bluuebunny/crossref_metadata_2025 huggingface dataset:
Hurricane or fresh breeze? Disentangling the populist effect on the quality of democracy
Authors: Juon Andreas , Bochsler Daniel
Published: June 2020

Are populist actors more like a hurricane that risks undermining democracy? Or do they aim for a different type of democracy, which strengthens popular control? This article offers one of the most extensive, systematic analyses on the impact of populism on multiple functions of the Quality of Democracy. Going beyond the view of ‘high-’ or ‘low-quality’ democracies, we emphasize that the Quality of Democracy is related to multiple dimensions or ‘functions of democracy’, characterized by important trade-offs. We argue that populist actors exert differentiated effects across these functions, depending on their degree of government access and host ideology. Our analysis relies on a new disaggregated dataset covering 53 established democracies in diverse world regions over the period between 1990 and 2016. We find that populist actors increase participation and representation, especially if they are confined to the opposition and especially if they belong to the political left-wing. In contrast, we find a negative impact of populists across the spectrum on institutional safeguards, such as the rule of law and state transparency. In sum, our findings indicate that populism has a variable impact on multiple aspects of democratic quality which should be systematically investigated in a disaggregated manner that is sensitive to these differences.
Intermittent explosive disorder subtypes in the general population: association with comorbidity, impairment and suicidality
Authors: Scott K. M. , de Vries Y. A. , Aguilar-Gaxiola S. , Al-Hamzawi A. , Alonso J. , Bromet E. J. , Bunting B. , Caldas-de-Almeida J. M. , Cía A. , Florescu S. , Gureje O. , Hu C-Y. , Karam E. G. , Karam A. , Kawakami N. , Kessler R. C. , Lee S. , McGrath J. , Oladeji B. , Posada-Villa J. , Stein D. J. , Zarkov Z. , de Jonge P.
Published: June 2020

Aims

Intermittent explosive disorder (IED) is characterised by impulsive anger attacks that vary greatly across individuals in severity and consequence. Understanding IED subtypes has been limited by lack of large, general population datasets including assessment of IED. Using the 17-country World Mental Health surveys dataset, this study examined whether behavioural subtypes of IED are associated with differing patterns of comorbidity, suicidality and functional impairment.

Methods

IED was assessed using the Composite International Diagnostic Interview in the World Mental Health surveys (n = 45 266). Five behavioural subtypes were created based on type of anger attack. Logistic regression assessed association of these subtypes with lifetime comorbidity, lifetime suicidality and 12-month functional impairment.

Results

The lifetime prevalence of IED in all countries was 0.8% (s.e.: 0.0). The two subtypes involving anger attacks that harmed people (‘hurt people only’ and ‘destroy property and hurt people’), collectively comprising 73% of those with IED, were characterised by high rates of externalising comorbid disorders. The remaining three subtypes involving anger attacks that destroyed property only, destroyed property and threatened people, and threatened people only, were characterised by higher rates of internalising than externalising comorbid disorders. Suicidal behaviour did not vary across the five behavioural subtypes but was higher among those with (v. those without) comorbid disorders, and among those who perpetrated more violent assaults.

Conclusions

The most common IED behavioural subtypes in these general population samples are associated with high rates of externalising disorders. This contrasts with the findings from clinical studies of IED, which observe a preponderance of internalising disorder comorbidity. This disparity in findings across population and clinical studies, together with the marked heterogeneity that characterises the diagnostic entity of IED, suggests that it is a disorder that requires much greater research.
Structural and Geophysical Characterization of the Western Termination of the South Pyrenean Triangle Zone
Authors: Santolaria P. , Ayala C. , Pueyo E. L. , Rubio F. M. , Soto R. , Calvín P. , Luzón A. , Rodríguez‐Pintó A. , Oliván C. , Casas‐Sainz A. M.
Published: June 2020

The South Pyrenean triangle zone represents the southernmost front of the Pyrenees at its central portion deforming the Upper Eocene‐Miocene Ebro Basin deposits. Two main structures characterize its western termination, the Barbastro anticline and the San Román backthrust, which detached on the Barbastro Formation (and lateral equivalents), an Upper Eocene‐Lower Oligocene syntectonic evaporite‐rich formation that acted as a multidetachment unit. Northward, the south directed Pyrenean thrust unit (i.e., Gavarnie‐Sierras thrust sheet) detached along the Middle‐Upper Triassic evaporitic rocks to finally ramp up and glide along the same Upper Eocene‐Lower Oligocene multidetachment unit. A multidisciplinary approach allowed constructing a detailed structural and stratigraphic model of the study area. The workflow consisted of (1) constraining the geometry and structural architecture based on surface geology, interpretation of seismic lines (>900 km), and wells and (2) obtaining the 3‐D density distribution of the multidetachment unit using gravity stochastic inversion (more than 7,000 gravity stations and 1,500 density data). The geometry of the sole thrust of the Gavarnie‐Sierras thrust sheet was controlled by the distribution of the evaporite‐rich units of the Barbastro Fm. Weak detachments promoted thrust salient formation and thrust flat geometries. The western termination of the South Pyrenean triangle zone is defined as a westward transition from a ramp‐dominated and multiple triangle zone to a detachment‐dominated one. Its geometry, kinematics, and location were controlled by the heterogeneous lithology of the Barbastro Fm. and its basal, halite‐based detachment southern pinch‐out.
The Evolving Paleobathymetry of the Circum‐Antarctic Southern Ocean Since 34 Ma: A Key to Understanding Past Cryosphere‐Ocean Developments
Authors: Hochmuth K. , Gohl K. , Leitchenkov G. , Sauermilch I. , Whittaker J. M. , Uenzelmann‐Neben G. , Davy B. , De Santis L.
Published: June 2020

The Southern Ocean is a key player in the climate, ocean, and atmospheric system. As the only direct connection between all three major oceans since the opening of the Southern Ocean gateways, the development of the Southern Ocean and its relationship with the Antarctic cryosphere has influenced the climate of the entire planet. Although the depths of the ocean floor have been recognized as an important factor in climate and paleoclimate models, appropriate paleobathymetric models including a detailed analysis of the sediment cover are not available. Here we utilize more than 40 years of seismic reflection data acquisition along the margins of Antarctica and its conjugate margins, along with multiple drilling campaigns by the International Ocean Discovery Program (IODP) and its predecessor programs. We combine and update the seismic stratigraphy across the regions of the Southern Ocean and calculate ocean‐wide paleobathymetry grids via a backstripping method. We present a suite of high‐resolution paleobathymetric grids from the Eocene‐Oligocene Boundary to modern times. The grids reveal the development of the Southern Ocean from isolated basins to an interconnected ocean affected by the onset and vigor of an Antarctic Circumpolar Current, as well as the glacial sedimentation and erosion of the Antarctic continent. The ocean‐wide comparison through time exposes patterns of ice sheet development such as switching of glacial outlets and the change from wet‐based to dry‐based ice sheets. Ocean currents and bottom‐water production interact with the sedimentation along the continental shelf and slope and profit from the opening of the ocean gateways.
Fine Structure of the Chenghai Fault Zone, Yunnan, China, Constrained From Teleseismic Travel Time and Ambient Noise Tomography
Authors: Yang Hongfeng , Duan Yaohui , Song Junhao , Jiang Xiaohuan , Tian Xiaofeng , Yang Wei , Wang Weitao , Yang Jun
Published: June 2020

To derive high‐resolution fault zone (FZ) structure of the Chenghai fault in Yunnan, southwestern China, we deployed a linear dense array crossing the fault from January to February 2018. The array consisted of 158 short‐period (5 s) three‐component instruments and spanned an aperture of ~8 km with average station spacing of 40–50 m. During the 1‐month deployment, 20 teleseismic earthquakes with moment magnitudes larger than 5.5 and 41 local earthquakes were recorded. We first analyzed the travel times of P and S waves from teleseismic earthquakes to determine the boundaries of the FZ. After correcting the station‐event geometry effects, teleseismic travel time differences between the reference station, and all other stations clearly marked a zone of 3.4 km in width with distinct travel time anomaly, suggesting a low‐velocity zone (LVZ) surrounding the Chenghai fault. We then conducted ambient noise tomography and found that the S wave velocity of the LVZ was reduced by 60% and 40% compared to the northwest and southeast of the LVZ, respectively. Our ambient noise results suggested the LVZ extending to ~1.5 km in depth, consistent with the travel time anomalies of teleseismic earthquakes. Integrating ambient noise tomography with teleseismic travel times in a dense array with such an aperture is an effective approach for resolving FZ structure and depth extent.
Assessment of Observational Evidence for Direct Convective Hydration of the Lower Stratosphere
Authors: Jensen E. J. , Pan Laura L. , Honomichl Shawn , Diskin Glenn S. , Krämer Martina , Spelten Nicole , Günther Gebhard , Hurst Dale F. , Fujiwara Masatomo , Vömel Holger , Selkirk Henry B. , Suzuki Junko , Schwartz Michael J. , Smith Jessica B.
Published: June 2020

In situ and remote sensing observations of water vapor are analyzed to assess the evidence for direct convective hydration of the lower stratosphere. We have examined several hundred balloon‐borne and airborne in situ measurements of lower stratospheric humidity in the tropics and northern midlatitudes. We find that the tropical lower stratospheric H2O enhancements above the background occur quite infrequently, and the height of the enhancements is within about 1 km of the cold‐point tropopause. Following Schwartz et al. (2013, https://doi.org/10.1002/grl.50421), we examine the anomalously high (above 8 ppmv) water vapor mixing ratios retrieved by the Aura Microwave Limb Sounder (MLS) at 100‐ and 82‐hPa pressure levels, and we determine their vertical location relative to the local tropopause based on both Global Forecast System (GFS) operational analysis and the ERA5 reanalysis temperature data. We find that essentially all of the >8‐ppmv MLS water vapor measurements over the extratropical North American monsoon region are above the relatively low lapse‐rate tropopause in the region, and most are above the local cold‐point tropopause. Over the Asian monsoon region, most (80/90%) of the high H2O values occur below the relatively high‐altitude local lapse‐rate/cold‐point tropopause. Anomalously high MLS water vapor retrievals at 100 and 82 hPa almost never occur in the deep tropics. We show that this result is consistent with the in situ observations given the broad vertical averaging kernel of the MLS measurement. The available evidence suggests that direct hydration of the lower stratosphere is important over North America during the monsoon season but likely has limited impact in the tropics.
Gα12/13 signaling in metabolic diseases
Authors: Yang Yoon Mee , Kuen Da-Sol , Chung Yeonseok , Kurose Hitoshi , Kim Sang Geon
Published: June 2020

As the key governors of diverse physiological processes, G protein-coupled receptors (GPCRs) have drawn attention as primary targets for several diseases, including diabetes and cardiovascular disease. Heterotrimeric G proteins converge signals from ~800 members of the GPCR family. Among the members of the G protein α family, the Gα12 family members comprising Gα12 and Gα13 have been referred to as gep oncogenes. Gα12/13 levels are altered in metabolic organs, including the liver and muscles, in metabolic diseases. The roles of Gα12/13 in metabolic diseases have been investigated. In this review, we highlight findings demonstrating Gα12/13 amplifying or dampening regulators of phenotype changes. We discuss the molecular basis of G protein biology in the context of posttranslational modifications to heterotrimeric G proteins and the cell signaling axis. We also highlight findings providing insights into the organ-specific, metabolic and pathological roles of G proteins in changes associated with specific cells, energy homeostasis, glucose metabolism, liver fibrosis and the immune and cardiovascular systems. This review summarizes the currently available knowledge on the importance of Gα12/13 in the physiology and pathogenesis of metabolic diseases, which is presented according to the basic understanding of their metabolic actions and underlying cellular and molecular bases.
Deazaflavin reductive photocatalysis involves excited semiquinone radicals
Authors: Graml Andreas , Neveselý Tomáš , Jan Kutta Roger , Cibulka Radek , König Burkhard
Published: June 2020

Flavin-mediated photocatalytic oxidations are established in synthetic chemistry. In contrast, their use in reductive chemistry is rare. Deazaflavins with a much lower reduction potential are even better suited for reductive chemistry rendering also deazaflavin semiquinones as strong reductants. However, no direct evidence exists for the involvement of these radical species in reductive processes. Here, we synthesise deazaflavins with different substituents at C5 and demonstrate their photocatalytic activity in the dehalogenation of p-halogenanisoles with best performance under basic conditions. Mechanistic investigations reveal a consecutive photo-induced electron transfer via the semiquinone form of the deazaflavin as part of a triplet-correlated radical pair after electron transfer from a sacrificial electron donor to the triplet state. A second electron transfer from the excited semiquinone to p-halogenanisoles triggers the final product formation. This study provides first evidence that the reductive power of excited deazaflavin semiquinones can be used in photocatalytic reductive chemistry.
Diaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment
Authors: Mei Yang , Han Xu , Liu Yijie , Yang Jing , Sumagin Ronen , Ji Peng
Published: June 2020

Bone marrow engraftment of the hematopoietic stem and progenitor cells (HSPCs) involves homing to the vasculatures and lodgment to their niches. How HSPCs transmigrate from the vasculature to the niches is unclear. Here, we show that loss of diaphanous-related formin mDia2 leads to impaired engraftment of long-term hematopoietic stem cells and loss of competitive HSPC repopulation. These defects are likely due to the compromised trans-endothelial migration of HSPCs since their homing to the bone marrow vasculatures remained intact. Mechanistically, loss of mDia2 disrupts HSPC polarization and induced cytoplasmic accumulation of MAL, which deregulates the activity of serum response factor (SRF). We further reveal that beta2 integrins are transcriptional targets of SRF. Knockout of beta2 integrins in HSPCs phenocopies mDia2 deficient mice. Overexpression of SRF or beta2 integrins rescues HSPC engraftment defects associated with mDia2 deficiency. Our findings show that mDia2-SRF-beta2 integrin signaling is critical for HSPC lodgment to the niches.
An amphipathic peptide with antibiotic activity against multidrug-resistant Gram-negative bacteria
Authors: Elliott Alysha G. , Huang Johnny X. , Neve Søren , Zuegg Johannes , Edwards Ingrid A. , Cain Amy K. , Boinett Christine J. , Barquist Lars , Lundberg Carina Vingsbo , Steen Jason , Butler Mark S. , Mobli Mehdi , Porter Kaela M. , Blaskovich Mark A. T. , Lociuro Sergio , Strandh Magnus , Cooper Matthew A.
Published: June 2020

Peptide antibiotics are an abundant and synthetically tractable source of molecular diversity, but they are often cationic and can be cytotoxic, nephrotoxic and/or ototoxic, which has limited their clinical development. Here we report structure-guided optimization of an amphipathic peptide, arenicin-3, originally isolated from the marine lugworm Arenicola marina. The peptide induces bacterial membrane permeability and ATP release, with serial passaging resulting in a mutation in mlaC, a phospholipid transport gene. Structure-based design led to AA139, an antibiotic with broad-spectrum in vitro activity against multidrug-resistant and extensively drug-resistant bacteria, including ESBL, carbapenem- and colistin-resistant clinical isolates. The antibiotic induces a 3–4 log reduction in bacterial burden in mouse models of peritonitis, pneumonia and urinary tract infection. Cytotoxicity and haemolysis of the progenitor peptide is ameliorated with AA139, and the ‘no observable adverse effect level’ (NOAEL) dose in mice is ~10-fold greater than the dose generally required for efficacy in the infection models.
Contribution of land use to the interannual variability of the land carbon cycle
Authors: Yue Chao , Ciais Philippe , Houghton Richard A. , Nassikas Alexander A.
Published: June 2020

Understanding the driving mechanisms of the interannual variability (IAV) of the net land carbon balance (Snet) is important to predict future climate–carbon cycle feedbacks. Past studies showed that the IAV of Snet was correlated with tropical climate variation and controlled by semiarid vegetation. But today’s land ecosystems are also under extensive human land use and management. Here, we report a previously hidden role of land use in driving the IAV of Snet by using an improved biosphere model. We found that managed land accounted for 30–45% of the IAV of Snet over 1959–2015, while the contribution of intact land is reduced by more than half compared with previous assessments of the global carbon budget. Given the importance of land use in modulating future land climate–carbon cycle feedbacks, climate mitigation efforts should strive to reduce land-use emissions and enhance the climate resilience of carbon sinks over managed land.
Widespread transcript shortening through alternative polyadenylation in secretory cell differentiation
Authors: Cheng Larry C. , Zheng Dinghai , Baljinnyam Erdene , Sun Fangzheng , Ogami Koichi , Yeung Percy Luk , Hoque Mainul , Lu Chi-Wei , Manley James L. , Tian Bin
Published: June 2020

Most eukaryotic genes produce alternative polyadenylation (APA) isoforms. Here we report that, unlike previously characterized cell lineages, differentiation of syncytiotrophoblast (SCT), a cell type critical for hormone production and secretion during pregnancy, elicits widespread transcript shortening through APA in 3’UTRs and in introns. This global APA change is observed in multiple in vitro trophoblast differentiation models, and in single cells from placentas at different stages of pregnancy. Strikingly, the transcript shortening is unrelated to cell proliferation, a feature previously associated with APA control, but instead accompanies increased secretory functions. We show that 3’UTR shortening leads to transcripts with higher mRNA stability, which augments transcriptional activation, especially for genes involved in secretion. Moreover, this mechanism, named secretion-coupled APA (SCAP), is also executed in B cell differentiation to plasma cells. Together, our data indicate that SCAP tailors the transcriptome during formation of secretory cells, boosting their protein production and secretion capacity.
The NIN transcription factor coordinates CEP and CLE signaling peptides that regulate nodulation antagonistically
Authors: Laffont Carole , Ivanovici Ariel , Gautrat Pierre , Brault Mathias , Djordjevic Michael Anthony , Frugier Florian
Published: June 2020

Legumes tightly regulate nodule number to balance the cost of supporting symbiotic rhizobia with the benefits of nitrogen fixation. C-terminally Encoded Peptides (CEPs) and CLAVATA3-like (CLE) peptides positively and negatively regulate nodulation, respectively, through independent systemic pathways, but how these regulations are coordinated remains unknown. Here, we show that rhizobia, Nod Factors, and cytokinins induce a symbiosis-specific CEP gene, MtCEP7, which positively regulates rhizobial infection. Via grafting and split root studies, we reveal that MtCEP7 increases nodule number systemically through the MtCRA2 receptor. MtCEP7 and MtCLE13 expression in rhizobia-inoculated roots rely on the MtCRE1 cytokinin receptor and on the MtNIN transcription factor. MtNIN binds and transactivates Mt
CEP7 and MtCLE13, and a NIN Binding Site (NBS) identified within the proximal MtCEP7 promoter is required for its symbiotic activation. Overall, these results demonstrate that a cytokinin-MtCRE1-MtNIN regulatory module coordinates the expression of two antagonistic, symbiosis-related, peptide hormones from different families to fine-tune nodule number.
Rad9/53BP1 promotes DNA repair via crossover recombination by limiting the Sgs1 and Mph1 helicases
Authors: Ferrari Matteo , Rawal Chetan C. , Lodovichi Samuele , Vietri Maria Y. , Pellicioli Achille
Published: June 2020

The DNA damage checkpoint (DDC) is often robustly activated during the homologous recombination (HR) repair of DNA double strand breaks (DSBs). DDC activation controls several HR repair factors by phosphorylation, preventing premature segregation of entangled chromosomes formed during HR repair. The DDC mediator 53BP1/Rad9 limits the nucleolytic processing (resection) of a DSB, controlling the formation of the 3′ single-stranded DNA (ssDNA) filament needed for recombination, from yeast to human. Here we show that Rad9 promotes stable annealing between the recombinogenic filament and the donor template in yeast, limiting strand rejection by the Sgs1 and Mph1 helicases. This regulation allows repair by long tract gene conversion, crossover recombination and break-induced replication (BIR), only after DDC activation. These findings shed light on how cells couple DDC with the choice and effectiveness of HR sub-pathways, with implications for genome instability and cancer.
Comparative targeting analysis of KLF1, BCL11A, and HBG1/2 in CD34+ HSPCs by CRISPR/Cas9 for the induction of fetal hemoglobin
Authors: Lamsfus-Calle Andrés , Daniel-Moreno Alberto , Antony Justin S. , Epting Thomas , Heumos Lukas , Baskaran Praveen , Admard Jakob , Casadei Nicolas , Latifi Ngadhnjim , Siegmund Darina M. , Kormann Michael S. D. , Handgretinger Rupert , Mezger Markus
Published: June 2020

β-hemoglobinopathies are caused by abnormal or absent production of hemoglobin in the blood due to mutations in the β-globin gene (HBB). Imbalanced expression of adult hemoglobin (HbA) induces strong anemia in patients suffering from the disease. However, individuals with natural-occurring mutations in the HBB cluster or related genes, compensate this disparity through γ-globin expression and subsequent fetal hemoglobin (HbF) production. Several preclinical and clinical studies have been performed in order to induce HbF by knocking-down genes involved in HbF repression (KLF1 and BCL11A) or disrupting the binding sites of several transcription factors in the γ-globin gene (HBG1/2). In this study, we thoroughly compared the different CRISPR/Cas9 gene-disruption strategies by gene editing analysis and assessed their safety profile by RNA-seq and GUIDE-seq. All approaches reached therapeutic levels of HbF after gene editing and showed similar gene expression to the control sample, while no significant off-targets were detected by GUIDE-seq. Likewise, all three gene editing platforms were established in the GMP-grade CliniMACS Prodigy, achieving similar outcome to preclinical devices. Based on this gene editing comparative analysis, we concluded that BCL11A is the most clinically relevant approach while HBG1/2 could represent a promising alternative for the treatment of β-hemoglobinopathies.
Multi-Domain Negative Capacitance Effects in Metal-Ferroelectric-Insulator-Semiconductor/Metal Stacks: A Phase-field Simulation Based Study
Authors: Saha Atanu K. , Gupta Sumeet K.
Published: June 2020

We analyze the ferroelectric domain-wall induced negative capacitance (NC) effect in Metal-FE-Insulator-Metal (MFIM) and Metal-FE-Insulator-Semiconductor (MFIS) stacks through phase-field simulations by self-consistently solving time-dependent Ginzburg Landau equation, Poisson’s equation and semiconductor charge equations. Considering Hf0.5Zr0.5O2 as the ferroelectric material, we study 180° ferroelectric domain formation in MFIM and MFIS stacks and their polarization switching characteristics. Our analysis signifies that the applied voltage-induced polarization switching via soft domain-wall displacement exhibits non-hysteretic characteristics. In addition, the change in domain-wall energy, due to domain-wall displacement, exhibits a long-range interaction and thus, leads to a non-homogeneous effective local negative permittivity in the ferroelectric. Such effects yield an average negative effective permittivity that further provides an enhanced charge response in the MFIM stack, compared to Metal-Insulator-Metal. Furthermore, we show that the domain-wall induced negative effective permittivity is not an intrinsic property of the ferroelectric material and therefore, is dependent on its thickness, the gradient energy coefficient and the in-plane permittivity of the underlying insulator. Similar to the MFIM stack, MFIS stack also exhibits an enhanced charge/capacitance response compared to Metal-Oxide-Semiconductor (MOS) capacitor. Simultaneously, the multi-domain state of the ferroelectric induces non-homogeneous potential in the underlying insulator and semiconductor layer. At low applied voltages, such non-homogeneity leads to the co-existence of electrons and holes in an undoped semiconductor. In addition, we show that with the ferroelectric layer being in the 180° multi-domain state, the minimum potential at the ferroelectric-dielectric interface and hence, the minimum surface potential in the semiconductor, does not exceed the applied voltage (in-spite of the local differential amplification and charge enhancement).
The hydrolytic water molecule of Class A β-lactamase relies on the acyl-enzyme intermediate ES* for proper coordination and catalysis
Authors: He Yunjiao , Lei Jinping , Pan Xuehua , Huang Xuhui , Zhao Yanxiang
Published: June 2020

Serine-based β-lactamases of Class A, C and D all rely on a key water molecule to hydrolyze and inactivate β-lactam antibiotics. This process involves two conserved catalytic steps. In the first acylation step, the β-lactam antibiotic forms an acyl-enzyme intermediate (ES*) with the catalytic serine residue. In the second deacylation step, an activated water molecule serves as nucleophile (WAT_Nu) to attack ES* and release the inactivated β-lactam. The coordination and activation of WAT_Nu is not fully understood. Using time-resolved x-ray crystallography and QM/MM simulations, we analyzed three intermediate structures of Class A β-lactamase PenP as it slowly hydrolyzed cephaloridine. WAT_Nu is centrally located in the apo structure but becomes slightly displaced away by ES* in the post-acylation structure. In the deacylation structure, WAT_Nu moves back and is positioned along the Bürgi–Dunitz trajectory with favorable energetic profile to attack ES*. Unexpectedly, WAT_Nu is also found to adopt a catalytically incompetent conformation in the deacylation structure forming a hydrogen bond with ES*. Our results reveal that ES* plays a significant role in coordinating and activating WAT_Nu through subtle yet distinct interactions at different stages of the catalytic process. These interactions may serve as potential targets to circumvent β-lactamase-mediated antibiotic resistance.
Amyloid precursor protein-b facilitates cell adhesion during early development in zebrafish
Authors: Banote Rakesh Kumar , Chebli Jasmine , Şatır Tuğçe Munise , Varshney Gaurav K. , Camacho Rafael , Ledin Johan , Burgess Shawn M. , Abramsson Alexandra , Zetterberg Henrik
Published: June 2020

Understanding the biological function of amyloid beta (Aβ) precursor protein (APP) beyond its role in Alzheimer’s disease is emerging. Yet, its function during embryonic development is poorly understood. The zebrafish APP orthologue, Appb, is strongly expressed during early development but thus far has only been studied via morpholino-mediated knockdown. Zebrafish enables analysis of cellular processes in an ontogenic context, which is limited in many other vertebrates. We characterized zebrafish carrying a homozygous mutation that introduces a premature stop in exon 2 of the appb gene. We report that appb mutants are significantly smaller until 2 dpf and display perturbed enveloping layer (EVL) integrity and cell protrusions at the blastula stage. Moreover, appb mutants surviving beyond 48 hpf exhibited no behavioral defects at 6 dpf and developed into healthy and fertile adults. The expression of the app family member, appa, was also found to be altered in appb mutants. Taken together, we show that appb is involved in the initial development of zebrafish by supporting the integrity of the EVL, likely by mediating cell adhesion properties. The loss of Appb might then be compensated for by other app family members to maintain normal development.
Evidence of Inverse Hall-Petch Behavior and Low Friction and Wear in High Entropy Alloys
Authors: Jones Morgan R. , Nation Brendan L. , Wellington-Johnson John A. , Curry John F. , Kustas Andrew B. , Lu Ping , Chandross Michael , Argibay Nicolas
Published: June 2020

We present evidence of inverse Hall-Petch behavior for a single-phase high entropy alloy (CoCrFeMnNi) in ultra-high vacuum and show that it is associated with low friction coefficients (~0.3). Grain size measurements by STEM validate a recently proposed dynamic amorphization model that accurately predicts grain size-dependent shear strength in the inverse Hall-Petch regime. Wear rates in the initially soft (coarse grained) material were shown to be remarkably low (~10–6mm3/N-m), the lowest for any HEA tested in an inert environment where oxidation and the formation of mixed metal-oxide films is mitigated. The combined high wear resistance and low friction are linked to the formation of an ultra-nanocrystalline near-surface layer. The dynamic amorphization model was also used to predict an average high angle grain boundary energy (0.87 J/m2). This value was used to explain cavitation-induced nanoporosity found in the highly deformed surface layer, a phenomenon that has been linked to superplasticity.
The Contribution of Oculomotor Functions to Rates of Visual Information Processing in Younger and Older Adults
Authors: Ebaid Deena , Crewther Sheila G.
Published: June 2020

Oculomotor functions are established surrogate measures of visual attention shifting and rate of information processing, however, the temporal characteristics of saccades and fixations have seldom been compared in healthy educated samples of younger and older adults. Thus, the current study aimed to compare duration of eye movement components in younger (18–25 years) and older (50–81 years) adults during text reading and during object/alphanumeric Rapid Automatic Naming (RAN) tasks. The current study also aimed to examine the contribution of oculomotor functions to threshold time needed for accurate performance on visually-driven cognitive tasks (Inspection Time [IT] and Change Detection [CD]). Results showed that younger adults fixated on individual stimuli for significantly longer than the older participants, while older adults demonstrated significantly longer saccade durations than the younger group. Results also demonstrated that older adults required longer threshold durations (i.e., performed slower) on the visually-driven cognitive tasks, however, the age-group time difference on the CD task was eradicated when the effects of saccade duration were covaried. Thus, these results suggest that age-related cognitive decline is also related to increased duration of saccades and hence, highlights the need to dissociate the age-related motor constraints on the temporal aspects of oculomotor function from visuo-cognitive speed of processing.
Bird-livestock interactions associated with increased cattle fecal shedding of ciprofloxacin-resistant Escherichia coli within feedlots in the United States
Authors: Carlson James C. , Chandler Jeffrey C. , Bisha Bledar , LeJeune Jeffrey T. , Wittum Thomas E.
Published: June 2020

This research study was conducted to determine if bird depredation in feedlots is associated with the prevalence of ciprofloxacin-resistantEscherichia coliin cattle and to determine if removal of invasive bird species could be an effective management strategy to help reduce ciprofloxacin-resistantE. coliin cattle within the United States. European starlings (Sturnus vulgaris) were collected from feedlots within multiple geographic regions within the United States and European starlings within all regions tested positive for ciprofloxacin-resistantE. coli, but prevalence differed by region. Total number of birds on feedlots were positively associated with increased cattle fecal shedding of ciprofloxacin-resistantE. coli. Targeted control of invasive European starlings reduced bird numbers on feedlots by 70.4%, but decreasing populations of European starlings was not associated with corresponding reductions in bovine fecal prevalence of ciprofloxacin-resistantE. coli. These data provide evidence for the role of wild bird depredation in feedlots contributing to fecal shedding of ciprofloxacin-resistantE. coli, but a single month of European starling control in feedlots was not sufficient to impact the fecal carriage of this organism in cattle.
Characterisation of CaCO3 phases during strain-specific ureolytic precipitation
Authors: Clarà Saracho Alexandra , Haigh Stuart K. , Hata Toshiro , Soga Kenichi , Farsang Stefan , Redfern Simon A. T. , Marek Ewa
Published: June 2020

Numerous microbial species can selectively precipitate mineral carbonates with enhanced mechanical properties, however, understanding exactly how they achieve this control represents a major challenge in the field of biomineralisation. We have studied microbial induced calcium carbonate (CaCO3) precipitation (MICP) in three ureolytic bacterial strains from the Sporosarcina family, including S. newyorkensis, a newly isolated microbe from the deep sea. We find that the interplay between structural water and strain-specific amino acid groups is fundamental to the stabilisation of vaterite and that, under the same conditions, different isolates yield distinctly different polymorphs. The latter is found to be associated with different urease activities and, consequently, precipitation kinetics, which change depending on pressure-temperature conditions. Further, CaCO3 polymorph selection also depends on the coupled effect of chemical treatment and initial bacterial concentrations. Our findings provide new insights into strain-specific CaCO3 polymorphic selection and stabilisation, and open up promising avenues for designing bio-reinforced geo-materials that capitalise on the different particle bond mechanical properties offered by different polymorphs.
Automated data cleaning of paediatric anthropometric data from longitudinal electronic health records: protocol and application to a large patient cohort
Authors: Phan Hang T. T. , Borca Florina , Cable David , Batchelor James , Davies Justin H. , Ennis Sarah
Published: June 2020

‘Big data’ in healthcare encompass measurements collated from multiple sources with various degrees of data quality. These data require quality control assessment to optimise quality for clinical management and for robust large-scale data analysis in healthcare research. Height and weight data represent one of the most abundantly recorded health statistics. The shift to electronic recording of anthropometric measurements in electronic healthcare records, has rapidly inflated the number of measurements. WHO guidelines inform removal of population-based extreme outliers but an absence of tools limits cleaning of longitudinal anthropometric measurements. We developed and optimised a protocol for cleaning paediatric height and weight data that incorporates outlier detection using robust linear regression methodology using a manually curated set of 6,279 patients’ longitudinal measurements. The protocol was then applied to a cohort of 200,000 patient records collected from 60,000 paediatric patients attending a regional teaching hospital in South England. WHO guidelines detected biologically implausible data in <1% of records. Additional error rates of 3% and 0.2% for height and weight respectively were detected using the protocol. Inflated error rates for height measurements were largely due to small but physiologically implausible decreases in height. Lowest error rates were observed when data was measured and digitally recorded by staff routinely required to do so. The protocol successfully automates the parsing of implausible and poor quality height and weight data from a voluminous longitudinal dataset and standardises the quality assessment of data for clinical and research applications.
Synergistic stabilization by nitrosoglutathione-induced thiol modifications in the stromal interaction molecule-2 luminal domain suppresses basal and store operated calcium entry
Authors: Novello Matthew J. , Zhu Jinhui , Zhang MengQi , Feng Qingping , Stathopulos Peter B.
Published: June 2020

Stromal interaction molecule−1 and −2 (STIM1/2) are endoplasmic reticulum (ER) membrane-inserted calcium (Ca2+) sensing proteins that, together with Orai1-composed Ca2+ channels on the plasma membrane (PM), regulate intracellular Ca2+ levels. Recent evidence suggests that S-nitrosylation of the luminal STIM1 Cys residues inhibits store operated Ca2+ entry (SOCE). However, the effects of thiol modifications on STIM2 during nitrosative stress and their role in regulating basal Ca2+ levels remain unknown. Here, we demonstrate that the nitric oxide (NO) donor nitrosoglutathione (GSNO) thermodynamically stabilizes the STIM2 Ca2+ sensing region in a Cys-specific manner. We uncovered a remarkable synergism in this stabilization involving the three luminal Cys of STIM2, which is unique to this paralog. S-Nitrosylation causes structural perturbations that converge on the face of the EF-hand and sterile α motif (EF-SAM) domain, implicated in unfolding-coupled activation. In HEK293T cells, enhanced free basal cytosolic Ca2+ and SOCE mediated by STIM2 overexpression could be attenuated by GSNO or mutation of the modifiable Cys located in the luminal domain. Collectively, we identify the Cys residues within the N-terminal region of STIM2 as modifiable targets during nitrosative stress that can profoundly and cooperatively affect basal Ca2+ and SOCE regulation.
Differences in the prescribing of potentially inappropriate medicines in older Australians: comparison of community dwelling and residential aged care residents
Authors: Bony Hosam , Lloyd Renae A. , Hotham Elizabeth D. , Corre Lauren J. , Corlis Megan E. , Loffler Helen A. , Scarlett Gregory K. , Tsimbinos Jacquie M. , Todd Ian P. , Suppiah Vijayaprakash
Published: June 2020

Potentially inappropriate medications (PIMs) can contribute to morbidity through exacerbations or progression of existing conditions among older people. In order to characterize the prevalence of PIMs according to the Beers Criteria in older Australians, three hundred and eleven participants were recruited from three residential aged care facilities (RACFs) and two hundred and twenty participants from three community pharmacies in South Australia for a retrospective audit of medication administration charts and community pharmacy dispensing histories. Although a similar number of participants were prescribed at least one PIM (P = 0.09), the average number of PIMs was significantly greater in the RACF cohort (1.96 vs 1.26, P < 0.05). Additionally, PIMs prescribed as pro re nata (PRN) in the RACF cohort had a significantly low administration rate compared to prescription rate (19.7% vs 40.7%). The mean number of PIMs within each cohort was statistically significant (RACF = 1.93 vs CDOA = 1.26, P < 0.05). RACF residents were at a slightly greater risk of being prescribed more than one PIM compared to those within the community. Routine medication reviews by pharmacists embedded in RACFs and within the community could be utilised to detect PIMs before such harm occurs.
Frailty: A cost incurred by reproduction?
Authors: Gordon E. H. , Peel N. M. , Chatfield M. D. , Lang I. A. , Hubbard R. E.
Published: June 2020

Evolutionary theories of senescence, such as the ‘disposable soma’ theory, propose that natural selection trades late survival for early fecundity. ‘Frailty’, a multidimensional measure of health status, may help to better define the long-term consequences of reproduction. We examined the relationship between parity and later life frailty (as measured by the Frailty Index) in a sample of 3,534 adults aged 65 years and older who participated in the English Longitudinal Study of Ageing. We found that the most parous adults were the most frail and that the parity-frailty relationship was similar for both sexes. Whilst this study provided some evidence for a ‘parity-frailty trade-off’, there was little support for our hypothesis that the physiological costs of childbearing influence later life frailty. Rather, behavioural and social factors associated with rearing many children may have contributed to the development of frailty in both sexes.
Limits on Anti-Phase Synchronization in Oscillator Networks
Authors: Vathakkattil Joseph George , Pakrashi Vikram
Published: June 2020

Anti-phase synchronization is the spontaneous formation of 2 clusters of oscillators synchronized between themselves within a cluster but opposite in phase with the other cluster. Neuronal networks in human and animal brains, ecological networks, climactic networks, and lasers are all systems that exhibit anti-phase synchronization although the phenomenon is encountered less frequently than the celebrated in-phase synchronization. We show that this disparity in occurrence is due to fundamental limits on the size of networks that can sustain anti-phase synchronization. We study the influence of network structure and coupling conditions on anti-phase synchronization in networks composed of coupled Stuart-Landau oscillators. The dependence of probability of anti-phase synchronization on connectivity of the network, strength of interaction over distance, and symmetry of the network is illustrated. Regardless of favourable network conditions, we show that anti-phase synchronization is limited to small networks, typically smaller than 20 nodes.
Label-free, automated classification of microsatellite status in colorectal cancer by infrared imaging
Authors: Kallenbach-Thieltges Angela , Großerueschkamp Frederik , Jütte Hendrik , Kuepper Claus , Reinacher-Schick Anke , Tannapfel Andrea , Gerwert Klaus
Published: June 2020

Challenging histopathological diagnostics in cancer include microsatellite instability-high (MSI-H) colorectal cancer (CRC), which occurs in 15% of early-stage CRC and is caused by a deficiency in the mismatch repair system. The diagnosis of MSI-H cannot be reliably achieved by visual inspection of a hematoxylin and eosin stained thin section alone, but additionally requires subsequent molecular analysis. Time- and sample-intensive immunohistochemistry with subsequent fragment length analysis is used. The aim of the presented feasibility study is to test the ability of quantum cascade laser (QCL)-based infrared (IR) imaging as an alternative diagnostic tool for MSI-H in CRC. We analyzed samples from 100 patients with sporadic CRC UICC stage II and III. Forty samples were used to develop the random forest classifier and 60 samples to verify the results on an independent blinded dataset. Specifically, 100% sensitivity and 93% specificity were achieved based on the independent 30 MSI-H- and 30 microsatellite stable (MSS)-patient validation cohort. This showed that QCL-based IR imaging is able to distinguish between MSI-H and MSS for sporadic CRC - a question that goes beyond morphological features - based on the use of spatially resolved infrared spectra used as biomolecular fingerprints.
A novel device for elimination of cancer cells from blood specimens
Authors: Weth Agnes , Krol Ilona , Priesner Kurt , Donato Cinzia , Pirker Stefan , Wolf Christoph , Aceto Nicola , Baumgartner Werner
Published: June 2020

Circulating tumor cells (CTCs) are derivatives of solid cancerous lesions that detach from the tumor mass and enter the blood circulation. CTCs are considered to be the precursors of metastasis in several cancer types. They are present in the blood of cancer patients as single cells or clusters, with the latter being associated with a higher metastatic potential. Methods to eliminate CTCs from the bloodstream are currently lacking. Here, we took advantage of the lower shear stress-resistance of cancer cells compared to blood cells, and developed a device that can eliminate cancer cells without blood damage. The device consists of an axial pump and a coupled rotating throttle, controllable to prevent local blood flow impairment, yet maintaining a constant shear performance. When processing cancer cells through our device, we observe cancer cell-cluster disruption and viability reduction of single cancer cells, without noticeable effects on human blood cells. When injecting cancer cell-containing samples into tumor-free recipient mice, processed samples fail to generate metastasis. Together, our data show that a selective disruption of cancer cells is possible while preserving blood cells, paving the way towards the development of novel, implantable tools for CTC disruption and metastasis prevention.
Development of metal adaptation in a tropical marine zooplankton
Authors: Dinh Khuong V. , Dinh Hanh T. , Pham Hong T. , Selck Henriette , Truong Kiem N.
Published: June 2020

Tropical marine ecosystems are highly vulnerable to pollution and climate change. It is relatively unknown how tropical species may develop an increased tolerance to these stressors and the cost of adaptations. We addressed these issues by exposing a keystone tropical marine copepod, Pseudodiaptomus annandalei, to copper (Cu) for 7 generations (F1–F7) during three treatments: control, Cu and pCu (the recovery treatment). In F7, we tested the “contaminant-induced climate change sensitivity” hypothesis (TICS) by exposing copepods to Cu and extreme temperature. We tracked fitness and productivity of all generations. In F1, Cu did not affect survival and grazing but decreased nauplii production. In F2-F4, male survival, grazing, and nauplii production were lower in Cu, but recovered in pCu, indicating transgenerational plasticity. Strikingly, in F5-F6 nauplii production of Cu-exposed females increased, and did not recover in pCu. The earlier result suggests an increased Cu tolerance while the latter result revealed its cost. In F7, extreme temperature resulted in more pronounced reductions in grazing, and nauplii production of Cu or pCu than in control, supporting TICS. The results suggest that widespread pollution in tropical regions may result in high vulnerability of species in these regions to climate change.