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.

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.

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.

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.

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.

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.

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.

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.

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.

Improving ADMET Prediction Accuracy for Candidate Drugs: Factors to Consider in QSPR Modeling Approaches.

Quantitative Structure-Property Relationship (QSPR) employs mathematical and statistical methods to reveal quantitative correlations between the pharmacokinetics of compounds and their molecular structures, as well as their physical and chemical properties. QSPR models have been widely applied in the prediction of drug absorption, distribution, metabolism, excretion, and toxicity (ADMET). However, the accuracy of QSPR models for predicting drug ADMET properties still needs improvement. Therefore, this paper comprehensively reviews the tools employed in various stages of QSPR predictions for drug ADMET. It summarizes commonly used approaches to building QSPR models, systematically analyzing the advantages and limitations of each modeling method to ensure their judicious application. We provide an overview of recent advancements in the application of QSPR models for predicting drug ADMET properties. Furthermore, this review explores the inherent challenges in QSPR modeling while also proposing a range of considerations aimed at enhancing model prediction accuracy. The objective is to enhance the predictive capabilities of QSPR models in the field of drug development and provide valuable reference and guidance for researchers in this domain.

Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study.

We aimed to investigate the diagnostic value of urinary Tamm-Horsfall protein (THP) and 24 h urine osmolality for recurrent calcium oxalate (CaOx) stones. Clinical data of 120 patients with upper urinary tract stones admitted to our hospital between January 2020 and January 2022 were retrospectively reviewed. Patients were divided into recurrence (53 patients) and non-recurrence (67 patients) groups based on postoperative stone recurrence. Meanwhile, 50 healthy patients were selected as the control group. Urinary THP levels, 24 h urine osmolality, and biochemical indices were compared between the three groups; their diagnostic values for stone recurrence were evaluated using receiver operating characteristic (ROC) curves. Urinary THP, 24 h urine osmolality, and biochemical indices were significantly higher in the recurrence group than in the non-recurrence and control groups (P < 0.05). The 24 h urine osmolality was positively correlated with urinary oxalic acid and calcium excretion. ROC curve analysis showed that optimal cutoff values of urinary THP and 24 h urine osmolality for the diagnosis of stone development were ≥27.01 mg/L and ≥577.69 mOsm/(kg H2O), respectively. Furthermore, these indices combined significantly improved the accuracy of diagnosis. Urinary THP and 24 h urine osmolality were higher in patients with recurrent CaOx stones. Detection of both parameters combined can accurately diagnose stone recurrence.

Trends in sperm quality by computer-assisted sperm analysis of 49,189 men during 2015-2021 in a fertility center from China.

Background: Sperm quality, including semen volume, sperm count, concentration, and total and progressive motility (collectively, "semen parameters"), has declined in the recent decades. Computer-assisted sperm analysis (CASA) provides sperm kinematic parameters, and the temporal trends of which remain unclear. Our objective is to examine the temporal trend of both semen parameters and kinematic parameters in Shanghai, China, in the recent years. Methods: This retrospective study analyzed semen parameters and kinematic parameters of 49,819 men attending our reproductive center by using CASA during 2015-2021. The total sample was divided into two groups: samples that surpassed the WHO guideline (2010) low reference limits ("above reference limit" group, ARL; n = 24,575) and samples that did not ("below reference limit" group, BRL; n = 24,614). One-way analysis of variance, Kruskal-Wallis test, independent samples t-test, and covariance analysis were used to assess the differences among groups. Year, age, and abstinence time were included in the multiple linear regression model of the ARL group to adjust the confounders and depict the trends in sperm quality. Results: Among all the total sample and the ARL and BRL groups, the age of subjects increased in recent years. Semen volume and sperm count showed declined tendency with years in the total sample, the ARL and BRL groups, and the subgroup of age or abstinence time, whereas sperm velocities showed increased tendency with years on the contrary. The multiple linear regression model of the ARL group, adjusting for age and abstinence time, confirmed these trends. Semen volume (ß1= -0.162; CI: -0.172, -0.152), sperm count (ß1= -9.97; CI: -10.813, -9.128), sperm concentration (ß1 = -0.535; CI: -0.772, -0.299), motility (ß1 = -1.751; CI: -1.830, -1.672), and progressive motility (ß1 = -1.12; CI: -0.201, -0.145) decreased with year, whereas curvilinear line velocity (VCL) (ß1 = 3.058; CI: 2.912, 3.203), straight line velocity (VSL) (ß1 = 2.075; CI: 1.990, 2.161), and average path velocity (VAP) (ß1 = 2.305; CI: 2.224, 2.386) increased over time (all p < 0.001). In addition, VCL, VSL, and VAP significantly declined with age and abstinence time. Conclusion: The semen parameters declined, whereas the kinematic parameters increased over the recent years. We propose that, although sperm count and motility declined over time, sperm motion velocity increased, suggesting a possible compensatory mechanism of male fertility.

Recent Advances in Computer-aided Virtual Screening and Docking Optimization for Aptamer.

Aptamers, as artificially synthesized short nucleotide sequences, have been widely used in protein analysis, gene engineering, and molecular diagnostics. Currently, the screening process of aptamers still relies on the traditional SELEX process, which is cumbersome and complex. Moreover, the success rate of aptamer screening through the SELEX process is not high, which has become a major challenge. In recent years, the development of computers has facilitated virtual screening, which can greatly accelerate the screening process of aptamers through computer-assisted screening. However, the accuracy and precision of current virtual screening software on the market vary. Therefore, this work summarizes the docking characteristics of four mainstream molecular docking software programs, including Auto dock, Auto dock Vina, MOE, and hex Dock, in recent years. Moreover, the accuracy and prediction performance of these four molecular docking software programs for aptamer docking based on experimental data is also evaluated. This will guide researchers in the selection of molecular docking software. Additionally, this review provides a detailed overview of the application of computer-aided virtual screening in aptamer screening, thus providing a direction for future development in this field.

A label-free fluorescent aptamer sensor for testosterone based on SYBR Green I.

Testosterone is a steroid hormone that plays an indispensable role in the normal metabolism of organisms. However, exogenous testosterone, even as low as nmol L-1, will harm the human body due to accumulation. In this study, we developed an unlabeled fluorescent sensor for testosterone based on SYBR Green I. SYBR Green I is a fluorescent dye that can be embedded into the G-quadruplex of the testosterone aptamer T5. The fluorescence quenching effect is utilized to achieve quantitative detection, which occurs by the competition between testosterone and SYBR Green I for the T5 aptamer binding sites. In this work, we optimized the detection conditions to make the fluorescent sensor more sensitive and verify the specificity, linear range, and detection ability in the buffer and real water samples. The sensor's LOD and LOQ values were 0.27 nmol L-1 and 0.91 nmol L-1, respectively, while the detection range was linear from 0.91 nmol L-1 to 2000 nmol L-1. According to the results, the sensor shows high specificity and good performance even in real sample detection such as tap water and river water, providing an alternative method for the quantitative detection of testosterone in the environment, which is more convenient and efficient.

Placental ischemia disrupts DNA methylation patterns in distal regulatory regions in rats.

Preeclampsia (PE) is a leading cause of maternal and fetal morbidity and mortality worldwide. However, the impact of PE on the organization of the functional architecture of the placental methylome remains largely unknown. We performed whole-genome bisulfite sequencing of placental DNA and applied a Hidden Markov Model to investigate epigenome-wide alterations in functional structures, including partially methylated domains (PMDs), low-methylated regions (LMRs), and unmethylated regions (UMRs), in a reduced uterine perfusion pressure (RUPP) rat model of PE. The remarkable similarity we observed between the rat and human placental DNA methylomes suggests that the RUPP rat model is appropriate to elucidate the epigenetic mechanisms underlying human PE. The notable changes in PMDs indicate RUPP-induced perturbation of the stressed placental methylome. This was probably regulated via modulation of the epigenetic modifier expression, including significant downregulation of Dnmt1 and Dnmt3a and upregulation of Tet2. More importantly, changes in RUPP-induced DNA methylation occurred predominately in LMRs (80 %), which represent active enhancers, rather than in canonical UMRs (3 %), which represent promoters, suggesting that placental ischemia disrupts enhancer DNA methylation. Our findings emphasize the role of enhancer methylation in response to PE, corroborating discoveries in human PE studies. We suggest paying more attention to enhancer regions in future studies on PE.

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.

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.

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.

Reassessment of the Proteomic Composition and Function of Extracellular Vesicles in the Seminal Plasma.

Seminal plasma contains a high concentration of extracellular vesicles (EVs). The heterogeneity of small EVs or the presence of nonvesicular extracellular matter (NV) pose major obstacles in understanding the composition and function of seminal EVs. In this study, we employed high-resolution density gradient fractionation to accurately characterize the composition and function of seminal EVs and NV. We found that the seminal EVs could be divided into 3 different subtypes-namely, high-density EV (EV-H), medium-density EV (EV-M), and low-density EV (EV-L)-after purification using iodixanol, while NV was successfully isolated. EVs and NV display different features in size, shape, and expression of some classic exosome markers. Both EV-H and NV could markedly promote sperm motility and capacitation compared with EV-M and EV-L, whereas only the NV fraction induced sperm acrosome reaction. Proteomic analysis results showed that EV-H, EV-M, EV-L, and NV had different protein components and were involved in different physiological functions. Further study showed that EV-M might reduce the production of sperm intrinsic reactive oxygen species through glutathione S-transferase mu 2. This study provides novel insights into important aspects of seminal EVs constituents and sounder footing to explore their functional properties in male fertility.

A simple unlabeled human chorionic gonadotropin biosensor based on a peptide aptamer.

As an essential biochemical indicator in the fields of pregnancy and oncology, human chorionic gonadotropin (HCG) can be evaluated using colloidal gold immunochromatographic paper and quantified using a biochemical analyzer based on the principle of the antibody sandwich method. In view of the inaccuracy of the former and the complication of the latter, this study constructed an accurate, sensitive and simple unlabeled biosensor based on peptide aptamer CGGGPPLRINRHILTR for HCG detection. Molecular Operating Environment (MOE) was used to simulate the aptamer and protein docking, and western blot (WB) was used to verify the binding effect and ratio. The peptide aptamer was characterized and was then reduced with tris-(2-carboxyethyl)-phosphine hydrochloride (TCEP). After electrochemical deposition of chloroauric acid on the screen-printed electrode (SPE), the aptamer was self-assembled on the electrode surface under optimal conditions. The active site of the electrode surface was blocked with 6-mercapto-1-hexanol (MCH) and BSA. The electrochemical impedance spectrum (EIS) was used to quantify HCG in the matrix. Showing a good linear relationship in the range of 5-1500 mIU mL-1, with a detection limit of 1 mIU mL-1, the biosensor remained stable at room temperature for 14 days. Because of its small size, stability, sensitivity and accuracy, this biosensor has great potential to become a portable diagnostic device for HCG.