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AJOG Global Reports May 2024In vitro fertilization is the most used assisted reproductive technology in the United States that is increasing in efficiency and in demand. Certain states have...
BACKGROUND
In vitro fertilization is the most used assisted reproductive technology in the United States that is increasing in efficiency and in demand. Certain states have mandated coverage that enable individuals with low income to undergo in vitro fertilization treatment.
OBJECTIVE
This study aimed to evaluate if socioeconomic status has an impact on the perinatal outcomes in in vitro fertilization pregnancies. We hypothesized that with greater coverage there may be an alleviation of the financial burden of in vitro fertilization that can facilitate the application of evidence-based practices.
STUDY DESIGN
This was a retrospective, population-based, observational study that was conducted in accordance with the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample database over the 6-year period from 2008 to 2014 during which period 10,000 in vitro fertilization deliveries were examined. Maternal outcomes of interest included preterm prelabor rupture of membranes, preterm birth (ie, before 37 weeks of gestation), placental abruption, cesarean delivery, operative vaginal delivery, spontaneous vaginal delivery, maternal infection, chorioamnionitis, hysterectomy, and postpartum hemorrhage. Neonatal outcomes included small for gestational age neonates, defined as birthweight <10th percentile, intrauterine fetal death, and congenital anomalies.
RESULTS
Our study found that the socioeconomic status did not have a statistically relevant effect on the perinatal outcomes among women who underwent in vitro fertilization to conceive after adjusting for the potential confounding effects of maternal demographic, preexisting clinical characteristics, and comorbidities.
CONCLUSION
The literature suggests that in states with mandated in vitro fertilization coverage, there are better perinatal outcomes because, in part, of the increased use of best in vitro fertilization practices, such as single-embryo transfers. Moreover, the quality of medical care in states with coverage is in the highest quartile in the country. Therefore, our findings of equivalent perinatal outcomes in in vitro fertilization care irrespective of socioeconomic status possibly suggests that a lack of access to quality medical care may be a factor in the health disparities usually seen among individuals with lower socioeconomic status.
PubMed: 38919707
DOI: 10.1016/j.xagr.2024.100329 -
Nature Communications Jun 2024Heparan sulfate (HS) is degraded in lysosome by a series of glycosidases. Before the glycosidases can act, the terminal glucosamine of HS must be acetylated by the...
Heparan sulfate (HS) is degraded in lysosome by a series of glycosidases. Before the glycosidases can act, the terminal glucosamine of HS must be acetylated by the integral lysosomal membrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT). Mutations of HGSNAT cause HS accumulation and consequently mucopolysaccharidosis IIIC, a devastating lysosomal storage disease characterized by progressive neurological deterioration and early death where no treatment is available. HGSNAT catalyzes a unique transmembrane acetylation reaction where the acetyl group of cytosolic acetyl-CoA is transported across the lysosomal membrane and attached to HS in one reaction. However, the reaction mechanism remains elusive. Here we report six cryo-EM structures of HGSNAT along the reaction pathway. These structures reveal a dimer arrangement and a unique structural fold, which enables the elucidation of the reaction mechanism. We find that a central pore within each monomer traverses the membrane and controls access of cytosolic acetyl-CoA to the active site at its luminal mouth where glucosamine binds. A histidine-aspartic acid catalytic dyad catalyzes the transfer reaction via a ternary complex mechanism. Furthermore, the structures allow the mapping of disease-causing variants and reveal their potential impact on the function, thus creating a framework to guide structure-based drug discovery efforts.
Topics: Mucopolysaccharidosis III; Humans; Lysosomes; Acetyltransferases; Cryoelectron Microscopy; Catalytic Domain; Mutation; Heparitin Sulfate; Acetyl Coenzyme A; Models, Molecular; Glucosamine; Acetylation; Intracellular Membranes
PubMed: 38918376
DOI: 10.1038/s41467-024-49614-1 -
Biomedical Materials (Bristol, England) Jun 2024The multiphase bioactive socket plug is designed to overcome the natural healing process of the extraction socket by maintaining the three-dimensional (3D) volume of...
The multiphase bioactive socket plug is designed to overcome the natural healing process of the extraction socket by maintaining the three-dimensional (3D) volume of extraction sockets, particularly in sockets with wall defects, and later provide sufficient alveolar bone volume for implant placement. The study aimed to fabricate and evaluate the physical, mechanical, and biological performance of a multiphase bioactive socket plug in vitro. A multiphase bioactive socket plug was fabricated through freeze-drying and layer-by-layer assembly, comprised of a base serving as a scaffold, a central portion for promoting bone regeneration, an upper buccal portion for maintaining alveolar socket dimension with a covering collagen membrane (Memb) on the top and upper buccal surface to prevent soft tissue infiltration. The multiphase bioactive socket plug (BP) as the experimental group, and a pure collagen plug (CP) as a control group were investigated and compared in physicochemical and in vitro biological properties. Scanning electron microscopy (SEM), radiograph and Energy-dispersive spectroscopy (EDS) mapping confirmed the four-part BP was successfully assembled and fabricated. Swelling rate analysis indicated that BP, CP, and Memb reached swelling equilibrium within 1 hour. BP exhibited a high percentage of the remaining weight in collagenase solution (68.81 ± 2.21% on day 90) and sustained calcium ion release, reaching the maximum 0.13 ± 0.04 mmol/L on day 14. In biological assays, BP exhibited excellent cell proliferation (The OD value increased from 0.02 on day 1 to 0.23 on day 21.). The BP group exhibited higher alkaline phosphatase (ALP) activity and Osteocalcin (OCN) content compared to the CP group within 21 days. Memb and BP exhibited outstanding barrier function, as evidenced by Hematoxylin and eosin (H&E) staining. In summary, the multiphase bioactive socket plug represents a promising scaffold for alveolar ridge preservation application.
PubMed: 38917815
DOI: 10.1088/1748-605X/ad5ba7 -
ACS Nano Jun 2024Parkinson's disease (PD) is an increasingly prevalent and currently incurable neurodegenerative disorder linked to the accumulation of α-synuclein (αS) protein...
Parkinson's disease (PD) is an increasingly prevalent and currently incurable neurodegenerative disorder linked to the accumulation of α-synuclein (αS) protein aggregates in the nervous system. While αS binding to membranes in its monomeric state is correlated to its physiological role, αS oligomerization and subsequent aberrant interactions with lipid bilayers have emerged as key steps in PD-associated neurotoxicity. However, little is known of the mechanisms that govern the interactions of oligomeric αS (OαS) with lipid membranes and the factors that modulate such interactions. This is in large part due to experimental challenges underlying studies of OαS-membrane interactions due to their dynamic and transient nature. Here, we address this challenge by using a suite of microfluidics-based assays that enable in-solution quantification of OαS-membrane interactions. We find that OαS bind more strongly to highly curved, rather than flat, lipid membranes. By comparing the membrane-binding properties of OαS and monomeric αS (MαS), we further demonstrate that OαS bind to membranes with up to 150-fold higher affinity than their monomeric counterparts. Moreover, OαS compete with and displace bound MαS from the membrane surface, suggesting that disruption to the functional binding of MαS to membranes may provide an additional toxicity mechanism in PD. These findings present a binding mechanism of oligomers to model membranes, which can potentially be targeted to inhibit the progression of PD.
PubMed: 38916260
DOI: 10.1021/acsnano.3c10889 -
BioRxiv : the Preprint Server For... Jun 2024Certain areas of the brain involved in episodic memory and behavior, such as the hippocampus, express high levels of insulin receptors and glucose transporter-4 (GLUT4)...
Certain areas of the brain involved in episodic memory and behavior, such as the hippocampus, express high levels of insulin receptors and glucose transporter-4 (GLUT4) and are responsive to insulin. Insulin and neuronal glucose metabolism improve cognitive functions and regulate mood in humans. Insulin-dependent GLUT4 trafficking has been extensively studied in muscle and adipose tissue, but little work has demonstrated either how it is controlled in insulin-responsive brain regions or its mechanistic connection to cognitive functions. In this study, we demonstrate that inhibition of WNK (With-No-lysine (K)) kinases improves learning and memory in mice. Neuronal inhibition of WNK enhances in vivo hippocampal glucose uptake. Inhibition of WNK enhances insulin signaling output and insulin-dependent GLUT4 trafficking to the plasma membrane in mice primary neuronal cultures and hippocampal slices. Therefore, we propose that the extent of neuronal WNK kinase activity has an important influence on learning, memory and anxiety-related behaviors, in part, by modulation of neuronal insulin signaling.
PubMed: 38915673
DOI: 10.1101/2024.06.09.598125 -
Cell-inspired, massive electromodulation of friction via transmembrane fields across lipid bilayers.Nature Materials Jun 2024Transient electric fields across cell bilayer membranes can lead to electroporation and cell fusion, effects crucial to cell viability whose biological implications have...
Transient electric fields across cell bilayer membranes can lead to electroporation and cell fusion, effects crucial to cell viability whose biological implications have been extensively studied. However, little is known about these behaviours in a materials context. Here we find that transmembrane electric fields can lead to a massive, reversible modulation of the sliding friction between surfaces coated with lipid-bilayer membranes-a 200-fold variation, up to two orders of magnitude greater than that achieved to date. Atomistic simulations reveal that the transverse fields, resembling those at cell membranes, lead to fully reversible electroporation of the confined bilayers and the formation of inter-bilayer bridges analogous to the stalks preceding intermembrane fusion. These increase the interfacial dissipation through reduced hydration at the slip plane, forcing it to revert in part from the low-dissipation, hydrated lipid-headgroup plane to the intra-bilayer, high-dissipation acyl tail interface. Our results demonstrate that lipid bilayers under transmembrane electric fields can have striking materials modification properties.
PubMed: 38914644
DOI: 10.1038/s41563-024-01926-9 -
JCI Insight May 2024Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators...
Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.
Topics: Animals; Membrane Proteins; Mice; Female; Signal Transduction; T-Lymphocytes, Cytotoxic; Triple Negative Breast Neoplasms; Indomethacin; Cell Line, Tumor; Humans; Lung Neoplasms; Cyclooxygenase Inhibitors; Nucleotidyltransferases; Interferon Type I; Cyclooxygenase 2; Lymphocytes, Tumor-Infiltrating; Mice, Inbred BALB C
PubMed: 38912586
DOI: 10.1172/jci.insight.165356 -
Industrial & Engineering Chemistry... May 2024The basic principles of a steady-state mass transfer model and the resistance-in-series film model are assessed with the aid of a series of experiments in a gas-liquid...
The basic principles of a steady-state mass transfer model and the resistance-in-series film model are assessed with the aid of a series of experiments in a gas-liquid contact membrane mini-module (3 M Liqui-Cel MM-1.7 × 5.5) using an aqueous solution of diethanolamine (DEA) of 0.25 M (mol/L) for biogas upgrading. Experimental data show that CO removal may exceed 67% and reach 100% in combination with the highest possible recovery of CH when employing biogas flow rates in the range of 2.8 × 10 - 3.6 × 10 m/s and solvent flow rates within 0.47 × 10 - 0.58 × 10 m/s. For the experimental data set, a correlation has been developed, effectively interpolating CO removal with the gas and liquid flow rates. The wetting values calculated are concentrated close to each other for the same liquid flow rate without considerably depending on the gas flow rate, especially when applying the Hikita-Yun (reaction rate-shell-side correlation) compared with the Hikita-Costello pair. Furthermore, the calculated wetting diminishes with increasing liquid flow rate, a result that is consistent with previous modeling attempts and relevant literature indications. The assumption of enhanced mass transfer in the liquid-filled part of the membrane pores due to the reaction is scrutinized, leading to objectionable computational wetting values. It is shown that for a concentration of DEA equal to 0.25 M the Hatta numbers and the enhancement factors are not equal in the whole reaction path; thus, the choice of the shell-side correlation has an appreciable impact on the overall analysis, especially for the determination of the wetting values.
PubMed: 38911336
DOI: 10.1021/acs.iecr.4c00525 -
RSC Medicinal Chemistry Jun 2024Synthetic cannabinoid receptor agonists (SCRAs) comprise the second largest class of new psychoactive substances (NPS), and typically α-amino acid moieties are...
Synthetic cannabinoid receptor agonists (SCRAs) comprise the second largest class of new psychoactive substances (NPS), and typically α-amino acid moieties are incorporated as part of their design. Limited investigation has been performed into elucidating structure-activity relationships around commonly used α-amino acid-derived head groups, mainly with valine and -leucine-derived compounds previously described. As such, proactive synthesis, characterisation and pharmacological evaluation were performed to explore structure-activity relationships of 15 α-amino acid derivatives, with both the natural isomers and their enantiomers at CB and CB investigated using a fluorescence-based membrane potential assay. This library was based around the detected SCRAs MPP-5F-PICA, MMB-5F-PICA, and MDMB-5F-PICA, with the latter showing significant receptor activation at CB (pEC = 8.34 ± 0.05 M; = 108 ± 3%) and CB (pEC = 8.13 ± 0.07 M; = 99 ± 2%). Most valine and leucine derivatives were potent and efficacious SCRAs, while smaller derivatives generally showed reduced activity at CB and CB, and larger derivatives also showed reduced activity. SAR trends observed were rationalised induced fit docking. Overall, while natural enantiomers showed equipotent or greater activity than the unnatural isomers in most cases, this was not universal. As such, a number of these compounds should be monitored as emerging NPS, and various substituents described herein.
PubMed: 38911147
DOI: 10.1039/d3md00758h -
Biochimica Et Biophysica Acta.... Jun 2024The natural transformation system of the thermophilic bacterium Thermus thermophilus comprises at least 16 competence proteins. Recently we found that the outer membrane...
The natural transformation system of the thermophilic bacterium Thermus thermophilus comprises at least 16 competence proteins. Recently we found that the outer membrane (OM) competence protein PilW interacts with the secretin channel, which guides type IV pili (T4P) and potential DNA transporter pseudopili through the OM. Here we have used biochemical techniques to study the interactions of cytoplasmic, inner membrane (IM) and OM components of the DNA transporter in T. thermophilus. We report that PilW is part of a heteropolymeric complex comprising of the cytoplasmic PilM protein, IM proteins PilN, PilO, PilC and the secretin PilQ. Co-purification studies revealed that PilO directly interacts with PilW. In vitro affinity co-purification studies using His-tagged PilC led to the detection of PilC-, PilW-, PilN- and PilO-containing complexes. PilO was identified as direct interaction partner of the polytopic IM protein PilC. PilC was also found to directly interact with the cytoplasmic T4P disassembly ATPase PilT1 thereby triggering PilT1 ATPase activity. This, together with the detection of heteropolymeric PilC complexes which contain PilT1 and the pilins PilA2, PilA4 and PilA5 is in line with the hypothesis that PilC connects the depolymerization ATPase to the base of the pili possibly allowing energy transduction for disassembly of the pilins.
PubMed: 38909880
DOI: 10.1016/j.bbamem.2024.184363