Super-Resolution Ultrasound Reveals Cerebrovascular Impairment in a Mouse Model of Alzheimer's Disease.

Increasing evidence has suggested a link between cerebrovascular disease and the cognitive impairment associated with Alzheimer's disease. However, detailed descriptions of microvascular changes across brain regions and how they relate to other more traditional pathology have been lacking. Additionally, the efforts to elucidate the interplay between cerebral microvascular function and Alzheimer's disease progression are complicated by the necessity of probing deep-brain structures since early-stage Alzheimer's disease typically involves hippocampal pathology. The purpose of this study was to examine changes in microvascular dynamics in a mouse model of Alzheimer's disease using cohorts that were age-matched to wild-type controls. Data from both sexes were included in this study. Super-resolution ultrasound localization microscopy revealed microvascular functional and structural features throughout the whole brain depth to visualize and quantify. We found that functional decreases in hippocampal and entorhinal flow velocity preceded structural derangements in regional vascular density. Co-registered histological sectioning confirmed the regionalized perfusion deficits seen on ultrasound imaging, which were co-localized with amyloid beta plaque deposition. In addition to providing global vascular quantifications of deep brain structures with a high local resolution, this technology also permitted velocity-profile analysis of individual vessels and, in some cases, allowed for decoupling of arterial and venous flow contributions. These data suggest that microvascular pathology is an early and pervasive feature of Alzheimer's disease and may represent a novel therapeutic target for this disease.

Lightweight and wearable magnetoencephalography system based on spatially-grid constrained coils and compact magnetically shielded room.

Magnetoencephalography based on optically pumped magnetometers can passively detect the ultra-weak brain magnetic field signals, which has significant clinical application prospects for the diagnosis and treatment of cerebral disorders. This paper proposes a brain magnetic signal measurement method on the basis of the active-passive coupling magnetic shielding strategy and helmet-mounted detection array, which has lower cost and comparable performance over the existing ones. We first utilized the spatially-grid constrained coils and biplanar coils with proportion-integration-differentiation controller with tracking differentiator to ensure a near-zero and stable magnetic field environment with large uniform region. Subsequently, we implemented the brain magnetic signal measurement with the subject randomly moving fingers through tapping a keyboard and with the condition of opening and closing the eyes. Effectively induced brain magnetic signals were detected at the motor functional area and occipital lobe area in the two experiments, respectively. The proposed method will contribute to the development of functional brain imaging.

SARS-CoV-2 induces blood-brain barrier and choroid plexus barrier impairments and vascular inflammation in mice.

The coronavirus disease of 2019 (COVID-19) pandemic has led to more than 700 million confirmed cases and nearly 7 million deaths. Although severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus mainly infects the respiratory system, neurological complications are widely reported in both acute infection and long-COVID cases. Despite the success of vaccines and antiviral treatments, neuroinvasiveness of SARS-CoV-2 remains an important question, which is also centered on the mystery of whether the virus is capable of breaching the barriers into the central nervous system. By studying the K18-hACE2 infection model, we observed clear evidence of microvascular damage and breakdown of the blood-brain barrier (BBB). Mechanistically, SARS-CoV-2 infection caused pericyte damage, tight junction loss, endothelial activation and vascular inflammation, which together drive microvascular injury and BBB impairment. In addition, the blood-cerebrospinal fluid barrier at the choroid plexus was also impaired after infection. Therefore, cerebrovascular and choroid plexus dysfunctions are important aspects of COVID-19 and may contribute to neurological complications both acutely and in long COVID.

Increased neutrophil-derived IL-17A identified in generalized pustular psoriasis.

Generalized pustular psoriasis (GPP) is considered to be a distinct clinical entity from psoriasis vulgaris (PV), with different clinical and histological manifestations. The pathogenesis of GPP has not been thoroughly elucidated, especially in those patients lacking interleukin (IL)36RN. In present study, we performed RNA sequence analysis on skin lesions from 10 GPP patients (4 with and 6 without IL36RN mutation) and 10 PV patients without IL36RN mutation. Compared with PV, significantly overexpressed genes in GPP patients were enriched in IL-17 signalling pathway (MMP1, MMP3, DEFB4A and DEFB4B, etc.) and associated with neutrophil infiltration (MMP1, MMP3, ANXA and SERPINB, etc.). GPP with IL36RN mutations evidenced WNT11 upregulation and IL36RN downregulation in comparison to those GPP without IL36RN mutations. The expression of IL-17A/IL-36 in skin or serum and the origin of IL-17A in skin were also investigated. IL-17A expression in skin was significantly higher in GPP than PV patients, whereas, there were no differences in skin IL-36α/IL-36γ/IL-36RA or serum IL-17A/IL-36α/IL-36γ between GPP than PV. Besides, double immunofluorescence staining of MPO/IL-17A or CD3/IL-17A further confirmed that the majority of IL-17A in GPP skin was derived from neutrophils, but not T cells. These data emphasized the role of neutrophil-derived IL-17A in the pathogenesis of GPP with or without IL36RN mutations. Targeting neutrophil-derived IL-17A might be a promising treatment for GPP.

Application of MXene-Based Materials for Cathode in Lithium-Sulfur Batteries.

The lithium-sulfur (Li-S) batteries have a high theoretical specific capacity of 1675 mAh ⋅ g-1 and have become the most promising high-energy storage system for the next generation batteries technology. However, their applications are hindered by insulated feature and volume expansion of sulfur, as well as the "shuttle effect" of polysulfides. MXenes own metallic conductivity and strong ability of polysulfides adsorption. Besides, their unique two-dimensional (2D) structure, large specific surface area, abundant functional groups, and adjustability are beneficial to overcome the drawbacks of the sulfur cathode. In this review, different mainstream preparation methods and excellent properties of MXenes are summarized. Significant achievements and recent progress of MXene-based cathodes and interlayers applied to Li-S cathodes are concluded later. Finally, the challenges, possible solutions and potential applications of MXenes for Li-S batteries are also presented.

Heterogeneous Photocatalytic C(sp2)-H Activation of Formate for Hydrocarboxylation of Alkenes.

Light-driven carboxylation offers a promising approach for synthesizing valuable fine chemicals under mild conditions. Here we disclose a heterogeneous photocatalytic strategy of C(sp2)-H activation of formate for hydrocarboxylation of alkenes over zinc indium sulfide (ZnIn2S4) under visible light. This protocol functions well with a variety of substituted styrenes with good to excellent yields; it also works for unactivated alkenes albeit with lower yields. Mechanistic studies confirm the existence of CO2⋅- as a key intermediate. It was found that C(sp2)-H activation of formate is induced by S⋅ species on the surface of ZnIn2S4 via hydrogen atom transfer (HAT) instead of a photogenerated hole oxidation mechanism. Moreover, both cleavage of the C(sp2)-H of HCOO- and formation of a benzylic anion were found to be involved in the rate-determining step for the hydrocarboxylation of styrene.

Highly Adhesive and Self-Healing Zwitterionic Hydrogels as Antibacterial Coatings for Medical Devices.

Bacterial infection of medical devices has caused incalculable losses to maintenance costs and health care. A single coating with antibacterial function cannot guarantee the long-term use of the device, because the coating will be damaged and fall off during reuse. To solve this problem, the development of coatings with high adhesion and self-healing ability is a wise direction. In this paper, a multifunctional polyzwitterionic antibacterial hydrogel coating (PZG) composed of amphozwitterion monomer, anionic monomer, and quaternary ammonium cationic monomer was synthesized by dipping UV photoinitiated polymerization. The structure of PZGs was characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy. Ascribing to the hydrogel internal electrostatic interaction, hydrogen bond, and cation-π interaction, the obtained PZGs exhibited high ductility (>1200% strain) and appropriate strength (>189 kPa). Remarkably, PZGs could also adhere firmly on different substrates through noncovalent interaction, and their adhesion could be controlled by adjusting the amount of zwitterionic. Reversible physical interactions in polymer networks endowed hydrogels with excellent self-healing properties. In addition, PZGs exhibit good antibacterial activity and biocompatibility due to the synergistic effect of quaternary ammonium cation and amphozwitterion monomer. This work provides a multifunctional antibacterial coating for medical equipment and has broad application prospects in the biomedical field.

Influence of SHMP Concentration on Rutile Flotation in BHA System: Guiding the Separation of Rutile and Hornblende.

Sodium hexametaphosphate (SHMP) is a common depressant used in rutile flotation, especially for silicate gangue minerals such as amphibole. However, the experiment found that in the benzyl hydroxamic acid (BHA) system, SHMP of small concentrations affected the flotation recovery of rutile. In this work, the influence mechanism of SHMP concentration on the flotation of rutile in the BHA system was studied by flotation test, adsorption capacity determination, ζ potential determination, infrared spectrum analysis, and X-ray photoelectron spectroscopy (XPS) analysis. The test results show that in the BHA system, SHMP chemically adsorbs on the rutile surface, hindering the effect of BHA on the rutile surface, and hydrolyzes in the pulp to form hydrophilic colloids. When the concentration of BHA is 40 mg/L and that of SHMP is 6 mg/L, the effect of SHMP is the most obvious. However, with the increase of SHMP concentration to 8-10 mg/L, its effect on the recovery of rutile became very weak. When the concentration of SHMP is lower than 6 mg/L, the SHMP anion-metaphosphate ion (SHMP-) interacts with the hydrophilic colloidal particles on the surface of rutile, which affects the combination of BHA and the active sites on the surface of rutile, thus affecting the recovery of rutile. When the concentration of SHMP continues to increase, the SHMP- adsorbed on the rutile surface is removed from the rutile surface due to the charge repulsion and the competitive adsorption of BHA.

Assessing the Impact of PM2.5-Bound Arsenic on Cardiovascular Risk among Workers in a Non-ferrous Metal Smelting Area: Insights from Chemical Speciation and Bioavailability.

Inhalation of fine particulate matter PM2.5-bound arsenic (PM2.5-As) may cause significant cardiovascular damage, due to its high concentration, long transmission range, and good absorption efficiency in organisms. However, both the contribution and the effect of the arsenic exposure pathway, with PM2.5 as the medium, on cardiovascular system damage in nonferrous smelting sites remain to be studied. In this work, a one-year site sample collection and analysis work showed that the annual concentration of PM2.5-As reached 0.74 µg/m3, which was 120 times the national standard. The predominant species in the PM2.5 samples were As (V) and As (III). A panel study among workers revealed that PM2.5-As exposure dominantly contributed to human absorption of As. After exposure of mice to PM2.5-As for 8 weeks, the accumulation of As in the high exposure group reached equilibrium, and its bioavailability was 24.5%. A series of animal experiments revealed that PM2.5-As exposure induced cardiac injury and dysfunction at the environmental relevant concentration and speciation. By integrating environmental and animal exposure assessments, more accurate health risk assessment models exposed to PM2.5-As were established for metal smelting areas. Therefore, our research provides an important scientific basis for relevant departments to formulate industry supervision, prevention and control policies.

Novel bibenzyl compound Ae exhibits anti-agiogenic activity in HUVECs in vitro and zebrafish in vivo.

The inhibition of angiogenesis has been considered as an attractive method for the discovery of potential anti-cancer drugs. Herein, we report our new synthesized bibenzyl compound Ae had potent anti-angiogenic activity(the lowest effective concentration is to 0.62-1.25 µM) in zebrafish in vivo and showed a concentration-dependent inhibition of inter-segmental blood vessels (ISVs) compared to control. Further, Ae exhibited the obvious inhibitory activity of proliferation, migration, invasion and tube formation in HUVEC cells in vitro. Moreover, qRT-PCR analysis revealed that the anti-angiogenic activity of compound Ae is connected with the ang-2, tek in ANGPT-TEK pathway and the kdr, kdrl signaling axle in VEGF-VEGFR pathway. Molecular docking studies revealed that compound Ae had an interaction with the angiopoietin-2 receptor(TEK) and VEGFR2. Additionally, analysis of the ADMET prediction data indicated that compound Ae possessed favorable physicochemical properties, drug-likeness, and synthetic accessibility. In conclusion, compound Ae had remarkable anti-angiogenic activity and could be served as an candidate for cancer therapy.

Novel bibenzyl compound 8Ae induces apoptosis and inhibits glycolysis by detaching hexokinase 2 from mitochondria in A549 cells.

In this paper, we investigated the anticancer effect and the mechanism of our newly synthesized bibenzyl 8Ae against human lung cancer A549 cells. Compound 8Ae could induce apoptosis by inhibiting the glycolysis in A549 cells. Hexokinase 2 (HK2), the first key enzyme in glycolysis process, was significantly down-regulated by 8Ae. Besides, compound 8Ae induced HK2 dissociated from mitochondria to cytosol, which could be induced by inhibiting the phosphorylation of Akt. In addition, 8Ae could induce mitochondrial-mediated apoptosis, and mitochondrial membrane potential (MMP) was decreased. After 8Ae treatment, the Bax/Bcl-2 ratio was increased and cytochrome c (Cyt c) was release from mitochondria to cytosol. Molecular docking indicated that 8Ae have an interaction with HK2 by extending into acitve pockets of the protein to form stable hydrogen bonds. Additionally, 8Ae had significantly improved pharmacokinetic properties through the prediction, comparison, and analysis of the ADMET properties of 8Ae and moscatilin (MST). Taken together, 8Ae might inhibit glycolysis by stimulating the shedding of HK2 from mitochondria and promoting mitochondria-regulated apoptosis to inhibit the proliferation of A549 cells. This article provides a research basis for bibenzyl compounds as new small molecule drugs for lung cancer.

Uncovering the selectivity mechanism of phosphodiesterase 7A/8A inhibitors through computational studies.

The expression of phosphodiesterase 7A (PDE7A) and phosphodiesterase 8A (PDE8) genes is integral to human signaling pathways, and the inhibition of PDE7A has been associated with the onset of various diseases, including effects on the immune system and nervous system. The development of PDE7 selective inhibitors can promote research on immune and nervous system diseases, such as multiple sclerosis, chronic inflammation, and autoimmune responses. PDE8A is expressed alongside PDE8B, and its inhibitory mechanism is still unclear. Studying the mechanisms of selective inhibitors against different PDE subtypes is crucial to prevent potential side effects, such as nausea and cardiac toxicity, and the sequence similarity of the two protein subtypes was 55.9%. Therefore, it is necessary to investigate the differences of both subtypes' ligand binding sites. Selective inhibitors of two proteins were chosen to summarize the reason for their selectivity through molecular docking, molecular dynamics simulation, alanine scanning mutagenesis, and MM-GBSA calculation. We found that Phe384PDE7A, Leu401PDE7A, Gln413PDE7A, Tyr419PDE7A, and Phe416PDE7A in the active site positively contribute to the selectivity towards PDE7A. Additionally, Asn729PDE8A, Phe767PDE8A, Gln778PDE8A, and Phe781PDE8A positively contribute to the selectivity towards PDE8A.

Design, synthesis, and biological evaluation of ß-carboline-cinnamic acid derivatives as DYRK1A inhibitors in the treatment of diabetes.

Dual-specificity tyrosine phosphorylation-regulated kinase A (DYRK1A) is a potential drug target for diabetes. The DYRK1A inhibitor can promote ß cells proliferation, increase insulin secretion and reduce blood sugar in diabetes. In this paper, a series ß-carboline-cinnamic acid skeletal derivatives were designed, synthesized and evaluated to inhibit the activity of DYRK1A and promote pancreatic islet ß cell proliferation. Pharmacological activity showed that all of the compounds could effectively promote pancreatic islet ß cell proliferation at a concentration of 1 µM, and the cell viability of compound A1, A4 and B4 reached to 381.5 %, 380.2 % and 378.5 %, respectively. Compound A1, A4 and B4 could also inhibit the expression of DYRK1A better than positive drug harmine. Further mechanistic studies showed that compound A1, A4 and B4 could inhibit DYRK1A protein expression via promoting its degradation and thus enhancing the expression of proliferative proteins PCNA and Ki67. Molecular docking showed that ß-carboline scaffold of these three compounds was fully inserted into the ATP binding site and formed hydrophobic interactions with the active pocket. Besides, these three compounds were predicted to possess better drug-likeness properties using SwissADME. In conclusion, compounds A1, A4 and B4 were potent pancreatic ß cell proliferative agents as DYRK1A inhibitors and might serve as promising candidates for the treatment of diabetes.

A water-immersible scanning mirror with hybrid polymer and elastomer hinges for high-speed and wide-field 3D ultrasound imaging.

This paper reports a new water-immersible single-axis scanning mirror using hybrid polymer and elastomer hinges to achieve both high scanning resonance frequencies and large tilting angles for high-speed and wide-field 3D ultrasound imaging. To demonstrate the concept, a prototype scanning mirror is designed, fabricated, and characterized. The fast- and slow-scanning were achieved by integrating stiff BoPET (biaxially oriented polyethylene terephthalate) and soft elastomer PDMS (Polydimethylsiloxane) hinges, respectively. The testing results have shown a resonance frequency of 270 Hz for the BoPET hinges and a resonance frequency of 10 Hz for the PDMS hinges when the scanning mirror was immersed in water. 3D ultrasound imaging is demonstrated by combining the fast- and slow-scanning together to provide both an augmented field of view (FoV) and high local imaging volume rate.

Estimating the direction of arrival of spatially spread sources using block-sparse Bayesian learning with an extended dictionary.

Estimating the direction of arrival (DOA) of spatially spread sources is a significant challenge in array signal processing. This work introduces an effective method within the sparse Bayesian framework to tackle this issue. A spatially spread source is modeled using a multi-dimensional Slepian signal subspace that expands the dictionary and results in a block-sparse structured solution. By taking advantage of block-sparse Bayesian learning, parameter estimation becomes feasible. A complex Gaussian posterior is derived under a multi-snapshot block-sparse framework with a complex Gaussian prior and varying noise conditions. The hyperparameters are estimated using the expectation-maximization algorithm. Through numerical tests and sea test data evaluations, the proposed method shows superior energy focusing for spatially spread signals. Under limited snapshots and challenging signal-to-noise ratios, the current method can still offer precise DOA determination for spatially spread sources.

Marked variations in gut microbial diversity, functions, and disease risk between wild and captive alpine musk deer.

Maintaining a healthy status is crucial for the successful captive breeding of endangered alpine musk deer (Moschus chrysogaster, AMD), and captive breeding programs are beneficial to the ex-situ conservation and wild population recovery of this species. Meanwhile, the gut microbiota is essential for host health, survival, and environmental adaptation. However, changes in feeding environment and food can affect the composition and function of gut microbiota in musk deer, ultimately impacting their health and adaptation. Therefore, regulating the health status of wild and captive AMD through a non-invasive method that targets gut microbiota is a promising approach. Here, 16S rRNA gene sequencing was employed to reveal the composition and functional variations between wild (N = 23) and captive (N = 25) AMD populations. The results indicated that the gut microbiota of wild AMD exhibited significantly higher alpha diversity (P < 0.001) and greater abundance of the phylum Firmicutes, as well as several dominant genera, including UCG-005, Christensenellaceae R7 group, Monoglobus, Ruminococcus, and Roseburia (P < 0.05), compared to captive AMD. These findings suggest that the wild AMD may possess more effective nutrient absorption and utilization, a more stable intestinal microecology, and better adaption to the complex natural environment. The captive individuals displayed higher metabolic functions with an increased abundance of the phylum Bacteroidetes and certain dominant genera, including Bacteroides, Rikenellaceae RC9 gut group, NK4A214 group, and Alistipes (P < 0.05), which contributed to the metabolic activities of various nutrients. Furthermore, captive AMD showed a higher level of 11 potential opportunistic pathogens and a greater enrichment of disease-related functions compared to wild AMD, indicating that wild musk deer have a lower risk of intestinal diseases and more stable intestinal structure in comparison to captive populations. These findings can serve as a valuable theoretical foundation for promoting the healthy breeding of musk deer and as a guide for evaluating the health of wild-released and reintroduced musk deer in the future. KEY POINTS: • Wild and captive AMD exhibit contrasting gut microbial diversity and certain functions. • With higher diversity, certain bacteria aid wild AMD's adaptation to complex habitats. • Higher potential pathogens and functions increase disease risk in captive AMD.

Optimal control by deep learning techniques and its applications on epidemic models.

We represent the optimal control functions by neural networks and solve optimal control problems by deep learning techniques. Adjoint sensitivity analysis is applied to train the neural networks embedded in differential equations. This method can not only be applied in classic epidemic control problems, but also in epidemic forecasting, discovering unknown mechanisms, and the ideas behind can give new insights to traditional mathematical epidemiological problems.

Human mobility and disease prevalence.

We examine the effect of human mobility on disease prevalence by studying the dependence of the total infected population at endemic equilibria with respect to population diffusion rates of a diffusive epidemic model. For small diffusion rates, our results indicate that the total infected population size is strictly decreasing with respect to the ratio of the diffusion rate of the infected population over that of the susceptible population. Moreover, when the disease local reproductive function is spatially heterogeneous, we found that: (i) for large diffusion rate of the infected population, the total infected population size is strictly maximized at large diffusion rate of the susceptible population when the recovery rate is spatially homogeneous, while it is strictly maximized at intermediate diffusion rate of the susceptible population when the difference of the transmission and recovery rates are spatially homogeneous; (ii) for large diffusion rate of the susceptible population, the total infected population size is strictly maximized at intermediate diffusion rate of the infected population when the recovery rate is spatially homogeneous, while it is strictly minimized at large diffusion rate of the infected population when the difference of the transmission and recovery rates is spatially homogeneous. Numerical simulations are provided to complement the theoretical results. Our studies may provide some insight into the impact of human mobility on disease outbreaks and the severity of epidemics.

Impacts of future climate on the distribution of 4 bumblebee species in the Qinghai-Tibet Plateau.

Climate warming threatens dozens of bumblebee species across the world, including alpine areas. In plateaus with vast and continuous high-altitude areas, bumblebees' response to climate warming may be relatively optimistic. To study the species' responses to future climate in the Qinghai-Tibet Plateau, we quantified the suitable areas for 4 local bumblebee indicator species under current and future climate scenarios (Shared Socio-economic Pathway 126, 245, 370, and 585 in 2,100) using MaxEnt models. Suitable areas of indicator species were stacked to obtain the species richness layer. According to the acreage and connectivity of suitable areas and the acreage of the high richness area, a warmed climate will be more suitable for bumblebees' distribution compared to the current climate. The SSP 126 and SSP 245 scenario will be the 2 most suitable. Meanwhile, with climate warming, suitable areas and the high richness areas will move to high altitudes and their altitude range will decrease. The greater suitability in warmed climates may be caused by the topography of plateaus, which provides an opportunity for bumblebees to migrate to cooler areas. However, mitigation of warming is still necessary because an excessively warm climate will decrease bumblebees' habitat suitability. In plateaus, species in lower altitudes will migrate to higher altitudes, conservation in high altitudes should pay attention to not only original species, but also immigrated species. In lower altitudes, many species will migrate to higher altitudes, then local bumblebee diversity will decrease. Local conservation should be focused on these lower altitude areas.

Research and Application of Contactless Measurement of Transformer Winding Tilt Angle Based on Machine Vision.

In the process of producing winding coils for power transformers, it is necessary to detect the tilt angle of the winding, which is one of the important parameters that affects the physical performance indicators of the transformer. The current detection method is manual measurement using a contact angle ruler, which is not only time-consuming but also has large errors. To solve this problem, this paper adopts a contactless measurement method based on machine vision technology. Firstly, this method uses a camera to take pictures of the winding image and performs a 0° correction and preprocessing on the image, using the OTSU method for binarization. An image self-segmentation and splicing method is proposed to obtain a single-wire image and perform skeleton extraction. Secondly, this paper compares three angle detection methods: the improved interval rotation projection method, quadratic iterative least squares method, and Hough transform method and through experimental analysis, compares their accuracy and operating speed. The experimental results show that the Hough transform method has the fastest operating speed and can complete detection in an average of only 0.1 s, while the interval rotation projection method has the highest accuracy, with a maximum error of less than 0.15°. Finally, this paper designs and implements visualization detection software, which can replace manual detection work and has a high accuracy and operating speed.