The translation of genetic findings from genome-wide association studies into actionable therapeutics persists as a critical challenge in Alzheimer's disease (AD) research. Here, we present PI4AD, a computational medicine framework that integrates multi-omics data, systems biology, and artificial neural networks for therapeutic discovery. This framework leverages multi-omic and network evidence to deliver three core functionalities: clinical target prioritisation; self-organising prioritisation map construction, distinguishing AD-specific targets from those linked to neuropsychiatric disorders; and pathway crosstalk-informed therapeutic discovery. PI4AD successfully recovers clinically validated targets like APP and ESR1, confirming its prioritisation efficacy. Its artificial neural network component identifies disease-specific molecular signatures, while pathway crosstalk analysis reveals critical nodal genes (e.g., HRAS and MAPK1), drug repurposing candidates, and clinically relevant network modules. By validating targets, elucidating disease-specific therapeutic potentials, and exploring crosstalk mechanisms, PI4AD bridges genetic insights with pathway-level biology, establishing a systems genetics foundation for rational therapeutic development. Importantly, its emphasis on Ras-centred pathways-implicated in synaptic dysfunction and neuroinflammation-provides a strategy to disrupt AD progression, complementing conventional amyloid/tau-focused paradigms, with the future potential to redefine treatment strategies in conjunction with mRNA therapeutics and thereby advance translational medicine in neurodegeneration.

Objective: To clarify the long-term characteristics of tinnitus following treatment of sudden deafness and its long-term physical and mental effects on patients. Methods: A retrospective analysis was performed on 88 patients (46 males and 42 females; Age from 11 to 89 years) with sudden deafness treated in Department of Otoscope Surgery of Peoples's Libration Army General Hospital in Beijing from April 2020 to January 2021, and the occurrence of tinnitus and treatment effect of all patients were analyzed. Follow-up was conducted for patients with residual tinnitus after treatment for more than 1 year by the investigation and filling in the survey information collection form, Tinnitus Evaluation Questionnaire (TEQ) and Tinnitus Handicap Inventory (THI). Descriptive statistics and SPSS 22.0 software were used for statistical data analysis. Results: In this study, 93.2% (82/88) of patients with sudden deafness were accompanied by tinnitus at the onset, and the proportion of long-term tinnitus after treatment was 90.2% (74/82). After 1 year of treatment for sudden deafness, the improvement of tinnitus was significant in low-frequency sudden deafness compared with those of high-frequency, flat and total deafness sudden deafness (χ2 value was 6.801, 4.568 and 4.038, all P<0.05). In patients with residual tinnitus, 9 (12.2%) patients felt minimal loudness or even no loudness, 34 (46.0%) patients felt slight loudness, 28 (37.8%) patients felt tinnitus was relatively loud, and 3 (4.1%) patients felt tinnitus was loud or noisy. Nine (12.2%) patients's sleep was often affected, 41 (55.4%) patients's sleep was sometimes affected, 9 (12.2%) patients's sleep was rarely affected, 15 (20.3%) patients's sleep was almost not affected. Twenty-eight (37.8%) patients basically completely adapted to tinnitus and 46 (62.2%) patients did not completely adapted to residual tinnitus. Eight (10.8%) patients had no impact on life, 39 (52.7%) patients had slight impact, 22 (29.7%) patients had moderate impact, and the other 5 (6.8%) patients had greater impact. According to tinnitus evaluation questionnaire(TEQ), there were 12 cases (16.2%) of grade Ⅰ, 26 cases (35.1%) of grade Ⅱ, 28 cases (37.8%) of grade Ⅲ, 7 cases (9.5%) of grade Ⅳ and 1 case (1.4%) of grade Ⅴ. According to tinnitus handicap inventory(THI), tinnitus disability was classified into grade Ⅰ, 22 cases (29.7%), grade Ⅱ, 14 cases (18.9%), Grade Ⅲ, 27 cases (36.5%) and grade Ⅳ, 11 cases (14.9%). Conclusion: The rate of residual tinnitus following treatment of sudden deafness is high. Some of the patients can completely adapt residual tinnitus after one year, but some of them will be affected when sleep, work and study. Residual tinnitus can lead to tinnitus disability in different degrees.
Male ; Female ; Humans ; Child ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Hearing Loss, Sudden/therapy* ; Tinnitus/therapy* ; Retrospective Studies ; Deafness/complications* ; Audiometry

Body Fluids ; Child ; Humans ; Otitis Media ; Otitis Media with Effusion/therapy*

Objective To study the association of prevalence of cardio-cerebro vascular diseases (CCVD) with metabolic syndrome (MS) defined by different criteria in middle and aged people.Methods A cross-section survey was conducted among 1458 people aged 55 years and over in urban and rural areas of Beijing in 2009.MS definitions by World Health Organization (WHO),National Cholesterol Education Program-Adult Treatment Panel Ⅲ (NCEP-ATP Ⅲ ) revised,international diabetes mellitus (IDF) and Chinese Diabetes Society (CDS) were applied to analyze the association MS with the prevalence of CCVD.Results The risks of CCVD were all significantly higher in patients with MS than with non-MS using 4 definitions of MS.The definitions of WHO and CDS showed well agreement with the prevalence of CCVD.OR values of MS for CCVD were 2.14 folds (95％ CI:1.59-2.87) for WHO definition and 1.91 folds (95％ CI:1.43-2.55) for CDS definition,while OR values of MS for CCVD were 1.68 folds (95％ CI:1.32-2.15) for NCEP-ATPⅢ definition and 1.64 folds (95％ CI:1.26-2.13) for IDF definition as compared to non-MS,respectively.After adjustment for age,sex,region,history of smoking and alcohol drinking,the OR values in above four definitions were 1.91,1.88,1.67 and 1.80,respectively.The OR value of MS was highest for stroke by CDS definition and highest for coronary heart disease by WHO definition.Conclusions MS values defined by WHO and CDS are the optimal index of prevalence for CCVD in middle and aged people.

BACKGROUNDGenome-wide association studies for type 2 diabetes mellitus (T2DM) identified FTO gene as a locus conferring increased risk for common obesity in many populations with European ancestry. However, the involvement of FTO gene in obesity or T2DM related metabolic traits has not been consistently established in Chinese populations. The objective of this study was to investigate the association of FTO genetic polymorphisms with metabolic syndrome (MetS) in Han Chinese.

METHODSWe tested 41 FTO single nucleotide polymorphisms (SNPs) for association between FTO and MetS-related traits. There were a total of 236 unrelated subjects (108 cases and 128 controls), grouped according to the International Diabetes Federation (IDF) criteria.

RESULTSOf the 41 SNPs examined, only SNP rs8047395 exhibited statistical significance (P = 0.026) under a recessive model, after Bonferroni adjustment for multiple testing (OR 1.64, 95%CI 1.11-2.42; P = 0.014). The common distributions of this polymorphism among Chinese--with a minor allele frequency (MAF) of 36% in the control group versus 48% in the MetS group--greatly improved our test power in a relatively small sample size for an association study. Previously identified obesity- (or T2DM-) associated FTO SNPs were less common in Han Chinese and were not associated with MetS in this study. No significant associations were found between our FTO SNPs and any endophenotypes of MetS.

CONCLUSIONSA more common risk-conferring variant of FTO for MetS was identified in Han Chinese. Our study substantiated that genetic variations in FTO locus are involved in the pathogenesis of MetS.

Alpha-Ketoglutarate-Dependent Dioxygenase FTO ; Asian Continental Ancestry Group ; Female ; Genetic Predisposition to Disease ; genetics ; Genetic Variation ; genetics ; Genotype ; Haplotypes ; genetics ; Humans ; Male ; Metabolic Syndrome ; genetics ; Middle Aged ; Polymorphism, Single Nucleotide ; genetics ; Proteins ; genetics

Objective To analyze the clinical and imaging features of subependymal giant cell astrocytomas in patients with tuberous sclerosis.Methods The clinical data of 48 patients with tuberous sclerosis,admitted to our hospital from July 2007 to August 2009,were collected.According to the patients' history,sign and MRI results,the clinical features and imaging characteristics of subependymal giant cell astrocytomas were analyzed.Results Four patients with tuberous sclerosis were diagnosed as having subependymal giant cell astrocytomas and 2 of them were also diagnosed as having obstructive hydrocephalus;these 4 patients were male with an average onset age of five years (ranged from 1 to 12 years old).Seizure and skin lesions were found in these 4 patients with 3 presenting cognitive dysfunction.CT scanning showed iso-density or slightly low density in subependymal giant cell astrocytornas and some of these tumors were calcified with high density.MRI showed TIWI iso-signal or low signal and T2WI iso-signai or high signal; FLAIR high signal was presented and asymmetrical signal was also shown when calcification happened;enhanced MRI showed significant intensification on the tumors.Conclusion Some patients with tuberous sclerosis can have subependymal giant cell astrocytomas,the slow-growing tumors,which are often adjacent to the foramen of Monro and lead to obstructive hydrocephalus.Long-term follow-up needs to be conducted to find tumors at an early stage in patients with tuberous sclerosis.

Hearing Loss ; diagnosis ; therapy ; Humans

OBJECTIVETo observe the protective effect of nitric oxide synthase inhibitor-N(G)-nitro-L-arginine methyl ester (L-NAME) with or without neurotrophin 3 (NT3) on hearing in acoustic trauma.

METHODSEighty pigmented male guinea pigs were randomly divided into two groups: sham-exposed group (n=20) and noise-exposed group. The latter was divided into three subgroups: saline group (n=20), L-NAME group (n=20) and L-NAME + NT3 group (n=20). Two days consecutively and 30 min before noise exposure (4 kHz octave band noise at 115 dB SPL for 5 h), subjects in L-NAME and L-NAME + NT3 groups received an intraperitoneal injection of 10 mg/kg; animals in saline group received the same dosage of physiological saline at the same time. Four days before noise exposure, NT3 in artificial perilymph was delivered to the right scala tympani via a mini-osmotic pump in noise + L-NAME + NT3 group. Auditory brainstem responses (ABR) were measured before and 10 days following noise exposure. The cochlear tissue was assayed for nitric oxide (NO) level 3 days after noise exposure. Protection was assessed physiologically by the change in ABR threshold shift, and histologically by outer hair cell (OHC) survival.

RESULTSThe hearing thresholds and the number of OHC were relatively stable in sham-exposed group. The obvious threshold shift and OHC loss were observed in the noise-exposed groups. The hearing thresholds, NO level of cochlear tissue and OHC loss in the noise + saline group were significantly higher than those in the noise + L-NAME group (P < 0.01) and noise + L-NAME + NT3 group (P < 0.01). NT3 provided an additive functional (P < 0.01), but not morphological protection with L-NAME (P = 0.095).

CONCLUSIONCompared to L-NAME alone, a combination of L-NAME and NT-3 can provide an additional protection against acoustic trauma in the guinea pig cochlear.

Animals ; Cochlea ; drug effects ; injuries ; Enzyme Inhibitors ; pharmacology ; Guinea Pigs ; Hair Cells, Auditory ; drug effects ; Hearing Loss, Noise-Induced ; prevention & control ; Male ; NG-Nitroarginine Methyl Ester ; pharmacology ; Neurotrophin 3 ; pharmacology ; Nitric Oxide Synthase ; antagonists & inhibitors

AIMTo study the characteristics of neural information encoding of the epileptic networks involved caudate-putamen(CPu) and the hippocampi induced by tetanization of the right CPu in rats.

METHODSExperiments were performed on 59 SD rats. Acute or chronic tetanization of the right CPu (ATRC or CTRC) (60Hz,0.4-0.6 mA, 2 s) was used to induce rat epilepsy.

RESULTS(1) The bursting or primary unit afterdischarges of single neurons were asymmetric in dual hippocampi induced by the ATRC. (2) Continuous sharp waves were observed in ipsilateral or contralateral CPu induced by the CTRC. The oscillatory network seizures with phase shift appeared between two sharp waves in ipsilateral CPu. The frequency of oscillatory waves was negatively correlated with the time and fluctuated from 70 Hz to 110 Hz, then to 35 Hz, and finally to 30 Hz. (3) In the contralateral side primary network after discharges in the CPu were induced by the CTRC. Therefore, the characteristic primary network afterdischarges could be shifted from the CPu or to the HPC, but amplified. On the other hand, HPC sharp waves could be depressed when the CPu network seizures occurred.

CONCLUSIONThe reestablishment of CPu-hippocampal epileptic networks could be transhemispherically promoted by over-activation of the right CPu network, in which bilateral hippocampal neuronal network and CPu neural network were involved in some particular pathophysiological information encoding.

Animals ; Caudate Nucleus ; metabolism ; Epilepsy ; physiopathology ; Hippocampus ; metabolism ; Male ; Neurons ; metabolism ; Putamen ; metabolism ; Rats ; Rats, Sprague-Dawley

BACKGROUNDHypoxia-inducible factor 1 (HIF-1), a transcription factor, is overexpressed in common human cancers and their metastases. This study aimed at determining the expression levels of HIF-1alpha and vascular endothelial growth factor (VEGF) in SW480 cells and in colorectal adenocarcinoma tissue and ascertaining whether HIF-1alpha and VEGF play important roles in tumor angiogenesis.

METHODSHIF-1alpha mRNA expression was analyzed using in situ hybridization and RT-PCR. HIF-1alpha and VEGF protein were detected in SW480 cells and colorectal adenomas and adenocarcinomas by immunohistochemistry using streptavidin/peroxidase (SP). Western blot was used to detect HIF-1alpha protein extracted from SW480 cells. Microvessel density (MVD) in colorectal carcinomas was determined by anti-CD34 immunostaining in colorectal carcinomas.

RESULTSOptical density values representing HIF-1alpha mRNA expression levels were found to be significantly higher in SW480 cells in hypoxic conditions than in cells under normoxic conditions (P < 0.05) or in hypoxic conditions but treated with genistein (P < 0.05). The levels of HIF-1alpha and VEGF protein expression in SW480 cells were significantly higher in the hypoxia group than in the normoxia group (P < 0.01, P < 0.05, respectively) and hypoxia/genistein group (P < 0.01, P < 0.05, respectively). The positive expression rates of HIF-1alpha mRNA changed dramatically when comparing colorectal adenomas with adenocarcinomas of different Dukes' stages (P < 0.05). HIF-1alpha mRNA was also expressed at higher levels in adenocarcinomas than that in adenomas (P < 0.01). HIF-1alpha protein expression correlated significantly with VEGF protein expression and MVD.

CONCLUSIONSHypoxia induces the expression of HIF-1alpha and VEGF in colorectal adenocarcinomas. HIF-1alpha may play an important role in angiogenesis and tumor progression by regulating the expression of VEGF in human colorectal carcinomas.

Adenocarcinoma ; blood supply ; pathology ; Adult ; Aged ; Aged, 80 and over ; Cell Line, Tumor ; Colorectal Neoplasms ; blood supply ; pathology ; DNA-Binding Proteins ; analysis ; genetics ; physiology ; Humans ; Hypoxia-Inducible Factor 1 ; Hypoxia-Inducible Factor 1, alpha Subunit ; Middle Aged ; Neovascularization, Pathologic ; etiology ; Nuclear Proteins ; analysis ; genetics ; physiology ; RNA, Messenger ; analysis ; Transcription Factors ; analysis ; genetics ; physiology ; Vascular Endothelial Growth Factor A ; analysis ; physiology