bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of nonobstructive coronary stenosis on coronary microvascular dysfunction and long‐term outcomes in patients with INOCA
Authors: Mohammed Ayman A. , Zhang Hengbin , Abdu Fuad A. , Liu Lu , Singh Shekhar , Lv Xian , Shi Tingting , Mareai Redhwan M. , Mohammed Abdul‐Quddus , Yin Guoqing , Zhang Wen , Xu Yawei , Che Wenliang
Published: December 2022

Background

Ischemic pain with no‐obstructive coronary artery (INOCA) is clinically significant and defined by nonobstructive coronary stenosis <50%. Coronary microvascular dysfunction (CMD) is a relevant cause associated with adverse outcomes.

Objectives

Investigated the effect of no‐stenosis (0% stenosis) and non‐obstructive (0% < stenosis < 50%) on the prognostic impact of CMD in INOCA.

Method

A retrospective study assessed the coronary microvascular function in 151 INOCA patients who underwent invasive angiography by the coronary angiography‐derived index of microcirculation‐resistance (caIMR). CZT‐SPECT was performed to evaluate myocardial perfusion imaging (MPI) abnormalities. Chi‐square test/Fisher exact test, Student t‐test, Kaplan–Meier curve, and Uni‐multivariable Cox proportional models were used for analysis. Clinical outcomes were major adverse cardiovascular events (MACE) during a median follow‐up of 35 months.

Result

No‐stenosis was present in 71 (47%) INOCA patients, and 80 (53%) were with nonobstructive. CMD (caIMR ≥ 25) was more prevalent in patients with no‐stenosis than nonobstructive (76.1% vs. 48.8%, p = .001), along with abnormal MPI (39.4% vs. 22.5%, p = .024). The MACE rates were not different between no‐stenosis and nonobstructive stenosis. CMD showed an increased risk of MACE for all INOCA. No‐stenosis with CMD had the worst prognosis. Cox regression analysis identified CMD and abnormal MPI as predictors of MACE in all INOCA and patients with no‐stenosis. However, no‐stenosis and nonobstructive stenosis were not predictors of MACE in INOCA.

Conclusion

CMD was more frequently present in INOCA with no‐stenosis. However, there was no difference in long‐term clinical outcomes between no‐stenosis and nonobstructive stenosis. CMD could independently predict poor outcomes in INOCA, particularly in patients with no‐stenosis.
Peptides Targeting RNA m6A Methylations Influence the Viability of Cancer Cells
Authors: Rauff Rushdhi , Abedeera Sudeshi M. , Schmocker Stefani , Xie Jiale , Abeysirigunawardena Sanjaya C.
Published: December 2022

N6‐methyladenosine (m6A) is the most abundant nucleotide modification observed in eukaryotic mRNA. Changes in m6A levels in transcriptome are tightly correlated to expression levels of m6A methyltransferases and demethylases. Abnormal expression levels of methyltransferases and demethylases are observed in various diseases and health conditions such as cancer, male infertility, and obesity. This research explores the efficacy of m6A‐modified RNA as an anticancer drug target. We discovered a 12‐mer peptide that binds specifically to m6A‐modified RNA using phage display experiments. Our fluorescence‐based assays illustrate the selected peptide binds to methylated RNA with lower micromolar affinity and inhibit the binding of protein FTO, a demethylase enzyme specific to m6A modification. When cancer cell lines were treated with mtp1, it led to an increase in m6A levels and a decrease in cell viability. Hence our results illustrate the potential of mtp1 to be developed as a drug for cancer.
NanoTag Nanobody Tools for Drosophila In Vitro and In Vivo Studies
Authors: Kim Ah‐Ram , Xu Jun , Cheloha Ross , Mohr Stephanie E. , Zirin Jonathan , Ploegh Hidde L. , Perrimon Norbert
Published: December 2022

Nanobodies have emerged as powerful protein‐binding tools to uncover protein functions. Using functionalized protein binders, proteins of interest can be visualized, degraded, delocalized, or post‐translationally modified in vivo. We recently reported the use of two short peptide tags, 10‐aa 127D01 and 14‐aa VHH05, and their corresponding nanobodies, Nb127D01 and NbVHH05, for both in vitro and in vivo studies in Drosophila. Here, we provide detailed protocols for nanobody production and for visualization of proteins of interest in either fixed or live samples. In addition, we include protocols for endogenous protein tagging using CRISPR‐mediated genome engineering. © 2022 Wiley Periodicals LLC.

Basic Protocol 1: Nanobody production in S2 cells

Basic Protocol 2: Nanobody expression and purification in bacterial cells

Basic Protocol 3: Immunostaining with nanobodies

Basic Protocol 4: Immunoblotting with nanobodies

Basic Protocol 5: Immunoprecipitation with nanobodies prepared from S2 cells

Basic Protocol 6: Immunoprecipitation with nanobodies prepared from bacteria

Basic Protocol 7: NbVHH05 and Nb127D01 used as chromobodies

Basic Protocol 8: NanoTag trap as a method to alter protein localization

Support Protocol: CRISPR‐mediated tagging of endogenous genes with NanoTags
Water Well Basics
Authors: Ernst Matt
Published: December 2022

Water wells—including abandoned wells—are commonplace in crop country. Potential water quality impacts, from both operating and abandoned wells, make them important for CCAs and their clients to understand. This article provides a review of water well basics to bear in mind as you advise clients about cropping and managing land with wells. Earn 1 CEU in Soil & Water Management by reading this article and taking the quiz at https://web.sciencesocieties.org/Learning‐Center/Courses.
Flexible Solid‐State Metal‐Air Batteries: The Booming of Portable Energy Supplies
Authors: Liu Ning , Liang Zhanhao , Yang Fan , Wang Xiaotong , Zhong Junjie , Gui Xuchun , Yang Guowei , Zeng Zhiping , Yu Dingshan
Published: December 2022

The rapid development of portable and wearable electronics has given rise to new challenges and provoked research in flexible, lightweight, and affordable energy storage devices. Flexible solid‐state metal‐air batteries (FSSMABs) are considered promising candidates, owing to their large energy density, mechanical flexibility, and durability. However, the practical applications of FSSMABs require further improvement to meet the demands of long‐term stability, high power density, and large operating voltage. This Review presents a detailed discussion of innovative electrocatalysts for the air cathode, followed by a sequential overview of high‐performance solid‐state electrolytes and metal anodes, and a summary of the current challenges and future perspectives of FSSMABs to promote practical application and large‐scale commercialization in the near future.
Oridonin ameliorates acetaminophen‐induced acute liver injury through ATF4/PGC‐1α pathway
Authors: Yu Dongsheng , Li Jiye , Wang Yu , Guo Danfeng , Zhang Xiaodan , Chen Mingming , Zhou Zheng
Published: December 2022

Acetaminophen (APAP) overdose‐induced acute liver injury (ALI) causes hepatocyte cell death, oxidative stress, and inflammation. Oridonin (Ori), a covalent NLRP3‐inflammasome inhibitor, ameliorates APAP‐induced ALI through an unclear molecular mechanism. This study found that Ori decreased hepatic cytochrome P450 2E1 level and increased glutathione content to prevent APAP metabolism, and then reduced the necrotic area, improved liver function, and inhibited APAP‐induced proinflammatory cytokines and oxidative stress. Ori also decreased activating transcription factor 4 (ATF4) protein levels and increased peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) to reduce APAP‐induced endoplasmic reticulum stress activation and mitochondrial dysfunction. Furthermore, western blot and luciferase assay found that ATF4 inhibited transcription in the PGC‐1α promoter −507 to −495 region to reduce PGC‐1α levels, while ATF4 knockdown neutralized the hepatoprotective effect of Ori. Molecular docking showed that Ori bound to ATF4's amino acid residue glutamate 302 through 6, 7, and 18 hydroxyl bands. Our findings demonstrated that Ori prevented metabolic activation of APAP and further inhibited the ATF4/PGC‐1α pathway to alleviate APAP overdose‐induced hepatic toxicity, which illuminated its potential therapeutic effects on ALI.
Renal fluid and acid/base balance during refeeding in restrictive eating disorders
Authors: Rosen Elaine , Wiley Evan , Hung Phoebe , Song Dana , Sharma Yamini , Moscicki Anna‐Barbara , Wesseling‐Perry Katherine
Published: December 2022

Background and Objectives

Fluid shifts have been ascribed to central diabetes insipidus in patients with anorexia nervosa hospitalized for refeeding. Recent data, however, suggest that vasopressin production is not dysregulated in this population. Our objective was to describe the trajectory of fluid imbalances in relationship to kidney function, electrolyte disturbances, and acid/base balance during refeeding.

Methods

A retrospective review of daily fluid balance and biochemical values was performed in 70 sequential unique patients admitted to University of California at Los Angeles Hospital Medical Stabilization Program for Eating Disorders from December 2018 to November 2020.

Results

Participants (2 males/68 females) were between 10 and 24 years of age and with a median body mass index of 16.1 (14.3, 18.1) kg/m2. A severe negative fluid balance (>−900 ml/day) was observed in 80% of patients at some point during hospitalization. Serum sodium concentrations were normal on admission and remained stable during refeeding. Serum bicarbonate concentrations were 25 ± 1 mEq/dl on admission and increased above the normal range in 31% of patients. Metabolic alkalosis was inversely associated with the development of a negative fluid balance. Estimated glomerular filtration rate was impaired in 54% of patients, improved with refeeding, and was not associated with the development of a severe negative fluid balance or metabolic alkalosis.

Discussion

Chronic energy deprivation alters the physiology of renal fluid and bicarbonate handling in ways that are independent of vasopressin and glomerular filtration. Further studies are warranted to understand the renal adaptations that occur during energy restriction and subsequent refeeding.

Public Significance

Massive urinary fluid losses occur in patients with restrictive eating disorders hospitalized for refeeding. In addition, many patients have impaired renal bicarbonate excretion. These findings suggest that chronic energy deprivation impairs the kidney's ability to handle the shifts in fluid and acid/base balance that occur when appropriate oral nutrition is re‐introduced.
Emotion word use patterns and eating disorder symptoms: Considering the circumplex model of affect and basic emotions theory
Authors: Romano Kelly A. , Heron Kristin E. , Ferguson Giselle , Scott Stacey B.
Published: December 2022

Objective

No prior research has examined whether the types of emotion words individuals use to describe their affective experiences cluster along affective dimensions inherent within leading affect theories, or how such emotion word use maps onto eating disorder (ED) symptoms.

Method

To address these gaps, latent profile analysis was used to empirically‐identify groups of young adults (N = 352) by how often they use emotion words characterized by the circumplex model of affect's valence‐arousal dimensions and basic emotions theory's basic versus complex emotion word categorizations. Auxiliary analyses examined differences in groups' ED symptoms (binge eating, purging, restricting, excessive exercising, muscle building, body dissatisfaction, and cognitive restraint).

Results

The 5‐profile valence‐arousal model and 4‐profile basic‐complex model were the best‐fitting theoretically‐supported solutions. Valence‐arousal profiles with greater negative affect valence generally exhibited worse ED pathology than others, whereas profiles with greater positive affect valence produced inconsistent risk‐ and protective‐factor relations with distinct ED symptoms. Basic‐complex profiles characterized by frequent use of both basic and complex emotion words generally had the greatest ED severity, and profiles with greater basic emotion word use exhibited elevated binge eating.

Discussion

Individual‐differences in young adults' emotion word use patterns, versus sample‐level averages only, warrant further consideration in ED prevention and research.

Public Significance

The present findings suggest that young adults differ in the types of words they use to describe their emotional experiences, and that these unique emotion word use patterns are linked to distinct eating disorder symptoms. These sources of variation warrant further consideration in eating disorders prevention efforts and future research seeking to advance affect‐based eating disorders theories.
The effect of decreasing human activity from COVID‐19 on the foraging of fallen fruit by omnivores
Authors: Osugi Shigeru , Baek Seungyun , Naganuma Tomoko , Tochigi Kahoko , Allen Maximilian L. , Koike Shinsuke
Published: December 2022

In 2020, a lockdown was implemented in many cities around the world to contain the COVID‐19 pandemic, resulting in a significant cessation of human activity which have had a variety of impacts on wildlife. But in many cases, due to limited pre‐lockdown information, and there are limited studies of how lockdowns have specifically affected behaviors. Foraging behavior is inherently linked to fitness and survival, is particularly affected by changes in temporal activity, and the influence of human disturbance on foraging behavior can be assessed quantitatively based on foraging duration and quantity. The purpose of this study was to determine whether and how the fruit‐foraging behaviors of two omnivores, the Japanese badger (Meles anakuma) and the raccoon dog (Nyctereutes procyonoides), were influenced by the decrease of human activity associated with lockdowns. Specifically, by comparing to a previous study in 2019–2020, we attempted to determine (1) whether foraging behavior increases during the daytime? (2) whether the duration of foraging per visit increases? and (3) what factors animals select for in fruiting trees? The results of the initial investigation showed that the foraging behavior of both species in 2019 was almost exclusively restricted to the nighttime. But as opportunities for foraging behavior without human interference increased in 2020 due to the lockdown, both species (but especially raccoon dogs) showed substantial changes in their activity patterns to be more diurnal. The duration of foraging per visit also increased in 2020 for both species, and the selection during foraging for both species shifted from selecting trees that provided greater cover in 2019 to trees with high fruit production in 2020. Our results show how human activity directly affects the foraging behavior of wildlife in an urban landscape.
Strong species structure but weak geographical structure in demersal Lake Victoria cichlids
Authors: van Rijssel Jacco C. , Moser Florian N. , Mwaiko Salome , Seehausen Ole
Published: December 2022

Studying phenotypic and genetic differentiation between very young species can be very informative with regard to learning about processes of speciation. Identifying and characterizing genetic species structure and distinguishing it from spatial genetic structure within a species is a prerequisite for this and is often not given sufficient attention. Young radiations of cichlid fish are classical speciation study systems. However, it is only during the past decade that population genomics based on next‐generation sequencing has begun to provide the power to resolve species and distinguish speciation from spatial population structure for the youngest of these radiations. The Lake Victoria haplochromine cichlids constitute the youngest large cichlid fish radiation, probably <20,000 years old. Earlier work showed that communities of rocky reef cichlids are composed of many reciprocally monophyletic species despite their very recent origins. Here, we build on this work by studying assemblages of offshore demersal cichlids, adding analyses of within‐species spatial structure to the sympatric species structure. We sampled seven multispecies communities along a 6‐km‐long transect from one side of the Mwanza Gulf to the other side. We investigated whether phenotypically diagnosed putative species are reciprocally monophyletic and whether such monophyly is stable across species geographic ranges. We show that all species are genetically strongly differentiated in sympatry, that they are reciprocally monophyletic, and that monophyly is stable across distribution ranges. We found significant differentiation between geographically distinct populations in two species, but no or weak isolation by distance. We further found subtle but significant morphological differences between all species and a linear relationship between genomic and morphological distance which suggests that differences in morphology begin to accumulate after speciation has already affected genome‐wide restrictions of gene flow.
Enhanced High‐Temperature Energy Storage Performance of All‐Organic Composite Dielectric via Constructing Fiber‐Reinforced Structure
Authors: Feng Mengjia , Feng Yu , Zhang Changhai , Zhang Tiandong , Tong Xu , Gao Qiang , Chen Qingguo , Chi Qingguo
Published: December 2022

Optimizing the high‐temperature energy storage characteristics of energy storage dielectrics is of great significance for the development of pulsed power devices and power control systems. Selecting a polymer with a higher glass transition temperature (Tg) as the matrix is one of the effective ways to increase the upper limit of the polymer operating temperature. However, current high‐Tg polymers have limitations, and it is difficult to meet the demand for high‐temperature energy storage dielectrics with only one polymer. For example, polyetherimide has high‐energy storage efficiency, but low breakdown strength at high temperatures. Polyimide has high corona resistance, but low high‐temperature energy storage efficiency. In this work, combining the advantages of two polymer, a novel high‐Tg polymer fiber‐reinforced microstructure is designed. Polyimide is designed as extremely fine fibers distributed in the composite dielectric, which will facilitate the reduction of high‐temperature conductivity loss for polyimide. At the same time, due to the high‐temperature resistance and corona resistance of polyimide, the high‐temperature breakdown strength of the composite dielectric is enhanced. After the polyimide content with the best high‐temperature energy storage characteristics is determined, molecular semiconductors (ITIC) are blended into the polyimide fibers to further improve the high‐temperature efficiency. Ultimately, excellent high‐temperature energy storage properties are obtained. The 0.25 vol% ITIC‐polyimide/polyetherimide composite exhibits high‐energy density and high discharge efficiency at 150 °C (2.9 J cm−3, 90%) and 180 °C (2.16 J cm−3, 90%). This work provides a scalable design idea for high‐performance all‐organic high‐temperature energy storage dielectrics.
Synthesis of [60]Fullerene Hybrids Endowed with Steroids and Monosaccharides: Theoretical Underpinning as Promising anti‐SARS‐CoV‐2 Agents
Authors: Lemos Reinier , Makowski Kamil , Almagro Luis , Tolón Blanca , Rodríguez Hortensia , Herranz M. Ángeles , Molero Dolores , Martín Nazario , Suárez Margarita
Published: December 2022

Cyclopropanation reactions between C60 and different malonates decorated with monosaccharides and steroids using the Bingel‐Hirsch methodology have allowed the obtention of a new family of hybrid compounds in good yields. A complete set of instrumental techniques has allowed us to fully characterize the hybrid derivatives and to determine the chemical structure of monocycloadducts. Besides, the proposed structures were investigated by cyclic voltammetry, which evidenced the exclusive reductive pattern of fullerene Bingel‐type monoadducts. Theoretical calculations at the DFT‐D3(BJ)/PBE 6‐311G(d,p) level of the synthesized conjugates predict the most stable conformation and determine the factors that control the hybrid molecules′ geometry. Some parameters such as polarity, lipophilicity, polar surface area, hydrophilicity index, and solvent‐accessible surface area were also estimated, predicting its potential permeability and capability as cell membrane penetrators. Additionally, a molecular docking simulation has been carried out using the main protease of SARS‐CoV‐2 (Mpro) as the receptor, thus paving the way to study the potential application of these hybrids in biomedicine.
Oral capsules of tetra‐hydro‐cannabinol (THC), cannabidiol (CBD) and their combination in peripheral neuropathic pain treatment
Authors: Zubcevic Kanita , Petersen Merete , Bach Flemming Winther , Heinesen Aksel , Enggaard Thomas Peter , Almdal Thomas Peter , Holbech Jakob Vormstrup , Vase Lene , Jensen Troels Stahelin , Hansen Christian Stevns , Finnerup Nanna Brix , Sindrup Søren H.
Published: December 2022

Background

Cannabinoids are often prescribed for neuropathic pain, but the evidence‐based recommendation is ‘weak against’.

Objectives

The aim was to examine the effect of two cannabinoids and their combination in peripheral neuropathic pain.

Methods

This was a randomized, double‐blind, trial with treatment arms for cannabidiol (CBD), tetra‐hydro‐cannabinol (THC), CBD and THC combination (CBD/THC), and placebo in a 1:1:1:1 ratio and flexible drug doses (CBD 5–50 mg, THC 2.5–25 mg, and CBD/THC 5 mg/2.5 mg–50 mg/25 mg). Treatment periods of 8‐week duration were proceeded by 1 week for baseline observations. Patients with painful polyneuropathy, post‐herpetic neuralgia and peripheral nerve injury (traumatic or surgical) failing at least one previous evidence‐based pharmacological treatment were eligible for inclusion. The primary outcome was the change in weekly average of daily pain measured with a numeric rating scale (NRS). Trail Making Test (TMT) was used as one of the tests of mental functioning.

Results

In all, 145 patients were included in the study of which 118 were randomized and 115 included in the intention‐to‐treat analysis. None of the treatments reduced pain compared to placebo (p = 0.04–0.60). Effect sizes as estimated in week 8 (positive values worse and negative better than placebo) were CBD mean 1.14 NRS points (95% CI 0.11–2.19), THC 0.38 (CI −0.65 to 1.4) and CBD/THC −0.12 (−1.13 to 0.89).

Conclusions

CBD, THC and their combination did not relieve peripheral neuropathic pain in patients failing at least one previous evidence‐based treatment for neuropathic pain.
Regulation and impact of VOC and CO2 emissions on low‐carbon energy systems resilient to climate change: A case study on an environmental issue in the oil and gas industry
Authors: Fetisov Vadim , Gonopolsky Adam M. , Davardoost Hadi , Ghanbari Ata Rezapour , Mohammadi Amir H.
Published: December 2022

The impact of emissions from the fuel and energy sectors adversely affects the environment on the economies of countries. One of these pollutants is volatile organic compounds (VOCs), which contribute to the formation of tropospheric ozone. Emissions of hydrocarbon formation in the form of VOCs occur in four stages of the fuel and energy industry sector: (1) production, (2) processing, (3) transportation, and (4) storage. The oil and gas industry ranks among the top polluting industries in terms of VOC emissions. Research on the negative impact of VOCs, as well as CO2 emissions from the consequences of the extraction, processing, transport, and storage of oil and gas on the ecosystem of the planet and the population, has begun to be studied by science recently. Typically, these studies were conducted using laboratory and field analyses, as well as using data on anthropogenic emissions in the development of regulatory documents and requirements governing the control of VOC and CO2 emissions in the oil and gas industry. This paper presents a critical analysis of the literature on research on the negative effects of VOC emissions on the ecosystem and human health because of such factors as production, processing, transportation, and storage of hydrocarbons. This analysis shows the global magnitude of VOC emissions. Data from human‐made emissions from the oil and gas industry and direct emissions from transportation and energy processing were used to figure out how VOCs affect the environment around the world and how far they spread. In conclusion, this study found patterns of VOC emissions that show how important it is to control VOCs during the production, processing, transportation, and storage of oil and gas, as well as how important it is to create a single research base on emissions for each industry sector and on sources of greenhouse gas absorption.
Design and key technology of the energy consumption management system for the liquid cooling data center
Authors: Lai Yibo , Fang Xiang , Han Rongjie , Xuan Yi , Huang Jiabin
Published: December 2022

In view of the serious problem of energy consumption waste in the application process of liquid cooling data center, a new energy consumption management system of liquid cooling data center is constructed in this research. Energy consumption predictor, resource controller and resource configurator are used to monitor and manage energy consumption and optimize resource allocation of liquid cooling data center. The S3C2440A microprocessor with the internal core of ARM920T is adopted as the core controller of the energy consumption data collection system, and the energy consumption sampling circuit is designed with the voltage transformer and the current transformer, and attenuation network is adopted to prevent frequency aliasing in data sampling. Particle swarm optimization algorithm is used to identify the parameters in the model estimator, and the resource coordinator is used to solve the power consumption and the performance models. When using multiple physical servers to simulate the data center environment, the experimental structure shows that the system in the research can control the overall energy consumption of the server within 260 W, and the prediction error of the model estimator is kept lower than 2.4%.
5G network slicing with unmanned aerial vehicles: Taxonomy, survey, and future directions
Authors: Bouzid Tarek , Chaib Noureddine , Bensaad Mohamed Lahcen , Oubbati Omar Sami
Published: December 2022

With the ever‐expanding rise of network demands and user expectations, the fifth generation (5G) of cellular networks was envisioned to support a plethora of use cases and conflicting user demands. Next to providing traditional connectivity like its previous generations, 5G also promises to be a heterogeneous network connecting humans, vehicles, unmanned aerial vehicles (UAVs), smart devices, and more. These challenging expectations proved to be overwhelming for traditional network infrastructures to handle. Network slicing has emerged as a promising solution that can achieve such diverse, taxing, and sometimes conflicting requirements in a dynamic and programmable way. There is no denying that UAVs have attained significant focus and research in recent years, and with 5G already being deployed, UAVs can now exploit the capabilities of the new networks. Extensive research is being taken to integrate UAVs into networks, assisting and improving aspects like latency, coverage, and capacity. Motivated by these facts, this survey distinguishes itself from other works by jointly exploring 5G, network slicing, and UAVs. The main contributions of this article are to showcase how UAVs can assist networks, provide a taxonomy of UAVs in the context of network slicing, and survey works that contribute to network slicing with UAVs. In this article, we present a comprehensive survey on UAVs in the context of network slicing, covering contributions, and state‐of‐the‐art literature. We discuss network slicing in‐depth, focusing especially on the three major slices: enhanced Mobile BroadBand, massive machine type communications, and ultra‐reliable low‐latency communications. We provide an overview of 5G enablers, including software‐defined networking and network function virtualization. We cover UAVs and identify their roles in networks as both users and assistants. Furthermore, this survey provides insight into open issues and future research directions related to network slicing and UAVs before concluding.
Human myeloid progenitor glucocorticoid receptor activation causes genomic instability, type 1 IFN‐ response pathway activation and senescence in differentiated microglia; an early life stress model
Authors: Wei Jingzhang , Arber Charles , Wray Selina , Hardy John , Piers Thomas M. , Pocock Jennifer M.
Published: December 2022

One form of early life stress, prenatal exposure to glucocorticoids (GCs), confers a higher risk of psychiatric and neurodevelopmental disorders in later life. Increasingly, the importance of microglia in these disorders is recognized. Studies on GCs exposure during microglial development have been limited, and there are few, if any, human studies. We established an in vitro model of ELS by continuous pre‐exposure of human iPS‐microglia to GCs during primitive hematopoiesis (the critical stage of iPS‐microglial differentiation) and then examined how this exposure affected the microglial phenotype as they differentiated and matured to microglia, using RNA‐seq analyses and functional assays. The iPS‐microglia predominantly expressed glucocorticoid receptors over mineralocorticoid receptors, and in particular, the GR‐α splice variant. Chronic GCs exposure during primitive hematopoiesis was able to recapitulate in vivo ELS effects. Thus, pre‐exposure to prolonged GCs resulted in increased type I interferon signaling, the presence of Cyclic GMP‐AMP synthase‐positive (cGAS) micronuclei, cellular senescence and reduced proliferation in the matured iPS‐microglia. The findings from this in vitro ELS model have ramifications for the responses of microglia in the pathogenesis of GC‐ mediated ELS‐associated disorders such as schizophrenia, attention‐deficit hyperactivity disorder and autism spectrum disorder.
LEP and LEPR are possibly a double‐edged sword for wound healing
Authors: Zhang Kai‐Wen , Jia Yuan , Li Yue‐Yue , Guo Dan‐Yang , Li Xiao‐Xiao , Hu Kai , Qian Xiao‐Xi , Chen Zhong‐Hua , Wu Jun‐Jie , Yuan Zheng‐Dong , Yuan Feng‐Lai
Published: December 2022

Wound healing is a complex and error‐prone process. Wound healing in adults often leads to the formation of scars, a type of fibrotic tissue that lacks skin appendages. Hypertrophic scars and keloids can also form when the wound‐healing process goes wrong. Leptin (Lep) and leptin receptors (LepRs) have recently been shown to affect multiple stages of wound healing. This effect, however, is paradoxical for scarless wound healing. On the one hand, Lep exerts pro‐inflammatory and profibrotic effects; on the other hand, Lep can regulate hair follicle growth. This paper summarises the role of Lep and LepRs on cells in different stages of wound healing, briefly introduces the process of wound healing and Lep and LepRs, and examines the possibility of promoting scarless wound healing through spatiotemporal, systemic, and local regulation of Lep levels and the binding of Lep and LepRs.
Evaluation of scale development and its regeneration potency in the desert killifish under laboratory conditions
Authors: Motamedi Mina , Teimori Azad , Esmaeili Mohammad Reza , Mostafavi Hossein
Published: December 2022

Scale development and its regeneration potency were evaluated in a desert killifish Aphaniops hormuzensis (family Aphaniidae) in laboratory conditions by using light and scanning electron microscopy. Scale development in A. hormuzensis took 156 days at room temperature. Four specific regions of scale formation were detected. The first scale development began 13 days post‐hatching (dph) (total length [TL] = 8.5 mm) at the caudal peduncle region and is extended anteriorly 26 dph (TL = 13.6 mm) at the area below the dorsal fin. Scales began forming independently in the head region at 33 dph (TL = 21.7 mm), and in the abdominal region, began at 41 dph (TL = 25.8 mm). Additional points of scale origin were detected on the sides of the operculum or behind and below the eyes. Scale regeneration in the caudal peduncle started 6 days after removal (dar). In 16 dar, the microstructural features appeared and the growth circles, a wide and oblong focus (focus length = 0.6 ± 0.05 µm), and lepidonts were also formed. In 36 dar, the scale shape was gradually changed from circular to a polygon, and radii were distinguishable in the anterior field. The pattern of scale formation could be useful in enhancing the understanding of systematics and phylogeny, functional morphology, and habitat use. It could also be useful in helping to define the Larval/juvenile transition period.
UK media reporting of NICE recommendation of crizanlizumab for patients with sickle cell disease
Authors: Buka Richard J , Roy Noémi , Nicolson Phillip LR
Published: December 2022

Crizanlizumab was recommended for use in patients with sickle cell disease in the UK in October 2021 and received widespread media coverage. Accuracy of reporting is paramount in building trust with this group of patients who are often wary of the medical profession. We carried out an analysis of internet‐based news articles and applied a validated scoring system to assess quality. 21 articles from 19 media organisations were identified. 71% of articles stated unproven benefits of the drug and only 14% were of satisfactory quality. The former was largely due to quoting of two NHS England press releases. Overstating of drug efficacy may be detrimental to the need to address healthcare inequalities.
Contraception use and HIV outcomes among women initiating dolutegravir‐containing antiretroviral therapy in Kenya: a retrospective cohort study
Authors: Humphrey John M. , Omodi Victor , Bernard Caitlin , Maina Mercy , Thorne Julie , Mwangi Ann , Wools‐Kaloustian Kara , Patel Rena C.
Published: December 2022

Introduction

The rollout of dolutegravir (DTG) in low‐ and middle‐income countries was disrupted by a potential association reported with periconceptional DTG exposure among women living with HIV (WLHIV) and infant neural tube defects. This prompted countries to issue interim guidance limiting DTG use among women of reproductive potential to those on effective contraception. Data to understand the potential impact of such guidance on WLHIV are limited.

Methods

We conducted a retrospective cohort analysis of WLHIV 15–49 years initiating DTG‐containing antiretroviral treatment (ART) in Kenya from 2017 to 2020. We determined baseline effective (oral, injectable or lactational amenorrhea) and very effective (implant, intrauterine device or female sterilization) contraception use among women who initiated DTG before (Group 1) or during (Group 2) the interim guideline period. We defined incident contraception use in each group as the number of contraceptive methods initiated ≤180 days post‐guideline (Group 1) or post‐DTG initiation (Group 2). We determined the proportions of all women who switched from DTG‐ to non‐nucleoside reverse transcriptase inhibitor (NNRTI)‐ (efavirenz or nevirapine) containing ART ≤12 months post‐DTG initiation, compared their viral suppression (<1000 copies/ml) and conducted multivariable logistic regression to determine factors associated with switching from DTG to NNRTI‐containing ART.

Results

Among 5155 WLHIV in the analysis (median age 43 years), 89% initiated DTG after transitioning from an NNRTI. Baseline effective and very effective contraception use, respectively, by the group were: Group 1 (12% and 13%) and Group 2 (41% and 35%). Incident contraception use in each group was <5%. Overall, 498 (10%) women switched from DTG to an NNRTI. Viral suppression among those remaining on DTG versus switched to NNRTI was 95% and 96%, respectively (p = 0.63). In multivariable analysis, incident effective and very effective contraception use was not associated with switching.

Conclusions

Baseline, but not incident, effective contraception use was higher during the interim guideline period compared to before it, suggesting women already using effective contraception were preferentially selected to initiate DTG after the guideline was released. These findings reveal challenges in the implementation of policy which ties antiretroviral access to contraceptive use. Future guidance should capture nuances of contraception decision‐making and support women's agency to make informed decisions.
CLEC5A expression can be triggered by spike glycoprotein and may be a potential target for COVID‐19 therapy
Authors: Machado Thiago L. , Santos Alanna C. , Azamor Tamiris , da Silva Andrea M. V. , Pimenta Vanessa R. , Tubarão Luciana N. , da Silva Alexandre dos Santos , Flores Rodrigues Daniela Del Rosário , Müller Rodrigo , Pinto Marcelo A. , Villar Livia M. , Bom Ana P. A. , Melgaço Juliana G.
Published: December 2022

The immune response is crucial for coronavirus disease 19 (COVID‐19) progression, with the participation of proinflammatory cells and cytokines, inducing lung injury and loss of respiratory function. CLEC5A expression on monocytes can be triggered by viral and bacterial infections, leading to poor outcomes. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is able to induce neutrophil activation by CLEC5A and Toll‐like receptor 2, leading to an aggressive inflammatory cascade, but little is known about the molecular interactions between CLEC5A and SARS‐CoV‐2 proteins. Here, we aimed to explore how CLEC5A expression could be affected by SARS‐CoV‐2 infection using immunological tools with in vitro, in vivo, and in silico assays. The findings revealed that high levels of CLEC5A expression were found in monocytes from severe COVID‐19 patients in comparison with mild COVID‐19 and unexposed subjects, but not in vaccinated subjects who developed mild COVID‐19. In hamsters, we detected CLEC5A gene expression during 3–15 days of Omicron strain viral challenge. Our results also showed that CLEC5A can interact with SARS‐CoV‐2, promoting inflammatory cytokine production, probably through an interaction with the receptor‐binding domain in the N‐acetylglucosamine binding site (NAG‐601). The high expression of CLEC5A and high levels of proinflammatory cytokine production were reduced in vitro by a human CLEC5A monoclonal antibody. Finally, CLEC5A was triggered by spike glycoprotein, suggesting its involvement in COVID‐19 progression; therapy with a monoclonal antibody could be a good strategy for COVID‐19 treatment, but vaccines are still the best option to avoid hospitalization/deaths.
Booster shot of inactivated SARS‐CoV‐2 vaccine induces potent immune responses in people living with HIV
Authors: Zhan Haoting , Gao Huixia , Liu Yongmei , Zhang Xihong , Li Haolong , Li Xiaomeng , Wang Lijing , Li Chen , Li Beilei , Wang Yuling , Dai Erhei , Li Yongzhe
Published: December 2022

This study aimed to investigate the immunogenicity to SARS‐CoV‐2 and evasive subvariants BA.4/5 in people living with HIV (PLWH) following a third booster shot of inactivated SARS‐CoV‐2 vaccine. We conducted a cross‐sectional study in 318 PLWH and 241 healthy controls (HC) using SARS‐CoV‐2 immunoassays. Vaccine‐induced immunological responses were compared before and after the third dose. Serum levels of IgG anti‐RBD and inhibition rate of NAb were significantly elevated at the “post‐third dose” sampling time compared with the pre‐third dose in PLWH, but were relatively decreased in contrast with those of HCs. Induced humoral and cellular responses attenuated over time after triple‐dose vaccination. The neutralizing capacity against BA.4/5 was also intensified but remained below the positive inhibition threshold. Seropositivity of SARS‐CoV‐2‐specific antibodies in PLWH was prominently lower than that in HC. We also identified age, CD4 cell counts, time after the last vaccination, and WHO staging type of PLWH as independent factors associated with the seropositivity of antibodies. PLWH receiving booster shot of inactivated vaccines generate higher antibody responses than the second dose, but lower than that in HCs. Decreased anti‐BA.4/5 responses than that of WT impede the protective effect of the third dose on Omicron prevalence.
Cryptic resolution sites in the vector plasmid lead to the heterogeneities in the rAAV vectors
Authors: Zhang Junping , Chrzanowski Matthew , Frabutt Dylan A. , Lam Anh K. , Mulcrone Patrick L. , Li Lei , Konkle Barbara A. , Miao Carol H. , Xiao Weidong
Published: December 2022

Recombinant adeno‐associated virus (rAAV) vectors carry a cassette of interest retaining only the inverted terminal repeats (ITRs) from the wild‐type virus. Conventional rAAV production primarily uses a vector plasmid as well as helper genes essential for AAV replication and packaging. Nevertheless, plasmid backbone related contaminants have been a major source of vector heterogeneity. The mechanism driving the contamination phenomenon has yet to be elucidated. Here we identified cryptic resolution sites in the plasmid backbone as a key source for producing snapback genomes, which leads to the increase of vector genome heterogeneity in encapsidated virions. By using a single ITR plasmid as a model molecule and mapping subgenomic particles, we found that there exist a few typical DNA break hotspots in the vector DNA plasmid backbone, for example, on the ampicillin DNA element, called aberrant rescue sites. DNA around these specific breakage sites may assume some typical secondary structures. Similar to normal AAV vectors, plasmid DNA with a single ITR was able to rescue and replicate efficiently. These subgenomic DNA species significantly compete for trans factors required for rAAV rescue, replication, and packaging. The replication of single ITR contaminants during AAV production is independent of size. Packaging of these species is greatly affected by its size. A single ITR and a cryptic resolution site in the plasmid work synergistically, likely causing a source of plasmid backbone contamination.
Risk of waning humoral responses after inactivated or subunit recombinant SARS‐CoV‐2 vaccination in patients with chronic diseases: Findings from a prospective observational study in China
Authors: Li Hu , Cai Dachuan , Jiang Depeng , Li Xingsheng , Liao Xiaohui , Liu Dongfang , Liu Zuojin , Zhu Peng , Yin Guobing , Ming Jia , Peng Mingli , Chen Min , Ling Ning , Lan Yinghua , Zhang Dazhi , Hu Peng , Ren Hong
Published: December 2022

Heterogeneity of antibody responses has been reported in SARS‐CoV‐2 vaccination recipients with underlying diseases. We investigated the impact of the presence of comorbidities on the humoral response to SARS‐CoV‐2 vaccination in patients with chronic disease (PWCD) and assessed the effect of the number of comorbidities on the humoral response to vaccination. In this study, neutralizing antibodies (NAbs) and IgG antibodies against the receptor‐binding domain (RBD‐IgG) were monitored following a full‐course vaccination. In total, 1400 PWCD (82.7%, inactivated vaccines; 17.3%, subunit recombinant vaccine) and 245 healthy controls (65.7% inactivated vaccines, 34.3% subunit recombinant vaccine) vaccinated with inactivated or subunit recombinant SARS‐CoV‐2 vaccines, were included. The seroconversion and antibody levels of the NAbs and RBD‐IgG were different in the PWCD group compared with those in the control group. Chronic hepatitis B (odds ratio [OR]: 0.65; 95% confidence interval [CI]: 0.46–0.93), cancer (OR: 0.65; 95% CI: 0.42–0.99), and diabetes (OR: 0.50; 95% CI: 0.28–0.89) were associated with lower seroconversion of NAbs. Chronic kidney disease (OR: 0.29; 95% CI: 0.11–0.76), cancer (OR: 0.38; 95% CI: 0.23–0.62), and diabetes (OR: 0.37; 95% CI: 0.20–0.69) were associated with lower seroconversion of RBD‐IgG. Only the presence of autoimmune disease showed significantly lower NAbs and RBD‐IgG titers. Patients with most types of chronic diseases showed similar responses to the controls, but humoral responses were still significantly associated with the presence of ≥2 coexisting diseases. Our study suggested that humoral responses following SARS‐CoV‐2 vaccination are impaired in patients with certain chronic diseases.
Cordyceps militaris polysaccharides modulate gut microbiota and improve metabolic disorders in mice with diet‐induced obesity
Authors: Huang Shishi , Zou Yuan , Tang Hongbiao , Zhuang Jingyu , Ye Zhiwei , Wei Tao , Lin Junfang , Zheng Qianwang
Published: December 2022

BACKGROUND

Cordyceps militaris is an edible and medicinal fungus, and its polysaccharides are among its main pharmacological components. They can display immunomodulation, anti‐oxidation, anti‐inflammation, anti‐hypolipidemic, and other functions. The anti‐obesity effect of C. militaris polysaccharides (CMP) is not yet fully understood, however.

RESULTS

In this study, a CMP diet intervention was applied over a 4 week period to mice with obesity induced by a high‐fat diet (HFD), followed by profiling of obesity‐induced dyslipidemia, low‐grade inflammation, and gut dysbiosis. The results suggested that CMP could significantly reduce HFD‐induced obesity, alleviate obesity‐induced hyperlipidemia and insulin resistance, and ameliorate systemic inflammation, showing a promising ability to protect mice from obesity. Further analyses revealed that CMP could regulate obesity‐induced gut dysbiosis by restoring the phylogenetic diversity of gut microbiota. It could also increase the relative abundance of short‐chain fatty acid (SCFA)‐producing bacteria, while down‐regulating the level of bacteria that were positively related to the development of obesity. A correlation analysis showed that Helicobacter, Allobaculum, Clostridium XVIII, Parabacteroides, Ligilactobacillus, Faecalibaculum, Adlercreutzia, and Mediterraneibacter were positively related to obese phenotypes.

CONCLUSION

This study highlights the potential of CMP as a prebiotic agent to protect obese individuals from metabolic disorders and gut dysbiosis. © 2022 Society of Chemical Industry.
Circular RNA Sec61 subunit alpha isoform 1 by competitive absorption of microRNA‐513a‐5p mediates peroxisomal biogenesis factor 5 expression and promotes the malignant phenotype of non‐small cell lung cancer
Authors: Duan Zhe‐Ping , Yu Xin‐Jiang , Wei Hua‐Lin
Published: December 2022

Circular RNAs (circRNAs) are functional RNAs in the development and metabolism of non‐small cell lung cancer (NSCLC). Therein, this paper particularly elucidated the circRNA SEC61 subunit alpha isoform 1 (circSEC61A1) in NSCLC has not been fully elucidated. Clinical analysis of circSEC61A1 expression was performed on specimens collected from 51 patients with primary NSCLC, together with patients' survival. Cell experiments were performed after interfering with circSEC61A1, microRNA (miR)‐513a‐5p, and peroxisomal biogenesis factor 5 (PEX5) expression, respectively, and cell malignant phenotypes and aerobic glycolysis were evaluated, as well as epithelial‐to‐mesenchymal transition (EMT)‐related markers and Wnt/β‐catenin pathway. Xenografts experiments studied the performance of circSEC61A1 in vivo. The downstream molecules of circSEC61A1 were searched. Our data demonstrated that circSEC61A1 was upregulated in NSCLC patients, showing an association with poorer survival outcomes. In cell experiments, circSEC61A1 overexpression promoted NSCLC malignant phenotypes, glycolysis, EMT, and Wnt/β‐catenin pathway activation, whereas circSEC61A1 underexpression did the opposite. Knockdown of circSEC61A1 limited tumor growth and metastasis. Furthermore, circSEC61A1 could regulate PEX5 expression through competitive absorption of miR‐513a‐5p. Generally, circSEC61A1 is a potential biomarker for NSCLC, and circSEC61A1 serves tumor‐promoting action in the progression of NSCLC.