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Nature Neuroscience Jun 2024Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII...
Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset of dysmorphic cells clustered within healthy brain tissue. Here we show a correlation between epileptiform activity in acute cortical slices obtained from human surgical FCDII brain tissues and the density of dysmorphic neurons. We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, SASP expression and senescence-associated β-galactosidase activity. We also show that administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an Mtor FCDII preclinical mouse model, providing proof of concept that senotherapy may be a useful approach to control seizures. These findings pave the way for therapeutic strategies selectively targeting mutated senescent cells in FCDII brain tissue.
Topics: Animals; TOR Serine-Threonine Kinases; Mice; Humans; Seizures; Senotherapeutics; Cellular Senescence; Dasatinib; Epilepsy; Male; Malformations of Cortical Development; Neurons; Female
PubMed: 38710875
DOI: 10.1038/s41593-024-01634-2 -
Scientific Reports May 2024Emotions experienced within sleep mentation (dreaming) affect mental functioning in waking life. There have been attempts at enhancing dream emotions using olfactory...
Emotions experienced within sleep mentation (dreaming) affect mental functioning in waking life. There have been attempts at enhancing dream emotions using olfactory stimulation. Odors readily acquire affective value, but to profoundly influence emotional processing, they should bear personal significance for the perceiver rather than be generally pleasant. The main objective of the present sleep laboratory study was to examine whether prolonged nocturnal exposure to self-selected, preferred ambient room odor while asleep influences emotional aspects of sleep mentation and valence of post-sleep core affect. We asked twenty healthy participants (12 males, mean age 25 ± 4 years) to pick a commercially available scented room diffuser cartridge that most readily evoked positively valenced mental associations. In weekly intervals, the participants attended three sessions. After the adaptation visit, they were administered the odor exposure and odorless control condition in a balanced order. Participants were awakened five minutes into the first rapid eye movement (REM) stage that took place after 2:30 a.m. and, if they had been dreaming, they were asked to rate their mental sleep experience for pleasantness, emotional charge, and magnitude of positive and negative emotions and also to evaluate their post-sleep core affect valence. With rs < 0.20, no practically or statistically significant differences existed between exposure and control in any outcome measures. We conclude that in young, healthy participants, the practical value of olfactory stimulation with self-selected preferred scents for enhancement of dream emotions and post-sleep core affect valence is very limited.
Topics: Humans; Male; Adult; Female; Dreams; Odorants; Young Adult; Emotions; Sleep; Smell; Sleep, REM; Wakefulness
PubMed: 38710748
DOI: 10.1038/s41598-024-60226-z -
Anaesthesia, Critical Care & Pain... May 2024Preventive anesthetic impact on the high rates of postoperative neurocognitive disorders in elderly patients is debated. The Prevention of postOperative Cognitive...
Preoperative ketamine administration for prevention of postoperative neurocognitive disorders after major orthopedic surgery in elderly patients: A multicenter randomized blinded placebo-controlled trial.
BACKGROUND
Preventive anesthetic impact on the high rates of postoperative neurocognitive disorders in elderly patients is debated. The Prevention of postOperative Cognitive dysfunction by Ketamine (POCK) study aimed to assess the effect of ketamine on this condition.
METHODS
This is a multicenter, randomized, double-blind, interventional study. Patients ≥60 years undergoing major orthopedic surgery were randomly assigned in a 1:1 ratio to receive preoperative ketamine 0.5 mg/kg as an intravenous bolus (n = 152) or placebo (n = 149) in random blocks stratified according to the study site, preoperative cognitive status and age. The primary outcome was the proportion of objective delayed neurocognitive recovery (dNR) defined as a decline of one or more neuropsychological assessment standard deviations on postoperative day 7. Secondary outcomes included a three-month incidence of objective postoperative neurocognitive disorder (POND), as well as delirium, anxiety, and symptoms of depression seven days and three months after surgery.
RESULTS
Among 301 patients included, 292 (97%) completed the trial. Objective dNR occurred in 50 (38.8%) patients in the ketamine group and 54 (40.9%) patients in the placebo group (OR [95% CI] 0.92 [0.56;1.51], p = 0.73) on postoperative day 7. Incidence of objective POND three months after surgery did not differ significantly between the two groups nor did incidence of delirium, anxiety, apathy, and fatigue. Symptoms of depression were less frequent in the ketamine group three months after surgery (OR [95%CI] 0.34 [0.13-0.86]).
CONCLUSIONS
A single preoperative bolus of intravenous ketamine does not prevent the occurrence of dNR or POND in elderly patients scheduled for major orthopedic surgery. (Clinicaltrials.gov NCT02892916.).
PubMed: 38710325
DOI: 10.1016/j.accpm.2024.101387 -
F1000Research 2024The majority of indie game development teams are driven by the desire to produce a blockbuster game. But there are many obstacles on the way to realizing this desire,...
The majority of indie game development teams are driven by the desire to produce a blockbuster game. But there are many obstacles on the way to realizing this desire, especially in the beginning. It is possible to create a game alone, but more often than not, something genuinely amazing involves a group of talented people working together toward a similar objective. Finding the correct stakeholders is one of the biggest problems with starting an independent game development team. People with the required technical talents, such as programmers and artists, as well as those with business acumen, like marketing and finance experts, are included in this. Success depends on being able to locate these people and manage them. But after the correct individuals have been identified, it is crucial to develop open lines of communication and a common comprehension of the project's objectives and expectations. Finding the perfect people to join their team is a problem that independent game development teams frequently encounter. Attracting talented individuals to a brand-new, unproven initiative might be difficult. The attention of skilled people interested in working on cutting-edge and intriguing initiatives might be attracted through networking. There are other things to consider as well since forming a team comes with the type of game one is making, finding skilled teammates, team chemistry, conflict resolution, communication, long-term relation maintenance and leadership aspects. In general, creating and leading an independent game team is a difficult process. There is no specific method for doing this, but with a little help from others' expertise, it is possible to assemble a team of creative people who can collaborate to produce a game that is genuinely enjoyable.
Topics: Humans; Cooperative Behavior; Communication
PubMed: 38708288
DOI: 10.12688/f1000research.139274.1 -
ACS Omega Apr 2024Recent studies show that nanofillers greatly contribute to the increase in the mechanical and abrasive behaviors of the polymer composite. In the current study, epoxy...
Recent studies show that nanofillers greatly contribute to the increase in the mechanical and abrasive behaviors of the polymer composite. In the current study, epoxy composites were made by hand lay-up with the reinforcement of carbon fabric and titanium dioxide (TiO) nanoparticles as secondary reinforcement in weight percentages of 0.5, 1.0, and 2.0. Hardness, tensile, and abrasive wear tests have been carried out for the fabricated composites. The obtained results confirm that as the percentage of filler addition increases, hardness of the carbon epoxy (CE) composite increases, and significant enhancement of 10.25% hardness is confirmed in 2 wt % nano TiO-added CE composite. The CE composite filled with 2 wt % of TiO nanofiller shows 15.77 and 9.15% improvement of tensile strength and modulus, respectively, compared to unfilled CE composites. The abrasive wear volume exhibits a nearly linear increasing trend as the abrading distance increases. In addition, it is discovered that the abrasive wear volume is greater for higher applied loads. The inclusion of nano TiO reduced the wear loss in the CE composite for all abrading distances, regardless of the load, low or high. The scanning electron microscopy analysis of worn surfaces was carried out to analyze the contribution of the filler to improve the wear resistance.
PubMed: 38708248
DOI: 10.1021/acsomega.3c07830 -
Heliyon May 2024To explore the effects of propofol and ciprofol on patient euphoric reactions during sedation in patients undergoing gastroscopy and to investigate potential factors...
OBJECTIVE
To explore the effects of propofol and ciprofol on patient euphoric reactions during sedation in patients undergoing gastroscopy and to investigate potential factors that may influence euphoric reactions in patients.
METHODS
A total of 217 patients were randomly divided into two groups: the propofol group (P group, n = 109) and the ciprofol group (C group, n = 108). The patients in the P group were given 2 mg/kg propofol, and those in the C group were given 0.5 mg/kg ciprofol. The patients were assessed using the Addiction Research Center Inventory-Chinese Version (ARCI-CV) to measure euphoric reactions at three time points: preexamination, 30 min after awakening, and 1 week after examination. Anxiety, depression, and sleep status were evaluated using appropriate scales at admission and 1 week after the examination. The dream rate, sedative effects, vital sign dynamics, and adverse reactions were documented during the sedation process.
RESULTS
After 30 min of awakening, the P group and C group showed no statistically significant differences in the mean morphine-benzedrine group (MBG) score (8.84 vs. 9.09, > 0.05), dream rate (42.2 % vs. 40.7 %, > 0.05), or MBG score one week after the examination (7.04 vs. 7.05, > 0.05). The regression analysis revealed that sex, dream status, Alcohol Use Disorders Identification Test (AUDIT) score, and examination time had notable impacts on the MBG-30 min score. No statistically significant differences were observed in sedative effects, anxiety, depression, or sleep status between the two groups ( > 0.05). The incidence of injection pain and severe hypotension was significantly lower in the C group ( < 0.05), and hemodynamics and SpO were more stable during sedation ( < 0.05).
CONCLUSION
There was no significant difference between propofol and ciprofol in terms of euphoria experienced by patients after sedation in patients undergoing gastroscopy. Ciprofol has demonstrated addictive potential similar to that of propofol, warranting careful attention to its addictive potential during clinical application.
PubMed: 38707441
DOI: 10.1016/j.heliyon.2024.e30378 -
NPJ Parkinson's Disease May 2024Observational studies in Parkinson's disease (PD) deeply characterize relatively small numbers of participants. The Molecular Integration in Neurological Diagnosis...
Observational studies in Parkinson's disease (PD) deeply characterize relatively small numbers of participants. The Molecular Integration in Neurological Diagnosis Initiative seeks to characterize molecular and clinical features of every PD patient at the University of Pennsylvania (UPenn). The objectives of this study are to determine the feasibility of genetic characterization in PD and assess clinical features by sex and GBA1/LRRK2 status on a clinic-wide scale. All PD patients with clinical visits at the UPenn PD Center between 9/2018 and 12/2022 were eligible. Blood or saliva were collected, and a clinical questionnaire administered. Genotyping at 14 GBA1 and 8 LRRK2 variants was performed. PD symptoms were compared by sex and gene groups. 2063 patients were approached and 1,689 (82%) were enrolled, with 374 (18%) declining to participate. 608 (36%) females were enrolled, 159 (9%) carried a GBA1 variant, and 44 (3%) carried a LRRK2 variant. Compared with males, females across gene groups more frequently reported dystonia (53% vs 46%, p = 0.01) and anxiety (64% vs 55%, p < 0.01), but less frequently reported cognitive impairment (10% vs 49%, p < 0.01) and vivid dreaming (53% vs 60%, p = 0.01). GBA1 variant carriers more frequently reported anxiety (67% vs 57%, p = 0.04) and depression (62% vs 46%, p < 0.01) than non-carriers; LRRK2 variant carriers did not differ from non-carriers. We report feasibility for near-clinic-wide enrollment and characterization of individuals with PD during clinical visits at a high-volume academic center. Clinical symptoms differ by sex and GBA1, but not LRRK2, status.
PubMed: 38702337
DOI: 10.1038/s41531-024-00690-6 -
Cell Chemical Biology Jun 2024The modulation of protein-protein interactions with small molecules is one of the most rapidly developing areas in drug discovery. In this review, we discuss advances... (Review)
Review
The modulation of protein-protein interactions with small molecules is one of the most rapidly developing areas in drug discovery. In this review, we discuss advances over the past decade (2014-2023) focusing on molecular glues (MGs)-monovalent small molecules that induce proximity, either by stabilizing native interactions or by inducing neomorphic interactions. We include both serendipitous and rational discoveries and describe the different approaches that were used to identify them. We classify the compounds in three main categories: degradative MGs, non-degradative MGs or PPI stabilizers, and MGs that induce self-association. Diverse, illustrative examples with structural data are described in detail, emphasizing the elements of molecular recognition and cooperative binding at the interface that are fundamental for a MG mechanism of action.
Topics: Protein Binding; Proteins; Humans; Small Molecule Libraries; Drug Discovery
PubMed: 38701786
DOI: 10.1016/j.chembiol.2024.04.002 -
BMC Neurology May 2024Sleep disorders are a prevalent non-motor symptom of Parkinson's disease (PD), although reliable biological markers are presently lacking.
BACKGROUND
Sleep disorders are a prevalent non-motor symptom of Parkinson's disease (PD), although reliable biological markers are presently lacking.
OBJECTIVES
To explore the associations between sleep disorders and serum neurofilament light chain (NfL) levels in individuals with prodromal and early PD.
METHODS
The study contained 1113 participants, including 585 early PD individuals, 353 prodromal PD individuals, and 175 healthy controls (HCs). The correlations between sleep disorders (including rapid eye movement sleep behavior disorder (RBD) and excessive daytime sleepiness (EDS)) and serum NfL levels were researched using multiple linear regression models and linear mixed-effects models. We further investigated the correlations between the rates of changes in daytime sleepiness and serum NfL levels using multiple linear regression models.
RESULTS
In baseline analysis, early and prodromal PD individuals who manifested specific behaviors of RBD showed significantly higher levels of serum NfL. Specifically, early PD individuals who experienced nocturnal dream behaviors (β = 0.033; P = 0.042) and movements of arms or legs during sleep (β = 0.027; P = 0.049) showed significantly higher serum NfL levels. For prodromal PD individuals, serum NfL levels were significantly higher in individuals suffering from disturbed sleep (β = 0.038; P = 0.026). Our longitudinal findings support these baseline associations. Serum NfL levels showed an upward trend in early PD individuals who had a higher total RBDSQ score (β = 0.002; P = 0.011) or who were considered as probable RBD (β = 0.012; P = 0.009) or who exhibited behaviors on several sub-items of the RBDSQ. In addition, early PD individuals who had a high total ESS score (β = 0.001; P = 0.012) or who were regarded to have EDS (β = 0.013; P = 0.007) or who exhibited daytime sleepiness in several conditions had a trend toward higher serum NfL levels.
CONCLUSION
Sleep disorders correlate with higher serum NfL, suggesting a link to PD neuronal damage. Early identification of sleep disorders and NfL monitoring are pivotal in detecting at-risk PD patients promptly, allowing for timely intervention. Regular monitoring of NfL levels holds promise for tracking both sleep disorders and disease progression, potentially emerging as a biomarker for evaluating treatment outcomes.
Topics: Humans; Parkinson Disease; Male; Female; Neurofilament Proteins; Middle Aged; Aged; Sleep Wake Disorders; Biomarkers; REM Sleep Behavior Disorder; Prodromal Symptoms
PubMed: 38693483
DOI: 10.1186/s12883-024-03642-y -
Scientific Reports May 2024Parkinson's disease is a progressive neurodegenerative disorder in which loss of dopaminergic neurons in the substantia nigra results in a clinically heterogeneous group...
Parkinson's disease is a progressive neurodegenerative disorder in which loss of dopaminergic neurons in the substantia nigra results in a clinically heterogeneous group with variable motor and non-motor symptoms with a degree of misdiagnosis. Only 3-25% of sporadic Parkinson's patients present with genetic abnormalities that could represent a risk factor, thus environmental, metabolic, and other unknown causes contribute to the pathogenesis of Parkinson's disease, which highlights the critical need for biomarkers. In the present study, we prospectively collected and analyzed plasma samples from 194 Parkinson's disease patients and 197 age-matched non-diseased controls. N-acetyl putrescine (NAP) in combination with sense of smell (B-SIT), depression/anxiety (HADS), and acting out dreams (RBD1Q) clinical measurements demonstrated combined diagnostic utility. NAP was increased by 28% in Parkinsons disease patients and exhibited an AUC of 0.72 as well as an OR of 4.79. The clinical and NAP panel demonstrated an area under the curve, AUC = 0.9 and an OR of 20.4. The assessed diagnostic panel demonstrates combinatorial utility in diagnosing Parkinson's disease, allowing for an integrated interpretation of disease pathophysiology and highlighting the use of multi-tiered panels in neurological disease diagnosis.
Topics: Humans; Parkinson Disease; Male; Biomarkers; Female; Aged; Middle Aged; Putrescine; Prospective Studies; Case-Control Studies
PubMed: 38693432
DOI: 10.1038/s41598-024-60872-3