Genetic Factor Research Articles

The vascular contribution of apolipoprotein E to Alzheimer's disease.

Alzheimer's disease, the most prevalent form of dementia, imposes a substantial societal burden. The persistent inadequacy of disease-modifying drugs targeting amyloid plaques and neurofibrillary tangles suggests the contribution of alternative pathogenic mechanisms. A frequently overlooked aspect is cerebrovascular dysfunction, which may manifest early in the progression of Alzheimer's disease pathology. Mounting evidence underscores the pivotal role of the apolipoprotein E gene, particularly the apolipoprotein ε4 allele as the strongest genetic risk factor for late-onset Alzheimer's disease, in the cerebrovascular pathology associated with Alzheimer's disease. In this review, we examine the evidence elucidating the cerebrovascular impact of both central and peripheral apolipoprotein E on the pathogenesis of Alzheimer's disease. We present a novel three-hit hypothesis, outlining potential mechanisms that shed light on the intricate relationship among different pathogenic events. Finally, we discuss prospective therapeutics targeting the cerebrovascular pathology associated with apolipoprotein E and explore their implications for future research endeavours.

Hotspots and trends of risk factors in gastric cancer: A visualization and bibliometric analysis.

The lack of specific symptoms of gastric cancer (GC) causes great challenges in its early diagnosis. Thus it is essential to identify the risk factors for early diagnosis and treatment of GC and to improve the survival rates. To assist physicians in identifying changes in the output of publications and research hotspots related to risk factors for GC, constructing a list of key risk factors, and providing a reference for early identification of patients at high risk for GC. Research articles on risk factors for GC were searched in the Web of Science core collection, and relevant information was extracted after screening. The literature was analyzed using Microsoft Excel 2019, CiteSpace V, and VOSviewer 1.6.18. A total of 2514 papers from 72 countries and 2507 research institutions were retrieved. China (n = 1061), National Cancer Center (n = 138), and Shoichiro Tsugane (n = 36) were the most productive country, institution, or author, respectively. The research hotspots in the study of risk factors for GC are summarized in four areas, namely: Helicobacter pylori (H. pylori) infection, single nucleotide polymorphism, bio-diagnostic markers, and GC risk prediction models. In this study, we found that H. pylori infection is the most significant risk factor for GC; single-nucleotide polymorphism (SNP) is the most dominant genetic factor for GC; bio-diagnostic markers are the most promising diagnostic modality for GC. GC risk prediction models are the latest current research hotspot. We conclude that the most important risk factors for the development of GC are H. pylori infection, SNP, smoking, diet, and alcohol.

Regarding repeated implantation failures coupled to assisted reproductive technologies

Embryo implantation is the first key step in successful pregnancy, but implantation failures remain quite common in patients undergoing assisted reproductive technology (ART) programs. The main known factors of repeated implantation failures (RIF) in patients undergoing ART are unhealthy lifestyle, genetic factor and low gamete quality, uterus pathology, endometriosis and adenomyosis, thrombophilia as well as male factor and embryonic factors. RIF factors and ways to overcome them have received much attention. Despite multiple RIF causes being identified, the underlying etiology and management remain poorly investigated. In clinical practice, studies and interventions providing no clear scientific rationale or convincing evidence on their effectiveness due to the lack of standardized diagnostic and treatment methods that are often used. An effective strategy for treating RIF risk factors is necessary to increase chances for successful pregnancy in ART programs.

Effects of SPI1-mediated transcriptome remodeling on Alzheimer’s disease-related phenotypes in mouse models of Aβ amyloidosis

SPI1 was recently reported as a genetic risk factor for Alzheimer’s disease (AD) in large-scale genome-wide association studies. However, it is unknown whether SPI1 should be downregulated or increased to have therapeutic benefits. To investigate the effect of modulating SPI1 levels on AD pathogenesis, we performed extensive biochemical, histological, and transcriptomic analyses using both Spi1-knockdown and Spi1-overexpression mouse models. Here, we show that the knockdown of Spi1 expression significantly exacerbates insoluble amyloid-β (Aβ) levels, amyloid plaque deposition, and gliosis. Conversely, overexpression of Spi1 significantly ameliorates these phenotypes and dystrophic neurites. Further mechanistic studies using targeted and single-cell transcriptomics approaches demonstrate that altered Spi1 expression modulates several pathways, such as immune response pathways and complement system. Our data suggest that transcriptional reprogramming by targeting transcription factors, like Spi1, might hold promise as a therapeutic strategy. This approach could potentially expand the current landscape of druggable targets for AD.

Natural variant of Rht27, a dwarfing gene, enhances yield potential in wheat.

Discovery of Rht27, a dwarf gene in wheat, showed potential in enhancing grain yield by reducing plant height. Plant height plays a crucial role in crop architecture and grain yield, and semi-dwarf Reduced Height (Rht) alleles contribute to lodging resistance and were important in "Green Revolution." However, the use of these alleles is associated with some negative side effects in some environments, such as reduced coleoptile length, low nitrogen use efficiency, and reduced yield. Therefore, novel dwarf gene resources are needed to pave an alternative route to overcome these side effects. In this study, a super-dwarf mutant rht27 was obtained by the mutagenesis of G1812 (Triticum urartu, the progenitor of the A sub-genome of common wheat). Genetic analysis revealed that the dwarf phenotype was regulated by a single recessive genetic factor. The candidate region for Rht27 was narrowed to a 1.55Mb region on chromosome 3, within which we found two potential candidate genes that showed polymorphisms between the mutant and non-mutagenized G1812. Furthermore, the natural variants and elite haplotypes of the two candidates were investigated in a natural population of common wheat. The results showed that the natural variants affect grain yield components, and the dwarf haplotypes show the potential in improving agronomic traits and grain yield. Although the mutation in Rht27 results in severe dwarf phenotype in T. urartu, the natural variants in common wheat showed desirable phenotype, which suggests that Rht27 has the potential to improve wheat yield by utilizing its weak allelic mutation or fine-tuning its expression level.

Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction.

Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. All hAPOE strains showed AD phenotype progression by 8months, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12months, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. This work highlights APOEε4 status in AD progression manifests as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker. We developed a novel analytical method to analyze PET imaging of 18F-FDG and 64Cu-PTSM data in both sexes of aging C57BL/6J, and hAPOEε3/ε3, hAPOEε4/ε4, and hAPOEε3/ε4 mice to assess metabolism-perfusion profiles termed neurovascular uncoupling. This analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated significant Type-2 uncoupling (increased glucose uptake, decreased perfusion) by 8 months which aligns with immunopathology and transcriptomic signatures. This work highlights that there may be different mechanisms underlying age related changes in APOEε4/ε4 compared with APOEε3/ε4. We predict that these changes may be driven by immunological activation and response, and may serve as an early diagnostic biomarker.

LRRK2 kinase inhibition protects against Parkinson's disease-associated environmental toxicants

Idiopathic Parkinson's disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that pollute our environment. While most are structurally distinct, a common cellular target for their toxicity is mitochondrial dysfunction, a key pathological trigger involved in the selective vulnerability of dopaminergic neurons. We and others have shown that environmental mitochondrial toxicants such as the pesticides rotenone and paraquat, and the organic solvent trichloroethylene (TCE) appear to be influenced by the protein LRRK2, a genetic risk factor for PD. As LRRK2 mediates vesicular trafficking and influences endolysosomal function, we postulated that LRRK2 kinase activity may inhibit the autophagic removal of toxicant damaged mitochondria, resulting in elevated oxidative stress. Conversely, we suspected that inhibition of LRRK2, which has been shown to be protective against dopaminergic neurodegeneration caused by mitochondrial toxicants, would reduce the intracellular production of reactive oxygen species (ROS) and prevent mitochondrial toxicity from inducing cell death. To do this, we tested in vitro if genetic or pharmacologic inhibition of LRRK2 (MLi2) protected against ROS caused by four toxicants associated with PD risk – rotenone, paraquat, TCE, and tetrachloroethylene (PERC). In parallel, we assessed if LRRK2 inhibition with MLi2 could protect against TCE-induced toxicity in vivo, in a follow up study from our observation that TCE elevated LRRK2 kinase activity in the nigrostriatal tract of rats prior to dopaminergic neurodegeneration. We found that LRRK2 inhibition blocked toxicant-induced ROS and promoted mitophagy in vitro, and protected against dopaminergic neurodegeneration, neuroinflammation, and mitochondrial damage caused by TCE in vivo. We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant-induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.

Three major effects of APOEε4 on Aβ immunotherapy induced ARIA.

The targeting of amyloid-beta (Aβ) plaques therapeutically as one of the primary causes of Alzheimer's disease (AD) dementia has been an ongoing effort spanning decades. While some antibodies are extremely promising and have been moved out of clinical trials and into the clinic, most of these treatments show similar adverse effects in the form of cerebrovascular damage known as amyloid-related imaging abnormalities (ARIA). The two categories of ARIA are of major concern for patients, families, and prescribing physicians, with ARIA-E presenting as cerebral edema, and ARIA-H as cerebral hemorrhages (micro- and macro-). From preclinical and clinical trials, it has been observed that the greatest genetic risk factor for AD, APOEε4, is also a major risk factor for anti-Aβ immunotherapy-induced ARIA. APOEε4 carriers represent a large population of AD patients, and, therefore, limits the broad adoption of these therapies across the AD population. In this review we detail three hypothesized mechanisms by which APOEε4 influences ARIA risk: (1) reduced cerebrovascular integrity, (2) increased neuroinflammation and immune dysregulation, and (3) elevated levels of CAA. The effects of APOEε4 on ARIA risk is clear, however, the underlying mechanisms require more research.

Study protocol of the GRoningen early-PD Ambroxol treatment (GREAT) trial: a randomized, double-blind, placebo-controlled, single center trial with ambroxol in Parkinson patients with a GBA mutation.

To date, no disease modifying therapies are available for Parkinson's disease (PD). Since PD is the second most prevalent neurodegenerative disorder, there is a high demand for such therapies. Both environmental and genetic risk factors play an important role in the etiology and progression of PD. The most common genetic risk factor for PD is a mutation in the GBA1(GBA)-gene, encoding the lysosomal enzyme glucocerebrosidase (GCase). The mucolytic ambroxol is a repurposed drug, which has shown the property to upregulate GCase activity in-vitro and in-vivo. Ambroxol therefore has the potency to become a disease modifying therapy in PD, which was the reason to design this randomized controlled trial with ambroxol in PD patients. This trial is a single-center, double-blind, randomized, placebo-controlled study, including 80 PD patients with a GBA mutation, receiving either ambroxol 1800 mg/day or placebo for 48 weeks. The primary outcome measure is the Unified Parkinson's Disease Rating Scale motor subscore (part III) of the Movement Disorder Society (MDS-UPDRSIII) in the practically defined off-state at 60 weeks (after a 12-week washout period). Secondary outcomes include a 3,4-dihydroxy-6-18F-fluoro-I-phenylalanine ([18F]FDOPA) PET-scan of the brain, Magnetic Resonance Imaging (with resting state f-MRI and Diffusion Tensor Imaging), GCase activity, both intra- and extracellularly, sphingolipid profiles in plasma, Montreal Cognitive Assessment (MoCA), quality of life (QoL) measured by the Parkinson's Disease Questionnaire (PDQ-39) and the Non-Motor Symptom Scale (NMSS) questionnaire. Ambroxol up to 1200 mg/day has shown effects on human cerebrospinal fluid endpoints, which supports at least passage of the blood-brain-barrier. The dose titration in this trial up to 1800 mg/day will reveal if this dose level is safe and also effective in modifying the course of the disease. NCT05830396. Registration date: March 20, 2023.

Статеві та клініко-інструментальні паралелі рівнів ліпопротеїн(а) в пацієнтів з дуже високим серцево-судинним ризиком

In recent years it has been established that elevated levels of Lp(a) are an independent genetic risk factor for the development of atherosclerotic cardiovascular diseases and aortic stenosis, however, issues of gender and age characteristics remain controversial.The aim of study was to analyze the gender characteristics of the relationship between Lp(a) levels and atherogenic changes in the lipid spectrum of the blood, clinical and instrumental characteristics, taking into account damage to the aortic valve and the results of coronary angiography in patients with stable coronary heart disease. Materials and methods. The 106 patients with chronic coronary heart disease (CAD) were examined. The average age of the subjects was 55.00±1.0 years (95% CI 51.11-58.89), among them: 78 men and 28 women.The entire cohort of patients was divided depending on the Lp(a) levels: 1group (n=58) with a Lp(a) level less than 50 mg/dl; 2 group (n=20) with Lp(a) level 50-100 mg/dl; 3 group (n=8) with Lp(a) level 101-150 mg/dl and 4 group (n=20) with Lp(a) level more than 150 mg/dl.Research methods included: 1. General clinical examination; 2. Laboratory characteristics of lipid (with determination of Lp(a)) and carbohydrate metabolism, as well as standard biochemical parameters; 3. Instrumental examination (electrocardiography, echocardiography, ultrasound peripheral vessels examination, coronary angiography); 4. Mathematical and statistical processing of the results obtained.Results and conclusions. In patients with CAD verified by clinical-instrumental and coronary angiographic criteria, it is noted that Lp(a) levels in women are on average significantly higher (P< 0.05) than in men and increase with the onset of menopause.Close correlations have not been recorded between Lp(a) in mg/dL and total cholesterol, LDL cholesterol and non-HDL cholesterol, as well as the concentrations of glucose, glycosylated hemoglobin, serum creatinine, and the concentration of thyroid-stimulating hormone (TSH).Determined that in patients with documented atherosclerotic lesions of the coronary arteries against the Lp(a) levels above 100 mg/dl, there is a greater need for coronary revascularization. A close relationship is observed between the increase in Lp(a) levels and the percentage of detection of aortic stenosis, which confirms the pathogenetic role of this lipoprotein in the formation of this acquired aortic valve disease.

Skeletal Muscle Mitochondrial Response to Diet Differs by Genotype and Sex in an Alzheimer’s Disease Mouse Model

Introduction: Skeletal muscle mass is reduced in the early stages of cognitive decline. Apolipoprotein ε4 ( APOE4) is the most prevalent genetic risk factor for Alzheimer’s disease (AD) and is associated with faster motor decline in cognitively healthy individuals. APOE4 also increases the risk of insulin resistance and cardiovascular disease, conditions associated with altered bioenergetic function in muscle. However, no studies have examined the role of APOE4 in modulating muscle physiology and the impact this would have on cognitive function. We sought to determine if APOE4 affects skeletal muscle mitochondrial metabolism in response to a high-fat diet (HFD) and if this is reflected in whole-body metabolism. We also examined the role of sex since APOE4 carriers who are female are more likely to develop AD. Methods: Male and female APOE3 (n=32) and APOE4 (n= 29) targeted-replacement mice on a C57BL/6 background purchased from Taconic were fed a standard chow diet until 4 months old. Mice were then switched to a low-fat diet (LFD, 10% kcal fat) or HFD (45% kcal fat) until sacrifice. Glucose tolerance was tested at 7 months by administering an intraperitoneal glucose injection of 1g/kg lean mass. Blood glucose was measured before and 15, 30, 45, 60, 90 and 120 minutes after glucose injection. Resting respiratory exchange ratio (RER) was determined using the Promethion Indirect Calorimetry system at 8 months to determine the relative contribution of carbohydrates versus lipids to whole body metabolism. Mice were sacrificed at 9 months and carbohydrate-driven oxygen consumption was measured at basal, state 3 (ADP), state 3 + glutamate, state 3S (succinate) and uncoupled respiratory states in mitochondria isolated from quadriceps tissue on the Oroboros Oxygraph-2k system. Results: Mice fed a HFD had greater glucose area under the curve (p<0.0001) and reduced RER (p= <0.001) compared to mice fed a LFD, regardless of sex or genotype. At the level of skeletal muscle, APOE4 female mice had increased state 3 (p=0.027) and state 3 + glutamate oxygen consumption (p=0.037) on a HFD compared to a LFD while no diet effect was observed in APOE4 males or any APOE3 mice. Conclusion: We provide evidence that female APOE4 mice are susceptible to diet-induced increases in carbohydrate-driven mitochondrial oxygen consumption in muscle. Future studies are needed to determine the underlying mechanism and consequences of increased muscle mitochondrial activity, which could help identify treatment targets in female APOE4 carriers. BHTP T32 AG078114, P30 AG072973 (Chelsea Johnson). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex differences in a novel transgenic mouse model of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia characterized by memory deficits, cognitive impairment, and presence of amyloid plaques and tau tangles in the brain. In the United States, six million people over the age of 65 live with AD, four million of whom are women. The apolipoprotein ( APOE) gene is the strongest genetic risk factor for late-onset AD, with the ε4 allele increasing AD risk relative to the ε3 allele. Mechanisms driving sex-based prevalence in the APOE4 genotype remain unknown. Previously, we have reported that female APOE4 mice develop hypertension and increased levels of vasoconstrictor angiotensin II (Ang II) in CSF with aging [FASEB J 2022: 36S1]. To better recapitulate human AD pathology and phenotype, we have recently generated unique mouse strains - 3XE4 and 3XE3 mice, by breeding human APOE4/APOE3-knockin with APPsw, PS1dE9, and tauP301S transgenes. Our goal is to study sex differences in the 3XE4 mice with AD. Blood pressure (BP, tail cuff), cognition (novel object recognition test), and cardiac function (echocardiography) were measured in both control 3XE3 (n=6) mice and 3XE4 (n=6) mice before and after Ang II (osmotic minipump, 1000 ng/kg/min). As expected, female mice weighed less than the male mice (Table). Basal BP and ejection fraction were higher in male 3XE4 mice compared to female 3XE4 mice (p<0.05). Total exploration time of novel object was significantly delayed in 3XE4 mice (p<0.05); the impairment was greater in the female 3XE4 mice. Notably, Ang II increased BP in male 3XE4 mice (151±5 mmHg) but not in female 3XE4 mice (125±2 mmHg). Unlike the 3XE3 mice, total exploration time of novel object was delayed (impaired) in both male and female 3XE4 mice at baseline and during Ang II. Although additional studies are needed to explore the underlying mechanisms, our results implicate potential sexual dimorphism in blood pressure regulation and cognition in Alzheimer’s Disease. [Formula: see text] Funding: NIH R01HL149677 and R21AG070188. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

PNPLA3 I148M Promotes Fatty Liver Disease While Preserving Cardiac Health

Metabolic-associated fatty liver disease (MAFLD) and cardiovascular disease (CVD) are commonly associated comorbidities. A common genetic variant in the PNPLA3 gene, rs738409 (I148M), is the greatest genetic risk factor for development and progression of MAFLD; however, MAFLD patients expressing PNPLA3 I148M display modest protection against coronary artery disease (CAD) and adverse cardiovascular events relative to wildtype carriers. Currently, the exact mechanisms by which PNPLA3 I148M causes MAFLD and preserves cardiac health are not well understood. Previous work suggests that the variant increases susceptibility to fatty liver disease by altering hepatic lipid metabolism, which may explain a potential mechanism for its cardioprotective effects. In order to investigate how PNPLA3 I148M might increase susceptibility to MAFLD while reducing risk of CVD we expressed either human wildtype (WT) PNPLA3 or PNPLA3 I148M as well as a GFP control specifically in the livers of PNPLA3 knockout mice. Our data demonstrate that hepatic expression of PNPLA3 I148M reduces secretion of VLDL TAGs from adipose tissue derived fatty acids. In agreement with prior investigations, mice expressing PNPLA3 I148M and fed a chow diet demonstrated significant increases in hepatic accumulation of neutral lipids (triglycerides & cholesterol esters) relative to WT and GFP expressing mice. Similarly, when fed a fatty liver promoting diet (D009100310) high in fructose, cholesterol, and saturated fats there remained a strong trend for greater liver to body weight ratios and hepatic TAGs in mice expressing the variant when compared to WT expressing mice (p=0.052 and p=0.071 respectively). Changes in hepatic lipid accumulation were not due to any alterations in insulin sensitivity, daily food consumption, energy expenditure or oxygen consumption between WT and I148M groups. Echocardiography revealed that hearts of mice expressing WT PNPLA3 had increases in left ventricular thickness (p=0.051) and left ventricle weights following dietary treatment that was not apparent in the I148M expressing mice. Moreover, there was a reduction in E/A ratios, a sensitive measure of diastolic functioning, in GFP and WT expressing mice post-treatment, that was not seen in the I148M mice. Overall, these findings indicate that PNPLA3 I148M promotes fatty liver, yet protects against diet-induced effects on ventricular remodeling and diastolic functioning. Our next steps will be to assess measures of atherosclerotic plaque formation around major blood vessels and investigate the metabolic pathways altered by PNPLA3 I148M. NIH R00 DK114471 NIH R01 DK126743 USDA grant no. 2021-09425 Pilot feasibility grant from University of Michigan: P30DK020572 Detroit Cardiovascular Training grant NIH 2T32HL120822. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Congenital Single Digit Deformities: Series of Cases in Multiple Families in Remote Villages of Haryana

Abstract Background and Purpose: Congenital deformities occur due to abnormal development of limbs in the intrauterine life. The exact cause of this type of defect is not known but can be associated with environmental factors (drug history or exposure of chemical effluents from factory) or genetic predisposition. Cases involving the occurrence of single digits in all four limbs were witnessed, and the aim was to study and trace the cause of such deformities. Knowledge of thalidomide induced phocomelia which has already being published in the literature also contributed to our knowledge and understanding. Objectives: (1) Primary objective was to identify the causative agent or genetic factor for the occurrence of single digits in hands and feet in multiple families. (2) Secondary objective was to create awareness among patients and the general public as well as local government authorities regarding such families of “Divyang” patients. We present a case series of multiple families with complete absence of all fingers and toes except one across villages in Haryana. Materials and Methods: Clinical setting: (1) Study was based on a detailed questionnaire which was taken from multiple villagers (Tarawari Village, Nilokheri Village, etc.) and (2) phenotypic examination. Five affected patients from multiple families for 1 year were taken for study from March 2022 to March 2023. Their habitus, lifestyle, and environmental status were all studied and compared with other studies. Efforts were taken to study the license and toxic effluent treatment plan of a chemical factory present in the near vicinity. Results: A strong genetic association was suggested for the occurrence of single digits in the hands and feet of multiple patients across multiple villages close to a chemical factory. They have well adjusted with writing, eating, riding bikes, and four-wheelers with single fingers and toes. Conclusion: There is a need to establish genetic analysis so that the cause of such deformities could be known and prevented. There is also a need for general and government awareness toward pollutants released from chemical factories and their effects.

Molecular and immunological characteristics of postoperative relapse in lymph node-positive esophageal squamous cell cancer.

The molecular and immunological characteristics of primary tumors and positive lymph nodes in esophageal squamous cell carcinoma (ESCC) are unknown and the relationship with recurrence is unclear, which this study attempted to explore. A total of 30 ESCC patients with lymph node positive (IIB-IVA) were enrolled. Among them, primary tumor and lymph node specimens were collected from each patient, and subjected to 551-tumor-targeted DNA sequencing and 289-immuno-oncology RNA panel sequencing to identify the different molecular basis and immunological features, respectively. The primary tumors exhibited a higher mutation burden than lymph nodes (p < 0.001). One-year recurrent ESCC exhibited a higher Mucin16 (MUC16) mutation rate (p = 0.038), as well as univariate and multivariate analysis revealed that MUC16 mutation is independent genetic factor associated with reduced relapse-free survival (univariate, HR: 5.39, 95% CI: 1.67-17.4, p = 0.005; multivariate, HR: 7.36, 95% CI: 1.79-30.23, p = 0.006). Transcriptomic results showed non-relapse group had higher cytolytic activity (CYT) score (p = 0.025), and was enriched in the IFN-α pathway (p = 0.036), while those in the relapsed group were enriched in the TNF-α/NF-κB (p = 0.001) and PI3K/Akt pathway (p = 0.014). The difference in molecular characteristics between primary lesions and lymph nodes may be the cause of the inconsistent clinical outcomes. Mutations of MUC16 and poor immune infiltration are associated with rapid relapse of nodes-positive ESCC.

Association between abnormal lipid metabolism and Alzheimer's disease: New research has revealed significant findings on the APOE4 genotype in microglia.

APOE4 is widely recognized as a genetic risk factor for Alzheimer's disease (AD), implicated in 60-80% of all AD cases. Recent research suggests that microglia carrying the APOE4 genotype display abnormal lipid metabolism and accumulate lipid droplets, which may exacerbate the pathology of AD. Microglia play a critical role in immune surveillance within the central nervous system and are responsible for removing harmful particles and preserving neuronal function. The APOE4 genotype causes abnormal lipid metabolism in microglia, resulting in excessive accumulation of lipid droplets. This accumulation not only impairs the phagocytic and clearance capabilities of microglia but also disrupts their interactions with neurons, resulting in disorganization and neurodegenerative alterations at the neuronal network level. In addition, the presence of APOE4 modifies the metabolic landscape of microglia, particularly affecting purinergic signaling and lipid metabolism, thereby exacerbating the pathological processes of AD. In conclusion, the accumulation of lipid droplets and abnormal lipid metabolism may be critical mechanisms in the progression of AD in microglia carrying the APOE4 genotype.

LDLR gene variant rs688 TT genotype; genetic association with obesity in Familial Hypercholesterolemia patients

The predominant genetic risk factor for familial hypercholesterolemia along with obesity is LDLR allele status. These receptors maintain cellular cholesterol homeostasis. For instance, a common SNP rs688 in different populations has been reported to be associated with elevatedplasma LDL, resulting in hypercholesterolemia. The potential role of variant rs688 with obesity in FH patients was observed. This is a case-control study with 120 blood samples of clinically diagnosed obese familial hypercholesterolemia patients by physicians and 120 healthy individuals’ blood samples were recruited for the study. Genomic DNA was extracted from blood samples. By using Tetra ARMS PCR, genotyping of LDLR rs688 (C&gt;T) exon 12 gene variation was performed. Moreover, BMI, BP, and BSL of obese FH patients were alsoobtained; a chi-square test was performed on the obtained data to evaluate the association between rs688 and obese FH patients. Genotype CC, CT, and TT frequencies reported in the obese FH patients’ group were 0.33, 0.41, and 0.25, while in healthy individuals were 0.37, 0.41, and 0.21 respectively. Chi–square values showed a significant association with BMI, BP, and BSL. It was assessed that there is a 4% increased susceptibility of FH development along with obesity in individuals with TT genotype. So, for obese familial hypercholesterolemia, the LDLR rs688 C&gt;T gene variation can be used as a predisposing genetic marker.

Targeted next-generation sequencing analysis in Italian patients with keratoconus.

To report variants in 26 candidate genes and describe the clinical features of Italian patients with keratoconus (KC). Sixty-four patients with a confirmed diagnosis of KC were enrolled in this genetic association study. Patients were classified into two study groups according to whether they had a confirmed diagnosis of progressive or stable KC. A purpose-developed Next Generation Sequencing (NGS) panel was used to identify and analyse the coding exons and flanking exon/intron boundaries of 26 genes known to be associated with KC and corneal dystrophies. Interpretation of the pathogenic significance of variants was performed using in silico predictive algorithms. The targeted NGS research identified a total of 167 allelic variants of 22 genes in the study population; twenty-four patients had stable keratoconus (n. 54 variants) and forty patients had progressive disease (n. 113 variants). We identified genetic variants of certain pathogenic significance in five patients with progressive KC; in addition, eight novel genetic variants were found in eight patients with progressive KC. Mutations of FLG, LOXHD1, ZNF469, and DOCK9 genes were twice more frequently identified in patients with progressive than stable disease. Filaggrin gene variants were found in 49 patients (76% of total), of whom 32 patients (80% of progressive KC group) had progressive disease. Targeted NGS research provided new insights into the causative effect of candidate genes in the clinical phenotype of keratoconus. Filaggrin mutations were found to represent a genetic risk factor for development of progressive disease in Italy.

Estradiol improves behavior in FAD transgenic mice that express APOE3 but not APOE4 after ovariectomy.

Increasing evidence suggests that female individuals have a higher Alzheimer's disease (AD) risk associated with post-menopausal loss of circulating estradiol (E2). However, clinical data are conflicting on whether E2 lowers AD risk. One potential contributing factor is APOE. The greatest genetic risk factor for AD is APOE4, a factor that is pronounced in female individuals post-menopause. Clinical data suggests that APOE impacts the response of AD patients to E2 replacement therapy. However, whether APOE4 prevents, is neutral, or promotes any positive effects of E2 is unclear. Therefore, our goal was to determine whether APOE modulates the impact of E2 on behavior and AD pathology in vivo. To that end, mice that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce Aβ42 were ovariectomized at either 4 months (early) or 8 months (late) and treated with vehicle or E2 for 4 months. In E3FAD mice, we found that E2 mitigated the detrimental effect of ovariectomy on memory, with no effect on Aβ in the early paradigm and only improved learning in the late paradigm. Although E2 lowered Aβ in E4FAD mice in the early paradigm, there was no impact on learning or memory, possibly due to higher Aβ pathology compared to E3FAD mice. In the late paradigm, there was no effect on learning/memory and Aβ pathology in E4FAD mice. Collectively, these data support the idea that, in the presence of Aβ pathology, APOE impacts the response to E2 supplementation post-menopause.

PREDICTING THE PROBABILITY OF DEVELOPING OBESITY DEPENDING ON LEPTIN AND LEPTIN RECEPTOR POLYMORPHISMS

Introduction. Metabolic syndrome is a heterogeneous pathological condition that combines different stages of obesity, impaired glucose tolerance, atherogenic dyslipidemia and arterial hypertension. Obesity itself is a key element of this syndrome. Hormonal disorders, the central one of which is insulin resistance, trigger a cascade of neuroendocrine changes that lead to the progression of MetS. Monogenic mutations are often detected in patients with severe obesity, as well as with early (up to 10 years) its debut. In recent years, it has been increasingly investigated for a genetically determined breakdown in the mechanism of leptin's influence on the development of obesity. The aim of this study – to evaluate the probability of obesity development in patients with LEP and LEPR polymorphisms in Ukrainian population. Research Methods. 53 obesity and 43 non-obesity patients underwent genotyping of the LEP and LEPR genes (K109R (rs1137100), Q223R (rs1137101), K656N (rs1805094), G2548A (rs7799039)) polymorphism was performed using TaqMan™ SNP Genotyping Human Assays (Thermo Fisher Scientific, USA). Results and Discussion. Comparing rs1137101 Allele A, rs1137101 Allele G statistically significant differences were revealed, while comparing rs1805094 Allele C, rs1805094 Allele G, rs7799039 Allele A, rs7799039 Allele G, rs1137100 Allele A, rs1137100 Allele G depending on group indicated no statistically significant differences. SNP (rs1137101) Allele A statistically significant differences depending on obesity degree (p &lt; 0.001). Comparing the rest of SNP`s Allele`s (rs1805094 Allele C, rs1805094 Allele G, rs7799039 Allele A, rs7799039 Allele G, rs1137101 Allele G, rs1137100 Allele A, rs1137100 Allele G, rs696217 Allele G) no statistically significant differences was noted. Prediction of the probability of developing obesity depending on the polymorphism of leptin and leptin receptors revealed the dependence of only mutations in LEPR (Q223R (rs1137101)) in the Ukrainian population. According to the results of the ROC analysis sensitivity and specificity of the method were 65.5 % and 67.8 %, respectively. Conclusions. Our analysis showed that LEPR Q223R (rs1137101) polymorphism could be a potential genetic risk factor for obesity in Ukrainian population regardless of the homozygous or heterozygous genotype (genotypes AA, AG, GG). At the same time, allele A was found in 70.83 % of cases of patients with 2nd and 3rd degree obesity. And homozygous AA and GG genotypes in 24.5 % and 28.3 %, respectively. The results obtained can be used in the practice for early diagnosis of different types of obesity and for prognosing of results of bariatric surgery.