Egg white-derived peptides reduced blood glucose in high-fat-diet and low-dose streptozotocin-induced type 2 diabetic mice via regulating the hepatic gluconeogenic signaling and metabolic profile.

Food proteins are considered an ideal source for the identification of bioactive peptides with the potential to intervene in nutrition-related chronic diseases such as cardiovascular disease, obesity, and diabetes. Egg white-derived peptides (EWPs) have been shown to improve glucose tolerance in insulin-resistant rats. However, underlying mechanisms are to be elucidated. Therefore, we hypothesized that EWP exerts a hypoglycemic effect by regulating hepatic glucose homeostasis. Our results showed that 7 weeks of EWP treatment reduced the fasting blood glucose in T2DM mice and the inhibition of the liver gluconeogenic pathway was involved in the mechanisms of actions. Using the untargeted metabolomics technique, we found that EWP treatment also altered the hepatic metabolic profile in T2DM mice, in which, the role of fatty acid esters of hydroxy fatty acids in mediating the hypoglycemic effect of EWPs might be pivotal.

Quinoxaline-based Y-type acceptors for organic solar cells.

Minimizing energy loss plays a critical role in the quest for high-performance organic solar cells (OSCs). However, the origin of large energy loss in OCSs is complicated, involving the strong exciton binding energy of organic semiconductors, nonradiative charge-transfer state decay, defective molecular stacking network, and so on. The recently developed quinoxaline (Qx)-based acceptors have attracted extensive interest due to their low reorganization energy, high structural modification possibilities, and distinctive molecular packing modes, which contribute to reduced energy loss and superior charge generation/transport, thus improving the photovoltaic performance of OSCs. This perspective summarizes the design strategies of Qx-based acceptors (including small-molecule, giant dimeric and polymeric acceptors) and the resulting optoelectronic properties and device performance. In addition, the ternary strategy of introducing Qx-based acceptors as the third component to reduce energy loss is briefly discussed. Finally, some perspectives for the further exploration of Qx-based acceptors toward efficient, stable, and industry-compatible OSCs are proposed.

Attenuating intervertebral disc degeneration through spermidine-delivery nanoplatform based on polydopamine for persistent regulation of oxidative stress.

As one of the most widespread musculoskeletal diseases worldwide, intervertebral disc degeneration (IVDD) remains an intractable clinical problem. Currently, oxidative stress has been widely considered as a significant risk factor in the IVDD pathological changes, and targeting oxidative stress injury to improve the harsh microenvironment may provide a novel and promising strategy for disc repair. It is evident that spermidine (SPD) has the ability to attenuate oxidative stress across several disease models. However, limited research exists regarding its impact on oxidative stress within the intervertebral disc. Moreover, enhancing the local utilization rate of SPD holds great significance in IVDD management. This study aimed to develop an intelligent biodegradable mesoporous polydopamine (PDA) nanoplatform for sustained release of SPD. The obtained PDA nanoparticles with spherical morphology and mesoporous structure released loaded-therapeutic molecules under low pH and H2O2. Combined treatment with SPD loaded into PDA nanoparticles (SPD/PDA) resulted in better therapeutic potential than those with SPD alone on oxidative stress injury. Furthermore, both SPD and SPD/PDA could induce anti-inflammatory M2 macrophage polarization. Upon injection into degenerative IVDs, the SPD/PDA group achieved a good repair efficacy with a long-term therapeutic effect. These findings indicated that the synergized use of SPD with responsive drug delivery nanocarriers may steadily scavenge reactive oxygen species and provide an effective approach toward the treatment of IVDD.

Molybdenum Disulfide-Supported Cuprous Oxide Nanocomposite for Near-Infrared-I Light-Responsive Synergistic Antibacterial Therapy.

Drug-resistant bacterial infections pose a serious threat to human health; thus, there is an increasingly growing demand for nonantibiotic strategies to overcome drug resistance in bacterial infections. Mild photothermal therapy (PTT), as an attractive antibacterial strategy, shows great potential application due to its good biocompatibility and ability to circumvent drug resistance. However, its efficiency is limited by the heat resistance of bacteria. Herein, Cu2O@MoS2, a nanocomposite, was constructed by the in situ growth of Cu2O nanoparticles (NPs) on the surface of MoS2 nanosheets, which provided a controllable photothermal therapeutic effect of MoS2 and the intrinsic catalytic properties of Cu2O NPs, achieving a synergistic effect to eradicate multidrug-resistant bacteria. Transcriptome sequencing (RNA-seq) results revealed that the antibacterial process was related to disrupting the membrane transport system, phosphorelay signal transduction system, oxidative stress response system, as well as the heat response system. Animal experiments indicated that Cu2O@MoS2 could effectively treat wounds infected with methicillin-resistant Staphylococcus aureus. In addition, satisfactory biocompatibility made Cu2O@MoS2 a promising antibacterial agent. Overall, our results highlight the Cu2O@MoS2 nanocomposite as a promising solution to combating resistant bacteria without inducing the evolution of antimicrobial resistance.

The role of the master cancer regulator Pin1 in the development and treatment of cancer.

This review examines the complex role of Pin1 in the development and treatment of cancer. Pin1 is the only peptidyl-prolyl isomerase (PPIase) that can recognize and isomerize phosphorylated Ser/Thr-Pro peptide bonds. Pin1 catalyzes a structural change in phosphorylated Ser/Thr-Pro motifs that can modulate protein function and thereby impact cell cycle regulation and tumorigenesis. The molecular mechanisms by which Pin1 contributes to oncogenesis are reviewed, including Pin1 overexpression and its correlation with poor cancer prognosis, and the contribution of Pin1 to aggressive tumor phenotypes involved in therapeutic resistance is discussed, with an emphasis on cancer stem cells, the epithelial-to-mesenchymal transition (EMT), and immunosuppression. The therapeutic potential of Pin1 inhibition in cancer is discussed, along with the promise and the difficulties in identifying potent, drug-like, small-molecule Pin1 inhibitors. The available evidence supports the efficacy of targeting Pin1 as a novel cancer therapeutic by analyzing the role of Pin1 in a complex network of cancer-driving pathways and illustrating the potential of synergistic drug combinations with Pin1 inhibitors for treating aggressive and drug-resistant tumors.

Nanoscale zero-valent iron reverses resistance of Pseudomonas aeruginosa to chloramphenicol.

Zero-valent iron (ZVI) has been extensively studied for its capacity to remove various contaminants in the environments. However, whether ZVI affects bacterial resistance to antibiotics has not been fully explored. Herein, it was unexpected that, compared with microscale ZVI (mZVI), nanoscale ZVI (nZVI) facilitated the susceptibility of Pseudomonas aeruginosa (P. aeruginosa) to chloramphenicol (CAP), with a decrease in the minimal inhibitory concentration (MIC) of about 60 %, demonstrating a nanosize-specific effect. nZVI enhanced CAP accumulation in P. aeruginosa via inhibitory effect on efflux pumps activated by MexT, thus conferring the susceptibility of P. aeruginosa to CAP. Circular dichroism spectroscopy revealed that the structure of MexT was changed during the evolution. More importantly, molecular dynamic simulations uncovered that, once the structure of MexT changed, it would be more likely to interact with nZVI, resulting in more serious changes in its secondary structure, which was consistent with the increasing susceptibility of P. aeruginosa to CAP. Collectively, this study elucidated the size-specific effect and the underlying mechanism of ZVI on the bacterial evolution of susceptibility toward antibiotics, highlighting the potentials of nZVI-based technologies on the prevention of bacterial resistance to antibiotics, one of the most important issue for globally public health.

Ziyin Bushen Fang improves Diabetic Osteoporosis by Inhibiting Autophagy and Oxidative Stress In vitro and In vivo.

OBJECTIVE: Diabetic osteoporosis (DOP) belongs to the group of diabetes-induced secondary osteoporosis and is the main cause of bone fragility and fractures in many patients with diabetes. The aim of this study was to determine whether Ziyin Bushen Fang (ZYBSF) can improve DOP by inhibiting autophagy and oxidative stress. METHODS: Type 1 diabetes mellitus (T1DM) was induced in rats using a high-fat high-sugar diet combined with streptozotocin. Micro-CT scanning was used to quantitatively observe changes in the bone microstructure in each group. Changes in the serum metabolites of DOP rats were analyzed using UHPLC-QTOF-MS. The DOP mouse embryonic osteoblast precursor cell model (MC3T3-E1) was induced using high glucose levels. RESULTS: After ZYBSF treatment, bone microstructure significantly improved. The bone mineral density, trabecular number, and trabecular thickness in the ZYBSF-M and ZYBSF-H groups significantly increased. After ZYBSF treatment, the femur structure of the rats was relatively intact, collagen fibers were significantly increased, and osteoporosis was significantly improved. A total of 1239 metabolites were upregulated and 1527 were downregulated in the serum of T1DM and ZYBSF-treated rats. A total of 20 metabolic pathways were identified. In cellular experiments, ZYBSF reduced ROS levels and inhibited the protein expression of LC3II / I, Beclin-1, and p-ERK. CONCLUSION: ZYBSF may improve DOP by inhibiting the ROS/ERK-induced autophagy signaling pathway.

Pin1-Catalyzed Conformation Changes Regulate Protein Ubiquitination and Degradation.

The unique prolyl isomerase Pin1 binds to and catalyzes cis-trans conformational changes of specific Ser/Thr-Pro motifs after phosphorylation, thereby playing a pivotal role in regulating the structure and function of its protein substrates. In particular, Pin1 activity regulates the affinity of a substrate for E3 ubiquitin ligases, thereby modulating the turnover of a subset of proteins and coordinating their activities after phosphorylation in both physiological and disease states. In this review, we highlight recent advancements in Pin1-regulated ubiquitination in the context of cancer and neurodegenerative disease. Specifically, Pin1 promotes cancer progression by increasing the stabilities of numerous oncoproteins and decreasing the stabilities of many tumor suppressors. Meanwhile, Pin1 plays a critical role in different neurodegenerative disorders via the regulation of protein turnover. Finally, we propose a novel therapeutic approach wherein the ubiquitin-proteasome system can be leveraged for therapy by targeting pathogenic intracellular targets for TRIM21-dependent degradation using stereospecific antibodies.

Long-term combination therapy with metformin and oxymetholone in a Fanconi anemia mouse model.

Fanconi anemia (FA) is a disease caused by defective deoxyribonucleic acid (DNA) repair that manifests as bone marrow failure, cancer predisposition, and developmental defects. We previously reported that monotherapy with either metformin (MET) or oxymetholone (OXM) improved peripheral blood (PB) counts and the number and functionality of bone marrow hematopoietic stem progenitor cells (HSPCs) number in Fancd2-/- mice. To evaluate whether the combination treatment of these drugs has a synergistic effect to prevent bone marrow failure in FA, we treated cohorts of Fancd2-/- mice and wildtype controls with either MET alone, OXM alone, MET+OXM, or placebo diet from age 3 weeks to 18 months. The OXM treated animals showed modest improvements in blood parameters including platelet count (p = .01) and hemoglobin levels (p < .05). In addition, the percentage of quiescent hematopoietic stem cell (HSC) (LSK [Lin-Sca+c-Kit+]) was significantly increased (p = .001) by long-term treatment with MET alone. The combination of metformin and oxymetholone did not result in a significant synergistic effect in any hematopoietic parameter. Gene expression analysis of liver tissue from these animals showed that some of the expression changes caused by Fancd2 deletion were partially normalized by metformin treatment. Importantly, no adverse effects of the individual or combination therapies were observed, despite the long-term administration. We conclude that androgen therapy is not a contraindication to concurrent metformin administration in clinical trials. HIGHLIGHTS: Long-term coadministration of metformin in combination with oxymetholone is well tolerated by Fancd2-/- mice. Hematopoietic stem cell quiescence in mutant mice was enhanced by treatment with metformin alone. Metformin treatment caused a partial normalization of gene expression in the livers of mutant mice.

Nonlinear model predictive control-Cross-coupling control with deep neural network feedforward for multi-hydraulic system synchronization control.

This paper studies a multi-hydraulic system (MHS) synchronization control algorithm. Firstly, a general nonlinear asymmetric MHS state space entirety model is established and subsequently the model form is simplified by nonlinear feedback linearization. Secondly, an entirety model-type solution is proposed, integrating a nonlinear model predictive control (NMPC) algorithm with a cross-coupling control (CCC) algorithm. Furthermore, a novel disturbance compensator based on the system's inverse model is introduced to effectively handle disturbances, encompassing unmodeled errors and noise. The proposed innovative controller, known as nonlinear model predictive control-cross-coupling control with deep neural network feedforward (NMPC-CCC-DNNF), is designed to minimize synchronization errors and counteract the impact of disturbances. The stability of the control system is rigorously demonstrated. Finally, simulation results underscore the efficacy of the NMPC-CCC-DNNF controller, showcasing a remarkable 60.8% reduction in synchronization root mean square error (RMSE) compared to other controllers, reaching up to 91.1% in various simulations. These results affirm the superior control performance achieved by the NMPC-CCC-DNNF controller.

Gut microbial ß-glucuronidases influence endobiotic homeostasis and are modulated by diverse therapeutics.

Hormones and neurotransmitters are essential to homeostasis, and their disruptions are connected to diseases ranging from cancer to anxiety. The differential reactivation of endobiotic glucuronides by gut microbial ß-glucuronidase (GUS) enzymes may influence interindividual differences in the onset and treatment of disease. Using multi-omic, in vitro, and in vivo approaches, we show that germ-free mice have reduced levels of active endobiotics and that distinct gut microbial Loop 1 and FMN GUS enzymes drive hormone and neurotransmitter reactivation. We demonstrate that a range of FDA-approved drugs prevent this reactivation by intercepting the catalytic cycle of the enzymes in a conserved fashion. Finally, we find that inhibiting GUS in conventional mice reduces free serotonin and increases its inactive glucuronide in the serum and intestines. Our results illuminate the indispensability of gut microbial enzymes in sustaining endobiotic homeostasis and indicate that therapeutic disruptions of this metabolism promote interindividual response variabilities.

Correlating Aggregation Ability of Polymer Donors with Film Formation Kinetics for Organic Solar Cells with Improved Efficiency and Processability.

Film formation kinetics significantly impact molecular processability and power conversion efficiency (PCE) of organic solar cells. Here, two ternary random copolymerization polymers are reported, D18─N-p and D18─N-m, to modulate the aggregation ability of D18 by introducing trifluoromethyl-substituted pyridine unit at para- and meta-positions, respectively. The introduction of pyridine unit significantly reduces material aggregation ability and adjusts the interactions with acceptor L8-BO, thereby leading to largely changed film formation kinetics with earlier phase separation and longer film formation times, which enlarge fiber sizes in blend films and improve carrier generation and transport. As a result, D18─N-p with moderate aggregation ability delivers a high PCE of 18.82% with L8-BO, which is further improved to 19.45% via interface engineering. Despite the slightly inferior small area device performances, D18─N-m shows improved solubility, which inspires to adjust the ratio of meta-trifluoromethyl pyridine carefully and obtain a polymer donor D18─N-m-10 with good solubility in nonhalogenated solvent o-xylene. High PCEs of 13.07% and 12.43% in 1 cm2 device and 43 cm2 module fabricated with slot-die coating method are achieved based on D18─N-m-10:L8-BO blends. This work emphasizes film formation kinetics optimization in device fabrication via aggregation ability modulation of polymer donors for efficient devices.

Splendidivirga corallicola gen. nov., sp. nov. and Agaribacillus aureus gen. nov., sp. nov., two bacteria isolated from coral Porites lutea, and proposal of Splendidivirgaceae fam. nov.

The Bacteroidota is one of the dominant bacterial phyla in corals. However, the exact taxa of those coral bacteria under the Bacteroidota are still unclear. Two aerobic, Gram-stain-negative, non-motile rods, designated strains BMA10T and BMA12T, were isolated from stony coral Porites lutea collected from Weizhou Island, PR China. Global alignment of 16S rRNA gene sequences indicated that both strains are closest to species of Fulvivirga with the highest identities being lower than 93 %, and the similarity value between these two strains was 92.3 %. Phylogenetic analysis based on 16S rRNA gene and genome sequences indicated that these two strains form an monophylogenetic lineage alongside the families Fulvivirgaceae, Reichenbachiellaceae, Roseivirgaceae, Marivirgaceae, Cyclobacteriaceae, and Cesiribacteraceae in the order Cytophagales, phylum Bacteroidota. The genomic DNA G+C contents of BMA10T and BMA12T were 38.4 and 41.9 mol%, respectively. The major polar lipids of BMA10T were phosphatidylethanolamine, unidentified aminophospholipid, four unidentified aminolipids, and five unidentified lipids. While those of BMA12T were phosphatidylethanolamine, two unidentified aminolipids, and five unidentified lipids. The major cellular fatty acids detected in both isolates were iso-C15 : 0 and C16 : 1 ω5c. Carbohydrate-active enzyme analysis indicated these two strains may utilize coral mucus or chitin. Based on above characteristics, these two strains are suggested to represent two new species in two new genera of a new family in the order Cytophagales, for which the name Splendidivirga corallicola gen. nov., sp. nov., Agaribacillus aureus gen. nov., sp. nov. and Splendidivirgaceae fam. nov. are proposed. The type strain of S. corallicola is BMA10T (=MCCC 1K08300T=KCTC 102045T), and that for A. aureus is BMA12T (=MCCC 1K08309T=KCTC 102046T).

Municipal solid waste management challenges in developing regions: A comprehensive review and future perspectives for Asia and Africa.

The rapid urbanization witnessed in developing countries in Asia and Africa has led to a substantial increase in municipal solid waste (MSW) generation. However, the corresponding disposal strategies, along with constraints in land resources and finances, compounded by unorganized public behaviour, have resulted in ineffective policy implementation and monitoring. This lack of systematic and targeted orientation, combined with blind mapping, has led to inefficient development in many areas. This review examines the key challenges of MSW management in developing countries in Asia and Africa from 2013 to 2023, drawing insights from 170 academic papers. Rather than solely focusing on recycling, the study proposes waste sorting at the source, optimization of landfill practices, thermal treatment measures, and strategies to capitalize on the value of waste as more pertinent solutions aligned with local realities. Barriers to optimizing management systems arise from socio-economic factors, infrastructural limitations, and cultural considerations. The review emphasizes the importance of integrating the study area into the circular economy framework, with a focus on enhancing citizen participation in solid waste reduction and promoting recycling initiatives, along with seeking economic assistance from international organizations.

Stable Interstrand Cross-Links Generated from the Repair of 1,N6-Ethenoadenine in DNA by α-Ketoglutarate/Fe(II)-Dependent Dioxygenase ALKBH2.

DNA cross-links severely challenge replication and transcription in cells, promoting senescence and cell death. In this paper, we report a novel type of DNA interstrand cross-link (ICL) produced as a side product during the attempted repair of 1,N6-ethenoadenine (εA) by human α-ketoglutarate/Fe(II)-dependent enzyme ALKBH2. This stable/nonreversible ICL was characterized by denaturing polyacrylamide gel electrophoresis analysis and quantified by high-resolution LC-MS in well-matched and mismatched DNA duplexes, yielding 5.7% as the highest level for cross-link formation. The binary lesion is proposed to be generated through covalent bond formation between the epoxide intermediate of εA repair and the exocyclic N6-amino group of adenine or the N4-amino group of cytosine residues in the complementary strand under physiological conditions. The cross-links occur in diverse sequence contexts, and molecular dynamics simulations rationalize the context specificity of cross-link formation. In addition, the cross-link generated from attempted εA repair was detected in cells by highly sensitive LC-MS techniques, giving biological relevance to the cross-link adducts. Overall, a combination of biochemical, computational, and mass spectrometric methods was used to discover and characterize this new type of stable cross-link both in vitro and in human cells, thereby uniquely demonstrating the existence of a potentially harmful ICL during DNA repair by human ALKBH2.

CacyBP promotes the development of lung adenocarcinoma by regulating OTUD5.

Lung cancer is the most common and lethal malignancy, with lung adenocarcinoma accounting for approximately 40% of all cases. Despite some progress in understanding the pathogenesis of this disease and developing new therapeutic approaches, the current treatments for lung adenocarcinoma remain ineffective due to factors such as high tumour heterogeneity and drug resistance. Therefore, there is an urgent need to identify novel therapeutic targets. CacyBP can regulate a variety of physiological processes by binding to different proteins, but its function in lung adenocarcinoma is unknown. Here, we show that CacyBP is highly expressed in lung adenocarcinoma tissues, and high CacyBP expression correlates with poorer patient survival. Moreover, overexpression of CacyBP promoted the proliferation, migration and invasion of lung adenocarcinoma cell lines. Further mechanistic studies revealed that CacyBP interacts with the tumour suppressor OTUD5, enhances the ubiquitination and proteasomal degradation of OTUD5, and regulates tumorigenesis via OTUD5. In conclusion, our study reveals a novel mechanism by which CacyBP promotes tumorigenesis by increasing the ubiquitination level and proteasome-dependent degradation of OTUD5, providing a potential target for the treatment of lung adenocarcinoma.

Rubellicoccus peritrichatus gen. nov., sp. nov., isolated from crustose coralline algae in a coral aquarium.

A Gram-stain-negative, motile, aerobic, non-spore-forming coccus, designated strain CR14T, was isolated from crustose coralline algae. Cells grew at 20-30 °C (optimum, 25 °C), at pH 6-9 (optimum, pH 7.6) and with NaCl concentrations of 0.5-9 % (w/v; optimum, 2-4 %). Global alignment based on 16S rRNA gene sequences indicated strain CR14T is closest to Ruficoccus amylovorans JCM 31066T with an identity of 92 %. The average nucleotide identity and average amino acid identity values between CR14T and R. amylovorans JCM 31066T were 68.4 and 59.9 %, respectively. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain CR14T forms an independent branch within the family Cerasicoccaeae, which was consistent with the phylogenomic results. The sole isoprenoid quinone was MK-7. The major fatty acids were C14 : 0, C18 : 1 ω9c, C19 : 0 cyc 9,10 DMA, C16 : 0, and C18 : 2 ω6c. The major cellular polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, and two unidentified lipids. The genome DNA G+C content was 48.7 mol%. Based on morphological, physiological and chemotaxonomic characteristics, strain CR14T is suggested to represent a novel species in a new genus, for which the name Rubellicoccus peritrichatus gen. nov., sp. nov. is proposed. The type strain is CR14T (=MCCC 1K03845T=KCTC 72139T).

Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry.

Induced oncoproteins degradation provides an attractive anti-cancer modality. Activation of anaphase-promoting complex (APC/CCDH1) prevents cell-cycle entry by targeting crucial mitotic proteins for degradation. Phosphorylation of its co-activator CDH1 modulates the E3 ligase activity, but little is known about its regulation after phosphorylation and how to effectively harness APC/CCDH1 activity to treat cancer. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1)-catalyzed phosphorylation-dependent cis-trans prolyl isomerization drives tumor malignancy. However, the mechanisms controlling its protein turnover remain elusive. Through proteomic screens and structural characterizations, we identify a reciprocal antagonism of PIN1-APC/CCDH1 mediated by domain-oriented phosphorylation-dependent dual interactions as a fundamental mechanism governing mitotic protein stability and cell-cycle entry. Remarkably, combined PIN1 and cyclin-dependent protein kinases (CDKs) inhibition creates a positive feedback loop of PIN1 inhibition and APC/CCDH1 activation to irreversibly degrade PIN1 and other crucial mitotic proteins, which force permanent cell-cycle exit and trigger anti-tumor immunity, translating into synergistic efficacy against triple-negative breast cancer.

The role of the Pin1-cis P-tau axis in the development and treatment of vascular contribution to cognitive impairment and dementia and preeclampsia.

Tauopathies are neurodegenerative diseases characterized by deposits of abnormal Tau protein in the brain. Conventional tauopathies are often defined by a limited number of Tau epitopes, notably neurofibrillary tangles, but emerging evidence suggests structural heterogeneity among tauopathies. The prolyl isomerase Pin1 isomerizes cis P-tau to inhibit the development of oligomers, tangles and neurodegeneration in multiple neurodegenerative diseases such as Alzheimer's disease, traumatic brain injury, vascular contribution to cognitive impairment and dementia (VCID) and preeclampsia (PE). Thus, cis P-tau has emerged as an early etiological driver, blood marker and therapeutic target for multiple neurodegenerative diseases, with clinical trials ongoing. The discovery of cis P-tau and other tau pathologies in VCID and PE calls attention for simplistic classification of tauopathy in neurodegenerative diseases. These recent advances have revealed the exciting novel role of the Pin1-cis P-tau axis in the development and treatment of vascular contribution to cognitive impairment and dementia and preeclampsia.