bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and Implementation of a Smart Home in a Box to Monitor the Wellbeing of Residents With Dementia in Care Homes
Authors: Garcia-Constantino Matias , Orr Claire , Synnott Jonathan , Shewell Colin , Ennis Andrew , Cleland Ian , Nugent Chris , Rafferty Joseph , Morrison Gareth , Larkham Leona , McIlroy Sharon , Selby Andrea
Published: December 2021

There is a global challenge related to the increasing number of People with Dementia (PwD) and the diminishing capacity of governments, health systems, and caregivers to provide the best care for them. Cost-effective technology solutions that enable and ensure a good quality of life for PwD via monitoring and interventions have been investigated comprehensively in the literature. The objective of this study was to investigate the challenges with the design and deployment of a Smart Home In a Box (SHIB) approach to monitoring PwD wellbeing within a care home. This could then support future SHIB implementations to have an adequate and prompt deployment allowing research to focus on the data collection and analysis aspects. An important consideration was that most care homes do not have the appropriate infrastructure for installing and using ambient sensors. The SHIB was evaluated via installation in the rooms of PwD with varying degrees of dementia at Kirk House Care Home in Belfast. Sensors from the SHIB were installed to test their capabilities for detecting Activities of Daily Living (ADLs). The sensors used were: (i) thermal sensors, (ii) contact sensors, (iii) Passive Infrared (PIR) sensors, and (iv) audio level sensors. Data from the sensors were collected, stored, and handled using a ‘SensorCentral’ data platform. The results of this study highlight challenges and opportunities that should be considered when designing and implementing a SHIB approach in a dementia care home. Lessons learned from this investigation are presented in addition to recommendations that could support monitoring the wellbeing of PwD. The main findings of this study are: (i) most care home buildings were not originally designed to appropriately install ambient sensors, and (ii) installation of SHIB sensors should be adapted depending on the specific case of the care home where they will be installed. It was acknowledged that in addition to care homes, the homes of PwD were also not designed for an appropriate integration with ambient sensors. This study provided the community with useful lessons, that will continue to be applied to improve future implementations of the SHIB approach.
Global Change Modulated Asian Inland Climate Since 7.3 Ma: Carbonate Manganese Records in the Western Qaidam Basin
Authors: Liu Yudong , Yang Yibo , Ye Chengcheng , Yang Rongsheng , Appel Erwin , Fang Xiaomin
Published: December 2021

Late Cenozoic drying of the Asian inland has not only exerted a profound impact on the regional environment but also affected global climate as an important source of global atmospheric dust. Continuous and accurately dated sediment records from the Asian interior are pivotal to a better understanding of the evolutionary history of Asian inland drying and the associated driving mechanisms. In this study, we present a continuous record of climate change in the Asian interior spanning the past 7.3 Myr, reconstructed by the redox evolution of a paleolake in the western Qaidam Basin, NE Tibetan Plateau. The paleolake redox conditions are linked to the oxygen concentration of lake bottom water and lake level, and were revealed by the manganese (Mn) concentration in the carbonate fraction (leached by the diluted acetic acid) of the carbonate-rich lacustrine sediments retrieved from two drill-cores (SG-1 and SG-1b). The reconstructed regional climate in the western Qaidam Basin shows long-term fluctuations, consistent with the secular evolution of the coeval global climate, especially the sea surface temperature variation in the high latitude North Atlantic. Three transitions of the paleolake hydrochemical system occurred at 6.2, 5.3, and 2.6 Ma, with a short drying stage at 6.2–5.3 Ma and prolonged Quaternary drying since 2.6 Ma. We argue that drying of the Asia interior has been dominantly forced by global cooling, in particular, the high-latitude cooling of the Northern Hemisphere.
Multi-Objective Comprehensive Charging/Discharging Scheduling Strategy for Electric Vehicles Based on the Improved Particle Swarm Optimization Algorithm
Authors: Fang Baling , Li Bo , Li Xingcheng , Jia Yunzhen , Xu Wenzhe , Liao Ying
Published: December 2021

To solve the problems that a large number of random and uncontrolled electric vehicles (EVs) connecting to the distribution network, resulting in a decrease in the performance and stability of the grid and high user costs, in this study, a multi-objective comprehensive charging/discharging scheduling strategy for EVs based on improved particle swarm optimization (IPSO) is proposed. In the distribution network, the minimum root-mean-square error and the minimum peak valley difference of system load are first designed as objective functions; on the user side, the lowest charge and discharge cost of electric vehicle users and the lowest battery loss cost are used as objective functions, then a multi-objective optimization scheduling model for EVs is established, and finally, the optimization through IPSO is performed. The simulation results show that the proposed method is effective, which enhances the peak regulating capacity of the power grid, and it optimizes the system load and reduces the user cost compared with the conventional methods.
The Role of Renewable Energy Consumption Towards Carbon Neutrality in BRICS Nations: Does Globalization Matter?
Authors: Dingru Liu , Ramzan Muhammad , Irfan Muhammad , Gülmez Özge , Isik Hayriye , Adebayo Tomiwa Sunday , Husam Rjoub
Published: December 2021

Although a number of studies have been conducted on the environmental Kuznets curve (EKC) and the pollution halo hypothesis (PHH), few researchers have assessed the scope in the light of the BRICS— Brazil, Russia, India, China, and South Africa—nations. Therefore, the current research assesses the income-induced EKC as well as the role of technological innovation and renewable energy consumption utilizing a dataset stretching from 1990 to 2018. The present research utilized the novel method of moments quantile regression (MMQR) developed by Machado and Silva (2019) to assess these interrelationships. The empirical outcomes from the MMQR affirmed an inverted U-shaped interrelationship between CO2 emissions and economic growth across all quantiles (first to ninth) for the BRICS nations, thus confirming the presence of the EKC hypothesis. Furthermore, we affirmed the PHH, thus confirming the negative interrelationship between globalization and ecological footprint across all quantiles (first to ninth). Moreover, it was found that renewable energy use plays a vital role in curbing the emissions of CO2 across all quantiles (first to ninth), while no evidence of significant connection was established between technological innovation and ecological footprint across all quantiles. In addition, the Granger causality outcomes revealed a feedback causality between income and ecological footprint, while a unidirectional causality was established from globalization and renewable energy use to ecological footprint.
Slow-Fast Cognitive Phenotypes and Their Significance for Social Behavior: What Can We Learn From Honeybees?
Authors: Naug Dhruba , Tait Catherine
Published: December 2021

Cognitive variation is proposed to be the fundamental underlying factor that drives behavioral variation, yet it is still to be fully integrated with the observed variation at other phenotypic levels that has recently been unified under the common pace-of-life framework. This cognitive and the resulting behavioral diversity is especially significant in the context of a social group, the performance of which is a collective outcome of this diversity. In this review, we argue about the utility of classifying cognitive traits along a slow-fast continuum in the larger context of the pace-of-life framework. Using Tinbergen’s explanatory framework for different levels of analyses and drawing from the large body of knowledge about honeybee behavior, we discuss the observed interindividual variation in cognitive traits and slow-fast cognitive phenotypes from an adaptive, evolutionary, mechanistic and developmental perspective. We discuss the challenges in this endeavor and suggest possible next steps in terms of methodological, statistical and theoretical approaches to move the field forward for an integrative understanding of how slow-fast cognitive differences, by influencing collective behavior, impact social evolution.
Prenatal Diagnosis of 17p11.2 Copy Number Abnormalities Associated With Smith–Magenis and Potocki–Lupski Syndromes in Fetuses
Authors: Cai Meiying , Fu Xianguo , Xu Liangpu , Lin Na , Huang Hailong
Published: December 2021

Smith-Magenis syndrome and Potocki-Lupski syndrome are rare autosomal dominant diseases. Although clinical phenotypes of adults and children have been reported, fetal ultrasonic phenotypes are rarely reported. A retrospective analysis of 6,200 pregnant women who received invasive prenatal diagnosis at Fujian Provincial Maternal and Child Health Hospital between October 2016 and January 2021 was performed. Amniotic fluid or umbilical cord blood was extracted for karyotyping and single nucleotide polymorphism array analysis. Single nucleotide polymorphism array analysis revealed six fetuses with copy number variant changes in the 17p11.2 region. Among them, one had a copy number variant microdeletion in the 17p11.2 region, which was pathogenically analyzed and diagnosed as Smith-Magenis syndrome. Five fetuses had copy number variant microduplications in the 17p11.2 region, which were pathogenically analyzed and diagnosed as Potocki-Lupski syndrome. The prenatal ultrasound phenotypes of the six fetuses were varied. The parents of two fetuses with Potocki-Lupski syndrome refused verification. Smith-Magenis syndrome in one fetus and Potocki-Lupski in another were confirmed as de novo. Potocki-Lupski syndrome in two fetuses was confirmed to be from maternal inheritance. The prenatal ultrasound phenotypes of Smith-Magenis syndrome and Potocki-Lupski syndrome in fetuses vary; single nucleotide polymorphism array analysis is a powerful diagnostic tool for these diseases. The ultrasonic phenotypes of these cases may enrich the clinical database.
Genetic Contributors of Incident Stroke in 10,700 African Americans With Hypertension: A Meta-Analysis From the Genetics of Hypertension Associated Treatments and Reasons for Geographic and Racial Differences in Stroke Studies
Authors: Armstrong Nicole D. , Srinivasasainagendra Vinodh , Patki Amit , Tanner Rikki M. , Hidalgo Bertha A. , Tiwari Hemant K. , Limdi Nita A. , Lange Ethan M. , Lange Leslie A. , Arnett Donna K. , Irvin Marguerite R.
Published: December 2021

Background: African Americans (AAs) suffer a higher stroke burden due to hypertension. Identifying genetic contributors to stroke among AAs with hypertension is critical to understanding the genetic basis of the disease, as well as detecting at-risk individuals.

Methods: In a population comprising over 10,700 AAs treated for hypertension from the Genetics of Hypertension Associated Treatments (GenHAT) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) studies, we performed an inverse variance-weighted meta-analysis of incident stroke. Additionally, we tested the predictive accuracy of a polygenic risk score (PRS) derived from a European ancestral population in both GenHAT and REGARDS AAs aiming to evaluate cross-ethnic performance.

Results: We identified 10 statistically significant (p < 5.00E-08) and 90 additional suggestive (p < 1.00E-06) variants associated with incident stroke in the meta-analysis. Six of the top 10 variants were located in an intergenic region on chromosome 18 (LINC01443-LOC644669). Additional variants of interest were located in or near the COL12A1, SNTG1, PCDH7, TMTC1, and NTM genes. Replication was conducted in the Warfarin Pharmacogenomics Cohort (WPC), and while none of the variants were directly validated, seven intronic variants of NTM proximal to our target variants, had a p-value <5.00E-04 in the WPC. The inclusion of the PRS did not improve the prediction accuracy compared to a reference model adjusting for age, sex, and genetic ancestry in either study and had lower predictive accuracy compared to models accounting for established stroke risk factors. These results demonstrate the necessity for PRS derivation in AAs, particularly for diseases that affect AAs disproportionately.

Conclusion: This study highlights biologically plausible genetic determinants for incident stroke in hypertensive AAs. Ultimately, a better understanding of genetic risk factors for stroke in AAs may give new insight into stroke burden and potential clinical tools for those among the highest at risk.
Whole Genome Methylation Analysis Reveals Role of DNA Methylation in Cow’s Ileal and Ileal Lymph Node Responses to Mycobacterium avium subsp. paratuberculosis Infection
Authors: Ibeagha-Awemu Eveline M. , Bissonnette Nathalie , Bhattarai Suraj , Wang Mengqi , Dudemaine Pier-Luc , McKay Stephanie , Zhao Xin
Published: December 2021

Johne’s Disease (JD), caused by Mycobacterium avium subsp paratuberculosis (MAP), is an incurable disease of ruminants and other animal species and is characterized by an imbalance of gut immunity. The role of MAP infection on the epigenetic modeling of gut immunity during the progression of JD is still unknown. This study investigated the DNA methylation patterns in ileal (IL) and ileal lymph node (ILLN) tissues from cows diagnosed with persistent subclinical MAP infection over a one to 4 years period. DNA samples from IL and ILLN tissues from cows negative (MAPneg) (n = 3) or positive for MAP infection (MAPinf) (n = 4) were subjected to whole genome bisulfite sequencing. A total of 11,263 and 62,459 differentially methylated cytosines (DMCs), and 1259 and 8086 differentially methylated regions (DMRs) (FDR<0.1) were found between MAPinf and MAPneg IL and ILLN tissues, respectively. The DMRs were found on 394 genes (denoted DMR genes) in the IL and on 1305 genes in the ILLN. DMR genes with hypermethylated promoters/5′UTR [3 (IL) and 88 (ILLN)] or hypomethylated promoters/5′UTR [10 (IL) and 25 (ILLN)] and having multiple functions including response to stimulus/immune response (BLK, BTC, CCL21, AVPR1A, CHRNG, GABRA4, TDGF1), cellular processes (H2AC20, TEX101, GLA, NCKAP5L, RBM27, SLC18A1, H2AC20BARHL2, NLGN3, SUV39H1, GABRA4, PPA1, UBE2D2) and metabolic processes (GSTO2, H2AC20, SUV39H1, PPA1, UBE2D2) are potential DNA methylation candidate genes of MAP infection. The ILLN DMR genes were enriched for more biological process (BP) gene ontology (GO) terms (n = 374), most of which were related to cellular processes (27.6%), biological regulation (16.6%), metabolic processes (15.4%) and response to stimulus/immune response (8.2%) compared to 75 BP GO terms (related to cellular processes, metabolic processes and transport, and system development) enriched for IL DMR genes. ILLN DMR genes were enriched for more pathways (n = 47) including 13 disease pathways compared with 36 enriched pathways, including 7 disease/immune pathways for IL DMR genes. In conclusion, the results show tissue specific responses to MAP infection with more epigenetic changes (DMCs and DMRs) in the ILLN than in the IL tissue, suggesting that the ILLN and immune processes were more responsive to regulation by methylation of DNA relative to IL tissue. Our data is the first to demonstrate a potential role for DNA methylation in the pathogenesis of MAP infection in dairy cattle.
The Placental Innate Immune System Is Altered in Early-Onset Preeclampsia, but Not in Late-Onset Preeclampsia
Authors: Broekhuizen Michelle , Hitzerd Emilie , van den Bosch Thierry P. P. , Dumas Jasper , Verdijk Robert M. , van Rijn Bas B. , Danser A. H. Jan , van Eijck Casper H. J. , Reiss Irwin K. M. , Mustafa Dana A. M.
Published: December 2021

Preeclampsia is a severe placenta-related pregnancy disorder that is generally divided into two subtypes named early-onset preeclampsia (onset <34 weeks of gestation), and late-onset preeclampsia (onset ≥34 weeks of gestation), with distinct pathophysiological origins. Both forms of preeclampsia have been associated with maternal systemic inflammation. However, alterations in the placental immune system have been less well characterized. Here, we studied immunological alterations in early- and late-onset preeclampsia placentas using a targeted expression profile approach. RNA was extracted from snap-frozen placenta samples (healthy n=13, early-onset preeclampsia n=13, and late-onset preeclampsia n=6). The expression of 730 immune-related genes from the Pan Cancer Immune Profiling Panel was measured, and the data were analyzed in the advanced analysis module of nSolver software (NanoString Technology). The results showed that early-onset preeclampsia placentas displayed reduced expression of complement, and toll-like receptor (TLR) associated genes, specifically TLR1 and TLR4. Mast cells and M2 macrophages were also decreased in early-onset preeclampsia compared to healthy placentas. The findings were confirmed by an immunohistochemistry approach using 20 healthy, 19 early-onset preeclampsia, and 10 late-onset preeclampsia placentas. We conclude that the placental innate immune system is altered in early-onset preeclampsia compared to uncomplicated pregnancies. The absence of these alterations in late-onset preeclampsia placentas indicates dissimilar immunological profiles. The study revealed distinct pathophysiological processes in early-onset and late-onset preeclampsia placentas and imply that a tailored treatment to each subtype is desirable.
MAP Kinase Phosphatase-5 Deficiency Protects Against Pressure Overload-Induced Cardiac Fibrosis
Authors: Zhong Chao , Min Kisuk , Zhao Zhiqiang , Zhang Cheng , Gao Erhe , Huang Yan , Zhang Xinbo , Baldini Margaret , Roy Rajika , Yang Xiaofeng , Koch Walter J. , Bennett Anton M. , Yu Jun
Published: December 2021

Cardiac fibrosis, a pathological condition due to excessive extracellular matrix (ECM) deposition in the myocardium, is associated with nearly all forms of heart disease. The processes and mechanisms that regulate cardiac fibrosis are not fully understood. In response to cardiac injury, macrophages undergo marked phenotypic and functional changes and act as crucial regulators of myocardial fibrotic remodeling. Here we show that the mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5) in macrophages is involved in pressure overload-induced cardiac fibrosis. Cardiac pressure overload resulting from transverse aortic constriction (TAC) leads to the upregulation of Mkp-5 gene expression in the heart. In mice lacking MKP-5, p38 MAPK and JNK were hyperactivated in the heart, and TAC-induced cardiac hypertrophy and myocardial fibrosis were attenuated. MKP-5 deficiency upregulated the expression of the ECM-degrading matrix metalloproteinase-9 (Mmp-9) in the Ly6Clow (M2-type) cardiac macrophage subset. Consistent with in vivo findings, MKP-5 deficiency promoted MMP-9 expression and activity of pro-fibrotic macrophages in response to IL-4 stimulation. Furthermore, using pharmacological inhibitors against p38 MAPK, JNK, and ERK, we demonstrated that MKP-5 suppresses MMP-9 expression through a combined effect of p38 MAPK/JNK/ERK, which subsequently contributes to the inhibition of ECM-degrading activity. Taken together, our study indicates that pressure overload induces MKP-5 expression and facilitates cardiac hypertrophy and fibrosis. MKP-5 deficiency attenuates cardiac fibrosis through MAPK-mediated regulation of MMP-9 expression in Ly6Clow cardiac macrophages.
Immune Checkpoint Inhibitor-Associated Colitis: From Mechanism to Management
Authors: Tang Liansha , Wang Jialing , Lin Nan , Zhou Yuwen , He Wenbo , Liu Jiyan , Ma Xuelei
Published: December 2021

Immune checkpoint inhibitors (ICIs), as one of the innovative types of immunotherapies, including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors, have obtained unprecedented benefit in multiple malignancies. However, the immune response activation in the body organs could arise immune-related adverse events (irAEs). Checkpoint inhibitor colitis (CIC) is the most widely reported irAEs. However, some obscure problems, such as the mechanism concerning gut microbiota, the confusing differential diagnosis with inflammatory bowel disease (IBD), the optimal steroid schedule, the reintroduction of ICIs, and the controversial prognosis features, influence the deep understanding and precise diagnosis and management of CIC. Herein, we based on these problems and comprehensively summarized the relevant studies of CIC in patients with NSCLC, further discussing the future research direction of this specific pattern of irAEs.
Reproductive Biology and Embryonic Diapause as a Survival Strategy for the East Asian Endemic Eagle Ray Aetobatus narutobiei
Authors: Yamaguchi Atsuko , Furumitsu Keisuke , Wyffels Jennifer
Published: December 2021

Batoids comprise five of the seven most threatened families of sharks and rays. The East Asian endemic Naru eagle ray Aetobatus narutobiei is a large bodied ray whose estuarine habitat overlaps with an economically valuable bivalve fishery. In response to decreased bivalve yields, the government initiated a predator control program and as a result, Naru eagle rays have faced intense and targeted fishing pressure during the last two decades. The long-term impacts of the predator control program on the population of rays and bivalves and their balance in the ecosystem are unknown because the life history of the Naru eagle ray has not been characterized. To begin to fill these critical knowledge gaps, the reproductive life history of the Naru eagle was described. Females mature at a larger size than males and require nearly twice as many years to reach maturity (DW50, 952.0 mm vs. 764.2 mm; Age50, 6.0 years vs. 3.5 years). Both males and females reproduce annually and their reproductive cycles are synchronized and seasonal. Females have a single ovary and paired uteri, are viviparous, and reproduce via matrotrophic histotrophy. Mating occurs in August and September and gestation lasts approximately 12 months including a 9.5-month diapause that begins soon after mating and ends in June of the following year, leaving 2.5 months for embryos to complete development. Fecundity ranged from 1 to 7 embryos per brood (n = 158, mean ± SD = 3.36 ± 1.26) and was positively correlated with female disc width (linear regression; F = 105.73, d.f. = 151, P < 0.05). Naru eagle rays are vulnerable to overfishing because of their low fecundity, long reproductive cycle and long time to reach sexual maturity. Obligate embryonic diapause during overwintering and seasonal migrations is a survival strategy that benefits the adults and neonates. This research is a valuable resource to help guide science-based management, conservation and protection of the endemic Asian A. narutobiei and its nursery areas.
Interactive Regulations of Dynamic Methylation and Transcriptional Responses to Recurring Environmental Stresses During Biological Invasions
Authors: Fu Ruiying , Huang Xuena , Chen Yiyong , Chen Zaohuang , Zhan Aibin
Published: December 2021

Deoxyribonucleic acid methylation and gene transcription have been proved as two underlying mechanisms involved in rapid plastic response to environmental stresses. However, it remains elusive on how DNA methylation regulates gene transcription under acute and recurring environmental challenges to form the stress memory, further contributing to invasion success during range expansions. Using a model invasive species Ciona robusta, we investigated the regulatory roles of DNA methylation on gene transcription and their contribution to the formation of stress memory at 30 genes under acute and recurring osmotic challenges simulated during the invasion process. We found the bimodal distribution of methylation level for the 68 mCpGs identified across all the genes after challenges, but only five sites were significantly correlated with the expression of their corresponding genes. These genes participated in the biological processes of Ca2+ transport and metabolism of lipid and proline. At the DNA methylation level, we found two early-responding and four tardy-responding sites of stress memory and these sites were functionally related to genes involved in the biosynthesis of proline, metabolism of lipid, and transport of taurine and Ca2+. At the transcriptional level, three tardy-responding and five early-responding memory genes were involved in the transport of ions, regulation of water channels, biosynthesis of taurine, and metabolism of lipid. Altogether, the findings here suggest that DNA methylation and gene transcription should work in concert to facilitate the formation of stress memory, thus further improving the performance of invaders under recurring environmental challenges during biological invasions.
Role of Grain Size and Shape in Superplasticity of Metals
Authors: Lu Zhaoyang , Huang Xuqiang , Huang Jingzhe
Published: December 2021

Superplasticity is characterized by an elongation to failure of >300% and a measured strain rate sensitivity (SRS), close to 0.5. The superplastic flow is controlled by diffusion processes; it requires the testing temperature of 0.5Tm or greater where Tm is the absolute melting temperature of metals. It is well established that a reduction in grain size improves the optimum superplastic response by lowering the deformation temperature and/or raising the strain rate. The low-temperature superplasticity (LTSP) is attractive for commercial superplastic forming, in view of lowering energy requirement, increasing life for conventional or cheaper forming dies, improving the surface quality of structural components, inhibiting quick grain growth and solute-loss from the surface layers, thus resulting in better post-forming mechanical properties. This paper will summarize the dependence of superplasticity on grain size and shape in various metallic materials, including ferrous and non-ferrous alloys, which has been considered as an effective strategy to enable the LTSP.
Glucose-Derived Carbon Nanospheres as Flame Retardant for Polyethylene Terephthalate
Authors: Li Jiaqian , Yang Yaru , Xiao Yunchao , Tang Bolin , Ji Yaming , Liu Shuqiang
Published: December 2021

To improve the flame retardant properties of polyethylene terephthalate (PET), glucose-derived carbon nanospheres (CNSs) were synthesized and introduced into PET matrix. The thermal property and flame retardancy of CNSs/PET composites were thoroughly investigated. Results showed that CNSs displayed good flame-retardant performance for PET. When blended with only 1.0 wt.% of CNSs, CNSs/PET exhibited a limiting oxygen index (LOI) of 26.3 and a vertical combustion class of V-2, and its peak-heat release rate (pk-HRR) was reduced by 41.6%. Importantly, the initial decomposition temperature and the maximum weight loss temperature of CNSs/PET were 52°C and 199°C higher than those of PET, respectively. Furthermore, a condensed phase flame-retardant mechanism appeared in CNSs/PET, which formed a dense and thermally stable protective char layer during combustion. Overall, this study disclosed the flame-retardant potential and possible mechanism of CNSs for polyesters, which would benefit the development of carbon-based materials and flame-retardant polymers.
Case Report: A Case of Cotton-Wool Spots After Intravitreal Injection of Conbercept in an Infant With Incontinentia Pigmenti
Authors: Liang Licong , Yang Yiliu , Bu Shaochong , Lu Fang
Published: December 2021

Introduction: Incontinentia pigmenti (IP) is a rare X-linked neuroectodermal dysplasia affecting multiple organs. One of its most significant ophthalmic manifestations is retinal neovascularization due to retinal ischemia, which has been traditionally treated with laser photocoagulation or cryotherapy. The application of anti-vascular endothelial growth factor (VEGF) has been reported for the treatment of retinopathy of IP with beneficial results. However, clinicians should be aware of the possible ocular and systemic side effects of the intravitreal injection of anti-VEGF agents.

Case Report: A 4-month-old female infant with IP was treated with intravitreal injection of conbercept in both eyes. However, cotton-wool spots were noticed in the left eye 1 week after the injection. Laser photocoagulation was performed as an adjunct treatment. The cotton-wool spots were absorbed 1 month after the first intravitreal injection and have eventually disappeared.

Discussion: The cotton-wool spots, after intravitreal injection of conbercept for the treatment of IP, indicated severe retinal ischemia resulting from the neutralization of excessive VEGF, which was shown on fundus photograph and fluorescent angiography. Anti-VEGF agents could cause retinal arteriolar vasoconstriction and artery occlusion on rare occasions. The administration of anti-VEGF agents in pediatric cases with severe neovascularization and retinal ischemia should be carefully considered.
Enterovirus A71 2B Inhibits Interferon-Activated JAK/STAT Signaling by Inducing Caspase-3-Dependent Karyopherin-α1 Degradation
Authors: Sun Menghuai , Lin Qian , Wang Chunyang , Xing Jiao , Yan Kunlong , Liu Zhifeng , Jin Yu , Cardona Carol J. , Xing Zheng
Published: December 2021

Enterovirus A71 (EV-A71) is a major pathogen that causes the hand, foot, and mouth disease, which could be fatal with neurological complications in children. The underlying mechanism for the severe pathogenicity remains obscure, but impaired or aberrant innate immunity is considered to play a key role in viral pathogenesis. We reported previously that EV-A71 suppressed type I interferon (IFN) responses by inducing degradation of karyopherin-α1 (KPNA1), a component of the p-STAT1/2 complex. In this report, we showed that 2B, a non-structural protein of EV-A71, was critical to the suppression of the IFN-α-induced type I response in infected cells. Among viral proteins, 2B was the only one that was involved in the degradation of KPNA1, which impeded the formation of the p-STAT1/2/KPNA1 complex and blocked the translocation of p-STAT1/2 into the nucleus upon IFN-α stimulation. Degradation of KPNA1 induced by 2B can be inhibited in the cells pre-treated with Z-DEVD-FMK, a caspase-3 inhibitor, or siRNA targeting caspase-3, indicating that 2B-induced degradation of KPNA1 was caspase-3 dependent. The mechanism by which 2B functioned in the dysregulation of the IFN signaling was analyzed and a putative hydrophilic domain (H1) in the N-terminus of 2B was characterized to be critical for the release of cytochrome c into the cytosol for the activation of pro-caspase-3. We generated an EV-A71 infectious clone (rD1), which was deficient of the H1 domain. In rD1-infected cells, degradation of KPNA1 was relieved and the infected cells were more sensitive to IFN-α, leading to decreased viral replication, in comparison to the cells infected with the virus carrying a full length 2B. Our findings demonstrate that EV-A71 2B protein plays an important role in dysregulating JAK-STAT signaling through its involvement in promoting caspase-3 dependent degradation of KPNA1, which represents a novel strategy employed by EV-A71 to evade host antiviral innate immunity.
Complete Genome Sequencing and Comparative Phenotypic Analysis Reveal the Discrepancy Between Clostridioides difficile ST81 and ST37 Isolates
Authors: Su Tongxuan , Chen Wei , Wang Daosheng , Cui Yingchao , Ni Qi , Jiang Cen , Dong Danfeng , Peng Yibing
Published: December 2021

Toxin A-negative, toxin B-positiveClostridioides difficilestrains, which primarily include the ST81 and ST37 genotypes, are predominant inC. difficileinfections leading to antibiotic-associated diarrhea in China. Recently, ST81 has been reported as the most prevalent genotype rather than ST37, although the genetic and functional characteristics of the two genotypes remain ambiguous. In this study, we conducted comprehensive comparative analysis of these two genotypes through complete genome sequencing and phenotypic profiling. The whole genome sequencing revealed that the ST81 and ST37 isolates were closely related genetically with similar gene compositions, and high rate of the core genome shared. The integrative and conjugative elements identified in ST81 were similar to those in ST37, albeit with more diverse and insertion regions. By characterizing the phenotypes related to colonization or survival in the host, we found that the ST81 isolates exhibited robust colonization ability and survival bothin vitroandin vivo, enhanced spore production, and slightly increased motility, which may be attributable to the discrepancy in non-synonymous single-nucleotide polymorphisms in the relevant functional genes. Furthermore, the ST81 isolates displayed a significantly higher rate of resistance to fluoroquinolones compared with the ST37 isolates (94.12% vs. 62.5%) and mostly carried the amino acid substitution Asp426Val in GyrB. In summary, the results of our study indicate that ST81 isolates exhibit enhanced ability to transmit between hosts and survive in harsh environments, providing key genetic insights for further epidemiological investigations and surveillance ofC. difficileinfection.
The Impact of Pipe Material on the Diversity of Microbial Communities in Drinking Water Distribution Systems
Authors: Lee Debbie , Calendo Gennaro , Kopec Kristin , Henry Rebekah , Coutts Scott , McCarthy David , Murphy Heather M.
Published: December 2021

As many cities around the world face the prospect of replacing aging drinking water distribution systems (DWDS), water utilities must make careful decisions on new pipe material (e.g., cement-lined or PVC) for these systems. These decisions are informed by cost, physical integrity, and impact on microbiological and physicochemical water quality. Indeed, pipe material can impact the development of biofilm in DWDS that can harbor pathogens and impact drinking water quality. Annular reactors (ARs) with cast iron and cement coupons fed with chloraminated water from a municipal DWDS were used to investigate the impact of pipe material on biofilm development and composition over 16 months. The ARs were plumbed as closely as possible to the water main in the basement of an academic building to simulate distribution system conditions. Biofilm communities on coupons were characterized using 16S rRNA sequencing. In the cast iron reactors, β-proteobacteria, Actinobacteria, and α-proteobacteria were similarly relatively abundant (24.1, 22.5, and 22.4%, respectively) while in the cement reactors, α-proteobacteria and Actinobacteria were more relatively abundant (36.3 and 35.2%, respectively) compared to β-proteobacteria (12.8%). Mean alpha diversity (estimated with Shannon H and Faith’s Phylogenetic Difference indices) was greater in cast iron reactors (Shannon: 5.00 ± 0.41; Faith’s PD: 15.40 ± 2.88) than in cement reactors (Shannon: 4.16 ± 0.78; Faith’s PD: 13.00 ± 2.01). PCoA of Bray-Curtis dissimilarities indicated that communities in cast iron ARs, cement ARs, bulk distribution system water, and distribution system pipe biofilm were distinct. The mean relative abundance of Mycobacterium spp. was greater in the cement reactors (34.8 ± 18.6%) than in the cast iron reactors (21.7 ± 11.9%). In contrast, the mean relative abundance of Legionella spp. trended higher in biofilm from cast iron reactors (0.5 ± 0.7%) than biofilm in cement reactors (0.01 ± 0.01%). These results suggest that pipe material is associated with differences in the diversity, bacterial composition, and opportunistic pathogen prevalence in biofilm of DWDS.
Extracellular Enzyme Activities and Carbon/Nitrogen Utilization in Mycorrhizal Fungi Isolated From Epiphytic and Terrestrial Orchids
Authors: Zhao Zeyu , Shao Shicheng , Liu Na , Liu Qiang , Jacquemyn Hans , Xing Xiaoke
Published: December 2021

Fungi employ extracellular enzymes to initiate the degradation of organic macromolecules into smaller units and to acquire the nutrients for their growth. As such, these enzymes represent important functional components in terrestrial ecosystems. While it is well-known that the regulation and efficiency of extracellular enzymes to degrade organic macromolecules and nutrient-acquisition patterns strongly differ between major fungal groups, less is known about variation in enzymatic activity and carbon/nitrogen preference in mycorrhizal fungi. In this research, we investigated variation in extracellular enzyme activities and carbon/nitrogen preferences in orchid mycorrhizal fungi (OMF). Previous research has shown that the mycorrhizal fungi associating with terrestrial orchids often differ from those associating with epiphytic orchids, but whether extracellular enzyme activities and carbon/nitrogen preference differ between growth forms remains largely unknown. To fill this gap, we compared the activities of five extracellular enzymes [cellulase, xylanase, lignin peroxidase, laccase, and superoxide dismutase (SOD)] between fungi isolated from epiphytic and terrestrial orchids. In total, 24 fungal strains belonging to Tulasnellaceae were investigated. Cellulase and xylanase activities were significantly higher in fungi isolated from terrestrial orchids (0.050 ± 0.006 U/ml and 0.531 ± 0.071 U/ml, respectively) than those from epiphytic orchids (0.043 ± 0.003 U/ml and 0.295 ± 0.067 U/ml, respectively), while SOD activity was significantly higher in OMF from epiphytic orchids (5.663 ± 0.164 U/ml) than those from terrestrial orchids (3.780 ± 0.180 U/ml). Carboxymethyl cellulose was more efficiently used by fungi from terrestrial orchids, while starch and arginine were more suitable for fungi from epiphytic orchids. Overall, the results of this study show that extracellular enzyme activities and to a lesser extent carbon/nitrogen preferences differ between fungi isolated from terrestrial and epiphytic orchids and may indicate functional differentiation and ecological adaptation of OMF to local growth conditions.
Workflow Intervals and Outcomes of Endovascular Treatment for Acute Large-Vessel Occlusion During On-Vs. Off-hours in China: The ANGEL-ACT Registry
Authors: Ding Yunlong , Gao Feng , Ji Yong , Zhai Tingting , Tong Xu , Jia Baixue , Wu Jian , Wu Jiaqi , Zhang Yanrong , Wei Can , Wang Wenjuan , Zhou Jue , Niu Jiali , Miao Zhongrong , Liu Yan
Published: December 2021

Background: There may be a delay in or a poor outcome of endovascular treatment (EVT) among acute ischemic stroke (AIS) patients with large-vessel occlusion (LVO) during off-hours. By using a prospective, nationwide registry, we compared the workflow intervals and radiological/clinical outcomes between patients with acute LVO treated with EVT presenting during off- and on-hours.

Methods: We analyzed prospectively collected Endovascular Treatment Key Technique and Emergency Work Flow Improvement of Acute Ischemic Stroke (ANGEL-ACT) data. Patients presenting during off-hours were defined as those presenting to the emergency department from Monday to Friday between 17:30 and 08:00, on weekends (from 17:30 on Friday to 08:00 on Monday), and on national holidays. We used logistic regression models with adjustment for potential confounders to determine independent associations between the time of presentation and outcomes.

Results: Among 1,788 patients, 1,079 (60.3%) presented during off-hours. The median onset-to-door time and onset-to-reperfusion time were significantly longer during off-hours than during on-hours (165 vs. 125 min, P = 0.002 and 410 vs. 392 min, P = 0.027). The rates of successful reperfusion and symptomatic intracranial hemorrhage were similar in both groups. The adjusted odds ratio (OR) for the 90-day modified Rankin Scale score was 0.892 [95% confidence interval (CI), 0.748–1.064]. The adjusted OR for the occurrence of functional independence was 0.892 (95% CI, 0.724–1.098), and the adjusted OR for mortality was 1.214 (95% CI, 0.919–1.603).

Conclusions: Off-hours presentation in the nationwide real-world registry was associated with a delay in the visit and reperfusion time of EVT in patients with AIS. However, this delay was not associated with worse functional outcomes or higher mortality rates.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03370939.
“How Long Have I Got?” in Stage IV NSCLC Patients With at Least 3 Months Up to 10 Years Survival, Accuracy of Long-, Intermediate-, and Short-Term Survival Prediction Is Not Good Enough to Answer This Question
Authors: Guo Huiru , Li Hegen , Zhu Lihua , Feng Jiali , Huang Xiange , Baak Jan P. A.
Published: December 2021

Background

Most lung cancer patients worldwide [stage IV nonsmall cell lung cancer (NSCLC)] have a poor survival: 25%–30% die <3 months. Yet, of those surviving >3 months, 10%–15% (70,000–105,000 new patients worldwide per year) survive (very) long. Surprisingly, little scientific attention has been paid to the question, which factors cause the good prognosis in these NSCLC stage IV long survivors. Therefore, “How long do I still have?” currently cannot be accurately answered. We evaluated in a large group of 737 stage IV NSCLC patients surviving 3.2–120.0 months, the accuracies of short- and long-term survival predictive values of baseline factors, radiotherapy (RT), platinum-based chemotherapy (PBT), and tyrosine kinase inhibitor targeted therapy (TKI-TT).

Methods

This is a noninterventional study of 998 consecutive first-onset stage IV NSCLC patients. A total of 737 (74%) survived 3.2–120.0 months, 47 refused RT, PBT, and TKI-TT. Single and multivariate survival analysis and receiver operating curve (ROC) analysis were used with dead of disease (DOD) or alive with disease (AWD) as endpoints.

Results

The median survival (16.1 months) of 47 patients who refused PBT, RT, and TKI-TT was significantly worse than those with RT, PBT, and/or TKI-TT (23.3 months, HR = 1.60, 95% CI = 1.06–2.42, p = 0.04). Of these latter 690 patients, 42% were females, 58% males, median age 63 years (range 27–85), 1-, 2-, 5-, and 10-year survival rates were 74%, 49%, 16%, and 5%. In total, 16% were alive with disease (AWD) at the last follow-up. Pathology subtype (adenocarcinoma vs. all others), performance score, TNM substage, the number of PBT cycles and TKI-TT had independent predictive value. However, with the multivariate combination of these features, identification results of short-term nonsurvivors and long-term survivors were poor.

Conclusions

In stage IV NSCLC patients with >3 months survival, baseline features, and systemic therapeutic modalities have strong survival predictive value but do not accurately identify short- and long-term survivors. The predictive value of other features and interventions discussed should be investigated in the worldwide very large group of stage IV NSCLC patients with >3 months survival.
Prognostic Value of an Immune-Related Gene Signature in Oral Squamous Cell Carcinoma
Authors: Zhu Chao , Gu Liqun , Yao Mianfeng , Li Jiang , Fang Changyun
Published: December 2021

The prognosis and immunotherapy response rates are unfavorable in patients with oral squamous cell carcinoma (OSCC). The tumor microenvironment is associated with tumor prognosis and progression, and the underlying mechanisms remain unclear. We obtained differentially expressed immune-related genes from OSCC mRNA data in The Cancer Genome Atlas (TCGA) database. Overall survival-related risk signature was constructed by univariate Cox regression analysis and LASSO Cox regression analysis. The prognostic performance was validated with receiver operating characteristic (ROC) analysis and Kaplan–Meier survival curves in the TCGA and Gene Expression Omnibus (GEO) datasets. The risk score was confirmed to be an independent prognostic factor and a nomogram was built to quantify the risk of outcome for each patient. Furthermore, a negative correlation was observed between the risk score and the infiltration rate of immune cells, as well as the expression of immunostimulatory and immunosuppressive molecules. Functional enrichment analysis between different risk score subtypes detected multiple immune-related biological processes, metabolic pathways, and cancer-related pathways. Thus, the immune-related gene signature can predict overall survival and contribute to the personalized management of OSCC patients.
Quantitative Proteomic Analysis of Plasma Exosomes to Identify the Candidate Biomarker of Imatinib Resistance in Chronic Myeloid Leukemia Patients
Authors: Li Mei-Yong , Zhao Cui , Chen Lian , Yao Fang-Yi , Zhong Fang-Min , Chen Ying , Xu Shuai , Jiang Jun-Yao , Yang Yu-Lin , Min Qing-Hua , Lin Jin , Zhang Hai-Bin , Liu Jing , Wang Xiao-Zhong , Huang Bo
Published: December 2021

Background

Imatinib (IM), a tyrosine kinase inhibitor (TKI), has markedly improved the survival and life quality of chronic myeloid leukemia (CML) patients. However, the lack of specific biomarkers for IM resistance remains a serious clinical challenge. Recently, growing evidence has suggested that exosome-harbored proteins were involved in tumor drug resistance and could be novel biomarkers for the diagnosis and drug sensitivity prediction of cancer. Therefore, we aimed to investigate the proteomic profile of plasma exosomes derived from CML patients to identify ideal biomarkers for IM resistance.

Methods

We extracted exosomes from pooled plasma samples of 9 imatinib-resistant CML patients and 9 imatinib-sensitive CML patients by ultracentrifugation. Then, we identified the expression levels of exosomal proteins by liquid chromatography-tandem mass spectrometry (LC-MS/MS) based label free quantification. Bioinformatics analyses were used to analyze the proteomic data. Finally, the western blot (WB) and parallel reaction monitoring (PRM) analyses were applied to validate the candidate proteins.

Results

A total of 2812 proteins were identified in plasma exosomes from imatinib-resistant and imatinib-sensitive CML patients, including 279 differentially expressed proteins (DEPs) with restricted criteria (fold change≥1.5 or ≤0.667, p<0.05). Compared with imatinib-sensitive CML patients, 151 proteins were up-regulated and 128 proteins were down-regulated. Bioinformatics analyses revealed that the main function of the upregulated proteins was regulation of protein synthesis, while the downregulated proteins were mainly involved in lipid metabolism. The top 20 hub genes were obtained using STRING and Cytoscape, most of which were components of ribosomes. Moreover, we found that RPL13 and RPL14 exhibited exceptional upregulation in imatinib-resistant CML patients, which were further confirmed by PRM and WB.

Conclusion

Proteomic analysis of plasma exosomes provides new ideas and important information for the study of IM resistance in CML. Especially the exosomal proteins (RPL13 and RPL14), which may have great potential as biomarkers of IM resistance.