PFASs in Cerebrospinal Fluids and Blood-CSF Barrier Permeability in Patients with Cognitive Impairment.

Attention has been drawn to the associations between PFASs and human cognitive decline. However, knowledge on the occurrence and permeability of PFASs in the brains of patients with cognitive impairment has not been reported. Here, we determined 30 PFASs in paired sera and cerebrospinal fluids (CSFs) from patients with cognitive impairment (n = 41) and controls without cognitive decline (n = 18). We revealed similar serum PFAS levels but different CSF PFAS levels, with lower CSF PFOA (median: 0.125 vs 0.303 ng/mL, p < 0.05), yet higher CSF PFOS (0.100 vs 0.052 ng/mL, p < 0.05) in patients than in controls. Blood-brain transfer rates also showed lower RCSF/Serum values for PFOA and higher RCSF/Serum values for PFOS in patients, implying potential heterogeneous associations with cognitive function. The RCSF/Serum values for C4-C14 perfluoroalkyl carboxylates exhibited a U-shape trend with increasing chain length. Logistic regression analyses demonstrated that CSF PFOS levels were linked to the heightened risk of cognitive impairment [odds ratio: 3.22 (1.18-11.8)] but not for serum PFOS. Toxicity inference results based on the Comparative Toxicogenomics Database suggested that PFOS in CSF may have a greater potential to impair human cognition than other PFASs. Our results contribute to a better understanding of brain PFAS exposure and its potential impact on cognitive function.

[Treatment of ornithine transcarbamylase deficiency in a child with glyceryl phenylbutyrate]. / è‹¯ä¸é ¸ç”˜æ²¹é ¯æ²»ç–—å„¿ç«¥é¸Ÿæ°¨é ¸æ°¨ç”²é °åŸºè½¬ç§»é ¶ç¼ºä¹ç—‡1例.

Glyceryl phenylbutyrate (GPB) serves as a long-term management medication for Ornithine transcarbamylase deficiency (OTCD), effectively controlling hyperammonemia, but there is a lack of experience in using this medicine in China. This article retrospectively analyzes the case of a child diagnosed with OTCD at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, including a review of related literature. After diagnosis, the patient was treated with GPB, followed by efficacy follow-up and pharmacological monitoring. The 6-year and 6-month-old male patient exhibited poor speech development, disobedience, temper tantrums, and aggressive behavior. Blood ammonia levels peaked at 327 µmol/L; urine organic acid analysis indicated elevated uracil levels; cranial MRI showed extensive abnormal signals in both cerebral hemispheres. Genetic testing revealed de novo mutation in the OTC gene (c.241T>C, p.S81P). Blood ammonia levels were approximately 43, 80, and 56 µmol/L at 1, 2, and 3 months after starting GPB treatment, respectively. During treatment, blood ammonia was well-controlled without drug-related adverse effects. The patient showed improvement in developmental delays, obedience, temperament, and absence of aggressive behavior.

The mixed subtype has a worse prognosis than other histological subtypes: a retrospective analysis of 217 patients with metaplastic breast cancer.

OBJECTIVE: Metaplastic breast cancer (MpBC) is an aggressive subtype of all breast cancer. We aimed to investigate the clinicopathological features, treatments and prognoses of MpBC patients. METHODS: We collected the data from MpBC patients diagnosed at Tianjin Medical University Cancer Hospital from 2010 to 2017. Kaplan Meier curves and Cox regression model were used to evaluating clinical outcomes and prognostic factors. After removing baseline differences by propensity score matching (PSM), we analyzed the prognosis between MpBC patients and invasive ductal carcinomas of no special type (IDC-NST) patients. RESULTS: A total of 217 MpBC patients were subsumed. Of all histological subtypes, 45.1% were mixed subtypes, followed by with mesenchymal differentiation (27.2%), pure squamous (15.2%) and pure spindle (12.4%) subtypes. 69.6% of MpBC were triple-negative, 25.3% and 6.5% were HR-positive and HER2-positive. MpBC patients had worse survival compared to IDC-NST patients, with 5-year RFS of 73.8 and 83.6% (HR = 1.177 95%CI (1.171-2.676) P = 0.0068), and 5-year BCSS of 79.0% and 89.7% (HR = 2.187 95%CI (1.357-3.523) P = 0.0013). In the multivariate COX model, AJCC stage, mixed subtype and chemotherapy were independent prognostic factors. Mixed MpBC is more aggressive than pure and with heterologous mesenchymal differentiation subtypes. And whether squamous or spindle MpBC, mixed forms have shorter outcomes than pure forms. CONCLUSIONS: MpBCs are associated with poorer prognoses than IDC-NSTs. They are heterogeneous with different clinicopathological features and clinical outcomes between histological subtypes. Pure and with heterologous mesenchymal differentiation subtypes have more survival benefits than the mixed subtype.

Ultra-broadband flat-top circular polarizer based on chiral fiber gratings near the dispersion turning point.

Based on the dual-resonance principle around the dispersion turning point, a scheme of chiral long-period fiber gratings (CLPGs) formed by twisting a high-birefringence (Hi-Bi) fiber is herein proposed to realise ultra-broadband flat-top circular polarizers. The coupling bandwidth is approximately seven times larger than that of traditional CLPGs. In addition, by introducing chirp characteristics in these CLPGs, an ultra-broadband flat-top circular polarizer with ∼200 nm@3 dB was conveniently achieved. Subsequently, by optimising the chirped CLPGs, a circular polarizer with a bandwidth extinction ratio of approximately 30 dB and a high level of ∼100 nm at 1 dB was realised. It was shown that the mode-controlling performances of the CLPGs can be remarkably improved, which has significant applications in light-field regulation. Finally, for the first time, it was proved that the CLPG cannot generate a vortex beam.

Clinical, biochemical, and genotype-phenotype correlations of 118 patients with Niemann-Pick disease Types A/B.

Niemann-Pick disease Types A and B (NPA/B) are autosomal recessive disorders caused by variants in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. This study aimed to describe and characterize a cohort of 118 patients diagnosed with NPA/B based on clinical, biochemical, and molecular findings, and to identify sound correlations between laboratory findings and clinical presentations. Decreased peripheral leukocyte acid sphingomyelinase activity levels and increased plasma 7-ketocholesterol levels were significantly correlated with disease onset and severity of the clinical course. We identified 92 different sequence SMPD1 variants, including 41 novel variants, in 118 NPA/B patients (19 NPA, 24 intermediate type, 75 NPB). The most prevalent mutation was p.Arg602His, which accounted for 9.3% of the alleles. Patients homozygous for p.Arg602His or p.Asn522Ser showed a late-onset form of the NPB phenotype. The homozygous SMPD1 variant p.Tyr500His correlated with the early-onset NPB clinical form. Additionally, homozygous variants p.His284SerfsX18, p.Phe465Ser, and p.Ser486Arg were associated with the neuronopathic NPA clinical form. The homozygous variant p.Arg3AlafsX74 was associated with the intermediate clinical form. Our study contributes to the understanding of the natural history of NPA/B and assists in the development of efficacious treatments for patients afflicted with this devastating lysosomal storage disorder.

Robust expression of p27Kip1 induced by viral infection is critical for antiviral innate immunity.

Influenza A virus (IAV) infection regulates the expression of numerous host genes. However, the precise mechanism underlying implication of these genes in IAV pathogenesis remains largely unknown. Here, we employed isobaric tags for relative and absolute quantification (iTRAQ) to identify host proteins regulated by IAV infection. iTRAQ analysis of mouse lungs infected or uninfected with IAV showed a total of 167 differentially upregulated proteins in response to the viral infection. Interestingly, we observed that p27Kip1, a potent cyclin-dependent kinase inhibitor, was markedly induced by IAV both at mRNA and protein levels through in vitro and in vivo studies. Furthermore, it was shown that innate immune signalling positively regulated p27Kip1 expression in response to IAV infection. Ectopic expression of p27Kip1 in A549 cells dramatically inhibited IAV replication, whereas, p27Kip1 knockdown significantly enhanced the virus replication. in vivo experiments demonstrated that p27Kip1 knockout (KO) mice were more susceptible to IAV than wild-type (WT) mice: exhibiting higher viral load in lung tissue, faster body-weight loss, reduced survival rate and more severe organ damage. Moreover, we found that p27Kip1 overexpression facilitated the degradation of viral NS1 protein, caused a dramatic STAT1 activation and promoted the expression of IFN-ß and several critical antiviral interferon-stimulated genes (ISGs). Increased p27Kip1 expression also restricted infections of several other viruses. Conversely, IAV-infected p27Kip1 KO mice exhibited a sharp increase in NS1 protein accumulation, reduced level of STAT1 activation and decreased expression of IFN-ß and the ISGs in the lung compared to WT animals. These findings reveal a key role of p27Kip1 in enhancing antiviral innate immunity.

Molecularly imprinted photoelectrochemical sensor for detecting tetrabromobisphenol A in indoor dust and water.

The gradual emissions of tetrabromobisphenol A (TBBPA) from the primitive recycling of E-waste create human health threats, which urgently require to develop an efficient, rapid yet simple detection method. The present study conducts a highly sensitive molecularly imprinted photoelectrochemical sensor (MIPES) containing molecularly imprinted (MI)-TiO2, Au, and reduced graphene oxide for the trace detection of TBBPA in indoor dust and surface water from an E-waste recycling area. The photocurrent response is used to evaluate the sensing performance of the MIPES toward TBBPA detection. The working potential for amperometry is 0.48 V. The wavelength range for photoelectrochemical detection is 320-780 nm. The sensor shows a detection range of 1.68 to 100 nM with a low limit of detection of 0.51 nM (LOD = 3 sb/S) and a limit of quantification of 1.68 nM (LOQ = 3.3 LOD). In addition, the MIPES sensor exhibits rapid, excellent reproducibility, selectivity, and long-term stability toward TBBPA detection. The relative standard deviation of three measurements for real samples is less than 7.0%, and the recovery range is 90.0-115%. The surface of molecular imprinting contributes to the high charge separation and sensing photocurrent response of TBBPA, which is confirmed by single-particle photoluminescence spectroscopy. The present study provides a new facile sensor with highly sensitive yet rapid response to detect environmental pollutants in E-waste by using the MIPES.

Accurate additive manufacturing of lightweight and elastic carbons using plastic precursors.

Despite groundbreaking advances in the additive manufacturing of polymers, metals, and ceramics, scaled and accurate production of structured carbons remains largely underdeveloped. This work reports a simple method to produce complex carbon materials with very low dimensional shrinkage from printed to carbonized state (less than 4%), using commercially available polypropylene precursors and a fused filament fabrication-based process. The control of macrostructural retention is enabled by the inclusion of fiber fillers regardless of the crosslinking degree of the polypropylene matrix, providing a significant advantage to directly control the density, porosity, and mechanical properties of 3D printed carbons. Using the same printed plastic precursors, different mechanical responses of derived carbons can be obtained, notably from stiff to highly compressible. This report harnesses the power of additive manufacturing for producing carbons with accurately controlled structure and properties, while enabling great opportunities for various applications.

Environmentally realistic dose of tire-derived metabolite 6PPD-Q exposure causes intestinal jejunum and ileum damage in mice via cannabinoid receptor-activated inflammation.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q) is a quinone derivative of a common tire additive 6PPD, whose occurrence has been widely reported both in the environment and human bodies including in adults, pregnant women and children. Yet, knowledge on the potential intestinal toxicity of 6PPD-Q in mammals at environmentally relevant dose remain unknown. In this study, the effects of 6PPD-Q on the intestines of adult ICR mice were evaluated by orally administering environmentally relevant dose or lower levels of 6PPD-Q (0.1, 1, 10, and 100 µg/kg) for 21 days. We found that 6PPD-Q disrupted the integrity of the intestinal barrier, mostly in the jejunum and ileum, but not in the duodenum or colon, in a dose-dependent manner. Moreover, intestinal inflammation manifested with elevated levels of TNF-α, IL-1, and IL-6 mostly observed in doses at 10 and 100 µg/kg. Using reverse target screening technology combining molecular dynamic simulation modeling we identified key cannabinoid receptors including CNR2 activation to be potentially mediating the intestinal inflammation induced by 6PPD-Q. In summary, this study provides novel insights into the toxic effects of emerging contaminant 6PPD-Q on mammalian intestines and that the chemical may be a cannabinoid receptor agonist to modulate inflammation.

Piezoelectric-channels in MoS2-embedded polyvinylidene fluoride membrane to activate peroxymonosulfate in membrane filtration for wastewater reuse.

The conjugation of membrane filtration (MF) with advanced oxidation process (AOPs) is being considered as an alternative advanced treatment process for the potable reuse of wastewater. Beyond conventional MF/AOPs conjugation, a new downstream MF process with piezoelectric-channels induced piezo-activated peroxymonosulfate (PMS) is herein constructed to deal with antiepileptic carbamazepine (CBZ) pollutants through polyvinylidene fluoride (PVDF) membrane (PVDF-M10). Through a MF process, ca. 93.8% CBZ pollutants can be removed under an ultrasonic-assisted piezo-activation PMS, whereas only 18.3% and 60.2% CBZ can be removed by using pure PVDF membrane under the same condition and PVDF-M10 membrane without ultrasonic-assisted piezo-activation. Even after 9-cycles, CBZ removal efficiency was maintained at 56.4% under this MF process. These superior performances are attributed to the piezoelectric exfoliated-MoS2 nanosheets (E-MoS2) embedded PVDF nanofibers in PVDF-M10 membrane, which lead to rich piezoelectric-channels in the membrane. These piezoelectric-channels not only produced more charges to activate PMS to boost the yield of reactive oxide species (ROS) but also provided an ideal platform for the rapid reaction between CBZ and ROS during MF process. This investigation develops a new MF technique to conjugate piezo-activation of PMS-AOPs for the efficient removal of emerging pollutants for the potable reuse of wastewater.

DrugormerDTI: Drug Graphormer for drug-target interaction prediction.

Drug-target interactions (DTI) prediction is a crucial task in drug discovery. Existing computational methods accelerate the drug discovery in this respect. However, most of them suffer from low feature representation ability, significantly affecting the predictive performance. To address the problem, we propose a novel neural network architecture named DrugormerDTI, which uses Graph Transformer to learn both sequential and topological information through the input molecule graph and Resudual2vec to learn the underlying relation between residues from proteins. By conducting ablation experiments, we verify the importance of each part of the DrugormerDTI. We also demonstrate the good feature extraction and expression capabilities of our model via comparing the mapping results of the attention layer and molecular docking results. Experimental results show that our proposed model performs better than baseline methods on four benchmarks. We demonstrate that the introduction of Graph Transformer and the design of residue are appropriate for drug-target prediction.

Mechanistic Insights into the Halophilic Xylosidase Xylo-1 and Its Role in Xylose Production.

The Xylo-1 xylosidase, which belongs to the GH43 family, exhibits a high salt tolerance. The present study demonstrated that the catalytic activity of Xylo-1 increased by 195% in the presence of 5 M NaCl. Additionally, the half-life of Xylo-1 increased 25.9-fold in the presence of 1 M NaCl. Through comprehensive analysis including circular dichroism, fluorescence spectroscopy, and molecular dynamics simulations, we elucidated that the presence of Na+ ions increased the contact frequency between the surface acidic amino acids and the surrounding water molecules. This resulted in the stabilization of the surrounding hydration layer of Xylo-1. Additionally, Na+ ions also stabilized the substrate-binding conformation and the fluctuation of water molecules within the active site, which enhanced the catalytic activity of Xylo-1 by increasing the nucleophilic attack by the water molecules. Ultimately, the optimal reaction conditions for the production of xylose by synergistic catalysis with Xylo-1 and xylanase were determined. The results demonstrated that the conversion yield of the method was high for various sources of xylan, indicating the method could have potential industrial applications. This study explored the structure-activity relationship of catalysis in Xylo-1 under high-salt conditions, provides novel insights into the mechanism of halophilic enzymes, and serves as a reference for the industrial application of Xylo-1.

Synthesis, Enzymatic Peptide Incorporation, and Applications of Diazirine-Containing Isoprenoid Diphosphate Analogues.

Prenylated proteins contain C15 or C20 isoprenoids linked to cysteine residues positioned near their C-termini. Here we describe the preparation of isoprenoid diphosphate analogues incorporating diazirine groups that can be used to probe interactions between prenylated proteins and other proteins that interact with them. Studies using synthetic peptides and whole proteins demonstrate that these diazirine analogues are efficient substrates for prenyltransferases. Photo-cross-linking experiments using peptides incorporating the diazirine-functionalized isoprenoids selectively cross-link to several different proteins. These new isoprenoid analogues should be broadly useful in the studies of protein prenylation.

Kupffer cells suppress perfluorononanoic acid-induced hepatic peroxisome proliferator-activated receptor α expression by releasing cytokines.

Kupffer cells (KCs) have been demonstrated to play a role in the regulation of intra-hepatic lipid metabolism through the synthesis and secretion of biologically active products. The involvement of KCs in the disturbance of lipid metabolism that induced by perfluorononanoic acid (PFNA), a known agonist of the peroxisome proliferator-activated receptor alpha (PPARα), was investigated in this study. Rats were exposed to PFNA or PFNA combined with gadolinium chloride, an inhibitor of KCs, for 14 days. PFNA exposure dose-dependently increased absolute and relative liver weights, induced triglyceride accumulation, up-regulated the expression of both SERBP-1c and PPARα, and stimulated the release of TNFα and IL-1ß. Inactivation of KCs markedly lowered TNFα and IL-1ß level, enhanced PFNA-induced expression of PPARα and its target genes, and reduced liver triglyceride levels. In vitro, PFNA-induced expression of PPARα in primary cultured hepatocytes was suppressed by recombinant rat TNFα and IL-1ß. However, inhibition of the NF-κB pathway prevented this. Transient transfection and promoter analysis further revealed that these two cytokines and NF-κB were coordinately involved in the suppression of PPARα promoter activity. Our data demonstrate that TNFα and IL-1ß released from KCs following PFNA exposure can suppress the expression of PPARα via NF-κB pathway, which partially contribute to the evident accumulation of triglycerides in rat liver.

Near-infrared light-assisted methanol oxidation reaction over the ferrous phosphide.

Ferrous phosphide (Fe2P) possesses both functions of near-infrared light (NIR) responsive and metal-support interactional behaviors, which will show great significance in photo-assisted electrocatalytic methanol oxidation reaction (MOR) areas. Hereby, we use Fe2P as the support to load Pt nanoparticles and investigate the performance of the as-obtained Pt-Fe2P for MOR. The results show that the synergistic effect of photocatalysis and electrocatalysis contributes to the high-performance MOR, especially under NIR irradiation. The as-obtained Pt-Fe2P also shows excellent photoelectric response performance and long-time stability of photo-electrocatalytic activity with the assistance of NIR illumination. The mass activities of the Pt-Fe2P catalysts with the assistance of NIR towards MOR is 2430.0 mA mg-1Pt, 4.7 times superior to the dark condition (521.1 mA mg-1Pt), which is obviously better than that of traditional electrocatalysts and some reported photo-electrocatalysts. The strong metal-support interaction between Pt and Fe2P together with NIR excited hot electrons from Fe2P result in the above superior photo-electrocatalytic methanol oxidation abilities. The present investigation offers a NIR-assisted electrocatalytic MOR strategy, which may be a feasible approach to further elevate the catalytic performance for MOR in photo-assisted direct methanol fuel cells (DMFCs).

Harvesting mechanical energy induces piezoelectric polarization of MIL-100(Fe) for cocatalyst-free hydrogen production.

To suit the urgency of a new strategy for hydrogen (H2) evolution, a metal-organic framework (MIL-100(Fe)) is applied in the piezoelectric-driven process for catalytic H2 generation. Herein, the piezoelectric property of MIL-100(Fe) was firstly reported and the material exhibited a high yield of H2 (2.80 mmol g-1 h-1) under mechanical vibration without cocatalysts.

Protruding Pt single-sites on hexagonal ZnIn2S4 to accelerate photocatalytic hydrogen evolution.

Single-site cocatalysts engineered on supports offer a cost-efficient pathway to utilize precious metals, yet improving the performance further with minimal catalyst loading is still highly desirable. Here we have conducted a photochemical reaction to stabilize ultralow Pt co-catalysts (0.26 wt%) onto the basal plane of hexagonal ZnIn2S4 nanosheets (PtSS-ZIS) to form a Pt-S3 protrusion tetrahedron coordination structure. Compared with the traditional defect-trapped Pt single-site counterparts, the protruding Pt single-sites on h-ZIS photocatalyst enhance the H2 evolution yield rate by a factor of 2.2, which could reach 17.5 mmol g-1 h-1 under visible light irradiation. Importantly, through simple drop-casting, a thin PtSS-ZIS film is prepared, and large amount of observable H2 bubbles are generated, providing great potential for practical solar-light-driven H2 production. The protruding single Pt atoms in PtSS-ZIS could inhibit the recombination of electron-hole pairs and cause a tip effect to optimize the adsorption/desorption behavior of H through effective proton mass transfer, which synergistically promote reaction thermodynamics and kinetics.

Photo-assisted simultaneous electrochemical detection of multiple heavy metal ions with a metal-free carbon black anchored graphitic carbon nitride sensor.

The simultaneous detection of multiple heavy metal ions in solution is an important yet highly challenging problem. In this work, a metal-free g-C3N4/carbon black (CB) composite electrode was synthesized by a one-step thermal polycondensation method and characterized by transmission electron microscopy, X-ray photoelectron spectroscopy, X-ray diffraction, and ultraviolet visible light spectroscopy. In addition, the photoelectrochemical response of the g-C3N4/CB nanocomposite to Cd2+, Pb2+ and Hg2+ both separately and as a mixture of the three analytes was investigated by differential pulse anodic stripping voltammetry. The g-C3N4/CB electrode demonstrated an excellent sensing performance to Cd2+, Pb2+ and Hg2+ in the range of 0-700 nM, 0-300 nM and 0-500 nM, respectively, with limits of detection (LOD) of Cd2+, Pb2+, and Hg2+ of 2.1, 0.26 and 0.22 nM, respectively. The LOD of the combined solution of the three analytes was slightly higher at 3.3 nM. Additionally, the metal-free g-C3N4/CB photoelectrochemical sensor exhibited excellent electrochemical stability and electrode reproducibility. Finally, g-C3N4/CB sensor also showed satisfactory results in the detection of trace analyte ions in real environmental systems. This work provides a novel and promising approach in the simultaneous detection of multiple heavy metal ions in solution for practical applications.

Surfactant assisted Cr-metal organic framework for the detection of bisphenol A in dust from E-waste recycling area.

Due to their highly porous structures, metal organic framework materials are widely used in analytic areas. In this paper, Cr-metal organic framework (MIL-101(Cr)) modified electrode was prepared and then was used as electrochemical sensor for the detection of bisphenol A (BPA). By using one kind of surfactant of cetyltrimethylammonium bromide (CTAB), the analytic performances of MIL-101 (Cr) towards BPA detection were greatly improved. Compared with pure MIL-101 (Cr), the differential pulse voltammetry (DPV) behavior of CTAB/MIL-101 (Cr) was improved 3.0 times in the presence of BPA. The hydrophobic long chain alkanes of CTAB can improve the enrichment and electrochemical oxidation for BPA. The CTAB/MIL-101 (Cr) sensor exhibited a linear range from 20 to 350 nM and a low detection limit of 9.95 nM (LOD = 3sb/S) and showed good reproducibility, stability and selectivity. Finally, real samples of dusts from E-waste recycling area in South China were collected and the CTAB/MIL-101 (Cr) sensor demonstrated satisfactory results for BPA detection from these dust samples.