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Background/Objectives: Uvulopalatopharyngoplasty (UPPP) is a prevalent surgical procedure for treating obstructive sleep apnea. Effective postoperative pain management is crucial for patient comfort and recovery. This study aimed to compare the analgesic efficacies of parecoxib and ketorolac in patients undergoing UPPP. Methods: A prospective, randomized, double-blind study was conducted on 83 patients who received either parecoxib (40 mg intravenously every 12 h) or ketorolac (30 mg intravenously every 8 h) for 2 days following UPPP. Postoperative pain and swallowing discomfort were assessed using visual analog scales (VASs) at 4, 24, 48, and 72 h. The time to resume eating and adverse reactions were also recorded. Results: At 24 and 48 h postoperatively, the mean VAS score was significantly higher in the ketorolac group compared to the parecoxib group (5.0 ± 2.3 vs. 3.6 ± 2.2, p = 0.005 and 3.9 ± 2.2 vs. 2.5 ± 1.7, p < 0.001, respectively). However, no significant difference in the mean VAS scores was observed between the two groups at 72 h postoperatively. With regards to postoperative swallowing pain, the ketorolac group exhibited significantly higher mean VAS scores than the parecoxib group at 4, 24, 48, and 72 h postoperatively. Conclusions: Intravenous parecoxib may offer superior analgesic benefits in the early postoperative period, particularly in alleviating swallowing pain, compared to ketorolac in UPPP procedures. [ABSTRACT FROM AUTHOR]

Introduction: Variants in the tau gene (MAPT) region are associated with breast cancer in women and Alzheimer's disease (AD) among persons lacking apolipoprotein E ε4 (ε4–). Methods: To identify novel genes associated with tau‐related pathology, we conducted two genome‐wide association studies (GWAS) for AD, one among 10,340 ε4– women in the Alzheimer's Disease Genetics Consortium (ADGC) and another in 31 members (22 women) of a consanguineous Hutterite kindred. Results: We identified novel associations of AD with MGMT variants in the ADGC (rs12775171, odds ratio [OR] = 1.4, P = 4.9 × 10–8) and Hutterite (rs12256016 and rs2803456, OR = 2.0, P = 1.9 × 10–14) datasets. Multi‐omics analyses showed that the most significant and largest number of associations among the single nucleotide polymorphisms (SNPs), DNA‐methylated CpGs, MGMT expression, and AD‐related neuropathological traits were observed among women. Furthermore, promoter capture Hi‐C analyses revealed long‐range interactions of the MGMT promoter with MGMT SNPs and CpG sites. Discussion: These findings suggest that epigenetically regulated MGMT expression is involved in AD pathogenesis, especially in women. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests epidemiological and pathological links between Alzheimer disease (AD) and breast cancer (BC). The 17q21 locus, including MAPT encoding tau, has been identified in genome‐wide association studies (GWAS) for BC in women and AD among persons lacking the APOE ε4 allele (ε4‐). We hypothesized that other genes involved in tau‐related pathology can be identified by GWAS in women stratified by ε4 status. Methods: We conducted a GWAS for AD among ε4‐ women (3,400 AD and 6,940 controls) in Alzheimer's Disease Genetics Consortium (ADGC) datasets and separately analyzed whole genome sequencing data obtained from five AD cases (all women; ε4+=4) and 26 controls (17 women, 9 men; ε4+=9) in a Hutterite kindred from South Dakota. Association tests were performed using logistic regression with covariates for age and principle components of ancestry in the ADGC datasets and for age, sex, and ε4 in the Hutterites. Potential mechanisms of top‐ranked findings were investigated by integrating omics data including gene expression, DNA‐methylation (DNAm), and AD‐related neuropathological traits in subsets stratified by sex and ε4 status in the Religious Orders Study and Memory and Aging Project (ROSMAP; 339 AD and 229 controls). Results: We identified genome‐wide significant associations with one novel locus MGMT in each sample (ADGC: rs12775171, odds ratio [OR]=1.4, P=4.9x10‐8; Hutterites: rs12256016, OR=2.0, P=1.9x10‐14). Rs12775171 showed no evidence of association with AD risk in ε4+ women or in men in the ADGC datasets (P>0.05). Rs12775171 is not in linkage disequilibrium with rs12256016. At least one of these SNPs was significantly associated with increased DNAm levels near/within MGMT (best association pair: rs11016864 [proxy for rs12256016] with cg01419164; P=4.0x10‐4 in women), which were also significantly associated with lower MGMT expression (P=0.03) and worse tau burden in all AD cohorts (neurofibrillary tangle; P=6.0x10‐3), women (Braak stage; P=4.0x10‐3), and ε4‐ women (neurofibrillary tangle; P=0.03), but not among ε4+ women, all men, or ε4+/ε4‐ men in ROSMAP. Conclusion: We identified a novel association of AD with the interaction of sex and MGMT. Our omics analysis confirmed that epigenetically regulated expression of MGMT (involved in DNA methylation damage repair) is significantly associated with tau in women. [ABSTRACT FROM AUTHOR]

Background: The Alzheimer's Disease Variant Portal (ADVP, https://advp.niagads.org) is a curated and harmonized interactive platform providing the research community with a unified way to access and visualize the largest up‐to‐date collection of Alzheimer's disease (AD) genetic findings from >200 genome‐wide association studies (GWASs). In this study, we aim to characterize the regulatory roles and mechanisms underlying these genetic signals in AD. Methods: We analyzed all Caucasian genome‐wide significant signals in ADVP (348 genetic variants and 186 loci) using FILER (Kuksa et al., 2021) and SparkINFERNO (Kuksa et al., 2020). The SparkINFERNO high throughput system analyses framework is coupled with the FILER (https://lisanwanglab.org/FILER), a rich resource of >50,000 harmonized functional genomic datasets across many different sources including ENCODE, FANTOM5, GTEx, Roadmap, DASHR2 and others. With this systematic, hypothesis‐free analysis approach, we analyzed and ranked relevant tissue categories by quantifying the significance and enrichment of tissue‐specific enhancer overlaps with ADVP variants compared to the empirical overlap distribution for matching background (non‐AD) variants. Further integration with the AMP‐AD expression quantitative trait loci (eQTL) datasets from three brain regions (dorsolateral prefrontal cortex, cerebellum and temporal cortex), enable us to discover the potentially causal genes affected by these variants. Results: The ADVP variants were enriched in regulatory elements profiled by FANTOM5 and Roadmap Epigenomics (ChromHMM). Top tissues enriched in Roadmap enhancers include blood (OR=3.7), digestive (OR=3.5), brain (OR=2.8), and skeletal muscles (OR=2.6). 31% of the analyzed ADVP variants were identified as significant eQTLs in at least one of the three AMP‐AD eQTL datasets (FDR<0.01), and 32% among these were eQTLs in all three brain regions. Altogether, these variants targeted 130 genes (including HLA regions), of which 31 were also the nearest genes reported in ADVP. These target genes (e.g. ACE, PVR, KANSL1, NARS2) were enriched in cell junction organization, DNA repair (nucleotide‐excision repair) and acetyltransferase activity (cholinergic system), which recapitulated some of the molecular and cellular mechanisms underlying the pathogenesis of AD. Conclusions: Conducted analysis of genetic associations across >200 GWASs in ADVP and identified known AD culprit genes, relevant tissue/cell type categories, and regulatory mechanisms. [ABSTRACT FROM AUTHOR]

Background: Estimation of heritability of Alzheimer's Disease (AD) ranges from 49‐79%, but the conventional single nucleotide variants (SNVs) identified to date account for <50% of the AD heritability. The involvement of genetic variants, such as SNVs and copy number variations (CNVs), has been proposed to explain part of the missing heritability. Method: To accelerate AD genetic discovery, the Alzheimer's Disease Sequencing Project (ADSP) sequenced cases and cognitively normal elder controls from multiple ethnic groups. Leveraging this large‐scale Whole Genome Sequence (WGS) collection, we could detect and conduct AD genetic analyses in full‐spectrum of CNVs (small or large, common or rare, and coding or non‐coding in genomic regions). We developed a bioinformatics pipeline consisting of four steps. First, we applied three calling algorithms, CNVnator, JAX‐CNV, and Smoove, on each sample. Results of each tool were then merged by Svimmer. Second, we employed GraphTyper for genotyping. GraphTyper is a graph‐pangenome‐based method that may mitigate bias of human references. Finally, we resolved issues of multiple CNVs overlapping in a region by bedtools. Once the CNV callset was obtained, we conducted an association study to identify CNV regions that contribute to AD. We consider conventional association methods as well as a new developed CNV‐curve‐centric strategy which models CNVs as piecewise constant curves to assess the CNV effect on AD. Result: For each sample, we identified an average of 7,959 CNVs by three algorithms. After merging CNVs of all samples, we obtained 56,316 deletions and 16,390 duplications for GraphTyper joint genotyping. The preliminary results of PLINK permutation‐based test on the chromosome 19 indicated significant CNVs (p‐value < 0.05 after adjusting for multiple tests) on genes UNC13A, IGSF23, KMT2B, LIN37, PSENEN, IGFLR1, and U2AF1L4. UNC13A, KMT2B, and PSENEN have been discovered to be associated in frontotemporal dementia, dystonia, and AD. Further validations of those CNVs are necessary. Conclusion: We developed a scalable CNV detection pipeline and applied it to 3,928 ADSP WGS samples. The preliminary results of the association study validate some known AD, dementia, and dystonia genes. To the best of our knowledge, this is the first large‐scale CNV investigation of AD using WGS data. [ABSTRACT FROM AUTHOR]

Background: NIAGADS is a national genomics data repository that facilitates access of genotypic and sequencing data to qualified investigators for the study of the genetics of Alzheimer's disease (AD) and related neurological diseases. Collaborations with large consortia and centers such as the Alzheimer's Disease Genetics Consortium (ADGC), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Alzheimer's Disease Sequencing Project (ADSP), and the Genome Center for Alzheimer's Disease (GCAD) allow NIAGADS to lead the effort in managing large AD datasets that can be easily accessed and fully utilized by the research community. Method: NIAGADS is supported by National Institute on Aging (NIA) under a cooperative agreement. All data derived from NIA funded AD genetics studies are expected to be deposited in NIAGADS or another NIA approved site. NIAGADS manages a Data Sharing Service (DSS) that facilitates the deposition and sharing of genomic data and association results with approved users in the neurodegenerative research community. In addition, researchers are able to freely use the NIAGADS Alzheimer's Genomics Database (www.niagads.org/genomics/) to search annotation resources that link published AD studies to AD‐relevant sequence features and genome‐wide annotations. Result: As of January 2021, NIAGADS houses 74 datasets comprised of >90,000 samples including GWAS, sequencing, gene expression, annotations, deep phenotypes, and summary statistics. Qualified investigators can retrieve ADSP sequencing data with ease and flexibility through the NIAGADS DSS. As of February 2021, the ADSP and other contributing studies have completed whole exome sequencing (WES) of 20,504 samples and whole‐genome sequencing (WGS) of 16,908 samples. Raw WES and WGS files, quality controlled VCF files, and phenotype data files are available via qualified access. The next round of sequencing currently underway will generate around 18,000 additional genomes to be released at the end of 2021. Conclusion: NIAGADS is a rich resource for AD researchers, with the goal of facilitating advances in Alzheimer's genetics research. By housing datasets from many projects and institutions, NIAGADS enables AD researchers to meet their research goals more efficiently. Datasets, guidelines, and new features are available on our website at https://www.niagads.org. [ABSTRACT FROM AUTHOR]

Characterisation targets usually include a set of physical coloured samples. A characterisation model can be derived between the colorimetric values (tristimulus values) and camera responses ( RGB values) taken from an imaging device such as a digital camera capturing the colours in the target. The performance of such a model is highly dependent upon the number of colours and the colour region in the characterisation target. An ideal characterisation target should provide accurate model prediction without requiring too many samples. In this paper, a computational method is presented for colour selections to train a camera characterisation model based on a fourth-order polynomial model including 35 terms. Compared with other available methods, the newly developed method performed better. It is proposed that this method be applied to generate generic targets in terms of colorimetric values. These targets should work reasonably well for a wide range of materials. [ABSTRACT FROM AUTHOR]

Aminoglycoside- and cisplatin-induced ototoxicity, which is a significant issue owing to the widespread use of these drugs in clinical practice, involves the entry of aminoglycosides and cisplatin into the endolymph and hair cells via specific channels or transporters, followed by reactive oxygen species (ROS) generation and hair cells apoptosis. Current strategies focalize primarily on interference with downstream ROS effects; however, recent evidence has demonstrated that inhibiting the uptake of aminoglycosides and cisplatin by hair cells is another promising strategy for tackling the upstream drug uptake pathway. With advances in structural biology, the conformations of certain aminoglycoside and cisplatin channels and transporters, such as the mechanoelectrical transduction channel and organic cation transporter-2, have been largely elucidated. These channels and transporters may become potential targets for the introduction of new otoprotective strategies. This review focuses on the strategies for inhibiting ototoxic drugs uptake by auditory hair cells and provides potential targets for recent developments in the field of otoprotection. Molecular dynamics (MD) simulations of these proteins could help identify the molecules that inhibit the uptake of aminoglycosides and cisplatin by hair cells. Integrating upstream drug uptake pathway targets and MD simulations may help dissect molecular mechanisms and develop novel otoprotective strategies for aminoglycoside- and cisplatin-induced ototoxicity., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

Introduction: Variants in the tau gene (MAPT) region are associated with breast cancer in women and Alzheimer's disease (AD) among persons lacking apolipoprotein E ε4 (ε4-)., Methods: To identify novel genes associated with tau-related pathology, we conducted two genome-wide association studies (GWAS) for AD, one among 10,340 ε4- women in the Alzheimer's Disease Genetics Consortium (ADGC) and another in 31 members (22 women) of a consanguineous Hutterite kindred., Results: We identified novel associations of AD with MGMT variants in the ADGC (rs12775171, odds ratio [OR] = 1.4, P = 4.9 × 10 -8 ) and Hutterite (rs12256016 and rs2803456, OR = 2.0, P = 1.9 × 10 -14 ) datasets. Multi-omics analyses showed that the most significant and largest number of associations among the single nucleotide polymorphisms (SNPs), DNA-methylated CpGs, MGMT expression, and AD-related neuropathological traits were observed among women. Furthermore, promoter capture Hi-C analyses revealed long-range interactions of the MGMT promoter with MGMT SNPs and CpG sites., Discussion: These findings suggest that epigenetically regulated MGMT expression is involved in AD pathogenesis, especially in women., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Three full length cDNAs (BoCLH1, 1140 bp; BoCLH2, 1104 bp; BoCLH3, 884 bp) encoding putative chlorophyllases were cloned from the cDNA pools of broccoli (Brassica oleracea) florets and characterized. The amino acid sequence analysis indicated that these three BoCLHs contained a highly conserved lipase motif (GXSXG). However, only BoCLH3 lacked the His residue which is the component of the catalytic triad (Ser-His-Asp). N-terminal sequences of BoCLH1 and BoCLH2 were predicted to have typical signal sequences for the chloroplast, whereas the plasma membrane-targeting sequence was identified in BoCLH3. The predicted molecular masses of BoCLH1, 2, and 3 were 34.7, 35.3, and 23.5 kDa, respectively. The recombinant BoCLHs were successfully expressed in Escherichia coli for the biochemical characterization. The recombinant BoCLH3 showed very low chlorophyllase activity possibly due to its incomplete catalytic triad. BoCLH1 and BoCLH2 showed significant differences in biochemical properties such as pH stability and temperature optimum. Kinetic analysis revealed that BoCLH1 preferably hydrolyzed Mg-free chlorophyll, while BoCLH2 hydrolyzed both chlorophyll and Mg-free chlorophyll at a similar level. Different characteristics between BoCLH1 and BoCLH2 implied that they may have different physiological functions in broccoli. The catalytic triad of recombinant BoCLH2 was identified as Ser141, His247, and Asp170 by site-directed mutagenesis. It suggested that the three broccoli chlorophyllase isozymes were serine hydrolases.