Exploring neuroadaptive cellular pathways in chronic morphine exposure: An in-vitro analysis of cabergoline and Mdivi-1 co-treatment effects on the autophagy-apoptosis axis.

The complex impacts of prolonged morphine exposure continue to be a significant focus in the expanding area of addiction studies. This research investigates the effectiveness of a combined treatment using Cabergoline and Mdivi-1 to counteract the neuroadaptive changes caused by in vitro morphine treatment. The impact of Methadone, Cabergoline, and a combination of Cabergoline and Mdivi-1 on the cellular and molecular responses associated with Morphine-induced changes was studied in human Neuroblastoma (SK-N-MC) and Glioblastoma (U87-MG) cell lines that were exposed to prolong Morphine treatment. Cabergoline and Mdivi-1 combined treatment effectively influenced the molecular alterations associated with neuroadaptation in chronic morphine-exposed neural cells. This combination therapy normalized autophagy and reduced oxidative stress by enhancing total-antioxidant capacity, mitigating apoptosis, restoring BDNF expression, and balancing apoptotic elements. Our research outlines morphine's dual role in modulating mitochondrial dynamics via the dysregulation of the autophagy-apoptosis axis. This emphasizes the significant involvement of DRP1 activity in neurological adaptation processes, as well as disturbances in the dopaminergic pathway during in vitro chronic exposure to morphine in neural cells. This study proposes a novel approach by recommending the potential effectiveness of combining Cabergoline and Mdivi-1 to modulate the neuroadaptations caused by morphine. Additionally, we identified BDNF and PCNA in neural cells as potential neuroprotective markers for assessing the effectiveness of drugs against opioid toxicity, emphasizing the need for further validation. The study uncovers diverse effects observed in pretreated morphine glioblastoma cells under treatment with Cabergoline and methadone. This highlights the potential for new treatments in the DRD2 pathway and underscores the importance of investigating the interplay between autophagy and apoptosis to advance research in managing cancer-related pain. The study necessitates an in-depth investigation into the relationship between autophagy and apoptosis, with a specific emphasis on protein interactions and the dynamics of cell signaling.

Excavatolide C/cisplatin combination induces antiproliferation and drives apoptosis and DNA damage in bladder cancer cells.

Excavatolide C (EXCC), a marine coral-derived compound, exhibits an antiproliferation effect on bladder cancer cells. The present study evaluated the improvement in the antiproliferation ability of EXCC by co-treatment with cisplatin in bladder cancer cells. EXCC/cisplatin (12.5 and 1 µg/mL) showed higher antiproliferation effects on bladder cancer cells than single treatments (EXCC or cisplatin alone) in the 48 h ATP assay. EXCC/cisplatin also enhanced the increase in subG1, annexin V-mediated apoptosis, and activation of poly (ADP-ribose) polymerase (PARP) and several caspases (caspases 3, 8, and 9) compared to the single treatments. Cellular and mitochondrial oxidative stress was enhanced with EXCC/cisplatin compared to the single treatments according to analyses of reactive oxygen species (ROS), mitochondrial superoxide, and mitochondrial membrane potential; in addition, cellular antioxidants, such as glutathione (GSH), and the mRNA expressions of antioxidant signaling genes (catalase and NFE2-like bZIP transcription factor 2) were downregulated. EXCC/cisplatin treatment produced more DNA damage than the single treatments, as indicated by γH2AX and 8-hydroxy-2'-deoxyguanosine levels. Moreover, several DNA repair genes for homologous recombination (HR) and non-homologous end joining (NHEJ) were downregulated in EXCC/cisplatin compared to others. The addition of the GSH precursor N-acetylcysteine, which has ROS scavenging activity, attenuated all EXCC/cisplatin-induced changes. Notably, EXCC/cisplatin showed lower antiproliferation, apoptosis, ROS induction, GSH depletion, and γH2AX DNA damage in normal cells than in bladder cancer cells. Therefore, the co-treatment of EXCC/cisplatin reduces the proliferation of bladder cancer cells via oxidative stress-mediated mechanisms with normal cell safety.

Speech-language pathologist, physical therapist, and occupational therapist experiences of interprofessional collaborations.

Interprofessional collaboration among speech-language pathology, physical therapy, and occupational therapy is considered to promote best practice in rehabilitation as it can enhance efficiency, patient outcomes, and clinician and patient satisfaction. Although clinician experiences with interprofessional collaboration have been studied in each of the rehabilitation professions separately, limited research has been conducted on the shared attitudes or experiences across speech-language pathology, physical therapy, and occupational therapy. The purpose of this study was to understand speech-language pathologist, physical therapist, and occupational therapist experiences of interprofessional collaborations. We conducted an exploratory cross-sectional online survey study. The survey included Likert-scale questions and open-ended questions that probed clinicians' general experiences with interprofessional practice and views and beliefs regarding barriers and facilitators to interprofessional collaboration. Responses from 213 clinician respondents were analyzed using descriptive quantitative methods and a qualitative content analysis. The results revealed overlap in attitudes and experiences across speech-language pathology, physical therapy, and occupational therapy about barriers and benefits to interprofessional collaboration. Perceived respect differed among the professions, with speech-language pathologists more frequently reporting that their role is often misunderstood or undervalued by other rehabilitation professionals. These results may guide future research focused upon the predictors of successful interprofessional collaborations and interactions.

Flavonoids as emerging notch signaling pathway modulators in cancer.

Notch signaling is an evolutionary conserved pathway important for the developmental processes and implicated in the tumor formation. Notch signaling pathway (NSP) inhibitors have been tested in clinical trials alone or in combination with the chemotherapy but none got clinical approval due to severe toxicity in patients. Flavonoids inhibit NSP by inhibiting notch receptor cleavage and/or inhibiting transcriptional regulation by Notch intracellular domain (NICD). Interestingly, some flavonoids are reported to inhibit NSP by mediating the microRNA expression. NSP inhibitory flavonoid(s) in combination with standard therapy is might be an effective strategy in cancer treatment.

Anaerobic-aerobic treatment of wastewater and leachate: A review of process integration, system design, performance and associated energy revenue.

Hybrid anaerobic-aerobic biological systems are an environmentally sustainable way of recovering bioenergy during the treatment of high-strength wastewaters and landfill leachate. This study provides a critical review of three major categories of anaerobic-aerobic processes such as conventional wetland, high-rate and integrated bioreactor systems applied for treatment of wastewaters and leachate. A comparative assessment of treatment mechanisms, critical operating parameters, bioreactor configurations, process control strategies, efficacies, and microbial dynamics of anaerobic-aerobic systems is provided. The review also explores the influence of wastewater composition on treatment performance, ammonium nitrogen removal efficacy, impact of mixing leachate, energy consumption, coupled bioenergy production and economic aspects of anaerobic-aerobic systems. Furthermore, the operational challenges, prospective modifications, and key future research directions are discussed. This review will provide in-depth understanding to develop sustainable engineering applications of anaerobic-aerobic processes for effective co-treatment of wastewaters and leachate.

The influence of combined treatment of municipal wastewater and landfill leachate on the spread of antibiotic resistance in the environment - A preliminary case study.

Environmentally-friendly management of landfill leachate (LL) poses a challenge, and LL is usually co-treated with municipal wastewater in wastewater treatment plants (WWTPs). The extent to which the co-treatment of LL and municipal wastewater influences the spread of antibiotic resistance (AR) in the environment has not been examined to date. Two WWTPs with similar wastewater composition and technology were studied. Landfill leachate was co-treated with wastewater in one of the studied WWTPs. Landfill leachate, untreated and treated wastewater from both WWTPs, and river water sampled upstream and downstream from the wastewater discharge point were analyzed. Physicochemical parameters, microbial diversity, and antibiotic resistance genes (ARGs) abundance were investigated to determine the impact of LL co-treatment on chemical and microbiological contamination in the environment. Landfill leachate increased pollutant concentrations in untreated wastewater and river water. Cotreatment of LL and wastewater could affect the abundance and diversity of microbial communities and the interactions between microbial species. Co-treatment also decreased the stability of microbial co-occurrence networks in the examined samples. The mexF gene was identified as a potential marker of environmental pollution with LL. This is the first study to explore the impact of LL on the occurrence of AR determinants in wastewater and rivers receiving effluents.

Thermal co-treatment of aluminum dross and municipal solid waste incineration fly ash: Mineral transformation, crusting prevention, detoxification, and low-carbon cementitious material preparation.

Harmless disposal and resource utilization of hazardous industrial wastes has become an important issue with the green development of human society. However, resource utilization of hazardous solid wastes, such as the production of cementitious materials, is usually accompanied by a pretreatment process to remove adverse impurities that contaminate the final product. In this study, aluminum dross (AD) was thermally co-treated with another hazardous waste, municipal solid incineration fly ash (MSWI-FA), to synergistically solidify F and Na, control leaching of heavy metals, and remove chloride impurities. Significant crusting was observed when AD was thermally treated by itself, but not when AD and MSWI-FA were thermally co-treated. In the process of co-thermal treatment, the remaining Cl, Na, and K contents were reduced to as low as 0.3%, 1.8%, and 0.6%, respectively. CaO and SiO2 in MSWI-FA reacted with Na3AlF6 and Al2O3 in AD, and formed CaF2 and Na6(AlSiO4)6, which contributed to the prevention of crusting and limited the leaching concentrations of F and Na to below detection thresholds and 270.6 mg/L, respectively. In addition, heavy metals were well solidified, and dioxins were fully decomposed during thermal treatment. Finally, a sulfoaluminate cementitious material (SACM) with high early- and later-age strengths was successfully created via synergetic complementarity using thermally co-treated AD and MSWI-FA together with other solid wastes. Collectively, this study outlines a promising method for the efficient and sustainable utilization of AD and MSWI-FA.

Co-treatment of municipal solid waste incineration fly ash (MSWI FA) and municipal sludge: A innovative method to improve sludge dewatering with fly ash dechlorination.

The complexity of municipal sludge dewatering is a bottleneck problem limiting resource utilization. In this paper, adding municipal solid waste incineration fly ash (MSWI FA) to municipal sludge for enhanced dewatering was applied, while the chlorine salt in MSWI FA was simultaneously removed using water in municipal sludge. The effects of different dosages and chemical components of MSWI FA on municipal sludge dewatering, and the removal effect of municipal sludge washing on Cl element were investigated. The results showed that the municipal sludge's specific resistance to filtration after co-treatment was significantly reduced, and more hydrophobic channels were formed in the vacuum suction filtration of the treated municipal sludge, conducive to efficient water removal. The moisture content of municipal sludge was reduced from 96.0% to 48.3%, and the moisture reduction rate increased from 17.7% to 32.1%. The chemical composition of MSWI FA could effectively promote the dewatering of municipal sludge, among which CaO was the best, followed by CaCl2 and NaCl, and KCl was the worst. Simultaneously, the municipal sludge showed a good effect on removing Cl from MSWI FA. The minimum Cl content in the mixture after Co-treatment is 1.5%. These results could provide a new way to dispose of MSWI FA and municipal sludge.

Design, synthesis and evaluation of novel thienopyridazine derivatives as Chk1/2 inhibitors.

In order to search for novel checkpoint kinase 1/2 (Chk1) inhibitors, we have designed and synthesized a series of new compounds incorporating thienopyridazine core. Bioevaluation showed that compounds 10j, 10i, 13e and 10o exhibited relatively good inhibitory activity. Notably, compound 10o displayed high selectivity against a panel of kinases and inhibited Chk1/2 signaling pathway stimulated by DNA damage drugs in cellular level. Molecular docking of 10o to the ATP-binding site of Chk1 kinase domain indicated the existence of polar interactions between 10o and the ATP-ribose-binding residues of Chk1. In mouse HT-29 xenografts, a synergistic effect was observed. Co-treatment by CPT-11 and 10o significantly diminished the tumor volume, indicating the great potential of 10o as a candidate of Chk1/2 inhibitor.

JAK2 Inhibitor, Fedratinib, Inhibits P-gp Activity and Co-Treatment Induces Cytotoxicity in Antimitotic Drug-Treated P-gp Overexpressing Resistant KBV20C Cancer Cells.

P-glycoprotein (P-gp) overexpression is one of the major mechanisms of multidrug resistance (MDR). Previously, co-treatment with Janus kinase 2 (JAK2) inhibitors sensitized P-gp-overexpressing drug-resistant cancer cells. In this study, we assessed the cytotoxic effects of JAK2 inhibitor, fedratinib, on drug-resistant KBV20C cancer cells. We found that co-treatment with fedratinib at low doses induced cytotoxicity in KBV20C cells treated with vincristine (VIC). However, fedratinib-induced cytotoxicity was little effect on VIC-treated sensitive KB parent cells, suggesting that these effects are specific to resistant cancer cells. Fluorescence-activated cell sorting (FACS), Western blotting, and annexin V analyses were used to further investigate fedratinib's mechanism of action in VIC-treated KBV20C cells. We found that fedratinib reduced cell viability, increased G2 arrest, and upregulated apoptosis when used as a co-treatment with VIC. G2 phase arrest and apoptosis in VIC-fedratinib-co-treated cells resulted from the upregulation of p21 and the DNA damaging marker pH2AX. Compared with dimethyl sulfoxide (DMSO)-treated cells, fedratinib-treated KBV20C cells showed two-fold higher P-gp-inhibitory activity, indicating that VIC-fedratinib sensitization is dependent on the activity of fedratinib. Similar to VIC, fedratinib co-treatment with other antimitotic drugs (i.e., eribulin, vinorelbine, and vinblastine) showed increased cytotoxicity in KBV20C cells. Furthermore, VIC-fedratinib had similar cytotoxic effects to co-treatment with other JAK2 inhibitors (i.e., VIC-CEP-33779 or VIC-NVP-BSK805) at the same dose; similar cytotoxic mechanisms (i.e., early apoptosis) were observed between treatments, suggesting that co-treatment with JAK2 inhibitors is generally cytotoxic to P-gp-overexpressing resistant cancer cells. Given that fedratinib is FDA-approved, our findings support its application in the co-treatment of P-gp-overexpressing cancer patients showing MDR.

Low-Dose Rifabutin Increases Cytotoxicity in Antimitotic-Drug-Treated Resistant Cancer Cells by Exhibiting Strong P-gp-Inhibitory Activity.

The cytotoxicity of various antibiotics at low doses in drug-resistant cancer cells was evaluated. Low doses of rifabutin were found to markedly increase the cytotoxicity of various antimitotic drugs, such as vincristine (VIC), to P-glycoprotein (P-gp)-overexpressing antimitotic-drug-resistant KBV20C cells. Rifabutin was also found to exert high levels of P-gp-inhibitory activity at 4 and 24 h posttreatment, suggesting that the cytotoxicity of VIC + rifabutin was mainly due to the direct binding of rifabutin to P-gp and the reduction of VIC efflux by P-gp. The combination of VIC + rifabutin also increased early apoptosis, G2 arrest, and the DNA damaging marker, pH2AX protein. Interestingly, only the combination of VIC + rifabutin induced remarkable levels of cytotoxicity in resistant KBV20C cells, whereas other combinations (VIC + rifampin, VIC + rifapentine, and VIC + rifaximin) induced less cytotoxicity. Such finding suggests that rifabutin specifically increases the cytotoxicity of VIC in KBV20C cells, independent of the toxic effect of the ansamycin antibiotic. Only rifabutin had high P-gp-inhibitory activity, which suggests that its high P-gp-inhibitory activity led to the increased cytotoxicity of VIC + rifabutin. As rifabutin has long been used in the clinic, repositioning this drug for P-gp-overexpressing resistant cancer could increase the availability of treatments for patients with drug-resistant cancer.

Terconazole, an Azole Antifungal Drug, Increases Cytotoxicity in Antimitotic Drug-Treated Resistant Cancer Cells with Substrate-Specific P-gp Inhibitory Activity.

Azole antifungal drugs have been shown to enhance the cytotoxicity of antimitotic drugs in P-glycoprotein (P-gp)-overexpressing-resistant cancer cells. Herein, we examined two azole antifungal drugs, terconazole (TCZ) and butoconazole (BTZ), previously unexplored in resistant cancers. We found that both TCZ and BTZ increased cytotoxicity in vincristine (VIC)-treated P-gp-overexpressing drug-resistant KBV20C cancer cells. Following detailed analysis, low-dose VIC + TCZ exerted higher cytotoxicity than co-treatment with VIC + BTZ. Furthermore, we found that VIC + TCZ could increase apoptosis and induce G2 arrest. Additionally, low-dose TCZ could be combined with various antimitotic drugs to increase their cytotoxicity in P-gp-overexpressing antimitotic drug-resistant cancer cells. Moreover, TCZ exhibited P-gp inhibitory activity, suggesting that the inhibitory activity of P-gp plays a role in sensitization afforded by VIC + TCZ co-treatment. We also evaluated the cytotoxicity of 12 azole antifungal drugs at low doses in drug-resistant cancer cells. VIC + TCZ, VIC + itraconazole, and VIC + posaconazole exhibited the strongest cytotoxicity in P-gp-overexpressing KBV20C and MCF-7/ADR-resistant cancer cells. These drugs exerted robust P-gp inhibitory activity, accompanied by calcein-AM substrate efflux. Given that azole antifungal drugs have long been used in clinics, our results, which reposition azole antifungal drugs for treating P-gp-overexpressing-resistant cancer, could be employed to treat patients with drug-resistant cancer rapidly.

The contribution of tipping fees to the operation, maintenance, and management of fecal sludge treatment plants: The case of Ghana.

Globally, collection of tipping fees is being promoted as a solution to sustain the operation of fecal sludge treatment plants (FSTPs). Currently, there are six large-scale FSTPs in Ghana, of which five were in operation in June 2017. In Kumasi, Sekondi-Takoradi and Tamale, fecal sludge (FS) is co-treated with landfill leachate using waste stabilization ponds (WSPs). In Tema and Accra, FS is treated using WSPs and a mechanical dewatering system coupled with an upflow anaerobic sludge blanket (UASB). The focus of this study is FSTPs and to assess how, and if, the tipping fees set by the municipalities could enable cost recovery to sustain their long-term operation. Using a questionnaire survey to interview plant managers from the public and private sectors, and directors of waste management departments, we found that the overall average operation, maintenance and management (OM&M) costs per 1000 m3 of treated waste (FS or FS + leachate) in 2017 were USD89 in Kumasi, USD150 in Tamale, USD179 in Tema, USD244 in Sekondi-Takoradi and USD1,743 in Accra. There were important disparities between FSTPs due to their scale, age, and level of treatment and monitoring. Currently, most FSTPs charge tipping fees that range between USD310 and USD530/1000 m3 of FS, averaging USD421 ± 98/1000 m3 of FS discharged at FSTPs. Our study also showed that the OM&M costs of large-scale intensive FSTPs cannot be sustained by relying solely on tipping fees. However, there could be potential to cover the routine expenditures associated with operating smaller FSTPs that relying on WSP technologies.

Dydrogesterone versus medroxyprogesterone acetate co-treatment ovarian stimulation for IVF: a matched cohort study of 236 freeze-all-IVF cycles.

This matched cohort study was retrospectively performed, with cycles extracted from freeze-all-IVF treatments performed between March and November 2019, to compare the efficacy of flexible-start dydrogesterone (DYG) co-treatment ovarian stimulations (OS) with flexible-start medroxyprogesterone acetate (MPA) co-treatment OS. DYG cycles were matched 1:1 with MPA cycles using female age and antral follicle count, resulting in 236 matched cycles. OS durations and total FSH doses were similar in DYG and MPA OS cycles. The numbers of mature oocytes retrieved were similar; however, the mature oocyte retrieval rate was significantly lower (66.7 vs. 78.2%; p = .001) and the cycle cancellation rates were higher (29.2 vs. 21.2%; p = .056) in DYG co-treatments. A linear regression selected OS co-treatment protocol (0.53 DYG (0.356-0.776), p = .001) into the final model to predict a ≥ 80% mature oocyte retrieval rate. The per transfer (47.2 vs. 49.7; p = .721) and per treatment ongoing pregnancy rates (32.2 vs. 38.1%, p = .210) were similar in the two co-treatment groups. Flexible-start DYG co-treatment OS was as effective in blastocyst freeze-all-IVF cycles as MPA co-treatment, with similar ongoing pregnancy rates; however, mature oocyte retrieval was significantly decreased and cycle cancellation increased in DYG cycles.Impact statementWhat is already known on this subject? Progestin (i.e. artificial progesterone) co-treatment has long been known to be a feasible alternative to conventional GnRH-analogue co-treatment in OS for IVF, because of the long-standing evidence that progestin formulations have in oral contraceptive therapies. The recent evolution of effective freeze-all-IVF (in which high mid-cycle progesterone levels is not of concern because of the postponement of embryo transfer) has now made it possible to investigate progestin co-treatment OS in IVF.What do the results of this study add? Ongoing pregnancy rates from blastocyst frozen embryo transfers in flexible-start dydrogesterone (DYG) co-treatment ovarian stimulation (OS) cycles were similar to rates in flexible-start medroxyprogesterone acetate (MPA) co-treatment OS cycles. The mature oocyte retrieval rate was significantly lower and the cycle cancellation rate higher in DYG than in MPA cycles.What are the implications of these findings for clinical practice and/or further research? The evidence suggests that MPA co-treatment should be preferred in OS for IVF. Further investigation is required to refine progestin co-treatment protocols, because of their potential to reduce the number of viable blastocysts.

Whole family-based Helicobacter pylori eradication is a superior strategy to single-infected patient treatment approach: A systematic review and meta-analysis.

BACKGROUND: Two critical concerns during Helicobacter pylori (H. pylori) eradication are the successful eradication and recurrence. It is debatable whether whole family-based H. pylori treatment regimen might have any advantage over single-infected patient treatment approach in increasing eradication rate and reducing recurrence rate. We conduct systematic review and meta-analysis to compare the efficacy of these two treatment regimens in order to provide clinical practice a better option for H. pylori eradication. METHODS: Randomized controlled trials evaluating H. pylori eradication and recurrence in whole family-based treatment group (WFTG) versus single-infected patient treatment group (SPTG) were collected from published literature up to July 2020 from common databases. Pooled results were analyzed using either fixed-effect or random-effect model. Results were expressed as the odds ratio (OR) and 95% confidence interval (CI). RESULTS: A total of 1751 relevant articles were identified, and 12 studies were eligible for analysis. Among them: (a) Eight articles including 1198 patients were selected to analyze H. pylori eradication rate, pooled result showed that eradication rate of WFTG was higher than that of SPTG (OR=2.93; 95% CI 1.68-5.13). Stratified analysis showed that H. pylori eradication rate in WFTG were higher over SPTG in children subgroup, but had no difference in spouse subgroup. (b) Six studies including 881 patients were analyzed for recurrence rate between the two groups, pooled analysis showed that the overall recurrence rate of WFTG was lower than that of SPTG (OR=0.3; 95% CI 0.19-0.48). Stratified analysis showed that the recurrence rate in WFTG was lower over SPTG at 6, 12, 18, and more than 24 months post-treatment subgroups. CONCLUSION: Whole family-based H. pylori treatment can partially increase eradication rate and reduce recurrence rate over single-infected patient treatment approach, the results provide clinical practice a novel notion for H. pylori eradication and infection prevention.

Co-Treatments of Edible Curcumin from Turmeric Rhizomes and Chemotherapeutic Drugs on Cytotoxicity and FLT3 Protein Expression in Leukemic Stem Cells.

This study aims to enhance efficacy and reduce toxicity of the combination treatment of a drug and curcumin (Cur) on leukemic stem cell and leukemic cell lines, including KG-1a and KG-1 (FLT3+ LSCs), EoL-1 (FLT3+ LCs), and U937 (FLT3- LCs). The cytotoxicity of co-treatments of doxorubicin (Dox) or idarubicin (Ida) at concentrations of the IC10-IC80 values and each concentration of Cur at the IC20, IC30, IC40, and IC50 values (conditions 1, 2, 3, and 4) was determined by MTT assays. Dox-Cur increased cytotoxicity in leukemic cells. Dox-Cur co-treatment showed additive and synergistic effects in several conditions. The effect of this co-treatment on FLT3 expression in KG-1a, KG-1, and EoL-1 cells was examined by Western blotting. Dox-Cur decreased FLT3 protein levels and total cell numbers in all the cell lines in a dose-dependent manner. In summary, this study exhibits a novel report of Dox-Cur co-treatment in both enhancing cytotoxicity of Dox and inhibiting cell proliferation via FLT3 protein expression in leukemia stem cells and leukemic cells. This is the option of leukemia treatment with reducing side effects of chemotherapeutic drugs to leukemia patients.

Restoration of PP2A levels in inflamed microglial cells: Important for neuroprotective M2 microglial viability.

PP2A, a trimeric Serine/Threonine Protein Phosphatase 2A highly expressed in brain, is a master regulator of cellular functions. Reduction in PP2A activity has been linked to progression of microglial mediated neuroinflammatory diseases. Inflammatory conditions are characterized by increased population of CD86+ve M1 cells and a therapeutic strategy to polarize microglial cells towards CD206+ve M2 cells is the need of hour. In this paper we analyzed A: whether the level of PP2A is altered in CD86+ve cells, B: whether FTY720, a known modulator of PP2A, is able to restore the level of PP2A in inflamed CD86+ve cells. Results revealed that PP2A activity was significantly diminished in inflamed cells but the surprising observation was the cell viability of only 35.99% upon FTY720 treatment in inflamed cells lacking basal PP2A activity. A sharp increase at mRNA level of CD95 and ASK-1 indicated that apoptosis occurred in these cells through CD95/ASK-1/JNK pathway. Importantly, flow cytometric analysis revealed apoptosis of not only CD86+ve cells but also CD206+ve cells. Previous studies have reported that FTY720 polarizes microglial cells towards M2 states; however apoptosis of M2 cells was not studied. As western blot analysis revealed that FTY720 failed to completely restore PP2A, another PP2A modulator, Memantine, was used for co-treatment. Upon co-treatment, the level of PP2A was completely restored and also viability of microglial cells was significantly improved with a significant reduction in apoptosis of M2 cells. These findings suggest that co-treatment strategy may prove beneficial to balance M1/M2 microglial population, thereby improving neuronal functions.

Medroxyprogesterone acetate used in ovarian stimulation is associated with reduced mature oocyte retrieval and blastocyst development: a matched cohort study of 825 freeze-all IVF cycles.

PURPOSE: To compare the effectivity of flexible-start medroxyprogesterone acetate (MPA) co-treatment ovarian stimulations (OS) with flexible-start gonadotropin-releasing hormone antagonist (GnRH-ant) co-treatment OS, in blastocyst freeze-all IVF cycles. METHOD: This matched cohort study was performed at a single IVF center. Study cycles were extracted from freeze-all IVF cycles performed between February 2015 and June 2018 with cycles grouped according to the co-treatment protocol (MPA and GnRH-ant groups) used. MPA cycles were matched 1:1 using antral follicle count, female age, infertility duration, and female body mass index, with GnRH-ant cycles, resulting in 825 matched cycles. MPA or CET co-treatment was started when leading follicles reached 11-12 mm. RESULTS: Duration of OS was significantly longer, and total FSH dose was significantly higher in the MPA group. Numbers of mature oocytes retrieved were similar; however, the mature oocyte retrieval rate (83.8 vs. 97.1%; p < 0.001), number of blastocysts, blastocyst rate (36.4 vs. 41.4%; p < 0.001) and > 2 viable blastocyst rate were all significantly lower in the MPA group. The live birth (LB) per transfer rates (51.6 vs. 55.7%; p = 0.155) were similar; however, the LB rate per treatment was significantly lower (40.9 vs. 45.8%; p = 0.05). A linear regression included the OS co-treatment protocol (GnRH-ant; 1.4 (1.07-1.81); p = 0.013) in the final model to predict having > 2 viable blastocysts. CONCLUSION: Flexible-start MPA co-treatment OS was as effective in freeze-all IVF cycles as GnRH-ant co-treatment, with similar LB per transfer rates; however, increased cycle cancellation and reduced blastocyst numbers reduced LB per treatment rates significantly.

Abatement of circumneutral mine drainage by Co-treatment with secondary municipal wastewater.

Acid mine drainage is a persistent and problematic source of water pollution. Co-treatment with municipal wastewater at existing wastewater treatment plants has several advantages; however, potential impacts on plant physicochemical and biological processes have not been well explored. The primary purpose of this bench-scale study was to examine the impact of co-treatment by combining a mild acid mine drainage at various ratios with municipal wastewater, followed by sludge settling and supernatant comparative analysis using a variety of effluent water quality parameters. These measurements were combined with carbonate system and adsorption isotherm modeling to elucidate the mechanisms underlying the experimental results. Acid mine drainage addition decreased municipal wastewater effluent PO43- concentrations below 0.2 mg/L with greater than 97% removal, demonstrating co-treatment as an alternative solution for municipal wastewater nutrient removal. Biochemical oxygen demand remained similar to controls with <10% variation after co-treatment. Coagulation from metals in acid mine drainage was incomplete due to PO43- adsorption, confirmed by comparing experimental results with Langmuir isotherm behavior. Sweep flocculation was the dominating particle aggregation mechanism, and co-treatment led to improved particle clarification outcomes. Improved clarification led to up to 50% Fe removal. Final pH had little variation with all conditions having pH > 6.0. Carbonate system modeling adequately explains pH effects, and can also be applied to varying acid mine drainage matrices. The impact of acid mine drainage addition on the municipal wastewater microbial community was also investigated which provided evidence of microbial adaptation. This study demonstrates post-aeration co-treatment enables mitigation of mild acid mine drainage without adversely affecting wastewater treatment plant processes. Reported results also frame required future studies to address extant questions prior to full-scale adaptation.

Determining the effects of Class I landfill leachate on biological nutrient removal in wastewater treatment.

The disposal of landfill leachate is a chronic problem facing the municipal solid waste industry. The composition of landfill leachate is highly variable and often dependent on site-specific conditions. Due to the potentially disruptive impact on wastewater treatment processes, wastewater treatment plants (WWTP) are reluctant to accept landfill leachate for co-treatment. To improve the ability of WWTPs to screen the impact of landfill leachate and reduce landfill owners' cost of disposal, two bench scale methods were evaluated. First, six landfill leachates were screened with the specific oxygen uptake rate (SOUR) test, and second, the effect of leachate on the efficacy of activated sludge processes using lab scale sequencing batch reactors (SBRs) was determined with volumetric loading rates ranging from 5% to 20%. Results suggested that these tools can be used to estimate the impacts of leachate loading on biological processes. Both tools were able to identify loadings where biological activity was increased and inhibition of biological processes was minimized. The loading that maximized microbial activity was leachate specific and typically ranged from 5% to 10%. Taken together, these results suggest that improved landfill leachate screening and testing may improve outcomes at WWTPs by identifying a "Goldilocks" loading rate that increases biological activity. Nevertheless, our results also demonstrated that the effluent quality was degraded even at loading rates that increased biological activity. It is uncertain at this time if biological acclimation can remedy increased effluent nutrient mass loadings, suggesting further research is needed.