EDITOR SPOTLIGHT: Interview with Cholinergic Mechanisms Special Issue Guest Editor Hermona Soreq.

Hermona Soreq holds a Hebrew University Slesinger Chair in Molecular Neuroscience and is among the founding members of the Edmond and Lily Safra Center of Brain Sciences (ELSC). Soreq's research (H-impact: 98) focuses on acetylcholine (ACh)-related pathways and combines RNA-sequencing technologies, transgenic engineering, and molecular biology tests with in-depth analysis approaches. Her work addresses microRNAs (miRs) and transfer RNA fragments (tRFs) which have rapidly acquired wide recognition as global controllers of regulatory processes in healthy and diseased brain and body, including anxiety, inflammation, and cognition. Altogether, Soreq's work leads to molecular neuroscience-driven prevention and/or intervention with diseases involving impaired ACh signaling, including schizophrenia, bipolar disorder, Alzheimer's disease, and stress. Hermona led this Special Issue based on the 17th Symposium on Cholinergic Mechanisms (ISCM2022). We interviewed her on the progress in the field, what she wants to achieve as Senior Editor for the Gene Regulation and Genetics category at the Journal of Neurochemistry, key moments, and future directions.

EDITOR SPOTLIGHT: Interview with Brain Proteostasis Special Issue Guest Editor Mychael Lourenco.

Mychael Lourenco is an Assistant Professor of Neuroscience at the Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro. Research in his lab focusses on understanding the molecular mechanisms underlying cognitive impairment in neurodegeneration and his research on Alzheimer's disease has been recognized by many awards both in Brazil and internationally. He serves as a Reviews Editor for the Journal of Neurochemistry and led this special issue on Brain Proteostasis as a Guest Editor. Here we interviewed him to hear his thoughts on the future of neuroscience and on career development and training.

Characterization of epidermal bladder cells in Chenopodium quinoa.

Chenopodium quinoa (quinoa) is considered a superfood with its favourable nutrient composition and being gluten free. Quinoa has high tolerance to abiotic stresses, such as salinity, water deficit (drought) and cold. The tolerance mechanisms are yet to be elucidated. Quinoa has epidermal bladder cells (EBCs) that densely cover the shoot surface, particularly the younger parts of the plant. Here, we report on the EBC's primary and secondary metabolomes, as well as the lipidome in control conditions and in response to abiotic stresses. EBCs were isolated from plants after cold, heat, high-light, water deficit and salt treatments. We used untargeted gas chromatography-mass spectrometry (GC-MS) to analyse metabolites and untargeted and targeted liquid chromatography-MS (LC-MS) for lipids and secondary metabolite analyses. We identified 64 primary metabolites, including sugars, organic acids and amino acids, 19 secondary metabolites, including phenolic compounds, betanin and saponins and 240 lipids categorized in five groups including glycerolipids and phospholipids. We found only few changes in the metabolic composition of EBCs in response to abiotic stresses; these were metabolites related with heat, cold and high-light treatments but not salt stress. Na+ concentrations were low in EBCs with all treatments and approximately two orders of magnitude lower than K+ concentrations.

Decarboxylative-coupling of allyl acetate catalyzed by group 10 organometallics, [(phen)M(CH3)]+.

Gas-phase carbon-carbon bond forming reactions, catalyzed by group 10 metal acetate cations [(phen)M(O2CCH3)](+) (where M = Ni, Pd or Pt) formed via electrospray ionization of metal acetate complexes [(phen)M(O2CCH3)2], were examined using an ion trap mass spectrometer and density functional theory (DFT) calculations. In step 1 of the catalytic cycle, collision induced dissociation (CID) of [(phen)M(O2CCH3)](+) yields the organometallic complex, [(phen)M(CH3)](+), via decarboxylation. [(phen)M(CH3)](+) reacts with allyl acetate via three competing reactions, with reactivity orders (% reaction efficiencies) established via kinetic modeling. In step 2a, allylic alkylation occurs to give 1-butene and reform metal acetate, [(phen)M(O2CCH3)](+), with Ni (36%) > Pd (28%) > Pt (2%). Adduct formation, [(phen)M(C6H11O2)](+), occurs with Pt (24%) > Pd (21%) > Ni(11%). The major losses upon CID on the adduct, [(phen)M(C6H11O2)](+), are 1-butene for M = Ni and Pd and methane for Pt. Loss of methane only occurs for Pt (10%) to give [(phen)Pt(C5H7O2)](+). The sequences of steps 1 and 2a close a catalytic cycle for decarboxylative carbon-carbon bond coupling. DFT calculations suggest that carbon-carbon bond formation occurs via alkene insertion as the initial step for all three metals, without involving higher oxidation states for the metal centers.

Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer's disease.

Background: Alzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation. Prior research has shown promising disease-modifying effects in experimental AD models. The present study (NCT03556280: OVERTURE) evaluated the feasibly, safety and efficacy of evoked gamma oscillation treatment using Cognito's medical device (CogTx-001) in participants with mild to moderate AD. Methods: The present study was a randomized, double blind, sham-controlled, 6-months clinical trial in participants with mild to moderate AD. The trial enrolled 76 participants, aged 50 or older, who met the clinical criteria for AD with baseline MMSE scores between 14 and 26. Participants were randomly assigned 2:1 to receive self-administered daily, one-hour, therapy, evoking EEG-verified gamma oscillations or sham treatment. The CogTx-001 device was use at home with the help of a care partner, over 6 months. The primary outcome measures were safety, evaluated by physical and neurological exams and monthly assessments of adverse events (AEs) and MRI, and tolerability, measured by device use. Although the trial was not statistically powered to evaluate potential efficacy outcomes, primary and secondary clinical outcome measures included several cognitive and functional endpoints. Results: Total AEs were similar between groups, there were no unexpected serious treatment related AEs, and no serious treatment-emergent AEs that led to study discontinuation. MRI did not show Amyloid-Related Imaging Abnormalities (ARIA) in any study participant. High adherence rates (85-90%) were observed in sham and treatment participants. There was no statistical separation between active and sham arm participants in primary outcome measure of MADCOMS or secondary outcome measure of CDR-SB or ADAS-Cog14. However, some secondary outcome measures including ADCS-ADL, MMSE, and MRI whole brain volume demonstrated reduced progression in active compared to sham treated participants, that achieved nominal significance. Conclusion: Our results demonstrate that 1-h daily treatment with Cognito's Evoked Gamma Therapy System (CogTx-001) was safe and well-tolerated and demonstrated potential clinical benefits in mild to moderate AD.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03556280.

Minimal expression of dysferlin prevents development of dysferlinopathy in dysferlin exon 40a knockout mice.

Dysferlin is a Ca2+-activated lipid binding protein implicated in muscle membrane repair. Recessive variants in DYSF result in dysferlinopathy, a progressive muscular dystrophy. We showed previously that calpain cleavage within a motif encoded by alternatively spliced exon 40a releases a 72 kDa C-terminal minidysferlin recruited to injured sarcolemma. Herein we use CRISPR/Cas9 gene editing to knock out murine Dysf exon 40a, to specifically assess its role in membrane repair and development of dysferlinopathy. We created three Dysf exon 40a knockout (40aKO) mouse lines that each express different levels of dysferlin protein ranging from ~ 90%, ~ 50% and ~ 10-20% levels of wild-type. Histopathological analysis of skeletal muscles from all 12-month-old 40aKO lines showed virtual absence of dystrophic features and normal membrane repair capacity for all three 40aKO lines, as compared with dysferlin-null BLAJ mice. Further, lipidomic and proteomic analyses on 18wk old quadriceps show all three 40aKO lines are spared the profound lipidomic/proteomic imbalance that characterises dysferlin-deficient BLAJ muscles. Collective results indicate that membrane repair does not depend upon calpain cleavage within exon 40a and that ~ 10-20% of WT dysferlin protein expression is sufficient to maintain the muscle lipidome, proteome and membrane repair capacity to crucially prevent development of dysferlinopathy.

Synthesis and fluorine-18 radiolabeling of a phospholipid as a PET imaging agent for prostate cancer.

INTRODUCTION: Altered lipid metabolism and subsequent changes in cellular lipid composition have been observed in prostate cancer cells, are associated with poor clinical outcome, and are promising targets for metabolic therapies. This study reports for the first time on the synthesis of a phospholipid radiotracer based on the phospholipid 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine (PC44:12) to allow tracking of polyunsaturated lipid tumor uptake via PET imaging. This tracer may aid in the development of strategies to modulate response to therapies targeting lipid metabolism in prostate cancer. METHODS: Lipidomics analysis of prostate tumor explants and LNCaP tumor cells were used to identify PC44:12 as a potential phospholipid candidate for radiotracer development. Synthesis of phosphocholine precursor and non-radioactive standard were optimised using click chemistry. The biodistribution of a fluorine-18 labeled analogue, N-{[4-(2-[18F]fluoroethyl)-2,3,4-triazol-1-yl]methyl}-1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine ([18F]2) was determined in LNCaP prostate tumor-bearing NOD SCID gamma mice by ex vivo biodistribution and PET imaging studies and compared to biodistribution of [18F]fluoromethylcholine. RESULTS: [18F]2 was produced with a decay-corrected yield of 17.8 ± 3.7% and an average radiochemical purity of 97.00 ± 0.89% (n = 6). Molar activity was 85.1 ± 3.45 GBq/µmol (2300 ± 93 mCi/µmol) and the total synthesis time was 2 h. Ex vivo biodistribution data demonstrated high liver uptake (41.1 ± 9.2%ID/g) and high splenic uptake (10.9 ± 9.1%ID/g) 50 min post-injection. Ex vivo biodistribution showed low absolute tumor uptake of [18F]2 (0.8 ± 0.3%ID/g). However, dynamic PET imaging demonstrated an increase over time of the relative tumor-to-muscle ratio with a peak of 2.8 ± 0.5 reached 1 h post-injection. In contrast, dynamic PET of [18F]fluoromethylcholine demonstrated no increase in tumor-to-muscle ratios due to an increase in both tumor and muscle over time. Absolute uptake of [18F]fluoromethylcholine was higher and peaked at 60 min post injection (2.25 ± 0.29%ID/g) compared to [18F]2 (1.44 ± 0.06%ID/g) during the 1 h dynamic scan period. CONCLUSIONS AND ADVANCES IN KNOWLEDGE: This study demonstrates the ability to radiolabel phospholipids and indicates the potential to monitor the in vivo distribution of phospholipids using fluorine-18 based PET.

Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome.

CONTEXT: Severe acute respiratory syndrome (SARS) is an emerging infectious disease with a 25% incidence of progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and mortality exceeding 10%. OBJECTIVE: To describe the clinical spectrum and outcomes of ALI/ARDS in patients with SARS-related critical illness. DESIGN, SETTING, AND PATIENTS: Retrospective case series of adult patients with probable SARS admitted to the intensive care unit (ICU) of a hospital in Singapore between March 6 and June 6, 2003. MAIN OUTCOME MEASURES: The primary outcome measure was 28-day mortality after symptom onset. RESULTS: Of 199 patients hospitalized with SARS, 46 (23%) were admitted to the ICU, including 45 who fulfilled criteria for ALI/ARDS. Mortality at 28 days for the entire cohort was 20 (10.1%) of 199 and for ICU patients was 17 (37%) of 46. Intensive care unit mortality at 13 weeks was 24 (52.2%) of 46. Nineteen of 24 ICU deaths occurred late (> or =7 days after ICU admission) and were attributed to complications related to severe ARDS, multiorgan failure, thromboembolic complications, or septicemic shock. ARDS was characterized by ease of derecruitment of alveoli and paucity of airway secretion, bronchospasm, or dynamic hyperinflation. Lower Acute Physiology and Chronic Health Evaluation II scores and higher baseline ratios of PaO2 to fraction of inspired oxygen were associated with earlier recovery. CONCLUSIONS: Critically ill patients with SARS and ALI/ARDS had characteristic clinical findings, high rates of complications; and high mortality. These findings may provide useful information for optimizing supportive care for SARS-related critical illness.

Management plan to reduce risks in perioperative care of patients with obstructive sleep apnoea averts the need for presurgical polysomnography.

INTRODUCTION: Obstructive sleep apnoea (OSA) is associated with increased perioperative morbidity and mortality. Patients at risk of OSA as determined by pre-anaesthesia screening based on the American Society of Anesthesiologists checklist were divided into 2 groups for comparison: (i) those who proceeded to elective surgery under a risk management protocol without undergoing formal polysomnography preoperatively and; (ii) those who underwent polysomnography and any subsequent OSA treatment as required before elective surgery. We hypothesised that it is clinically safe and acceptable for patients identified on screening as OSA at-risk to proceed for elective surgery without delay for polysomnography, with no increase in postoperative complications if managed on a perioperative risk reduction protocol. MATERIALS AND METHODS: A retrospective review of patients presenting to the preanaesthesia clinic over an 18-month period and identified to be OSA at-risk on screening checklist was conducted (n = 463). The incidence of postoperative complications for each category of OSA severity (mild-moderate and severe) in the 2 study groups was compared. RESULTS: There was no statistically significant difference in the incidence of cardiac (3.3% vs 2.3%), respiratory (14.3% vs 12.5%), and neurologic complications (0.6% vs 0%) between the screening-only and polysomnography-confirmed OSA groups respectively (P >0.05). There was good agreement of the OSA risk that is identified by screening checklist with OSA severity as determined on formal polysomnography (kappa coefficient = 0.953). CONCLUSION: Previously undiagnosed OSA is common in the presurgical population. In our study, there was no significant increase in postoperative complications in patients managed on the OSA risk management protocol. With this protocol, it is clinically safe to proceed with elective surgery without delay for formal polysomnography confirmation.

2,3-diarylpyran-4-ones: a new series of selective cyclooxygenase-2 inhibitors.

A new series of cyclooxygenase-2 (COX-2) inhibitors with gamma-pyrone as central scaffold unit has been synthesized and their biological activities were evaluated against cyclooxygenase inhibitory activity. The changes of physical properties of the molecules were performed according to the medicinal chemistry principles and moderate oral anti-inflammatory activity was obtained with this series of inhibitors.