Pharmacological induction of the fetal γ globin gene and the consequent formation of HbF (α
2
/γ
2
) in adult erythroid cells are one feasible therapeutic strategy for sickle cell disease (SCD) and ...severe β-thalassemias. Hydroxyurea (HU) is the current drug of choice for SCD, but serious side effects limit its clinical use. Moreover, 30 to 50% of patients are irresponsive to HU treatment. We have used high-throughput screening to identify benzodebenzo4,5imidazo2,1-aisoquinolin-7-one and its derivatives (compounds I to VI) as potent γ globin inducers. Of the compounds, I to V exert superior γ globin induction and have better therapeutic potential than HU, likely because of their activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway and modulation of expression levels and/or chromosome binding of γ globin gene regulators, including BCL11A, and chromatin structure over the γ globin promoter. Unlike sodium butyrate (NaB), the global levels of acetylated histones H3 and H4 are not changed by compound II treatment. Remarkably, compound II induces the γ globin gene in HU-resistant primary human adult erythroid cells, the p38 signaling pathway of which appears to be irresponsive to HU and NaB as well as compound II. This study provides a new framework for the development of new and superior compounds for treating SCD and severe β-thalassemias.
It is intriguing to speculate on how continental crust grew and differentiated during the Archean and which tectonic regimes and magmatic mechanisms were responsible for such a process. The ...continental nucleus of the Kaapvaal Craton, which includes the Barberton granitoid-greenstone terrane (BGGT) in South Africa and the Ancient Gneiss Complex (AGC) in Swaziland, exhibits the best preserved geological record from 3.6 to 3.0 Ga and thus provides the optimal location to address this issue. In this study, combined U-Pb, O and Lu-Hf isotope and trace element analyses were carried out on detrital zircon grains from two Moodies Group sandstones and three modern river sand samples in the Barberton and Swaziland regions, southern Africa. The results, in conjunction with previously published data, show that the detrital zircons in the Moodies sandstones on both sides of the Inyoka Fault, had two similar U-Pb age clusters of 3.25–3.30 Ga and 3.40–3.47 Ga and the oldest age up to 3.57 Ga. This suggests that they were derived from older felsic volcanic rocks of the greenstone belt and the granitoid gneisses in the BGGT and AGC. Using the approach created for Earth’s oldest zircons (i.e., Jack Hills detrital zircons), we inferred that the source magmas of the studied detrital zircons had average arc-like andesitic compositions (SiO2 = 58.0 ± 5.6 wt.%; Th/Nb = 5.0 ± 3.2), similar to those of the Jack Hills detrital zircons. However, these inferred compositions conflict with the source rocks of the detrital zircons, namely, the felsic volcanic rocks and the granitoid gneisses in the BGGT and AGC, which have high SiO2 contents (average = 70 ± 4.3 wt.%) and moderate Th/Nb ratios (average = 0.76 ± 0.44). These findings suggest that the inferred average andesitic compositions for the Earth’s oldest zircons should be reevaluated. The U-Pb age spectra of detrital zircons in modern river sands suggest that the exposed rocks in southwestern Swaziland are dominantly ca. 3.45 Ga tonalitic, trondhjemitic and granodioritic (TTG) gneisses without Eoarchean crust. The concordant zircon U-Pb age data reveal four major magmatic episodes for the eastern Kaapvaal Craton at 3.52, 3.46, 3.26 and 3.10 Ga. The first magmatic episode is suggested to dictate crustal growth, whereas the other three magmatic episodes are predominated by crustal reworking. This process is manifested by major positive changes in εHf(t) and εNd(t) values starting at ∼3.5 Ga, gradual decreases in εHf(t) and εNd(t) values afterwards, and increases in δ18O values at ∼3.25 Ga. Combined with other geological observations, we suggest that modern-style plate tectonic processes, such as subduction, may not have been a requirement for crustal growth and reworking in the eastern Kaapvaal Craton during the Paleoarchean (3.6–3.2 Ga). Instead, they could be ascribed to episodic partial convective overturns at different crustal depths.
In this study, thin-film-nanocomposite forward-osmosis membranes (TFC-FOMs) were assembled with the top polyamide layer being modified by using titanium dioxide (TiO2) nanoparticles with ...camphorsulfonic acid and triethylamine (CT) agents to enhance the separation performance and surface hydrophilicity. The TFC-FOMs were characterized and tested for aquaculture wastewater (AWW) recovery in a bench-scale FO system and a multilayer electro-FO (e-FO) system, respectively. Results show that the CT modified FOM had the highest selectivity, followed by the CT-TiO2 modified FOM. A considerably lower reverse solute flux (RSF) and higher permeate flux were achieved in the separation of the electrolyte from the draw feed or solution under the bipolar membrane (BPM)–BPM modes and anion-exchange-membrane (AEM)–cation-exchange-membrane (CEM). When the CT FOM was used in the e-FO system worked in the AEM–CEM mode under a voltage of 1.5 V, the water production degree reached 711.5 L m−2 in continuous AWW recovery for 6 days, and the energy consumption considerably decreased as the number of membrane sheets was raised from 1 to 4. Overall, the consequences indicated the technical viability of the designed e-FO system for achieving high and stable separation efficiency and low energy consumption in long-duration AWW recovery. Thus, this system shows promise for practical field applications.
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•The CT-modified FOM had the highest selectivity.•A considerably lower RSF and higher permeate flux were achieved in AEM–CEM mode.•The water production rate reached 711.5 L m−2 in the e-FO system during continuous AWW recovery.•The e-FO system operated in the AEM–CEM mode can enhance separation efficiency while maintaining low energy consumption.
MicroRNAs (miRNAs) have vital functions in tumorigenesis and cancer progression. The significance of miR‐1908 in cervical cancer has not been determined. We revealed that miR‐1908 was notably ...upregulated in cervical cancer. Upregulation of miR‐1908 increased cervical carcinoma cell growth and invasion. Downregulation of miR‐1908 caused the opposite effects. We confirmed that histone deacetylase 10 (HDAC10) was a potential target of miR‐1908 using bioinformatics analysis and luciferase reporter gene assays. Western blot analysis showed that miR‐1908 regulated the expression of HDAC10 by binding its 3′‐UTR. In addition, ectopic expression of HDAC10 partially reversed the promoting effects of miR‐1908. In conclusion, our findings indicated that miR‐1908 targets HDAC10 in cervical cancer and regulates aggressive cervical cancer cell phenotypes.
Objectives. A recent work has reported that the elevated osteopontin (OPN) levels in the articular cartilage and synovial fluid are correlated with the progressive osteoarthritis (OA) joint damage, ...and OPN has a protective effect against OA by suppressing the expressions of OA-associated genes. The present study examined whether the OPN deficiency was susceptible to OA through the regulation of chondrocyte senescence and apoptosis and the expressions of OA-associated genes. Methods. The mRNA levels of COL2A1 and OPN were compared between human OA chondrocytes and normal chondrocytes. The effects of OPN siRNA on the SA-β-Gal expressions and the percentage of apoptotic chondrocytes were examined by using SA-β-Gal staining and apoptosis assay, and the effects on the expressions of COL2A1 and OA-associated genes (COL10A1, IL-1β, TNF-ɑ, MMP-13, and ADAMTS5) were examined by western blot analysis and quantitative real-time RT-PCR. Furthermore, an in vivo OA model was established to examine the effects of OPN siRNA on the senescence and apoptosis of OA chondrocytes and the expressions of OA-associated genes. Results. The mRNA levels of COL2A1 and OPN were decreased in knee OA chondrocytes in comparison with those in normal chondrocytes. The OPN deficiency enhanced the senescence and apoptosis of OA chondrocytes and increased the expressions of COL10A1, IL-1β, TNF-ɑ, MMP-13, and ADAMTS5 but decreased the expression of COL2A1. Meanwhile, OPN deficiency could result in severe, accelerated OA in vivo, which was also associated with enhanced senescence and apoptosis of chondrocytes and elevated expressions of OA-associated genes. Conclusions. The findings of this study suggest that the OPN deficiency can result in accelerated OA, which is associated with enhanced senescence and apoptosis of OA chondrocytes and the upregulated expressions of OA-associated genes.
The environmental release and fate of estrogens are becoming an increasing public concern. Bacterial degradation has been considered the main process for eliminating estrogens from wastewater ...treatment plants. Various bacterial isolates are reportedly capable of aerobic estrogen degradation, and several estrogen degradation pathways have been proposed in proteobacteria and actinobacteria. However, the ecophysiological relevance of estrogen-degrading bacteria in the environment is unclear. In this study, we investigated the estrogen degradation pathway and corresponding degraders in activated sludge collected from the Dihua Sewage Treatment Plant, Taipei, Taiwan. Cultivation-dependent and cultivation-independent methods were used to assess estrogen biodegradation in the collected activated sludge. Estrogen metabolite profile analysis revealed the production of pyridinestrone acid and two A/B-ring cleavage products in activated sludge incubated with estrone (1 mM), which are characteristic of the 4,5-
pathway. PCR-based functional assays detected sequences closely related to alphaproteobacterial
, a key gene of the 4,5-
pathway. Metagenomic analysis suggested that
spp. are major estrogen degraders in estrone-amended activated sludge.
sp. strain SLCC, an estrone-degrading alphaproteobacterium, was isolated from the examined activated sludge. The general physiology and metabolism of this strain were characterized. Pyridinestrone acid and the A/B-ring cleavage products were detected in estrone-grown strain SLCC cultures. The production of pyridinestrone acid was also observed during the aerobic incubation of strain SLCC with 3.7 nM (1 μg/liter) estrone. This concentration is close to that detected in many natural and engineered aquatic ecosystems. The presented data suggest the ecophysiological relevance of
spp. in activated sludge.
Estrogens, which persistently contaminate surface water worldwide, have been classified as endocrine disruptors and human carcinogens. We contribute new knowledge on the major estrogen biodegradation pathway and estrogen degraders in wastewater treatment plants. This study considerably advances the understanding of environmental estrogen biodegradation, which is instrumental for the efficient elimination of these hazardous pollutants. Moreover, this study substantially improves the understanding of microbial estrogen degradation in the environment.
ObjectiveGGC repeat expansions in the human-specific NOTCH2NLC gene have been reported as the cause of neuronal intranuclear inclusion disease (NIID). Given the clinical overlap of cognitive ...impairment in NIID and cerebral small vessel disease (CSVD), both diseases have white matter hyperintensity on T2-fluid-attenuated inversion recovery sequences of brain MRI, and white matter hyperintensity is a primary neuroimaging marker of CSVD on MRI. Therefore, we hypothesised that the GGC repeat expansions might also contribute to CSVD. To further investigate the relationship between NOTCH2NLC GGC repeat expansions and CSVD, we performed a genetic analysis of 814 patients with the disease.MethodsWe performed a comprehensive GGC repeat expansion screening in NOTCH2NLC from 814 patients with sporadic CSVD. Their Fazekas score was greater than or equal to 3 points. Repeat-primed PCR and fluorescence amplicon length analyses were performed to identify GGC repeat expansions, and whole-exome sequencing was used to detect any pathogenic mutation in previously reported genes associated with CSVD.ResultsWe identified nine (1.11%) patients with pathogenic GGC repeat expansions ranging from 41 to 98 repeats. The minor allele frequency of expanded GGC repeats in NOTCH2NLC was 0.55%.ConclusionOur findings suggest that intermediate-length and longer-length GGC repeat expansions in NOTCH2NLC are associated with sporadic CSVD. This provides new thinking for studying the pathogenesis of CSVD.
Protein homeostasis is well accepted as the prerequisite for proper operation of various life activities. As the main apparatus of protein translation, ribosomes play an indispensable role in the ...maintenance of protein homeostasis. Nevertheless, upon stimulation of various internal and external factors, malfunction of ribosomes may be evident with the excessive production of aberrant proteins, accumulation of which can result in deleterious effects on cellular fate and even cell death. Ribosomopathies are characterized as a series of diseases caused by abnormalities of ribosomal compositions and functions. Correspondingly, cell evolves several ribosome quality control mechanisms in maintaining the quantity and quality of intracellular ribosomes, namely ribosome quality control system (RQCS). Of note, RQCS can tightly monitor the entire process from ribosome biogenesis to its degradation, with the capacity of coping with ribosomal dysfunction, including misassembled ribosomes and incorrectly synthesized ribosomal proteins. In the current literature review, we mainly introduce the RQCS and elaborate on the underlying pathogenesis of several ribosomopathies. With the in-depth understanding of ribosomal dysfunction and molecular basis of RQCS, therapeutic strategy by specifically targeting RQCS remains a promising option in treating patients with ribosomopathies and other ribosome-associated human diseases.
Regulating the doping of carbon dots (CDs) and the generation of reactive oxygen species (ROS) is essential to selectively control their application in photocatalytic organic reactions. This study ...successfully synthesized five newly developed nitrogen-doped carbon dots (CDs 1–5) with varying nitrogen content, which have the ability to generate ROS when exposed to light radiation, specifically superoxide anion radicals (
O
2
-
) and singlet oxygen (
1
O
2
). The utilization of the aforementioned nitrogen-doped CDs as photocatalysts enables the realization of their potential in facilitating efficient photocatalytic organic conversion. Simultaneously, it was observed that the photocatalytic efficiency exhibited a gradual decrease when the nitrogen content in the CDs increased. In order to provide more evidence for this claim, we employed a set of five CDs in the context of photocatalytic dehalogenation of α-bromoacetophenone, photocatalytic oxidative coupling reaction of amines to imines, photooxidation reaction of sulfides to sulfoxides, and cross-dehydrogenation coupling (CDC) reaction, in which it was further observed that there was a steady decrease in the yields of photocatalytic organic reactions as the nitrogen content in CDs increased. Notably, CDs 1 exhibited the best photocatalytic efficiency, thereby reinforcing the hypothesis that a higher nitrogen content corresponds to a decreased catalytic efficiency. This study not only investigates the impact of the nitrogen content on the catalytic performance of CDs, but also offers valuable insights for the future utilization of CDs for photocatalytic organic reactions in water.
This study evaluates the feasibility and efficacy of implanting a leadless pacemaker at the right atrial appendage (RAA) in a preclinical minipig model, aiming to address the limitations of atrial ...pacing with current leadless devices like the Medtronic Micra, which is typically used for right ventricular implantation.
Four minipigs, each with a median body weight of 45.8 ± 10.0 kg, underwent placement of the Micra transcatheter pacing system (TPS) via the right femoral vein into the RAA apex. The pacing performance was assessed over 1-week (short-term) and 3-month (long-term) periods.
The initial findings indicated successful implantation, with satisfactory intrinsic R-wave amplitudes and pacing threshold. In the following period, the sensitivity, threshold, and impedance were stable with time. Notably, upon explanation at 3 months, a deep myocardial penetration by the device was observed, necessitating a redesign for safe long-term use in a growing subject's heart.
While initial results suggest that RAA apex placement of the Micra TPS is promising for potential inclusion in a dual-chamber pacing system, the issue of myocardial penetration highlights the need for device redesign to ensure safety and effectiveness in long-term applications.
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