bluuebunny/crossref_metadata_2025 huggingface dataset:
The multiple landscapes of Biedjovággi: Ontological conflicts on indigenous land
Authors: Kramvig Britt , Avango Dag
Published: September 2021

In this article, we engage with environmental conflicts on indigenous land through a focus on an attempt to gain social licence to reopen and operate the Biedjovággi mine in Guovdageainnu/Kautokeino in Sápmi, Norway. We argue that mining prospects bring forth ontological conflicts concerning land use, as well as ways to know the landscape and the envisioned future that the land holds. It is a story of a conflict between two different ways of knowing. The paper explores the Sámi landscape through different concepts, practices and stories. We then contrast this to the way the same landscape is understood and narrated by a mining company, through the programmes and documents produced according to the Norwegian law and standards. We follow Ingold’s argument that the Sámi landscape practices are taskscapes, where places, times and tasks are interconnected. These were not acknowledged in the plans and documents of the mining company. We conclude by addressing the tendency of extractive industries to reduce different landscapes in ways that fit with modern understandings, which oppose culture to nature.
INDIVIDUAL DIFFERENCES IN L2 LITERACY ACQUISITION
Authors: Brice Henry , Siegelman Noam , van den Bunt Mark , Frost Stephen J. , Rueckl Jay G. , Pugh Kenneth R. , Frost Ram
Published: September 2021

Statistical learning (SL) approaches to reading maintain that proficient reading requires assimilation of rich statistical regularities in the writing system. Reading skills in developing first-language readers are predicted by individual differences in sensitivity to regularities in mappings from orthography to phonology (O-P) and semantics (O-S), where good readers rely more on O-P consistency, and less on O-S associations. However, how these regularities are leveraged by second-language (L2) learners remains an open question. We utilize an individual-differences approach, measuring L2 English learners’ sensitivity to O-P, O-S, and frequency during word-naming, across two years of immersion. We show that reliance on O-P is leveraged by better readers, while reliance on O-S is slower to develop, characterizing less proficient readers. All factors explain substantial individual variance in L2 reading skills. These findings show how SL plays a key role in L2 reading development through its role in assimilating sublexical regularities between print and speech.
Structure and function of the gap junctional network of photoreceptive ganglion cells
Authors: Zhao Xiwu , Wong Kwoon Y.
Published: September 2021

Intrinsically photosensitive retinal ganglion cells (ipRGCs) signal not only anterogradely to drive behavioral responses, but also retrogradely to some amacrine interneurons to modulate retinal physiology. We previously found that all displaced amacrine cells with spiking, tonic excitatory photoresponses receive gap-junction input from ipRGCs, but the connectivity patterns and functional roles of ipRGC-amacrine coupling remained largely unknown. Here, we injected PoPro1 fluorescent tracer into all six types of mouse ipRGCs to identify coupled amacrine cells, and analyzed the latter’s morphological and electrophysiological properties. We also examined how genetically disrupting ipRGC-amacrine coupling affected ipRGC photoresponses. Results showed that ipRGCs couple with not just ON- and ON/OFF-stratified amacrine cells in the ganglion-cell layer as previously reported, but also OFF-stratified amacrine cells in both ganglion-cell and inner nuclear layers. M1- and M3-type ipRGCs couple mainly with ON/OFF-stratified amacrine cells, whereas the other ipRGC types couple almost exclusively with ON-stratified ones. ipRGCs transmit melanopsin-based light responses to at least 93% of the coupled amacrine cells. Some of the ON-stratifying ipRGC-coupled amacrine cells exhibit transient hyperpolarizing light responses. We detected bidirectional electrical transmission between an ipRGC and a coupled amacrine cell, although transmission was asymmetric for this particular cell pair, favoring the ipRGC-to-amacrine direction. We also observed electrical transmission between two amacrine cells coupled to the same ipRGC. In both scenarios of coupling, the coupled cells often spiked synchronously. While ipRGC-amacrine coupling somewhat reduces the peak firing rates of ipRGCs’ intrinsic melanopsin-based photoresponses, it renders these responses more sustained and longer-lasting. In summary, ipRGCs’ gap junctional network involves more amacrine cell types and plays more roles than previously appreciated.
K-MODULI OF CURVES ON A QUADRIC SURFACE AND K3 SURFACES
Authors: Ascher Kenneth , Devleming Kristin , Liu Yuchen
Published: September 2021

We show that the K-moduli spaces of log Fano pairs
$\left(\mathbb {P}^1\times \mathbb {P}^1, cC\right)$
, where C is a
$(4,4)$
curve and their wall crossings coincide with the VGIT quotients of
$(2,4)$
, complete intersection curves in
$\mathbb {P}^3$
. This, together with recent results by Laza and O’Grady, implies that these K-moduli spaces form a natural interpolation between the GIT moduli space of
$(4,4)$
curves on
$\mathbb {P}^1\times \mathbb {P}^1$
and the Baily–Borel compactification of moduli of quartic hyperelliptic K3 surfaces.
Pseudo-Random Mating with Multiple Alleles
Authors: Stark Alan E.
Published: September 2021

The conditions on the mating matrix associated with a stable equilibrium are specified for an autosomal locus with four alleles. An example illustrates how Hardy–Weinberg proportions are maintained with nonrandom mating. The ABO blood group provides an illustration.
Congratulations to the 2021 AGU Union Medal, Award, and Prize Recipients
Authors: Lozier Susan , Myles LaToya
Published: September 2021

AGU awards its highest honors for excellence in scientific research, education, communication, and outreach.
Landslides in the Upper Submarine Slopes of Volcanic Islands: The Central Azores
Authors: Chang Yu‐Chun , Mitchell Neil C. , Quartau Rui
Published: September 2021

Small landslides in the upper submarine slopes of volcanic islands present potential hazards locally because of their high frequency. We examine evidence for landsliding in high‐resolution bathymetric data from Faial, Pico, São Jorge, and Terceira islands of the Azores. Because the rugged morphology of the upper slopes makes landslides difficult to interpret, we develop two classification schemes for the 1,227 identified slope valleys. One scheme addresses how recognizable the valleys were as originating from landslides (whether scarps are prominent or indefinite), whereas the other scheme addresses valley types (whether apparently produced by single or multiple failures). Size distributions are used to assess the relative occurrence of large versus small landslides. Thirteen landslides are predicted to have generated tsunami heights at source of >1 m and one with height of >7 m. Some slopes have gradients far above 30°, the angle of repose of incohesive clastic sediment, so the seabed in those areas is strengthened perhaps by carbonate cementation, by seismic shaking or by the presence of coherent lava or lava talus. Using all types of slope valleys, Faial and Pico have smaller affected volumes per unit slope area than those of São Jorge and Terceira. These differences could be associated with varied seismic activity, with more frequent earthquakes beneath Faial and Pico preventing the build‐up of sediments on their slopes. Submarine landslide statistics are therefore potentially useful for assessing long‐term earthquake hazards of volcanic islands in seismically active environments such as the Azores.
Fate of Fugitive Natural Gas in Heterogeneous Near‐Surface Sediments in a Region of Extensive Petroleum Resource Development
Authors: Chao Jessie Tse‐Hua , Cahill Aaron G. , Van De Ven Cole J. C. , Beckie Roger D.
Published: September 2021

Fugitive natural gas released in the subsurface from leaking oil and gas wells can affect groundwater quality and generate significant greenhouse gas emissions to the atmosphere. We released natural gas into a Western Canada Sedimentary Basin (WCSB) groundwater system located in an area of petroleum resource development. Through 55 depth‐discrete monitoring points installed up to 26 m deep, we tracked spatiotemporal evolution of dissolved gases over 760 days. Fugitive gas was diverted and mostly retained in the subsurface by capillary barriers, resulting in highly irregular distribution and dissolution of multicomponent gas constituents. Gas wetness changed significantly during migration, although stable‐carbon isotope ratios did not. We expect that where a surface diamict is present, typical of the WCSB, a significant portion of fugitive gas released from leaky wells will be retained in the subsurface, mitigating greenhouse gas emissions to the atmosphere but inferring greater risk on groundwater.
Stable Barium Isotope Dynamics During Estuarine Mixing
Authors: Cao Zhimian , Rao Xinting , Yu Yang , Siebert Christopher , Hathorne Ed C. , Liu Bo , Wang Guizhi , Lian Ergang , Wang Zhibing , Zhang Ruifeng , Gao Lei , Wei Gangjian , Yang Shouye , Dai Minhan , Frank Martin
Published: September 2021

Stable barium isotopes are a potential proxy for riverine inputs into the ocean that reflect monsoon variability and climate change. However, dissolved Ba isotope (δ138BaDBa) geochemistry in river estuaries, a dynamic land to ocean transition zone, has rarely been systematically examined to date. Here, we show that significant Ba isotope fractionation occurs at near‐zero salinities in the Yangtze and Pearl River Estuary, whereas conservative mixing dominates δ138BaDBa distributions beyond low salinities, which are well predicted by an ion exchange model. Elevated δ138BaDBa in the river endmember results from preferential removal of light Ba isotopes by adsorption to fluvial particles. Subsequently, δ138BaDBa rapidly drops to minimum signatures at increased salinities indicating particle desorption of isotopically light Ba. Nevertheless, the apparently conservative δ138BaDBa‐salinity relationship beyond the low‐salinity minimum in both estuaries provides a modern calibration for using Ba isotopes as a proxy for paleosalinity and river water inputs into the ocean.
Evaluating Models for Lithospheric Loss and Intraplate Volcanism Beneath the Central Appalachian Mountains
Authors: Long Maureen D. , Wagner Lara S. , King Scott D. , Evans Rob L. , Mazza Sarah E. , Byrnes Joseph S. , Johnson Elizabeth A. , Kirby Eric , Bezada Maximiliano J. , Gazel Esteban , Miller Scott R. , Aragon John C. , Liu Shangxin
Published: September 2021

The eastern margin of North America has been shaped by a series of tectonic events including the Paleozoic Appalachian Orogeny and the breakup of Pangea during the Mesozoic. For the past ∼200 Ma, eastern North America has been a passive continental margin; however, there is evidence in the Central Appalachian Mountains for post‐rifting modification of lithospheric structure. This evidence includes two co‐located pulses of magmatism that post‐date the rifting event (at 152 and 47 Ma) along with low seismic velocities, high seismic attenuation, and high electrical conductivity in the upper mantle. Here, we synthesize and evaluate constraints on the lithospheric evolution of the Central Appalachian Mountains. These include tomographic imaging of seismic velocities, seismic and electrical conductivity imaging along the Mid‐Atlantic Geophysical Integrative Collaboration array, gravity and heat flow measurements, geochemical and petrological examination of Jurassic and Eocene magmatic rocks, and estimates of erosion rates from geomorphological data. We discuss and evaluate a set of possible mechanisms for lithospheric loss and intraplate volcanism beneath the region. Taken together, recent observations provide compelling evidence for lithospheric loss beneath the Central Appalachians; while they cannot uniquely identify the processes associated with this loss, they narrow the range of plausible models, with important implications for our understanding of intraplate volcanism and the evolution of continental lithosphere. Our preferred models invoke a combination of (perhaps episodic) lithospheric loss via Rayleigh‐Taylor instabilities and subsequent small‐scale mantle flow in combination with shear‐driven upwelling that maintains the region of thin lithosphere and causes partial melting in the asthenosphere.
Combined associations of 25-hydroxivitamin D and parathyroid hormone with diabetes risk and associated comorbidities among U.S. white and black women
Authors: Xia Jin , Tu Wanzhu , Manson JoAnn E. , Nan Hongmei , Shadyab Aladdin H. , Bea Jennifer W. , Gower Emily W. , Qi Lihong , Cheng Ting-Yuan David , Song Yiqing
Published: September 2021

Background/objectives

There is evidence of black–white differences in vitamin D status and cardiometabolic health. This study aimed to further evaluate the joint associations of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) with risks of diabetes and related cardiometabolic comorbidities among white and black women.

Subjects/methods

We cross-sectionally and prospectively analyzed data from 1850 black and 3000 white postmenopausal women without cardiovascular disease or dialysis at baseline from the Women’s Health Initiative—Observational Study. Weighted Cox proportional hazards analyses and weighted logistic regression models were used to examine the joint associations of 25(OH)D and PTH with incident diabetes and prevalence of other diabetes-related cardiometabolic comorbidities (including CKD, hypertension, or obesity).

Results

We identified 3322 cases of obesity (n = 1629), hypertension (n = 2759), or CKD (n = 318) at baseline and 453 incident cases of diabetes during 11 years of follow-up. Cross-sectionally, lower 25(OH)D and higher PTH were independently associated with higher prevalence of hypertension [odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.72–0.87 and OR = 1.55; 95% CI: 1.39–1.73] among white women only. When stratified by diabetes status, compared to women with 25(OH)D ≥50 nmol/L and PTH ≤6.89 pmol/L (65 pg/mL), women who did not have diabetes with vitamin D deficiency (<50 nmol/L) and PTH excess (>6.89 pmol/L) had higher prevalence of CKD, hypertension, or obesity (OR = 4.23; 95% CI: 2.90–6.18) than women who had diabetes (OR = 1.89; 95% CI: 0.96–3.71). Prospectively, lower 25(OH)D was associated with lower diabetes incidence [hazard ratio (HR) = 0.73; 95% CI: 0.62–0.86] in white women. Jointly, compared to the group with 25(OH)D ≥50 nmol/L and PTH ≤6.89 pmol/L, white women with 25(OH)D deficiency (<50 nmol/L) had elevated risk for diabetes, regardless of PTH levels.

Conclusions

Low 25(OH)D and high PTH were jointly associated with increased risk of diabetes among white women only. Their joint associations with high prevalence of CKD, hypertension, and obesity were more pronounced among women without diabetes.
S19W, T27W, and N330Y mutations in ACE2 enhance SARS-CoV-2 S-RBD binding toward both wild-type and antibody-resistant viruses and its molecular basis
Authors: Ye Fei , Lin Xi , Chen Zimin , Yang Fanli , Lin Sheng , Yang Jing , Chen Hua , Sun Honglu , Wang Lingling , Wen Ao , Zhang Xindan , Dai Yushan , Cao Yu , Yang Jingyun , Shen Guobo , Yang Li , Li Jiong , Wang Zhenling , Wang Wei , Wei Xiawei , Lu Guangwen
Published: September 2021

SARS-CoV-2 recognizes, via its spike receptor-binding domain (S-RBD), human angiotensin-converting enzyme 2 (ACE2) to initiate infection. Ecto-domain protein of ACE2 can therefore function as a decoy. Here we show that mutations of S19W, T27W, and N330Y in ACE2 could individually enhance SARS-CoV-2 S-RBD binding. Y330 could be synergistically combined with either W19 or W27, whereas W19 and W27 are mutually unbeneficial. The structures of SARS-CoV-2 S-RBD bound to the ACE2 mutants reveal that the enhanced binding is mainly contributed by the van der Waals interactions mediated by the aromatic side-chains from W19, W27, and Y330. While Y330 and W19/W27 are distantly located and devoid of any steric interference, W19 and W27 are shown to orient their side-chains toward each other and to cause steric conflicts, explaining their incompatibility. Finally, using pseudotyped SARS-CoV-2 viruses, we demonstrate that these residue substitutions are associated with dramatically improved entry-inhibition efficacy toward both wild-type and antibody-resistant viruses. Taken together, our biochemical and structural data have delineated the basis for the elevated S-RBD binding associated with S19W, T27W, and N330Y mutations in ACE2, paving the way for potential application of these mutants in clinical treatment of COVID-19.
Role of dietary factors in the prevention and treatment for depression: an umbrella review of meta-analyses of prospective studies
Authors: Xu Yujie , Zeng Linan , Zou Kun , Shan Shufang , Wang Xiaoyu , Xiong Jingyuan , Zhao Li , Zhang Lingli , Cheng Guo
Published: September 2021

The role of diet in depression is becoming increasingly acknowledged. This umbrella review aimed to summarize comprehensively the current evidence reporting the effects of dietary factors on the prevention and treatment of depression. PubMed, Embase, and the Cochrane Library were searched up to June 2021 to identify relevant meta-analyses of prospective studies. Twenty-eight meta-analyses, with 40 summary estimates on dietary patterns (n = 8), food and beverages (n = 19), and nutrients (n = 13) were eligible. The methodological quality of most meta-analyses was low (50.0%) or very low (25.0%). Quality of evidence was moderate for inverse associations for depression incidence with healthy diet [risk ratio (RR): 0.74, 95% confidential interval (CI), 0.48–0.99, I2 = 89.8%], fish (RR: 0.88, 95% CI, 0.79–0.97, I2 = 0.0%), coffee (RR: 0.89, 95% CI, 0.84–0.94, I2 = 32.9%), dietary zinc (RR: 0.66, 95% CI 0.50–0.82, I2 = 13.9%), light to moderate alcohol (<40 g/day, RR: 0.77, 95% CI, 0.74–0.83, I2 = 20.5%), as well as for positive association with sugar-sweetened beverages (RR: 1.05, 95% CI, 1.01–1.09, I2 = 0.0%). For depression treatment, moderate-quality evidence was identified for the effects of probiotic [standardized mean difference (SMD): −0.31, 95% CI, −0.56 to −0.07, I2 = 48.2%], omega-3 polyunsaturated fatty acid (SMD: −0.28, 95% CI, −0.47 to −0.09, I2 = 75.0%) and acetyl-l-carnitine (SMD: −1.10, 95% CI, −1.65 to −0.56, I2 = 86.0%) supplementations. Overall, the associations between dietary factors and depression had been extensively evaluated, but none of them were rated as high quality of evidence, suggesting further studies are likely to change the summary estimates. Thus, more well-designed research investigating more detailed dietary factors in association with depression is warranted.
The impact of changing risk thresholds on the number of people in England eligible for urgent investigation for possible cancer: an observational cross-sectional study
Authors: Moore Sarah F. , Price Sarah J. , Chowienczyk Sarah , Bostock Jennifer , Hamilton Willie
Published: September 2021

Background

Expediting cancer diagnosis may be achieved by targeted decreases in referral thresholds to increase numbers of patients referred for urgent investigation.

Methods

Clinical Practice Research Datalink data from England for 150,921 adults aged ≥40 were used to identify participants with features of possible cancer equating to risk thresholds ≥1%, ≥2% or ≥3% for breast, lung, colorectal, oesophago-gastric, pancreatic, renal, bladder, prostatic, ovarian, endometrial and laryngeal cancers.

Results

The mean age of participants was 60 (SD 13) years, with 73,643 males (49%). In 2016, 8576 consultation records contained coded features having a positive predictive value (PPV) of ≥3% for any of the 11 cancers. This equates to a rate of 5682/100,000 patients compared with 4601/100,000 Suspected Cancer NHS referrals for these cancers from April 2016–March 2017. Nine thousands two hundred ninety-one patient-consultation records had coded features equating to a ≥2% PPV, 8% more than met PPV ≥ 3%. Similarly, 19,517 had features with a PPV ≥ 1%, 136% higher than for PPV ≥ 3%.

Conclusions

This study estimated the number of primary-care patients presenting at lower thresholds of cancer risk. The resource implications of liberalising this threshold to 2% are modest and manageable. The details across individual cancer sites should assist planning of English cancer services.
Insulin-like growth factor binding protein-1 regulates HIF-1α degradation to inhibit apoptosis in hypoxic cardiomyocytes
Authors: Tang Xiaoyan , Jiang Huilin , Lin Peiyi , Zhang Zhenhui , Chen Meiting , Zhang Yi , Mo Junrong , Zhu Yongcheng , Liu Ningning , Chen Xiaohui
Published: September 2021

Hypoxia is important in ischemic heart disease. Excessive Insulin-like growth factor binding protein-1 (IGFBP-1) amounts are considered to harm cardiomyocytes in acute myocardial infarction. However, the mechanisms by which IGFBP-1 affects cardiomyocytes remain undefined. The present study demonstrated that hypoxia up-regulates IGFBP-1 and HIF-1α protein expression in cardiomyocytes. Subsequent assays showed that IGFBP-1 suppression decreased HIF-1α expression and inhibited hypoxia-induced apoptosis in cardiomyocytes, which was reversed by HIF-1α overexpression, indicating that HIF-1α is essential to IGFBP-1 function in cellular apoptosis. In addition, we showed that IGFBP-1 regulated HIF-1α stabilization through interacting with VHL. The present findings suggest that IGFBP-1–HIF-1α could be targeted for treating ischemic heart disease.
miR-139-5p sponged by LncRNA NEAT1 regulates liver fibrosis via targeting β-catenin/SOX9/TGF-β1 pathway
Authors: Wang Qi , Wei Song , Li Lei , Bu Qingfa , Zhou Haoming , Su Wantong , Liu Zheng , Wang Mingming , Lu Ling
Published: September 2021

Liver fibrosis is a patho-physiological process which can develop into cirrhosis, and hepatic carcinoma without intervention. Our study extensively investigated the mechanisms of lncRNA NEAT1 and miR-139-5p in regulating liver fibrosis progression. Our results demonstrated that the expression of lncRNA NEAT1 was increased and the expression of miR-139-5p was decreased in fibrotic liver tissues. LncRNA NEAT1 could sponge miR-139-5p and promoted hepatic stellate cells (HSCs) activation by directly inhibiting the expression of miR-139-5p. The co-localization of lncRNA NEAT1 with miR-139-5p was shown in the cytosols of activated HSCs. miR-139-5p upregulation could suppress the expression of β-catenin. The overexpression of β-catenin promoted HSCs activation. Moreover, we found that β-catenin could interact with SOX9 promoted HSCs activation. Our further studies demonstrated that SOX9 could bind with the TGF-β1 promoter and promoted the transcription activity of TGF-β1. The upregulation of TGF-β1 further promoted HSCs activation. In vivo study also suggested that lncRNA NEAT1 knockdown and miR-139-5p overexpression alleviated murine liver fibrosis. LncRNA NEAT1 exacerbated liver fibrosis by suppressing the expression of miR-139-5p. Collectively, our study suggested that miR-139-5p sponged by lncRNA NEAT1 regulated liver fibrosis via targeting β-catenin/SOX9/TGF-β1 Pathway.
Radiation-induced liver injury and hepatocyte senescence
Authors: Zhu Wei , Zhang Xiaofen , Yu Mengli , Lin Bingru , Yu Chaohui
Published: September 2021

Radiation-induced liver injury (RILI) is a major complication of radiotherapy during treatment for liver cancer and other upper abdominal malignant tumors that has poor pharmacological therapeutic options. A series of pathological changes can be induced by radiation. However, the underlying mechanism of RILI remains unclear. Radiation can induce cell damage via direct energy deposition or reactive free radical generation. Cellular senescence can be observed due to the DNA damage response (DDR) caused by radiation. The senescence-associated secretory phenotype (SASP) secreted from senescent cells can cause chronic inflammation and aggravate liver dysfunction for a long time. Oxidative stress further activates the signaling pathway of the inflammatory response and affects cellular metabolism. miRNAs clearly have differential expression after radiation treatment and take part in RILI development. This review aims to systematically profile the overall mechanism of RILI and the effects of radiation on hepatocyte senescence, laying foundations for the development of new therapies.
Effects of intrapolyp steroid injection on intraocular pressure and recurrent polyp treatment
Authors: Lee Tae-Hoon , Nam Jung-Gwon , Lee Chang Kyu
Published: September 2021

Purpose

To examine the effects of intrapolyp triamcinolone acetonide (TA) injections on intraocular pressure (IOP) and recurrence of nasal polyps after endoscopic sinus surgery.

Patients and methods

This was a prospective, randomized, double-blind, placebo-controlled study. Patients were randomized into either the TA injection group (Group I, 20 mg/ml, 2 mL) or the placebo normal saline injection group (group II, 2 mL). There were a total of five study visits: one baseline visit and one at 2, 4, 8, and 12 w after the injection. The primary safe outcome was the change in IOP between two groups at 4 w. The secondary safe outcome was the IOP at each visit and proportion of patients having IOP above 21 mmHg at 4 and 8 w. Changes in the nasal polyp size were measured between two groups at each visit.

Results

A total of 43 consenting participants completed this study (22 in group I and 21 in group II). The mean IOP elevation in both eyes was not significantly different between the groups (p > 0.05) and was not over 2 mmHg at the 4-w mark. There was also no significant difference in the proportion of patients having IOP above 21 mmHg at 4 and 8 w between the groups (p > 0.05). However, there was a significant difference in the change in polyp size until 8 w between both groups (p < 0.01).

Conclusions

Intrapolyp TA injection is a safe and effective method for the management of recurrent polyps after endoscopic sinus surgery.
Unravelling the therapeutic potential of IL-33 for atrophic AMD
Authors: Clare Alison J. , Liu Jian , Copland David A. , Theodoropoulou Sofia , Dick Andrew D.
Published: September 2021

Age-related macular degeneration (AMD), a degenerative disease affecting the retinal pigment epithelium (RPE) and photoreceptors in the macula, is the leading cause of central blindness in the elderly. AMD progresses to advanced stages of the disease, atrophic AMD (aAMD), or in 15% of cases “wet” or neovascular AMD (nAMD), associated with substantial vision loss. Whilst there has been advancement in therapies treating nAMD, to date, there are no licenced effective treatments for the 85% affected by aAMD, with disease managed by changes to diet, vitamin supplements, and regular monitoring. AMD has a complex pathogenesis, involving highly integrated and common age-related disease pathways, including dysregulated complement/inflammation, impaired autophagy, and oxidative stress. The intricacy of AMD pathogenesis makes therapeutic development challenging and identifying a target that combats the converging disease pathways is essential to provide a globally effective treatment. Interleukin-33 is a cytokine, classically known for the proinflammatory role it plays in allergic disease. Recent evidence across degenerative and inflammatory disease conditions reveals a diverse immune-modulatory role for IL-33, with promising therapeutic potential. Here, we will review IL-33 function in disease and discuss the future potential for this homeostatic cytokine in treating AMD.
Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits
Authors: Palacios-Filardo Jon , Udakis Matt , Brown Giles A. , Tehan Benjamin G. , Congreve Miles S. , Nathan Pradeep J. , Brown Alastair J. H. , Mellor Jack R.
Published: September 2021

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations. An influential but largely untested theory proposes that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory-inhibitory balance and CA1 activation by entorhinal inputs. Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M3 and M4 receptors, respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation.
Deep learning ferroelectric polarization distributions from STEM data via with and without atom finding
Authors: Nelson Christopher T. , Ghosh Ayana , Oxley Mark , Zhang Xiaohang , Ziatdinov Maxim , Takeuchi Ichiro , Kalinin Sergei V.
Published: September 2021

Over the last decade, scanning transmission electron microscopy (STEM) has emerged as a powerful tool for probing atomic structures of complex materials with picometer precision, opening the pathway toward exploring ferroelectric, ferroelastic, and chemical phenomena on the atomic scale. Analyses to date extracting a polarization signal from lattice coupled distortions in STEM imaging rely on discovery of atomic positions from intensity maxima/minima and subsequent calculation of polarization and other order parameter fields from the atomic displacements. Here, we explore the feasibility of polarization mapping directly from the analysis of STEM images using deep convolutional neural networks (DCNNs). In this approach, the DCNN is trained on the labeled part of the image (i.e., for human labelling), and the trained network is subsequently applied to other images. We explore the effects of the choice of the descriptors (centered on atomic columns and grid-based), the effects of observational bias, and whether the network trained on one composition can be applied to a different one. This analysis demonstrates the tremendous potential of the DCNN for the analysis of high-resolution STEM imaging and spectral data and highlights the associated limitations.
Minimal-active-space multistate density functional theory for excitation energy involving local and charge transfer states
Authors: Zhao Ruoqi , Hettich Christian P. , Chen Xin , Gao Jiali
Published: September 2021

Multistate density functional theory (MSDFT) employing a minimum active space (MAS) is presented to determine charge transfer (CT) and local excited states of bimolecular complexes. MSDFT is a hybrid wave function theory (WFT) and density functional theory, in which dynamic correlation is first incorporated in individual determinant configurations using a Kohn–Sham exchange-correlation functional. Then, nonorthogonal configuration-state interaction is performed to treat static correlation. Because molecular orbitals are optimized separately for each determinant by including Kohn–Sham dynamic correlation, a minimal number of configurations in the active space, essential to representing low-lying excited and CT states of interest, is sufficient to yield the adiabatic states. We found that the present MAS-MSDFT method provides a good description of covalent and CT excited states in comparison with experiments and high-level computational results. Because of the simplicity and interpretive capability through diabatic configuration weights, the method may be useful in dynamic simulations of CT and nonadiabatic processes.
Yield of clinically reportable genetic variants in unselected cerebral palsy by whole genome sequencing
Authors: van Eyk C. L. , Webber D. L. , Minoche A. E. , Pérez-Jurado L. A. , Corbett M. A. , Gardner A. E. , Berry J. G. , Harper K. , MacLennan A. H. , Gecz J.
Published: September 2021

Cerebral palsy (CP) is the most common cause of childhood physical disability, with incidence between 1/500 and 1/700 births in the developed world. Despite increasing evidence for a major contribution of genetics to CP aetiology, genetic testing is currently not performed systematically. We assessed the diagnostic rate of genome sequencing (GS) in a clinically unselected cohort of 150 singleton CP patients, with CP confirmed at >4 years of age. Clinical grade GS was performed on the proband and variants were filtered, and classified according to American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines. Variants classified as pathogenic or likely pathogenic (P/LP) were further assessed for their contribution to CP. In total, 24.7% of individuals carried a P/LP variant(s) causing or increasing risk of CP, with 4.7% resolved by copy number variant analysis and 20% carrying single nucleotide or indel variants. A further 34.7% carried one or more rare, high impact variants of uncertain significance (VUS) in variation intolerant genes. Variants were identified in a heterogeneous group of genes, including genes associated with hereditary spastic paraplegia, clotting and thrombophilic disorders, small vessel disease, and other neurodevelopmental disorders. Approximately 1/2 of individuals were classified as likely to benefit from changed clinical management as a result of genetic findings. In addition, no significant association between genetic findings and clinical factors was detectable in this cohort, suggesting that systematic sequencing of CP will be required to avoid missed diagnoses.
Analyzing climate change impacts on health, energy, water resources, and biodiversity sectors for effective climate change policy in South Korea
Authors: Moon Tae Hoon , Chae Yeora , Lee Dong-Sung , Kim Dong-Hwan , Kim Hyun-gyu
Published: September 2021

This study analyzes how climate change affects the economy, society, and environment in South Korea. Then, the study explores the ways to strengthen capabilities that can alleviate climate change impacts. To find them, the study employs a system dynamics simulation method and builds a model with several sectors including the urban, rural, population, and social-environmental sectors. The study compares the size of climate change damages in rural and urban areas. The results with representative concentration path (RCP) 8.5 show that the size of climate change damage will continue to increase by 2050. The projected damages from the reduced industrial outputs in urban areas will be larger than that in rural areas. The results also show that the service sector will face stronger impacts from climate change than the manufacturing and agricultural sectors. However, the total size of damage in the rural areas will be bigger than that of the urban areas. It is because the size of reduced industrial outputs per capita in the rural areas is twice bigger than that of the urban areas. The climate change damage in the social and environmental sectors (including a loss of biodiversity and an increase in health costs) account for the largest part of the total damage. The study finally provides suggestions and policies that can improve the capabilities to reduce the climate change damages. One of the major suggestions of this study is that the increase in the climate change budget corresponding to the GDP growth can minimize the size of climate change impacts.
Cell polarity and cell adhesion associated gene expression differences between invasive micropapillary and no special type breast carcinomas and their prognostic significance
Authors: Kramer Zsófia , Kenessey István , Gángó Ambrus , Lendvai Gábor , Kulka Janina , Tőkés Anna-Mária
Published: September 2021

Invasive micropapillary carcinoma of the breast (IMPC) has been in the focus of several studies given its specific histology and clinicopathological course. We analysed mRNA expression profiles and the prognostic value of 43 genes involved in cell polarity, cell-adhesion and epithelial–mesenchymal transition (EMT) in IMPC tumors and compared them to invasive breast carcinomas of no special type (IBC-NST). IMPCs (36 cases), IBC-NSTs (36 cases) and mixed IMPC-IBC NSTs (8 cases) were investigated. mRNA expression level of selected genes were analysed using the NanoString nCounter Analysis System. Distant metastases free survival (DMFS) intervals were determined. Statistical analysis was performed using Statistica 13.5 software. Twelve genes showed significantly different expression in the IMPC group. There was no difference in DMFS according to histological type (IBC-NST vs. IMPC). High CLDN3, PALS1 and low PAR6 expression levels in the entire cohort were associated with shorter DMFS, and PALS1 was proven to be grade independent prognostic factor. Positive lymph node status was associated with higher levels of AKT1 expression. Differences in gene expression in IMPC versus IBC-NST may contribute to the unique histological appearance of IMPCs. No marked differences were observed in DMFS of the two groups. Altered gene expression in the mTOR signaling pathway in both tumor subtypes highlights the potential benefit from AKT/mTOR inhibitors in IMPCs similarly to IBC-NSTs.
The noncoding RNA LINC00152 conveys contradicting effects in different glioblastoma cells
Authors: Binder Stefanie , Zipfel Ivonne , Müller Claudia , Wiedemann Karolin , Schimmelpfennig Carolin , Pfeifer Gabriele , Reiche Kristin , Hauschildt Sunna , Lehmann Jörg , Köhl Ulrike , Horn Friedemann , Friedrich Maik
Published: September 2021

Glioblastoma multiforme (GBM) is an extremely aggressive brain tumor, characterized by its high genetic heterogeneity. In search of novel putative therapeutic RNA targets we investigated the role of the oncogenic long noncoding RNA LINC00152 (CYTOR, and STAiR18) in A172 glioblastoma cells. Here, we are the first to describe, that LINC00152 unexpectedly acts in a tumor suppressive manner in this cell line. SiRNA-based knockdown of LINC00152 enhanced malignant tumor behaviors including proliferation, cell cycle entry, migration, and invasion, contradicting previous studies using U87-MG and LN229 glioblastoma cells. Furthermore, LINC00152 knockdown had no influence on survival of A172 glioblastoma cells. In a genome wide transcription analysis of A172 and U87-MG glioblastoma cells, we identified 70 LINC00152 target genes involved in locomotion, cell migration, and motility in A172 cells, whereas in U87-MG cells only 40 target genes were detected. The LINC00152-regulated genes found in A172 differed from those identified in U87-MG glioblastoma cells, none of them being regulated in both cell lines. These findings underline the strong genetic heterogeneity of glioblastoma and point to a potential, yet unknown risk addressing LINC00152 lncRNA as a prospective therapeutic target in GBM.
Antitumorigenic effect of insect-derived peptide poecilocorisin-1 in human skin cancer cells through regulation of Sp1 transcription factor
Authors: Lee Ra Ham , Oh Jae-Don , Hwang Jae Sam , Lee Hak-Kyo , Shin Donghyun
Published: September 2021

Malignant melanoma is highly resistant to conventional treatments and is one of the most aggressive types of skin cancers. Conventional cancer treatments are limited due to drug resistance, tumor selectivity, and solubility. Therefore, new treatments with fewer side effects and excellent effects should be developed. In previous studies, we have analyzed antimicrobial peptides (AMPs), which showed antibacterial and anti-inflammatory effects in insects, and some AMPs also exhibited anticancer efficacy. Anticancer peptides (ACPs) are known to have fewer side effects and high anticancer efficacy. In this study, the insect-derived peptide poecilocorisin-1 (PCC-1) did not induce toxicity in the human epithelial cell line HaCaT, but its potential as an anticancer agent was confirmed through specific effects of antiproliferation, apoptosis, and cell cycle arrest in two melanoma cell lines, SK-MEL-28 and G361. Additionally, we discovered a novel anticancer mechanism of insect-derived peptides in melanoma through the regulation of transcription factor Sp1 protein, which is overexpressed in cancer, apoptosis, and cell cycle-related proteins. Taken together, this study aims to clarify the anticancer efficacy and safety of insect-derived peptides and to present their potential as future therapeutic agents.
A nationwide study of patients with monoclonal gammopathy of undetermined significance with a 10-year follow-up in South Korea
Authors: Kang Ka-Won , Song Ji Eun , Lee Byung-Hyun , Jeon Min Ji , Yu Eun Sang , Kim Dae Sik , Lee Se Ryeon , Sung Hwa Jung , Choi Chul Won , Park Yong , Kim Byung Soo
Published: September 2021

In clinical practice, most patients with monoclonal gammopathy of undetermined significance (MGUS) undergo long-term follow-up without disease progression. There is insufficient real-world data about how closely and whether anything other than disease progression should be monitored. Herein, we performed a nationwide study of 470 patients with MGUS with a 10-year follow-up to determine the patterns of disease progression and other comorbidities. During the follow-up period, 158 of 470 patients with MGUS (33.62%) progressed to symptomatic monoclonal gammopathies. Most of these were multiple myeloma (134/470 patients, 28.51%), and those diagnosed within 2 years after diagnosis of MGUS was high. Approximately 30–50% of patients with MGUS had hypertension, diabetes, hyperlipidemia, and osteoarthritis at the time of diagnosis, and these comorbidities were newly developed during the follow-up period in approximately 50% of the remaining patients with MGUS. Approximately 20–40% of patients with MGUS have acute or chronic kidney failure, thyroid disorders, disc disorders, peripheral neuropathy, myocardial infarction, stroke, and heart failure during the follow-up period. Altogether, when MGUS is diagnosed, close follow-up of the possibility of progression to multiple myeloma is required, especially within 2 years after diagnosis; simultaneously, various comorbidities should be considered and monitored during the follow-up of patients with MGUS. Continuous research is needed to establish appropriate follow-up guidelines.
Single-cell adhesion strength and contact density drops in the M phase of cancer cells
Authors: Ungai-Salánki Rita , Haty Eleonóra , Gerecsei Tamás , Francz Barbara , Béres Bálint , Sztilkovics Milán , Székács Inna , Szabó Bálint , Horvath Robert
Published: September 2021

The high throughput, cost effective and sensitive quantification of cell adhesion strength at the single-cell level is still a challenging task. The adhesion force between tissue cells and their environment is crucial in all multicellular organisms. Integrins transmit force between the intracellular cytoskeleton and the extracellular matrix. This force is not only a mechanical interaction but a way of signal transduction as well. For instance, adhesion-dependent cells switch to an apoptotic mode in the lack of adhesion forces. Adhesion of tumor cells is a potential therapeutic target, as it is actively modulated during tissue invasion and cell release to the bloodstream resulting in metastasis. We investigated the integrin-mediated adhesion between cancer cells and their RGD (Arg-Gly-Asp) motif displaying biomimetic substratum using the HeLa cell line transfected by the Fucci fluorescent cell cycle reporter construct. We employed a computer-controlled micropipette and a high spatial resolution label-free resonant waveguide grating-based optical sensor calibrated to adhesion force and energy at the single-cell level. We found that the overall adhesion strength of single cancer cells is approximately constant in all phases except the mitotic (M) phase with a significantly lower adhesion. Single-cell evanescent field based biosensor measurements revealed that at the mitotic phase the cell material mass per unit area inside the cell-substratum contact zone is significantly less, too. Importantly, the weaker mitotic adhesion is not simply a direct consequence of the measured smaller contact area. Our results highlight these differences in the mitotic reticular adhesions and confirm that cell adhesion is a promising target of selective cancer drugs as the vast majority of normal, differentiated tissue cells do not enter the M phase and do not divide.
A forward genetic screen identifies modifiers of rocaglate responsiveness
Authors: Shen Leo , Pugsley Lauren , Cencic Regina , Wang HanChen , Robert Francis , Naineni Sai Kiran , Sahni Ananya , Morin Geneviève , Zhang Wenhan , Nijnik Anastasia , Porco John A. , Langlais David , Huang Sidong , Pelletier Jerry
Published: September 2021

Rocaglates are a class of eukaryotic translation initiation inhibitors that are being explored as chemotherapeutic agents. They function by targeting eukaryotic initiation factor (eIF) 4A, an RNA helicase critical for recruitment of the 40S ribosome (and associated factors) to mRNA templates. Rocaglates perturb eIF4A activity by imparting a gain-of-function activity to eIF4A and mediating clamping to RNA. To appreciate how rocaglates could best be enabled in the clinic, an understanding of resistance mechanisms is important, as this could inform on strategies to bypass such events as well as identify responsive tumor types. Here, we report on the results of a positive selection, ORFeome screen aimed at identifying cDNAs capable of conferring resistance to rocaglates. Two of the most potent modifiers of rocaglate response identified were the transcription factors FOXP3 and NR1I3, both of which have been implicated in ABCB1 regulation—the gene encoding P-glycoprotein (Pgp). Pgp has previously been implicated in conferring resistance to silvestrol, a naturally occurring rocaglate, and we show here that this extends to additional synthetic rocaglate derivatives. In addition, FOXP3 and NR1I3 impart a multi-drug resistant phenotype that is reversed upon inhibition of Pgp, suggesting a potential therapeutic combination strategy.
Evaluation of endothelial function and subclinical atherosclerosis in patients with HIV infection
Authors: Arnaiz de las Revillas F. , Gonzalez-Quintanilla V. , Parra J. A. , Palacios E. , Gonzalez-Rico C. , Armiñanzas C. , Gutiérrez-Cuadra M. , Oterino A. , Fariñas-Alvarez C. , Fariñas M. C.
Published: September 2021

The aim of this study was to analyse the association between human immunodeficiency virus (HIV) related clinical and analytical parameters and the presence of subclinical atherosclerosis as well as endothelial dysfunction. This was a prospective cohort study of HIV-positive patients who underwent intima media thickness (IMT) determination and coronary artery calcium scoring to determine subclinical atherosclerosis. To detect endothelial dysfunction, the breath holding index, flow-mediated dilation and the concentration of endothelial progenitor cells (EPCs) were measured. Patients with an IMT ≥ 0.9 mm had an average of 559.3 ± 283.34 CD4/μl, and those with an IMT < 0.9 mm had an average of 715.4 ± 389.92 CD4/μl (p = 0.04). Patients with a low calcium score had a significantly higher average CD4 cell value and lower zenith viral load (VL) than those with a higher score (707.7 ± 377.5 CD4/μl vs 477.23 ± 235.7 CD4/μl (p = 0.01) and 7 × 104 ± 5 × 104 copies/ml vs 23.4 × 104 ± 19 × 104 copies/ml (p = 0.02)). The number of early EPCs in patients with a CD4 nadir < 350/µl was lower than that in those with a CD4 nadir ≥ 350 (p = 0.03). In HIV-positive patients, low CD4 cell levels and high VL were associated with risk of developing subclinical atherosclerosis. HIV patients with CD4 cell nadir < 350/µl may have fewer early EPCs.