Adults with 22q11.2 deletion syndrome have a different velopharyngeal anatomy with predisposition to velopharyngeal insufficiency

To find out if subjects with 22q11.2 deletion syndrome (DS) have a different velopharyngeal anatomy which could cause velopharyngeal insufficiency (VPI).

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Proteomic analysis of the soil filamentous fungus Aspergillus nidulans exposed to a Roundup formulation at a dose causing no macroscopic effect: a functional study

Abstract

Roundup® is a glyphosate-based herbicide (GBH) used worldwide both in agriculture and private gardens. Thus, it constitutes a substantial source of environmental contaminations, especially for water and soil, and may impact a number of non-target organisms essential for ecosystem balance. The soil filamentous fungus Aspergillus nidulans has been shown to be highly affected by a commercial formulation of Roundup® (R450), containing 450 g/L of glyphosate (GLY), at doses far below recommended agricultural application rate. In the present study, we used two-dimensional gel electrophoresis combined to mass spectrometry to analyze proteomic pattern changes in A. nidulans exposed to R450 at a dose corresponding to the no-observed-adverse-effect level (NOAEL) for macroscopic parameters (31.5 mg/L GLY among adjuvants). Comparative analysis revealed a total of 82 differentially expressed proteins between control and R450-treated samples, and 85% of them (70) were unambiguously identified. Their molecular functions were mainly assigned to cell detoxification and stress response (16%), protein synthesis (14%), amino acid metabolism (13%), glycolysis/gluconeogenesis/glycerol metabolism/pentose phosphate pathway (13%) and Krebs TCA cycle/acetyl-CoA synthesis/ATP metabolism (10%). These results bring new insights into the understanding of the toxicity induced by higher doses of this herbicide in the soil model organism A. nidulans. To our knowledge, this study represents the first evidence of protein expression modulation and, thus, possible metabolic disturbance, in response to an herbicide treatment at a dose that does not cause any visible effect. These data are likely to challenge the concept of "substantial equivalence" when applied to herbicide-tolerant plants.

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5-Aminolevulinic acid-based photodynamic therapy of chordoma: in vitro experiments on a human tumor cell line

Publication date: Available online 22 September 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Jan F. Cornelius, Lennert Eismann, Lara Ebbert, Brigitte Senger, Athanasios K. Petridis, Marcel Alexander Kamp, Rüdiger V. Sorg, Hans Jakob Steiger
BackgroundChordomas are very rare tumors of the skull base and the sacrum. They show infiltrating and destructive growth and are known to be chemo- and radio-resistant. After surgical resection, the recurrence rate is high and overall survival limited. As current adjuvant treatments are ineffective, new treatment concepts are urgently needed. 5-aminolevulinic acid-based photodynamic therapy (5-ALA based PDT) showed promising results for malignant gliomas. However, it is unknown so far, whether chordomas accumulate protoporphyrin IX (PPIX) after application of 5-ALA and whether they are sensitive to subsequent 5-ALA based PDT.MethodsThe immortalized human chordoma cells U-CH2 were used as in vitro model. After incubation for 4h or 6h with different 5-ALA concentrations, PPIX accumulation was determined by flow cytometry. To assess sensitivity to PDT, chordoma cells were incubated at 30.000cells/well (high cell density) or 15.000cells/well (low cell density) with graded doses of 5-ALA (0–50μg/ml) in 96-well plates and subsequently exposed to laser light of 635nm wavelength (18.75J/cm²). Cell survival was measured 24h after exposure to laser light using the WST-1 assay.ResultsU-CH2 cells dose-dependently accumulated PPIX (ANOVA; p<0.0001). PPIX fluorescence was significantly higher, when cells were incubated with 5-ALA for 6h compared to 4h at higher 5-ALA concentrations (ANOVA/Bonferroni; p≤0.05 for≥30μg/ml 5-ALA). For both cell densities, a 5-ALA dose-dependent decline in viability was observed (ANOVA; p<0.0001). Viability was significantly lower at higher 5-ALA concentrations, when 30.000 cells/wells were treated compared to 15.000cells/well (ANOVA/Bonferroni; p≤0.001 for≥30μg/ml 5-ALA). LD50 was 30.25μg/ml 5-ALA.ConclusionThe human UCH-2 cell line was a very useful in vitro model to study different effects of 5-ALA based PDT. For the first time, it could be shown that human chordoma cells may be destroyed by 5-ALA/PDT.



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Carboxylate cross-linked cyclodextrin: A nanoporous scaffold for enhancement of rosuvastatin oral bioavailability

Publication date: 1 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 111
Author(s): Mai Mahmoud Gabr, Sana Mohamed Mortada, Marwa Ahmed Sallam
Cyclodextrins play an important role in supramolecular chemistry acting as building blocks than can be cross-linked by various linker molecules forming nano-porous structures called nanosponges (NS). NS have the ability to enhance the stability, solubility and bioavailability of various actives. This work aimed at elaborating rosuvastatin (ROS) loaded NS to improve its oral bioavailability. Carboxylate-linked NS were synthesized by reacting β-CD with pyromellitic dianhydride (PDA) at different molar ratios under specific conditions. ROS-loaded NS were prepared by lyophilisation technique and characterized for particle size, zeta potential, entrapment efficiency and drug release. Occurrence of cross-linking and ROS incorporation within the NS were assessed by DSC, FT-IR and SEM micrographs. NS prepared at a molar ratio of 1:6 of β-CD: PDA demonstrated the highest entrapment efficiency (88.76%), an optimum particle size of 275nm, a narrow size distribution (PDI of 0.392), and zeta potential of −61.9 indicating good colloidal stability. In vivo oral pharmacokinetics study in male Sprague Dawley rats showed that ROS-NS provided an outstanding enhancement in oral bioavailability compared to drug suspension and marketed tablets besides their physicochemical stability for 3month. Accordingly, ROS-NS represent a superior alternative to the conventional marketed formulation for effective ROS delivery.

Graphical abstract

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Short progressive muscle relaxation or motor coordination training does not increase performance in a brain-computer interface based on sensorimotor rhythms (SMR)

Publication date: November 2017
Source:International Journal of Psychophysiology, Volume 121
Author(s): L. Botrel, L. Acqualagna, B. Blankertz, A. Kübler
Brain computer interfaces (BCIs) allow for controlling devices through modulation of sensorimotor rhythms (SMR), yet a profound number of users is unable to achieve sufficient accuracy. Here, we investigated if visuo-motor coordination (VMC) training or Jacobsen's progressive muscle relaxation (PMR) prior to BCI use would increase later performance compared to a control group who performed a reading task (CG). Running the study in two different BCI-labs, we achieved a joint sample size of N=154 naïve participants. No significant effect of either intervention (VMC, PMR, control) was found on resulting BCI performance. Relaxation level and visuo-motor performance were associated with later BCI performance in one BCI-lab but not in the other. These mixed results do not indicate a strong potential of VMC or PMR for boosting performance. Yet further research with different training parameters or experimental designs is needed to complete the picture.



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Biological control of wilt disease complex on tomato crop caused by Meloidogyne javanica and Fusarium oxysporum f.sp. lycopersici by Verticillium leptobactrum

Abstract

The efficacy of Verticillium leptobactrum isolate (HR1) was evaluated in the control of root-knot nematode and Fusarium wilt fungus under laboratory and greenhouse conditions. Five concentrations of V. leptobactrum (HR1) isolate were tested for their nematicidal and fungicidal activities against Meloidogyne javanica and Fusarium oxysporum f.sp. lycopersici in vitro. Laboratory trials showed that mycelium growth inhibition of Fusarium wilt fungus was correlated to the increase of the concentration of culture filtrate. All dilutions showed efficiency in reducing the growth of Fusarium oxysporum f.sp. lycopersici. The greatest nematicidal activity was observed at 50, 75, and 100% filtrate dilutions. The egg hatching percentage reached 42%, and the juvenile's corrected mortality registered 90% for the above treatments. In greenhouse experiment, the biocontrol agent fungus enhanced significantly tomato growth components (height and weight of plant and root). The multiplication rate of root-knot nematode and the Fusarium wilt disease incidence declined significantly with soil application of V. leptobactrum as with chemical treatments. The isolate HR1 was efficient to control wilt disease complex caused by M. javanica and Fusarium oxysporum f.sp. lycopersici.

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The Ubiquitin Code in the Ubiquitin-Proteasome System and Autophagy

Publication date: Available online 22 September 2017
Source:Trends in Biochemical Sciences
Author(s): Yong Tae Kwon, Aaron Ciechanover
The conjugation of the 76 amino acid protein ubiquitin to other proteins can alter the metabolic stability or non-proteolytic functions of the substrate. Once attached to a substrate (monoubiquitination), ubiquitin can itself be ubiquitinated on any of its seven lysine (Lys) residues or its N-terminal methionine (Met1). A single ubiquitin polymer may contain mixed linkages and/or two or more branches. In addition, ubiquitin can be conjugated with ubiquitin-like modifiers such as SUMO or small molecules such as phosphate. The diverse ways to assemble ubiquitin chains provide countless means to modulate biological processes. We overview here the complexity of the ubiquitin code, with an emphasis on the emerging role of linkage-specific degradation signals (degrons) in the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system (hereafter autophagy).



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Safety and immunogenicity of a recombinant Plasmodium falciparum AMA1-DiCo malaria vaccine adjuvanted with GLA-SE or Alhydrogel® in European and African adults: A phase 1a/1b, randomized, double-blind multi-centre trial

Publication date: Available online 22 September 2017
Source:Vaccine
Author(s): S.B. Sirima, C. Durier, L. Kara, S. Houard, A. Gansane, P. Loulergue, M. Bahuaud, N. Benhamouda, I. Nebié, B. Faber, E. Remarque, O. Launay
BackgroundPlasmodium falciparum Apical Membrane Antigen 1 Diversity Covering (PfAMA1-DiCo) candidate vaccine is a formulation of three recombinant variants of AMA1 designed to provide broader protection against parasites with varying AMA1 sequences.MethodsIn this staggered phase Ia/Ib randomized, double blind trial, healthy French adults received AMA1-DiCo with either Alhydrogel® (n=15) or GLA-SE (n=15). Following a safety assessment in French volunteers, GLA-SE was chosen for the phase Ib trial where healthy Burkinabe adults received either AMA1-DiCo/GLA-SE (n=18) or placebo (n=18). AMA1-DiCo (50µg) was administered intramuscularly at baseline, Week 4 and 26.ResultsAMAI-DiCo was safe, well tolerated either with Alhydrogel® or GLA-SE. In European volunteers, the ratios of IgG increase from baseline were about 100 fold in Alhydrogel® group and 200–300 fold in GLA-SE group for the three antigens. In African volunteers, immunization resulted in IgG levels exceeding those observed for the European volunteers with a 4-fold increase. DiCo-specific IgG remained higher 26weeks after the third immunization than at baseline in both European and African volunteers. Induced antibodies were reactive against whole parasite derived from different strains.ConclusionAMA1-DiCo vaccine was safe and immunogenic whatever the adjuvant although GLA-SE appeared more potent than Alhydrogel® at inducing IgG responses.Clinical Trials Registration. ClinicalTrials.gov NCT02014727; PACTR201402000719423.



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Using the 4 Pillars™ Practice Transformation Program to increase adolescent human papillomavirus, meningococcal, tetanus-diphtheria-pertussis and influenza vaccination

Publication date: Available online 22 September 2017
Source:Vaccine
Author(s): Richard K. Zimmerman, Jonathan M. Raviotta, Mary Patricia Nowalk, Krissy K. Moehling, Evelyn Cohen Reis, Sharon G. Humiston, Chyongchiou Jeng Lin
ObjectivesTo report the results of an intervention using the 4 Pillars™ Practice Transformation Program (4 Pillars™ Program) to increase adolescent vaccinations including human papillomavirus vaccine (HPV) and influenza vaccines, which remain underutilized in this population.Study designEleven pediatric and family medicine practices, previously control sites from a randomized controlled cluster trial, with ≥50 adolescent patients participated. The 4 Pillars™ Program was the foundation of the intervention. De-identified demographic, office visit and vaccination data were derived from electronic medical record extractions for patients whose date of birth was 4/1/1997 to 4/1/2004 (ages 11–17years at baseline). Vaccination rates for HPV, influenza, tetanus-pertussis-diphtheria (Tdap) and meningococcal (MenACWY) vaccines were determined for all eligible patients pre- and post intervention (i.e., vaccination rates on 4/1/2015 and 4/30/2016).ResultsAmong 9473 patients ages 11–17years at baseline (4/1/2015), mean pre-intervention vaccination rates for HPV initiation and completion, meningococcal, Tdap and influenza vaccines were below national levels. Rates increased significantly post intervention (P<0.001) for HPV initiation which increased 17.1 percentage points (PP) from 51.4%; HPV completion increased 14.8PP from 30.7%, meningococcal vaccine uptake increased 16.6PP from 79.1%, Tdap vaccine uptake increased 14.6PP from 76.9%. Influenza vaccine uptake did not increase significantly (2.3PP from 40.1%). In the regression using generalized estimating equations, odds of vaccination were higher for younger, non-white adolescents for all vaccines; being in a smaller practice decreased the odds of Tdap vaccination but increased the odds of influenza vaccination.ConclusionClinically and statistically significant improvements in HPV series initiation and completion, and meningococcal and Tdap vaccinations were observed in primary care practices implementing the 4 Pillars™ Practice Transformation Program.Clinical Trial Registry Number: NCT02165722.



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How many deficits in the same dyslexic brains? A behavioural and fMRI assessment of comorbidity in adult dyslexics

Publication date: Available online 22 September 2017
Source:Cortex
Author(s): L. Danelli, M. Berlingeri, G. Bottini, N.A. Borghese, M. Lucchese, M. Sberna, C.J. Price, E. Paulesu
Dyslexia can have different manifestations: this has motivated different theories on its nature, on its underlying brain bases and enduring controversies on how to best treat it. The relative weight of the different manifestations has never been evaluated using both behavioural and fMRI measures, a challenge taken here to assess the major systems called into play in dyslexia by different theories.We found that adult well-compensated dyslexics were systematically impaired only in reading and in visuo-phonological tasks, while deficits for other systems (e.g. motor/cerebellar, visual magnocellular/motion perception) were only very occasional. In line with these findings, fMRI showed a reliable hypoactivation only for the task of reading, in the left occipito-temporal cortex (l-OTC).The l-OTC, normally a crossroad between the reading system and other systems did not show the same level of intersection in dyslexics; yet, it was not totally silent because it responded, in segregated parts, during auditory phonological and visual motion perception tasks.This minimal behavioural and functional anatomical comorbidity demonstrates that a specific deficit of reading is the best description for developmental dyslexia, at least for adult well compensated cases, with clear implications for rehabilitation strategies. The reduced intersection of multiple systems in the l-OTC suggests that dyslexics suffer from a coarser connectivity, leading to disconnection between the multiple domains that normally interact during reading.



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Coupling motion between rearfoot and hip and knee joints during walking and single-leg landing

Publication date: Available online 22 September 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Yuta Koshino, Masanori Yamanaka, Yuya Ezawa, Takumi Okunuki, Tomoya Ishida, Mina Samukawa, Harukazu Tohyama
The objective of the current study was to investigate the kinematic relationships between the rearfoot and hip/knee joint during walking and single-leg landing. Kinematics of the rearfoot relative to the shank, knee and hip joints during walking and single-leg landing were analyzed in 22 healthy university students. Kinematic relationships between two types of angular data were assessed by zero-lag cross-correlation coefficients and coupling angles, and were compared between joints and between tasks. During walking, rearfoot eversion/inversion and external/internal rotation were strongly correlated with hip adduction/abduction (R = 0.69 and R = 0.84), whereas correlations with knee kinematics were not strong (R ≤ 0.51) and varied between subjects. The correlations with hip adduction/abduction were stronger than those with knee kinematics (P < 0.001). Most coefficients during single-leg landing were strong (R ≥ 0.70), and greater than those during walking (P < 0.001). Coupling angles indicated that hip motion relative to rearfoot motion was greater than knee motion relative to rearfoot motion during both tasks (P < 0.001). Interventions to control rearfoot kinematics may affect hip kinematics during dynamic tasks. The coupling motion between the rearfoot and hip/knee joints, especially in the knee, should be considered individually.



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Contraction intensity and sex differences in knee-extensor fatigability

Publication date: Available online 21 September 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Paul Ansdell, Kevin Thomas, Glyn Howatson, Sandra Hunter, Stuart Goodall
Females are less fatigable than males during isometric contractions across various muscles and intensities. However, sex differences in knee-extensor fatigability remain relatively unexploredPurposeTo determine the sex difference in performance fatigability for intermittent, isometric contractions of the knee-extensor muscles.MethodsEighteen participants (10 males, 8 females) performed intermittent, isometric, knee-extensor contractions at 30% of their maximal voluntary force (MVC) for 30 min and in a separate session at 50% MVC until task-failure. During both fatiguing protocols a MVC was performed every 60 s and electromyography (EMG) was recorded during all contractions.ResultsAt task completion males had a larger reduction in MVC force for the 30% MVC task (−32±15% vs. −15±16%, P=0.042) and the 50% MVC task (−34±8% vs. −24±1%, P=0.045). Furthermore, for the 50% MVC task, females had a longer task duration (937±525 s vs. 397±153 s, P=0.007). The rise in EMG activity and force fluctuations were more rapid for the males than females (P<0.05). When participants were matched for strength post-hoc (n=10), a sex difference in fatigability for both tasks was still evident.ConclusionsFemales were less fatigable than males during intermittent, isometric, knee-extensor contractions at moderate relative forces and this difference was independent of strength.



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Complexity of the genomic landscape of renal cell carcinoma: Implications for targeted therapy and precision immuno-oncology

Publication date: Available online 21 September 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Joseph M. Sanfrancesco, Liang Cheng
The topic of tumoral heterogeneity at the genetic level has become relevant in various solid origin tumors, particularly in an age of targeted treatment. Renal cell carcinoma is known for a sizable subset of tumors presenting at advanced clinical stage, further highlighting the importance and timeliness of this topic and its potential impact on adjuvant therapy. Recent studies have shown that molecular aberrations in renal cell carcinoma go beyond known truncal mutations and that downstream, subclonal aberrations are spatially heterogenous. Intratumoral heterogeneity as well as the differences in the molecular landscape between primary and metastatic lesions remains underappreciated, often due to inadequate sampling of tumors. The overall effect of these factors on the efficacy of current treatment options in renal cell carcinoma remains unknown; however, several recent studies have attempted to elucidate the extent and impact genetic heterogeneity in renal cell neoplasia may have on patient treatment and prognosis.



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Small groups, open doors: Fostering individual and group creativity within research communities

Publication date: Available online 22 September 2017
Source:Medical Hypotheses
Author(s): Thomas C. Erren, David M. Shaw, Philip Lewis
While abundant publications attempt to analyze and understand what makes humans creative, much less attention is being paid to institutional conditions which may enhance or impede creative work. On the basis of evidence from Cambridge and AT&T's Bell Laboratories, and as a condensation of the Janelia Experiment, an institutional focus on "small groups" and "open doors" may foster individual and group creativity. The evidence suggests that small organizational units of up to seven scientists and open door concepts could nurture interactions within and between groups and enhance the critical mass for individual and group creativity.



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Interleukin 35 and hepatocyte growth factor; as a Novel Combined Immune Gene Therapy for Multiple Sclerosis Disease

Publication date: Available online 22 September 2017
Source:Medical Hypotheses
Author(s): Samira Moghadam, Maryam Erfanmanesh, Abdolreza Esmaeilzadeh
An autoimmune demyelination disease of the Central Nervous System, Multiple Sclerosis, is a chronic inflammation which mostly involves young adults. Suffering people face functional loss with a severe pain. Most current MS treatments are focused on the immune response suppression. Approved drugs suppress the inflammatory process, but factually, there is no definite cure for Multiple Sclerosis. Recently developed knowledge has demonstrated that gene and cell therapy as a hopeful approach in tissue regeneration. The authors propose a novel combined immune gene therapy for Multiple Sclerosis treatment using anti-inflammatory and remyelination of Interleukine-35 and Hepatocyte Growth Factor properties, respectively. In this hypothesis Interleukine-35 and Hepatocyte Growth Factor introduce to Mesenchymal Stem Cells of EAE mouse model via an adenovirus based vector. It is expected that Interleukine-35 and Hepatocyte Growth Factor genes expressed from MSCs could effectively perform in immunotherapy of Multiple Sclerosis.



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Letter to the editor: Hepatitis B vaccine non-response: A predictor of latent autoimmunity?

Publication date: Available online 22 September 2017
Source:Medical Hypotheses
Author(s): D Poddighe




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Not Breathing Is Not An Option: How To Deal With Oxidative DNA Damage

Publication date: Available online 22 September 2017
Source:DNA Repair
Author(s): Enni Markkanen
Oxidative DNA damage constitutes a major threat to genetic integrity, and thus has been implicated in the pathogenesis of a wide variety of diseases, including cancer and neurodegeneration. 7,8-dihydro-8oxo-deoxyGuanine (8-oxo-G) is one of the best characterised oxidative DNA lesions, and it can give rise to point mutations due to its miscoding potential that instructs most DNA polymerases (Pols) to preferentially insert Adenine (A) opposite 8-oxo-G instead of the correct Cytosine (C). If uncorrected, A:8-oxo-G mispairs can give rise to CG→AT transversion mutations. Cells have evolved a variety of pathways to mitigate the mutational potential of 8-oxo-G that include i) mechanisms to avoid incorporation of oxidized nucleotides into DNA through nucleotide pool sanitisation enzymes (by MTH1, MTH2, MTH3 and NUDT5), ii) base excision repair (BER) of 8-oxo-G in DNA (involving MUTYH, OGG1, Pol λ, and other components of the BER machinery), and iii) faithful bypass of 8-oxo-G lesions during replication (using a switch between replicative Pols and Pol λ). In the following, the fate of 8-oxo-G in mammalian cells is reviewed in detail. The differential origins of 8-oxo-G in DNA and its consequences for genetic stability will be covered. This will be followed by a thorough discussion of the different mechanisms in place to cope with 8-oxo-G with an emphasis on Pol λ-mediated correct bypass of 8-oxo-G during MUTYH-initiated BER as well as replication across 8-oxo-G. Furthermore, the multitude of mechanisms in place to regulate key proteins involved in 8-oxo-G repair will be reviewed. Novel functions of 8-oxo-G as an epigenetic-like regulator and insights into the repair of 8-oxo-G within the cellular context will be touched upon. Finally, a discussion will outline the relevance of 8-oxo-G and the proteins involved in dealing with 8-oxo-G to human diseases with a special emphasis on cancer.



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Bacillus subtilis DisA helps to circumvent replicative stress during spore revival

Publication date: Available online 22 September 2017
Source:DNA Repair
Author(s): Marina Raguse, Rubén Torres, Elena M. Seco, Carolina Gándara, Silvia Ayora, Ralf Moeller, Juan C. Alonso
The mechanisms that allow to circumvent replicative stress, and to resume DNA synthesis are poorly understand in Bacillus subtilis. To study the role of the diadenylate cyclase DisA and branch migration translocase (BMT) RadA/Sms in restarting a stalled replication fork, we nicked and broke the circular chromosome of an inert mature haploid spore, damaged the bases, and measured survival of reviving spores. During undisturbed ripening, nicks and breaks should repaired by pathways that do not invoke long-range end resection or genetic exchange by homologous recombination, after which DNA replication might be initiated. We found that DNA damage reduced the viability of spores that lacked DisA, BMT (RadA/Sms, RuvAB or RecG), the Holliday junction resolvase RecU, or the translesion synthesis DNA polymerases (PolY1 or PolY2). DisA and RadA/Sms, in concert with RuvAB, RecG, RecU, PolY1 or PolY2, are needed to bypass replication-blocking lesions. DisA, which binds to stalled or reversed forks, did not apparently affect initiation of PriA-dependent DNA replication in vitro. We propose that DisA is necessary to coordinate responses to replicative stress; they could help to circumvent damaged template bases that otherwise impede fork progression.



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Role of RAD51AP1 in homologous recombination DNA repair and carcinogenesis

Publication date: Available online 22 September 2017
Source:DNA Repair
Author(s): Elena Pires, Patrick Sung, Claudia Wiese
Homologous recombination (HR) serves to repair DNA double-strand breaks and damaged replication forks and is essential for maintaining genome stability and tumor suppression. HR capacity also determines the efficacy of anticancer therapy. Hence, there is an urgent need to better understand all HR proteins and sub-pathways. An emerging protein that is critical for RAD51-mediated HR is RAD51-associated protein 1 (RAD51AP1). Although much has been learned about its biochemical attributes, the precise molecular role of RAD51AP1 in the HR reaction is not yet fully understood. The available literature also suggests that RAD51AP1 expression may be relevant for cancer development and progression. Here, we review the efforts that led to the discovery of RAD51AP1 and elaborate on our current understanding of its biochemical profile and biological function. We also discuss how RAD51AP1 may help to promote cancer development and why it could potentially represent a promising new target for therapeutic intervention.

Graphical abstract

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Quantitative multiphoton microscopy of murine urinary bladder morphology during in situ uniaxial loading

Publication date: Available online 22 September 2017
Source:Acta Biomaterialia
Author(s): Jack Hornsby, Donna M Daly, David Grundy, Fangzhou Cheng, Anne M Robertson, Paul N Watton, Mark S Thompson
Urodynamic tests are the gold standard for the diagnosis of bladder dysfunction, and the mechanical compliance of the bladder is an important parameter in these tests. The bladder wall has a layered structure, differentially affected by pathology, so knowledge of the contribution and role of these layers and their constituents to overall bladder compliance will enhance interpretation of these clinical tests. In this study we document the functional morphology of the detrusor and lamina propria of the murine bladder wall using a custom in-situ tensile loading system under multiphoton microscopy (MPM) observation in unloaded state and under incremental uniaxial stretch. Features in the stress-stretch curves of bladder samples were then directly related to corresponding MPM images. Collagen organisation across wall depth was quantified using image analysis techniques. The hypothesis that the lamina propria deformed at low strain by unfolding of the rugae and rearranging collagen fibrils was confirmed. A novel 'pocket' feature in the detrusor was observed along with extensive rearrangement of fibrils in two families at different depths, providing higher stiffness at high stretches in the detrusor. The very different deformations of detrusor and lamina propria were accommodated by the highly coiled structure of collagen in the lamina propria. Imaging and mechanical studies presented here allow gross mechanical response to be attributed to specific components of the bladder wall and further, may be used to investigate the impact of microstructural changes due to pathology or aging, and how they impair tissue functionality.Statement of significanceThis article reports the first in-situ multiphoton microscopy observations of microstructural deformation under uniaxial tensile loading of ex vivo bladder. We describe collagen rearrangement through the tissue thickness and relate this directly to the stress-stretch behaviour. We confirm for the first time the unfolding of rugae and realignment of fibrils in the lamina propria during extension and the rapid stiffening as two fibril families in the detrusor are engaged. This technique provides new insight into microstructure function and will enhance understanding of the impact of changes due to pathology or aging.

Graphical abstract

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