Development and validation of a nutrition-related genetic-clinical-radiological nomogram associated with behavioral and psychological symptoms in Alzheimer’s disease

Background:Few evidence is available in the early prediction models of behavioral and psychological symptoms of dementia(BPSD)in Alzheimer’s disease(AD).This study aimed to develop and validate a novel genetic-clinical-radiological nomogram for evaluating BPSD in patients with AD and explore its underlying nutritional mechanism.Methods:This retrospective study included 165 patients with AD from the Chinese Imaging,Biomarkers,and Lifestyle(CIBL)cohort between June 1,2021,and March 31,2022.Data on demographics,neuropsychological assessments,single-nucleotide polymorphisms of AD risk genes,and regional brain volumes were collected.A multivariate logistic regression model identified BPSD-associated factors,for subsequently constructing a diagnostic nomogram.This nomogram was internally validated through 1000-bootstrap resampling and externally validated using a time-series split based on the CIBL cohort data between June 1,2022,and February 1,2023.Area under receiver operating characteristic(ROC)curves,calibration curves,and decision curve analysis(DCA)were used to assess the discrimination,calibration,and clinical applicability of the nomogram.Results:Factors independently associated with BPSD were:CETP rs1800775(odds ratio[OR]=4.137,95%confidence interval[CI]:1.276-13.415,P=0.018),decreased Mini Nutritional Assessment score(OR=0.187,95%CI:0.086-0.405,P<0.001),increased caregiver burden inventory score(OR=8.993,95%CI:3.830-21.119,P<0.001),and decreased brain stem volume(OR=0.006,95%CI:0.001-0.191,P=0.004).These variables were incorporated into the nomogram.The area under the ROC curve was 0.925(95%CI:0.884-0.967,P<0.001)in the internal validation and 0.791(95%CI:0.686-0.895,P<0.001)in the external validation.The calibration plots showed favorable consistency between the prediction of nomogram and actual observations,and the DCA showed that the model was clinically useful in both validations.Conclusion:A novel nomogram was established and validated based on lipid metabolism-related genes,nutritional status,and brain stem volumes,which may allow patients with AD to benefit from early triage and more intensive monitoring of BPSD.Registration:Chictr.org.cn,ChiCTR2100049131.

Synthesis and Evaluation of the Analogues of Penicillide against Cholesterol Ester Transfer Protein

A series ofpenicillide analogues, with modifications at C-3 and C-9 positions, are synthesized as potential cho-lesteryl ester transfer protein （CETP） inhibitors. The preliminary in vitro inhibition assay provided some valuable structure-activity relationship information about penicillide.

Deciphering lipid dysregulation in ALS:from mechanisms to translational medicine

Lipids,defined by low solubility in water and high solubility in nonpolar solvents,can be classified into fatty acids,glycerolipids,glycerophospholipids,sphingolipids,and sterols.Lipids not only regulate integrity and fluidity of biologi-cal membranes,but also serve as energy storage and bioactive molecules for signaling.Causal mutations in SPTLC1(serine palmitoyltransferase long chain subunit 1)gene within the lipogenic pathway have been identified in amyo-trophic lateral sclerosis(ALS),a paralytic and fatal motor neuron disease.Furthermore,lipid dysmetabolism within the central nervous system and circulation is associated with ALS.Here,we aim to delineate the diverse roles of different lipid classes and understand how lipid dysmetabolism may contribute to ALS pathogenesis.Among the different lipids,accumulation of ceramides,arachidonic acid,and lysophosphatidylcholine is commonly emerging as detri-mental to motor neurons.We end with exploring the potential ALS therapeutics by reducing these toxic lipids.

Cloning and characterization of cholesteryl ester transfer protein isolated from the tree shrew

Objective To obtain the nucleotide sequence and deduced amino acid sequence of cholesteryl ester transfer protein (CETP) cDNA from the tree shrew (Tupaia glis).Methods The cDNA sequence of the tree shrew CETP was obtained by utilizing the technique of switching mechanism at 5' end of RNA transcript (SMART) and rapid amplification of cDNA end (RACE) from the first strand of the cDNA. The amino acid sequence of CETP was deduced from the cDNA sequence and its primary and secondary structures were predicted.Results The sequence of CETP cDNA from tree shrew (GenBank accession number AF334033) covers 1636 bp, including 178 bp at the 3' end of the untranslated region and a 1458 bp fragment in a coding region, which provides the complete sequence of mature tree shrew CETP, although not the initiator methionine. The first 24 bp encodes a partial signal peptide. The mature protein consists of 477 amino acids and is longer than the human version by one amino acid (Gly318). Comparing this amino acid sequence with those of other animals' CETPs, the identity between tree shrew and human and rabbit CETP is 88% and 82%, respectively. The protein is extremely hydrophobic as it contains many hydrophobic residues, especially at the C-terminal, consistent with its function in the transfer of neutral lipids. The amino acid residues concerning with binding and transferring neutral lipids are highly conserved. There is a deletion of an N-linked glycosylation site at Asn342 in the tree shrew CETP protein that may participate in the removal of peripheral cholesterol and cholesteryl ester by increasing its activity of transferring cholesteryl ester.Conclusion The possible glycosylation in the tree shrew CETP may be involved in the molecular mechanism of its insusceptibility to atherosclerosis.