Neurotrophic factors includes nerve growth factors (NGF) family, glial cell line-derived neurotrophic factors (GDNF) family and other neurotrophic factors. NGF, BDNF, NT-3, NT-4/5 and NT-6 constitute NGF family (the neurotrophins), which may enhance both survival and differentiation of neurons from the EGF-responsive hippocampal and the subventricular zone neural stem cells. GDNF family includes GDNF, NTN, PSP and ART, whose major role is in peripheral neurodevelopment. This family enhance proliferation and survival of enteric neural crest precursor cells and is critical for the development of peripheral sensory nerve. Other growth factors such as bFGF and EGF can enhance proliferation and survival of neural stem cell. CNTF and LIF are critical for differentiation of neural stem cells.

BACKGROUND

Emergency surgical patients account for around half of all NHS surgical workload and 80 % of surgical deaths. Few trainees opt to CCT in General Surgery, and there is no recognised subspecialty training program in Emergency General Surgery (EGS). Despite this lack of training and relevant assessment by examination, there appears to be an increasing number of EGS posts advertised. This study aims to provide information about potential future employment opportunities for surgical trainees.

METHODS

All consultant surgeon posts, advertised in the British Medical Journal between January 2009 and December 2014 were included. Data collected included specialty, region and institute of advertised post. For the purposes of statistical analysis, data was divided into two separate year bands: 2009-2011 and 2012-2014. Statistical analysis was by Chi-squared test; p <0.01 was considered statistically significant. An online tool was also used to determine experience and attitudes towards EGS amongst Consultant members of the ASGBI and all UK trainees in national training number (NTN) posts.

RESULTS

Over the six-year study period, there were 1240 consultant job adverts in a general surgical specialty. Nine hundred and 75 were substantive posts; the region with the most jobs was London and the South East (n = 278). There were 55 jobs advertised in EGS, either with (20) or without (35) another subspecialty. The number of EGS adverts increased significantly in 2012-14 compared to 2009-11 (p = 0.008). 229 (28 %) Consultants and 309 (22 %) trainees responded to the survey. 16 % of consultants work in NHS institutions with Emergency General Surgeons. Only 21 % of trainees believe EGS will be delivered by EGS consultants in the future whilst 8.2 % of trainees stated EGS as their career plan. Less than half of all UK consultant surgeons see EGS as a subspecialty.

CONCLUSIONS

This data demonstrates increasing societal need for EGS consultants over the last six years and the emergence of Emergency Surgery as a new subspecialty. In order to meet the EGS needs of the NHS, general surgical training and the examination system need to be revised.

Potato virus Y (PVY) is the most important virus infecting potato (Solanum tuberosum), causing potato tuber necrotic ringspot disease (PTNRD), with a great impact on seed potato production. Numerous PVY strain groups with different pathogenicity and economical impact are distributed worldwide. Tools for accurate and reliable detection and discrimination of PVY strain groups are therefore essential for successful disease management. Two state of the art characterization tools based on detecting molecular markers - RT-qPCR (Kogovsek et al., 2008) and SNaPshot (Rolland et al., 2008) - were assessed for their ability to assign PVY accurately to the correct group. The results were validated by bioassay, ELISA and in silico sequence analysis. The spectrum of PVY strain groups distinguished by SNaPshot is broader than that by RT-qPCR. However, the latter was more reliable in discriminating the PVY(NTN) group members, known for their ability to induce PTNRD on selected potato cultivars. The difference in discrimination precision was due to different molecular markers being targeted by RT-qPCR and SNaPshot. Both tools use genotypic markers for detecting PVY(NTN) strain groups. Future development, however, should be focused on identifying the genomic determinants of the tuber necrosis property. Until then, the RT-qPCR and SNaPshot methods remain the most powerful diagnostic tools for detecting the PVY subgroup isolates found in Europe.

The potato tuber ringspot necrosis isolate of potato virus Y (PVY(NTN)) is a recently recognized and highly aggressive isolate of the PVY(N) group of strains. In order to screen specifically sources of resistance to PVY(NTN) a method to separate PVY(NTN) from PVY(N) is needed. To achieve this, 61 isolates from 13 imported and locally developed potato cultivars in Slovenia were studied. On the basis of the reactions in indicator plants Nicotiana tabacum cv. Samsun and Solanum brachycarpum and with a PVY(N) specific monoclonal antibody (4E7), all Slovenian isolates (Sl-NTN) were identified as PVY(N). Using two primer pairs from the P1 gene of a Hungarian isolate of PVY(NTN) by a conventional single primer pair, reverse transcription polymerase chain reaction (RT-PCR) both PVY(NTN) and PVY(N) were amplified similarly. However, specific amplification of PVY(NTN) was achieved by a nested-PCR at an annealing temperature of 63 degrees C. A simplified form of the nested-PCR, termed 3-primer PCR was developed, which is applicable for large-scale testing of samples. Using the 3-primer PCR at annealing temperature of 63 degrees C, known mixtures of PVY(NTN) and PVY(N) were correctly separated. PVY(NTN) was detected in dormant tubers and leaves from all Sl-NTN isolates. The 3-primer PCR was specific to PVY(NTN) and did not react with nine isolates of PVY(N), 13 isolates of PVY(o), one isolate of PVY(C), six commonly occurring potato viruses and a viroid.

The process of glomerular injury in nephrotoxic serum nephritis (NTN) is dependent on proinflammatory cytokines. In the present investigation, we assessed the actions of neutralizing antibody against IL-1 beta, TNF-alpha, IL-6 and TGF-beta 1 on glomerular injury. Marked increase in IL-1 beta and IL-6 was detected in cultured glomeruli of NTN in mice throughout the experiments from disease induction. Protein of TNF-alpha and TGF-beta 1 also increased in NTN mice 1 day after disease induction. Treatment with either IL-1 beta or TNF-alpha neutralizing antibody reduced proteinuria from 71 +/- 11.2 m g/24 hr to 32.2 +/- 6.0 (P < 0.01). 34.3 +/- 6.8 mg/24 hr (P < 0.01), respectively. Although the effect of IL-6 neutralizing antibody on proteinuria was not remarkable, the decreased creatinine clearance was improved more than that of IL-1 beta or TNF-alpha. Antibody against TGF-beta 1 had no effect on proteinuria and creatinine clearance. Treatments with IL-1 beta, TNF-alpha and IL-6 neutralizing antibodies inhibited glomerular hypercellularity in NTN mice. TGF-beta 1 neutralizing antibody suppressed the index of mesangial matrix expansion. IL-1 beta and TNF-alpha neutralizing antibodies prevented the increase in the number of macrophages in the glomeruli. The number of PCNA positive cells and alpha-smooth muscle actin expression in glomeruli was significantly reduced in the IL-6 neutralizing antibody-treated group. These results confirm the direct involvement of IL-1 beta, TNF-alpha and IL-6 in mouse NTN. We speculate that TGF-beta 1 may inhibit excessive proliferation in glomerular cells.

This study assesses the impact of the lightning nitric oxide (LNO) production schemes in the Community Multiscale Air Quality (CMAQ) model on ground-level air quality as well as aloft atmospheric chemistry through detailed evaluation of model predictions of nitrogen oxides (NO _x ) and ozone (O₃) with corresponding observations for the US. For ground-level evaluations, hourly O₃ and NO _x values from the U.S. EPA Air Quality System (AQS) monitoring network are used to assess the impact of different LNO schemes on model prediction of these species in time and space. Vertical evaluations are performed using ozonesonde and P-3B aircraft measurements during the Deriving Information on Surface Conditions from Column and Vertically Resolved Observations Relevant to Air Quality (DISCOVER-AQ) campaign conducted in the Baltimore- Washington region during July 2011. The impact on wet deposition of nitrate is assessed using measurements from the National Atmospheric Deposition Program's National Trends Network (NADP NTN). Compared with the Base model (without LNO), the impact of LNO on surface O₃ varies from region to region depending on the Base model conditions. Overall statistics suggest that for regions where surface O₃ mixing ratios are already overestimated, the incorporation of additional NO from lightning generally increased model overestimation of mean daily maximum 8 h (DM8HR) O₃ by 1-2 ppb. In regions where surface O₃ is underestimated by the Base model, LNO can significantly reduce the underestimation and bring model predictions close to observations. Analysis of vertical profiles reveals that LNO can significantly improve the vertical structure of modeled O₃ distributions by reducing underestimation aloft and to a lesser degree decreasing overestimation near the surface. Since the Base model underestimates the wet deposition of nitrate in most regions across the modeling domain with the exception of the Pacific Coast, the inclusion of LNO leads to reduction in biases and errors and an increase in correlation coefficients at almost all the NADP NTN sites. Among the three LNO schemes described in Kang et al. (2019), the hNLDN scheme, which is implemented using hourly observed lightning flash data from National Lightning Detection Network (NLDN), performs best for comparisons with ground-level values, vertical profiles, and wet deposition of nitrate; the mNLDN scheme (the monthly NLDN-based scheme) performed slightly better. However, when observed lightning flash data are not available, the linear regression-based parameterization scheme, pNLDN, provides an improved estimate for nitrate wet deposition compared to the base simulation that does not include LNO.

Noradrenergic neurons of the locus coeruleus (LC) express the receptor tyrosine kinase c-ret, which binds ligands of the glial cell line-derived neurotrophic factor (GDNF) family. In the present study, we evaluated the function of neurturin (NTN), a GDNF family ligand whose function on LC neurons is unknown. Interestingly, we found that tyrosine hydroxylase (TH)-positive neurons in the LC express both GFRalpha1 and 2 receptors in a developmentally regulated fashion, suggesting a function for their preferred ligands: GDNF and NTN, respectively. Moreover, our results show that NTN mRNA expression is developmentally down-regulated in the LC and peaks in the postnatal hippocampus and cerebral cortex, during the target innervation period. In order to examine the function of NTN, we next performed LC primary cultures, and found that neither GDNF nor NTN promoted the survival of TH-positive neurons. However, both factors efficiently induced neurite outgrowth in noradrenergic neurons (147% and 149% over controls, respectively). Similarly, grafting of fibroblast cell lines engineered to express high levels of NTN did not prevent the loss of LC noradrenergic neurons in a 6-hydroxydopamine (6-OHDA) lesion model, but induced the sprouting of TH-positive cells. Thus our findings show that NTN does not promote the survival of LC noradrenergic neurons, but induces neurite outgrowth in developing noradrenergic neurons in vitro and in a model of neurodegeneration in vivo. These data, combined with data in the literature, suggest that GDNF family ligands are able to independently regulate neuronal survival and/or neuritogenesis.

Role of reactive oxygen species (ROS) was studied in accelerated nephrotoxic nephritis (NTN) in rats. In this experimental model, histological examination, and luminol amplified chemiluminescence (CL) assay of peripheral polymorphonuclear neutrophils (PMN), peritoneal macrophages (M phi), and isolated glomeruli were performed time-sequentially. Effect of ROS scavengers were also examined in this experiment. Daily dosages of bovine liver catalase and SOD were 550,000 and 1,000 units respectively. After nephrotoxic IgG injection, CL of glomeruli increased strikingly attaining peak at day 1, and remained high until the end of the experiment. This increase of CL may have reflected the release of ROS by glomerular cells and/or infiltrating cells stimulated in situ. In fact, peripheral PMN and peritoneal M phi showed no increase of CL after nephrotoxic IgG injection. Glomerular cells increased as early as 3 hours after induction of nephritis. Accumulation of PMN was noted for the first three days, whereas that of M phi became prominent after 4 days. Favourable effect was obtained in terms of proteinuria by administration of catalase, only when catalase was given at initial 3 days of nephritis. The data suggest that generation of ROS reflected by increase of CL in glomeruli of NTN rats is attributable to the PMN and M phi infiltrated in glomeruli as well as glomerular resident cells per se. It is also suggested that glomerular PMN increasing in the early phase of NTN plays a considerable role in glomerular injury.

The effect of the antiplatelet agents, ticlopidine and dipyridamole, on nephrotoxic serum nephritis (NTN) was evaluated in rats. An accelerated form of NTN was induced with preimmunization of rabbit IgG 7 days before injection of rabbit antirat nephrotoxic serum. Twelve animals received a peroral dose of 20 mg of ticlopidine daily, and 12 animals received a peroral dose of 10 mg of dipyridamole twice daily for 7 days. It was shown that both ticlopidine and dipyridamole were able to significantly reduce urinary protein excretion. There was, however, no significant difference in glomerular changes between treated animals and nontreated controls. Ticlopidine and dipyridamole were found to suppress the development of proteinuria in accelerated NTN. Although the antiaggregative action of dipyridamole was relatively weak in vivo, dipyridamole was found to be rather effective on protein excretion in the present study. These results support the significant role of platelets in the development of proteinuria in glomerulonephritis, and it is suggested that dipyridamole may have an antiproteinuric effect other than inhibition of platelet aggregation.

Anabolic Androgenic Steroids (AASs) misuse has increased among adolescents and recreational athletes due to their potential effects on muscle hypertrophy. On the other hand, AAS might induce alterations on cardiovascular system, although some controversies regarding AAS on vascular properties remain unknown. To address this question, we aimed to investigate the effects of high doses of nandrolone combined with strenuous resistance training (RT) on function and structure of thoracic aorta. Rats were randomized into four groups: non-trained vehicle (NTV), trained vehicle (TV), non-trained nandrolone (NTN), and trained nandrolone (TN), and submitted to 6 weeks of treatment with nandrolone (5 mg/kg, twice a week) and/or resistance training. In vitro response of thoracic aorta to acetylcholine (ACh) was analyzed. Vascular nitric oxide (NO) and reactive oxygen species (ROS) synthesis were evaluated using 4,5-diaminofluorescein diacetate (DAF-2) and hydroethidine fluorescent techniques, respectively. Thoracic aorta was processed for microscopy analyses and tunica media thickness was measured. ACh-mediated relaxation response was impaired in endothelium intact aortic rings isolated from trained rats (TV and TN) as compared with their matched non-trained groups. TN rats showed reduced ACh-mediated vasodilatation than NTN rats. NO production and bioavailability decreased in thoracic aorta of nandrolone-treated rats in relation to their matched non-trained group (NTN vs. NTV; TN vs. TV). ROS production and tunica media thickness were increased in TN rats when compared with TV rats. These findings indicate that high doses of nandrolone combined with strenuous RT affect NO bioavailability and might induce endothelial dysfunction and arterial morphological alterations.

A survey of six potato viruses, Potato virus A (PVA), Potato virus M (PVM), Potato virus S(PVS), Potato virus X (PVX), Potato virus Y (PVY), and Potato leafroll virus (PLRV), was conducted in New York and Maine during 2002 and 2003. Leaf samples were tested by enzyme-linked immunosorbent assay and PVY-positive samples were further tested to determine whether a necrotic strain of PVY (PVY^N) or a strain able to induce necrosis in tobacco and in potato tubers (PVY^NTN) were present. In both years, PVY and PVS were identified in a majority of the samples, and mixed infections predominated in 83% of the symptomatic leaves in 2002. Of the total 394 PVY-positive samples, 3 reacted with monoclonal antibody (MAb) 1F5 and caused veinal necrosis (VN) in tobacco. Two of these isolates caused tuber necrosis in the potato cv. Yukon Gold. Three PVY isolates reacted with MAb 1F5 but did not cause VN in tobacco, and two caused VN but did not react with MAb 1F5. None of these eight isolates were able to overcome the Ry resistance gene in the potato cultivar Eva, but several were able to overcome the Ny resistance gene found in Allegany. PVY^N isolates were not widespread in the northeastern United States; however, several PVY isolates differed from both PVY^N and the ordinary strain of PVY and may represent strain recombinants.

Potato virus Y (PVY) is an economically important and reemerging potato pathogen in North America. PVY infection reduces yield, and some necrotic and recombinant strains render tubers unmarketable. Although PVY(O) is the most prevalent strain in the United States, the necrotic and recombinant strains PVY(NTN) and PVY(N:O) are becoming more widespread. Infection rates in aphid-inoculated (Myzus persicae (Sulzer)) and mechanically inoculated plants were compared across two potato genotypes ('Yukon Gold' and A98345-1), three PVY strains (PVY(O), PVY(N:O), and PVY(NTN)), and two growth stages at inoculation (pre- and postflowering). Susceptibility of genotypes was measured as infection rate using a double-antibody sandwich-enzyme-linked immunosorbent assay; virus titer and tuber mass also were recorded from the infected plants. Yukon Gold generally was more susceptible than A98345-1 to all three PVY strains, especially following mechanical inoculation. Within genotypes, Yukon Gold was most susceptible to PVY(O) and A98345-1 was most susceptible to PVY(N:O). Plants exhibited age-based resistance, with both genotypes showing higher susceptibility at the pre- than postflowering stage. The overall ranking pattern of virus titer in infected plants was PVY(O)>> PVY(NTN)>> PVY(N:O); across all three strains, infected Yukon Gold had higher titer than infected A98345-1 plants. Yukon Gold plants had lower tuber mass than A98345-1 when infected, and there were differences between the two inoculation methods in regard to tuber mass for the three stains. The results showed differences in infection response between inoculation methods and as a function of genotype, strain, inoculation stage, and their interactions. These factors should be considered when screening genotypes for resistance.

Potato virus Y (PVY) exists as several strains with distinct symptomology and tuber yield effects in different potato varieties. Recently, new recombinant strains have proliferated and dominated local populations around the world. In this study, PVY^O, PVY^N:O, PVY^N-Wi, and PVY^NTN strains were tracked across Canada from 2014 to 2017, showing rapid evolution of populations away from the traditionally dominant PVY^O to recombinants PVY^N-Wi (western Canada) and PVY^NTN (eastern Canada). Simultaneously, 30 potato varieties were inoculated with PVY^O, PVY^N:O, and PVY^NTN in controlled greenhouse experiments. Foliar symptoms of primary (mechanical inoculation mimicking aphid infection) and secondary (tuber seedborne) infection were cataloged, and tuber yield measured. On average, and generally similar in primary and secondary infection, symptom expression and yield reduction were most severe with PVY^O, followed by PVY^N:O and PVY^NTN. Strong mosaic symptoms were most commonly expressed with PVY^O infection, and only seen with PVY^N:O or PVY^NTN in 15 and 3 varieties, respectively. Across variety-strain combinations, yield reduction was correlated with symptom severity, most strongly in PVY^O-infected plants (e.g., AC Chaleur, Beljade, Envol, Norland, and Pacific Russet), and four varieties exhibited tuber necrotic ringspot disease with PVY^NTN (AC Chaleur, Envol, Pacific Russet, and Yukon Gold).

A collection of 147 Potato virus Y (PVY) isolates from tomato, originating from several commercial fields and greenhouses in different regions of Poland, was tested for the presence of PVY by reverse-transcription polymerase chain reaction. However, in some cases, the results obtained were ambiguous. Therefore, a sensitive reverse-transcription loop-mediated isothermal amplification method was developed for rapid detection of PVY isolates. Phylogenetic and recombination analyses were performed based on sequences of the coat protein gene. In comparison with results obtained in 2008, the presence of other strains besides PVY(N)Wi-P was confirmed. A novel recombinant between PVY(NTN) and PVY(N)Wi-P strains was detected. Our results indicate an increasing distribution and variability of the PVY population on tomato in Poland.

Potato is one of the staple crops in Egypt, grown under irrigation almost continuously year-round. Potato virus Y (PVY) has been reported as one of the main viruses affecting potatoes in Egypt, but limited information is available on PVY strains circulating in potato fields in the country. From 2014 to 2016, virus surveys were conducted in several potato-growing governorates of Egypt, and PVY-positive samples were found to represent at least five distinct recombinant PVY strains, including PVY^NTN and PVY^N-Wi. Whole genome sequences were determined for four isolates representing strains PVY-SYR-III (Egypt7), PVY-261-4 (Egypt11), PVY^NTNa (Egypt35), and a novel recombinant named Egypt24 that combined molecular properties of strains PVY-261-4 and PVY-Wilga156var. At least three recombinants found in Egypt in potato were previously found associated with potato tuber necrotic ringspot disease (PTNRD). The identification of multiple recombinant types of PVY in potato in Egypt, including the novel recombinant Egypt24, suggests a wide presence of PTNRD-inducing virus strains in the country.

Angiotensin II type 1 receptor can activate number of signalling pathways upon stimulation and consequently its involvement in cancer progression have also been revealed. But which epigenetic mechanisms are involved in its regulation, need to be further explored. In-silico analysis revealed a promoter CpG island (CGI) which was cloned and assayed for functional activity using reporter gene system. The effect of methylation on this CGI was analysed through varying degree of methyltransferase treatment of cloned fragment. Results thus obtained were validated by direct sequencing. To further establish the status of this effect, in-vivo analysis was done through screening of methylation pattern in the targeted region among hypertensives (HTN) and normotensives (NTN) using PCR-Bisulphite sequencing. Additionally, clinical details of all participants, biochemical parameters and lifestyle related information was also collected and statistically evaluated. Reporter gene assay assigned functional activity to the cloned promoter CpG island. Increased dose and durations of methyltransferase treatment decreased the expression of reporter gene indicating the role of promoter DNA methylation. Among all the human samples screened, only one of the HTN individual was found to have single hemi-methylated CpG site at a position which happens to be a part of Sp1 transcription factor binding site. To conclude, CpG island in the promoter region of AT1R (CpG.P.AT1R) gets regulated through epigenetic mechanism of DNA methylation.

BACKGROUND

A recent clinical trial found that pharmacological blockade of V1b receptors reduces alcohol relapse in alcohol-dependent patients. SSR149415 is a selective V1b receptor antagonist that has potential for development as an alcohol dependency treatment. In this study, we investigated whether SSR149415 alone or in combination with the mu-opioid receptor (MOP-r) antagonist naltrexone (NTN) would alter excessive alcohol drinking in mice.

METHODS

Both sexes of C57BL/6J (B6) mice were subjected to a chronic intermittent access (IA) drinking paradigm (2-bottle choice, 24-hour access every other day) for 3 weeks. Sucrose and saccharin drinking were used as controls for alcohol-specific drug effects. Neuronal proopiomelanocortin (POMC) enhancer (nPE) knockout mice with hypothalamic-specific loss of POMC (including beta-endorphin, the main endogenous ligand of MOP-r) were used as a genetic control for the effects of NTN.

RESULTS

Acute administration of SSR149415 (1 to 30 mg/kg) reduced alcohol intake and preference in a dose-dependent manner in both male and female B6 mice after IA. To investigate potential synergistic effects between NTN and SSR149415, we tested 6 different combination doses of SSR149415 and NTN, and found that a combination of SSR149415 (3 mg/kg) and NTN (1 mg/kg) reduced alcohol intake profoundly at doses lower than the individual effective doses in both sexes of B6 mice. We confirmed the effect of SSR149415 on reducing alcohol intake in nPE-/- male mice, consistent with independent mechanisms by which SSR149415 and NTN decrease alcohol drinking.

CONCLUSIONS

The combination of V1b antagonist SSR149415 with NTN at individual subthreshold doses shows potential in alcoholism treatment, possibly with less adverse effects.

Potato virus Y (PVY) is the most economically important viral pathogen of potato worldwide. Different potato cultivars react to the pathogen differently, resulting in resistant, tolerant or disease outcome of the interaction. Here we focus on tolerant interaction between potato cv. Désirée and PVY^NTN. To capture the response in its full complexity, we analyzed the dynamic changes on multiple molecular levels, including transcriptomics, sRNAomics, degradomics, proteomics and hormonomics. The analysis was complemented by the measurements of viral accumulation, photosynthetic activity and phenotypisation of the symptoms. Besides cv. Désirée we also studied its transgenic counterpart depleted for the accumulation of salicylic acid (NahG-Désirée). This multiomics analysis provides better insights into the mechanisms leading to tolerant response of potato to viral infection and can be used as a base in further studies of plant immunity regulation.

BACKGROUND

Chronic kidney disease (CKD) is a global health concern, but the current treatments only slow down the progression. Thus an improved understanding of the pathogenesis and novel treatments of CKD are needed. The nephrotoxic nephritis (NTN) model has the potential to study the pathogenesis of CKD as it resembles human CKD. The classical treatments with angiotensin II receptor blocker (ARB) or the angiotensin-converting enzyme inhibitor (ACE I) have shown a clinical effect in CKD.

METHODS

We characterized the disease development in the NTN model over 11 weeks by investigating functional and histopathological changes. We tested doses of 15 and 30 mg/kg/day enalapril and losartan in the NTN model in order to investigate the effect of inhibiting the renin-angiotensin-system (RAS).

RESULTS

The NTN model displayed albuminuria peaking on days 6-7, mesangial expansion (ME), renal fibrosis, inflammation and iron accumulation peaking on day 42. However, albuminuria, ME, renal fibrosis and inflammation were still significantly present on day 77, suggesting that the NTN model is useful for studying both the acute and chronic disease phases. Enalapril and losartan significantly enhanced the glomerular filtration rate (GFR) and decreased albuminuria, ME, renal fibrosis and inflammation of NTN-induced kidney disease in mice.

CONCLUSIONS

This is the first study showing a comprehensive pathological description of the chronic features of the murine NTN model and that inhibiting the RAS pathway show a significant effect on functional and morphological parameters.

Background: Chronic kidney disease (CKD) is a global health burden, and the current treatment options only slow down the disease progression. GLP-1 receptor agonists (GLP-1 RA) have shown a renal protective effect in models of CKD; however, the mechanism behind the beneficial effect is not understood. In this study, we investigate the effect of the GLP-1 RA liraglutide in the nephrotoxic serum nephritis (NTN) CKD model. Moreover, we compare the gene expression pattern of liraglutide-treated mice to the gene expression pattern of mice treated with the angiotensin converting enzyme inhibitor, enalapril.

Methods: The effect of liraglutide was tested in the NTN model by evaluating the glomerular filtration rate (GFR), albuminuria, mesangial expansion, renal fibrosis, and renal inflammation. Furthermore, the regulation of selected genes involved in CKD and in glomerular, cortical tubulointerstitial, and whole kidney structures was analyzed using a gene expression array on samples following laser capture microdissection.

Results: Treatment with liraglutide improved CKD hallmarks including GFR, albuminuria, mesangial expansion, renal inflammation, and renal fibrosis. The gene expression revealed that both liraglutide and enalapril reversed the regulation of several fibrosis and inflammation associated genes, which are also regulated in human CKD patients. Furthermore, liraglutide and enalapril both regulated genes in the kidney involved in blood pressure control.

Conclusions: Treatment with liraglutide improved the kidney function and diminished renal lesions in NTN-induced mice. Both liraglutide and enalapril reversed the regulation of genes involved in CKD and regulated genes involved in blood pressure control.

Keywords: Chronic kidney disease; Gene expression; Hemodynamics; Liraglutide; Nephrotoxic serum nephritis model.

The prevalence of substrate cross-reactivity between AHL acylases and β-lactam acylases provides a glimpse of probable links between quorum sensing and antibiotic resistance in bacteria. Both these enzyme classes belong to the N-terminal nucleophile (Ntn)-hydrolase superfamily. Penicillin V acylases alongside bile salt hydrolases constitute the cholylglycine hydrolase (CGH) group of the Ntn-hydrolase superfamily. Here we report the ability of two acylases, Slac1 and Slac2, from the marine bacterium Shewanella loihica-PV4 to hydrolyze AHLs. Three-dimensional structure of Slac1reveals the conservation of the Ntn hydrolase fold and CGH active site, making it a unique CGH exclusively active on AHLs. Slac1homologs phylogenetically cluster separate from reported CGHs and AHL acylases, thereby representing a functionally distinct sub-class of CGH that might have evolved as an adaptation to the marine environment. We hypothesize that Slac1 could provide the structural framework for understanding this subclass, and further our understanding of the evolutionary link between AHL acylases and β-lactam acylases.

Keywords: AHL acylase; Cholyolglycine hydrolase; Homodimer; Ntn-fold; Shewanella loihica-PV4.

Weeds, as alternative hosts of plant viruses and nutrient plants of virus vectors play important role in virus ecology and epidemiology. The aim of our study was to discover new weed-virus relations. Therefore some weed species were mechanically inoculated with 28 viruses (strains or isolates) maintained in our glasshouse. Different weed species with and without visible symptoms were collected from agro-, water ecosystems and wastelands of Hungary between 1997 and 2003. Virus infections were evaluated by biotests, DAS ELISA serological methods, electronmicroscopy and immunosorbent electronmicroscopy (ISEM). Under glasshouse conditions Ambrosia artemisifolia was considered as a virophob species, showing resistance to all viruses listed above. A series of new artificial (Chenopodium album--SoMV (LH+SH)*, AMV (LH+SH); C. berlandieri--PVY(NTN) (LH), AMV (LH+SH), CMV (LH), SoMV (LH+SH), ObPV (LH+SH), ZYMV-10 (LH): C. ugandae--ObPV (LH), SoMV (L); C. glaucum--ObPV (LH), SoMV (L); Echinocystis lobata--PVX (L), ZYMV (LH+SH); Solanum nigrum--MYFV (LH+SH), PVY(N) (L), PVY(NTN) (LH+SH), SoMV (LH), TMV (SH), CMV (SH); S. dulcamara--CMV-U/246 (SH), PVY(NTN) (LH), SoMV-H (L), TMV-O (L); S. luteum--PVY(N) (SH), PVY(NTN) (LH+L), TMV(SH).) and natural (Asclepias syriaca--TMV, AMV, TSWV; Alisma plantago-aquatica--PVY, SoMV; Ambrosia artemisiifolia--CMV; Chenopodium album--CMV, PVS, PLRV; C. hybridum--CMV; Cirsium canum--CMV, PVM; Carex vulpina--CMV; Comium maculatum--PVY; Datura stramonium--PVA, PVX, PVS, PVM, CMV, TMV; Lysimachia vulgaris--ArMV, BNYVV, CMV, TMV; Lythrum salicaria--ArMV; Malva neglecta--CMV; Mercurialis annua--SoMV; Solanum nigrum--CMV, PVY, PVY(N); Solidago gigantea--CMV, RpRSV, BNYVV; Stenactis annua--PVM, PVA) weed--virus relations were detected. The epidemiological role of perennial hosts (A. syriaca, A. planlago aquatica, C. canurm, L. vulgaris, L. salicaria, S. gigantea) is especially high, because they can serve as infection sources as well as overwintering hosts of different plant viruses.

In Brazil, Potato virus Y (PVY) currently presents a significant problem for potato production, reducing tuber yield and quality. Recombinant tuber necrotic isolates of PVY had been reported to occur in the country but no systematic study of the PVY isolate diversity was conducted thus far. Here, a panel of 36 PVY isolates, randomly collected in Brazil from potato between 1985 and 2009, was subjected to a systematic molecular and serological typing using reverse-transcription polymerase chain reaction and a series of PVY^O- and PVY^N-specific monoclonal antibodies. The data collected were combined with biological characterization of the same isolates in tobacco. Of the 36 isolates tested, 3 were typed as PVY^O, 10 as PVY^N:O/N-Wi, 21 as PVY^NTN, and 2 as "unusual" or inconclusive. Of the 10 isolates from the recombinant PVY^N:O/N-Wi strain group, 1 isolate, MAF-VOY, was found to have an unusual serological profile identical to the nonrecombinant PVY^O-O5 strain group. The 21 tested PVY^NTN isolates included 1 isolate that did not induce vein necrosis in tobacco and 2 isolates with an unusual serological profile (i.e., displaying negative reactivity to one commercial PVY^N-specific monoclonal antibody). Whole genome sequences were determined for four PVY isolates from Brazil, representing PVY^O, PVY^NTN, and PVY^N-Wi strains. The genome of the MAF-VOY isolate was found to be recombinant, having characteristic N-Wi structure with two recombinant junctions and carrying a single mutation in the capsid protein at position 98, which led to an unusual O5 serological reactivity. Taken together, the data obtained suggest that the two recombinant strains, PVY^NTN and PVY^N:O/N-Wi, now are apparently dominant in the Brazilian potato crop. The data also suggest that recombinant isolates in Brazil often have unusual serological reactivity which may hamper their correct identification by conventional typing based on enzyme-linked immunosorbent assay.

Objective: Breast cancer (BC) is the main cause of cancer-related deaths in women across the world. It can be classified into different subtypes, including triple-negative (TN), which is characterized by the absence of hormone receptors for estrogen and progesterone and the lack of the human epidermal growth factor receptor 2. These tumors have high heterogeneity, acquire therapeutic resistance, and have no established target-driven treatment yet. The identification of differentially expressed genes in TN breast tumors and the in silico validation of their prognostic role in these tumors.

Materials and methods: We employed a microarray dataset and, by using the GEO2R tool, we identified a list of differentially expressed genes. The in silico validation was conducted using several online platforms including the KM Plotter, cBioPortal, bc-GenExMiner, Prognoscan, and Roc Plotter.

Results: We observed that FZD9 was among the top differentially expressed genes in a cohort of patients with different TNBC subtypes. The FZD9 expression was significantly different in TN breast tumors than in non-TN (nTN) breast tumors (p<0.0001), and the basal TN subtype showed the highest levels (p<0.0001). In addition, the FZD9 levels were significantly inversely and positively proportional (p<0.0001) to estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 clinical parameters. The high levels of FZD9 were associated with worse overall survival (p=0.007), relapse-free survival (p=5.8e-05), and worse survival in patients who received chemotherapy (p=3.2e-05; 0.007).

Conclusion: Our cumulative results demonstrated that FZD9 plays an important role in TNBC and may be a potential prognostic biomarker. Nevertheless, further in vitro and in vivo assays are necessary to confirm our findings and to strengthen the evidences about the mechanisms by which FZD9 functions in these tumors.

Keywords: FZD9; biomarkers; breast cancer; in silico analysis; triple-negative breast cancer.