Fifty shades of CHI: the perverse and humiliating human-computer relationship

This paper presents a critical lens on the nature of the relationship between people and contemporary technology. Specifically, the form and language of erotic BDSM romance fiction, a genre that deals specifically with the nature of power in relationships, and which has proved extremely popular recently, are used as a means for provoking reflection on the nature of power in the human-computer relationship. Three sexually explicit scenarios are presented, in which technology is portrayed in a dominant and controlling role, highlighting the often subservient and apologetic nature of human interaction with technology. We suggest that readers offended by graphic and explicit descriptions of sexual behaviour do not read further than this abstract

Deletion of the Nucleotide Excision Repair Gene Ercc1 Reduces Immunoglobulin Class Switching and Alters Mutations Near Switch Recombination Junctions

The structure-specific endonuclease ERCC1-XPF is an essential component of the nucleotide excision DNA repair pathway. ERCC1-XPF nicks double-stranded DNA immediately adjacent to 3′ single-strand regions. Substrates include DNA bubbles and flaps. Furthermore, ERCC1 interacts with Msh2, a mismatch repair (MMR) protein involved in class switch recombination (CSR). Therefore, ERCC1-XPF has abilities that might be useful for antibody CSR. We tested whether ERCC1 is involved in CSR and found that Ercc1−/− splenic B cells show moderately reduced CSR in vitro, demonstrating that ERCC1-XPF participates in, but is not required for, CSR. To investigate the role of ERCC1 in CSR, the nucleotide sequences of switch (S) regions were determined. The mutation frequency in germline Sμ segments and recombined Sμ-Sγ3 segments cloned from Ercc1−/− splenic B cells induced to switch in culture was identical to that of wild-type (WT) littermates. However, Ercc1−/− cells show increased targeting of the mutations to G:C bp in RGYW/WRCY hotspots and mutations occur at sites more distant from the S–S junctions compared with WT mice. The results indicate that ERCC1 is not epistatic with MMR and suggest that ERCC1 might be involved in processing or repair of DNA lesions in S regions during CSR

Shaping social innovation in local communities: The contribution of intermediaries

Participatory social innovation projects often involve the coming together of design researchers, community development groups, and community members to develop (often technological) solutions to social problems or challenges. "Intermediaries" are specific individuals and organisations who contribute to these projects by translating intentions, values and experiences between design researchers and communities. Previous research has not yet critically examined the role of intermediaries in such projects. This paper does so in a project carried out in rural areas of Europe, which sought to test and develop a technology to support the creation of FM community radio stations in isolated areas. We present the project as a biography of infrastructures to provide an account of intermediaries' interactions during the project's unfolding. We find that how intermediaries shape the social base and ends of the project, and the interpretation of the technology involved, is influenced by their position, goals, and relationships in the process

Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-β signaling

<p>Abstract</p> <p>Background</p> <p>Germline mutations in the <it>FLCN </it>gene are responsible for the development of fibrofolliculomas, lung cysts and renal neoplasia in Birt-Hogg-Dube' (BHD) syndrome. The encoded protein folliculin (FLCN) is conserved across species but contains no classic motifs or domains and its function remains unknown. Somatic mutations or loss of heterozygosity in the remaining wild type copy of the <it>FLCN </it>gene have been found in renal tumors from BHD patients suggesting that <it>FLCN </it>is a classic tumor suppressor gene.</p> <p>Results</p> <p>To examine the tumor suppressor function of <it>FLCN</it>, wild-type or mutant <it>FLCN </it>(H255R) was stably expressed in a <it>FLCN-null </it>renal tumor cell line, UOK257, derived from a BHD patient. When these cells were injected into nude mice, tumor development was inversely dependent upon the level of wild-type <it>FLCN </it>expression. We identified genes that were differentially expressed in the cell lines with or without wild-type <it>FLCN</it>, many of which are involved in TGF-β signaling, including <it>TGF-β2 </it>(<it>TGFB2</it>)<it>, inhibin β A chain </it>(<it>INHBA</it>)<it>, thrombospondin 1 </it>(<it>THBS1</it>), <it>gremlin </it>(<it>GREM1</it>), and <it>SMAD3</it>. In support of the <it>in vitro </it>data, <it>TGFB2</it>, <it>INHBA</it>, <it>THBS1 </it>and <it>SMAD3 </it>expression levels were significantly lower in BHD-associated renal tumors compared with normal kidney tissue. Although receptor mediated SMAD phosphorylation was not affected, basal and maximal TGF-β-induced levels of <it>TGFB2</it>, <it>INHBA </it>and <it>SMAD7 </it>were dramatically reduced in <it>FLCN-null </it>cells compared with <it>FLCN</it>-restored cells. Secreted TGF-β2 and activin A (homo-dimer of INHBA) protein levels were also lower in <it>FLCN-null </it>cells compared with <it>FLCN</it>-restored cells. Consistent with a growth suppressive function, activin A (but not TGF-β2) completely suppressed anchorage-independent growth of <it>FLCN-null </it>UOK257 cells.</p> <p>Conclusions</p> <p>Our data demonstrate a role for <it>FLCN </it>in the regulation of key molecules in TGF-β signaling and confirm deregulation of their expression in BHD-associated renal tumors. Thus, deregulation of genes involved in TGF-β signaling by <it>FLCN </it>inactivation is likely to be an important step for tumorigenesis in BHD syndrome.</p

Overcoming Barriers to Skills Training in Borderline Personality Disorder: A Qualitative Interview Study

Despite evidence suggesting that skills training is an important mechanism of change in dialectical behaviour therapy, little research exploring facilitators and barriers to this process has been conducted. The study aimed to explore clients’ experiences of barriers to dialectical behaviour therapy skills training and how they felt they overcame these barriers, and to compare experiences between treatment completers and dropouts. In-depth qualitative interviews were conducted with 40 clients with borderline personality disorder who had attended a dialectical behaviour therapy programme. A thematic analysis of participants’ reported experiences found that key barriers to learning the skills were anxiety during the skills groups and difficulty understanding the material. Key barriers to using the skills were overwhelming emotions which left participants feeling unable or unwilling to use them. Key ways in which participants reported overcoming barriers to skills training were by sustaining their commitment to attending therapy and practising the skills, personalising the way they used them, and practising them so often that they became an integral part of their behavioural repertoire. Participants also highlighted a number of key ways in which they were supported with their skills training by other skills group members, the group therapists, their individual therapist, friends and family. Treatment dropouts were more likely than completers to describe anxiety during the skills groups as a barrier to learning, and were less likely to report overcoming barriers to skills training via the key processes outlined above. The findings of this qualitative study require replication, but could be used to generate hypotheses for testing in further research on barriers to skills training, how these relate to dropout, and how they can be overcome. The paper outlines several such suggestions for further research

The Use of Virtual Reality Facilitates Dialectical Behavior Therapy® “Observing Sounds and Visuals” Mindfulness Skills Training Exercises for a Latino Patient with Severe Burns: A Case Study

Sustaining a burn injury increases an individual’s risk of developing psychological problems such as generalized anxiety, negative emotions, depression, acute stress disorder, or post-traumatic stress disorder. Despite the growing use of Dialectical Behavioral Therapy® (DBT®) by clinical psychologists, to date, there are no published studies using standard DBT® or DBT® skills learning for severe burn patients. The current study explored the feasibility and clinical potential of using Immersive Virtual Reality (VR) enhanced DBT® mindfulness skills training to reduce negative emotions and increase positive emotions of a patient with severe burn injuries. The participant was a hospitalized (in house) 21-year-old Spanish speaking Latino male patient being treated for a large (>35% TBSA) severe flame burn injury. Methods: The patient looked into a pair of Oculus Rift DK2 virtual reality goggles to perceive the computer-generated virtual reality illusion of floating down a river, with rocks, boulders, trees, mountains, and clouds, while listening to DBT® mindfulness training audios during 4 VR sessions over a 1 month period. Study measures were administered before and after each VR session. Results: As predicted, the patient reported increased positive emotions and decreased negative emotions. The patient also accepted the VR mindfulness treatment technique. He reported the sessions helped him become more comfortable with his emotions and he wanted to keep using mindfulness after returning home. Conclusions: Dialectical Behavioral Therapy is an empirically validated treatment approach that has proved effective with non-burn patient populations for treating many of the psychological problems experienced by severe burn patients. The current case study explored for the first time, the use of immersive virtual reality enhanced DBT® mindfulness skills training with a burn patient. The patient reported reductions in negative emotions and increases in positive emotions, after VR DBT® mindfulness skills training. Immersive Virtual Reality is becoming widely available to mainstream consumers, and thus has the potential to make this treatment available to a much wider number of patient populations, including severe burn patients. Additional development, and controlled studies are needed

The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding

The ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific "client" proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. FNIPs compete with the activating co-chaperone Aha1 for binding to Hsp90, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins. Lastly, downregulation of FNIPs desensitizes cancer cells to Hsp90 inhibitors, whereas FNIPs overexpression in renal tumours compared with adjacent normal tissues correlates with enhanced binding of Hsp90 to its inhibitors. Our findings suggest that FNIPs expression can potentially serve as a predictive indicator of tumour response to Hsp90 inhibitors

Seventh BHD international symposium: recent scientific and clinical advancement.

The 7th Birt-Hogg-Dubé (BHD) International Symposium convened virtually in October 2021. The meeting attracted more than 200 participants internationally and highlighted recent findings in a variety of areas, including genetic insight and molecular understanding of BHD syndrome, structure and function of the tumor suppressor Folliculin (FLCN), therapeutic and clinical advances as well as patients' experiences living with this malady

Inactivation of the FLCN Tumor Suppressor Gene Induces TFE3 Transcriptional Activity by Increasing Its Nuclear Localization

Germline mutations in a tumor suppressor gene FLCN lead to development of fibrofolliculomas, lung cysts and renal cell carcinoma (RCC) in Birt-Hogg-Dubé syndrome. TFE3 is a member of the MiTF/TFE transcription factor family and Xp11.2 translocations found in sporadic RCC involving TFE3 result in gene fusions and overexpression of chimeric fusion proteins that retain the C-terminal DNA binding domain of TFE3. We found that GPNMB expression, which is regulated by MiTF, was greatly elevated in renal cancer cells harboring either TFE3 translocations or FLCN inactivation. Since TFE3 is implicated in RCC, we hypothesized that elevated GPNMB expression was due to increased TFE3 activity resulting from the inactivation of FLCN.TFE3 knockdown reduced GPNMB expression in renal cancer cells harboring either TFE3 translocations or FLCN inactivation. Moreover, FLCN knockdown induced GPNMB expression in FLCN-restored renal cancer cells. Conversely, wildtype FLCN suppressed GPNMB expression in FLCN-null cells. FLCN inactivation was correlated with increased TFE3 transcriptional activity accompanied by its nuclear localization as revealed by elevated GPNMB mRNA and protein expression, and predominantly nuclear immunostaining of TFE3 in renal cancer cells, mouse embryo fibroblast cells, mouse kidneys and mouse and human renal tumors. Nuclear localization of TFE3 was associated with TFE3 post-translational modifications including decreased phosphorylation.Increased TFE3 activity is a downstream event induced by FLCN inactivation and is likely to be important for renal tumor development. This study provides an important novel mechanism for induction of TFE3 activity in addition to TFE3 overexpression resulting from Xp11.2 translocations, suggesting that TFE3 may be more broadly involved in tumorigenesis