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| 2. |
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| 3. |
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| 4. |
- Bruder, CEG, et al.
(författare)
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High resolution deletion analysis of constitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH
- 2001
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Ingår i: Human Molecular Genetics. - Oxford, United Kingdom : Oxford University Press. - 0964-6906 .- 1460-2083. ; 1, s. 271-
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Tidskriftsartikel (refereegranskat)abstract
- Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder whose hallmark is bilateral vestibular schwannoma. It displays a pronounced clinical heterogeneity with mild to severe forms. The NF2 tumor suppressor (merlin/schwannomin) has been cloned and extensively analyzed for mutations in patients with different clinical variants of the disease. Correlation between the type of the NF2 gene mutation and the patient phenotype has been suggested to exist. However, several independent studies have shown that a fraction of NF2 patients with various phenotypes have constitutional deletions that partly or entirely remove one copy of the NF2 gene. The purpose of this study was to examine a 7 Mb interval in the vicinity of the NF2 gene in a large series of NF2 patients in order to determine the frequency and extent of deletions. A total of 116 NF2 patients were analyzed using high-resolution array-comparative genomic hybridization (CGH) on an array covering at least 90% of this region of 22q around the NF2 locus. Deletions, which remove one copy of the entire gene or are predicted to truncate the schwannomin protein, were detected in 8 severe, 10 moderate and 6 mild patients. This result does not support the correlation between the type of mutation affecting the NF2 gene and the disease phenotype. This work also demonstrates the general usefulness of the array-CON methodology for rapid and comprehensive detection of small (down to 40 kb) heterozygous and/or homozygous deletions occurring in constitutional or tumor-derived DNA.
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| 5. |
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| 7. |
- Devarajan, R., et al.
(författare)
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Targeting collagen XVIII improves the efficiency of ErbB inhibitors in breast cancer models
- 2023
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 133:18
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Tidskriftsartikel (refereegranskat)abstract
- The tumor extracellular matrix (ECM) critically regulates cancer progression and treatment response. Expression of the basement membrane component collagen XVIII (ColXVIII) is induced in solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII was markedly upregulated in human breast cancer (BC) and was closely associated with a poor prognosis in high-grade BCs. We discovered a role for ColXVIII as a modulator of epidermal growth factor receptor tyrosine kinase (ErbB) signaling and show that it forms a complex with ErbB1 and-2 (also known as EGFR and human epidermal growth factor receptor 2 [HER2]) and alpha 6-integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/AKT cascades. Studies using Col18a1 mouse models crossed with the mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT) mammary carcinogenesis model showed that ColXVIII promoted BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in the MMTV-PyMT and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII substantially improved the efficacy of ErbB-targeting therapies in both preclinical models. In summary, ColXVIII was found to sustain the stemness properties of BC cells and tumor progression and metastasis through ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have important therapeutic potential.
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| 8. |
- Hansen, Lea B.S., et al.
(författare)
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A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- © 2018, The Author(s). Adherence to a low-gluten diet has become increasingly common in parts of the general population. However, the effects of reducing gluten-rich food items including wheat, barley and rye cereals in healthy adults are unclear. Here, we undertook a randomised, controlled, cross-over trial involving 60 middle-aged Danish adults without known disorders with two 8-week interventions comparing a low-gluten diet (2 g gluten per day) and a high-gluten diet (18 g gluten per day), separated by a washout period of at least six weeks with habitual diet (12 g gluten per day). We find that, in comparison with a high-gluten diet, a low-gluten diet induces moderate changes in the intestinal microbiome, reduces fasting and postprandial hydrogen exhalation, and leads to improvements in self-reported bloating. These observations suggest that most of the effects of a low-gluten diet in non-coeliac adults may be driven by qualitative changes in dietary fibres.
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| 9. |
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| 10. |
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| 11. |
- Rask, Marie, 1974-, et al.
(författare)
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Women with abnormal Pap smear result: : a qualitative study of Swedish healthcare professionals' experiences
- 2016
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Ingår i: European Journal of Cancer Care. - : John Wiley & Sons. - 0961-5423 .- 1365-2354. ; 25:6, s. 980-991
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Tidskriftsartikel (refereegranskat)abstract
- A Papanicolaou (Pap) smear can be used to detect pre-cancerous cellular changes, so that they can be treated before they develop into cervical cancer. When the results of a Pap smear test are abnormal, women need further investigation, treatment and follow-up. Healthcare professionals (HCPs) are in a position to care for these women with abnormalities. The aim of this study was to explore the experiences of HCPs in caring for women with abnormal Pap smear results. In total, 20 HCPs from two counties in south-eastern Sweden participated in individual interviews, based on two open-ended questions. Interviews were recorded, transcribed verbatim and analysed using content analysis. The results showed that HCPs experienced that abnormal Pap smear results created anxiety in women, who often sought information from the Internet as a way to cope. Furthermore, the HCPs thought that it was a problem that women chose not to attend investigation, treatment and follow-ups. However, information about the seriousness of abnormal Pap smear results causes women to participate. It is a challenge for HCPs to inform in a reassuring manner. Finally, HCPs should collaborate with women to meet their information needs and to also provide support regarding finding and filtering reliable information on the Internet.
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| 12. |
- Eckhard, A, et al.
(författare)
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Regulation of the perilymphatic-endolymphatic water shunt in the cochlea by membrane translocation of aquaporin-5
- 2015
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Ingår i: Pflügers Archiv. - : Springer Science and Business Media LLC. - 0031-6768 .- 1432-2013. ; 467:12, s. 2571-2588
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Tidskriftsartikel (refereegranskat)abstract
- Volume homeostasis of the cochlear endolymph depends on radial and longitudinal endolymph movements (LEMs). LEMs measured in vivo have been exclusively recognized under physiologically challenging conditions, such as experimentally induced alterations of perilymph osmolarity or endolymph volume. The regulatory mechanisms that adjust LEMs to the physiological requirements of endolymph volume homeostasis remain unknown. Here, we describe the formation of an aquaporin (AQP)-based "water shunt" during the postnatal development of the mouse cochlea and its regulation by different triggers. The final complementary expression pattern of AQP5 (apical membrane) and AQP4 (basolateral membrane) in outer sulcus cells (OSCs) of the cochlear apex is acquired at the onset of hearing function (postnatal day (p)8-p12). In vitro, hyperosmolar perfusion of the perilymphatic fluid spaces or the administration of the muscarinic agonist pilocarpine in cochlear explants (p14) induced the translocation of AQP5 channel proteins into the apical membranes of OSCs. AQP5 membrane translocation was blocked by the muscarinic antagonist atropine. The muscarinic M3 acetylcholine (ACh) receptor (M3R) was identified in murine OSCs via mRNA expression, immunolabeling, and in vitro binding studies using an M3R-specific fluorescent ligand. Finally, the water shunt elements AQP4, AQP5, and M3R were also demonstrated in OSCs of the human cochlea. The regulation of the AQP4/AQP5 water shunt in OSCs of the cochlear apex provides a molecular basis for regulated endolymphatic volume homeostasis. Moreover, its dysregulation or disruption may have pathophysiologic implications for clinical conditions related to endolymphatic hydrops, such as Ménière's disease.
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| 13. |
- Egana, I, et al.
(författare)
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Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 15453-
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Tidskriftsartikel (refereegranskat)abstract
- Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.
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| 14. |
- Ek, Weronica E., et al.
(författare)
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Tea and coffee consumption in relation to DNA methylation in four European cohorts
- 2017
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 26:16, s. 3221-3231
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Tidskriftsartikel (refereegranskat)abstract
- Lifestyle factors, such as food choices and exposure to chemicals, can alter DNA methylation and lead to changes in gene activity. Two such exposures with pharmacologically active components are coffee and tea consumption. Both coffee and tea has been suggested to play an important role in modulating disease-risk in humans by suppressing tumour progression, decreasing inflammation and influencing estrogen metabolism. These mechanisms may be mediated by changes in DNA methylation.To investigate if DNA methylation in blood is associated with coffee and tea consumption we performed a genome-wide DNA methylation study for coffee and tea consumption in four European cohorts (N = 3,096). DNA methylation was measured from whole blood at 421,695 CpG sites distributed throughout the genome and analysed in men and women both separately and together in each cohort. Meta-analyses of the results and additional regional-level analyses were performed.After adjusting for multiple testing, the meta-analysis revealed that two individual CpG-sites, mapping to DNAJC16 and TTC17, were differentially methylated in relation to tea consumption in women. No individual sites were associated in men or in the sex-combined analysis for tea or coffee. The regional analysis revealed that 28 regions were differentially methylated in relation to tea consumption in women. These regions contained genes known to interact with estradiol metabolism and cancer. No significant regions were found in the sex-combined and male-only analysis for either tea or coffee consumption.
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| 15. |
- Henson, M.M., et al.
(författare)
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Smooth muscle in the annulus fibrosus of the tympanic membrane in bats, rodents, insectivores and humans
- 2005
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Ingår i: Hearing Research. - : Elsevier BV. - 0378-5955 .- 1878-5891. ; 200:1-2, s. 29-37
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Tidskriftsartikel (refereegranskat)abstract
- The annulus fibrosus and its attachment to the bony tympanic ring were studied in a series of mammals. In the pallid bat, Antrozous pallidus, there is an extensive plexus of large interconnected blood sinuses in the part of the annulus that borders the tympanic bone. The spaces between the sinuses are packed with smooth muscle cells. Most of the cells have a predominately radial orientation; they extend from the bony tympanic sulcus to a dense collagenous matrix (apical zone) where radially oriented fibers of the pars tensa are confluent with the annulus. The muscles and vessels constitute a myovascular zone. A structurally similar myovascular zone is also present in the European hedgehog. In rodents, the annulus lacks the large interconnected blood sinuses but many small vessels are present. Smooth muscle is concentrated in the broad area of attachment of the annulus to the tympanic bone. In the gerbil, smooth muscle seems to be concentrated in the central part of the width of the annulus where it is attached to bone and radiates toward the tympanic membrane. In humans collections of radially oriented smooth muscle cells were found in several locations. The smooth muscle in all species studied appears to form a rim of contractile elements for the pars tensa. This arrangement suggests a role in controlling blood flow and/or creating and maintaining tension on the tympanic membrane.
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| 16. |
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| 17. |
- Li, Hao, 1984-, et al.
(författare)
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Unlocking the human inner ear for therapeutic intervention
- 2022
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- The human inner ear contains minute three-dimensional neurosensory structures that are deeply embedded within the skull base, rendering them relatively inaccessible to regenerative therapies for hearing loss. Here we provide a detailed characterisation of the functional architecture of the space that hosts the cell bodies of the auditory nerve to make them safely accessible for the first time for therapeutic intervention. We used synchrotron phase-contrast imaging which offers the required microscopic soft-tissue contrast definition while simultaneously displaying precise bony anatomic detail. Using volume-rendering software we constructed highly accurate 3-dimensional representations of the inner ear. The cell bodies are arranged in a bony helical canal that spirals from the base of the cochlea to its apex; the canal volume is 1.6 mu L but with a diffusion potential of 15 mu L. Modelling data from 10 temporal bones enabled definition of a safe trajectory for therapeutic access while preserving the cochlea's internal architecture. We validated the approach through surgical simulation, anatomical dissection and micro-radiographic analysis. These findings will facilitate future clinical trials of novel therapeutic interventions to restore hearing.
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| 18. |
- Rosén, Stefan, et al.
(författare)
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Molecular characterization of a saline-soluble lectin from a parasitic fungus : Extensive sequence similarities between fungal lectins
- 1996
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Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 238:3, s. 822-829
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Tidskriftsartikel (refereegranskat)abstract
- It has been proposed that the interactions between several parasite and pathogenic fungi and their hosts are mediated by soluble lectins present in the fungus. We have cloned and analyzed a gene encoding such a lectin (AOL) from the nematophagous fungus Arthrobotrys oligospora (deuteromycete). The deduced primary structure of the AOL gene displayed an extensive similarity (identity 46.3%) to that of a gene encoding a lectin (ABL) recently isolated from the mushroom Agaricus bisporus (basidiomycete), but not to any other fungal, microbial, plant, or animal lectins. The similarities between AOL and ABL were further demonstrated by the observation that an antibody specific for AOL cross-reacted with ABL. Together with data showing that AOL has a binding specificity that is similar to that of ABL [Rosen, S., Bergstrom, J., Karlsson, K.-A., and Tunlid, A. (1996) Eur. J. Biochem. 238, 830-837], these results indicate that AOL and ABL are members of a novel family of saline- soluble lectins present in fungi. Southern blots indicated that there is only one AOL gene in the genome encoding a subunit (monomer) of the lectin. The primary structure of AOL did not show the presence of a typical N-terminal signal sequence. Comparison of the deduced primary structure with the molecular mass of AOL as determined by electrospray mass spectrometry (16153 Da), indicated that AOL has an acetylated N-terminal but no other post- translational modifications, and that a minor isoform is formed by deamidation. Circular dichroism (CD) spectroscopy suggested that the secondary structure of AOl contains 34% β-sheets, 21% α-helix, and 45% turns and coils.
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| 19. |
- Welander, Nike Zoe, et al.
(författare)
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Migraine, inflammatory bowel disease and celiac disease : A Mendelian randomization study
- 2023
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Ingår i: Headache. - : John Wiley & Sons. - 0017-8748 .- 1526-4610. ; 63:5, s. 642-651
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease.BACKGROUND: Migraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition.METHODS: Linkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed.RESULTS: Migraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99-1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99-1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96-1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79-1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00-1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92-0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02-1.29, p = 0.025). However, the results were not significant after multiple testing correction.CONCLUSIONS: We found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes.
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| 20. |
- Agrawal, Sumit, et al.
(författare)
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The secondary spiral lamina and its relevance in cochlear implant surgery
- 2018
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Ingår i: Upsala Journal of Medical Sciences. - : TAYLOR & FRANCIS LTD. - 0300-9734 .- 2000-1967. ; 123:1, s. 9-18
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We used synchrotron radiation phase contrast imaging (SR-PCI) to study the 3D microanatomy of the basilar membrane (BM) and its attachment to the spiral ligament (SL) (with a conceivable secondary spiral lamina [SSL] or secondary spiral plate) at the round window membrane (RWM) in the human cochlea. The conception of this complex anatomy may be essential for accomplishing structural preservation at cochlear implant surgery.Material and methods: Sixteen freshly fixed human temporal bones were used to reproduce the BM, SL, primary and secondary osseous spiral laminae (OSL), and RWM using volume-rendering software. Confocal microscopy immunohistochemistry (IHC) was performed to analyze the molecular constituents.Results: SR-PCI reproduced the soft tissues including the RWM, Reissner's membrane (RM), and the BM attachment to the lateral wall (LW) in three dimensions. A variable SR-PCI contrast enhancement was recognized in the caudal part of the SL facing the scala tympani (ST). It seemed to represent a SSL allied to the basilar crest (BC). The SSL extended along the postero-superior margin of the round window (RW) and immunohistochemically expressed type II collagen.Conclusions: Unlike in several mammalian species, the human SSL is restricted to the most basal portion of the cochlea around the RW. It anchors the BM and may influence its hydro-mechanical properties. It could also help to shield the BM from the RW. The microanatomy should be considered at cochlear implant surgery.
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| 21. |
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| 22. |
- Al-Sabri, Mohamed H., et al.
(författare)
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Statins Induce Locomotion and Muscular Phenotypes in Drosophila melanogaster That Are Reminiscent of Human Myopathy : Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes
- 2022
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 11:22
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Tidskriftsartikel (refereegranskat)abstract
- The underlying mechanisms for statin-induced myopathy (SIM) are still equivocal. In this study, we employ Drosophila melanogaster to dissect possible underlying mechanisms for SIM. We observe that chronic fluvastatin treatment causes reduced general locomotion activity and climbing ability. In addition, transmission microscopy of dissected skeletal muscles of fluvastatin-treated flies reveals strong myofibrillar damage, including increased sarcomere lengths and Z-line streaming, which are reminiscent of myopathy, along with fragmented mitochondria of larger sizes, most of which are round-like shapes. Furthermore, chronic fluvastatin treatment is associated with impaired lipid metabolism and insulin signalling. Mechanistically, knockdown of the statin-target Hmgcr in the skeletal muscles recapitulates fluvastatin-induced mitochondrial phenotypes and lowered general locomotion activity; however, it was not sufficient to alter sarcomere length or elicit myofibrillar damage compared to controls or fluvastatin treatment. Moreover, we found that fluvastatin treatment was associated with reduced expression of the skeletal muscle chloride channel, C1C-a (Drosophila homolog of CLCN1), while selective knockdown of skeletal muscle C1C-a also recapitulated fluvastatin-induced myofibril damage and increased sarcomere lengths. Surprisingly, exercising fluvastatin-treated flies restored C1C-a expression and normalized sarcomere lengths, suggesting that fluvastatin-induced myofibrillar phenotypes could be linked to lowered C1C-a expression. Taken together, these results may indicate the potential role of C1C-a inhibition in statinassociated muscular phenotypes. This study underlines the importance of Drosophila melanogaster as a powerful model system for elucidating the locomotion and muscular phenotypes, promoting a better understanding of the molecular mechanisms underlying SIM.
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| 23. |
- Al-Sabri, Mohamed H., et al.
(författare)
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The regulatory role of AP-2 beta in monoaminergic neurotransmitter systems : insights on its signalling pathway, linked disorders and theragnostic potential
- 2022
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Ingår i: Cell & Bioscience. - : BioMed Central (BMC). - 2045-3701. ; 12:1
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Forskningsöversikt (refereegranskat)abstract
- Monoaminergic neurotransmitter systems play a central role in neuronal function and behaviour. Dysregulation of these systems gives rise to neuropsychiatric and neurodegenerative disorders with high prevalence and societal burden, collectively termed monoamine neurotransmitter disorders (MNDs). Despite extensive research, the transcriptional regulation of monoaminergic neurotransmitter systems is not fully explored. Interestingly, certain drugs that act on these systems have been shown to modulate central levels of the transcription factor AP-2 beta (AP-2 beta, gene: TFAP2B). AP-2 beta regulates multiple key genes within these systems and thereby its levels correlate with monoamine neurotransmitters measures; yet, its signalling pathways are not well understood. Moreover, although dysregulation of TFAP2B has been associated with MNDs, the underlying mechanisms for these associations remain elusive. In this context, this review addresses AP-2 beta, considering its basic structural aspects, regulation and signalling pathways in the controlling of monoaminergic neurotransmitter systems, and possible mechanisms underpinning associated MNDS. It also underscores the significance of AP-2 beta as a potential diagnostic biomarker and its potential and limitations as a therapeutic target for specific MNDs as well as possible pharmaceutical interventions for targeting it. In essence, this review emphasizes the role of AP-2 beta as a key regulator of the monoaminergic neurotransmitter systems and its importance for understanding the pathogenesis and improving the management of MNDs.
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| 24. |
- Andersson, P, et al.
(författare)
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Youth with severe mental illness and complex non-somatic motor abnormalities: conflicting conceptualizations and unequal treatment
- 2022
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Ingår i: Npj mental health research. - : Springer Science and Business Media LLC. - 2731-4251. ; 1:1, s. 13-
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Tidskriftsartikel (refereegranskat)abstract
- Two emerging diagnostic concepts promote distinct treatments for youth with acute-onset motor abnormalities and severe concurrent psychiatric symptoms: Pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric catatonia. Both have institutional approval in parts of Europe and in the USA, meriting an unconditional comparison of supporting evidence. Here we report results of qualitative and quantitative analyses of literature and Swedish National Registry Data suggesting that (1) catatonic patients are liable to fulfilling diagnostic criteria for PANS, (2) three conservatively assessed PANS case-reports present with possible unrecognized catatonia, (3) lithium and electroconvulsive therapy usage frequencies in Swedish minors (exclusively recommended for severe mental illness) are strongly intercorrelated and unequally distributed across Swedish counties, (4) established severe mental disorders are rarely overtly considered amongst PANS-specific research and (5) best-available evidence treatments appear markedly superior for pediatric catatonia compared to PANS in both childhood and adolescence. Prioritizing treatments for pediatric catatonia in concerned subjects could markedly improve treatment outcomes.
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| 25. |
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| 26. |
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| 27. |
- Attwood, Misty M., et al.
(författare)
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Orphan Drugs and Their Impact on Pharmaceutical Development
- 2018
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Ingår i: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 39:6, s. 525-535
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Forskningsöversikt (refereegranskat)abstract
- High levels of productivity, with an increasing number of approvals for new molecular entities (NMEs) by the FDA during the past decade, have coincided with the emergence of innovative drugs for treatments of rare diseases that have utilized the FDA orphan drug program. Since 2000, NMEs with orphan designation encompass a significant portion of approved drugs and constitute about 80% of the approved drugs that have established novel human genome-encoded products in recent years. Biological approvals are also expanding, with 40% of the approved biological agents having orphan designation. This trend illustrates a pivot within the pharmaceutical industry: from research programs that focus on canonical blockbuster indications and targets, towards the establishment of new treatments for rare and difficult to treat diseases.
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| 28. |
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| 29. |
- Attwood, Misty M., et al.
(författare)
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Soluble ligands as drug targets
- 2020
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Ingår i: Nature reviews. Drug discovery. - : NATURE RESEARCH. - 1474-1776 .- 1474-1784. ; 19:10, s. 695-710
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Forskningsöversikt (refereegranskat)abstract
- Historically, the main classes of drug targets have been receptors, enzymes, ion channels and transporters. However, owing largely to the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. In this Review, we analyse drugs targeting ligands that have reached clinical development at some point since 1992. We identify 291 drugs that target 99 unique ligands, and we discuss trends in the characteristics of the ligands, drugs and indications for which they have been tested. In the last 5 years, the number of ligand-targeting drugs approved by the FDA has doubled to 34, while the number of clinically validated ligand targets has doubled to 22. Cytokines and growth factors are the predominant types of targeted ligands (70%), and inflammation and autoimmune disorders, cancer and ophthalmological diseases are the top therapeutic areas for both approved agents and agents in clinical studies, reflecting the central role of cytokine and/or growth factor pathways in such diseases. With the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. This Review analyses drugs targeting ligands that have reached clinical development in the past three decades and discusses strategic issues such as the pros and cons of different ligand-targeting therapeutic modalities.
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| 30. |
- Chacko, L. Johnson, et al.
(författare)
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Role of BDNF and neurotrophic receptors in human inner ear development
- 2017
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Ingår i: Cell and Tissue Research. - : SPRINGER. - 0302-766X .- 1432-0878. ; 370:3, s. 347-363
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Tidskriftsartikel (refereegranskat)abstract
- The expression patterns of the neurotrophin, brain-derived neurotrophic factor, BDNF, and the neurotrophic receptors-p75NTR and Trk receptors-in the developing human fetal inner ear between the gestational weeks (GW) 9 to 12 are examined via in situ hybridization and immunohistochemistry. BDNF mRNA expression was highest in the cochlea at GW 9 but declined in the course of development. In contrast to embryonic murine specimens, a decline in BDNF expression from the apical to the basal turn of the cochlea could not be observed. p75NTR immunostaining was most prominent in the nerve fibers that penetrate into the sensory epithelia of the cochlea, the urticule and the saccule as gestational age progresses. TrkB and TrkC expression intensified towards GW 12, at which point the BDNF mRNA localization was at its lowest. TrkA expression was limited to fiber subpopulations of the facial nerve at GW 10. In the adult human inner ear, we observed BDNF mRNA expression in the apical poles of the cochlear hair cells and supporting cells, while in the adult human utricle, the expression was localized in the vestibular hair cells. We demonstrate the highly specific staining patterns of BDNF mRNA and its putative receptors over a developmental period in which multiple hearing disorders are manifested. Our findings suggest that BDNF and neurotrophin receptors are important players during early human inner ear development. In particular, they seem to be important for the survival of the afferent sensory neurons.
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| 31. |
- Eckhard, A, et al.
(författare)
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Water permeability of the mammalian cochlea : functional features of an aquaporin-facilitated water shunt at the perilymph-endolymph barrier
- 2014
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Ingår i: Pflügers Archiv. - : Springer Science and Business Media LLC. - 0031-6768 .- 1432-2013. ; 466:10, s. 1963-1985
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Tidskriftsartikel (refereegranskat)abstract
- The cochlear duct epithelium (CDE) constitutes a tight barrier that effectively separates the inner ear fluids, endolymph and perilymph, thereby maintaining distinct ionic and osmotic gradients that are essential for auditory function. However, in vivo experiments have demonstrated that the CDE allows for rapid water exchange between fluid compartments. The molecular mechanism governing water permeation across the CDE remains elusive. We computationally determined the diffusional (P D) and osmotic (P f) water permeability coefficients for the mammalian CDE based on in silico simulations of cochlear water dynamics integrating previously derived in vivo experimental data on fluid flow with expression sites of molecular water channels (aquaporins, AQPs). The P D of the entire CDE (P D = 8.18 × 10(-5) cm s(-1)) and its individual partitions including Reissner's membrane (P D = 12.06 × 10(-5) cm s(-1)) and the organ of Corti (P D = 10.2 × 10(-5) cm s(-1)) were similar to other epithelia with AQP-facilitated water permeation. The P f of the CDE (P f = 6.15 × 10(-4) cm s(-1)) was also in the range of other epithelia while an exceptionally high P f was determined for an epithelial subdomain of outer sulcus cells in the cochlear apex co-expressing AQP4 and AQP5 (OSCs; P f = 156.90 × 10(-3) cm s(-1)). The P f/P D ratios of the CDE (P f/P D = 7.52) and OSCs (P f/P D = 242.02) indicate an aqueous pore-facilitated water exchange and reveal a high-transfer region or "water shunt" in the cochlear apex. This "water shunt" explains experimentally determined phenomena of endolymphatic longitudinal flow towards the cochlear apex. The water permeability coefficients of the CDE emphasise the physiological and pathophysiological relevance of water dynamics in the cochlea in particular for endolymphatic hydrops and Ménière's disease.
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| 32. |
- Ellerström, Mats, 1961, et al.
(författare)
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Ectopic Expression of EFFECTOR OF TRANSCRIPTION Perturbs Gibberellin-Mediated Plant Developmental Processes
- 2005
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Ingår i: Plant Molecular Biology. - : Springer Science and Business Media LLC. - 0167-4412 .- 1573-5028. ; 59:4, s. 663-681
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Tidskriftsartikel (refereegranskat)abstract
- The plant hormone gibberellin (GA) is known to modulate various aspects of plant cell differentiation and development. The current model of GA-mediated regulation is based on a de-repressible system and includes specific protein modification and degradation. HRT, a zinc finger protein from barley has been shown to have GA-dependent transcriptional repressing activity on the seed-specific α-amylase promoter [Raventos, D., Skriver, K., Schlein, M., Karnahl, K., Rogers, S.W., Rogers, J.C. and Mundy, J. 1998. J.␣Biol. Chem. 273: 2331323320]. Here we report the characterization of a dicot homologue from Brassica napus (BnET) and provide evidence for its role in GA response modulation suggesting that this could be a conserved feature of this gene family. When BnET is ectopically expressed in either Arabidopsis or tobacco the phenotypes include dwarfism due to shorter internodes and late flowering, reduced germination rate, increased anthocyanin content and reduced xylem lignification as a marker for terminal cell differentiation. Transient expression in protoplasts supports the notion that this most likely is due to a transcriptional repression of GA controlled genes. Finally, histological analysis showed that in contrast to other GA deficient mutants the shorter internodes were due to fewer but not smaller cells, suggesting a function of BnET in GA-mediated cell division control.
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| 33. |
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| 34. |
- Enghag, Sara, et al.
(författare)
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Incus Necrosis and Blood Supply : A Micro-CT and Synchrotron Imaging Study
- 2019
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Ingår i: Otology and Neurotology. - : LIPPINCOTT WILLIAMS & WILKINS. - 1531-7129 .- 1537-4505. ; 40:7, s. E713-E722
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Tidskriftsartikel (refereegranskat)abstract
- Background: Incus necrosis is a common complication following stapes surgery and is associated with impaired microcirculation. The objective of this study was to investigate the vascular anatomy of the human incus by using light microscopy, micro-computed tomography (micro-CT), and synchrotron phase-contrast imaging (SR-PCI) for a novel three-dimensional (3D) analysis of the middle ear, mucosal folds, major vascular pathways, and intraosseous vascular bone channels. Methods: One-hundred-and-fifty temporal bones from the Uppsala collection were analyzed under light microscopy. Twenty temporal bones underwent high-resolution micro-CT scanning, and an additional seven specimens underwent SR-PCI at the Canadian Lightsource in Saskatoon, Canada. One of these specimens was from an individual who had undergone stapes surgery. Data were processed with volume-rendering software to create 3D reconstructions using scalar opacity mapping for bone transparency, cropping, and soft tissue analyses. Results: Micro-CT and SR-PCI with 3D rendering revealed the extensive vascular plexus within the un-decalcified incus bone communicating with the exterior surface. The relationship between the vessels, lenticular process, and incudostape-dial joint were clearly observed. SR-PCI allowed for histologic-level detail while preserving the specimen and its 3D relationships. Conclusion: SR-PCI with 3D reconstructions confirmed the main vascular supply to the lenticular process along the intraosseous lenticular vessels. This is the first synchrotron analysis of a patient having undergone stapes surgery, and it suggests that incus necrosis associated with stapes surgery may be caused by a disruption of the lenticular blood flow induced by the prosthesis loop, and not by strangulation of mucosal vessels as has been previously described.
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| 35. |
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| 36. |
- Ezcurra, Inés, et al.
(författare)
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Transactivation of the Brassica napus napin promoter by ABI3 requires interaction of the conserved B2 and B3 domains of ABI3 with different cis-elements : B2 mediates activation through an ABRE, whereas B3 interacts with an RY/G-box
- 2000
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Ingår i: The Plant Journal. - : Wiley. - 0960-7412 .- 1365-313X. ; 24:1, s. 57-66
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Tidskriftsartikel (refereegranskat)abstract
- The transcriptional activator ABI3 is a key regulator of gene expression during embryo maturation in crucifers. In monocots, the related VP1 protein regulates the Em promoter synergistically with abscisic acid (ABA). We identified cis-elements in the Brassica napus napin napA promoter mediating regulation by ABI3 and ABA, by analyzing substitution mutation constructs of napA in transgenic tobacco plantlets ectopically expressing ABI3. In transient analysis using particle bombardment of tobacco leaf sections, a tetramer of the distB ABRE (abscisic acid-responsive element) mediated transactivation by ABI3 and ABI3-dependent response to ABA, whereas a tetramer of the composite RY/G complex, containing RY repeats and a G-box, mediated only ABA-independent transactivation by ABI3. Deletion of the conserved B2 and B3 domains of ABI3 abolished transactivation of napA by ABI3. The two domains of ABI3 interact with different cis-elements: B2 is necessary for ABA-independent and ABA-dependent activations through the distB ABRE, whereas B3 interacts with the RY/G complex. Thus B2 mediates the interaction of ABI3 with the protein complex at the ABRE. The regulation of napA by ABI3 differs from Em regulation by VP1, in that the B3 domain of ABI3 is essential for the ABA-dependent regulation of napA.
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| 37. |
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| 38. |
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| 39. |
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| 40. |
- Geldart, M., et al.
(författare)
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A direct comparison of the machining performance of a variax 5 axis parallel kinetic machining centre with conventional 3 and 5 axis machine tools
- 2003
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Ingår i: International journal of machine tools & manufacture. - 0890-6955 .- 1879-2170. ; 43:11, s. 1107-1116
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Tidskriftsartikel (refereegranskat)abstract
- The current trend within the Tool and Die manufacturing sector is to machine components directly from hardened material using high speed 5-axis machining. This has been driven by the increasing requirements for cost competitiveness and lead-time reduction. Significant research effort has been applied to the optimisation of the process with factors such as tooling and machining strategies being considerably improved. However, the underlying structures of the machine tools used have remained unchanged and still consist of a serial kinematic chain. One of the standard justifications for the development of machines designed around parallel kinematic chains is that they should exhibit inherently greater stiffness, have higher axis accelerations and be capable of generating significantly higher cutting forces than conventional serial machines. This suggests that they should be ideally suited to the direct manufacture of tools and dies from hardened material. The comparison of different machine tool types is a complex and difficult process, particularly when their structures are fundamentally different. This paper describes an approach used to compare the performance of three very different types of machines. The technique uses two parameters; surface finish and geometric accuracy to assess the relative performance of different machine tools when cutting hardened material. The method is used to compare a serial kinematic 5-axis machining centre, a serial kinematic 3-axis machining centre and a parallel kinematic 6-axis machining centre. The results of the comparison are presented in this paper and show that all the machine tools performed to an equal standard for materials with a hardness of 54HRc but for very hard materials, 62HRc, the parallel kinematic machine out performed the serial machine tools.
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| 41. |
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| 42. |
- Hauser, Alexander S, et al.
(författare)
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Trends in GPCR drug discovery : new agents, targets and indications
- 2017
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Ingår i: Nature reviews. Drug discovery. - : Springer Science and Business Media LLC. - 1474-1776 .- 1474-1784. ; 16:12, s. 829-842
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Tidskriftsartikel (refereegranskat)abstract
- G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.
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| 43. |
- Helpard, Luke, et al.
(författare)
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An Approach for Individualized Cochlear Frequency Mapping Determined From 3D Synchrotron Radiation Phase-Contrast Imaging
- 2021
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Ingår i: IEEE Transactions on Biomedical Engineering. - : Institute of Electrical and Electronics Engineers (IEEE). - 0018-9294 .- 1558-2531. ; 68:12, s. 3602-3611
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Cochlear implants are traditionally programmed to stimulate according to a generalized frequency map, where individual anatomic variability is not considered when selecting the centre frequency of stimulation of each implant electrode. However, high variability in cochlear size and spatial frequency distributions exist among individuals. Generalized cochlear implant frequency maps can result in large pitch perception errors and reduced hearing outcomes for cochlear implant recipients. The objective of this work was to develop an individualized frequency mapping technique for the human cochlea to allow for patient-specific cochlear implant stimulation.Methods: Ten cadaveric human cochleae were scanned using synchrotron radiation phase-contrast imaging (SR-PCI) combined with computed tomography (CT). For each cochlea, ground truth angle-frequency measurements were obtained in three-dimensions using the SR-PCI CT data. Using an approach designed to minimize perceptual error in frequency estimation, an individualized frequency function was determined to relate angular depth to frequency within the cochlea.Results: The individualized frequency mapping function significantly reduced pitch errors in comparison to the current gold standard generalized approach.Conclusion and Significance: This paper presents for the first time a cochlear frequency map which can be individualized using only the angular length of cochleae. This approach can be applied in the clinical setting and has the potential to revolutionize cochlear implant programming for patients worldwide.
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| 44. |
- Helpard, Luke, et al.
(författare)
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Characterization of the human helicotrema : implications for cochlear duct length and frequency mapping
- 2020
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Ingår i: Journal of Otolaryngology - Head & Neck Surgery. - : BMC. - 1916-0216. ; 49
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite significant anatomical variation amongst patients, cochlear implant frequency-mapping has traditionally followed a patient-independent approach. Basilar membrane (BM) length is required for patient-specific frequency-mapping, however cochlear duct length (CDL) measurements generally extend to the apical tip of the entire cochlea or have no clearly defined end-point. By characterizing the length between the end of the BM and the apical tip of the entire cochlea (helicotrema length), current CDL models can be corrected to obtain the appropriate BM length. Synchrotron radiation phase-contrast imaging has made this analysis possible due to the soft-tissue contrast through the entire cochlear apex.Methods: Helicotrema linear length and helicotrema angular length measurements were performed on synchrotron radiation phase-contrast imaging data of 14 cadaveric human cochleae. On a sub-set of six samples, the CDL to the apical tip of the entire cochlea (CDLTIP) and the BM length (CDLBM) were determined. Regression analysis was performed to assess the relationship between CDLTIP and CDLBM.Results: The mean helicotrema linear length and helicotrema angular length values were 1.6 +/- 0.9 mm and 67.8 +/- 37.9 degrees, respectively. Regression analysis revealed the following relationship between CDLTIP and CDLBM: CDLBM = 0.88(CDLTIP) + 3.71 (R-2 = 0.995).Conclusion: This is the first known study to characterize the length of the helicotrema in the context of CDL measurements. It was determined that the distance between the end of the BM and the tip of the entire cochlea is clinically consequential. A relationship was determined that can predict the BM length of an individual patient based on their respective CDL measured to the apical tip of the cochlea.
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| 45. |
- Helpard, Luke, et al.
(författare)
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Three-Dimensional Modeling and Measurement of the Human Cochlear Hook Region : Considerations for Tonotopic Mapping
- 2021
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Ingår i: Otology and Neurotology. - : Lippincott Williams & Wilkins. - 1531-7129 .- 1537-4505. ; 42:6, s. E658-E665
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Tidskriftsartikel (refereegranskat)abstract
- Hypothesis: Measuring the length of the basilar membrane (BM) in the cochlear hook region will result in improved accuracy of cochlear duct length (CDL) measurements.Background: Cochlear implant pitch mapping is generally performed in a patient independent approach, which has been shown to result in place-pitch mismatches. In order to customize cochlear implant pitch maps, accurate CDL measurements must be obtained. CDL measurements generally begin at the center of the round window (RW) and ignore the basal-most portion of the BM in the hook region. Measuring the size and morphology of the BM in the hook region can improve CDL measurements and our understanding of cochlear tonotopy.Methods: Ten cadaveric human cochleae underwent synchrotron radiation phase-contrast imaging. The length of the BM through the hook region and CDL were measured. Two different CDL measurements were obtained for each sample, with starting points at the center of the RW (CDLRW) and the basal-most tip of the BM (CDLHR). Regression analysis was performed to relate CDLRW to CDLHR. A three-dimensional polynomial model was determined to describe the average BM hook region morphology.Results: The mean CDLRW value was 33.03 ± 1.62 mm, and the mean CDLHR value was 34.68 ± 1.72 mm. The following relationship was determined between CDLRW and CDLHR: CDLHR = 1.06(CDLRW)-0.26 (R2 = 0.99).Conclusion: The length and morphology of the hook region was determined. Current measurements underestimate CDL in the hook region and can be corrected using the results herein.
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| 46. |
- Hillerdal, Gunnar, et al.
(författare)
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Pleural disease during treatment with bromocriptine in patients previously exposed to asbestos
- 1997
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 10:12, s. 2711-2715
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Tidskriftsartikel (refereegranskat)abstract
- Bromocriptine, which is used in the treatment of Parkinson's disease, can cause adverse pleuropulmonary reactions. Exposure to asbestos can result in similar lesions. Fifteen patients with former exposure to asbestos, who developed pleural fibrosis after treatment with bromocriptine, were observed independently in Sweden (11 patients) and Australia (four patients). The patients complained of malaise, often associated with weight loss, dyspnoea, and a disturbing cough. Laboratory values included increased erythrocyte sedimentation rate and a low haemoglobin level. Lung function tests showed a restrictive lung function defect. Chest radiographs showed bilateral pleural fibrosis, with small amounts of fluid in some cases. Soon after bromocriptine was withdrawn, the patients improved clinically, and the laboratory values returned to normal. However, in most cases, pleural fibrosis and a restrictive lung function defect persisted to some extent. In conclusion, in patients who develop pleuropulmonary fibrosis whilst being treated with bromocriptine, former exposure to asbestos should be investigated. Conversely, when pleural changes develop in a patient on bromocriptine and with prior exposure to asbestos, the possible causative role of the drug should be discussed. Special follow-up may be indicated when bromocriptine is planned in a patient with previous asbestos exposure, and if symptoms or signs of pleural fibrosis develop, bromocriptine withdrawal should be considered.
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| 47. |
- Hirt, B., et al.
(författare)
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The subcellular distribution of aquaporin 5 in the cochlea reveals a water shunt at the perilymph-endolymph barrier
- 2010
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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522 .- 1873-7544. ; 168:4, s. 957-970
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Tidskriftsartikel (refereegranskat)abstract
- Aquaporins are membrane water channel proteins that have also been identified in the cochlea. Auditory function critically depends on the homeostasis of the cochlear fluids perilymph and endolymph. In particular, the ion and water regulation of the endolymph is essential for sensory transduction. Within the cochlear duct the lateral wall epithelium has been proposed to secrete endolymph by an aquaporin-mediated flow of water across its epithelial tight junction barrier. This study identifies interspecies differences in the cellular distribution of aquaporin 5 (AQP5) in the cochlear lateral wall of mice, rats, gerbils and guinea pigs. In addition the cellular expression pattern of AQP5 is described in the human cochlea. Developmental changes in rats demonstrate longitudinal and radial gradients along the cochlear duct. During early postnatal development a pancochlear expression is detected. However a regression to the apical quadrant and limitation to outer sulcus cells (OSCs) is observed in the adult. This developmental loss of AQP5 expression in the basal cochlear segments coincides with a morphological loss of contact between OSCs and the endolymph. At the subcellular level, AQP5 exhibits polarized expression in the apical plasma membrane of the OSCs. Complementary, the basolateral membrane in the root processes of the OSCs exhibits AQP4 expression. This differential localization of AQP5 and AQP4 in the apical and basolateral membranes of the same epithelial cell type suggests a direct aquaporin-mediated transcellular water shunt between the perilymph and endolymph in the OSCs of the cochlear lateral wall. In the human cochlea these findings may have pathophysiological implications attributed to a dysfunctional water regulation by AQP5 such as endolymphatic hydrops (i.e. in Meniere's disease) or sensorineural hearing loss (i.e. in Sjögren's syndrome).
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| 48. |
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| 49. |
- Kjebon, Olle, et al.
(författare)
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1.55 μm buried heterostructure laser via regrowth of semi-insulating InP:Fe around vertical mesas fabricated by reactive ion etching using methane and hydrogen
- 1991
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 59:3, s. 235-255
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Tidskriftsartikel (refereegranskat)abstract
- A GaInAsP/InP Fabry-Perot-type buried-heterostructure quantum well laser operating at 1.55 μm has been realized utilizing iron-doped semi-insulating InP around vertical mesas fabricated by reactive ion etching using methane and hydrogen. A maximum cw output power of 19 mW has been achieved on as-cleaved chips of 300 μm length with a quantum efficiency of 21% per facet. Threshold currents lie between 20 and 25 mA. As low as 2 Ω series resistance has been measured despite an ohmic contact area not exceeding that of the 2-μm-wide mesa. A 3 dB bandwidth of 7.5 GHz at 12 mW output power is obtained from the small-signal frequency modulation measurements.
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| 50. |
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