Faculty Bibliography
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Department/Unit:Neurology
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24318
Regulation of human oocyte maturation in vivo during the final maturation of follicles
STUDY QUESTION:Which substances and signal transduction pathways are potentially active downstream to the effect of FSH and LH in the regulation of human oocyte maturation in vivo? SUMMARY ANSWER:The regulation of human oocyte maturation appears to be a multifactorial process in which several different signal transduction pathways are active. WHAT IS KNOWN ALREADY:Many studies in animal species have provided insight into the mechanisms that govern the final maturation of oocytes. Currently, these studies have identified several different mechanisms downstream to the effects of FSH and LH. Some of the identified mechanisms include the regulation of cAMP/cGMP levels in oocytes involving C-type natriuretic peptide (CNP), effects of epidermal growth factor (EGF)-related peptides such as amphiregulin (AREG) and/or epiregulin (EREG), effect of TGF-β family members including growth differentiation factor 9 (GDF9) and morphogenetic protein 15 (BMP15), activins/inhibins, follicular fluid meiosis activating sterol (FF-MAS), the growth factor midkine (MDK), and several others. However, to what extent these pathways and mechanisms are active in humans in vivo is unknown. STUDY DESIGN, SIZE, DURATION:This prospective cohort study included 50 women undergoing fertility treatment in a standard antagonist protocol at a university hospital affiliated fertility clinic in 2016-2018. PARTICIPANTS/MATERIALS, SETTING, METHODS:We evaluated the substances and signalling pathways potentially affecting human oocyte maturation in follicular fluid (FF) and granulosa cells (GCs) collected at five time points during the final maturation of follicles. Using ELISA measurement and proteomic profiling of FF and whole genome gene expression in GC, the following substances and their signal transduction pathways were collectively evaluated: CNP, the EGF family, inhibin-A, inhibin-B, activins, FF-MAS, MDK, GDF9, and BMP15. MAIN RESULTS AND THE ROLE OF CHANCE:All the evaluated substances and signal transduction pathways are potentially active in the regulation of human oocyte maturation in vivo except for GDF9/BMP15 signalling. In particular, AREG, inhibins, and MDK were significantly upregulated during the first 12-17 h after initiating the final maturation of follicles and were measured at significantly higher concentrations than previously reported. Additionally, the genes regulating FF-MAS synthesis and metabolism were significantly controlled in favour of accumulation during the first 12-17 h. In contrast, concentrations of CNP were low and did not change during the process of final maturation of follicles, and concentrations of GDF9 and BMP15 were much lower than reported in small antral follicles, suggesting a less pronounced influence from these substances. LARGE SCALE DATA:None. LIMITATIONS, REASONS FOR CAUTION:Although GC and cumulus cells have many similar features, it is a limitation of the current study that information for the corresponding cumulus cells is not available. However, we seldom recovered a cumulus-oocyte complex during the follicle aspiration from 0 to 32 h. WIDER IMPLICATIONS OF THE FINDINGS:Delineating the mechanisms governing the regulation of human oocyte maturation in vivo advances the possibility of developing a platform for IVM that, as for most other mammalian species, results in healthy offspring with good efficacy. Mimicking the intrafollicular conditions during oocyte maturation in vivo in small culture droplets during IVM may enhance oocyte nuclear and cytoplasmic maturation. The primary outlook for such a method is, in the context of fertility preservation, to augment the chances of achieving biological children after a cancer treatment by subjecting oocytes from small antral follicles to IVM. Provided that aspiration of oocytes from small antral follicles in vivo can be developed with good efficacy, IVM may be applied to infertile patients on a larger scale and can provide a cheap alternative to conventional IVF treatment with ovarian stimulation. Successful IVM has the potential to change current established techniques for infertility treatment. STUDY FUNDING/COMPETING INTEREST(S):This research was supported by the University Hospital of Copenhagen, Rigshospitalet, the Independent Research Fund Denmark (grant number 0134-00448), and the Interregional EU-sponsored ReproUnion network. There are no conflicts of interest to be declared.
PMID: 36762771
ISSN: 1460-2350
CID: 5942592
Circular-SWAT for deep learning based diagnostic classification of Alzheimer's disease: application to metabolome data
BACKGROUND:Deep learning has shown potential in various scientific domains but faces challenges when applied to complex, high-dimensional multi-omics data. Alzheimer's Disease (AD) is a neurodegenerative disorder that lacks targeted therapeutic options. This study introduces the Circular-Sliding Window Association Test (c-SWAT) to improve the classification accuracy in predicting AD using serum-based metabolomics data, specifically lipidomics. METHODS:The c-SWAT methodology builds upon the existing Sliding Window Association Test (SWAT) and utilizes a three-step approach: feature correlation analysis, feature selection, and classification. Data from 997 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) served as the basis for model training and validation. Feature correlations were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA), and Convolutional Neural Networks (CNN) were employed for feature selection. Random Forest was used for the final classification. FINDINGS/RESULTS:The application of c-SWAT resulted in a classification accuracy of up to 80.8% and an AUC of 0.808 for distinguishing AD from cognitively normal older adults. This marks a 9.4% improvement in accuracy and a 0.169 increase in AUC compared to methods without c-SWAT. These results were statistically significant, with a p-value of 1.04 × 10ˆ-4. The approach also identified key lipids associated with AD, such as Cer(d16:1/22:0) and PI(37:6). INTERPRETATION/CONCLUSIONS:Our results indicate that c-SWAT is effective in improving classification accuracy and in identifying potential lipid biomarkers for AD. These identified lipids offer new avenues for understanding AD and warrant further investigation. FUNDING/BACKGROUND:The specific funding of this article is provided in the acknowledgements section.
PMCID:10579282
PMID: 37806288
ISSN: 2352-3964
CID: 5933622
HEPATOLOGY COMMUNICATIONS
ISI:001058457700001
CID: 5923712
Evaluating sleep in covert encephalopathy with wearable technology: results from the WATCHES study
BACKGROUND AND AIMS:Covert HE (CHE) is a common early stage of HE associated with poor outcomes. Available neuropsychiatric diagnostic testing is underutilized and has significant clinical limitations. Sleep deterioration is consistently associated with CHE and HE; however, objective data is sparse and it has not been studied longitudinally. We longitudinally study and describe an association of sleep metrics with CHE as detected by a commercial wearable technology. METHODS:We monitored sleep for 6 months using a commercial fitness tracker in 25 participants with cirrhosis, hypothesizing that CHE as diagnosed by psychometric testing would be associated with significant reductions in sleep quality, especially restorative sleep (deep sleep + rapid eye movement). Mixed-effects modeling was performed to evaluate sleep factors associated with CHE and developed and internally validated a score based on these sleep metrics for associated CHE. RESULTS:Across 2862 nights with 66.3% study adherence, we found that those with CHE had consistently worse sleep, including an average of 1 hour less of nightly restorative sleep, driven primarily by reductions in rapid eye movement. A model including albumin, bilirubin, rapid eye movement, sleep disturbances, and sleep consistency showed good discrimination (area under the receiver operating curve=0.79) for CHE status with a sensitivity of 76% and specificity of 69%. CONCLUSIONS:Our large longitudinal study of sleep in cirrhosis suggests that sleep derangements in CHE can be detected using wearable technology. Given the known importance of sleep to overall health and CHE/HE to prognosis in cirrhosis, the ability to associate dynamic sleep metrics with CHE may in the future help with the detection and passive monitoring as factors that precipitate decompensation of cirrhosis become better understood and mobile health data validation and integration improves.
PMID: 36724117
ISSN: 2471-254x
CID: 5923592
FRONTIERS IN ONCOLOGY
ISI:001078621400001
ISSN: 2234-943x
CID: 5920702
Memory deficit following resection of an intraventricular myxoid glioneuronal tumor impinging on the bilateral fornix: A case report [Case Report]
BACKGROUND/UNASSIGNED:Recently recognized as a distinct entity, a myxoid glioneuronal tumor (MGNT) is a rare, low-grade central nervous system tumor. MGNTs are commonly located at the septum pellucidum or in the third ventricle, increasing the likelihood of tumor or treatment-related damage to adjacent structures critical for memory, such as the fornix. Though there have been a handful of case reports of neurosurgical and oncological outcomes of MGNTs, memory outcomes following resection of MGNTs adjacent to the fornix have not been previously reported. METHODS/UNASSIGNED:We present a case of a high functioning female for whom an MRI revealed an incidental finding of an intraventricular tumor adjacent to the fornix bilaterally. The patient underwent resection of the tumor followed by MRI surveillance without additional oncologic intervention. Due to reported cognitive problems, the patient was referred for serial neuropsychological evaluations. RESULTS/UNASSIGNED:Post-operative MRI following resection revealed cytotoxic edema followed by selective, progressive atrophy of the bilateral anterior fornices. Post-surgically, the patient developed an isolated verbal memory impairment, which persisted one-year post resection with minimal improvement. The memory impairment impacted the patient's everyday functioning, including the ability to work in a cognitively demanding job. CONCLUSION/UNASSIGNED:This unique case demonstrates the critical role of the bilateral fornix in verbal memory and underscores the importance of a careful risk/benefit analysis when considering neurosurgical intervention to MGNTs and other intracranial lesions adjacent to this structure during neurosurgical planning.
PMCID:10565212
PMID: 37829343
ISSN: 2234-943x
CID: 5920652
American heart journal plus : cardiology research & practice. 2023:34.DOI: 10.1016/j.ahjo.2023.100313
Association of electrocardiographic and echocardiographic variables with neurological outcomes after ischemic Stroke
BACKGROUND/UNASSIGNED:Cardiac dysfunction is often seen following neurological injury. Data regarding cardiac involvement after ischemic stroke is sparse. We investigated the association of electrocardiographic (ECG) and echocardiographic variables with neurological outcomes after an acute ischemic stroke. METHODS/UNASSIGNED:We retrospectively collected baseline characteristics, stroke location, National Institute of Health Stroke Scale (NIHSS) at the time of admission, acute reperfusion treatment, ECG parameters, and echocardiographic data on 174 patients admitted with acute ischemic stroke. Outcomes of the stroke were based on cerebral performance category (CPC) with a CPC score of 1-2 indicating a good outcome and a CPC score of 3-5 indicating a poor outcome. RESULTS/UNASSIGNED: = 0.049, OR = 0.55, 95 % CI 0.10-2.55) were associated with poor neurological outcomes. However, when adjusted for age and NIHSS, heart rate and QTc were no longer statistically significant. None of the other ECG and echocardiographic variables were associated neurological outcomes. CONCLUSIONS/UNASSIGNED:Elevated heart rate and longer QTc intervals may potentially predict poor neurological outcomes. Further studies are needed for validation and possible integration of these variables in outcome predicting models.
PMCID:10945909
PMID: 38510950
ISSN: 2666-6022
CID: 5923112
Limits to Gauge Coupling in the Dark Sector Set by the Nonobservation of Instanton-Induced Decay of Super-Heavy Dark Matter in the Pierre Auger Observatory Data
Instantons, which are nonperturbative solutions to Yang-Mills equations, provide a signal for the occurrence of quantum tunneling between distinct classes of vacua. They can give rise to decays of particles otherwise forbidden. Using data collected at the Pierre Auger Observatory, we search for signatures of such instanton-induced processes that would be suggestive of super-heavy particles decaying in the Galactic halo. These particles could have been produced during the post-inflationary epoch and match the relic abundance of dark matter inferred today. The nonobservation of the signatures searched for allows us to derive a bound on the reduced coupling constant of gauge interactions in the dark sector: α_{X}≲0.09, for 10^{9}≲M_{X}/GeV<10^{19}. Conversely, we obtain that, for instance, a reduced coupling constant α_{X}=0.09 excludes masses M_{X}≳3×10^{13} GeV. In the context of dark matter production from gravitational interactions alone, we illustrate how these bounds are complementary to those obtained on the Hubble rate at the end of inflation from the nonobservation of tensor modes in the cosmological microwave background.
PMID: 36827568
ISSN: 1079-7114
CID: 5911432
A Bibliometric Analysis on Viral Central Nervous System Infection Research Productivity in Southeast Asia
Research productivity on viral infections of the nervous system in Southeast Asia (SEA) is unknown. We aimed to determine the research productivity of SEA in terms of bibliometric indices and PlumX metrics and their correlation with socioeconomic factors. A comprehensive search of major electronic databases was done to identify studies on viral infections of the nervous system with at least one author from SEA. Socioeconomic factors and collaborations outside SEA were determined. Correlational analysis was done on bibliometric indices and socioeconomic factors. A total of 542 articles were analyzed. The majority came from Thailand (n = 164, 30.2%). Most articles used a descriptive study design (n = 175, 32.2%). The most common topic was Japanese encephalitis (n = 170, 31.3%). The % gross domestic product allotted for research, number of neurologists, and number of collaborations outside SEA correlated with the bibliometric indices and PlumX metrics. In conclusion, the number of research from SEA was low but the quality was comparable to the global benchmark. Improving resource allocation and collaboration between SEA nations and other countries may support this endeavor.
PMCID:10042504
PMID: 36994271
ISSN: 2168-8184
CID: 5909792
Negative urgency, PTSD symptoms, and alcohol risk in college students
Theoretical models of trauma and alcohol use suggest that trauma-exposed individuals with higher levels of PTSD symptoms are at increased risk of problematic and coping-oriented alcohol use to alleviate unwanted internal states. The goal of the current study was to evaluate whether these associations are enhanced among young adults who report engaging in impulsive behavior in the context of negative affect (i.e., high negative urgency). It was hypothesized that (a) higher negative urgency would be associated with problematic alcohol use; and that (b) negative urgency would moderate the association between PTSD symptoms and problematic alcohol use. Methods: This study used a cross-sectional, secondary data analysis design run on 213 participants: college students, ages 18-25, who endorsed both having an interpersonal traumatic event and current weekly alcohol use. Participants completed a series of assessments and self-report questionnaires. Results: Results of hierarchical linear regression models indicated that greater negative urgency was significantly associated with greater negative alcohol-related consequences and greater coping motives for alcohol, but not past 30-day binge frequency or past 30-day alcohol quantity. Negative urgency did not moderate associations between PTSD symptoms and alcohol outcomes. Conclusions: PTSD symptoms and negative urgency are uniquely associated with indices of alcohol risk in college students with a history of trauma exposure. However, individuals high in negative urgency are not necessarily consuming more alcohol, nor does negative urgency increase the association between PTSD symptoms and drinking outcomes in this population.
PMCID:9868323
PMID: 36698484
ISSN: 2352-8532
CID: 5885852
