Design, synthesis and biological evaluation of novel tricyclics as dual cholinesterase (ChE) and amyloid aggregation inhibitors with antioxidant properties

Alzheimer’s disease (AD) is a complex neurodegenerative disease affecting the cholinergic region of the brain. Its prevalence is steadily increasing and it is becoming one of the highest costing diseases to modern society. Current drug therapies only provide symptomatic relief and are not a viable option for long-term treatment. Thus, there is a need for more effective disease-modifying therapeutics. Since the discovery of AD, research in the field has led to a number of proposed theories behind the causes of AD including the (i) cholinergic hypothesis (ii) amyloid beta hypothesis and (iii) oxidative stress hypothesis. The major class of drug therapies are cholinesterase inhibitors; however, this “one drug, one target” approach has proved to be ineffective during the later stages of disease progression. Here we examined two novel classes of tricyclics; phenothiazines (5, 6, 7a-l) and phenoselenazines (13, 14, 15a-l) to target the cholinesterases (ChE), amyloid aggregation, and oxidative stress pathways of AD. This new design approach is aimed at discovering potential disease-modifying therapeutics with multi-targeting abilities. Chapter 1 encompasses background information pertaining to the role of each hypothesis in AD including the cholinesterase, amyloid and oxidative stress hypothesis. Chapter 2 provides a summary of the design and hypothesis behind the project. Chapter 3 describes the chemistry conducted including the chemical protocols, reaction schemes and mechanisms in synthesizing the target molecules. Chapter 4 reviews the biological evaluation and the SAR analysis of the synthesized compounds. Furthermore, it describes the principles behind the biological assays conducted including cholinesterase inhibition, amyloid aggregation inhibition, antioxidant properties and cell viability in neuroblastoma cell lines. Chapter 5 consists of the molecular modeling results and their application to help rationalize the results in both the cholinesterase and amyloid aggregation SAR data. Chapter 6 reviews all the data acquired and iv provides ideas for future directions. Finally chapter 7 provides the full experimental details for synthetic chemistry as well as the analytical data for synthesized compounds and protocols for biological evaluations. The research project conducted identified novel tricyclics as dual cholinesterase inhibitors with multi-target abilities in anti-amyloid aggregation inhibition and antioxidant properties. The most potent AChE inhibitor was 15d ((4-methoxyphenyl)-10H-phenoselenazin-10-ylmethanone; AChE IC50 = 4.63 μM), whereas the most potent BuChE inhibitor was 13 (10H-phenoselenazine; BuChE IC50 = 3.00 μM). Overall the best dual cholinesterase derivative was identified as compound 15j (2-chloro-10H-phenoselenazin-10-yl(4-methoxyphenyl)methanone; AChE IC50 = 5.79 μM, BuChE IC50 = 4.91 μM). Both PTZ and PSZ derivatives exhibited good antioxidant properties with weak anti-aggregation activity. In conclusion, our studies provide a new class of tricyclics in the design and development of small molecules to target multiple pathways of AD.1 yea

The language of malaria in Abui: An interdisciplinary investigation of healthcare practices in Alor, Eastern Indonesia

We report on an interdisciplinary collaboration between public health experts, linguists, and botanists which seeks to better understand indigenous perspectives on malaria among the Abui [abz] speaking communities of Alor Island, Eastern Indonesia. Malaria is endemic in Alor and is highly resistant to common conventional treatment regimens (Sutanto et al. 2009). There is a low rate of compliance with modern malaria treatments, and a correspondingly high reliance on traditional treatment methods (Krentel 2008). Our research attempts to understand traditional knowledge of malaria in Abui and its relevance to modern healthcare. We analyze a corpus of unstructured interviews concerning health-related problems in Abui in order to better understand the conceptualization of disease (Forster 1976). This includes the systematic study of metaphor (Author 2016), sequencing of symptom descriptions (Author 2016), symptom-based indigenous classification of malaria, an inventory of traditional health-protecting practices, and an inventory of medical plants. The plant terminology reveals a syncretism between terms referring to diseases and the plants which either treat or cause those diseases. For example, the term takaya denotes both the ti plant (Cordyline fruticosa) and a severe form of malaria (Plasmodium falciparum). The leaves of the ti plant takaya are tied onto valuable trees such as candlenut, areca palm, and jackfruit to create a protective spell which wards off theft of the fruits or nuts of that tree. Transgressing this protection by taking the fruits or nuts without permission will cause the transgressor to suffer the takaya disease. The existence of supernatural causes may go unnoticed when interviews are conducted in Indonesian, the national language closely associated with modernity. However, the pervasiveness of plant-disease syncretism within Abui belies the continuing significance of traditional beliefs regarding disease. The collaborative methodology described here shows great promise for improving our understanding of the conceptualization of malaria in Abui and thus increasing treatment efficacy for this disease. Moreover, this approach provides a platform for documentary linguistics which includes a high level of community engagement. The healthcare interviews yield a culturally significant corpus of spontaneous speech which also serves as an independent knowledge base to evaluate the reliability and accuracy of ethnobotanical research. Finally, we suggest several ways in which our approach can be applied to future healthcare research in other domains and with other communities. References Author. 2016. The Pragmatics Behind the Medical and Health Knowledge in Alor: An Understanding of how disease is conceptualized in the Abui language. Honors thesis. Nanyang Technological University, Singapore. Du Bois, Cora. 1944. The People of Alor: a social-psychological study of an East Indian island. Minnesota: The University of Minnesota Press Forster, George M. 1976. Disease Etiologies in Non-Western Medical Systems. American Anthropologist 78(4): 773-782. Krentel, Alison. 2008. Why do individuals comply with mass drug administration for lymphatic filariasis? A case study from Alor District, Indonesia. PhD dissertation. London School of Hygiene & Tropical Medicine. Sutanto, I. Nurhayati, S. S., Manoempil, P., Baird, J.K. 2009. Resistance to Choloroquine by Plasmodium vivax at Alor in the Lesser Sundas Archipelago in Eastern Indonesia. The American Society of Tropical Medicine and Hygiene, 81(2), 338-342. Author. 2016. The Semantics of Complex Sentences in the Discourse of Health and Diseases: A Case Study in Abui. Honors thesis. Nanyang Technological University, Singapore

Benchmarking global biodiversity of decapod crustaceans (Crustacea: Decapoda)

A new assessment of the global biodiversity of decapod Crustacea (to 31 December 2022) records 17,229 species in 2,550 genera and 203 families. These figures are derived from a well-curated dataset maintained on the online platform DecaNet, a subsidiary of the World Register of Marine Species (WoRMS). Distinct phases are recognised in the discovery process (as measured by species descriptions) corresponding to major historical and geopolitical time periods, with the current rate of species descriptions being more than three times higher than in the Victorian age of global exploration. Future trends are briefly explored, and it is recognised that a large number of species remain to be discovered and described

Multi-ethnic GWAS and meta-analysis of sleep quality identify MPP6 as a novel gene that functions in sleep center neurons

Poor sleep quality can have harmful health consequences. Although many aspects of sleep are heritable, the understandings of genetic factors involved in its physiology remain limited. Here, we performed a genome-wide association study (GWAS) using the Pittsburgh Sleep Quality Index (PSQI) in a multi-ethnic discovery cohort (n = 2868) and found two novel genome-wide loci on chromosomes 2 and 7 associated with global sleep quality. A meta-analysis in 12 independent cohorts (100 000 individuals) replicated the association on chromosome 7 between NPY and MPP6. While NPY is an important sleep gene, we tested for an independent functional role of MPP6. Expression data showed an association of this locus with both NPY and MPP6 mRNA levels in brain tissues. Moreover, knockdown of an orthologue of MPP6 in Drosophila melanogaster sleep center neurons resulted in decreased sleep duration. With convergent evidence, we describe a new locus impacting human variability in sleep quality through known NPY and novel MPP6 sleep genes.Peer reviewe

Robotic-assisted surgery for left sided colon and rectal resections is associated with reduction in the postoperative surgical stress response and improved short-term outcomes: a cohort study

Introduction: There is growing evidence that the use of robotic-assisted surgery (RAS) in colorectal cancer resections is associated with improved short-term outcomes when compared to laparoscopic surgery (LS) or open surgery (OS), possibly through a reduced systemic inflammatory response (SIR). Serum C-reactive protein (CRP) is a sensitive SIR biomarker and its utility in the early identification of post-operative complications has been validated in a variety of surgical procedures. There remains a paucity of studies characterising post-operative SIR in RAS. Methods: Retrospective study of a prospectively collected database of consecutive patients undergoing OS, LS and RAS for left-sided and rectal cancer in a single high-volume unit. Patient and disease characteristics, post-operative CRP levels, and clinical outcomes were reviewed, and their relationships explored within binary logistic regression and propensity scores matched models. Results: A total of 1031 patients were included (483 OS, 376 LS, and 172 RAS). RAS and LS were associated with lower CRP levels across the first 4 post-operative days (p < 0.001) as well as reduced complications and length of stay compared to OS in unadjusted analyses. In binary logistic regression models, RAS was independently associated with lower CRP levels at Day 3 post-operatively (OR 0.35, 95% CI 0.21-0.59, p < 0.001) and a reduction in the rate of all complications (OR 0.39, 95% CI 0.26-0.56, p < 0.001) and major complications (OR 0.5, 95% CI 0.26-0.95, p = 0.036). Within a propensity scores matched model comparing LS versus RAS specifically, RAS was associated with lower post-operative CRP levels in the first two post-operative days, a lower proportion of patients with a CRP ≥ 150 mg/L at Day 3 (20.9% versus 30.5%, p = 0.036) and a lower rate of all complications (34.7% versus 46.7%, p = 0.033). Conclusions: The present observational study shows that an RAS approach was associated with lower postoperative SIR, and a better postoperative complications profile

P‐wave durations from automated electrocardiogram analysis to predict atrial fibrillation and mortality in heart failure

Background: P-wave indices have been used to predict incident atrial fibrillation (AF), stroke, and mortality. However, such indices derived from automated ECG measurements have not been explored for their predictive values in heart failure (HF). We investigated whether automated P-wave indices can predict adverse outcomes in HF. Methods: This study included consecutive Chinese patients admitted to a single tertiary centre, presenting with HF but without prior AF, and with at least one baseline ECG, between 1 January 2010 and 31 December 2016, with last follow-up of 31 December 2019. Results: A total of 2718 patients were included [median age: 77.4, interquartile range (IQR): (66.9–84.3) years; 47.9 males]. After a median follow-up of 4.8 years (IQR: 1.9–9.0 years), 1150 patients developed AF (8.8/year), 339 developed stroke (2.6/year), 563 developed cardiovascular mortality (4.3/year), and 1972 had all-cause mortality (15.1/year). Compared with 101–120 ms as a reference, maximum P-wave durations predicted new-onset AF at ≤90 ms [HR: 1.17(1.11, 1.50), P < 0.01], 131–140 ms [HR: 1.29(1.09, 1.54), P < 0.001], and ≥141 ms [HR: 1.52(1.32, 1.75), P < 0.001]. Similarly, they predicted cardiovascular mortality at ≤90 ms [HR: 1.50(1.08, 2.06), P < 0.001] or ≥141 ms [HR: 1.18(1.15, 1.45), P < 0.001], and all-cause mortality at ≤90 ms [HR: 1.26(1.04, 1.51), P < 0.001], 131–140 ms [HR: 1.15(1.01, 1.32), P < 0.01], and ≥141 ms [HR: 1.31(1.18, 1.46), P < 0.001]. These remained significant after adjusting for significant demographics, past co-morbidities, P-wave dispersion, and maximum P-wave amplitude. Conclusions: Extreme values of maximum P-wave durations (≤90 ms and ≥141 ms) were significant predictors of new-onset AF, cardiovascular mortality, and all-cause mortality

Plasminogen Alleles Influence Susceptibility to Invasive Aspergillosis

Invasive aspergillosis (IA) is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855) correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser) where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn) was also identified in the human homolog (PLG; Gene ID 5340). An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT) recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection

The Magnitude of Global Marine Species Diversity

Background: The question of how many marine species exist is important because it provides a metric for how much we do and do not know about life in the oceans. We have compiled the first register of the marine species of the world and used this baseline to estimate how many more species, partitioned among all major eukaryotic groups, may be discovered. Results: There are ∼226,000 eukaryotic marine species described. More species were described in the past decade (∼20,000) than in any previous one. The number of authors describing new species has been increasing at a faster rate than the number of new species described in the past six decades. We report that there are ∼170,000 synonyms, that 58,000–72,000 species are collected but not yet described, and that 482,000–741,000 more species have yet to be sampled. Molecular methods may add tens of thousands of cryptic species. Thus, there may be 0.7–1.0 million marine species. Past rates of description of new species indicate there may be 0.5 ± 0.2 million marine species. On average 37% (median 31%) of species in over 100 recent field studies around the world might be new to science. Conclusions: Currently, between one-third and two-thirds of marine species may be undescribed, and previous estimates of there being well over one million marine species appear highly unlikely. More species than ever before are being described annually by an increasing number of authors. If the current trend continues, most species will be discovered this century

1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

HapMap imputed genome-wide association studies (GWAS) have revealed &gt;50 loci at which common variants with minor allele frequency &gt;5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value &lt; 5 × 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR &lt; 0.05) genes and 127 significantly (FDR &lt; 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples