Miracle-dz/UniFAR-FTUs huggingface dataset:
Flexibility In Vitro of Amino Acid 226 in the Receptor-Binding Site of an H9 Subtype Influenza A Virus and Its Effect In Vivo on Virus Replication, Tropism, and Transmission

A single amino acid change at position 226 in the hemagglutinin (HA) from glutamine (Q) to leucine (L) has been shown to play a key role in receptor specificity switching in various influenza virus HA subtypes, including H9. We tested the flexibility of amino acid usage and determined the effects of such changes. The results reveal that amino acids other than L226 and Q226 are well tolerated and that some amino acids allow for the recognition of both avian and human influenza virus receptors in the absence of other changes. Our results can inform better avian influenza virus surveillance efforts as well as contribute to rational vaccine design and improve structural molecular dynamics algorithms. ABSTRACT Influenza A viruses (IAVs) remain a significant public health threat, causing more than 300,000 hospitalizations in the United States during the 2015–2016 season alone. While only a few IAVs of avian origin have been associated with human infections, the ability of these viruses to cause zoonotic infections further increases the public health risk of influenza. Of these, H9N2 viruses in Asia are of particular importance as they have contributed internal gene segments to other emerging zoonotic IAVs. Notably, recent H9N2 viruses have acquired molecular markers that allow for a transition from avian-like to human-like terminal sialic acid (SA) receptor recognition via a single amino acid change at position 226 (H3 numbering), from glutamine (Q226) to leucine (L226), within the hemagglutinin (HA) receptor-binding site (RBS). We sought to determine the plasticity of amino acid 226 and the biological effects of alternative amino acids on variant viruses. We created a library of viruses with the potential of having any of the 20 amino acids at position 226 on a prototypic H9 HA subtype IAV. We isolated H9 viruses that carried naturally occurring amino acids, variants found in other subtypes, and variants not found in any subtype at position 226. Fitness studies in quails revealed that some natural amino acids conferred an in vivo replication advantage. This study shows the flexibility of position 226 of the HA of H9 influenza viruses and the resulting effect of single amino acid changes on the phenotype of variants in vivo and in vitro. IMPORTANCE A single amino acid change at position 226 in the hemagglutinin (HA) from glutamine (Q) to leucine (L) has been shown to play a key role in receptor specificity switching in various influenza virus HA subtypes, including H9. We tested the flexibility of amino acid usage and determined the effects of such changes. The results reveal that amino acids other than L226 and Q226 are well tolerated and that some amino acids allow for the recognition of both avian and human influenza virus receptors in the absence of other changes. Our results can inform better avian influenza virus surveillance efforts as well as contribute to rational vaccine design and improve structural molecular dynamics algorithms.
Suppression of Light-Induced Oxidative Stress in the Retina by Mitochondria-Targeted Antioxidant

Light-induced oxidation of lipids and proteins provokes retinal injuries and results in progression of degenerative retinal diseases, such as, for instance, iatrogenic photic maculopathies. Having accumulated over years retinal injuries contribute to development of age-related macular degeneration (AMD). Antioxidant treatment is regarded as a promising approach to protecting the retina from light damage and AMD. Here, we examine oxidative processes induced in rabbit retina by excessive light illumination with or without premedication using mitochondria-targeted antioxidant SkQ1 (10-(6’-plastoquinonyl)decyltriphenyl-phosphonium). The retinal extracts obtained from animals euthanized within 1–7 days post exposure were analyzed for H2O2, malondialdehyde (MDA), total antioxidant activity (AOA), and activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) using colorimetric and luminescence assays. Oxidation of visual arrestin was monitored by immunoblotting. The light exposure induced lipid peroxidation and H2O2 accumulation in the retinal cells. Unexpectedly, it prominently upregulated AOA in retinal extracts although SOD and GPx activities were compromised. These alterations were accompanied by accumulation of disulfide dimers of arrestin revealing oxidative stress in the photoreceptors. Premedication of the eyes with SkQ1 accelerated normalization of H2O2 levels and redox-status of lipids and proteins, contemporarily enhancing AOA and, likely, sustaining normal activity of GPx. Thus, SkQ1 protects the retina from light-induced oxidative stress and could be employed to suppress oxidative damage of proteins and lipids contributing to AMD.
Tissue Resident CCR2− and CCR2+ Cardiac Macrophages Differentially Orchestrate Monocyte Recruitment and Fate Specification Following Myocardial Injury

Rationale: Recent advancements have brought to light the origins, complexity, and functions of tissue-resident macrophages. However, in the context of tissue injury or disease, large numbers of monocytes infiltrate the heart and are thought to contribute to adverse remodeling and heart failure pathogenesis. Little is understood about the diversity of monocytes and monocyte-derived macrophages recruited to the heart after myocardial injury, including the mechanisms that regulate monocyte recruitment and fate specification. Objective: We sought to test the hypothesis that distinct subsets of tissue-resident CCR2− (C-C chemokine receptor 2) and CCR2+ macrophages orchestrate monocyte recruitment and fate specification after myocardial injury. Methods and Results: We reveal that in numerous mouse models of cardiomyocyte cell death (permanent myocardial infarction, reperfused myocardial infarction, and diphtheria toxin cardiomyocyte ablation), there is a shift in macrophage ontogeny whereby tissue-resident macrophages are predominately replaced by infiltrating monocytes and monocyte-derived macrophages. Using syngeneic cardiac transplantation to model ischemia-reperfusion injury and distinguish tissue-resident from recruited cell populations in combination with intravital 2-photon microscopy, we demonstrate that monocyte recruitment is differentially orchestrated by distinct subsets of tissue-resident cardiac macrophages. Tissue-resident CCR2+ macrophages promote monocyte recruitment through an MYD88 (myeloid differentiation primary response 88)-dependent mechanism that results in release of MCPs (monocyte chemoattractant proteins) and monocyte mobilization. In contrast, tissue-resident CCR2− macrophages inhibit monocyte recruitment. Using CD (cluster of differentiation) 169-DTR (diphtheria toxin receptor) and CCR2-DTR mice, we further show that selective depletion of either tissue-resident CCR2− or CCR2+ macrophages before myocardial infarction results in divergent effects on left ventricular function, myocardial remodeling, and monocyte recruitment. Finally, using single-cell RNA sequencing, we show that tissue-resident cardiac macrophages differentially instruct monocyte fate specification. Conclusions: Collectively, these observations establish the mechanistic basis by which monocytes are initially recruited to the injured heart and provide new insights into the heterogeneity of monocyte-derived macrophages.
The advent of IL-17A blockade in ankylosing spondylitis: secukinumab, ixekizumab and beyond

ABSTRACT Introduction: Secukinumab, an interleukin-17A (IL-17A) antagonist, is the first non-TNF alpha inhibitor agent licensed for ankylosing spondylitis (AS), which opens up a new era of alternative cytokine targets beyond TNF. Areas covered: This review explores the pathophysiology and scientific evidence behind the use of this new mode of action and discusses the basis for its efficacy and clinical utility in the management of AS. In particular, how the emergent data points towards the efficacy of secukinumab and ixekizumab, a second emergent IL-17A blocker, in AS has helped focus research into the IL-23/17 axis in entheseal driven disease in man and how IL-17A inhibition may be linked to the presence of innate and adaptive immune cell populations capable of IL-17A elaboration in these target tissues. Expert commentary: Collectively these emergent data point towards an efficacious role of IL-17A inhibition strategies targeting AS pathogenesis in a fundamental way whilst carrying a good safety profile.
STOP 101: A Phase 1, Randomized, Open‐Label, Comparative Bioavailability Study of INP104, Dihydroergotamine Mesylate (DHE) Administered Intranasally by a I123 Precision Olfactory Delivery (POD®) Device, in Healthy Adult Subjects

Investigate the safety and pharmacokinetics (PK) of INP104, intranasal dihydroergotamine mesylate (DHE) administered via a Precision Olfactory Delivery (POD®) device, (Impel NeuroPharma, Seattle, WA) vs intravenous (IV) DHE and DHE nasal spray (Migranal®) in healthy adult subjects.
Prehospital National Early Warning Score predicts early mortality

National Early Warning Score (NEWS) has been shown to be the best early warning score to predict in‐hospital mortality but there is limited information on its predictive value in a prehospital setting. The aim of the current study was to investigate the diagnostic accuracy of NEWS in a prehospital setting using large population‐based databases in terms of short‐term mortality.
Verification of a dose rate-responsive dynamic equilibrium model on radiation-induced mutation frequencies in mice

Abstract Purpose: We have proposed a mathematical model (WAM model) expressing increment of the dose-rate dependent mutation frequency caused by artificial radiations. In this model, it is defined that the pool of mutant cells in dynamic equilibrium in organisms. We verified the accuracy of the WAM prediction of mutation frequency in mice. Materials and methods: The theoretical values calculated by the WAM model were compared with the experimental values obtained from the large mouse genetics program at the Oak Ridge National Laboratory (ORNL). Results: Most of all the theoretical values in acute and chronic irradiation conditions nearly coincided with the experimental values. However, the theoretical value of the chronic conditions at the dose-rate of 0.8 R/min was significantly higher than its experimental value. This discordance was able to be minimized in the WAM assumption, when the period from the end of exposure to start mating was two weeks longer. Conclusions: As a result of comparison between experimental and theoretical data, the certainty of the WAM model was confirmed in mice and it was shown that the genetic influence varies depending on the dose-rate.
Balance control, agility, eye–hand coordination, and sport performance of amateur badminton players

Abstract In this study, balance performance, agility, eye–hand coordination, and sports performance were compared between amateur badminton players and active controls. Thirty young adult badminton players and 33 active controls participated in the study. Static single-leg standing balance (with eyes closed) was measured using a force platform, and dynamic balance was measured using the Y Balance Test (lower quarter). Agility was measured using a hexagon agility test, and eye–hand coordination was measured using a computerized finger-pointing task. Sports performance was quantified by the number of times a shuttlecock fell in a designated area following a badminton serve. The badminton players had superior accuracy in badminton serving (P < .001) relative to the active controls. However, no significant between-group differences were noted in all other outcome variables (P > .05). Amateur badminton players had more favorable sports performance, but not balance performance, agility, or eye–hand coordination, than controls.
Sted og sprogforandring: en undersøgelse af sprogforandring i virkelig tid hos mobile og bofaste informanter fra Odder, Vinderup og Tinglev

Denne ph.d.-afhandling rummer resultaterne af et panel-studie i virkelig tid af sprogforandringen hos 23 informanter fra tre velkendte steder i den danske dialektologi og sociolingvistik: Odder i Ostjylland, Vinderup i Vestjylland og Tinglev i Sonderjylland. Informanterne blev interviewet forste gang som unge i perioden 1978-1989 og indgar i tidligere dialektundersogelser. I 2005-2010 blev de geninterviewet af medarbejdere fra Danmarks Grundforskningsfonds Center for Sociolingvistiske Sprogforandringsstudier og Institut for Graenseregionsforskning ved Syddansk Universitet. Ved hjaelp af kvantitative analyser af udvalgte morfologiske og fonologiske traek har jeg undersogt sprogforandringen i virkelig tid hos en kvinde og en mand fra hvert sted, der har vaeret geografisk og socialt mobil mellem de to optagelser. Disse informanters sprogforandring sammenlignes med sprogforandringen hos 17 bofaste informanter. Analyserne viser, at de mobile informanter allerede som born markerede sig sprogligt anderledes og benyttede markant faerre lokale varianter af de undersogte variable, end de bofaste informanter. Endvidere viser analyserne, at der er store forskelle mellem sprogforandringen hos de bofaste informanter i de tre kommuner: i Odder forandres sprogbrugen en smule i retning af standarddansk, i Vinderup sker der (isaer blandt kvinderne) en forholdsvis drastisk dialektnivellering, og i Tinglev er sprogbrugen stabil hos de undersogte informanter. For at forklare de forskellige sprogforandringsmonstre har jeg foretaget en raekke kvalitative analyser - dels pa individniveau og dels af de tre sprogsamfund. Det viser sig, at der er sammenhaenge mellem informanternes sprogforandring og en raekke sprogeksterne forhold (fx deres mentale orientering i barndommen) samt deres fremstilling af hjembyen/hjemegnen som 'place' i humangeografisk betydning. Desuden er der klare sammenhaenge mellem graden af dialektnivellering de tre steder og en raekke historiske, demografiske og socio-okonomiske faktorer knyttet til det enkelte sted.
XP‐endo Finisher R instrument optimizes the removal of root filling remnants in oval‐shaped canals

AIM To evaluate the performance of XP-endo Finisher R instruments when removing root filling remnants from oval-shaped canals using microcomputed tomographic (micro-CT) imaging as the analytical tool. Passive ultrasonic irrigation (PUI) was used as a reference technique for comparison. METHODOLOGY Twenty mandibular incisors with oval-shaped canals were matched based on similar anatomic features of the canal (volume, aspect ratio and 3D configuration) after scanning procedures. The canals were prepared with Reciproc R25 instruments, filled with gutta-percha and AH Plus sealer using the single-cone technique and retreated up to a Reciproc R40 instrument. After retreatment procedures, the specimens were rescanned, and the homogeneity between the specimens, the oval-shaped anatomy and the remaining filling material were confirmed. The pair-matched samples were assigned to two experimental groups (n = 10), according to the supplementary approach used: XP-endo Finisher R or PUI. Each sample was scanned after each endodontic procedure. The volume of remaining root filling material was quantified before and after the use of each supplementary approach. This analysis was performed considering the total canal (Student t-test) and also by thirds (anova procedure followed by a Bonferroni correction). Data were analysed statistically with a significance level of 5%. RESULTS The volume of root filling material at baseline was similar between the groups (t-test, P = 0.787). XP-endo Finisher R removed significantly more root filling material compared to PUI (t-test, P = 0.015), as it removed a mean of ≅32% material compared to 12% for the PUI. There was no difference in the amount of root filling material removed in the root canal thirds after using both supplementary approaches (one-way anova, P = 0.07 for XP-endo Finisher R and P = 0.886 for PUI). CONCLUSIONS Both supplementary approaches significantly reduced the volume of remaining root filling material from oval-shaped canals. The XP-endo Finisher R instrument removed significantly more root filling material than PUI. None of the supplementary approaches was able to render oval-shaped canals completely free from remaining root filling material.
Semantic interference in speech error production in a randomised continuous naming task: evidence from aphasia

ABSTRACT Naming pictures from the same semantic category hinders subsequent naming from that category (i.e. semantic interference), irrespective of the number of intervening different-category exemplars named. Persistent semantic interference has been well documented in chronometric studies, and has been attributed to experience-driven adjustments in the strength of connections between semantic and lexical representations. However, whether parallel effects exist in speech error data remains unclear. In the current study, people with aphasia, a speaker population prone to naming errors, provided naming responses to a large picture corpus presented in random order that comprised multiple exemplars drawn from several different categories. We found persistent semantic interference in the task in semantic error rates specifically, and that semantic similarity between consecutive related exemplars modulated the effect. The results provide further evidence for the presumed lexical-semantic locus and mechanism(s) underlying semantic interference.
Functional Concerns and Treatment Priorities Among Veterans Receiving VHA Primary Care Behavioral Health Services

Introduction: The Primary Care–Mental Health Integration program is a component of the Veterans Health Administration’s patient-centered medical home, which emphasizes comprehensive, patient-centered care. One model of primary care–mental health integration, known as Primary Care Behavioral Health (PCBH), positions trained behavioral health providers as members of the primary care team. Whereas patient perspectives are essential to effective patient-centered care, little empirical information exists regarding patients’ goals and priorities for addressing their biopsychosocial concerns in PCBH. Method: A regional mail survey of Veterans Health Administration patients was used. We collected data from 281 veterans (27% response rate) who received PCBH services in a northeastern region. Results: Respondents identified difficulty with sleep (80%), low energy/amotivation (78%), and managing stress (72%) as the most prevalent individual concerns, although the majority endorsed concerns in multiple domains of functioning. Overwhelmingly, patients who endorsed any biopsychosocial problem area reported that they did (53–93%) or would like to (56–81%) address that concern with a behavioral health provider. Respondents most frequently identified anger as a top priority for future care, followed by stress management, energy/motivation, and sleep disturbance. Whereas sample means signaled neutral or better quality of life in most individual domains, total Quality of Life Inventory scores suggested very low (32%) to average (30%) overall quality-of -life ratings for most participants. Discussion: In addition to symptom-focused PCBH assessments, providers should gather biopsychosocial data to identify and monitor functional and quality-of -life concerns and evaluate patient preferences in addressing these concerns over the course of clinical care.
Targeting SUMO Modification of the Non-Structural Protein 5 of Zika Virus as a Host-Targeting Antiviral Strategy

Post-translational modifications of host or viral proteins are key strategies exploited by viruses to support virus replication and counteract host immune response. SUMOylation is a post-translational modification process mediated by a family of ubiquitin-like proteins called small ubiquitin-like modifier (SUMO) proteins. Multiple sequence alignment of 78 representative flaviviruses showed that most (72/78, 92.3%) have a putative SUMO-interacting motif (SIM) at their non-structural 5 (NS5) protein’s N-terminal domain. The putative SIM was highly conserved among 414 pre-epidemic and epidemic Zika virus (ZIKV) strains, with all of them having a putative SIM core amino acid sequence of VIDL (327/414, 79.0%) or VVDL (87/414, 21.0%). Molecular docking predicted that the hydrophobic SIM core residues bind to the β2 strand of the SUMO-1 protein, and the acidic residues flanking the core strengthen the binding through interactions with the basic surface of the SUMO protein. The SUMO inhibitor 2-D08 significantly reduced replication of flaviviruses and protected cells against ZIKV-induced cytopathic effects in vitro. A SIM-mutated ZIKV NS5 failed to efficiently suppress type I interferon signaling. Overall, these findings may suggest SUMO modification of the viral NS5 protein to be an evolutionarily conserved post-translational modification process among flaviviruses to enhance virus replication and suppress host antiviral response.
Timely double-strand break repair and pathway choice in pericentromeric heterochromatin depend on the histone demethylase dKDM4A

In this study, Janssen et al. investigated whether differential histone-modifying activities are required for DSB repair in euchromatin and heterochromatin domains. They used locus-specific DSB induction in Drosophila animal tissues and cultured cells to more deeply interrogate the impact of dKDM4A on chromatin changes, temporal progression, and pathway utilization during DSB repair and found that distinct pre-existing chromatin states require specialized epigenetic alterations to ensure proper DSB repair.
The Effects of Secondary Pneumonia on the Curative Efficacy of Multidrug-resistant Tuberculosis: A Retrospective Cohort Study.

doi: 10.3967/bes2018.123 This work was supported by Guangzhou Municipal Industry and Research Collaborative Innovation Program [201508020248, 201604020019]; Guangzhou Municipal Clinical Medical Center Program [155700012]; and partially by the Key Project Grant [SKLRD2016ZJ003] from the State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Diseases; Science and Technology Innovation Leader of Guangdong Province [2016TX03R095, to TZ]; and by the UCAS Fellowship Program (to H.M.A.H) and by the CAS-TWAS President’s Fellowship (to G.C). 1. State Key Laboratory of Respiratory Disease, Guangzhou Chest Hospital, Guangzhou 510095, Guangdong, China; 2. School of Public Health, Sun Yat-sen University, Guangzhou 510080, Guangdong, China; 3. State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, Guangdong, China; 4. University of Chinese Academy of Sciences, Beijing 100049, China Letter to the Editor