Optimization Of Sludge Settleability And Dewaterability Using Pilot Scale Liquid State Bioconversion Process Under Non-Controlled Conditions

The study of microbial treatment of domestic wastewater treatment plant (DWTP) sludge, by liquid state bioconversion (LSB) process, was conducted using several approaches under sterilized controlled conditions in a bench scale with co-substrate supplementation. For this purpose, the mixed strains (P/A) of two selected filamentous fungi SCahmA103 (Aspergillus niger) and WWZP1003 (Penicillium corylophilum) were used to evaluate the performance of the LSB process in the bench scale and pilot scale, under optimized non-controlled conditions without cosubstrate in terms of biodegradation, bioseparation, biosolid accumulations, settling and dewatering of the DWTP sludge. Three numerical parameters, namely sludge concentrations TSS (w/w %), inoculum sizes (v/w %) and inoculum feeding intervals (hrs.), with three levels statistical design under the response surface methodology (RSM), were optimized with and without co-substrate supplementation to evaluate the performance of the process in terms of acclimatization and biodegradation of the DWTP sludge, under non controlled (natural) conditions. The optimum process parameters of the TSS (w/w %), inoculum size (v/w%) and inoculum feeding interval (hrs.) were observed to be 1% w/w, 5 %v/w and 11 hrs, respectively, without any co-substrate supplementation to get the maximum predicted values of adaptation, and the COD removal of 98% and 96.7%, respectively, in the fungal-treated sludge by LSB under the noncontrolled (natural) conditions in shake flasks. Another three-level statistical design under RSM was used to optimize the process parameters of aeration rates (vvm) and mixing rate (rpm) in a 100 L pilot-scale using the optimized value obtained from the shake flasks. This design was selected to evaluate the bioconversion performance, using the mixed culture P/A, under natural conditions in the pilot-scale in terms of biodegradability and biodewaterability of the DWTP sludge. The optimum aeration rate (vvm) and mixing rate (rpm) of 0 vvm and 10.5 rpm were respectively used to obtain the maximum predicted COD and SRF responses of 98.9% and 98%, respectively in the fungal-treated sludge by the LSB, under the natural conditions in the pilot-scale. In terms of biodegradation, bioseparation and biosolid accumulations of the DWTP sludge, the validation results gathered from the statistical models in the shake flasks and pilot-scale showed that the LSB efficiency was higher in the pilot-scale than in the shake flasks. Consequently, the optimized values obtained from the two statistical models were used at a 200 L pilot-scale to investigate the settleability and dewaterability characteristics in fungal treated with DWTP sludge, under natural conditions. The results for settleability suggested that 65% of the sludge was settled after one minute of settling period, with a maximum TSS reduction of 99%. The sludge volume index (SVI) reduction of 86% for the treated and untreated sludge was 10 minutes and 180 minutes, respectively. Specific resistance to filtration (SRF) was found to decrease by 98% in the treated sludge after 3 days of fungal treatment, as compared to the untreated sludge. This suggested that the settleability and dewaterability of the DWTP sludge, in the developed LSB process, were highly influenced by the fungal mycelial entrapment under the non-controlled (natural) conditions in the pilot scale

Biohydrogen Production From Palm Oil Mill Effluent Using A Thermophilic Semi-Continuous Process With Recycling

The effluent resulted from the palm oil industry can cause serious pollution if left untreated. This is a problem of considerable magnitude, notably in Malaysia. Anaerobic biological treatment processes, have effectively used to treat POME. Currently, methane production is the most commonly used method to treat POME, but hydrogen production is an innovative alternative because of the methane green house nature. Processes under thermophilic anaerobic conditions showed superior production rates and less variety in fermentation by products which is economically and technically interesting. A fermentation process for hydrogen production by anaerobic micro flora under controlled conditions (pH 5, T 60oC and 200rpm) in a semi-continuous process with recycling was developed for this study. The substrate used in this study was POME (Palm Oil Mill Effluent) and POME sludge for the biogas production was collected to be used as source of inocula. The experimental setup conducted using a 5-L fermenter and six steady states were achieved. The POME sludge possessed a maximum hydrogen evolution rate of 0.83 L H2 gas/Lmed.hr at the fifth steady state with a maximum hydrogen percentage in the biogas of 64% at the fourth steady state. Increasing the organic loading rate from 10.3 to 25.5 kgCOD/m3/d resulted in increasing biomass productivity up to 25.325 g/L at the sixth steady associated with increasing biogas emission throughout the six steady states, and an increase in the total gas yield up to 0.97 L gas/gCOD/d at the fifth steady state. It is also noted that increasing the organic loading rates resulted in increasing hydrogen yield up to 0.6 L gas/g COD/d at the fifth steady state, and decreasing the COD removal efficiencies from (66.33 to 59.32%) throughout the system, this might be due to the decrease of hydraulic retention time (HRT) and solids retention time (SRT) from 5 to 2.94 days and 52.282 to 12.260 days, respectively. The minimum solids retention time (SRTm) for this study was 1.99 days. A mathematical model was developed to understand the kinetics of the digester operations. The growth yield coefficient, Y and the specific microorganism death rate, kd for anaerobic semi-continuous system, were found to be 0.3075 (gVSS/gCOD) and 0.1035 day-1 respectively. The maximum specific growth rate, μmax , maximum substrate utilization rate, K, half-velocity coefficient, Ks for the process were found to be 0.502369 day-1,1.63372gCOD/gVSS.day, 50.336546 mgCOD/l respectively. This study suggests that using thermophilic semi-continuous process with recycling is suitable for hydrogen production from POME and POME biomass and increasing the organic loading rate esulted in an increase of biogas production throughout the system

Aβ43 aggregates exhibit enhanced prion-like seeding activity in mice.

When injected into genetically modified mice, aggregates of the amyloid-β (Aβ) peptide from the brains of Alzheimer's disease (AD) patients or transgenic AD mouse models seed cerebral Aβ deposition in a prion-like fashion. Within the brain, Aβ exists as a pool of distinct C-terminal variants with lengths ranging from 37 to 43 amino acids, yet the relative contribution of individual C-terminal Aβ variants to the seeding behavior of Aβ aggregates remains unknown. Here, we have investigated the relative seeding activities of Aβ aggregates composed exclusively of recombinant Aβ38, Aβ40, Aβ42, or Aβ43. Cerebral Aβ42 levels were not increased in AppNL-F knock-in mice injected with Aβ38 or Aβ40 aggregates and were only increased in a subset of mice injected with Aβ42 aggregates. In contrast, significant accumulation of Aβ42 was observed in the brains of all mice inoculated with Aβ43 aggregates, and the extent of Aβ42 induction was comparable to that in mice injected with brain-derived Aβ seeds. Mice inoculated with Aβ43 aggregates exhibited a distinct pattern of cerebral Aβ pathology compared to mice injected with brain-derived Aβ aggregates, suggesting that recombinant Aβ43 may polymerize into a unique strain. Our results indicate that aggregates containing longer Aβ C-terminal variants are more potent inducers of cerebral Aβ deposition and highlight the potential role of Aβ43 seeds as a crucial factor in the initial stages of Aβ pathology in AD

Optimization of process parameters for pilot-scale liquid-state bioconversion of sewage sludge by mixed fungal inoculation

Liquid-state bioconversion (LSB) technique has great potential for application in bioremediation of sewage sludge. The purpose of this study is to determine the optimum level of LSB process of sewage sludge treatment by mixed fungal (Aspergillus niger and Penicillium corylophilum) inoculation in a pilot-scale bioreactor. The optimization of process factors was investigated using response surface methodology based on Box–Behnken design considering hydraulic retention time (HRT) and substrate influent concentration (S0) on nine responses for optimizing and fitted to the regression model. The optimum region was successfully depicted by optimized conditions, which was identified as the best fit for convenient multiple responses. The results from process verification were in close agreement with those obtained through predictions. Considering five runs of different conditions of HRT (low, medium and high 3.62, 6.13 and 8.27 days, respectively) with the range of S0 value (the highest 12.56 and the lowest 7.85 g L−1), it was monitored as the lower HRT was considered as the best option because it required minimum days of treatment than the others with influent concentration around 10 g L−1. Therefore, optimum process factors of 3.62 days for HRT and 10.12 g L−1 for S0 were identified as the best fit for LSB process and its performance was deviated by less than 5% in most of the cases compared to the predicted values. The recorded optimized results address a dynamic development in commercial-scale biological treatment of wastewater for safe and environment-friendly disposal in near future

The long non-coding {RNA} {H19} suppresses carcinogenesis and chemoresistance in hepatocellular carcinoma

The long non-coding RNA (lncRNA) H19 represents a maternally expressed and epigenetically regulated imprinted gene product and is discussed to have either tumor-promoting or tumor-suppressive actions. Recently, H19 was shown to be regulated under inflammatory conditions. Therefore, aim of this study was to determine the function of H19 in hepatocellular carcinoma (HCC), an inflammation-associated type of tumor. In four different human HCC patient cohorts H19 was distinctly downregulated in tumor tissue compared to normal or non-tumorous adjacent tissue. We therefore determined the action of H19 in three different human hepatoma cell lines (HepG2, Plc/Prf5, and Huh7). Clonogenicity and proliferation assays showed that H19 overexpression could suppress tumor cell survival and proliferation after treatment with either sorafenib or doxorubicin, suggesting chemosensitizing actions of H19. Since HCC displays a highly chemoresistant tumor entity, cell lines resistant to doxorubicin or sorafenib were established. In all six chemoresistant cell lines H19 expression was significantly downregulated. The promoter methylation of the H19 gene was significantly different in chemoresistant cell lines compared to their sensitive counterparts. Chemoresistant cells were sensitized after H19 overexpression by either increasing the cytotoxic action of doxorubicin or decreasing cell proliferation upon sorafenib treatment. An H19 knockout mouse model (H19Δ3) showed increased tumor development and tumor cell proliferation after treatment with the carcinogen diethylnitrosamine (DEN) independent of the reciprocally imprinted insulin-like growth factor 2 (IGF2). In conclusion, H19 suppresses hepatocarcinogenesis, hepatoma cell growth, and HCC chemoresistance. Thus, mimicking H19 action might be a potential target to overcome chemoresistance in future HCC therapy

ClpP protease activation results from the reorganization of the electrostatic interaction networks at the entrance pores

Bacterial ClpP is a highly conserved, cylindrical, self-compartmentalizing serine protease required for maintaining cellular proteostasis. Small molecule acyldepsipeptides (ADEPs) and activators of self-compartmentalized proteases 1 (ACP1s) cause dysregulation and activation of ClpP, leading to bacterial cell death, highlighting their potential use as novel antibiotics. Structural changes in Neisseria meningitidis and Escherichia co ClpP upon binding to novel ACP1 and ADEP analogs were probed by X-ray crystallography, methyl-TROSY NMR, and small angle X-ray scattering. ACP1 and ADEP induce distinct conformational changes in the ClpP structure. However, reorganization of electrostatic interaction networks at the ClpP entrance pores is necessary and sufficient for activation. Further activation is achieved by formation of ordered N-terminal axial loops and reduction in the structural heterogeneity of the ClpP cylinder. Activating mutations recapitulate the structural effects of small molecule activator binding. Our data, together with previous findings, provide a structural basis for a unified mechanism of compound-based ClpP activation2CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP306943/2015-8; 420567/2016-099999.004913/2015-092015/15822-1; 2012/01953-9; 2016/05019-0; 2012/50161-8Precision Medicine Initiative (PRiME) at the University of Toronto internal fellowship [PMRF2019-007]; Canadian Institutes of Health Research (CIHR) postdoctoral fellowshipCanadian Institutes of Health Research (CIHR); CNPq-Brazil fellowship [202192/2015-6]; Saskatchewan Health Research Foundation postdoctoral fellowship; Ontario Graduate Scholarship (OGS)Ontario Graduate Scholarship; Department of Biochemistry at the University of Toronto; Centre for Pharmaceutical Oncology (University of Toronto); CIHR Training Program in Protein Folding and Interaction Dynamics: Principles and Diseases fellowshipCanadian Institutes of Health Research (CIHR) [TGF-53910]; University of Toronto Fellowship from the Department of Biochemistry; OGS fellowship; NSERC PGS-D2 fellowship; CIHR Emerging Team Grants from the Institute of Infection and ImmunityCanadian Institutes of Health Research (CIHR) [XNE-86945]; CIHR Project grantCanadian Institutes of Health Research (CIHR) [PJT-148564]; Global Affairs Canada (Canada); CAPES (Brazil)CAPES [99999.004913/2015-09]; NSERCNatural Sciences and Engineering Research Council of Canada [RGPIN-2015-04877, DG-20234]; Canada Research Chairs ProgramCanada Research Chairs; CIHR new investigator programCanadian Institutes of Health Research (CIHR); FAPESPFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2015/15822-1, 2012/01953-9, 2016/05019-0, 2012/50161-8]; CNPqNational Council for Scientific and Technological Development (CNPq) [306943/2015-8, 420567/2016-0]; AbbVie [1097737]; BayerBayer AG [1097737]; Boehringer IngelheimBoehringer Ingelheim [1097737]; Genome Canada through Ontario Genomics Institute GrantGenome Canada [1097737, OGI-055]; GlaxoSmithKlineGlaxoSmithKline [1097737]; JanssenJohnson & Johnson USAJanssen Biotech Inc [1097737]; Lilly CanadaEli Lilly [1097737]; MerckMerck & Company [1097737]; Novartis Research Foundation [1097737]; Ontario Ministry of Economic Development and Innovation [1097737]; PfizerPfizer [1097737]; TakedaTakeda Pharmaceutical Company Ltd [1097737]; Wellcome Trust GrantWellcome Trust [1097737, 092809/Z/10/Z]; Canada Foundation for InnovationCanada Foundation for Innovation; NSERCNatural Sciences and Engineering Research Council of Canada; University of Saskatchewan; Government of Saskatchewan; Western Economic Diversification Canada; National Research Council Canada; CIHRCanadian Institutes of Health Research (CIHR

Development of spiro-3-indolin-2-one containing compounds of antiproliferative and anti-SARS-CoV-2 properties

Abstract: A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2′-pyrrolidine-3′,3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d, h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Surgical site infections after emergency hernia repair: substudy from the Management of Acutely Symptomatic Hernia (MASH) study

Introduction Acutely symptomatic abdominal wall and groin hernias (ASH) are a common acute surgical presentation. There are limited data to guide decisions related to surgical repair technique and use of antibiotics, which can be driven by increased risk of surgical site infection (SSI) in this group. This study aims to report rates of SSI following ASH repair and explore the use of patient-reported outcome measure reporting in this setting. Methods An 18-week, UK-based, multicentre prospective cohort study (NCT04197271) recruited adults with ASH. This study reports operatively managed patients. Data on patient characteristics, inpatient management, quality of life, complications, and wound healing (Bluebelle score) were collected. Descriptive analyses were performed to estimate event rates of SSI and regression analysis explored the relationship between Bluebelle scores and SSI. The 30 and 90-day follow-up visits assessed complications and quality of life. Results The MASH study recruited 273 patients, of whom 218 were eligible for this study, 87.2 per cent who underwent open repair. Mesh was used in 123 patients (50.8 per cent). Pre- and postoperative antibiotics were given in 163 (67.4 per cent) and 28 (11.5 per cent) patients respectively. There were 26 reported SSIs (11.9 per cent). Increased BMI, incisional, femoral, and umbilical hernia were associated with higher rates of SSI (P = 0.006). In 238 patients, there was a difference in healthy utility values at 90 days between patients with and without SSI (P = 0.025). Also, when analysing 191 patients with Bluebelle scores, those who developed an SSI had higher Bluebelle values (P < 0.001). Conclusion SSI is frequent in repair of acutely symptomatic hernia and correlates with BMI and site of hernia

Optimization of process parameters for pilot-scale liquid-state bioconversion of sewage sludge by mixed fungal inoculation

Liquid-state bioconversion (LSB) technique has great potential for application in bioremediation of sewage sludge. The purpose of this study is to determine the optimum level of LSB process of sewage sludge treatment by mixed fungal (Aspergillus Niger and Penicillium corylophilum) inoculation in a pilot-scale bioreactor. The optimization of process factors was investigated using response surface methodology based on Box-Behnken design considering hydraulic retention time (HRT) and substrate influent concentration (S0) on nine responses for optimizing and fitted to the regression model. The optimum region was successfully depicted by optimized conditions, which was identified as the best fit for convenient multiple responses. The results from process verification were in close agreement with those obtained through predictions. Considering five runs of different conditions of HRT (low, medium and high 3.62, 6.13 and 8.27 days, respectively) with the range of S0 value (the highest 12.56 and the lowest 7.8514g14L-1), it was monitored as the lower HRT was considered as the best option because it required minimum days of treatment than the others with influent concentration around 1014g14L-1. Therefore, optimum process factors of 3.62 days for HRT and 10.1214g14L-1 for S0 were identified as the best fit for LSB process and its performance was deviated by less than 5% in most of the cases compared to the predicted values. The recorded optimized results address a dynamic development in commercial-scale biological treatment of wastewater for safe and environment-friendly disposal in near future