Causal relationship between gut microbiota and constipation: a bidirectional Mendelian randomization study.

Background: Constipation is a prevalent gastrointestinal disorder affecting approximately 15% of the global population, leading to significant healthcare burdens. Emerging evidence suggests that gut microbiota plays a pivotal role in the pathogenesis of constipation, although causality remains uncertain due to potential confounding factors in observational studies. This study aims to clarify the causal relationships between gut microbiota and constipation using a bidirectional Mendelian Randomization (MR) approach, which helps to overcome confounding issues and reverse causality. Methods: Utilizing data from genome-wide association studies (GWAS) from the MiBioGen consortium and other sources, we identified genetic variants as instrumental variables (IVs) for 196 bacterial traits and constipation. These IVs were rigorously selected based on their association with the traits and absence of linkage with confounding factors. We applied several MR methods, including Inverse Variance Weighted (IVW), MR Egger, and MR-PRESSO, to examine the causal effects in both directions. Results: Our analysis revealed a significant causal relationship where specific bacterial taxa such as Coprococcus1 (OR = 0.798, 95%CI: 0.711-0.896, p < 0.001), Coprococcus3 (OR = 0.851, 95%CI: 0.740-0.979, p = 0.024), Desulfovibrio (OR = 0.902, 95%CI: 0.817-0.996, p = 0.041), Flavonifractor (OR = 0.823, 95%CI: 0.708-0.957, p < 0.001), and Lachnospiraceae UCG004, whereas others including Ruminococcaceae UCG005 (OR = 1.127, 95%CI: 1.008-1.261, p = 0.036), Eubacterium nodatum group (OR = 1.080, 95%CI: 1.018-1.145, p = 0.025), Butyricimonas (OR = 1.118, 95%CI: 1.014-1.233, p = 0.002), and Bacteroidetes (OR = 1.274, 95%CI: 1.014-1.233, p < 0.001) increase constipation risk. In the reverse MR analysis, constipation was found to influence the abundance of certain taxa, including Family XIII, Porphyromonadaceae, Proteobacteria, Lentisphaeria, Veillonellaceae, Victivallaceae, Catenibacterium, Sellimonas, and Victivallales, indicating a bidirectional relationship. Sensitivity analyses confirmed the robustness of these findings, with no evidence of heterogeneity or horizontal pleiotropy. Conclusion: The relationship between our study gut microbiota and constipation interacts at the genetic level, which gut microbiota can influence the onset of constipation, and constipation can alter the gut microbiota. Coprococcus1, Coprococcus3, Desulfovibrio, Flavonifractor and Lachnospiraceae UCG004 play a protective role against constipation, while Ruminococcaceae UCG005, Eubacterium nodatum group, Butyricimonas, and Bacteroidetes are associated with an increased risk. In addition, constipation correlates positively with the abundance of Family XIII, Porphyromonadaceae and Proteobacteria, while negatively with Lentisphaeria, Veillonellaceae, Victivallaceae, Catenibacterium, Sellimonas, and Victivallales.

Distinct structural brain network properties in children with familial versus non-familial attention-deficit/hyperactivity disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is among the most prevalent, inheritable, and heterogeneous childhood-onset neurodevelopmental disorders. Children with a hereditary background of ADHD have heightened risk of having ADHD and persistent impairment symptoms into adulthood. These facts suggest distinct familial-specific neuropathological substrates in ADHD that may exist in anatomical components subserving attention and cognitive control processing pathways during development. The objective of this study is to investigate the topological properties of the gray matter (GM) structural brain networks in children with familial ADHD (ADHD-F), non-familial ADHD (ADHD-NF), as well as matched controls. A total of 452 participants were involved, including 132, 165 and 155 in groups of ADHD-F, ADHD-NF and typically developed children, respectively. The GM structural brain network was constructed for each group using graph theoretical techniques with cortical and subcortical structures as nodes and correlations between volume of each pair of the nodes within each group as edges, while controlled for confounding factors using regression analysis. Relative to controls, children in both ADHD-F and ADHD-NF groups showed significantly higher nodal global and nodal local efficiencies in the left caudal middle frontal gyrus. Compared to controls and ADHD-NF, children with ADHD-F showed distinct structural network topological patterns associated with right precuneus (significantly higher nodal global efficiency and significantly higher nodal strength), left paracentral gyrus (significantly higher nodal strength and trend toward significantly higher nodal local efficiency) and left putamen (significantly higher nodal global efficiency and trend toward significantly higher nodal local efficiency). Our results for the first time in the field provide evidence of familial-specific structural brain network alterations in ADHD, that may contribute to distinct clinical/behavioral symptomology and developmental trajectories in children with ADHD-F.

SnF2-Catalyzed Lithiophilic-Lithiophobic Gradient Interface for High-Rate PEO-based All-Solid-State Batteries.

Polyethylene oxide (PEO)-based all solid-state lithium metal batteries (ASSLMBs) are strongly hindered by the fast dendrite growth at the Li metal/electrolyte interface, especially under large rates. The above issue stems from the suboptimal interfacial chemistry and poor Li+ transport kinetics during cycling. Herein, a SnF2-catalyzed lithiophilic-lithiophobic gradient solid electrolyte interphase (SCG-SEI) of LixSny/LiF-Li2O is in-situ formed. The superior ionic LiF-Li2O rich upper layer (17.1 nm) possesses high interfacial energy and fast Li+ diffusion channels, wherein lithiophilic LixSny alloy layer (8.4 nm) could highly reduce the nucleation overpotential with lower diffusion barrier and promote rapid electron transportation for reversible Li+ plating/stripping. Simultaneously, the insoluble SnF2-coordinated PEO promotes the rapid Li+ ion transport in the bulk phase. As a result, an over 46.7 and 3.5 times improvements for lifespan and critical current density of symmetrical cells are achieved, respectively. Furthermore, LiFePO4-based ASSLMBs deliver a recorded cycling performance at 5 C (over 1000 cycles with a capacity retention of 80.0%). More importantly, impressive electrochemical performances and safety tests with LiNi0.8Mn0.1Co0.1O2 and pouch cell with LiFePO4, even under extreme conditions (i.e., 100 ℃), are also demonstrated, reconfirmed the importance of lithiophilic-lithiophobic gradient interfacial chemistry in the design of high-rate ASSLMBs for safety applications.

Rationale and design of the multi organ inflammation with serial testing study: a comprehensive assessment of functional and structural abnormalities in patients with recovered COVID-19.

Introduction: Short-term clinical outcomes from SARS-CoV-2 infection are generally favorable. However, 15-20% of patients report persistent symptoms of at least 12 weeks duration, often referred to as long COVID. Population studies have also demonstrated an increased risk of incident diabetes and cardiovascular disease at 12 months following infection. While imaging studies have identified multi-organ injury patterns in patients with recovered COVID-19, their respective contributions to the disability and morbidity of long COVID is unclear. Methods: A multicenter, observational study of 215 vaccine-naïve patients with clinically recovered COVID-19, studied at 3-6 months following infection, and 133 healthy volunteers without prior SARS-CoV-2 infection. Patients with recovered COVID-19 were screened for long COVID related symptoms and their impact on daily living. Multi-organ, multi-parametric magnetic resonance imaging (MRI) and circulating biomarkers were acquired to document sub-clinical organ pathology. All participants underwent pulmonary function, aerobic endurance (6 min walk test), cognition testing and olfaction assessment. Clinical outcomes were collected up to 1 year from infection. The primary objective of this study is to identify associations between organ injury and disability in patients with long-COVID symptoms in comparison to controls. As a secondary objective, imaging and circulating biomarkers with the potential to exacerbate cardiovascular health were characterized. Discussion: Long-term sequelae of COVID-19 are common and can result in significant disability and cardiometabolic disease. The overall goal of this project is to identify novel targets for the treatment of long COVID including mitigating the risk of incident cardiovascular disease. Study registration: clinicaltrials.gov (MOIST late cross-sectional study; NCT04525404).

H3K36 methyltransferase SMYD2 affects cell proliferation and migration in Hirschsprung's disease by regulating METTL3.

The pathogenesis of Hirschsprung's disease (HSCR) is complex. Recently, it has been found that histone modifications can alter genetic susceptibility and play important roles in the proliferation, differentiation and migration of neural crest cells. H3K36 methylation plays a significant role in gene transcriptional activation and expression, but its pathogenic mechanism in HSCR has not yet been studied. This study aimed to elucidate its role and molecular mechanism in HSCR. Western blot analysis, immunohistochemistry (IHC) and reverse transcription-quantitative PCR (RT‒qPCR) were used to investigate H3K36 methylation and methyltransferase levels in dilated and stenotic colon tissue sections from children with. We confirm that SMYD2 is the primary cause of differential H3K36 methylation and influences cell proliferation and migration in HSCR. Subsequently, quantitative detection of m6A RNA methylation revealed that SMYD2 can alter m6A methylation levels. Western blot analysis, RT-qPCR, co-immunoprecipitation (co-IP), and immunofluorescence colocalization were utilized to confirm that SMYD2 can regulate METTL3 expression and affect m6A methylation, affecting cell proliferation and migration. These results confirm that the H3K36 methyltransferase SMYD2 can affect cell proliferation and migration in Hirschsprung's disease by regulating METTL3. Our study suggested that H3K36 methylation plays an important role in HSCR, confirming that the methyltransferase SMYD2 can affect m6A methylation levels and intestinal nervous system development by regulating METTL3 expression.

van der Waals-bonded graphene clusters enhance thermal conductivity of phase-change materials for advanced thermal energy management.

Organic phase-change materials possess immense application potential, but their low thermal conductivity (≤0.5 W m-1 K-1) severely limits the thermal energy charge/discharge rate, impeding their practical implementation in the field of advanced energy. While incorporating thermally conductive fillers into the phase-change matrix can address this issue, achieving a thermal conductivity exceeding 10 W m-1 K-1 at a filler content below 30 vol% remains challenging, attributed to the absence of a well-designed filler interface and structure. Herein, a strategy for developing planar graphene clusters and subsequently integrating them with phase-change microcapsules to fabricate composites using compression molding was demonstrated. The proposed graphene clusters are formed by closely aligned and overlapping graphene sheets that bond together through van der Waals forces, resulting in a significant decrease in junction thermal resistance within the composites. Combining this interface design with compression-induced construction of a highly oriented structure, the composites achieved a remarkable thermal conductivity of 103 W m-1 K-1 with ≈29 vol% filler addition, enhancing the thermal energy charge/discharge rate by over two orders of magnitude. Furthermore, we demonstrated that the composites possess the essential enthalpy values, competent strength, and ease of shaping, making them applicable across various domains of thermal energy management.

Mechanism of Action of NvZhen ErXian HeJi in Ovariectomized Rats with Myocardial Infarction based on Network Pharmacology.

OBJECTIVE: Nv Zhen Er Xian He Ji (NZEXHJ) is used to treat perimenopausal syndrome (PS), but its effect on perimenopausal coronary heart disease is unclear. Furthermore, the aim of this research is to study the effect of NZEXHJ on perimenopausal coronary heart disease (PMCHD) in a rat model based on a network pharmacology approach. MATERIALS AND METHODS: Based on network pharmacological analysis combined with molecular docking, we predicted the potential therapeutic target and pharmacological mechanism of NZEXHJ in the treatment of PMCHD. We used an ovariectomized rat (OVR) model to understand the effect of NZEXHJ on myocardial injury and further verified the target of NZEXHJ in the intervention of PMCHD. RESULTS: We selected 52 active components of NZEXHJ against PMCHD and an intersection of their targets on network pharmacology, to which SCN5A, SER1, AR, and PGR were significantly correlated. The protein- protein interaction network revealed CASP3, CXCL8, IL6, MAPK1, TNF, TP53, and VEGFA in the treatment of PMCHD with NZEXHJ. Kaempferol, luteolin, and mistletoe presented good affinity towards the aforementioned targets by Molecular docking NZEXHJ exerted protecting cardiomyocytes for OVR. The mechanism was related to a reduction in the expression levels of the CXCL8, TNF, and regulating PI3K-AKT signaling pathways. CONCLUSION: This study reveals the potential multi-component, multi-target, and multi-pathway pharmacological effects of NZEXHJ and predicts its protection against myocardial infarction in ovariectomized rats through the PI3K Akt pathway, providing a theoretical basis for the treatment of PMCHD.

Iron Corrole-Catalyzed Intramolecular Amination Reactions of Alkyl Azides. Spectroscopic Characterization and Reactivity of [FeV(Cor)(NAd)].

As nitrogen analogues of iron-oxo species, high-valent iron-imido species have attracted great interest in the past decades. FeV-alkylimido species are generally considered to be key reaction intermediates in Fe(III)-catalyzed C(sp3)─H bond aminations of alkyl azides but remain underexplored. Here, it is reported that iron-corrole (Cor) complexes can catalyze a wide range of intramolecular C─H amination reactions of alkyl azides to afford a variety of 5-, 6- and 7-membered N-heterocycles, including alkaloids and natural product derivatives, with up to 3880 turnover numbers (TONs) and excellent diastereoselectivity (>99:1 d.r.). Mechanistic studies including density functional theory (DFT) calculations and intermolecular hydrogen atom abstraction (HAA) reactions reveal key reactive FeV-alkylimido intermediates. The [FeV(Cor)(NAd)] (Ad = adamantyl) complex is independently prepared and characterized through electron paramagnetic resonance (EPR), resonance Raman (rR) measurement, and X-ray photoelectron spectroscopy (XPS). This complex is reactive toward HAA reactions with kinetic isotope effects (KIEs) similar to [Fe(Cor)]-catalyzed intramolecular C─H amination of alkyl azides.

In Situ Alloying Enabled by Active Liquid Metal Filler for Self-Healing Composite Polymer Electrolytes.

Solid inorganics, known for kinetically inhibiting polymer crystallization and enhancing ionic conductivity, have attracted significant attention in solid polymer electrolytes. However, current composite polymer electrolytes (CPEs) are still facing challenges in Li metal batteries, falling short of inhibiting severe dendritic growth and resulting in very limited cycling life. This study introduces Ga62.5In21.5Sn16 (Galinstan) liquid metal (LM) as an active liquid alternative to conventional passive solid fillers, aiming at realizing self-healing protection against dendrite problems. Compared to solid inorganics, for example silica, LM droplets could more significantly reduce polymer crystallinity and enhance Li-ion conductivity due to their liquid nature, especially at temperatures below the polymer melting point. More importantly, LMs are unraveled as dynamic chemical traps, which are capable of blocking and consuming lithium dendrites upon contact via in situ alloying during battery operation and further inhibiting dendritic growth due to the lower deposition energy barrier of the formed Li-LM alloy. As a proof of concept, by strategically designing an asymmetric CPE with the active LM filling, a solid-state Li/LiFePO4 battery achieves promising full-cell functionality with notable rate performance and stable cycle life. This active filler-mediated self-healing approach could bring new insights into the battery design in versatile solid-state systems.

Crystallinity Control and Strain Release in Wide-Bandgap Perovskite Film via Seed-Induced Growth for Efficient Photovoltaics.

The seed method stands out as a straightforward and efficient approach for fabricating high-performance perovskite solar cells (PSCs). In this study, we propose the utilization of an antisolvent as an additive to induce crystal seeding, thereby facilitating the growth of wide-bandgap perovskite grains. Specifically, we introduce three commonly used antisolvents─ethyl acetate (EA), isopropanol (IPA), and chlorobenzene (CB)─directly into the perovskite precursor solution to generate perovskite seeds, which serve to promote subsequent nucleation. This antisolvent-crystal seeding method (ACSM) results in increased grain sizes, reduced film defects, and overall improved film quality. Consequently, the power conversion efficiencies (PCEs) of 1.647 eV PSCs with EA, IPA, and CB additives are recorded at 19.86%, 20.61%, and 20.45%, respectively, surpassing that of the reference device with a PCE of 18.83%. Furthermore, the stability of the PSCs prepared through ACSM is notably enhanced. Notably, PSCs optimized with IPA retain 75% of the original PCE after being stored in ambient air conditions (25 °C, RH ∼ 15%) for 30 days, better than the CB-added (64%) and the EA-added devices (53%), while the reference devices only retain 31% of the initial PCE. Moreover, even after continuous thermal annealing at 50 °C for 200 h, IPA-assisted devices demonstrate the best stability, followed by those with CB and EA, with the reference exhibiting the poorest stability.

Facial recognition models for identifying genetic syndromes associated with pulmonary stenosis in children.

BACKGROUND: Williams-Beuren syndrome, Noonan syndrome, and Alagille syndrome are common types of genetic syndromes (GSs) characterized by distinct facial features, pulmonary stenosis, and delayed growth. In clinical practice, differentiating these three GSs remains a challenge. Facial gestalts serve as a diagnostic tool for recognizing Williams-Beuren syndrome, Noonan syndrome, and Alagille syndrome. Pretrained foundation models (PFMs) can be considered the foundation for small-scale tasks. By pretraining with a foundation model, we propose facial recognition models for identifying these syndromes. METHODS: A total of 3297 (n = 1666) facial photos were obtained from children diagnosed with Williams-Beuren syndrome (n = 174), Noonan syndrome (n = 235), and Alagille syndrome (n = 51), and from children without GSs (n = 1206). The photos were randomly divided into five subsets, with each syndrome and non-GS equally and randomly distributed in each subset. The proportion of the training set and the test set was 4:1. The ResNet-100 architecture was employed as the backbone model. By pretraining with a foundation model, we constructed two face recognition models: one utilizing the ArcFace loss function, and the other employing the CosFace loss function. Additionally, we developed two models using the same architecture and loss function but without pretraining. The accuracy, precision, recall, and F1 score of each model were evaluated. Finally, we compared the performance of the facial recognition models to that of five pediatricians. RESULTS: Among the four models, ResNet-100 with a PFM and CosFace loss function achieved the best accuracy (84.8%). Of the same loss function, the performance of the PFMs significantly improved (from 78.5% to 84.5% for the ArcFace loss function, and from 79.8% to 84.8% for the CosFace loss function). With and without the PFM, the performance of the CosFace loss function models was similar to that of the ArcFace loss function models (79.8% vs 78.5% without PFM; 84.8% vs 84.5% with PFM). Among the five pediatricians, the highest accuracy (0.700) was achieved by the senior-most pediatrician with genetics training. The accuracy and F1 scores of the pediatricians were generally lower than those of the models. CONCLUSIONS: A facial recognition-based model has the potential to improve the identification of three common GSs with pulmonary stenosis. PFMs might be valuable for building screening models for facial recognition. Key messages What is already known on this topic:  Early identification of genetic syndromes (GSs) is crucial for the management and prognosis of children with pulmonary stenosis (PS). Facial phenotyping with convolutional neural networks (CNNs) often requires large-scale training data, limiting its usefulness for GSs. What this study adds:  We successfully built multi-classification models based on face recognition using a CNN to accurately identify three common PS-associated GSs. ResNet-100 with a pretrained foundation model (PFM) and CosFace loss function achieved the best accuracy (84.8%). Pretrained with the foundation model, the performance of the models significantly improved, although the impact of the type of loss function appeared to be minimal. How this study might affect research, practice, or policy:  A facial recognition-based model has the potential to improve the identification of GSs in children with PS. The PFM might be valuable for building identification models for facial detection.

Engineering of charge density at the anode/electrolyte interface for long-life Zn anode in aqueous zinc ion battery.

The aqueous zinc ion battery emerges as the promising candidate applied in large-scale energy storage system. However, Zn anode suffers from the issues including Zn dendrite, Hydrogen evolution reaction and corrosion. These challenges are primarily derived from the instability of anode/electrolyte interface, which is associated with the interfacial charge density distribution. In this context, the recent advancements concentrating on the strategies and mechanism to regulate charge density at the Zn anode/electrolyte interface are summarized. Different characterization techniques for charge density distribution have been analysed, which can be applied to assess the interfacial zinc ion transport. Additionally, the charge density regulations at the Zn anode/electrolyte interface are discussed, elucidating their roles in modulating electrostatic interactions, electric field, structure of solvated zinc ion and electric double layer, respectively. Finally, the perspectives and challenges on the further research are provided to establish the stable anode/electrolyte interface by focusing on charge density modifications, which is expected to facilitate the development of aqueous zinc ion battery.

Evaluation of a novel vaginal cells self-sampling device for human papillomavirus testing in cervical cancer screening: A clinical trial assessing reliability and acceptability.

Cervical cancer is a significant public health concern, particularly in low- and middle-income countries where resources for prevention and treatment are limited. Routine screening, such as the Papanicolaou test (Pap smears) and human papillomavirus (HPV) testing, plays a crucial role in the early detection and prevention of cervical cancer. However, the participation rate in cervical cancer screening programs remains below optimal levels due to various factors. This study aimed to evaluate the reliability and acceptability of the HygeiaTouch Self Sampling Kit for Women in collecting vaginal samples for HPV typing, comparing the results with samples collected by physicians. The study included 1210 women aged 21-65 from three medical centers in Taiwan. The findings indicated that the self-sampling kit was as effective as physician-collected specimens in terms of obtaining valid samples and identifying HPV. The agreement between the two methods was 88%, with a κ value of 0.75. Furthermore, the study assessed the mechanical characteristics of the self-sampling applicator through tensile, bending, and torque tests, and determined that it was safe for intravaginal use. Additionally, the study evaluated the safety and satisfaction of self-sampling and found a low rate of adverse events (0.7%) and high levels of satisfaction (over 90%) among participants. Overall, we demonstrated that the HygeiaTouch Self Sampling Kit for Women is a reliable and acceptable device for HPV testing and cervical screening, providing a convenient, safe, and effective alternative for women.

Adaptive Changes in Neurovascular Properties With Binocular Accommodation Functions in Myopic Participants by 3D Visual Training: An EEG and fNIRS Study.

Although three-dimensional visual training (3DVT) has been used for myopia intervention, its neural mechanisms remain largely unknown. In this study, visual function was examined before and after 3DVT, while resting-state EEG-fNIRS signals were recorded from 38 myopic participants. A graph theoretical analysis was applied to compute the neurovascular properties, including static brain networks (SBNs), dynamic brain networks (DBNs), and dynamic neurovascular coupling (DNC). Correlations between the changes in neurovascular properties and the changes in visual functions were calculated. After 3DVT, the local efficiency and node efficiency in the frontal lobes increased in the SBNs constructed from EEG δ -band; the global efficiency and node efficiency in the frontal-parietal lobes decreased in the DBNs variability constructed from EEG δ -band. For the DNC constructed with EEG α -band and oxyhemoglobin (HbO), the local efficiency decreased, for EEG α -band and deoxyhemoglobin (HbR), the node efficiency in the frontal-occipital lobes decreased. For the SBNs constructed from HbO, the functional connectivity (FC) between the frontal-occipital lobes increased. The DNC constructed between the FC of the frontal-parietal lobes from EEG ß -band and the FC of the frontal-occipital lobes from HbO increased, and between the FC of the frontal-occipital lobes from EEG ß -band and the FC of the inter-frontal lobes from HbR increased. The neurovascular properties were significantly correlated with the amplitude of accommodation and accommodative facility. The result indicated the positive effects of 3DVT on myopic participants, including improved efficiency of brain networks, increased FC of SBNs and DNC, and enhanced binocular accommodation functions.

Novel diagnostic and prognostic approach for rapidly progressive dementias: Indicators based on amyloid/tau/neurodegeneration (ATN) framework.

AIMS: Apply established cerebrospinal fluid (CSF) and serum biomarkers and novel combined indicators based on the amyloid/tau/neurodegeneration (ATN) framework to improve diagnostic and prognostic power in patients with rapidly progressive dementias (RPDs). METHODS: CSF and serum biomarkers of Alzheimer's disease (AD) common neuropathology including Aß42, Aß40, p-Tau, and t-Tau were measured in cognitively normal (CN) controls (n = 33) and three RPD groups with rapidly progressive AD (rpAD, n = 23), autoimmune encephalitis (AE, n = 25), and Creutzfeldt-Jakob disease (CJD, n = 28). Logistic regression and multiple linear regression were used for producing combined indicators and prognostic assessment, respectively, including A&T, A&N, T&N, A&T&N, etc. RESULTS: Combined diagnostic indicator with A&T&N had the potential for differentiating AE from other types of RPDs, identifying 62.51% and 75% of AE subjects based on CSF and serum samples, respectively, compared to 39.13% and 37.5% when using autoantibodies. CSF t-Tau was associated with survival in the CJD group (adjusted R-Square = 0.16, p = 0.02), and its prognosis value improved when using combined predictors based on the ATN framework (adjusted R-Square = 0.273, p = 0.014). CONCLUSION: Combined indicators based on the ATN framework provide a novel perspective for establishing biomarkers for early recognition of RPDs due to treatment-responsive causes.

Lack of signal peptide in insect prophenoloxidase to avoid glycosylation to damage the zymogen activity.

Insect prophenoloxidases (PPOs) are important immunity proteins for defending against the invading pathogens and parasites. As a Type-Ⅲ copper-containing proteins, unlike Homo sapiens tyrosinases, the insect PPOs and most bacterial tyrosinases contain no signal peptides for unknown reason, however they can still be released. To this end, we fused different signal peptides to Drosophila melanogaster PPOs for in vitro and in vivo expression, respectively. We demonstrate that an artificial signal peptide can help PPO secretion in vitro. The secreted PPO appeared larger than wild-type PPO on molecular weight sizes due to glycosylation when expressed in S2 cells. Two asparagine residues for potential glycosylation in PPO1 were identified when a signal peptide was fused. After purification, the glycosylated PPO1 lost zymogen activity. When PPO1 containing a signal peptide was over-expressed in Drosophila larvae, the glycosylation and secretion of PPO1 was detected in vivo. Unlike insect PPO, human tyrosinase needs a signal peptide for protein expression and maintaining enzyme activity. An artificial signal peptide fused to bacterial tyrosinase had no influence on the protein expression and enzyme activity. These Type-Ⅲ copper-containing proteins from different organisms may evolve to perform their specific functions. Intriguingly, our study revealed that the addition of calcium inhibits PPO secretion from the transiently cultured larval hindguts in vitro, indicating that the calcium concentration may regulate PPO secretion. Taken together, insect PPOs can maintain enzyme activities without any signal peptide.

Leveraging Ion Pairing and Transport in Localized High-Concentration Electrolytes for Reversible Lithium Metal Anodes at Low Temperatures.

Coulombic efficiency of over 99% is rarely achieved for Li metal anode below -40°C, hindering the practical application of high-energy-density Li metal batteries under extreme conditions. Herein, limiting factors for Li metal reversibility are investigated utilizing ether-based localized high-concentration electrolytes of different solvent-diluent combinations. We find that along with the desolvation barrier, bulk ion transport properties including ionic conductivity, transference number, and diffusivity are also crucial factors for low-temperature Li deposition behavior. Superior Li metal reversibility was observed within the combination of the solvent with moderately weak solvating power and the diluent with minimal viscosity, highlighting the role of ion transport and the necessity for a trade-off with desolvation. The optimized electrolyte composed of lithium bis(fluorosulfonyl)imide, methyl n-propyl ether, and 1,1,2,2-tetrafluoroethyl methyl ether delivers exceptional Coulombic efficiency of 99.34% at -40°C and 98.96% at -60°C under a current density of 0.5 mA cm-2. Furthermore, Li||LiCoO2 (2.7 mAh cm-2) cells demonstrate impressive reversible capacity and cycling stability at these temperatures. This work sheds light on the less-recognized relevance of bulk ion transport to low-temperature performance and provides guidelines for the electrolyte design of Li metal batteries operating in cold environments.

Stereochemical Control of Redox CoII/CoIII-Cages with Switchable Cotton Effects Based on Labile-Static States.

The structural dynamics of artificial assemblies, in aspects such as molecular recognition and structural transformation, provide us with a blueprint to achieve bioinspired applications. Here, we describe the assembly of redox-switchable chiral metal-organic cages Λ8/Δ8-[Pd6(CoIIL3)8]28+ and Λ8/Δ8-[Pd6(CoIIIL3)8]36+. These isomeric cages demonstrate an on-off chirality logic gate controlled by their chemical and stereostructural dynamics tunable through redox transitions between the labile CoII-state and static CoIII-state with a distinct Cotton effect. The transition between different states is enabled by a reversible redox process and chiral recognition originating in the tris-chelate Co-centers. All cages in two states are thoroughly characterized by NMR, ESI-MS, CV, CD, and X-ray crystallographic analysis, which clarify their redox-switching behaviors upon chemical reduction/oxidation. The stereochemical lability of the CoII-center endows the Λ8/Δ8-CoII-cages with efficient chiral-induction by enantiomeric guests, leading to enantiomeric isomerization to switch between Λ8/Δ8-CoII-cages, which can be stabilized by oxidation to their chemically inert forms of Λ8/Δ8-CoIII-cages. Kinetic studies reveal that the isomerization rate of the Δ8-CoIII-cage is at least an order of magnitude slower than that of the Δ8-CoII-cage even at an elevated temperature, while its activation energy is 16 kcal mol-1 higher than that of the CoII-cage.

Inhibition of autophagy via 3-methyladenine alleviates the progression of preeclampsia.

Autophagy is a cellular mechanism for self-renewal that involves the breakdown of cytoplasmic proteins or organelles within lysosomes. Although preeclampsia (PE) exhibits several characteristics that could imply disrupted autophagy, there is limited evidence supporting the notion that impaired placental autophagy directly causes PE, as indicated by differential expression profiling of whole placental tissue. In this study, we aim to explore the significance of autophagy in maintaining pregnancy and its association with PE. First, the RNA-seq results show that 218 genes are differentially expressed in placentas from preeclamptic pregnancies. Notably, KEGG pathway analysis reveals significant enrichment of genes related to autophagy-related signaling pathways, including the PI3K-Akt signaling pathway, the AMPK signaling pathway, and the mTOR signaling pathway. Additionally, our findings indicate an increase in autophagy in placentas from pregnancies complicated by preeclampsia as well as in trophoblasts subjected to hypoxic conditions. Next, we examine the impact of 3-methyladenine (3-MA), a targeted inhibitor of autophagy, on the progression of PE. The administration of 3-MA profoundly alleviates the severity of PE-like symptoms in rats subjected to reduced uterine perfusion pressure (RUPP). The findings from our study suggest that inhibiting autophagy may serve as a promising approach for adjuvant chemotherapy for PE.