Synchronous improvement of methane production and digestate dewaterability in sludge anaerobic digestion by nanobubble.

The subsequence anaerobic digestion (AD) of dewatered sludge (DWS) from wastewater treatment plants necessitates an emphasis on enhancing methane production and dewaterability. The effect of different nanobubble water (NBW) on AD of DWS was investigated under mesophilic conditions. Cumulative methane production was improved by 9.0-27.8% with the addition of different NBW (Air, CO2, He, and N2). NBW improved methanogenic performance by significantly enhancing the hydrolysis of sludge AD. Results from the digestate, the capillary suction time, specific resistance to filtration, and moisture content could be decreased by 14.6-18.2%, 18.8-29.6%, and 13.6-19.5%, respectively. The addition of NBW can improve the dewaterability of digestate by reducing the digestate particle size and increasing the zeta potential of digestate. The addition of NBW significantly increased methane production and improved dewaterability in AD; Air-NBW showed the best improvement.

Enhanced hydrolysis and methane yield of temperature-phased dewatered sludge anaerobic digestion by microbial electrolysis cell.

Temperature-phased anaerobic digestion (TPAD) and microbial electrolysis cell (MEC) are both able to improve hydrolysis and methane yield during anaerobic digestion (AD) of dewatered sludge. However, the effect of TPAD and MEC integration at different temperatures and different phases is unclear. This study investigated the effect of the integration of intermittent energization MEC in different phases of TPAD on the digestion of dewatered sludge. Thermophilic and MEC hydrolysis could release higher total ammonia nitrogen of 186.0% and 10.3% than control, mesophilic methanogenesis phase integrated with MEC relieved the ammonia inhibition and accelerated the acid utilization leading to the relief of acid accumulation. The ultimate methane yield of the TPAD integrated with MEC was increased by 118.9%, in which the relative abundance of Methanothermobacteria and Methanosarcina was increased. Therefore, intermittent energization MEC integrated TPAD synchronously improved the hydrolysis and methane yield.

Nanobubble water promotes anaerobic digestion of high-solids cattle manure under mesophilic and thermophilic conditions.

The gradual increase in cattle farming has led to a huge production of cattle manure (CM), but the conventional treatment methods are less efficient. In this study, the treatment method of anaerobic digestion (AD) of high-solids CM by combining nanobubble water (NBW) with different gases was proposed to present a new idea for the reduction, harmlessness, and resourcefulness of CM. It was found that the performance of the digester with added NBW was better than the control. Among them, the cumulative methane yield T-Air: 227.09 mL g-1 VSadded and T-CO2: 226.12 mL g-1 VSadded increased by 17.72 % and 17.22 %, respectively, compared with the control T: 192.90 mL g-1 VSadded under thermophilic conditions. Under mesophilic conditions, M-Air: 162.39 mL g-1 VSadded increased by 9.68 % compared with control M: 148.05 mL g-1 VSadded. Microbial communities analyzed at the genus level revealed that the relative abundance of bacteria favorable to hydrolysis and acid-producing processes, such as Defluviitalea, Haloplasma, and Bacillus, increased to varying degrees. Moreover, the relative abundance of archaea favorable for methanogenesis, such as Methanoculleus, Methanobrevibacter, and Methanosarcina, also increased to varying degrees. Therefore, the addition of NBW promoted the hydrolysis of high-solids CM, enhanced the stability of the reaction, improved the methanogenic performance, and increased the RA of favorable genera, which ultimately led to a better performance of the AD of high-solids CM.

Gender differences in prevalence and clinical correlates of anxiety in first-episode and drug-naïve patients with major depressive disorder comorbid with metabolic syndrome.

BACKGROUND: Although gender differences in major depressive disorder (MDD) have been widely reported, there has not been much focus on gender differences in comorbidity. In patients with MDD and comorbid metabolic syndrome (Mets), the goal of this study was to investigate potential gender differences in the prevalence and clinical correlates of concomitant anxiety. METHODS: Seven hundred and ninety-four first-episode and drug-naïve patients (FEDN) patients with MDD and comorbid Mets were recruited. For each patient, sociodemographic data, thyroid function indicators, and Mets parameters were acquired. Each participant completed the 14-item Hamilton Assessment Scale for Anxiety (HAMA) and the 17-item Hamilton Assessment Scale for Depression (HAMD). RESULTS: There were no gender differences in the prevalence of anxiety in patients with MDD and comorbid Mets. Female patients with MDD had a shorter duration of illness. Correlation analysis showed that HAMD score, TSH, TgAb, and TPOAb were associated with anxiety prevalence in female patients, whereas anxiety onset in male patients was only associated with TSH, TgAb, and TPOAb levels. In addition, multiple logistic regression analysis showed that TSH and TgAb predicted anxiety in male patients, whereas HAMD score and age of onset significantly predicted anxiety in female patients. LIMITATIONS: Cross-sectional design and no control for anxiety-related factors. CONCLUSIONS: Our study showed no gender differences in the prevalence of anxiety in patients with MDD and comorbid Mets. HAMD score was associated with anxiety in female patients, whereas TSH, TgAb, and TPOAb were associated with anxiety in male patients.

Resurrected and Tunable Conductivity and Ferromagnetism in the Secondary Growth La0.7Ca0.3MnO3 on Transferred SrTiO3 Membranes.

To avoid the epitaxy dilemma in various thin films, such as complex oxide, silicon, organic, metal/alloy, etc., their stacking at an atomic level and secondary growth are highly desired to maximize the functionality of a promising electronic device. The ceramic nature of complex oxides and the demand for accurate and long-range-ordered stoichiometry face severe challenges. Here, the transport and magnetic properties of the La0.7Ca0.3MnO3 (LCMO) secondary growth on single-crystal freestanding SrTiO3 (STO) membranes are demonstrated. It has been experimentally found that on an only 10 nm thick STO membrane, the LCMO can offer a bulk-like Curie temperature (TC) of 253 K and negative magnetoresistance of -64%, with a weak dependence on the thickness. The resurrected conductivity and ferromagnetism in LCMO confirm the advantages of secondary growth, which benefits from the excellent flexibility and transferability. Additionally, this study explores the integration strategy of complex oxides with other functional materials.

Prenatal exposure to poly- and perfluoroalkyl substances and postpartum depression in women with twin pregnancies.

BACKGROUND: Women with multiple pregnancies are vulnerable to experience postpartum depression (PPD). Emerging evidence indicates an association between poly- and perfluoroalkyl substances (PFAS) exposure and PPD in women delivering singletons. The health risks of PFAS may also be present in women delivering twins. OBJECTIVE: To estimate the impacts of prenatal PFAS exposure on the risk of PPD in women with twin pregnancies. METHODS: Our study included 150 mothers who gave birth to twins and were enrolled in the Wuhan Twin Birth Cohort. The concentrations of maternal plasma PFAS were measured in each trimester and averaged. Eight individual PFAS were included in analyses. We used Edinburgh Postnatal Depression Scale to evaluate maternal depression at early pregnancy and 1 and 6 months after childbirth. The outcome was dichotomized using a cutoff value of ≥10 for main analyses. Associations were examined using multiple informant models and modified Poisson regressions. PFAS mixture effects were estimated using quantile g-computation. RESULTS: Using quantile g-computation models, a quartile increase in the PFAS mixture during the first, second, third, and average pregnancy was significantly associated with a relative risk (RR) of 1.73 (95% CI: 1.42, 2.12), 1.54 (95% CI: 1.27, 1.84), 1.75 (95% CI: 1.49, 2.08), and 1.63 (95% CI: 1.35, 1.97) for PPD at 6 months after childbirth, respectively. The results of the single-PFAS models also indicated significant positive associations between individual PFAS and PPD at both 1 and 6 months. CONCLUSIONS: The first study of women with twin pregnancies suggests that prenatal exposure to PFAS increases PPD risk up to 6 months postpartum. Twin pregnant women should receive long-term follow-up after delivery and extensive social support.

Psychiatric disorders associated with PCSK9 inhibitors: A real-world, pharmacovigilance study.

BACKGROUND: The relationship between Protein Convertase Subtilisin Kexin Type 9 inhibitor (PCSK9i) and psychiatric adverse events (AEs) remains unclear due to the limitations of clinical trials. In this study, PCSK9i-related psychiatric AEs were realistically observed and systematically summarized in the real world by data mining the FDA AE Reporting System (FAERS). METHOD: Total AEs between the third quarter of 2015 and the first quarter of 2023 were obtained from FAERS. Psychiatric AEs were identified using disproportionality analysis and clinical prioritization of signals using a rating scale, followed by univariate logistic regression to explore factors influencing psychiatric AEs. RESULTS: Psychiatric AEs accounted for 6.7% of the total number of PCSK9i reports. Eighteen psychiatric AEs were defined as PCSK9i-related psychiatric adverse events (ppAEs) (lower 95% CI of both ROR >1 and IC025 > 0). The median age of ppAE reports was 68 years, and female patients accounted for 22.67% of reports, including 41.40% of reports with a serious outcome. Eleven (61.11%) and seven (38.89%) ppAEs were classified as weak and moderate clinical priority, respectively. The median time to onset of ppAEs was 149 and 196 days after treatment with evolocumab and alirocumab, respectively. Patients weighing ≥80 kg were 1.59 times more likely to experience ppAEs. CONCLUSION: The results of this study facilitate the prioritization of psychiatric AE signals by healthcare professionals with the goal of mitigating the risk of PCSK9i-related psychiatric AEs. However, as an exploratory study, our findings need to be confirmed in large-scale prospective studies.

Aggregation Dynamics Characteristics of Seven Different Aß Oligomeric Isoforms-Dependence on the Interfacial Interaction.

The aggregation of ß-amyloid (Aß) peptides has been confirmed to be associated with the onset of Alzheimer's disease (AD). Among the three phases of Aß aggregation, the lag phase has been considered to be the best time for early Aß pathological deposition clinical intervention and prevention for potential patients with normal cognition. Aß peptide exists in various lengths in vivo, and Aß oligomer in the early lag phase is neurotoxic but polymorphous and metastable, depending on Aß length (isoform), molecular weight, and specific phase, and therefore hardly characterized experimentally. To cope with the problem, molecular dynamics simulation was used to investigate the aggregation process of five monomers for each of the seven common Aß isoforms during the lag phase. Results showed that Aß(1-40) and Aß(1-38) monomers aggregated faster than their truncated analogues Aß(4-40) and Aß(4-38), respectively. However, the aggregation rate of Aß(1-42) was slower than that of its truncated analogues Aß(4-42) rather than that of Aßpe(3-42). More importantly, Aß(1-38) is first predicted as more likely to form stable hexamer than the remaining five Aß isoforms, as Aß(1-42) does. It is hydrophobic interaction mainly (>50%) from the interfacial ß1 and ß2 regions of two reactants, pentamer and monomer, aggregated by Aß(1-38)/Aß(1-42) rather than by other Aß isoforms, that drives the hexamer stably as a result of the formation of the effective hydrophobic collapse. This paper provides new insights into the aggregation characteristics of Aß with different lengths and the conditions necessary for Aß to form oligomers with a high molecular weight in the early lag phase, revealing the dependence of Aß hexamer formation on the specific interfacial interaction.

Alternative splicing of IRF3 plays an important role in the development of hepatocarcinoma.

Alternative splicing is a process causing mRNA translation to produce different proteins, and it is crucial for the development of tumours. In this study, we constructed a prognostic model related to alternative splicing events in hepatocarcinoma using bioinformatics analysis, including the alternative splicing of CSAD, AFMID, ZDHHC16, and IRF3. The model is an independent prognostic factor and can accurately predict a patient's prognosis. IRF3 is a transcription factor related to the immune response. Its alternative splicing can affect the expression of various genes related to prognosis and plays an essential role in the tumour microenvironment. We also verified the expression of IRF3 exon skipping isoform in hepatocarcinoma at the mRNA level. In conclusion, we discovered that the alternative splicing of IRF3 is essential for the development of hepatocarcinoma. This study provides new insight into the development of treatments for hepatocarcinoma.

Identification and characterization of the conformation and size of amyloid-ß (42) oligomers targeting the receptor LilrB2.

Experimental observations revealed that the amyloid-ß 42 oligomer (AßO) can directly bind to the LilrB2 D1D2(LDD) receptor with nanomolar-affinity, leading to changes in synaptic plasticity and cognitive deficits. However, the dependence of neurotoxicity on the morphology, size, and aggregation stage (SP1, SP2) of AßO, as well as the specific molecular mechanism of AßO-LDD interaction, remain uncertain. To address these uncertainties, we investigated the interaction between the LDD neuroreceptor and AßO with different Aß42 species (nontoxic species, toxic species, and protofibril) and sizes. Our results showed that the LDD selectively binds AßO species rather than the Aß42 monomer, accommodating various Aß42 dimers and trimers as well as SP2 AßO, in a specific pose in the pocket of the LDD receptor (region I). Additionally, protofibrils with exposed ß1/ß2 regions can also bind to region I of the LDD receptor, as observed experimentally (Cao, et al., Nat. Chem., 2018, 10, 1213; and Aim et al., Nat. Commun., 2021, 12, 3451). More extensively, we identified two additional regions of the LDD receptor, regions II and III, suitable for binding to larger AßO species at the SP1 with different molecular weights and conformations, accounting for the stronger binding strength obtained experimentally. We suggest that the two regions are more competitive than region I in causing toxicity by AßO binding. The detailed and systematic characterization for the complexes generated between the LDD receptor and various AßO species, including the protofibril, offers deep insight into the dependence of neurotoxicity on the AßO size and conformation at the molecular level, and provides novel and specific targets for drug design of Alzheimer's disease.

Origin of stronger binding of ionic pair (IP) inhibitor to Aß42 than the equimolar neutral counterparts: synergy mechanism of IP in disrupting Aß42 protofibril and inhibiting Aß42 aggregation under two pH conditions.

Fibrous aggregates of beta-amyloid (Aß) is a hallmark of Alzheimer's disease (AD). Several major strategies of drugs or inhibitors, including neutral molecules, positive or negative ions, and dual-inhibitor, are used to inhibit the misfolding or aggregation of Aß42, among which a kind of dual-inhibitor composed of a pair of positive and negative ions is emerging as the most powerful candidate. This knowledge lacks the origin of the strong inhibitory effect and synergy mechanisms blocking the development and application of such inhibitors. To this end, we employed 1 : 1 ionic pairs (IP) of oppositely charged benzothiazole molecules (+)BAM1-EG6 (Pos) and (-)BAM1-EG6 (Neg) as well as equimolar neutral BAM1-EG6 (Neu) counterpart at two pH conditions (5.5 and 7.0) to bind Aß42 targets, Aß42 monomer (AßM), soluble pentamer (AßP), and pentameric protofibril (AßF) models, respectively, corresponding to the products of three toxic Aß42 development pathways, lag, exponential and fibrillation phases. Simulated results illustrated the details of the inhibitory mechanisms of IP and Neu for the AßY (Y = M, P, or F) in the three different phases, characterizing the roles of Pos and Neg of IP as well as their charged, hydrophobic groups and linker playing in the synergistic interaction, and elucidated a previously unknown molecular mechanism governing the IP-Aß42 interaction. Most importantly, we first revealed the origin of the stronger binding of IP inhibitors to Aß42 than that of the equimolar neutral counterparts, observing a perplexing phenomenon that the physiological condition (pH = 7.0) than the acidic one (pH = 5.5) is more favorable to the enhancement of IP binding, and finally disclosed that solvation is responsible to the enhancement because at pH 7.0, AßP and AßF act as anionic membranes, where solvation plays a critical role in the chemoelectromechanics. The result not only provides a new dimension in dual-inhibitor/drug design and development but also a new perspective for uncovering charged protein disaggregation under IP-like inhibitors.

Clinical correlates and metabolic indicators of elevated fasting glucose in overweight/obese Chinese Han patients with first-episode and drug-naive major depressive disorder.

Background: Overweight/obese major depressive disorder (MDD) patients have a high probability of developing glucose metabolism disorders; however, the results are inconsistent due to the confounding variables involved in the studies. The purpose of this study was to explore the prevalence and risk factors for elevated fasting glucose in Chinese Han patients with overweight/obese first-episode and drug naïve (FEDN) MDD. Methods: The study used a cross-sectional design and recruited 1718 FEDN MDD patients between the ages of 18 and 60 years. Socio-demographic information, anthropometric data, and biochemical parameters were collected. The 17-item Hamilton Assessment Scale for Depression (HAMD), the 14-item Hamilton Anxiety Scale (HAMA), and the Positive and Negative Syndrome Scale (PANSS) positive subscale were used to assess symptoms of all patients. Results: MDD patients with elevated fasting glucose had higher TSH, TPOAb, TC, TG, LDL-C, systolic and diastolic blood pressure levels than those with normal fasting glucose. Logistic regression analysis showed that age, TSH, TgAb, TPOA, and TG were related factors for elevated fasting glucose, while TSH and combination all these five parameters had the potential to differentiate between patients with elevated fasting glucose and those with normal fasting glucose. Multifactorial regression analysis showed that TSH, TG, and LDL-C were independently associated with elevated fasting glucose. Conclusion: Our findings suggest a high prevalence of elevated fasting glucose in overweight/obese FEDN MDD patients. Several clinically relevant factors and metabolic parameters are associated with elevated fasting glucose in overweight/obese FEDN MDD patients. Limitation: Due to the cross-sectional design, no causal relationship could be derived.

Piperine ameliorates psoriatic skin inflammation by inhibiting the phosphorylation of STAT3.

Psoriasis is a common chronic inflammatory skin disease that is easy to relapse and difficult to cure. Piperine is the main alkaloid extracted from black pepper, and its role in psoriasis has not been previously reported. We identified that piperine ameliorated M5-induced psoriatic skin lesions. Furthermore, piperine alleviated psoriasis pathological features including epidermal hyperplasia and inflammatory cell infiltration, decreased the expression of psoriasis-characteristic cytokines, chemokines and proteins in IMQ-induced psoriasiform dermatitis. Moreover, we determined that piperine inhibited the phosphorylation of STAT3 in M5- and IMQ-induced psoriasis-like skin lesions. Our data demonstrated that piperine ameliorated psoriatic skin inflammation by inhibiting the phosphorylation of STAT3. Therefore, piperine may be one potential compound candidate for psoriasis therapy, providing new strategies for clinical intervention.

Deep eutectic solvent-based manganese dioxide nanosheets composites for determination of DNA by a colorimetric method.

BACKGROUND: Nucleic acid is the carrier of genetic information and the keymolecule in life science. It is important to establish a simple and feasible method for nucleic acid quantification in complex biological samples. METHODS: Four kinds of hydrogen bond acceptors (choline chloride (ChCl), L-carnitine, tetrabutylammonium chloride (TBAC) and cetyltrimethylammonium bromide (CTAB)) were used to synthesize deep eutectic solvents (DESs) with hexafluoroisopropanol (HFIP). DESs based manganese dioxide (MnO2) nanosheets composites was synthesized and characterized. DNA concentration was determined by a UVVis spectrometer. The mechanism of DNA-DES/MnO2 colorimetric system was further discussed. RESULTS: The composite composed of DES/MnO2 exhibited excellent oxidase-like activity and could oxidize 3,3',5,5' -tetramethylbenzidine (TMB) to produce a clear blue change with an absorbance maximum at 652 nm. When DNA is introduced, the DNA can interact with the DES by hydrogen bonding and electrostatic interactions, thereby inhibiting the color reaction of DES/MnO2 with TMB. After condition optimization, ChCl/HFIP DES in 1:3 molar ratio was used for the colorimetric method of DNA determination. The linear range of DNA was 10-130 µg/mL and exhibited good selectivity. CONCLUSION: A colorimetric method based on DES/MnO2 was developed to quantify the DNA concentration. The proposed method can be successfully used to quantify DNA in bovine serum samples.

Association between neutrophil-lymphocyte ratio and perinatal depressive symptoms among Chinese women.

OBJECTIVE: The prevalence of depression has increased dramatically in the past few decades, and pregnant women are at high risk for depression. It is widely thought that inflammation plays a critical role in the pathogenesis of depression. Therefore, we aimed to evaluate the association between the neutrophil-lymphocyte ratio (NLR), a marker of chronic immune inflammation, and perinatal depressive symptoms. METHODS: A cohort study involving 535 pregnant women was conducted based on a prospective birth cohort in Wuhan, China. The Edinburgh Postnatal Depression Scale (EPDS) was used to assess antepartum depression (APD) and postpartum depression (PPD) during the second trimester of pregnancy and one month after delivery. The NLR during the second trimester was determined based on a routine blood test. The association between NLR and depressive symptoms was evaluated using logistic regression analysis and restricted cubic spline (RCS) regression. RESULTS: We found that the prevalence of APD and PPD was 8.4% and 15.1%, respectively. NLR levels were positively associated with APD (OR = 1.52, 95% CI: 1.20--1.91). After adjusting for potential confounders, the OR (95% CI) of APD for the highest NLR quartile was 4.56 (1.58, 13.13) compared with the lowest quartile. No significant association was found between NLR and PPD. RCS regression model analysis indicated a linear correlation between NLR and APD (P for non-linearity = 0.58). CONCLUSION: Overall, elevated mid-trimester NLR is independently associated with APD but not PPD.

Combination Analysis of Ferroptosis and Immune Status Predicts Patients Survival in Breast Invasive Ductal Carcinoma.

Ferroptosis is a new form of iron-dependent cell death and plays an important role during the occurrence and development of various tumors. Increasingly, evidence shows a convincing interaction between ferroptosis and tumor immunity, which affects cancer patients' prognoses. These two processes cooperatively regulate different developmental stages of tumors and could be considered important tumor therapeutic targets. However, reliable prognostic markers screened based on the combination of ferroptosis and tumor immune status have not been well characterized. Here, we chose the ssGSEA and ESTIMATE algorithms to evaluate the ferroptosis and immune status of a TCGA breast invasive ductal carcinoma (IDC) cohort, which revealed their correlation characteristics as well as patients' prognoses. The WGCNA algorithm was used to identify genes related to both ferroptosis and immunity. Univariate COX, LASSO regression, and multivariate Cox regression models were used to screen prognostic-related genes and construct prognostic risk models. Based on the ferroptosis and immune scores, the cohort was divided into three groups: a high-ferroptosis/low-immune group, a low-ferroptosis/high-immune group, and a mixed group. These three groups exhibited distinctive survival characteristics, as well as unique clinical phenotypes, immune characteristics, and activated signaling pathways. Among them, low-ferroptosis and high-immune statuses were favorable factors for the survival rates of patients. A total of 34 differentially expressed genes related to ferroptosis-immunity were identified among the three groups. After univariate, Lasso regression, and multivariate stepwise screening, two key prognostic genes (GNAI2, PSME1) were identified. Meanwhile, a risk prognosis model was constructed, which can predict the overall survival rate in the validation set. Lastly, we verified the importance of model genes in three independent GEO cohorts. In short, we constructed a prognostic model that assists in patient risk stratification based on ferroptosis-immune-related genes in IDC. This model helps assess patients' prognoses and guide individualized treatment, which also further eelucidatesthe molecular mechanisms of IDC.

Identification of personalized neoantigen-based vaccines and immune subtype characteristic analysis of glioblastoma based on abnormal alternative splicing.

The development of personalized neoantigen-based vaccines in cancer immunotherapy has shown promise. In this study, a large-scale bioinformatics analysis was performed to identify potential GBM-associated neoantigens based on abnormal alternative splicing, and then screen suitable patients for vaccination. Gene expression profiles and clinical information were collected from TCGA. We filtered the percent-spliced-in (PSI) spectrum of alternative splicing events in the dataset to identify abnormal alternative splicing events. MAF package was used to identify and analyse tumour mutation burden (TMB) in cancer samples. Tumour Immune Estimation Resource (TIMER) was used to calculate and visualize the infiltration of antigen presenting cells (APCs). In addition, consistent clustering algorithm utilized to identify immune subtypes of GBM. Five potential tumour neoantigens (LRP1, TCF12, DERL3, WIPI2, and TSHZ3) were identified in GBM by selecting genes both with abnormal alternative splicing (upregulated) and gene frameshift mutations, in which LRP1 was significantly associated with APCs. According to the expressions of five potential tumour neoantigens, 160 patients with GBM were divided into three immune subtypes. Patients in cluster3 exhibited good prognoses. Furthermore, the characteristics, including TMB, abnormal alternative splicing events, immune activity, immune cells proportion, and association with tumour biomarkers, were unique in each immune subtypes. The characteristics of cluster3 illustrated that cluster3 participants were more suitable candidates for vaccination. LRP1 was identified as a potential neoantigen for immunotherapy against GBM, and patients in cluster3 were more suitable for vaccination. Our findings provide important guidance for the development of novel neoantigens and therapeutic targets in patients with GBM.

Recognition of Aß oligomer by LilrB2 acceptor: a tetracoordinated zipper mechanism.

Leukocyte immunoglobulin-like receptor B2 (LilrB2) is one of discovered cell surface ß-amyloid (Aß) receptors and taken as a promising therapeutic target for the treatment of Alzheimer's disease (AD). Aß42 oligomer rather than monomer is toxic to neuronal cells and can directly bind to LilrB2, resulting in synaptic loss and cognitive impairment in the development of AD. Therefore, uncovering the mechanism of interaction between Aß42 oligomer and LilrB2 becomes the first step to obtain a clear drug target and specific binding sites. Herein, a tetracoordinated mechanism for the Aß oligomer-LilrB2 binding was first put forward by employing Aß42 dimer mimic-antiparallel copies of Aß42 core fragment 16KLVFFA21, to bind LilrB2 as models, in which four key residues (F5/F6/L12/F14) in the Aß42 mimic are bound strongly with LilrB2 residue(s) or accommodated by four hydrophobic cavities in LilrB2 to generate a stable complex. Bi-dentate binding, however, cannot keep the complex Aß42 mimic-LilrB2 stable. The inhibitor fluspirilene can disturb the binding of four key residues of Aß42 to LilrB2, justifying the tetracoordinated zipper mechanism on the other hand.

Land use, hydrology, and climate influence water quality of China's largest river.

Influences of multiple environmental factors on water quality patterns is less studied in large rivers. Landscape analysis, multiple statistical methods, and the water quality index (WQI) were used to detect water quality patterns and influencing factors in China's largest river, the Yangtze River. Compared with the dry season, the wet season had significantly higher total phosphorus (TP), chemical oxygen demand (COD), total suspended solids (TSS), and turbidity (TUR). The WQI indicated "Moderate" and "Good" water quality in the wet and dry seasons, respectively. Compared with other sites, the upper reach sites that immediately downstream of the Three Gorges Dam had lower TP, TN, TSS and TUR in both seasons, and had lower and higher water temperature in the wet and dry seasons, respectively. Water quality patterns were mainly driven by heterogeneity in land use (i.e., wetland, cropland, and urban land), hydrology (i.e., water flow, water level), and climate (i.e., rainfall, air temperature). Water quality in the wet season was primarily driven by land use while the joint effect of land use and hydrology primarily drove in the dry season. Decision-makers and regulators of large river basin management may need to develop programs that consider influences from both human and natural drivers for water quality conservation.

Molecular engineering and activity improvement of acetylcholinesterase inhibitors: Insights from 3D-QSAR, docking, and molecular dynamics simulation studies.

The carbamate molecule rivastigmine was found to possess promising anti-acetylcholinesterase activity, enabling to target and occupy choline binding sites, and as a result, widely used to improve the treatment of Alzheimer's disease (AD). Higher dose of rivastigmine indicates rapid onset but more adverse effects, such as the large fluctuations in plasma concentration level and frequent incidence of gastrointestinal side effect. To solve the dilemma, we developed a three-dimensional quantitative structure-activity relationship (3D-QSAR), docking and molecular dynamics (MD) simulation strategy to construct a dismountable nanoplatform of inhibitor engineering, verification and application for improving the inhibitory activity per unit concentration. With the aid of 3D-QSAR method, we constructed a model by using 25 molecules reported, and verified well the rationality of these QSAR models by non-cross validation coefficient (r2 = 0.902). Docking and MD results show that rivastigmine, as a control, does target exactly the binding sites of acetylcholinesterase, those already observed experimentally, in turn, confirming the reliability of the present 3D-QSAR results. The method suggests that groups with electron-donating chemical property can improve the inhibitory activity, and screens out two novel inhibitors L-1 and L-2 with more activity from database (about 8000 compounds). Moreover, L-1 and L-2 not only target exactly the same binding sites of acetylcholinesterase as the rivastigmine does, but also hold stronger binding energy, showing a more powerful inhibitory ability. More broadly, this work showcases an approach in the engineering of carbamate inhibitors to enhance their inhibitory activity using electron-donating groups, which simplifies the design process of complex bioactive molecules.