Isolation and characterization of pure cultures for metabolizing 1,4-dioxane in oligotrophic environments.

1,4-Dioxane concentration in most contaminated water is much less than 1 mg/L, which cannot sustain the growth of most reported 1,4-dioxane-metabolizing pure cultures. These pure cultures were isolated following enrichment of mixed cultures at high concentrations (20 to 1,000 mg/L). This study is based on a different strategy: 1,4-dioxane-metabolizing mixed cultures were enriched by periodically spiking 1,4-dioxane at low concentrations (≤1 mg/L). Five 1,4-dioxane-metabolizing pure strains LCD6B, LCD6D, WC10G, WCD6H, and WD4H were isolated and characterized. The partial 16S rRNA gene sequencing showed that the five bacterial strains were related to Dokdonella sp. (98.3%), Acinetobacter sp. (99.0%), Afipia sp. (99.2%), Nitrobacter sp. (97.9%), and Pseudonocardia sp. (99.4%), respectively. Nitrobacter sp. WCD6H is the first reported 1,4-dioxane-metabolizing bacterium in the genus of Nitrobacter. The net specific growth rates of these five cultures are consistently higher than those reported in the literature at 1,4-dioxane concentrations <0.5 mg/L. Compared to the literature, our newly discovered strains have lower half-maximum-rate concentrations (1.8 to 8.2 mg-dioxane/L), lower maximum specific 1,4-dioxane utilization rates (0.24 to 0.47 mg-dioxane/(mg-protein ⋅ d)), higher biomass yields (0.29 to 0.38 mg-protein/mg-dioxane), and lower decay coefficients (0.01 to 0.02 d-1). These are characteristics of microorganisms living in oligotrophic environments.

Effect of 1,4-Dioxane Solvent on ß-Glucuronidation Using Methyl 1,2,3,4-Tetra-O-acetyl-ß-D-glucuronate as the Glycosyl Donor.

A facile and selective ß-D-glucuronidation of alcohols, such as (-)-menthol, cholestanol, (+)- and (-)-borneols, and 2-adamantanol, using commercially available methyl 1,2,3,4-tetra-O-acetyl-ß-D-glucuronate as the glycosyl donor and trimethylsilyl bis(trifluoromethanesulfonyl)imide (Tf2NTMS) (0.5 equivalent) as the activator in 1,4-dioxane at 60 °C gave products in moderate yields. The addition of MS4A increased the ß : α ratios of D-glucuronides when cholestanol, (+)-borneol, and 2-adamantanol were used as the acceptor substrate.

Biomimicking covalent organic frameworks nanocomposite coating for integrated enhanced anticorrosion and antifouling properties of a biodegradable magnesium stent.

The utilization of biodegradable magnesium (Mg) alloys in the fabrication of temporary non-vascular stents is an innovative trend in biomedical engineering. However, the heterogeneous degradation profiles of these biomaterials, together with potential bacterial colonization that could precipitate infectious or stenotic complications, are critical obstacles precluding their widespread clinical application. In pursuit of overcoming these limitations, this study applies the principles of biomimicry, particularly the hydrophobic and anti-fouling characteristics of lotus leaves, to pioneer the creation of nanocomposite coatings. These coatings integrate poly-trimethylene carbonate (PTMC) with covalent organic frameworks (COFs), to modify the stent's surface property. The strategic design of the coating's topography, porosity, and self-polishing capabilities collectively aims to decelerate degradation processes and minimize biological adhesion. The protective qualities of the coatings were substantiated through rigorous testing in both in vitro dynamic bile tests and in vivo New Zealand rabbit choledochal models. Empirical findings from these trials confirmed that the implementation of COF-based nanocomposite coatings robustly fortifies Mg implantations, conferring heightened resistance to both biocorrosion and biofouling as well as improved biocompatibility within bodily environments. The outcomes of this research elucidate a comprehensive framework for the multifaceted strategies against stent corrosion and fouling, thereby charting a visionary pathway toward the systematic conception of a new class of reliable COF-derived surface modifications poised to amplify the efficacy of Mg-based stents. STATEMENT OF SIGNIFICANCE: Biodegradable magnesium (Mg) alloys are widely utilized in temporary stents, though their rapid degradation and susceptibility to bacterial infection pose significant challenges. Our research has developed a nanocomposite coating inspired by the lotus, integrating poly-trimethylene carbonate with covalent organic frameworks (COF). The coating achieved self-polishing property and optimal surface energy on the Mg substrate, which decelerates stent degradation and reduces biofilm formation. Comprehensive evaluations utilizing dynamic bile simulations and implantation in New Zealand rabbit choledochal models reveal that the coating improves the durability and longevity of the stent. The implications of these findings suggest the potential COF-based Mg alloy stent surface treatments and a leap forward in advancing stent performance and endurance in clinical applications.

Comparison of efficacy between clazosentan and fasudil hydrochloride-based management of vasospasm after subarachnoid hemorrhage focusing on older and WFNS grade V patients: a single-center experience in Japan.

Subarachnoid hemorrhage often leads to poor outcomes owing to vasospasm, even after successful aneurysm treatment. Clazosentan, an endothelin receptor inhibitor, has been proven to be an effective treatment for vasospasms in a Japanese randomized controlled trial. However, its efficacy in older patients (≥ 75 years old) and those with World Federation of Neurosurgical Societies (WFNS) grade V has not been demonstrated. We retrospectively evaluated the efficacy of clazosentan in older patients and those with WFNS grade V, using real-world data. Patients with subarachnoid hemorrhage treated before and after the introduction of clazosentan were retrospectively evaluated. The patients were categorized into two groups (clazosentan era versus pre-clazosentan era), in which vasospasm management and outcomes were compared. Vasospasms were managed with fasudil hydrochloride-based (pre-clazosentan era) or clazosentan-based treatment (clazosentan era). Seventy-eight patients were included in this study: the clazosentan era (n = 32) and pre-clazosentan era (n = 46). Overall, clazosentan significantly reduced clinical vasospasms (clazosentan era: 31.3% versus pre-clazosentan era: 60.9%, p = 0.01), delayed cerebral ischemia (DCI) (9.4% versus 39.1%, p = 0.004), and vasospasm-related morbidity and mortality (M/M) (3.1% versus 19.6%, p = 0.03). In subgroup analysis of older patients or those with WFNS grade V, no significant difference was observed in clinical outcomes, although both DCI and vasospasm-related M/M were lower in the clazosentan era. Clazosentan was more effective than fasudil-based management in preventing DCI and reducing vasospasm-related M/M. Clazosentan could be used safely in older patients and those with WFNS grade V, although clinical outcomes in these patients were comparable to those of conventional treatment.

Fabrication and characterization of poly(lactic acid-trimethylene carbonate) based biodegradable composite films.

Two biobased composite films have been prepared with poly (lactic acid-trimethylene carbonate), polylactic acid and Laponite by solvent evaporation method. The 1H NMR and FTIR spectrums illustrate that P (LA-TMC) polymer is successfully synthesized and designed composite films are produced. Morphometric analyses demonstrate that the roughnesses of the film's surface and cross-section are on the increase with higher PLA and Laponite content. Mechanical performances reveal that the rise in tensile strength and modulus while maintaining excellent elongation at break is mainly due to the increase in the content of polylactic acid and Laponite. By utilizing the nano effect of Laponite, the maximum tensile strength of the composite film reaches 34.59 MPa. Thermal property results illustrate that the Tg and initial decomposition temperature are on the growth with the increase of PLA content. However, it is not significant on the effect of Laponite on the initial decomposition temperature. The water vapor permeability measurements prove that the barrier property of P(LA-TMC)/PLA/Laponite composite film is on the ascent with the Laponite addition. Hydrolytic degradation tests indicate that PLA and Laponite play avital part in accelerating the degradation rate of composite films and alkaline media is superior acidic and neutral conditions.

A natural butter glyceride as a plasticizer for improving thermal, mechanical, and biodegradable properties of poly(lactide acid).

Polylactic acid (PLA) is a biobased and biodegradable thermoplastic polyester with great potential to replace petroleum-based plastics. However, its poor toughness and slow biodegradation rate affect broad applications of PLA in many areas. In this study, a glycerol triester existing in natural butter, glycerol tributyrate, was creatively explored and compared with previously investigated triacetin and tributyl citrate, as potential plasticizers of PLA for achieving improved mechanical and biodegradation performances. The compatibilities of these agents with PLA were assessed quantitively via the Hansen solubility parameter (HSP) and measured by using different testing methods. The incorporation of these compounds with varied contents ranging from 1 to 30 % in PLA altered thermal, mechanical, and biodegradation properties consistently, and the relationship and impacts of chemical structures and properties of these agents were systematically investigated. The results demonstrated that glycerol tributyrate is a novel excellent plasticizer for PLA and the addition of this triester not only effectively reduced the glass transition, cold crystallization, and melting temperatures and Young's modulus, but also led to a significant improvement in the enzymatic degradation rate of the plasticized PLA. This study paves a way for the development of sustainable and eco-friendly food grade plasticized PLA products.

Effect of stereo-complexation on crystallization behavior and barrier properties of poly-lactide.

The unique stere-complex crystal formed by poly(ʟ-lactide)/poly(ᴅ-lactide) (PLLA/PDLA) has a significant impact on properties of poly-lactide materials and is considered an effective means to improve the barrier properties of poly-lactide (PLA). In this work, poly-lactide films with different aggregate structures were prepared and the relationship of aggregate structure and barrier properties were explored. The results show that the crystal structure including crystallinity and crystal forms can be controlled by adjusting the isothermal crystallization time and crystallization temperature during the molding process. PLLA/PDLA composite films contain both homochiral crystallites and stereo-complex crystallites, and there is a synergistic crystallization effect between the two of them, which provides the composite films with high crystallinity and excellent barrier properties. Compared to the PLLA with homochiral crystallites, the PLLA/PDLA composite film with only stereo-complex crystallites exhibits higher barrier properties. The linear correlation between the crystallinity and the barrier properties is weak due to the changes in crystallization behavior and then the structure of poly-lactide caused by stereo-complexation. The linear correlation between the crystallinity and the barrier properties of the blend film is strong in the low crystallinity but weak at high crystallinity. Compared to homochiral crystallites, stereo-complex crystallites exhibits lower crystallinity dependence. It has been proven that different crystal forms have different design ideas for preparing high-barrier films, but the stereo-complexation resulting from the intermolecular forces between PLLA and PDLA having complementary chemical structure, is an effective method for enhancing the barrier performances of poly-lactide sustainably.

Fe-ZSM-5 zeolite catalyst for heterogeneous Fenton oxidation of 1,4-dioxane: effect of Si/Al ratios and contributions of reactive oxygen species.

Heterogeneous Fenton oxidation using traditional catalysts with H2O2 for the degradation of 1,4-dioxane (1,4-DX) still presents challenge. In this study, we explored the potential of Fe-ZSM-5 zeolites (Fe-zeolite) with three Si/Al ratios (25, 100, 300) as heterogeneous Fenton catalysts for the removal of 1,4-DX from aqueous solution. Fe2O3 or ZSM-5 alone provided ineffective in degrading 1,4-DX when combined with H2O2. However, the efficient removal of 1,4-DX using H2O2 was observed when Fe2O3 was loaded on ZSM-5. Notably, the Brønsted acid sites of Fe-zeolite played a crucial role during the degradation of 1,4-DX. Fe-zeolites, in combination with H2O2, effectively removed 1,4-DX via a combination of adsorption and oxidation. Initially, Fe-zeolites demonstrated excellent affinity for 1,4-DX, achieving adsorption equilibrium rapidly in about 10 min, followed by effective catalytic oxidative degradation. Among the Fe-ZSM-5 catalysts, Fe-ZSM-5 (25) exhibited the highest catalytic activity and degraded 1,4-DX the fastest. We identified hydroxyl radicals (·OH) and singlet oxygen (1O2) as the primary reactive oxygen species (ROS) responsible for 1,4-DX degradation, with superoxide anions (HO2·/O2·-) mainly converting into 1O2 and ·OH. The degradation primarily occurred at the Fe-zeolite interface, with the degradation rate constants proportional to the amount of Brønsted acid sites on the Fe-zeolite. Fe-zeolites were effective over a wide working pH range, with alkaline pH conditions favoring 1,4-DX degradation. Overall, our study provides valuable insights into the selection of suitable catalysts for effective removal of 1,4-DX using a heterogeneous Fenton technology.

Occurrence of Rhodococcus sp. RR1 prmA and Rhodococcus jostii RHA1 prmA across microbial communities and their enumeration during 1,4-dioxane biodegradation.

1,4-Dioxane, a likely human carcinogen, is a co-contaminant at many chlorinated solvent contaminated sites. Conventional treatment technologies, such as carbon sorption or air stripping, are largely ineffective, and so many researchers have explored bioremediation for site clean-up. An important step towards this involves examining the occurrence of the functional genes associated with 1,4-dioxane biodegradation. The current research explored potential biomarkers for 1,4-dioxane in three mixed microbial communities (wetland sediment, agricultural soil, impacted site sediment) using monooxygenase targeted amplicon sequencing, followed by quantitative PCR (qPCR). A BLAST analysis of the sequencing data detected only two of the genes previously associated with 1,4-dioxane metabolism or co-metabolism, namely propane monooxygenase (prmA) from Rhodococcus jostii RHA1 and Rhodococcus sp. RR1. To investigate this further, qPCR primers and probes were designed, and the assays were used to enumerate prmA gene copies in the three communities. Gene copies of Rhodococcus RR1 prmA were detected in all three, while gene copies of Rhodococcus jostii RHA1 prmA were detected in two of the three sample types (except impacted site sediment). Further, there was a statistically significant increase in RR1 prmA gene copies in the microcosms inoculated with impacted site sediment following 1,4-dioxane biodegradation compared to the control microcosms (no 1,4-dioxane) or to the initial copy numbers before incubation. Overall, the results indicate the importance of Rhodococcus associated prmA, compared to other 1,4-dioxane degrading associated biomarkers, in three different microbial communities. Also, the newly designed qPCR assays provide a platform for others to investigate 1,4-dioxane biodegradation potential in mixed communities and should be of particular interest to those considering bioremediation as a potential 1,4-dioxane remediation approach.

Ubiquitous occurrence of 1,4-dioxane in drinking water of China and its ecological and human health risk.

The occurrence and distribution of 1,4-dioxane was investigated in 280 source and finished drinking water samples from 31 Chinese cities, based on which its ecological and health risks were systematically evaluated. The findings demonstrated that 1,4-dioxane was detected in about 80.0 % samples with values ranging from n.d. to 7757 ng/L in source water and n.d. to 2918 ng/L in drinking water. 1,4-Dioxane showed limited removal efficiency using conventional coagulation-sedimentation-filtration processes (14 % ± 48 %), and a removal efficiency of 35 % ± 44 % using ozonation-biological activated carbon advanced treatment processes. Relatively higher concentrations, detection frequency and environmental risk were observed in Taihu Lake, Yellow River, Yangtze River, Zhujiang River, and Huaihe River mainly in the eastern and southern regions, where there are considerable industrial activities and comparatively high population densities. The widespread presence as by-products during manufacturing consumer products e.g., ethoxylated surfactants, suggested municipal wastewater discharges were the dominant source for the ubiquitous occurrence of 1,4-dioxane, while industrial activities, e.g. resin manufacturing, also contribute considerably to the elevated concentrations of 1,4-dioxane. The estimated risk quotients were in the range of <1.5 × 10-4 for ecological risk, <5.0 × 10-3 by oral exposure and < 5.0 × 10-2 by inhalation exposure for health risk, illustrating limited ecological harm to water environment or chronic toxicity to human health. For carcinogenic risk, 1,4-Dioxane presented a mean risk of 1.8 × 10-6 by oral exposure, which slightly surpassed the recommended acceptable levels of U.S. EPA (<10-6), and risk from inhalation exposure could be negligible. The pervasiveness in drinking water, low removal efficiencies during water treatment processes, and suspected health impacts, highlighted the necessity to set related water quality standards of 1,4-dioxane in order to improve water environment in China.

Factors Influencing Discontinuation of Clazosentan Therapy in Elderly Patients with Aneurysmal Subarachnoid Hemorrhage: A Retrospective Study from a Japanese Single Center.

BACKGROUND Clazosentan is an endothelin receptor antagonist approved in Japan for preventing cerebral vasospasm and vasospasm-associated cerebral ischemia and infarction. This study included elderly patients aged ≥75 years with aneurysmal subarachnoid hemorrhage (SAH) and aimed to evaluate the factors associated with discontinuing anti-vasospasm therapy with clazosentan. MATERIAL AND METHODS In this single-center retrospective observational study, we extracted diagnostic and therapeutic work-up data of consecutive 40 patients with SAH treated with clazosentan infusion (10 mg/h) as first-line anti-vasospasm therapy between May 2022 and August 2023. Patient data were compared between the discontinued and completed groups, and related factors for the discontinuation were further analyzed. RESULTS Clazosentan was discontinued in 22% (n=9) of patients due to intolerable dyspnea accompanied by hypoxemia at 5±3 days after therapy initiation, in which 44% (n=4) were elderly (≥75 years). Patients who discontinued clazosentan therapy showed significantly lower urine volumes compared with those who completed the therapy (P<0.05). Multivariate regression analysis revealed that day-to-day urine volume variance and older age were independent risk factors for drug cessation (P<0.05). The cut-off value for predicting clazosentan discontinuation was -0.7 mL/kg/h with sensitivity of 86% and specificity of 75% (area under the curve: 0.76±0.10; 95% confidence interval: 0.56-0.96; P=0.035). CONCLUSIONS Our results suggest that approximately 20% of SAH patients suffered from intolerable respiratory symptoms attributable to hypoxemia. We found that both reduced day-to-day urine volume variation and older age are independent risk factors for drug discontinuation.

Experimental evidence for immiscibility of enantiomeric polymers: Phase separation of high-molecular-weight poly(ʟ-lactide)/poly(ᴠ-lactide) blends and its impact on hindering stereocomplex crystallization.

Although polymers tend not to mix, it remains challenging to characterize the immiscibility of enantiomeric poly(ʟ-lactide) (PLLA) and poly(ᴅ-lactide) (PDLA), particularly with equivalent and high molecular weight (high MW), which frustratingly disfavors the exclusive stereocomplexation. By introducing a random copolymer (PLC) of ʟ-lactide and caprolactone to form binary blends with PLLA and PDLA, the phase behavior of high-MW PLLA/PDLA blends was investigated mainly by using differential scanning calorimetry (DSC) and atomic force microscopy (AFM). DSC results showed that PLLA/PLC blends exhibited a single glass transition temperature (Tg), which depended on the blending ratio and precisely corresponded with the theoretical values calculated from the Fox equation. In comparison, PDLA/PLC blends showed composition-dependent heat-capacity increment at two unchanged Tg values of pure PLC and PDLA. AFM observation revealed that PLC is completely miscible with PLLA at high MW but is immiscible with PDLA, logically suggesting immiscibility of high-MW PLLA and PDLA. Moreover, AFM results demonstrated that high-MW PLLA/PDLA blends exhibited spherical droplets in asymmetric blends and bicontinuous interpenetrating worm-like patterns in symmetric counterparts, showing distinct and well-defined interfaces, confirming the microphase separation. Additionally, different MWs fundamentally led to significant differences in miscibility, which consequently affected the crystallization behaviors of PLLA/PDLA blends. This work provides evidence for (im)miscibility and its crucial impact on the crystallization of PLLA/PDLA blends and has important implications for understanding the stereocomplexation of polymers.

Resorbable bilayer membrane made of L-lactide-ε-caprolactone in guided bone regeneration: an in vivo experimental study.

PURPOSE: Guided bone regeneration (GBR) is an accepted method in dental practice that can successfully increase the bone volume of the host at sites chosen for implant placement; however, existing GBR membranes exhibit rapid absorption and lack of adequate space maintenance capabilities. We aimed to compare the effectiveness of a newly developed resorbable bilayer membrane composed of poly (L-lactic acid) and poly (-caprolactone) (PLACL) with that of a collagen membrane in a rat GBR model. METHODS: The rat calvaria was used as an experimental model, in which a plastic cylinder was placed. We operated on 40 male Fisher rats and subsequently performed micro-computed tomography and histomorphometric analyses to assess bone regeneration. RESULTS: Significant bone regeneration was observed, which was and similar across all the experimental groups. However, after 24 weeks, the PLACL membrane demonstrated significant resilience, and sporadic partial degradation. This extended preservation of the barrier effect has great potential to facilitate optimal bone regeneration. CONCLUSIONS: The PLACL membrane is a promising alternative to GBR. By providing a durable barrier and supporting bone regeneration over an extended period, this resorbable bilayer membrane could address the limitations of the current membranes. Nevertheless, further studies and clinical trials are warranted to validate the efficacy and safety of The PLACL membrane in humans.

Cardiopulmonary Events of the Elderly (≥75 Years) during Clazosentan Therapy after Subarachnoid Hemorrhage: A Retrospective Study from a Tertiary Stroke Center in Japan.

Clazosentan has been shown to prevent vasospasm and reduce mortality in patients after aneurysmal subarachnoid hemorrhage (SAH) and has been approved for clinical use in Japan; however, its systemic events in the elderly (aged ≥ 75 years) have not been well-documented. Here, we report serious/intolerable cardiopulmonary complications requiring discontinuation of drug therapy in elderly SAH patients. In this single-center case series study, medical records of consecutive SAH patients treated postoperatively with clazosentan (10 mg/h) between June 2022 and May 2023 were reviewed retrospectively. Thirty-three patients received clazosentan therapy, of whom six were elderly with a mean age of 80.3 ± 5.2 (range 75-89) years. Among them, despite no obvious medical history of systemic abnormalities, clazosentan was discontinued in three (50%) patients due to pleural effusion and hypoxemia with or without hypotension at 5 ± 3 days after therapy initiation, which was higher than the incidence for younger patients (15%). The elderly patients had significantly lower urine output (1935 ± 265 vs. 1123 ± 371 mL/day, p = 0.03) and greater weight gain (2.1 ± 1.1 vs. 4.2 ± 1.9 kg from baseline, p = 0.04) than patients who completed the therapy. One 89-year-old female developed congestive heart failure and hydrostatic pulmonary edema associated with increased intravascular and lung volumes even after therapy was discontinued, while the remaining two cases recovered within 2 days after drug cessation. These results suggest that elderly patients are more vulnerable to fluid retention and have a higher risk of cardiopulmonary complications during clazosentan therapy than younger patients. Careful monitoring of urine volume and weight gain and caution regarding age- and therapy-related hemodynamic insufficiencies are required.

Formation of bis-spiropyrrolidines from isatin, secondary amines, and alkylidene Meldrum's acids.

A catalyst-free synthesis of stable bis-spiropyrrolidines from isatin, secondary amines, and alkylidene Meldrum's acids in MeCN in 75-95% yield is described. The antioxidant and antimicrobial properties of the synthesized compounds are investigated. For this purpose, the radical scavenging activities of four derivatives were studied by radical trapping of diphenylpicrylhydrazine and ferric reduction power experiments. Disk diffusion test on Gram-positive and Gram-negative bacteria was employed to investigate antibacterial activities of five derivatives.

The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype, promoting a favorable response to anti-PD-1 therapy via NLRP3 activation.

The main challenges in the use of immune checkpoint inhibitors (ICIs) are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+ T cells. Transforming the tumor microenvironment (TME) from "cold" to "hot" and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment. We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+ mouse models. Using single-cell RNA sequencing, we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion, restoring T-cell function and promoting a favorable immunotherapy response. Mechanistically, we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling, thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production. As a result, APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment, thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity. Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86, p-NF-κB p65 and NLRP3 levels, accompanied by lower CD206 expression on macrophages. Collectively, these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.

Injectable long-acting ivacaftor-loaded poly (lactide-co-glycolide) microparticle formulations for the treatment of cystic fibrosis: In vitro characterization and in vivo pharmacokinetics in mice.

Optimizing a sustained-release drug delivery system for the treatment of cystic fibrosis (CF) is crucial for decreasing the dosing frequency and improving patients' compliance with the treatment regimen. In the current work, we developed an injectable poly(D,L-lactide-co-glycolide) (PLGA) microparticle formulation loaded with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that increases the open probability of the CFTR anion channel, using a single emulsion solvent evaporation technique. We aimed to study the effect of different parameters on the characteristics of the prepared formulations to select an optimized microparticle formulation to be used in an in vivo pharmacokinetic study in mice. First, a suite of ivacaftor-loaded microparticles were prepared using different formulation parameters in order to study the effect of varying these parameters on microparticle size, morphology, drug loading, encapsulation efficiency, and in vitro release profiles. Prepared microparticles were spherical with diameters ranging from 1.91-6.93 µm, percent drug loading (% DL) of 3.91-10.3%, percent encapsulation efficiencies (% EE) of 26.6-100%, and an overall slow cumulative release profile. We selected the formulation that demonstrated optimal combined % DL and % EE values (8.25 and 90.7%, respectively) for further studies. These microparticles had an average particle size of 6.83 µm and a slow tri-phasic in vitro release profile (up to 6 weeks). In vivo pharmacokinetic studies in mice showed that the subcutaneously injected microparticles resulted in steady plasma levels of ivacaftor over a period of 28 days, and a 6-fold increase in AUC 0 - t (71.6 µg/mL*h) compared to the intravenously injected soluble ivacaftor (12.3 µg/mL*h). Our results suggest that this novel ivacaftor-loaded microparticle formulation could potentially eliminate the need for the frequent daily administration of ivacaftor to people with CF thus improving their compliance and ensuring successful treatment outcomes.

Dual phytoremediation and biochar production by Eichhornia crassipes in hydroponic system receiving different 1,4-dioxane dosages.

This study focuses on applying phytoremediation as a low-effective and simple process to treat wastewater laden with 1,4 dioxane (DIOX). A floating macrophyte (Eichhornia crassipes) was cultivated under hydroponic conditions (relative humidity 50-67%, photoperiod cycle 18:6 h light/dark, and 28-33 °C) and subjected to different DIOX loads between 0.0 (control) and 11.5 mg/g fresh mass (FM). The aquatic plant achieved DIOX and chemical oxygen demand (COD) removal efficiencies of 76-96% and 67-94%, respectively, within 15 days. E. crassipes could tolerate elevated DIOX-associated stresses until a dose of 8.2 mg DIOX/g, which highly influenced the oxidative defense system. Malondialdehyde (MDA) content, hydrogen peroxide (H2O2), and total phenolic compounds (TPC) increased by 7.3, 8.4, and 4.5-times, respectively, in response to operating the phytoremediation unit at a DIOX load of 11.5 mg/g. The associated succulent value, proteins, chlorophyll-a, chlorophyll-b, and pigments dropped by 39.6%, 45.8%, 51.5%, 80.8%, and 55.5%, respectively. The suggested removal mechanism of DIOX by E. crassipes could be uptake followed by phytovolatilization, whereas direct photodegradation from sunlight contributed to about 19.36% of the total DIOX removal efficiencies. Recycling the exhausted E. crassipes for biochar production was a cost-efficient strategy, making the payback period of the phytoremediation project equals to 6.96 yr.

Eichhornia crassipes could be used in phytoremediation of 1,4 dioxane (DIOX)-laden water at DIOX load< 8.2 mg/g FM. E. crassipes removed 77­97% DIOX via uptake and phytovolatilization. Recycling exhausted-plant to produce biochar was cost-efficient with 7 yr-payback period.

Detection and elimination of trace d-lactic acid in lignocellulose biorefining chain: Generation, flow, and impact on chiral lactide synthesis.

High chiral purity of lactic acid is a crucial indicator for the synthesis of chiral lactide as the primary intermediate chemical for ring-open polymerization of high molecular weight polylactic acid (PLA). Lignocellulose biomass is the most promising carbohydrate feedstock for commercial production of PLA, but the presence of trace d-lactic acid in the biorefinery chain adversely affects the synthesis and quality of chiral lactide. This study analyzed the fingerprint of trace  d-lactic acid in the biorefinery chain and found that the major source of  d-lactic acid comes from lignocellulose feedstock. The naturally occurring lactic acid bacteria and water-soluble carbohydrates in lignocellulose feedstock provide the necessary conditions for  d-lactic acid generation. Three strategies were proposed to eliminate the generation pathway of  d-lactic acid, including reduction of moisture content, conversion of water-soluble carbohydrates to furan aldehydes in pretreatment, and conversion to  l-lactic acid by inoculating engineered  l-lactic acid bacteria. The natural reduction of lactic acid content in lignocellulose feedstock during storage was observed due to the lactate oxidase-catalyzed oxidation of  l- and  d-lactic acids. This study provided an important support for the production of cellulosic  l-lactic acid with high chiral purity.

Application of portable liquid scintillation counter for on-field measurement of tritium in aqueous samples during radiation emergency.

Screening of aqueous samples for 3H contamination is required to decide suitability of water intended for human consumption during radiation emergency. BARC, Trombay has recently procured Portable Triathler liquid scintillation counter as a screening tool for on-site response to radiation emergency. For this purpose, parameters like, different available scintillators, scintillator to sample ratio and influence of different capacity scintillation vials were optimized for 3H concentration measurement. The study indicated that for 7 mL vials, the optimized scintillator to sample ratio was 4:1 for Optiphase Hisafe II, Ultima Gold Ultra Low Level Tritium, Aqualight AB and Dioxane based scintillators whereas for Ultima Gold AB and Optiphase Hisafe III scintillators it was 3:1. In case of 20 mL vials, the ratio was optimized to 8:1 for all the above mentioned six scintillators. Additionally, the effect of applying counting efficiency using calibration curves generated using distilled water and that obtained using optimized scintillator to sample ratio in various spiked water samples was also studied. Results in 3H concentration (2000-5700 Bq/mL) indicate about ±10% deviation using both the methods for commercially available scintillators. However, in case of Dioxane based scintillator, the deviation was higher (20%). For analysis of 3H concentration ∼200 Bq/mL using commercially available scintillators results in higher deviation of about 21% due to unreliable quench indicating parameter for count rate less than 4000. The study indicated that calibration curves constructed using optimized parameters are universally applicable for determination of 3H concentration in wide variety of water samples.