Geo-cultural influences and critical factors in inter-firm collaboration

Inter-firm collaboration and other forms of inter-organisational activity are increasingly the means by which technological innovation occurs. This paper draws on evidence from two studies of the same set of firms to examine the conduct of collaborations over time across different contexts. The purpose is to examine the critical factors associated with successful collaboration and explore the importance of the geo-cultural context in understanding the conduct of inter-firm collaboration. The conceptual framework draws on two main sources: - Storper’s concept of ‘conventions’ of identity and participation and Lorenz’s classification of different types of knowledge. These are used to indicate the kinds and sources of adjustments required for successful collaboration

PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy

Mitochondrial fission is essential for the degradation of damaged mitochondria. It is currently unknown how the dynamin-related protein 1 (DRP1)-associated fission machinery is selectively targeted to segregate damaged mitochondria. We show that PTEN-induced putative kinase (PINK1) serves as a pro-fission signal, independently of Parkin. Normally, the scaffold protein AKAP1 recruits protein kinase A (PKA) to the outer mitochondrial membrane to phospho-inhibit DRP1. We reveal that after damage, PINK1 triggers PKA displacement from A-kinase anchoring protein 1. By ejecting PKA, PINK1 ensures the requisite fission of damaged mitochondria for organelle degradation. We propose that PINK1 functions as a master mitophagy regulator by activating Parkin and DRP1 in response to damage. We confirm that PINK1 mutations causing Parkinson disease interfere with the orchestration of selective fission and mitophagy by PINK1

HSJ1 and Motor Neuropathy

Homo sapiens DnaJ 1 (HSJ1) is a neuronal DnaJ protein that functions to target misfolded and aggregated proteins for degradation. The accumulation of misfolded and aggregated protein can be toxic to cells, causing neurodegeneration; therefore, proteins that function in protein quality control, such as HSJ1, play a critical role in maintaining protein homeostasis and promoting cell survival. The protective nature of HSJ1 is highlighted by the ability of the HSJ1a isoform to combat protein aggregation in cell and mouse models of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), a disease caused by the progressive loss of motor neurons. Based on the anti-aggregation function of HSJ1a towards ALS-associated proteins, I sought to determine whether HSJ1a could also protect against mutant ubiquilin-2 aggregation, a protein recently implicated in X-linked ALS. I identified wild-type ubiquilin-2 as a binding partner of HSJ1a and demonstrated that HSJ1a retained the ability to bind to ubiquilin-2 mutants, suggesting HSJ1a could potentially modulate mutant ubiquilin-2 aggregation in cells. Recently, three mutations in HSJ1 have been identified in autosomal recessive cases of hereditary motor neuropathies, diseases caused by the degeneration of lower motor neurons. I sought to determine the pathogenicity of the most recently identified variant, HSJ1-Y5C. Using a combination of the heterologous expression of HSJ1-Y5C in SK-N-SH neuroblastoma cells and the examination of endogenous HSJ1-Y5C in patient fibroblasts, I characterised the Y5C substitution as a disease-causing, loss of function mutation that reduces the half-life of HSJ1, leading to a loss of protein. To investigate how the loss of HSJ1 function causes motor neuron degeneration, I examined the cellular phenotype of motor neurons in Hsj1 knockout mice. I demonstrated that a significant 12% of motor neurons degenerate between P15 and P20. Prior to motor neuron loss, motor neurons appear\ud chromatolytic and signs of impaired protein homeostasis are observed, with an increase in protein ubiquitylation, a possible increase in autophagosome formation and activation of the IRE1 and PERK branches of the unfolded protein response. The activation of these cellular stress responses suggests that HSJ1 is a critical component of the protein quality control network in motor neurons

ATR, CHK1 and WEE1 inhibitors cause homologous recombination repair deficiency to induce synthetic lethality with PARP inhibitors

\ua9 The Author(s) 2024.Purpose: PARP inhibitors (PARPi) are effective in homologous recombination repair (HRR) defective (HRD) cancers. To (re)sensitise HRR proficient (HRP) tumours to PARPi combinations with other drugs are being explored. Our aim was to determine the mechanism underpinning the sensitisation to PARPi by inhibitors of cell cycle checkpoint kinases ATR, CHK1 and WEE1. Experimental design: A panel of HRD and HRP cells (including matched BRCA1 or 2 mutant and corrected pairs) and ovarian cancer ascites cells were used. Rucaparib (PARPi) induced replication stress (RS) and HRR (immunofluorescence microscopy for γH2AX and RAD51 foci, respectively), cell cycle changes (flow cytometry), activation of ATR, CHK1 and WEE1 (Western Blot for pCHK1S345, pCHK1S296 and pCDK1Y15, respectively) and cytotoxicity (colony formation assay) was determined, followed by investigations of the impact on all of these parameters by inhibitors of ATR (VE-821, 1 \ub5M), CHK1 (PF-477736, 50 nM) and WEE1 (MK-1775, 100 nM). Results: Rucaparib induced RS (3 to10-fold), S-phase accumulation (2-fold) and ATR, CHK1 and WEE1 activation (up to 3-fold), and VE-821, PF-477736 and MK-1775 inhibited their targets and abrogated these rucaparib-induced cell cycle changes in HRP and HRD cells. Rucaparib activated HRR in HRP cells only and was (60-1,000x) more cytotoxic to HRD cells. VE-821, PF-477736 and MK-1775 blocked HRR and sensitised HRP but not HRD cells and primary ovarian ascites to rucaparib. Conclusions: Our data indicate that, rather than acting via abrogation of cell cycle checkpoints, ATR, CHK1 and WEE1 inhibitors cause an HRD phenotype and hence “induced synthetic lethality” with PARPi

Acoustic Emission Monitoring of Fatigue Damage in Metals

Acoustic emission (AE) consists of high frequency stress waves generated by the rapid release of energy due to fracture, plastic deformation, wear or interfacial friction [1]. Acoustic emission monitoring is a very sensitive method with a wide dynamic range and can be used as a diagnostic means of continuous assessment of damage in materials and components. Acoustic emission methods can be applied to metallic components and specimens subjected to monotonic or fatigue loading. In general, acoustic emission can be used to monitor crack initiation and propagation and to locate the source of the emission

Strong Lefschetz elements of the coinvariant rings of finite Coxeter groups

For the coinvariant rings of finite Coxeter groups of types other than H$_4$, we show that a homogeneous element of degree one is a strong Lefschetz element if and only if it is not fixed by any reflections. We also give the necessary and sufficient condition for strong Lefschetz elements in the invariant subrings of the coinvariant rings of Weyl groups.Comment: 18 page

Novel splice variants associated with one of the zebrafish dnmt3 genes

BACKGROUND: DNA methylation and the methyltransferases are known to be important in vertebrate development and this may be particularly true for the Dnmt3 family of enzymes because they are thought to be the de novo methyltransferases. Mammals have three Dnmt3 genes; Dnmt3a, Dnmt3b, and Dnmt3L, two of which encode active enzymes and one of which produces an inactive but necessary cofactor. However, due to multiple promoter use and alternative splicing there are actually a number of dnmt3 isoforms present. Six different dnmt3 genes have recently been identified in zebrafish. RESULTS: We have examined two of the dnmt3 genes in zebrafish that are located in close proximity in the same linkage group and we find that the two genes are more similar to each other than they are to the other zebrafish dnmt3 genes. We have found evidence for the existence of several different splice variants and alternative splice sites associated with one of the two genes and have examined the relative expression of these genes/variants in a number of zebrafish developmental stages and tissues. CONCLUSION: The similarity of the dnmt3-1 and dnmt3-2 genes suggests that they arose due to a relatively recent gene duplication event. The presence of alternative splice and start sites, reminiscent of what is seen with the human DNMT3s, demonstrates strong parallels between the control/function of these genes across vertebrate species. The dynamic expression levels of these genes/variants suggest that they may well play a role in early development and this is particularly true for dnmt3-2-1 and dnmt3-1. dnmt3-2-1 is the predominantly expressed form prior to zygotic gene activation whereas dnmt3-1 predominates post zygotic gene activation suggesting a distinct developmental role for each

Identifying the cellular targets of drug action in the central nervous system following corticosteroid therapy

Corticosteroid (CS) therapy is used widely in the treatment of a range of pathologies, but can delay production of myelin, the insulating sheath around central nervous system nerve fibers. The cellular targets of CS action are not fully understood, that is, "direct" action on cells involved in myelin genesis [oligodendrocytes and their progenitors the oligodendrocyte precursor cells (OPCs)] versus "indirect" action on other neural cells. We evaluated the effects of the widely used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes, employing complementary histological and transcriptional analyses. Histological assessments showed no DEX effects on OPC proliferation or oligodendrocyte genesis/maturation (key processes underpinning myelin genesis). Immunostaining and RT-PCR analyses show that both cell types express glucocorticoid receptor (GR; the target for DEX action), ruling out receptor expression as a causal factor in the lack of DEX-responsiveness. GRs function as ligand-activated transcription factors, so we simultaneously analyzed DEX-induced transcriptional responses using microarray analyses; these substantiated the histological findings, with limited gene expression changes in DEX-treated OPCs and oligodendrocytes. With identical treatment, microglial cells showed profound and global changes post-DEX addition; an unexpected finding was the identification of the transcription factor Olig1, a master regulator of myelination, as a DEX responsive gene in microglia. Our data indicate that CS-induced myelination delays are unlikely to be due to direct drug action on OPCs or oligodendrocytes, and may occur secondary to alterations in other neural cells, such as the immune component. To the best of our knowledge, this is the first comparative molecular and cellular analysis of CS effects in glial cells, to investigate the targets of this major class of anti-inflammatory drugs as a basis for myelination deficits