👤 Michele Vacca

We evaluated the accuracy of standard machine learning (ML) algorithms in predicting 1-year cognitive decline in Alzheimer's disease patients with mild cognitive impairment (ADMCI) using resting-state electroencephalographic (rsEEG) biomarkers enriched with APOE genotype, sex, age, and educational attainment data. The study analyzed datasets from 63 ADMCI patients obtained from an international archive. The ML algorithms included Simple Logistic Regression, Model Trees, Logistic Regression, K-nearest neighbor, and Support Vector Machine. Input features comprised lobar rsEEG source activities across delta (<4 Hz) to alpha (≈10-12 Hz) bands, cerebrospinal fluid (CSF Aβ1-42/p-tau), and structural magnetic resonance imaging (sMRI) biomarkers. Cognitive decline was assessed over a 1-year follow-up ("stable" vs. "decliner") based on Mini-Mental State Examination (MMSE) scores. The four independent ML algorithms accurately predicted changes in the MMSE score over a 1-year follow-up, with accuracies of 77-78% in ADMCI participants aged ≥ 70 years and 74-77% in those aged < 70 years. These findings suggest that rsEEG biomarkers in ADMCI patients may not only reveal underlying pathophysiological mechanisms affecting cortical arousal and vigilance but also hold predictive value for cognitive outcomes. Show less

Liver X receptors (LXRs) are transcriptional regulators of cholesterol metabolism, controlling cholesterol flow into cells, catabolism, and efflux. Cholesterol controls cell proliferation; disruptions in cholesterol metabolism have been associated with the development of colon cancer. We investigated whether expression of activated LXR protects against intestinal tumorigenesis in mice. We analyzed the development of colon cancer in mice that express a constitutive active form of LXRα only in the intestinal epithelium, under the control of villin promoter (iVP16LXRα). These mice were crossed with adenomatous polyposis coli (Apc)(min/+) mice, or given azoxymethane followed by dextran sodium sulfate, to assess intestinal tumor formation. We also assessed proliferation and apoptosis of a human colorectal cancer cell line (HT29) transfected with an adenoviral vector that expressed Ad VP16hLXRα, compared with cells expressing AdVP16 (control), and their ability to form xenograft tumors in mice. HT29 cells also were incubated with the LXR ligand GW3965. In human colorectal cancer cells, ligand-induced activation of LXR or transfection with Ad VP16hLXRα blocked the G1 phase, increased caspase-dependent apoptosis, and slowed growth of xenograft tumors in mice. iVP16LXRα mice formed fewer, smaller tumors than VP16 (control) mice after administration of azoxymethane and dextran sodium sulfate. APC(min/+)/iVP16LXRα mice also developed fewer, smaller intestinal tumors than APC(min/+)/iVP16 mice. Gene expression analysis indicated that activation of LXRα affected lipid metabolic networks and increased cholesterol efflux in the intestine. Expression of activated LXRα blocks proliferation of human colorectal cancer cells and slows the growth of xenograft tumors in mice. It also reduces intestinal tumor formation after administration of chemical carcinogens, and in Apc(min/+) mice. LXR agonists therefore might be developed as therapeutic treatments for colorectal cancer. Show less

Cholesterol homeostasis is critical for cellular proliferation. Liver X receptor (LXR) alpha and beta are the nuclear receptors responsible for regulation of cholesterol metabolism. In physiological conditions, high intracellular cholesterol levels cause increased synthesis of oxysterols, which activate LXR, thus triggering a transcriptional response for cholesterol secretion and catabolism. Here we employed a mouse model of partial hepatectomy (PH) to dissect the molecular pathways connecting cholesterol homeostasis, cellular proliferation, and LXR. First, we show that hepatic cholesterol content increases after PH, whereas the entire LXR transcriptome is down-regulated. Although LXR messenger RNA (mRNA) levels are unmodified, LXR target genes are significantly down-regulated on day 1 after PH and restored to control levels on day 7, when the liver reaches normal size. The inactivation of LXR following PH is related to the reduced oxysterol availability by way of decreased synthesis, and increased sulfation and secretion. On the contrary, cholesterol synthesis is up-regulated, and extracellular matrix remodeling is enhanced. Second, we show that reactivation of LXR by way of a synthetic ligand determines a negative modulation of hepatocyte proliferation. This effect is sustained by the reactivation of hepatic cholesterol catabolic and secretory pathways, coupled with a significant reduction of cholesterol biosynthesis. Our data unveil a previously unrecognized and apparently paradoxical scenario of LXR modulation. During liver regeneration LXR activity is abated in spite of increasing intracellular cholesterol levels. Turning off LXR-transcriptional pathways is crucial to guaranteeing the requisite intracellular cholesterol levels of regenerating hepatocytes. In line with this hypothesis, pharmacological LXR reactivation during PH significantly reduces liver regeneration capacity. Show less

Chromatin-derived acidic peptides (ACPs) have been shown to acutely modulate hypothalamic catecholamine release. To investigate whether this effect is mediated through membrane polysialylated neural-cell adhesion molecule (PSA-N-CAM), we pretreated rat hypothalamic synaptosomes with neuraminidase enzyme, which partially cleaves sialic acid residues from N-CAM, and perfused them with ACP-1 (Asp-Asp-Ser-Asp-Glu-Glu-Asn) or a more lipophilic derivative, ACP-2 ([Ala-Ile-Ser-Pro]-Asp-Asp-Ser-Asp-Glu-Glu-Asn). We have found that neuraminidase completely abolish the inhibitory effect of ACP-1 on dopamine release, while the inhibitory activity of ACP-1 on norepinephrine release is partially lost. On the other hand, ACP-2 inhibition of dopamine release is not modified by neuraminidase pretreatment. Show less

We have studied the neuromodulatory effects of three synthetic peptides, structurally related to chromatin-derived acidic peptides (ACPs): ACP-1 (Asp-Asp-Ser-Asp-Glu-Glu-Asn), corresponding to the C-terminal fragment of the largest subunit of eukaryotic RNA polymerase II; a more lipophilic derivative, ACP-2 (Ala-Ile-Ser-Pro-Asp-Asp-Ser-Asp-Glu-Glu-Asn); and its phosphorylated form ACP-3 (Ala-Ile-Ser-Pro-Asp-Asp-Ser(P)-Asp-Glu-Glu-Asn). Rat hypothalamic synaptosomes, loaded with [(3)H]norepinephrine or [(3)H]dopamine, were perfused with the above peptides, both basally and during a depolarizing stimulus. We have found: ACP-1 inhibited both dopamine and norepinephrine release; ACP-2 inhibited dopamine release, without affecting norepinephrine release; ACP-3 was almost ineffective, except for a weak dopamine inhibiting effect only at a higher concentration. Show less