Rapid depletion of "catch-and-release" anti-ASGR1 antibody in vivo.

Targeting antigens with antibodies exhibiting pH/Ca2+-dependent binding against an antigen is an attractive strategy to mitigate target-mediated disposition and antigen buffering. Studies have reported improved serum exposure of antibodies exhibiting pH/Ca2+-binding against membrane-bound receptors. Asialoglycoprotein receptor 1 (ASGR1) is a membrane-bound receptor primarily localized in hepatocytes. With a high expression level of approximately one million receptors per cell, high turnover, and rapid recycling, targeting this receptor with a conventional antibody is a challenge. In this study, we identified an antibody exhibiting pH/Ca2+-dependent binding to ASGR1 and generated antibody variants with increased binding to neonatal crystallizable fragment receptor (FcRn). Serum exposures of the generated anti-ASGR1 antibodies were analyzed in transgenic mice expressing human FcRn. Contrary to published reports of increased serum exposure of pH/Ca2+-dependent antibodies, the pH/Ca2+-dependent anti-ASGR1 antibody had rapid serum clearance in comparison to a conventional anti-ASGR1 antibody. We conducted sub-cellular trafficking studies of the anti-ASGR1 antibodies along with receptor quantification analysis for mechanistic understanding of the rapid serum clearance of pH/Ca2+-dependent anti-ASGR1 antibody. The findings from our study provide valuable insights in identifying the antigens, especially membrane bound, that may benefit from targeting with pH/Ca2+-dependent antibodies to obtain increased serum exposure.

Knockout of lws1 in zebrafish (Danio rerio) reveals its role in regulating feeding and vision-guided behavior.

Long-wave sensitive (LWS) is a G protein-coupled receptor expressed in the retina, and zebrafish is a better model organism for studying vision, but the role of LWS1 in vision-guided behavior of larvae fish has rarely been reported. In this study, we found that zebrafish lws1 and lws2 are tandemly replicated genes, both with six exons, with lws1 being more evolutionarily conserved. The presence of Y277F in the amino acid sequence of lws2 may have contributed to the shift of λmax to green light. We established a lws1 knockout zebrafish model using CRISPR/Cas9 technology. Lws1-/- larvae showed significantly higher levels of feeding and appetite gene (agrp) expression than WT, and significantly lower levels of anorexia gene (pomc, cart) expression. In addition, green light gene compensation was observed in lws1-/- larvae with significantly increased expression levels of rh2-1. The light-dark movement test showed that lws1-/- larvae were more active under light-dark transitions or vibrational stimuli, and the expression of phototransduction-related genes was significantly up-regulated. This study reveals the important role of lws1 gene in the regulation of vision-guided behavior in larvae.

Regulatory effect of NK homeobox 1 (NKX2.1) on melanocortin 4 receptor (Mc4r) promoter in Mandarin fish.

The melanocortin 4 receptor (MC4R) is a G protein-coupled transporter that mediates the regulation of thyroid hormones and leptin on energy balance and food intake. However, the mechanisms of transcriptional regulation of Mc4r by thyroid hormone and leptin in fish have been rarely reported. The messenger RNA expression of Mc4r gene was significantly higher in brain than those in other tissues of mandarin fish. We analyzed the structure and function of a 2029 bp sequence of Mc4r promoter. Meanwhile, overexpression of NKX2.1 and incubation with leptin significantly increased Mc4r promoter activity, but triiodothyronine showed the opposite effect. In addition, mutations in the NKX2.1 binding site abolished not only the activation of Mc4r promoter activity by leptin but also the inhibitory effect of thyroid hormones on Mc4r promoter activity. In summary, these results suggested that thyroid hormones and leptin might regulate the transcriptional expression of Mc4r through NKX2.1.

Hyperbolic optics and superlensing in room-temperature KTN from self-induced k-space topological transitions.

A hyperbolic medium will transfer super-resolved optical waveforms with no distortion, support negative refraction, superlensing, and harbor nontrivial topological photonic phases. Evidence of hyperbolic effects is found in periodic and resonant systems for weakly diffracting beams, in metasurfaces, and even naturally in layered systems. At present, an actual hyperbolic propagation requires the use of metamaterials, a solution that is accompanied by constraints on wavelength, geometry, and considerable losses. We show how nonlinearity can transform a bulk KTN perovskite into a broadband 3D hyperbolic substance for visible light, manifesting negative refraction and superlensing at room-temperature. The phenomenon is a consequence of giant electro-optic response to the electric field generated by the thermal diffusion of photogenerated charges. Results open new scenarios in the exploration of enhanced light-matter interaction and in the design of broadband photonic devices.

Evidence of Chaotic Dynamics in Three-Soliton Collisions.

We observe chaotic optical wave dynamics characterized by erratic energy transfer and soliton annihilation and creation in the aftermath of a three-soliton collision in a photorefractive crystal. Irregular dynamics are found to be mediated by the nonlinear Raman effect, a coherent interaction that leads to nonreciprocal soliton energy exchange. Results extend the analogy between solitons and particles to the emergence of chaos in three-body physics and provide new insight into the origin of the irregular dynamics that accompany extreme and rogue waves.

Direct Observation of Fractal-Dimensional Percolation in the 3D Cluster Dynamics of a Ferroelectric Supercrystal.

We perform percolation analysis of crossed-polarizer transmission images in a biased nanodisordered bulk KTN:Li perovskite. Two distinct percolative transitions are identified at two electric field thresholds. The low-field transition involves a directional fractal chain of dimension D=1.65, while the high-field transition has a dimension D>2. Direct cluster imaging in the volume is achieved using high-resolution orthographic 3D projections based on giant refraction. Percolation is attributed to a full-3D domain reorientation that mediates the transition from a ferroelectric supercrystal state to a disordered domain mosaic.

Research progress of pharmacogenomics of new oral anticoagulant / 中国临床药理学与治疗学

The new oral anticoagulants (NOAC) dabigatran, rivaroxaban, apixaban, and edoxaban are widely used in clinical anticoagulation because of their fixed doses and superior safety. Studies have pointed out that there are large inter-individual differences in the pharmacokinetic parameters and response of NOAC, which may be related to the genetic polymorphisms of transporters and metabolic enzymes involved in in-vivo processes. This article reviews the influence of gene polymorphism on the pharmacokinetics and adverse reactions of NOAC, and provides directions for future research.

Soliton Maxwell demons and long-tailed statistics in fluctuating optical fields.

We demonstrate experimentally in biased photorefractive crystals that collisions between random-amplitude optical spatial solitons produce long-tailed statistics from input Gaussian fluctuations. The effect is mediated by Raman nonlocal corrections to Kerr self-focusing that turn soliton-soliton interaction into a Maxwell demon for the output wave amplitude.

The prognosis value of comprehensive geriatric assessment in elder patients with acute myeloid leukemia in a single center / 中华血液学杂志

Objective@#To evaluate the prognostic significance of comprehensive geriatric assessment (CGA) in Chinese elderly acute myeloid leukemia (AML) patients.@*Methods@#73 AML patients over the age of 60 were enrolled. CGA stratification included the following 3 instrument assessment: activity of daily living (ADL) ; instrumental activity of daily living (IADL) ; comorbidity score according to the Modified cumulative illness rating score for geriatrics (MCIRS-G) . According to CGA and age, the enrolled patients were grouped into 'fit’, 'unfit’ and 'frail’ categories.@*Results@#The median age of 73 elderly AML patients were 75 years old. According to CGA, 37 (50.1%) patients were classified as 'fit’, 14 (19.2%) as 'unfit’, and 22 (30.7%) as 'frail’. 33 (89.2%) patients in fit group received induction chemotherapy, or demethylation treatment, as 8 (57.9%) in unfit, 10 (45.5%) in frail. The overall response rate was 68.7%、62.5%, 75.0% in fit, unfit, and frail group, respectively (χ2=0.615, P=0.769) .The early mortality (8 weeks) in three groups were different: 5.4%, 7.1%, 27.3%, respectively (P<0.05) . The 1-year overall survival in the 'fit’, 'unfit’ and 'frail’ groups was 64.9%, 28.6% and 22.7%, respectively (P<0.05) . The CGA score, age, ECOG score, WHO classification (2016) were the prognostic factors of AML patients.@*Conclusion@#CGA can be used to determine the prognosis of elderly AML patients.

The prognosis value of comprehensive geriatric assessment in elder patients with acute myeloid leukemia in a single center / 中华血液学杂志

Objective: To evaluate the prognostic significance of comprehensive geriatric assessment (CGA) in Chinese elderly acute myeloid leukemia (AML) patients. Methods: 73 AML patients over the age of 60 were enrolled. CGA stratification included the following 3 instrument assessment: activity of daily living (ADL) ; instrumental activity of daily living (IADL) ; comorbidity score according to the Modified cumulative illness rating score for geriatrics (MCIRS-G) . According to CGA and age, the enrolled patients were grouped into 'fit', 'unfit' and 'frail' categories. Results: The median age of 73 elderly AML patients were 75 years old. According to CGA, 37 (50.1%) patients were classified as 'fit', 14 (19.2%) as 'unfit', and 22 (30.7%) as 'frail'. 33 (89.2%) patients in fit group received induction chemotherapy, or demethylation treatment, as 8 (57.9%) in unfit, 10 (45.5%) in frail. The overall response rate was 68.7%、62.5%, 75.0% in fit, unfit, and frail group, respectively (χ(2)=0.615, P=0.769) .The early mortality (8 weeks) in three groups were different: 5.4%, 7.1%, 27.3%, respectively (P<0.05) . The 1-year overall survival in the 'fit', 'unfit' and 'frail' groups was 64.9%, 28.6% and 22.7%, respectively (P<0.05) . The CGA score, age, ECOG score, WHO classification (2016) were the prognostic factors of AML patients. Conclusion: CGA can be used to determine the prognosis of elderly AML patients.

A prospective study of comprehensive geriatric assessment in elderly patients with acute myeloid leukemia / 中华老年医学杂志

Objective To evaluate the performance on comprehensive geriatric assessment (CGA) in elderly patients with acute myeloid leukemia (AML)and to investigate the differences between Eastern Cooperative Oncology Group (ECOG) performance status (PS) and CGA scoring.Methods Patients aged 60 years or over diagnosed with AML at Beijing Hospital from September 2008 to April 2018 were enrolled in this study.CGA was performed during staging procedures through application of age,activities of daily living(ADL)/instrumental activities of daily living(IADL)and the comorbidity score based on the cumulative illness rating scale for geriatrics(CIRS-G).According to CGA scores,patients were classified into a not-applicable group,an applicable group and a frail group.The difference between ECOG-PS and CGA scoring was compared.Results A total of 73 patients were enrolled in this study.There were 37 (50.7 ％),14 (19.2 ％) and 22 (30.1％) patients in the applicable,not-applicable and frail groups,respectively.Comorbidities were observed in the majority of patients,with cardiovascular disease,diabetes mellitus and hypertension among the most common disorders.In patients aged 60 to 64 years,16.7％ (1/6) were considered as frail,and the percentage of frail patients increased to 36.4％ (8/22)in patients aged 80 years and over.Moreover,functional impairment evaluated by CGA was observed in 36.5 ％ (19/52)of patients with ECOG-PS ≤ 1.Conclusions According to CGA scoring,approximately half of AML patients aged 60 years or over have functional impairment.Functional impairment is observed in some patients with ECOG-PS ≤1,indicating that ECOG-PS may underestimate functional impairment in elderly AML patients.

A comparative study of comprehensive geriatric assessment in elder patients with non-Hodgkin's lymphoma / 中华内科杂志

Objective To measure the comprehensive geriatric assessment (CGA) in elder non-Hodgkin's Lymphoma (NHL) patients in a cross-sectional study;to compare the differences between Eastern Cooperative Oncology Group (ECOG)-performance status (PS) and CGA.Methods CGA stratification included the following 3 instrument assessments:activity of daily living (ADL);instrumental activity of daily living (IADL);comorbidity score according to the modified cumulative illness rating score for geriatrics (MCIRS-G).According to CGA and age,NHL patients,aged ≥60 years,were classified as "fit","unfit" and "frail" groups.ECOG-PS was evaluated and compared with CGA.Results According to CGA,51.6％ senior NHL patients (33 cases) were classified as "fit",12.5％(8 cases) as " unfit" and 35.9％ (23 cases) as "frail".Several comorbidities were observed in majority patients,such as cardiovascular disease,diabetes nellitus and hypertension.In the "younger aged" patients between 60 to 64ys,25％(3/12) was considered as "frail".However,this proportion increased to 42.9％ (6/14) in patients older than 80ys.Moreover,impaired CGA was observed in 38.9％(21/54) of ECOG-PS ≤1 patient.Conclusions Impaired CGA is as common as approximately half in elderly NHL patients and more than one third even in ECOG-PS ≤ 1 patients.ECOG-PS may underestimate the impaired fitness function in elder NHL patients.

Observation of replica symmetry breaking in disordered nonlinear wave propagation.

A landmark of statistical mechanics, spin-glass theory describes critical phenomena in disordered systems that range from condensed matter to biophysics and social dynamics. The most fascinating concept is the breaking of replica symmetry: identical copies of the randomly interacting system that manifest completely different dynamics. Replica symmetry breaking has been predicted in nonlinear wave propagation, including Bose-Einstein condensates and optics, but it has never been observed. Here, we report the experimental evidence of replica symmetry breaking in optical wave propagation, a phenomenon that emerges from the interplay of disorder and nonlinearity. When mode interaction dominates light dynamics in a disordered optical waveguide, different experimental realizations are found to have an anomalous overlap intensity distribution that signals a transition to an optical glassy phase. The findings demonstrate that nonlinear propagation can manifest features typical of spin-glasses and provide a novel platform for testing so-far unexplored fundamental physical theories for complex systems.

Observation of polarization-maintaining light propagation in depoled compositionally disordered ferroelectrics.

We investigate the evolution of the state of polarization of light propagating through bulk depoled composite ferroelectrics below the Curie temperature. In contrast to standard depoled ferroelectrics, where random birefringence causes depolarization and scattering, light is observed to suffer varying degrees of depolarization and remains fully polarized when linearly polarized along the crystal principal axes. The effect is found to be supported by the formation of polarized speckles organized into a spatial lattice and occurs as the ferroelectric settles into a spontaneous super-crystal, a three-dimensional coherent mosaic of ferroelectric clusters. The polarization lattices gradually disappear as the ferroelectric state reduces to a disordered distribution of polar nanoregions above the critical point.

Turbulent Transitions in Optical Wave Propagation.

We report the direct observation of the onset of turbulence in propagating one-dimensional optical waves. The transition occurs as the disordered hosting material passes from being linear to one with extreme nonlinearity. As the response grows, increased wave interaction causes a modulational unstable quasihomogeneous flow to be superseded by a chaotic and spatially incoherent one. Statistical analysis of high-resolution wave behavior in the turbulent regime unveils the emergence of concomitant rogue waves. The transition, observed in a photorefractive ferroelectric crystal, introduces a new and rich experimental setting for the study of optical wave turbulence and information transport in conditions dominated by large fluctuations and extreme nonlinearity.

PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor's role.

Lipoprotein (a) [Lp(a)] is independently associated with CVD risk. Evolocumab, a monoclonal antibody (mAb) to proprotein convertase subtilisin/kexin type 9 (PCSK9), decreases Lp(a). The potential mechanisms were assessed. A pooled analysis of Lp(a) and LDL cholesterol (LDL-C) in 3,278 patients from 10 clinical trials (eight phase 2/3; two extensions) was conducted. Within each parent study, biweekly and monthly doses of evolocumab statistically significantly reduced Lp(a) at week 12 versus control (P < 0.001 within each study); pooled median (quartile 1, quartile 3) percent reductions were 24.7% (40.0, 3.6) and 21.7% (39.9, 4.2), respectively. Reductions were maintained through week 52 of the open-label extension, and correlated with LDL-C reductions [with and without correction for Lp(a)-cholesterol] at both time points (P < 0.0001). The effect of LDL and LDL receptor (LDLR) availability on Lp(a) cell-association was measured in HepG2 cells: cell-associated LDL fluorescence was reversed by unlabeled LDL and Lp(a). Lp(a) cell-association was reduced by coincubation with LDL and PCSK9 and reversed by adding PCSK9 mAb. These studies support that reductions in Lp(a) with PCSK9 inhibition are partly due to increased LDLR-mediated uptake. In most situations, Lp(a) appears to compete poorly with LDL for LDLR binding and internalization, but when LDLR expression is increased with evolocumab, particularly in the setting of low circulating LDL, Lp(a) is reduced.

Intrinsic Negative Mass from Nonlinearity.

We propose and provide experimental evidence of a mechanism able to support negative intrinsic effective mass. The idea is to use a shape-sensitive nonlinearity to change the sign of the mass in the leading linear propagation equation. Intrinsic negative-mass dynamics is reported for light beams in a ferroelectric crystal substrate, where the diffusive photorefractive nonlinearity leads to a negative-mass Schrödinger equation. The signature of inverted dynamics is the observation of beams repelled from strongly guiding integrated waveguides irrespective of wavelength and intensity and suggests shape-sensitive nonlinearity as a basic mechanism leading to intrinsic negative mass.

Super-crystals in composite ferroelectrics.

As atoms and molecules condense to form solids, a crystalline state can emerge with its highly ordered geometry and subnanometric lattice constant. In some physical systems, such as ferroelectric perovskites, a perfect crystalline structure forms even when the condensing substances are non-stoichiometric. The resulting solids have compositional disorder and complex macroscopic properties, such as giant susceptibilities and non-ergodicity. Here, we observe the spontaneous formation of a cubic structure in composite ferroelectric potassium-lithium-tantalate-niobate with micrometric lattice constant, 10(4) times larger than that of the underlying perovskite lattice. The 3D effect is observed in specifically designed samples in which the substitutional mixture varies periodically along one specific crystal axis. Laser propagation indicates a coherent polarization super-crystal that produces an optical X-ray diffractometry, an ordered mesoscopic state of matter with important implications for critical phenomena and applications in miniaturized 3D optical technologies.

Construction of fusion expression vector pET22b-SUMO-FGFR4 and optimization of expression conditions in E.coli / 吉林大学学报(医学版)

Objective:To design the small ubiquitin modification-fibroblast growth factor receptor 4 (SUMO-FGFR4) fusion gene and construct the expression vector pET22b-SUMO-FGFR4, to optimize the expression conditions. Methods:The SUMO-FGFR4 fusion gene was obtained by Overlap PCR and was connected to pET22b;the recombinant expression vector pET22b-SUMO-FGFR4 was obtained. The influence of lactose concentration, induction time,induction temperature,induction point and adding mode of lactose in the expression levels was observed,and the best induction condition was determined; then the solubility of recombinant protein was analyzed.Results:The SUMO-FGFR4 fusion protein was highly expressed,the molecular weight of the fusion protein was about 40 000 and it could bind with FGFR4 specific antibody.When the lactose concentration was 1.0 g·L-1 ,the induction time was 3 h,the induction temperature was 37℃,the value of A (600)was 0.8,the expression level was highest;but adding mode of lactose had no remarkable effect on the protein expression.The expression level of recombinant protein induced by lactose was higher than IPTG.SUMO-FGFR4 protein existed in a form of inclusion body.Conclusion:The SUMO-FGFR4 fusion protein is expressed successfully in this study while lactose is used as inducer and the best expression conditions are confirmed.

Spatial Rogue Waves in Photorefractive Ferroelectrics.

Rogue waves are observed as light propagates in the extreme nonlinear regime that occurs when a photorefractive ferroelectric crystal is undergoing a structural phase transition. The transmitted spatial light distribution contains bright localized spots of anomalously large intensity that follow a signature long-tail statistics that disappears as the nonlinearity is weakened. The isolated wave events form as out-of-equilibrium response and disorder enhance the Kerr-saturated nonlinearity at the critical point. Self-similarity associable to the individual observed filaments and numerical simulations of the generalized nonlinear Schrödinger equation suggests that dynamics of soliton fusions and scale invariance can microscopically play an important role in the observed rogue intensities and statistics.