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Background: The p27KIP1 gene, whose protein product is a negative regulator of the cell cycle, is a potential tumor suppressor gene; however, no tumor-specific mutations of this gene have been found in humans. This study was undertaken to identify and to assess potential alterations of p27KIP1 gene expression in patients with benign prostatic hyperplasia (BPH) and patients with prostate cancer.Methods: We analyzed 130 prostate carcinomas from primary and metastatic sites, as well as prostate samples from normal subjects and from patients with BPH. Immunohistochemistry and in situ hybridization were used to determine the levels of expression and the microanatomical localization of p27 protein and messenger RNA (mRNA), respectively. Immunoblotting and immunodepletion assays were performed on a subset of the prostate tumors. Associations between alterations in p27KIP1 expression and clinicopathologic variables were evaluated with a nonparametric test. The Kaplan-Meier method and the logrank test were used to compare disease-relapse-free survival. Prostate tissues of p27Kip1 null (i.e., knock-out) and wild-type mice were also evaluated.Results: Normal human prostate tissue exhibited abundant amounts of p27 protein and high levels of p27KIP1 mRNA in both epithelial cells and stromal cells. However, p27 protein and p27KIP1 mRNA were almost undetectable in epithelial cells and stromal cells of BPH lesions. Furthermore, p27Kip1 null mice developed enlarged (hyperplastic) prostate glands. In contrast to BPH, prostate carcinomas were found to contain abundant p27KIP1 mRNA but either high or low to undetectable levels of p27 protein. Primary prostate carcinomas expressing lower levels of p27 protein appeared to be biologically more aggressive (two-sided P = .019 [Cox regression analysis]).Conclusions/implications: On the basis of these results, we infer that loss of p27Kip1 expression in the human prostate may be causally linked to BPH and that BPH is not a precursor to prostate cancer. [ABSTRACT FROM AUTHOR]

Importance: "Awake" cannulation for venovenous extracorporeal membrane oxygenation (ECMO), where patients remain spontaneously breathing without invasive mechanical ventilation during the cannulation procedure, may reduce lung injury from positive pressure ventilation and promote patient mobility., Objectives: To examine the association between "awake" cannulation for venovenous ECMO and patient outcomes., Design, Setting, and Participants: Analysis of the prospectively collected by the multicenter Extracorporeal Life Support Organization registry. Patients 18 years old or older who were cannulated for venovenous ECMO between 2016 and 2022 were included., Main Outcomes and Measures: Propensity score matching techniques were used to examine the association between the primary exposure of "awake" cannulation and the primary outcome of hospital mortality., Results: This study analyzed data from 28,627 patients who received venovenous ECMO, including 797 (2.8%) who underwent awake cannulation. Patients undergoing awake cannulation were older (52.2 vs. 47.8 yr), had greater prevalence of chronic lung diseases (50.6% vs. 48.9%), and ischemic heart disease (4.3% vs. 2.7%) compared with those cannulated while receiving mechanical ventilation. Hospital survival to discharge was did not differ significantly between awake and nonawake cannulation groups after propensity score matching (2.4% increased rate of survival for patients cannulated awake; 95% CI, -1.7% to 6.4%; p = 0.26)., Conclusions and Relevance: In this large, multicenter study, awake cannulation for venovenous ECMO was uncommon but increasingly used over time. Survival to hospital discharge was similar to patients cannulated while on mechanical ventilation. Future research should focus on identification of patient cohorts most likely to benefit from ""awake" cannulation., Competing Interests: Dr. Gong received grant funding from the National Institutes of Health (NIH), the Agency for Healthcare Research and Quality, and the Centers for Disease Control and Prevention; she received fees for serving on Data and Safety Monitoring Boards for NIH-funded Behavioral Economic and Staffing Strategies to Increase Adoption of the ABCDEF Bundle in the ICU (BEST ICU) trial, Replacing protein via enteral nutrition in a stepwise approach in critically ill patients (REPLENISH) trial, and Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock (ANDROMEDA) trial; and she received fees for serving on the scientific advisory panel for Philips Healthcare, Radiometer. Dr. Mohamed received consulting fees from Baxter Healthcare unrelated to this work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 ( MECP2 ) gene. Despite advancements in research, no cure exists due to an incomplete understanding of the molecular effects of MeCP2 deficiency. Previous studies have identified impaired tropomyosin receptor kinase (Trk) neurotrophin (NTP) signaling and mitochondrial redox imbalances as key drivers of the pathology. Moreover, altered glycosphingolipid metabolism has been reported in RTT. GM1 ganglioside is a known regulator of the nervous system, and growing evidence indicates its importance in maintaining neuronal homeostasis via its oligosaccharide chain, coded as GM1-OS. GM1-OS directly interacts with the Trk receptors on the cell surface, triggering neurotrophic and neuroprotective pathways in neurons. In this study, we demonstrate that GM1-OS ameliorates RTT deficits in the Mecp2 -null model. GM1-OS restored synaptogenesis and reduced mitochondrial oxidative stress of Mecp2 -knock-out (ko) cortical neurons. When administered in vivo, GM1-OS mitigated RTT-like symptoms. Our findings indicate that GM1-OS effects were mediated by Trk receptor activation on the neuron's plasma membrane. Overall, our results highlight GM1-OS as a promising candidate for RTT treatment.

Oxidative stress has long been implicated in Parkinson's disease (PD) pathogenesis, although the sources and regulation of reactive oxygen species (ROS) production are poorly defined. Pathogenic mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are associated with increased kinase activity and a greater risk of PD. The substrates and downstream consequences of elevated LRRK2 kinase activity are still being elucidated, but overexpression of mutant LRRK2 has been associated with oxidative stress, and antioxidants reportedly mitigate LRRK2 toxicity. Here, using CRISPR-Cas9 gene-edited HEK293 cells, RAW264.7 macrophages, rat primary ventral midbrain cultures, and PD patient-derived lymphoblastoid cells, we found that elevated LRRK2 kinase activity was associated with increased ROS production and lipid peroxidation and that this was blocked by inhibitors of either LRRK2 kinase or NADPH oxidase 2 (NOX2). Oxidative stress induced by the pesticide rotenone was ameliorated by LRRK2 kinase inhibition and was absent in cells devoid of LRRK2. In a rat model of PD induced by rotenone, a LRRK2 kinase inhibitor prevented the lipid peroxidation and NOX2 activation normally seen in nigral dopaminergic neurons in this model. Mechanistically, LRRK2 kinase activity was shown to regulate phosphorylation of serine-345 in the p47 phox subunit of NOX2. This, in turn, led to translocation of p47 phox from the cytosol to the membrane-associated gp91 phox (NOX2) subunit, activation of the NOX2 enzyme complex, and production of ROS. Thus, LRRK2 kinase activity may drive cellular ROS production in PD through the regulation of NOX2 activity.

Objective: To evaluate the impact of preimplantation genetic testing for aneuploidy (PGT-A) on first transfer live birth rate (LBR) and cumulative LBR (CLBR) in donor oocyte in vitro fertilization (IVF) cycles., Design: Retrospective cohort study of the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database., Setting: Fertility centers reporting to Society for Assisted Reproductive Technology., Patient(s): A total of 11,348 fresh and 7,214 frozen-thawed donor oocyte IVF cycles were analyzed., Intervention(s): The first reported donor stimulation cycle per patient between January 1, 2014, and December 31, 2015, and all linked embryo transfer cycles between January 1, 2014, and December 31, 2016, were included in the study., Main Outcome Measure(s): Live birth rate was compared for patients using fresh and frozen-thawed donor oocytes, with or without PGT-A. Logistic regression models were adjusted for age, body mass index, gravidity, infertility etiology, and prior IVF cycles., Result(s): Among patients who had blastocysts available for transfer or PGT-A, the use of PGT-A was associated with a decreased first transfer LBR (46.9 vs. 53.2%) and CLBR (58.4 vs. 66.6%) in fresh oocyte donor cycles compared with no PGT-A. Live birth rate in frozen-thawed oocyte donor cycles with PGT-A were nominally higher than those without PGT-A (48.3% vs. 40.5%) but were not statistically significant in multivariable logistic regression models. Early pregnancy loss was not significantly different with and without PGT-A. Multiple gestation, preterm birth, and low birth weight infants were all reduced with the addition of PGT-A in fresh donor oocyte cycles, although these outcomes were not significantly different when comparing single embryo transfers in fresh oocyte cycles and also not significantly different among frozen-thawed donor oocyte cycles., Conclusion(s): Preimplantation genetic testing for aneuploidy in fresh oocyte donor cycles was associated with decreased LBR and CLBR, whereas effects on frozen-thawed oocyte donor cycles were clinically negligible. Obstetric benefits associated with PGT-A in fresh donor cycles appear linked to increased single embryo transfer., Competing Interests: Declaration of Interests J.A.G. has nothing to disclose. A.K. has nothing to disclose. H.W. has nothing to disclose. M.F. has nothing to disclose. H.L. has nothing to disclose. G.D.B. has nothing to disclose. K.D. has nothing to disclose. S.J. has nothing to disclose., (Copyright © 2024 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Mutations in leucine-rich repeat kinase 2 (LRRK2) that increase its kinase activity are strongly linked to genetic forms of Parkinson's disease (PD). However, the regulation of endogenous wild-type (WT) LRRK2 kinase activity remains poorly understood, despite its frequent elevation in idiopathic PD (iPD) patients. Various stressors such as mitochondrial dysfunction, lysosomal dyshomeostasis, or vesicle trafficking deficits can activate WT LRRK2 kinase, but the specific molecular mechanisms are not fully understood. We found that the production of 4-hydroxynonenal (4-HNE), a lipid hydroperoxidation end-product, is a common biochemical response to these diverse stimuli. 4-HNE forms post-translational adducts with Cys2024 and Cys2025 in the kinase activation loop of WT LRRK2, significantly increasing its kinase activity. Additionally, we discovered that the 4-HNE responsible for regulating LRRK2 is generated by the action of 15-lipoxygenase (15-LO), making 15-LO an upstream regulator of the pathogenic hyperactivation of LRRK2 kinase activity. Pharmacological inhibition or genetic ablation of 15-LO prevents 4-HNE post-translational modification of LRRK2 kinase and its subsequent pathogenic hyperactivation. Therefore, 15-LO inhibitors, or methods to lower 4-HNE levels, or the targeting of Cys2024/2025 could provide new therapeutic strategies to modulate LRRK2 kinase activity and treat PD.

Background: Mycoplasma genitalium (MG) is an emerging sexually transmitted infection. Treatment of MG is complicated by increasing resistance to primary treatment regimens, including macrolides and fluoroquinolones. Understanding the various clinical presentations and relative effectiveness of treatments for MG is crucial to optimizing care., Methods: Patients with a positive MG nucleic acid amplification test between July 1, 2019, and June 30, 2021, at a large health system in New York City were included in a retrospective cohort. Demographics, clinical presentations, coinfections, treatment, and follow-up microbiologic tests were obtained from the electronic medical record. Associations with microbiologic cure were evaluated in bivariate and multivariable logistic regression models., Results: Five hundred two unique patients had a positive MG nucleic acid amplification test result during the study period. Male individuals presented predominantly with urethritis (117 of 187 [63%]) and female individuals with vaginal symptoms (142 of 315 [45%]). Among patients with follow-up testing who received a single antibiotic at the time of treatment, 43% (90 of 210) had persistent infection and 57% (120 of 210) had microbiologic cure. Eighty-two percent of patients treated with moxifloxacin had microbiologic cure compared with 41% of patients receiving azithromycin regimens ( P < 0.001). In multivariable analysis, treatment with moxifloxacin was associated with 4 times the odds of microbiologic cure relative to low-dose azithromycin (adjusted odds ratio [aOR], 4.18; 95% confidence interval, 1.73-10.13; P < 0.01)., Conclusions: Clinical presentations of MG vary, with urethritis or vaginal symptoms in most cases. Among patients who received a single antibiotic, only treatment with moxifloxacin was significantly associated with microbiologic cure relative to low-dose azithromycin., Competing Interests: Conflict of Interest and Sources of Funding: The authors declare they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Sexually Transmitted Diseases Association.)

Objectives: Electronic health records (EHRs) have transformed the way modern medicine is practiced, but they remain a major source of documentation burden among physicians. This study aims to use data from Signal, a tool provided by the Epic EHR, to analyze physician metadata in the Montefiore Health System via cluster analysis to assess EHR burden and efficiency. Methods: Data were obtained for a one-month period (July 2020) representing a return to normal operation post-telemedicine implementation. Six metrics from Signal were used to phenotype physicians: time on unscheduled days, pajama time, time outside of 7 AM to 7 PM, turnaround time, proficiency score, and visits closed the same day. k-Means clustering was employed to group physicians, and the clusters were assessed overall and by sex and specialty. Results: Our results demonstrate the partitioning of physicians into a higher-efficiency, lower-time outside of scheduled hours (TOSH) cluster and a lower-efficiency, higher-TOSH cluster even when stratified by sex and specialty. Intra-cluster comparisons showed general homogeneity of physician metrics with the exception of the higher-efficiency, lower-TOSH cluster when stratified by sex. Conclusions: Taken together, the clusters uniquely reflect the EHR efficiency-burden of the Montefiore Health System. Applying k-means clustering to readily available EHR data allows for a scalable, efficient, and adaptable approach of assessing physician EHR burden and efficiency, allowing health systems to examine documentation trends and target wellness interventions.

Since the 1980s, it has been known that the administration of ganglioside GM1 to cultured cells induced or enhanced neuronal differentiation. GM1 mechanism of action relies on its direct interaction and subsequent activation of the membrane tyrosine kinase receptor, TrkA, which naturally serves as NGF receptor. This process is mediated by the sole oligosaccharide portion of GM1, the pentasaccharide β-Gal-(1-3)-β-GalNAc-(1-4)-[α-Neu5Ac-(2-3)]-β-Gal-(1-4)-β-Glc. Here we detailed the minimum structural requirements of the oligosaccharide portion of GM1 for mediating the TrkA dependent neuritogenic processing. By in vitro and in silico biochemical approaches, we demonstrated that the minimal portion of GM1 required for the TrkA activation is the inner core of the ganglioside's oligosaccharide β-Gal-(1-3)-β-GalNAc-(1-4)-[α-Neu5Ac-(2-3)]-β-Gal. The addition of a sialic acid residue at position 3 of the outer galactose of the GM1 oligosaccharide, which forms the oligosaccharide of GD1a, prevented the interaction with TrkA and the resulting neuritogenesis. On the contrary, the addition of a fucose residue at position 2 of the outer galactose, forming the Fucosyl-GM1 oligosaccharide, did not prevent the TrkA-mediated neuritogenesis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alterations in glycosphingolipid metabolism have been linked to the pathophysiological mechanisms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Accordingly, administration of GM1, a sialic acid-containing glycosphingolipid, is protective against neuronal damage and supports neuronal homeostasis, with these effects mediated by its bioactive component, the oligosaccharide head (GM1-OS). Here, we add new evidence to the therapeutic efficacy of GM1 in ALS: Its administration to WT and SOD1 G93A motor neurons affected by glutamate-induced excitotoxicity significantly increased neuronal survival and preserved neurite networks, counteracting intracellular protein accumulation and mitochondria impairment. Importantly, the GM1-OS faithfully replicates GM1 activity, emphasizing that even in ALS the protective function of GM1 strictly depends on its pentasaccharide., (© 2023 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

A series of biologically unexplored substituted 1,3,4-subtituted-pyrrolo[3,2-c]quinoline derivatives (PQs) was evaluated against a panel of about 60 tumor cells (NCI). Based on the preliminary antiproliferative data, the optimizations efforts permitted us to design and synthesize a new series of derivatives allowing us to individuate a promising hit (4g). The insertion of a 4-benzo[d] [1,3]dioxol-5-yl moiety on increased and extended the activity towards five panel tumor cell lines such as leukemia, CNS, melanoma, renal and breast cancer, reaching IG 50 in the low μM range. Replacement of this latter with a 4-(OH-di-Cl-Ph) group (4i) or introduction a Cl-propyl chain in position 1 (5), selectively addressed the activity against the entire leukemia sub-panel (CCRF-CEM, K-562, MOLT-4, RPMI-8226, SR). Preliminary biological assays on MCF-7 such as cell cycle, clonogenic assay, ROS content test alongside a comparison of viability between MCF-7 and non-tumorigenic MCF-10 were investigated. Among the main anticancer targets involved in breast cancer, HSP90 and ER receptors were selected for in silico studies. Docking analysis revealed a valuable affinity for HSP90 providing structural insights on the binding mode, and useful features for optimization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Hospitalizations among people living with HIV (PLWH) are frequent and costly. This study examined the association between psychiatric, HIV-related, and demographic factors and hospitalization rates among PLWH using data from the Einstein-Rockefeller-City University of New York Center for AIDS Research Clinical Cohort Database. Of the 10,215 PLWH included in the sample, 45% had at least one non-psychiatric hospitalization between 2009 and 2018, with significant risk factors including prior psychiatric outpatient visits, depression, or alcohol-related disorder diagnoses, female sex, older age, CD4 count < 500 cells/uL, and detectable viral load. Additionally, 14% had an HIV-related hospitalization, with significant risk factors including prior psychiatric outpatient visits, alcohol- and substance-related disorder diagnoses, female sex, older age, CD4 count < 500 cells/uL, and detectable viral load. The study emphasizes the need for tailored interventions, including integrated treatment and comprehensive case management, for PLWH with comorbid psychiatric disorders, women, and older adults., (© 2023. The Author(s).)

Fibrillary aggregated α-synuclein represents the neurologic hallmark of Parkinson's disease and is considered to play a causative role in the disease. Although the causes leading to α-synuclein aggregation are not clear, the GM1 ganglioside interaction is recognized to prevent this process. How GM1 exerts these functions is not completely clear, although a primary role of its soluble oligosaccharide (GM1-OS) is emerging. Indeed, we recently identified GM1-OS as the bioactive moiety responsible for GM1 neurotrophic and neuroprotective properties, specifically reverting the parkinsonian phenotype both in in vitro and in vivo models. Here, we report on GM1-OS efficacy against the α-synuclein aggregation and toxicity in vitro. By amyloid seeding aggregation assay and NMR spectroscopy, we demonstrated that GM1-OS was able to prevent both the spontaneous and the prion-like α-synuclein aggregation. Additionally, circular dichroism spectroscopy of recombinant monomeric α-synuclein showed that GM1-OS did not induce any change in α-synuclein secondary structure. Importantly, GM1-OS significantly increased neuronal survival and preserved neurite networks of dopaminergic neurons affected by α-synuclein oligomers, together with a reduction of microglia activation. These data further demonstrate that the ganglioside GM1 acts through its oligosaccharide also in preventing the α-synuclein pathogenic aggregation in Parkinson's disease, opening a perspective window for GM1-OS as drug candidate., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABA A Rs). BZ clinical use is hampered by tolerance and withdrawal symptoms including heightened seizure susceptibility, panic, and sleep disturbances. Here, we investigated inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation. Repeated diazepam (DZP) treatment diminished sedative effects and decreased DZP potentiation of GABA A R synaptic currents without impacting overall synaptic inhibition. While DZP did not alter γ2-GABA A R subunit composition, there was a redistribution of extrasynaptic GABA A Rs to synapses, resulting in higher levels of synaptic BZ-insensitive α4-containing GABA A Rs and a concomitant reduction in tonic inhibition. Conversely, excitatory glutamatergic synaptic transmission was increased, and NMDAR subunits were upregulated at synaptic and total protein levels. Quantitative proteomics further revealed cortex neuroadaptations of key pro-excitatory mediators and synaptic plasticity pathways highlighted by Ca 2+ /calmodulin-dependent protein kinase II (CAMKII), MAPK, and PKC signaling. Thus, reduced inhibitory GABAergic tone and elevated glutamatergic neurotransmission contribute to disrupted excitation/inhibition balance and reduced BZ therapeutic power with benzodiazepine tolerance., Competing Interests: Declaration of Competing Interest The authors have no disclosures and declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ethnic and racial disparities have recently been observed both in treatment-related toxicities and rates of long-lasting cure in acute lymphoblastic leukemia (ALL) and acute lymphoblastic lymphoma (ALLy), the most common pediatric malignancy. Despite significant improvements in overall survival in the recent past, a large number of children die from aggressive disease., Methods: We performed a retrospective cohort analysis of 274 pediatric ALL/ALLy patients within Montefiore Health System from 2004 to 2021 to determine differences in all-cause mortality within the Pediatric Hematologic Malignancies Cohort using Cox Proportional Hazard regression modeling, adjusted for age at diagnosis, race/ethnicity, administration of intensive chemotherapy, preferred language, maximum glucose, and hypertension., Results: Among our 274 patients, 132 were Hispanic, 54 Non-Hispanic Black, and 25 Non-Hispanic White, with 25 identified as "Non-Hispanic Other," including Asian, Arabic, and Other. Hispanic patients were 78% less likely to die (HR 0.22; 95% CI 0.07, 0.73) when compared with Non-Hispanic Black individuals. Spanish speakers were 2.91 times more likely to die compared with those who spoke English (HR 2.91; 95% CI 1.08, 7.82). Among those English speakers, the diagnosis of hypertension and Hispanic ethnicity significantly impacted the risk of death, while these factors did not impact survival in Spanish speakers. High-risk cytogenetics did not impact survival., Conclusions: Hispanic children with ALL/ALLy have improved survival outcomes compared with Non-Hispanic Blacks. Additionally, Spanish language preference was strongly associated with poorer survival, a novel finding that should be validated in future studies., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: Cognitive dysfunction (CD) is a common manifestation of SLE that can have detrimental consequences for those affected. To date, no treatments have been approved for SLE-CD. This study aims to assess the association of azathioprine (AZA) and mycophenolate (MMF) use with SLE-CD, given that these medications have demonstrated neuroprotective qualities in prior studies., Methods: Consecutive adult SLE patients presenting to a single healthcare center were considered for participation. The ACR neuropsychological battery for SLE was administered to consenting patients at 0, 6 and 12 months. Scores were compared with age- and sex-matched controls. Primary outcome was CD, defined as a z-score ≤-1.5 in two or more cognitive domains. Mixed-effects logistic regression models were constructed to estimate the odds of CD with respect to AZA and MMF use., Results: A total of 300 participants representing 676 patient visits completed the study; 114 (38%) met criteria for CD at baseline. The cumulative AZA dose (g/kg) was associated with reduced odds of CD [odds ratio (OR) 0.76 (95% CI 0.58, 0.98), P = 0.04]. Years of AZA treatment was also associated with reduced odds of CD [OR 0.72 (95% CI 0.54, 0.97), P = 0.03]. MMF use was not associated with CD., Conclusion: AZA use was associated with significantly lower odds of SLE-CD, while MMF use was not. Additional studies are warranted to further investigate the relationship of AZA and SLE-CD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Past evidence has shown that the exogenous administration of GM1 ganglioside slowed neuronal death in preclinical models of Parkinson's disease, a neurodegenerative disorder characterized by the progressive loss of dopamine-producing neurons: however, the physical and chemical properties of GM1 (i.e., amphiphilicity) limited its clinical application, as the crossing of the blood-brain barrier is denied. Recently, we demonstrated that the GM1 oligosaccharide head group (GM1-OS) is the GM1 bioactive portion that, interacting with the TrkA-NGF complex at the membrane surface, promotes the activation of a multivariate network of intracellular events regulating neuronal differentiation, protection, and reparation. Here, we evaluated the GM1-OS neuroprotective potential against the Parkinson's disease-linked neurotoxin MPTP, which destroys dopaminergic neurons by affecting mitochondrial bioenergetics and causing ROS overproduction. In dopaminergic and glutamatergic primary cultures, GM1-OS administration significantly increased neuronal survival, preserved neurite network, and reduced mitochondrial ROS production enhancing the mTOR/Akt/GSK3β pathway. These data highlight the neuroprotective efficacy of GM1-OS in parkinsonian models through the implementation of mitochondrial function and reduction in oxidative stress.

To date there are no therapeutic strategies that limit the progression of Parkinson's disease (PD). The mechanisms underlying PD-related nigrostriatal neurodegeneration remain incompletely understood, with multiple factors modulating the course of PD pathogenesis. This includes Nrf2-dependent gene expression, oxidative stress, α-synuclein pathology, mitochondrial dysfunction, and neuroinflammation. In vitro and sub-acute in vivo rotenone rat models of PD were used to evaluate the neuroprotective potential of a clinically-safe, multi-target metabolic and inflammatory modulator, the electrophilic fatty acid nitroalkene 10-nitro-oleic acid (10-NO 2 -OA). In N27-A dopaminergic cells and in the substantia nigra pars compacta of rats, 10-NO 2 -OA activated Nrf2-regulated gene expression and inhibited NOX2 and LRRK2 hyperactivation, oxidative stress, microglial activation, α-synuclein modification, and downstream mitochondrial import impairment. These data reveal broad neuroprotective actions of 10-NO 2 -OA in a sub-acute model of PD and motivate more chronic studies in rodents and primates., (© 2023. The Author(s).)

Introduction: Electrical isolation of pulmonary veins (PVI) is a cornerstone for atrial fibrillation (AF) ablation. The overall effect of AF ablation, and especially lesions beyond PVI, on left atrial (LA) function is currently poorly understood. Our aim was to determine if LA function is different in patients after extensive LA ablation compared to PVI only. We performed non-inferiority analysis of LA function after PVI with additional nonpulmonary vein ablation lesions in LA (PVI+) and PVI alone., Methods: We studied 68 patients consecutive patients who underwent AF ablation and who had complete transthoracic echocardiogram (TTE) within 12 months before AF ablation and 1-12 months after the procedure. Patients were stratified into two groups: PVI only and PVI+. Primary outcome was change in LA reservoir strain (LASr). Noninferiority margin was defined at 6%., Results: The PVI only group had a higher proportion of patients with paroxysmal AF (70% vs. 30%). The PVI+ group was observed to have a slightly higher increase in LASr compared to PVI alone (5.0% vs. 4.3%, p < .01 for noninferiority). LASr noninferiority was confirmed when adjusted for age, sex, coronary artery disease, hyperlipidemia, and AF type, rhythm at preprocedure TTE in a multivariable linear regression model, 90% CI (-5.46 to 2.04), p < .01., Conclusion: LA functional improvement evaluated by LASr was noninferior after PVI with additional LA ablation lesions compared to PVI alone. These findings were confirmed when adjusted for confounding clinical variables, suggesting that more extensive ablation does not negatively affect LA function., (© 2022 Wiley Periodicals LLC.)

Purpose: To evaluate the impact of preimplantation genetic testing for aneuploidy (PGT-A) on cumulative live birth rate (CLBR) in IVF cycles., Methods: Retrospective cohort study of the SART CORS database, comparing CLBR for patients using autologous oocytes, with or without PGT-A. The first reported autologous ovarian stimulation cycle per patient between January 1, 2014, and December 31, 2015, and all linked embryo transfer cycles between January 1, 2014, and December 31, 2016, were included in the study. Exclusion criteria were donor oocyte cycles, donor embryo cycles, gestational carrier cycles, cycles which included both a fresh embryo transfer (ET) combined with a thawed embryo previously frozen (ET plus FET), or cycles with a fresh ET after PGT-A., Results: A total of 133,494 autologous IVF cycles were analyzed. Amongst patients who had blastocysts available for either ET or PGT-A, including those without transferrable embryos, decreased CLBR was noted in the PGT-A group at all ages, except ages > 40 (p < 0.01). A subgroup analysis of only those patients who had PGT-A and a subsequent FET, excluding those without transferrable embryos, demonstrated a very high CLBR, ranging from 71.2% at age < 35 to 50.2% at age > 42. Rates of multiple gestations, preterm birth, early pregnancy loss, and low birth weight were all greater in the non-PGT-A group., Conclusions: PGT-A was associated with decreased CLBR amongst all patients who had blastocysts available for ET or PGT-A, except those aged > 40. The negative association of PGT-A use and CLBR per cycle start was especially pronounced at age < 35., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The interactions between gangliosides and proteins belonging to the same or different lipid domains and their influence on physiological and pathological states have been analysed in detail. A well-known factor impacting on lipid-protein interactions and their biological outcomes is the dynamic composition of plasma membrane. This review focuses on GM1 and GM3 gangliosides because they are an integral part of protein-receptor complexes and dysregulation of their concentration shows a direct correlation with the onset of pathological conditions. We first discuss the interaction between GM3 and insulin receptor in relation to insulin responses, with an increase in GM3 correlating with the onset of metabolic dysfunction. Next, we describe the case of the GM1-TrkA interaction, relevant to nerve-cell differentiation and homeostasis as deficiency in plasma-membrane GM1 is known to promote neurodegeneration. These two examples highlight the fact that interactions between gangliosides and receptor proteins within the plasma membrane are crucial in controlling cell signalling and pathophysiological cellular states., (© 2022 Federation of European Biochemical Societies.)

Recent reports have clearly demonstrated a tight correlation between obesity and elevated circulating uric acid levels (hyperuricemia). However, nearly all preclinical work in this area has been completed with male mice, leaving the field with a considerable gap in knowledge regarding female responses to obesity and hyperuricemia. This deficiency in sex as a biological variable extends beyond unknowns regarding uric acid (UA) to several important comorbidities associated with obesity including nonalcoholic fatty liver disease (NAFLD). To attempt to address this issue, herein we describe both phenotypic and metabolic responses to diet-induced obesity (DIO) in female mice. Six-week-old female C57BL/6J mice were fed a high-fat diet (60% calories derived from fat) for 32 weeks. The DIO female mice had significant weight gain over the course of the study, higher fasting blood glucose, impaired glucose tolerance, and elevated plasma insulin levels compared to age-matched on normal chow. While these classic indices of DIO and NAFLD were observed such as increased circulating levels of ALT and AST, there was no difference in circulating UA levels. Obese female mice also demonstrated increased hepatic triglyceride (TG), cholesterol, and cholesteryl ester. In addition, several markers of hepatic inflammation were significantly increased. Also, alterations in the expression of redox-related enzymes were observed in obese mice compared to lean controls including increases in extracellular superoxide dismutase (Sod3), heme oxygenase (Ho)-1, and xanthine dehydrogenase (Xdh). Interestingly, hepatic UA levels were significantly elevated (~2-fold) in obese mice compared to their lean counterparts. These data demonstrate female mice assume a similar metabolic profile to that reported in several male models of obesity in the context of alterations in glucose tolerance, hepatic steatosis, and elevated transaminases (ALT and AST) in the absence of hyperuricemia affirming the need for further study., Competing Interests: Declaration of Competing Interest We have no conflict of interest.