BACKGROUND

Six-pyruvoyl-tetrahydrobiopterin synthase (6-PTPS) deficiency is an inherited metabolic disorder which results in tetrahydrobiopterin (BH4) deficiency causing hyperphenylalaninemia.

This study aimed to describe the clinical, biochemical, and radiologic profiles, and neurologic and developmental outcomes of patients diagnosed with 6-pyruvoyl tetrahydrobiopterin (PTPS) deficiency through newborn screening and confirmed by BH4 loading test, pterin analysis, and gene sequencing who were following-up with the metabolic team.

The research was a single-center descriptive case series study design that was done at the Philippine General Hospital, a tertiary government hospital. The clinical, biochemical, radiologic profiles and neurodevelopmental evaluation of each patient were described.

Nine patients from 1 year 2 months to 14 years 5 months of age were enrolled in the study. Clinical manifestations before treatment were hypotonia, poor suck, and seizure. The most common clinical manifestation even after treatment initiation was seizure. The mean phenylalanine level on newborn screening was 990.68 umol/L, but after treatment was started, mean levels ranged from 75.69 to 385.09 umol/L. Two of the patients had focal atrophy of the posterior lobe on brain imaging. Pathogenic variants on molecular analysis were all missense, with two predominant variants, c.155A>G and c.58T>C. Eight of the nine patients had varying degrees of developmental delay or intellectual disability, while the remaining patient had signs of a learning disorder.

Newborn screening has played a crucial role in the early identification and management of patients with hyperphenylalaninemia due to 6-PTPS deficiency. Confirmation of diagnosis through determination of DHPR activity, urine pterins and/or molecular analysis is necessary for appropriate management. However, despite early initiation of treatment, neurodevelopmental findings of patients with 6-PTPS deficiency were still unsatisfactory.

Moringa oleifera, widely utilized in Ayurvedic medicine, is recognized for its leaves, seeds, and velamen possessing traditional effects such as vātahara(wind alleviation), sirovirecaka(brain clearing), and hridya(mental nourishment). This study aims to identify the medicinal part of ■ in the Sārasvata ghee formulation as described in the Bower Manuscript, while investigating the ameliorative effects of different medicinal parts of M. oleifera on learning and memory deficits in mice and elucidating the underlying molecular mechanisms. A total of 144 male ICR mice were randomly assigned to the following groups: control, model(scopolamine hydrobromide, Sco, 2 mg·kg~(-1)), donepezil(donepezil hydrochloride, Don, 3 mg·kg~(-1)), M. oleifera leaf low-, medium-, and high-dose groups(0.5, 1, 2 g·kg~(-1)), M. oleifera seeds low-, medium-, and high-dose groups(0.25, 0.5, 1 g·kg~(-1)), and M. oleifera velamen low-, medium-, and high-dose groups(0.31, 0.62, 1.24 g·kg~(-1)). Learning and memory abilities were assessed using the passive avoidance test and Morris water maze. Nissl and HE staining were employed to examine histopathological changes in the hippocampus. Transcriptomics and targeted metabolomics were used to screen differential genes and metabolites, with MetaboAnalyst 6.0 and O2PLS methods applied to identify key disease-related targets and pathways. RESULTS:: demonstrated that M. oleifera leaf(1 g·kg~(-1)) significantly ameliorated Sco-induced learning and memory deficits, outperforming M. oleifera seeds(0.25 g·kg~(-1)) and M. oleifera velamen(1.24 g·kg~(-1)). This was evidenced by improved behavioral performance, reversal of neuronal damage, and reduced acetylcholinesterase(AChE) activity. Multi-omics analysis revealed that M. oleifera leaf upregulated Tuba1c gene expression through the synaptic vesicle cycle, enhancing glutamate(Glu), dopamine(DA), and acetylcholine(ACh) release via Tuba1c-Glu associations for neuroprotection. M. oleifera seeds targeted the dopaminergic synapse pathway, promoting memory consolidation through Drd2-ACh associations. M. oleifera velamen was associated with the cocaine addiction pathway, modulating dopamine metabolism via Adora2a-DOPAC, with limited relevance to learning and memory. In conclusion, M. oleifera leaf exhibits superior efficacy and mechanistic advantages over M. oleifera seeds and velamen, suggesting that the ■ in the Sārasvata ghee formulation is likely M. oleifera leaf, providing scientific evidence for its identification in ancient texts.
Animals ; Moringa oleifera/chemistry* ; Male ; Mice ; Seeds/chemistry* ; Plant Leaves/chemistry* ; Mice, Inbred ICR ; Memory Disorders/psychology* ; Transcriptome/drug effects* ; Memory/drug effects* ; Learning/drug effects* ; Metabolomics ; Humans ; Drugs, Chinese Herbal/administration & dosage* ; Maze Learning/drug effects*

Cardiovascular diseases and psychological disorders represent two major threats to human physical and mental health. Research on electrocardiogram (ECG) signals offers valuable opportunities to address these issues. However, existing methods are constrained by limitations in understanding ECG features and transferring knowledge across tasks. To address these challenges, this study developed a multi-resolution feature encoding network based on residual networks, which effectively extracted local morphological features and global rhythm features of ECG signals, thereby enhancing feature representation. Furthermore, a model compression-based continual learning method was proposed, enabling the structured transfer of knowledge from simpler tasks to more complex ones, resulting in improved performance in downstream tasks. The multi-resolution learning model demonstrated superior or comparable performance to state-of-the-art algorithms across five datasets, including tasks such as ECG QRS complex detection, arrhythmia classification, and emotion classification. The continual learning method achieved significant improvements over conventional training approaches in cross-domain, cross-task, and incremental data scenarios. These results highlight the potential of the proposed method for effective cross-task knowledge transfer in ECG analysis and offer a new perspective for multi-task learning using ECG signals.
Humans ; Electrocardiography/methods* ; Mental Health ; Algorithms ; Signal Processing, Computer-Assisted ; Machine Learning ; Arrhythmias, Cardiac/diagnosis* ; Cardiovascular Diseases ; Neural Networks, Computer ; Mental Disorders

Specific learning disorder (SLD) is a common neurodevelopmental disorder in children that significantly affects academic performance and quality of life. At present, diagnosis mainly relies on standardized tests and professional evaluations, a process that is complex and time-consuming. Multiple studies have shown that machine learning can analyze diverse data, including test scores, handwriting samples, eye movement data, neuroimaging data, and genetic data, to automatically learn the relationships between input features and output labels and achieve efficient prediction. It shows great potential for early screening, auxiliary diagnosis, and research on underlying mechanisms in SLD. This article reviews the applications of machine learning in the auxiliary diagnosis of SLD and discusses its performance when handling different data types.
Humans ; Machine Learning ; Specific Learning Disorder/diagnosis* ; Child

Alzheimer's disease (AD), a neurodegenerative disorder with complex etiologies, manifests through a cascade of pathological changes before clinical symptoms become apparent. Among these early changes, alterations in the expression of non-coding RNAs (ncRNAs) have emerged as pivotal events. In this study, we focused on the aberrant expression of ncRNAs and revealed that Lamr1-ps1, a pseudogene of the laminin receptor, significantly exacerbates early spatial learning and memory deficits in APP/PS1 mice. Through a combination of bioinformatics prediction and experimental validation, we identified the miR-29c/Bace1 pathway as a potential regulatory mechanism by which Lamr1-ps1 influences AD pathology. Importantly, augmenting the miR-29c-3p levels in mice ameliorated memory deficits, underscoring the therapeutic potential of targeting miR-29c-3p in early AD intervention. This study not only provides new insights into the role of pseudogenes in AD but also consolidates a foundational basis for considering miR-29c as a viable therapeutic target, offering a novel avenue for AD research and treatment strategies.
Animals ; Alzheimer Disease/pathology* ; Pseudogenes/genetics* ; Mice ; Memory Disorders/metabolism* ; MicroRNAs/genetics* ; Disease Models, Animal ; Spatial Learning/physiology* ; Mice, Transgenic ; Presenilin-1/genetics* ; Male ; Amyloid Precursor Protein Secretases/metabolism* ; Mice, Inbred C57BL ; Aspartic Acid Endopeptidases/metabolism*

OBJECTIVE: To explore the mechanism of electroacupuncture (EA) at "Fengchi" (GB 20) and "Sishencong" (EX-HN 1) on learning and memory impairment in vascular dementia (VD) rats by observing the influences on the N-methyl-D-aspartate receptor (NMDAR)/cyclic adenosine monophosphate response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway and the excitotoxicity induced by hippocampal calcium overload. METHODS: Thirty-two male SD rats of SPF grade were selected and randomized into a normal group (6 rats), a sham-operation group (6 rats) and an operation group (20 rats). VD model was established with the modified Pulsinelli's four-vessel occlusion (4-VO) method. Twelve rats after successfully modeled were assigned randomly into a model group and an EA group, 6 rats in each one. In the EA group, EA was delivered at bilateral "Fengchi" (GB 20) and "Sishencong" (EX-HN 1), with the continuous wave, the frequency of 2 Hz and the electric current of 1 mA. Stimulation intensity was adjusted depending on the slightly trembling of rat head. EA was given once daily, 30 min each time; and EA intervention was delivered for 21 days continuously. Using Morris water maze test, the learning and memory function was assessed. The neuronal morphology in the hippocampal CA1 was observed with HE staining; the level of glutamate (GLU) in serum and hippocampal tissue, as well as the activity of calcium pump (Ca²⁺-ATP) in the hippocampus were detected using colorimetric method. The protein expression of NMDAR, calmodulin-dependent protein kinase Ⅱ (CaMKⅡ), phosphorylated calmodulin-dependent protein kinase Ⅱ (p-CaMKⅡ), phosphorylated cyclic phosphoradenosine effector element binding proteins (p-CREB), CREB, and BDNF in the hippocampal CA1 was detected using immunohistochemistry. The protein expression of NMDAR, CREB, p-CREB and BDNF in the hippocampal tissue was detected using Western blot method. RESULTS: Compared to the sham-operation group, in the model group, the escape latency was prolonged and the platform crossing times of rats were reduced (P<0.01), the hippocampal neuron structure was damaged to different degrees, the structure in hippocampal CA1 was loosened, the arrangement disorganized, with clear grid-like structure; the neuronal morphology was irregular, pyknosis and even dissolution occurred, glial cells increased, blood capillary was dilated and the inflammatory cells were infiltrated and scattered. The level of GLU in the serum and hippocampal tissue and the protein expression of hippocampal NMDAR were elevated (P<0.01), the activity of Ca²⁺-ATP and the protein expression of CaMKⅡ, p-CaMKⅡ, CREB, p-CREB and BDNF were reduced (P<0.01, P<0.05); and the ratio of p-CaMKⅡ/CaMKⅡ and that of p-CREB/CREB were dropped (P<0.05). In comparison with the model group, in the EA group, the escape latency was shortened and the platform crossing times of rats rose (P<0.01), the arrangement was improved in the hippocampal CA1, the neuronal morphology was intact, the nucleoli were clear relatively and the pyknosis or dissolution were attenuated, the numbers of glial cells reduced relatively, the dilation of blood capillary was alleviated. The level of GLU in the serum and hippocampal tissue and the protein expression of NMDAR were reduced in the hippocampal tissue (P<0.01), the activity of Ca²⁺-ATP and the protein expression of CaMKⅡ, p-CaMKⅡ, CREB, p-CREB and BDNF were elevated (P<0.05, P<0.01); and the ratio of p-CaMKⅡ/CaMKⅡ and that of p-CREB/CREB increased (P<0.05). CONCLUSION EA at "Fengchi" (GB 20) and "Sishencong" (EX-HN 1) can attenuate learning and memory impairment in VD rats, which may be obtained by reducing GLU level in hippocampal tissue, inhibiting hippocampal excitotoxicity, mediating protein expression related to the NMDAR/CREB/BDNF signaling pathway, and maintaining neuronal survival and growth.
Electroacupuncture ; Male ; Animals ; Rats, Sprague-Dawley ; Learning ; Memory ; Signal Transduction ; Cyclic AMP Response Element-Binding Protein/metabolism* ; Memory Disorders/therapy* ; Brain-Derived Neurotrophic Factor/metabolism* ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Dementia, Vascular/therapy*

This study aimed to explore the effect of Ganmai Dazao Decoction on the ethology of rats with posttraumatic stress disorder(PTSD) and study the related mechanism through the changes in magnetic resonance imaging and protein expression. Sixty rats were randomly divided into 6 groups, namely the normal group, the model group, the low(1 g·kg~(-1)), medium(2 g·kg~(-1)), and high-dose Ganmai Dazao Decoction groups(4 g·kg~(-1)), and the positive control group(intragastric administration with 10.8 mg·kg~(-1) of fluoxetine), with 10 rats in each group. Two weeks after inducing PTSD by single-prolonged stress(SPS) in rats, the positive control group was given fluoxetine hydrochloride capsule by gavage, the low, medium, and high-dose groups were given Ganmai Dazao Decoction by gavage, and both the normal group and the model group were given the same volume of normal saline by gavage, each for 7 days. The open field experiment, elevated cross elevated maze, forced swimming experiment, and new object recognition test were carried out for the behavioral test. Three rats in each group were selected to detect the expression of neuropeptide receptor Y1(NPY1R) protein in the hippocampus by Western blot. Then, the other three rats in each group were selected to use the 9.4T magnetic resonance imaging experiment to observe the overall structural changes in the brain region and the anisotropy fraction of the hippocampus. The results of the open field experiment showed that the total distance and central distance of rats in the model group were significantly lower than those in the normal group, and the total distance and central distance of rats in the middle and high-dose Ganmai Dazao Decoction groups were higher than those in the model group. The results of the elevated cross maze test showed that medium and high-dose Ganmai Dazao Decoction remarkably increased the number of open arm entries and the residence time of open arm of rats with PTSD. The results of the forced swimming experiment showed that the immobility time in the water of the model group rats was significantly higher than that of the normal group, and Ganmai Dazao Decoction hugely reduced the immobility time in the water of rats with PTSD. The results of the new object recognition test showed that Ganmai Dazao Decoction significantly increased the exploration time of new objects and familiar objects in rats with PTSD. The results of Western blot showed that Ganmai Dazao Decoction significantly reduced the expression of NYP1R protein in the hippocampus of rats with PTSD. The 9.4T magnetic resonance examination found that there was no significant difference in the structural image among the groups. In the functional image, the fractional anisotropy(FA value) of the hippocampus in the model group was significantly lower than that in the normal group. The FA value of the hippocampus in the middle and high-dose Ganmai Dazao Decoction groups was higher than that in the model group. Ganmai Dazao Decoction reduces the injury of hippocampal neurons by inhibiting the expression of NYP1R in the hippocampus of rats with PTSD, thereby improving the nerve function injury of rats with PTSD and playing a neuroprotective role.
Animals ; Rats ; Ethology ; Stress Disorders, Post-Traumatic ; Fluoxetine ; Hippocampus ; Maze Learning

OBJECTIVES: Firefighters are prone to suffer from psychological trauma and post-traumatic stress disorder (PTSD) in the workplace, and have a poor prognosis after PTSD. Reliable models for predicting PTSD allow for effective identification and intervention for patients with early PTSD. By collecting the psychological traits, psychological states and work situations of firefighters, this study aims to develop a machine learning algorithm with the aim of effectively and accurately identifying the onset of PTSD in firefighters, as well as detecting some important predictors of PTSD onset. METHODS: This study conducted a cross-sectional survey through convenient sampling of firefighters from 20 fire brigades in Changsha, which were evenly distributed across 6 districts and Changsha County, with a total of 628 firefighters. We used the synthetic minority oversampling technique (SMOTE) to process data sets and used grid search to finish the parameter tuning. The predictive capability of several commonly used machine learning models was compared by 5-fold cross-validation and using the area under the receiver operating characteristic curve (ROC-AUC), accuracy, precision, recall, and F1 score. RESULTS: The random forest model achieved good performance in predicting PTSD with an average AUC score at 0.790. The mean accuracy of the model was 90.1%, with an F1 score of 0.945. The three most important predictors were perseverance, forced thinking, and reflective deep thinking, with weights of 0.165, 0.158, and 0.152, respectively. The next most important predictors were employment time, psychological power, and optimism. CONCLUSIONS PTSD onset prediction model for Changsha firefighters constructed by random forest has strong predictive ability, and both psychological characteristics and work situation can be used as predictors of PTSD onset risk for firefighters. In the next step of the study, validation using other large datasets is needed to ensure that the predictive models can be used in clinical setting.
Humans ; Stress Disorders, Post-Traumatic/diagnosis* ; Firefighters/psychology* ; Cross-Sectional Studies ; Algorithms ; Machine Learning

The purpose of this study was to investigate the effects of post-traumatic stress disorder (PTSD) on electrophysiological characteristics of glutamatergic and GABAergic neurons in dorsal hippocampus (dHPC) and ventral hippocampus (vHPC) in mice, and to elucidate the mechanisms underlying the plasticity of hippocampal neurons and memory regulation after PTSD. Male C57Thy1-YFP/GAD67-GFP mice were randomly divided into PTSD group and control group. Unavoidable foot shock (FS) was applied to establish PTSD model. The spatial learning ability was explored by water maze test, and the changes in electrophysiological characteristics of glutamatergic and GABAergic neurons in dHPC and vHPC were examined using whole-cell recording method. The results showed that FS significantly reduced the movement speed, and enhanced the number and percentage of freezing. PTSD significantly prolonged the escape latency in localization avoidance training, shortened the swimming time in the original quadrant, extended the swimming time in the contralateral quadrant, and increased absolute refractory period, energy barrier and inter-spike interval of glutamatergic neurons in dHPC and GABAergic neurons in vHPC, while decreased absolute refractory period, energy barrier and inter-spike interval of GABAergic neurons in dHPC and glutamatergic neurons in vHPC. These results suggest that PTSD can damage spatial perception of mice, down-regulate the excitability of dHPC and up-regulate the excitability of vHPC, and the underlying mechanism may involve the regulation of spatial memory by the plasticity of neurons in dHPC and vHPC.
Mice ; Male ; Animals ; Stress Disorders, Post-Traumatic ; Hippocampus ; Spatial Learning ; GABAergic Neurons

Objective: To explore the effect of lead exposure on the neurobehavior and gut microbiota community structure in mice. Methods: In August 2019, 64 C57BL/6 mice were randomly divided into 4 groups: control group (0 ppm) , low lead exposure group (20 mg/l) , medium lead exposure group (100 mg/l) and high lead exposure group (500 mg/l) . During the experiment, they were free to eat and drink. The drinking water of the lead exposure group was mixed with lead acetate, and sodium acetate was added in the control group. After 10 weeks of exposure, the Morris water maze was used to test the learning and memory ability of each group of mice, and then they were sacrificed for sampling. ICP-MS was used to detect lead content in whole blood and brain tissue. ELISA was used to determine the level of IL-1β in mouse serum. 16S rRNA sequencing was used to detect the structural diversity of the intestinal flora in feces, and then the correlation between the flora and behavior indicators was analyzed. Results: In the Morris water maze experiment, compared with the control group, there was no significant difference in the body weight and swimming speed of the mice in the lead exposure groups. The escape latency of the mice in the 100 mg/l and 500 mg/l dose groups was prolonged, and the number of platform crossings decreased (P<0.05) ; meanwhile, the staying time of the mice in the 500 mg/l Pb-treated group in the target quadrant was lower than that of the control group, and the difference was statistically significant (P<0.05) . Compared with the control group, the blood lead content of the mice in each lead exposure group was significantly increased, and the brain lead content of mice in the 500 mg/l dose group was significantly elevated (P<0.05) . The serum IL-1β levels of mice in each lead exposure group were higher than those of the control group (P<0.05) . At the phylum level, the relative abundance of the Proteobacteria phylum in all of Pb-treated groups was significantly increased (P<0.05) ; at the genus level, Allobaculum, Desulfovibrio, Lachnospiraceae_NK4A136_group, Turicibacter and Ureaplasma were significantly increased (P<0.05) . Among them. The relative abundance of Desuffaoibrio, Turici bacter, and Ureaplasma was negatively correlated with the residence time of mice in the quadrant of the platform (r=-0.32, -0.29, -0.44, P<0.05) . Conclusion: Lead exposure induced learning and memory impairments in mice, which may be related to the disturbance of the gut microbiota.
Animals ; Gastrointestinal Microbiome ; Lead/toxicity* ; Maze Learning ; Memory Disorders ; Mice ; Mice, Inbred C57BL ; RNA, Ribosomal, 16S/genetics*