Transplantation of fecal microbiota from APP/PS1 mice and Alzheimer’s disease patients enhanced endoplasmic reticulum stress in the cerebral cortex of wild-type mice

Background and purposeThe gut-brain axis is bidirectional and the imbalance of the gut microbiota usually coexists with brain diseases, including Alzheimer’s disease (AD). Accumulating evidence indicates that endoplasmic reticulum (ER) stress is a core lesion in AD and persistent ER stress promotes AD pathology and impairs cognition. However, whether the imbalance of the gut microbiota is involved in triggering the ER stress in the brain remains unknown.Materials and methodsIn the present study, fecal microbiota transplantation (FMT) was performed with gut microbiota from AD patients and APP/PS1 mice, respectively, resulting in two mouse models with dysregulated gut microbiota. The ER stress marker protein levels in the cerebral cortex were assessed using western blotting. The composition of the gut microbiota was assessed using 16S rRNA sequencing.ResultsExcessive ER stress was induced in the cerebral cortex of mice after FMT. Elevated ER stress marker proteins (p-perk/perk, p-eIF2α/eIF2α) were observed, which were rescued by 3,3-dimethyl-1-butanol (DMB). Notably, DMB is a compound that significantly attenuates serum trimethylamine-N-oxide (TMAO), a metabolite of the gut microbiota widely reported to affect cognition.ConclusionThe findings indicate that imbalance of the gut microbiota induces ER stress in the cerebral cortex, which may be mediated by TMAO

Assessing the Performance of GPS Precise Point Positioning Under Different Geomagnetic Storm Conditions during Solar Cycle 24

The geomagnetic storm, which is an abnormal space weather phenomenon, can sometimes severely affect GPS signal propagation, thereby impacting the performance of GPS precise point positioning (PPP). However, the investigation of GPS PPP accuracy over the global scale under different geomagnetic storm conditions is very limited. This paper for the first time presents the performance of GPS dual-frequency (DF) and single-frequency (SF) PPP under moderate, intense, and super storms conditions during solar cycle 24 using a large data set collected from about 500 international GNSS services (IGS) stations. The global root mean square (RMS) maps of GPS PPP results show that stations with degraded performance are mainly distributed at high-latitude, and the degradation level generally depends on the storm intensity. The three-dimensional (3D) RMS of GPS DF PPP for high-latitude during moderate, intense, and super storms are 0.393 m, 0.680 m and 1.051 m, respectively, with respect to only 0.163 m on quiet day. RMS errors of mid- and low-latitudes show less dependence on the storm intensities, with values less than 0.320 m, compared to 0.153 m on quiet day. Compared with DF PPP, the performance of GPS SF PPP is inferior regardless of quiet or disturbed conditions. The degraded performance of GPS positioning during geomagnetic storms is attributed to the increased ionospheric disturbances, which have been confirmed by our global rate of TEC index (ROTI) maps. Ionospheric disturbances not only lead to the deteriorated ionospheric correction but also to the frequent cycle-slip occurrence. Statistical results show that, compared with that on quiet day, the increased cycle-slip occurrence are 13.04%, 56.52%, and 69.57% under moderate, intense, and super storms conditions, respectively

Stimulation of Tetrabromobisphenol A Binding to Soil Humic Substances by Birnessite and the Chemical Structure of the Bound Residues

Studies have shown the main fate of the flame retardant tetrabromobisphenol A (TBBPA) in soils is the formation of bound residues, and mechanisms on it are less-understood. This study investigated the effect of birnessite (δ-MnO₂), a naturally occurring oxidant in soils, on the formation of bound residues. ¹⁴C-labeled TBBPA was used to investigate the pH dependency of TBBPA bound-residue formation to two soil humic acids (HAs), Elliott soil HA and Steinkreuz soil HA, in the presence of δ-MnO₂. The binding of TBBPA and its transformation products to both HAs was markedly increased (3- to 17-fold) at all pH values in the presence of δ-MnO₂. More bound residues were formed with the more aromatic Elliott soil HA than with Steinkreuz soil HA. Gel-permeation chromatography revealed a uniform distribution of the bound residues within Steinkreuz soil HA and a nonuniform distribution within Elliott soil HA. ¹³C NMR spectroscopy of ¹³C-TBBPA residues bound to ¹³C-depleted HA suggested that in the presence of δ-MnO₂, binding occurred via ester and ether and other types of covalent bonds besides HA sequestration. The insights gained in this study contribute to an understanding of the formation of TBBPA bound residues facilitated by δ-MnO₂

Coupling biological assays with diffusive gradients in thin-films technique to study the biological responses of Eisenia fetida to cadmium in soil

This work sets out to investigate biological responses of Eisenia fetida to Cd, based on the bioavailable rather than total concentration of Cd, in soils. E. fetida was cultured for 14 d in three selected Chinese soils amended with 0.1–40 mg kg−1 Cd. Potentially bioavailable concentrations of Cd were measured in soil solution, in extractions using CaCl2 and HAc solutions, and using the technique of diffusive gradients in thin-films (DGT). Antioxidant system responses in E. fetida to Cd were measured as biological endpoints. Biological responses were more highly correlated with Cd concentrations evaluated using bioavailable methods than with total concentrations. Cd concentration measured using DGT and CaCl2 extraction provided the narrowest ranges of lowest observed effect concentration (LOEC) values based on biological responses, indicating the potential use of these measurements in management of soil quality and setting soil remediation standards. The LOEC values obtained from 15 field soils contaminated by Cd were similar to those from the three Cd-amended soils and suggested that DGT in particular can be a good tool to predict stress responses of E. fetida to Cd in soils. The study shows the potential of combining biological response and DGT measurements in risk assessment

Atypical Kinetics and Albumin Effect of Glucuronidation of 5-n-Butyl-4-{4-[2-(1H-tetrazole-5- yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6- dichlorophenyl)-3H-1,2,4-triazol-3-one, a Novel Nonpeptide Angiotensin Type 1 Receptor Antagonist, in Liver Microsomes and UDP-Glucuronosyl-transferase

Ib is a new nonpeptide AT1 receptor antagonist, which plays an active role in cardiovascular protection. Ib monoglucuronide has been identified as its main metabolite. A detailed study of Ib glucuronidation is important for predicting potential DDI. Besides, the elucidation of the “BSA effect” in Ib glucuronidation would make obtained kinetic parameters more predictive in IVIVE. “BSA effect” means that there is a significant change in in vitro kinetic parameters when generated from incubations performed in the presence of bovine serum albumin (BSA). Five UGTs (UGT1A3, UGT2B4, UGT2B7, UGT1A9 and UGT1A8) were identified that produced abundant Ib monoglucuronide, especially UGT1A3. We investigated Ib glucuronidation in liver microsomes from different species (rat, dog, human) and in five identified major human UGTs. Ib glucuronidation in liver microsomes and recombinant human UGTs all showed substrate inhibition kinetics. DLM showed the strongest affinity and activity, HLM showed the lowest affinity, and RLM showed the weakest activity. The addition of BSA did not alter the enzyme kinetics, but significantly altered enzyme kinetic parameters resulting in a reduction in Km value and an increase in CLint value. However, high concentrations of BSA could significantly attenuate this positive effect on enzyme affinity and activity, and the effect of BSA on the Vmax of Ib glucuronidation was opposite in different enzyme sources. In conclusion, this study demonstrated the substrate inhibition kinetics of Ib glucuronidation in the liver metabolism and the effect of BSA on its kinetic parameters, in order to provide more accurate in vitro data for in vivo prediction

Characterization of the Metabolome of Breast Tissues from Non-Hispanic Black and Non-Hispanic White Women Reveals Correlations between Microbial Dysbiosis and Enhanced Lipid Metabolism Pathways in Triple-Negative Breast Tumors

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that is non-responsive to hormonal therapies and disproportionately impact women of African ancestry. We previously showed that TN breast tumors have a distinct microbial signature that differs from less aggressive breast tumor subtypes and normal breast tissues. However, it is unknown whether these differences in breast tumor microbiota may be driven by alterations in microbial metabolites, leading to potentially protective or pathogenic consequences. The goal of this global metabolomic profiling study was to investigate alterations in microbial metabolism pathways in normal and breast tumor tissues, including TNBC, of non-Hispanic black (NHB) and non-Hispanic white (NHW) women. In this study, we profiled the microbiome (16S rRNA) from breast tumor tissues and analyzed 984 metabolites from a total of 51 NHB and NHW women. Breast tumor tissues were collected from 15 patients with TNBC, 12 patients with less aggressive luminal A-type (Luminal) breast cancer, and 24 healthy controls for comparison using UHPLC-tandem mass spectrometry. Principal component analysis and hierarchical clustering of the global metabolomic profiling data revealed separation between metabolic signatures of normal and breast tumor tissues. Random forest analysis revealed a unique biochemical signature associated with elevated lipid metabolites and lower levels of microbial-derived metabolites important in controlling inflammation and immune responses in breast tumor tissues. Significant relationships between the breast microbiome and the metabolome, particularly lipid metabolism, were observed in TNBC tissues. Further investigations to determine whether alterations in sphingolipid, phospholipid, ceramide, amino acid, and energy metabolism pathways modulate Fusobacterium and Tenericutes abundance and composition to alter host metabolism in TNBC are necessary to help us understand the risk and underlying mechanisms and to identify potential microbial-based targets

Mesenteric Neural Crest Cells Are the Embryological Basis of Skip Segment Hirschsprung’s DiseaseSummary

Background & Aims: Defective rostrocaudal colonization of the gut by vagal neural crest cells (vNCCs) results in Hirschsprung's disease (HSCR), which is characterized by aganglionosis in variable lengths of the distal bowel. Skip segment Hirschsprung’s disease (SSHD), referring to a ganglionated segment within an otherwise aganglionic intestine, contradicts HSCR pathogenesis and underscores a significant gap in our understanding of the development of the enteric nervous system. Here, we aimed to identify the embryonic origin of the ganglionic segments in SSHD. Methods: Intestinal biopsy specimens from HSCR patients were prepared via the Swiss-roll technique to search for SSHD cases. NCC migration from the neural tube to the gut was spatiotemporally traced using targeted cell lineages and gene manipulation in mice. Results: After invading the mesentery surrounding the foregut, vNCCs separated into 2 populations: mesenteric NCCs (mNCCs) proceeded to migrate along the mesentery, whereas enteric NCCs invaded the foregut to migrate along the gut. mNCCs not only produced neurons and glia within the gut mesentery, but also continuously complemented the enteric NCC pool. Two new cases of SSHD were identified from 183 HSCR patients, and Ednrb-mutant mice, but not Ret-/- mice, showed a high incidence rate of SSHD-like phenotypes. Conclusions: mNCCs, a subset of vNCCs that migrate into the gut via the gut mesentery to give rise to enteric neurons, could provide an embryologic explanation for SSHD. These findings lead to novel insights into the development of the enteric nervous system and the etiology of HSCR

Threshold Concentrations of Silver Ions Exist for the Sunlight-Induced Formation of Silver Nanoparticles in the Presence of Natural Organic Matter

Sunlight-induced photoformation of silver nanoparticles (nAg), mediated by natural organic matter (NOM), is significantly affected by the concentration of Ag­(I) and chloride. The initial photoformation rates of nAg in Suwannee River humic acid (SRHA) and Suwannee River natural organic matter (SRNOM) solutions were examined under simulated sunlight irradiation. A critical induction concentration (CIC) of Ag­(I) (10 mg/L for SRHA and 5 mg/L for SRNOM, respectively) was observed, below which the nAg formation was minimal. The threshold is attributed to the interplay of reduction and oxidation reactions mediated by NOM, reflecting the need to achieve sufficiently fast growth of silver clusters to outcompete oxidative dissolution. The CIC can be reduced by scavenging oxidative radicals or be increased by promoting singlet oxygen and hydrogen peroxide generation. The presence of chloride effectively reduced the CIC by forming AgCl, which facilitates reduction reactions and provides deposition surfaces. SRNOM is more efficient in mediating photoformation of nAg than SRHA, owing to their differed phototransient generation. These results highlight prerequisites for the photoformation of nAg mediated by NOM, in which the photochemistry and solution chemistry are both important