Metabolic associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, including steatosis, nonalcoholic steatohepatitis (NASH) and fibrosis. We demonstrated that ...phosphoenolpyruvate carboxykinase 1 (PCK1) plays a central role in MAFLD progression. Male mice with liver Pck1 deficiency fed a normal diet displayed hepatic lipid disorder and liver injury, whereas fibrosis and inflammation were aggravated in mice fed a high-fat diet with drinking water containing fructose and glucose (HFCD-HF/G). Forced expression of hepatic PCK1 by adeno-associated virus ameliorated MAFLD in male mice. PCK1 deficiency stimulated lipogenic gene expression and lipid synthesis. Moreover, loss of hepatic PCK1 activated the RhoA/PI3K/AKT pathway by increasing intracellular GTP levels, increasing secretion of platelet-derived growth factor-AA (PDGF-AA), and promoting hepatic stellate cell activation. Treatment with RhoA and AKT inhibitors or gene silencing of RhoA or AKT1 alleviated MAFLD progression in vivo. Hepatic PCK1 deficiency may be important in hepatic steatosis and fibrosis development through paracrine secretion of PDGF-AA in male mice, highlighting a potential therapeutic strategy for MAFLD.
BACKGROUND
Cervical cytology screening is usually laborious with a heavy workload and poor diagnostic consistency. The authors have developed an artificial intelligence (AI) microscope that can ...provide onsite diagnostic assistance for cervical cytology screening in real time.
METHODS
A total of 2167 cervical cytology slides were selected from a cohort of 10,601 cases from Shenzhen Maternity and Child Healthcare Hospital, and the training data set consisted of 42,073 abnormal cervical epithelial cells. The recognition results of an AI technique were presented in a microscope eyepiece by an augmented reality technique. Potentially abnormal cells were highlighted with binary classification results in a 10× field of view (FOV) and with multiclassification results according to the Bethesda system in 20× and 40× FOVs. In addition, 486 slides were selected for the reader study to evaluate the performance of the AI microscope.
RESULTS
In the reader study, which compared manual reading with AI assistance, the sensitivities for the detection of low‐grade squamous intraepithelial lesions and high‐grade squamous intraepithelial lesions were significantly improved from 0.837 to 0.923 (P < .001) and from 0.830 to 0.917 (P < .01), respectively; the κ score for atypical squamous cells of undetermined significance (ASCUS) was improved from 0.581 to 0.637; the averaged pairwise κ of consistency for multiclassification was improved from 0.649 to 0.706; the averaged pairwise κ of consistency for binary classification was improved from 0.720 to 0.798; and the averaged pairwise κ of ASCUS was improved from 0.557 to 0.639.
CONCLUSIONS
The results of this study show that an AI microscope can provide real‐time assistance for cervical cytology screening and improve the efficiency and accuracy of cervical cytology diagnosis.
In this study, an artificial intelligence microscope has been developed that can provide real‐time assistance for cervical cytology screening. This artificial intelligence microscope can improve the efficiency and accuracy of cervical cytology diagnosis.
Continuous theta burst stimulation and intermittent theta burst stimulation are clinically popular models of repetitive transcranial magnetic stimulation. However, they are limited by high ...variability between individuals in cortical excitability changes following stimulation. Although electroencephalography oscillations have been reported to modulate the cortical response to transcranial magnetic stimulation, their association remains unclear. This study aims to explore whether machine learning models based on EEG oscillation features can predict the cortical response to transcranial magnetic stimulation.
Twenty-three young, healthy adults attended two randomly assigned sessions for continuous and intermittent theta burst stimulation. In each session, ten minutes of resting-state electroencephalography were recorded before delivering brain stimulation. Participants were classified as responders or non-responders based on changes in resting motor thresholds. Support vector machines and multi-layer perceptrons were used to establish predictive models of individual responses to transcranial magnetic stimulation.
Among the evaluated algorithms, support vector machines achieved the best performance in discriminating responders from non-responders for intermittent theta burst stimulation (accuracy: 91.30%) and continuous theta burst stimulation (accuracy: 95.66%). The global clustering coefficient and global characteristic path length in the beta band had the greatest impact on model output.
These findings suggest that EEG features can serve as markers of cortical response to transcranial magnetic stimulation. They offer insights into the association between neural oscillations and variability in individuals' responses to transcranial magnetic stimulation, aiding in the optimization of individualized protocols.
●Machine learning based on EEG was used to identify individual response to TMS.●Combination of different EEG features contributed to the high predictive accuracy.●These findings help understand TMS variability and optimize TMS protocols.
During the COVID-19 pandemic, wastewater surveillance of the SARS CoV-2 virus has been demonstrated to be effective for population surveillance at the county level down to the building level. At the ...University of California, San Diego, daily high-resolution wastewater surveillance conducted at the building level is being used to identify potential undiagnosed infections and trigger notification of residents and responsive testing, but the optimal determinants for notifications are unknown. To fill this gap, we propose a pipeline for data processing and identifying features of a series of wastewater test results that can predict the presence of COVID-19 in residences associated with the test sites. Using time series of wastewater results and individual testing results during periods of routine asymptomatic testing among UCSD students from 11/2020 to 11/2021, we develop hierarchical classification/decision tree models to select the most informative wastewater features (patterns of results) which predict individual infections. We find that the best predictor of positive individual level tests in residence buildings is whether or not the wastewater samples were positive in at least 3 of the past 7 days. We also demonstrate that the tree models outperform a wide range of other statistical and machine models in predicting the individual COVID-19 infections while preserving interpretability. Results of this study have been used to refine campus-wide guidelines and email notification systems to alert residents of potential infections.
The ability of motor-inhibitory control is critical in daily life. The physiological mechanisms underlying motor inhibitory control deficits remain to be elucidated. Beta band oscillations have been ...suggested to be related to motor performance, but whether they relate to motor-inhibitory control remains unclear. This study is aimed at systematically investigating the relationship between beta band oscillations and motor-inhibitory control to determine whether beta band oscillations were related to the ability of motor-inhibitory control.
We studied 30 healthy young adults (age: 21.6 ± 1.5 years). Stop-signal reaction time (SSRT) was derived from stop signal task, indicating the ability of motor-inhibitory control. Resting-state electroencephalography (EEG) was recorded for 12 min. Beta band power and functional connectivity (including global efficiency) were calculated. Correlations between beta band oscillations and SSRT were performed.
Beta band EEG power in left and right motor cortex (MC), right somatosensory cortex (SC), and right inferior frontal cortex (IFC) was positively correlated with SSRT (
's = 0.031, 0.021, 0.045, and 0.015, respectively). Beta band coherence between bilateral MC, SC, and IFC was also positively correlated with SSRT (
's < 0.05). Beta band global efficiency was positively correlated with SSRT (
= 0.01).
This is the first study to investigate the relationship between resting-state cortical beta oscillations and response inhibition. Our findings revealed that individuals with better ability of motor inhibitory control tend to have less cortical beta band power and functional connectivity. This study has clinical significance on the underlying mechanisms of motor inhibitory control deficits.
Highly active antiretroviral therapy (ART) can effectively inhibit virus replication and restore immune function in most people living with human immunodeficiency virus (HIV). However, an important ...proportion of patients fail to achieve a satisfactory increase in CD4
T cell counts. This state is called incomplete immune reconstitution or immunological nonresponse (INR). Patients with INR have an increased risk of clinical progression and higher rates of mortality. Despite widespread attention to INR, the precise mechanisms remain unclear. In this review, we will discuss the alterations in the quantity and quality of CD4
T as well as multiple immunocytes, changes in soluble molecules and cytokines, and their relationship with INR, aimed to provide cellular and molecular insights into incomplete immune reconstitution.
Efforts to control the HIV epidemic can benefit from knowledge of the relationships between the characteristics of people who have transmitted HIV and those who became infected by them. Investigation ...of this relationship is facilitated by the use of HIV genetic linkage analyses, which allows inference about possible transmission events among people with HIV infection. Two persons with HIV (PWH) are considered linked if the genetic distance between their HIV sequences is less than a given threshold, which implies proximity in a transmission network. The tendency of pairs of nodes (in our case PWH) that share (or differ in) certain attributes to be linked is denoted homophily. Below, we describe a novel approach to modeling homophily with application to analyses of HIV viral genetic sequences from clinical series of participants followed in San Diego. Over the 22-year period of follow-up, increases in cluster size results from HIV transmissions to new people from those already in the cluster-either directly or through intermediaries.
Our analytical approach makes use of a logistic model to describe homophily with regard to demographic, clinical, and behavioral characteristics-that is we investigate whether similarities (or differences) between PWH in these characteristics are associated with their sequences being linked. To investigate the performance of our methods, we conducted on a simulation study for which data sets were generated in a way that reproduced the structure of the observed database.
Our results demonstrated strong positive homophily associated with hispanic ethnicity, and strong negative homophily, with birth year difference. The second result implies that the larger the difference between the age of a newly-infected PWH and the average age for an available cluster, the lower the odds of a newly infected person joining that cluster. We did not observe homophily associated with prior diagnosis of sexually transmitted diseases. Our simulation studies demonstrated the validity of our approach for modeling homophily, by showing that the estimates it produced matched the specified values of the statistical network generating model.
Our novel methods provide a simple and flexible statistical network-based approach for modeling the growth of viral (or other microbial) genetic clusters from linkage to new infections based on genetic distance.
NAFLD (Nonalcoholic fatty liver disease) is becoming an increasingly common cause of chronic liver disease. Metabolic dysfunction, overweight/obesity, and diabetes are thought to be closely ...associated with increased NAFLD risk. However, few studies have focused on the mechanisms of NAFLD occurrence in T1DM.
We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal association between T1DM and NAFLD with/without complications, such as coma, renal complications, ketoacidosis, neurological complications, and ophthalmic complications. Multiple Mendelian randomization methods, such as the inverse variance weighted (IVW) method, weighted median method, and MR-Egger test were performed to evaluate the causal association of T1DM and NAFLD using genome-wide association study summary data from different consortia, such as Finngen and UK biobank.
We selected 37 SNPs strongly associated with NAFLD/LFC (at a significance level of
< 5 × 10-8) as instrumental variables from the Finnish database based on the T1DM phenotype (8,967 cases and 308,373 controls). We also selected 14/16 SNPs based on with or without complications. The results suggest that the genetic susceptibility of T1DM does not increase the risk of NAFLD (OR=1.005 0.99, 1.02, IVW p=0.516, MR Egger
=0.344, Weighted median
=0.959, Weighted mode
=0.791), regardless of whether complications are present. A slight causal effect of T1DM without complications on LFC was observed (OR=1.025 1.00, 1.03, MR Egger
=0.045). However, none of the causal relationships were significant in the IVW (
=0.317), Weighted median (
=0.076), and Weighted mode (
=0.163) methods.
Our study did not find conclusive evidence for a causal association between T1DM and NAFLD, although clinical observations indicate increasing abnormal transaminase prevalence and NAFLD progression in T1DM patients.
Background
Repetitive transcranial magnetic stimulation (rTMS) is a promising intervention for stroke rehabilitation. Several studies have demonstrated the effectiveness of rTMS in restoring motor ...function. This meta-analysis aimed to summarize the current evidence of the effect of rTMS in improving upper limb function and fine motor recovery in stroke patients.
Methods
Three online databases (Web of Science, PubMed, and Embase) were searched for relevant randomized controlled trials. A total of 45 studies (combined
n
= 2064) were included. Random effects model was used for meta-analysis and effect size was reported as standardized mean difference (SMD).
Results
rTMS was effective in improving fine motor function in stroke patients (SMD, 0.38; 95% CI 0.19–0.58;
P
= 0). On subgroup analyses, for post-stroke functional improvement of the upper extremity, bilateral hemisphere stimulation was more effective than unilateral stimulation during the acute phase of stroke, and a regimen of 20 rTMS sessions produced greater improvement than <20 sessions. In the subacute phase of stroke, affected hemispheric stimulation with a 40-session rTMS regimen was superior to unaffected hemispheric stimulation or bilateral hemispheric stimulation with <40 sessions. Unaffected site stimulation with a 10-session rTMS regimen produced significant improvement in the chronic phase compared to affected side stimulation and bilateral stimulation with >10 rTMS sessions. For the rTMS stimulation method, both TBS and rTMS were found to be significantly more effective in the acute phase of stroke, but TBS was more effective than rTMS. However, rTMS was found to be more effective than TBS stimulation in patients in the subacute and chronic phases of stroke. rTMS significantly improved upper limb and fine function in the short term (0–1-month post-intervention) and medium term (2–5 months), but not for upper limb function in the long term (6 months+). The results should be interpreted with caution due to significant heterogeneity.
Conclusions
This updated meta-analysis provides robust evidence of the efficacy of rTMS treatment in improving upper extremity and fine function during various phases of stroke.
Systematic Review Registration
https://inplasy.com/inplasy-2022-5-0121/
, identifier: INPLASY202250121.
Gluconeogenesis, generates glucose from small carbohydrate substrates, and drives the metabolic flux in parallel but opposite to glycolysis. The cytoplasmic isoform of phosphoenolpyruvate ...carboxykinase (PCK1 or PEPCK-C), a rate-limiting enzyme in gluconeogenesis, initiates the gluconeogenesis process and is reportedly dysregulated in multiple types of cancer. Gluconeogenesis mainly occurs in the liver during fasting, and previous studies have demonstrated that PCK1 acts as a tumor suppressor in hepatocellular carcinoma (HCC); however, the role of PCK1 in cancer progression remains incompletely understood. In the current study, we found that PCK1 expression was decreased in HCC as compared to adjacent normal liver tissues, and low PCK1 expression correlated with poor patient prognosis. Furthermore, overexpression of PCK1 suppressed reactive oxygen species (ROS) production and nuclear translocation of Nrf2 in hepatoma cells. In addition, thioredoxin reductase 1 (TXNRD1), an antioxidant enzyme regulated by the Nrf2/Keap1 pathway, was downregulated upon overexpression of PCK1 in HCC cell lines. Furthermore, we verified this axis using nude mouse xenograft model. Finally, we found that auranofin, a TXNRD1 inhibitor, enhanced the sensitivity of PCK1-knockout hepatoma cells to sorafenib-induced apoptosis. Taken together, our findings suggest that PCK1 deficiency promotes hepatoma cell proliferation via the induction of oxidative stress and the activation of transcription factor Nrf2, and that targeting the TXNRD1 antioxidant pathway sensitizes PCK1-knockout hepatoma cells to sorafenib treatment
.
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