Stiff Person Spectrum Disorders—An Update and Outlook on Clinical, Pathophysiological and Treatment Perspectives

Stiff person spectrum disorders (SPSD) are paradigm autoimmune movement disorders characterized by stiffness, spasms and hyperekplexia. Though rare, SPSD represent a not-to-miss diagnosis because of the associated disease burden and treatment implications. After decades as an enigmatic orphan disease, major advances in our understanding of the evolving spectrum of diseases have been made along with the identification of multiple associated autoantibodies. However, the most important recent developments relate to the recognition of a wider affection, beyond the classic core motor symptoms, and to further insights into immunomodulatory and symptomatic therapies. In this review, we summarize the recent literature on the clinical and paraclinical spectrum, current pathophysiological understanding, as well as current and possibly future therapeutic strategies

Side Channels: Faculty Support Networks

This article examines a project at our institution that unfolded in unexpected ways. Faculty members had expressed interest in loose networks for collaboration and resource-sharing, so we implemented “Faculty Support Networks” (FSNs) to foster connection among faculty members interested in central teaching and learning topics:  course-based assessment, developing future faculty, experiential learning, inclusive teaching, and the scholarship of teaching and learning. We present a case study of these FSNs, from the program design to their influences on our communication with faculty. Although asynchronous engagement was sparse, the FSNs did help extend our reach and draw faculty to our services

A Low Temperature Functioning CoFeB/MgO Based Perpendicular Magnetic Tunnel Junction for Cryogenic Nonvolatile Random Access Memory

We investigated the low temperature performance of CoFeB/MgO based perpendicular magnetic tunnel junctions (pMTJs) by characterizing their quasi-static switching voltage, high speed pulse write error rate and endurance down to 9 K. pMTJ devices exhibited high magnetoresistance (>120%) and reliable (error rate<10-4) bi-directional switching with 2 to 200 ns voltage pulses. The endurance of the devices at 9 K surpassed that at 300 K by three orders of magnitude under the same write conditions, functioning for more than 10^12 cycles with 10 ns write pulses. The critical switching voltage at 9 K was observed to increase by 33% to 93%, depending on pulse duration, compared to that at 350 K. Ferromagnetic resonance and magnetization measurements on blanket pMTJ film stacks suggest that the increased switching voltage is associated with an increase in effective magnetic anisotropy and magnetization of free layer with decreasing temperature. Our work demonstrates that CoFeB/MgO based pMTJs have great potential to enable cryogenic MRAM and that their low temperature magnetization and effective magnetic anisotropy can be further optimized to lower operating power and improve endurance

Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition

Hedgehog signaling drives oncogenesis in several cancers and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened. However, resistance to Smoothened inhibitors occurs via genetic changes of Smoothened or other downstream Hedgehog components. Here, we overcome these resistance mechanisms by modulating GLI transcription via inhibition of BET bromodomain proteins. We show the BET bromodomain protein, BRD4, regulates GLI transcription downstream of SMO and SUFU and chromatin immunoprecipitation studies reveal BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites upon treatment with JQ1, a small molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid/rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists

Biochemical systems identification by a random drift particle swarm optimization approach

BACKGROUND: Finding an efficient method to solve the parameter estimation problem (inverse problem) for nonlinear biochemical dynamical systems could help promote the functional understanding at the system level for signalling pathways. The problem is stated as a data-driven nonlinear regression problem, which is converted into a nonlinear programming problem with many nonlinear differential and algebraic constraints. Due to the typical ill conditioning and multimodality nature of the problem, it is in general difficult for gradient-based local optimization methods to obtain satisfactory solutions. To surmount this limitation, many stochastic optimization methods have been employed to find the global solution of the problem. RESULTS: This paper presents an effective search strategy for a particle swarm optimization (PSO) algorithm that enhances the ability of the algorithm for estimating the parameters of complex dynamic biochemical pathways. The proposed algorithm is a new variant of random drift particle swarm optimization (RDPSO), which is used to solve the above mentioned inverse problem and compared with other well known stochastic optimization methods. Two case studies on estimating the parameters of two nonlinear biochemical dynamic models have been taken as benchmarks, under both the noise-free and noisy simulation data scenarios. CONCLUSIONS: The experimental results show that the novel variant of RDPSO algorithm is able to successfully solve the problem and obtain solutions of better quality than other global optimization methods used for finding the solution to the inverse problems in this study

Development and Validation of a Socioeconomic Kidney Transplant Derailers Index

Background: Socioeconomic barriers can prevent successful kidney transplant (KT) but are difficult to measure efficiently in clinical settings. We created and validated an individual-level, single score Kidney Transplant Derailers Index (KTDI) and assessed its association with waitlisting and living donor KT (LDKT) rates. Methods: The dataset included 733 patients presenting for KT evaluation in a transplant center in California. Exploratory factor analysis was used to identify socioeconomic barriers to KT (derailers) to include in the index. Potential KT derailers included health insurance, employment, financial insecurity, educational attainment, perception of neighborhood safety, access to a vehicle, having a washer/dryer, and quality of social support. Validity was tested with associations between KTDI scores and the following: (1) the Area Deprivation Index (ADI) and (2) time to KT waitlisting and LDKT. Results: Nine derailers were retained, omitting only social support level from the original set. The KTDI was scored by summing the number of derailers endorsed (mean: 3.0; range: 0–9). Black patients had higher estimated KTDI scores than other patient groups (versus White patients, 3.8 versus 2.1; P \u3c 0.001, effect size = 0.81). In addition, the KTDI was associated with the ADI (γ = 0.70, SE = 0.07; P \u3c 0.001). Finally, in comparison to the lower tertile, patients in the upper and middle KTDI tertiles had lower hazard of waitlisting (upper tertile hazard ratio [HR]: 0.34, 95% confidence interval [CI]: 0.25-0.45; middle tertile HR: 0.54, 95% CI: 0.40-0.72) and receiving an LDKT (upper tertile HR: 0.15, 95% CI: 0.08-0.30; middle tertile HR: 0.35, 95% CI: 0.20-0.62). These associations remained significant when adjusting for the ADI and other patient characteristics. Conclusions: The KTDI is a valid indicator of socioeconomic barriers to KT for individual patients that can be used to identify patients at risk for not receiving a KT

Childhood Adversity Is Associated With Increased KITLG Methylation in Healthy Individuals but Not in Bipolar Disorder Patients

Background: Childhood adversity increases the risk of a range of mental disorders including bipolar disorder, but the underlying mechanisms are still unknown. Previous studies identified DNA methylation levels at the cg27512205 locus on the KIT Ligand (KITLG) gene as a mediator between childhood adversity and stress responsivity. This raises the question whether this locus also plays a role in stress related disorders such as bipolar disorder. Therefore, the current study aims to compare the level of KITLG (cg27512205) methylation between bipolar patients and healthy individuals and its relation to childhood adversity.Methods:KITLG (cg27512205) methylation was measured in 50 bipolar disorder patients and 91 healthy control participants using the HumanMethylation450K BeadChip platform. Childhood adversity in each individual was assessed using the Childhood Trauma Questionnaire. Analyses of the association of KITLG methylation with bipolar disorder, the association of childhood adversity with bipolar disorder as well as the association of KITLG methylation with childhood adversity in bipolar patients and controls were conducted using linear regression with age, gender, childhood adversity, smoking, and cell-type composition estimates as covariates.Results:KITLG (cg27512205) methylation level was significantly lower in bipolar disorder patients (β = −0.351, t = −6.316 p &lt; 0.001). Childhood adversity levels were significantly higher in the bipolar disorder group (β = 4.903, t = 2.99, p = 0.003). In the bipolar disorder patients KITLG methylation was not associated with childhood adversity (β = 0.004, t = 1.039, p = 0.304) in contrast to the healthy controls (β = 0.012, t = 3.15, p = 0.002).Conclusions:KITLG methylation was lower in bipolar disorder despite high levels of childhood adversity, whereas childhood adversity was associated with higher KITLG methylation in healthy controls. In addition to lower methylation at this locus there is an indication that failure to adjust KITLG methylation to high levels of childhood adversity is a risk factor for bipolar disorder

The diploid genome sequence of an Asian individual

Here we present the first diploid genome sequence of an Asian individual. The genome was sequenced to 36-fold average coverage using massively parallel sequencing technology. We aligned the short reads onto the NCBI human reference genome to 99.97% coverage, and guided by the reference genome, we used uniquely mapped reads to assemble a high-quality consensus sequence for 92% of the Asian individual's genome. We identified approximately 3 million single-nucleotide polymorphisms (SNPs) inside this region, of which 13.6% were not in the dbSNP database. Genotyping analysis showed that SNP identification had high accuracy and consistency, indicating the high sequence quality of this assembly. We also carried out heterozygote phasing and haplotype prediction against HapMap CHB and JPT haplotypes (Chinese and Japanese, respectively), sequence comparison with the two available individual genomes (J. D. Watson and J. C. Venter), and structural variation identification. These variations were considered for their potential biological impact. Our sequence data and analyses demonstrate the potential usefulness of next-generation sequencing technologies for personal genomics

Modeling the deformation and failure behavior of FCC and HCP nanocrystalline materials

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2006.Includes bibliographical references (p. 175-188).As foreseen by Richard Feynman in his famous talk titled There's Plenty of Room at the Bottom in 1959, scientists nowadays are miniaturizing structures in materials to achieve better performance as concerned in technical applications. Reducing grain sizes in polycrystalline materials into the range of less than 100nm, for example, could achieve extraordinary high strength in these so called nanocrystalline (nc) materials. The reduced grain size gives rise to new deformation mechanisms in nc materials. It is now widely accepted that there is a strong interplay between dislocation-based deformation in the crystalline grain interiors and the inelastic deformation mechanisms operative in the grain-boundary regions. Grain-boundary regions play an increasingly significant role as the grain size decreases below the 100nm level. In this dissertation, constitutive models have been developed to investigate the deformation mechanisms of nc materials, with focus on modeling grain-boundary decohesion in nc materials. Two micromechanical models have been developed to capture the deformation in grain boundaries in nc materials.(cont.) To the end, a phenomenological constitutive model has been developed for powder-processed nc materials, where the plastic flow could be pressure-dependent, plastically-dilatant, and non-normal. To model the deformation in grain boundaries, we made the assumption that the mechanical behavior of a grain boundary is governed by the interaction of two coupled surfaces of neighboring grains. Mechanical response due to the relative sliding and separation between the two coupled surfaces is represented by traction-separation laws. An isothermal, rate-independent elastic-plastic interface model has been developed, which accounts for both reversible elastic, as well as irreversible inelastic separation-sliding deformations at the interface prior to failure. The interface model, which represents the deformation in grain boundaries, is coupled with an isothermal, rate-independent crystal-plasticity model for grain interiors, and to study the deformation and fracture response of nc nickel. Secondly, motivated by the fact that the ultimate size limit for nc materials would be bulk amorphous materials, we treated the non-equilibrium, more or less disordered grain boundaries in nc material as amorphous layers with finite thickness of [approx.] 1nm.(cont.) A viscoplastic amorphous constitutive model is applied to capture the deformation in grain-boundary regions. The model has been applied to predict the mechanical behavior of nc nickel with different grain sizes and subject to tensile deformation at different strain-rates. Many nanocrystalline materials are made by powder-consolidation; and their macroscopic response is reminiscent of cohesive granular materials. Based on the deformation behavior observed on powder consolidated nc materials from different groups, we have formulated a model for the response of pressure-sensitive and plastically-dilatant elastic-viscoplastic powder consolidated nc materials; where the plastic flow could be pressure-dependent, plastically dilatant, and non-normal.by Yujie Wei.Ph.D

Land Use and Land Cover Affect the Depth Distribution of Soil Carbon: Insights From a Large Database of Soil Profiles

Soils contain a large and dynamic fraction of global terrestrial carbon stocks. The distribution of soil carbon (SC) with depth varies among ecosystems and land uses and is an important factor in calculating SC stocks and their vulnerabilities. Systematic analysis of SC depth distributions across databases of SC profiles has been challenging due to the heterogeneity of soil profile measurements, which vary in depth sampling. Here, we fit over 40,000 SC depth profiles to an exponential decline relationship with depth to determine SC concentration at the top of the mineral soil, minimum SC concentration at depth, and the characteristic “length” of SC concentration decline with depth. Fitting these parameters allowed profile characteristics to be analyzed across a large and heterogeneous dataset. We then assessed the differences in these depth parameters across soil orders and land cover types and between soil profiles with or without a history of tillage, as represented by the presence of an Ap horizon. We found that historically tilled soils had more gradual decreases of SC with depth (greater e-folding depth or Z∗), deeper SC profiles, lower SC concentrations at the top of the mineral soil, and lower total SC stocks integrated to 30 cm. The large database of profiles allowed these results to be confirmed across different land cover types and spatial areas within the Continental United States, providing robust evidence for systematic impacts of historical tillage on SC stocks and depth distributions