bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of vaccine effectiveness against the Omicron (B.1.1.529) variant in patients receiving haemodialysis
Authors: Spensley Katrina , Gleeson Sarah , Martin Paul , Thomson Tina , Clarke Candice L. , Pickard Graham , Thomas David , McAdoo Stephen P. , Randell Paul , Kelleher Peter , Bedi Rachna , Lightstone Liz , Prendecki Maria , Willicombe Michelle
Published: January 2022

Background

Emerging data suggest a reduction in SARS-CoV-2 vaccine effectiveness against Omicron SARS-CoV-2 infection. There is also evidence to show that Omicron is less pathogenic than previous variants. For clinically vulnerable populations, a less pathogenic variant may still have significant impact on morbidity and mortality. Herein we assess the clinical impact of Omicron infection, and vaccine effectiveness, in an in-centre haemodialysis (IC-HD) population.

Methods

One thousand, one hundred and twenty-one IC-HD patients were included in the analysis, all patients underwent weekly screening for SARS-CoV-2 infection via RT-PCR testing between 1st December 2021 and 16th January 2022. Screening for infection via weekly RT-PCR testing and 3-monthly serological assessment started prior to the vaccine roll out in 2020.

Results

Omicron infection was diagnosed in 145/1121 (12.9%) patients over the study period, equating to an infection rate of 3.1 per 1000 patient days. Vaccine effectiveness (VE) against Omicron infection in patients who had received a booster vaccine was 58 (23-75)%, p=0.002; VE was seen in patients who received either ChAdOx1, VE of 47(2-70)%, p=0.034, or BNT162b2, VE of 66 (36-81)%, p=0.0005, as their first two doses. No protection against infection was seen in patients who were partially vaccinated (2-doses), p=0.83. Prior infection was associated with reduced likelihood of Omicron infection, HR 0.69 (0.50-0.96), p=0.0289. Four (2.8%) patients died within 28 days of infection diagnosis, with no excess mortality was seen in patients with infection.

Conclusion

3-doses of SARS-CoV-2 vaccines are required in ICHD to provide protection against Omicron infection.
Pleiotropic enhancers are ubiquitous regulatory elements in the human genome
Authors: Laiker Ian , Frankel Nicolas
Published: January 2022

Enhancers are regulatory elements of genomes that determine spatio-temporal patterns of gene expression. The human genome contains a vast number of enhancers, which largely outnumber protein-coding genes. Classically, enhancers have been regarded as highly tissue-specific. However, recent evidence suggests that many enhancers are pleiotropic, with activity in multiple developmental contexts. Yet, the extent and impact of pleiotropy remain largely unexplored. In this study we predicted active enhancers across human organs based on the analysis of both eRNA transcription (FANTOM5 consortium datasets) and chromatin architecture (ENCODE consortium datasets). We show that pleiotropic enhancers are pervasive in the human genome and that most enhancers active in a particular organ are also active in other organs. In addition, our analysis suggests that the proportion of context-specific enhancers of a given organ is explained, at least in part, by the proportion of context-specific genes in that same organ. The notion that such a high proportion of human enhancers can be pleiotropic suggests that small regions of regulatory DNA contain abundant regulatory information and that these regions evolve under important evolutionary constraints.
Live biotherapeutic throat spray for respiratory virus inhibition and interferon pathway induction
Authors: Spacova Irina , De Boeck Ilke , Cauwenberghs Eline , Delanghe Lize , Bron Peter A. , Henkens Tim , Simons Alix , Gamgami Imane , Persoons Leentje , Claes Ingmar , van den Broek Marianne F. L. , Schols Dominique , Delputte Peter , Coenen Samuel , Verhoeven Veronique , Lebeer Sarah
Published: January 2022

Respiratory viruses such as influenza viruses, respiratory syncytial virus (RSV), and coronaviruses initiate infection at the mucosal surfaces of the upper respiratory tract (URT), where the resident respiratory microbiome has an important gatekeeper function. In contrast to gut-targeting administration of beneficial bacteria against respiratory viral disease, topical URT administration of probiotics is currently underexplored, especially for the prevention and/or treatment of viral infections. Here, we report the selection and formulation of a broad-acting throat spray with live lactobacilli which induce interferon regulatory pathways and are able to inhibit respiratory viruses. Rational selection of Lactobacillaceae strains was based on safety, applicability, and potential antiviral and immunostimulatory efficacy in the URT. Three strains, Lacticaseibacillus casei AMBR2, Lacticaseibacillus rhamnosus GG and Lactiplantibacillus plantarum WCFS1 significantly reduced the cytopathogenic effects of RSV, influenza A/H1N1 and B viruses, and HCoV-229E coronavirus in co-culture models with bacteria, virus and host cells. Subsequently, these strains were formulated in a throat spray and human monocytes were employed to confirm the formulation process did not reduce the interferon regulatory pathway-inducing capacity. Administration of the throat spray in healthy volunteers revealed that the lactobacilli were capable of temporary colonization of the throat in a metabolically active form.
Impacts of development and adult sex on brain cell numbers in the Black Soldier Fly, Hermetia illucens L. (Diptera: Stratiomyidae)
Authors: Barrett Meghan , Godfrey R. Keating , Sterner Emily J. , Waddell Edward A.
Published: January 2022

The Black Soldier Fly (Hermetia illucens, Diptera: Stratiomyidae) has been introduced across the globe, with numerous industry applications predicated on its tremendous growth during the larval stage. However, basic research onH. illucensbiology (for example, studies of their central nervous system) are lacking. Despite their small brain volumes, insects are capable of complex behaviors; understanding how these behaviors are completed with such a small amount of neural tissue requires understanding processing power (e.g. number of cells) within the brain. Brain cell counts have been completed in only a few insect species (mostly Hymenoptera), and almost exclusively in adults. This limits the taxonomic breadth of comparative analyses, as well as any conclusions about how development and body size growth may impact brain cell populations. Here, we present the first images and cell counts of theH. illucensbrain at four time points across development (early, mid, and late larval stages, and both male and female adults) using immunohistochemistry and isotropic fractionation. To assess sexual dimorphism in adults, we quantified the number of cells in the central brain vs. optic lobes of males and females separately. To assess if increases in body size during development might independently affect different regions of the CNS, we quantified the larval ventral nerve cord and central brain separately at all three stages. Together, these data provide the first description of the nervous system of a popular, farmed invertebrate and the first study of brain cell numbers using IF across developmental stages in any insect.
Verification of extracellular vesicle-mediated functional mRNA delivery via RNA editing
Authors: Somiya Masaharu , Kuroda Shun’ichi
Published: January 2022

The secretion and delivery of mRNA by extracellular vesicles (EVs) may contribute to intercellular communications. Several reporter assays have been developed to quantify EV-mediated functional delivery of mRNA into recipient cells. However, mRNA delivery efficiency can often be overestimated by experimental artifacts, resulting in “pseudo-delivery” of reporter proteins rather than mRNA. In this study, we revealed that substantial amounts of reporter proteins expressed in donor cells are secreted into the medium and interfere with the reporter assay. To eliminate this pseudo-delivery, we established a functional RNA delivery assay that employs an RNA editing tool, enabling the verification of bona fide delivery of mRNA into recipient cells. The donor cells expressed a reporter gene containing a stop codon in a non-functional open reading frame. After EV-mediated delivery of reporter mRNAs to the recipient cells, guide RNAs and RNA editing enzymes (dCas13b-hADAR2 fusion proteins) correct the RNA sequence and induce the expression of functional reporter proteins in the recipient cells. Using this system, we showed that EVs containing alphavirus-derived replicon successfully delivered functional RNA and expressed the reporter proteins. The RNA delivery assay using RNA editing enables the precise analysis of EV-mediated mRNA delivery.
Structural insight into antibody evasion of SARS-CoV-2 omicron variant
Authors: Verma Jyoti , Subbarao Naidu
Published: January 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to mutate and evolve with the emergence of omicron (B.1.1.529) as the new variant of concern. The rapid spread of this variant regionally and globally could be an allusion to increased infectivity, transmissibility, and antibody resistance. The omicron variant has a large set of mutations in its spike protein, specifically in the receptor binding domain (RBD), reflecting their significance in ACE2 interaction and antibody recognition. We have carried out the present study to understand how these mutations structurally impact the binding of the antibodies to their target epitope. We have computationally evaluated the binding of different classes of RBD targeted antibodies, namely, CB6 (etesevimab), REGN10933 (casirivimab), S309 (sotrovimab), and S2X259 to the omicron mutation-induced RBD. Molecular dynamics simulations and binding free energy calculations unveil the binding affinity and stability of the antibody-RBD complexes. All the four antibodies show reduced binding affinity towards the omicron RBD. The therapeutic antibody CB6 aka etesevimab was substantially affected due to numerous omicron mutations occurring in its target epitope. This study provides a structural insight into the reduced efficacy of RBD targeting antibodies against the SARS-CoV-2 omicron variant.
Aβ/APP-induced hyperexcitability and dysregulation of homeostatic synaptic plasticity in models of Alzheimer’s disease
Authors: Martinsson I , Quintino L , Garcia MG , Konings SC , Torres-Garcia L , Svanbergson A , Stange O , England R , Deierborg T , Li JY , Lundberg C , Gouras GK
Published: January 2022

The proper function of the nervous system is dependent on the appropriate timing of neuronal firing. Synapses continually undergo rapid activity-dependent modifications that require feedback mechanisms to maintain network activity within a window in which communication is energy efficient and meaningful. Homeostatic synaptic plasticity (HSP) and homeostatic intrinsic plasticity (HIP) are such negative feedback mechanisms. Accumulating evidence implicates that Alzheimer’s disease (AD)-related amyloid precursor protein (APP) and its cleavage product amyloid-beta (Aβ) play a role in the regulation of neuronal network activity, and in particular HSP. AD features impaired neuronal activity with regional early hyper-activity and Aβ-dependent hyperexcitability has also been demonstrated in AD transgenic mice. We demonstrate similar hyper-activity in AD transgenic neurons in culture that have elevated levels of both human APP and Aβ. To examine the individual roles of APP and Aβ in promoting hyperexcitability we used an APP construct that does not generate Aβ, or elevated Aβ levels independently of APP. Increasing either APP or Aβ in wild type (WT) neurons leads to increased frequency and amplitude of calcium transients. Since HSP/HIP mechanisms normally maintain a setpoint of activity, we examined whether homeostatic synaptic/intrinsic plasticity was altered in AD transgenic neurons. Using methods known to induce HSP/HIP, we demonstrate that APP protein levels are regulated by chronic modulation of activity and show that AD transgenic neurons have an impaired response to global changes in activity. Further, AD transgenic compared to WT neurons failed to adjust the length of their axon initial segments (AIS), an adaptation known to alter excitability. Thus, we present evidence that both APP and Aβ influence neuronal activity and that mechanisms of HSP/HIP are disrupted in neuronal models of AD.
Reduced inflammatory response and promoted multiciliated cell differentiation in mice protected by defective interfering influenza virus
Authors: Wang Chang , Honce Rebekah , Salvatore Mirella , Yang Jianjun , Twells Nicholas M. , Mahal Lara K. , Schultz-Cherry Stacey , Ghedin Elodie
Published: January 2022

Influenza defective interfering (DI) viruses have long been considered promising antiviral candidates because of their ability to interfere with replication-competent viruses and to induce antiviral immunity. However, the mechanisms underlying DI-mediated antiviral immunity have not been extensively explored. Here, we demonstrated interferon (IFN) independent protection conferred by influenza DI virus against homologous virus infection in mice deficient in type I and III IFN signaling. By integrating transcriptional and post-transcriptional regulatory data we identified unique host signatures in response to DI co-infection. DI-treated mice exhibited reduced viral transcription, less intense inflammatory and innate immune responses, and primed multiciliated cell differentiation in their lungs at an early stage of infection, even in the absence of type I or III IFNs. Overall, our study provides mechanistic insight into the protection mediated by DIs, implying a unifying theme involving inflammation and multiciliogenesis in maintaining respiratory homeostasis, and reveals their IFN-independent antiviral activity.
The endoplasmic reticulum membrane protein complex (EMC) negatively regulates intestinal homeostasis through the Hippo signaling pathway
Authors: Shi Lin , Ma Hubing , Zhao Hang , Ma Meifang , Wang Jinjun , Kong Ruiyan , Li Zhengran , Ma Rui , Wang Jian-Hua , Wu Shian , Dong Meng-qiu , Li Zhouhua
Published: January 2022

Disruption of tissue homeostasis often results in many diseases. Balanced control of stem cell proliferation and differentiation underlines tissue homeostasis. However, how endogenous factors influence the proliferation and differentiation of intestinal stem cells (ISCs) under physiological conditions remains not fully understood. Here, we find that the endoplasmic reticulum membrane protein complex (EMC) negatively regulates ISC proliferation in adultDrosophilamidgut. Compromising EMC function in progenitors leads to excessive ISC proliferation and intestinal homeostasis disruption. Mechanistically, the EMC complex associates with and stabilizes Hippo (Hpo), the key component of the Hpo signaling pathway. In the absence of the EMC complex, Yki (Yorkie) is activated to promote ISC proliferation. Furthermore, the role of the EMC complex in stem cell proliferation control is evolutionarily conserved. Thus, our study uncovers the molecular mechanism of the EMC complex in controlling stem cell proliferation. Our results provide new insight into the underlying mechanisms of how stem cell proliferation is properly controlled under physiological conditions.
Whole-brain in vivo base editing reverses autistic-like behaviors in mice
Authors: Li Weike , Chen Jinlong , Peng Wanling , Yuan Bo , Han Wenjian , Yuan Yiting , Xue Zhenyu , Wang Jincheng , Chen Zhifang , Shan Shifang , Zhu Shujia , Xu Min , Cheng Tianlin , Qiu Zilong
Published: January 2022

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder associated with deficits in social communication and stereotypical behaviors. Numerous ASD-related genetic mutations have been identified and genome editing methods have been developed but successful genome editing in the whole-brain scale to alleviate autistic-like behaviors in animal models has not been achieved. Here we report the development of a new CRISPR-mediated cytidine base editor (CBE) system, which converts C·G base pairs to T·A. We demonstrate the effectiveness of this system by targeting an ASD-associated de novo mutation in the MEF2C gene (c.104T>C, p.L35P). We constructed a Mef2c L35P knock-in mouse and observed that Mef2c L35P heterozygous mice displayed autistic-like behaviors, including deficits in social behaviors and repetitive behaviors. We programmed the CBE to edit the C·G base pairs of the mutated Mef2c gene (c.104T>C, p.L35P) to T·A base pairs and delivered it via a single dose intravenous injection of blood brain barrier (BBB)-crossing AAV-PHP.eB vector into the mouse brain. This treatment restored MEF2C protein levels and reversed impairments in social interactions and repetitive behaviors in Mef2c L35P heterozygous mice. Together, this work presents an in vivo gene editing strategy in which correcting a single nucleotide mutation in the whole-brain scale could be successfully achieved, further providing a new therapeutic framework for neurodevelopmental disorders.
Replicative Aging Remodels Cell Wall and is Associated with Increased Intracellular Trafficking in Human Pathogenic Yeasts
Authors: Silva Vanessa K.A. , Bhattacharya Somanon , Oliveira Natalia Kronbauer , Savitt Anne G. , Zamith-Miranda Daniel , Nosanchuk Joshua D. , Fries Bettina C.
Published: January 2022

Replicative aging is an underexplored field of research in medical mycology.Cryptococcus neoformans(Cn) andCandida glabrata(Cg) are dreaded fungal pathogens that cause fatal invasive infections. The fungal cell wall is essential for yeast viability and pathogenesis. In this study, we provide data characterizing age-associated modifications to the cell wall ofCnandCg. Here, we report that old yeast cells upregulate genes of cell wall biosynthesis, leading to cell wall reorganization, and increased levels of all major components, including glucan, chitin and its derivatives, as well as mannan. This results in a significant thickening of the cell wall in aged cells. Old generation yeast cells exhibited drastic ultrastructural changes, including the presence of abundant vesicle-like particles in the cytoplasm, and enlarged vacuoles with altered pH homeostasis. Our findings suggest that the cell wall modifications could be enabled by augmented intracellular trafficking. This work furthers our understanding of the cell phenotype that emerges during aging. It highlights differences in these two fungal pathogens and elucidates mechanisms that explain the enhanced resistance of old cells to antifungals and phagocytic attacks.

IMPORTANCE

Cryptococcus neoformansandCandida glabrataare two opportunistic human fungal pathogens that cause life-threatening diseases. During infection, both microorganisms have the ability to persist for long periods, and treatment failure can occur even if standard testing identifies the yeasts to be sensitive to antifungals. Replicative lifespan is a trait that is measured by the number of divisions a cell undergoes before death. Aging in fungi is associated with enhanced tolerance to antifungals and resistance to phagocytosis, and characterization of old cells may help identify novel antifungal targets. The cell wall remains an attractive target for new therapies because it is essential for fungi and is not present in humans. This study shows that the organization of the fungal cell wall changes remarkably during aging and becomes thicker and is associated with increased intracellular trafficking as well as the alteration of vacuole morphology and pH homeostasis.
Biogenesis and Function of c-type Cytochromes in the Methanogenic Archaeon, Methanosarcina acetivorans
Authors: Gupta Dinesh , Shalvarjian Katie E. , Nayak Dipti D.
Published: January 2022

C-type cytochromes (cyt c) are proteins that covalently bind heme and are integral to electron transport chains. A growing body of evidence suggests that cyt c play a vital role in both intra- and extra-cellular electron transfer processes in Archaea, especially in members that metabolize methane and other short chain alkanes. Elaborate mechanisms for the biogenesis of cyt c are known in Bacteria and Eukarya but this process remains largely uncharacterized in Archaea. Here, we have used the model methanogenic archaeon Methanosarcina acetivorans to characterize a distinct form of the system I cyt c maturation machinery (referred to as the Ccm machinery henceforth) that is broadly distributed in members of the Archaea. Phenotypic analyses of M. acetivorans mutants deficient in essential components of the Ccm machinery reveal that cyt c are broadly important for growth and methanogenesis, but the magnitude of their impact can vary substantially depending on the growth substrate. Heterologous expression of a synthetic operon with the Ccm machinery (CcmABCEF) from M. acetivorans is both necessary and sufficient for cyt c biogenesis in a non-native host (M. barkeri Fusaro) that is incapable of cyt c biogenesis. Even though components of the Ccm machinery are universally conserved across the Archaea, our evolutionary analyses indicate that different clades of Archaea acquired this pathway through multiple independent horizontal gene transfer events from different groups of Bacteria. Overall, we have demonstrated the convergent evolution of a novel Archaea-specific Ccm machinery for cyt c biogenesis and its role in methane metabolism.

Significance Statement

Microorganisms belonging to the domain Archaea play an especially important role in regulating atmospheric methane levels. Specifically, methanogens are the primary source of biogenic methane and anaerobic methanotrophic archaea (ANME) consume a substantial proportion of methane released in marine sediments. Genomic studies have implicated a class of electron-transfer proteins called c-type cytochromes as being crucial in mediating archaeal methane metabolism in the environment. However, neither the biogenesis nor the role of c-type cytochromes in methane metabolism has ever been investigated. Here, we have used a model methanogen, Methanosarcina acetivorans, to characterize a distinct pathway for maturation of c-type cytochromes that seems to be uniformly conserved across the Archaea and have also identified substrate-specific functional roles for c-type cytochromes during methanogenesis.
Genome biology of the darkedged splitfin, Girardinichthys multiradiatus, and the evolution of sex chromosomes and placentation
Authors: Du Kang , Pippel Martin , Kneitz Susanne , Feron Romain , da Cruz Irene , Winkler Sylke , Wilde Brigitta , Avila Luna Edgar G. , Myers Gene , Guiguen Yann , Macias Garcia Constantino , Schartl Manfred
Published: January 2022

Viviparity evolved independently about 150 times in vertebrates and more than 20 times in fish. Several lineages added to the protection of the embryo inside the body of the mother, the provisioning of nutrients, and physiological exchange. This often led to the evolution of a placenta. Among fish, one of the most complex systems serving the function of the placenta is the embryonal trophotaenia/ovarian luminal epithelium of the goodeid fishes. For a better understanding of this feature and others of this group of fishes, high-quality genomic resources are essential. We have sequenced the genome of the darkedged splitfin, Girardinichthys multiradiatus. The assembly is chromosome level and includes the X and Y Chromosomes. A large male-specific region on the Y was identified covering 80% of Chromosome 20, allowing some first inferences on the recent origin and a candidate male sex determining gene. Genome-wide transcriptomics uncovered sex-specific differences in brain gene expression with an enrichment for neurosteroidogenesis and testis genes in males. The expression signatures of the splitfin embryonal and maternal placenta showed overlap with homologous tissues including human placenta, the ovarian follicle epithelium of matrotrophic poeciliid fish species and the brood pouch epithelium of the seahorse. Our comparative analyses on the evolution of embryonal and maternal placenta indicate that the evolutionary novelty of maternal provisioning development repeatedly made use of genes that already had the same function in other tissues. In this way, preexisting modules are assembled and repurposed to provide the molecular changes for this novel trait.
Housing debt and elderly housing tenure choices
Authors: Bian Xun , Lin Zhenguo
Published: January 2022

We examine the impact of financial leverage, measured by the loan‐to‐value (LTV) ratios , on elderly homeowners' mobility and housing tenure choices. Using a 1999–2019 sample from the Panel Study of Income Dynamics (PSID), we find that a higher LTV ratio substantially increases an elderly homeowner's likelihood of exiting homeownership. In particular, elderly homeowners with an LTV ratio greater than 80% are more than four times likely to exit homeownership than their debt‐free counterparts. By distinguishing recent leverage changes either from house price movement or from equity extraction/injection, we further find that the impact of financial leverage is path‐dependent. Holding the LTV ratio constant, elderly homeowners are less likely to depart from homeownership if they recently extracted equity from their homes. In addition, we find both financial constraint and long‐term indebtedness are important in predicting the likelihood of elderly homeowners exiting homeownership. We further extend our analysis by exploring the effect of the housing market cycle and find the relationship between financial leverage and elderly tenure choices varies across different stages of the cycle. Our findings have several important implications. They not only point to a linkage between housing and mortgage/rental markets but also help to explain the limited size of the U.S. reverse mortgage market.
Emerging drying techniques for food safety and quality: A review
Authors: Fathi Faezeh , N. Ebrahimi Samad , Matos Luís Carlos , P. P. Oliveira M. Beatriz , Alves Rita C.
Published: January 2022

The new trends in drying technology seek a promising alternative to synthetic preservatives to improve the shelf‐life and storage stability of food products. On the other hand, the drying process can result in deformation and degradation of phytoconstituents due to their thermal sensitivity. The main purpose of this review is to give a general overview of common drying techniques with special attention to food industrial applications, focusing on recent advances to maintain the features of the active phytoconstituents and nutrients, and improve their release and storage stability. Furthermore, a drying technique that extends the shelf‐life of food products by reducing trapped water, will negatively affect the spoilage of microorganisms and enzymes that are responsible for undesired chemical composition changes, but can protect beneficial microorganisms like probiotics. This paper also explores recent efficient improvements in drying technologies that produce high‐quality and low‐cost final products compared to conventional methods. However, despite the recent advances in drying technologies, hybrid drying (a combination of different drying techniques) and spray drying (drying with the help of encapsulation methods) are still promising techniques in food industries. In conclusion, spray drying encapsulation can improve the morphology and texture of dry materials, preserve natural components for a long time, and increase storage times (shelf‐life). Optimizing a drying technique and using a suitable drying agent should also be a promising solution to preserve probiotic bacteria and antimicrobial compounds.
Receptor for advanced glycation end products aggravates cognitive deficits in type 2 diabetes through binding of C‐terminal AAs 2‐5 to mitogen‐activated protein kinase kinase 3 (MKK3) and facilitation of MEKK3‐MKK3‐p38 module assembly
Authors: Zhou Xiao‐Yan , Ying Chang‐Jiang , Hu Bin , Zhang Yu‐Sheng , Gan Tian , Zhu Yan‐Dong , Wang Nan , Li An‐An , Song Yuan‐Jian
Published: January 2022

In this study, we explored the precise mechanisms underlying the receptor for advanced glycation end products (RAGE)‐mediated neuronal loss and behavioral dysfunction induced by hyperglycemia. We used immunoprecipitation (IP) and GST pull‐down assays to assess the interaction between RAGE and mitogen‐activated protein kinase kinase 3 (MKK3). Then, we investigated the effect of specific mutation of RAGE on plasticity at hippocampal synapses and behavioral deficits in db/db mice through electrophysiological recordings, morphological assays, and behavioral tests. We discovered that RAGE binds MKK3 and that this binding is required for assembly of the MEKK3‐MKK3‐p38 signaling module. Mechanistically, we found that activation of p38 mitogen‐activated protein kinase (MAPK)/NF‐κB signaling depends on mediation of the RAGE‐MKK3 interaction by C‐terminal RAGE (ctRAGE) amino acids (AAs) 2‐5. We found that ctRAGE R2A‐K3A‐R4A‐Q5A mutation suppressed neuronal damage, improved synaptic plasticity, and alleviated behavioral deficits in diabetic mice by disrupting the RAGE‐MKK3 conjugation. High glucose induces direct binding of RAGE and MKK3 via ctRAGE AAs 2‐5, which leads to assembly of the MEKK3‐MKK3‐p38 signaling module and subsequent activation of the p38MAPK/NF‐κB pathway, and ultimately results in diabetic encephalopathy (DE).
Association between childhood maltreatment and the clinical course of bipolar disorders: A survival analysis of mood recurrences
Authors: Grillault Laroche Diane , Godin Ophélia , Belzeaux Raoul , M’Bailara Katia , Loftus Joséphine , Courtet Philippe , Dubertret Caroline , Haffen Emmanuel , Llorca Pierre Michel , Olie Emilie , Passerieux Christine , Polosan Mircea , Schwan Raymund ,   The FACE‐BD collaborators, Leboyer Marion , Bellivier Frank , Marie‐Claire Cynthia , Etain Bruno
Published: January 2022

Objectives

Childhood maltreatment, also referred as childhood trauma, increases the severity of bipolar disorders (BD). Childhood maltreatment has been associated with more frequent mood recurrences, however, mostly in retrospective studies. Since scarce, further prospective studies are required to identify whether childhood maltreatment may be associated with the time to recurrence in BD.

Methods

Individuals with BD (N = 2008) were assessed clinically and for childhood maltreatment at baseline, and followed up for two years. The cumulative probability of mood recurrence over time was estimated with the Turnbull’s extension of the Kaplan–Meier analysis for interval‐censored data, including childhood maltreatment as a whole, and then maltreatment subtypes as predictors. Analyses were adjusted for potential confounding factors.

Results

The median duration of follow‐up was 22.3 months (IQR:12.0–24.8). Univariable analyses showed associations between childhood maltreatment, in particular all types of abuses (emotional, physical, and sexual) or emotional neglect, and a shorter time to recurrence (all p < 0.001). When including potential confounders into the multivariable models, the time to mood recurrence was associated with multiple/severe childhood maltreatment (i.e., total score above the 75th percentile) (HR = 1.32 95%CI (1.11–1.57), p = 0.002), and more specifically with moderate/severe physical abuse (HR = 1.44 95%CI(1.21–1.73), p < 0.0001). Living alone, lifetime anxiety disorders, lifetime number of mood episodes, baseline depressive and (hypo)manic symptoms, and baseline use of atypical antipsychotics were also associated with the time to recurrence.

Conclusions

In addition to typical predictors of mood recurrences, an exposure to multiple/severe forms of childhood maltreatment, and more specifically to moderate to severe physical abuse, may increase the risk for a mood recurrence in BD. This leads to the recommendations of more scrutiny and denser follow‐up of the individuals having been exposed to such early‐life stressors.
Post‐treatment effects of topiramate on alcohol‐related outcomes: A combined analysis of two placebo‐controlled trials
Authors: Kranzler Henry R. , Feinn Richard , Pond Timothy , Hartwell Emily , Gelernter Joel , Crist Richard C. , Witkiewitz Katie
Published: January 2022

Topiramate reduces drinking and alcohol‐related problems and is increasingly being used to treat alcohol use disorder (AUD). In a randomized controlled trial (RCT) of topiramate, rs2832407, a single nucleotide polymorphism (SNP) in the GRIK1 gene moderated topiramate's effects (Study 1). However, a second RCT (Study 2) did not replicate the SNP's moderating effect during treatment. The current analysis combines data from these two studies to examine topiramate's effects on alcohol‐related outcomes and on its pharmacogenetic moderation during a 6‐month post‐treatment period. This analysis includes 308 individuals with problematic alcohol use (67% male; mean age = 51.1; topiramate: 49%, placebo: 51%). It uses generalized linear mixed models to examine changes in self‐reported alcohol consumption and alcohol‐related problems and concentrations of the liver enzyme γ‐glutamyltransferase. The report combines published 3‐ and 6‐month follow‐up data from Study 1 with similar, unpublished data from Study 2. Despite robust effects of topiramate on drinking during treatment, the overall multivariate medication effects on outcomes during 3‐ and 6‐month follow‐up were not significant (p = 0.08 and p = 0.26, respectively). The moderating effect of the SNP on primary treatment outcomes was also not significant during either follow‐up period (p = 0.13 and p = 0.16, respectively). However, during the 3‐month post‐treatment period, drinks per day was significantly lower in the topiramate group than the placebo group in the rs2832407*CC‐genotype group. The robust effects of topiramate on alcohol‐related outcomes during treatment diminish substantially once the medication is discontinued. Research is needed both to determine the optimal treatment duration and to identify clinically useful pharmacogenetic moderators of topiramate for treating AUD.
Catheter‐based system for the treatment of left ventricular assist device thrombosis
Authors: Joyce David L. , Lynch Bryan E. , Freed Julie , Kreuziger Lisa Baumann , Salinger Michael H. , Joyce Lyle D.
Published: January 2022

Background

Thrombotic complications continue to pose challenges to patients on left ventricular assist device (LVAD) support. The Hoplon system was developed to administer catheter‐based lytic therapy with a novel approach to embolic protection.

Methods

Two porcine non‐survival surgeries were performed in which off‐pump LVAD insertion was followed by injection of thrombus into the impeller, isolation of the pump using the Hoplon system, and administration of lytic therapy to the pump chamber. Successful thrombus resolution was confirmed by pathological examination of the LVAD and brain tissue after animal sacrifice.

Results

Limitations of the prototype design resulted in the extrusion of thrombus from around the catheter in the first animal. Subsequent device modifications resulted in the resolution of LVAD thrombus as confirmed on removal and examination of the pump. Pathological examination of the brain tissue revealed the absence of any embolic or hemorrhagic complications.

Conclusions

Early animal studies suggest feasibility in restoring function to an LVAD while at the same time preventing cerebroembolic events using the Hoplon system.
Association of the prolonged use of anti‐glaucoma medications with the surgical failure of ab interno microhook trabeculotomy
Authors: Okuda Mina , Mori Sotaro , Takano Fumio , Murai Yusuke , Ueda Kaori , Sakamoto Mari , Kurimoto Takuji , Yamada‐Nakanishi Yuko , Nakamura Makoto
Published: January 2022

Purpose

This study examined the perioperative factors affecting surgical success in ab interno microhook trabeculotomy (μTLO).

Methods

A total of 146 consecutive patients who underwent μTLO were included in this retrospective study. We performed Cox proportional hazard modelling by setting surgical success at 1 year as an objective variable. The explanatory variables included age, sex, glaucoma type, preoperative intraocular pressure (IOP), glaucoma drug score, mean deviation (MD) of the Humphrey visual field test, duration of glaucoma drug use, antithrombotic drug use, combined cataract surgery, incision range and diabetes mellitus. Additionally, we performed 1:1 matching using propensity score analysis and compared the perioperative parameters between durations of glaucoma drug use of <4.5 years and ≥ 4.5 years (50 patients each). We defined surgical success as satisfaction of all three criteria: IOP 5–21 mmHg, IOP reduction of ≥20% from the preoperative IOP and no additional glaucoma surgery.

Results

The Cox proportional hazard model revealed that a longer duration of anti‐glaucoma medication was significantly associated with surgical failure. Propensity score matching analysis showed that the <4.5‐year users of anti‐glaucoma drugs had significantly higher success rates than the ≥4.5‐year users (72% versus 52%; p = 0.04).

Conclusions

The prolonged use of multiple glaucoma drugs adversely affected the outcome of μTLO at least at 1 year postoperatively.
Topical noninvasive retinal drug delivery of a tyrosine kinase inhibitor: 3% cediranib maleate cyclodextrin nanoparticle eye drops in the rabbit eye
Authors: Lorenzo‐Soler Laura , Praphanwittaya Pitsiree , Olafsdottir Olof Birna , Kristinsdottir Iris Myrdal , Asgrimsdottir Gudrun Marta , Loftsson Thorsteinn , Stefansson Einar
Published: January 2022

Purpose

Tyrosine kinase inhibitors inhibit VEGF receptors. If delivered to the retina, they might inhibit oedema and neovascularization such as in age‐related macular degeneration and diabetic retinopathy. The aim of this study was to formulate cediranib maleate, a potent VEGF inhibitor, as γ‐cyclodextrin nanoparticle eye drops and measure the retinal delivery and overall ocular pharmacokinetics after a single‐dose administration in rabbits.

Methods

A novel formulation technology with 3% cediranib maleate as γ‐cyclodextrin micro‐suspension was prepared by autoclaving method. Suitable stabilizers were tested for heat‐stable eye drops. The ophthalmic formulation was topically applied to one eye in rabbits. The pharmacokinetics in ocular tissues, tear film and blood samples were studied at 1, 3 and 6 hr after administration.

Results

γ‐cyclodextrin formed complex with cediranib maleate. The formation of γ‐cyclodextrin nanoparticles occurred in concentrated complexing media. Combined stabilizers prevented the degradation of drug during the autoclaving process. Three hours after administration of the eye drops, treated eyes showed cediranib levels of 737 ± 460 nM (mean ± SD) in the retina and 10 ± 6 nM in the vitreous humour.

Conclusions

Cediranib maleate in γ‐cyclodextrin nanoparticles were stable to heat in presence of stabilizers. The drug as eye drops reached the retina in concentrations that are more than 100 times higher than the 0.4 nM IC50 value reported for the VEGF type‐II receptor and thus, presumably, above therapeutic level. These results suggest that γ‐cyclodextrin‐based cediranib maleate eye drops deliver effective drug concentrations to the retina in rabbits after a single‐dose administration.
Multiplex analysis of mass imaging data: Application to the pathology of experimental myocardial infarction
Authors: Shi Han , El Kazzi Mary , Liu Yuyang , Gao Antony , Schroder Angie L. , Vuong Sally , Young Pamela A. , Rayner Benjamin S. , van Vreden Caryn , King Nicholas J. C. , Witting Paul K.
Published: January 2022

Aim

Imaging mass cytometry (IMC) affords simultaneous immune‐labelling/imaging of multiple antigens in the same tissue. Methods utilizing multiplex data beyond co‐registration are lacking. This study developed and applied an innovative spatial analysis workflow for multiplex imaging data to IMC data determined from cardiac tissues and revealed the mechanism(s) of neutrophil‐mediated post‐myocardial‐infarction damage.

Methods

IMC produced multiplex images with various redox/inflammatory markers. The cardiac peri‐infarct zone (PIZ) was determined to be up to 240 µm from the infarct border based on the presence of neutrophils. The tissue region beyond the infarct was defined as the remote area (RA). ImageJ was used to quantify the immunoreactivity. Functional assessments included infarct size, cell necro/apoptosis, total thiol assay and echocardiogram.

Results

Expression of damage markers decreased in order from the infarct area to PIZ and then RA, reflecting the neutrophil density in the regions. Concentrically spaced “shoreline contour analysis” around the cardiac infarct extending into the PIZ showed that immunoreactivity for damage markers decreased linearly with increasing distance from the infarct, concomitant with a decreasing neutrophil‐myeloperoxidase (MPO) gradient from the infarct to the PIZ. Stratifying by concentric bands around individual MPO+‐signal identified that the immunoreactivity of haem‐oxygenase‐1 (HO‐1) and phosphorylated‐p38 mitogen‐activated protein kinase (pP38) peaked near neutrophils. Furthermore, spatial dependence between neutrophils and markers of cardiac cellular damage was confirmed by nearest‐neighbour distance analysis. Post‐infarction tissue exhibited declined functional parameters that were associated with neutrophil migration from the infarct to PIZ.

Conclusion

This image‐based quantitative protocol revealed the spatial association and provided potential molecular pathways responsible for neutrophil‐mediated damage post‐infarction.
Gut microbiota modulates osteoclast glutathione synthesis and mitochondrial biogenesis in mice subjected to ovariectomy
Authors: Yuan Yin , Yang Jing , Zhuge Aoxiang , Li Lanjuan , Ni Shuo
Published: January 2022

Objectives

Osteoporosis is a common bone disease in the elderly mainly regulated by osteoblasts (OBs) and osteoclasts (OCs). The gut microbiota has been recognized as an important factor in many physiological and pathological processes in the host. Thus, we hypothesize that the gut microbiota is necessary for postmenopausal osteoporosis and that germ‐free (GF) mice are protected from osteoporosis.

Material and Methods

Osteoporosis models were established by performing ovariectomy (OVX) in mice. Bone mass was measured by micro‐CT, and gut microbiota were assessed by 16s rDNA sequencing. Reactive oxygen species (ROS) were detected by dihydroethidium (DHE) staining in vivo and 2’,7'‐dichlorodihydrofluorescein diacetate (DCFH‐DA) staining in vitro.

Results

Firmicutes and Bacteroidetes in the intestine are pivotal in OC differentiation, and the Firmicutes/Bacteroidetes ratio (F/B ratio) is a specific indicator of osteoporosis. Furthermore, we found that Firmicutes and Bacteroidetes affect the de novo synthesis of glutathione (GSH) by regulating its key enzyme glutamate–cysteine ligase catalytic subunit (Gclc) and inhibiting mitochondrial biogenesis and ROS accumulation via the cAMP response element‐binding (CREB) pathway. In addition, supplementing OVX mice with the probiotic Lactobacillus salivarius LI01 from the Firmicutes phylum prevented osteoporosis.

Conclusions

Our results reveal that GSH plays a vital role in OVX‐induced bone loss, and probiotics that affect GSH metabolism are potential therapeutic targets for overcoming osteoporosis.
Balance impairment and cognitive dysfunction in patients with chronic obstructive pulmonary disease under 65 years
Authors: Kaygusuz Melike Hanim , Oral Tapan Ozge , Tapan Utku , Genc Sebahat
Published: January 2022

Objective

Balance and cognitive problems may develop in COPD. Studies investigating cognitive functions are mostly in elderly patients, and the number of studies on balance impairment is less than studies about cognitive dysfunction in COPD. We aimed to evaluate both balance and cognitive functions in patients with COPD under 65 years.

Methods

A total of 60 COPD patients and 60 healthy control group were enrolled. The patients with COPD were divided into two groups due to dyspnea severity. Demographic data and dyspnea scores of all patients were recorded. BECK depression scale, standardized Mini Mental Test (MMT), and BERG balance scale were applied to the individuals. Factors affecting BERG balance scale were evaluated.

Results

BERG balance scale and MMT values were found to be significantly lower in patients with COPD compared with the control group (p = 0.009). It was observed that the mean values of BERG balance scale and MMT were significantly low in the severe dyspnea group. BERG scale had significant correlations with MMT (rho = 0.331, p = 0.001), BECK (rho = −0.222, p = 0.016), age (rho = −0.318, p = 0.018), MMRC (rho = −0.368, p < 0.001), CAT (rho = −0.338, p = 0.008), FEV1% (rho = 0.307, p = 0.017), SpO2 (rho = 0.448, p < 0.001), and number of hospitalization per year (rho = −0.316, p = 0.014). According to the results of multiple linear regression analysis, the effect of oxygen saturation on BERG was found to be statistically significant (B = 0.512, p = 0.008).

Conclusions

Balance tests in patients with COPD under the age of 65 are significantly low when compared with healthy controls at the same age. Balance and cognitive functions are significantly associated with each other. It may be beneficial to perform balance and cognitive function tests earlier even at the beginning of the treatment period of COPD, and strategies should be planned to prevent the progression of functional losses.
The who and what of women's drinking: Examining risky drinking and associated socio‐demographic factors among women aged 40–65 years in Australia
Authors: Miller Mia , Mojica‐Perez Yvette , Livingston Michael , Kuntsche Emmanuel , Wright Cassandra J. C. , Kuntsche Sandra
Published: January 2022

Introduction

Recent trends in Australian national survey data show an increase in alcohol use among middle‐aged people, amidst declines in alcohol use among other population groups. There is limited research, however, on middle‐aged women's alcohol use. This study aimed to examine patterns in alcohol use among Australian women aged 40–65 and the associated sociodemographic and contextual factors.

Methods

Cross‐sectional data from six waves of the National Drug Strategy Household Survey (2001–2019). We estimated the prevalence of long‐term risky drinking (>2 Australian standard drinks per day) and risky‐single occasion drinking (>5 Australian standard drinks on one occasion) among middle‐aged women. Logistic regression models were estimated using 2019 data to examine demographic characteristics and contextual factors associated with alcohol use.

Results

Since 2001, there has been a statistically significant increase in long‐term risky drinking and risky‐single occasion drinking amongst middle‐aged women in Australia. Educational attainment, marital status and employment status were negatively associated with risky drinking, whereas rurality, age and location of use were positively associated with risky drinking. Beverage type was both positively and negatively associated with risky drinking.

Discussion and Conclusions

Given the significant increase in alcohol use amongst middle‐aged women in Australia, prevention efforts are needed for this group, which may focus in particular on home drinking and the impact of rurality on alcohol use.