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Nature Communications May 2024Histone deacetylases (HDACs) play a crucial role in transcriptional regulation and are implicated in various diseases, including cancer. They are involved in histone...
Histone deacetylases (HDACs) play a crucial role in transcriptional regulation and are implicated in various diseases, including cancer. They are involved in histone tail deacetylation and canonically linked to transcriptional repression. Previous studies suggested that HDAC recruitment to cell-cycle gene promoters via the retinoblastoma (RB) protein or the DREAM complex through SIN3B is essential for G1/S and G2/M gene repression during cell-cycle arrest and exit. Here we investigate the interplay among DREAM, RB, SIN3 proteins, and HDACs in the context of cell-cycle gene repression. Knockout of SIN3B does not globally derepress cell-cycle genes in non-proliferating HCT116 and C2C12 cells. Loss of SIN3A/B moderately upregulates several cell-cycle genes in HCT116 cells but does so independently of DREAM/RB. HDAC inhibition does not induce general upregulation of RB/DREAM target genes in arrested transformed or non-transformed cells. Our findings suggest that E2F:RB and DREAM complexes can repress cell-cycle genes without relying on HDAC activity.
Topics: Humans; Histone Deacetylases; HCT116 Cells; Repressor Proteins; E2F Transcription Factors; Retinoblastoma Protein; Mice; Animals; Sin3 Histone Deacetylase and Corepressor Complex; Kv Channel-Interacting Proteins; Cell Cycle; Promoter Regions, Genetic; Gene Expression Regulation; Genes, cdc
PubMed: 38789411
DOI: 10.1038/s41467-024-48724-0 -
Psychiatry Research Jul 2024This study aimed to investigate the association between pre-pregnancy, prenatal and perinatal exposures to cannabis use disorder (CUD) and the risk of autism spectrum...
This study aimed to investigate the association between pre-pregnancy, prenatal and perinatal exposures to cannabis use disorder (CUD) and the risk of autism spectrum disoder (ASD) in offspring. Data were drawn from the New South Wales (NSW) Perinatal Data Collection (PDC), population-based, linked administrative health data encompassing all-live birth cohort from January 2003 to December 2005. This study involved 222 534 mother-offspring pairs. . The exposure variable (CUD) and the outcome of interest (ASD) were identified using the 10th international disease classification criteria, Australian Modified (ICD-10-AM). We found a three-fold increased risk of ASD in the offspring of mothers with maternal CUD compared to non-exposed offspring. In our sensitivity analyses, male offspring have a higher risk of ASD associated with maternal CUD than their female counterparts. In conclusion, exposure to maternal CUD is linked to a higher risk of ASD in offspring, with a stronger risk in male offspring. Further research is needed to understand these gender-specific effects and the relationship between maternal CUD and ASD risk in children.
Topics: Humans; Female; Autism Spectrum Disorder; Male; Pregnancy; Prenatal Exposure Delayed Effects; Adult; Cohort Studies; Marijuana Abuse; New South Wales; Child; Young Adult; Information Storage and Retrieval; Child, Preschool; Sex Factors
PubMed: 38788554
DOI: 10.1016/j.psychres.2024.115971 -
Neural Networks : the Official Journal... Sep 2024In this work we approach attractor neural networks from a machine learning perspective: we look for optimal network parameters by applying a gradient descent over a...
In this work we approach attractor neural networks from a machine learning perspective: we look for optimal network parameters by applying a gradient descent over a regularized loss function. Within this framework, the optimal neuron-interaction matrices turn out to be a class of matrices which correspond to Hebbian kernels revised by a reiterated unlearning protocol. Remarkably, the extent of such unlearning is proved to be related to the regularization hyperparameter of the loss function and to the training time. Thus, we can design strategies to avoid overfitting that are formulated in terms of regularization and early-stopping tuning. The generalization capabilities of these attractor networks are also investigated: analytical results are obtained for random synthetic datasets, next, the emerging picture is corroborated by numerical experiments that highlight the existence of several regimes (i.e., overfitting, failure and success) as the dataset parameters are varied.
Topics: Neural Networks, Computer; Machine Learning; Algorithms; Neurons; Humans
PubMed: 38788291
DOI: 10.1016/j.neunet.2024.106389 -
European Journal of Investigation in... Apr 2024Long COVID refers to the persistence or development of signs and symptoms well after the acute phase of COVID-19.
BACKGROUND
Long COVID refers to the persistence or development of signs and symptoms well after the acute phase of COVID-19.
OBJECTIVE OF THE STUDY
To investigate the long-term outcomes of the SARS-CoV-2 infection in terms of psychological, social, and relational consequences within the Italian population.
MATERIALS AND METHODS
We conducted an observational, cross-sectional, and multicenter study using an online questionnaire distributed to a sample of the Italian population. By utilizing the Short Form 12 Health Survey (SF-12) and the Hikikomori scale, we assessed perceived quality of life and social isolation, respectively. The questionnaire also included an open-answer question: "What will you remember about the pandemic period?". We used generative artificial intelligence to analyze and summarize the corresponding answers.
RESULTS
A total of 1097 people participated in this study. A total of 79.3% (n = 870) of participants declared that they had been hospitalized and 62.8% (n = 689) received home care. Physical symptoms included headaches (43%, n = 472) and asthma (30.4%, n = 334). Additionally, 29.2% (n = 320) developed an addiction during the pandemic and, among these, 224 claimed internet addiction while 73 declared an emotional addiction. Furthermore, 51.8% (n = 568) experienced limitations in carrying out daily life activities. According to the Hikikomori scale, participants with positive SARS-CoV-2 infection exhibited higher levels of isolation compared to the others ( < 0.001). Participants without COVID-19 showed higher levels of emotional support ( < 0.001). Our semiautomatic analysis of the open-ended responses, obtained by a procedure based on a free large language model, allowed us to deduce and summarize the main feelings expressed by the interviewees regarding the pandemic.
CONCLUSIONS
The data collected emphasize the urgent need to investigate the consequences of long COVID in order to implement interventions to support psychological well-being.
PubMed: 38785574
DOI: 10.3390/ejihpe14050076 -
Journal of Diabetes Jun 2024Type 2 diabetes mellitus (T2DM) is a complicated disease related to metabolism that results from resistance to insulin and sustained hyperglycemia. Traditional... (Review)
Review
Type 2 diabetes mellitus (T2DM) is a complicated disease related to metabolism that results from resistance to insulin and sustained hyperglycemia. Traditional antidiabetic drugs cannot meet the demand of different diabetes patients for reaching the glycemic targets; thus, the identification of new antidiabetic drugs is urgently needed for the treatment of T2DM to enhance glycemic control and the prognosis of patients suffering from T2DM. Recently, glucokinase (GK) has attracted much attention and is considered to be an effective antidiabetic agent. Glucokinase activators (GKA) represented by dorzagliatin could activate GK and mimic its function that triggers a counter-regulatory response to blood glucose changes. Dorzagliatin has shown great potential for glycemic control in diabetic patients in a randomized, double-blind, placebo-controlled Phase 3 trial (SEED study) and had a favorable safety profile and was well tolerated (DAWN study). In the SEED study, dorzagliatin significantly reduced glycosylated hemoglobin (HbA1c) by 1.07% and postprandial blood glucose by 2.83 mol/L, showing the great potential of this drug to control blood glucose in diabetic patients, with good safety and good tolerance. An extension of the SEED study, the DREAM study, confirmed that dorzagliatin monotherapy significantly improved 24-h glucose variability and increased time in range (TIR) to 83.7% over 46 weeks. Finally, the clinical study of dorzagliatin combined with metformin (DAWN study) confirmed that dorzagliatin could significantly reduce HbA1c by 1.02% and postprandial blood glucose by 5.45 mol/L. The current review summarizes the development of GK and GKA, as well as the prospects, trends, applications, and shortcomings of these treatments, especially future directions of clinical studies of dorzagliatin.
Topics: Humans; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Glucokinase; Blood Glucose; Drug Development; Enzyme Activators; Glycated Hemoglobin
PubMed: 38783768
DOI: 10.1111/1753-0407.13563 -
Heliyon May 2024Global sustainability challenges such as climate change are linked to carbon emissions from fossil fuel powered energy needed for commercial and household consumption.... (Review)
Review
Global sustainability challenges such as climate change are linked to carbon emissions from fossil fuel powered energy needed for commercial and household consumption. South Africa is highly depended on coal for energy production hence the transition to renewable energy sources such as solar PV is seen as a pathway towards emissions reduction and a sustainable future. Yet, despite the huge potential for solar PV technologies adoption remains very low. This scoping review examines the barriers to household solar PV adoption in South Africa to advance our understanding beyond case study level studies. We analysed all published literature on household solar PV in South Africa as a basis for finding themes, gaps, and trends on solar PV research. Review results show that key barriers can be grouped into financial, personal, institutional, technical and societal barriers, however there were no studies on barriers across an income gradient, a glaring omission given debates on just transitions. Given the complexity of the barriers ranging from personal, societal, to technical barriers, it is not reasonable to expect the government to facilitate transition to solar PV alone. Rather, collective approaches are needed to create enabling conditions for solar PV adoption such as the financial means and information availability. The private sector has a key role to play either in supporting state-initiated programmes or creating the means for solar PV adoption such as power purchase agreements. That said, the state remains a central player in facilitating an enabling economic and political environment to leverage responsiveness from other actors. Without an integrated approach to addressing barriers to solar PV adoption, solar adoption will remain a source of energy for the economically privileged, and the imperative to just transition to renewable energy a pipe dream, in a country characterised by large inequalities among households.
PubMed: 38778934
DOI: 10.1016/j.heliyon.2024.e30937 -
Alzheimer's Research & Therapy May 2024Maximizing the efficiency to screen amyloid-positive individuals in asymptomatic and non-demented aged population using blood-based biomarkers is essential for future...
BACKGROUND
Maximizing the efficiency to screen amyloid-positive individuals in asymptomatic and non-demented aged population using blood-based biomarkers is essential for future success of clinical trials in the early stage of Alzheimer's disease (AD). In this study, we elucidate the utility of combination of plasma amyloid-β (Aβ)-related biomarkers and tau phosphorylated at threonine 217 (p-tau217) to predict abnormal Aβ-positron emission tomography (PET) in the preclinical and prodromal AD.
METHODS
We designed the cross-sectional study including two ethnically distinct cohorts, the Japanese trial-ready cohort for preclinica and prodromal AD (J-TRC) and the Swedish BioFINDER study. J-TRC included 474 non-demented individuals (CDR 0: 331, CDR 0.5: 143). Participants underwent plasma Aβ and p-tau217 assessments, and Aβ-PET imaging. Findings in J-TRC were replicated in the BioFINDER cohort including 177 participants (cognitively unimpaired: 114, mild cognitive impairment: 63). In both cohorts, plasma Aβ(1-42) (Aβ42) and Aβ(1-40) (Aβ40) were measured using immunoprecipitation-MALDI TOF mass spectrometry (Shimadzu), and p-tau217 was measured with an immunoassay on the Meso Scale Discovery platform (Eli Lilly).
RESULTS
Aβ-PET was abnormal in 81 participants from J-TRC and 71 participants from BioFINDER. Plasma Aβ42/Aβ40 ratio and p-tau217 individually showed moderate to high accuracies when detecting abnormal Aβ-PET scans, which were improved by combining plasma biomarkers and by including age, sex and APOE genotype in the models. In J-TRC, the highest AUCs were observed for the models combining p-tau217/Aβ42 ratio, APOE, age, sex in the whole cohort (AUC = 0.936), combining p-tau217, Aβ42/Aβ40 ratio, APOE, age, sex in the CDR 0 group (AUC = 0.948), and combining p-tau217/Aβ42 ratio, APOE, age, sex in the CDR 0.5 group (AUC = 0.955), respectively. Each subgroup results were replicated in BioFINDER, where the highest AUCs were seen for models combining p-tau217, Aβ42/40 ratio, APOE, age, sex in cognitively unimpaired (AUC = 0.938), and p-tau217/Aβ42 ratio, APOE, age, sex in mild cognitive impairment (AUC = 0.914).
CONCLUSIONS
Combination of plasma Aβ-related biomarkers and p-tau217 exhibits high performance when predicting Aβ-PET positivity. Adding basic clinical information (i.e., age, sex, APOE ε genotype) improved the prediction in preclinical AD, but not in prodromal AD. Combination of Aβ-related biomarkers and p-tau217 could be highly useful for pre-screening of participants in clinical trials of preclinical and prodromal AD.
Topics: Humans; Amyloid beta-Peptides; Female; Male; tau Proteins; Aged; Positron-Emission Tomography; Biomarkers; Cross-Sectional Studies; Brain; Aged, 80 and over; Cohort Studies; Phosphorylation; Middle Aged; Alzheimer Disease; Peptide Fragments; Cognitive Dysfunction
PubMed: 38778353
DOI: 10.1186/s13195-024-01469-w -
European Heart Journal. Case Reports May 2024Excluding spontaneous coronary artery dissection (SCAD) as an aetiology of acute coronary syndrome in young adults is imperative.
BACKGROUND
Excluding spontaneous coronary artery dissection (SCAD) as an aetiology of acute coronary syndrome in young adults is imperative.
CASE SUMMARY
A previously healthy 39-year-old woman experienced sudden severe chest pain, ST-segment elevation on electrocardiogram, necessitating high-dose aspirin and urgent transfer to a revascularization centre. Suffering ventricular tachycardia (VT) and ventricular fibrillation (VF), she underwent two rounds of advanced life support and venoarterial extracorporeal membrane oxygenation. Diagnosed with left main coronary artery (LMCA) SCAD, she was initially started on conservative therapy for declining left ventricular ejection fraction. However, she continued to experience an escalating anginal symptoms, worsening biomarkers, and LMCA SCAD progression, which urged the need for surgical intervention with coronary artery bypass graft surgery (CABG). Following her CABG, she experienced a worsening of her functional mitral regurgitating, which she underwent transcatheter edge-to-edge repair of her severe mitral regurgitation. Despite being listed for orthotopic heart transplantation (OHTx), her low body mass index and elevated antibodies necessitated the HeartMate III left ventricular assist device (LVAD) for bridge to transplant. After treating frequent VT episodes with medications, she eventually received a LVAD as a bridge to cardiac transplantation. Within 1 year of her receiving LVAD, she underwent a successful OHTx.
DISCUSSION
The pathogenesis of SCAD involves intramural haematoma formation through intimal tears or vasa vasorum haemorrhage. Adverse outcomes that could occur in SCAD patients include cardiac arrest, cardiogenic shock, reduced left ventricle systolic function, and occasionally serious cardiac arrhythmia-such as VF-which can lead to sudden cardiac death. Although most SCAD cases heal spontaneously, revascularization can be considered in case of worsening SCAD progression. Advanced therapeutic intervention including mechanical circulatory support and OHTx should be considered in refractory cases.
PubMed: 38774773
DOI: 10.1093/ehjcr/ytae234 -
European Heart Journal. Digital Health May 2024The accuracy of voice-assisted technologies, such as Amazon Alexa, to collect data in patients who are older or have heart failure (HF) is unknown. The aim of this study...
AIMS
The accuracy of voice-assisted technologies, such as Amazon Alexa, to collect data in patients who are older or have heart failure (HF) is unknown. The aim of this study is to analyse the impact of increasing age and comorbid HF, when compared with younger participants and caregivers, and how these different subgroups classify their experience using a voice-assistant device, for screening purposes.
METHODS AND RESULTS
Subgroup analysis (HF vs. caregivers and younger vs. older participants) of the VOICE-COVID-II trial, a randomized controlled study where participants were assigned with subsequent crossover to receive a SARS-CoV2 screening questionnaire by Amazon Alexa or a healthcare personnel. Overall concordance between the two methods was compared using unweighted kappa scores and percentage of agreement. From the 52 participants included, the median age was 51 (34-65) years and 21 (40%) were HF patients. The HF subgroup showed a significantly lower percentage of agreement compared with caregivers (95% vs. 99%, = 0.03), and both the HF and older subgroups tended to have lower unweighted kappa scores than their counterparts. In a post-screening survey, both the HF and older subgroups were less acquainted and found the voice-assistant device more difficult to use compared with caregivers and younger individuals.
CONCLUSION
This subgroup analysis highlights important differences in the performance of a voice-assistant-based technology in an older and comorbid HF population. Younger individuals and caregivers, serving as facilitators, have the potential to bridge the gap and enhance the integration of these technologies into clinical practice.
STUDY REGISTRATION
ClinicalTrials.gov Identifier: NCT04508972.
PubMed: 38774370
DOI: 10.1093/ehjdh/ztae012 -
Indian Journal of Ophthalmology May 2024The quest of every dedicated phaco surgeon is to develop skills to emulsify all forms of hard nuclei efficiently with minimal damage to the endothelium and reducing the...
The quest of every dedicated phaco surgeon is to develop skills to emulsify all forms of hard nuclei efficiently with minimal damage to the endothelium and reducing the risk of wound burn. Obtaining a pristine cornea the very next day in a hard cataract is a dream far from reality. Prechop means nuclear division without the use of phaco energy. In this article, we describe a prechopping technique using a new sickle-shaped (saber tooth curvature and tip) novel prechopper that has a slender, sleek, and elegant design well suited for nuclear disassembly. The novel prechopper has proved to be a wonder device for hard, soft, white, posterior polar, and exfoliation cataracts. All maneuvers of prechop are performed in the bag away from the endothelium to be easily emulsified, subsequently making phacoemulsification easier, faster, and safer.
PubMed: 38773834
DOI: 10.4103/IJO.IJO_2792_23