bluuebunny/crossref_metadata_2025 huggingface dataset:
The presence of autoantibodies as a potential prognostic biomarker for breast cancer
Authors: Ouyang Libo , Jing Keying , Zhu Chunkai , Wang Rong , Zheng Peiming
Published: February 2024

The presence of autoantibodies is closely associated with the occurrence and development of cancer. Autoantibodies can be used as biomarkers for early breast cancer diagnosis. However, the relationship between autoantibodies and the prognosis of breast cancer patients remains elusive. This retrospective study aimed to investigate the correlation between the presence of autoantibodies and outcomes in breast cancer patients. This study included a total of 155 patients from People's Hospital of Henan University (Zhengzhou, China) who were diagnosed with breast cancer from January 2017 to December 2021. The enrolled patients' clinicopathological features were collected, and 88 patients were ultimately involved in the analysis. Univariate and multivariate Cox regression analyses were performed to search for the risk factors related to the poor prognosis of breast cancer patients. The association between the presence of autoantibodies and patients' survival was analysed using Kaplan–Meier curves. After screening, there were 38 autoantibody‐positive cases and 50 autoantibody‐negative cases. Breast cancer patients with autoantibody‐positive had a 57% lower risk of death compared with autoantibody‐negative patients. Multivariate Cox regression analysis indicated that the presence of autoantibody could be a potential prognostic predictor for breast cancer, independent of age, histological grade, pathological classification, clinical stage, and the expression levels of hormonal receptors. In addition, autoantibody‐positive breast cancer patients had longer progression‐free survival and overall survival compared with autoantibody‐negative cases. Positive autoantibody was found as an independent biomarker of better prognosis in breast cancer patients, providing a new strategy for the prognostic assessment of breast cancer patients.
Labor‐capital relations on digital platforms: Organization, algorithmic discipline and the social factory again
Authors: Wang June , Tomassetti Julia
Published: February 2024

Digital platform labor and its complex relationship with capital have stirred scholarly inquiry, calling for a systemic review that bridges foundational theories and various currents of development. In this review, we revisit Marxist and autonomist Marxist theses on the changing nature of work in the platform economy. Following that, we review two major strands of studies on the organization of production at the macro level and labour control at the micro level, which have revealed variegated types of workplace fissuring and different techniques of algorithmic control over bodies. However, we argue that the path forward must transcend these boundaries. We call for a revival of the ‘social factory’ thesis to rekindle ‘networking’ as a way of understanding labor‐capital relations on digital platforms. Our premise is that capital and labor mutually constitute the platform economy through their agency of networking the internet and ‘outernet’. We outline four key directions for future research based on this premise: networking with public elements, networking with market‐driven elements, networking for financialization in the digital landscape, and networking for resistance. By reinvigorating the social factory approach, we aim to enrich scholarly understandings of labor‐capital relations in the platform economy by articulating digital labor in a wider web of sociocultural, technical, political and economic relationships extending beyond and transcending the internet.
Patient video cases in large‐group medical student teaching: A qualitative study of learner and educator perspectives
Authors: Al‐Jarshawi Mustafa , Al‐Jasim Ameer , Bird Terese , Williams Christopher
Published: February 2024

Background

Patient video cases (PVCs) are short video recordings of real patients during clinical encounters or instructed activities. Although widely used in healthcare professionals' education, their use in large group teaching (LGT) remains relatively unexplored. This study aims to explore the perceptions of medical students and academic staff regarding the use of PVCs to support LGT.

Methods

A purposive sample of medical students and academic staff from Leicester Medical School was obtained. Data were collected through focus groups (students) and semi‐structured interviews (staff) in which two sensitising PVCs were used as a stimulus to discussion. Data analysis was undertaken using grounded theory through a process of open, axial, and selective coding, leading to core categories and themes.

Results

Sixteen medical students and four academic staff members participated. Four overarching themes were identified covering the benefits of using PVCs, ways in which they are used in LGT, the challenges faced by and how to optimise PVCs for LGT. This final theme covered design, choice of clip and how it is then used by the educator within the teaching session. Key considerations were the need to align the PVC with other content and to consider the student experience.

Conclusion

Our findings support the use of well‐chosen and well‐designed PVCs within LGT and offer practical insights to use them effectively. PVCs are a potentially powerful tool within medical undergraduate LGT (a widely used instructional method) and further research into its use is needed.
Running on empty: Factors underpinning impaired cardiac output reserve in heart failure with preserved ejection fraction
Authors: Sagmeister Paula , Rosch Sebastian , Fengler Karl , Kresoja Karl‐Patrik , Gori Tommaso , Thiele Holger , Lurz Philipp , Burkhoff Daniel , Rommel Karl‐Philipp
Published: February 2024

Heart failure with preserved ejection fraction (HFpEF) is frequently attributed etiologically to an underlying left ventricular (LV) diastolic dysfunction, although its pathophysiology is far more complex and can exhibit significant variations among patients. This review endeavours to systematically unravel the pathophysiological heterogeneity by illustrating diverse mechanisms leading to an impaired cardiac output reserve, a central and prevalent haemodynamic abnormality in HFpEF patients. Drawing on previously published findings from our research group, we propose a pathophysiology‐guided phenotyping based on the presence of: (1) LV diastolic dysfunction, (2) LV systolic pathologies, (3) arterial stiffness, (4) atrial impairment, (5) right ventricular dysfunction, (6) tricuspid valve regurgitation, and (7) chronotopic incompetence. Tailored to each specific phenotype, we explore various potential treatment options such as antifibrotic medication, diuretics, renal denervation and more. Our conclusion underscores the pivotal role of cardiac output reserve as a key haemodynamic abnormality in HFpEF, emphasizing that by phenotyping patients according to its individual pathomechanisms, insights into personalized therapeutic approaches can be gleaned.
Monetary Policy, Homeowner Balance Sheet Channel, and Integration: A Lesson from South Korea during the 2000s
Authors: Kim Yejin , Shin Wonmun
Published: February 2024

We estimate the household consumption function using the Korean labor and income panel data (2001-2012) with the instrument of the housing supply to figure out the homeowner balance sheet channel of monetary policy in South Korea during the 2000s and the early 2010s. We find that monetary policy has a significant effect through both the wealth and collateral effects comprising the homeowner balance sheet transmission channel. Furthermore, the wealth effect shows a significant result across all income quantile groups, whereas the collateral effect is significant in the low- and middle-income quantile groups. This finding implies that the lower-income groups are more sensitive to changes in the value of real estate assets. Based on the analysis, we derive policy implication that socio-economic integration will be enhanced under the considerately targetted monetary policy, which is a lesson for the emerging or developing countries whose current economic situation is similar to the past South Korea.
Efectos de la pandemia en hábitos de niños y adolescentes: una oportunidad para reflexionar y actuar
Authors: Luna Viaña Mariana , Puche Varón Laura Daniela , García Tissot Lorenzo , Londoño de Vivero Natalia , Granados Rugeles Claudia Marcela , Estrada Cano Diana Carolina
Published: February 2024

La pandemia por COVID-19 causó cambios en los estilos de vida, la salud y la forma de relacionarse socialmente. Ello repercutió en la vida de niños y adolescentes de todo el mundo y generó preocupación en los cuidadores. La encuesta llevada a cabo indagaba por el cambio percibido por los cuidadores en el consumo de pantallas, hábitos alimentarios, horas de sueño, y alteraciones en el mismo, y actividad física. Se obtuvieron 132 registros completos de la encuesta, en los que se analizaron los aspectos mencionados antes de la cuarentena estricta, durante y después de esta, a efectos de identificar diferencias dietarias importantes, cambios en la actividad física, consumo de pantallas y cambios en el sueño de la población estudiada. En conjunto, los hallazgos indicaron un aumento en el número de veces en que los niños se pasaban a la cama de sus cuidadores durante las noches, un aumento en el consumo de dulces y fritos, una marcada disminución en la actividad física, incluso en el número de días en que los niños caminaban y un gran aumento en el consumo de pantallas. Este estudio brinda información relevante sobre las afectaciones de la población escolar durante la pandemia.
In Silico Investigation of Biomechanical Response of a Human Brain Subjected to Primary Blast
Authors: Sutar Sunil , Ganpule S. G.
Published: February 2024

The brain response to the explosion-induced primary blast waves is actively sought. Over the past decade, reasonable progress has been made in the fundamental understanding of blast traumatic brain injury (bTBI) using head surrogates and animal models. Yet, the current understanding of how blast waves interact with human is in nascent stages, primarily due to the lack of data in human. The biomechanical response in human is critically required to faithfully establish the connection to the aforementioned bTBI models. In this work, the biomechanical cascade of the brain under a primary blast has been elucidated using a detailed, full-body human model. The full-body model allowed us to holistically probe short- (<5 ms) and long-term (200 ms) brain responses. The full-body model has been extensively validated against impact loading in the past. We have further validated the head model against blast loading. We have also incorporated the structural anisotropy of the brain white matter. The blast wave transmission, and linear and rotational motion of the head were dominant pathways for the loading of the brain, and these loading paradigms generated distinct biomechanical fields within the brain. Blast transmission and linear motion of the head governed the volumetric response, whereas the rotational motion of the head governed the deviatoric response. Blast induced head rotation alone produced diffuse injury pattern in white matter fiber tracts. The biomechanical response under blast was comparable to the impact event. These insights will augment laboratory and clinical investigations of bTBI and help devise better blast mitigation strategies.
Analysis of Plastic Deformation of Pipes Due to Deflagration to Detonation Transition Using Static Equivalent Pressure
Authors: Müller Matthias , Bernhardi Otto-Ernst , Denecke Jens , Schildberg Hans-Peter , Schmidt Jürgen
Published: February 2024

Explosions of premixed gases with deflagration to detonation transition (DDT) are a risk in the process industry with potentially catastrophic consequences. Robust and simple design methods are required for industrial use. Such a simplified design method based on finite element analysis is proposed to model the dynamic behavior of pipes loaded by gas explosions of premixed gases including DDT. The focus is on so-called long pipes, where the DDT is not affected by reflections at blind flanges. First, it is reviewed how the pressure load of the gas explosion and the resulting material behavior has been modeled in previous publications. The analytical equations are then extended for describing the pressure load as a function of time and location by considering the leading compression wave as it affects the pressure load of the overdriven detonation. The extended analytical equations are parameterized using Chapman-Jouguet conditions and experimental results from publications for both static equivalent pressure and the location of the DDT. To describe the plastic material behavior at high strain rates, the well-known Johnson-Cook plasticity model is used. The material parameters of the model are derived from simple experiments, which are available in an industrial environment. The comparison of a finite element simulation with experimental data shows that the concept of equivalent static pressure can be extended to an finite element analysis, which in the future will allow the sizing of complete pipe systems including tees, bends, and flanges while considering plastic deformation.
Spatially differentiated crystalline inorganic coatings deposited by an atmospheric pressure dielectric barrier discharge with immobilized filaments
Authors: Brabant M. , Demaude A. , Zveny J. , Remy A. , Segato T. , Petitjean D. , Delplancke-Ogletree M. P. , Reniers F.
Published: February 2024

The one-step deposition of spatially differentiated crystalline vanadium oxide coatings (V2O5) using an atmospheric pressure dielectric barrier discharge is reported. This feasibility study uses an original combination of immobilized filaments inside the plasma and an inductive heating device. Preliminary results show that thick crystalline deposits are achieved under the immobilized filaments, whether the interfilament spacing leads to much thinner deposits, with a different chemical composition. The gas flow inside the reactor, combined to the filament reactivity, leads to local depletions of reactants.
Intrinsic and extrinsic contributions in the ferroelectric response of chemically synthesized BiFeO3-xPbTiO3 thin films
Authors: Zia Layiq , Razia Eesha Tur , Hassnain Jaffari G. , Ismat Shah S.
Published: February 2024

Multiferroic (BiFeO3)1−x-(PbTiO3)x (1−x)BF−xPT thin films exhibit very high electromechanical properties in the vicinity of the morphotropic phase boundary (MPB), making them important candidates for use in several modern device applications. However, preparing high-quality (1−x)BF−xPT thin films is challenging due to the high conductivity caused by oxygen vacancies produced during the synthesis process. This study aims to understand the effect of size and porosity density on the electrical properties of (1−x)BF−xPT thin films. A series of (1−x)BF−xPT solid solution thin films were fabricated using the spin-coating method on Pt/TiO2/SiO2/Si(100) substrates through chemical solution deposition. X-ray diffraction studies revealed a polycrystalline structure. Surface SEM images showed that the films have a uniform surface with average grain sizes ranging between 50 and 200 nm and an average film thickness of 1.5 μm. A decrease in average pore size and an increase in the number of pores were observed with the increase in PT concentration in the prepared films. Ferroelectric characterization revealed that the films exhibit room-temperature ferroelectric hysteresis loops. Sources of various contributions to polarization were extracted from hysteresis loops, including true ferroelectric switching and space charge contributions. Thin films with 0.30 < x < 0.45 show higher remanent and saturation polarization values, suggesting that these compositions exhibit the MPB. The highest remanent polarization value (PR = 16.68 μC/cm2) was observed for the thin film with x = 0.40. The correlation between the phase, composition, film morphology, and ferroelectric response is described and discussed.
Induction of durable remission by dual immunotherapy in SHIV-infected ART-suppressed macaques
Authors: Lim So-Yon , Lee Jina , Osuna Christa E. , Vikhe Pratik , Schalk Dane R. , Chen Elsa , Fray Emily , Kumar Mithra , Schultz-Darken Nancy , Rakasz Eva , Capuano Saverio , Ladd Ruby A , Gil Hwi Min , Evans David T. , Jeng Emily K. , Seaman Michael , Martin Malcolm , Van Dorp Christiaan , Perelson Alan S. , Wong Hing C. , Siliciano Janet D. , Siliciano Robert , Safrit Jeffrey T. , Nixon Douglas F. , Soon-Shiong Patrick , Nussenzweig Michel , Whitney James B.
Published: February 2024

The eradication of the viral reservoir represents the major obstacle to the development of a clinical cure for established HIV-1 infection. Here, we demonstrate that the administration of N-803 (brand name Anktiva) and broadly neutralizing antibodies (bNAbs) results in sustained viral control after discontinuation of antiretroviral therapy (ART) in simian-human AD8 (SHIV-AD8)–infected, ART-suppressed rhesus macaques. N-803+bNAbs treatment induced immune activation and transient viremia but only limited reductions in the SHIV reservoir. Upon ART discontinuation, viral rebound occurred in all animals, which was followed by durable control in approximately 70% of all N-803+bNAb–treated macaques. Viral control was correlated with the reprogramming of CD8
+
T cells by N-803+bNAb synergy. Thus, complete eradication of the replication-competent viral reservoir is likely not a prerequisite for the induction of sustained remission after discontinuation of ART.
A morphological basis for path-dependent evolution of visual systems
Authors: Varney Rebecca M. , Speiser Daniel I. , Cannon Johanna T. , Aguilar Morris A. , Eernisse Douglas J. , Oakley Todd H.
Published: February 2024

Path dependence influences macroevolutionary predictability by constraining potential outcomes after critical evolutionary junctions. Although it has been demonstrated in laboratory experiments, path dependence is difficult to demonstrate in natural systems because of a lack of independent replicates. Here, we show that two types of distributed visual systems recently evolved twice within chitons, demonstrating rapid and path-dependent evolution of a complex trait. The type of visual system that a chiton lineage can evolve is constrained by the number of openings for sensory nerves in its shell plates. Lineages with more openings evolve visual systems with thousands of eyespots, whereas those with fewer openings evolve visual systems with hundreds of shell eyes. These macroevolutionary outcomes shaped by path dependence are both deterministic and stochastic because possibilities are restricted yet not entirely predictable.
Touch sensation requires the mechanically gated ion channel ELKIN1
Authors: Chakrabarti Sampurna , Klich Jasmin D. , Khallaf Mohammed A. , Hulme Amy J. , Sánchez-Carranza Oscar , Baran Zuzanna M. , Rossi Alice , Huang Angela Tzu-Lun , Pohl Tobias , Fleischer Raluca , Fürst Carina , Hammes Annette , Bégay Valérie , Hörnberg Hanna , Finol-Urdaneta Rocio K. , Poole Kate , Dottori Mirella , Lewin Gary R.
Published: February 2024

Touch perception is enabled by mechanically activated ion channels, the opening of which excites cutaneous sensory endings to initiate sensation. In this study, we identify ELKIN1 as an ion channel likely gated by mechanical force, necessary for normal touch sensitivity in mice. Touch insensitivity in

Elkin1
−/−

mice was caused by a loss of mechanically activated currents (MA currents) in around half of all sensory neurons activated by light touch (low-threshold mechanoreceptors). Reintroduction of
Elkin1
into sensory neurons from

Elkin1
−/−

mice restored MA currents. Additionally, small interfering RNA–mediated knockdown of
ELKIN1
from induced human sensory neurons substantially reduced indentation-induced MA currents, supporting a conserved role for ELKIN1 in human touch. Our data identify ELKIN1 as a core component of touch transduction in mice and potentially in humans.
Aminative Suzuki–Miyaura coupling
Authors: Onnuch Polpum , Ramagonolla Kranthikumar , Liu Richard Y.
Published: February 2024

The Suzuki–Miyaura and Buchwald–Hartwig coupling reactions are widely used to form carbon-carbon (C–C) and carbon-nitrogen (C–N) bonds, respectively. We report the incorporation of a formal nitrene insertion process into the Suzuki–Miyaura reaction, altering the products from C–C–linked biaryls to C–N–C–linked diaryl amines and thereby joining the Suzuki–Miyaura and Buchwald–Hartwig coupling pathways to the same starting-material classes. A combination of a bulky ancillary phosphine ligand on palladium and a commercially available amination reagent enables efficient reactivity across aryl halides and pseudohalides, boronic acids and esters, and many functional groups and heterocycles. Mechanistic insights reveal flexibility on the order of bond-forming events, suggesting potential for expansion of the aminative cross-coupling concept to encompass diverse nucleophiles and electrophiles as well as four-component variants.
Critical junctions in evolution
Authors: Sumner-Rooney Lauren
Published: February 2024

Key traits set the course of de novo visual system evolution in marine mollusks
Regulatory functions of homeobox domain transcription factors in fungi
Authors: Calvo A. M. , Dabholkar A. , Wyman E. M. , Lohmar J. M. , Cary J. W.
Published: February 2024

Homeobox domain (HD) proteins present a crucial involvement in morphological differentiation and other functions in eukaryotes. Most HD genes encode transcription factors (TFs) that orchestrate a regulatory role in cellular and developmental decisions. In fungi, multiple studies have increased our understanding of these important HD regulators in recent years. These reports have revealed their role in fungal development, both sexual and asexual, as well as their importance in governing other biological processes in these organisms, including secondary metabolism, pathogenicity, and sensitivity to environmental stresses. Here, we provide a comprehensive review of the current knowledge on the regulatory roles of HD-TFs in fungi, with a special focus on
Aspergillus
species.
Pathogenesis of viral infections during pregnancy
Authors: Creisher Patrick S. , Klein Sabra L.
Published: February 2024

Viral infections during pregnancy are associated with significant adverse perinatal and fetal outcomes. Pregnancy is a unique immunologic and physiologic state, which can influence control of virus replication, severity of disease, and vertical transmission. The placenta is the organ of the maternal-fetal interface and provides defense against microbial infection while supporting the semi-allogeneic fetus via tolerogenic immune responses. Some viruses, such as cytomegalovirus, Zika virus, and rubella virus, can breach these defenses, directly infecting the fetus and having long-lasting consequences. Even without direct placental infection, other viruses, including respiratory viruses like influenza viruses and severe acute respiratory syndrome coronavirus 2, still cause placental damage and inflammation. Concentrations of progesterone and estrogens rise during pregnancy and contribute to immunological adaptations, placentation, and placental development and play a pivotal role in creating a tolerogenic environment at the maternal-fetal interface. Animal models, including mice, nonhuman primates, rabbits, and guinea pigs, are instrumental for mechanistic insights into the pathogenesis of viral infections during pregnancy and identification of targetable treatments to improve health outcomes of pregnant individuals and offspring.
Cryo-EM structure of rotavirus B NSP2 reveals its unique tertiary architecture
Authors: Chamera Sebastian , Wycisk Krzysztof , Czarnocki-Cieciura Mariusz , Nowotny Marcin
Published: February 2024

Rotavirus (RV) NSP2 is a multifunctional RNA chaperone that exhibits numerous activities that are essential for replication and viral genome packaging. We performed an
in silico
analysis that highlighted a distant relationship of NSP2 from rotavirus B (RVB) to proteins from other human RVs. We solved a cryo-electron microscopy structure of RVB NSP2 that shows structural differences with corresponding proteins from other human RVs. Based on the structure, we identified amino acid residues that are involved in RNA interactions. Anisotropy titration experiments showed that these residues are important for nucleic acid binding. We also identified structural motifs that are conserved in all RV species. Collectively, our data complete the structural characterization of rotaviral NSP2 protein and demonstrate its structural diversity among RV species.

IMPORTANCE

Rotavirus B (RVB), also known as adult diarrhea rotavirus, has caused epidemics of severe diarrhea in China, India, and Bangladesh. Thousands of people are infected in a single RVB epidemic. However, information on this group of rotaviruses remains limited. As NSP2 is an essential protein in the viral life cycle, including its role in the formation of replication factories, it may be a target for future antiviral strategy against viruses with similar mechanisms.
Interaction between the SFTSV envelope glycoprotein Gn and STING inhibits the formation of the STING-TBK1 complex and suppresses the NF-κB signaling pathway
Authors: Jia Yupei , Li Feifei , Liu Zixiang , Liu Sihua , Huang Mengqian , Gao Xiaoning , Su Xin , Wang Zhiyun , Wang Tao
Published: February 2024

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus with high pathogenicity. There has been a gradual increase in the number of reported cases in recent years, with high morbidity and mortality rates. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway plays an important role in the innate immune defense activated by viral infection; however, the role of the cGAS-STING signaling pathway during SFTSV infection is still unclear. In this study, we investigated the relationship between SFTSV infection and cGAS-STING signaling. We found that SFTSV infection caused the release of mitochondrial DNA into the cytoplasm and inhibits downstream innate immune signaling pathways by activating the cytoplasmic DNA receptor cGAS. We found that the SFTSV envelope glycoprotein Gn was a potent inhibitor of the cGAS-STING pathway and blocked the nuclear accumulation of interferon regulatory factor 3 and p65 to inhibit downstream innate immune signaling. Gn of SFTSV interacted with STING to inhibit STING dimerization and inhibited K27-ubiquitin modification of STING to disrupt the assembly of the STING-TANK-binding kinase 1 complex and downstream signaling. In addition, Gn was found to be involved in inducing STING degradation, further inhibiting the downstream immune response. In conclusion, this study identified the important role of the glycoprotein Gn in the antiviral innate immune response and revealed a novel mechanism of immune escape for SFTSV. Moreover, this study increases the understanding of the pathogenic mechanism of SFTSV and provides new insights for further treatment of SFTS.

IMPORTANCE

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly discovered virus associated with severe hemorrhagic fever in humans. However, the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway during SFTSV infection is still unclear. We found that SFTSV infection inhibits downstream innate immune signaling pathways by activating the cytoplasmic DNA receptor cGAS. In addition, SFTSV Gn blocked the nuclear accumulation of interferon regulatory factor 3 and p65 to inhibit downstream innate immune signaling. Moreover, we determined that Gn of SFTSV inhibited K27-ubiquitin modification of STING to disrupt the assembly of the STING-TANK-binding kinase 1 complex and downstream signaling. We found that the SFTSV envelope glycoprotein Gn is a potent inhibitor of the cGAS-STING pathway. In conclusion, this study highlights the crucial function of the glycoprotein Gn in the antiviral innate immune response and reveals a new method of immune escape of SFTSV.
Biosynthesis and function of 7-deazaguanine derivatives in bacteria and phages
Authors: de Crécy-Lagard Valérie , Hutinet Geoffrey , Cediel-Becerra José D. D. , Yuan Yifeng , Zallot Rémi , Chevrette Marc G. , Ratnayake R. M. Madhushi N. , Jaroch Marshall , Quaiyum Samia , Bruner Steven
Published: February 2024

Deazaguanine modifications play multifaceted roles in the molecular biology of DNA and tRNA, shaping diverse yet essential biological processes, including the nuanced fine-tuning of translation efficiency and the intricate modulation of codon-anticodon interactions. Beyond their roles in translation, deazaguanine modifications contribute to cellular stress resistance, self-nonself discrimination mechanisms, and host evasion defenses, directly modulating the adaptability of living organisms. Deazaguanine moieties extend beyond nucleic acid modifications, manifesting in the structural diversity of biologically active natural products. Their roles in fundamental cellular processes and their presence in biologically active natural products underscore their versatility and pivotal contributions to the intricate web of molecular interactions within living organisms. Here, we discuss the current understanding of the biosynthesis and multifaceted functions of deazaguanines, shedding light on their diverse and dynamic roles in the molecular landscape of life.
New aspects characterizing non-obese NAFLD by the analysis of the intestinal flora and metabolites using a mouse model
Authors: Zhang Wenji , Cheng Wenli , Li JingHui , Huang Zhenrui , Lin Hui , Zhang Wenjuan
Published: February 2024

Non-alcoholic fatty liver disease (NAFLD) is a major public health problem due to the high incidence affecting approximately one-third of the world’s population. NAFLD is usually linked to obesity and excessive weight. A subset of patients with NAFLD expresses normal or low body mass index; thus, the condition is called non-obese NAFLD or lean NAFLD. However, patients and healthcare professionals have little awareness and understanding of NAFLD in non-obese individuals. Furthermore, preclinical results from non-obese animal models with NAFLD are unclear. Gut microbiota and their metabolites in non-obese/lean-NAFLD patients differ from those in obese NAFLD patients. Therefore, we analyzed the biochemical indices, intestinal flora, and intestinal metabolites in a non-obese NAFLD mouse model established using a methionine-choline-deficient (MCD) diet. The significantly lean MCD mice had a remarkable fatty liver with lower serum triglyceride and free fatty acid levels, as well as higher alanine transaminase and aspartate transaminase levels than normal mice. 16S RNA sequencing of fecal DNA showed that the overall richness and diversity of the intestinal flora decreased in MCD mice, whereas the Firmicutes:Bacteroidota ratio was increased. g_
Tuzzerella
, s_
Bifidobacterium pseudolongum
, and s_
Faecalibaculum rodentium
were the predominant species in non-obese NAFLD mice. Fecal metabolomics using liquid chromatography-tandem mass spectrometry revealed the potential biomarkers for the prognosis and diagnosis of non-obese NAFLD, including high levels of tyramine glucuronide, 9,12,13-TriHOME, and pantetheine 4′-phosphate, and low levels of 3-carbamoyl-2-phenylpropionaldehyde, N-succinyl-L,L-2,6-diaminopimelate, 4-methyl-5-thiazoleethanol, homogentisic acid, and estriol. Our findings could be useful to identify and develop drugs to treat non-obese NAFLD and lean NAFLD.

IMPORTANCE

Patients and healthcare professionals have little awareness and understanding of NAFLD in non-obese individuals. In fact, about 40% of people with NAFLD worldwide are non-obese, and nearly one-fifth are lean. Lean NAFLD unfortunately may be unnoticed for years and remains undetected until hepatic damage is advanced and the prognosis is compromised. This study focused on the lean NAFLD, screened therapeutic agents, and biomarkers for the prognosis and diagnosis using MCD-induced male C57BL/6J mice. The metabolites tyramine glucuronide, 9,12,13-TriHOME, and pantetheine 4′-phosphate, together with the predominant flora including g_
Tuzzerella
, s_
Bifidobacterium pseudolongum
, and s_
Faecalibaculum rodentium
, were specific in non-obese NAFLD mice and might be used as targets for non-obese NAFLD drug exploration. This study is particularly significant for non-obese NAFLDs that need to be more actively noticed and vigilant.
Sleep deprivation-induced anxiety-like behaviors are associated with alterations in the gut microbiota and metabolites
Authors: Zhang Nana , Gao Xuefeng , Li Donghao , Xu Lijuan , Zhou Guanzhou , Xu Mengqi , Peng Lihua , Sun Gang , Pan Fei , Li Yan , Ren Rongrong , Huang Ruolan , Yang Yunsheng , Wang Zikai
Published: February 2024

The present study aimed to characterize the gut microbiota and serum metabolome changes associated with sleep deprivation (SD) as well as to explore the potential benefits of multi-probiotic supplementation in alleviating SD-related mental health disorders. Rats were subjected to 7 days of SD, followed by 14 days of multi-probiotics or saline administration. Open-field tests were conducted at baseline, end of SD (day 7), and after 14 days of saline or multi-probiotic gavage (day 21). Metagenomic sequencing was conducted on fecal samples, and serum metabolites were measured by untargeted liquid chromatography tandem-mass spectrometry. At day 7, anxiety-like behaviors, including significant decreases in total movement distance (
P
= 0.0002) and staying time in the central zone (
P
= 0.021), were observed. In addition, increased levels of lipopolysaccharide (LPS;
P
= 0.028) and decreased levels of uridine (
P
= 0.018) and tryptophan (
P
= 0.01) were detected in rats after 7 days of SD. After SD, the richness of the gut bacterial community increased, and the levels of
Akkermansia muciniphila
,
Muribaculum intestinale
, and
Bacteroides caecimuris
decreased. The changes in the host metabolism and gut microbiota composition were strongly associated with the anxiety-like behaviors caused by SD. In addition, multi-probiotic supplementation for 14 days modestly improved the anxiety-like behaviors in SD rats but significantly reduced the serum level of LPS (
P
= 0.045). In conclusion, SD induces changes in the gut microbiota and serum metabolites, which may contribute to the development of chronic inflammatory responses and affect the gut-brain axis, causing anxiety-like behaviors. Probiotic supplementation significantly reduces serum LPS, which may alleviate the influence of chronic inflammation.

IMPORTANCE

The disturbance in the gut microbiome and serum metabolome induced by SD may be involved in anxiety-like behaviors. Probiotic supplementation decreases serum levels of LPS, but this reduction may be insufficient for alleviating SD-induced anxiety-like behaviors.
Epidrugs: alternative chemotherapy targeting
Theileria annulata
schizont stage parasites
Authors: Kamble Sonam , Singh Sakshi , Suresh Akash , Singothu Siva , Dandesena Debabrata , Bhandari Vasundhra , Sharma Paresh
Published: February 2024

The growing emergence of resistance to current anti-theilerial agents necessitates the exploration of alternative approaches to drug discovery. This study evaluated the antiparasitic efficacy of 148 compounds derived from an epigenetic inhibitor library against the schizont stage of a
Theileria annulata
-infected cell line. Initial screening at a concentration of 10 µM identified 27 compounds exhibiting promising anti-theilerial activity. Further investigation, including determination of the 50% inhibitory concentration (IC
50
) and host cell cytotoxicity assay, highlighted seven highly effective compounds (SAHA, BVT-948, Trichostatin A, Methylstat, Plumbagin, Ryuvidine, and TCE-5003) against
T. annulata
-infected cells. Analysis of the active compounds revealed their inhibitory action against various human targets, such as HDAC (SAHA and Trichostatin A), SET domain (Ryuvidine), PRMT (BVT-948 and TCE-5003), histone demethylase (Methylstat), and ROS/apoptosis inducer (Plumbagin). We identified gene orthologs of these targets in
Theileria
and conducted molecular docking studies, demonstrating effective binding of the compounds with their respective targets in the parasite, supported by
in vitro
data. Additionally, we performed
in silico
ADME/T predictions, which indicated potential mutagenic and hepatotoxic effects of Plumbagin, Methylstat, and TCE-5003, rendering them unsuitable for drug development. Conversely, SAHA, Trichostatin A, and BVT-948 showed promising characteristics and may represent potential candidates for future development as chemotherapeutic agents against tropical theileriosis. These findings provide valuable insights into the search for novel anti-theilerial drugs and offer a basis for further research in this area.

IMPORTANCE

Theileria annulata
is a protozoan parasite responsible for tropical theileriosis, a devastating disease affecting cattle. Traditional chemotherapy has limitations, and the study explores the potential of epidrugs as an alternative treatment approach. Epidrugs are compounds that modify gene expression without altering the underlying DNA sequence, offering a novel way to combat parasitic infections. This research is pivotal as it addresses the urgent need for innovative therapies against
T. annulata
, contributing to the development of more effective and targeted treatments for infected livestock. Successful implementation of epidrugs could not only enhance the well-being of cattle but also have broader implications for the control of parasitic diseases, showcasing the paper’s significance in advancing veterinary science and improving livestock health globally.
Identification of fungal natural products with potent inhibition in
Toxoplasma gondii
Authors: Jiang Tiantian , Godinez-Macias Karla P. , Collins Jennifer E. , Lee Jin Woo , Wendt Karen L. , Carolino Krypton , Chakrabarti Debopam , Cichewicz Robert H. , Winzeler Elizabeth A.
Published: February 2024

In an effort to identify novel compounds with potent inhibition against
Toxoplasma gondii,
a phenotypic screen was performed utilizing a library of 683 pure compounds derived primarily from terrestrial and marine fungi. An initial screen with a fixed concentration of 5 µM yielded 91 hits with inhibition comparable to an equal concentration of artemisinin. These compounds were then triaged based on known biological and chemical concerns and liabilities. From these, 49 prioritized compounds were tested in a dose response format with
T. gondii
and human foreskin fibroblasts (HFFs) for cytotoxicity. Ten compounds were identified with an IC
50
less than 150 nM and a selectivity index (SI) greater than 100. An additional eight compounds demonstrated submicromolar IC
50
and SI values equal to or greater than 35. While the majority of these scaffolds have been previously implicated against apicomplexan parasites, their activities in
T. gondii
were largely unknown. Herein, we report the
T. gondii
activity of these compounds with chemotypes including xanthoquinodins, peptaibols, heptelidic acid analogs, and fumagillin analogs, with multiple compounds demonstrating exceptional potency in
T. gondii
and limited toxicity to HFFs at the highest concentrations tested.

IMPORTANCE

Current therapeutics for treating toxoplasmosis remain insufficient, demonstrating high cytotoxicity, poor bioavailability, limited efficacy, and drug resistance. Additional research is needed to develop novel compounds with high efficacy and low cytotoxicity. The success of artemisinin and other natural products in treating malaria highlights the potential of natural products as anti-protozoan therapeutics. However, the exploration of natural products in
T. gondii
drug discovery has been less comprehensive, leaving untapped potential. By leveraging the resources available for the malaria drug discovery campaign, we conducted a phenotypic screen utilizing a set of natural products previously screened against
Plasmodium falciparum
. Our study revealed 18 compounds with high potency and low cytotoxicity in
T. gondii
, including four novel scaffolds with no previously reported activity in
T. gondii
. These new scaffolds may serve as starting points for the development of toxoplasmosis therapeutics but could also serve as tool compounds for target identification studies using chemogenomic approach.
Safeguarding in practice: anticipating, minimising and mitigating risk in teenage pregnancy research in urban informal settlements in Nairobi, Kenya
Authors: Otiso Lilian , Steege Rosie , Njoroge Inviolata , Okoth Linet , Tubb Phil , Nyothach Elizabeth , Phillips-Howard Penelope A , Theobald Sally , Taegtmeyer Miriam
Published: February 2024

Safeguarding challenges in global health research include sexual abuse and exploitation, physical and psychological abuse, financial exploitation and neglect. Intersecting individual identities (such as gender and age) shape vulnerability to risk. Adolescents, who are widely included in sexual and reproductive health research, may be particularly vulnerable. Sensitive topics like teenage pregnancy may lead to multiple risks. We explored potential safeguarding risks and mitigation strategies when studying teenage pregnancies in informal urban settlements in Nairobi, Kenya. Risk mapping was initiated by the research team that had prolonged engagement with adolescent girls and teen mothers. The team mapped potential safeguarding risks for both research participants and research staff due to, and unrelated to, the research activity. Mitigation measures were agreed for each risk. The draft risk map was validated by community members and coresearchers in a workshop. During implementation, safeguarding risks emerged across the risk map areas and are presented as case studies. Risks to the girls included intimate partner violence because of a phone provided by the study; male participants faced potential disclosure of their perceived criminal activity (impregnating teenage girls); and researchers faced psychological and physical risks due to the nature of the research. These cases shed further light on safeguarding as a key priority area for research ethics and implementation. Our experience illustrates the importance of mapping safeguarding risks and strengthening safeguarding measures throughout the research lifecycle. We recommend co-developing and continuously updating a safeguarding map to enhance safety, equity and trust between the participants, community and researchers.
Market making and the production of nurses for export: a case study of India–UK health worker migration
Authors: Merz Sibille , Hunter Benjamin M , Murray Susan F , Bisht Ramila
Published: February 2024

Background

High-income countries increasingly look to the international recruitment of health workers to address domestic shortages, especially from low-income and middle-income countries. We adapt conceptual frameworks from migration studies to examine the networked and commercialised nature of the Indian market for nurse migration to the UK.

Methods

We draw on data from 27 expert interviews conducted with migration intermediaries, healthcare providers and policymakers in India and the UK.

Findings

India–UK nurse migration occurs within a complex and evolving market encompassing ways to educate, train and recruit nursing candidates. For-profit actors shape the international orientation of nursing curricula, broker on-the-job training and offer language, exam and specialised clinical training. Rather than merely facilitate travel, these brokers produce both generic, emigratory nurses as well as more customised nurses ready to meet specific shortages in the UK.

Discussion

The dialectic of producing emigratory and customised nurses is similar to that seen in the Post-Fordist manufacturing model characterised by flexible specialisation and a networked structure. As the commodity in this case are people attempting to improve their position in life, these markets require attention from health policy makers. Nurse production regimes based on international market opportunities are liable to change, subjecting nurses to the risk of having trained for a market that can no longer accommodate them. The commercial nature of activities further entrenches existing socioeconomic inequalities in the Indian nurse force. Negative repercussions for the source healthcare system can be anticipated as highly qualified, specialised nurses leave to work in healthcare systems abroad.
Work Engagement and Well-being Study (SWELL): a randomised controlled feasibility trial evaluating the effects of mindfulness versus light physical exercise at work
Authors: Vainre Maris , Dalgleish Tim , Watson Peter , Haag Christina , Dercon Quentin , Galante Julieta , Hitchcock Caitlin
Published: February 2024

Background

Mindfulness-based programmes (MBPs) are increasingly offered at work, often in online self-guided format. However, the evidence on MBPs’ effect on work performance (WP) is inconsistent.

Objective

This pragmatic randomised controlled feasibility trial assessed procedural uncertainties, intervention acceptability and preliminary effect sizes of an MBP on WP, relative to an alternative intervention.

Methods

241 employees from eight employers were randomised (1:1) to complete a 4-week, self-guided, online MBP or a light physical exercise programme (LE)(active control). Feasibility and acceptability measures were of primary interest. WP at postintervention (PostInt) was the primary outcome for preliminary assessment of effect sizes. Secondary outcomes assessed mental health (MH) and cognitive processes hypothesised to be targeted by the MBP. Outcomes were collected at baseline, PostInt and 12-week follow-up (12wFUP). Prospective trial protocol:NCT04631302.

Findings

87% of randomised participants started the course. Courses had high acceptability. Retention rates were typical for online trials (64% PostInt; 30% 12wFUP). MBP, compared with the LE control, offered negligible benefits for WP (PostInt (d=0.06, 95% CI −0.19 to 0.32); 12wFUP (d=0.02, 95% CI −0.30 to 0.26)). Both interventions improved MH outcomes (ds=−0.40 to 0.58, 95% CI −0.32 to 0.18); between-group differences were small (ds=−0.09 to 0.04, 95% CI −0.15 to 0.17).

Conclusion

The trial is feasible; interventions are acceptable. Results provide little support for a later phase trial comparing an MBP to a light exercise control. To inform future trials, we summarise procedural challenges.

Clinical implications

Results suggest MBPs are unlikely to improve WP relative to light physical exercise. Although the MBP improved MH, other active interventions may be just as efficacious.

Trial registration number

NCT04631302.