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BMC Neurology May 2024To investigate the risk factors and underlying causes of pregnancy-related cerebral venous thrombosis (PCVT).
OBJECTIVES
To investigate the risk factors and underlying causes of pregnancy-related cerebral venous thrombosis (PCVT).
METHODS
A retrospective cohort of 16 patients diagnosed with CVT during pregnancy and postpartum (within six weeks after delivery) in a comprehensive hospital in China between 2009 and 2022 were carefully reviewed, focusing on demographic, clinical, and etiological characteristics, especially underlying causes. We matched 16 PCVT patients with 64 pregnant and puerperal women without PCVT to explore risk factors and clinical susceptibility to PCVT.
RESULTS
PCVT occurred commonly during the first trimester (43.75%) and the puerperium (37.5%). The frequency of anemia, thrombocytosis and thrombocytopenia during pregnancy, dehydration, and pre-pregnancy anemia was significantly higher in women with PCVT than in those without PCVT (P < 0.05). Among the 16 patients, five were diagnosed with antiphospholipid syndrome and one was diagnosed with systemic lupus erythematosus. Three patients had distinct protein S deficiency and one had protein C deficiency. Whole Exome Sequencing (WES) was performed for five patients and revealed likely pathogenic mutations associated with CVT, including heterozygous PROC c.1218G > A (p. Met406Ile), heterozygous PROS1 c.301C > T (p. Arg101Cys), composite heterozygous mutation in the F8 gene (c.144-1259C > T; c.6724G > A (p. Val2242Met)) and homozygous MTHFR c.677C > T (p. Ala222Val).
CONCLUSIONS
The occurrence of anemia, thrombocytopenia and thrombocytosis during pregnancy, dehydration and pre-pregnancy anemia suggested a greater susceptibility to PCVT. For confirmed PCVT patients, autoimmune diseases, hereditary thrombophilia, and hematological disorders were common causes. Screening for potential etiologies should be paid more attention, as it has implications for treatment and long-term management.
Topics: Humans; Female; Pregnancy; Retrospective Studies; Adult; Intracranial Thrombosis; Risk Factors; Venous Thrombosis; China; Young Adult; Pregnancy Complications, Hematologic; Protein S Deficiency
PubMed: 38822265
DOI: 10.1186/s12883-024-03676-2 -
Journal of Thrombosis and Haemostasis :... May 2024Unique among all amino acids, Ser is encoded by 2 sets of codons, TCN and AGY (N = any nucleotide, Y = pyrimidine), that cannot interconvert through single nucleotide...
BACKGROUND
Unique among all amino acids, Ser is encoded by 2 sets of codons, TCN and AGY (N = any nucleotide, Y = pyrimidine), that cannot interconvert through single nucleotide substitutions. Both codons are documented at the essential residues S195 and S214 within the active site of serine proteases. However, it is not known how the codons interconverted during evolution because replacement of S195 or S214 by other amino acids typically results in loss of activity.
OBJECTIVE
To characterize the prevalence of codon switching among essential and non-essential Ser residues in coagulation and fibrinolytic proteases from different vertebrate lineages.
METHODS
TCN and AGY codon usage was analyzed in >550 sequences.
RESULTS
Evolutionary pressure to preserve the codon of S195 is absolute, with no evidence of interconversion. Pressure to preserve the codon of S214 is also strong, but an AGY↔TCN interconversion is observed in factor VII-inactive and protein C from ray-finned fish. In both cases, the interconversion occurred in genes that were rapidly evolving. In contrast, codon switching at nonessential Ser residues in the kringle domains of coagulation and fibrinolytic proteases is quite common and could be identified in half of the kringles analyzed.
CONCLUSION
Codon interconversion of essential Ser residues of coagulation and fibrinolytic proteases only occurred in genes that were rapidly evolving and that-at least in some cases-evolved following genome duplication. Interconversion is common at nonessential Ser residues as found in kringle domains.
PubMed: 38821294
DOI: 10.1016/j.jtha.2024.05.021 -
Nature Communications May 2024Nasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising...
Nasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising immunotherapies. In this study, we identify tumor-intrinsic FLI1 as a critical mediator in impairing T cell anti-tumor immunity. A mechanistic inquiry reveals that FLI1 orchestrates the expression of CBP and STAT1, facilitating chromatin accessibility and transcriptional activation of IDO1 in response to T cell-released IFN-γ. This regulatory cascade ultimately leads to augmented IDO1 expression, resulting in heightened synthesis of kynurenine (Kyn) in tumor cells. This, in turn, fosters CD8 T cell exhaustion and regulatory T cell (Treg) differentiation. Intriguingly, we find that pharmacological inhibition of FLI1 effectively obstructs the CBP/STAT1-IDO1-Kyn axis, thereby invigorating both spontaneous and checkpoint therapy-induced immune responses, culminating in enhanced tumor eradication. In conclusion, our findings delineate FLI1-mediated Kyn metabolism as an immune evasion mechanism in NPC, furnishing valuable insights into potential therapeutic interventions.
Topics: Kynurenine; Interferon-gamma; Animals; Proto-Oncogene Protein c-fli-1; Indoleamine-Pyrrole 2,3,-Dioxygenase; Tumor Microenvironment; Humans; Mice; T-Lymphocytes, Regulatory; STAT1 Transcription Factor; Cell Line, Tumor; Nasopharyngeal Carcinoma; CD8-Positive T-Lymphocytes; Mice, Inbred C57BL; Nasopharyngeal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Tumor Escape; Mice, Knockout
PubMed: 38816360
DOI: 10.1038/s41467-024-48397-9 -
Genes & Development Jun 2024The ability to sense and respond to proteotoxic insults declines with age, leaving cells vulnerable to chronic and acute stressors. Reproductive cues modulate this...
The ability to sense and respond to proteotoxic insults declines with age, leaving cells vulnerable to chronic and acute stressors. Reproductive cues modulate this decline in cellular proteostasis to influence organismal stress resilience in We previously uncovered a pathway that links the integrity of developing embryos to somatic health in reproductive adults. Here, we show that the nuclear receptor NHR-49, an ortholog of mammalian peroxisome proliferator-activated receptor α (PPARα), regulates stress resilience and proteostasis downstream from embryo integrity and other pathways that influence lipid homeostasis and upstream of HSF-1. Disruption of the vitelline layer of the embryo envelope, which activates a proteostasis-enhancing intertissue pathway in somatic cells, triggers changes in lipid catabolism gene expression that are accompanied by an increase in fat stores. NHR-49, together with its coactivator, MDT-15, contributes to this remodeling of lipid metabolism and is also important for the elevated stress resilience mediated by inhibition of the embryonic vitelline layer. Our findings indicate that NHR-49 also contributes to stress resilience in other pathways known to change lipid homeostasis, including reduced insulin-like signaling and fasting, and that increased NHR-49 activity is sufficient to improve proteostasis and stress resilience in an HSF-1-dependent manner. Together, our results establish NHR-49 as a key regulator that links lipid homeostasis and cellular resilience to proteotoxic stress.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Proteostasis; Signal Transduction; Receptors, Cytoplasmic and Nuclear; Lipid Metabolism; Stress, Physiological; Reproduction
PubMed: 38816072
DOI: 10.1101/gad.351829.124 -
Turkish Journal of Medical Sciences 2023To evaluate whether there is a relationship between serum myosin-binding protein C (MyBP-C) levels measured in the first trimester and the timing of delivery, and, if a...
BACKGROUND/AIM
To evaluate whether there is a relationship between serum myosin-binding protein C (MyBP-C) levels measured in the first trimester and the timing of delivery, and, if a relationship is detected, the potential of this relationship in distinguishing between preterm and term labor.
MATERIALS AND METHODS
This prospective case-control study was conducted with 701 pregnant women who applied to the Obstetrics Outpatient Clinic of Gaziosmanpaşa Training and Research Hospital in the first trimester, between 11 and 14 gestational weeks. MyBP-C serum samples from the first trimester were stored under appropriate conditions until the time of delivery. Of these pregnant women, 628 completed the study. According to the delivery time, the pregnant women were divided into two groups, as those who delivered prematurely before 37 weeks and those who gave birth at term. The case group comprised 45 women who gave birth prematurely, while 583 women gave birth at term. A control group was formed with 45 pregnant women of the same age, who were selected by randomization using a simple random sampling method from the 583 pregnant women. The MyBP-C levels were measured and compared from the first-trimester serum materials of both groups.
RESULTS
The MyBP-C levels of the preterm delivery group were significantly higher than those of the term delivery control group (4.51 ± 1.69 vs. 3.09 ± 1.44 pg/mL, respectively; p < 0.001). Receiver operating characteristic (ROC) curve analysis showed that the MyBP-C levels in the first trimester with a cut-off value of 4.76 ng/dL indicated women with preterm delivery with a sensitivity of 42.22% and specificity of 95.56% (AUC: 0.734, 95% CI: 0.630-0.822). The overall differential diagnosis performance of the MyBP-C level for preterm delivery was determined as 73.4% (p < 0.001). The MyBP-C levels were found to be significantly higher both in the early preterm group compared with the late preterm group (p < 0.001), and in those with premature rupture of membranes (PROM) compared with those without (p < 0.001).
CONCLUSION
The preterm delivery group exhibited high serum MyBP-C levels in the serum samples taken in the first trimester. First-trimester serum MyBP-C levels seem to be a simple and easy way to exclude preterm delivery risk in a significant manner. In addition, levels are significantly higher for early preterm compared with late preterm and early PROM compared with intact membranes.
Topics: Humans; Female; Pregnancy; Premature Birth; Prospective Studies; Biomarkers; Adult; Case-Control Studies; Carrier Proteins; Pregnancy Trimester, First; ROC Curve
PubMed: 38813022
DOI: 10.55730/1300-0144.5717 -
Scientific Reports May 2024Loss of the tumor suppressor PTEN homolog daf-18 in Caenorhabditis elegans (C. elegans) triggers diapause cell division during L1 arrest. While prior studies have delved...
Loss of the tumor suppressor PTEN homolog daf-18 in Caenorhabditis elegans (C. elegans) triggers diapause cell division during L1 arrest. While prior studies have delved into established pathways, our investigation takes an innovative route. Through forward genetic screening in C. elegans, we pinpoint a new player, F12E12.11, regulated by daf-18, impacting cell proliferation independently of PTEN's typical phosphatase activity. F12E12.11 is an ortholog of human estradiol 17-beta-dehydrogenase 8 (HSD17B8), which converts estradiol to estrone through its NAD-dependent 17-beta-hydroxysteroid dehydrogenase activity. We found that PTEN engages in a physical interplay with HSD17B8, introducing a distinctive suppression mechanism. The reduction in estrone levels and accumulation of estradiol may arrest tumor cells in the G2/M phase of the cell cycle through MAPK/ERK. Our study illuminates an unconventional protein interplay, providing insights into how PTEN modulates tumor suppression by restraining cell division through intricate molecular interactions.
Topics: PTEN Phosphohydrolase; Animals; Cell Proliferation; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Humans; 17-Hydroxysteroid Dehydrogenases; Estradiol; Estrone
PubMed: 38811827
DOI: 10.1038/s41598-024-63052-5 -
Cell Death & Disease May 2024Mitochondria dysfunctions and mitophagy failure have been associated with several Alzheimer's disease (AD) related molecular actors including amyloid beta (Aβ) and...
Mitochondria dysfunctions and mitophagy failure have been associated with several Alzheimer's disease (AD) related molecular actors including amyloid beta (Aβ) and recently the amyloid precursor protein-C terminal fragments (APP-CTFs). The efficacy of the mitophagy process in neurons relies on regulated mitochondrial transport along axons involving a complex molecular machinery. The contribution of the amyloid precursor protein (APP) and its derived fragments to the mitochondrial transport machinery alterations in AD have not been investigated before. We report herein a change of the expression of mitochondrial transport proteins (SNPH and Miro1), motor adapters (TRANK1 and TRAK2), and components of the dynein and kinesin motors (i.e., IC1,2 and Kif5 (A, B, C) isoforms) by endogenous APP and by overexpression of APP carrying the familial Swedish mutation (APPswe). We show that APP-CTFs and Aβ concomitantly regulate the expression of a set of transport proteins as demonstrated in APPswe cells treated with β- and γ-secretase inhibitors and in cells Knock-down for presenilin 1 and 2. We further report the impact of APP-CTFs on the expression of transport proteins in AAV-injected C99 mice brains. Our data also indicate that both Aβ oligomers (Aβo) and APP-CTFs impair the colocalization of mitochondria and transport proteins. This has been demonstrated in differentiated SH-SY5Y naive cells treated with Aβo and in differentiated SH-SY5Y and murine primary neurons expressing APPswe and treated with the γ-secretase inhibitor. Importantly, we uncover that the expression of a set of transport proteins is modulated in a disease-dependent manner in 3xTgAD mice and in human sporadic AD brains. This study highlights molecular mechanisms underlying mitochondrial transport defects in AD that likely contribute to mitophagy failure and disease progression.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Mitochondria; Humans; Mice; Mice, Transgenic; Neurons; Amyloid beta-Peptides; Mitochondrial Proteins; Amyloid Precursor Protein Secretases; Kinesins; Biological Transport; Mitophagy; Nerve Tissue Proteins; rho GTP-Binding Proteins; Intracellular Signaling Peptides and Proteins
PubMed: 38806484
DOI: 10.1038/s41419-024-06742-2 -
Communications Biology May 2024In striated muscle, the sarcomeric protein myosin-binding protein-C (MyBP-C) is bound to the myosin thick filament and is predicted to stabilize myosin heads in a docked...
In striated muscle, the sarcomeric protein myosin-binding protein-C (MyBP-C) is bound to the myosin thick filament and is predicted to stabilize myosin heads in a docked position against the thick filament, which limits crossbridge formation. Here, we use the homozygous Mybpc2 knockout (C2) mouse line to remove the fast-isoform MyBP-C from fast skeletal muscle and then conduct mechanical functional studies in parallel with small-angle X-ray diffraction to evaluate the myofilament structure. We report that C2 fibers present deficits in force production and calcium sensitivity. Structurally, passive C2 fibers present altered sarcomere length-independent and -dependent regulation of myosin head conformations, with a shift of myosin heads towards actin. At shorter sarcomere lengths, the thin filament is axially extended in C2, which we hypothesize is due to increased numbers of low-level crossbridges. These findings provide testable mechanisms to explain the etiology of debilitating diseases associated with MyBP-C.
Topics: Animals; Mice, Knockout; Carrier Proteins; Mice; Sarcomeres; Myofibrils; Muscle, Skeletal; Actin Cytoskeleton; Male; Myosins
PubMed: 38802450
DOI: 10.1038/s42003-024-06265-8 -
BioRxiv : the Preprint Server For... May 2024In biological systems, ATP provides an energetic driving force for peptide bond formation, but protein chemists lack tools that emulate this strategy. Inspired by the...
In biological systems, ATP provides an energetic driving force for peptide bond formation, but protein chemists lack tools that emulate this strategy. Inspired by the eukaryotic ubiquitination cascade, we developed an ATP-driven platform for C-terminal activation and peptide ligation based on MccB, a bacterial ancestor of ubiquitin-activating (E1) enzymes that natively catalyzes C-terminal phosphoramidate bond formation. We show that MccB can act on non-native substrates to generate an -AMPylated electrophile that can react with exogenous nucleophiles to form diverse C-terminal functional groups including thioesters, a versatile class of biological intermediates that have been exploited for protein semisynthesis. To direct this activity towards specific proteins of interest, we developed the Thioesterification C-terminal Handle (TeCH)-tag, a sequence that enables high-yield, ATP-driven protein bioconjugation via a thioester intermediate. By mining the natural diversity of the MccB family, we developed two additional MccB/TeCH-tag pairs that are mutually orthogonal to each other and to the system, facilitating the synthesis of more complex bioconjugates. Our method mimics the chemical logic of peptide bond synthesis that is widespread in biology for high-yield manipulation of protein structure with molecular precision.
PubMed: 38798401
DOI: 10.1101/2024.05.13.593989 -
BioRxiv : the Preprint Server For... May 2024Myosin-binding protein H (MyBP-H) is a component of the vertebrate skeletal muscle sarcomere with sequence and domain homology to myosin-binding protein C (MyBP-C)....
Myosin-binding protein H (MyBP-H) is a component of the vertebrate skeletal muscle sarcomere with sequence and domain homology to myosin-binding protein C (MyBP-C). Whereas skeletal muscle isoforms of MyBP-C (fMyBP-C, sMyBP-C) modulate muscle contractility via interactions with actin thin filaments and myosin motors within the muscle sarcomere "C-zone," MyBP-H has no known function. This is in part due to MyBP-H having limited expression in adult fast-twitch muscle and no known involvement in muscle disease. Quantitative proteomics reported here reveal MyBP-H is highly expressed in prenatal rat fast-twitch muscles and larval zebrafish, suggesting a conserved role in muscle development, and promoting studies to define its function. We take advantage of the genetic control of the zebrafish model and a combination of structural, functional, and biophysical techniques to interrogate the role of MyBP-H. Transgenic, FLAG-tagged MyBP-H or fMyBP-C both localize to the C-zones in larval myofibers, whereas genetic depletion of endogenous MyBP-H or fMyBP-C leads to increased accumulation of the other, suggesting competition for C-zone binding sites. Does MyBP-H modulate contractility from the C-zone? Globular domains critical to MyBP-C's modulatory functions are absent from MyBP-H, suggesting MyBP-H may be functionally silent. However, our results suggest an active role. Small angle x-ray diffraction of intact larval tails revealed MyBP-H contributes to the compression of the myofilament lattice accompanying stretch or contraction, while motility experiments indicate MyBP-H shares MyBP-C's capacity as a molecular "brake". These results provide new insights and raise questions about the role of the C-zone during muscle development.
PubMed: 38798399
DOI: 10.1101/2024.05.10.593199