A novel copy number variant in the murine Cdh23 gene gives rise to profound deafness and vestibular dysfunction.

Hearing loss is the most common congenital sensory deficit worldwide and exhibits high genetic heterogeneity, making molecular diagnoses elusive for most individuals. Detecting novel mutations that contribute to hearing loss is crucial to providing accurate personalized diagnoses, tailored interventions, and improving prognosis. Copy number variants (CNVs) are structural mutations that are understudied, potential contributors to hearing loss. Here, we present the Abnormal Wobbly Gait (AWG) mouse, the first documented mutant exhibiting waltzer-like locomotor dysfunction, hyperactivity, circling behaviour, and profound deafness caused by a spontaneous CNV deletion in cadherin 23 (Cdh23). We were unable to identify the causative mutation through a conventional whole-genome sequencing (WGS) and variant detection pipeline, but instead found a linked variant in hexokinase 1 (Hk1) that was insufficient to recapitulate the AWG phenotype when introduced into C57BL/6J mice using CRISPR-Cas9. Investigating nearby deafness-associated genes revealed a pronounced downregulation of Cdh23 mRNA and a complete absence of full-length CDH23 protein, which is critical for the development and maintenance of inner ear hair cells, in whole head extracts from AWG neonates. Manual inspection of WGS read depth plots of the Cdh23 locus revealed a putative 10.4 kb genomic deletion of exons 11 and 12 that was validated by PCR and Sanger sequencing. This study underscores the imperative to refine variant detection strategies to permit identification of pathogenic CNVs easily missed by conventional variant calling to enhance diagnostic precision and ultimately improve clinical outcomes for individuals with genetically heterogenous disorders such as hearing loss.

Suspended LRSPP for the development of highly integrated active plasmonic devices.

We present a novel long-range surface plasmon polariton (LRSPP) device consisting of a suspended dielectric matrix in which an electrically active, millimeter-long metallic waveguide is embedded. We show that, by opening an air gap under the lower cladding, the influence of the substrate is suppressed and the symmetry of the thermo-optical distribution around the LRSPP waveguide is preserved over extended ranges of applied electrical current with minimal optical losses. Experimental results show that, compared to a standard nonsuspended structure, our device allows either the induction of a phase change that is three times larger, for a fixed electrical power, or, equivalently, a scaling down of the device to one-tenth of its original length, for a fixed phase change.

Juniperanol: First total synthesis and evaluation in Type 2 Diabetes disease.

The first total synthesis of juniperanol, the tricyclic sesquiterpenoid enantiomer of α-cedrol is described. The synthesis relies on stereoselective gold-catalyzed Ohloff-type propargylic ester rearrangement performed on a 10 g scale, and a carbocationic cascade in the presence of acetyl methanesulfonate. The ability of juniperanol to interfere in glucose processes in different cell types is described.

Flow morphometry to assess the red blood cell storage lesion.

We present a novel automated system for morphology analysis of red blood cells (RBC) under flow. RBC concentrates collected by blood banks for transfusions are stored for periods of up to several weeks, during which time a number of changes occur, collectively termed the storage lesion. Typically the extent of hemolysis is the defining criterion to determine the acceptability of the RBCs for transfusions. Morphological changes are related with biochemical alteration during the storage of RBCs. The typical blood smear procedure for determining such changes is a labor-intensive and potentially biased manual process. The advantage of the flow morphometry system presented here is that it provides fully automated morphological classification of RBCs with large sample numbers in a short time. Our system uses a commercially available flow cell and flow conditions that prevent adhesion of RBCs, thus eliminating the need for blocking agents such as albumin that affect the distribution of cell shapes. Our morphometry results are validated by comparison with standard biochemical assays (hemolysis, ATP) for blood from 17 donors stored under blood bank conditions for 13 weeks. We show that the percentage of spherocytes present can be used to estimate the status of RBC concentrates. © 2017 International Society for Advancement of Cytometry.

Dynamics of soliton cascades in fiber amplifiers.

We study numerically the formation of cascading solitons when femtosecond optical pulses are launched into a fiber amplifier with less energy than required to form a soliton of equal duration. As the pulse is amplified, cascaded fundamental solitons are created at different distances, without soliton fission, as each fundamental soliton moves outside the gain bandwidth through the Raman-induced spectral shifts. As a result, each input pulse creates multiple, temporally separated, ultrashort pulses of different wavelengths at the amplifier output. The number of pulses depends not only on the total gain of the amplifier but also on the width of the input pulse.

Fetal Monitoring of Patients Diagnosed with Systemic Lupus Erythematosus - A Case Report.

We report a case of pathological foetal Doppler velocity, specifically the absence of end diastolic flow in the umbilical artery (AEDV/REDV), suspected diabetic pregnancy and mesangioproliferative glomerulonephritis, at 32 weeks of gestation. The foetal heart rate tracings were evaluated using a computerised cardiotocogram (Oxford Sonicaid system 8002 Chichester, England) 1 for 20-30 min parallel to the routine cardiotocogram. The ultrasound control at 33 weeks of gestation showed oligohydramnion, foetal centralisation and reduced interval foetal growth. Due to small gestational age (SGA) and oligohydramnion, labour was induced at 36 weeks gestation with vaginal prostaglandin and an amniotomy. Due to cephalopelvic disproportion, a Caesarean section was performed. Signs and symptoms of neonatal lupus were not found.

¹9F nuclear magnetic resonance screening of glucokinase activators.

Human hexokinase enzyme IV (EC 2.7.1.1) catalyzes the phosphorylation of glucose and regulates the level of glucose. This enzyme exhibits strong positive cooperativity due to an allosteric transition between an inactive form and a closed active form. This form can be stabilized by activators and, thus, can increase its turnover by a kinetic memory effect characterized by a slow decay to the inactive state. The structural details of this kinetic allostery are known. Several synthetic activators have been reported. We present a preliminary nuclear magnetic resonance (NMR) screening of a chemical library in search of molecules with some affinity for glucokinase (GK). The library, composed of eight molecules with known activity as well as molecules that display no interaction, has been tested using the FAXS (fluorine chemical shift anisotropy and exchange for screening) method, based on monitoring the R2 relaxation of the (19)F spin. To ensure a valid interaction measurement, the enzyme was placed in the presence of glucose and magnesium. The binding signal of one known fluorinated ligand was measured by determining the displacement of the known ligand. This simple measure of the (19)F signal intensity after an 80-ms spin echo correlates nicely with the EC50, opening a route for NMR screening of GK activators.

Supercontinuum optimization for dual-soliton based light sources using genetic algorithms in a grid platform.

We present a numerical strategy to design fiber based dual pulse light sources exhibiting two predefined spectral peaks in the anomalous group velocity dispersion regime. The frequency conversion is based on the soliton fission and soliton self-frequency shift occurring during supercontinuum generation. The optimization process is carried out by a genetic algorithm that provides the optimum input pulse parameters: wavelength, temporal width and peak power. This algorithm is implemented in a Grid platform in order to take advantage of distributed computing. These results are useful for optical coherence tomography applications where bell-shaped pulses located in the second near-infrared window are needed.

Multi-peak-spectra generation with Cherenkov radiation in a non-uniform single mode fiber.

We propose, by means of numerical simulations, a simple method to design a non-uniform standard single mode fiber to generate spectral broadening in the form of "ad-hoc" chosen peaks from dispersive waves. The controlled multi-peak generation is possible by an on/off switch of Cherenkov radiation, achieved by tailoring the fiber dispersion when decreasing the cladding diameter by segments. The interplay between the fiber dispersion and the soliton self-frequency shift results in discrete peaks of efficiently emitted Cherenkov radiation from low order solitons, despite the small amount of energy contained in a pulse. These spectra are useful for applications that demand low power bell-shaped pulses at specific carrier wavelengths.

[Ideal treatment for Helicobacter pylori: a systematic review]. / Tratamiento ideal del Helicobacter pylori: una revisión sistemática.

BACKGROUND: The success rates of therapies for treating Helicobacter pylori vary greatly worldwide and the ideal treatment has yet to be clearly established. AIMS: A systematic review was carried out to evaluate the effectiveness of current first and second-line therapies in treating H.pylori infection. METHODS: Two researchers independently carried out Internet search engine reviews (PUBMED, EMBASE, MEDLINE) of clinical trials on adults published between 1990 and 2012 in both English and Spanish. RESULTS: Forty-three (n=8,123) clinical trials were evaluated that included first and second-line triple, quadruple, and sequential therapies. The eradication rates of the standard triple therapy are unacceptable (≤80%) in countries where H.pylori is highly resistant to clarithromycin and metronidazole. Administration of the standard triple therapy for more than 7 days does not improve its effectiveness. No statistically significant differences were observed between the eradication rates of the quadruple therapy with bismuth and the standard triple therapy. Even though the sequential and concomitant therapies are equally successful regimens, the triple therapy with levofloxacin offers the best results as first and second-line treatment, but quinolone resistance can diminish its effectiveness. The triple therapy with levofloxacin and the sequential and concomitant treatments were superior to the standard triple regimen as first-line therapy. CONCLUSIONS: Currently there is no ideal first or second-line treatment for achieving 100% eradication. The therapeutic order should be carried out according to the initial treatment and local antimicrobial resistance studies.

Systematic integration of protein-affecting mutations, gene fusions, and copy number alterations into a comprehensive somatic mutational profile.

Somatic mutations occur as random genetic changes in genes through protein-affecting mutations (PAMs), gene fusions, or copy number alterations (CNAs). Mutations of different types can have a similar phenotypic effect (i.e., allelic heterogeneity) and should be integrated into a unified gene mutation profile. We developed OncoMerge to fill this niche of integrating somatic mutations to capture allelic heterogeneity, assign a function to mutations, and overcome known obstacles in cancer genetics. Application of OncoMerge to TCGA Pan-Cancer Atlas increased detection of somatically mutated genes and improved the prediction of the somatic mutation role as either activating or loss of function. Using integrated somatic mutation matrices increased the power to infer gene regulatory networks and uncovered the enrichment of switch-like feedback motifs and delay-inducing feedforward loops. These studies demonstrate that OncoMerge efficiently integrates PAMs, fusions, and CNAs and strengthens downstream analyses linking somatic mutations to cancer phenotypes.

Induction of Aryl Hydrocarbon Receptor-Mediated Cancer Cell-Selective Apoptosis in Triple-Negative Breast Cancer Cells by a High-Affinity Benzimidazoisoquinoline.

Triple-negative breast cancer (TNBC) remains a disease with a paucity of targeted treatment opportunities. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is involved in a wide range of physiological processes, including the sensing of xenobiotics, immune function, development, and differentiation. Different small-molecule AhR ligands drive strikingly varied cellular and organismal responses. In certain cancers, AhR activation by select small molecules induces cell cycle arrest or apoptosis via activation of tumor-suppressive transcriptional programs. AhR is expressed in triple-negative breast cancers, presenting a tractable therapeutic opportunity. Here, we identify a novel ligand of the aryl hydrocarbon receptor that potently and selectively induces cell death in triple-negative breast cancer cells and TNBC stem cells via the AhR. Importantly, we found that this compound, Analog 523, exhibits minimal cytotoxicity against multiple normal human primary cells. Analog 523 represents a high-affinity AhR ligand with potential for future clinical translation as an anticancer agent.

Suppression of Ah Receptor (AhR) increases the aggressiveness of TNBC cells and 11-Cl-BBQ-activated AhR inhibits their growth.

Triple-negative breast cancer (TNBC) represents around 15% of the 2.26 million breast cancers diagnosed worldwide annually and has the worst outcome. Despite recent therapeutic advances, there remains a lack of targeted therapies for this breast cancer subtype. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with biological roles in regulating development, xenobiotic metabolism, cell cycle progression and cell death. AhR activation by select ligands can promote tumor suppression in multiple cancer types. AhR can negatively regulate the activity of different oncogenic signaling pathways and can directly upregulate tumor suppressor genes such as p27Kip1. To determine the role of AhR in TNBC, we generated AhR-deficient cancer cells and investigated the impact of AhR loss on TNBC cell growth phenotypes. We found that AhR-deficient MDA-MB-468 TNBC cells have increased proliferation and formed significantly more colonies compared to AhR expressing cells. These cells without AhR expression grew aggressively in vivo. To determine the molecular targets driving this phenotype, we performed transcriptomic profiling in AhR expressing and AhR knockout MDA-MB-468 cells and identified tyrosine receptor kinases, as well as other genes involved in proliferation, survival and clonogenicity that are repressed by AhR. In order to determine therapeutic targeting of AhR in TNBC, we investigated the anti-cancer effects of the novel AhR ligand 11-chloro-7H-benzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (11-Cl-BBQ), which belongs to a class of high affinity, rapidly metabolized AhR ligands called benzimidazoisoquinolines (BBQs). 11-Cl-BBQ induced AhR-dependent cancer cell-selective growth inhibition and strongly inhibited colony formation in TNBC cells.

The Impact of Victim Blaming and Locus of Control on Mental Health Outcomes Among Female Sexual Assault Survivors.

To elucidate individual differences in sexual assault survivor outcomes, we examined locus of control as a moderator of the relationship between victim blaming and both posttraumatic stress disorder (PTSD) symptoms and unhealthy alcohol use. The sample consisted of 82 female sexual assault survivors who had disclosed their victimization to at least one person. The results of this survey demonstrated that locus of control did not moderate the relationship between victim blaming and PTSD, or the relationship between victim blaming and unhealthy alcohol use. The findings further supported the direct relationship between victim blaming and a range of negative mental health outcomes among survivors.

Microbial community succession of submerged bones in an aquatic habitat.

After death, microbes (including bacteria and fungi) colonize carrion from a variety of sources during the decomposition process. The predictable succession of microbes could be useful for forensics, such as postmortem submersion interval estimation (PMSI) for aquatic deaths. However, gaps exist in our understanding of microbial succession on submerged bone, particularly regarding longer-term decomposition (>1 year), fungal composition, and differences between internal and external microbial communities. To further explore this potential forensic tool, we described the postmortem microbial communities (bacteria and fungi) on and within submerged bones using targeted amplicon sequencing. We hypothesized predictable successional patterns of microbial colonization would be detected on the surface and within submerged bones, which would eventually converge to a similar microbial community. To best replicate forensic contexts, we sampled bones from replicate swine (Sus scrofa domesticus) carcasses submerged in a freshwater pond, every three months for nearly two years. Microbial bone (internal vs. external) community structure (taxa abundance and diversity) of bones differed for both bacteria and fungi, but internal and external communities did not converge to a similar structure. PMSI estimation models built with random forest regression of postmortem microbiomes were highly accurate (>80% variation explained in PMSI) and showed promise for forensic purposes. Overall, we provide further evidence that internal and external bone microbial communities submerged in an aquatic habitat are distinct and each community undergoes predictable succession, demonstrating potential utility in forensics for modeling PMSI in unattended deaths and/or cold cases.

Grasping Embodiment: Haptic Feedback for Artificial Limbs.

Upper-limb prostheses are subject to high rates of abandonment. Prosthesis abandonment is related to a reduced sense of embodiment, the sense of self-location, agency, and ownership that humans feel in relation to their bodies and body parts. If a prosthesis does not evoke a sense of embodiment, users are less likely to view them as useful and integrated with their bodies. Currently, visual feedback is the only option for most prosthesis users to account for their augmented activities. However, for activities of daily living, such as grasping actions, haptic feedback is critically important and may improve sense of embodiment. Therefore, we are investigating how converting natural haptic feedback from the prosthetic fingertips into vibrotactile feedback administered to another location on the body may allow participants to experience haptic feedback and if and how this experience affects embodiment. While we found no differences between our experimental manipulations of feedback type, we found evidence that embodiment was not negatively impacted when switching from natural feedback to proximal vibrotactile feedback. Proximal vibrotactile feedback should be further studied and considered when designing prostheses.

Healthy Aging Biomarkers: The INSPIRE's Contribution.

The find solutions for optimizing healthy aging and increase health span is one of the main challenges for our society. A novel healthcare model based on integration and a shift on research and care towards the maintenance of optimal functional levels are now seen as priorities by the WHO. To address this issue, an integrative global strategy mixing longitudinal and experimental cohorts with an innovative transverse understanding of physiological functioning is missing. While the current approach to the biology of aging is mainly focused on parenchymal cells, we propose that age-related loss of function is largely determined by three elements which constitute the general ground supporting the different specific parenchyma: i.e. the stroma, the immune system and metabolism. Such strategy that is implemented in INSPIRE projects can strongly help to find a composite biomarker capable of predicting changes in capacity across the life course with thresholds signalling frailty and care dependence.

Formation of Environmentally Persistent Free Radicals (EPFRs) on the Phenol-Dosed α-Fe2O3(0001) Surface.

Environmentally persistent free radicals (EPFRs) are a class of toxic air pollutants that are found to form by the chemisorption of substituted aromatic molecules on the surface of metal oxides. In this study, we employ X-ray photoelectron spectroscopy (XPS) and ultraviolet photoelectron spectroscopy (UPS) to perform a temperature-dependent study of phenol adsorption on α-Fe2O3(0001) to probe the radical formation mechanism by monitoring changes in the electronic structure of both the adsorbed phenol and metal oxide substrate. Upon dosing at room temperature, new phenol-derived electronic states have been clearly observed in the UPS spectrum at saturation coverage. However, upon dosing at high temperature (>200 °C), both photoemission techniques have shown distinctive features that strongly suggest electron transfer from adsorbed phenol to Fe2O3 surface atoms and consequent formation of a surface radical. Consistent with the experiment, DFT calculations show that phenoxyl adsorption on the iron oxide surface at RT leads to a minor charge transfer to the adsorbed molecule. The experimental findings at high temperatures agree well with the EPFRs' proposed formation mechanism and can guide future experimental and computational studies.

Towards a Large-Scale Assessment of the Relationship between Biological and Chronological Aging: The INSPIRE Mouse Cohort.

Aging is the major risk factor for the development of chronic diseases. After decades of research focused on extending lifespan, current efforts seek primarily to promote healthy aging. Recent advances suggest that biological processes linked to aging are more reliable than chronological age to account for an individual's functional status, i.e. frail or robust. It is becoming increasingly apparent that biological aging may be detectable as a progressive loss of resilience much earlier than the appearance of clinical signs of frailty. In this context, the INSPIRE program was built to identify the mechanisms of accelerated aging and the early biological signs predicting frailty and pathological aging. To address this issue, we designed a cohort of outbred Swiss mice (1576 male and female mice) in which we will continuously monitor spontaneous and voluntary physical activity from 6 to 24 months of age under either normal or high fat/high sucrose diet. At different age points (6, 12, 18, 24 months), multiorgan functional phenotyping will be carried out to identify early signs of organ dysfunction and generate a large biological fluids/feces/organs biobank (100,000 samples). A comprehensive correlation between functional and biological phenotypes will be assessed to determine: 1) the early signs of biological aging and their relationship with chronological age; 2) the role of dietary and exercise interventions on accelerating or decelerating the rate of biological aging; and 3) novel targets for the promotion of healthy aging. All the functional and omics data, as well as the biobank generated in the framework of the INSPIRE cohort will be available to the aging scientific community. The present article describes the scientific background and the strategies employed for the design of the INSPIRE Mouse cohort.

[Effect of pamidronate infusion time on renal function in patients with multiple myeloma]. / Influencia del tiempo de perfusión de pamidronato en la función renal de pacientes con mieloma múltiple.

INTRODUCTION: Administration of biphosphonates in patients with renal failure requires a dosage adjustment. OBJECTIVES: Analyse renal function evolution in multiple myeloma patients after reducing infusion time for 90 mg pamidronate by 2 h. METHODS: In 2007, a retrospective study was carried out on all patients who presented multiple myeloma and bone metastasis treated with pamidronate administered every 4 h. Following a review of the literature, a protocol for administering pamidronate every 2 h was created in partnership with Haematology, and a specific dose reduction framework was established for patients with baseline renal failure. Additionally, a prospective follow-up study of those patients' renal function was completed to analyse its evolution after the change in infusion time. RESULTS: A total of six patients received 90 mg pamidronate every 4 h. 33.32% of the patients (2/6) presented baseline renal insufficiency, and therefore needed to have the pamidronate dose adjusted according to the new protocol. Subsequently, all of them received the treatment every 2 h, and one patient (16.6%) experienced altered renal function after two treatment cycles. DISCUSSION: Reducing administration time for pamidronate from four to 2 h did not lead to significant variations in patients' renal function. This therapeutic practice can improve patients' quality of life by shortening their hospital stay without aggravating their renal function.