Synergistic Effect of He for the Fabrication of Ne and Ar Gas-Charged Silicon Thin Films as Solid Targets for Spectroscopic Studies.

Sputtering of silicon in a He magnetron discharge (MS) has been reported as a bottom-up procedure to obtain He-charged silicon films (i.e., He nanobubbles encapsulated in a silicon matrix). The incorporation of heavier noble gases is demonstrated in this work with a synergistic effect, producing increased Ne and Ar incorporations when using He-Ne and He-Ar gas mixtures in the MS process. Microstructural and chemical characterizations are reported using ion beam analysis (IBA) and scanning and transmission electron microscopies (SEM and TEM). In addition to gas incorporation, He promotes the formation of larger nanobubbles. In the case of Ne, high-resolution X-ray photoelectron and absorption spectroscopies (XPS and XAS) are reported, with remarkable dependence of the Ne 1s photoemission and the Ne K-edge absorption on the nanobubble's size and composition. The gas (He, Ne and Ar)-charged thin films are proposed as "solid" targets for the characterization of spectroscopic properties of noble gases in a confined state without the need for cryogenics or high-pressure anvils devices. Also, their use as targets for nuclear reaction studies is foreseen.

Improved Dual Network Model for Aging of Rubber Composites under Set Strains.

A new model is presented to predict rubber behavior during chemical aging at fixed strains. The model is validated using a carbon black-filled nitrile butadiene rubber aged in air at 125 °C. The model improves upon Tobolsky's dual network theory, designed for unfilled elastomers undergoing conventional aging but which has also often been used in rubber composites undergoing more complex aging scenarios. This work explores the shortcomings of the original model and demonstrates how the new model overcomes them. The model was validated using uniaxial tensile samples aged at 125 °C for 24-72 h at strains from 0-30%. The permanent set was measured, and the samples were tested on an Instron uniaxial test machine after aging. The cross-link density was estimated by equilibrium swelling. Results show that the new model more accurately models the stress-strain behavior to higher strains and provides more reliable estimates of chain scission and cross-linking after aging.

The Influence of Carbon Black Colloidal Properties on the Parameters of the Kraus Model.

The Payne Effect (also known as the Fletcher-Gent Effect) has a fundamental impact on the behavior of filled rubber composites and therefore must be considered during their design. This study investigates the influence of carbon black (CB) surface area and structure on the observed Payne Effect and builds on the existing models of Kraus and Ulmer to explain this phenomenon. Dynamic strain sweeps were carried out on natural rubber (NR) compounds containing eight different grades of CB at equivalent volume fractions. The loss and storage moduli were modeled according to the Kraus and Ulmer equations, using a curve optimization tool in SciPy. Subsequent regression analysis provided strong correlations between the fitting parameters and the CB structure and surface area. Using this regression analysis, this work provides further insight into the physical meaning behind the Kraus and Ulmer models, which are phenomenological in nature.

Psychosis and autism without functional regression in a patient with Kleefstra syndrome.

Kleefstra syndrome is a rare genetic disorder caused by haploinsufficiency of the euchromatic histone lysine methyltransferase 1 (EHMT1) gene. It is characterized by a variety of dysmorphic features, comorbid medical issues, and developmental delays/intellectual disability. Neuropsychiatric symptoms may also occur, including autistic features and psychosis, and are often accompanied by functional regression. However, the phenomenology of psychotic symptoms in this syndrome has not been well described in the literature. As such, in this brief report, we review the literature with respect to the occurrence of psychosis in Kleefstra syndrome and describe the symptom profile of a 35-year-old affected male with an intellectual disability, autism spectrum disorder, and schizophrenia (in association with manic features). This is the first report of psychotic symptoms fully remitting in response to zuclopenthixol therapy in an individual with Kleefstra syndrome. This case is also unique as it demonstrates that functional regression does not necessarily coincide with the development of schizophrenia-like presentations in affected individuals.

Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer.

Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells frequently exhibit Akt-driven lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing lamin A/C expression in highly invasive breast cancer cells reflected gene expression changes characteristic of human breast tumors with higher LMNA expression, and specifically affected pathways related to cell-ECM interactions, cell metabolism, and PI3K/Akt signaling. Further supporting an important role of lamins in breast cancer metastasis, analysis of lamin levels in human breast tumors revealed a significant association between lower lamin A levels, Akt signaling, and decreased disease-free survival. These findings suggest that downregulation of lamin A/C in breast cancer cells may influence both cellular physical properties and biochemical signaling to promote metastatic progression.

Rustling ants: Vibrational communication performed by two Camponotus species in Borneo.

Interactions between ants and plants are classic examples of cooperation between individuals of different species. Usually, plants provide shelter or food for ants and in turn are defended against herbivores by their insect allies. To coordinate attacks, ants use multi-modal alarm signals consisting of vibrational and chemical components. This can also be observed in Borneo, where two Camponotus species inhabit the ocreas (diverging, tubular leaf sheaths) of the rattan palm Korthalsia robusta. When ants are disturbed, they beat or scratch mandibles and abdomens on the plant surface resulting in loud rustling sounds. To describe the characteristics of these signals, we recorded them with a Laser-Doppler-vibrometer in the field. Analyses of temporal patterns and dominant frequency revealed that the signals of the two species differ fundamentally. To assess transmission characteristics of the rattan palm, we conducted experiments under controlled lab-conditions. We show that the ocrea is an adequate structure for converting airborne sound into substrate vibrations, acting as a mediator between these two modalities. We hypothesize that the ants' vibratory signal has multiple functions, with the substrate-borne component used as an alarm signal for conspecifics, and the airborne component acting as vibro-acoustic aposematism against predators or herbivores to protect the host plant.

Examining age-dependent DNA methylation patterns and gene expression in the male and female mouse hippocampus.

DNA methylation is a well-characterized epigenetic modification involved in numerous molecular and cellular functions. Methylation patterns have also been associated with aging mechanisms. However, how DNA methylation patterns change within key brain regions involved in memory formation in an age- and sex-specific manner remains unclear. Here, we performed reduced representation bisulfite sequencing (RRBS) from mouse dorsal hippocampus - which is necessary for the formation and consolidation of specific types of memories - in young and aging mice of both sexes. Overall, our findings demonstrate that methylation levels within the dorsal hippocampus are divergent between sexes during aging in genomic features correlating to mRNA functionality, transcription factor binding sites, and gene regulatory elements. These results define age-related changes in the methylome across genomic features and build a foundation for investigating potential target genes regulated by DNA methylation in an age- and sex-specific manner.

Very Low Vitamin D in a Patient With a Novel Pathogenic Variant in the GC Gene That Encodes Vitamin D-Binding Protein.

Circulating plasma vitamin D metabolites are highly bound to vitamin D-binding protein (DBP), also known as group-specific component or Gc-globulin. DBP, encoded by the GC gene, is a member of the albumin family of globular serum transport proteins. We previously described a homozygous GC gene deletion in a patient with apparent severe vitamin D deficiency, fragility fractures, and ankylosing spondylitis. Here, we report an unrelated patient free of fractures or rheumatologic disease, but with very low 25-hydroxyvitamin D and 1,25-hydroxyvitamin D, as well as undetectable DBP measured by liquid chromatography-tandem mass spectrometry. A whole gene deletion was excluded by microarray, and Sanger sequencing of GC revealed a homozygous pathogenic variant affecting a canonical splice site (c0.702-1G > A). These findings indicate that loss of function variants in GC that eliminate DBP, and severely reduced total circulating vitamin D levels, do not necessarily result in significant metabolic bone disease. Together with our previous report, these cases support the free-hormone hypothesis, and suggest free vitamin D metabolites may serve as preferable indicators of bone and mineral metabolism, particularly when clinical suspicion of DBP deficiency is high.

DNA methylation analysis reveals epimutation hotspots in patients with dilated cardiomyopathy-associated laminopathies.

BACKGROUND: Mutations in LMNA, encoding lamin A/C, lead to a variety of diseases known as laminopathies including dilated cardiomyopathy (DCM) and skeletal abnormalities. Though previous studies have investigated the dysregulation of gene expression in cells from patients with DCM, the role of epigenetic (gene regulatory) mechanisms, such as DNA methylation, has not been thoroughly investigated. Furthermore, the impact of family-specific LMNA mutations on DNA methylation is unknown. Here, we performed reduced representation bisulfite sequencing on ten pairs of fibroblasts and their induced pluripotent stem cell (iPSC) derivatives from two families with DCM due to distinct LMNA mutations, one of which also induces brachydactyly. RESULTS: Family-specific differentially methylated regions (DMRs) were identified by comparing the DNA methylation landscape of patient and control samples. Fibroblast DMRs were found to enrich for distal regulatory features and transcriptionally repressed chromatin and to associate with genes related to phenotypes found in tissues affected by laminopathies. These DMRs, in combination with transcriptome-wide expression data and lamina-associated domain (LAD) organization, revealed the presence of inter-family epimutation hotspots near differentially expressed genes, most of which were located outside LADs redistributed in LMNA-related DCM. Comparison of DMRs found in fibroblasts and iPSCs identified regions where epimutations were persistent across both cell types. Finally, a network of aberrantly methylated disease-associated genes revealed a potential molecular link between pathways involved in bone and heart development. CONCLUSIONS: Our results identified both shared and mutation-specific laminopathy epimutation landscapes that were consistent with lamin A/C mutation-mediated epigenetic aberrancies that arose in somatic and early developmental cell stages.

Adsorption of titanium dioxide nanoparticles onto zebrafish eggs affects colonizing microbiota.

Teleost fish embryos are protected by two acellular membranes against particulate pollutants that are present in the water column. These membranes provide an effective barrier preventing particle uptake. In this study, we tested the hypothesis that the adsorption of antimicrobial titanium dioxide nanoparticles onto zebrafish eggs nevertheless harms the developing embryo by disturbing early microbial colonization. Zebrafish eggs were exposed during their first day of development to 2, 5 and 10 mg TiO2 L-1 (NM-105). Additionally, eggs were exposed to gold nanorods to assess the effectiveness of the eggs' membranes in preventing particle uptake, localizing these particles by way of two-photon microscopy. This confirmed that particles accumulate onto zebrafish eggs, without any detectable amounts of particles crossing the protective membranes. By way of particle-induced X-ray emission analysis, we inferred that the titanium dioxide particles could cover 25-45 % of the zebrafish egg surface, where the concentrations of sorbed titanium correlated positively with concentrations of potassium and correlated negatively with concentrations of silicon. A combination of imaging and culture-based microbial identification techniques revealed that the adsorbed particles exerted antimicrobial effects, but resulted in an overall increase of microbial abundance, without any change in heterotrophic microbial activity, as inferred based on carbon substrate utilization. This effect persisted upon hatching, since larvae from particle-exposed eggs still comprised higher microbial abundance than larvae that hatched from control eggs. Notably, pathogenic aeromonads tolerated the antimicrobial properties of the nanoparticles. Overall, our results show that the adsorption of suspended antimicrobial nanoparticles on aquatic eggs can have cascading effects across different life stages of oviparous animals. Our study furthermore suggests that aggregation dynamics may occur that could facilitate the dispersal of pathogenic bacteria through aquatic ecosystems.

Time is of the essence: containment of the SARS-CoV-2 epidemic in Switzerland from February to May 2020

AIMIn late February and early March 2020, Switzerland experienced rapid growth of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections with 30,243 confirmed cases and 1,860 deaths as of 10 May 2020. The sequential introduction of non-pharmaceutical interventions (NPIs) resulted in successful containment of the epidemic. A better understanding of how the timing of implementing NPIs influences the dynamics and outcome of SARS-CoV-2 epidemics will be crucial for the management of a potential resurgence in Switzerland. METHODSWe developed a dynamic transmission model that describes infection, hospitalization, recovery and death due to SARS-CoV-2 in Switzerland. Using a maximum likelihood framework, we fitted the model to aggregated daily numbers of hospitalized patients, ICU occupancy and death from 25 February to 10 May 2020. We estimated critical parameters of SARS-CoV-2 transmission in Switzerland and explored counterfactual scenarios of an earlier and later implementation of NPIs. RESULTSWe estimated the basic reproduction number R0 = 2.61 (95% compatibility interval, CI: 2.51-2.71) during the early exponential phase of the SARS-CoV-2 epidemic in Switzerland. After the implementation of NPIs, the effective reproduction number approached Re = 0.64 (95% CI: 0.61-0.66). Based on the observed doubling times of the epidemic before and after the implementation of NPIs, we estimated that one week of early exponential spread required 3.1 weeks (95% CI: 2.8-3.3 weeks) of lockdown to reduce the number of infections to the same level. Introducing the same sequence of NPIs one week earlier or later would have resulted in substantially lower (399, 95% prediction interval, PI: 347-458) and higher (8,683, 95% PI: 8,038-9,453) numbers of deaths, respectively. CONCLUSIONSThe introduction of NPIs in March 2020 prevented thousands of SARS-CoV-2-related deaths in Switzerland. Early implementation of NPIs during SARS-CoV-2 outbreaks can reduce the number of deaths and the necessary duration of strict control measures considerably.

A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome.

There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.

[Comparing outcomes of Immediate Breast reconstruction with and without use of radiotherapy]. / Comparaison des résultats de reconstruction mammaire immédiate par prothèse avec et sans radiothérapie.

BACKGROUND: Breast cancer and its treatment remains a public health problem. There is still a lack of epidemiological data concerning complications and aesthetic results bound to radiotherapy after an immediate breast reconstruction. The objective of this study was to compare outcomes of immediate breast reconstruction regardless to the use of radiotherapy (history of radiotherapy or adjuvant radiation therapy), in order to determine risk factor of complications and bad aesthetic results. METHODS: We conducted a retrospective study between January 2014 and December 2016 at the hospital "Gustave Roussy" in Paris, concerning breast cancer patients who needed immediate breast reconstruction after total mastectomy. The primary endpoint was to assess the failure rate of reconstruction and the aesthetic result, the secondary endpoint assessed the early and late rate of complications. We realized a multivariate analysis in order to identify risks factors that may predict complications. RESULTS: Three hundred and thirty three patients have been included: 157 in the "radiotherapy group" compared to 176 in the "no radiotherapy group". Preoperative characteristics were comparable. Average follow-up was between 1 and 3years without missing. Patients who benefited from radiotherapy had an equal risk failure of reconstruction. The subgroup analysis revealed non-significant differences: 12.7% failure rate reconstruction in the "radiotherapy group" vs. 12.5%. We could notify a better rate of "excellent results" in the "no radiotherapy group": 35% vs. 8.2%. Secondary outcomes were comparable. CONCLUSIONS: Radiotherapy related to immediate breast reconstruction didn't increase the failure rate of reconstruction or aesthetic results, comparatively to non-irradiated patients. It is therefore permissible to suggest an immediate breast reconstruction to any patients which would benefit from a total mastectomy followed by radiotherapy; in order to prevent them from a secondary breast reconstruction, who could be physically and psychologically more impactful.

Tatton-Brown-Rahman syndrome: Six individuals with novel features.

Tatton-Brown Rahman syndrome (TBRS) is an overgrowth-intellectual disability syndrome caused by heterozygous variants in DNMT3A. Seventy-eight individuals have been reported with a consistent phenotype of somatic overgrowth, mild to moderate intellectual disability, and similar dysmorphisms. We present six individuals with TBRS, including the youngest individual thus far reported, first individual to be diagnosed with tumor testing and two individuals with variants at the Arg882 domain, bringing the total number of reported cases to 82. Patients reported herein have additional clinical features not previously reported in TBRS. One patient had congenital diaphragmatic hernia. One patient carrying the recurrent p.Arg882His DNMT3A variant, who was previously reported as having a phenotype due to a truncating variant in the CLTC gene, developed a ganglioneuroblastoma at 18 months and T-cell lymphoblastic lymphoma at 6 years of age. Four patients manifested symptoms suggestive of autonomic dysfunction, including central sleep apnea, postural orthostatic hypotension, and episodic vasomotor instability in the extremities. We discuss the molecular and clinical findings in our patients with TBRS in context of existing literature.

Enabling Global Clinical Collaborations on Identifiable Patient Data: The Minerva Initiative.

The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies. This includes the application of cutting-edge machine learning methods to image data. As with most digital tools employed in health care, there are ethical and data governance challenges associated with using identifiable personal image data. There are also risks with failing to deliver on the patient benefits of these new technologies, the biggest of which is posed by data siloing. The Minerva Initiative has been designed to enable the public good of deep phenotyping while mitigating these ethical risks. Its open structure, enabling collaboration and data sharing between individuals, clinicians, researchers and private enterprise, is key for delivering precision public health.

Vitamin D-Binding Protein Deficiency and Homozygous Deletion of the GC Gene.

A 58-year-old woman with debilitating ankylosing spondylitis who was born to consanguineous parents was found to have an apparent severe vitamin D deficiency that did not respond to supplementation. Liquid chromatography-tandem mass spectrometry showed the absence of circulating vitamin D-binding protein, and chromosomal microarray confirmed a homozygous deletion of the group-specific component (GC) gene that encodes the protein. Congenital absence of vitamin D-binding protein resulted in normocalcemia and a relatively mild disruption of bone metabolism, in this case complicated by severe autoimmune disease. (Funded by the National Institutes of Health and the University of Washington.).

Graphene onto medical grade titanium: an atom-thick multimodal coating that promotes osteoblast maturation and inhibits biofilm formation from distinct species.

The time needed for the osseointegration of titanium implants is deemed too long. Moreover, the bacterial colonization of their surfaces is a major cause of failure. Graphene can overcome these issues but its wet transfer onto substrates employs hazardous chemicals limiting the clinical applications. Alternatively, dry transfer technique has been developed, but the biological properties of this technique remain unexplored. Here, a dry transfer technique based on a hot-pressing method allowed to coat titanium substrates with high-quality graphene and coverage area >90% with a single transfer. The graphene-coated titanium is cytocompatible, did not induce cell membrane damage, induced human osteoblast maturation (gene and protein level), and increased the deposition of mineralized matrix compared to titanium alone. Moreover, graphene decreased the formation of biofilms from Streptococcus mutans, Enterococcus faecalis and even from whole saliva on titanium without killing the bacteria. These findings confirm that coating of titanium with graphene via a dry transfer technique is a promising strategy to improve osseointegration and prevent biofilm formation on implants and devices.

Fast, asymmetric and nonhomogeneous clearance of SiC nanoaerosol assessed by micro-particle-induced x-ray emission.

AIM: To study the biopersistence of a silicon carbide (SiC) nanoaerosol in rat lungs, as time-dependent clearance and spatial distribution. MATERIALS & METHODS: Sprague-Dawley rats were exposed 6 h/day during 5 days to a SiC nanoaerosol at 4.91 mg SiC/l. SiC biopersistence in rat lungs sections was assessed over 28 days by micro-particle-induced x-ray emission (µPIXE) as 2D maps and by particle-induced x-ray emission (PIXE) for whole-lung quantification. 2D maps were analyzed for SiC spatial distribution as skewness and kurtosis. RESULTS: Half-time clearance was 10.9 ± 0.9 days, agreeing with PIXE measurements. Spatial-temporal analysis of SiC indicated decreased symmetry and homogeneity. CONCLUSION: Fast SiC clearance points that current nanoaerosol exposure may not be enough to trigger lung overload. Spatial distribution shows an asymmetric and nonhomogeneous SiC clearance.