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Abstract Background Nucleic acid aptamers have long demonstrated the capacity to bind viral envelope proteins and to inhibit the progression of pathogenic virus infections. Here we report on initial efforts to develop and screen DNA aptamers against recombinant envelope proteins or synthetic peptides and whole inactivated viruses from several virulent arboviruses including Chikungunya, Crimean-Congo hemorrhagic fever (CCHF), dengue, tickborne encephalitis and West Nile viruses. We also analyzed sequence data and secondary structures for commonalities that might reveal consensus binding sites among the various aptamers. Some of the highest affinity and most specific aptamers in the down-selected libraries were demonstrated to have diagnostic utility in lateral flow chromatographic assays and in a fluorescent aptamer-magnetic bead sandwich assay. Some of the reported aptamers may also be able to bind viral envelope proteins in vivo and therefore may have antiviral potential in passive immunity or prophylactic applications. Results Several arbovirus DNA aptamer sequences emerged multiple times in the various down selected aptamer libraries thereby suggesting some consensus sequences for binding arbovirus envelope proteins. Screening of aptamers by enzyme-linked aptamer sorbent assay (ELASA) was useful for ranking relative aptamer affinities against their cognate viral targets. Additional study of the aptamer sequences and secondary structures of top-ranked anti-arboviral aptamers suggest potential virus binding motifs exist within some of the key aptamers and are highlighted in the supplemental figures for this article. One sequence segment (ACGGGTCCGGACA) emerged 60 times in the anti-CCHF aptamer library, but nowhere else in the anti-arbovirus library and only a few other times in a larger library of aptamers known to bind bacteria and rickettsia or other targets. Diagnostic utility of some of the aptamers for arbovirus detection in lateral flow chromatographic assays and a fluorescent sandwich assay on the surface of magnetic microbeads is also demonstrated. Conclusions This article catalogues numerous DNA aptamer sequences which can bind various important pathogenic arboviruses and have, in some cases, already demonstrated diagnostic potential. These aptamer sequences are proprietary, patent-pending, and partially characterized. Therefore, they are offered to the scientific community for potential research use in diagnostic assays, biosensor applications or for possible passive immunity and prophylaxis against pathogenic viruses.

This article evaluates the effect of discovery-based learning (DBL) in an undergraduate course in literature. The DBL method asked students in an introductory course on the Bible to discover facts about authorship and genres of various books through guided reading, followed by expository comments. The control method, in contrast, directly presented students with the expository comments. We show that students retained the target facts better in the short term with the DBL method than with the control method. Statistical analysis suggests that DBL plays a more decisive role in determining this outcome than the student's general academic competence or background. The gain with DBL is more significant for students who successfully discovered the target facts during treatment. According to a survey, twice as many students preferred DBL than the expository approach.

Extracurricular reading is important for learning foreign languages. Text recommendation systems typically classify users and documents into levels, and then match users with documents at the same level. Although this approach can be effective, it has two significant shortcomings. First, the levels assume a standard order of language acquisition and cannot be personalized to the users' learning patterns. Second, recommendation decisions are not transparent because the leveling algorithms can be difficult for users to interpret. We propose a novel method for text recommendation that addresses these two issues. To enhance personalization, an open, editable learner model estimates user knowledge of each word in the foreign language. The documents are ranked by new-word density (NWD) -- that is, the percentage of words that are new to the user in the document. The system then recommends documents according to a user-specified target NWD. This design offers complete transparency as users can scrutinize recommendations by reviewing the NWD estimation of the learner model. This article describes an implementation of this method in a mobile app for learners of Chinese as a foreign language. Evaluation results show that users were able to manipulate the learner model and NWD parameters to adjust the difficulty of the recommended documents. In a survey, users reported satisfaction with both the concept and implementation of this text recommendation method.

The synthesis is demonstrated for a heteroleptic Ni(II) complex, with a tridentate ligand bearing N-heterocyclic carbene (NHC), aryloxide, and picolyl donor groups. The compound was reacted with a variety of hydroxide sources, several of which resulted in complex mixtures. Reaction with [NH4]OH affords a bis-ligated nickel compound, in which the ligands are each bound in a bidentate fashion through the NHC and aryloxide donor groups. A desired nickel(II)-hydroxo product was not observed. DFT studies suggest that ligand redistribution is thermodynamically preferred over stabilization of a Ni-hydroxo in either a monomeric or dimeric form. [ABSTRACT FROM AUTHOR]

A text recommendation system helps language learners find suitable reading materials. Similar to graded readers, most systems assign difficulty levels or school grades to the documents in their database, and then identify the documents that best match the language proficiency of the learner. This graded approach has two main limitations. First, the common grade scale assumes that all learners find the same words difficult, ignoring different orders in vocabulary acquisition. Second, it cannot cater to the incremental vocabulary expansion typical of language learners, since discrete grades do not facilitate fine-grained adaptation in text recommendation. This article evaluates a personalized and adaptive method for text recommendation that aims to mitigate these limitations. This method recommends documents according to the new-word density preferred by the user. It estimates a document's new-word density with an open learner model that predicts the user's vocabulary knowledge. Users can dynamically update the learner model as they acquire new vocabulary. We conducted a user study involving ten learners of Chinese as a foreign language. Results shows that this method can estimate the learner model at 77.6% accuracy, outperforming the graded approach. Further, a user simulation demonstrates that it can recommend documents within 0.22% of the target new-word density, satisfying user preferences more accurately than the graded approach. [ABSTRACT FROM AUTHOR]

Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance. [ABSTRACT FROM AUTHOR]

Patients with inflammatory arthritis (IA) are at increased risk of severe COVID-19 due to medication-induced immunosuppression that impairs host defenses. The aim of this study was to assess antibody and B cell responses to COVID-19 mRNA vaccination in IA patients receiving immunomodulatory therapies. Adults with IA were enrolled through the Johns Hopkins Arthritis Center and compared with healthy controls (HC). Paired plasma and peripheral blood mononuclear cell (PBMC) samples were collected prior to and 30 days or 6 months following the first two doses of mRNA vaccines (D2; HC=77 and IA=31 patients), or 30 days following a third dose of mRNA vaccines (D3; HC=11 and IA=96 patients). Neutralizing antibody titers, total binding antibody titers, and B cell responses to vaccine and Omicron variants were analyzed. Anti-Spike (S) IgG and S-specific B cells developed appropriately in most IA patients following D3, with reduced responses to Omicron variants, and negligible effects of medication type or drug withholding. Neutralizing antibody responses were lower compared to healthy controls after both D2 and D3, with a small number of individuals demonstrating persistently undetectable neutralizing antibody levels. Most IA patients respond as well to mRNA COVID-19 vaccines as immunocompetent individuals by the third dose, with no evidence of improved responses following medication withholding. These data suggest that IA-associated immune impairment may not hinder immunity to COVID-19 mRNA vaccines in most individuals. [ABSTRACT FROM AUTHOR]

This article presents the first study on using a parallel corpus to teach Cantonese, the variety of Chinese spoken in Hong Kong. We evaluated this approach with Mandarin-speaking undergraduate students at the beginner level. Exploiting their knowledge of Mandarin, a closely related language, the students studied Cantonese with authentic material in a Cantonese-Mandarin parallel corpus, transcribed from television programs. They were given a list of Mandarin words that yield a range of possible Cantonese translations, depending on the linguistic context. Leveraging sentence and word alignments in the parallel corpus, the students independently searched for example sentences to discover these translation equivalents. Experimental results showed that, in both the short- and long-term, this data-driven learning approach helped students improve their knowledge of Cantonese vocabulary. These results suggest the potential of applying parallel corpora at even the beginners' level for other L1-L2 pairs of closely related languages.

The Military Order of the Knights Templar acquired property within English towns, established residences and chapels for its brethren there and developed new urban settlements and markets. This article argues that the role that the Templars played as urban landlords in England has been seriously understated, and that the Order made an impact through their urban property holdings, their privileges and their urban chapels, and in establishing new towns, which were integral to the wider exploitation of their rural resources. [ABSTRACT FROM AUTHOR]

Inhalation anthrax has three clinical stages: early-prodromal, intermediate-progressive, and late-fulminant. We report the comprehensive characterization of anthrax toxins, including total protective antigen (PA), total lethal factor (LF), total edema factor (EF), and their toxin complexes, lethal toxin and edema toxin in plasma, during the course of inhalation anthrax in 23 cynomolgus macaques. The toxin kinetics were predominantly triphasic with an early rise (phase-1), a plateau/decline (phase-2), and a final rapid rise (phase-3). Eleven animals had shorter survival times, mean±standard deviation of 58.7±7.6 hours (fast progression), 11 animals had longer survival times, 113±34.4 hours (slow progression), and one animal survived. Median (lower–upper quartile) LF levels at the end-of-phase-1 were significantly higher in animals with fast progression [138 (54.9–326) ng/mL], than in those with slow progression [23.8 (15.6–26.3) ng/mL] (p = 0.0002), and the survivor (11.1 ng/mL). The differences were also observed for other toxins and bacteremia. Animals with slow progression had an extended phase-2 plateau, with low variability of LF levels across all time points and animals. Characterization of phase-2 toxin levels defined upper thresholds; critical levels for exiting phase-2 and entering the critical phase-3, 342 ng/mL (PA), 35.8 ng/mL (LF), and 1.10 ng/mL (EF). The thresholds were exceeded earlier in animals with fast progression (38.5±7.4 hours) and later in animals with slow progression (78.7±15.2 hours). Once the threshold was passed, toxin levels rose rapidly in both groups to the terminal stage. The time from threshold to terminal was rapid and similar; 20.8±7.4 hours for fast and 19.9±7.5 hours for slow progression. The three toxemic phases were aligned with the three clinical stages of anthrax for fast and slow progression which showed that anthrax progression is toxin- rather than time-dependent. This first comprehensive evaluation of anthrax toxins provides new insights into disease progression. Author summary: This first analysis of all major anthrax toxins during inhalation anthrax revealed three stages of toxemia that align with the three clinical stages, early-, intermediate-, and late-stage anthrax. High toxin levels in the early stages led to faster progression and lower levels to slower progression. Critical toxin levels were defined for entering the late-stage where treatment usually fails. This study provides new details of anthrax progression which has the potential to improve treatment and save lives. [ABSTRACT FROM AUTHOR]

Using sources and contexts from early modern Korea, this article analyses how sylvan landscapes produced - and were produced by - the anxieties of forest administrators and rustic literati. First, through an examination of government records from the fifteenth century, this article argues that perceived threats to pine forests were critical to administrative expansion and the making of Korean landscapes. Recurrent anxieties about deforestation became embodied in the conservation of a single conifer, in turn producing the pine-dominant landscapes that are the lasting legacy of Chosŏn state forestry. Second, this article examines treatises of literati from the seventeenth to early nineteenth centuries to uncover how elite anxieties became embodied in the local management of sylvan landscapes. The East Asian practice of geomancy became a crucial tool of environmental modification for local elites facing socio-political change and diminishing power. [ABSTRACT FROM AUTHOR]

The Ebola virus disease outbreak that occurred in Western Africa from 2013–2016, and subsequent smaller but increasingly frequent outbreaks of Ebola virus disease in recent years, spurred an unprecedented effort to develop and deploy effective vaccines, therapeutics, and diagnostics. This effort led to the U.S. regulatory approval of a diagnostic test, two vaccines, and two therapeutics for Ebola virus disease indications. Moreover, the establishment of fieldable diagnostic tests improved the speed with which patients can be diagnosed and public health resources mobilized. The United States government has played and continues to play a key role in funding and coordinating these medical countermeasure efforts. Here, we describe the coordinated U.S. government response to develop medical countermeasures for Ebola virus disease and we identify lessons learned that may improve future efforts to develop and deploy effective countermeasures against other filoviruses, such as Sudan virus and Marburg virus. [ABSTRACT FROM AUTHOR]

Human vascular malformations cause disease as a result of changes in blood flow and vascular hemodynamic forces. Although the genetic mutations that underlie the formation of many human vascular malformations are known, the extent to which abnormal blood flow can subsequently influence the vascular genetic program and natural history is not. Loss of the SH2 domain-containing leukocyte protein of 76 kDa (SLP76) resulted in a vascular malformation that directed blood flow through mesenteric lymphatic vessels after birth in mice. Mesenteric vessels in the position of the congenital lymphatic in mature Slp76-null mice lacked lymphatic identity and expressed a marker of blood vessel identity. Genetic lineage tracing demonstrated that this change in vessel identity was the result of lymphatic endothelial cell reprogramming rather than replacement by blood endothelial cells. Exposure of lymphatic vessels to blood in the absence of significant flow did not alter vessel identity in vivo, but lymphatic endothelial cells exposed to similar levels of shear stress ex vivo rapidly lost expression of PROX1, a lymphatic fate-specifying transcription factor. These findings reveal that blood flow can convert lymphatic vessels to blood vessels, demonstrating that hemodynamic forces may reprogram endothelial and vessel identity in cardiovascular diseases associated with abnormal flow., Introduction Human vascular malformations are common congenital diseases that can result in a variety of clinical disorders later in life. Patients may present with stroke and neurologic impairment from lesions [...]

Hantaan virus (HTNV), the etiologic agent for hemorrhagic fever with renal syndrome (HFRS), accounts for [approximately equal to] 70% of all HFRS cases in South Korea and is the most [...]

Ticks comprising five species from the 'Hemaphysalis' spp. and 'Ixodes' spp. genera were screened through molecular techniques in the course of an investigation into the prevalence of tick-borne infectious agents in ticks in the Republic of Korea (ROK). A high rate of infection with 'Ehrlichia' and 'Anaplasma' sp. pathogens was demonstrated.

PB2452, a neutralizing monoclonal antibody fragment that binds the antiplatelet drug ticagrelor with high affinity, is being developed as a ticagrelor reversal agent. To identify a clinically useful intravenous (i.v.) reversal regimen, a semimechanistic exposure‐response model was developed during the PB2452 first‐in‐human phase I study. From a randomized, double‐blind, placebo‐controlled, single‐dose trial to evaluate the safety, efficacy, and pharmacokinetics (PKs) of PB2452 in 61 healthy volunteers pretreated with ticagrelor, sequential dose cohort data were used to build and refine an exposure‐response model that combined population PK models for ticagrelor (TICA), ticagrelor active metabolite (TAM), and PB2452, and related their binding relationships to the PK of uncomplexed TICA and TAM which is predictive of platelet inhibition. Platelet function was assessed by multiple assays. The model was developed using Bayesian methods in NONMEM. Human PK and pharmacodynamic data from sequential dose cohorts were used to initially define and then refine model parameters. Model simulations indicated that an initial i.v. bolus of PB2452, followed by a high‐rate infusion, and then a slower‐rate infusion would provide immediate and sustained reversal of the antiplatelet effects of ticagrelor. Based on model predictions, a 6 g i.v. bolus followed by 6 g infused over 4 h and then 6 g over 12 h was identified and tested in study subjects and shown to provide complete reversal within 5 min of infusion onset that was sustained for 20–24 h. The model is predictive of the reversal profile of PB2452 and will inform future trials of PB2452. [ABSTRACT FROM AUTHOR]

In 2017, 43.9% of US physicians reported symptoms of burnout. Poor electronic health record (EHR) usability and time-consuming data entry contribute to burnout. However, less is known about how modifiable dimensions of EHR use relate to burnout and how these associations vary by medical specialty. Using the KLAS Arch Collaborative's large-scale nationwide physician (MD/DO) data, we used ordinal logistic regression to analyze associations between self-reported burnout and after-hours charting and organizational EHR support. We examined how these relationships differ by medical specialty, adjusting for confounders. Physicians reporting ≤ 5 hours weekly of after-hours charting were twice as likely to report lower burnout scores compared to those charting ≥6 hours (aOR: 2.43, 95% CI: 2.30, 2.57). Physicians who agree that their organization has done a great job with EHR implementation, training, and support (aOR: 2.14, 95% CI: 2.01, 2.28) were also twice as likely to report lower scores on the burnout survey question compared to those who disagree. Efforts to reduce after-hours charting and improve organizational EHR support could help address physician burnout. [ABSTRACT FROM AUTHOR]

While studies on diachronic Chinese syntax have identified a number of linguistic changes in Medieval Chinese, they have mostly been underpinned by qualitative analyses. In the most large-scale quantitative analysis to-date, this article investigates changes in the use of classifiers, demonstratives, and copulae. Our analysis, based on the Chinese Buddhist Canon, examines over 40 million characters in texts spanning a millennium. Results suggest that from the late Eastern Han period (circa 150 CE) onwards, the vernacular style became increasingly widespread, at the expense of the literary style, as reflected by changes in the use of classifiers and demonstratives, and in the construction of nominal sentences. However, the vernacular style became less frequently used in the Northern Sung period (960–1127 CE). This reversal may shed light on the work of the Stylists, editors appointed by the Sung court to polish Buddhist texts with more literary elements. [ABSTRACT FROM AUTHOR]

This article describes a Greek-Chinese interlinear glossed text consisting of the four gospels in the New Testament. Each word in the original Koine Greek text is annotated with several layers of linguistic information, including its Chinese gloss; word alignments to its Chinese counterparts in the Revised Chinese Union Version, a modern Chinese translation of the Bible; and its morphological and syntactic information, adapted from the PROIEL project. We evaluate the precision and consistency of the Chinese gloss. We report a pilot study on using this interlinear to teach Greek to beginner students, illustrating how it can facilitate data-driven learning for aspects of grammar and lexical usage. [ABSTRACT FROM AUTHOR]

A series of Mn12O12(OAc)16-xLx(H2O)4 molecular clusters (L = acetate, benzoate, benzenesulfonate, diphenylphosphonate, dichloroacetate) were electrocatalytically investigated as water oxidation electrocatalysts on a fluorine-doped tin oxide glass electrode. Four of the [Mn12O12] compounds demonstrated water oxidation activity at pH 7.0 at varying overpotentials (640-820 mV at 0.2 mA/cm²) and with high Faradaic efficiency (85-93%). For the most active complex, more than 200 turnovers were observed after 5 min. Two structure-function relationships for these complexes were developed. First, these complexes must undergo at least one-electron oxidation to become active catalysts, and complexes that cannot be oxidized in this potential window were inactive. Second, a greater degree of distortion at Mn1 and Mn3 centers correlated with higher catalytic activity. From this distortion analysis, either or both of these two Mn centers are proposed to be the catalytically active site. [ABSTRACT FROM AUTHOR]

A case study is presented on the local history of the manor, market and the parish church in Masham, Yorkshire, England during the medieval period. The article heavily references public records of Masham during the Middle Ages, including the Domesday Book, taxation records and Yorkshire county records.