Significant effort in optical-fibre research has been put in recent years into realizing mode-division multiplexing (MDM) in conjunction with wavelength-division multiplexing (WDM) to enable further ...scaling of the communication bandwidth per fibre. In contrast, almost all integrated photonics operate exclusively in the single-mode regime. MDM is rarely considered for integrated photonics because of the difficulty in coupling selectively to high-order modes, which usually results in high inter-modal crosstalk. Here we show the first microring-based demonstration of on-chip WDM-compatible mode-division multiplexing with low modal crosstalk and loss. Our approach can potentially increase the aggregate data rate by many times for on-chip ultrahigh bandwidth communications.
SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an ...important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein–ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.
Identification and structure-guided optimization of a series of 4-(pyrazol-4-yl)-pyrimidines as selective CDK4/6 inhibitors is reported herein. Several potency and selectivity determinants were ...established based on the X-ray crystallographic analysis of representative compounds bound to monomeric CDK6. Significant selectivity for CDK4/6 over CDK1 and CDK2 was demonstrated with several compounds in both enzymatic and cellular assays.
Background:
There has been limited research on upper limb dysfunction in people with multiple sclerosis (PwMS).
Objective:
The objective of this paper is to study unilateral and bilateral upper limb ...dysfunction at different International Classification of Functioning (ICF) levels according to overall disability in PwMS.
Methods:
A total of 105 PwMS (16 with EDSS<4 (mild); 17 with EDSS 4–5.5 (moderate); 37 with EDSS 6–6.5 (severe); 35 with EDSS>6.5 (severe non-ambulant)) were recruited from two rehabilitation centers and assessed in a cross-sectional study.
Results:
The whole sample showed a diminished sensory function (median (first/third interquartile)) score of 3 (2/3) on the Monofilament Test and a reduced strength 91 (76/100) points on the Motricity Index (Body-Function level). Sensory dysfunction did not increase with higher EDSS while strength decreased from 100 (86/100) in the mild subgroups to 91 (80/100) points in the severe subgroup. All showed diminished dexterity, scoring 0.28 peg/s (0.17/0.35) on the Nine-Hole Peg Test (NHPT) (activity level). Score was better for the mild (0.38 (0.35/0.46)) peg/s compared to the severe subgroup (0.28 (0.17/0.35)). Sixty-eight percent, 44% and 75% of PwMS showed bilateral disorders in sensation, strength and dexterity, respectively. The Community Integration Questionnaire (participation level) showed a 35% reduction in home activities, even among PwMS with EDSS<4.
Conclusion:
This study showed uni-/bilateral upper limb abnormalities at all ICF levels increasing with the overall disability.
The actin regulatory protein, cofilin, increases the bending and twisting elasticity of actin filaments and severs them. It has been proposed that filaments partially decorated with cofilin ...accumulate stress from thermally driven shape fluctuations at bare (stiff) and decorated (compliant) boundaries, thereby promoting severing. This mechanics-based severing model predicts that changes in actin filament compliance due to cofilin binding affect severing activity. Here, we test this prediction by evaluating how the severing activities of vertebrate and yeast cofilactin scale with the flexural rigidities determined from analysis of shape fluctuations. Yeast actin filaments are more compliant in bending than vertebrate actin filaments. Severing activities of cofilactin isoforms correlate with changes in filament flexibility. Vertebrate cofilin binds but does not increase the yeast actin filament flexibility, and does not sever them. Imaging of filament thermal fluctuations reveals that severing events are associated with local bending and fragmentation when deformations attain a critical angle. The critical severing angle at boundaries between bare and cofilin-decorated segments is smaller than in bare or fully decorated filaments. These measurements support a cofilin-severing mechanism in which mechanical asymmetry promotes local stress accumulation and fragmentation at boundaries of bare and cofilin-decorated segments, analogous to failure of some nonprotein materials.
To explore the factor structure of the Kessler Foundation Neglect Assessment Process (KF-NAP), and evaluate the prevalence and clinical significance of spatial neglect among stroke survivors.
...Inception cohort.
Inpatient rehabilitation facility (IRF).
Participants (N=121) with unilateral brain damage from their first stroke were assessed within 72 hours of admission to an IRF, and 108 were assessed again within 72 hours before IRF discharge.
Usual and standard IRF care.
During each assessment session, occupational therapists measured patients' functions with the KF-NAP, FIM, and Barthel Index (BI).
The KF-NAP showed excellent internal consistency with a single-factor structure. The exploratory factor analysis revealed the KF-NAP to be unique from both the FIM and BI even though all 3 scales were correlated. Symptoms of spatial neglect (KF-NAP>0) were present in 67.8% of the participants at admission and 47.2% at discharge. Participants showing the disorder at IRF admission were hospitalized longer than those showing no symptoms. Among those presenting with symptoms, the regression analysis showed that the KF-NAP scores at admission negatively predicted FIM scores at discharge, after controlling for age, FIM at admission, and length of stay.
The KF-NAP uniquely quantifies symptoms of spatial neglect by measuring functional difficulties that are not captured by the FIM or BI. Using the KF-NAP to measure spatial neglect, we found the disorder persistent after inpatient rehabilitation, and replicated previous findings showing that spatial neglect adversely affects rehabilitation outcome even after prolonged IRF care.
This paper proposes a method to directly compute controller parameter values in a synchronverter augmented with a so-called damping correction loop, and in so doing, achieve desired transient and ...steady-state response. The proposed approach is grounded in a reduced third-order system model that captures pertinent dynamic characteristics of the synchronverter active-power loop (APL), particularly those of the dominant mode. This reduced-order model helps to identify and explain a shortcoming in a previous parameter tuning method. Central to the proposed parameter computation method is to express APL parameters of the original system as closed-form functions of the poles of the reduced-order system. Since the reduced-order model retains dominant-mode dynamic behaviors of the original system, APL parameters can be directly computed according to specified APL dominant mode. Time-domain simulations are provided to validate the accuracy of the reduced-order model and the proposed direct-computation parameter tuning method.
ABSTRACT We present the first images of four debris disks observed in scattered light around the young (4-250 Myr old) M dwarfs TWA 7 and TWA 25, the K6 star HD 35650, and the G2 star HD 377. We ...obtained these images by reprocessing archival Hubble Space Telescope NICMOS coronagraph data with modern post-processing techniques as part of the Archival Legacy Investigation of Circumstellar Environments program. All four disks appear faint and compact compared with other debris disks resolved in scattered light. The disks around TWA 25, HD 35650, and HD 377 appear very inclined, while TWA 7's disk is viewed nearly face-on. The surface brightness of HD 35650's disk is strongly asymmetric. These new detections raise the number of disks resolved in scattered light around M and late-K stars from one (the AU Mic system) to four. This new sample of resolved disks enables comparative studies of heretofore scarce debris disks around low-mass stars relative to solar-type stars.
During the Spitzer Space Telescope cryogenic mission, Guaranteed Time Observers, Legacy Teams, and General Observers obtained Infrared Spectrograph (IRS) observations of hundreds of debris disk ...candidates. We calibrated the spectra of 571 candidates, including 64 new IRAS and Multiband Imaging Photometer for Spitzer (MIPS) debris disks candidates, modeled their stellar photospheres, and produced a catalog of excess spectra for unresolved debris disks. For 499 targets with IRS excess but without strong spectral features (and a subset of 420 targets with additional MIPS 70 mu m observations), we modeled the IRS (and MIPS data) assuming that the dust thermal emission was well-described using either a one- or two-temperature blackbody model. We calculated the probability for each model and computed the average probability to select among models. We found that the spectral energy distributions for the majority of objects (~66%) were better described using a two-temperature model with warm (T sub(gr) ~ 100-500 K) and cold (T sub(gr) ~ 50-150 K) dust populations analogous to zodiacal and Kuiper Belt dust, suggesting that planetary systems are common in debris disks and zodiacal dust is common around host stars with ages up to ~ 1 Gyr. We found that younger stars generally have disks with larger fractional infrared luminosities and higher grain temperatures and that higher-mass stars have disks with higher grain temperatures. We show that the increasing distance of dust around debris disks is inconsistent with self-stirred disk models, expected if these systems possess planets at 30-150 AU. Finally, we illustrate how observations of debris disks may be used to constrain the radial dependence of material in the minimum mass solar nebula.
The human immune system displays substantial variation between individuals, leading to differences in susceptibility to autoimmune disease. We present single-cell RNA sequencing (scRNA-seq) data from ...1,267,758 peripheral blood mononuclear cells from 982 healthy human subjects. For 14 cell types, we identified 26,597 independent cis-expression quantitative trait loci (eQTLs) and 990 trans-eQTLs, with most showing cell type-specific effects on gene expression. We subsequently show how eQTLs have dynamic allelic effects in B cells that are transitioning from naïve to memory states and demonstrate how commonly segregating alleles lead to interindividual variation in immune function. Finally, using a Mendelian randomization approach, we identify the causal route by which 305 risk loci contribute to autoimmune disease at the cellular level. This work brings together genetic epidemiology with scRNA-seq to uncover drivers of interindividual variation in the immune system.
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