bluuebunny/crossref_metadata_2025 huggingface dataset:
Local stabilization of subunit-subunit contacts causes global destabilization of Hepatitis B virus capsids
Authors: Schlicksup Christopher John , Laughlin Patrick , Dunkelbarger Steven , Wang Joseph Che-Yen , Zlotnick Adam
Published: January 2020

Development of antiviral molecules that bind virion is a strategy that remains in its infancy and the details of their mechanisms are poorly understood. Here we investigate the behavior of DBT1, a dibenzothiazapine, which specifically interacts with the capsid protein of Hepatitis B Virus (HBV). We found that DBT1 stabilizes protein-protein interaction, accelerates capsid assembly, and can induce formation of aberrant particles. Paradoxically, DBT1 can cause pre-formed capsids to dissociate. These activities may lead to (i) assembly of empty and defective capsids, inhibiting formation of new virus and (ii) disruption of mature viruses, which are metastable, to inhibit new infection. Using cryo-electron microscopy we observed that DBT1 led to asymmetric capsids where well-defined DBT1 density was bound at all inter-subunit contacts. These results suggest that DBT1 can support assembly by increasing buried surface area but induce disassembly of metastable capsids by favoring asymmetry to induce structural defects.
Tandem tension sensor reveals substrate rigidity-dependence of integrin molecular tensions in live cells
Authors: Sarkar Anwesha , LeVine Dana , Zhao Yuanchang , Mollaeian Keyvan , Ren Juan , Wang Xuefeng
Published: January 2020

Response of integrin tensions to substrate rigidity is important in cell rigidity sensing but has not been confirmed. Current fluorescent tension sensors produce cellular force signals collectively resulted from integrin tension magnitude, tension dwell time, integrin density and activity, ligand density and accessibility, etc., making it challenging to monitor the absolute molecular force level of integrin tensions in live cells. Here we developed a tandem tension sensor (TTS) consisting of two coupled tension sensing units which are subject to the same tension and respond with different activation probabilities to the tension. Reported by fluorescence, the activation probability ratio of these two units solely responds to the force level of local integrin tensions, excluding the bias from other non-force factors. We verified the feasibility of TTS in detecting integrin tensions and applied it to study cells on elastic substrates. TTS unambiguously reported that integrin tensions in platelets decrease monotonically with the substrate rigidity, verifying the rigidity-dependence of integrin tensions in live cells.
An atlas of cell types in the mammalian epididymis and vas deferens
Authors: Rinaldi Vera D. , Donnard Elisa , Gellatly Kyle J. , Rasmussen Morten , Kucukural Alper , Yukselen Onur , Garber Manuel , Sharma Upasna , Rando Oliver J.
Published: January 2020

Following spermatogenesis in the testis, mammalian sperm continue to mature over the course of approximately 10 days as they transit a long epithelial tube known as the epididymis. The epididymis is comprised of multiple segments/compartments that, in addition to concentrating sperm and preventing their premature activation, play key roles in remodeling the protein, lipid, and RNA composition of maturing sperm. In order to understand the complex roles for the epididymis in reproductive biology, we generated a single cell atlas of gene expression from the murine epididymis and vas deferens. We recovered all the key cell types of the epididymal epithelium, including principal cells, clear cells, and basal cells, along with associated support cells that include fibroblasts, smooth muscle, macrophages and other immune cells. Moreover, our data illuminate extensive regional specialization of principal cell populations across the length of the epididymis, with a substantial fraction of segment-specific genes localized in genomic clusters of functionally-related genes. In addition to the extensive region-specific specialization of principal cells, we find evidence for functionally-specialized subpopulations of stromal cells, and, most notably, two distinct populations of clear cells. Analysis of ligand/receptor expression reveals a network of potential cellular signaling connections, with several predicted interactions between cell types that may play roles in immune cell recruitment and other aspects of epididymal function. Our dataset extends on existing knowledge of epididymal biology, and provides a wealth of information on potential regulatory and signaling factors that bear future investigation.
Assessing Goodness-of-Fit in Marked-Point Process Models of Neural Population Coding via Time and Rate Rescaling
Authors: Yousefi Ali , Amidi Yalda , Nazari Behzad , Eden Uri. T.
Published: January 2020

Marked-point process models have recently been used to capture the coding properties of neural populations from multi-unit electrophysiological recordings without spike sorting. These ‘clusterless’ models have been shown in some instances to better describe the firing properties of neural populations than collections of receptive field models for sorted neurons and to lead to better decoding results. To assess their quality, we previously proposed a goodness-of-fit technique for marked-point process models based on time-rescaling, which for a correct model, produces a set of uniform samples over a random region of space. However, assessing uniformity over such a region can be challenging, especially in high dimensions. Here, we propose a set of new transformations both in time and in the space of spike waveform features, which generate events that are uniformly distributed in the new mark and time spaces. These transformations are scalable to multi-dimensional mark spaces and provide uniformly distributed samples in hypercubes, which are well suited for uniformity tests. We discuss properties of these transformations and demonstrate aspects of model fit captured by each transformation. We also compare multiple uniformity tests to determine their power to identify lack-of-fit in the rescaled data. We demonstrate an application of these transformations and uniformity tests in a simulation study. Proofs for each transformation are provided in the Appendix section. We have made the MATLAB code used for the analyses in this paper publicly available through our Github repository athttps://github.com/YousefiLab/Marked-PointProcess-Goodness-of-Fit
Removing mains power artefacts from EEG – a novel template-based method
Authors: Zhang Shenghuan , McCane Brendan , Neo Phoebe S-H , McNaughton Neil
Published: January 2020

EEG signals are often contaminated with artefacts, particularly with mains power from electrical equipment. Low-pass filtering and notch filtering can lose valuable data. Here we describe a novel mains power noise removal method based on the fact that mains power noise is a sine wave component with an essentially fixed frequency and the same phase across all channels. This removes the mains power component, leaving uncontaminated EEG largely unchanged. Mains removal had a success rate of >99.9% recovered variance of the original EEG when removing synthesised mains power components. We compared this method with two other popular mains power noise removal methods. Our method was better than Cleanline which is an ICA based method and multiple PLI which is an adaptive notch filter based method. With the higher recovery, our method shows clear advantages over Cleanline and multiple PLI for removing mains power noise. From the aspect of data loss, it is obviously better than low-pass filter and normal notch filter.
Morality recruits neural reward circuitry to shape economic decision making
Authors: Liu Jie , Huang Xiaoxuan , Liao Chong , Cui Fang
Published: January 2020

The present study combined a novel hypothetical investment game with functional magnetic resonance imaging systemtically examined how morality modulates economic decision making in decision phase and outcome phase. We manipulated the morality of the investments by choosing each investment project based on subjective ratings on their moral valence and social benefits. There were three categories of investment morality: Green (moral), Red (immoral), and Neutral. The behavioral and neural responses during the investment decision and outcome phases were recorded and compared. Results showed that: behaviorally, people are willing to invest a larger amount of money into a moral project that may benefit society than they are into an immoral project that they think will harm society. They also rate gains in moral investments as more pleasant and losses as the most unpleasant. In the brain, we found that the reward system, especially the bilateral striatum, was involved in modulating functional connectivity during both phases, but in different ways. During decision making, the functional connectivity between fusiform gyrus and striatum might underlie the observed investing bias (Green over Red projects), while the covariation of BOLD signals in bilateral striatum with the behavioral tendency might explain the effect observed during the outcome evaluations. Our study provides evidence that morality modulates both the decision making and the outcome evaluation in economic situations.
MicroRNA-9 Mediated the Protective Effect of Ferulic Acid on Hypoxic-Ischemic Brain Injury in Neonatal Rats
Authors: Yao Keli , Yang Qin , Li Yajuan , Lan Ting , Yu Hong , Yu Yang
Published: January 2020

Neonatal hypoxic-ischemic brain damage (NHIBD) leads to cognitive and memory impairments, and there is no effective clinical treatment. Ferulic acid (FA) is found within members of the genusAngelica, reportedly shows protective effects on neuronal damage; however, the mechanism of the protective effects of FA on rats following NHIBD remains unclear. Using the Morris water maze task, we herein found that the impairment of spatial memory formation in adult rats exposed to NHIBD was significantly reversed by FA treatment and the administration of LNA-miR-9. RT-PCR analyses revealed that miRNA-9 was significantly increased in the hippocampus of neonatal rats and neuronal PC12 cells following NHIBD and that FA and LNA-miR-9 both inhibited the expression of miRNA-9, suggesting that the therapeutic effect of FA was mainly attributed to the inhibition of miRNA-9 expression. Indeed, the silencing of miR-9 by LNA-miR-9 or FA similarly attenuated neuronal damage and cerebral atrophy in the rat hippocampus after NHIBD, which was consistent with the restored expression levels of brain-derived neurotrophic factor (BDNF). Therefore, FA treatment may protect against neuronal death through the inhibition of miRNA-9 induction in the rat hippocampus following hypoxic-ischemic damage.
Matrix Stiffness Regulates Liver Sinusoidal Endothelial Cell Function Mimicking Responses in Fatty Liver Disease
Authors: Natarajan Vaishaali , Moeller Michael , Casey Carol A. , Harris Edward N. , Kidambi Srivatsan
Published: January 2020

Liver sinusoidal endothelial cells (LSECs) are a highly specialized endothelial cell that participates in numerous liver metabolic activities and collectively function as a scavenger system in the liver by removing waste macromolecules playing a vital role in the balance of lipids, cholesterol, and vitamins. Prior to hepatic fibrosis, independent of their etiology, LSECs become highly pro-inflammatory, capillarized (loss in fenestrations), and loss in specialized receptors (Stabilin-1, Stabilin-2, CD31 and SE-1). Liver fibrosis also leads to significant loss in the endocytosis function of LSECs. Thus understanding regulation of LSEC phenotype may be critical to understanding fibrosis. Extensive remodeling of the extracellular matrix occurs during fibrosis that leads to liver stiffening. The role of matrix stiffness as related to subtle but pivotal changes in LSECs physiology is under explored. Theoverall goalof our study is the development and implementation of a platform that enables the convergence of engineered cell microenvironments with the phenotypic and functional analysis of LSECs. Using our innovative biomimetic liver fibrosis model that allows modulation of substrate stiffness, we investigated the role of liver matrix stiffness in modulating LSECs function in fibrotic-like microenvironment. Primary LSECs were cultured on our novel polymer film coated polydimethylsiloxane (PDMS) gels with 2 kPa, 9 kPa 25 kPa and 55 kPa elastic modulus mimicking healthy, early fibrotic, fibrotic and extremely fibrotic substrates. SEM was used to image to fenestrations of LSECs and HA endocytosis assay was performed to measure the LSECs function. LSECs cultured on stiffer environment had significant remodeling of cytoskeletal proteins and morphology indicated of stress fibers. Also we observed that LSECs on fibrotic substrates resulted in loss of fenestrations (capillarization). This is critical as capillarization has been show to precede hepatic fibrosis and “capillarized” LSECs lose the ability to promote hepatic stellate cell (HSC) quiescence. LSECs on stiffer environment also had higher expression of cell adhesion molecules, VCAM-1 and ICAM-1 indicating the loss of phenotype of the cells. Fibrotic stiffness also impeded the HA endocytosis in LSECs, one of the main functions of the cells. These data suggest a plausible mechanism that increased stiffness modulates hepatocyte and LSEC function causing liver functional failure. Similar effect was observed in LSECs isolated from Non-Alcoholic Fatty Liver Disease (NAFLD) rat models indicating correlation to physiological conditions. Together, all these data demonstrates the plausible role of stiffness in regulating LSECs function and contribute to HSC activation and progression of liver fibrosis.
Mapping physiological ADP-ribosylation using Activated Ion Electron Transfer Dissociation (AI-ETD)
Authors: Buch-Larsen Sara C. , Hendriks Ivo A. , Lodge Jean M. , Rykær Martin , Furtwängler Benjamin , Shishkova Evgenia , Westphall Michael S. , Coon Joshua J. , Nielsen Michael L.
Published: January 2020

ADP-ribosylation (ADPr) is a post-translational modification that plays pivotal roles in a wide range of cellular processes. Mass spectrometry (MS)-based analysis of ADPr under physiological conditions, without relying on genetic or chemical perturbation, has been hindered by technical limitations. Here, we describe the applicability of Activated Ion Electron Transfer Dissociation (AI-ETD) for MS-based proteomics analysis of physiological ADPr using our unbiased Af1521 enrichment strategy. To benchmark AI-ETD, we profiled 9,000 ADPr peptides mapping to >5,000 unique ADPr sites from a limited number of cells exposed to oxidative stress, corresponding to 120% and 28% more ADPr peptides compared to contemporary strategies using ETD and EThcD, respectively. Under physiological conditions AI-ETD identified 450 ADPr sites on low-abundant proteins, includingin vivocysteine auto-modifications on PARP8 and tyrosine auto-modifications on PARP14, hinting at specialist enzymatic functions for these enzymes. Collectively, our data provides new insights into the physiological regulation of ADP-ribosylation.
Architecture of the AP2:clathrin coat on the membranes of clathrin-coated vesicles
Authors: Kovtun Oleksiy , Kane Dickson Veronica , Kelly Bernard T. , Owen David. J. , Briggs John A. G.
Published: January 2020

Clathrin-mediated endocytosis (CME) is crucial for modulating the protein composition of a cell’s plasma membrane. Clathrin forms a cage-like, polyhedral outer scaffold around a vesicle, to which cargo-selecting clathrin adaptors are attached. AP2 is the key adaptor in CME. Crystallography has shown AP2 to adopt a range of conformations. Here we used cryo-electron microscopy, tomography and subtomogram averaging to determine structures, interactions and arrangements of clathrin and AP2 at the key steps of coat assembly, from AP2 in solution to membrane-assembled clathrin-coated vesicles (CCVs). AP2 binds cargo and PtdIns(4,5)P2-containing membranes via multiple interfaces, undergoing conformational rearrangement from its cytosolic state. The binding mode of AP2 β2-appendage into the clathrin lattice in CCVs and buds implies how the adaptor structurally modulates coat curvature and coat disassembly.
Assortative mating, sexual selection and their consequences for gene flow inLittorina
Authors: Perini Samuel , Rafajlović Marina , Westram Anja M. , Johannesson Kerstin , Butlin Roger K.
Published: January 2020

When divergent populations are connected by gene flow, the establishment of complete reproductive isolation usually requires the joint action of multiple barrier effects. One example where multiple barrier effects are coupled consists of a single trait that is under divergent natural selection and also mediates assortative mating. Such multiple-effect traits can strongly reduce gene flow. However, there are few cases where patterns of assortative mating have been described quantitatively and their impact on gene flow has been determined. Two ecotypes of the coastal marine snail,Littorina saxatilis, occur in North Atlantic rocky-shore habitats dominated by either crab predation or wave action. There is evidence for divergent natural selection acting on size, and size-assortative mating has previously been documented. Here, we analyze the mating pattern inL. saxatiliswith respect to size in intensively-sampled transects across boundaries between the habitats. We show that the mating pattern is mostly conserved between ecotypes and that it generates both assortment and directional sexual selection for small male size. Using simulations, we show that the mating pattern can contribute to reproductive isolation between ecotypes but the barrier to gene flow is likely strengthened more by sexual selection than by assortment.
Measuring ‘Islamic accountability’ in Islamic social enterprise (ISE)
Authors: Kamaruddin Muhammad Iqmal Hisham , Auzair Sofiah Md
Published: January 2020

Purpose

This study aims to present an effort to construct a measurement instrument to capture Islamic accountability from “accountability for what” aspect. These measurement instruments are developed by considering both social and economic natures in Islamic organisations.

Design/methodology/approach

This study defined the concept of Islamic accountability from the perspective of “accountability for what”. It is decomposed into specific items that suit an Islamic social enterprise (ISE). Next, these items are operationalised into scale items and re-composed empirically through factor analysis on data obtained from ISE stakeholders in Malaysia.

Findings

This study successfully developed an Islamic accountability measurement instruments from the “accountability for what” perspective for ISE. A total of 25 items are recognised and validated under four accountability dimensions, namely, accountability for input, accountability for output, accountability for procedural and accountability for Islamic principles and values.

Research limitations/implications

Not all measurement instruments are fit for every Islamic organisation type because of the different characteristics of Islamic organisations.

Practical implications

Developed items can be used as part of Islamic accountability index, especially by ISE and other similar organisations to measure their accountability practices. Besides, these developed items can also be adopted for reporting purposes. In the case of Malaysia, respective government agencies, such as the Companies Commission of Malaysia , the Registry of Society, the Ministry of Entrepreneur Development as well as the Malaysia Institute of Accountant, should have a look at the developed items to be considered into their respective guidelines or standards.

Originality/value

This study is believed to be a pioneering study in developing measurement instruments of Islamic accountability specific for ISE. It proposes measurement instruments of Islamic accountability that can be re-used for future research and is among the few studies of ISE.
The role of sexual reproduction in the maintenance of established Zostera marina meadows
Authors: Johnson Andrew J. , Orth Robert J. , Moore Kenneth A.
Published: January 2020

For clonal plants, the role of sexual reproduction in the maintenance of populations can vary widely. Some species are dependent on repeated seedling recruitment. For other species, interactions between adults and seedlings within existing populations can affect seedling survival and limit sexual reproduction in existing populations. Genetic studies of seagrass populations increasingly suggest sexual reproduction is important for the resilience and stability of their populations, but as of yet little observational data support these findings. Because seagrass populations provide important ecosystem services and are threatened with increasing anthropogenic impacts, understanding their reliance on sexual reproduction is evolutionarily and ecologically important.

The goals of this study were to determine (a) whether seedlings of a marine angiosperm, Zostera marina, establish and recruit within existing Z. marina meadows and (b) whether interactions between seedlings and surrounding adult shoots influence the survival of established seedlings. To meet these goals, surveys estimated seedling establishment and tracked seedling survival within multiple populations. Manipulative experiments then tested the impact of neighbouring adult shoots on seedling survival and the overall trajectory of experimental plots with and without sexual reproduction.

A 3‐year survey identified established seedlings within Z. marina meadows each year. Additionally, concurrent seed addition experiments indicated seed supply could influence seedling establishment rates. A survey tracking the survival of tagged seedlings, as well as the height and density of surrounding adult shoots, showed adult shoots may negatively impact seedling survival. Experiments then demonstrated that seedlings without neighbouring shoots survived longer than those with neighbouring shoots. Lastly, two transplant garden experiments comparing the survival of plots with and without seeds highlighted that seedling recruitment is likely most important to maintain bottom cover where disturbances generate gaps in the adult population.

Synthesis. This study demonstrates that seedlings do establish within existing seagrass meadows, and that some survive to recruit into the adult population. Competition with existing vegetation, however, can be a factor compromising seedling survival. Sexual reproduction may thus most likely occur in, and be most important for, clonal plant populations that experience seasonal disturbance.
Additive negative effects of decadal warming and nitrogen addition on grassland community stability
Authors: Wu Qian , Ren Haiyan , Wang Zhongwu , Li Zhiguo , Liu Yinghao , Wang Zhen , Li Yuanheng , Zhang Ruiyang , Zhao Mengli , Chang Scott X. , Han Guodong
Published: January 2020

Much recent research has explored how global warming and increased nitrogen (N) deposition, two important components of global environmental changes, influence the structure and functioning of natural ecosystems. However, how ecosystem dynamics respond to the combination of long‐term warming and N enrichment remains largely unexplored.

We investigated the impact of warming and N addition on the temporal stability of plant communities in a decade‐long field experiment, conducted in a desert steppe in northern China, using a split‐plot design with warming as the main‐plot factor and N addition as the split‐plot factor.

Long‐term warming and N addition had additive, negative effects on plant community stability. A warming‐induced decrease in species richness was not a significant driver of decreased community stability, which was instead driven by the decreased stability of dominant species under warming. On the other hand, a N‐induced decrease in community stability was ascribed to both decreased stability of dominant and common species and decreased asynchronous population dynamics under N addition.

Synthesis. Our results suggest that ongoing anthropogenic environmental changes may have appreciable consequences for the stability of natural grassland functions and services while also highlighting the different mechanisms associated with the similar effects of climate warming and increased N deposition on grassland community stability.
Challenges to community transitions through Money Follows the Person
Authors: Robison Julie , Shugrue Noreen , Porter Martha , Baker Kristin
Published: January 2020

Objective

To examine the effects of transition challenges on the success and timeliness of transitions from institutions to community living for long‐stay participants in the Money Follows the Person (MFP) Rebalancing Demonstration and determine whether outcomes vary by age and disability.

Data Source

Secondary data on transition challenges for individuals enrolled in Connecticut's MFP program between December 2008 and December 2017.

Study Design

Challenges were analyzed for older adults, people with mental health disability, and people with physical disability. Bivariate and multivariate analyses investigated which transition challenges and selected demographic variables predict transition versus closure and length of transition period for each group.

Data Extraction Methods

The sample includes 3506 persons who attempted transition from institutions to community living and whose case concluded with transition or closure from 2015 to 2017.

Principal Findings

The association between most transition challenges and the ability of long‐stay institutional residents to return to the community, and to do so in a timely manner, varies significantly among older adults and younger persons with physical or mental health disabilities. For all groups, however, consumer engagement challenges predicted closure without transition (OR: 1.3‐3.9) and housing challenges predicted longer transition periods (84‐132 days). Length of institutional stay was associated with both outcomes for older adults and persons with physical disability. Other challenges, such as issues with services and supports, differed among the three groups on both outcomes.

Conclusions

Knowledge of the effects of transition challenges on success and timeliness of transition for each group allows program managers and health and service providers to focus resources on addressing the most serious challenges. Particular emphasis should be placed on consumer engagement and housing challenges, and on targeting persons for transition early in their institutional stay. Federal and state transition programs can benefit by individualizing supports for residents to yield successful outcomes.
Seismic Characteristics and Development Patterns of Miocene Carbonate Platform in the Beikang Basin, Southern South China Sea
Authors: YAN Wei , ZHANG Guangxue , XIA Bin , ZHANG Li , YANG Zhen , LEI Zhenyu , YAO Huiqiang
Published: January 2020

The Beikang Basin is located in the southern part of the South China Sea (SCS), which is one of most tectonically complex sea areas. It is a deepwater sedimentary basin that was mainly deposited during the Cenozoic era. Owing to data restrictions, the research on carbonate platforms of this area is still in its infancy. High‐resolution seismic data are analyzed to identify the Miocene carbonate platforms and reconstruct the architecture and growth history. The carbonate platforms of Beikang Basin began to develop in the Late Oligocene‐Early Miocene, were extended in the Middle Miocene, and declined in the Late Miocene. The carbonate platform mainly developed during two periods: the Oligocene to the Early Miocene, and the Middle Miocene. The carbonate platforms that developed in the Middle Miocene were the most prosperous. The Middle Miocene carbonate platform in the Beikang Basin can be divided into three stages. In the first stage, the platforms had wide range which were thin. During the second stage, the platforms had a smaller range that was controlled by faults. In the third stage, the platforms were gradually submerged. The platform structure developed in the Middle Miocene at the Beikang Basin was controlled by the rate of rising/falling of the sea level and the carbonate growth rate. Based on an analysis of these changes and relationship, the platform can be divided into several patterns: retrogradation, submerged, aggradation, progradation, outward with up‐stepping, outward with down‐stepping, and down‐stepping platforms. At the top of the carbonate platforms in the Beikang Basin a set of carbonate wings or mushrooms usually appeared. These were formed during a period of relative sea‐level decline. It is believed that the Miocene carbonate platforms in the Beikang Basin are mainly controlled by tectonic and sedimentary environments, and are also affected by terrestrial detritus.
Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice
Authors: Yousefzadeh Matthew J. , Zhao Jing , Bukata Christina , Wade Erin A. , McGowan Sara J. , Angelini Luise A. , Bank Michael P. , Gurkar Aditi U. , McGuckian Collin A. , Calubag Mariah F. , Kato Jonathan I. , Burd Christin E. , Robbins Paul D. , Niedernhofer Laura J.
Published: January 2020

Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence‐associated secretory phenotype (SASP). Many types of stress induce senescence, including genotoxic stress. ERCC1‐XPF is a DNA repair endonuclease required for multiple DNA repair mechanisms that protect the nuclear genome. Humans or mice with reduced expression of this enzyme age rapidly due to increased levels of spontaneous, genotoxic stress. Here, we asked whether this corresponds to an increased level of senescent cells. p16Ink4a and p21Cip1 mRNA were increased ~15‐fold in peripheral lymphocytes from 4‐ to 5‐month‐old Ercc1−/∆ and 2.5‐year‐old wild‐type (WT) mice, suggesting that these animals exhibit a similar biological age. p16Ink4a and p21Cip1 mRNA were elevated in 10 of 13 tissues analyzed from 4‐ to 5‐month‐old Ercc1−/∆ mice, indicating where endogenous DNA damage drives senescence in vivo. Aged WT mice had similar increases of p16Ink4a and p21Cip1 mRNA in the same 10 tissues as the mutant mice. Senescence‐associated β–galactosidase activity and p21Cip1 protein also were increased in tissues of the progeroid and aged mice, while Lamin B1 mRNA and protein levels were diminished. In Ercc1−/Δ mice with a p16Ink4a luciferase reporter, bioluminescence rose steadily with age, particularly in lung, thymus, and pancreas. These data illustrate where senescence occurs with natural and accelerated aging in mice and the relative extent of senescence among tissues. Interestingly, senescence was greater in male mice until the end of life. The similarities between Ercc1−/∆ and aged WT mice support the conclusion that the DNA repair‐deficient mice accurately model the age‐related accumulation of senescent cells, albeit six‐times faster.
Validation of growth‐related quantitative trait loci markers in different Exopalaemon carinicauda families for marker‐assisted selection
Authors: Wang J. , Li M. , Qin Z. , Li J. , Li J.
Published: January 2020

We detected growth‐related QTL and associated markers from the backcross population of Exopalaemon carinicauda in the previous study. Based on our previous study, the 47 SNP markers associated with candidate growth trait QTL were selected to analyze the association between these markers and body weight (BW), body length and abdominal segment length traits in four different populations including wild population, a full‐sib family, a half‐sib family and a backcross population for evaluating their potential application of marker‐assisted selection in E. carinicauda. The general linear model (GLM) and mixed linear model were applied and the associations between SNP loci and three growth‐related traits verified. The results showed that the Marker79268 and Marker100644 were significantly associated with the BW trait in more than three populations by the GLM method. The Marker100644 was significantly associated with BW in the full‐sib family, half‐sib family and backcross populations by the GLM and mixed linear model methods. Our findings will provide useful SNP markers to go forward to improve growth performance through more refined marker‐assisted selection in E. carinicauda.
Influence of angle kappa‐customized implantation of rotationally asymmetric multifocal intraocular lens on visual quality and patient satisfaction
Authors: Liu Yiyun , Gao Yufei , Liu Rongjun , Hu Chenxi , Ma Baikai , Miao Jinhong , Luo Jinhua , Qi Hong
Published: January 2020

Purpose

To evaluate the visual outcomes and patient satisfaction with angle kappa‐customized implantation of SBL‐3 (Lenstec, Inc.; +3 D), a rotationally asymmetric multifocal intraocular lens (MIOL).

Methods

This was a prospective randomized control study. Data from consecutive patients, who underwent bilateral implantation of SBL‐3 MIOL from June 2017 to August 2018, were enrolled in the study. One eye of each patient was randomly chosen to receive a horizontal IOL placement (control group), while the other eye received angle kappa‐customized placement (design group). The outcomes include uncorrected distance visual acuity (UDVA), uncorrected intermediate visual acuity (UIVA), uncorrected near visual acuity (UNVA), defocus curve, contrast sensitivity, quality of vision and patient satisfaction. The follow‐up was 3 months.

Results

The study enrolled 80 eyes of 40 patients. There was no significant difference in mean UDVA, UIVA and UNVA between the two groups. The design group showed significantly better visual acuity at −1.50 D of defocus, based on the defocus curve (p = 0.022), and less vertical coma (p = 0.002) than the control group. No significant differences in contrast sensitivity, modulation transfer function, Strehl ratio and patient satisfaction were found between the two groups.

Conclusion

Angle kappa‐customized implantation of SBL‐3 had little impact on visual outcomes and patient satisfaction, except for a moderate impact on intermediate visual acuity.
Higher incidence of retinopathy of prematurity in extremely preterm infants associated with improved survival rates
Authors: Taner Aylin , Tekle Senait , Hothorn Torsten , Adams Mark , Bassler Dirk , Gerth‐Kahlert Christina
Published: January 2020

Aim

This study assessed possible reasons for the increasing incidence of retinopathy of prematurity (ROP) since mid‐2015 at our institution.

Methods

Retrospective analysis of all preterm infants born July 2013 to June 2017 with a gestational age (GA) <29 completed weeks admitted to the neonatal intensive care unit at the University Hospital Zurich during the first 28 days of life. The primary outcome measures were severest ROP stage. Statistical analysis was performed using generalised additive models in R.

Results

During the study period, survival increased in extremely preterm infants. Significant predictors for severest ROP stage were GA, days of mechanical ventilation and multiple gestation (P = .0322). A composite of severe comorbidities had no significant effect on severest ROP stage. GA was identified as the only significant risk factor the for severest ROP stage (P = .0045).

Conclusion

Increased survival rate of extremely preterm infants was associated with an increased incidence of ROP at our institution. Despite the increase, the incidence is still very low compared with other countries. No other additive factors were identified.
Psychological sequelae of colonic resections
Authors: Powell‐Chandler A. , Boyce K. , James O. , Scourfield L. , Torkington J. , Bisson J. , Cornish J. A. ,   PISA Trial Management Group
Published: January 2020

Aim

The prevalence of anxiety, depression and post‐traumatic stress disorder (PTSD) in the general population has been estimated to be 5.9%, 3.3% and 4.4% respectively. The aim of this study was to determine whether psychological problems are more prevalent following colorectal surgery.

Method

Patients who had undergone colorectal resection in a 2‐year period across four centres were asked to complete validated screening questionnaires for anxiety, depression and PTSD (GAD‐7, PHQ‐9, PCL‐5) 12–48 months after surgery. Risk factors were identified using multiple linear regression analysis.

Results

After excluding those who had died or received palliative diagnoses, questionnaires were sent to 1150 patients. 371 responded (32.3% response rate); median age 67 (20–99) years; 51% were men. 58% of patients underwent surgery for cancer; 23% had emergency surgery. 28% of patients screened positive for at least one psychological condition, with 20% screening positive for anxiety, 22% for depression and 14% for PTSD. Patients who were younger, women, had surgery as an emergency, for benign conditions, had stomas and had critical care stay were more likely to have poorer psychological outcomes. Multiple linear regression found that only younger age (P = 0.000) and female gender (P = 0.048) were significant risk factors.

Conclusion

The prevalence of anxiety, depression and PTSD appears to be high in patients who have undergone colorectal surgery. Younger patients and women are particularly at risk. Further work is needed to determine how best to prevent, detect and treat people with adverse psychological outcomes following colorectal surgery.
A hybrid multi‐objective tour route optimization algorithm based on particle swarm optimization and artificial bee colony optimization
Authors: Beed Romit , Roy Arindam , Sarkar Sunita , Bhattacharya Durba
Published: January 2020

Computational intelligence techniques have widespread applications in the field of engineering process optimization, which typically comprises of multiple conflicting objectives. An efficient hybrid algorithm for solving multi‐objective optimization, based on particle swarm optimization (PSO) and artificial bee colony optimization (ABCO) has been proposed in this paper. The novelty of this algorithm lies in allocating random initial solutions to the scout bees in the ABCO phase which are subsequently optimized in the PSO phase with respect to the velocity vector. The last phase involves loyalty decision‐making for the uncommitted bees based on the waggle dance phase of ABCO. This procedure continues for multiple generations yielding optimum results. The algorithm is applied to a real life problem of intercity route optimization comprising of conflicting objectives like minimization of travel cost, maximization of the number of tourist spots visited and minimization of the deviation from desired tour duration. Solutions have been obtained using both pareto optimality and the classical weighted sum technique. The proposed algorithm, when compared analytically and graphically with the existing ABCO algorithm, has displayed consistently better performance for fitness values as well as for standard benchmark functions and performance metrics for convergence and coverage.
Severe human pressures in the Sundaland biodiversity hotspot
Authors: Verma Megha , Symes William S. , Watson James E. M. , Jones Kendall R. , Allan James R. , Venter Oscar , Rheindt Frank E. , Edwards David P. , Carrasco Luis R.
Published: January 2020

We assess the magnitude and the extent of recent change of significant human footprint within protected areas, key biodiversity areas and the habitat range of 308 lowland forest specialist birds in Sundaland, a global hotspot of biodiversity in Southeast Asia. Using the most recent human footprint dataset, we find that 70% of Sundaland has been heavily modified by humans. This represents a 55% increase in areas under intense human pressure since 1993. Areas under intense human pressure covered on average 50% of the extent of key biodiversity areas, 78% of each protected area and 38% of the range of lowland forest specialist birds. The results imply that the actual level of protection by protected areas is only one‐third to half of that on paper once human footprint is accounted for. While all protected areas were impacted by human pressures, those managed strictly for biodiversity conservation presented the largest increases. These results highlight an exceptionally high human footprint across Sundaland and an impending further deepening of the biodiversity crisis across the region.
A 3‐week nonalcoholic steatohepatitis mouse model shows elafibranor benefits on hepatic inflammation and cell death
Authors: Briand François , Heymes Christophe , Bonada Lucile , Angles Thibault , Charpentier Julie , Branchereau Maxime , Brousseau Emmanuel , Quinsat Marjolaine , Fazilleau Nicolas , Burcelin Rémy , Sulpice Thierry
Published: January 2020

The long duration of animal models represents a clear limitation to quickly evaluate the efficacy of drugs targeting nonalcoholic steatohepatitis (NASH). We, therefore, developed a rapid mouse model of liver inflammation (i.e., the mouse fed a high‐fat/high‐cholesterol diet, where cyclodextrin is co‐administered to favor hepatic cholesterol loading, liver inflammation, and NASH within 3 weeks), and evaluated the effects of the dual peroxisome proliferator‐activated receptor alpha/delta agonist elafibranor (ELA). C57BL6/J mice were fed a 60% high‐fat, 1.25% cholesterol, and 0.5% cholic acid diet with 2% cyclodextrin in drinking water (HFCC/CDX diet) for 3 weeks. After 1 week of the diet, mice were treated orally with vehicle or ELA 20 mg/kg q.d. for 2 weeks. Compared with vehicle, ELA markedly reduced liver lipids and nonalcoholic fatty liver disease activity scoring, through steatosis, inflammation, and fibrosis (all P < 0.01 vs. vehicle). Flow cytometry analysis showed that ELA significantly improved the HFCC/CDX diet‐induced liver inflammation by preventing the increase in total number of immune cells (CD45+), Kupffer cells, dendritic cells, and monocytes population, as well as the reduction in natural killer and natural killer T cells, and by blocking conversion of T cells in regulatory T cells. ELA did not alter pyroptosis (Gasdermin D), but significantly reduced necroptosis (cleaved RIP3) and apoptosis (cleaved caspase 3) in the liver. In conclusion, ELA showed strong benefits on NASH, including improvement in hepatic inflammation, necroptosis, and apoptosis in the 3‐week NASH mouse. This preclinical model will be useful to rapidly detect the effects of novel drugs targeting NASH.
In Vitro‐to‐In Vivo Extrapolation of Transporter Inhibition Data for Drugs Approved by the US Food and Drug Administration in 2018
Authors: Yu Jingjing , Ragueneau‐Majlessi Isabelle
Published: January 2020

A systematic analysis of the inhibition transporter data available in New Drug Applications of drugs approved by the US Food and Drug Administration (FDA) in 2018 (N = 42) was performed. In vitro‐to‐in vivo predictions using basic models were available for the nine transporters currently recommended for evaluation. Overall, 29 parents and 16 metabolites showed in vitro inhibition of at least one transporter, with the largest number of drugs found to be inhibitors of P‐gp followed by BCRP. The most represented therapeutic areas were oncology drugs and anti‐infective agents, each comprising 31%. Among drugs with prediction values greater than the FDA recommended cutoffs and further evaluated in vivo, 56% showed positive clinical interactions (area under the concentration‐time curve ratio (AUCRs) ≥ 1.25). Although all the observed or simulated inhibitions were weak (AUCRs < 2), seven of the nine interactions (involving five drugs) resulted in labeling recommendations. Interestingly, more than half of the drugs with predictions greater than the cutoffs had no further evaluations, highlighting that current basic models represent a useful, simple first step to evaluate the clinical relevance of in vitro findings, but that multiple other factors are considered when deciding the need for clinical studies. Four drugs had prediction values less than the cutoffs but had clinical evaluations or physiologically‐based pharmacokinetic simulations available. Consistent with the predictions, all of them were confirmed not to inhibit these transporters in vivo (AUCRs of 0.94–1.09). Overall, based on the clinical evaluations available, drugs approved in 2018 were found to have a relatively limited impact on drug transporters, with all victim AUCRs < 2.
Twenty years with diabetes and amputations: a retrospective population‐based cohort study
Authors: Røikjer J. , Jensen M. H. , Vestergaard P. , Sørensen A. M. , Laursen H. V. B. , Ejskjær N.
Published: January 2020

Aim

To investigate the trends in non‐traumatic lower limb amputation in people with and without diabetes.

Methods

From the Danish National Patient Register, all people with either type 1 or type 2 diabetes (n = 462 743) as well as a group of people without diabetes from the general population (n = 1 388 886) were identified and separated into three groups based on diabetes type. Among these, 17 265 amputations were identified between 1997 and 2017 and stratified into trans‐femoral amputations, trans‐tibial amputations and amputations below the ankle using surgical codes. Annual changes were described using least‐squares linear regression.

Results

The yearly mean decrease in incidence rate of amputation per 1000 person‐years was −0.032 [95% CI: −0.062, −0.001], −0.022 [−0.032, −0.012] and −0.006 [−0.009, −0.003] for trans−femoral amputation, −0.072 [−0.093, −0.052], −0.090 [−0.102, −0.078] and −0.015 [−0.016, −0.013] for trans‐tibial amputation, and −0.055 [−0.080, −0.020], −0.075 [−0.090, −0.060] and −0.011 [−0.014, −0.007] for amputation below the ankle in people with type 1 diabetes, people with type 2 diabetes and people without diabetes, respectively.

Conclusions

Over recent decades, the incidence of amputation has decreased significantly in people with diabetes and in the general population without diabetes.
Public investment efficiency and sectoral economic growth in Pakistan
Authors: Qazi Masood Ahmed , Ammad Syed
Published: January 2020

Motivation

The issue of the effect of public investment on private investment and consequently on growth is much debated in economic literature. On the one hand the classical school believes that increment in public spending reduces economic growth by crowding out private investment, whereas Keynesians, on the other hand, consider government spending a key variable for economic growth.

Purpose

Like other developing economies Pakistan is also facing a high budget deficit which curtails public spending. This study estimates the relative effects of public investment in physical (infrastructure and energy) and social (health and education) sectors on output by estimating long term marginal productivity.

Approach and Methods

This study used the vector autoregressive/vector error correction model (VAR/VECM) technique to measure the effect of public investment on output, private investment and employment; separate VAR models are estimated for each sector and each type of public spending. Further, in order to attain these uncorrelated residuals, Cholesky decomposition is used and the resulting accumulated impulse response measures the cumulative response of all variables due to change in policy variable i.e. public investment.

Findings

This study indicates that public investments have a crowding in effect in 49 cases, while in 21 cases there is crowding out, 34 cases indicate labour absorption effect, while 36 cases show labour substitutions and 52 cases show a positive output effect, while in 18 cases output effects are negative. Overall, these results indicate that all types of public investments are growth stimulating through both crowding‐in and labour absorption effects.

Policy Implications

The overwhelming results illuminate that public investment had attracted private investment in Pakistan in the past and therefore to attract private investment in future, the government of Pakistan should increase public investment. This lesson can also be substantiated from the experience of several developing countries, particularly India. In India, the last 20 years have seen very high public investment despite high fiscal deficit, which has led to very high economic growth.