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Carbamazepine (CBZ), a pharmaceutical compound, has been proposed as an anthropogenic marker to assess water quality due to its persistence in conventional treatment plants and widespread presence in water bodies. This paper presents a comprehensive literature review on sources and occurrences of CBZ in water bodies, as well as toxicological effects and regulations of the drug. Given the documented side effects of CBZ on the human body when taken medicinally, its careful monitoring in water is recommended. CBZ residues in drinking water may provide a pathway to embryos and infants via intrauterine exposure or breast-feeding, which may cause congenital malformations and/or neurodevelopmental problems over long term exposure. An in-depth technical assessment of the conventional and advanced treatment technologies revealed the inadequacy of the standalone technologies. Compared to conventional activated sludge and membrane bioreactor processes, effective removal of CBZ can be achieved by nanofiltration and reverse osmosis membranes. However, recent studies have revealed that harsh chemical cleaning, as required to mitigate membrane fouling, can often reduce the long-term removal efficiency. Furthermore, despite the efficient performance of activated carbon adsorption and advanced oxidation processes, a few challenges such as cost of chemicals and regeneration of activated carbon need to be carefully considered. The limitations of the individual technologies point to the advantages of combined and hybrid systems, namely, membrane bioreactor coupled with nanofiltration, adsorption or advanced oxidation process.

The house dust mite (HDM) is widely recognized as the most prevalent allergen in allergic diseases. Allergen-specific immunotherapy (AIT) has been successfully implemented in clinical treatment for HDM. Hypoallergenic B-cell epitope-based vaccine designed by artificial intelligence (AI) represents a significant progression of recombinant hypoallergenic allergen derivatives. The three-dimensional protein structure of Der f 36 was constructed using Alphafold2. AI-based tools were employed to predict B-cell epitopes, which were subsequently verified through IgE-reaction testing. Hypoallergenic Der f 36 was then synthesized, expressed, and purified. The reduced allergenicity was assessed by enzyme-linked immunosorbent assay (ELISA), immunoblotting, and basophil activation test. T-cell response to hypoallergenic Der f 36 and Der f 36 was evaluated based on cytokine expression in the peripheral blood mononuclear cells (PBMCs) of patients. The immunogenicity was evaluated and compared through rabbit immunization with hypoallergenic Der f 36 and Der f 36, respectively. The inhibitory effect of the blocking IgG antibody on the specific IgE-binding activity and basophil activation of Der f 36 allergen was also examined. The final selected non-allergic B-cell epitopes were 25-48, 57-67, 107-112, 142-151, and 176-184. Hypoallergenic Der f 36 showed significant reduction in IgE-binding activity. The competitive inhibition of IgE-binding to Der f 36 was investigated using the hypoallergenic Der f 36, and only 20% inhibition could be achieved, which is greatly reduced when compared with inhibition by Der f 36 (98%). The hypoallergenic Der f 36 exhibited a low basophil-stimulating ratio similar to that of the negative control, and it could induce an increasing level of IFN-γ but not Th2 cytokines IL-5 and IL-13 in PBMCs. The vaccine-specific rabbit blocking IgG antibodies could inhibit the patients' IgE binding and basophil stimulation activity of Derf 36. This study represents the first application of an AI strategy to facilitate the development of a B-cell epitope-based hypoallergenic Der f 36 vaccine, which may become a promising immunotherapy for HDM-allergic patients due to its reduced allergenicity and its high immunogenicity in inducing blocking of IgG.

This study aimed to explore the effects of peroxisome proliferator-activated receptor α (PPAR-α), a known inhibitor of ferroptosis, in Myocardial ischemia/reperfusion injury (MIRI) and its related mechanisms. In vivo and in vitro MIRI models were established. Our results showed that activation of PPAR-α decreased the size of the myocardial infarct, maintained cardiac function, and decreased the serum contents of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and Fe 2+ in ischemia/reperfusion (I/R)-treated mice. Additionally, the results of H&E staining, DHE staining, TUNEL staining, and transmission electron microscopy demonstrated that activation of PPAR-α inhibited MIRI-induced heart tissue and mitochondrial damage. It was also found that activation of PPAR-α attenuated MIRI-induced ferroptosis as shown by a reduction in malondialdehyde, total iron, and reactive oxygen species (ROS). In vitro experiments showed that intracellular contents of malondialdehyde, total iron, LDH, reactive oxygen species (ROS), lipid ROS, oxidized glutathione disulphide (GSSG), and Fe 2+ were reduced by the activation of PPAR-α in H9c2 cells treated with anoxia/reoxygenation (A/R), while the cell viability and GSH were increased after PPAR-α activation. Additionally, changes in protein levels of the ferroptosis marker further confirmed the beneficial effects of PPAR-α activation on MIRI-induced ferroptosis. Moreover, the results of immunofluorescence and dual-luciferase reporter assay revealed that PPAR-α achieved its activity via binding to the 14-3-3η promoter, promoting its expression level. Moreover, the cardioprotective effects of PPAR-α could be canceled by pAd/14-3-3η-shRNA or Compound C11 (14-3-3η inhibitor). In conclusion, our results indicated that ferroptosis plays a key role in aggravating MIRI, and PPAR-α/14-3-3η pathway-mediated ferroptosis and mitochondrial injury might be an effective therapeutic target against MIRI.

Ring-shaped DNA sliding clamps are essential for DNA replication and genome maintenance. Clamps need to be opened and chaperoned onto DNA by clamp loader complexes (CLCs). Detailed understanding of the mechanisms by which CLCs open and place clamps around DNA remains incomplete. Here, we present a series of six structures of the Escherichia coli CLC bound to an open or closed clamp prior to and after binding to a primer-template DNA, representing the most significant intermediates in the clamp loading process. We show that the ATP-bound CLC first binds to a clamp, then constricts to hold onto it. The CLC then expands to open the clamp with a gap large enough for double-stranded DNA to enter. Upon binding to DNA, the CLC constricts slightly, allowing clamp closing around DNA. These structures provide critical high-resolution snapshots of clamp loading by the E. coli CLC, revealing how the molecular machine works. Replicative sliding clamp loading is critical for DNA replication and repair. Here, authors report structures of major clamp loading intermediates in a bacterial system, revealing how the clamp is opened and loaded onto DNA.

Deficits in the clearance of amyloid β-protein (Aβ) play a pivotal role in the pathogenesis of sporadic Alzheimer’s disease (AD). The roles of blood monocytes in the development of AD remain unclear. In this study, we sought to investigate the alterations in the Aβ phagocytosis function of peripheral monocytes during ageing and in AD patients. A total of 104 cognitively normal participants aged 22–89 years, 24 AD patients, 25 age- and sex-matched cognitively normal (CN) subjects, 15 Parkinson’s disease patients (PD), and 15 age- and sex-matched CN subjects were recruited. The Aβ uptake by blood monocytes was measured and its alteration during ageing and in AD patients were investigated. Aβ 1-42 uptake by monocytes decreased during ageing and further decreased in AD but not in PD patients. Aβ 1-42 uptake by monocytes was associated with Aβ 1-42 levels in the blood. Among the Aβ uptake-related receptors and enzymes, the expression of Toll-like receptor 2 (TLR2) was reduced in monocytes from AD patients. Our findings suggest that monocytes regulate the blood levels of Aβ and might be involved in the development of AD. The recovery of the Aβ uptake function by blood monocytes represents a potential therapeutic strategy for AD.

(HJ) pollen is a predominant autumn allergen in northern China. Two decades ago, a 10 kDa protein termed Hum j 1 was proposed as a major allergen, but its uncertainty hindered its clinical application. This study aims to investigate the clinical relevance of Hum j 1 and screen hypoallergenic peptides for potential application in molecular diagnosis and immunotherapy. Serum samples from 93 HJ pollen-allergic patients were analyzed for IgE reactivity against recombinant Hum j 1 (rHum j 1). We evaluated correlations between IgE responses to rHum j 1 and HJ pollen crude extracts using Spearman's rank correlation analysis. The association between clinical symptoms and Hum j 1-IgE positivity was evaluated by group comparisons and multivariable analyses. Allergenicity of Hum j 1 was further investigated by immunoblotting and basophil activation tests. Six KLH-coupled peptides (21-25 amino acids) spanning the complete Hum j 1 sequence were synthesized to assess hypoallergenicity and IgG-mediated inhibitory effects against allergen-specific IgE binding using a murine passive immunization model. rHum j 1 demonstrated IgE reactivity in 74.2% (69/93) of the patients and induced significant basophil activation. rHum j 1-specific IgE levels showed a moderate positive correlation with crude extract-specific IgE levels (Spearman's ρ = 0.529, < 0.0001). Patients with allergic rhinitis complicated by asthma had significantly higher levels of Hum j 1-sIgE ( = 0.014). We found a significant association between Hum j 1 sensitization and asthma in the multivariate analysis [odds ratio (OR) = 3.98, 95% confidence interval (CI): 1.2-13.0, = 0.02], with Hum j 1-sensitized patients showing higher asthma prevalence compared to non-sensitized individuals (46% vs. 17%, = 0.010). All six peptides showed significantly reduced IgE reactivity ( < 0.0001) and minimal basophil activation. Immunized mice produced high-titer IgG antibodies that inhibited patient IgE binding to rHum j 1 by 22.09%-64.61%. Hum j 1 could enhance the sensitivity of HJ pollen crude extract-based IgE assays. IgE reactivity to Hum j 1 was more frequently associated with allergic asthma. The hypoallergenic linear peptides of Hum j 1 laid the foundation for the development of a molecular vaccine for allergen-specific immunotherapy. These findings would contribute to developing diagnostic and therapeutic strategies for HJ pollinosis.

Myelin loss has been implicated in the development of Alzheimer’s disease (AD). We investigated the changes in myelin basic protein (MBP) levels in cerebrospinal fluid (CSF) in an ageing cohort comprising 116 cognitively normal and Aβ-negative controls aged 26 to 82 years, as well as in a clinical cohort. We found that CSF MBP levels was positively correlated with age in a nonlinear pattern over the lifetime of the ageing cohort and that CSF MBP continually increased until it began to decline around age of 51 years and rose again around age 62. CSF MBP levels were correlated with the Mini-Mental State Examination (MMSE) score and CSF phosphorylated tau-181 (p-tau181) and total tau (t-tau) levels but not the Aβ42/Aβ40 ratio. CSF MBP levels moderated age-related changes in cognitive function. In the clinical cohort, CSF MBP levels were higher in the CSF Aβ+ patients than in the CSF Aβ- participants, and CSF MBP levels were higher in the Aβ–PET+ patients than in the Aβ–PET- participants. CSF MBP levels were higher in apolipoprotein E ε4 allele (APOE-ε4) carriers than in APOE-ε4 noncarriers in the clinical cohort. Our study reveals the possible changes in CSF MBP levels during ageing and in AD patients, providing evidence that demyelination is involved in brain ageing and AD pathogenesis in humans.

The Tus– Ter termination site of Escherichia coli is not completely efficient in stopping DNA replication, with about half of replisomes bypassing this blockade; here the speed of the replication machinery is shown to determine the outcome of the encounter between the replisome and Tus– Ter . DNA replication termination in a bacterium The bacterium Escherichia coli has a single origin of DNA replication, from which two replication complexes, or replisomes, move in opposite directions. They meet about half way round the single circular chromosome, at a termination region, Ter . The Ter site is bound by Tus protein, but this is not completely efficient in stopping replication; about half of the replisomes will bypass this blockade. Samir Hamdan and colleagues now show that a combination of the rate of replisome movement, and the dynamics of Tus interaction with Ter and its displacement, dictate termination efficiency. Consequently, it is the speed of the replication machinery that determines the outcome of the encounter. In all domains of life, DNA synthesis occurs bidirectionally from replication origins. Despite variable rates of replication fork progression, fork convergence often occurs at specific sites 1 . Escherichia coli sets a ‘replication fork trap’ that allows the first arriving fork to enter but not to leave the terminus region 2 , 3 , 4 , 5 . The trap is set by oppositely oriented Tus-bound Ter sites that block forks on approach from only one direction 3 , 4 , 5 , 6 , 7 . However, the efficiency of fork blockage by Tus– Ter does not exceed 50% in vivo despite its apparent ability to almost permanently arrest replication forks in vitro 8 , 9 . Here we use data from single-molecule DNA replication assays and structural studies to show that both polarity and fork-arrest efficiency are determined by a competition between rates of Tus displacement and rearrangement of Tus– Ter interactions that leads to blockage of slower moving replisomes by two distinct mechanisms. To our knowledge this is the first example where intrinsic differences in rates of individual replisomes have different biological outcomes.

Cerebrospinal fluid (CSF) biomarkers are essential for the accurate diagnosis of Alzheimer’s disease (AD), yet their measurement levels vary widely across centers and regions, leaving no uniform cutoff values to date. Diagnostic cutoff values of CSF biomarkers for AD are lacking for the Chinese population. As a member of the Alzheimer’s Association Quality Control program for CSF biomarkers, we aimed to establish diagnostic models based on CSF biomarkers and risk factors for AD in a Chinese cohort. A total of 64 AD dementia patients and 105 age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing & Dementia Study cohort were included. CSF Aβ42, P-tau181, and T-tau levels were measured by ELISA. Combined biomarker models and integrative models with demographic characteristics were established by logistic regression. The cutoff values to distinguish AD from CN were 933 pg/mL for Aβ42, 48.7 pg/mL for P-tau181 and 313 pg/mL for T-tau. The AN model, including Aβ42 and T-tau, had a higher diagnostic accuracy of 89.9%. Integrating age and APOE ε4 status to AN model (the ANA’E model) increased the diagnostic accuracy to 90.5% and improved the model performance. This study established cutoff values of CSF biomarkers and optimal combined models for AD diagnosis in a Chinese cohort.

Tus protein bound to Ter sites on circular bacterial chromosomes provides a way to avoid random crashes of opposing replication forks. DNA-unzipping experiments show that the Tus– Ter –induced lock during unzipping at the nonpermissive face requires only DNA-strand separation. The bidirectional replication of a circular chromosome by many bacteria necessitates proper termination to avoid the head-on collision of the opposing replisomes. In Escherichia coli , replisome progression beyond the termination site is prevented by Tus proteins bound to asymmetric Ter sites. Structural evidence indicates that strand separation on the blocking (nonpermissive) side of Tus– Ter triggers roadblock formation, but biochemical evidence also suggests roles for protein-protein interactions. Here DNA unzipping experiments demonstrate that nonpermissively oriented Tus– Ter forms a tight lock in the absence of replicative proteins, whereas permissively oriented Tus– Ter allows nearly unhindered strand separation. Quantifying the lock strength reveals the existence of several intermediate lock states that are impacted by mutations in the lock domain but not by mutations in the DNA-binding domain. Lock formation is highly specific and exceeds reported in vivo efficiencies. We postulate that protein-protein interactions may actually hinder, rather than promote, proper lock formation.