Exploring Twitter as a game platform; strategies and opportunities for microblogging-based games

Recent years have seen the massive daily engagement of players with games that are integrated with online social networking sites, such as Facebook. However, few games have successfully created engaging experiences through integration with microblogging websites. In this paper, we explore the opportunities and challenges in using Twitter as a platform for playing games, through the case study of the game Hashtag Dungeon, a dungeon-crawling game that uses Twitter for collaborative creation of game content. Two studies were carried out. A quantitative user study with 32 participants demonstrated that players found the game engaging and rewarding. A follow-up qualitative study with 8 participants suggests that Twitter integration in this game is meaningful, but that there are concerns over the impact of the game on players’ Twitter profiles. Based on findings from both studies, we propose strategies for the design of Microblogging-based games, and discuss wider implications of social media integration in games

Missing-in-metastasis and IRSp53 deform PI(4,5)P-2-rich membranes by an inverse BAR domain-like mechanism

The actin cytoskeleton plays a fundamental role in various motile and morphogenetic processes involving membrane dynamics. We show that actin-binding proteins MIM (missing-in-metastasis) and IRSp53 directly bind PI(4,5)P-2-rich membranes and deform them into tubular structures. This activity resides in the N-terminal IRSp53/MIM domain (IMD) of these proteins, which is structurally related to membrane-tubulating BAR (Bin/amphiphysin/Rvs) domains. We found that because of a difference in the geometry of the PI(4,5)P-2-binding site, IMDs induce a membrane curvature opposite that of BAR domains and deform membranes by binding to the interior of the tubule. This explains why IMD proteins induce plasma membrane protrusions rather than invaginations. We also provide evidence that the membrane-deforming activity of IMDs, instead of the previously proposed F-actin - bundling or GTPase-binding activities, is critical for the induction of the filopodia/microspikes in cultured mammalian cells. Together, these data reveal that interplay between actin dynamics and a novel membrane-deformation activity promotes cell motility and morphogenesis

Process in family business internationalisation: The state of the art and ways forward

Although the internationalisation of family businesses (FBs) has received increasing attention in recent years, much remains to be learned about how FB internationalisation unfolds as a process. Our review of 172 empirical studies from the period of 1991-2018 indicates that only 25 studies included both longitudinal data and strong process theorising, even though internationalisation is inherently processual, and FBs are longitudinal in nature. We acknowledge that both variance-and process-based theorising are needed to build an understanding of the FB internationalisation process. We contribute to the field by building an FB internationalisation process model based on a review analysis. Within the model, process-based internationalisation pathways are combined with variance-based capabilities (positive influences) and liabilities (negative influences) that affect internationalisation, with economic and non-economic goals viewed as driving the various internationalisation processes. On the basis of the model, we suggest that future research could adopt more longitudinal and individually focused approaches, as a means to understand the FB internationalisation process in various FBs and contexts, over various time periods, life cycles, and FB generations

Prolonged and tunable residence time using reversible covalent kinase inhibitors.

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo

Kendomycin Cytotoxicity against Bacterial, Fungal, and Mammalian Cells Is Due to Cation Chelation

Kendomycin is a small-molecule natural product that has gained significant attention due to reported cytotoxicity against pathogenic bacteria and fungi as well as a number of cancer cell lines. Despite significant biomedical interest and attempts to reveal its mechanism of action, the cellular target of kendomycin remains disputed. Herein it is shown that kendomycin induces cellular responses indicative of cation stress comparable to the effects of established iron chelators. Furthermore, addition of excess iron and copper attenuated kendomycin cytotoxicity in bacteria, yeast, and mammalian cells. Finally, NMR analysis demonstrated a direct interaction with cations, corroborating a close link between the observed kendomycin polypharmacology across different species and modulation of iron and/or copper levels.Peer reviewe

Thalamic Atrophy Without Whole Brain Atrophy Is Associated With Absence of 2-Year NEDA in Multiple Sclerosis

Purpose: To study which brain volume measures best differentiate early relapsing MS (RMS) and secondary progressive MS (SPMS) patients and correlate with disability and cognition. To test whether isolated thalamic atrophy at study baseline correlates with NEDA (no evidence of disease activity) at 2 years.Methods: Total and regional brain volumes were measured from 24 newly diagnosed RMS patients 6 months after initiation of therapy and 2 years thereafter, and in 36 SPMS patients. Volumes were measured by SIENAX and cNeuro. The patients were divided into subgroups based on whole brain parenchyma (BP) and thalamic atrophy at baseline. Standard scores (z-scores) were computed by comparing individual brain volumes against healthy controls. A z-score cut-off of - 1.96 was applied to separate atrophic from normal brain volumes. The Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT) were assessed at baseline and at 2 years. Differences in achieving NEDA-3, NEDA-4, EDSS progression, and SDMT change were analyzed between patients with no thalamic or BP atrophy and in patients with isolated thalamic atrophy at baseline.Results: At baseline, 7 SPMS and 12 RMS patients had no brain atrophy, 8 SPMS and 10 RMS patients had isolated thalamic atrophy and 2 RMS and 20 SPMS patients had both BP and thalamic atrophy. NEDA-3 was reached in 11/19 patients with no brain atrophy but only in 2/16 patients with isolated thalamic atrophy (p = 0.012). NEDA-4 was reached in 7/19 patients with no brain atrophy and in 1/16 of the patients with isolated thalamic atrophy (p = 0.047). At 2 years, EDSS was same or better in 16/19 patients with no brain atrophy but only in 5/17 patients with isolated thalamic atrophy (p = 0.002). There was no significant difference in the EDSS, relapses or SDMT between patients with isolated thalamic atrophy and no atrophy at baseline.Conclusion: Patients with isolated thalamic atrophy were at a higher risk for not reaching 2-year NEDA-3 and for EDSS increase than patients with no identified brain atrophy. The groups were clinically indistinguishable. A single measurement of thalamic and whole brain atrophy could help identify patients needing most effective therapies from early on

Nonstop mRNAs generate a ground state of mitochondrial gene expression noise

Funding Information: This work was supported by the Academy of Finland (307431 and 314706 to B.J.B.), the Sigrid Juselius Foundation Senior Investigator Award to B.J.B., and United Mitochondrial Disease Foundation (PI-16-0598 to B.J.B.) and donations from the Hereditary Neuropathy Foundation, Lindsey Flynt, and Medtronic to B.J.B.; the Orion Research Foundation and the Finnish Cultural Foundation to K.Y.N.; the Academy of Finland (321961 to U.R.); the Sigrid Juselius Foundation, the Academy of Finland (331556), and the Jane and Aatos Erkko Foundation to C.D.D.; Action Medical Research (GN2494 to W.G.N.) and the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007 to W.G.N.); the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z to R.W.T.), the Mitochondrial Disease Patient Cohort (UK) (G0800674 to R.W.T.), the Medical Research Council International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1 to R.W.T.), the Lily Foundation, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, the Pathological Society, and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children to R.W.T.; Medical Research Council (MR/W019027/1 to W.G.N. and R.W.T.); the Academy of Finland (338836 and 314672 to V.O.P.); and the Sigrid Juselius Foundation and the Jane and Aatos Erkko Foundation. Publisher Copyright: Copyright © 2022 The Authors, some rights reserved;A stop codon within the mRNA facilitates coordinated termination of protein synthesis, releasing the nascent polypeptide from the ribosome. This essential step in gene expression is impeded with transcripts lacking a stop codon, generating nonstop ribosome complexes. Here, we use deep sequencing to investigate sources of nonstop mRNAs generated from the human mitochondrial genome. We identify diverse types of nonstop mRNAs on mitochondrial ribosomes that are resistant to translation termination by canonical release factors. Failure to resolve these aberrations by the mitochondrial release factor in rescue (MTRFR) imparts a negative regulatory effect on protein synthesis that is associated with human disease. Our findings reveal a source of underlying noise in mitochondrial gene expression and the importance of responsive ribosome quality control mechanisms for cell fitness and human health.Peer reviewe

Snapshots of actin and tubulin folding inside the TRiC chaperonin

The integrity of a cell's proteome depends on correct folding of polypeptides by chaperonins. The chaperonin TCP-1 ring complex (TRiC) acts as obligate folder for >10% of cytosolic proteins, including he cytoskeletal proteins actin and tubulin. Although its architecture and how it recognizes folding substrates are emerging from structural studies, the subsequent fate of substrates inside the TRiC chamber is not defined. We trapped endogenous human TRiC with substrates (actin, tubulin) and cochaperone (PhLP2A) at different folding stages, for structure determination by cryo-EM. The already-folded regions of client proteins are anchored at the chamber wall, positioning unstructured regions toward the central space to achieve their native fold. Substrates engage with different sections of the chamber during the folding cycle, coupled to TRiC open-and-close transitions. Further, the cochaperone PhLP2A modulates folding, acting as a molecular strut between substrate and TRiC chamber. Our structural snapshots piece together an emerging model of client protein folding within TRiC. Tagging of the endogenous type II chaperonin TRiC complex using CRISPR knock-in enables its purification for cryo-EM. A series of structures reveal the fate of substrates and co-chaperones inside the TRiC chamber to uncover its inner workings.Peer reviewe