Estimating cell type compositions for complex diseases is an important step to investigate the cellular heterogeneity for understanding disease etiology and potentially facilitate early disease diagnosis and prevention. Here, we developed a computationally statistical method, referring to Multi-Omics Matrix Factorization (MOMF), to estimate the cell-type compositions of bulk RNA sequencing (RNA-seq) data by leveraging cell type-specific gene expression levels from single-cell RNA sequencing (scRNA-seq) data. MOMF not only directly models the count nature of gene expression data, but also effectively accounts for the uncertainty of cell type-specific mean gene expression levels. We demonstrate the benefits of MOMF through three real data applications, i.e., Glioblastomas (GBM), colorectal cancer (CRC) and type II diabetes (T2D) studies. MOMF is able to accurately estimate disease-related cell type proportions, i.e., oligodendrocyte progenitor cells and macrophage cells, which are strongly associated with the survival of GBM and CRC, respectively.

Among the array of structurally and toxicologically diverse mycotoxins, aflatoxins have attracted the most interest of scientific research due to their high toxicity and incidence in foods and feeds. Despite the undeniable progress made in various aspects related to aflatoxins, the ultimate goal consisting of reducing the associated public health risks worldwide is far from being reached due to multiplicity of social, political, economic, geographic, climatic, and development factors. However, a reasonable degree of health protection is attained in industrialized countries owing to their scientific, administrative, and financial capacities allowing them to use high-tech agricultural management systems. Less fortunate situations exist in equatorial and sub-equatorial developing countries mainly practicing traditional agriculture managed by smallholders for subsistence, and where the climate is suitable for mould growth and aflatoxin production. This situation worsens due to climatic change producing conditions increasingly suitable for aflatoxigenic mould growth and toxin production. Accordingly, it is difficult to harmonize the regulatory standards of aflatoxins worldwide, which prevents agri-foods of developing countries from accessing the markets of industrialized countries. To tackle the multi-faceted aflatoxin problem, actions should be taken collectively by the international community involving scientific research, technological and social development, environment protection, awareness promotion, etc. International cooperation should foster technology transfer and exchange of pertinent technical information. This review presents the main historical discoveries leading to our present knowledge on aflatoxins and the challenges that should be addressed presently and in the future at various levels to ensure higher health protection for everybody. In short, it aims to elucidate where we come from and where we should go in terms of aflatoxin research/development.

The objectives were to investigate whether restraint stress (which is known as a mixture of psychologic and physical stress) exerts negative effects on the stomach and spleen, and whether the phenolic compound resveratrol (RES) exerts any protective roles. Fifty adult male mice were divided into five groups, with 10 mice per group as follows: control (C), restraint stress (RS), RS with vehicle (RS + V), RS with 2 mg/kg of resveratrol (RS + 2 mg RES), and RS with 20 mg/kg of resveratrol (RS + 20 mg RES). Mice were restrained in conical centrifuge tubes for 4 h daily to establish the RS model. RS + 2 mg RES, RS + 20 mg RES, and RS + V groups were given an oral dose of resveratrol or vehicle for 15 consecutive days, while the control group was not exposed to restraint stress. Herein, we showed that restraint stress decreased body weight and food and water consumption in stressed groups RS and RS + V compared to controls, while the groups treated with resveratrol showed improvements. Moreover, restraint stress caused acute damage to the morphology of gastric cells and reduced the quantitative distribution of parietal cells along with their decreased size and diameter, pointing to gastritis or ulcer. Furthermore, the antibody against the apoptosis-inducing factor (AIF) was highly attached in the RS groups. Splenic size, weight, and length were also greatly augmented in the stressed groups compared to the controls, while these phenomena were not observed in the RS + 2 mg RES group. Our findings proved significant ameliorating effects of resveratrol against restraint stress in adult male mice.

Streptomyces clavuligerus is a gram-positive filamentous bacterium notable for producing clavulanic acid (CA), an inhibitor of β-lactamase enzymes, which confers resistance to bacteria against several antibiotics. Here we present a comparative analysis of the morphological and metabolic response of S. clavuligerus linked to the CA production under low and high shear stress conditions in a 2D rocking-motion single-use bioreactor (CELL-tainer ®) and stirred tank bioreactor (STR), respectively. The CELL-tainer® guarantees high turbulence and enhanced volumetric mass transfer at low shear stress, which (in contrast to bubble columns) allows the investigation of the impact of shear stress without oxygen limitation. The results indicate that high shear forces do not compromise the viability of S. clavuligerus cells; even higher specific growth rate, biomass, and specific CA production rate were observed in the STR. Under low shear forces in the CELL-tainer® the mycelial diameter increased considerably (average diameter 2.27 in CELL-tainer® vs. 1.44 µm in STR). This suggests that CA production may be affected by a lower surface-to-volume ratio which would lead to lower diffusion and transport of nutrients, oxygen, and product. The present study shows that there is a strong correlation between macromorphology and CA production, which should be an important aspect to consider in industrial production of CA.

Bronchopulmonary dysplasia (BPD), caused by hyperoxia in newborns and infants, results in lung damage and abnormal pulmonary function. However, the current treatments for BPD are steroidal and pharmacological therapies, which cause neurodevelopmental impairment. Treatment with umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) is an efficient alternative approach. To prevent pulmonary inflammation in BPD, this study investigated the hypothesis that a key regulator was secreted by MSCs to polarize inflammatory macrophages into anti-inflammatory macrophages at inflammation sites. Lipopolysaccharide-induced macrophages co-cultured with MSCs secreted low levels of the inflammatory cytokines, IL-8 and IL-6, but high levels of the anti-inflammatory cytokine, IL-10. Silencing decorin in MSCs suppressed the expression of CD44, which mediates anti-inflammatory activity in macrophages. The effects of MSCs were examined in a rat model of hyperoxic lung damage. Macrophage polarization differed depending on the levels of decorin secreted by MSCs. Moreover, intratracheal injection of decorin-silenced MSCs or MSCs secreting low levels of decorin confirmed impaired alveolarization of damaged lung tissues by down-regulation of decorin. In tissues, a decrease in the anti-inflammatory macrophage marker, CD163, was observed via CD44. Thus, we identified decorin as a key paracrine factor, inducing macrophage polarization via CD44, a master immunoregulator in mesenchymal stem cells.

Mosquitoes are vectors of arboviruses affecting animal and human health. Arboviruses circulate primarily within an enzootic cycle and recurrent spillovers contribute to the emergence of human-adapted viruses able to initiate an urban cycle involving anthropophilic mosquitoes. The increasing volume of travel and trade offers multiple opportunities for arbovirus introduction in new regions. This scenario has been exemplified recently with the Zika pandemic. To incriminate a mosquito as vector of a pathogen, several criteria are required such as the detection of natural infections in mosquitoes. In this study, we used a high-throughput chip based on the BioMark™ Dynamic arrays system capable of detecting 64 arboviruses in a single experiment. A total of 17,958 mosquitoes collected in Zika-endemic/epidemic countries (Brazil, French Guiana, Guadeloupe, Suriname, Senegal, and Cambodia) were analyzed. Here we show that this new tool can detect endemic and epidemic viruses in different mosquito species in an epidemic context. Thus, this fast and low-cost method can be suggested as a novel epidemiological surveillance tool to identify circulating arboviruses.

The eradication of bacteria from wound sites and promotion of healing are essential for treating infected wounds. Nitric oxide (NO) is desirable for these purposes due to its ability to accelerate wound healing and its broad-spectrum antibacterial effects. We developed an in situ hydrogel-forming/NO-releasing powder dressing (NO/GP), which is a powder during storage and forms a hydrogel when applied to wounds, as a novel NO-releasing formulation to treat infected wounds. An NO/GP fine powder (51.5 μm) was fabricated by blending and micronizing S-nitrosoglutathione (GSNO), alginate, pectin, and polyethylene glycol (PEG). NO/GP remained stable for more than four months when stored at 4 or 37 °C. When applied to wounds, NO/GP absorbed wound fluid and immediately converted to a hydrogel. Additionally, wound fluid triggered a NO release from NO/GP for more than 18 h. The rheological properties of hydrogel-transformed NO/GP indicated that NO/GP possesses similar adhesive properties to marketed products (Vaseline). NO/GP resulted in a 6-log reduction in colony forming units (CFUs) of methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, which are representative drug-resistant gram-positive and -negative bacteria, respectively. The promotion of wound healing by NO/GP was demonstrated in mice with full-thickness wounds challenged with MRSA and P. aeruginosa. Thus, NO/GP is a promising formulation for the treatment of infected wounds.

The calcineurin pathway is an important signaling cascade for growth, sexual development, stress response, and pathogenicity in fungi. In this study, we investigated the function of CrzA, a key transcription factor of the calcineurin pathway, in an aflatoxin-producing fungus Aspergillus flavus (A. flavus). To examine the role of the crzA gene, crzA deletion mutant strains in A. flavus were constructed and their phenotypes, including fungal growth, spore formation, and sclerotial formation, were examined. Absence of crzA results in decreased colony growth, the number of conidia, and sclerocia production. The crzA-deficient mutant strains were more susceptible to osmotic pressure and cell wall stress than control or complemented strains. Moreover, deletion of crzA results in a reduction in aflatoxin production. Taken together, these results demonstrate that CrzA is important for differentiation and mycotoxin production in A. flavus.

Influenza viruses are important pathogens causing respiratory disease in humans and animals. In contrast to influenza A virus (IAV) that can infect a wide range of animal species, other influenza viruses, including influenza B virus (IBV), influenza C virus (ICV), and influenza D virus (IDV) have a limited host range. Swine can be infected with all four different genera of influenza viruses. IAV infection of pigs causes the well-known swine influenza that poses significant threats to human and animal health. However, influenza virus infection of pigs with IBV, ICV, and IDV are not well-characterized. Herein, we compared pathogenicity of IBV and IDV using intratracheal and intranasal infection of pigs, which are IAV seropositive, and commingled naïve pigs with the infected animals to determine their transmissibility. Both viruses caused fever and some lung lesions, replicated in the lungs of infected pigs, but only IDV transmitted to the contact animals. Although IBV and IDV displayed differing levels of replication in the respiratory tract of infected pigs, no significant differences in pathogenicity of both viruses were observed. These results indicate that both IBV and IDV can replicate, and are pathogenic in pigs.

Previous experiments have shown that the application of fertilizer granules containing elemental sulfur (S0) as an ingredient (FBS0) in durum wheat crops produced a higher yield than that produced by conventional ones (F), provided that the soils of the experimental fields (F vs. FBS0) were of comparable quality and with the Olsen P content of the field's soil above 8 mg kg-1. In this experiment the FBS0 treatment took place in soil with Olsen P at 7.8 mg kg-1, compared with the F treatment's soil with Olsen P of 16.8 mg kg-1, aiming at reducing the imbalance in soil quality. To assess and evaluate the effect of FBS0 on the dynamics of the rhizospheric bacteria in relation to F, rhizospheric soil at various developmental stages of the crops was collected. The agronomic profile of the rhizospheric cultivable bacteria was characterized and monitored, in connection with the dynamics of phosphorus, iron, organic sulfur, and organic nitrogen, in both the rhizosoil and the aerial part of the plant during development. Both crops were characterized by a comparable dry mass accumulation per plant throughout development, while the yield of the FBS0 crop was 3.4% less compared to the F crop's one. The FBS0 crop's aerial part showed a transient higher P and Fe concentration, while its organic N and S concentrations followed the pattern of the F crop. The incorporation of S0 into the conventional fertilizer increased the percentage of arylsulfatase (ARS)-producing bacteria in the total bacterial population, suggesting an enhanced release of sulfate from the soil's organic S pool, which the plant could readily utilize. The proportion of identified ARS-producing bacteria possessing these traits exhibited a maximum value before and after topdressing. Phylogenetic analysis of the 68 isolated ARS-producing bacterial strains revealed that the majority of the isolates belonged to the Pseudomonas genus. A large fraction also possessed phosphate solubilization, and/or siderophore production, and/or ureolytic traits, thus improving the crop's P, Fe, S, and N balance. The aforementioned findings imply that the used FBS0 substantially improved the quality of the rhizosoil at the available phosphorus limiting level by modulating the abundance of the bacterial communities in the rhizosphere and effectively enhancing the microbially mediated nutrient mobilization towards improved plant nutritional dynamics.

To analyze if non-surgical treatment of periodontitis in a pregnant Caucasian women population can reduce adverse pregnancy outcomes.

When plants are exposed to sulfur limitation, they upregulate the sulfate assimilation pathway at the expense of growth-promoting measures. Upon cessation of the stress, however, protective measures are deactivated, and growth is restored. In accordance with these findings, transcripts of sulfur-deficiency marker genes are rapidly degraded when starved plants are resupplied with sulfur. Yet it remains unclear which enzymes are responsible for the degradation of transcripts during the recovery from starvation. In eukaryotes, mRNA decay is often initiated by the cleavage of poly(A) tails via deadenylases. As mutations in the poly(A) ribonuclease PARN have been linked to altered abiotic stress responses in Arabidopsis thaliana, we investigated the role of PARN in the recovery from sulfur starvation. Despite the presence of putative PARN-recruiting AU-rich elements in sulfur-responsive transcripts, sulfur-depleted PARN hypomorphic mutants were able to reset their transcriptome to pre-starvation conditions just as readily as wildtype plants. Currently, the subcellular localization of PARN is disputed, with studies reporting both nuclear and cytosolic localization. We detected PARN in cytoplasmic speckles and reconciled the diverging views in literature by identifying two PARN splice variants whose predicted localization is in agreement with those observations.

Cockles are highly appreciated mollusks and provide important services in coastal areas. The two European species, edible (Cerastodermaedule) and lagoon (Cerastodermaglaucum) cockles, are not easily distinguishable, especially when young. Interestingly, the species show different resistance to Marteilia cochillia, the parasite responsible for marteiliosis outbreaks, which is devastating cockle production in some areas. C.edule is severely affected by the parasite, while C. glaucum seems to be resistant, although underlying reasons are still unknown. Hybrids between both species might be interesting to introgress allelic variants responsible for tolerance, either naturally or through artificial selection, from lagoon into edible cockle. Here, we used 2b restriction site-associated DNA sequencing (2b-RAD) to identify single nucleotide polymorphisms (SNP) diagnostic for cockle discrimination (fixed for alternative allelic variants). Among the nine diagnostic SNPs selected, seven were validated using a SNaPshot assay in samples covering most of the distribution range of both species. The validated SNPs were used to check cockles that were suggested to be hybrids by a claimed diagnostic tool based on the internal transcribed spacers of the ribosomal RNA. Although these were shown to be false positives, we cannot rule out the fact that hybrids can occur and be viable. The SNP tool here developed will be valuable for their identification and management.

In clinical practice, patients' tissues are fixed and paraffin-embedded in order to enable histological diagnosis. Nowadays, those tissues are also used for molecular characterization. Formalin is the most used fixative worldwide, and Bouin's solution in some worldwide institutions. Among molecular targets, micro RNAs (miRNAs), the single-stranded non-coding RNAs comprised of 18 to 24 nucleotides, have been demonstrated to be resistant to fixation and paraffin-embedding processes, with consequent possible application in clinical practice. In the present study, let-7e-5p, miR-423-3p, miR-92a-1-5p, miR-30d-5p, miR-155-5p, miR-200a-3p, and miR-429 were investigated in formalin and matched Bouin's solution-fixed tissues of high grade serous ovarian cancers by means of real-time and droplet digital PCR (ddPCR). Micro RNAs were detectable and analyzable in both formalin- and Bouin's-fixed specimens, but on average, higher Ct values and lower copies/µL were found in Bouin's-fixed samples. Data from formalin-fixed samples correlated significantly for most targets with Bouin's ones, except for let-7e-5p and miR-155-5p. This study shows that miRNAs are analyzable in both formalin- and Bouin's-fixed specimens, with the possibility, after proper data normalization, to compare miRNA-based data from formalin-fixed samples to those of Bouin's-fixed ones.

No studies, to date, have examined the relationship between dietary fiber and recurrence or survival after head and neck cancer diagnosis. The aim of this study was to determine whether pretreatment intake of dietary fiber or whole grains predicted recurrence and survival outcomes in newly diagnosed head and neck cancer (HNC) patients. This was a prospective cohort study of 463 participants baring a new head and neck cancer diagnosis who were recruited into the study prior to the initiation of any cancer therapy. Baseline (pre-treatment) dietary and clinical data were measured upon entry into the study cohort. Clinical outcomes were ascertained at annual medical reviews. Cox proportional hazard models were fit to examine the relationships between dietary fiber and whole grain intakes with recurrence and survival. There were 112 recurrence events, 121 deaths, and 77 cancer-related deaths during the study period. Pretreatment dietary fiber intake was inversely associated with risk of all-cause mortality (hazard ratio (HR): 0.37, 95% confidence interval (CI): 0.14-0.95, ptrend = 0.04). No statistically significant associations between whole grains and prognostic outcomes were found. We conclude that higher dietary fiber intake, prior to the initiation of treatment, may prolong survival time, in those with a new HNC diagnosis.

Manganese (Mn) is an essential micronutrient with many functional roles in plant metabolism. Manganese acts as an activator and co-factor of hundreds of metalloenzymes in plants. Because of its ability to readily change oxidation state in biological systems, Mn plays and important role in a broad range of enzyme-catalyzed reactions, including redox reactions, phosphorylation, decarboxylation, and hydrolysis. Manganese(II) is the prevalent oxidation state of Mn in plants and exhibits fast ligand exchange kinetics, which means that Mn can often be substituted by other metal ions, such as Mg(II), which has similar ion characteristics and requirements to the ligand environment of the metal binding sites. Knowledge of the molecular mechanisms catalyzed by Mn and regulation of Mn insertion into the active site of Mn-dependent enzymes, in the presence of other metals, is gradually evolving. This review presents an overview of the chemistry and biochemistry of Mn in plants, including an updated list of known Mn-dependent enzymes, together with enzymes where Mn has been shown to exchange with other metal ions. Furthermore, the current knowledge of the structure and functional role of the three most well characterized Mn-containing metalloenzymes in plants; the oxygen evolving complex of photosystem II, Mn superoxide dismutase, and oxalate oxidase is summarized.

Pericoronary adipose tissue inflammation might lead to the development and destabilization of coronary plaques in prediabetic patients. Here, we evaluated inflammation and leptin to adiponectin ratio in pericoronary fat from patients subjected to coronary artery bypass grafting (CABG) for acute myocardial infarction (AMI). Furthermore, we compared the 12-month prognosis of prediabetic patients compared to normoglycemic patients (NG). Finally, the effect of metformin therapy on pericoronary fat inflammation and 12-months prognosis in AMI-prediabetic patients was also evaluated.

Human TRDMT1 is a transfer RNA (tRNA) methyltransferase for cytosine-5 methylation and has been suggested to be involved in the regulation of numerous developmental processes. However, little is known about the molecular mechanisms or their biological significance. In this study, we investigated the effects of CRISPR-based TRDMT1 knockdown on phenotypes, mRNA m5C modifications and gene expression changes in HEK293 cells. We found that knockdown of TRDMT1 significantly inhibited cell proliferation and migration but had no effect on clonogenic potential. The inhibitory effects could be attenuated by re-expression of TRDMT1 in HEK293 cells. RNA sequencing (RNA-Seq) and RNA bisulfite sequencing (RNA-BisSeq) were performed in TRDMT1 knockdown and wild-type HEK293 cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that the differentially expressed genes were associated with the cell cycle, RNA transport, and RNA degradation and were enriched in cancer and Notch signaling pathways. We also found that TRDMT1 knockdown could change mRNA methylation levels. For the first time, these findings clarify the role of TRDMT1 in regulating mRNA methylation and inhibiting the proliferation and migration of HEK293 cells. These results provide new insights into a new function of TRDMT1 and elucidate the molecular mechanisms of aberrant RNA m5C during tumorigenesis.

Renal function declines with aging and is pathologically characterized by chronic inflammation and fibrosis. Renal senescence is induced not only by aging but also by various stimuli, including ischemia reperfusion injury. Recently, the accumulation of p16INK4a-positive cells in the kidney has been considered a molecular feature of renal senescence, with the p16INK4a gene reportedly regulated by mixed-lineage leukemia 1 (MLL1)/WD-40 repeat protein 5 (WDR5)-mediated histone 3 lysine 4 trimethylation (H3K4me3). Here, we determined whether inhibition of MLL1/WDR5 activity attenuates renal senescence, inflammation, and fibrosis in mice with ischemia reperfusion injury and in cultured rat renal fibroblasts. MM-102 or OICR-9429, both MLL1/WDR5 protein-protein interaction inhibitors, and small interfering RNA (siRNA) for MLL1 or WDR5 suppressed the expression of p16INK4a in mice with ischemia reperfusion injury, accompanied by downregulation of H3K4me3 expression. MM-102 attenuated renal fibrosis and inflammation in the kidney of mice with ischemia reperfusion injury. Moreover, in vitro study showed that transforming growth factor-β1 induced the expression of MLL1, WDR5, H3K4me3, and p16INK4a. Finally, chromatin immunoprecipitation identified the p16INK4a promoter at an H3K4me3 site in renal fibroblasts. Thus, our findings show that H3K4me3 inhibition ameliorates ischemia reperfusion-induced renal senescence along with fibrosis and inflammation.

Seprehvir (HSV1716) is an oncolytic herpes simplex virus-1 (HSV-1) previously demonstrated to be well tolerated in pediatric patients when administered intratumorally. To determine the safety of administering Seprehvir systemically, we conducted the first-in-human phase I trial of intravenous injection in young patients with relapsed or refractory extra-cranial solid cancers. We delivered a single dose of 5 × 104 infectious units (iu)/kg (maximum dose of 2 × 106) or 2.5 × 105 iu/kg (maximum dose of 1 × 107 iu) of Seprehvir via the peripheral vein, monitored adverse events, and measured tumor responses by imaging. We monitored HSV-1 serology as well as viremia and shedding by PCR and culture. We administered a single dose of Seprehvir to seven patients and multiple doses to two patients. We did not observe any dose-limiting toxicities. All five HSV-1 seronegative patients seroconverted by day 28. Four of nine patients had detectable HSV-1 genomes in peripheral blood appearing on day +4 consistent with de novo virus replication. Two patients had stable disease in response to Seprehvir. Intravenous Seprehvir is well tolerated without viral shedding in children and young adults with late-stage cancer. Viremia consistent with virus replication holds promise for future Seprehvir studies at higher doses and/or in combination with other anti-neoplastic therapies.