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Thrombosis Journal Jun 2024About 13-25% of cerebral venous thrombosis (CVT) cases lack clear etiology, which may be associated with underlying genetic factors. This study aims to investigate...
BACKGROUND
About 13-25% of cerebral venous thrombosis (CVT) cases lack clear etiology, which may be associated with underlying genetic factors. This study aims to investigate genetic factors in CVT patients using whole exome sequencing (WES).
METHODS
Thirty-eight CVT patients hospitalized underwent WES. 977 subjects with WES data from a community cohort study --the Shunyi cohort were as the control group. Using bioinformatics analysis, differential genes with rare damaging variants between two groups were filtered (P < 0.05). KEGG enrichment analysis was performed on the screened genes to identify pathways associated with CVT.
RESULTS
Through analysis of medical history, routine tests, and imaging examinations, the etiology of 38 patients: 8 cases of antiphospholipid syndrome, 6 cases with hematologic diseases, 3 cases of protein C deficiency, and 2 cases of protein S deficiency. Five cases occurred during pregnancy or puerperium, and 3 cases had a history of oral contraceptive use, and so on. The etiology was unknown in 12 cases (31.6%), and the etiology of 4 patients were further clarified through WES: F9 c.838 + 1_838 + 16del, Hemizygote: F9 EX1-EX7 Dup; CBS c.430G > A, CBS c.949 A > G; F2 c.1787G > A; SERPINC1 c.409-11G > T. Comparing the WES data of two groups, a total of 179 different genes with rare damaging variants were screened (P < 0.05), with 5 genes of interest (JAK2, C3, PROC, PROZ, SERPIND1). Enrichment analysis of the 179 different genes revealed the complement and coagulation pathway and the mitogen activated protein kinases (MAPK) pathway were associated with CVT.
CONCLUSION
For CVT patients with unknown etiology, WES could help identify the cause of CVT early, which is of great significance for treatment decisions and prognosis. In addition to the complement and coagulation pathway, MAPK pathway is associated with CVT, potentially related to platelet regulation and inflammatory response.
PubMed: 38886735
DOI: 10.1186/s12959-024-00621-8 -
International Journal of Biological... Jun 2024The Nucleocapsid (N) protein of SARS-CoV-2 plays a crucial role in viral replication and pathogenesis, making it an attractive target for developing antiviral...
The Nucleocapsid (N) protein of SARS-CoV-2 plays a crucial role in viral replication and pathogenesis, making it an attractive target for developing antiviral therapeutics. In this study, we used differential scanning fluorimetry to establish a high-throughput screening method for identifying high-affinity ligands of N-terminal domain of the N protein (N-NTD). We screened an FDA-approved drug library of 1813 compounds and identified 102 compounds interacting with N-NTD. The screened compounds were further investigated for their ability to inhibit the nucleic-acid binding activity of the N protein using electrophoretic mobility-shift assays. We have identified three inhibitors, Ceftazidime, Sennoside A, and Tannic acid, that disrupt the N protein's interaction with RNA probe. Ceftazidime and Sennoside A exhibited nano-molar range binding affinities with N protein, determined through surface plasmon resonance. The binding sites of Ceftazidime and Sennoside A were investigated using [H, N]-heteronuclear single quantum coherence (HSQC) NMR spectroscopy. Ceftazidime and Sennoside A bind to the putative RNA binding site of the N protein, thus providing insights into the inhibitory mechanism of these compounds. These findings will contribute to the development of novel antiviral agents targeting the N protein of SARS-CoV-2.
PubMed: 38885868
DOI: 10.1016/j.ijbiomac.2024.133167 -
The Journal of Physical Chemistry... Jun 2024Aggregation of human α-synuclein protein is regarded to be a key stage in the etiology of Parkinson's disease and numerous other neurodegenerative illnesses....
Aggregation of human α-synuclein protein is regarded to be a key stage in the etiology of Parkinson's disease and numerous other neurodegenerative illnesses. Microplastics pollution can be a potential agent to promote various neurodegenerative disorders. In this study, we have employed various multispectroscopic analytical methods to investigate the binding interactions between polyethylene (PE-MPs), polyvinyl chloride (PVC-MPs), polystyrene (PS-MPs) microplastics, and human α-synuclein protein. Spectroscopic investigations using UV-vis absorption, circular dichroism, and Fourier transform infrared have indicated different alterations in α-synuclein protein's secondary structures induced by the formation of the α-synuclein protein-MP binding complex. This study suggests that PS-MPs are found to be the most effective microplastic that promote amyloidogenic oligomer emergence because of their tiny size (100 nm).
Topics: alpha-Synuclein; Humans; Microplastics; Polystyrenes; Circular Dichroism; Spectroscopy, Fourier Transform Infrared; Protein Binding; Polyvinyl Chloride; Polyethylene; Protein Structure, Secondary; Amyloid
PubMed: 38885454
DOI: 10.1021/acs.jpclett.4c00731 -
PLoS Computational Biology Jun 2024Periplasmic binding proteins (PBPs) are bacterial proteins commonly used as scaffolds for substrate-detecting biosensors. In these biosensors, effector proteins (for...
Periplasmic binding proteins (PBPs) are bacterial proteins commonly used as scaffolds for substrate-detecting biosensors. In these biosensors, effector proteins (for example fluorescent proteins) are inserted into a PBP such that the effector protein's output changes upon PBP-substate binding. The insertion site is often determined by comparison of PBP apo/holo crystal structures, but random insertion libraries have shown that this can miss the best sites. Here, we present a PBP biosensor design method based on residue contact analysis from molecular dynamics. This computational method identifies the best previously known insertion sites in the maltose binding PBP, and suggests further previously unknown sites. We experimentally characterise fluorescent protein insertions at these new sites, finding they too give functional biosensors. Furthermore, our method is sufficiently flexible to both suggest insertion sites compatible with a variety of effector proteins, and be applied to binding proteins beyond PBPs.
Topics: Biosensing Techniques; Periplasmic Binding Proteins; Molecular Dynamics Simulation; Computational Biology; Binding Sites; Protein Binding
PubMed: 38885277
DOI: 10.1371/journal.pcbi.1012212 -
Cureus May 2024The clotting system has evolved as an adaptive mechanism to prevent blood loss during vascular damage. However, the intricate nature of the clotting cascade and the...
The clotting system has evolved as an adaptive mechanism to prevent blood loss during vascular damage. However, the intricate nature of the clotting cascade and the complexities of human life can sometimes lead to the unnatural activation of this delicate cascade. This can result in blood clot formation within the cardiovascular system, contributing to a wide range of pathological conditions. Abnormal intravascular coagulation most commonly occurs in the deep veins of the lower extremities, and can emboli to other organs, hence, it is termed "venous thromboembolism" (VTE). In this report, we introduce a challenging case of VTE that poses a dilemma for current medical management. The patient with possible protein S deficiency underwent various guideline-directed medical treatments, yet experienced recurrent VTE episodes, including deep vein thrombosis (DVT) and pulmonary embolism (PE), leading to hospital readmissions. This case report sheds light on our challenges in effectively treating VTE.
PubMed: 38883011
DOI: 10.7759/cureus.60517 -
Journal of Medical Ultrasound 2024Tissue-mimicking phantoms (TMPs) have been used extensively in clinical and nonclinical settings to simulate the thermal effects of focus ultrasound (FUS) technology in...
BACKGROUND
Tissue-mimicking phantoms (TMPs) have been used extensively in clinical and nonclinical settings to simulate the thermal effects of focus ultrasound (FUS) technology in real tissue or organs. With recent technological developments in the FUS technology and its monitoring/guided techniques such as ultrasound-guided FUS and magnetic resonance-guided FUS (MRgFUS) the need for TMPs are more important than ever to ensure the safety of the patients before being treated with FUS for a variety of diseases (e.g., cancer or neurological). The purpose of this study was to prepare a tumor-mimicking phantom (TUMP) model that can simulate competently a tumor that is surrounded by healthy tissue.
METHODS
The TUMP models were prepared using polyacrylamide (PAA) and agar solutions enriched with MR contrast agents (silicon dioxide and glycerol), and the thermosensitive component bovine serum albumin (BSA) that can alter its physical properties once thermal change is detected, therefore offering real-time visualization of the applied FUS ablation in the TUMPs models. To establish if these TUMPs are good candidates to be used in thermoablation, their thermal properties were characterized with a custom-made FUS system in the laboratory and a magnetic resonance imaging (MRI) setup with MR-thermometry. The BSA protein's coagulation temperature was adjusted at 55°C by setting the pH of the PAA solution to 4.5, therefore simulating the necrosis temperature of the tissue.
RESULTS
The experiments carried out showed that the TUMP models prepared by PAA can change color from transparent to cream-white due to the BSA protein coagulation caused by the thermal stress applied. The TUMP models offered a good MRI contrast between the TMPs and the TUMPs including real-time visualization of the ablation area due to the BSA protein coagulation. Furthermore, the -weighted MR images obtained showed a significant change in when the BSA protein is thermally coagulated. MR thermometry maps demonstrated that the suggested TUMP models may successfully imitate a tumor that is present in soft tissue.
CONCLUSION
The TUMP models developed in this study have numerous uses in the testing and calibration of FUS equipment including the simulation and validation of thermal therapy treatment plans with FUS or MRgFUS in oncology applications.
PubMed: 38882616
DOI: 10.4103/jmu.jmu_68_23 -
ACS Polymers Au Jun 2024The precise sequence of a protein's primary structure is essential in determining its folding pathways. To emulate the complexity of these biomolecules, functional block...
The precise sequence of a protein's primary structure is essential in determining its folding pathways. To emulate the complexity of these biomolecules, functional block copolymers consisting of segmented triblocks with distinct functionalities positioned in a sequence-specific manner are designed to control the polymer chain compaction. Triblock polymers and and random diblock copolymer consist of a hydrophilic poly(ethylene oxide) (PEO) block and a hydrophobic block with coumarin () and ferrocene () moieties that are grafted in a sequence-specific or random manner onto the hydrophilic block. External stimuli such as UV light, redox, and chemical cues influence the functional hydrophobic block to alter the packing parameters that are monitored with spectroscopic and scattering techniques. Interestingly, the positioning of the stimuli-responsive moiety within the hydrophobic block of , , and affects the extent of the hydrophobic-hydrophilic balance in block copolymers that renders orthogonal control in stimuli-responsive transformation of self-assembled vesicles to micelles.
PubMed: 38882035
DOI: 10.1021/acspolymersau.4c00009 -
Journal of Human Genetics Jun 2024Variants in voltage-gated sodium channel (VGSC) genes are implicated in seizures, epilepsy, and neurodevelopmental disorders, constituting a significant aspect of...
Variants in voltage-gated sodium channel (VGSC) genes are implicated in seizures, epilepsy, and neurodevelopmental disorders, constituting a significant aspect of hereditary epilepsy in the Chinese population. Through retrospective analysis utilizing next-generation sequencing (NGS), we examined the genotypes and phenotypes of VGSC-related epilepsy cases from a cohort of 691 epilepsy subjects. Our findings revealed that 5.1% of subjects harbored VGSC variants, specifically 22 with SCN1A, 9 with SCN2A, 1 with SCN8A, and 3 with SCN1B variants; no SCN3A variants were detected. Among these, 14 variants were previously reported, while 21 were newly identified. SCN1A variant carriers predominantly presented with Dravet Syndrome (DS) and Genetic Epilepsy with Febrile Seizures Plus (GEFS + ), featuring a heightened sensitivity to fever-induced seizures. Statistically significant disparities emerged between the SCN1A-DS and SCN1A-GEFS+ groups concerning seizure onset and genetic diagnosis age, incidence of status epilepticus, mental retardation, anti-seizure medication (ASM) responsiveness, and familial history. Notably, subjects with SCN1A variants affecting the protein's pore region experienced more frequent cluster seizures. All SCN2A variants were of de novo origin, and 88.9% of individuals with SCN2A variations exhibited cluster seizures. This research reveals a significant association between variations in VGSC-related genes and the clinical phenotype diversity of epilepsy subjects in China, emphasizing the pivotal role of NGS screening in establishing accurate disease diagnoses and guiding the selection of ASM.
PubMed: 38880818
DOI: 10.1038/s10038-024-01257-2 -
Scientific Reports Jun 2024Data on the pathophysiological mechanisms of hemostatic alterations in the thrombotic events that occur during Ramadan intermittent fasting (RIF), particularly in the...
Data on the pathophysiological mechanisms of hemostatic alterations in the thrombotic events that occur during Ramadan intermittent fasting (RIF), particularly in the natural coagulation inhibitors, are very limited. Thus, our objective was to evaluate the effect of RIF on the natural anticoagulants level, antithrombin, protein C, and total and free protein S (PS) in healthy participants. Participants were divided into two groups. Group I consisted of 29 healthy fasting participants whose blood samples were taken after 20 days of fasting. Group II included 40 healthy non-fasting participants whose blood samples were taken 2-4 weeks before the month of Ramadan. Coagulation screening tests including prothrombin time (PT), activated partial thromboplastin time (APTT) and plasma fibrinogen level, natural anticoagulants; antithrombin, protein C, free and total PS and C4 binding protein (C4BP) levels were evaluated in the two groups. High levels of total and free PS without change in antithrombin, protein C, and C4BP levels were noted in the fasting group as compared with non-fasting ones (p < 0.05). PT and APTT showed no difference between the two groups. However, the fibrinogen level was higher in the fasting group. In conclusion, RIF was found to be associated with improved anticoagulant activity in healthy participants, which may provide temporal physiological protection against the development of thrombosis in healthy fasting people.
Topics: Humans; Fasting; Male; Adult; Female; Case-Control Studies; Blood Coagulation; Anticoagulants; Islam; Protein C; Protein S; Blood Coagulation Tests; Healthy Volunteers; Fibrinogen; Middle Aged; Young Adult; Prothrombin Time; Antithrombins; Partial Thromboplastin Time; Intermittent Fasting
PubMed: 38879576
DOI: 10.1038/s41598-024-64582-8 -
Nature Communications Jun 2024Factor-dependent termination uses molecular motors to remodel transcription machineries, but the associated mechanisms, especially in eukaryotes, are poorly understood....
Factor-dependent termination uses molecular motors to remodel transcription machineries, but the associated mechanisms, especially in eukaryotes, are poorly understood. Here we use single-molecule fluorescence assays to characterize in real time the composition and the catalytic states of Saccharomyces cerevisiae transcription termination complexes remodeled by Sen1 helicase. We confirm that Sen1 takes the RNA transcript as its substrate and translocates along it by hydrolyzing multiple ATPs to form an intermediate with a stalled RNA polymerase II (Pol II) transcription elongation complex (TEC). We show that this intermediate dissociates upon hydrolysis of a single ATP leading to dissociation of Sen1 and RNA, after which Sen1 remains bound to the RNA. We find that Pol II ends up in a variety of states: dissociating from the DNA substrate, which is facilitated by transcription bubble rewinding, being retained to the DNA substrate, or diffusing along the DNA substrate. Our results provide a complete quantitative framework for understanding the mechanism of Sen1-dependent transcription termination in eukaryotes.
Topics: Saccharomyces cerevisiae Proteins; Saccharomyces cerevisiae; RNA Polymerase II; Transcription Termination, Genetic; Adenosine Triphosphate; DNA Helicases; Single Molecule Imaging; RNA Helicases; Transcription, Genetic; RNA, Fungal; DNA, Fungal; Hydrolysis
PubMed: 38879529
DOI: 10.1038/s41467-024-49527-z