C1 Function Research Articles

RRM but not the Asp/Glu domain of hnRNP C1/C2is required for splicing regulation of Ron exon 11 pre-mRNA

The Ron proto-oncogene is a human receptor for macrophage-stimulating protein (MSP). The exclusion of exon 11 in alternative splicing generates ΔRON protein that is constitutively activated. Heterogenous ribonucleaoprotein (hnRNP) C1/C2 is one of the most abundant proteins in cells. In this manuscript, we showed that both hnRNP C1 and C2 promoted exon 11 inclusion of Ron pre-mRNA and that hnRNP C1 and hnRNP C2 functioned independently but not cooperatively. Moreover, hnRNP C1 stimulated exon 11 splicing through intron 10 activation but not through intron 11 splicing. Furthermore, we showed that, whereas the RRM domain was required for hnRNP C1 function, the Asp/Glu domain was not. In conclusion, hnRNP C1/C2 promoted exon 11 splicing independently by stimulating intron 10 splicing through RRM but not through the Asp/Glu domain.

Centers of planar generalized Abel equations

We deal with the differential equationr˙=drdθ=a(θ)rn+b(θ)rm, where (r,θ) are the polar coordinates in the plane R2, m and n are integers such that m>n≥2, and a,b are C1 functions. Note that when n=2 and m=3 we have an Abel differential equation. For this class of generalized Abel equations we characterize a new family of centers.

Effects of age on feeding response: Focus on the rostral C1 neuron and its glucoregulatory proteins.

Older people are likely to develop anorexia of aging. Rostral C1 (rC1) catecholaminergic neurons in rostral ventrolateral medulla (RVLM) are recently discovered its role in food intake control. It is well established that these neurons regulate cardiovascular function. This study aims to determine the effect of age on the function of rostral C1 (rC1) neurons in mediating feeding response. Male Sprague Dawley rats at 3-months (n = 22) and 24-months (n = 22) old were used and further divided into two subgroups; 1) treatment group with 2-deoxy-d-glucose (2DG) and 2) vehicle group. Feeding hormones such as cholecystokinin (CCK), ghrelin and leptin were analysed using enzyme-linked immunosorbent assay (ELISA). Rat brain was carefully dissected to obtain the brainstem RVLM region. Further analysis was carried out to determine the level of proteins and genes in RVLM that were associated with feeding pathway. Protein expression of tyrosine hydroxylase (TH), phosphorylated TH at Serine40 (pSer40TH), AMP-activated protein kinase (AMPK), phosphorylated AMPK (phospho AMPK) and neuropeptide Y Y5 receptor (NPY5R) were determined by western blot. Expression of TH, AMPK and NPY genes were determined by real-time PCR. This study showed that blood glucose level was elevated in young and old rats following 2DG administration. Plasma CCK-8 concentration was higher in the aged rats at basal and increased with 2DG administration in young rats, but the leptin and ghrelin showed no changes. Old rats showed higher TH and lower AMPK mRNA levels. Glucoprivation decreased AMPK mRNA level in young rats and decreased TH mRNA in old rats. Aged rC1 neurons showed higher NPY5R protein level. Following glucoprivation, rC1 neurons produced distinct molecular changes across age in which, in young rats, AMPK phosphorylation level was increased and in old rats, TH phosphorylation level was increased. These findings suggest that glucose-counterregulatory responses by rC1 neurons at least, contribute to the ability of young and old rats in coping glucoprivation. Age-induced molecular changes within rC1 neurons may attenuate the glucoprivic responses. This situation may explain the impairment of feeding response in the elderly.

Dual-Wavelength (UV and Blue) Controlled Photopolymerization Confinement for 3D-Printing: Modeling and Analysis of Measurements.

The kinetics and modeling of dual-wavelength (UV and blue) controlled photopolymerization confinement (PC) are presented and measured data are analyzed by analytic formulas and numerical data. The UV-light initiated inhibition effect is strongly monomer-dependent due to different C=C bond rate constants and conversion efficacies. Without the UV-light, for a given blue-light intensity, higher initiator concentration (C10) and rate constant (k’) lead to higher conversion, as also predicted by analytic formulas, in which the total conversion rate (RT) is an increasing function of C1 and k’R, which is proportional to k’[gB1C1]0.5. However, the coupling factor B1 plays a different role that higher B1 leads to higher conversion only in the transient regime; whereas higher B1 leads to lower steady-state conversion. For a fixed initiator concentration C10, higher inhibitor concentration (C20) leads to lower conversion due to a stronger inhibition effect. However, same conversion reduction was found for the same H-factor defined by H0 = [b1C10 − b2C20]. Conversion of blue-only are much higher than that of UV-only and UV-blue combined, in which high C20 results a strong reduction of blue-only-conversion, such that the UV-light serves as the turn-off (trigger) mechanism for the purpose of spatial confirmation within the overlap area of UV and blue light. For example, UV-light controlled methacrylate conversion of a glycidyl dimethacrylate resin is formulated with a tertiary amine co-initiator, and butyl nitrite. The system is subject to a continuous exposure of a blue light, but an on-off exposure of a UV-light. Finally, we developed a theoretical new finding for the criterion of a good material/candidate governed by a double ratio of light-intensity and concentration, [I20C20]/[I10C10].

From Isocyanides to Iminonitriles via Silver-mediated Sequential Insertion of C(sp3)-H Bond.

SummaryHeterocycles are prevalent constituents of many marketing drugs and biologically active molecules to meet modern medical challenges. Isocyanide insertion into C(sp3)–H bonds is challenging especially for the construction of quaternary carbon centers. Herein, we describe an efficient strategy for the synthesis of α-iminonitrile substituted isochromans and tetrahydroisoquinolines (THIQs) with quaternary carbon centers through silver-triflate-mediated sequential isocyanide insertion of C(sp3)–H bonds, where isocyanide acts as the crucial “CN” and “imine” sources. The produced α-iminonitriles have extensive applications as valuable synthetic building blocks for pharmacologically interesting heterocycles. This protocol could be further applied for the synthesis of iminonitrile-decorated phenanthridines and azapyrene. Interestingly, a remarkable aggregation-induced emission (AIE) effect was first observed for an iminonitrile-decorated pyrene derivative, which may open a particular area for iminonitrile applications in materials science.

Extraction of critical points of smooth functions on Banach spaces

Let E be an infinite-dimensional separable Hilbert space. We show that for every C1 function f:E→Rd, every open set U with Cf:={x∈E:Df(x)is not surjective}⊂U and every continuous function ε:E→(0,∞) there exists a C1 mapping φ:E→Rd such that ||f(x)−φ(x)||≤ε(x) for every x∈E, f=φ outside U and φ has no critical points (Cφ=∅). This result can be generalized to the case where E=c0 or E=lp, 1<p<∞. In the case E=c0 it is also possible to get that ||Df(x)−Dφ(x)||≤ε(x) for every x∈E.

A note on breaking of symmetry for a class of variational problems

In this note we present a symmetry breaking result for a class of 2π− periodic problems of the form −u′′(t)=g(u(t))+f(t)u(0)−u(2π)=u′(0)−u′(2π)=0where g:R→R is a given C1 function and f:[0,2π]→R is continuous. Our approach is inspired on Willem’s paper (Willem, 1989) and uses actions of finite groups which are not usually considered in the literature.

Finitely Additive Measures on the Unstable Leaves of Anosov Diffeomorphisms

We obtain a qualitative characterization of the convergence rate of the averages (with respect to the Margulis measure) of C2 functions over the iterations of domains in unstable manifolds of a topologically mixing C3 Anosov diffeomorphism with oriented invariant foliations. For this purpose, we extend the constructions of Margulis and Bufetov and introduce holonomy invariant families of finitely additive measures on unstable leaves and a Banach space in which holonomy invariant measures correspond to the (generalized) eigenfunctions of the transfer operator with biggest eigenvalues.

Uniform continuity of nonautonomous superposition operators in ΛBV-spaces

Abstract In this paper we investigate the problem of uniform continuity of nonautonomous superposition operators acting between spaces of functions of bounded Λ-variation. In particular, we give the sufficient conditions for nonautonomous superposition operators to continuously map a space of functions of bounded Λ-variation into itself. The conditions cover the generators being functions of C 1 {C^{1}} -class (in view of two variables), but also allow for less regular functions, including discontinuous generators.

Optimal mechanisms for selling two items to a single buyer having uniformly distributed valuations

We consider the design of a revenue-optimal mechanism when two items are available to be sold to a single buyer whose valuation is uniformly distributed over an arbitrary rectangle [c1,c1+b1]×[c2,c2+b2] in the positive quadrant. We provide an explicit, complete solution for arbitrary nonnegative values of (c1,c2,b1,b2). We identify eight simple structures, each with at most 4 (possibly stochastic) menu items, and prove that the optimal mechanism has one of these eight structures. We also characterize the optimal mechanism as a function of (c1,c2,b1,b2). The structures indicate that the optimal mechanism involves (a) an interplay of individual sale and a bundle sale when c1 and c2 are low, (b) a bundle sale when c1 and c2 are high, and (c) an individual sale when one of them is high and the other is low. To the best of our knowledge, our results are the first to show the existence of optimal mechanisms with no exclusion region. We further conjecture, based on promising preliminary results, that our methodology can be extended to a wider class of distributions.

An optimal quasi solution for the Cauchy problem for Laplace equation in the framework of inverse ECG

The inverse ECG problem is set as a boundary data completion for the Laplace equation: at each time the potential is measured on the torso and its normal derivative is null. One aims at reconstructing the potential on the heart. A new regularization scheme is applied to obtain an optimal regularization strategy for the boundary data completion problem. We consider the ℝn+1domain Ω. The piecewise regular boundary of Ω is defined as the union∂Ω = Γ1∪ Γ0∪ Σ, where Γ1and Γ0are disjoint, regular, andn-dimensional surfaces. Cauchy boundary data is given in Γ0, and null Dirichlet data in Σ, while no data is given in Γ1. This scheme is based on two concepts: admissible output data for an ill-posed inverse problem, and the conditionally well-posed approach of an inverse problem. An admissible data is the Cauchy data in Γ0corresponding to an harmonic function inC2(Ω) ∩H1(Ω). The methodology roughly consists of first characterizing the admissible Cauchy data, then finding the minimum distance projection in theL2-norm from the measured Cauchy data to the subset of admissible data characterized by givena prioriinformation, and finally solving the Cauchy problem with the aforementioned projection instead of the original measurement.

Collision-Free Dynamical Systems

Abstract Collision-freeness is an important structural property of particle dynamics. A nonlinear ODE system ẋ(t) = f(x(t)) is called collision-free if the solution to the initial value problem with x(0)=x° has distinct components for all times t whenever the initial state x° has distinct components. Both the general case of a C1–function f and the special case of a polynomial (or even linear) function f will be addressed.

Rhodium(II)‐Catalyzed Highly Stereoselective C3 Functionalization of Indolizines with N‐Sulfonyl‐1,2,3‐triazoles

AbstractAn efficient and highly stereoselective approach for the C3 functionalization of indolizines through rhodium(II)‐catalyzed insertion of aza‐vinyl carbenes to synthesize N‐sulfonylamine alkenyl derivatives of indolizines is disclosed. Variably functionalized indolizines underwent C3 functionalization to afford moderate to good yields. Under similar reaction conditions pyrrolo[1,2‐a]quinolines resulted in regioselective C1 functionalization to give their N‐sulfonylamine alkenyl derivatives. The reaction methodology was successfully extended for the preparation of 1,3‐bis(N‐sulfonylamine alkenyl)indolizine derivatives and C3‐functionalized indolizines were used for the preparation of new molecular entities.

Selective N-Formylation and N-Methylation of Amines Using Methanol as a Sustainable C1 Source

Methanol was utilized for C1 functionalization of primary amines; N-formylation, N-methylation, and N,N-formylmethylation. The reactions were achieved via dehydrogenation of methanol with a ruthenium-based catalyst. Various amines were selectively functionalized in moderate to excellent yields (30% to 99%). Mechanistic studies revealed that control of the reversibility between dehydrogenation of the hemiaminal to formamide and hydrogenation of the formamide back to the hemiaminal promotes the selectivity. The hemiaminal intermediate is further dehydrated to an imine, followed by irreversible hydrogenation to generate the N-methyl secondary amine. The N-methyl secondary amine can then undergo formylation to produce N,N-formylmethylamine. It can be also reversibly hydrogenated to the corresponding hemiaminal intermediate. Further dehydration and subsequent hydrogenation can generate N,N-dimethylamine. The hydrogen pressure and reaction temperature are critical to controlling the equilibria and reaction path...

PATIENT WITH LYMPHOMA AND ACQUIRED ANGIOEDEMA: NAVIGATING THE BLURRED LINES IN DIAGNOSIS AND TREATMENT

Introduction In acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE), the gastrointestinal (GI) tract is a common site of angioedema attack. Abdominal involvement occurring by itself is difficult to diagnose as it may masquerade as other GI pathologies, including acute surgical abdomen. Case Description A 63 yr female diagnosed with stage IV marginal zone lymphoma was referred for management of acquired angioedema due to C1-INH deficiency (C1-INH-AAE). Patient had two episodes of angioedema requiring intubation, at which time C1 esterase inhibitor level was low. She had recurrent episodes of abdominal pain and distention for 6 months. Labs included C4: < 1.5 mg/dL, C1 esterase inhibitor: 5 mg/dL, and C1 function: 26%, C1q level < 3.6 mg/dL. It was unclear whether her abdominal complaints were secondary to angioedema versus progression of lymphoma. As exogenous replacement C1-inhibitor could potentially induce further autoantibodies against the rescue agent, and may be less effective, as needed bradykinin receptor antagonist was prescribed for attacks. CT scan during abdominal distension showed ascites and portal hypertension from splenic enlargement, rather than gastrointestinal angioedema as the cause of her pain. With chemotherapy, symptoms improved and angioedema did not recur. Discussion C1-INH-AAE is a rare disease and commonly associated with lymphoproliferative disorders, such as non-Hodgkin lymphoma. Bradykinin-driven angioedema involves the skin, GI tract; and most harrowingly the larynx. This case represents important aspects in the workup and management of C1-INH-AAE including symptom overlap between underlying malignancy and angioedema, the optimal treatment agent and recognition that the most definitive treatment of C1-INH-AAE is to treat underlying malignancy. In acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE), the gastrointestinal (GI) tract is a common site of angioedema attack. Abdominal involvement occurring by itself is difficult to diagnose as it may masquerade as other GI pathologies, including acute surgical abdomen. A 63 yr female diagnosed with stage IV marginal zone lymphoma was referred for management of acquired angioedema due to C1-INH deficiency (C1-INH-AAE). Patient had two episodes of angioedema requiring intubation, at which time C1 esterase inhibitor level was low. She had recurrent episodes of abdominal pain and distention for 6 months. Labs included C4: < 1.5 mg/dL, C1 esterase inhibitor: 5 mg/dL, and C1 function: 26%, C1q level < 3.6 mg/dL. It was unclear whether her abdominal complaints were secondary to angioedema versus progression of lymphoma. As exogenous replacement C1-inhibitor could potentially induce further autoantibodies against the rescue agent, and may be less effective, as needed bradykinin receptor antagonist was prescribed for attacks. CT scan during abdominal distension showed ascites and portal hypertension from splenic enlargement, rather than gastrointestinal angioedema as the cause of her pain. With chemotherapy, symptoms improved and angioedema did not recur. C1-INH-AAE is a rare disease and commonly associated with lymphoproliferative disorders, such as non-Hodgkin lymphoma. Bradykinin-driven angioedema involves the skin, GI tract; and most harrowingly the larynx. This case represents important aspects in the workup and management of C1-INH-AAE including symptom overlap between underlying malignancy and angioedema, the optimal treatment agent and recognition that the most definitive treatment of C1-INH-AAE is to treat underlying malignancy.

SCREENING FOR HEREDITARY ANGIOEDEMA IN INFANCY

Introduction Hereditary angioedema (HAE) can be difficult to diagnose in infancy because C1 esterase inhibitor levels and function do not reach normal values until about one year of age. We describe a case of a 4-month-old boy who required screening for HAE. Case Description Patient is a 4-month-old boy who presented for screening for HAE because both father and grandfather have HAE. Patient has not had any symptoms of angioedema. No testing was done at the initial visit due to high rates of false positives in infancy. The patient was monitored regularly throughout his first year of life for any symptoms of HAE. At one year of age, testing was performed which showed C1 esterase level of 15 mg/dL (21-39) and function of 61% (normal >67, equivocal 41-67, abnormal Discussion Family members of those with HAE should be screened for HAE. C1 esterase inhibitor level and function is typically lower in infants than in adults, leading to false positive results in infancy. This makes it difficult to diagnose HAE in infants and no clear consensus exists on how to appropriately screen these individuals. For our patient, we chose to follow regularly until he was one year of age and advised his family to contact us if he had any symptoms or required any surgical procedure. At one year of age, testing revealed he had type 1 HAE. We prescribed plasma derived C1 inhibitor concentrate, which is the only approved medication for acute treatment of HAE in children under 12.

SUBCUTANEOUS C1-INHIBITOR FOR LONG-TERM PROPHYLAXIS IN HEREDITARY ANGIOEDEMA WITH NORMAL C1 INHIBITOR

Introduction Hereditary angioedema (HAE) is a rare disorder characterized by episodes of swelling without urticaria. HAE presents with decreased C1 inhibitor (C1INH) antigen (type I) or function (type II), or with normal C1INH (HAE-nC1INH). Case Description A 25-year-old female presented with intermittent airway, abdominal and extremity angioedema without hives every 2-4 weeks for 3 years, often coinciding with ovulation or menstruation. She had up to 24 emergency room (ER) visits and 5 hospitalizations annually, historically requiring intubation, abdominal laparoscopy and appendectomy. Pathology revealed normal appendix. C4, ANA, tryptase, C1INH antigen level, C1INH function, C1q and Factor XII gene testing were normal. Angioedema was unresponsive to high-dose antihistamines, systemic corticosteroids, and omalizumab. She was diagnosed with suspected HAE-nC1INH. Progesterone contraceptives and fresh frozen plasma were ineffective. On-demand ecallantide or icatibant reduced episode duration but she continued with frequent symptoms. Prophylactic tranexamic acid and subsequently IV C1INH 1000 units every 3-4 days resulted in modest preventative effects but she had ER visits, hospitalizations and decreased quality of life due to angioedema. In September 2017, she transitioned to prophylactic subcutaneous C1INH replacement 60 IU/kg twice weekly and has since experienced only 3 ER visits with rapid recovery, no hospitalizations, international travel and permanent employment. Discussion Plasma-derived human C1-INH has been reported as a successful acute treatment in HAE-nC1INH. A lower threshold for contact system activation might explain the benefit of higher C1INH levels in some HAE-nC1INH patients. Our report demonstrates that SQ C1INH may be effective for long-term prophylaxis in a subset of HAE-nC1INH.

Characterization of f-extremal disks

We show uniqueness for overdetermined elliptic problems defined on topological disks Ω with C2 boundary, i.e., positive solutions u to Δu+f(u)=0 in Ω⊂(M2,g) so that u=0 and ∂u∂η→=cte along ∂Ω, η→ the unit outward normal along ∂Ω under the assumption of the existence of a candidate family. To do so, we adapt the Gálvez–Mira generalized Hopf-type Theorem [19] to the realm of overdetermined elliptic problem.When (M2,g) is the standard sphere S2 and f is a C1 function so that f(x)>0 and f(x)≥xf′(x) for any x∈R+⁎, we construct such candidate family considering rotationally symmetric solutions. This proves the Berestycki–Caffarelli–Nirenberg conjecture in S2 for this choice of f. More precisely, this shows that if u is a positive solution to Δu+f(u)=0 on a topological disk Ω⊂S2 with C2 boundary so that u=0 and ∂u∂η→=cte along ∂Ω, then Ω must be a geodesic disk and u is rotationally symmetric. In particular, this gives a positive answer to the Schiffer conjecture D (cf. [33,35]) for the first Dirichlet eigenvalue and classifies simply-connected harmonic domains (cf. [28], also called Serrin Problem) in S2.

Blended B-spline construction on unstructured quadrilateral and hexahedral meshes with optimal convergence rates in isogeometric analysis

We present a novel blended B-spline method to construct bicubic/tricubic splines over unstructured quadrilateral and hexahedral meshes for isogeometric analysis. C1 and (truncated) C2 B-spline functions are used in regular elements, whereas C0 and (truncated) C1 B-spline functions are adopted in boundary elements and interior irregular elements around extraordinary edges/vertices. The truncation mechanism is employed for a seamless transition from irregular to regular elements. The resulting smoothness of the blended construction is C2-continuous everywhere except C0-continuous around extraordinary edges and C1-continuous across the interface between irregular and regular elements. The blended B-spline construction yields consistent parameterization during refinement and exhibits optimal convergence rates. Spline functions in the blended construction form a non-negative partition of unity, are linearly independent, and support Bézier extraction such that the construction can be used in existing finite element frameworks. Several examples provide numerical evidence of optimal convergence rates.

How Well Do Low- and High-Concentration Protein Interactions Predict Solution Viscosities of Monoclonal Antibodies?

Protein-protein interactions (PPI) and solution viscosities were measured at low and high protein concentrations under a range of formulation conditions for 4 different monoclonal antibodies. Static light scattering was used to quantify the osmotic second virial coefficient (B22) and the zero-q limit static structure factor (Sq=0), versus protein concentration (c2) from low to high c2. Dynamic light scattering was used to measure the collective diffusion coefficient as a function of c2 and to determine the protein interaction parameter (kD). Static light scattering and dynamic light scattering were combined to determine the hydrodynamic factor (Hq=0), which accounts for changes in hydrodynamic PPI as a function of c2. The net PPI ranged from strongly repulsive to attractive interactions, via changes in buffer pH, ionic strength, and choice of monoclonal antibodies. Multiple-particle tracking microrheology and capillary viscometery were used to measure monoclonal antibodies solution viscosities under the same solution conditions. In most cases, even large and qualitative changes in PPI did not result in significant changes in protein solution viscosity. This highlights the complex nature of PPI and how they influence protein solution viscosity and raises questions as to the validity of using experimental PPI metrics such as kD or B22 as predictors of high viscosity.