Human Microbiome and Its Medical Applications

The commensal microbiome is essential for human health and is involved in many processes in the human body, such as the metabolism process and immune system activation. Emerging evidence implies that specific changes in the microbiome participate in the development of various diseases, including diabetes, liver diseases, tumors, and pathogen infections. Thus, intervention on the microbiome is becoming a novel and effective method to treat such diseases. Synthetic biology empowers researchers to create strains with unique and complex functions, making the use of engineered microbes for clinical applications attainable. The aim of this review is to summarize recent advances about the roles of the microbiome in certain diseases and the underlying mechanisms, as well as the use of engineered microbes in the prevention, detection, and treatment of various diseases.

High-Risk NAFLD among Patients with Irritable Bowel Syndrome: Frequency and Effect on Disease Severity

Background Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disease that can change a patient's quality of life and impair their daily activities. Non-alcoholic fatty liver disease (NAFLD), on the other hand, has become a widespread condition as the global obesity rates rises. The prevalence of NAFLD has reached up to 25% of the adolescent population. The etiology of both diseases is still not clearly understood. The mechanism linking the two seemingly similar diseases could be immune system activation and tissue inflammation; thus, the goal of our study was to see if there was a common link between them and to examine NAFLD prevalence and severity in IBS patients. Our study included 150 patients who have symptoms of IBS with different degrees of severity. IBS was diagnosed according to modified ROME IV criteria. Patients were examined to see if they had NAFLD based on abdominal ultrasonography and NAFLD fibrosis score calculation. Results Our current study showed that regarding evaluating the association of IBS with NAFLD, there was a highly statistically significant association between both diseases. Furthermore, there was a high statistical significant association between higher grades of NAFLD and lipid profile parameters. Conclusion Patients with IBS had a higher frequency of NAFLD. In addition, a significant association was noted between IBS severity and increased NAFLD grades.

Comparative Transcriptome Analysis of Gayal (Bos frontalis), Yak (Bos grunniens), and Cattle (Bos taurus) Reveal the High-Altitude Adaptation

Gayal and yak are well adapted to the local high-altitude environments, yet the transcriptional regulation difference of the plateau environment among them remains obscure. Herein, cross-tissue and cross-species comparative transcriptome analysis were performed for the six hypoxia-sensitive tissues from gayal, yak, and cattle. Gene expression profiles for all single-copy orthologous genes showed tissue-specific expression patterns. By differential expression analysis, we identified 3020 and 1995 differentially expressed genes (DEGs) in at least one tissue of gayal vs. cattle and yak vs. cattle, respectively. Notably, we found that the adaptability of the gayal to the alpine canyon environment is highly similar to the yak living in the Qinghai-Tibet Plateau, such as promoting red blood cell development, angiogenesis, reducing blood coagulation, immune system activation, and energy metabolism shifts from fatty acid β-oxidation to glycolysis. By further analyzing the common and unique DEGs in the six tissues, we also found that numerous expression regulatory genes related to these functions are unique in the gayal and yak, which may play important roles in adapting to the corresponding high-altitude environment. Combined with WGCNA analysis, we found UQCRC1, COX5A are the shared differentially expression hub genes related to the energy supply of myocardial contraction in the heart-related modules of gayal and yak, and CAPS is a shared differentially hub gene among the hub genes of the lung-related module, which is related to pulmonary artery smooth muscle contraction. Additionally, EDN3 is the unique differentially expression hub gene related to the tracheal epithelium and pulmonary vasoconstriction in the lung of gayal. CHRM2 is a unique differentially expression hub gene that was identified in the heart of yak, which has an important role in the autonomous regulation of the heart. These results provide a basis for further understanding the complex transcriptome expression pattern and the regulatory mechanism of high-altitude domestication of gayal and yak.

Plant immunity inducers: from discovery to agricultural application

While conventional chemical fungicides directly eliminate pathogens, plant immunity inducers activate or prime plant immunity. In recent years, considerable progress has been made in understanding the mechanisms of immune regulation in plants. The development and application of plant immunity inducers based on the principles of plant immunity represent a new field in plant protection research. In this review, we describe the mechanisms of plant immunity inducers in terms of plant immune system activation, summarize the various classes of reported plant immunity inducers (proteins, oligosaccharides, chemicals, and lipids), and review methods for the identification or synthesis of plant immunity inducers. The current situation, new strategies, and future prospects in the development and application of plant immunity inducers are also discussed.

Novel Probable Glance at Inflammatory Scenario Development in Autistic Pathology

Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social communication and restricted-repetitive patterns of behavior, interests, or activities. ASD is generally associated with chronic inflammatory states, which are linked to immune system dysfunction and/or hyperactivation. The latter might be considered as one of the factors damaging neuronal cells. Several cell types trigger and sustain such neuroinflammation. In this study, we traced different markers of immune system activation on both cellular (immune cell phenotypes) and mediatory levels (production of cytokines) alongside adverse hematology and biochemistry screening in a group of autistic children. In addition, we analyzed the main metabolic pathways potentially involved in ASD development: energy (citric acid cycle components), porphyrin, and neurotransmitter metabolism. Several ASD etiological factors, like heavy metal intoxication, and risk factors—genetic polymorphisms of the relevant neurotransmitters and vitamin D receptors—were also analyzed. Finally, broad linear regression analysis allowed us to elucidate the possible scenario that led to the development of chronic inflammation in ASD patients. Obtained data showed elevated levels of urinary cis-aconitate, isocitrate, alfa-ketoglutarate, and HMG. There were no changes in levels of metabolites of monoamine neurotransmitters, however, the liver-specific tryptophan kinurenine pathway metabolites showed increased levels of quinolinate (QUIN) and picolinate, whereas the level of kynurenate remained unchanged. Abovementioned data demonstrate the infringement in energy metabolism. We found elevated levels of lead in red blood cells, as well as altered porphyrin metabolism, which support the etiological role of heavy metal intoxication in ASD. Lead intoxication, the effect of which is intensified by a mutation of the VDR-Taq and MAO-A, leads to quinolinic acid increase, resulting in energy metabolism depletion and mitochondrial dysfunction. Moreover, our data backing the CD4+CD3+ T-cell dependence of mitochondrial dysfunction development in ASD patients reported in our previous study leads us to the conclusion that redox-immune cross-talk is considered a main functional cell damaging factor in ASD patients.

Bacterial Outer Membrane Vesicles Induce a Transcriptional Shift in Arabidopsis Towards Immune System Activation Leading to Suppression of Pathogen Growth in Planta

Gram negative bacteria form spherical blebs on their cell periphery, which later dissociate and released into the surrounding environment. Previous studies have shown that these nano scale structures, derived primarily from the bacterial outer membrane and are termed outer membrane vesicles (OMVs), induce typical immune outputs in both mammals and plants. On the other hand, these same structures have been shown to promote infection and disease. To better understand the broad transcriptional change plants undergo following exposure to OMVs, we treated Arabidopsis thaliana (Arabidopsis) seedlings with OMVs purified from the Gram-negative plant pathogenic bacterium Xanthomonas campestris pv. campestris and performed RNA-seq analysis on OMV- and mock-treated samples at 2, 6 and 24 h post challenge. We found that the most pronounced transcriptional shift occurred in the first two time points, as was reflected by both the number of differentially expressed genes (DEGs) and the average fold change. Gene ontology enrichment analysis revealed that OMVs induce a major transcriptional shift in Arabidopsis towards immune system activation, upregulating a multitude of immune-related pathways including a variety of immune receptors and transcriptional factors. Comparing Arabidopsis response to OMVs and to single purified elicitors, revealed that while OMVs induce a similar suite of genes and pathways as single elicitors, some differential pathways activated by OMVs were detected including response to drug and apoptosis, which may indicate exposure to toxic compounds via OMV. To examine whether the observed transcriptional shift in Arabidopsis leads to an effective immune response, plants were pretreated with OMVs and then inoculated with a bacterial pathogen. OMV-mediated priming led to a significant reduction in bacterial titer in inoculated leaves two days following inoculation. Mutations in the elongation factor receptor (EFR), flagellin receptor (FLS2), or the brassinosteroid-insensitive 1-associated kinase (BAK1) receptor, did not significantly affect OMV-priming. All together these results show that OMV induce a broad transcriptional shift in Arabidopsis leading to upregulation of multiple immune pathways, and that this transcriptional change is reflected in the ability to better resist bacterial infection.

High Dose Vardenafil Blunts the Hypertensive Effects of Toll-Like Receptor 3 Activation During Pregnancy

The maternal innate immune system plays a central role in preeclampsia (PE). Toll-like receptors (TLRs) are innate immune system receptors that recognize characteristics of extracellular endogenous ligands or pathogens, and their activation leads to a pro-inflammatory immune response. We and others have reported that excessive activation of TLRs causes pregnancy-dependent hypertension in animals and is associated with PE in women. Activation of TLR3 by poly I:C mimics the innate immune system activation by viruses that women who develop PE encounter during pregnancy. Vardenafil was approved by the FDA for erectile dysfunction but has recently been examined as a potential PE medication due to studies done with a similar drug, sildenafil. Preclinical as well as recent clinical studies demonstrate the potential effectiveness of sildenafil for PE. However, vardenafil is more potent than sildenafil and acts by increasing expression of placental growth factor in addition to increasing cGMP levels. We hypothesized that vardenafil will be more potent and effective in reducing the negative health effects in a mouse model of virus-induced PE. Pregnant mice were injected with the TLR3 agonist poly I:C (PPIC) on gestational days 13, 15, and 17. We treated PPIC mice with a high dose of vardenafil (50 mg human equivalent), a lower dose of vardenafil (20 mg human equivalent), or sildenafil (50 mg human equivalent) on gestational days 15–17 after hypertension was established. Daily i.p. injections of either high dose or low dose vardenafil significantly decreased systolic blood pressure in PPIC mice whereas sildenafil had no effect. There were no differences in body weight between the groups. The splenomegaly induced in PPIC mice was ameliorated in high dose vardenafil-treated PPIC mice, while low dose vardenafil-treated and sildenafil-treated PPIC mice still exhibited splenomegaly. High dose vardenafil-treated PPIC mice also did not exhibit any fetal demise characteristic of PPIC mice, while low dose vardenafil-treated and sildenafil-treated PPIC mice still had significantly increased incidences of fetal demise. These data support the notion that high dose vardenafil may be safe and effective at reducing blood pressure during a virus-associated hypertensive pregnancy.

Brains in Metamorphosis: Temporal Transcriptome Dynamics in Hatchery-Reared Flatfishes

Metamorphosis is a captivating process of change during which the morphology of the larva is completely reshaped to face the new challenges of adult life. In the case of fish, this process initiated in the brain has traditionally been considered to be a critical rearing point and despite the pioneering molecular work carried out in other flatfishes, the underlying molecular basis is still relatively poorly characterized. Turbot brain transcriptome of three developmental stages (pre-metamorphic, climax of metamorphosis and post-metamorphic) were analyzed to study the gene expression dynamics throughout the metamorphic process. A total of 1570 genes were differentially expressed in the three developmental stages and we found a specific pattern of gene expression at each stage. Unexpectedly, at the climax stage of metamorphosis, we found highly expressed genes related to the immune response, while the biological pathway enrichment analysis in pre-metamorphic and post-metamorphic were related to cell differentiation and oxygen carrier activity, respectively. In addition, our results confirm the importance of thyroid stimulating hormone, increasing its expression during metamorphosis. Based on our findings, we assume that immune system activation during the climax of metamorphosis stage could be related to processes of larval tissue inflammation, resorption and replacement, as occurs in other vertebrates.

740 A case of acute Campylobacter COLI myocarditis post-mRNA anti-SARS-CoV-2 vaccine. Was vaccination an innocent bystander or a determining factor?

A 24-year-old healthy man, smoker (2 pack-years), was admitted to the Cardiology Unit for chest pain and fever occurred 2 days after anti-SARS-CoV-2 vaccination. There were no pathological findings at physical examination. The electrocardiogram showed diffuse ST elevation. Laboratory tests showed a significant increment of Troponin I levels (4697 ng/l → 6236 ng/l after 3 h), White Blood Cells (17 610/mmc) and C-Reactive Protein (8.36 mg/dl). Echocardiography showed normal left ventricular systolic function with no evidence of pericarditis. These findings were consistent with a probable case of acute myocarditis. Cardiac magnetic imaging demonstrated myocardial oedema of the posterior wall of the left ventricle at T2-weighted images, with patchy areas of subepicardial late gadolinium enhancement. Based on Centers for Disease Control and Prevention myocarditis diagnostic criteria, a diagnosis of acute myocarditis was made and treatment with Non-Steroidal Anti-Inflammatory Drugs was started. Regarding etiology agent determination, in the COVID19 era, the first suspect was anti-SARS-CoV-2 mRNA-vaccine-induced myocarditis. Several case series and analyses of a large national health care organization database helped to identify features linked to these types of myocarditis. The highest incidence was observed among male juvenile subjects, usually 48–72 h after the second dose of vaccination, with elevated levels of spike antibody for SARS-CoV-2. Nevertheless, in the presented clinical case, the patient had received the first dose of BNT162b2 vaccination two days before hospital admission and showed negative serology tests for SARS-CoV-2. In recent medical history, two days before the onset of fever and chest pain, the patient had episodes of diarrhea which persisted during the first week of hospitalization. All immunological and microbiological tests result negative, except for a stool culture positive for Campylobacter coli. Interestingly a revision of literature showed several cases of myocarditis linked to Campylobacter species. In particular, of 13 reported cases, 12 (92%) were male with a mean age of 26 ± 8.8 years, and cardiac symptoms present generally 2–4 days after diarrhea. In this particular setting, the first and more obvious hypothesis was strongly questioned because of an unexpected finding in the stool culture. In fact, Campylobacter spp. related myocarditis is an extremely rare condition, even if this pathogen is associated with important immunological interferences, as shown by its relationship with the Guillain-Barre syndrome. Further, myocarditis related to mRNA anti-SARS-CoV-2 vaccine is considered a rare complication. We hypothesized that the association of the two components could have acted synergistically to produce an immune system activation against cardiac muscle. Additional investigations are required to clarify the link between vaccination and possible improper immune response. In conclusion, this case represents a typical example in which the cause of the disease should be well investigated because the initial etiological theory is not definitive, especially in the SARS-CoV-2 era.

A single dose of Ultraviolet-A induces proteome remodeling and senescence in primary human keratinocytes

Epidermal photoaging contributes to skin fragility over time and it is a risk factor for skin cancer. Photoaging has been associated for a long time with exposure to Ultraviolet-A (UVA) light, the predominant component of the solar ultraviolet radiation. While the cellular mechanisms underlying UVA-induced photoaging in the dermis have been well characterized, UVA’s action on the epidermis remains elusive. Here, proteomic analysis was conducted to derive the cellular responses induced by an environmentally relevant dose of UVA in primary human keratinocytes. We also investigated the effects of UVA on non-transformed immortalized keratinocytes (HaCaT cells), bearing potentially oncogenic mutations. We showed that UVA induces proteome remodeling and senescence in primary keratinocytes, eliciting potent antioxidant and pro-inflammatory responses. Additionally, we showed that UVA modulates the secretory phenotype of these cells to the extent of inducing paracrine oxidative stress and immune system activation in pre-malignant keratinocytes. These observations offer insights into the cellular mechanisms by which UVA drives photoaging in the skin.