bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Aging and Toll-like Receptor 2 Deficiency on the Clinical Outcomes of Staphylococcus aureus Bacteremia
Authors: Hu Zhicheng , Kopparapu Pradeep Kumar , Deshmukh Meghshree , Jarneborn Anders , Gupta Priti , Ali Abukar , Fei Ying , Engdahl Cecilia , Pullerits Rille , Mohammad Majd , Jin Tao
Published: February 2023

Staphylococcus aureus (S. aureus) causes a broad range of infections. Toll-like receptor (TLR) 2 senses the S. aureus lipoproteins in S. aureus infections. Aging raises the risk of infection. Our aim was to understand how aging and TLR2 affect the clinical outcomes of S. aureus bacteremia. Four groups of mice (wild type/young, wild type/old, TLR2−/−/young, and TLR2−/−/old) were intravenously infected with S. aureus, and the infection course was followed. Both TLR2 deficiency and aging enhanced the susceptibility to disease. Increased age was the main contributing factor for increased mortality rates and changes in spleen weight, whereas other clinical parameters, such as weight loss and kidney abscess formation, were more TLR2 dependent. Importantly, aging increased mortality rates without relying on TLR2. In vitro, both aging and TLR2 deficiency down-regulated cytokine/chemokine production of immune cells with distinct patterns. In summary, we demonstrate that aging and TLR2 deficiency impair the immune response to S. aureus bacteremia in distinct ways.
U.S. Agency Experts in Shackles: The Quest for Information
Authors: McGarity Thomas , Wagner Wendy
Published: February 2023

In taking stock of environmental and administrative scholarship for the future, one area in need of investigation is whether expert agencies are actually given the authority and tools they need to carry out their delegated assignments. We know that the political branches and courts often impose constraints on agency experts in ways that are likely to compromise the agencies’ ability to fulfill their statutory assignments. But we have little understanding of how many constraints there are, how they operate, or how to think of them more generally. In our contribution to this Special Issue, we spotlight the importance of this topic for regulatory studies in the USA and abroad by mapping out the multi-faceted ways that agencies in the USA are constrained from carrying out their delegated assignments. We discover numerous and consequential constraints that are both invisible and undermine the agencies’ ability to carry out their statutory mandates.
Epigenetic potential: Promoter CpG content positively covaries with lifespan and is dependent on gene function among vertebrates
Authors: Sheldon Elizabeth L , Schrey Aaron W , Lauer M Ellesse , Martin Lynn B
Published: February 2023

Variation in DNA methylation is associated with many ecological and life history traits, including niche breadth and lifespan. In vertebrates, DNA methylation occurs almost exclusively at “CpG” dinucleotides. Yet, how variation in the CpG content of the genome impacts organismal ecology has been largely overlooked. Here, we explore associations between promoter CpG content, lifespan and niche breadth among 60, amniote vertebrate species. The CpG content of 16 functionally relevant gene promoters was strongly, positively associated with lifespan in mammals and reptiles, but was not related to niche breadth. Possibly, by providing more substrate for CpG methylation to occur, high promoter CpG content extends the time taken for deleterious, age-related errors in CpG methylation patterns to accumulate, thereby extending lifespan. The association between CpG content and lifespan was driven by gene promoters with intermediate CpG enrichment—those known to be predisposed to regulation by methylation. Our findings provide novel support for the idea that high CpG content has been selected for in long-lived species to preserve the capacity for gene expression regulation by CpG methylation. Intriguingly, promoter CpG content was also dependent on gene function in our study; immune genes had on average 20% less CpG sites than metabolic- and stress-related genes.
Core root-associated prokaryotic community and its relationship to host traits across wheat varieties
Authors: Zheng Yuyin , Wang Jialong , Zhang Xue , Lei Li , Yu Rui , Yao Minjie , Han Dejun , Zeng Qingdong , Li Xiangzhen
Published: February 2023

The root-associated microbiomes play important roles in plant growth. However, it is largely unknown how wheat variety evolutionary relatedness shapes each subcommunity in the root microbiome and, in turn, how these microbes affect wheat yield and quality. Here we studied the prokaryotic communities associated with the rhizosphere and root endosphere in 95 wheat varieties at regreening and heading stages. The results indicated that the less diverse but abundant core prokaryotic taxa occurred among all varieties. Among these core taxa, we identified 49 and 108 heritable amplicon sequence variants, whose variations in relative abundances across the root endosphere and rhizosphere samples were significantly affected by wheat variety. The significant correlations between phylogenetic distance of wheat varieties and prokaryotic community dissimilarity were only observed in non-core and abundant subcommunities in the endosphere samples. Again, wheat yield was only significantly associated with root endosphere microbiota at the heading stage. Additionally, wheat yield could be predicted using the total abundance of 94 prokaryotic taxa as an indicator. Our results demonstrated that the prokaryotic communities in the root endosphere had higher correlations with wheat yield and quality than those in the rhizosphere; thus, managing root endosphere microbiota, especially core taxa, through agronomic practices and crop breeding, is important for promoting wheat yield and quality.
Electromyostimulation With Blood Flow Restriction for Patellofemoral Pain Syndrome in Active Duty Military Personnel: A Randomized Controlled Trial
Authors: Talbot Laura A , Webb Lee , Morrell Christopher , Enochs Kayla , Hillner Jesse , Fagan Mathias , Metter E Jeffrey
Published: February 2023

Introduction

The high prevalence of patellofemoral pain in military service members results in strength loss, pain, and functional limitations during required physical performance tasks. Knee pain is often the limiting factor during high-intensity exercise for strengthening and functional improvement, thus limiting certain therapies. Blood flow restriction (BFR) improves muscle strength when combined with resistance or aerobic exercise and may serve as a possible alternative to high-intensity training during recovery. In our previous work, we showed that Neuromuscular electrical stimulation (NMES) improves pain, strength, and function in patellofemoral pain syndrome (PFPS), which led us to ask whether the addition of BFR to NMES would result in further improvements. This randomized controlled trial compared knee and hip muscle strength, pain, and physical performance of service members with PFPS who received BFR-NMES (80% limb occlusion pressure [LOP]) or BFR-NMES set at 20 mmHg (active control/sham) over 9 weeks.

Methods

This randomized controlled trial randomly assigned 84 service members with PFPS to one of the two intervention groups. In-clinic BFR-NMES was performed two times per week, while at-home NMES with exercise and at-home exercise alone were performed on alternating days and omitted on in-clinic days. The outcome measures included strength testing of knee extensor/flexor and hip posterolateral stabilizers, 30-second chair stand, forward step-down, timed stair climb, and 6-minute walk.

Results

Improvement was observed in knee extensor (treated limb, P < .001) and hip strength (treated hip, P = .007) but not flexor over 9 weeks of treatment; however, there was no difference between high BFR (80% LOP) and BFR-sham. Physical performance and pain measures showed similar improvements over time with no differences between groups. In analyzing the relationship between the number of BFR-NMES sessions and the primary outcomes, we found significant relationships with improvements in treated knee extensor strength (0.87 kg/session, P < .0001), treated hip strength (0.23 kg/session, P = .04), and pain (−0.11/session, P < .0001). A similar set of relationships was observed for the time of NMES usage for treated knee extensor strength (0.02/min, P < .0001) and pain (−0.002/min, P = .002).

Conclusion

NMES strength training offers moderate improvements in strength, pain, and performance; however, BFR did not provide an additive effect to NMES plus exercise. Improvements were positively related to the number of BFR-NMES treatments and NMES usage.
Evolution of Spatial and Temporalcis-Regulatory Divergence in Sticklebacks
Authors: Mack Katya L , Square Tyler A , Zhao Bin , Miller Craig T , Fraser Hunter B
Published: February 2023

Cis-regulatory changes are thought to play a major role in adaptation. Threespine sticklebacks have repeatedly colonized freshwater habitats in the Northern Hemisphere, where they have evolved a suite of phenotypes that distinguish them from marine populations, including changes in physiology, behavior, and morphology. To understand the role of gene regulatory evolution in adaptive divergence, here we investigate cis-regulatory changes in gene expression between marine and freshwater ecotypes through allele-specific expression (ASE) in F1 hybrids. Surveying seven ecologically relevant tissues, including three sampled across two developmental stages, we identified cis-regulatory divergence affecting a third of genes, nearly half of which were tissue-specific. Next, we compared allele-specific expression in dental tissues at two timepoints to characterize cis-regulatory changes during development between marine and freshwater fish. Applying a genome-wide test for selection on cis-regulatory changes, we find evidence for lineage-specific selection on several processes between ecotypes, including the Wnt signaling pathway in dental tissues. Finally, we show that genes with ASE, particularly those that are tissue-specific, are strongly enriched in genomic regions of repeated marine-freshwater divergence, supporting an important role for these cis-regulatory differences in parallel adaptive evolution of sticklebacks to freshwater habitats. Altogether, our results provide insight into the cis-regulatory landscape of divergence between stickleback ecotypes across tissues and during development, and support a fundamental role for tissue-specific cis-regulatory changes in rapid adaptation to new environments.
Comprehensive chromatin proteomics resolves functional phases of pluripotency and identifies changes in regulatory components
Authors: Ugur Enes , de la Porte Alexandra , Qin Weihua , Bultmann Sebastian , Ivanova Alina , Drukker Micha , Mann Matthias , Wierer Michael , Leonhardt Heinrich
Published: February 2023

The establishment of cellular identity is driven by transcriptional and epigenetic regulators of the chromatin proteome - the chromatome. Comprehensive analyses of the chromatome composition and dynamics can therefore greatly improve our understanding of gene regulatory mechanisms. Here, we developed an accurate mass spectrometry (MS)-based proteomic method called Chromatin Aggregation Capture (ChAC) followed by Data-Independent Acquisition (DIA) and analyzed chromatome reorganizations during major phases of pluripotency. This enabled us to generate a comprehensive atlas of proteomes, chromatomes, and chromatin affinities for the ground, formative and primed pluripotency states, and to pinpoint the specific binding and rearrangement of regulatory components. These comprehensive datasets combined with extensive analyses identified phase-specific factors like QSER1 and JADE1/2/3 and provide a detailed foundation for an in-depth understanding of mechanisms that govern the phased progression of pluripotency. The technical advances reported here can be readily applied to other models in development and disease.
Flanking strand separation activity of RecA nucleoprotein filaments in DNA strand exchange reactions
Authors: Yu Fangzhi , Zhang Dapeng , Zhao Chubin , Zhao Qiang , Jiang Guibin , Wang Hailin
Published: February 2023

The recombinase RecA/Rad51 ATPase family proteins catalyze paramount DNA strand exchange reactions that are critically involved in maintaining genome integrity. However, it remains unclear how DNA strand exchange proceeds when encountering RecA-free defects in recombinase nucleoprotein filaments. Herein, by designing a series of unique substrates (e.g. truncated or conjugated incoming single-stranded DNA, and extended donor double-stranded DNA) and developing a two-color alternating excitation-modified single-molecule real-time fluorescence imaging assay, we resolve the two key steps (donor strand separation and new base-pair formation) that are usually inseparable during the reaction, revealing a novel long-range flanking strand separation activity of synaptic RecA nucleoprotein filaments. We further evaluate the kinetics and free energetics of strand exchange reactions mediated by various substrates, and elucidate the mechanism of flanking strand separation. Based on these findings, we propose a potential fundamental molecular model involved in flanking strand separation, which provides new insights into strand exchange mechanism and homologous recombination.
Umberto Eco
Authors: Pacchioni Federico , Kelly Sawyer
Published: February 2023

Umberto Eco (b. 1932–d. 2016) was an Italian author and theorist whose contributions to the academic and creative zeitgeists ripple into inter- and multidisciplinary fields including, but not limited to, semiotics, linguistics, communication theory, narrative theory, politics, pop culture, history, and aesthetic theory. Best known for his groundbreaking work surrounding the relationships between language, texts, authors, and audiences, Eco’s theoretical work has prompted a reckoning of modern discourses surrounding interpretation and the rights of readers and authors respectively. Eco’s discursive style is characterized by its emphasis on intertextual ideation—the conceptualization of history, culture, theory, and language as sedimentary accumulations, the combination of which may yield increased and deepened insight into each discipline both separately, and as a coalesced unit. A champion of expressive forms, Eco demolished the false binary between “high” and “low” art forms, recognizing mass media and pop culture as compelling, rich areas of academic pursuit. In this way, Eco’s theoretical and fictional work may also be conceptualized as efforts to demystify and expand the ivory tower frequently associated with the academic and artistic spheres. His works posit the notion that interpretative validity cannot be singularly conferred by virtue of a source’s academic or artistic ethos, but rather both creation and interpretation of work constitutes a living dialogic process wherein meaning is negotiated through complex semiotic communicative systems. As an author, Eco single-handedly crafts a literary world that is as entrancing as it is mysterious. Traversing the boundaries of genre, perspective, reality, fiction, and history, Eco’s literary works are in many ways embodied narrative manifestos of the way Eco views reality—as a kaleidoscopic (and at times, contradictory) ontological mosaic. A totalizing bibliographic account of Eco’s contributions and academia’s responses is nearly impossible. However, the following resources below present several different avenues through which to begin to engage with both his theoretical and creative work. Included below are Eco’s own most notable writings in English translation, as well as a selection of English-language scholarly sources that reflect and respond to Eco. Ultimately, although encapsulating Eco in textual form is in many ways unattainable, these bibliographic entries hope to offer a semblance of a map for (to borrow Joseph Consoli’s metaphor) navigating Eco’s labyrinth.
Diaspora in the Caribbean
Authors: Singh Sherry-Ann , Jahgoo Danalee
Published: February 2023

Between 1838 and 1920, approximately 550,000 Indians (South Asians) came to the Caribbean as laborers under the system of Indian indenture. Of this number, close to 85 percent were classified as Hindus. When the system of Indian indenture came to a close by 1920, about 75 percent of the immigrants had opted to stay in the Caribbean. One hundred seventy-nine years later, the impressions of time, space, and circumstance, varyingly conditioned by the processes of truncation, dilution, intensification, reconstitution, telescoping, and excision, have yielded a strand of Hinduism in the Caribbean that is homogeneous enough to be often classified as “Caribbean Hinduism” or “Hinduism in the Caribbean,” yet imbibed with a sufficient degree of geographic divergence that often allows for country-specific orientations of the religion. In Trinidad and Tobago (18.2 percent), Guyana (28.4 percent), and Suriname (22.3 percent), Hinduism is very visible as a major religion. Although substantially smaller, Hinduism in Jamaica, Martinique, Guadeloupe, and Belize is still practiced. However, in such locations as Grenada, St. Lucia, St. Vincent, and St. Kitts, there has been an almost total absorption of Hinduism into the respective societies. The bulk of the indentured labor to the Caribbean was drawn from the Uttar Pradesh and Bihar regions of India, with significantly smaller numbers coming from South India and Bengal. This has generated Hindu religious transfigurations throughout the Caribbean that are firmly and predominantly rooted in the religious traditions of Uttar Pradesh and Bihar, the most prominent of which are Vaishnavism, Shaivism, Shaktism, and the teachings of the most popular Hindu religious text in the Caribbean, the Ramcharitmanas. Hinduism in the various Caribbean locations has also been highly characterized by localized schisms which have contributed to the perpetuation of divergences in belief, practice, and doctrine; yet, all locate themselves under the umbrella of its respective national configuration, such as “Trinidad Hinduism” or “Hinduism in Guyana.” As such, the literature on Hinduism in the Caribbean is reflective of the history, diversity, transformation, and diasporic assignation of the religion. This article seeks to outline some of the most prominent writings on Hinduism in the Caribbean, along with a variety of secondary academic and non-academic works that document the emergence, transformation, and application of the religion through a multitude of divergent yet congruent lenses.
Historical Pragmatics
Authors: Jucker Andreas H.
Published: February 2023

Pragmatics is a branch of linguistics. In a narrow sense it studies the way in which the linguistic properties of an utterance interact with its context to provide situational interpretations for the recipient of the utterance. In a wider sense, pragmatics studies all aspects of language use in an interactional and a social context. Historical pragmatics as a well-established subfield of pragmatics focuses on language use in historical contexts. This includes the study of usage patterns at particular points in the history of a given language, the study of the diachronic developments of such usage patterns and the study of the underlying principles of such developments. Work on historical pragmatics has a long history but until the mid-1990s relevant publications were rare and did not describe themselves as historical pragmatics. In the second half of the 1990s and in the early 2000s, the field quickly established itself as an important branch of pragmatics. Several factors were instrumental in this development. After the early focus of pragmatics on philosophical methods on the one hand and on spontaneous face-to-face interactions on the other, it opened its scope to a broader range of data, including written data. At the same time, the 1990s brought an increased availability of language corpora and, in particular, the availability of historical corpora. This opened up new ways of investigating language histories. In the early work of historical pragmatics, researchers regularly justified their choice of data. Plays, courtroom proceedings, and personal correspondence were considered to be particularly good, albeit imperfect, approximations to natural spoken interactions and therefore the privileged data for historical pragmatics. Today, data is no longer assessed solely in terms of its proximity to natural spoken interaction, but each type of data is considered in its own right and within its own communicative contexts. Topics of interest in historical pragmatics have always covered a broad range of pragmatic entities, including speech actions (greetings, promises, requests, apologies, and the like), discourse markers and interjections, nominal and pronominal terms of address, and issues of politeness and impoliteness. Researchers investigate such elements at specific points in time or in their diachronic developments over longer periods. And they also try to isolate general underlying principles of diachronic change that explain these developments within a larger theoretical framework.
Child Sacrifice in the Ancient Near and Middle East
Authors: Tatlock Jason
Published: February 2023

Child sacrifice is a specific subset of the wider category of human sacrifice, which is a form of slaying that attempts to bring about a shift in the suprahuman realm. Child sacrifice is a subset because it points to the young age of victims or to the parent-child relationship. The practice is closely intertwined with the religious history of the ancient Near East and wider Mediterranean world. It is noticeable in artwork, textual traditions, and a variety of archaeological contexts. Because the practice goes back into prehistory, it is not always clear why certain child sacrifices were performed, such as sacrifices accomplished at the founding of buildings. Through artistic and textual representations, it is possible to gain a better understanding of the meanings attached to sacrificial rites. Nevertheless, there are still ambiguities that exist, and scholars must dig into ancient contexts to discovery how child sacrifices were perceived. This entails careful linguistic analysis, including of biblical texts. Child sacrifice is still a topic of interest to those adhering to the Abrahamic faith traditions that developed out of this area of the world. In this respect, the sacrifice, or almost sacrifice, of a firstborn son would be of greatest significance. Yet the early Israelite story about Abraham’s mountain-top binding of his son to the altar (called the Akedah in Judaism) has neither been viewed identically in Judaism, Christianity, and Islam nor meant the same thing to every generation. It could be said that child sacrifice more generally has experienced shifts within faith traditions, and practices accepted in one time period may not have been agreeable later. This is certainly the case with human sacrifice more broadly. Not only did ancient views on child sacrifice change, but so too have academic opinions varied. Indeed, scholars living in the same period even disagree on the existence or interpretation of particular practices. There are a variety of perspectives on diverse issues, and it is not always clear that child sacrifice actually transpired in some circumstances. Not only are textual sources difficult at times to interpret, but so too are archaeological remains. Some of the complexities of studying child sacrifice are outlined here. What follows is a brief overview of scholarship on child sacrifice organized into seven topics: Mesopotamia and Anatolia, North Africa and Punic Sites, Nonbiblical Levantine finds, Ancient Israelite Traditions, Postbiblical Jewish Views, Christian Perspectives, and Islamic Understandings.
Grant Allen
Authors: Ruddick Nicholas
Published: February 2023

Evolutionist, naturalist, atheist, socialist, Celtophile, armchair sexual radical, Grant Allen was one of the most prolific, versatile, and controversial men of letters in the Victorian fin de siècle. Charles Grant Blairfindie Allen was born on 24 February 1848 in Alwington, Canada West, now a suburb of Kingston, Ontario. His father was an Irish-born minister of the (Protestant) Church of Ireland; his mother came from a distinguished Canadian military family. In 1861 the Allens moved to Connecticut, and thereafter to Dieppe, France and Birmingham, England. When his family returned to Canada in 1866, Allen remained in England, entering Oxford University on a scholarship in 1867. In 1868 he married a woman of a lower social class who would die of tuberculosis in 1872. This first marriage, which caused Allen to lose his scholarship, may have been motivated by a desire to save his wife from the streets, and probably underlay his later determination to confront the problem of prostitution in his writings. In 1873 Allen married Ellen (Nellie) Jerrard; they would remain happily espoused until Allen’s death. Later that year Allen was appointed a professor at a new, short-lived college in Spanish Town, Jamaica. His (for their time) radical views on further education, gender roles, race, and colonialism were intensified by his Caribbean experience. From 1876 he was based in England, publishing his first book, Physiological Aesthetics, in 1877. In 1878 Nellie bore their only child, a son, and Allen found he could not support his family with scientific-philosophical writing. He expanded his literary scope to include popular fiction, and continued to write on an enormous variety of subjects. In a relatively short literary career blighted by ill health, he published about eighty books, including novels, short story collections, poetry, works on scientific subjects, collections of nonfiction essays, biographical and historical works, and travel guides. Much of his vast body of writing was ephemeral journalism and potboiling fiction. But his best-selling novel-with-a-purpose The Woman Who Did (1895) remains a landmark response to first-wave feminism, and he made pioneering contributions to scientific romance, horror, and detective fiction. And because he spoke eloquently for both progressive and transgressive elements in fin-de-siècle culture, his oeuvre and the records of his dealings with fellow-writers, editors, and publishers increasingly interest literary and social historians. Allen died at the age of 51 on 25 October 1899 at his home in Hindhead, Surrey.
Paul Gauguin
Authors: Perelman Allison
Published: February 2023

Paul Gauguin (b. 1848–d. 1903) is perhaps equally well known for his life story as for his art. Born in Paris, he spent most of the first six years of his life in Peru until his family returned to their native France. As a young man, Gauguin sailed internationally in the Merchant Marines before becoming an assistant to a stockbroker in Paris. In the 1870s, his interest in art collecting led to meeting several prominent avant-garde artists, including the Impressionist Camille Pissarro. Soon Gauguin was not only buying art, but he was also practicing painting and sculpture in his spare time. By the early 1880s, he was pursuing a fulltime career as an artist. Gauguin worked in a broad range of media, such as painting, wood carving, ceramics, drawing, and printmaking, in addition to his written manuscripts. He was one of the most radically experimental artists of his time, and his oeuvre reflects the breadth of his material interests and international inspirations. Known for his extensive travels, he lived and worked not only in Paris but also the French regions of Brittany and Provence as well as Denmark, Martinique, Tahiti, and the Marquesas Islands. In 1891, Gauguin left Paris for Tahiti, in search of new subject matter for his art and to cement his reputation as a primitivist. After a brief return to France, where his Polynesian-inspired paintings, sculptures, and prints shocked and confounded audiences, he traveled back to Tahiti. He remained there for six years before moving to the Marquesas Islands, where he lived the last two years of his life. Gauguin is best known for his paintings of Polynesian subjects, particularly female figures. Found in museums around the world, his canvases are often characterized by bright colors, flat application of paint, and a style that emphasized subjective feeling and fantastical imagery over naturalistic representation. Although he began his career with the Impressionists, he is also associated with styles and art movements of Cloisonnism, Symbolism, and Primitivism. Posthumously, he has also been categorized as a Post-Impressionist along with Vincent van Gogh, with whom he had a productive yet combative collaboration. The conflation between Gauguin’s life and art can be traced back to the artist himself. He was a savvy promoter of his own work and created a self-mythology in which he embraced a dual persona as both cerebral avant-gardist and uncivilized savage. During his lifetime, he recognized the value of controversy and defiant aesthetic and political stances in his efforts to promote his career. Gauguin remains a controversial figure, however, largely due to his sexual relationships with girls and young women; his participation in French imperialist and colonialist endeavors overseas; and his utilization of motifs, myths, and figures from other, often marginalized, cultures. With the rise of gender, race, and postcolonial theory in recent decades, scholars around the world continue to grapple with the artist, his work, and his lasting cultural impact.
What is the Source of Infections Causing Invasive NontyphoidalSalmonellaDisease?
Authors: Chirwa Esmeda B , Dale Helen , Gordon Melita A , Ashton Philip M
Published: February 2023

Invasive nontyphoidal Salmonella (iNTS) disease is a clinical condition distinct from Salmonella gastroenteritis. With an overall case-fatality rate of 14.5%, iNTS remains a major cause of morbidity and mortality, particularly in sub-Saharan Africa. However, the sources of infections that lead to cases of iNTS remain unclear. Broadly, there are 2 hypotheses as to the source of infections: (i) transmission from a zoonotic reservoir, similar to other nontyphoidal salmonelloses; or (ii) person-to-person transmission. Here we review several recent studies that have asked, “What is the source of infections causing invasive nontyphoidal Salmonella disease?” Two studies reported isolates in the stool of household members of iNTS cases that were very closely related (<3 single-nucleotide polymorphisms) to the iNTS case isolates; this is consistent with the hypothesis of person-to-person transmission, but infection from a common source (eg, a foodstuff) cannot be excluded. On the other hand, thorough investigations of the domestic environment of iNTS cases and the food pathway found only a single iNTS-associated Salmonella Enteritidis isolate. Therefore, we recommend that future studies test the hypothesis that iNTS is transmitted between people within the domestic environment. Further studies of food and water pathways are also warranted.
On the Epistemic Significance of Perceptual Structure
Authors: Alford-Duguid Dominic
Published: February 2023

Our awareness of the boundedness of the spatial sensory field—a paradigmatic structural feature of visual experience—possesses a distinctive epistemic role. Properly understood, this result undermines a widely assumed picture of how visual experience permits us to learn about the world. This paper defends an alternative picture in which visual experience provides at least two kinds of non-inferential justification for beliefs about the external world. Accommodating this justification in turn requires recognising a new way for visual experience to encode information about the world. Reflection upon the epistemic contribution of sensory experience's structural features thus forces us to revise our understanding of how perception, cognition, and the world fit together.
Myelomonocytic cells in giant cell arteritis activate trained immunity programs sustaining inflammation and cytokine production
Authors: Cantoni Eleonora , Merelli Ivan , Stefanoni Davide , Tomelleri Alessandro , Campochiaro Corrado , Giordano Vito , Panigada Maddalena , Baldissera Elena M , Merlo Pich Laura , Natoli Valentina , Ziogas Athanasios , Domínguez-Andrés Jorge , De Luca Giacomo , Mazza Davide , Zambrano Samuel , Gnani Daniela , Ferrarini Marina , Ferrero Elisabetta , Agresti Alessandra , Vergani Barbara , Leone Biagio Eugenio , Cenci Simone , Ravelli Angelo , Matucci-Cerinic Marco , D’Alessandro Angelo , Joosten Leo A B , Dagna Lorenzo , Netea Mihai G , Molteni Raffaella , Cavalli Giulio
Published: February 2023

Objective

Trained immunity (TI) is a de facto memory program of innate immune cells, characterized by immunometabolic and epigenetic changes sustaining enhanced production of cytokines. TI evolved as a protective mechanism against infections; however, inappropriate activation can cause detrimental inflammation and might be implicated in the pathogenesis of chronic inflammatory diseases. In this study, we investigated the role of TI in the pathogenesis of giant cell arteritis (GCA), a large-vessel vasculitis characterized by aberrant macrophage activation and excess cytokine production.

Methods

Monocytes from GCA patients and from age- and sex-matched healthy donors were subjected to polyfunctional studies, including cytokine production assays at baseline and following stimulation, intracellular metabolomics, chromatin immunoprecipitation-qPCR, and combined ATAC/RNA sequencing. Immunometabolic activation (i.e. glycolysis) was assessed in inflamed vessels of GCA patients with FDG-PET and immunohistochemistry (IHC), and the role of this pathway in sustaining cytokine production was confirmed with selective pharmacologic inhibition in GCA monocytes.

Results

GCA monocytes exhibited hallmark molecular features of TI. Specifically, these included enhanced IL-6 production upon stimulation, typical immunometabolic changes (e.g. increased glycolysis and glutaminolysis) and epigenetic changes promoting enhanced transcription of genes governing pro-inflammatory activation. Immunometabolic changes of TI (i.e. glycolysis) were a feature of myelomonocytic cells in GCA lesions and were required for enhanced cytokine production.

Conclusions

Myelomonocytic cells in GCA activate TI programs sustaining enhanced inflammatory activation with excess cytokine production.
First Report of Resistance to Pyraclostrobin in Pseudocercospora spp. from Blackberry (Rubus fruticosus) in Georgia, United States
Authors: Oliver Jonathan E. , Lewis Kippy J. , Aktaruzzaman Md. , Ali Md. Emran
Published: February 2023

Pseudocercospora leaf spot is frequently observed in blackberry production in the southeastern United States. To manage the impacts of leaf spot diseases, blackberry growers in the southeastern United States typically rely on the application of single-site fungicides, including the quinone outside inhibitors (QoIs) (FRAC 11) pyraclostrobin and azoxystrobin. In recent years, despite the regular application of chemical fungicides to manage leaf spots, blackberry growers and extension personnel in Georgia have noticed relatively poor control of these diseases. To investigate potential control failures due to fungicide resistance development, Pseudocercospora were isolated from symptomatic leaves collected from blackberry ( Rubus fruticosus) in five commercial fields in southeastern Georgia. Using a mycelial growth inhibition assay, isolates were screened for resistance to pyraclostrobin. Among the 13 isolates tested, 12 were determined to be resistant to the fungicide. Subsequent sequencing of the cytochrome b gene indicated the presence of the G143A mutation in all fungicide-resistant isolates. The identification of fungicide resistance in 12 of 13 isolates and 4 of 5 examined commercial blackberry sites in Georgia suggests that resistance to this fungicide may be prevalent among Pseudocercospora on blackberry in Georgia and that future fungicide resistance monitoring efforts in Georgia blackberry plantings may be warranted. This represents the first report of QoI fungicide resistance in Pseudocercospora spp. from blackberry.
Cholic acid exposure during late pregnancy causes placental dysfunction and fetal growth restriction by reactive oxygen species‐mediated activation of placental GCN2/eIF2α pathway
Authors: Lin Shuai , Ye Meng‐Ying , Fu Qian‐Yun , Pan Chao‐Lin , Liu Ya‐Jie , Zheng Li‐Ming , Hong Qiang , Chen Yuan‐Hua
Published: February 2023

Epidemiological studies suggest that fetal growth restriction (FGR) caused by gestational cholestasis is associated with elevated serum cholic acid (CA). Here, we explore the mechanism by which CA induces FGR. Pregnant mice except controls were orally administered with CA daily from gestational day 13 (GD13) to GD17. Results found that CA exposure decreased fetal weight and crown‐rump length, and increased the incidence of FGR in a dose‐dependent manner. Furthermore, CA caused placental glucocorticoid (GC) barrier dysfunction via down‐regulating the protein but not the mRNA level of placental 11β‐Hydroxysteroid dehydrogenase‐2 (11β‐HSD2). Additionally, CA activated placental GCN2/eIF2α pathway. GCN2iB, an inhibitor of GCN2, significantly inhibited CA‐induced down‐regulation of 11β‐HSD2 protein. We further found that CA caused excessive reactive oxygen species (ROS) production and oxidative stress in mouse placentas and human trophoblasts. NAC significantly rescued CA‐induced placental barrier dysfunction by inhibiting activation of GCN2/eIF2α pathway and subsequent down‐regulation of 11β‐HSD2 protein in placental trophoblasts. Importantly, NAC rescued CA‐induced FGR in mice. Overall, our results suggest that CA exposure during late pregnancy induces placental GC barrier dysfunction and subsequent FGR may be via ROS‐mediated placental GCN2/eIF2α activation. This study provides valuable insight for understanding the mechanism of cholestasis‐induced placental dysfunction and subsequent FGR.
Use of Pediatric Outcomes Data Collection Instrument to Evaluate Functional Outcomes in Multiple Hereditary Exostoses
Authors: Sundin Palmeira de Oliveira Nathalia , Rocha Dias da Silva Marcela , Bedeschi Rego de Mattos Camila
Published: February 2023

Background:

The Pediatric Outcomes Data Collection Instrument (PODCI) is a validated quality-of-life questionnaire with 6 domains designed to provide a standardized method of measuring outcomes in pediatric musculoskeletal conditions. To our knowledge there are no reports on its use in children with multiple hereditary exostosis (MHE).

Questions/Purposes:

Most published studies on MHE patients have described the efficacy of specific surgical techniques or the specification of deformities. Little is known about the general health status of pediatric patients, the severity of pain, loss of function, and how MHE influences the activities of daily life. We aim to assess the functional levels of MHE pediatric patients with PODCI questionnaire.

Patients and Methods:

As a cross-sectional study, we prospectively administered PODCI to 34 pediatric patients diagnosed with MHE and their families. The score distributions were compared with values published earlier for children and adolescents without musculoskeletal disorders using the Student and Welch t tests. Parents and adolescents’ reports were compared using Wilcoxon signed rank test. Physical examination and PODCI score relation were evaluated by Spearman test.

Results:

Children with MHE have significantly lower scores (P<0,05) in comparison with unaffected children in all domains using the Student and Welch t test. Parents score differs from children score with statistically relevance in pain and comfort domain (P<0,5). The Spearman test showed a negative correlation between physical examination and PODCI score with statistical significance.

Conclusions:

These results point towards PODCI’s capacity in evaluating functional outcomes of pediatric patients with MHE.

Level of Evidence:

Diagnostic Study, Level III.
Ambient fine particulate matter and cardiopulmonary health risks in China
Authors: Li Tiantian , Zhang Yi , Jiang Ning , Du Hang , Chen Chen , Wang Jiaonan , Li Qiutong , Feng Da , Shi Xiaoming
Published: February 2023

In China, the level of ambient fine particulate matter (PM2.5) pollution far exceeds the air quality standards recommended by the World Health Organization. Moreover, the health effects of PM2.5 exposure have become a major public health issue. More than half of PM2.5-related excess deaths are caused by cardiopulmonary disease, which has become a major health risk associated with PM2.5 pollution. In this review, we discussed the latest epidemiological advances relating to the health effects of PM2.5 on cardiopulmonary diseases in China, including studies relating to the effects of PM2.5 on mortality, morbidity, and risk factors for cardiovascular and respiratory diseases. These data provided important evidence to highlight the cardiopulmonary risk associated with PM2.5 across the world. In the future, further studies need to be carried out to investigate the specific relationship between the constituents and sources of PM2.5 and cardiopulmonary disease. These studies provided scientific evidence for precise reduction measurement of pollution sources and public health risks. It is also necessary to identify effective biomarkers and elucidate the biological mechanisms and pathways involved; this may help us to take steps to reduce PM2.5 pollution and reduce the incidence of cardiopulmonary disease.
Pharmacokinetics-Pharmacodynamics Modeling and Evaluation of Tumor Response to Bortezomib Proteasome Inhibitor in Waldenstrom Macroglobulinemia
Authors: Munir Anum , Fazal Sahar , Bhatti Aamer Iqbal , Sajjad Bilawal
Published: February 2023

Background:

Waldenstrom’s macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is a type of non-Hodgkin’s lymphoma in which the malignant cells produce many macroglobulin proteins. It originates from B cells and develops in the bone marrow, where Wm cells combine to produce distinct types of blood cells, resulting in reduced volumes of red blood cells, white blood cells, and platelets, making it harder for the body to fight diseases. Chemoimmunotherapy is being used for the clinical management of WM, but new targeted agents, the BTK inhibitor ibrutinib and the proteasome inhibitor bortezomib, have shown significant improvements in patients with relapsed/refractory WM. However, given its effectiveness, drug resistance and relapse are normal, and there is little research on the pathways responsible for drug effects on the tumor.

Methods:

In this study, Pharmacokinetics-pharmacodynamic simulations were done to assess the effect of the proteasome inhibitor bortezomib on the tumor. For this purpose, the Pharmacokinetics-pharmacodynamic model was developed. The model parameters were determined and calculated using the Ordinary Differential Equation solver toolbox and the least-squares function. Pharmacokinetic profiles and pharmacodynamic analysis were performed to determine the change in tumor weight associated with the use of proteasome inhibitors.

Results:

Bortezomib and ixazomib have been found to reduce tumor weight briefly, but once the dose is reduced, the tumor begins to grow again. Carfilzomib and oprozomib had better results, and rituximab reduced tumor weight more effectively.

Conclusion:

Once validated, it is proposed that a combination of selected drugs can be evaluated in the laboratory to treat WM.
Hepatic mitochondrial NAD+ transporter SLC25A47 activates AMPKα mediating lipid metabolism and tumorigenesis
Authors: Cheng Lili , Deepak R.N.V. Krishna , Wang Guoqiang , Meng Ziyi , Tao Lei , Xie Mengqing , Chi Wenna , Zhang Yuming , Yang Mingming , Liao Yilie , Chen Ruiqun , Liang Yu , Zhang Junyu , Huang Yuedong , Wang Weihua , Guo Zhiying , Wang Yunfang , Lin Jiandie D. , Fan Hao , Chen Ligong
Published: February 2023

Background & Aims:

SLC25A47 was initially identified as a mitochondrial HCC-downregulated carrier protein, but its physiological functions and transport substrates are unknown. We aimed to investigate the physiological role of SLC25A47 in hepatic metabolism.

Approach & Results:

In the treatment of hepatocytes with metformin, we found that metformin can transcriptionally activate the expression of Slc25a47, which is required for AMP-activated protein kinase α (AMPKα) phosphorylation. Slc25a47-deficient mice had increased hepatic lipid content, triglycerides, and cholesterol levels, and we found that Slc25a47 deficiency suppressed AMPKα phosphorylation and led to an increased accumulation of nuclear SREBPs, with elevated fatty acid and cholesterol biosynthetic activities. Conversely, when Slc25a47 was overexpressed in mouse liver, AMPKα was activated and resulted in the inhibition of lipogenesis. Moreover, using a diethylnitrosamine-induced mouse HCC model, we found that the deletion of Slc25a47 promoted HCC tumorigenesis and development through the activated mammalian target of rapamycin cascade. Employing homology modeling of SLC25A47 and virtual screening of the human metabolome database, we demonstrated that NAD+ was an endogenous substrate for SLC25A47, and the activity of NAD+-dependent sirtuin 3 declined in Slc25a47-deficient mice, followed by inactivation of AMPKα.

Conclusions:

Our findings reveal that SLC25A47, a hepatocyte-specific mitochondrial NAD+ transporter, is one of the pharmacological targets of metformin and regulates lipid homeostasis through AMPKα, and may serve as a potential drug target for treating NAFLD and HCC.
Standard vs total keratometry for intraocular lens power calculation in cataract surgery combined with DMEK
Authors: Khan Asher , Rangu Neal , Murphy David A. , Cooke David L. , Siatkowski Rhea L. , Mittal Aman , Wendelstein Jascha A. , Riaz Kamran M.
Published: February 2023

Purpose:

To compare the prediction accuracy of standard keratometry (K) and total keratometry (TK) for intraocular lens (IOL) power calculation in eyes undergoing combined cataract surgery and Descemet membrane endothelial keratoplasty (triple DMEK).

Setting:

Tertiary care academic referral center.

Design:

Retrospective case series.

Methods:

Review of 83 eyes (63 patients) that underwent triple DMEK between 2019 and 2021. Biometry measurements were obtained using a swept-source optical biometer (IOLMaster 700). 63 eyes were used for statistical analysis. Mean error, mean absolute error (MAE), SD, median absolute error, maximum absolute error, root mean squared prediction error, and the percentage of eyes within prediction errors of ±0.50 diopters (D) and ±1.00 D were calculated for 9 multivariate and third-generation formulas using K and TK values (Barrett Universal II, Yeo EVO 2.0, Cooke K6, Kane, Pearl-DGS, Haigis, Holladay 1, Hoffer Q, and SRK/T). Formulas were additionally tested by using the prediction for an IOL power 1 D below the IOL used (IOLup1D).

Results:

For all formulas, MAE was lower for K than for TK by an average of 0.21 D. The lowest MAE value observed was 0.67 D for “adjusted” SRK/T using K, and the highest MAE values observed were 1.24 D and 1.24 D for nonadjusted Hoffer Q and Haigis using TK, respectively. Overall, lower MAE values were observed for multivariate formulas and SRK/T.

Conclusions:

In triple DMEK eyes, the prediction accuracy of K was higher than that of TK. The most accurate formulas were SRK/T and multivariate formulas using K with the IOLup1D adjustment.