bluuebunny/crossref_metadata_2025_split huggingface dataset:
NDRG2 suppression as a molecular hallmark of photoreceptor-specific cell death in the mouse retina
Authors: Hu Cheng-Biao , Sui Bing-Dong , Wang Bao-Ying , Li Gao , Hu Cheng-Hu , Zheng Chen-Xi , Du Fang-Ying , Zhu Chun-Hui , Li Hong-Bo , Feng Yan , Jin Yan , Yu Xiao-Rui 
Published: September 2018

AbstractPhotoreceptor cell death is recognized as the key pathogenesis of retinal degeneration, but the molecular basis underlying photoreceptor-specific cell loss in retinal damaging conditions is virtually unknown. The N-myc downstream regulated gene (NDRG) family has recently been reported to regulate cell viability, in particular NDRG1 has been uncovered expression in photoreceptor cells. Accordingly, we herein examined the potential roles of NDRGs in mediating photoreceptor-specific cell loss in retinal damages. By using mouse models of retinal degeneration and the 661 W photoreceptor cell line, we showed that photoreceptor cells are indeed highly sensitive to light exposure and the related oxidative stress, and that photoreceptor cells are even selectively diminished by phototoxins of the alkylating agent N-Methyl-N-nitrosourea (MNU). Unexpectedly, we discovered that of all the NDRG family members, NDRG2, but not the originally hypothesized NDRG1 or other NDRG subtypes, was selectively expressed and specifically responded to retinal damaging conditions in photoreceptor cells. Furthermore, functional experiments proved that NDRG2 was essential for photoreceptor cell viability, which could be attributed to NDRG2 control of the photo-oxidative stress, and that it was the suppression of NDRG2 which led to photoreceptor cell loss in damaging conditions. More importantly, NDRG2 preservation contributed to photoreceptor-specific cell maintenance and retinal protection both in vitro and in vivo. Our findings revealed a previously unrecognized role of NDRG2 in mediating photoreceptor cell homeostasis and established for the first time the molecular hallmark of photoreceptor-specific cell death as NDRG2 suppression, shedding light on improved understanding and therapy of retinal degeneration.
Alpha kinase 1 controls intestinal inflammation by suppressing the IL-12/Th1 axis
Authors: Ryzhakov Grigory , West Nathaniel R. , Franchini Fanny , Clare Simon , Ilott Nicholas E. , Sansom Stephen N. , Bullers Samuel J. , Pearson Claire , Costain Alice , Vaughan-Jackson Alun , Goettel Jeremy A. , Ermann Joerg , Horwitz Bruce H. , Buti Ludovico , Lu Xin , Mukhopadhyay Subhankar , Snapper Scott B. , Powrie Fiona 
Published: September 2018

AbstractInflammatory bowel disease (IBD) are heterogenous disorders of the gastrointestinal tract caused by a spectrum of genetic and environmental factors. In mice, overlapping regions of chromosome 3 have been associated with susceptibility to IBD-like pathology, including a locus called Hiccs. However, the specific gene that controls disease susceptibility remains unknown. Here we identify a Hiccs locus gene, Alpk1 (encoding alpha kinase 1), as a potent regulator of intestinal inflammation. In response to infection with the commensal pathobiont Helicobacter hepaticus (Hh), Alpk1-deficient mice display exacerbated interleukin (IL)-12/IL-23 dependent colitis characterized by an enhanced Th1/interferon(IFN)-γ response. Alpk1 controls intestinal immunity via the hematopoietic system and is highly expressed by mononuclear phagocytes. In response to Hh, Alpk1−/− macrophages produce abnormally high amounts of IL-12, but not IL-23. This study demonstrates that Alpk1 promotes intestinal homoeostasis by regulating the balance of type 1/type 17 immunity following microbial challenge.
Highly-sensitive optical organic vapor sensor through polymeric swelling induced variation of fluorescent intensity
Authors: Jiang Xiangyu , Gao Hanfei , Zhang Xiqi , Pang Jinhui , Li Yunqi , Li Kan , Wu Yuchen , Li Shuzhou , Zhu Jia , Wei Yen , Jiang Lei 
Published: September 2018

AbstractTraditional optical organic vapor sensors with solvatochromic shift mechanisms have lower sensitivity due to weak intermolecular interactions. Here, we report a general strategy to prepare a higher sensitivity optical organic vapor sensor through polymeric swelling-induced variation of fluorescent intensity. We combine one-dimensional polymeric structures and aggregation-induced emission (AIE) molecules together to form a polymer/AIE microwires array as a sensor. The prepared sensors based on different commercial polymers can successfully classify and identify various organic vapors. Among them, the poly(vinyl butyral)/AIE microwires array can detect methanol vapor as low as 0.05% of its saturation vapor pressure. According to the theory of like dissolves like, we further fabricate a polymer/AIE microwires array derived from designable polyethersulfones, through regulating their side chains, to distinguish similar organic vapors of benzene and toluene. Both experimental and theoretical simulation results reveal that specific molecular interactions between the polyethersulfones and organic vapors can improve the specific recognition performance of the sensors.
Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome
Authors: Bridgford Jessica L. , Xie Stanley C. , Cobbold Simon A. , Pasaje Charisse Flerida A. , Herrmann Susann , Yang Tuo , Gillett David L. , Dick Lawrence R. , Ralph Stuart A. , Dogovski Con , Spillman Natalie J. , Tilley Leann 
Published: September 2018

AbstractArtemisinin and its derivatives (collectively referred to as ARTs) rapidly reduce the parasite burden inPlasmodium falciparuminfections, and antimalarial control is highly dependent on ART combination therapies (ACTs). Decreased sensitivity to ARTs is emerging, making it critically important to understand the mechanism of action of ARTs. Here we demonstrate that dihydroartemisinin (DHA), the clinically relevant ART, kills parasites via a two-pronged mechanism, causing protein damage, and compromising parasite proteasome function. The consequent accumulation of proteasome substrates, i.e., unfolded/damaged and polyubiquitinated proteins, activates the ER stress response and underpins DHA-mediated killing. Specific inhibitors of the proteasome cause a similar build-up of polyubiquitinated proteins, leading to parasite killing. Blocking protein synthesis with a translation inhibitor or inhibiting the ubiquitin-activating enzyme, E1, reduces the level of damaged, polyubiquitinated proteins, alleviates the stress response, and dramatically antagonizes DHA activity.
A variant NuRD complex containing PWWP2A/B excludes MBD2/3 to regulate transcription at active genes
Authors: Zhang Tianyi , Wei Guifeng , Millard Christopher J. , Fischer Roman , Konietzny Rebecca , Kessler Benedikt M. , Schwabe John W. R. , Brockdorff Neil 
Published: September 2018

AbstractTranscriptional regulation by chromatin is a highly dynamic process directed through the recruitment and coordinated action of epigenetic modifiers and readers of these modifications. Using an unbiased proteomic approach to find interactors of H3K36me3, a modification enriched on active chromatin, here we identify PWWP2A and HDAC2 among the top interactors. PWWP2A and its paralog PWWP2B form a stable complex with NuRD subunits MTA1/2/3:HDAC1/2:RBBP4/7, but not with MBD2/3, p66α/β, and CHD3/4. PWWP2A competes with MBD3 for binding to MTA1, thus defining a new variant NuRD complex that is mutually exclusive with the MBD2/3 containing NuRD. In mESCs, PWWP2A/B is most enriched at highly transcribed genes. Loss of PWWP2A/B leads to increases in histone acetylation predominantly at highly expressed genes, accompanied by decreases in Pol II elongation. Collectively, these findings suggest a role for PWWP2A/B in regulating transcription through the fine-tuning of histone acetylation dynamics at actively transcribed genes.
Lipid-Coated Mesoporous Silica Nanoparticles for the Delivery of the ML336 Antiviral to Inhibit Encephalitic Alphavirus Infection
Authors: LaBauve Annette E. , Rinker Torri E. , Noureddine Achraf , Serda Rita E. , Howe Jane Y. , Sherman Michael B. , Rasley Amy , Brinker C. Jeffery , Sasaki Darryl Y. , Negrete Oscar A. 
Published: September 2018

AbstractVenezuelan equine encephalitis virus (VEEV) poses a major public health risk due to its amenability for use as a bioterrorism agent and its severe health consequences in humans. ML336 is a recently developed chemical inhibitor of VEEV, shown to effectively reduce VEEV infection in vitro and in vivo. However, its limited solubility and stability could hinder its clinical translation. To overcome these limitations, lipid-coated mesoporous silica nanoparticles (LC-MSNs) were employed. The large surface area of the MSN core promotes hydrophobic drug loading while the liposome coating retains the drug and enables enhanced circulation time and biocompatibility, providing an ideal ML336 delivery platform. LC-MSNs loaded 20 ± 3.4 μg ML336/mg LC-MSN and released 6.6 ± 1.3 μg/mg ML336 over 24 hours. ML336-loaded LC-MSNs significantly inhibited VEEV in vitro in a dose-dependent manner as compared to unloaded LC-MSNs controls. Moreover, cell-based studies suggested that additional release of ML336 occurs after endocytosis. In vivo safety studies were conducted in mice, and LC-MSNs were not toxic when dosed at 0.11 g LC-MSNs/kg/day for four days. ML336-loaded LC-MSNs showed significant reduction of brain viral titer in VEEV infected mice compared to PBS controls. Overall, these results highlight the utility of LC-MSNs as drug delivery vehicles to treat VEEV.
Low-Frequency Oscillatory Correlates of Auditory Predictive Processing in Cortical-Subcortical Networks: A MEG-Study
Authors: Recasens Marc , Gross Joachim , Uhlhaas Peter J. 
Published: September 2018

AbstractEmerging evidence supports the role of neural oscillations as a mechanism for predictive information processing across large-scale networks. However, the oscillatory signatures underlying auditory mismatch detection and information flow between brain regions remain unclear. To address this issue, we examined the contribution of oscillatory activity at theta/alpha-bands (4–8/8–13 Hz) and assessed directed connectivity in magnetoencephalographic data while 17 human participants were presented with sound sequences containing predictable repetitions and order manipulations that elicited prediction-error responses. We characterized the spectro-temporal properties of neural generators using a minimum-norm approach and assessed directed connectivity using Granger Causality analysis. Mismatching sequences elicited increased theta power and phase-locking in auditory, hippocampal and prefrontal cortices, suggesting that theta-band oscillations underlie prediction-error generation in cortical-subcortical networks. Furthermore, enhanced feedforward theta/alpha-band connectivity was observed in auditory-prefrontal networks during mismatching sequences, while increased feedback connectivity in the alpha-band was observed between hippocampus and auditory regions during predictable sounds. Our findings highlight the involvement of hippocampal theta/alpha-band oscillations towards auditory prediction-error generation and suggest a spectral dissociation between inter-areal feedforward vs. feedback signalling, thus providing novel insights into the oscillatory mechanisms underlying auditory predictive processing.
Connexin 26 Expression in Mammalian Cardiomyocytes
Authors: Moscato S. , Cabiati M. , Bianchi F. , Vaglini F. , Morales M. A. , Burchielli S. , Botta L. , Sabbatini A. R. M. , Falleni A. , Del Ry S. , Mattii L. 
Published: September 2018

AbstractConnexins are a family of membrane-spanning proteins named according to their molecular weight. They are known to form membrane channels mediating cell-cell communication, which play an essential role in the propagation of electrical activity in the heart. Cx26 has been described in a number of tissues but not in the heart, and its mutations are frequently associated with deafness and skin diseases. The aim of this study was to assess the possible Cx26 expression in heart tissues of different mammalian species and to demonstrate its localization at level of cardiomyocytes. Samples of pig, human and rat heart and H9c2 cells were used for our research. Immunohistochemical and molecular biology techniques were employed to test the expression of Cx26. Interestingly, this connexin was found in cardiomyocytes, at level of clusters scattered over the cell cytoplasm but not at level of the intercalated discs where the other cardiac connexins are usually located. Furthermore, the expression of Cx26 in H9c2 myoblast cells increased when they were differentiated into cardiac-like phenotype. To our knowledge, the expression of Cx26 in pig, human and rat has been demonstrated for the first time in the present paper.
Enhanced ANGPTL2 expression in adipose tissues and its association with insulin resistance in obese women
Authors: Kim Jimin , Lee Seul Ki , Jang Yeon Jin , Park Hye Soon , Kim Jong-Hyeok , Hong Joon Pio , Lee Yeon Ji , Heo Yoon-Suk 
Published: September 2018

AbstractAngiopoietin-like protein 2 has been proposed to be a key mediator linking obesity and insulin resistance. However, no detailed study of ANGPTL2 expression in human adipose tissues has yet been reported. To investigate the pattern and regulation of ANGPTL2 expression in human adipose tissues in obesity and its related diseases, we recruited 32 non-diabetic and 13 type 2 diabetic obese women and 32 normal-weight women. ANGPTL2 mRNA was expressed at a similar level in visceral and subcutaneous adipose tissues. Adipose tissue ANGPTL2 mRNA was much higher in obese patients. Adipose tissue ANGPTL2 mRNA and serum ANGPTL2 levels showed strong associations with metabolic parameters associated with insulin resistance. In adipose tissue, ANGPTL2 mRNA was closely correlated with the expression of genes involved in inflammation and ER stress. ANGPTL2 mRNA was principally expressed in adipocytes, and its expression was markedly higher in the adipocyte but non-adipocyte fraction of obese adipose tissues. Culture of human adipocytes under conditions mimicking the microenvironment of obese adipose tissue (especially, increased ER stress) stimulated ANGPTL2 gene expression and secretion. In addition, co-culture of adipocytes and macrophages suggested that ANGPTL2 excessively produced by adipocytes, may contribute inflammation and remodeling in obese adipose tissues, thereby promoting insulin resistance.
Speed–Accuracy Trade-Offs and Adaptation Deficits in Aphasia: Finding the “Sweet Spot” Between Overly Cautious and Incautious Responding
Authors: Evans William S. , Hula William D. , Starns Jeffrey J. 
Published: September 2018

Purpose

After stroke, how well do people with aphasia (PWA) adapt to the altered functioning of their language system? When completing a language-dependent task, how well do PWA balance speed and accuracy when the goal is to respond both as quickly and accurately as possible? The current work investigates adaptation theory (
Kolk & Heeschen, 1990
) in the context of speed–accuracy trade-offs in a lexical decision task. PWA were predicted to set less beneficial speed–accuracy trade-offs than matched controls, and at least some PWA were predicted to present with adaptation deficits, with impaired accuracy or response times attributable to speed–accuracy trade-offs.

Method

The study used the diffusion model (
Ratcliff, 1978
), a computational model of response time for simple 2-choice tasks. Parameters of the model can be used to distinguish basic processing efficiency from the overall level of caution in setting response thresholds and were used here to characterize speed–accuracy trade-offs in 20 PWA and matched controls during a lexical decision task.

Results
Models showed that PWA and matched control groups did not differ overall in how they set response thresholds for speed–accuracy trade-offs. However, case series analyses showed that 40% of the PWA group displayed the predicted adaptation deficits, with impaired accuracy or response time performance directly attributable to overly cautious or overly incautious response thresholds.

Conclusions
Maladaptive speed–accuracy trade-offs appear to be present in some PWA during lexical decision, leading to adaptation deficits in performance. These adaptation deficits are potentially treatable, and clinical implications and next steps for translational research are discussed.
Diagnosing Middle Ear Pathology in 6- to 9-Month-Old Infants Using Wideband Absorbance: A Risk Prediction Model
Authors: Myers Joshua , Kei Joseph , Aithal Sreedevi , Aithal Venkatesh , Driscoll Carlie , Khan Asaduzzaman , Manuel Alehandrea , Joseph Anjali , Malicka Alicja N. 
Published: September 2018

Purpose
The aim of this study was to develop a risk prediction model for detecting middle ear pathology in 6- to 9-month-old infants using wideband absorbance measures.

Method

Two hundred forty-nine infants aged 23–39 weeks (
Mdn
= 28 weeks) participated in the study. Distortion product otoacoustic emissions and high-frequency tympanometry were tested in both ears of each infant to assess middle ear function. Wideband absorbance was measured at ambient pressure in each participant from 226 to 8000 Hz. Absorbance results from 1 ear of each infant were used to predict middle ear dysfunction, using logistic regression. To develop a model likely to generalize to new infants, the number of variables was reduced using principal component analysis, and a penalty was applied when fitting the model. The model was validated using the opposite ears and with bootstrap resampling. Model performance was evaluated through measures of discrimination and calibration. Discrimination was assessed with the area under the receiver operating characteristic curve (AUC); and calibration, with calibration curves, which plotted actual against predicted probabilities.

Results
AUC of the fitted model was 0.887. The model validated adequately when applied to the opposite ears (AUC = 0.852) and with bootstrap resampling (AUC = 0.874). Calibration was satisfactory, with high agreement between predictions and observed results.

Conclusions
The risk prediction model had accurate discrimination and satisfactory calibration. Validation results indicate that it may generalize well to new infants. The model could potentially be used in diagnostic and screening settings. In the context of screening, probabilities provide an intuitive and flexible mechanism for setting the referral threshold that is sensitive to the costs associated with true and false-positive outcomes. In a diagnostic setting, predictions could be used to supplement visual inspection of absorbance for individualized diagnoses. Further research assessing the performance and impact of the model in these contexts is warranted.
Facing the Challenges of Primary Progressive Aphasia: The Spousal Perspective
Authors: Pozzebon Margaret , Douglas Jacinta , Ames David 
Published: September 2018

PurposePrimary progressive aphasia (PPA) is a cognitive–neurodegenerative disorder. Little is known about the personal impact PPA has on those living with this condition, particularly from a spousal perspective. The aim of this qualitative study was to gain an understanding of the personal experiences of spouses living with a partner diagnosed with variant forms of PPAMethodThirteen spouses whose partners were diagnosed with PPA participated in 1:1 semistructured, in-depth interviews to explore their lived experiences of this illness. Using a constructivist grounded theory approach, analysis moved through a process of data-driven open and focused coding for the identification of emergent categories, themes, and subthemes that captured the challenges faced by spouses while supporting their partners.ResultsA constructivist grounded theory analysis of the interview data revealed an overarching theme of “facing the challenges of PPA” that captured the experience spouses encountered when living with a partner diagnosed with PPA. Four interdependent and overlapping themes that sat within this overarching theme included acknowledging disconnect in the spousal relationship, living the decline, readjusting sense of self, and getting on with living. Each of these core themes revealed how spouses dealt with the ongoing and evolving challenges of PPA, particularly concerning changing relational dynamics with their partner and adjusting their own self-conceptualization.ConclusionsGreater understanding of the spousal experiences of PPA is crucial to the development of intervention to help sustain spouses' emotional and relational connections with their partner.
A Phonetic Complexity-Based Approach for Intelligibility and Articulatory Precision Testing: A Preliminary Study on Talkers With Amyotrophic Lateral Sclerosis
Authors: Kuruvilla-Dugdale Mili , Custer Claire , Heidrick Lindsey , Barohn Richard , Govindarajan Raghav 
Published: September 2018

Purpose
This study describes a phonetic complexity-based approach for speech intelligibility and articulatory precision testing using preliminary data from talkers with amyotrophic lateral sclerosis.

Method
Eight talkers with amyotrophic lateral sclerosis and 8 healthy controls produced a list of 16 low and high complexity words. Sixty-four listeners judged the samples for intelligibility, and 2 trained listeners completed phoneme-level analysis to determine articulatory precision. To estimate percent intelligibility, listeners orthographically transcribed each word, and the transcriptions were scored as being either accurate or inaccurate. Percent articulatory precision was calculated based on the experienced listeners' judgments of phoneme distortions, deletions, additions, and/or substitutions for each word. Articulation errors were weighted based on the perceived impact on intelligibility to determine word-level precision.

Results
Between-groups differences in word intelligibility and articulatory precision were significant at lower levels of phonetic complexity as dysarthria severity increased. Specifically, more severely impaired talkers showed significant reductions in word intelligibility and precision at both complexity levels, whereas those with milder speech impairments displayed intelligibility reductions only for more complex words. Articulatory precision was less sensitive to mild dysarthria compared to speech intelligibility for the proposed complexity-based approach.

Conclusions
Considering phonetic complexity for dysarthria tests could result in more sensitive assessments for detecting and monitoring dysarthria progression.