Combustion dynamics in steady compressible flows

We study the evolution of a reactive field advected by a one-dimensional compressible velocity field and subject to an ignition-type nonlinearity. In the limit of small molecular diffusivity the problem can be described by a spatially discretized system, and this allows for an efficient numerical simulation. If the initial field profile is supported in a region of size l < lc one has quenching, i.e., flame extinction, where lc is a characteristic length-scale depending on the system parameters (reacting time, molecular diffusivity and velocity field). We derive an expression for lc in terms of these parameters and relate our results to those obtained by other authors for different flow settings.Comment: 6 pages, 5 figure

Regulation of Tcf7l1 DNA Binding and Protein Stability as Principal Mechanisms of Wnt/β-Catenin Signaling

SummaryWnt/β-catenin signal transduction requires direct binding of β-catenin to Tcf/Lef proteins, an event that is classically associated with stimulating transcription by recruiting coactivators. This molecular cascade plays critical roles throughout embryonic development and normal postnatal life by affecting stem cell characteristics and tumor formation. Here, we show that this pathway utilizes a fundamentally different mechanism to regulate Tcf7l1 (formerly named Tcf3) activity. β-catenin inactivates Tcf7l1 without a switch to a coactivator complex by removing it from DNA, which leads to Tcf7l1 protein degradation. Mouse genetic experiments demonstrate that Tcf7l1 inactivation is the only required effect of the Tcf7l1-β-catenin interaction. Given the expression of Tcf7l1 in pluripotent embryonic and adult stem cells, as well as in poorly differentiated breast cancer, these findings provide mechanistic insights into the regulation of pluripotency and the role of Wnt/β-catenin in breast cancer

Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease

IMPORTANCE: Disease severity of childhood Charcot-Marie-Tooth disease (CMT) has not been extensively characterized, either within or between types of CMT to date. OBJECTIVE: To assess the variability of disease severity in a large cohort of children and adolescents with CMT. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study was conducted among 520 children and adolescents aged 3 to 20 years at 8 universities and hospitals involved in the Inherited Neuropathies Consortium between August 6, 2009, and July 31, 2014, in Australia, Italy, the United Kingdom, and the United States. Data analysis was conducted from August 1, 2014, to December 1, 2015. MAIN OUTCOMES AND MEASURES: Scores on the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), a well-validated unidimensional clinical outcome measure to assess disease severity. This instrument includes 11 items assessing fine and gross motor function, sensation, and balance to produce a total score ranging from 0 (unaffected) to 44 (severely affected). RESULTS: Among the 520 participants (274 males) aged 3 to 20 years, CMT type 1A (CMT1A) was the most prevalent type (252 [48.5%]), followed by CMT2A (31 [6.0%]), CMT1B (15 [2.9%]), CMT4C (13 [2.5%]), and CMTX1 (10 [1.9%]). Disease severity ranged from 1 to 44 points on the CMTPedS (mean [SD], 21.5 [8.9]), with ankle dorsiflexion strength and functional hand dexterity test being most affected. Participants with CMT1B (mean [SD] CMTPedS score, 24.0 [7.4]), CMT2A (29.7 [7.1]), and CMT4C (29.8 [8.6]) were more severely affected than those with CMT1A (18.9 [7.7]) and CMTX1 (males: 15.3 [7.7]; females: 13.0 [3.6]) (P < .05). Scores on the CMTPedS tended to worsen principally during childhood (ages, 3-10 years) for participants with CMT4C and CMTX1 and predominantly during adolescence for those with CMT1B and CMT2A (ages, 11-20 years), while CMT1A worsened consistently throughout childhood and adolescence. For individual items, participants with CMT4C recorded more affected functional dexterity test scores than did those with all other types of CMT (P < .05). Participants with CMT1A and CMTX1 performed significantly better on the 9-hole peg test and balance test than did those with all other types of CMT (P < .05). Participants with CMT2A had the weakest grip strength (P < .05), while those with CMT2A and CMT4C exhibited the weakest ankle plantarflexion and dorsiflexion strength, as well as the lowest long jump and 6-minute walk test distances (P < .05). Multiple regression modeling identified increasing age (r = 0.356, β = 0.617, P < .001) height (r = 0.251, β = 0.309, P = .002), self-reported foot pain (r = 0.162, β = .114, P = .009), and self-reported hand weakness (r = 0.243, β = 0.203, P < .001) as independent predictors of disease severity. CONCLUSIONS AND RELEVANCE: These results highlight the phenotypic variability within CMT genotypes and mutation-specific manifestations between types. This study has identified distinct functional limitations and self-reported impairments to target in future therapeutic trials

Development of Dual-Gain SiPM Boards for Extending the Energy Dynamic Range

Astronomical observations with gamma rays in the range of several hundred keV to hundreds of MeV currently represent the least explored energy range. To address this so-called MeV gap, we designed and built a prototype CsI:Tl calorimeter instrument using a commercial off-the-shelf (COTS) SiPMs and front-ends which may serve as a subsystem for a larger gamma-ray mission concept. During development, we observed significant non-linearity in the energy response. Additionally, using the COTS readout, the calorimeter could not cover the four orders of magnitude in energy range required for the telescope. We, therefore, developed dual-gain silicon photomultiplier (SiPM) boards that make use of two SiPM species that are read out separately to increase the dynamic energy range of the readout. In this work, we investigate the SiPM's response with regards to active area ($3\times3 \ \mathrm{mm}^2$ and $1 \times 1 \ \mathrm{mm}^2$) and various microcell sizes ($10$, $20$, and $35 \ \mu \mathrm{m}$). We read out $3\times3\times6 \ \mathrm{cm}^3$ CsI:Tl chunks using dual-gain SiPMs that utilize $35 \ \mu \mathrm{m}$ microcells for both SiPM species and demonstrate the concept when tested with high-energy gamma-ray and proton beams. We also studied the response of $17 \times 17 \times 100 \ \mathrm{mm}^3$CsI bars to high-energy protons. With the COTS readout, we estimate (with several assumptions) that the dual-gain prototype has an energy range of$0.25-400 \ \mathrm{MeV}$with the two SiPM species overlapping at a range of around$2.5-30 \ \mathrm{MeV}$. This development aims to demonstrate the concept for future scintillator-based high-energy calorimeters with applications in gamma-ray astrophysics

Development of a CsI Calorimeter for the Compton-Pair (ComPair) Balloon-Borne Gamma-Ray Telescope

There is a growing interest in astrophysics to fill in the observational gamma-ray MeV gap. We, therefore, developed a CsI:Tl calorimeter prototype as a subsystem to a balloon-based Compton and Pair-production telescope known as ComPair. ComPair is a technology demonstrator for a gamma-ray telescope in the MeV range that is comprised of 4 subsystems: the double-sided silicon detector, virtual Frisch grid CdZnTe, CsI calorimeter, and a plastic-based anti-coincidence detector. The prototype CsI calorimeter is composed of thirty CsI logs, each with a geometry of $1.67 \times 1.67 \times 10 \ \mathrm{cm^3}$. The logs are arranged in a hodoscopic fashion with 6 in a row that alternate directions in each layer. Each log has a resolution of around $8 \%$ full-width-at-half-maximum (FWHM) at $662 \ \mathrm{keV}$ with a dynamic energy range of around $250\ \mathrm{keV}-30 \ \mathrm{MeV}$. A $2\times2$ array of SensL J-series SiPMs read out each end of the log to estimate the depth of interaction and energy deposition with signals read out with an IDEAS ROSSPAD. We also utilize an Arduino to synchronize with the other ComPair subsystems that comprise the full telescope. This work presents the development and performance of the calorimeter, its testing in thermal and vacuum conditions, and results from irradiation by $2-25 \ \mathrm{MeV}$ monoenergetic gamma-ray beams. The CsI calorimeter will fly onboard ComPair as a balloon experiment in the summer of 2023

Two novel missense mutations in the myelin protein zero gene causes Charcot-Marie-Tooth type 2 and Déjérine-Sottas syndrome

<p>Abstract</p> <p>Background</p> <p>The Charcot-Marie-Tooth (CMT) phenotype caused by mutation in the <it>myelin protein zero (MPZ) </it>gene varies considerably, from early onset and severe forms to late onset and milder forms. The mechanism is not well understood. The myelin protein zero (P₀) mediates adhesion in the spiral wraps of the Schwann cell's myelin sheath. The crystalline structure of the extracellular domain of the myelin protein zero (P₀ex) is known, while the transmembrane and intracellular structure is unknown.</p> <p>Findings</p> <p>One novel missense mutation caused a milder late onset CMT type 2, while the second missense mutation caused a severe early onset phenotype compatible with Déjérine-Sottas syndrome.</p> <p>Conclusions</p> <p>The phenotypic variation caused by different missense mutations in the <it>MPZ </it>gene is likely caused by different conformational changes of the MPZ protein which affects the functional tetramers. Severe changes of the MPZ protein cause dysfunctional tetramers and predominantly uncompacted myelin, i.e. the severe phenotypes congenital hypomyelinating neuropathy and Déjérine-Sottas syndrome, while milder changes cause the phenotypes CMT type 1 and 2.</p

CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis

BACKGROUND: The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. METHODS: We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). RESULTS: 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. CONCLUSIONS: Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. CLINICAL TRIAL REGISTRATION ID NUMBER: NCT0119307

Tube Models for Rubber-Elastic Systems

In the first part of the paper we show that the constraining potentials introduced to mimic entanglement effects in Edwards' tube model and Flory's constrained junction model are diagonal in the generalized Rouse modes of the corresponding phantom network. As a consequence, both models can formally be solved exactly for arbitrary connectivity using the recently introduced constrained mode model. In the second part, we solve a double tube model for the confinement of long paths in polymer networks which is partially due to crosslinking and partially due to entanglements. Our model describes a non-trivial crossover between the Warner-Edwards and the Heinrich-Straube tube models. We present results for the macroscopic elastic properties as well as for the microscopic deformations including structure factors.Comment: 15 pages, 8 figures, Macromolecules in pres

The risk of menstrual abnormalities after tubal sterilization: a case control study

BACKGROUND: Tubal sterilization is the method of family planning most commonly used. The existence of the post-tubal-ligation syndrome of menstrual abnormalities has been the subject of debate for decades. METHODS: In a cross-sectional study, 112 women with the history of Pomeroy type of tubal ligation achieved by minilaparatomy as the case group and 288 women with no previous tubal ligation as the control group were assessed for menstrual abnormalities. RESULTS: Menstrual abnormalities were not significantly different between the case and control groups (p = 0.824). The abnormal uterine bleeding frequency differences in two different age groups (30–39 and 40–45 years old) were statistically significant (p = 0.0176). CONCLUSION: Tubal sterilization does not cause menstrual irregularities