Miracle-dz/UniFAR-FTUs huggingface dataset:
The Significance of Comparative Genomics in Modern Evolutionary Venomics

Venoms evolved convergently in diverse animal lineages as key adaptations that increase the evolu-tionary fitness of species which are manifold employed for defense, predation and competition. They constitute complex cocktails of various toxins that feature a broad range of bioactivities. The majority of described venom proteins belong to protein families that are known to comprise housekeeping genes or harbor protein-domains, which are present in genes with non-venom related functions. However, the evolutionary processes and mechanisms that foster the origin of these venom proteins and triggered their recruitment into the venom delivery system are still critically discussed. In most instances single or combined proteomic and transcriptomic approaches are applied to de-scribe venom compositions and the biological context of venoms. For neglected species these studies represent crucial contributions to improve our understanding of venom diversity on a broader scale. Nonetheless, the inference of the evolutionary origin of putative toxins in these studies could be mis-leading without appropriate coverage of gene populations from different tissue samples (gene com-pleteness) or complementary genome data. Providing a valid backbone to correctly map transcriptome and proteome data, whole genome sequences facilitate a clear distinction between variability of venom proteins or toxins due to posttranslational modifications, alternative splicing and false-positive matches that stem from sequencing or read processing and assembly errors. High-quality whole genome sequence data of venomous species are still sparse and unevenly distrib-uted within taxon lineages. However, to reveal the evolutionary pattern of putative toxins in venom-ous lineages and to identify ancestral variants of venom proteins, the appropriate sampling of ge-nomes from venomous and non-venomous species is crucial. Nevertheless, larger comparative studies based on multiple whole genome data sets are still sparse to uncover processes of venom evolution. Here, we review the general potential of comparative genomics in venomics to unravel mechanisms and patterns of evolutionary origin of toxin genes. Finally, we discuss the benefit of whole genome data to improve transcriptomics and proteomics-only studies, in particular if datasets are applied to assess the evolutionary origin of venom proteins.
Local Probiotic Lactobacillus crispatus and Lactobacillus delbrueckii Exhibit Strong Antifungal Effects Against Vulvovaginal Candidiasis in a Rat Model

A comprehensive knowledge of the vaginal ecosystem is critical for the development of successful approaches to the treatment of infections. The role of Lactobacilli in preventing vulvovaginal candidiasis (VVC) is controversial. In this study, we investigated the therapeutic effects and mechanism of Lactobacillus crispatus or delbrueckii on vaginitis caused by Candida albicans in a Sprague–Dawley rat model. A microbiological evaluation was performed by Gram staining and fungal colonies were enumerated. The antifungal efficacy of the two Lactobacillus strains was assessed by hematoxylin and eosin (HE) staining, transmission electron microscopy (TEM), immunohistochemical detection of interferon-γ (IFN-γ), interleukin (IL)-4, IL-17, and epithelial-derived IgG (RP125). Our in vitro results showed that the inhibitory activity against Candida colony-forming unit (CFU) counts was demonstrated by the two Lactobacillus strains (P < 0.001). Our results indicated that Lactobacillus administration played an indispensable role in maintaining the immune homeostasis, and decreasing the Th1/Th2 ratio (IFN-γ/IL-4) by regulating the epithelial secretion of cytokines that inhibit epithelial proinflammatory cytokine release, while increasing epithelial-derived IgG expression (P < 0.05), suggesting antibody-mediated protection. Our results implicate L. crispatus and L. delbrueckii as a potential adjunct biotherapeutic agent in women with VVC, especially for those with drug resistance, adverse effects or contraindications when using antifungal agents. Further large, long-term, well-planned clinical studies should be performed in clinical practice to determine their clinical potential of L. crispatus and L. delbrueckii as an adjunct treatment for VVC.
The Effects of Soy Protein and Cocoa With or Without Isoflavones on Glycemic Control in Type 2 Diabetes. A Double-Blind, Randomized, Placebo-Controlled Study

Objective: Soy and cocoa have been suggested to be beneficial for diabetes. The aim of this study was to identify the effects of soy protein, isoflavones, and cocoa on glycemic control parameters. Research design and methods: The study was a parallel, double-blind, placebo-controlled study where patients with diet or metformin controlled type 2 diabetes were randomized to, casein soy protein with or without isoflavones (SPI, SP), and with or without cocoa (SPIC, SPC) arms for an 8 week period. Glycemic control and cardiovascular risk factors were assessed prior to and after the completion of the dietary intervention. Sixty participants completed the study. Results: Soy protein improved HbA1c compared to casein (p < 0.05). The addition of isoflavones improved indices of insulin resistance and LDL [delta QUICKIE (SPI: −0.12 ± 0.04 vs. SP: 0.03 ± 0.06, p = 0.03); delta LDL (−0.27 ± 0.41 vs. 0.22 ± 0.43, p = 0.02); percentage change in HOMA (31.02 ± 54.75 vs. −14.42 ± 27.07, p = 0.02); percentage change in QUICKIE (−3.89 ± 7.07 vs. 6.11 ± 10.54, p = 0.01)]. However, the addition of cocoa provided no benefit with or without isoflavones. Summary: Soy protein had intrinsic activity on glycemic control compared to casein. Isoflavones improved both insulin resistance and LDL, but cocoa did not have added benefit on these indices. Clinical Trial Registration: www.ClinicalTrials. gov, identifier NCT01754662.
Berberine Influences Blood Glucose via Modulating the Gut Microbiome in Grass Carp

Berberine (BBR), an isoquinoline alkaloid, is a major pharmacological component of the Chinese herb Coptis chinensis, which has been listed in the Chinese Fisheries Pharmacopeia as a common drug for the control of bacterial fish diseases. However, BBR is poorly absorbed into the systemic circulation but is significantly accumulated in the intestine. It is difficult to explain the mechanism of clinical effects of BBR based on systemic genes and pathways; it has been proved that the function of BBR in mammals is associated with the host metabolic phenotypes mediated by the structural modulation of gut microbiota. The mechanism of pharmacological effects of BBR in fish remains unclear. Here, we fed grass carp (Ctenopharyngodon idellus) a diet supplemented with BBR at a dose of 30 mg/Kg body weight daily and compared them with grass carp fed a regular fish feed diet. Biochemical analysis revealed that fish fed BBR had significantly reduced serum glucose, total cholesterol (TC), and triglyceride (TG) levels, and increased TC (p < 0.05) and TG (p < 0.01) levels in the liver. Deep amplicon sequencing of the V4 region of 16S rRNA genes of the gut microbiota revealed: (i) the composition of gut microbiota after BBR feeding was more diverse than that in the control group; (ii)before fish were fed BBR, the enriched operational taxonomic units (OTUs) mainly belonged to Firmicutes while most enriched OTUs came from Proteobacteria, Planctomycetes, Bacteroidetes, and Firmicutes during BBR feeding and after BBR feeding stopped; (iii) the ratio of Firmicutes to Bacteroidetes was significantly decreased in fish fed BBR. Spearman’s rank correlation showed that 32 berberine-OTUs were significantly negative correlated with glucose (p < 0.05). It indicates that BBR may affect the levels of serum glucose by the structural modulation of gut microbiota. Our results provide insight into the effect of BBR on fish metabolism and gut microbiomes, which would be beneficial for the fish welfare.
Candida albicans Pma1p Contributes to Growth, pH Homeostasis, and Hyphal Formation

Candida albicans occupies diverse ecological niches within the host and must tolerate a wide range of environmental pH. The plasma membrane H+-ATPase Pma1p is the major regulator of cytosolic pH in fungi. Pma1p extrudes protons from the cytosol to maintain neutral-to-alkaline pH and is a potential drug target due to its essentiality and fungal specificity. We characterized mutants in which one allele of PMA1 has been deleted and the other truncated by 18–38 amino acids. Increasing C-terminal truncation caused corresponding decreases in plasma membrane ATPase-specific activity and cytosolic pH. Pma1p is regulated by glucose: glucose rapidly activates the ATPase, causing a sharp increase in cytosolic pH. Increasing Pma1p truncation severely impaired this glucose response. Pma1p truncation also altered cation responses, disrupted vacuolar morphology and pH, and reduced filamentation competence. Early studies of cytosolic pH and filamentation have described a rapid, transient alkalinization of the cytosol preceding germ tube formation; Pma1p has been proposed as a regulator of this process. We find Pma1p plays a role in the establishment of cell polarity, and distribution of Pma1p is non-homogenous in emerging hyphae. These findings suggest a role of PMA1 in cytosolic alkalinization and in the specialized form of polarized growth that is filamentation.
Supply, Demand, and In-Stream Retention of Dissolved Organic Carbon and Nitrate During Storms in Mediterranean Forested Headwater Streams

The capacity of headwater streams to transform and retain organic matter and nutrients during base flow conditions has been largely demonstrated in the literature. Yet, most solute export occurs during storms, and thus, it becomes essential to understand the role of in-stream processes on regulating solute concentrations and exports during storm flow conditions. In this study, we explored patterns of solute supply, solute demand, and resulting in-stream solute retention for a number of individual storms from two Mediterranean streams (intermittent and perennial) that together encompassed a wide range of hydrological conditions. Our results indicate that >70% of the individual storms were chemodynamic (i.e. solute concentrations either increased or decreased with increasing discharge) at the two sites and for both dissolved organic carbon (DOC) and nitrate (NO3-). At the perennial stream, DOC and NO3- concentrations did not show any clear pattern of storm response during both dry and wet periods, though deviations from chemostasis were generally larger for those events showing higher concentrations during storm flow. At the intermittent stream, DOC and NO3- showed positive divergences from chemostasis during the wet period. In this site, DOC showed no clear pattern of storm response during the dry period, while many storms showed low NO3- concentrations compared to chemostasis, suggesting either limited NO3- sources or in-stream retention. At the two streams, in-stream biogeochemical demand during individual storms was either similar or higher than during base flow conditions for both DOC and NO3-. In-stream NO3- demand resulted in substantial whole-reach retention during storms (up to 40%), indicating that in-stream biogeochemical processes substantially reduced downstream flux of terrestrial NO3- inputs during storm events. Conversely, whole-reach DOC retention was relatively low during storms (< 10%), suggesting little ability to regulate DOC export and an energy subsidy to downstream ecosystems during storms. This study indicates that in-stream biogeochemical demand during storms can counterbalance solute supply to some extent, and stresses the importance of considering the potential role of in-stream processes on shaping stream solute export during storms.
Prevention of adhesion formations following repair of abdominal wall defects with prosthetic materials (an experimental study).

BACKGROUND/AIMS Adhesion formation after abdominal surgery or incisional hernia repair with prosthetic materials may cause chronic pain, intestinal obstruction, enterocutaneous fistulae, difficulty in reoperative procedures and infertility in females. The aim of this study was to compare different modalities in terms of adhesion prevention in a rat model of abdominal wall defect repaired with prosthetic materials. METHODOLOGY Forty-eight female Wistar-Albino rats were divided into four groups. In all rats, laparotomy was performed through a 3-cm midline incision and an abdominal wall defect (2 x 3 cm) was created in rats in groups II, III and IV. Following procedures were performed in all rats: seroza of the cecum was abraded and sutured with 4-0 silk and two ischemic buttons were created by ligating with 4-0 silk on the left and right sides of abdominal parietal peritoneum. In Group I, abdominal closure was obtained with a running 4-0 prolene suture. In Group II, abdominal wall defect was repaired with polypropylene mesh. In Group III, Seprafilm, an absorbable adhesion barrier, was laid over the abdominal viscera and defect was repaired with polypropylene mesh. In Group IV, defect was repaired with Composix mesh. Adhesion density score, adhered organ and strength of mesh incorporation were evaluated. Biochemical analysis and histopathological examination were performed. RESULTS Groups II and III had more adhesion density scores than groups I and IV, (P < 0.001). Group II had more cecal and ischemic button adhesions than groups I, III and IV, (P < 0.001). Strength of mesh incorporation was higher in groups II and III than group IV, (P < 0.001). Abscess formation was more common in group IV than those in groups II and III, (P < 0.001). There were no differences between groups, regarding serum levels of C-reactive protein and fibrinogen. The most common adhered organ was omentum. CONCLUSIONS There is no single treatment modality to prevent adhesion formation after abdominal wall defect repaired with prosthetic materials. While intraperitoneal adhesions were less common in Seprafilm group, adhesions to mesh were less common in the Composix mesh group.
Inflation Expectations and Readiness to Spend: Cross-Sectional Evidence

There have recently been suggestions for monetary policy to engineer higher inflation expectations so as to stimulate current spending. But what is the empirical relationship between inflation expectations and spending? We use the underlying micro data from the Michigan Survey of Consumers to test whether increased inflation expectations are indeed associated with greater reported readiness to spend. Cross-sectional data deliver the necessary variation to test whether the relationship between inflation expectations and spending changes in the recent zero lower bound regime compared to normal times, as suggested by many standard models. We find that the impact of inflation expectations on the reported readiness to spend on durable goods is statistically insignificant and small in absolute value when compared to other variables, such as household income or expected business conditions. Moreover, it appears that higher expected price changes have an adverse impact on the reported readiness to spend. A one percent increase in expected inflation reduces the probability that households have a positive attitude towards spending by about 0.1 percentage points. At the zero lower bound this small adverse effect remains, and is, if anything, slightly stronger. We also extend our analysis to the reported readiness to spend on cars and houses and obtain similar results. Altogether our results tell a cautionary tale for monetary (or fiscal) policy designed to engineer inflation expectations in order to generate greater current spending.
Role of Neutrophil Extracellular Traps and Vesicles in Regulating Vascular Endothelial Permeability

The microvascular endothelium serves as the major barrier that controls the transport of blood constituents across the vessel wall. Barrier leakage occurs during infection or sterile inflammation, allowing plasma fluid and cells to extravasate and accumulate in surrounding tissues, an important pathology underlying a variety of infectious diseases and immune disorders. The leak process is triggered and regulated by bidirectional communications between circulating cells and vascular cells at the blood-vessel interface. While the molecular mechanisms underlying this complex process remain incompletely understood, emerging evidence supports the roles of neutrophil-endothelium interaction and neutrophil-derived products, including neutrophil extracellular traps and vesicles, in the pathogenesis of vascular barrier injury. In this review, we summarize the current knowledge on neutrophil-induced changes in endothelial barrier structures, with a detailed presentation of recently characterized molecular pathways involved in the production and effects of neutrophil extracellular traps and extracellular vesicles. Additionally, we discuss the therapeutic implications of altering neutrophil interactions with the endothelial barrier in treating inflammatory diseases.
Non-invasive Motor Cortex Neuromodulation Reduces Secondary Hyperalgesia and Enhances Activation of the Descending Pain Modulatory Network

Central sensitization is a driving mechanism in many chronic pain patients, and manifests as hyperalgesia and allodynia beyond any apparent injury. Recent studies have demonstrated analgesic effects of motor cortex (M1) stimulation in several chronic pain disorders, yet its neural mechanisms remain uncertain. We evaluated whether anodal M1 transcranial direct current stimulation (tDCS) would mitigate central sensitization as measured by indices of secondary hyperalgesia. We used a capsaicin-heat pain model to elicit secondary mechanical hyperalgesia in 27 healthy subjects. In an assessor and subject-blind randomized, sham-controlled, crossover trial, anodal M1 tDCS decreased the intensity of pinprick hyperalgesia more than cathodal or sham tDCS. To elucidate the mechanism driving analgesia, subjects underwent fMRI of painful mechanical stimuli prior to and following induction of the pain model, after receiving M1 tDCS. We hypothesized that anodal M1 tDCS would enhance engagement of a descending pain modulatory (DPM) network in response to mechanical stimuli. Anodal tDCS normalized the effects of central sensitization on neurophysiological responses to mechanical pain in the medial prefrontal cortex, pregenual anterior cingulate cortex, and periaqueductal gray, important regions in the DPM network. Taken together, these results provide support for the hypothesis that anodal M1-tDCS reduces central sensitization-induced hyperalgesia through the DPM network in humans.
Influence of Whole-Body Electrostimulation on the Deformability of Density-Separated Red Blood Cells in Soccer Players

Red blood cell nitric oxide synthase (RBC-NOS) dependent NO production positively affects RBC deformability which is known to improve oxygen supply to the working tissue. Whole-body electrostimulation (WB-EMS) has been shown to improve maximum strength, sprinting and jumping performance, and to increase deformability in elite soccer players during the season. The aim of the present study was to investigate whether WB-EMS affects RBC turnover which might affect overall deformability of circulating RBC by rejuvenation of the RBC population and if this might be related to improved endurance capacity. Thirty male field soccer players were assigned in either a WB-EMS group (EG, n = 10), a training group (TG, n = 10), or a control group (CG, n = 10). EG performed 3 × 10 squat jumps superimposed with WB-EMS twice per week in concurrent to 2–4 soccer training sessions and one match per week. TG only performed 3 × 10 squat jumps without EMS in addition to their soccer routine and the CG only performed the usual soccer training and match per week. Subjects were tested before (Baseline) and in week 7 (wk-7), with blood sampling before (Pre), 15–30 min after (Post), and 24 h after (24 h post) the training. Endurance capacity was determined before and directly after the training period. The key findings of the investigation indicate an increase in young RBC in the EG group along with improved overall RBC deformability, represented by decreased SS1/2:EImax Ratio. Analysis of the different RBC subfractions revealed improved RBC deformability of old RBC during study period. This improvement was not only observed in the EG but also in TG and CG. Changes in RBC deformability were not associated to altered RBC-NOS/NO signaling pathway. Endurance capacity remained unchanged during study period. In summary, the effect of WB-EMS on RBC physiology seems to be rather low and results are only in part comparable to previous findings. According to the lower training volume of the present study it can be speculated that the soccer specific training load in addition to the WB-EMS was too low to induce changes in RBC physiology.
ccf-mtDNA as a Potential Link Between the Brain and Immune System in Neuro-Immunological Disorders

Fragments of mitochondrial DNA (mtDNA) are released outside the cell and they appear to persist in extracellular fluids as circulating, cell-free, mtDNA (ccf-mtDNA). When compared to nuclear DNA, such a double stranded mtDNA is more resistant to nuclease degradation. In fact, it is stable extracellularly where it can be detected in both plasma and cerebrospinal fluid (CSF), here acting as a potential biomarker in various disorders. In neurological diseases (Alzheimer's disease, Parkinson's disease and end-stage progressive Multiple Sclerosis), a decreased amount of CSF ccf-mtDNA is related with progressive cell dysfunction. This suggests an alteration in neuronal mtDNA levels (mtDNA replication, degradation and depletion) in vulnerable brain regions at early stages of neurodegeneration leading to reduced mtDNA release, which takes place before actual cell death occurs. On the other hand, elevated CSF ccf-mtDNA levels are reported in acute phases of relapsing-remitting Multiple Sclerosis (RRMS). This occurs during acute inflammation, which anticipates the neurodegenerative process. Thus, an increase in inflammatory cells in the affected regions is expected to add on mtDNA release into the CSF. In addition, similarly to bacterial DNA, the non-methylated CpG sites of mtDNA, which activate innate immunity and inflammation, are likely to participate in the molecular mechanisms of disease. Thus, ccf-mtDNA may represent a powerful biomarker for disease screening and prognosis at early stage, although its biological role may extend to generating the neurobiology of disease. The present manuscript discusses recent experimental findings in relationship with clinical evidence comparing neuro-immunological features of neurodegenerative disorders with frankly neuro-infectious diseases.