The Brain Economy: Advancing Brain Science to Better Understand the Modern Economy.

The coming years are likely to be turbulent due to a myriad of factors or polycrisis, including an escalation in climate extremes, emerging public health threats, weak productivity, increases in global economic instability and further weakening in the integrity of global democracy. These formidable challenges are not exogenous to the economy but are in some cases generated by the system itself. They can be overcome, but only with far-reaching changes to global economics. Our current socio-economic paradigm is insufficient for addressing these complex challenges, let alone sustaining human development, well-being and happiness. To support the flourishing of the global population in the age of polycrisis, we need a novel, person-centred and collective paradigm. The brain economy leverages insights from neuroscience to provide a novel way of centralising the human contribution to the economy, how the economy in turn shapes our lives and positive feedbacks between the two. The brain economy is primarily based on Brain Capital, an economic asset integrating brain health and brain skills, the social, emotional, and the diversity of cognitive brain resources of individuals and communities. People with healthy brains are essential to navigate increasingly complex systems. Policies and investments that improve brain health and hence citizens' cognitive functions and boost brain performance can increase productivity, stimulate greater creativity and economic dynamism, utilise often underdeveloped intellectual resources, afford social cohesion, and create a more resilient, adaptable and sustainability-engaged population.

Airway inflammatory changes in the lungs of patients with asthma-COPD overlap (ACO): a bronchoscopy endobronchial biopsy study.

BACKGROUND: Although asthma and chronic obstructive pulmonary disease (COPD) are two distinct chronic airway inflammatory diseases, they often co-exist in a patient and the condition is referred to as asthma-COPD overlap (ACO). Lack of evidence regarding the inflammatory cells in ACO airways has led to their poor prognosis and treatment. The objective of this endobronchial biopsy (EBB) study was to enumerate inflammatory cellular changes in the airway wall of ACO compared with asthma, COPD current smokers (CS) and ex-smokers (ES), normal lung function smokers (NLFS), and non-smoker controls (HC). METHODS: EBB tissues from 74 patients were immunohistochemically stained for macrophages, mast cells, eosinophils, neutrophils, CD8+ T-cells and CD4+ T-cells. The microscopic images of stained tissues were evaluated in the epithelium, reticular basement membrane (RBM) cells/mm RBM length, and lamina propria (LP) cells/mm2 up to a depth of 120 µM using the image analysis software Image-Pro Plus 7.0. The observer was blinded to the images and disease diagnosis. Statistical analysis was performed using GraphPad Prism v9. RESULTS: The tissue macrophages in ACO were substantially higher in the epithelium and RBM than in HC (P < 0.001 for both), COPD-ES (P < 0.001 for both), and -CS (P < 0.05 and < 0.0001, respectively). The ACO LP macrophages were significantly higher in number than COPD-CS (P < 0.05). The mast cell numbers in ACO were lower than in NLFS (P < 0.05) in the epithelium, lower than COPD (P < 0.05) and NLFS (P < 0.001) in RBM; and lower than  HC (P < 0.05) in LP. We noted lower eosinophils in ACO LP than HC (P < 0.05) and the lowest neutrophils in both ACO and asthma. Furthermore, CD8+ T-cell numbers increased in the ACO RBM than HC (P < 0.05), COPD-ES (P < 0.05), and NLFS (P < 0.01); however, they were similar in number in epithelium and LP across groups. CD4+ T-cells remained lower in number across all regions and groups. CONCLUSION: These results suggest that the ACO airway tissue inflammatory cellular profile differed from the contributing diseases of asthma and COPD with a predominance of macrophages.

Synthesis and in vitro antiprotozoal evaluation of novel metronidazole-Schiff base hybrids.

Herein we report the synthesis of 21 novel small molecules inspired by metronidazole and Schiff base compounds. The compounds were evaluated against Trichomonas vaginalis and cross-screened against other pathogenic protozoans of clinical relevance. Most of these compounds were potent against T. vaginalis, exhibiting IC50 values < 5 µM. Compound 20, the most active compound against T. vaginalis, exhibited an IC50 value of 3.4 µM. A few compounds also exhibited activity against Plasmodium falciparum and Trypanosomal brucei brucei, with compound 6 exhibiting an IC50 value of 0.7 µM against P. falciparum and compound 22 exhibiting an IC50 value of 1.4 µM against T.b. brucei. Compound 22 is a broad-spectrum antiprotozoal agent, showing activities against all three pathogenic protozoans under investigation.

Differential airway remodeling changes were observed in patients with asthma COPD overlap compared to patients with asthma and COPD alone.

Management of patients with asthma COPD overlap (ACO) is clinically challenging due to insufficient evidence of pathological changes in these patients. In this cross-sectional study, we evaluated airway remodeling in endobronchial biopsies from a total of 90 subjects, which included 12 ACO, 14 patients with asthma, 12 COPD exsmokers (ES), 11 current smokers (CS), 28 healthy controls (HC), and 13 normal lung function smokers (NLFS). Tissue was stained with Masson's trichrome. Epithelium, goblet cells, reticular basement membrane (RBM), cellularity, lamina propria (LP), and smooth muscle (SM) changes were measured using Image-Pro Plus v7 software. Differential airway remodeling pattern was seen in patients with ACO. A limited change was noted in the ACO epithelium compared with other pathological groups. RBM was substantially thicker in patients with ACO than in HC (P < 0.0002) and tended to be thicker than in patients with asthma and NLFS. The total RBM cells were higher in ACO than in the HC (P < 0.0001), COPD-CS (P = 0.0559), -ES (P = 0.0345), and NLFS (P < 0.0002), but did not differ from patients with asthma. Goblet cells were higher in the ACO than in the HC (P = 0.0028) and COPD-ES (P = 0.0081). The total LP cells in ACO appeared to be higher than in HC, COPD-CS, and NLFS but appeared to be lower than in patients with asthma. Finally, SM area was significantly lower in the ACO than in patients with asthma (P = 0.001), COPD-CS (=0.0290), and NLFS (P = 0.0011). This first comprehensive study suggests that patients with ACO had distinguishable tissue remodeling that appeared to be more severe than patients with asthma and COPD. This study will help in informed decision-making for better patient management in clinical practice.

Emergency department childhood anaphylaxis presentations in regional/remote Australia.

AIM: Explore the prevalence of childhood anaphylaxis and clinical presentation of anaphylaxis in children across two regional emergency departments over a 7-year period. METHODS: Retrospective audit of all children (0-18 years) presenting to emergency from 1 January 2010 to 31 December 2016 with anaphylaxis, defined by Australasian Society of Clinical Immunology and Allergy definitions and doctor diagnosis. RESULTS: Seven hundred and twenty-four patients were identified with allergic diagnosis, 60% were diagnosed with non-anaphylaxis allergic reactions or unspecified urticaria and 40% with anaphylaxis (n = 286). Annual prevalence of anaphylaxis remained stable over the study period (M = 30.9/10 000 cases, range: 20.8-48.3/10 000). Gender distribution was equal, median age was 9.48 years (interquartile range = 4-15). Most (71%) arrived by private transport. 23% had a prior history of anaphylaxis. Food triggers (44%) were the most common cause of anaphylaxis. Insect bites/stings triggers occurred in 21%. Patients were promptly assessed (average wait time = 13 min), 16% received prior adrenaline injections. Adrenaline was administered in 26% and 20% were admitted to hospital. On discharge, 29% had a follow-up plan, 9% received an allergy clinic referral, 6% anaphylaxis action plan, 26% adrenaline autoinjector prescriptions and allergy testing performed in 6%. CONCLUSIONS: We found a relatively low prevalence of overall childhood anaphylaxis in a regional area. The two most common causes of anaphylaxis in this population (food and bites/stings) recorded increased prevalence providing an opportunity for further study. Significant gaps in evidence-based care of anaphylaxis were noted, demonstrating the need for improved recognition and treatment guideline implementation in regional areas.

Phytochemical, Antiplasmodial, and Cytotoxic Investigation of Euclea natalensis A.DC. subsp. natalensis Leaves.

Previous research shows that the root and bark extracts of Euclea natalensis have antiplasmodial activity, but the leaves have not been examined yet. This study investigated the phytochemical, antiplasmodial, and cytotoxic properties of the plant leaves. The activity against 3D7 Plasmodium falciparum was determined using the parasite lactate dehydrogenase assay, and the cytotoxicity against Vero and HeLa cells was evaluated using the MTT and resazurin assays, respectively. The bioactive compounds were isolated by chromatography, and their structures were established with spectroscopic and spectrometric techniques. The extract showed antiplasmodial activity (IC50 =25.6 µg/mL) and was not cytotoxic against Vero cells (IC50 =403.7 µg/mL). Purification of the extract afforded six flavonoid glycosides, four triterpenoids, and a coumarin. The glycosides showed antiplasmodial and cytotoxic activities, against HeLa cells, at 50 µg/mL, but the activity was reduced at 10 µg/mL. Naphthoquinones, which are among the predominant phytochemicals in the root and root bark of E. natalensis, were not detected in the leaves.

Dysregulation of endocytic machinery and ACE2 in small airways of smokers and COPD patients can augment their susceptibility to SARS-CoV-2 (COVID-19) infections.

Lungs of smokers and chronic obstructive pulmonary disease (COPD) are severely compromised and are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attack. The dangerous combination of enhanced SARS-CoV-2 attachment receptor protein ACE2 along with an increase in endocytic vacuoles will enable viral attachment, entry, and replication. The objective of the study was to identify the presence of SARS-CoV-2 host attachment receptor angiotensin-converting enzyme-2 (ACE2) along with endocytic vacuoles, early endosome antigen-1 (EEA1), late endosome marker RAB7, cathepsin-L, and lysosomal associated membrane protein-1 (LAMP-1) as lysosome markers in the airways of smokers and COPD patients. The study design was cross-sectional and involved lung resections from 39 patients in total, which included 19 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I or GOLD stage II COPD, of which 9 were current smokers with COPD (COPD-CS) and 10 were ex-smokers with COPD (COPD-ES), 10 were normal lung function smokers, and 10 were never-smoking normal controls. Immunostaining for ACE2, EEA1, RAB7, and cathepsin-L was done. A comparative description for ACE2, EEA1, RAB7, and cathepsin-L expression pattern is provided for the patient groups. Furthermore, staining intensity for LAMP-1 lysosomes was measured as the ratio of the LAMP-1-stained areas per total area of epithelium or subepithelium, using Image ProPlus v7.0 software. LAMP-1 expression showed a positive correlation to patient smoking history while in COPD LAMP-1 negatively correlated to lung function. The active presence of ACE2 protein along with endocytic vacuoles such as early/late endosomes and lysosomes in the small airways of smokers and COPD patients provides evidence that these patient groups could be more susceptible to COVID-19.

Design, synthesis and biological evaluation of mono- and bisquinoline methanamine derivatives as potential antiplasmodial agents.

Several classes of antimalarial drugs are currently available, although issues of toxicity and the emergence of drug resistant malaria parasites have reduced their overall therapeutic efficiency. Quinoline based antiplasmodial drugs have unequivocally been long-established and continue to inspire the design of new antimalarial agents. Herein, a series of mono- and bisquinoline methanamine derivatives were synthesised through sequential steps; Vilsmeier-Haack, reductive amination, and nucleophilic substitution, and obtained in low to excellent yields. The resulting compounds were investigated for in vitro antiplasmodial activity against the 3D7 chloroquine-sensitive strain of Plasmodium falciparum, and compounds 40 and 59 emerged as the most promising with IC50 values of 0.23 and 0.93 µM, respectively. The most promising compounds were also evaluated in silico by molecular docking protocols for binding affinity to the {001} fast-growing face of a hemozoin crystal model.

Antiplasmodial and Cytotoxic Activities of Extract and Compounds from Ozoroa obovata (Oliv.) R. & A. Fern. var. obovata.

Ozoroa obovata (Oliv.) R. & A. Fern. var. obovata found in KwaZulu-Natal in South Africa was investigated for phytochemical constituents, and for antiplasmodial and cytotoxic effects. The plant leaves were collected from the University of KwaZulu-Natal (UKZN) arboretum on the Pietermaritzburg Campus, in March 2019. The inhibitory activity against 3D7 Plasmodium falciparum was determined using the parasite lactate dehydrogenase (pLDH) assay and cytotoxicity against HeLa cells was evaluated using the resazurin assay. The bioactive compounds were isolated by chromatographic purification and their structures were established with spectroscopic and spectrometric techniques. The plant leaf extract displayed significant antiplasmodial activity at 50 µg/mL and was also cytotoxic against HeLa cells. Chromatographic purification of the extract led to the isolation of two biflavonoids, four flavonoid glycosides, a steroid glycoside, and a megastigmene derivative. The compounds displayed antiplasmodial and antiproliferative activities at 50 µg/mL but the activity was substantially reduced at 10 µg/mL. The activities and compounds are being reported in O. obovata for the first time.

Synthesis of 2-(N-cyclicamino)quinoline combined with methyl (E)-3-(2/3/4-aminophenyl)acrylates as potential antiparasitic agents.

A rationally designed series of 2-(N-cyclicamino)quinolines coupled with methyl (E)-3-(2/3/4-aminophenyl)acrylates was synthesized and subjected to in vitro screening bioassays for potential antiplasmodial and antitrypanosomal activities against a chloroquine-sensitive (3D7) strain of Plasmodium falciparum and nagana Trypanosoma brucei brucei 427, respectively. Substituent effects on activity were evaluated; meta-acrylate 24 and the ortho-acrylate 29 exhibited the highest antiplasmodial (IC50 = 1.4 µM) and antitrypanosomal (IC50 = 10.4 µM) activities, respectively. The activity against HeLa cells showed that the synthesized analogs are not cytotoxic at the maximum tested concentration. The ADME (absorption, distribution, metabolism, and excretion) drug-like properties of the synthesized compounds were predicted through the SwissADME software.

Antiplasmodial and Cytotoxic Flavonoids from Pappea capensis (Eckl. & Zeyh.) Leaves.

Ethnobotanical surveys indicate that the Masai and Kikuyu in Kenya, the Venda in South Africa, and the Gumuz people of Ethiopia use Pappea capensis for the treatment of malaria. The present study aimed to investigate the phytochemical and antiplasmodial properties of the plant leaves. The bioactive compounds were isolated using chromatographic techniques. The structures were established using NMR, HRMS, and UV spectroscopy. Antiplasmodial activity of P. capensis leaf extract and isolated compounds against chloroquine-sensitive 3D7 P. falciparum was evaluated using the parasite lactate dehydrogenase assay. Cytotoxicity against HeLa (human cervix adenocarcinoma) cells was determined using the resazurin assay. The extract inhibited the viability of Plasmodium falciparum by more than 80% at 50 µg/mL, but it was also cytotoxic against HeLa cells at the same concentration. Chromatographic purification of the extract led to the isolation of four flavonoid glycosides and epicatechin. The compounds displayed a similar activity pattern with the extract against P. falciparum and HeLa cells. The results from this study suggest that the widespread use of P. capensis in traditional medicine for the treatment of malaria might have some merits. However, more selectivity studies are needed to determine whether the leaf extract is cytotoxic against noncancerous cells.

Easy-To-Access Quinolone Derivatives Exhibiting Antibacterial and Anti-Parasitic Activities.

The cell wall of Mycobacterium tuberculosis (Mtb) has a unique structural organisation, comprising a high lipid content mixed with polysaccharides. This makes cell wall a formidable barrier impermeable to hydrophilic agents. In addition, during host infection, Mtb resides in macrophages within avascular necrotic granulomas and cavities, which shield the bacterium from the action of most antibiotics. To overcome these protective barriers, a new class of anti-TB agents exhibiting lipophilic character have been recommended by various reports in literature. Herein, a series of lipophilic heterocyclic quinolone compounds was synthesised and evaluated in vitro against pMSp12::GFP strain of Mtb, two protozoan parasites (Plasmodium falciparum and Trypanosoma brucei brucei) and against ESKAPE pathogens. The resultant compounds exhibited varied anti-Mtb activity with MIC90 values in the range of 0.24-31 µM. Cross-screening against P. falciparum and T.b. brucei, identified several compounds with antiprotozoal activities in the range of 0.4-20 µM. Compounds were generally inactive against ESKAPE pathogens, with only compounds 8c, 8g and 13 exhibiting moderate to poor activity against S. aureus and A. baumannii.

Coumarin-Annulated Ferrocenyl 1,3-Oxazine Derivatives Possessing In Vitro Antimalarial and Antitrypanosomal Potency.

A tailored series of coumarin-based ferrocenyl 1,3-oxazine hybrid compounds was synthesized and investigated for potential antiparasitic activity, drawing inspiration from the established biological efficacy of the constituent chemical motifs. The structural identity of the synthesized compounds was confirmed by common spectroscopic techniques: NMR, HRMS and IR. Biological evaluation studies reveal that the compounds exhibit higher in vitro antiparasitic potency against the chemosensitive malarial strain (3D7 P. falciparum) over the investigated trypanosomiasis causal agent (T. b. brucei 427) with mostly single digit micromolar IC50 values. When read in tandem with the biological performance of previously reported structurally similar non-coumarin, phenyl derivatives (i.e., ferrocenyl 1,3-benzoxazines and α-aminocresols), structure-activity relationship analyses suggest that the presence of the coumarin nucleus is tolerated for biological activity though this may lead to reduced efficacy. Preliminary mechanistic studies with the most promising compound (11b) support hemozoin inhibition and DNA interaction as likely mechanistic modalities by which this class of compounds may act to produce plasmocidal and antitrypanosomal effects.

The in Vitro Antiplasmodial and Antiproliferative Activity of New Ferrocene-Based α-Aminocresols Targeting Hemozoin Inhibition and DNA Interaction.

The conjugation of organometallic complexes to known bioactive organic frameworks is a proven strategy revered for devising new drug molecules with novel modes of action. This approach holds great promise for the generation of potent drug leads in the quest for therapeutic chemotypes with the potential to overcome the development of clinical resistance. Herein, we present the in vitro antiplasmodial and antiproliferative investigation of ferrocenyl α-aminocresol conjugates assembled by amalgamation of the organometallic ferrocene unit and an α-aminocresol scaffold possessing antimalarial activity. The compounds pursued in the study exhibited higher toxicity towards the chemosensitive (3D7) and -resistant (Dd2) strains of the Plasmodium falciparum parasite than to the human HCC70 triple-negative breast cancer cell line. Indication of cross-resistance was absent for the compounds evaluated against the multi-resistant Dd2 strain. Structure-activity analysis revealed that the phenolic hydroxy group and rotatable σ bond between the α-carbon and NH group of the α-amino-o-cresol skeleton are crucial for the biological activity of the compounds. Spectrophotometric techniques and in silico docking simulations performed on selected derivatives suggest that the compounds show a dual mode of action involving hemozoin inhibition and DNA interaction via minor-groove binding. Lastly, compound 9 a, identified as a possible lead, exhibited preferential binding for the plasmodial DNA isolated from 3D7 P. falciparum trophozoites over the mammalian calf thymus DNA, thereby substantiating the enhanced antiplasmodial activity of the compounds. The presented research demonstrates the strategy of incorporating organometallic complexes into known biologically active organic scaffolds as a viable avenue to fashion novel multimodal compounds with potential to counter the development drug resistance.

Synthesis and biological evaluation of bis-N2,N2'-(4-hydroxycoumarin-3-yl)ethylidene]-2,3-dihydroxysuccinodihydrazides.

A series of N2,N2'-bis[4-hydroxycoumarin-3-yl)ethylidene]-2,3-dihydroxysuccino-hydrazides, containing 4-hydroxycoumarin, hydrazine and tartaric acid moieties, have been prepared and examined for possible biological activity. Several of these compounds exhibit promising HIV-1 integrase inhibition (IC50 = 3.5 µM), and anti-T. brucei (32% viability) and anti-mycobacterial (Visual MIC90 = 15.63 µM) activity.

Synthesis and anti-parasitic activity of N-benzylated phosphoramidate Mg2+-chelating ligands.

A series of N-benzylated phosphoramidate esters, containing a 3,4-dihydroxyphenyl Mg2+-chelating group, has been synthesised in five steps as analogues of fosmidomycin, a Plasmodium falciparum 1-deoxy-1-d-xylulose-5-phosphate reductoisomerase (PfDXR) inhibitor. The 3,4-dihydroxyphenyl group effectively replaces the Mg2+-chelating hydroxamic acid group in fosmidomycin. The compounds showed very encouraging anti-parasitic activity with IC50 values of 5.6-16.4 µM against Plasmodium falciparum parasites and IC50 values of 5.2 - 10.2 µM against Trypanosoma brucei brucei (T.b.brucei). Data obtained from in silico docking of the ligands in the PfDXR receptor cavity (3AU9)5 support their potential as PfDXR inhibitors.

Synthesis and anti-parasitic activity of achiral N-benzylated phosphoramidic acid derivatives.

Synthetic pathways have been developed to access a series of N-benzylated phosphoramidic acid derivatives as novel, achiral analogues of the established Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductase (PfDXR) enzyme inhibitor, FR900098. Bioassays of the targeted compounds and their synthetic precursors have revealed minimal antimalarial activity but encouraging anti-trypanosomal activity - in one case with an IC50 value of 5.4 µM against Trypanosoma brucei, the parasite responsible for Nagana (African cattle sleeping sickness). The results of relevant in silico modelling and docking studies undertaken in the design and evaluation of these compounds are discussed.

In Vitro Studies on Antioxidant and Anti-Parasitic Activities of Compounds Isolated from Rauvolfia caffra Sond.

As part of an ongoing study of natural products from local medicinal plants, the methanol extract of stem bark of Rauvolfia caffra Sond was investigated for biological activity. Column chromatography and preparative thin-layer chromatography were used to isolate lupeol (1), raucaffricine (2), N-methylsarpagine (3), and spegatrine (4). The crude extract, fractions and isolated compounds were tested for anti-oxidant, antitrypanosomal and anti-proliferation activities. Two fractions displayed high DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical scavenging activity and reducing power with IC50 (The half maximal inhibitory concentration) and IC0.5 values of 0.022 ± 0.003 mg/mL and 0.036 ± 0.007 mg/mL, and 0.518 ± 0.044 mg/mL and 1.076 ± 0.136 mg/mL, respectively. Spegatrine (4) was identified as the main antioxidant compound in R. caffra with IC50 and IC0.5 values of 0.119 ± 0.067 mg/mL and 0.712 ± 0 mg/mL, respectively. One fraction displayed high antitrypanosomal activity with an IC50 value of 18.50 µg/mL. However, the major constituent of this fraction, raucaffricine (2), was not active. The crude extract, fractions and pure compounds did not display any cytotoxic effect at a concentration of 50 µg/mL against HeLa cells. This study shows directions for further in vitro studies on the antioxidant and antitrypanosomal activities of Rauvolfia caffra Sond.

Synthesis, Structure and In Vitro Anti-Trypanosomal Activity of Non-Toxic Arylpyrrole-Based Chalcone Derivatives.

With an intention of identifying chalcone derivatives exhibiting anti-protozoal activity, a cohort of relatively unexplored arylpyrrole-based chalcone derivatives were synthesized in moderate to good yields. The resultant compounds were evaluated in vitro for their potential activity against a cultured Trypanosoma brucei brucei 427 strain. Several compounds displayed mostly modest in vitro anti-trypanosomal activity with compounds 10e and 10h emerging as active candidates with IC50 values of 4.09 and 5.11 µM, respectively. More importantly, a concomitant assessment of their activity against a human cervix adenocarcinoma (HeLa) cell line revealed that these compounds are non-toxic.

Novobiocin-ferrocene conjugates possessing anticancer and antiplasmodial activity independent of HSP90 inhibition.

A series of tailored novobiocin-ferrocene conjugates was prepared in moderate yields and investigated for in vitro anticancer and antiplasmodial activity against the MDA-MB-231 breast cancer line and Plasmodium falciparum 3D7 strain, respectively. While the target compounds displayed moderate anticancer activity against the breast cancer cell line with IC50 values in the mid-micromolar range, compounds 10a-c displayed promising antiplasmodial activity as low as 0.889 µM. Furthermore, the most promising compounds were tested for inhibitory effects against a postulated target, heat shock protein 90 (Hsp90). A selection of tailored novobiocin derivatives bearing the organometallic ferrocene unit were synthesized and characterized by common spectroscopic techniques. The target compounds were investigated for in vitro anticancer and antimalarial activity against the MDA-MB-231 breast cancer cell line and Plasmodium falciparum 3D7 strain, respectively.