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Throughout their career, people living with autoimmune diseases must navigate workplace precarity amidst ongoing disruptions to health and wellbeing. Informed by the communication theory of resilience (CTR), we conduct semi-structured, narrative interviews with 25 individuals living with autoimmune diseases to examine their career-related disruptions and communicative resilience enactments. Data analysis reveals two major themes: (1) disability as a discursive-material disruption and (2) career-triggering illness complications. Theoretically, our findings extend anticipatory and adaptive-transformative CTR tensions through the moment-to-moment disruptions that intersect this community's careers and health journeys. Practically, we seek to re-imagine workplace accommodations and disability to better meet both the health and work needs of stigmatized and chronically ill individuals, such as individuals with autoimmune diseases.

There is a need to understand the journey of patients with melanoma, including any associated gender differences, to identify aspects in the patient journey that could be improved. We used data collected from an online survey completed by adults with stage III or IV melanoma at three Swiss melanoma centres to understand patients' perceptions of their healthcare journeys from melanoma diagnosis to treatment and the relevance of treatment attributes (Figure 1). We identified that there is a need to improve communication about the testing process and gender differences in terms on information needs, relevance of treatment attributes and attitudes towards psychological support., Competing Interests: CL declared receiving institutional honoraria for lectures and advisory boards from Bristol Myers Squibb (BMS), MSD, Novartis and Sanofi. BCO declared receiving institutional honoraria for lectures and advisory boards from BMS, Ipsen, Janssen, MSD, Merck, Novartis, Pfizer, Roche and Sanofi. HL received travel grants and consultant fees from BMS, Alector, InterVenn, GlycoEra and Merck, Sharp and Dohme (MSD) and received research support from BMS, Novartis, GlycoEra and Palleon Pharmaceuticals. JM has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp and Dohme, Amgen, Novartis, Roche, BMS and Pierre Fabre and has received travel support from Ultrasun, L’Oreal, Merck Sharp and Dohme, BMS and Pierre Fabre outside of the submitted work. VDP declared current or previous collaboration projects with Novartis, MSD, and Pierre Fabre. LM declared project focused advisory relationship with BMS, Merck, MSD and Novartis. LVM served as adviser for, and/or received speaking fees from, and/or participated in clinical trials sponsored by Almirall, Amgen, Eli Lilly, MSD, Novartis, Pierre Fabre, Roche and Sanofi (all fees to institution). DK declared honoraria (Amgen and Sanofi), attending meetings/travel (Amgen and Sanofi) and advisory boards (AstraZeneca, Merck and MSD) (all fees to institution). FD receives/received honoraria and travel support from BMS, MSD and Sun Pharma. RD declared collaboration with Novartis, MSD, BMS, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, CatalYm, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer and touchIME outside the submitted work. SK, JL, AM, NP and BS are employees of Novartis Pharma Schweiz AG, Switzerland., (© 2024 The Author(s). Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Epithelial skin cancers are extremely common, but the mechanisms underlying their malignant progression are still poorly defined. Here, we identify the NRF3 transcription factor as a tumor suppressor in the skin. NRF3 protein expression is strongly downregulated or even absent in invasively growing cancer cells of patients with basal and squamous cell carcinomas (BCC and SCC). NRF3 deficiency promoted malignant conversion of chemically induced skin tumors in immunocompetent mice, clonogenic growth and migration of human SCC cells, their invasiveness in 3D cultures, and xenograft tumor formation. Mechanistically, the tumor-suppressive effect of NRF3 involves HSPA5, a key regulator of the unfolded protein response, which we identified as a potential NRF3 interactor. HSPA5 levels increased in the absence of NRF3, thereby promoting cancer cell survival and migration. Pharmacological inhibition or knock-down of HSPA5 rescued the malignant features of NRF3-deficient SCC cells in vitro and in preclinical mouse models. Together with the strong expression of HSPA5 in NRF3-deficient cancer cells of SCC patients, these results suggest HSPA5 inhibition as a treatment strategy for these malignancies in stratified cancer patients., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

N,N -Dimethylacetamide (DMA) is FDA approved as an excipient and is used as drug-delivery vehicle. Due to its amphipathic nature and diverse bioactivities, it appears to be a good combination of biodegradable poly-lactide-co-glycolide (PLGA)-based guided bone regeneration membranes. Here we show that the solvent DMA can be loaded to PLGA membranes by different regimes, leading to distinct release profiles, and enhancing the bone regeneration in vivo. Our results highlight the potential therapeutic benefits of DMA in guided bone regeneration procedures, in combination with biodegradable PLGA membranes., Competing Interests: The authors declare no conflict of interest. C.G. and F.E.W. are listed as inventors of the patent hold by the University mentioned above.

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of the cellular stress response, but the biological functions of the related Nrf3 protein are largely unknown. Here we demonstrate a novel pro-apoptotic function of Nrf3 in mouse and human keratinocytes. In response to UV irradiation, Nrf3-deficient keratinocytes were protected from apoptosis in vitro and in vivo. The protective function was also seen under oxidative or hyperosmotic stress conditions, but not when apoptosis was induced by disruption of cell-matrix interactions. Mechanistically, we show that Nrf3-deficient keratinocytes exhibit stronger cell-cell and cell-matrix adhesion, which correlates with higher cell surface integrin levels and enhanced activation of focal adhesion kinase. Nrf3-deficient cells also formed more and larger focal adhesions and exhibited a higher motility. These results suggest that the strong expression of Nrf3 in basal keratinocytes promotes their elimination in response to DNA damage-inducing agents, thereby preventing accumulation of mutated stem and transit amplifying cells in the epidermis.

(1) Background: In an adult skeleton, bone is constantly renewed in a cycle of bone resorption, followed by bone formation. This coupling process, called bone remodeling, adjusts the quality and quantity of bone to the local needs. It is generally accepted that osteoporosis develops when bone resorption surpasses bone formation. Osteoclasts and osteoblasts, bone resorbing and bone forming cells respectively, are the major target in osteoporosis treatment. Inside bone and forming a complex network, the third and most abundant cells, the osteocytes, have long remained a mystery. Osteocytes are responsible for mechano-sensation and -transduction. Increased expression of the osteocyte-derived bone inhibitor sclerostin has been linked to estrogen deficiency-induced osteoporosis and is therefore a promising target for osteoporosis management. (2) Methods: Recently we showed in vitro and in vivo that NMP ( N -Methyl-2-pyrrolidone) is a bioactive drug enhancing the BMP-2 (Bone Morphogenetic Protein 2) induced effect on bone formation while blocking bone resorption. Here we tested the effect of NMP on the expression of osteocyte-derived sclerostin. (3) Results: We found that NMP significantly decreased sclerostin mRNA and protein levels. In an animal model of osteoporosis, NMP prevented the estrogen deficiency-induced increased expression of sclerostin. (4) Conclusions: These results support the potential of NMP as a novel therapeutic compound for osteoporosis management, since it preserves bone by a direct interference with osteoblasts and osteoclasts and an indirect one via a decrease in sclerostin expression by osteocytes.

Additive manufacturing of bone tissue engineering scaffolds will become a key element for personalized bone tissue engineering in the near future. Several additive manufacturing processes are based on extrusion where the deposition of the filament will result in a three-dimensional lattice structure. Recently, we studied diverse lattice structures for bone tissue engineering realized by laser sintering of titanium. In this work, we used lithography-based ceramic manufacturing of lattice structures to produce scaffolds from tricalcium phosphates (TCP) and compared them in vivo to congruent titanium scaffolds manufactured with the identical computer-aided design data to look for material-based differences in bony healing. The results show that, during a 4-week period in a noncritical-size defect in a rabbit calvarium, both scaffolds with the identical microarchitecture performed equally well in terms of bony regeneration and bony bridging of the defect. A significant increase in both parameters could only be achieved when the TCP-based scaffolds were doped with bone morphogenetic protein-2. In a critical-size defect in the calvarial bone of rabbits, however, the titanium scaffold performed significantly better than the TCP-based scaffold, most likely due to its higher mechanical stability. We conclude that titanium and TCP-based scaffolds of the same microarchitecture perform equally well in terms of bone regeneration, provided the microarchitecture meets the mechanical demand at the site of implantation.

N,N-Dimethylacetamide (DMA) is a water-miscible solvent, FDA approved as excipient and therefore widely used as drug-delivery vehicle. As such, DMA should be devoid of any bioactivity. Here we report that DMA is epigenetically active since it binds bromodomains and inhibits osteoclastogenesis and inflammation. Moreover, DMA enhances bone regeneration in vivo. Therefore, our in vivo and in vitro data reveal DMA's potential as an anti-osteoporotic agent via the inhibition of osteoclast mediated bone resorption and enhanced bone regeneration. Our results highlight the potential therapeutic benefits of DMA and the need for reconsideration of previous reports where DMA was used as an 'inactive' drug-delivery vehicle., Competing Interests: The University holds a patent on DMA in conjunction with osteoporosis. The authors, other than CG and FEW have no competing interests that might be perceived to influence the results and/or discussion reported in this article.

Conventional root canal treatment in immature permanent teeth can lead to early tooth loss in children because root formation is discontinued. We investigated whether the stem cell factor (SCF) could facilitate cell homing in the pulpless immature root canal and promote regeneration of a functional pulp. In vitro, human mesenchymal stem cells (hMSCs) were exposed to SCF at various concentrations for assessing cell migration, proliferation, and differentiation toward odonto/osteoblasts by 3D-chemotaxis slides, WST-1 assay, and alkaline phosphatase activity, respectively. Fibrin gels were used to deliver 15 μg/mL SCF for in vivo experiments. The release kinetic of SCF was assessed in vitro. Two corresponding human immature premolars, with or without SCF, were placed at rat calvariae for 6 and 12 weeks. All tooth specimens were either analyzed histologically and the percentage of tissue ingrowth determined or the cells were extracted from the pulp space, and the mRNA level of DMP1, DSPP, Col1, NGF, and VEGF were assessed by quantitative polymerase chain reaction. In the presence of SCF, we saw an increase in hMSCs directional migration, proliferation, and odonto/osteogenic differentiation. SCF also increased the extent of tissue ingrowth at 6 weeks but not at 12 weeks. However, at this time point, the formed tissue appeared more mature in samples with SCF. In terms of gene transcription, DMP1, Col1, and VEGF were the significantly upregulated genes, while DSPP and NGF were not affected. Our results suggest that SCF can accelerate cell homing and the maturation of the pulp-dentin complex in human immature teeth.

Guided bone regeneration (GBR) has been utilized for several decades for the healing of cranio-maxillofacial bone defects and, particularly in the dental field, by creating space with a barrier membrane to exclude soft tissue and encourage bone growth in the membrane-protected volume. Although the first membranes were non-resorbable, a new generation of GBR membranes aims to biodegrade and provide bioactivity for better overall results. The Inion GTR™ poly(lactide-co-glycolide) (PLGA) membrane is not only resorbable but also bioactive, since it includes N-methylpyrrolidone (NMP), which has been shown to promote bone regeneration. In this study, the effects of loading different amounts of NMP onto the membrane through chemical vapour deposition or dipping have been explored. In vitro release demonstrated that lower levels of NMP led to lower NMP concentrations and slower release, based on total NMP loaded in the membrane. The dipped membrane released almost all of the NMP within 15 min, leading to a high NMP concentration. For the in vivo studies in rabbits, 6 mm calvarial defects were created and left untreated or covered with an ePTFE membrane or PLGA membranes dipped in, or preloaded with, NMP. Evaluation of the bony regeneration revealed that the barrier membranes improved bony healing and that a decrease in NMP content improved the performance. Overall, we have demonstrated the potential of these PLGA membranes with a more favourable NMP release profile and the significance of exploring the effect of NMP on these PLGA membranes with regard to bone ingrowth. Copyright © 2014 John Wiley & Sons, Ltd., (Copyright © 2014 John Wiley & Sons, Ltd.)

Currently, there are several treatments for osteoporosis however; they all display some sort of limitation and/or side effects making the need for new treatments imperative. We have previously demonstrated that NMP is a bioactive drug which enhances bone regeneration in vivo and acts as an enhancer of bone morphogenetic protein (BMP) in vitro. NMP also inhibits osteoclast differentiation and attenuates bone resorption. In the present study, we tested NMP as a bromodomain inhibitor and for osteoporosis prevention on ovariectomized (OVX) induced rats while treated systemically with NMP. Female Sprague-Dawley rats were ovariectomized and weekly NMP treatment was administrated 1 week after surgery for 15 weeks. Bone parameters and related serum biomarkers were analyzed. 15 weeks of NMP treatment decreased ovariectomy-induced gained weight in average by 43% and improved bone mineral density (BMD) and bone volume over total volume (BV/TV) in rat femur on average by 25% and 41% respectively. Moreover, mineral apposition rate and bone biomarkers of bone turnover in the treatment group were at similar levels with those of the Sham group. Due to the function of NMP as a low affinity bromodomain inhibitor and its mechanism of action involving osteoblasts/osteoclasts balance and inhibitory effect on inflammatory cytokines, NMP is a promising therapeutic compound for the prevention of osteoporosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: N-methyl pyrrolidone (NMP), a small bioactive molecule, stimulates bone formation and inhibits osteoclast differentiation and bone resorption. The present study was aimed to evaluate the anti-inflammatory potentials of NMP on the inflammatory process and the underlying molecular mechanisms in RAW264.7 macrophages., Materials and Methods: RAW264.7 macrophages and mouse primary bone marrow macrophages (mBMMs) were used as an in vitro model to investigate inflammatory processes. Cells were pre-treated with or without NMP and then stimulated with lipopolysaccharides (LPS). The productions of cytokines and NO were determined by proteome profiler method and nitrite analysis, respectively. The expressions of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were measured by Western blotting and/or qPCR. Western blot, ELISA-base reporter assay, and immunofluorescence were used to evaluate the activation of MAP kinases and NF-κB., Results: LPS-induced mRNA expressions of TNF-α, IL-1β, IL-6, iNOS, and COX-2 were inhibited by NMP in a dose-dependent manner. NMP also suppressed the LPS-increased productions of iNOS and NO. The proteome profiler array showed that several cytokines and chemokines involved in inflammation and up-regulated by LPS stimulation were significantly down-regulated by NMP. Additionally, this study shows that the effect of NMP is mediated through down-regulation of NFκB pathway., Conclusions: Our results show that NMP inhibits the inflammatory mediators in macrophages by an NFκB-dependent mechanism, based on the epigenetical activity of NMP as bromodomain inhibitor. In the light of its action on osteoblast and osteoclast differentiation process and its anti-inflammatory potential, NMP might be used in inflammation-related bone loss.

Bone morphogenetic proteins (BMPs) are growth and differentiation factors involved during development in morphogenesis, organogenesis and later mainly in regeneration processes, in particular in bone where they are responsible for osteoinduction. For more than a decade, recombinant human (rh)BMP-2 has been used in the clinic for lumbar spinal fusion at non-physiological high dosages that appear to be causative for side effects, like male sterility. A possible strategy to reduce the effective amount of rhBMP-2 in the clinic is the co-delivery with an enhancer of BMPs' activity. In an earlier study, we showed that N-methylpyrrolidone (NMP) enhances BMP activity in vitro and in vivo. Here we report on the development of a slow and sustained double delivery of rhBMP-2 and NMP via an in situ forming implant based on poly(lactide-co-glycolide). The results showed that the release of NMP can be adjusted by varying the lactide/glycolide ratio and the polymer's molecular weight. The same applied to rhBMP-2, with release rates that could be sustained from two to three weeks. In the in vivo model of a critical size defect in the calvarial bone of rabbits, the implant containing 50mol% lactide performed better than the one having 75mol% lactide in terms of defect bridging and extent of bony regenerated area. In situ forming implants for the double delivery of the BMP enhancer NMP and rhBMP-2 appear to be promising delivery systems in bone regeneration., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Current clinically used delivery methods for bone morphogenetic proteins (BMPs) are collagen based and require large concentrations that can lead to dangerous side effects. Fibrin hydrogels can serve as osteoinductive bone substitute materials in non-load bearing bone defects in combination with BMPs. Two strategies to even further optimize such a fibrin based system include employing more potent BMP heterodimers and engineering growth factors that can be covalently tethered to and slowly released from a fibrin matrix. Here we present an engineered BMP-2/BMP-7 heterodimer where an N-terminal transglutaminase substrate domain in the BMP-2 portion provides covalent attachment to fibrin together with a central plasmin substrate domain, a cleavage site for local release of the attached BMP-2/BMP-7 heterodimer under the influence of cell-activated plasmin. In vitro and in vivo results revealed that the engineered BMP-2/BMP-7 heterodimer induces significantly more alkaline phosphatase activity in pluripotent cells and bone formation in a rat calvarial model than the engineered BMP-2 homodimer. Therefore, the engineered BMP-2/BMP-7 heterodimer could be used to reduce the amount of BMP needed for clinical effect.

The liver has a unique regenerative capability, which involves extensive remodelling of cell-cell and cell-matrix contacts. Here we study the role of integrins in mouse liver regeneration using Cre/loxP-mediated gene deletion or intravenous delivery of β1-integrin siRNA formulated into nanoparticles that predominantly target hepatocytes. We show that although short-term loss of β1-integrin has no obvious consequences for normal livers, partial hepatectomy leads to severe liver necrosis and reduced hepatocyte proliferation. Mechanistically, loss of β1-integrin in hepatocytes impairs ligand-induced phosphorylation of the epidermal growth factor and hepatocyte growth factor receptors, thereby attenuating downstream receptor signalling in vitro and in vivo. These results identify a crucial role and novel mechanism of action of β1-integrins in liver regeneration and demonstrate that protein depletion by nanoparticle-based delivery of specific siRNA is a powerful strategy to study gene function in the regenerating liver.

Alzheimer's disease (AD) is characterized by cerebral deposition of β-amyloid (Aβ) peptides, which are generated from amyloid precursor protein (APP) by β- and γ-secretases. APP and the secretases are membrane associated, but whether membrane trafficking controls Aβ levels is unclear. Here, we performed an RNAi screen of all human Rab-GTPases, which regulate membrane trafficking, complemented with a Rab-GTPase-activating protein screen, and present a road map of the membrane-trafficking events regulating Aβ production. We identify Rab11 and Rab3 as key players. Although retromers and retromer-associated proteins control APP recycling, we show that Rab11 controlled β-secretase endosomal recycling to the plasma membrane and thus affected Aβ production. Exome sequencing revealed a significant genetic association of Rab11A with late-onset AD, and network analysis identified Rab11A and Rab11B as components of the late-onset AD risk network, suggesting a causal link between Rab11 and AD. Our results reveal trafficking pathways that regulate Aβ levels and show how systems biology approaches can unravel the molecular complexity underlying AD., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Recombinant bovine interferon-alpha(I)1 (rBolFN-alpha) may be useful for enhancing fertility in sheep because it has extensive sequence homology with ovine trophoblast protein-1. To test the effectiveness of rBolFN-alpha, several experiments were performed in which bred females were given intramuscular injections of rBolFN-alpha around the time of maintenance of the corpus luteum. Treatment with rBolFN-alpha enhanced the fertility of ewes that were bred via natural service or embryo transfer of whole or demi-embryos. Interferon treatment was successful in enhancing lambing rate if injections were given twice daily from Days 11 to 18, 12 to 14, 12 to 15 or 12 to 16. Overall, the lambing rate for ewes bred via natural service was 94/126 (74.6%) for control ewes and 101/126 (80.2%) for rBolFN-alpha treated ewes. Litter size was not affected by treatment. Interferon treatment was not successful in increasing the lambing rate if given as a single injection on Day 12 or as a series of once-daily injections from Days 11 to 16. These results demonstrate that rBolFN-alpha can increase the lambing rate in ewes.

The in vivo effects of a single prophylactic dose of recombinant bovine interferon (rBoIFN)-alpha I1 in calves with salmonellosis were investigated, using a Salmonella typhimurium infection model. Treatment with rBoIFN-alpha I1 reduced the degree of septicemia compared with that in control groups, and, in one experiment, using disease of reduced severity, body temperature was lower in treated calves than in controls.

The reliability of SRT and speech intelligibility tests has been studied on adults. Reliability estimates for SRT are between .60 and .90, with standard error estimates from 1.5 to over five dB. For speech intelligibility tests the reliability estimates range from .50 to 90, with standard error of estimates from 2.5% to over 10%. Little has been reported on test reliability with children. For this study the TIP and DIP tests, for threshold and discrimination, respectively, were given to 295 normal and 138 hypacusic children three through twelve years of age. Subjects were retested within one week. TIP test-retest reliability was .72 for normals, and .89 to .99 for hypacusics. DIP test-retest reliability was .46 to .51 for normals and .60 to .93 for hypacusics. Standard error of estimate was about 3 dB for TIP, and 10% for DIP. These values are about the same as the reliability values for adults.

Research on central functions presents difficult problems, including heterogeneity among normals and subjects with central nervous system (CNS) defects. General conclusions are that there is an ear advantage related to cerebral dominance; testing for results of CNS damage requires stimuli of reduced redundancy; and fusion of dichotic stimuli is a brainstem function. Responses to digits presented dichotically were obtained. Data were in agreement with the usual findings that brain injury results in a reduced ability to understand dichotic speech and that injury to the dominant cerebral hemisphere results in lower speech perception via the opposite ear than by the ipsilateral ear. Significantly almost one third of the subjects performed differently than other members of their respective subgroups. A direction for additional research is to consider factors in otherwise apparently homogeneous groups that lead to nonhomogenous responses.

Eleven hearing-impaired subjects were tested using a speechreading test employing the CID Everyday Sentence Lists read by a male speaker under four different conditions: full beard and moustache, trimmed beard and moustache, moustache only, and clean shaven. The results indicated that varying amounts of facial hair do not have significant effects on speechreading performance. Mean scores for speechreading performance decreased somewhat with reduction of facial hair, however, as confirmed by a test of linear trend (p less than 0.05).