TLR4 promotes smooth muscle cell-derived foam cells formation by inducing receptor-independent macropinocytosis.

Foam cells are primarily formed through scavenger receptors that mediate the uptake of various modified low-density lipoproteins (LDL) into cells. In addition to the receptor-dependent pathway, macropinocytosis is an essential non-receptor endocytic pathway for vascular smooth muscle cells (VSMCs) to take up lipids. However, the molecular mechanisms underlying this process remain unclear. Primary cultured VSMCs were stimulated with 200 ng/ml lipopolysaccharide (LPS) and 200 µg/ml native LDL (nLDL). We observed a significant increase in TLR4 protein expression and a significant activation of macropinocytosis, which correlated with the highest uptake of nLDL and intracellular lipid deposition in WT VSMCs. However, macropinocytosis was inhibited and lipid accumulation decreased after treatment with macropinocytosis inhibitors and Syk inhibitors in WT VSMCs. Consistently, TLR4 knockout significantly suppressed macropinocytosis and lipid droplets accumulation in VSMCs. Taken together, our findings suggest a critical role of TLR4/Syk signaling in promoting receptor-independent macropinocytosis leading to VSMC-derived foam cells formation.

Two PNPLA2 heterozygous mutations result in neutral lipid storage disease with myopathy: a case report.

BACKGROUND: Neutral Lipid Storage Disease with Myopathy (NLSDM) is a rare lipid metabolism disorder caused by PNPLA2 gene mutations. Clinical manifestations are heterogeneous, and diagnosis is often delayed, usually gaining patients' attention due to the increased risk of cardiomyopathy. CASE PRESENTATION: We herein report a 36-year-old Asian male presenting with progressive limb weakness, muscle atrophy of limbs and trunk, dysarthria, and heart failure. Electromyography indicated myogenic changes, and muscle biopsy results revealed characteristics of lipid storage myopathy. Genetic analysis of PNPLA2 revealed two heterozygous mutations: c.757 + 1G > T (chr11-823588, splice-5) on intron 6 and c.919delG (chr11-823854, p.A307Pfs*13) on exon 7. The patient improved limb strength, and dysarthria disappeared after the Medium Chain Fatty Acids diet. CONCLUSIONS: In conclusion, we report for the first time that the two heterozygous mutations PNPLA2 c.919delG and c.757 + 1G > T together induced NLSDM, which was confirmed by muscle biopsy.

Atomic Origins of Enhanced Ferroelectricity in Nanocolumnar PbTiO3 /PbO Composite Thin Films.

Nanocomposite films hold great promise for multifunctional devices by integrating different functionalities within a single film. The microstructure of the precipitate/secondary phase is an essential element in designing composites' properties. The interphase strain between the matrix and secondary phase is responsible for strain-mediated functionalities, such as magnetoelectric coupling and ferroelectricity. However, a quantitative microstructure-dependent interphase strain characterization has been scarcely studied. Here, it is demonstrated that the PbTiO3 (PTO)/PbO composite system can be prepared in nano-spherical and nanocolumnar configurations by tuning the misfit strain, confirmed by a three-dimensional reconstructive microscopy technique. With the atomic resolution quantitative microscopy with a depth resolution of a few nanometers, it is discovered that the strained region in PTO is much larger and more uniform in nanocolumnar compared to nano-spherical composites, resulting in much enhanced ferroelectric properties. The interphase strain between PbO and PTO in the nanocolumnar structure leads to a giant c/a ratio of 1.20 (bulk value of 1.06), accompanied by a Ti polarization displacement of 0.48 Å and an effective ferroelectric polarization of 241.7 µC cm-2 , three times compared to the bulk value. The quantitative atomic-scale strain and polarization analysis on the interphase strain provides an important guideline for designing ferroelectric nanocomposites.

A case of progressive multifocal leukoencephalopathy with hypogammaglobulinemia and a TCF3 mutation.

Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal demyelinating disease of the central nervous system (CNS) caused by JC virus; it was previously seen predominantly in immunocompromised patients and those under intense immune suppression. Here, we report the case of a patient with PML with hypogammaglobulinemia and a heterozygous mutation in the TCF3 gene. As the TCF3 gene has been demonstrated to play an important role in the B cell differentiation process and the patient had no other medical history of the immune system, he was diagnosed with common variable immunodeficiency (CVID). To our knowledge, this is the first case of patient with a TCF3 gene deficiency and hypogammaglobulinemia who developed PML.

Sustained Effects of CGRP Blockade on Cortical Spreading Depolarization-Induced Alterations in Facial Heat Pain Threshold, Light Aversiveness, and Locomotive Activity in the Light Environment.

A migraine is clinically characterized by repeated headache attacks that entail considerable disability. Many patients with migraines experience postdrome, the symptoms of which include tiredness and photophobia. Calcitonin gene-related peptide (GGRP) is critically implicated in migraine pathogenesis. Cortical spreading depolarization (CSD), the biological correlate of migraine aura, sensitizes the trigeminovascular system. In our previous study, CSD caused hypomotility in the light zone and tendency for photophobia at 72 h, at which time trigeminal sensitization had disappeared. We proposed that this CSD-induced disease state would be useful for exploring therapeutic strategies for migraine postdrome. In the present study, we observed that the CGRP receptor antagonist, olcegepant, prevented the hypomotility in the light zone and ameliorated light tolerability at 72 h after CSD induction. Moreover, olcegepant treatment significantly elevated the threshold for facial heat pain at 72 h after CSD. Our results raise the possibility that CGRP blockade may be efficacious in improving hypoactivity in the light environment by enhancing light tolerability during migraine postdrome. Moreover, our data suggest that the CGRP pathway may lower the facial heat pain threshold even in the absence of overt trigeminal sensitization, which provides an important clue to the potential mechanism whereby CGRP blockade confers migraine prophylaxis.

Characteristic Lengths of Interlayer Charge Transfer in Correlated Oxide Heterostructures.

Using interlayer interaction to control functional heterostructures with atomic-scale designs has become one of the most effective interface-engineering strategies nowadays. Here, we demonstrate the effect of a crystalline LaFeO3 buffer layer on amorphous and crystalline LaAlO3/SrTiO3 heterostructures. The LaFeO3 buffer layer acts as an energetically favored electron acceptor in both LaAlO3/SrTiO3 systems, resulting in modulation of interfacial carrier density and hence metal-to-insulator transition. For amorphous and crystalline LaAlO3/SrTiO3 heterostructures, the metal-to-insulator transition is found when the LaFeO3 layer thickness crosses 3 and 6 unit cells, respectively. Such different critical LaFeO3 thicknesses are explained in terms of distinct characteristic lengths of the redox-reaction-mediated and polar-catastrophe-dominated charge transfer, controlled by the interfacial atomic contact and Thomas-Fermi screening effect, respectively. Our results not only shed light on the complex interlayer charge transfer across oxide heterostructures but also provide a new route to precisely tailor the charge-transfer process at a functional interface.

Characteristics of cortical spreading depression and c-Fos expression in transgenic mice having a mutation associated with familial hemiplegic migraine 2.

BACKGROUND: Cortical spreading depression is thought to be the underlying mechanism of migraine aura. In 2006, three relatives having the point mutation E700K in ATP1A2 exon 15 were diagnosed with familial hemiplegic migraine 2 characterized by complicated forms of aura. Here, we generated a transgenic mouse model having the human E700K mutation in the Atp1a2 orthologous gene. OBJECTIVE: To investigate the characteristics of cortical spreading depression in a mouse model with E700K mutation in the Atp1a2. METHODS: Cortical spreading depression was induced by applying stepwise increases of KCl concentration or electrical stimulation intensity to C57BL/6J-Tg(Atp1a2*E700K)9151Kwk mice (Tg, both sexes) and corresponding wild-type animals. Under urethane anesthesia, the responsiveness and threshold to cortical spreading depression were examined and the distribution of c-Fos expression, a neuronal activity marker, was immunohistochemically determined. RESULTS: Overall, Tg mice showed significantly faster propagation velocity (p < 0.01) and longer full-width-at-half-maximum (p < 0.01) than wild-type animals, representing a slower recovery from direct current potential deflection. The cortical spreading depression threshold tended to be lower in Tg, especially in females. c-Fos-positive cells were significantly enhanced in the ipsilateral somatosensory cortex, piriform cortex, amygdala and striatum (each p < 0.05 vs. contralateral side). Numbers of c-Fos positive cells were significantly higher in the ipsilateral amygdala of Tg, as compared with wild-type animals (p < 0.01). CONCLUSION: The effect of cortical spreading depression may be greater in E700K transgenic mice than that in wild-type animals, while the threshold for cortical spreading depression shows little change. Higher c-Fos expression in the amygdala may indicate alterations of the limbic system in Tg, suggesting an enhanced linkage between cortical spreading depression and amygdala connectivity in familial hemiplegic migraine 2 patients.

CRISPR/Cas9-mediated genome editing reveals the synergistic effects of ß-defensin family members on sperm maturation in rat epididymis.

The epididymis is a male reproductive organ involved in posttesticular sperm maturation and storage, but the mechanism underlying sperm maturation remains unclear. ß-Defensins (Defbs) belong to a family of small, cysteine-rich, cationic peptides that are antimicrobial and modulate the immune response. A large number of Defb genes are expressed abundantly in the male reproductive tract, especially in the epididymis. We and other groups have shown the involvement of several Defb genes in regulation of sperm function. In this study, we found that Defb23, Defb26, and Defb42 were highly expressed in specific regions of the epididymis. Rats with CRISPR/Cas9-mediated single-gene disruption of Defb23, Defb26, or Defb42 had no obvious fertility phenotypes. Those with the deletion of Defb23/ 26 or Defb23/ 26/ 42 became subfertile, and sperm isolated from the epididymal cauda of multiple-mutant rats were demonstrated decreased motility. Meanwhile, the sperm showed precocious capacitation and increased spontaneous acrosome reaction. Consistent with premature capacitation and acrosome reaction, sperm from multiple-gene-knockout rats had significantly increased intracellular calcium. These results suggest that Defb family members affect sperm maturation by a synergistic pattern in the epididymis.-Zhang, C., Zhou, Y., Xie, S., Yin, Q., Tang, C., Ni, Z., Fei, J., Zhang, Y. CRISPR/Cas9-mediated genome editing reveals the synergistic effects of ß-defensin family members on sperm maturation in rat epididymis.

On-Chip Tailorability of Capacitive Gas Sensors Integrated with Metal-Organic Framework Films.

Gas sensing technologies for smart cities require miniaturization, cost-effectiveness, low power consumption, and outstanding sensitivity and selectivity. On-chip, tailorable capacitive sensors integrated with metal-organic framework (MOF) films are presented, in which abundant coordinatively unsaturated metal sites are available for gas detection. The in situ growth of homogeneous Mg-MOF-74 films is realized with an appropriate metal-to-ligand ratio. The resultant sensors exhibit selective detection for benzene vapor and carbon dioxide (CO2 ) at room temperature. Postsynthetic modification of Mg-MOF-74 films with ethylenediamine decreases sensitivity toward benzene but increases selectivity to CO2 . The reduced porosity and blocked open metal sites caused by amine coordination account for a deterioration in the sensing performance for benzene (by ca. 60 %). The enhanced sensitivity for CO2 (by ca. 25 %) stems from a tailored amine-CO2 interaction. This study demonstrates the feasibility of tuning gas sensing properties by adjusting MOF-analyte interactions, thereby offering new perspectives for the development of MOF-based sensors.

Fragmentation of Red Blood Cells Caused Pseudothrombocytosis in a Patient.

BACKGROUND: Pseudothrombocytopenia, caused by platelet (PLT) clumping, is often found in clinical studies [1]. However, pseudothrombocytosis resulting from the fragmentation of red blood cells (RBCs) is a very rare phenomenon. METHODS: EDTA-K2 anticoagulation was used on a sample of venous blood extracted from the patient. A Symex XN9000 automatic blood analyzer was used to conduct CBC + DIFF mode and CBC + DIFF + RET mode tests, stained smear microscopy. RESULTS: The Symex XN9000 automatic blood analyzer was used to conduct CBC + DIFF mode test; PLTs were measured at 570 x 109/L. Stained smear microscopy revealed the number of PLTs did not conform to the instrument measured 570 x 109/L. "RET" alarm instrument, switch to CBC + DIFF + RET mode for testing. The second test result showed PLTs at 128 x 109/L, which accords with artificial microscopy. CONCLUSIONS: This was a case of a very rare phenomenon: the fragmentation of RBCs caused pseudothrombocytosis.

(CH3 NH3 )2 PdCl4 : A Compound with Two-Dimensional Organic-Inorganic Layered Perovskite Structure.

The synthesis of previously unknown perovskite (CH3 NH3 )2 PdCl4 is reported. Despite using an organic cation with the smallest possible alkyl group, a 2D organic-inorganic layered Pd-based perovskites was still formed. This demonstrates that Pd-based 2D perovskites can be obtained even if the size of the organic cation is below the size limit predicted by the Goldschmidt tolerance-factor formula. The (CH3 NH3 )2 PdCl4 phase has a bulk resistivity of 1.4â€…Ω cm, a direct optical gap of 2.22 eV, and an absorption coefficient on the order of 104  cm-1 . XRD measurements suggest that the compound is moderately stable in air, an important advantage over several existing organic-inorganic perovskites that are prone to phase degradation problems when exposed to the atmosphere. Given the recent interest in organic-inorganic perovskites, the synthesis of this new Pd-based organic-inorganic perovskite may be helpful in the preparation and understanding of other organic-inorganic perovskites.

Tuning Rashba-Dresselhaus effect with ferroelectric polarization at asymmetric heterostructural interface.

The spin-orbit interaction (SOI) plays an essential role in materials properties, and controlling its intensity has great potential in the design of materials. In this work, asymmetric [(La0.7Sr0.3MnO3)8/(BaTiO3)t/(SrTiO3)2]8 superlattices were fabricated on (001) SrTiO3 substrate with SrO or TiO2 termination, labelled as SrO-SL and TiO2-SL, respectively. The in-plane angular magnetoresistance of the superlattices shows a combination of two- and four-fold symmetry components. The coefficient of two-fold symmetry component has opposite sign with current I along [100] and [110] directions for TiO2-SL, while it has the same sign for SrO-SL. Detailed study shows that the asymmetric cation inter-mixing and ferroelectricity-modulated electronic charge transfer induce asymmetric electronic potential for SrO-SL with dominating Rashba SOI, and symmetric electronic potential for TiO2-SL with dominating Dresselhaus SOI induced by BaTiO3. This work shows that the Rashba and Dresselhaus SOIs are sensitive to the ferroelectric polarization in the asymmetric structure.

Cerebral toxoplasmosis mimicking stroke in a woman living with undiagnosed HIV.

Toxoplasma gondii is an opportunistic pathogen that can intrude into the blood-brain barrier and reside in the brain only with low inflammatory reaction. When infected with HIV, the immune system becomes severely compromised and leads to the reactivation of latent toxoplasmosis infection, which can mimic the clinical manifestation of stroke. We report a case of a 65-year-old female patient who presented with sudden right limb weakness, walking difficulty, and numbness without other typical symptoms, raising suspicion of acute ischemic stroke. The HIV serology returned positive, which expedited the diagnostic workup for opportunistic infection. Combining imageological examination and metagenomics next-generation sequencing of cerebrospinal fluid, HIV-associated cerebral toxoplasmosis was confirmed. The patient underwent treatment for toxoplasmosis and HIV. Six months after onset, the patient can walk independently but still exhibits weakness in the right upper limb. In HIV-infected patients, cerebral toxoplasmosis, particularly presenting as isolated stroke-like episodes, poses a more significant challenge, emphasizing the need for more thorough investigations to reduce the potential for misdiagnosis.

Endovascular treatment without postoperative decompressive craniectomy in an acute stroke patient with very large ischemic infarct core: A case report and literature review.

Introduction: The benefits of endovascular treatment (EVT) on large ischemic infarct core mainly focus on a core size of 70-150 ml. The relationship between EVT and very large ischemic infarct core (>150 ml) is unclear. We herein present an acute stroke patient who achieved functional independence after EVT without postoperative decompressive craniectomy despite very large ischemic infarct core. Case report: A 50-year-old Asian male was admitted to our hospital with "sudden disturbance of consciousness with left limb weakness for 11 hours". The patient had a history of clipping treatment for ruptured aneurysms. After an emergency CTA and CTP, very large ischemic core of 190 ml and a mismatch ratio (Tmax > 6s volume/core volume) of 1.9 were shown in preoperative imaging. EVT was performed, and postoperative strict monitoring was conducted without decompressive craniectomy. The patient was discharged from the hospital on the 16th day, scoring 2 on the modified Rankin scale at a 2-year follow-up. Conclusion: Imaging suggests very large ischemic infarct core; if there is a substantial mismatch between major functional areas (large ischemic penumbra) and the patient is relatively young, aggressive EVT may be beneficial.

Brainstem dominant form of X-linked adrenoleukodystrophy with a novel ABCD1 missense variant: A case report and literature review.

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder attributed to ABCD1 mutations. Case reports with predominant brainstem involvement are rare. CASE PRESENTATION: In this study, we reported a plateau male worker of X-ALD characterized by progressive weakness accompanied by gait instability, mild nystagmus, and constipation. After 2 years of onset, a brain Magnetic Resonance Image (MRI) scan showed no abnormality but genetic analysis revealed a heterozygous mutation (c.1534G>A) in the ABCD1 gene. After 7 years of onset, although the patient was given aggressive dietary and symptomatic treatment in the course of the disease, a brain MRI scan showed predominantly brainstem damage, but serum concentrations of very long-chain fatty acids were normal, and he had been bedridden for almost 2 years with severe bladder dysfunction, forcing him to undergo cystostomy. The patient was discharged with improved urinary retention and renal function. CONCLUSIONS: We reported an X-ALD patient with a novel ABCD1 variation characterized by brainstem damage and retrospectively summarized the clinical manifestation, MRI features, and genetic features of X-ALD patients with brainstem damage.

Advances in screening, synthesis, modification, and biomedical applications of peptides and peptide aptamers.

Peptides and peptide aptamers have emerged as promising molecules for a wide range of biomedical applications due to their unique properties and versatile functionalities. The screening strategies for identifying peptides and peptide aptamers with desired properties are discussed, including high-throughput screening, display screening technology, and in silico design approaches. The synthesis methods for the efficient production of peptides and peptide aptamers, such as solid-phase peptide synthesis and biosynthesis technology, are described, along with their advantages and limitations. Moreover, various modification techniques are explored to enhance the stability, specificity, and pharmacokinetic properties of peptides and peptide aptamers. This includes chemical modifications, enzymatic modifications, biomodifications, genetic engineering modifications, and physical modifications. Furthermore, the review highlights the diverse biomedical applications of peptides and peptide aptamers, including targeted drug delivery, diagnostics, and therapeutic. This review provides valuable insights into the advancements in screening, synthesis, modification, and biomedical applications of peptides and peptide aptamers. A comprehensive understanding of these aspects will aid researchers in the development of novel peptide-based therapeutics and diagnostic tools for various biomedical challenges.

Monitoring Blood Glucose in Mouse Offspring after Intracytoplasmic sperm injection - Embryo Transfer.

Human lifespan is considerably long, while mouse models can simulate the entire human lifespan in a relatively short period, with one year of mouse life roughly equivalent to 40 human years. Intracytoplasmic sperm injection (ICSI) is a commonly used assisted reproductive technology in clinical practice. However, given its relatively recent emergence about 30 years ago, the long-term effects of this technique on human development remain unclear. In this study, we established the ICSI combined with embryo transfer (ET) method using a mouse model. The results demonstrated that normal mouse sperm, after undergoing in vitro culture and subsequent ICSI, exhibited a fertilization rate of 89.57% and a two-cell rate of 87.38%. Following ET, the birth rate of offspring was approximately 42.50%. Furthermore, as the mice aged, fluctuations in glucose metabolism levels were observed, which may be associated with the application of the ICSI technique. These findings signify that the mouse ICSI-ET technique provides a valuable platform for evaluating the impact of sperm abnormalities on embryo development and their long-term effects on offspring health, particularly concerning glucose metabolism. This study provides important insights for further research on the potential effects of the ICSI technique on human development, emphasizing the necessity for in-depth investigation into the long-term implications of this technology.

A New Advanced Approach: Design and Screening of Affinity Peptide Ligands Using Computer Simulation Techniques.

Peptides acquire target affinity based on the combination of residues in their sequences and the conformation formed by their flexible folding, an ability that makes them very attractive biomaterials in therapeutic, diagnostic, and assay fields. With the development of computer technology, computer-aided design and screening of affinity peptides has become a more efficient and faster method. This review summarizes successful cases of computer-aided design and screening of affinity peptide ligands in recent years and lists the computer programs and online servers used in the process. In particular, the characteristics of different design and screening methods are summarized and categorized to help researchers choose between different methods. In addition, experimentally validated sequences are listed, and their applications are described, providing directions for the future development and application of computational peptide screening and design.

Non-immobilized GO-SELEX screening of aptamers against cyclosporine A and its application in a AuNPs colorimetric aptasensor.

Cyclosporine A (CsA) is an immunosuppressive drug that is widely used in clinical practice. Due to its narrow therapeutic window and the significant differences between individuals, the therapeutic drug monitoring (TDM) of CsA is required to ensure patient safety. In this study, we screened a novel aptamer, named CsA7, which could specifically recognize CsA, and developed a AuNPs colorimetric aptasensor for the rapid detection of CsA. In the SELEX process, after eight rounds of screening, four aptamer candidate sequences were obtained and subjected to binding affinity and specificity tests. Finally, the CsA7 aptamer (Kd = 41.21 ng mL-1) showed the highest affinity for CsA. Based on CsA7, we also developed a AuNPs colorimetric aptasensor, which had a detection limit of 0.1 ng mL-1 and a quantitative range of 0.1-500 ng mL-1 and showed good selectivity among CsA and its analogs. According to the results, the CsA7 aptamer provides an alternative recognition molecule to the antibody in biosensor applications and shows great potential for the rapid and convenient detection of CsA.

An AuNPs-based electrochemical aptasensor for the detection of 25-hydroxy vitamin D3.

Vitamin D3 (VD3) is the main form of vitamin D and an essential nutrient for maintaining human life. Currently, traditional methods for detecting 25-hydroxyvitamin D3(25(OH)D3) are complex and expensive. In this study, we constructed an accurate, sensitive, simple, and cost-effective label-free biosensor based on an aptamer for the detection of 25(OH)D3. The aptamer-modified sulfhydryl adopted self-assembly as a way to stably immobilize at the glassy carbon electrode (GCE) surface modified by gold nanoparticles (AuNPs). Upon 25(OH)D3 binding to the aptamer, the complexes inhibit electron transfer at the electrode surface, leading to reduced [Fe(CN)6]3-/4- redox peak current. Consequently, the quantity of 25(OH)D3 that interacts with the electrode-bound aptamer correlates with the observed electric current response values. The Aptamer/AuNPs/GCE aptasensor achieved direct and highly sensitive detection of 25(OH)D3 over a wide concentration range (1.0-1000 nM), with a limit of detection of 1.0 nM. At the same time, other molecules with a similar structure, such as 25(OH)D2, Vitamin D3, and Vitamin D2, had lower response interference than 25(OH)D3. Therefore, this biosensor has great potential to become a portable diagnostic device for 25(OH)D3.