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Social and economic barriers that students face during their studies can impact severely on their attainment and can be due to many factors. This study investigated how different socio-economic factors, with a focus on digital poverty and workspace availability may have affected students' attainment (during October 2021 - March 2022) at university post-COVID-19. Quantitative data collected during the first teaching block of the 2021-2022 academic year using specific questions in a paper-based questionnaire indicated that a good proportion of life science students did not have access to a home internet source (35%) or proper workspace facilities (34%) and had the requirement to work alongside their degree in order to fund their studies. In contrast to the lack of internet students experienced, many of the surveyed students did have access to a personal computer within their household. Possible reasons for some of the findings, and the implications of the findings, are discussed here.

The activation of microglia, the inflammatory cells of the central nervous system (CNS), has been linked to the pathogenesis of Alzheimer’s disease and other neurodegenerative diseases. How microglia sense the changing brain environment, in order to respond appropriately, is still being elucidated. Microglia are able to sense and respond to the mechanical properties of their microenvironment, and the physical and molecular pathways underlying this mechanosensing/mechanotransduction in microglia have recently been investigated. The Hippo pathway functions through mechanosensing and subsequent protein kinase cascades, and is critical for neuronal development and many other cellular processes. In this review, we examine evidence for the potential involvement of Hippo pathway components specifically in microglia in the pathogenesis of Alzheimer’s disease. We suggest that the Hippo pathway is worth investigating as a mechanosensing pathway in microglia, and could be one potential therapeutic target pathway for preventing microglial-induced neurodegeneration in AD.

In order to ascertain their external environment, cells and tissues have the capability to sense and process a variety of stresses, including stretching and compression forces. These mechanical forces, as experienced by cells and tissues, are then converted into biochemical signals within the cell, leading to a number of cellular mechanisms being activated, including proliferation, differentiation and migration. If the conversion of mechanical cues into biochemical signals is perturbed in any way, then this can be potentially implicated in chronic disease development and processes such as neurological disorders, cancer and obesity. This review will focus on how the interplay between mechanotransduction, cellular structure, metabolism and signalling cascades led by the Hippo-YAP/TAZ axis can lead to a number of chronic diseases and suggest how we can target various pathways in order to design therapeutic targets for these debilitating diseases and conditions.

Mechanical stretch forces can control the growth of epithelial tissues such as mammalian skin, whose surface area is precisely coordinated with body size. In skin keratinocytes cultured in vitro, mechanical forces acting via Integrin adhesions and the actin cytoskeleton have been shown to induce nuclear translocation of YAP/TAZ co-activators to induce cell proliferation. Furthermore, conditional knockouts of both YAP (also called YAP1) and TAZ (also called WWTR1) in mouse skin resemble the phenotype of skin-specific loss of Integrin beta1 (ITGB1), indicating that this signalling mechanism is important in vivo. Curiously, Integrins are dispensable in Drosophila to activate the sole YAP/TAZ homolog Yorkie (Yki), which has lost the C-terminal PDZ-binding motif needed to promote nuclear localization of YAP/TAZ in mammalian cells. Differences in the structure of the epidermis between deuterostomes (e.g.: stratified squamous skin of mammals) and protostomes (e.g.: monolayered columnar epidermis of Drosophila) may explain this evolutionary divergence. Monolayered columnar epithelia feature a well-differentiated apical membrane domain, where proteins such as Crumbs, Expanded, Merlin and Kibra activate the Hippo pathway to repress Drosophila Yki. Stratified squamous epithelia lack an apical domain and thus depend primarily on basal Integrin adhesions to activate YAP/TAZ in basal layer stem cells via multiple postulated signalling mechanisms. Finally, YAP and TAZ retain the ability to sense the apical domain in the columnar epithelial cells lining internal organs such as the lung bronchus, where YAP/TAZ localize to the nucleus in proliferating basal layer stem cells but translocate to the cytoplasm in differentiated columnar cells.

Summary Epithelial cells are polarized along their apical-basal axis by the action of the small GTPase Cdc42, which is known to activate the aPKC kinase at the apical domain. However, loss of aPKC kinase activity was reported to have only mild effects on epithelial cell polarity. Here, we show that Cdc42 also activates a second kinase, Pak1, to specify apical domain identity in Drosophila and mammalian epithelia. aPKC and Pak1 phosphorylate an overlapping set of polarity substrates in kinase assays. Inactivating both aPKC kinase activity and the Pak1 kinase leads to a complete loss of epithelial polarity and morphology, with cells losing markers of apical polarization such as Crumbs, Par3/Bazooka, or ZO-1. This function of Pak1 downstream of Cdc42 is distinct from its role in regulating integrins or E-cadherin. Our results define a conserved dual-kinase mechanism for the control of apical membrane identity in epithelia., Graphical Abstract, Highlights • aPKC is not the only kinase responsible for epithelial cell polarization in Drosophila • Loss of another Cdc42 effector, Pak1 kinase, causes a moderate polarity phenotype • aPKC and Pak1 kinases act redundantly to maintain apical domain identity • The dual-kinase mechanism of aPKC and Pak1 is conserved in mammalian epithelia, Downstream of Cdc42, the atypical protein kinase C (aPKC) is thought to be the main effector at the apical domain. Aguilar-Aragon et al. identify a second kinase, Pak1, as being an additional essential effector downstream of Cdc42 at the apical domain in both Drosophila and mammalian epithelial cells.

The Hippo signalling pathway restricts cell proliferation in animal tissues by inhibiting Yes-associated protein (YAP or YAP1) and Transcriptional Activator with a PDZ domain (TAZ or WW-domain–containing transcriptional activator [WWTR1]), coactivators of the Scalloped (Sd or TEAD) DNA-binding transcription factor. Drosophila has a single YAP/TAZ homolog named Yorkie (Yki) that is regulated by Hippo pathway signalling in response to epithelial polarity and tissue mechanics during development. Here, we show that Yki translocates to the nucleus to drive Sd-mediated cell proliferation in the ovarian follicle cell epithelium in response to mechanical stretching caused by the growth of the germline. Importantly, mechanically induced Yki nuclear localisation also requires nutritionally induced insulin/insulin-like growth factor 1 (IGF-1) signalling (IIS) via phosphatidyl inositol-3-kinase (PI3K), phosphoinositide-dependent kinase 1 (PDK1 or PDPK1), and protein kinase B (Akt or PKB) in the follicular epithelium. We find similar results in the developing Drosophila wing, where Yki becomes nuclear in the mechanically stretched cells of the wing pouch during larval feeding, which induces IIS, but translocates to the cytoplasm upon cessation of feeding in the third instar stage. Inactivating Akt prevents nuclear Yki localisation in the wing disc, while ectopic activation of the insulin receptor, PI3K, or Akt/PKB is sufficient to maintain nuclear Yki in mechanically stimulated cells of the wing pouch even after feeding ceases. Finally, IIS also promotes YAP nuclear localisation in response to mechanical cues in mammalian skin epithelia. Thus, the Hippo pathway has a physiological function as an integrator of epithelial cell polarity, tissue mechanics, and nutritional cues to control cell proliferation and tissue growth in both Drosophila and mammals., This study shows that the PI3K-Akt pathway promotes cell proliferation via the Yorkie/YAP transcriptional coactivator in response to mechanical stretching in vivo; the Hippo kinase acts as a key integrator of Akt and mechanical cues to control Yorkie/YAP activity and cell proliferation, with implications for human cancer, in which PI3K-Akt and mechanical forces play key roles in driving cell proliferation and malignancy.

Mask family proteins were discovered in Drosophila to promote the activity of the transcriptional coactivator Yorkie (Yki), the sole fly homolog of mammalian YAP (YAP1) and TAZ (WWTR1). The molecular function of Mask, or its mammalian homologs Mask1 (ANKHD1) and Mask2 (ANKRD17), remains unclear. Mask family proteins contain two ankyrin repeat domains that bind Yki/YAP as well as a conserved nuclear localisation sequence (NLS) and nuclear export sequence (NES), suggesting a role in nucleo-cytoplasmic transport. Here we show that Mask acts to promote nuclear import of Yki, and that addition of an ectopic NLS to Yki is sufficient to bypass the requirement for Mask in Yki-driven tissue growth. Mammalian Mask1/2 proteins also promote nuclear import of YAP, as well as stabilising YAP and driving formation of liquid droplets. Mask1/2 and YAP normally colocalise in a granular fashion in both nucleus and cytoplasm, and are co-regulated during mechanotransduction.

The elaboration of polarity is central to organismal development and to the maintenance of functional epithelia. Amongst the controls determining polarity are the PAR proteins, PAR6/aPKCiota-PAR3, regulating both known and unknown effectors. Here we identify FARP2 as a "RIPR" motif dependent partner and substrate of aPKCiota that is required for efficient polarisation and junction formation. Binding is conferred by a FERM/FA domain-Kinase\ud domain interaction and detachment promoted by aPKCiota dependent phosphorylation. FARP2 is shown to promote GTP loading of Cdc42 consistent with upstream regulation of the polarising PAR6-aPKCiota complex. However, it is shown that aPKCiota acts to promote the localised activity of FARP2 through phosphorylation. We conclude that this aPKCiota FARP2 complex formation acts as a positive feedback control to drive polarisation through aPKCiota and other Cdc42 effectors.\ud \ud Ahmed , Yixiao , Mathias , Philippe , Ray S. , Selene K. Roberts, Chris Tynan, Roger George, Svend Kjaer, Marisa L. Martin-Fernandez, Barry J. Thompson, Neil Q. McDonald, Peter J. Parker

First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Mathias Cobbaut and Ahmed Elbediwy are co-first authors on ‘The Rho family GEF FARP2 is activated by aPKCι to control tight junction formation and polarity’, published in JCS. Mathias is a postdoc in the lab of Prof. Peter Parker at The Francis Crick Institute, London, investigating protein kinase regulation/biochemistry and the functional role of protein kinase signaling. Ahmed is a lecturer at Kingston University, investigating cancer biology, polarity and signaling.

The Mask family of multiple ankyrin repeat and KH domain proteins were discovered in Drosophila to promote the activity of the transcriptional coactivator Yorkie (Yki), the sole fly homolog of mammalian YAP (YAP1) and TAZ (WWTR1). The molecular function of Mask, or its mammalian homologs Mask1 (ANKHD1) and Mask2 (ANKRD17), remains unclear. Mask family proteins contain two Ankyrin repeat domains that bind Yki/YAP as well as a conserved nuclear localisation sequence (NLS) and nuclear export sequence (NES), suggesting a role in nucleo-cytoplasmic transport. Here we show that Mask acts to promote nuclear import of Yki, and that addition of an ectopic NLS to Yki is sufficient to bypass the requirement for Mask in Yki-driven tissue growth. Mammalian Mask1/2 proteins also promote nuclear import of YAP, as well as stabilising YAP and driving colloidal phase separation into large liquid droplets. Mask1/2 and YAP normally colocalise in a granular fashion in both nucleus and cytoplasm, and are co-regulated during mechanotransduction. Our results suggest that Mask family proteins promote YAP nuclear import and phase separation to regulate YAP stability and transcriptional activity.

The elaboration of polarity is central to organismal development and to the maintenance of functional epithelia. Among the controls determining polarity are the PAR proteins, PAR6, aPKCι and PAR3, regulating both known and unknown effectors. Here, we identify FARP2 as a 'RIPR' motif-dependent partner and substrate of aPKCι that is required for efficient polarisation and junction formation. Binding is conferred by a FERM/FA domain-kinase domain interaction and detachment promoted by aPKCι-dependent phosphorylation. FARP2 is shown to promote GTP loading of Cdc42, which is consistent with it being involved in upstream regulation of the polarising PAR6-aPKCι complex. However, we show that aPKCι acts to promote the localised activity of FARP2 through phosphorylation. We conclude that this aPKCι-FARP2 complex formation acts as a positive feedback control to drive polarisation through aPKCι and other Cdc42 effectors.This article has an associated First Person interview with the first author of the paper.

The elaboration of polarity is central to organismal development and to the maintenance of functional epithelia. Amongst the controls determining polarity are the PAR proteins, PAR6/aPKCι/PAR3, regulating both known and unknown effectors. Here we identify FARP2 as a "RIPR" motif dependent partner and substrate of aPKCι that is required for efficient polarisation and junction formation. Binding is conferred by a FERM/FA domain-Kinase domain interaction and detachment promoted by aPKCι dependent phosphorylation. FARP2 is shown to promote GTP loading of Cdc42 consistent with upstream regulation of the polarising PAR6-aPKCι complex. However, it is shown that aPKCι acts to promote the localised activity of FARP2 through phosphorylation. We conclude that this aPKCι−FARP2 complex formation acts as a positive feedback control to drive polarisation through aPKCι and other Cdc42 effectors

First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Ahmed Elbediwy is the first author on ‘Enigma proteins regulate YAP mechanotransduction’, published in Journal of Cell Science. Ahmed is a postdoctoral fellow in the lab of Barry Thompson at The Francis Crick Institute, London, UK, investigating the cytoskeleton, RhoGTPases and the regulation of YAP/TAZ oncoproteins.

Human cells can sense mechanical stress acting upon integrin adhesions and respond by sending the YAP (also known as YAP1) and TAZ (also known as WWTR1) transcriptional co-activators to the nucleus to drive TEAD-dependent transcription of target genes. How integrin signaling activates YAP remains unclear. Here, we show that integrin-mediated mechanotransduction requires the Enigma and Enigma-like proteins (PDLIM7 and PDLIM5, respectively; denoted for the family of PDZ and LIM domain-containing proteins). YAP binds to PDLIM5 and PDLIM7 (hereafter PDLIM5/7) via its C-terminal PDZ-binding motif (PBM), which is essential for full nuclear localization and activity of YAP. Accordingly, silencing of PDLIM5/7 expression reduces YAP nuclear localization, tyrosine phosphorylation and transcriptional activity. The PDLIM5/7 proteins are recruited from the cytoplasm to integrin adhesions and F-actin stress fibers in response to force by binding directly to the key stress fiber component α-actinin. Thus, forces acting on integrins recruit Enigma family proteins to trigger YAP activation during mechanotransduction. This article has an associated First Person interview with the first author of the paper., Summary: The Enigma family proteins (PDLIM5/7) link YAP with F-actin stress fibers to participate in integrin-mediated mechanotransduction.

First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Ahmed Elbediwy is the first author on ‘Enigma proteins regulate YAP mechanotransduction’, published in Journal of Cell Science. Ahmed is a postdoctoral fellow in the lab of Barry Thompson at The Francis Crick Institute, London, UK, investigating the cytoskeleton, RhoGTPases and the regulation of YAP/TAZ oncoproteins.

Squamous cell carcinoma (SCC) can progress to malignant metastatic cancer, including an aggressive subtype known as spindle cell carcinoma (spSCC). spSCC formation involves epithelial-to-mesenchymal transition (EMT), yet the molecular basis of this event remains unknown. The transcriptional co-activator YAP undergoes recurrent amplification in human SCC and overexpression of YAP drives SCC formation in mice. Here, we show that human spSCC tumours also feature strong nuclear localisation of YAP and overexpression of activated YAP (NLS-YAP-5SA) with Keratin-5 (K5-CreERt) is sufficient to induce rapid formation of both SCC and spSCC in mice. spSCC tumours arise at sites of epithelial scratch wounding, where tumour-initiating epithelial cells undergo EMT to generate spSCC. Expression of the EMT transcription factor ZEB1 arises upon wounding and is a defining characteristic of spSCC in mice and humans. Thus, the wound healing response synergises with YAP to drive metaplastic transformation of SCC to spSCC.

The elaboration of polarity is central to organismal development and to the maintenance of functional epithelia. Among the controls determining polarity are the PAR proteins, PAR6, aPKCι and PAR3, regulating both known and unknown effectors. Here, we identify FARP2 as a ‘RIPR’ motif-dependent partner and substrate of aPKCι that is required for efficient polarisation and junction formation. Binding is conferred by a FERM/FA domain–kinase domain interaction and detachment promoted by aPKCι-dependent phosphorylation. FARP2 is shown to promote GTP loading of Cdc42, which is consistent with it being involved in upstream regulation of the polarising PAR6–aPKCι complex. However, we show that aPKCι acts to promote the localised activity of FARP2 through phosphorylation. We conclude that this aPKCι−FARP2 complex formation acts as a positive feedback control to drive polarisation through aPKCι and other Cdc42 effectors. This article has an associated First Person interview with the first author of the paper., Summary: The exchange factor FARP2 is identified as a polarity-determining protein that is a partner and substrate of aPKCι. Phosphorylation by aPKCι is shown to control the localised action of FARP2 on Cdc42.

In this paper, an efficient CORDIC-based hardware implementation of the Izhikevich neuron model is introduced. The CORDIC (COordinate Rotation Digital Computer) algorithm is used to approximate the square term in Izhikevich equations that describe the neuron response. The approximation is evaluated by defining four types of errors where the CORDIC approximation shows significant improvement in error performance compared to the Piecewise Linear (PWL) model [1]. The power consumption of the CORDIC-based neuron hardware implementation ranges from 0.26 mW to 0.4 mW whereas the PWL-based neuron as well as the original Izhikevich neuron hardware implementations consume 0.3 mW and 1.06 mW, respectively. A Figure of Merit (FoM) is defined to show the tradeoff among errors, power and area. By comparing with the PWL-based neuron hardware implementation, it is found that the CORDIC-based model is preferred as an approximation method from the error, power and area perspective.

In epithelial tissues, polarisation of microtubules and actin microvilli occurs along the apical-basal axis of each cell, yet how these cytoskeletal polarisation events are coordinated remains unclear. Here, we examine the hierarchy of events during cytoskeletal polarisation in Drosophila melanogaster epithelia. Core apical-basal polarity determinants polarise the spectrin cytoskeleton to recruit the microtubule-binding proteins Patronin (CAMSAP1, CAMSAP2 and CAMPSAP3 in humans) and Shortstop [Shot; MACF1 and BPAG1 (also known as DST) in humans] to the apical membrane domain. Patronin and Shot then act to polarise microtubules along the apical-basal axis to enable apical transport of Rab11 endosomes by the Nuf–Dynein microtubule motor complex. Finally, Rab11 endosomes are transferred to the MyoV (also known as Didum in Drosophila) actin motor to deliver the key microvillar determinant Cadherin 99C to the apical membrane to organise the biogenesis of actin microvilli., Summary: In Drosophila, microtubules are polarised along the apical-basal axis of epithelial cells by the concerted action of Shot and Patronin, two apically localised microtubule binding proteins.