ResearchPad - 23 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SIK3 suppresses neuronal hyperexcitability by regulating the glial capacity to buffer K<sup>+</sup> and water]]> https://www.researchpad.co/article/elastic_article_15319 Glial regulation of extracellular potassium (K+) helps to maintain appropriate levels of neuronal excitability. While channels and transporters mediating K+ and water transport are known, little is understood about upstream regulatory mechanisms controlling the glial capacity to buffer K+ and osmotically obliged water. Here we identify salt-inducible kinase 3 (SIK3) as the central node in a signal transduction pathway controlling glial K+ and water homeostasis in Drosophila. Loss of SIK3 leads to dramatic extracellular fluid accumulation in nerves, neuronal hyperexcitability, and seizures. SIK3-dependent phenotypes are exacerbated by K+ stress. SIK3 promotes the cytosolic localization of HDAC4, thereby relieving inhibition of Mef2-dependent transcription of K+ and water transport molecules. This transcriptional program controls the glial capacity to regulate K+ and water homeostasis and modulate neuronal excitability. We identify HDAC4 as a candidate therapeutic target in this pathway, whose inhibition can enhance the K+ buffering capacity of glia, which may be useful in diseases of dysregulated K+ homeostasis and hyperexcitability.

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<![CDATA[Glial SIK3: A central player in ion and volume homeostasis in <i>Drosophila</i> peripheral nerves]]> https://www.researchpad.co/article/elastic_article_15313 The electrical properties of neuronal cells rely on gradients of ions across their membranes and the extracellular fluid (ECF) in which they are bathed. Little is known regarding how the ECF volume and content is maintained. In this issue, Li et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201907138) identify the kinase SIK3 in glia as a key signal transduction regulator in ion and volume homeostasis in Drosophila peripheral nerves.

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<![CDATA[Stress granules regulate stress-induced paraspeckle assembly]]> https://www.researchpad.co/article/elastic_article_15308 Eukaryotic cells contain a variety of RNA-protein macrocomplexes termed RNP granules. Different types of granules share multiple protein components; however, the crosstalk between spatially separated granules remains unaddressed. Paraspeckles and stress granules (SGs) are prototypical RNP granules localized exclusively in the nucleus and cytoplasm, respectively. Both granules are implicated in human diseases, such as amyotrophic lateral sclerosis. We characterized the composition of affinity-purified paraspeckle-like structures and found a significant overlap between the proteomes of paraspeckles and SGs. We further show that paraspeckle hyperassembly is typical for cells subjected to SG-inducing stresses. Using chemical and genetic disruption of SGs, we demonstrate that formation of microscopically visible SGs is required to trigger and maintain stress-induced paraspeckle assembly. Mechanistically, SGs may sequester negative regulators of paraspeckle formation, such as UBAP2L, alleviating their inhibitory effect on paraspeckles. Our study reveals a novel function for SGs as positive regulators of nuclear RNP granule assembly and suggests a role for disturbed SG-paraspeckle crosstalk in human disease.

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<![CDATA[Structure–behaviour correlations between two genetically closely related snail species]]> https://www.researchpad.co/article/N34ae456a-4468-4991-abda-6f0c6f32bda7

Species, through their structure and composition, have evolved to respond to environmental constraints. Predator–prey interactions are among environmental pressures that can lead to speciation, but it remains unclear how this pressure can be related to the material structure and performance. Recently, two land snails, Karaftohelix editha and Karaftohelix gainesi, were found to exhibit divergent phenotypes and responses to predation despite sharing the same habitat and most of their genome. Indeed, under attack from a beetle, K. editha snails retract into their shell whereas K. gainesi snails swing their shell. In this paper, we looked at the microstructure, composition, morphology and mechanics of the shells of those two species and discuss potential relationships between material structure and the snail defence behaviour. The results of this study provide additional arguments for the role of predator–prey interactions on speciation, as well as an unusual approach for the design of biomimetic structures adapted to a particular function.

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<![CDATA[Wednesday posters]]> https://www.researchpad.co/article/N19c7ed87-c80c-46f1-bedc-4ddeabe0c3eb ]]> <![CDATA[Thursday posters]]> https://www.researchpad.co/article/N50c37668-91e9-43b8-aadf-3c08854ae4fc ]]> <![CDATA[Exploring the visual world of fossilized and modern fungus gnat eyes (Diptera: Keroplatidae) with X-ray microtomography]]> https://www.researchpad.co/article/N174fb572-c9b0-44b0-8e7a-973b8d8c76c9

Animal eyes typically possess specialized regions for guiding different behavioural tasks within their specific visual habitat. These specializations, and evolutionary changes to them, can be crucial for understanding an animal's ecology. Here, we explore how the visual systems of some of the smallest flying insects, fungus gnats, have adapted to different types of forest habitat over time (approx. 30 Myr to today). Unravelling how behavioural, environmental and phylogenetic factors influence the evolution of visual specializations is difficult, however, because standard quantitative techniques often require fresh tissue and/or provide data in eye-centric coordinates that prevent reliable comparisons between species with different eye morphologies. Here, we quantify the visual world of three gnats from different time periods and habitats using X-ray microtomography to create high-resolution three-dimensional models of the compound eyes of specimens in different preservation states—fossilized in amber, dried or stored in ethanol. We present a method for analysing the geometric details of individual corneal facets and for estimating and comparing the sensitivity, spatial resolution and field of view of species across geographical space and evolutionary time. Our results indicate that, despite their miniature size, fungus gnats do have variations in visual properties across their eyes. We also find some indication that these visual specializations vary across species and may represent adaptations to their different forest habitats. Overall, the findings demonstrate how such investigations can be used to study the evolution of visual specializations—and sensory ecology in general—across a range of insect taxa from different geographical locations and across time.

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<![CDATA[Challenges and Opportunities to Updating Prescribing Information for Longstanding Oncology Drugs]]> https://www.researchpad.co/article/Nd33e5ed6-68bf-4ee4-85e7-ef8662ba5a4b

Abstract

A number of important drugs used to treat cancer—many of which serve as the backbone of modern chemotherapy regimens—have outdated prescribing information in their drug labeling. The Food and Drug Administration is undertaking a pilot project to develop a process and criteria for updating prescribing information for longstanding oncology drugs, based on the breadth of knowledge the cancer community has accumulated with the use of these drugs over time. This article highlights a number of considerations for labeling updates, including selecting priorities for updating; data sources and evidentiary criteria; as well as the risks, challenges, and opportunities for iterative review to ensure prescribing information for oncology drugs remains relevant to current clinical practice.

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<![CDATA[Clinical risk factors in SUDEP]]> https://www.researchpad.co/article/N7c3dc4d0-baa8-4b16-8e38-7123ee1e00e3

Objective

We conducted a nationwide case-control study in Sweden to test the hypothesis that specific clinical characteristics are associated with increased risk of sudden unexpected death in epilepsy (SUDEP).

Methods

The study included 255 SUDEP cases (definite and probable) and 1,148 matched controls. Clinical information was obtained from medical records and the National Patient Register. The association between SUDEP and potential risk factors was assessed by odds ratios (ORs) and 95% confidence intervals (CIs) and interaction assessed by attributable proportion due to interaction (AP).

Results

Experiencing generalized tonic-clonic seizures (GTCS) during the preceding year was associated with a 27-fold increased risk (OR 26.81, 95% CI 14.86–48.38), whereas no excess risk was seen in those with exclusively non-GTCS seizures (OR 1.15, 95% CI 0.54–48.38). The presence of nocturnal GTCS during the last year of observation was associated with a 15-fold risk (OR 15.31, 95% CI 9.57–24.47). Living alone was associated with a 5-fold increased risk of SUDEP (OR 5.01, 95% CI 2.93–8.57) and interaction analysis showed that the combination of not sharing a bedroom and having GTCS conferred an OR of 67.10 (95% CI 29.66–151.88), with AP estimated at 0.69 (CI 0.53–0.85). Among comorbid diseases, a previous diagnosis of substance abuse or alcohol dependence was associated with excess risk of SUDEP.

Conclusions

Individuals with GTCS who sleep alone have a dramatically increased SUDEP risk. Our results indicate that 69% of SUDEP cases in patients who have GTCS and live alone could be prevented if the patients were not unattended at night or were free from GTCS.

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<![CDATA[Psychometric properties of the Friedreich Ataxia Rating Scale]]> https://www.researchpad.co/article/Nd7fbac11-63bd-4c2f-a9a2-3b4c14e6afbb

Objective

To investigate the psychometric properties of the Friedreich Ataxia Rating Scale neurologic examination (FARSn) and its subscores, as well as the influence of the modifications resulting in the now widely used modified FARS (mFARS) examination.

Methods

Based on cross-sectional FARS data from the FA–Clinical Outcome Measures cohort, we conducted correlation-based psychometric analyses to investigate the interplay of items and subscores within the FARSn/mFARS constructs.

Results

The results provide support for both the FARSn and the mFARS constructs, as well as individually for their upper limb and lower limb coordination components. The omission of the peripheral nervous system subscore (D) and 2 items of the bulbar subscore (A) in the mFARS strengthens the overall construct compared with the complete FARS.

Conclusions

A correlation-based psychometric analysis of the neurologic FARSn score justifies the overall validity of the scale. In addition, omission of items of limited functional significance as created in the mFARS improves the features of the measures. Such information is crucial to the ongoing application of the mFARS in natural history studies and clinical trials. Additional analyses of longitudinal changes will be necessary to fully ascertain its utility, especially in nonambulant patients.

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<![CDATA[Longitudinal associations between diurnal cortisol variation and later-life cognitive impairment]]> https://www.researchpad.co/article/N88869aef-7b1e-4406-8053-e6b222dffe4e

Objective

To determine whether hypothalamus-pituitary-adrenal axis (HPAA) dysfunction is prospectively associated with global cognitive impairment in later life.

Methods

This cross-cohort study integrates 2 large longitudinal datasets, Whitehall II and the National Survey for Health and Development (NSHD), on data collected in the Whitehall II study between 2002–2004, 2007–2009, and 2012–2013; and for NSHD between 2006–2010 and in 2015. Serial salivary cortisol samples were collected multiple times within a 24-hour period at mean ages 61.2 and 65.9 years in Whitehall II and at age 60–64 years from NSHD participants. Cortisol profile is defined using cortisol awakening response and am:pm ratio. Cognitive function was measured using the Mini-Mental State Examination in Whitehall II and Addenbrooke’s Cognitive Examination, third version, in NSHD, harmonized into a 30-point score. Models were adjusted for age, sex, diagnoses of hypertension and diabetes, body mass index (BMI), educational attainment, and interval between HPAA and cognitive assessments.

Results

In fully adjusted models, increased am:pm cortisol ratio was prospectively associated with better later-life cognitive function years later (0.02 fewer errors per SD increase in am:pm cortisol ratio, p < 0.01) and verbal fluency (0.03 SD increase in verbal fluency per SD increase in am:pm ratio, p < 0.01). Increasing age, lower educational attainment, diagnosis of hypertension, diagnosis of diabetes, and increased BMI were associated with worse cognitive function and poorer verbal fluency. There were no associations between depression and later-life cognition or reverse associations between cognition and later-life cortisol profiles.

Conclusions

Loss of diurnal HPAA variation is evident in individuals subsequently experiencing more cognitive impairment. It may serve as an early preclinical marker of cognitive decline.

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<![CDATA[Large variation in effects during 10 years of enzyme therapy in adults with Pompe disease]]> https://www.researchpad.co/article/N987010e1-e3ef-4f97-91f5-d2667313a9d4

Objective

To determine the effects of 10 years of enzyme replacement therapy (ERT) in adult patients with Pompe disease, focusing on individual variability in treatment response.

Methods

In this prospective, multicenter cohort study, we studied 30 patients from the Netherlands and France who had started ERT during the only randomized placebo-controlled clinical trial with ERT in late-onset Pompe disease (NCT00158600) or its extension (NCT00455195) in 2005 to 2008. Main outcomes were walking ability (6-minute walk test [6MWT]), muscle strength (manual muscle testing using Medical Research Council [MRC] grading), and pulmonary function (forced vital capacity [FVC] in the upright and supine positions), assessed at 3- to 6-month intervals before and after the start of ERT. Data were analyzed with linear mixed-effects models for repeated measurements.

Results

Median follow-up duration on ERT was 9.8 years (interquartile range [IQR] 8.3–10.2 years). At the group level, baseline 6MWT was 49% of predicted (IQR 41%–60%) and had deteriorated by 22.2 percentage points (pp) at the 10-year treatment point (p < 0.001). Baseline FVC upright was 54% of predicted (IQR 47%–68%) and decreased by 11 pp over 10 years (p < 0.001). Effects of ERT on MRC sum score and FVC supine were similar. At the individual level, 93% of patients had initial benefit of ERT. Depending on the outcome measured, 35% to 63% of patients had a secondary decline after ≈3 to 5 years. Still, at 10 years of ERT, 52% had equal or better 6MWT and/or FVC upright compared to baseline.

Conclusions

The majority of patients with Pompe disease benefit from long-term ERT, but many patients experience some secondary decline after ≈3 to 5 years. Individual variation, however, is considerable.

Classification of evidence

This study provides Class IV evidence that for the majority of adults with Pompe disease, long-term ERT positively affects, or slows deterioration in, muscle strength, walking ability, and/or pulmonary function.

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<![CDATA[LTK is an ER-resident receptor tyrosine kinase that regulates secretion]]> https://www.researchpad.co/article/Nb241a4e3-9203-4bab-87dd-85c699f4a230

The endoplasmic reticulum (ER) is a major regulator of cellular proteostasis. However, only little is known about signaling molecules resident to this organelle. Centonze et al. identify LTK as the first ER-resident receptor tyrosine kinase and show that it stimulates secretory trafficking out of the ER.

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<![CDATA[Formation of neural networks with structural and functional features consistent with small-world network topology on surface-grafted polymer particles]]> https://www.researchpad.co/article/N94425748-a9ab-4345-8a24-5350cc77e8ef

In vitro electrophysiological investigation of neural activity at a network level holds tremendous potential for elucidating underlying features of brain function (and dysfunction). In standard neural network modelling systems, however, the fundamental three-dimensional (3D) character of the brain is a largely disregarded feature. This widely applied neuroscientific strategy affects several aspects of the structure–function relationships of the resulting networks, altering network connectivity and topology, ultimately reducing the translatability of the results obtained. As these model systems increase in popularity, it becomes imperative that they capture, as accurately as possible, fundamental features of neural networks in the brain, such as small-worldness. In this report, we combine in vitro neural cell culture with a biologically compatible scaffolding substrate, surface-grafted polymer particles (PPs), to develop neural networks with 3D topology. Furthermore, we investigate their electrophysiological network activity through the use of 3D multielectrode arrays. The resulting neural network activity shows emergent behaviour consistent with maturing neural networks capable of performing computations, i.e. activity patterns suggestive of both information segregation (desynchronized single spikes and local bursts) and information integration (network spikes). Importantly, we demonstrate that the resulting PP-structured neural networks show both structural and functional features consistent with small-world network topology.

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<![CDATA[Refining the adipose progenitor cell landscape in healthy and obese visceral adipose tissue using single-cell gene expression profiling]]> https://www.researchpad.co/article/N2ce6d53f-4c52-4ce4-8f2a-39be5bb7b353

This work dissects adipose progenitor cell (APC) heterogeneity in normal and obese adipose tissue using single-cell expression profiling. Novel APC subpopulations are identified and characterized.

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<![CDATA[Real-world persistence and benefit–risk profile of fingolimod over 36 months in Germany]]> https://www.researchpad.co/article/5c973e40d5eed0c48496b2ca

Objective

To assess the long-term real-world benefit–risk profile of fingolimod in patients with relapsing MS in Germany.

Methods

This analysis used data from the noninterventional real-world study, Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA), to assess prospectively the persistence, effectiveness, and safety of fingolimod over 36 months (±90 days) in Germany. For inclusion in the effectiveness analysis (n = 2,537), patients were required to have received fingolimod for the first time in PANGAEA, to have at least 12 months of data, and to have completed each 12-month follow-up period. For the safety analysis (n = 3,266), patients were additionally allowed to have received fingolimod before enrollment.

Results

At baseline, 94.7% of patients in the effectiveness analysis had received a previous disease-modifying therapy. After 36 months, 70.4% of patients were still receiving fingolimod. Over this period, annualized relapse rates decreased to 0.265 (95% CI: 0.244–0.286) from 1.79 (95% CI: 1.75–1.83), and mean Expanded Disability Status Scale scores remained stable (mean change from baseline: +0.049 [95% CI: −0.015 to +0.114]). In total, 16% of patients had 6-month confirmed disability improvement, 12.5% had 6-month confirmed disability worsening, and 52.4% were free from relapses and 6-month confirmed disability worsening. Adverse events (AEs) and serious AEs were experienced by up to 23.4% and 3.9% of patients, respectively, during any of the 12-month follow-up periods. The frequency and nature of AEs were in line with previous findings.

Conclusions

Using systematically collected data from PANGAEA, this analysis demonstrates the sustained effectiveness, high persistence, and manageable safety profile of fingolimod over 36 months.

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<![CDATA[Responses of apoptosis and matrix metabolism of annulus fibrosus cells to different magnitudes of mechanical tension in vitro]]> https://www.researchpad.co/article/5c94bd6dd5eed0c484613215

Background: Annulus fibrosus (AF) is important to confine disc nucleus pulposus (NP) tissue during mechanical load experience. However, the knowledge on AF cell biology under mechanical load is much limited compared with disc NP. Objective: The present study aimed to investigate responses of apoptosis and matrix metabolism of AF cells to different magnitudes of mechanical tension in vitro. Methods: Rat AF cells were subjected to different magnitudes (5, 10, and 20% elongations at a frequency of 1.0 Hz for 6 h per day) of mechanical tension for 7 days. Control AF cells were cultured without mechanical tension. Cell apoptosis ratio, caspase-3 activity, gene/protein expression of apoptosis-related molecules (Bcl-2, Bax, caspase-3/cleaved caspase-3 and cleaved PARP), matrix macromolecules (aggrecan and collagen I) and matrix metabolism-related enzymes (TIMP-1, TIMP-3, MMP-3, and ADAMTS-4) were analyzed. Results: Compared with 5% tension group and control group, 10 and 20% tension groups significantly increased apoptosis ratio, caspase-3 activity, up-regulated gene/protein expression of Bax, caspase-3/cleaved caspase-3, cleaved PARP, MMP-3, and ADAMTS-4, whereas down-regulated gene/protein expression of Bcl-2, aggrecan, collagen I, TIMP-1, and TIMP-3. No significant difference was found in these parameters apart from Bcl-2 expression between the control group and 5% tension group. Conclusion: High mechanical tension promotes AF cell apoptosis and suppresses AF matrix synthesis compared with low mechanical tension. The present study indirectly indicates how mechanical overload induces disc degeneration through affecting AF biology.

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<![CDATA[MiR-384 induces apoptosis and autophagy of non-small cell lung cancer cells through the negative regulation of Collagen α-1(X) chain gene]]> https://www.researchpad.co/article/5c6863edd5eed0c484023c67

The present study aims to investigate the mechanism of miR-384 in non-small cell lung cancer (NSCLC) cell apoptosis and autophagy by regulating Collagen α-1(X) chain (COL10A1). Bioinformatics methods were applied to evaluate potential miRNAs and genes that might correlate with NSCLC. Tumor tissues and adjacent tissues from 104 NSCLC patients were collected and human NSCLC A549 cell line was selected for subsequent experiments. A549 cells were treated with miR-384 mimic, miR-384 inhibitor, or knockdown of COL10A1. Quantitative real-time PCR (qRT-PCR) and Western blotting were utilized to detect the levels of miR-384, COL10A, Survivin, Bcl-2, Bax, Bcl-xl, Beclin 1, and LC3 in tissues and cells. A series of biological assays including MTT assay, Annexin V-FITC/PI (propidium iodide) staining, immunofluorescence, monodansylcadaverine (MDC) staining were conducted to investigate the effects of miR-384 and COL10A1 on NSCLC cells. Tumorigenicity assay for nude rats was applied. Results obtained from the present study indicated that miR-384 down-regulated COL10A1 by targetting it. Compared with adjacent tissues, miR-384 expression was obviously reduced while COL10A1 expression was significantly enhanced in NSCLC tissues (all P<0.05). Outcomes in vivo and in vitro suggested that cell proliferation and tumorigenicity were inhibited while cell apoptosis and autophagy were induced in NSCLC cells treated with up-regulation of miR-384 or silence of COL10A1. In miR-384 inhibitor group, cell proliferation was improved, while cell apoptosis was reduced and cell autophagy was decreased whereas tumorigenicity of cells was strengthened. Based on the findings of our study, it was established that miR-384 could down-regulate COL10A1 levels, subsequently inhibiting cell proliferation and promoting cell apoptosis and autophagy in NSCLC cells.

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<![CDATA[FDA Approval Summary: Pembrolizumab for Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Expressing PD‐L1]]> https://www.researchpad.co/article/5c4b91d3d5eed0c484877353

This report presents evidence for FDA approval of pembrolizumab for the treatment of adult and pediatric patients with either unresectable or metastatic, microsatellite instability‐high (MSI‐H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment, and who have no satisfactory alternative treatment options, or who have metastatic, MSI‐H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

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<![CDATA[Variants of DNMT3A cause transcript-specific DNA methylation patterns and affect hematopoiesis]]> https://www.researchpad.co/article/5c26b25bd5eed0c48475d2bc

Modulation of DNMT3A splice variants causes transcript-specific DNA methylation and gene expression changes and affects differentiation. Particularly, transcript 2 is relevant in acute myeloid leukemia.

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