julilili42/papers huggingface dataset:
Targeting cGMP‐signalling to protect photoreceptors in hereditary retinal degeneration
2019-12-01

Abstract cGMP‐signalling is fundamental to the phototransduction cascade in retinal photoreceptors. Paradoxically, high levels of cGMP lead to photoreceptor loss in hereditary retinal degeneration (RD) caused by a variety of different gene mutations. This makes cGMP‐signalling a prime target for the development of new treatment approaches. The presentation will give details about the development of compounds and drug delivery technology designed for a targeted interference with cGMP‐signalling in photoreceptors. As an example, in vivo treatment data on a liposomal formulation of the inhibitory cGMP analogue DF003/CN03 will be presented. Overall, cGMP analogues may constitute a new class of compounds for RD treatment and, when combined with suitable drug delivery vehicles, they provide a clear perspective for clinical translation, potentially bringing the very first pharmacological treatment to patients suffering from RD.
Pharmacological modulation of the VCP/ERAD/proteasome axis rescues photoreceptor degeneration in P23H rhodopsin
2019-12-01

Abstract Purpose One of the most prevalent mutations in rhodopsin (Rh) causing autosomal dominant retinitis pigmentosa (adRP) Rh P23H , results in its misfolding and its retention in the Endoplasmic Reticulum (ER). VCP is an ATP driven molecular checkpoint at the ER before these proteins are released from the ER towards plasma membrane. Misfolded proteins are selectively identified, retained at the ER and cleared by a process called ER‐associated degradation (ERAD). ERAD overload due to Rh P23H misfolding causes cell death. As several pathways regulating protein homeostasis are associated with ERAD, we tested their specific impact on photoreceptor (PR) degeneration through pharmacological inhibition. Methods Organotypic cultures from Rh P23H retinas of transgenic rats at PN9 cultured for 6 days and treated with different concentrations of pathway specific inhibitors: NMS‐873 interferes with quality control mechanisms by VCP inhibition; the proteasome inhibitor Bortezomib (BO) suppresses proteasomal degradation; the mannosidase inhibitor Kifunensine (KIF) blocks processing of glycoproteins, and Geldanamycin (GA) inhibits the protein‐folding mechanism in the ER. PR cell survival was assessed by counting cell rows and measuring the percentage of TUNEL‐positive cells. Rh distribution was checked using a specific antibody. Results VCP inhibitor caused strong and dose‐dependent protection at 5μM. Proteasome inhibition by BO significantly reduced the number of dying cells at 10μM. The number of PR cell rows in the ONL was increased by both. Only VCP inhibitor corrected aberrant inner segment distribution of Rh shifting it to physiological outer segment (OS). In contrary, KIF and GA accelerated PR cell degeneration. Conclusions Modulation of the VCP/ERAD/proteasome axis by inhibiting VCP and proteasome rescues PR cells in Rh P23H . Inhibition of VCP activity establishes proper transport of Rh to the OS. These results strongly suggest that the VCP/ERAD/proteasome axis acts as a critical checkpoint in PR homeostasis.
Orthobunyavirus recruits host ESCRT machinery to Golgi compartments to achieve efficient viral particle production
2019-12-01

Oropouche virus (OROV) is the etiological agent of Oropouche fever, a febrile illness frequent in South America. Despite its importance, the replicative cycle of this Orthobunyavirus is only starting to emerge. In this study we described the assembly pathway of OROV in Hela cells. After a thorough description of OROV one-step replication cycle, we observed by Immunofluorescence large vesicle-like structures enriched in OROV proteins termed viral factories (Vfs). These vesicles were associated with cis-Golgi (Giantin), trans-Golgi network (TGN46) and endosomal (HRS) proteins. Immuno-EM analysis of these Vfs revealed a resemblance with multivesicular body structure, which also contained viral particles. Interestingly, no leakage of late endosomal proteins (CD63 and Lamp1) was observed associated with Vfs. Therefore, we looked if ESCRT (Endosomal Sorting Complexes required for Transport) machinery could play a role in OROV replication. Depletion of Tsg101 (ESCRT-I) and Alix by siRNA compromised Vfs formation (∼40% in both cases) that contained a significantly lower number of intra-luminal viral-like particles (∼50% in both cases). Additionally, depletion of Alix led to a strong reduction in viral production (∼80%). Moreover, the overexpression of a dominant negative form of the AAATPase Vps4A (Vps4E/Q), which disrupts the MVB pathway, led to an enlargement in Vfs’ area (∼119%), where Vps4E/Q accumulated. Importantly, we also detected a colocalization between Vps4E/Q/TGN46 and Alix/TGN46 in viral factories, suggesting an involvement of ESCRT machinery, which is re-localized to the TGN in virus assembly. Therefore, our data represents an unprecedented mechanism of how viruses hijack host cell components for coordinated morphogenesis.
Topographic Shelf Waves Control Seasonal Melting Near Antarctic Ice Shelf Grounding Lines
2019-12-01

The buttressing potential of ice shelves is modulated by changes in subshelf melting, in response to changing ocean conditions. We analyze the temporal variability in subshelf melting using an autonomous phase-sensitive radio-echo sounder near the grounding line of the Roi Baudouin Ice Shelf in East Antarctica. When combined with additional oceanographic evidence of seasonal variations in the stratification and the amplification of diurnal tides around the shelf break topography (Gunnerus Bank), the results suggest an intricate mechanism in which topographic waves control the seasonal melt rate variability near the grounding line. This mechanism has not been considered before and has the potential to enhance local melt rates without advecting different water masses. As topographic waves seem to strengthen in a stratified ocean, the freshening of Antarctic surface water, predicted by observations and models, is likely to increase future basal melting in this area.
The role of extracellular matrix in biomechanics and its impact on bioengineering of cells and 3D tissues
2019-12-02

The cells and tissues of the human body are constantly exposed to exogenous and endogenous forces that are referred to as biomechanical cues. They guide and impact cellular processes and cell fate decisions on the nano-, micro- and macro-scale, and are therefore critical for normal tissue development and maintaining tissue homeostasis. Alterations in the extracellular matrix composition of a tissue combined with abnormal mechanosensing and mechanotransduction can aberrantly activate signaling pathways that promote disease development. Such processes are therefore highly relevant for disease modelling or when aiming for the development of novel therapies. In this mini review, we describe the main biomechanical cues that impact cellular fates. We highlight their role during development, homeostasis and in disease. We also discuss current techniques and tools that allow us to study the impact of biomechanical cues on cell and tissue development under physiological conditions, and we point out directions, in which in vitro biomechanics can be of use in the future.
Role of Chemodenitrification for N2O Emissions from Nitrate Reduction in Rice Paddy Soils
2019-12-02

Atmospheric nitrous oxide (N2O) causes global warming and ozone depletion. Nitrate and nitrite reduction are the main sources for N2O emission in anoxic environments including both microbial (denitrification) and abiotic reactions (chemodenitrification), besides nitrification in oxic habitats. In flooded paddy soils, substantial concentrations of Fe(II) and nitrite are available, potentially triggering chemodenitrification. It is currently unknown to what extent chemodenitrification contributes to N2O emissions in such environments. We conducted anoxic microcosm experiments with two paddy soils that differ in natural Fe(II) and organic carbon content. We amended them with nitrite or nitrate and quantified N2O emissions. In sterilized soils, nitrite and not nitrate was abiotically reduced, pointing toward chemodenitrification. In microbially active soils, nitrate reduction was accompanied by nitrite accumulation, ammonium production, and N2O emission, implying the co-occurrence of denitrification, dissimilatory nitrate reduction to ammonium (DNRA), and chemodenitrification. N2O emissions from chemodenitrification accounted for 6.8–67.6% of the total N2O emissions, depending on the concentrations of Fe(II), nitrite, nitrate, and organic carbon, and the N2O emission rate from abiotic reactions was up to 2.4 mg N kg–1 d–1. Elevated Fe(II) levels in soils facilitated nitrite accumulation, chemodenitrification, and high abiotic N2O emission (up to 42.9%). In low organic carbon soil, more N2O was emitted by chemodenitrification in nitrite-amended setups (20.5% of total N2O emission) compared to nitrate-amended setups (6.8%). High organic carbon content in soils indirectly enhanced the proportion of abiotic N2O production (up to 67.6%), potentially favoring DNRA over denitrification, which decreased the biotic contribution to N2O formation. Our results suggest that chemodenitrification could be a significant contributor for N2O emissions in paddy soils via a complex network of biotic and abiotic processes involving C, Fe, and N biogeochemical cycling.
Shade‐induced plasticity in invasive Impatiens glandulifera populations
2019-12-02

Summary Phenotypic plasticity, which confers a fitness advantage under heterogeneous and novel environments, has been commonly suggested to contribute to the success of invasive plants in their introduced range. For example, plasticity in response to changes in light availability could facilitate invasiveness by allowing plants to both rapidly establish in unshaded, disturbed habitats, and tolerate shaded or crowded environments. The plastic responses of invasive plants to shade were mostly studied in morphological traits. However, plasticity in physiological traits might provide more rapid and reversible responses and thus be more effective in environments with rapid temporal variations. Here, we compared plasticity in a range of morphological and physiological traits that provide shade avoidance or tolerance between two native and six introduced populations of Impatiens glandulifera . In a common garden, we subjected second‐generation siblings of native and invasive plants to two light availability treatments and measured their morphological, physiological and performance responses. Impatiens glandulifera from invasive populations exhibited greater phenotypic plasticity in response to light availability in four out of 12 measured traits. Moreover, this greater plasticity was mostly limited to physiological traits associated with photosynthetic acclimation. These results suggest high phenotypic plasticity in response to light availability could have facilitated I. glandulifera 's spread in both disturbed habitats and woodlands or under intense light competition. The results of this study highlight the importance of considering physiological traits when studying the role of plasticity in the success of invasive plants.
Percutaneous Ultrasound-Guided Core Needle Biopsy: Comparison of 16-Gauge versus 14-Gauge Needle and the Effect of Coaxial Guidance in 1065 Breast Biopsies – A Prospective Randomized Clinical Noninferiority Trial
2019-12-02

Abstract Purpose Ultrasound-guided core needle biopsy (CNB) is considered the standard assessment to diagnose sonographically visible suspicious breast mass lesions. Based on nonrandomized trials, the current German guidelines recommend at least three cylinders with ≤ 14-gauge needle biopsy. However, no recommendation is made as to how many specimens are needed with a smaller needle size, such as 16-gauge, or if biopsy with coaxial guidance improves diagnostic accuracy and quality. Therefore, in a prospective monocentric unblinded randomized controlled clinical noninferiority trial, the diagnostic accuracy of 16-gauge versus 14-gauge core needle biopsy, with and without coaxial guidance, was evaluated. Materials and Methods 1065 breast biopsies were included in order to analyze the number of core samples necessary to obtain an appropriate rate of diagnostic quality adequate for histological evaluation, and to achieve high diagnostic accuracy and diagnostic yield. Histological results were verified by surgery or long-term follow-up of at least two years up to five years. Results In order to obtain an additive diagnostic accuracy of &gt; 99 %, a minimum of two cylinders with 14-gauge biopsy were required. The diagnostic accuracy and the diagnostic quality of 14-gauge biopsy were not affected by the coaxial technique. When performing a 16-gauge biopsy, five cylinders were required to achieve an additive diagnostic accuracy of &gt; 99 %. Without coaxial guidance, 16-gauge CNB required at least three samples, whereas five needle passes with coaxial-guided 16-gauge biopsy were needed. Conclusion The diagnostic accuracy and quality of ultrasound-guided 16-gauge core needle biopsy were inferior to the 14-gauge needle size, regardless of the use of a coaxial technique.
Transtemporal Ultrasound (US) Assessment of Third Ventricle Diameter (TVD): Comparison of US and MRI TVD in Pediatric Patients
2019-12-02

Abstract Introduction In a retrospective magnetic resonance imaging (MRI)-based study, we showed that changes of the third ventricle diameter (TVD) are a reliable mirror of changes of the entire ventricular system. The third ventricle is easily accessible in more than 90% of children and adults using ultrasound (US) via the transtemporal bone-window; thus it can be assessed quickly and free of radiation. In order to use transtemporal US determination of TVD instead of MRI/CT in clinical practice, it is important to know if there is a correlation and bias between both methods, which is addressed in this study. Materials and Method This prospective study investigates 122 children (newborn–18 years). Diagnoses encompassed hydrocephalus (50%), tumors (14.8%), and other intracranial pathologies (35.2%). US-based TVD was measured via the transtemporal bone-window using a phased array 1 to 4MHz transducer. Results were compared with TVD measured on simultaneously acquired axial T1-weighted axial MRI or computed tomography (CT) scans. Results Overall mean values for TVD were 6.56 ± 5.84 and 6.47 ± 5.64 mm for US and MRI, respectively. There was an outstanding correlation between TVD measured by MRI and US (r = 0.991, p &lt; 0.01). Bland–Altman analysis showed a mean bias of 0.096 mm with limits of agreement of –0.99 and 1.18 mm. Conclusion US- and MRI-based TVD measurements correlate excellently and measure almost identical TVD values. US-based TVD is in mean ∼0.096 mm larger than MRI-based TVD due to a more angulated measurement plane. US is equal to the gold-standard MRI, a fact, opening new avenues for US-based TVD as a first-line assessment tool of ventricular width.
The Acquittal (After Pretrial Detention) – a Rare but Fascinating Phenomenon of the Criminal Justice System
2019-12-02

The acquittal leads – compared to other phenomena – a shadowy existence in German criminal law and criminological science. A research team from the Institute of Criminology in Tübingen investigated criminal proceedings where the accused were held in pretrial detention before eventually being acquitted and categorized and described the proceedings from various perspectives utilising a multidisciplinary approach. The article deals with the role of doubt in such proceedings and the way in which so-called “second class acquittals” are expressed in written judgements. Furthermore, this article, besides providing an overview of exemplary main results, aims to inspire the scholarly community to pay more attention to acquittal decisions taken in different parts of criminal procedures, also within a comparative perspective.
Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 × 2, Phase II Trial
2019-12-03

PURPOSE DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all- trans retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML). PATIENTS AND METHODS Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m 2 intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety. RESULTS The addition of ATRA resulted in a higher remission rate (21.9% with ATRA v 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided P = .06). For valproate, no effect was observed (17.8% with valproate v 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided P = .44). Median overall survival was 8.2 months with ATRA v 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided P = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms. CONCLUSION The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.
Multiple Negative Emotions During Learning With Digital Learning Environments – Evidence on Their Detrimental Effect on Learning From Two Methodological Approaches
2019-12-03

Emotions are a core factor of learning. Studies have shown that multiple emotions are co-experienced during learning and have a significant impact on learning outcomes. The present study investigated the importance of multiple, co-occurring emotions during learning about human biology with MetaTutor, a hypermedia-based tutoring system. Person-centered as well as variable-centered approaches of cluster analyses were used to identify emotion clusters. The person-centered clustering analyses indicated three emotion profiles: a positive, negative and neutral profile. Students with a negative profile learned less than those with other profiles and also reported less usage of emotion regulation strategies. Emotion patterns identified through spectral co-clustering confirmed these results. Throughout the learning activity, emotions built a stable correlational structure of a positive, a negative, a neutral and a boredom emotion pattern. Positive emotion pattern scores before the learning activity and negative emotion pattern scores during the learning activity predicted learning, but not consistently. These results reveal the importance of negative emotions during learning with MetaTutor. Potential moderating factors and implications for the design and development of educational interventions that target emotions and emotion regulation with digital learning environments are discussed.
Transcription-independent Induction of ERBB1 through Hypoxia-inducible Factor 2A Provides Cardioprotection during Ischemia and Reperfusion
2019-12-03

Abstract Background During myocardial ischemia, hypoxia-inducible factors are stabilized and provide protection from ischemia and reperfusion injury. Recent studies show that myocyte-specific hypoxia-inducible factor 2A promotes myocardial ischemia tolerance through induction of epidermal growth factor, amphiregulin. Here, the authors hypothesized that hypoxia-inducible factor 2A may enhance epidermal growth factor receptor 1 (ERBB1) expression in the myocardium that could interface between growth factors and its effect on providing tolerance to ischemia and reperfusion injury. Methods Human myocardial tissues were obtained from ischemic heart disease patients and normal control patients to compare ERBB1 expression. Myocyte-specific Hif2a or ErbB1 knockout mice were generated to observe the effect of Hif2a knockdown in regulating ERBB1 expression and to examine the role of ERBB1 during myocardial ischemia and reperfusion injury. Results Initial studies of myocardial tissues from patients with ischemic heart disease showed increased ERBB1 protein (1.12 ± 0.24 vs . 13.01 ± 2.20, P &lt; 0.001). In contrast, ERBB1 transcript was unchanged. Studies using short hairpin RNA repression of Hif2A or Hif2a loxP/loxP Myosin Cre+ mice directly implicated hypoxia-inducible factor 2A in ERBB1 protein induction during hypoxia or after myocardial ischemia, respectively. Repression of RNA-binding protein 4 abolished hypoxia-inducible factor 2A–dependent induction of ERBB1 protein. Moreover, ErbB1 loxP/loxP Myosin Cre+ mice experienced larger infarct sizes (22.46 ± 4.06 vs . 46.14 ± 1.81, P &lt; 0.001) and could not be rescued via amphiregulin treatment. Conclusions These findings suggest that hypoxia-inducible factor 2A promotes transcription-independent induction of ERBB1 protein and implicates epidermal growth factor signaling in protection from myocardial ischemia and reperfusion injury. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New
Targeting chronic NFAT activation with calcineurin inhibitors in diffuse large B-cell lymphoma
2019-12-03

Abstract Diffuse large B-cell lymphoma (DLBCL) represents the most common adult lymphoma and can be divided into 2 major molecular subtypes: the germinal center B-cell-like and the aggressive activated B-cell-like (ABC) DLBCL. Previous studies suggested that chronic B-cell receptor signaling and increased NF-κB activation contribute to ABC DLBCL survival. Here we show that the activity of the transcription factor NFAT is chronically elevated in both DLBCL subtypes. Surprisingly, NFAT activation is independent of B-cell receptor signaling, but mediated by an increased calcium flux and calcineurin-mediated dephosphorylation of NFAT. Intriguingly, although NFAT is activated in both DLBCL subtypes, long-term calcineurin inhibition with cyclosporin A or FK506, both clinically approved drugs, triggers potent cytotoxicity specifically in ABC DLBCL cells. The antitumor effects of calcineurin inhibitors are associated with the reduced expression of c-Jun, interleukin-6, and interleukin-10, which were identified as NFAT target genes that are particularly important for the survival of ABC DLBCL. Furthermore, calcineurin blockade synergized with BCL-2 and MCL-1 inhibitors in killing ABC DLBCL cells. Collectively, these findings identify constitutive NFAT signaling as a crucial functional driver of ABC DLBCL and highlight calcineurin inhibition as a novel strategy for the treatment of this aggressive lymphoma subtype.