Thousand-and-one amino acid kinases (TAOK) 1 and 2 are activated catalytically during mitosis and can contribute to mitotic cell rounding and spindle positioning. Here, we characterize a compound that inhibits TAOK1 and TAOK2 activity with IC values of 11 to 15 nmol/L, is ATP-competitive, and targets these kinases selectively. TAOK inhibition or depletion in centrosome-amplified SKBR3 or BT549 breast cancer cell models increases the mitotic population, the percentages of mitotic cells displaying amplified centrosomes and multipolar spindles, induces cell death, and inhibits cell growth. In contrast, nontumorigenic and dividing bipolar MCF-10A breast cells appear less dependent on TAOK activity and can complete mitosis and proliferate in the presence of the TAOK inhibitor. We demonstrate that TAOK1 and TAOK2 localize to the cytoplasm and centrosomes respectively during mitosis. Live cell imaging shows that the TAOK inhibitor prolongs the duration of mitosis in SKBR3 cells, increases mitotic cell death, and reduces the percentages of cells exiting mitosis, whereas MCF-10A cells continue to divide and proliferate. Over 80% of breast cancer tissues display supernumerary centrosomes, and tumor cells frequently cluster extra centrosomes to avoid multipolar mitoses and associated cell death. Consequently, drugs that stimulate centrosome declustering and induce multipolarity are likely to target dividing centrosome-amplified cancer cells preferentially, while sparing normal bipolar cells. Our results demonstrate that TAOK inhibition can enhance centrosome declustering and mitotic catastrophe in cancer cells, and these proteins may therefore offer novel therapeutic targets suitable for drug inhibition and the potential treatment of breast cancers, where supernumerary centrosomes occur. .

The teneurins, also known as Ten-m/Odz, are highly conserved type II transmembrane glycoproteins widely expressed throughout the nervous system. Functioning as dimers, these large cell-surface adhesion proteins play a key role in regulating neurodevelopmental processes such as axon targeting, synaptogenesis and neuronal wiring. Synaptic specificity is driven by molecular interactions, which can occur either in a trans-homophilic manner between teneurins or through a trans-heterophilic interaction across the synaptic cleft between teneurins and other cell-adhesion molecules, such as latrophilins. The significance of teneurins interactions during development is reflected in the widespread expression pattern of the four existing paralogs across interconnected regions of the nervous system, which we demonstrate here via in situ hybridization and the generation of transgenic BAC reporter lines in zebrafish. Focusing on the visual system, we will also highlight the recent developments that have been made in furthering our understanding of teneurin interactions and their functionality, including the instructive role of teneurin-3 in specifying the functional wiring of distinct amacrine and retinal ganglion cells in the vertebrate visual system underlying a particular functionality. Based on the distinct expression pattern of all teneurins in different retinal cells, it is conceivable that the combination of different teneurins is crucial for the generation of discrete visual circuits. Finally, mutations in all four human teneurin genes have been linked to several types of neurodevelopmental disorders. The opportunity therefore arises that findings about the roles of zebrafish teneurins or their orthologs in other species shed light on the molecular mechanisms in the etiology of such human disorders.

Neonatal hypoxia–ischemia (HI) is a brain injury caused by oxygen deprivation to the brain due to birth asphyxia or reduced cerebral blood perfusion, and it often leads to lifelong limiting sequelae such as cerebral palsy, seizures, or mental retardation. HI remains one of the leading causes of neonatal mortality and morbidity worldwide, and current therapies are limited. Hypothermia has been successful in reducing mortality and some disabilities, but it is only applied to a subset of newborns that meet strict inclusion criteria. Given the unpredictable nature of the obstetric complications that contribute to neonatal HI, prophylactic treatments that prevent, rather than rescue, HI brain injury are emerging as a therapeutic alternative. Nutraceuticals are natural compounds present in the diet or used as dietary supplements that have antioxidant, anti-inflammatory, or antiapoptotic properties. This review summarizes the preclinical in vivo studies, mostly conducted on rodent models, that have investigated the neuroprotective properties of nutraceuticals in preventing and reducing HI-induced brain damage and cognitive impairments. The natural products reviewed include polyphenols, omega-3 fatty acids, vitamins, plant-derived compounds (tanshinones, sulforaphane, and capsaicin), and endogenous compounds (melatonin, carnitine, creatine, and lactate). These nutraceuticals were administered before the damage occurred, either to the mothers as a dietary supplement during pregnancy and/or lactation or to the pups prior to HI induction. To date, very few of these nutritional interventions have been investigated in humans, but we refer to those that have been successful in reducing ischemic stroke in adults. Overall, there is a robust body of preclinical evidence that supports the neuroprotective properties of nutraceuticals, and these may represent a safe and inexpensive nutritional strategy for the prevention of neonatal HI encephalopathy.

Class II antiarrhythmics or b-blockers are antisympathetic nervous system agents that act by blocking b-adrenoceptors. Despite their common clinical use, little is known about the effects of b-blockers on free intracellular calcium (Ca 21 i), an important cytosolic second messenger and a key regulator of cell function. We investigated the role of four chemical analogs, commonly prescribed b-blockers (atenolol, metoprolol, propranolol, and sotalol), on Ca 21 i release and whole-cell currents in mammalian cancer cells (PC3 prostate cancer and MCF7 breast cancer cell lines). We discovered that only propranolol activated free Ca 21 i release with distinct kinetics, whereas atenolol, metoprolol, and sotalol did not. The propranololinduced Ca 21 i release was significantly inhibited by the chelation of extracellular calcium with ethylene glycol tetraacetic acid (EGTA) and by dantrolene, an inhibitor of the endoplasmic reticulum (ER) ryanodine receptor channels, and it was completely abolished by 2-aminoethoxydiphenyl borate, an inhibitor of the ER inositol-1,4,5-trisphosphate (IP 3) receptor channels. Exhaustion of ER stores with 4-chloro-m-cresol, a ryanodine receptor activator, or thapsigargin, a sarco/ER Ca 21 ATPase inhibitor, precluded the propranolol-induced Ca 21 i release. Finally, preincubation of cells with sotalol or timolol, nonselective blockers of b-adrenoceptors, also reduced the Ca 21 i release activated by propranolol. Our results show that different b-blockers have differential effects on whole-cell currents and free Ca 21 i release and that propranolol activates store-operated Ca 21 i release via a mechanism that involves calcium-induced calcium release and putative downstream transducers such as IP 3. The differential action of class II antiarrhythmics on Ca 21 i release may have implications on the pharmacology of these drugs.

The FEBS‐IUBMB‐ENABLE 1st International Molecular Biosciences PhD and Postdoc Conference was held in Seville, Spain, from the 16–18th of November 2022. Nearly 300 participants from all over the globe were welcomed by the host institution, the Institute of Biomedicine of Seville (IBiS). Following the theme “The perfect tandem: How technology expands the frontiers of biomedicine”, the Scientific Symposium of the conference hosted eight world‐renowned keynote speakers who presented their work in one of the four sessions: Innovation, Basic Research, Translational and Clinical Research, and Computational Biology and Artificial Intelligence. Participants had the chance to present their research to their peers: more than 200 posters were presented during the dedicated poster sessions and 19 selected PhD students and postdocs presented their work as short talks. The Career Day featured a wide range of workshops fully devoted to trainees' professional development, as well as a job fair and career chats with professionals to discuss future perspectives. Besides, several outreach activities were organised before and during the conference to engage with the general public and bring science closer to society. The success of this conference will be followed by the next FEBS‐IUBMB‐ENABLE conferences in Cologne, Germany, in 2023 and Singapore in 2024.

<p>Live images showing compound 43 delays mitosis and induces mitotic catastrophe in CA SKBR3 cells. Representative time-lapse video images showing GFP-α-tubulin expressing SKBR3 cells incubated in growth medium containing compound 43 (5 µM) for 48 hours.</p>

<p>Live images of growing SKBR3 cells. Representative time-lapse video images showing GFP-α-tubulin expressing SKBR3 cells incubated in growth medium containing equivalent DMSO (0.05%) for 48 hours.</p>

<p>Live images of growing MCF-10A cells treated with compound 43. Representative time-lapse video images showing GFP-α-tubulin expressing MCF10-A cells incubated in growth medium containing compound 43 (5 µM) for 48 hours.</p>