Multiomics identifies metabolic subtypes based on fatty acid degradation allocating personalized treatment in hepatocellular carcinoma.

BACKGROUND AND AIMS: Molecular classification is a promising tool for prognosis prediction and optimizing precision therapy for HCC. Here, we aimed to develop a molecular classification of HCC based on the fatty acid degradation (FAD) pathway, fully characterize it, and evaluate its ability in guiding personalized therapy. APPROACH AND RESULTS: We performed RNA sequencing (RNA-seq), PCR-array, lipidomics, metabolomics, and proteomics analysis of 41 patients with HCC, in which 17 patients received anti-programmed cell death-1 (PD-1) therapy. Single-cell RNA sequencing (scRNA-seq) was performed to explore the tumor microenvironment. Nearly, 60 publicly available multiomics data sets were analyzed. The associations between FAD subtypes and response to sorafenib, transarterial chemoembolization (TACE), immune checkpoint inhibitor (ICI) were assessed in patient cohorts, patient-derived xenograft (PDX), and spontaneous mouse model ls. A novel molecular classification named F subtype (F1, F2, and F3) was identified based on the FAD pathway, distinguished by clinical, mutational, epigenetic, metabolic, and immunological characteristics. F1 subtypes exhibited high infiltration with immunosuppressive microenvironment. Subtype-specific therapeutic strategies were identified, in which F1 subtypes with the lowest FAD activities represent responders to compounds YM-155 and Alisertib, sorafenib, anti-PD1, anti-PD-L1, and atezolizumab plus bevacizumab (T + A) treatment, while F3 subtypes with the highest FAD activities are responders to TACE. F2 subtypes, the intermediate status between F1 and F3, are potential responders to T + A combinations. We provide preliminary evidence that the FAD subtypes can be diagnosed based on liquid biopsies. CONCLUSIONS: We identified 3 FAD subtypes with unique clinical and biological characteristics, which could optimize individual cancer patient therapy and help clinical decision-making.

Regioselective On-Surface Synthesis of [3]Triangulene Graphene Nanoribbons.

The integration of low-energy states into bottom-up engineered graphene nanoribbons (GNRs) is a robust strategy for realizing materials with tailored electronic band structure for nanoelectronics. Low-energy zero-modes (ZMs) can be introduced into nanographenes (NGs) by creating an imbalance between the two sublattices of graphene. This phenomenon is exemplified by the family of [n]triangulenes (n ∈ N). Here, we demonstrate the synthesis of [3]triangulene-GNRs, a regioregular one-dimensional (1D) chain of [3]triangulenes linked by five-membered rings. Hybridization between ZMs on adjacent [3]triangulenes leads to the emergence of a narrow band gap, Eg,exp ∼ 0.7 eV, and topological end states that are experimentally verified using scanning tunneling spectroscopy. Tight-binding and first-principles density functional theory calculations within the local density approximation corroborate our experimental observations. Our synthetic design takes advantage of a selective on-surface head-to-tail coupling of monomer building blocks enabling the regioselective synthesis of [3]triangulene-GNRs. Detailed ab initio theory provides insights into the mechanism of on-surface radical polymerization, revealing the pivotal role of Au-C bond formation/breakage in driving selectivity.

Olfactory-trigeminal integration in the primary olfactory cortex.

Humans naturally integrate signals from the olfactory and intranasal trigeminal systems. A tight interplay has been demonstrated between these two systems, and yet the neural circuitry mediating olfactory-trigeminal (OT) integration remains poorly understood. Using functional magnetic resonance imaging (fMRI), combined with psychophysics, this study investigated the neural mechanisms underlying OT integration. Fifteen participants with normal olfactory function performed a localization task with air-puff stimuli, phenylethyl alcohol (PEA; rose odor), or a combination thereof while being scanned. The ability to localize PEA to either nostril was at chance. Yet, its presence significantly improved the localization accuracy of weak, but not strong, air-puffs, when both stimuli were delivered concurrently to the same nostril, but not when different nostrils received the two stimuli. This enhancement in localization accuracy, exemplifying the principles of spatial coincidence and inverse effectiveness in multisensory integration, was associated with multisensory integrative activity in the primary olfactory (POC), orbitofrontal (OFC), superior temporal (STC), inferior parietal (IPC) and cingulate cortices, and in the cerebellum. Multisensory enhancement in most of these regions correlated with behavioral multisensory enhancement, as did increases in connectivity between some of these regions. We interpret these findings as indicating that the POC is part of a distributed brain network mediating integration between the olfactory and trigeminal systems. PRACTITIONER POINTS: Psychophysical and neuroimaging study of olfactory-trigeminal (OT) integration. Behavior, cortical activity, and network connectivity show OT integration. OT integration obeys principles of inverse effectiveness and spatial coincidence. Behavioral and neural measures of OT integration are correlated.

Altered functional connectivity of primary olfactory cortex-hippocampus-frontal cortex in subjective cognitive decline during odor stimulation.

Subjective cognitive decline (SCD) is a high-risk population in the preclinical stage of Alzheimer's disease (AD), and olfactory dysfunction is a risk factor for dementia progression. The present study aimed to explore the patterns of functional connectivity (FC) changes in the olfactory neural circuits during olfactory stimulation in SCD subjects. A total of 56 SCD subjects and 56 normal controls (NCs) were included. All subjects were assessed with a cognitive scale, an olfactory behavior test, and olfactory task-based functional magnetic resonance imaging scanning. The FC differences in olfactory neural circuits between the two groups were analyzed by the generalized psychophysiological interaction. Additionally, we calculated and compared the activation of brain regions within the olfactory neural circuits during odor stimulation, the volumetric differences in brain regions showing FC differences between groups, and the correlations between neuroimaging indicators and olfactory behavioral and cognitive scale scores. During odor stimulation, the FC between the bilateral primary olfactory cortex (bPOC) and the right hippocampus in the SCD group was significantly reduced; while the FC between the right hippocampus and the right frontal cortex was significantly increased in the SCD group. The bPOC of all subjects showed significant activation, but no significant difference in activation between groups was found. No significant differences were observed in the volume of the brain regions within the olfactory neural circuits or in olfactory behavior between groups. The volume of the bPOC and right frontal cortex was significantly positively correlated with olfactory identification, and the volume of the right frontal cortex and right hippocampus was significantly correlated with cognitive functions. Furthermore, a significant correlation between the activation of bPOC and the olfactory threshold was found in the whole cohort. These results suggested that while the structure of the olfactory neural circuits and olfactory behavior in SCD subjects remained stable, there were significant changes observed in the FC of the olfactory neural circuits (specifically, the POC-hippocampus-frontal cortex neural circuits) during odor stimulation. These findings highlight the potential of FC alterations as sensitive imaging markers for identifying high-risk individuals in the early stage of AD.

Prediction of false-positive PI-RADS 5 lesions on prostate multiparametric MRI: development and internal validation of a clinical-radiological characteristics based nomogram.

BACKGROUND: To develop a risk model including clinical and radiological characteristics to predict false-positive The Prostate Imaging Reporting and Data System (PI-RADS) 5 lesions. METHODS: Data of 612 biopsy-naïve patients who had undergone multiparametric magnetic resonance imaging (mpMRI) before prostate biopsy were collected. Clinical variables and radiological variables on mpMRI were adopted. Lesions were divided into the training and validation cohort randomly. Stepwise multivariate logistic regression analysis with backward elimination was performed to screen out variables with significant difference. A diagnostic nomogram was developed in the training cohort and further validated in the validation cohort. Calibration curve and receiver operating characteristic (ROC) analysis were also performed. RESULTS: 296 PI-RADS 5 lesions in 294 patients were randomly divided into the training and validation cohort (208 : 88). 132 and 56 lesions were confirmed to be clinically significant prostate cancer in the training and validation cohort respectively. The diagnostic nomogram was developed based on prostate specific antigen density, the maximum diameter of lesion, zonality of lesion, apparent diffusion coefficient minimum value and apparent diffusion coefficient minimum value ratio. The C-index of the model was 0.821 in the training cohort and 0.871 in the validation cohort. The calibration curve showed good agreement between the estimation and observation in the two cohorts. When the optimal cutoff values of ROC were 0.288 in the validation cohort, the sensitivity, specificity, PPV, and NPV were 90.6%, 67.9%, 61.7%, and 92.7% in the validation cohort, potentially avoiding 9.7% unnecessary prostate biopsies. CONCLUSIONS: We developed and validated a diagnostic nomogram by including 5 factors. False positive PI-RADS 5 lesions could be distinguished from clinically significant ones, thus avoiding unnecessary prostate biopsy.

Altered spontaneous brain activity as a potential imaging biomarker for generalized and focal to bilateral tonic-clonic seizures: A resting-state fMRI study.

OBJECTIVE: We aimed to determine whether alterations in spontaneous regional brain activity in those with generalized tonic-clonic seizures (GTCS) and focal to bilateral tonic-clonic seizures (FBTCS) and explore whether the alterations could be used as biomarkers to classify disease subtypes through support vector machine analysis (SVM). METHODS: The fractional amplitude of low-frequency fluctuations (fALFF) and regional homogeneity (ReHo) from resting-state functional magnetic resonance imaging (rs-fMRI) data were extracted from 57 patients with GTCS, 35 patients with FBTCS, and 50 age-matched and sex-matched normal controls (NCs) using the DPARSF 5.0 toolbox. Between-group comparisons were adjusted for covariates (age, sex, and equipment). Correlation analyses between imaging biomarkers and the frequency or duration of seizure activity were calculated using partial correlations. The differential imaging indicators, age, and sex were considered as the discriminative features in the SVM to evaluate classification performance. RESULTS: The patients with GTCS showed lower fALFF values (voxel p < 0.001, cluster p < 0.05, Gaussian random field corrected, GRF corrected) in the right postcentral gyrus and precentral gyrus and lower ReHo values (GRF corrected) in the middle temporal gyrus than the NCs. The patients with FBTCS showed higher fALFF (GRF corrected) values in the right postcentral and precentral gyrus and higher ReHo (GRF corrected) values in the right postcentral gyrus. Both fALFF (GRF corrected) and ReHo (GRF corrected) values were lower in the right postcentral gyrus and precentral gyrus in the GTCS group than in the FBTCS group. In patients with FBTCS, fALFF values in the right postcentral and precentral gyrus were positively correlated with duration (r = 0.655, p = 0.008, Bonferroni corrected) in the low-duration group, and ReHo values in the right postcentral gyrus were positively correlated with frequency (r = 0.486, p = 0.022, uncorrected) in the low-frequency group. SVM results showed receiver operating characteristic curves of 0.89, 0.87, and 0.76 for the classification between GTCS and NC, between FBTCS and NC, and GTCS and FBTCS, respectively. SIGNIFICANCE: This study detected alterations in fALFF and ReHo in the postcentral gyrus and precentral gyrus in patients with GTCS and FBTCS, which might contribute to understanding the pathogenesis, disease classification, and clinical targeted therapy.

Deep Learning for Detection of Intracranial Aneurysms from Computed Tomography Angiography Images.

The accuracy of computed tomography angiography (CTA) image interpretation depends on the radiologist. This study aims to develop a new method for automatically detecting intracranial aneurysms from CTA images using deep learning, based on a convolutional neural network (CNN) implemented on the DeepMedic platform. Ninety CTA scans of patients with intracranial aneurysms are collected and divided into two datasets: training (80 subjects) and test (10 subjects) datasets. Subsequently, a deep learning architecture with a three-dimensional (3D) CNN model is implemented on the DeepMedic platform for the automatic segmentation and detection of intracranial aneurysms from the CTA images. The samples in the training dataset are used to train the CNN model, and those in the test dataset are used to assess the performance of the established system. Sensitivity, positive predictive value (PPV), and false positives are evaluated. The overall sensitivity and PPV of this system for detecting intracranial aneurysms from CTA images are 92.3% and 100%, respectively, and the segmentation sensitivity is 92.3%. The performance of the system in the detection of intracranial aneurysms is closely related to their size. The detection sensitivity for small intracranial aneurysms (≤ 3 mm) is 66.7%, whereas the sensitivity of detection for large (> 10 mm) and medium-sized (3-10 mm) intracranial aneurysms is 100%. The deep learning architecture with a 3D CNN model on the DeepMedic platform can reliably segment and detect intracranial aneurysms from CTA images with high sensitivity.

High uric acid induces liver fat accumulation via ROS/JNK/AP-1 signaling.

Uric acid is the end metabolite derived from the oxidation of purine compounds. Overwhelming evidence shows the vital interrelationship between hyperuricemia (HUA) and nonalcoholic fatty liver disease (NAFLD). However, the mechanisms for this association remain unclear. In this study, we established a urate oxidase-knockout (Uox-KO) mouse model by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 technology. To study the correlation between HUA and NAFLD, human HepG2 hepatoma cells were treated in culture medium with high level of uric acid. In vivo, the Uox-KO mice spontaneously developed hyperuricemia and aberrant lipid-metabolism, concomitant with abnormal hepatic fat accumulation. HUA activated c-Jun N-terminal kinase (JNK) in vivo and in vitro. Furthermore, inhibiting JNK activation by a JNK-specific inhibitor, SP600125, decreased fat accumulation and lipogenic gene expression induced by HUA. Overexpression of the lipogenic enzymes fatty acid synthase and acetyl-CoA carboxylase 1 was via activation of JNK, which was blocked by the JNK inhibitor SP600125. HUA activated AP-1 to upregulate lipogenic gene expression via JNK activation. In addition, HUA caused mitochondrial dysfunction and reactive oxygen species production. Pretreatment with the antioxidant N-acetyl-l-cysteine could ameliorate HUA-activated JNK and hepatic steatosis. These data suggest that ROS/JNK/AP-1 signaling plays an important role in HUA-mediated fat accumulation in liver.NEW & NOTEWORTHY Hyperuricemia and nonalcoholic fatty liver disease are global public health problems, which are strongly associated with metabolic syndrome. In this study, we demonstrate that uric acid induces hepatic fat accumulation via the ROS/JNK/AP-1 pathway. This study identifies a new mechanism of NAFLD pathogenesis and new potential therapeutic strategies for HUA-induced NAFLD.

Causal structural covariance network revealing atrophy progression in Alzheimer's disease continuum.

The structural covariance network (SCN) has provided a perspective on the large-scale brain organization impairment in the Alzheimer's Disease (AD) continuum. However, the successive structural impairment across brain regions, which may underlie the disrupted SCN in the AD continuum, is not well understood. In the current study, we enrolled 446 subjects with AD, mild cognitive impairment (MCI) or normal aging (NA) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The SCN as well as a casual SCN (CaSCN) based on Granger causality analysis were applied to the T1-weighted structural magnetic resonance images of the subjects. Compared with that of the NAs, the SCN was disrupted in the MCI and AD subjects, with the hippocampus and left middle temporal lobe being the most impaired nodes, which is in line with previous studies. In contrast, according to the 194 subjects with records on CSF amyloid and Tau, the CaSCN revealed that during AD progression, the CaSCN was enhanced. Specifically, the hippocampus, thalamus, and precuneus/posterior cingulate cortex (PCC) were identified as the core regions in which atrophy originated and could predict atrophy in other brain regions. Taken together, these findings provide a comprehensive view of brain atrophy in the AD continuum and the relationships among the brain atrophy in different regions, which may provide novel insight into the progression of AD.

Uric acid inhibits HMGB1-TLR4-NF-κB signaling to alleviate oxygen-glucose deprivation/reoxygenation injury of microglia.

Mounting evidence has implicated inflammation in ischemia-reperfusion injury following acute ischemic stroke (AIS). Microglia remain the primary initiator and participant of brain inflammation. Emerging evidence has indicated that uric acid has promise for the treatment of AIS, but its explicit mechanisms remain elusive. Here, we observed that uric acid reduced the severity of cerebral infarction and attenuated the activation of microglia in the cerebral cortex in a mouse middle cerebral-artery occlusion/reperfusion model. Thus, we speculated that uric acid may play a role by directly interfering with the inflammatory response of microglia. First, we investigated whether the HMGB1-TLR4-NF-κB signaling plays a role in oxygen glucose deprivation and reperfusion (OGD/R) injury of BV2 cells. Inhibition of the signaling significantly reduced the release of the proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 1ß (IL1ß), and IL6 caused by OGD/R in BV2 cells. Second, uric acid weakened the decreased cell viability and lactate dehydrogenase release induced by OGD/R in BV2 cells. Finally, uric acid reduced the release of the proinflammatory cytokines TNF-α, IL1ß, and IL6 caused by OGD/R in BV2 cells by dampening HMGB1-TLR4-NF-κB signaling, which was reversed by probenecid treatment, an inhibitor of the uric acid channel. Hence, uric acid halted the release of inflammatory factors and the decreased cell viability induced by ODG/R via inhibiting the microglia HMGB1-TLR4-NF-κB signaling, thereby alleviating the damage to microglia. This may be part of the molecular mechanisms by which uric acid protects mice against the brain damage of middle cerebral-artery occlusion/reperfusion.

Impaired olfactory neural circuit in patients with SLE at early stages.

OBJECTIVE: To investigate the changes of olfactory function and odor-induced brain activation in patients with systemic lupus erythematosus (SLE) at early stages compared with healthy controls. MATERIALS AND METHODS: Olfactory function and odor-induced brain activation in 12 SLE patients at early stages and 12 age, gender and education matched healthy controls were evaluated using olfactory behavior test and odor-induced task-functional magnetic resonance imaging (task-fMRI). RESULTS: No significant differences in olfactory behavior scores (including olfactory threshold, olfactory identification, and olfactory memory) were found in the patients with SLE at early stages compared with the healthy controls, while significantly decreased odor-induced activations in olfactory-related brain regions were observed in the patients. In the SLE group, the patients with better performance in the olfactory threshold test had significantly lower levels of anti-dsDNA antibody. CONCLUSION: The current study demonstrated that significant alterations in odor-induced brain activations occurred prior to measurable olfactory decline in SLE at early stages, which provided a new method for early diagnosis of olfactory dysfunction in SLE.

Palladium Catalysis for Aerobic Oxidation Systems Using Robust Metal-Organic Framework.

Described here is a new and viable approach to achieve Pd catalysis for aerobic oxidation systems (AOSs) by circumventing problems associated with both the oxidation and the catalysis through an all-in-one strategy, employing a robust metal-organic framework (MOF). The rational assembly of a PdII catalyst, phenanthroline ligand, and CuII species (electron-transfer mediator) into a MOF facilitates the fast regeneration of the PdII active species, through an enhanced electron transfer from in situ generated Pd0 to CuII , and then CuI to O2 , trapped in the framework, thus leading to a 10 times higher turnover number than that of the homogeneous counterpart for Pd-catalyzed desulfitative oxidative coupling reactions. Moreover, the MOF catalyst can be reused five times without losing activity. This work provides the first exploration of using a MOF as a promising platform for the development of Pd catalysis for AOSs with high efficiency, low catalyst loading, and reusability.

Detectability and reproducibility of the olfactory fMRI signal under the influence of magnetic susceptibility artifacts in the primary olfactory cortex.

For human olfactory functional MRI studies, the primary olfactory cortex (POC) suffers severe magnetic susceptibility artifacts, which adversely influences the detectability and reproducibility of the olfactory fMRI data and its clinical applications. The goal of this work is to assess the impacts of the image artifacts on the detectability and reproducibility of the olfactory activation in the POC. The severity of artifacts in the POC were classified into three levels using a Subjective Artifact score (SA_score). The mean temporal signal-to-noise ratio (tSNR) of the fMRI data acquired by a given MRI sequence and olfactory activation (ß value) in POC were evaluated and compared to the concurrent activations in the primary visual cortex (Brodmann area 17, BA17) by an odor-visual association paradigm using ninety-nine normal human subjects. Our study revealed that the mean tSNR in POC was above the threshold for reliable detection of the functional activation signal, and, consequently, the mean olfactory activations in the POC were not significantly different from those in BA17. The reproducibility of the activation in the POC was assessed by a random half-split stimulation of a test-retest experiment. The overlap of the activation maps for all the trials (n = 1000) in the POC were not statistically different from that observed in BA17. These results show that the detectability and reproducibility of olfactory activation in the presence of susceptibility artifacts in the POC was at similar level of that in the visual cortex.

The Role of MRI Biomarkers and Their Interactions with Cognitive Status and APOE ε4 in Nondemented Elderly Subjects.

PURPOSE: (1) To investigate atrophy patterns of hippocampal subfield volume and Alzheimer's disease (AD)-signature cortical thickness in mild cognitive impairment (MCI) patients; (2) to explore the association between the neuropsychological (NP) and the brain structure in the MCI and older normal cognition group; (3) to determine whether these associations were modified by the apolipoprotein E (APOE) ε4 gene and cognitive status. METHODS: The FreeSurfer software was used for automated segmentation of hippocampal subfields and AD-signature cortical thickness for 22 MCI patients and 23 cognitive normal controls (NC). The volume, cortical thickness, and the neuropsychological scale were compared with two-sample t tests. Linear regression models were used to determine the association between the NP and the brain structure. RESULTS: Compared with the NC group, MCI patients showed a decreased volume of the left presubiculum, subiculum and right CA2_3 and CA4_DG (p < 0.05, FDR corrected). The volume of these regions was positively correlated with NP scores. Of note, these associations depended on the cognitive status but not on the APOE ε4 status. The left subiculum and presubiculum volume were positively correlated with the Montreal Cognitive Assessment (MoCA) scores only in the MCI patients. CONCLUSION: Atrophy of the hippocampal subfields may be a powerful biomarker for MCI in the Chinese population.

A study on the roles of Helicobacter pylori in bile reflux gastritis and gastric cancer.

PURPOSE: To observe the infection rates of Helicobacter pylori (HP) in bile reflux gastritis (BRG) and gastric cancer and the clinical significance of HP eradication in BRG and gastric cancer patients complicated with HP. METHODS: 248 patients diagnosed with BRG and gastric cancer via gastroscopy were enrolled in this study. HP detection and infection rates of HP were evaluated. Then, BRG and gastric cancer patients complicated with HP were randomly divided into BRG group 1, BRG group 2, gastric cancer group 1 and gastric cancer group 2. BRG group 1 and gastric cancer group 1 were treated with conventional anti-inflammatory drugs for 10 days, and BRG group 2 and gastric cancer group 2 were treated with anti-HP drugs in addition to conventional anti-inflammatory drugs. One month after drug withdrawal, the infection rates of HP in each group were evaluated, and prognostic follow-up was performed to record the post-therapy patient conditions. RESULTS: HP infection rate was 35.8% (57/159) in the BRG group and 73.0% (65/89) in the gastric cancer group, with statistically significant difference (p<0.01). In patients treated with anti-HP drugs had the HP infection rate effectively reduced. The treatment effective rates of patients with BRG and gastric cancer complicated with HP infection after eradication of HP were 82.8 and 68.8%, respectively, while those of patients with non-eradicated HP were only 46.4 and 37.5 %, respectively. The differences between the two groups were statistically significant (p<0.05). CONCLUSION: HP is directly and closely related to the occurrence of gastric diseases, HP infection rate in patients with gastric cancer is significantly higher than that in patients with BRG, and the treatment of HP can effectively improve the rehabilitation rate in patients with gastric diseases.

Clinical manifestations of severe enterovirus 71 infection and early assessment in a Southern China population.

BACKGROUND: Enterovirus 71 (EV-A71) shows a potential of rapid death, but the natural history of the infection is poorly known. This study aimed to examine the natural history of EV-A71 infection. METHODS: This was a prospective longitudinal observational study performed between January 1st and October 31st, 2012, at three hospitals in Guangdong, China. Subjects with positive EV-A71 RNA laboratory test results were included. Disease progression was documented with MRI, autopsies, and follow-up. Symptoms/signs with potential association with risk of death were analyzed. RESULTS: Among the 288 patients, neurologic symptoms and signs were observed (emotional movement disorders, dyskinesia, involuntary movements, autonomic dysfunction, and disturbance of consciousness). Some of them occurred as initial symptoms. Myoclonic jerks/tremors were observed among >50% of the patients; nearly 40% of patients presented fatigue and 25% were with vomiting. Twenty-eight patients (9.7%) presented poor peripheral perfusion within 53.4 ± 26.1 h; 23 patients (8.0%) presented pulmonary edema and/or hemorrhage within 62.9 ± 28.6 h. Seventeen (5.9%) patients were in a coma. Seven (2.4%) patients died within 62.9 ± 28.6 h. Seventy-seven survivors underwent head and spinal cord MRI and 37.7% (29/77) showed abnormalities. Two fatal cases showed neuronal necrosis, softening, perivascular cuffing, colloid, and neuronophagia phenomenon in the brainstem. CONCLUSIONS: Patients with EV-A71 infection showed high complexity of symptoms and onset timing. Death risk may be indicated by autokinetic eyeball, eyeball ataxia, severe coma, respiratory rhythm abnormality, absent pharyngeal reflex, ultrahyperpyrexia, excessive tachycardia, pulmonary edema and/or hemorrhage, and refractory shock and ataxic respiration. Early assessment of these symptoms/signs is important for proper management.

The constitutive activation of Egr-1/C/EBPa mediates the development of type 2 diabetes mellitus by enhancing hepatic gluconeogenesis.

The sequential secretion of insulin and glucagon delicately maintains glucose homeostasis by inhibiting or enhancing hepatic gluconeogenesis during postprandial or fasting states, respectively. Increased glucagon/insulin ratio is believed to be a major cause of the hyperglycemia seen in type 2 diabetes. Herein, we reveal that the early growth response gene-1 (Egr-1) can be transiently activated by glucagon in hepatocytes, which mediates glucagon-regulated gluconeogenesis by increasing the expression of gluconeogenesis genes. Blockage of Egr-1 function in the liver of mice led to lower fasting blood glucose, better pyruvate tolerance, and higher hepatic glycogen content. The mechanism analysis demonstrated that Egr-1 can directly bind to the promoter of C/EBPa and regulate the expression of gluconeogenesis genes in the later phase of glucagon stimulation. The transient increase of Egr-1 by glucagon kept the glucose homeostasis after fasting for longer periods of time, whereas constitutive Egr-1 elevation found in the liver of db/db mice and high serum glucagon level overactivated the C/EBPa/gluconeogenesis pathway and resulted in hyperglycemia. Blockage of Egr-1 activation in prediabetic db/db mice was able to delay the progression of diabetes. Our results suggest that dysregulation of Egr-1/C/EBPa on glucagon stimulation may provide an alternative mechanistic explanation for type 2 diabetes.

Investigating the prevalence burden of peptic ulcer disease in older adults aged 70+ from 1990 to 2019: an analysis of Global Disease Burden Studies.

BACKGROUND: Peptic ulcer disease (PUD) affects individuals aged ≥70 years globally, exerting a significant impact on their health and well-being. Understanding its epidemiological evolution and associated factors is crucial for guiding interventions and improving management. METHODS: This study utilized Global Burden of Disease Study data to examine the prevalence and temporal changes of PUD in individuals aged 70 years and older between 1990 and 2019. The analysis included assessing estimated annual percentage changes (EAPCs) to investigate temporal trends and regional variations. RESULTS: Over the past 30 years, the number of individuals aged 70 years and above suffering from PUD globally has increased from 1 065 730 cases in 1990 to 1 608 463 cases in 2019. Despite an increasing number of cases, the prevalence of PUD among the elderly has exhibited a steady decline, with an EAPC of -1.47 (95% confidence interval: -1.57 to -1.37) over this timeframe. In 2019, the prevalence rates of PUD among individuals aged 70-74, 75-79, 80-84, and 85 years and older were 313.36, 365.77, 388.45, and 352.51 per 100 000 population, respectively. South Asia, high-income North America, and Central Sub-Saharan Africa were the regions with the highest prevalence rates of PUD in 2019, with rates of 624.90, 575.48, and 474.80 per 100 000 population, respectively. At the national level, Ireland, Australia, Brazil, Brunei Darussalam, and Bangladesh have effectively managed the burden of PUD among the elderly, achieving the greatest reduction. Additionally, regions with higher levels of socioeconomic development tended to have relatively lower burdens of PUD among the elderly, and prevalence rates varied across different regions and age groups. CONCLUSION: Our study highlights the enduring burden of PUD among the global elderly population, emphasizing the significance of tailored interventions to address this pressing issue. This research underscores the critical need for targeted public health strategies aimed at improving outcomes specifically for older adults affected by PUD.

Cortical and subcortical gray matter abnormalities in mild cognitive impairment.

Gray matter changes are thought to be closely related to cognitive decline in mild cognitive impairment (MCI) patients. The study aimed to explore cortical and subcortical structural alterations in MCI and their association with cognitive assessment. 24 MCI patients and 22 normal controls (NCs) were included. Voxel-based morphometry (VBM), vertex-based shape analysis and surface-based morphometry (SBM) analysis were applied to explore subcortical nuclei volume, shape and cortical morphology. Correlations between structural changes and cognition were explored using spearman correlation analysis. Support vector machine (SVM) classification evaluated MCI identification accuracy. MCI patients showed significant atrophy in the left thalamus, left hippocampus, left amygdala, right pallidum, right hippocampus, along with inward deformation in the left amygdala. SBM analysis revealed that MCI group exhibited shallower sulci depth in the left hemisphere and increased cortical gyrification index (GI) in the right frontal gyrus. Correlation analysis showed the positive correlation between right hippocampus volume and episodic memory, while negative correlation between the altered GI and memory performance in MCI group. SVM analysis demonstrated superior performance of sulci depth and GI derived from SBM in MCI identification. When combined with cortical and subcortical metrics, SVM achieved a peak accuracy of 89 % in distinguishing MCI from NC. The study reveals significant gray matter structural changes in MCI, suggesting their potential role in underlying functional differences and neural mechanisms behind memory impairment in MCI.

Altered regional brain activity and functional connectivity in primary intravaginal anejaculation patients revealed by resting-state fMRI.

ABSTRACT: Ejaculation is regulated by the central nervous system. However, the central pathophysiology of primary intravaginal anejaculation (PIAJ) is unclear. The present study aimed to examine the changes in regional brain activity and functional connectivity underlying PIAJ. A total of 20 PIAJ patients and 16 healthy controls (HCs) were enrolled from September 2020 to September 2022 in the Department of Andrology, Nanjing Drum Tower Hospital (Nanjing, China). Magnetic resonance imaging data were acquired from all participants and then were preprocessed. The measures of fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and functional connectivity (FC) were calculated and compared between the groups. PIAJ patients showed increased fALFF values in the left precuneus compared with HCs. Additionally, PIAJ patients showed increased ReHo values in the left precuneus, left postcentral gyrus, left superior occipital gyrus, left calcarine fissure, right precuneus, and right middle temporal gyrus, and decreased ReHo values in the left inferior parietal gyrus, compared with HCs. Finally, brain regions with altered fALFF and ReHo values in PIAJ patients showed increased FC with widespread cortical regions, which included the frontal, parietal, temporal, and occipital regions, compared with HCs. In conclusion, increased regional brain activity in the parietal, temporal, and occipital regions, and increased FC between these brain regions, may be associated with PIAJ occurrence.