Insights into spinal muscular atrophy from molecular biomarkers.

Spinal muscular atrophy is a devastating motor neuron disease characterized by severe cases of fatal muscle weakness. It is one of the most common genetic causes of mortality among infants aged less than 2 years. Biomarker research is currently receiving more attention, and new candidate biomarkers are constantly being discovered. This review initially discusses the evaluation methods commonly used in clinical practice while briefly outlining their respective pros and cons. We also describe recent advancements in research and the clinical significance of molecular biomarkers for spinal muscular atrophy, which are classified as either specific or non-specific biomarkers. This review provides new insights into the pathogenesis of spinal muscular atrophy, the mechanism of biomarkers in response to drug-modified therapies, the selection of biomarker candidates, and would promote the development of future research. Furthermore, the successful utilization of biomarkers may facilitate the implementation of gene-targeting treatments for patients with spinal muscular atrophy.

Advancements and challenges in biomimetic materials for food preservation: A review.

The exploration of biomimetic materials within the food industry has seen recent advancements, yet their practical application remains limited, particularly in food preservation. Significant challenges currently persist from the research and development phase to the investigation of practical applications. Therefore, it is imperative to promptly review the existing research, discuss the challenges, and propose constructive suggestions for current scientific trends. This paper initially summarizes naturally occurring superhydrophobic and superhydrophilic organisms, followed by an analysis of the primary obstacles hindering the practical use of these materials. Subsequently, we delve into fresh-keeping materials inspired by plants, insects, shellfish, and fish. Finally, we forecast the trajectory of this field to direct future research, given the extensive potential of biomimetic materials in food preservation. This study aims to effectively guide the research and development of biomimetic materials and their application within the food preservation industry.

Automated High-Throughput Atomic Force Microscopy Single-Cell Nanomechanical Assay Enabled by Deep Learning-Based Optical Image Recognition.

Mechanical forces are essential for life activities, and the mechanical phenotypes of single cells are increasingly gaining attention. Atomic force microscopy (AFM) has been a standard method for single-cell nanomechanical assays, but its efficiency is limited due to its reliance on manual operation. Here, we present a study of deep learning image recognition-assisted AFM that enables automated high-throughput single-cell nanomechanical measurements. On the basis of the label-free identification of the cell structures and the AFM probe in optical bright-field images as well as the consequent automated movement of the sample stage and AFM probe, the AFM probe tip could be accurately and sequentially moved onto the specific parts of individual living cells to perform a single-cell indentation assay or single-cell force spectroscopy in a time-efficient manner. The study illustrates a promising method based on deep learning for achieving operator-independent high-throughput AFM single-cell nanomechanics, which will benefit the application of AFM in mechanobiology.

Global fishing patterns amplify human exposures to methylmercury.

Global pollution has exacerbated accumulation of toxicants like methylmercury (MeHg) in seafood. Human exposure to MeHg has been associated with long-term neurodevelopmental delays and impaired cardiovascular health, while many micronutrients in seafood are beneficial to health. The largest MeHg exposure source for many general populations originates from marine fish that are harvested from the global ocean and sold in the commercial seafood market. Here, we use high-resolution catch data for global fisheries and an empirically constrained spatial model for seafood MeHg to examine the spatial origins and magnitudes of MeHg extracted from the ocean. Results suggest that tropical and subtropical fisheries account for >70% of the MeHg extracted from the ocean because they are the major fishing grounds for large pelagic fishes and the natural biogeochemistry in this region facilitates seawater MeHg production. Compounding this issue, micronutrients (selenium and omega-3 fatty acids) are lowest in seafood harvested from warm, low-latitude regions and may be further depleted by future ocean warming. Our results imply that extensive harvests of large pelagic species by industrial fisheries, particularly in the tropics, drive global public health concerns related to MeHg exposure. We estimate that 84 to 99% of subsistence fishing entities globally likely exceed MeHg exposure thresholds based on typical rates of subsistence fish consumption. Results highlight the need for both stringent controls on global pollution and better accounting for human nutrition in fishing choices.

Association between serum neurofilament light chains and depression: A cross-sectional study based on NHANES 2013-2014 database.

BACKGROUND: Serum neurofilament light chain (sNfl), identified as a promising biomarker, is a protein released into the bloodstream post-axonal damage. Studies on its correlation with depression, however, remains scarce. The purpose of this study was to investigate the potential relationship between sNfL levels and risk of depression among a representative segment of the U. S. populace. METHODS: This study included 1,909 participants from the 2013-2014 National Health and Nutrition Examination Survey. The 9-item Patient Health Questionnaire (PHQ-9 scale) assessed depression symptoms, while sNfl concentrations were measured using the Attelica fully automated immunoassay system. The logistic regression, restricted cubic splines (RCS), and subgroup analysis were performed to assess the relationship between sNfL, lnsNfL (log-transformed values of sNfl), and depression. RESULTS: After adjusting for sociodemographic variables, lifestyle, and chronic conditions, sNfl and lnsNfL levels positively correlated with depression. A unit increase in sNfL and lnsNfL levels was linked to a 0.7 % and 33.8 % rise in depression risk, respectively [OR (95 % CI): 1.007 (1.000, 1.014), p = 0.041 for sNfl; 1.338 (1.015, 1.764), p = 0.039 for lnsNfl]. Additionally, a positive linear association was observed between lnsNfl levels and the risk of depression (p for overall = 0.039, p for nonlinear = 0.189 in RCS). No significant differences were observed across subgroups between lnsNfl and depression, with no significant impact on this relationship from subgroups (All p for interaction >0.05). CONCLUSION: The findings of our study suggest a significant positive correlation between sNfl and depression, warranting further investigation into the molecular dynamics linking sNfL to depression and subgroup variability.

Exploring Drivers of Historic Mercury Trends in Beluga Whales Using an Ecosystem Modeling Approach.

While mercury occurs naturally in the environment, human activity has significantly disturbed its biogeochemical cycle. Inorganic mercury entering aquatic systems can be transformed into methylmercury, a strong neurotoxicant that builds up in organisms and affects ecosystem and public health. In the Arctic, top predators such as beluga whales, an ecologically and culturally significant species for many Inuit communities, can contain high concentrations of methylmercury. Historical mercury concentrations in beluga in the western Canadian Arctic's Beaufort Sea cannot be explained by mercury emission trends alone; in addition, they could potentially be driven by climate change impacts, such as rising temperatures and sea ice melt. These changes can affect mercury bioaccumulation through different pathways, including ecological and mercury transport processes. In this study, we explore key drivers of mercury bioaccumulation in the Beaufort Sea beluga population using Ecopath with Ecosim, an ecosystem modeling approach, and scenarios of environmental change informed by Western Science and Inuvialuit Knowledge. Comparing the effect of historical sea ice cover, sea surface temperature, and freshwater discharge time series, modeling suggests that the timing of historical increases and decreases in beluga methylmercury concentrations can be better explained by the resulting changes to ecosystem productivity rather than by those to mercury inputs and that all three environmental drivers could partially explain the decrease in mercury concentrations in beluga after the mid-1990s. This work highlights the value of multiple knowledge systems and exploratory modeling methods in understanding environmental change and contaminant cycling. Future work building on this research could inform climate change adaptation efforts and inform management decisions in the region.

Novel Guanidinium-Functionalized Stigmasterol for Bile Salt Binding and Serum Cholesterol Reduction: Synthesis, Interaction Mechanisms, and In Vivo Function.

A novel amphiphilic guanidyl-functionalized stigmasterol hydrochloride (GFSH) was designed and synthesized as bile salt sequestrants for cholesterol reduction. GFSH exhibited a considerable in vitro capacity for bile salt binding in gastrointestinal digestion and alleviated hypercholesterolemia in vivo. GFSH spontaneously interacted with sodium cholate via synergistic electrostatic, hydrophobic, and hydrogen-bonding interactions. The effects of GFSH on serum cholesterol reduction in mice fed a high-fat-high-cholesterol diet were explored by measuring the expression of key transcription factors related to bile acid metabolism. GFSH produced a dose-dependent reduction in weight gain, hepatic fat accumulation, and fecal and blood markers. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot analyses demonstrated GFSH-induced expression of hepatic CYP7A, LXRα, and LDL-R. GFSH exerts the cholesterol-lowering activity by inducing the bile acid metabolism.

Structural and virologic mechanism of the emergence of resistance to Mpro inhibitors in SARS-CoV-2.

We generated SARS-CoV-2 variants resistant to three SARS-CoV-2 main protease (Mpro) inhibitors (nirmatrelvir, TKB245, and 5h), by propagating the ancestral SARS-CoV-2WK521WT in VeroE6TMPRSS2 cells with increasing concentrations of each inhibitor and examined their structural and virologic profiles. A predominant E166V-carrying variant (SARS-CoV-2WK521E166V), which emerged when passaged with nirmatrelvir and TKB245, proved to be resistant to the two inhibitors. A recombinant SARS-CoV-2E166V was resistant to nirmatrelvir and TKB245, but sensitive to 5h. X-ray structural study showed that the dimerization of Mpro was severely hindered by E166V substitution due to the disruption of the presumed dimerization-initiating Ser1'-Glu166 interactions. TKB245 stayed bound to MproE166V, whereas nirmatrelvir failed. Native mass spectrometry confirmed that nirmatrelvir and TKB245 promoted the dimerization of Mpro, and compromised the enzymatic activity; the Ki values of recombinant MproE166V for nirmatrelvir and TKB245 were 117±3 and 17.1±1.9 µM, respectively, indicating that TKB245 has a greater (by a factor of 6.8) binding affinity to MproE166V than nirmatrelvir. SARS-CoV-2WK521WT selected with 5h acquired A191T substitution in Mpro (SARS-CoV-2WK521A191T) and better replicated in the presence of 5h, than SARS-CoV-2WK521WT. However, no significant enzymatic or structural changes in MproA191T were observed. The replicability of SARS-CoV-2WK521E166V proved to be compromised compared to SARS-CoV-2WK521WT but predominated over SARS-CoV-2WK521WT in the presence of nirmatrelvir. The replicability of SARS-CoV-2WK521A191T surpassed that of SARS-CoV-2WK521WT in the absence of 5h, confirming that A191T confers enhanced viral fitness. The present data should shed light on the understanding of the mechanism of SARS-CoV-2's drug resistance acquisition and the development of resistance-repellant COVID-19 therapeutics.

PLK2-mediated phosphorylation of SQSTM1 S349 promotes aggregation of polyubiquitinated proteins upon proteasomal dysfunction.

Dysregulation in protein homeostasis results in accumulation of protein aggregates, which are sequestered into dedicated insoluble compartments so-called inclusion bodies or aggresomes, where they are scavenged through different mechanisms to reduce proteotoxicity. The protein aggregates can be selectively scavenged by macroautophagy/autophagy called aggrephagy, which is mediated by the autophagic receptor SQSTM1. In this study, we have identified PLK2 as an important regulator of SQSTM1-mediated aggregation of polyubiquitinated proteins. PLK2 is upregulated following proteasome inhibition, and then associates with and phosphorylates SQSTM1 at S349. The phosphorylation of SQSTM1 S349 strengthens its binding to KEAP1, which is required for formation of large SQSTM1 aggregates/bodies upon proteasome inhibition. Our findings suggest that PLK2-mediated phosphorylation of SQSTM1 S349 represents a critical regulatory mechanism in SQSTM1-mediated aggregation of polyubiquitinated proteins.

Atomic force microscopy as a nanomechanical tool for cancer liquid biopsy.

Liquid biopsies have been receiving tremendous attention for their potential to reshape cancer management. Though current studies of cancer liquid biopsy primarily fucus on applying biochemical assays to characterize the genetic/molecular profiles of circulating tumor cells (CTCs) and their secondary products shed from tumor sites in bodily fluids, delineating the nanomechanical properties of tumor-associated materials in liquid biopsy specimens yields complementary insights into the biology of tumor dissemination and evolution. Particularly, atomic force microscopy (AFM) has become a standard and versatile toolbox for characterizing the mechanical properties of living biological systems at the micro/nanoscale, and AFM has been increasingly utilized to probe the nanomechanical properties of various tumor-derived analytes in liquid biopsies, including CTCs, tumor-associated cells, circulating tumor DNA (ctDNA) molecules, and extracellular vesicles (EVs), offering additional possibilities for understanding cancer pathogenesis from the perspective of mechanobiology. Herein, the applications of AFM in cancer liquid biopsy are summarized, and the challenges and future directions of AFM as a nanomechanical analysis tool in cancer liquid biopsy towards clinical utility are discussed and envisioned.

π-electron injection activated dormant ligands in graphitic carbon nitride for efficient and stable uranium extraction.

Graphitic carbon nitride (CN) as an adsorbent exhibit promising potential for the removal of uranium in water. However, the lack of active sites seriously restricts its practical application. In contrast to the traditional method of introducing new ligands, we propose a strategy to activate original ligands on CN by injecting π electrons, which can be realized by grafting 4-phenoxyphenol (PP) on CN (PCN). Compared with CN, the maximum adsorption capacity of PCN for uranium increased from 150.9 mg/g to 380.6 mg/g. Furthermore, PCN maintains good adsorption properties over a wide range of uranium concentrations (1 ∼ 60 mg/L) and pH (4 ∼ 8). After 5 consecutive cycles, PCN exhibited sustained uranium removal performance with a little of losses. The experimental and theoretical results show that the enhancement of adsorption performance is mainly due to the ligands activation of CN by delocalization of π electrons from PP. Furthermore, this activation can be enhanced by irradiation, as the CN can be photoexcited to provide additional photoelectrons for PP. As a result, dormant ligands such as N-CN, C-O-C, C-N-H and N-(C)3 can be activated to participate in coordination with uranium. This work provides theoretical guidance for the design and preparation of high efficiency uranium adsorbent.

The monkeypox virus-host interplays.

Monkeypox virus (MPXV) is a DNA virus belonging to the Orthopoxvirus genus within the Poxviridae family which can cause a zoonotic infection. The unexpected non-endemic outbreak of mpox in 2022 is considered as a new global threat. It is imperative to take proactive measures, including enhancing our understanding of MPXV's biology and pathogenesis, and developing novel antiviral strategies. The host immune responses play critical roles in defensing against MPXV infection while the virus has also evolved multiple strategies for immune escape. This review summarizes the biological features, antiviral immunity, immune evasion mechanisms, pathogenicity, and prevention strategies for MPXV.

Low Molecular Weight Cyclin E Confers a Vulnerability to PKMYT1 Inhibition in Triple-Negative Breast Cancer.

Cyclin E is a regulatory subunit of CDK2 that mediates S phase entry and progression. Cleavage of full-length cyclin E (FL-cycE) to low molecular weight isoforms (LMW-E) dramatically alters the substrate specificity, promoting G1/S cell cycle transition and accelerating mitotic exit. Approximately 70% of triple-negative breast cancers (TNBC) express LMW-E, which correlates with poor prognosis. PKMYT1 also plays an important role in mitosis by inhibiting CDK1 to block premature mitotic entry, suggesting it could be a therapeutic target in TNBC expressing LMW-E. Here, analysis of TNBC patient tumor samples revealed that co-expression of LMW-E and PKMYT1-catalyzed CDK1 phosphorylation predicted poor response to neoadjuvant chemotherapy. Compared to FL-cycE, LMW-E specifically upregulated PKMYT1 expression and protein stability, elevating CDK1 phosphorylation. Inhibiting PKMYT1 with the selective inhibitor RP-6306 (lunresertib) elicited LMW-E dependent antitumor effects, accelerating premature mitotic entry, inhibiting replication fork restart, and enhancing DNA damage, chromosomal breaks, apoptosis, and replication stress. Importantly, TNBC cell line xenografts expressing LMW-E showed greater sensitivity to RP-6306 than tumors with empty vector or FL-cycE. Furthermore, RP-6306 exerted tumor suppressive effects in LMW-E transgenic murine mammary tumors and LMW-E-high TNBC patient-derived xenografts but not in the LMW-E null models examined in parallel. Lastly, transcriptomic and immune profiling demonstrated that RP-6306 treatment induced interferon responses and T-cell infiltration in the LMW-E-high tumor microenvironment, enhancing the antitumor immune response. These findings highlight the LMW-E/PKMYT1/CDK1 regulatory axis as a promising therapeutic target in TNBC, providing the rationale for further clinical development of PKMYT1 inhibitors in this aggressive breast cancer subtype.

Update on aquaporin-4 antibody detection: the early diagnosis of neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-mediated primary inflammatory myelinopathy of the central nervous system that primarily affects the optic nerve and spinal cord. The aquaporin 4 antibody (AQP4-Ab) is a specific autoantibody marker for NMOSD. Most patients with NMOSD are seropositive for AQP4-Ab, thus aiding physicians in identifying ways to treat NMOSD. AQP4-Ab has been tested in many clinical and laboratory studies, demonstrating effectiveness in diagnosing NMOSD. Recently, novel assays have been developed for the rapid and accurate detection of AQP4-Ab, providing further guidance for the diagnosis and treatment of NMOSD. This article summarizes the importance of rapid and accurate diagnosis for treating NMOSD based on a review of the latest relevant literature. We discussed current challenges and methods for improvement to offer new ideas for exploring rapid and accurate AQP4-Ab detection methods, aiming for early diagnosis of NMOSD.

Feasibility and Success of Muscular Ventricular Septal Defect Occluders and Mushroom-Shaped Occluders in Transcatheter Patent Ductus Arteriosus Closure in Low-Weight Children: A Propensity Score-Matched Retrospective Analysis from a Chinese National Regional Health Center.

INTRODUCTION: Muscular ventricular septal defect occluders (MVSDOs) have been attempted as an option in low-weight patients with patent ductus arteriosus (PDA). However, few studies have assessed the safety of transcatheter patent ductus arteriosus closure (TCPC) using MVSDO. Therefore, we compared the outcomes in low-weight patients who used MVSDO and mushroom-shaped occluder (MSO). METHODS: Medical records of children under 10 kg (n = 417) who underwent TCPC from 2015 to 2021 at a Chinese health center were reviewed. They were divided into MSO (n = 372) and MVSDO (n = 45) groups. A 1:1 propensity score matching (PSM) was done considering gender, height, weight, body surface area (BSA), PDA diameter, and BSA-corrected PDA diameter. RESULTS: All 45 children in the MVSDO group (mean weight: 5.92 ± 1.32 kg) achieved successful immediate occlusion. One case in the MVSDO group experienced device migration within 24 h requiring unplanned surgery. MVSDO significantly ameliorated pulmonary artery hypertension. After PSM, each group comprised 41 children. The MVSDO group had a smaller effect on platelet counts (MVSDO vs. MSO = 259.85 ± 114.82 vs. 356.12 ± 134.37, p < 0.001), a reduced incidence of thrombocytopenia (MVSDO vs. MSO = 2/41 vs. 7/41, p = 0.001), and a higher rate of residual shunting (MVSDO vs. MSO = 16/41 vs. 5/41, p = 0.005), compared with the MSO group. Thrombocytopenia resolved during hospitalization and micro-shunts disappeared by 6 months. No pulmonary artery or descending aortic secondary stenosis was observed in 1-year follow-up. CONCLUSIONS: MVSDO used in low-weight children is feasible, with high success and satisfactory postoperative and short-term follow-up outcomes, including lower thrombocytopenia incidence, compared to MSO. Further long-term studies with larger samples are recommended.

Thermoelectric Properties Regulated by Quantum Size Effects in Quasi-One-Dimensional γ-Graphdiyne Nanoribbons.

Using density functional theory combined with the first principles calculation method of non-equilibrium Green's function (NEGF-DFT), we studied the thermoelectric (TE) characteristics of one-dimensional γ-graphdiyne nanoribbons (γ-GDYNRs). The study found that the thermal conductivity of γ-GDYNRs has obvious anisotropy. At the same temperature and geometrical size, the lattice thermal conductivity of zigzag-edged γ-graphdiyne nanoribbons (γ-ZGDYNRs) is much lower than that of armchair-edged γ-graphdiyne nanoribbons (γ-AGDYNRs). We disclose the underlying mechanism for this intrinsic orientation. That is, γ-AGDYNRs have more phonon dispersion over the entire frequency range. Furthermore, the orientation dependence increases when the width of the γ-GDYNRs decreases. These excellent TE properties allow armchair-edged γ-graphdiyne nanoribbons with a planar width of 1.639 nm (γ-Z(2)GDYNRs) to have a higher power factor and lower thermal conductivity, ultimately resulting in a significantly higher TE conversion rate than other γ-GDYNR structures.

Research Progress on the Anti-Cancer Effects of Astragalus membranaceus Saponins and Their Mechanisms of Action.

Astragalus membranaceus saponins are the main components of A. membranaceus, a plant widely used in traditional Chinese medicine. Recently, research on the anti-cancer effects of A. membranaceus saponins has received increasing attention. Numerous in vitro and in vivo experimental data indicate that A. membranaceus saponins exhibit significant anti-cancer effects through multiple mechanisms, especially in inhibiting tumor cell proliferation, migration, invasion, and induction of apoptosis, etc. This review compiles relevant studies on the anti-cancer properties of A. membranaceus saponins from various databases over the past two decades. It introduces the mechanism of action of astragalosides, highlighting their therapeutic benefits in the management of cancer. Finally, the urgent problems in the research process are highlighted to promote A. membranaceus saponins as an effective drug against cancer.

Metformin-Induced Invertase Unfolding: Enzyme Kinetics and Activity Regulation.

The effects of metformin on invertase activity and its inhibition on sucrose digestion were studied. The rapid unfolding kinetics of invertases, followed a two-state model with an inactive intermediate formation. The dynamic interaction between metformin and invertase caused the secondary structure of the enzyme to become less ß-sheet, more α-helix, and random coiling oriented, which weakened the binding force between enzyme and its substrate. Metformin acted as a chaotrope and disrupted the hydrogen bonds of water, which facilitated the unfolding of invertase. However, some sugar alcohols, which promoted the H-bond formation of water, could repair the secondary structure of metformin-denatured invertase and therefore regulate the enzyme activity. This research enriches our understanding of the mechanism of enzyme unfolding induced by guanidine compounds. Moreover, because metformin and sugar substitutes are of concern to diabetes, this research also provides useful information for understanding the activity of the digestive enzyme that coexists with metformin and sugar alcohols.