC and provide potential therapy targets for overcoming gemcitabine resistance.

PMID:33674273 | DOI:10.1158/1078-0432.CCR-19-3975

Development. 2021 Mar 5:dev.198960. doi: 10.1242/dev.198960. Online ahead of print.

ABSTRACT

During Xenopus gastrulation, leading edge mesendoderm (LEM) advances animally as wedge-shaped cell mass over the vegetally moving blastocoel roof (BCR). We show that close contact across the BCR-LEM interface correlates with attenuated net advance of the LEM, which is therefore pulled forward by tip cells while the remaining LEM frequently separates from the BCR. Nevertheless, lamellipodia persist on the detached LEM surface. They attach to adjacent LEM cells and depend on PDGF-A, cell surface fibronectin and cadherin. We argue that active cell motility on the LEM surface prevents adverse capillary effects in the liquid LEM tissue as it moves by being pulled. It counters tissue surface tension effects with oriented cell movement and bulges the LEM surface out to keep it close to the curved BCR without attaching to it. Proximity to the BCR is necessary in turn for the maintenance and orientation of lamellipodia that permit mass cell movement with minimal substratum contact. Together with a similar process in epithelial invagination, vertical telescoping, the cell movement at the LEM surface defines a novel type of cell rearrangement, vertical shearing.

PMID:33674259 | DOI:10.1242/dev.198960

Trends Plant Sci. 2021 Mar 2:S1360-1385(21)00031-5. doi: 10.1016/j.tplants.2021.02.002. Online ahead of print.

ABSTRACT

Feral plants have been known since the inception of modern agriculture, but the genetic changes during what seemed to be a simple reversion of a domesticated form are poorly understood. Recent studies, revealing the changes occurring in weedy rice, show an unexpected degree of differentiation in these feral escapes.

PMID:33674174 | DOI:10.1016/j.tplants.2021.02.002

Trends Plant Sci. 2021 Mar 2:S1360-1385(21)00028-5. doi: 10.1016/j.tplants.2021.01.005. Online ahead of print.

ABSTRACT

Pathogens produce effectors to overcome plant immunity, thereby threatening crop yields and global food security. Large-scale interactomic studies have revealed that pathogens from different kingdoms of life target common plant proteins during infection, the so-called effector hubs. These hubs often play central roles in numerous plant processes through their ability to interact with multiple plant proteins. This ability arises partly from the presence of intrinsically disordered domains (IDDs) in their structure. Here, we highlight the role of the TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR (TCP) and JASMONATE-ZIM DOMAIN (JAZ) transcription regulator families as plant signaling and effector hubs. We consider different evolutionary hypotheses to rationalize the existence of diverse effectors sharing common targets and the possible role of IDDs in this interaction.

PMID:33674173 | DOI:10.1016/j.tplants.2021.01.005

Int J Mol Sci. 2021 Feb 12;22(4):1846. doi: 10.3390/ijms22041846.

ABSTRACT

Notch signaling is critical for controlling a variety of cell fate decisions during metazoan development and homeostasis. This unique, highly conserved signaling pathway relies on cell-to-cell contact, which triggers the proteolytic release of the cytoplasmic domain of the membrane-anchored transcription factor Notch from the membrane. A disintegrin and metalloproteinase (ADAM) proteins are crucial for Notch activation by processing its S2 site. While ADAM10 cleaves Notch1 under physiological, ligand-dependent conditions, ADAM17 mainly cleaves Notch1 under ligand-independent conditions. However, the mechanism(s) that regulate the distinct contributions of these ADAMs in Notch processing remain unclear. Using cell-based assays in mouse embryonic fibroblasts (mEFs) lacking ADAM10 and/or ADAM17, we aimed to clarify what determines the relative contributions of ADAM10 and ADAM17 to ligand-dependent or ligand-independent Notch processing. We found that EDTA-stimulated ADAM17-dependent Notch1 processing is rapid and requires the ADAM17-regulators iRhom1 and iRhom2, whereas the Delta-like 4-induced ligand-dependent Notch1 processing is slower and requires ADAM10. The selectivity of ADAM17 for EDTA-induced Notch1 processing can most likely be explained by a preference for ADAM17 over ADAM10 for the Notch1 cleavage site and by the stronger inhibition of ADAM10 by EDTA. The physiological ADAM10-dependent processing of Notch1 cannot be compensated for by ADAM17 in Adam10-/- mEFs, or by other ADAMs shown here to be able to cleave the Notch1 cleavage site, such as ADAMs9, 12, and 19. Collectively, these results provide new insights into the mechanisms underlying the substrate selectivity of ADAM10 and ADAM17 towards Notch1.

PMID:33673337 | DOI:10.3390/ijms22041846

Microorganisms. 2021 Feb 12;9(2):365. doi: 10.3390/microorganisms9020365.

ABSTRACT

The strictly anaerobic bactGIerium Dehalococcoides mccartyi obligatorily depends on organohalide respiration for energy conservation and growth. The bacterium also plays an important role in bioremediation. Since there is no guarantee of a continuous supply of halogenated substrates in its natural environment, the question arises of how D. mccartyi maintains the synthesis and activity of dehalogenating enzymes under these conditions. Acetylation is a means by which energy-restricted microorganisms can modulate and maintain protein levels and their functionality. Here, we analyzed the proteome and Nε-lysine acetylome of D. mccartyi strain CBDB1 during growth with 1,2,3-trichlorobenzene as an electron acceptor. The high abundance of the membrane-localized organohalide respiration complex, consisting of the reductive dehalogenases CbrA and CbdbA80, the uptake hydrogenase HupLS, and the organohalide respiration-associated molybdoenzyme OmeA, was shown throughout growth. In addition, the number of acetylated proteins increased from 5% to 11% during the transition from the exponential to the stationary phase. Acetylation of the key proteins of central acetate metabolism and of CbrA, CbdbA80, and TatA, a component of the twin-arginine translocation machinery, suggests that acetylation might contribute to maintenance of the organohalide-respiring capacity of the bacterium during the stationary phase, thus providing a means of ensuring membrane protein integrity and a proton gradient.

PMID:33673241 | DOI:10.3390/microorganisms9020365

Viruses. 2021 Feb 12;13(2):289. doi: 10.3390/v13020289.

ABSTRACT

Studies of conditionally lethal mutants can help delineate the structure-function relationships of biomolecules. Temperature-sensitive (ts) mammalian reovirus (MRV) mutants were isolated and characterized many years ago. Two of the most well-defined MRV ts mutants are tsC447, which contains mutations in the S2 gene encoding viral core protein σ2, and tsG453, which contains mutations in the S4 gene encoding major outer-capsid protein σ3. Because many MRV ts mutants, including both tsC447 and tsG453, encode multiple amino acid substitutions, the specific amino acid substitutions responsible for the ts phenotype are unknown. We used reverse genetics to recover recombinant reoviruses containing the single amino acid polymorphisms present in ts mutants tsC447 and tsG453 and assessed the recombinant viruses for temperature-sensitivity by efficiency-of-plating assays. Of the three amino acid substitutions in the tsG453 S4 gene, Asn16-Lys was solely responsible for the tsG453ts phenotype. Additionally, the mutant tsC447 Ala188-Val mutation did not induce a temperature-sensitive phenotype. This study is the first to employ reverse genetics to identify the dominant amino acid substitutions responsible for the tsC447 and tsG453 mutations and relate these substitutions to respective phenotypes. Further studies of other MRV ts mutants are warranted to define the sequence polymorphisms responsible for temperature sensitivity.

PMID:33673179 | DOI:10.3390/v13020289

Cancers (Basel). 2021 Feb 14;13(4):801. doi: 10.3390/cancers13040801.

ABSTRACT

Colorectal cancer (CRC) is a heterogeneous disease that can currently be subdivided into four distinct consensus molecular subtypes (CMS) based on gene expression profiling. The CMS4 subtype is marked by high expression of mesenchymal genes and is associated with a worse overall prognosis compared to other CMSs. Importantly, this subtype responds poorly to the standard therapies currently used to treat CRC. We set out to explore what regulatory signalling networks underlie the CMS4 phenotype of cancer cells, specifically, by analysing which kinases were more highly expressed in this subtype compared to others. We found AKT3 to be expressed in the cancer cell epithelium of CRC specimens, patient derived xenograft (PDX) models and in (primary) cell cultures representing CMS4. Importantly, chemical inhibition or knockout of this gene hampers outgrowth of this subtype, as AKT3 controls expression of the cell cycle regulator p27KIP1. Furthermore, high AKT3 expression was associated with high expression of epithelial-mesenchymal transition (EMT) genes, and this observation could be expanded to cell lines representing other carcinoma types. More importantly, this association allowed for the identification of CRC patients with a high propensity to metastasise and an associated poor prognosis. High AKT3 expression in the tumour epithelial compartment may thus be used as a surrogate marker for EMT and may allow for a selection of CRC patients that could benefit from AKT3-targeted therapy.

PMID:33673003 | DOI:10.3390/cancers13040801

J Pers Med. 2021 Feb 14;11(2):127. doi: 10.3390/jpm11020127.

ABSTRACT

Pancreatic cancer is one of the most fatal malignancies and the seventh leading cause of cancer-related deaths related to late diagnosis, poor survival rates, and high incidence of metastasis. Unfortunately, pancreatic cancer is predicted to become the third leading cause of cancer deaths in the future. Therefore, diagnosis at the early stages of pancreatic cancer for initial diagnosis or postoperative recurrence is a great challenge, as well as predicting prognosis precisely in the context of biomarker discovery. From the personalized medicine perspective, the lack of molecular biomarkers for patient selection confines tailored therapy options, including selecting drugs and their doses or even diet. Currently, there is no standardized pancreatic cancer screening strategy using molecular biomarkers, but CA19-9 is the most well known marker for the detection of pancreatic cancer. In contrast, recent innovations in high-throughput techniques have enabled the discovery of specific biomarkers of cancers using genomics, transcriptomics, proteomics, metabolomics, glycomics, and metagenomics. Panels combining CA19-9 with other novel biomarkers from different "omics" levels might represent an ideal strategy for the early detection of pancreatic cancer. The systems biology approach may shed a light on biomarker identification of pancreatic cancer by integrating multi-omics approaches. In this review, we provide background information on the current state of pancreatic cancer biomarkers from multi-omics stages. Furthermore, we conclude this review on how multi-omics data may reveal new biomarkers to be used for personalized medicine in the future.

PMID:33672926 | DOI:10.3390/jpm11020127

Toxics. 2021 Feb 20;9(2):40. doi: 10.3390/toxics9020040.

ABSTRACT

Salinity can interact with organic compounds and modulate their toxicity. Studies have shown that the fraction of pyrethroid insecticides in the aqueous phase increases with increasing salinity, potentially increasing the risk of exposure for aquatic organisms at higher salinities. In the San Francisco Bay Delta (SFBD) estuary, pyrethroid concentrations increase during the rainy season, coinciding with the spawning season of Delta Smelt (Hypomesus transpacificus), an endangered, endemic fish. Furthermore, salinity intrusion in the SFBD is exacerbated by global climate change, which may change the dynamics of pyrethroid toxicity on aquatic animals. Therefore, examining the effect of salinity on the sublethal toxicity of pyrethroids is essential for risk assessments, especially during the early life stages of estuarine fishes. To address this, we investigated behavioral effects of permethrin and bifenthrin at three environmentally relevant concentrations across a salinity gradient (0.5, 2 and 6 PSU) on Delta Smelt yolk-sac larvae. Our results suggest that environmentally relevant concentrations of pyrethroids can perturb Delta Smelt larvae behavior even at the lowest concentrations (<1 ng/L) and that salinity can change the dynamic of pyrethroid toxicity in terms of behavioral effects, especially for bifenthrin, where salinity was positively correlated with anti-thigmotaxis at each concentration.

PMID:33672739 | DOI:10.3390/toxics9020040

Plants (Basel). 2021 Feb 23;10(2):411. doi: 10.3390/plants10020411.

ABSTRACT

Upregulation of acetate fermentation in plants has recently been described as an evolutionarily conserved drought survival strategy, with the amount of acetate produced directly correlating to survival. However, destructive measurements are required to evaluate acetate-linked drought responses, limiting the temporal and spatial scales that can be studied. Here, 13C-labeling studies with poplar (Populus trichocarpa) branches confirmed that methyl acetate is produced in plants from the acetate-linked acetylation of methanol. Methyl acetate emissions from detached leaves were strongly stimulated during desiccation, with total emissions decreasing with the leaf developmental stage. In addition, diurnal methyl acetate emissions from whole physiologically active poplar branches increased as a function of temperature, and light-dark transitions resulted in significant emission bursts lasting several hours. During experimental drought treatments of potted poplar saplings, light-dark methyl acetate emission bursts were eliminated while strong enhancements in methyl acetate emissions lasting > 6 days were observed with their initiation coinciding with the suppression of transpiration and photosynthesis. The results suggest that methyl acetate emissions represent a novel non-invasive tracer of acetate-mediated temperature and drought survival response in plants. The findings may have important implications for the future understanding of acetate-mediated drought responses to transcription, cellular metabolism, and hormone signaling, as well as its associated changes in carbon cycling and water use from individual plants to whole ecosystems.

PMID:33672332 | DOI:10.3390/plants10020411

Cells. 2021 Feb 23;10(2):478. doi: 10.3390/cells10020478.

ABSTRACT

The Hippo pathway regulates a complex signalling network which mediates several biological functions including cell proliferation, organ size and apoptosis. Several scaffold proteins regulate the crosstalk of the members of the pathway with other signalling pathways and play an important role in the diverse output controlled by this pathway. In this study we have identified the scaffold protein IQGAP1 as a novel interactor of the core kinases of the Hippo pathway, MST2 and LATS1. Our results indicate that IQGAP1 scaffolds MST2 and LATS1 supresses their kinase activity and YAP1-dependent transcription. Additionally, we show that IQGAP1 is a negative regulator of the non-canonical pro-apoptotic pathway and may enable the crosstalk between this pathway and the ERK and AKT signalling modules. Our data also show that bile acids regulate the IQGAP1-MST2-LATS1 signalling module in hepatocellular carcinoma cells, which could be necessary for the inhibition of MST2-dependent apoptosis and hepatocyte transformation.

PMID:33672268 | DOI:10.3390/cells10020478

Mar Drugs. 2021 Feb 15;19(2):112. doi: 10.3390/md19020112.

ABSTRACT

Persistent hypoxia is a main clinical feature of chronic wounds. Intriguingly, oxygen-loaded nanodroplets (OLNDs), filled with oxygen-solving 2H,3H-decafluoropentane and shelled with polysaccharides, have been proposed as a promising tool to counteract hypoxia by releasing a clinically relevant oxygen amount in a time-sustained manner. Here, four different types of chitosan (low or medium weight (LW or MW), glycol-(G-), and methylglycol-(MG-) chitosan) were compared as candidate biopolymers for shell manufacturing. The aim of the work was to design OLND formulations with optimized physico-chemical characteristics, efficacy in oxygen release, and biocompatibility. All OLND formulations displayed spherical morphology, cationic surfaces, ≤500 nm diameters (with LW chitosan-shelled OLNDs being the smallest), high stability, good oxygen encapsulation efficiency, and prolonged oxygen release kinetics. Upon cellular internalization, LW, MW, and G-chitosan-shelled nanodroplets did not significantly affect the viability, health, or metabolic activity of human keratinocytes (HaCaT cell line). On the contrary, MG-chitosan-shelled nanodroplets showed very poor biocompatibility. Combining the physico-chemical and the biological results obtained, LW chitosan emerges as the best candidate biopolymer for future OLND application as a skin device to treat chronic wounds.

PMID:33672056 | DOI:10.3390/md19020112

Viruses. 2021 Feb 15;13(2):305. doi: 10.3390/v13020305.

ABSTRACT

Coronavirus disease-19 (COVID-19) pandemic, caused by the novel SARS-CoV-2 virus, continues to be a global threat. The number of cases and deaths will remain escalating due to the lack of effective therapeutic agents. Several studies have established the importance of the viral main protease (Mpro) in the replication of SARS-CoV-2 which makes it an attractive target for antiviral drug development, including pharmaceutical repurposing and other medicinal chemistry approaches. Identification of natural products with considerable inhibitory potential against SARS-CoV-2 could be beneficial as a rapid and potent alternative with drug-likeness by comparison to de novo antiviral drug discovery approaches. Thereof, we carried out the structure-based screening of natural products from Echinacea-angustifolia, commonly used to prevent cold and other microbial respiratory infections, targeting SARS-CoV-2 Mpro. Four natural products namely, Echinacoside, Quercetagetin 7-glucoside, Levan N, Inulin from chicory, and 1,3-Dicaffeoylquinic acid, revealed significant docking energy (>-10 kcal/mol) in the SARS-CoV-2 Mpro catalytic pocket via substantial intermolecular contacts formation against co-crystallized ligand (<-4 kcal/mol). Furthermore, the docked poses of SARS-CoV-2 Mpro with selected natural products showed conformational stability through molecular dynamics. Exploring the end-point net binding energy exhibited substantial contribution of Coulomb and van der Waals interactions to the stability of respective docked conformations. These results advocated the natural products from Echinacea angustifolia for further experimental studies with an elevated probability to discover the potent SARS-CoV-2 Mpro antagonist with higher affinity and drug-likeness.

PMID:33672054 | DOI:10.3390/v13020305

J Clin Med. 2021 Feb 15;10(4):769. doi: 10.3390/jcm10040769.

ABSTRACT

Migraine is a primary headache with high prevalence among the general population, characterized by functional hypersensitivity to both exogenous and endogenous stimuli particularly affecting the nociceptive system. The hyperresponsivity of cortical neurons could be due to a disequilibrium in the excitatory/inhibitory signaling. This study aimed to investigate the anatomo-functional pathway from the retina to the primary visual cortex using visual evoked potentials (VEP). Contrast gain protocol was used in 15 patients diagnosed with migraine without aura (at baseline and after 3 months of topiramate therapy) and 13 controls. A saturation (S) index was assessed to monitor the response of VEP's amplitude to contrast gain. Non-linear nor monotone growth of VEP (S < 0.95) was defined as supersaturation. A greater percentage of migraine patients (53%) relative to controls (7%) showed this characteristic. A strong inverse correlation was found between the S index and the number of days separating the registration of VEP from the next migraine attack. Moreover, allodynia measured through the Allodynia Symptoms Check-list (ASC-12) correlates with the S index both at baseline and after 3 months of topiramate treatment. Other clinical characteristics were not related to supersaturation. Topiramate therapy, although effective, did not influence electrophysiological parameters suggesting a non-intracortical nor retinal origin of the supersaturation (with possible involvement of relay cells from the lateral geniculate nucleus). In conclusion, the elaboration of visual stimuli and visual cortex activity is different in migraine patients compared to controls. More data are necessary to confirm the potential use of the S index as a biomarker for the migraine cycle (association with the pain-phase) and cortical sensitization (allodynia).

PMID:33671875 | DOI:10.3390/jcm10040769

Int J Environ Res Public Health. 2021 Feb 15;18(4):1868. doi: 10.3390/ijerph18041868.

ABSTRACT

Digital games have been successfully applied in different working sectors as an occupational safety training method, but with a very limited application in agriculture. In agriculture and other productive sectors, unintentional injuries tend to occur with similar dynamics. A literature review was carried out to understand how occupational risks are addressed during game-based safety training in different productive sectors and how this can be transferred to agriculture. Literature about "serious game" and "gamification" as safety training methods was searched in WEB OF SCIENCE, SCOPUS, PUBMED and PsycINFO databases. In the forty-two publications retained, the computer was identified as the most adopted game support, whereas "points", "levels", "challenges" and "discovery" were the preferred game mechanics. Moreover, an association can be detected between the game mechanics and the elements developed in the game. Finally, during the game assessment, much positive feedback was collected and the games proved to be able to increase the operators' skills and safety knowledge. In light of the results, insights are provided to develop an effective, satisfying and engaging safety game training for workers employed in agriculture. Games can be best used to learn and they are certain to improve over the next few years.

PMID:33671867 | DOI:10.3390/ijerph18041868

Biomolecules. 2021 Feb 15;11(2):284. doi: 10.3390/biom11020284.

ABSTRACT

The gastrointestinal (GI) tract has an intriguing and critical role beyond digestion in both modern and complementary and alternative medicine (CAM), as demonstrated by its link with the immune system. In this review, we attempted to explore the interrelationships between increased GI permeability and phlegm, an important pathological factor in CAM, syndrome, and therapeutic herbs for two disorders. The leaky gut and phlegm syndromes look considerably similar with respect to related symptoms, diseases, and suitable herbal treatment agents, including phytochemicals even though limitations to compare exist. Phlegm may be spread throughout the body along with other pathogens via the disruption of the GI barrier to cause several diseases sharing some parts of symptoms, diseases, and mechanisms with leaky gut syndrome. Both syndromes are related to inflammation and gut microbiota compositions. Well-designed future research should be conducted to verify the interrelationships for evidence based integrative medicine to contribute to the promotion of public health. In addition, systems biology approaches should be adopted to explore the complex synergistic effects of herbal medicine and phytochemicals on conditions associated with phlegm and leaky gut syndromes.

PMID:33671865 | DOI:10.3390/biom11020284