bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thermally controlled intein splicing of engineered DNA polymerases provides a robust and generalizable solution for accurate and sensitive molecular diagnostics
Authors: Wang You , Shi Yuqian , Hellinga Homme W , Beese Lorena S 
Published: May 2023

Abstract
DNA polymerases are essential for nucleic acid synthesis, cloning, sequencing and molecular diagnostics technologies. Conditional intein splicing is a powerful tool for controlling enzyme reactions. We have engineered a thermal switch into thermostable DNA polymerases from two structurally distinct polymerase families by inserting a thermally activated intein domain into a surface loop that is integral to the polymerase active site, thereby blocking DNA or RNA template access. The fusion proteins are inactive, but retain their structures, such that the intein excises during a heat pulse delivered at 70–80°C to generate spliced, active polymerases. This straightforward thermal activation step provides a highly effective, one-component ‘hot-start’ control of PCR reactions that enables accurate target amplification by minimizing unwanted by-products generated by off-target reactions. In one engineered enzyme, derived from Thermus aquaticus DNA polymerase, both DNA polymerase and reverse transcriptase activities are controlled by the intein, enabling single-reagent amplification of DNA and RNA under hot-start conditions. This engineered polymerase provides high-sensitivity detection for molecular diagnostics applications, amplifying 5–6 copies of the tested DNA and RNA targets with &gt;95% certainty. The design principles used to engineer the inteins can be readily applied to construct other conditionally activated nucleic acid processing enzymes.
OnTarget: in silico design of MiniPromoters for targeted delivery of expression
Authors: Fornes Oriol , Av-Shalom Tamar V , Korecki Andrea J , Farkas Rachelle A , Arenillas David J , Mathelier Anthony , Simpson Elizabeth M , Wasserman Wyeth W 
Published: May 2023

Abstract
MiniPromoters, or compact promoters, are short DNA sequences that can drive expression in specific cells and tissues. While broadly useful, they are of high relevance to gene therapy due to their role in enabling precise control of where a therapeutic gene will be expressed. Here, we present OnTarget (http://ontarget.cmmt.ubc.ca), a webserver that streamlines the MiniPromoter design process. Users only need to specify a gene of interest or custom genomic coordinates on which to focus the identification of promoters and enhancers, and can also provide relevant cell-type-specific genomic evidence (e.g. accessible chromatin regions, histone modifications, etc.). OnTarget combines the provided data with internal data to identify candidate promoters and enhancers and design MiniPromoters. To illustrate the utility of OnTarget, we designed and characterized two MiniPromoters targeting different cell populations relevant to Parkinson Disease.
Enrichr-KG: bridging enrichment analysis across multiple libraries
Authors: Evangelista John Erol , Xie Zhuorui , Marino Giacomo B , Nguyen Nhi , Clarke Daniel J B , Ma’ayan Avi 
Published: May 2023

Abstract
Gene and protein set enrichment analysis is a critical step in the analysis of data collected from omics experiments. Enrichr is a popular gene set enrichment analysis web-server search engine that contains hundreds of thousands of annotated gene sets. While Enrichr has been useful in providing enrichment analysis with many gene set libraries from different categories, integrating enrichment results across libraries and domains of knowledge can further hypothesis generation. To this end, Enrichr-KG is a knowledge graph database and a web-server application that combines selected gene set libraries from Enrichr for integrative enrichment analysis and visualization. The enrichment results are presented as subgraphs made of nodes and links that connect genes to their enriched terms. In addition, users of Enrichr-KG can add gene-gene links, as well as predicted genes to the subgraphs. This graphical representation of cross-library results with enriched and predicted genes can illuminate hidden associations between genes and annotated enriched terms from across datasets and resources. Enrichr-KG currently serves 26 gene set libraries from different categories that include transcription, pathways, ontologies, diseases/drugs, and cell types. To demonstrate the utility of Enrichr-KG we provide several case studies. Enrichr-KG is freely available at: https://maayanlab.cloud/enrichr-kg.
Protecting workers in the temporary staffing industry
Authors: Forst L , Chaudhry A , Lopez A , McCarthy M , Hebert-Beirne J 
Published: May 2023

Abstract

Background
Workers hired through temporary staffing companies have a high rate of severe and fatal injuries despite the legally mandated, shared responsibility of the temporary staffing company and the host company to assure safe work.

Aims
The aim of this study was to elucidate the perspective of temporary staffing personnel on approaches to mitigating injury risk among the workers they hire.

Methods
Based on a conceptual model representing the interplay between work and health, we conducted a ‘brainstorm’ of temporary staffing personnel regarding perceived barriers to protecting temporary workers. A content/context analysis used standard qualitative methods, and the findings were triangulated with notes taken during the discussion.

Results
Temporary staffing employers describe loss of control of the working conditions once workers are placed at host/client companies. Further, they describe a contentious relationship between temporary staffing and host companies, where it is difficult to hold host companies to account. Other barriers to providing temporary workers with a safe work environment include the temp companies’ lack of knowledge of site-specific hazards, the poor quality of onsite Occupational Safety and Health training, and ignoring Occupational Safety and Health Administration (OSHA) requirements.

Conclusions
The perspective of temporary staffing companies should be considered to address the lack of cooperation and shifted responsibility described in this study. Policy and practice changes could include requiring contract language, implementing communication about safety, either sharing workers’ compensation purchase or removing exclusive remedy protections from hosts, and prescribing safety training, such as an OSHA 10-h programme. Suggested interventions need further study.
Antiviral Prescribing Among Patients at an Ambulatory Cancer Center With Laboratory-Confirmed Influenza
Authors: Sorey Woody , Krantz Elizabeth M , Morris Jessica , Klaassen John , Sweet Ania , Tverdek Frank , Escobar Zahra K , McCulloch Denise J , Pergam Steven A , Liu Catherine 
Published: May 2023

Abstract
Among 133 cancer outpatients diagnosed with influenza between 2016 and 2018, 110 (83%) were prescribed oseltamivir. Among 109 with a known symptom onset date, 53% presented for care and 31% were prescribed oseltamivir within 48 hours. Patient/provider education and rapid diagnostics are needed to improve early oseltamivir use among cancer patients with influenza.
Dalbavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infection in Patients With Obesity or Diabetes: A Subgroup Analysis of Pooled Phase 3 Clinical Trials
Authors: Riccobene Todd , Lock John , Lyles Rosie D , Georgiades Benjamin , Nowak Michael , Gonzalez Pedro L , Park Jenny , Rappo Urania 
Published: May 2023

Abstract

Background
We assessed the efficacy and safety of dalbavancin, a long-acting lipoglycopeptide with activity against Gram-positive pathogens, for treatment of acute bacterial skin and skin structure infections (ABSSSI) in patients with high body mass index (BMI) and/or diabetes.

Methods
Data from two phase 3 trials of dalbavancin (1000 mg intravenous [IV], day 1; 500 mg IV, day 8) versus comparator and one phase 3b trial of single-dose (1500 mg IV, day 1) versus 2-dose (1000 mg IV, day 1; 500 mg IV, day 8) dalbavancin in adults with ABSSSI were pooled and summarized separately by baseline BMI and diabetes status. Clinical success at 48 to 72 hours (≥20% reduction in lesion size), end of treatment ([EOT] day 14), and day 28 was evaluated in the intent-to-treat (ITT) and microbiological ITT (microITT) populations. Safety data were reported in patients who received ≥1 dose of study drug.

Results
In the dalbavancin ITT population (BMI, n = 2001; diabetes, n = 2010), at 48 to 72 hours (and EOT) clinical success was achieved in 89.3% (EOT, 90.9%) of patients with normal BMI and 78.9% to 87.6% (EOT, 91.0% to 95.2%) of patients with elevated BMI. Clinical success after dalbavancin treatment was achieved in 82.4% (EOT, 90.8%) of patients with diabetes and 86.0% (EOT, 91.6%) of patients without diabetes. Similar trends were observed for infections due to methicillin-resistant Staphylococcus aureus or methicillin-susceptible S aureus (microITT population).

Conclusions
Dalbavancin is effective, with sustained clinical success rates in patients with obesity or diabetes, with a similar safety profile across patient groups.
Prevalence and Predictors of Physician-Patient Discordance in Prognostic Perceptions in Advanced Cancer
Authors: van der Velden Naomi Cornelia Anna , Han Paul K J , van Laarhoven Hanneke W M , de Vos Filip Y F L , Hendriks Lizza E L , Burgers Sjaak A , Dingemans Anne-Marie C , van Haarst Jan Maarten W , Dits Joyce , Smets Ellen M A , Henselmans Inge 
Published: May 2023

AbstractBackgroundDiscordance between physicians’ and patients’ prognostic perceptions in advanced cancer care threatens informed medical decision-making and end-of-life preparation, yet this phenomenon is poorly understood. We sought to: (1) describe the extent and direction of prognostic discordance, patients’ prognostic information preferences in cases of prognostic discordance, and physicians’ awareness of prognostic discordance; and (2) examine which patient, physician, and caregiver factors predict prognostic discordance.Materials and MethodsOncologists and advanced cancer patients (median survival ≤12 months; n = 515) from 7 Dutch hospitals completed structured surveys in a cross-sectional study. Prognostic discordance was operationalized by comparing physicians’ and patients’ perceptions of the likelihood of cure, 2-year mortality risk, and 1-year mortality risk.ResultsPrognostic discordance occurred in 20% (likelihood of cure), 24%, and 35% (2-year and 1-year mortality risk) of physician-patient dyads, most often involving patients with more optimistic perceptions than their physician. Among patients demonstrating prognostic discordance, the proportion who preferred not knowing prognosis varied from 7% (likelihood of cure) to 37% (1-year mortality risk), and 45% (2-year mortality risk). Agreement between physician-perceived and observed prognostic discordance or concordance was poor (kappa = 0.186). Prognostic discordance was associated with several patient factors (stronger fighting spirit, self-reported absence of prognostic discussions, an information source other than the healthcare provider), and greater physician-reported uncertainty about prognosis.ConclusionUp to one-third of the patients perceive prognosis discordantly from their physician, among whom a substantial proportion prefers not knowing prognosis. Most physicians lack awareness of prognostic discordance, raising the need to explore patients’ prognostic information preferences and perceptions, and to tailor prognostic communication.
The ATR–WEE1 kinase module promotes SUPPRESSOR OF GAMMA RESPONSE 1 translation to activate replication stress responses
Authors: Chen Hanchen , Pan Ting , Zheng Xueao , Huang Yongchi , Wu Chong , Yang Tongbin , Gao Shan , Wang Lili , Yan Shunping 
Published: May 2023

Abstract
DNA replication stress threatens genome stability and is a hallmark of cancer in humans. The evolutionarily conserved kinases ATR (ATM and RAD3-related) and WEE1 are essential for the activation of replication stress responses. Translational control is an important mechanism that regulates gene expression, but its role in replication stress responses is largely unknown. Here we show that ATR–WEE1 control the translation of SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1), a master transcription factor required for replication stress responses in Arabidopsis thaliana. Through genetic screening, we found that the loss of GENERAL CONTROL NONDEREPRESSIBLE 20 (GCN20) or GCN1, which function together to inhibit protein translation, suppressed the hypersensitivity of the atr or wee1 mutant to replication stress. Biochemically, WEE1 inhibits GCN20 by phosphorylating it; phosphorylated GCN20 is subsequently polyubiquitinated and degraded. Ribosome profiling experiments revealed that that loss of GCN20 enhanced the translation efficiency of SOG1, while overexpressing GCN20 had the opposite effect. The loss of SOG1 reduced the resistance of wee1 gcn20 to replication stress, whereas overexpressing SOG1 enhanced the resistance to atr or wee1 to replication stress. These results suggest that ATR–WEE1 inhibits GCN20–GCN1 activity to promote the translation of SOG1 during replication stress. These findings link translational control to replication stress responses in Arabidopsis.
Callose synthesis at the center point of plant development—An evolutionary insight
Authors: Ušák David , Haluška Samuel , Pleskot Roman 
Published: May 2023

AbstractPolar callose deposition into the extracellular matrix is tightly controlled in time and space. Its presence in the cell wall modifies the properties of the surrounding area, which is fundamental for the correct execution of numerous processes such as cell division, male gametophyte development, intercellular transport, or responses to biotic and abiotic stresses. Previous studies have been invaluable in characterizing specific callose synthases (CalSs) during individual cellular processes. However, the complex view of the relationships between a particular CalS and a specific process is still lacking. Here we review the recent proceedings on the role of callose and individual CalSs in cell wall remodelling from an evolutionary perspective and with a particular focus on cytokinesis. We provide a robust phylogenetic analysis of CalS across the plant kingdom, which implies a 3-subfamily distribution of CalS. We also discuss the possible linkage between the evolution of CalSs and their function in specific cell types and processes.
Slowly activating voltage-gated potassium current potentiation by ML277 is a novel cardioprotective intervention
Authors: Brennan Sean , Alnaimi Abrar I M , McGuinness Lauren R , Abdelaziz Muhammad I M , McKenzie Robert A , Draycott Sophie , Whitmore Jacob , Sharma Parveen , Rainbow Richard D 
Published: May 2023

Abstract
Cardiovascular disease is thought to account for nearly a third of deaths worldwide, with ischemic heart disease, including acute coronary syndromes such as myocardial infarction, accounting for 1.7 million deaths per year. There is a clear need for interventions to impart cardioprotection against ischemia. Here, we show that the slowly activating voltage-gated potassium current (IKs) potentiator ML277 imparts cardioprotection against ischemia in cellular and whole-heart models by modulating the action potential duration. In three different metabolic inhibition and reperfusion models, an increased contractile recovery and cell survival was observed with ML277, indicative of protection. Finally, ML277 reduced infarct size in an ex vivo Langendorff coronary ligation model, including if only applied on reperfusion. In conclusion, potentiation of the IKs with ML277 imparted a cardioprotection that was equivalent to the protection reported previously by ischemic preconditioning. These data suggest that IKs potentiation may be therapeutically useful in acute coronary syndromes.
The microbiota–gut–brain axis and neurodevelopmental disorders
Authors: Wang Qinwen , Yang Qianyue , Liu Xingyin 
Published: May 2023

Abstract
The gut microbiota has been found to interact with the brain through the microbiota–gut–brain axis, regulating various physiological processes. In recent years, the impacts of the gut microbiota on neurodevelopment through this axis have been increasingly appreciated. The gut microbiota is commonly considered to regulate neurodevelopment through three pathways, the immune pathway, the neuronal pathway, and the endocrine/systemic pathway, with overlaps and crosstalks in between. Accumulating studies have identified the role of the microbiota–gut–brain axis in neurodevelopmental disorders including autism spectrum disorder, attention deficit hyperactivity disorder, and Rett Syndrome. Numerous researchers have examined the physiological and pathophysiological mechanisms influenced by the gut microbiota in neurodevelopmental disorders (NDDs). This review aims to provide a comprehensive overview of advancements in research pertaining to the microbiota-gut-brain axis in NDDs. Furthermore, we analyzed both the current state of research progress and discuss future perspectives in this field.
Assessing the construct validity of musculoskeletal ultrasound and the rheumatoid arthritis foot disease activity index (RADAI-F5) for managing rheumatoid foot disease
Authors: Hoque Anika , Steultjens Martijn , Dickson Diane M , Hendry Gordon J 
Published: May 2023

Abstract

Objective
The RA foot disease activity index (RADAI-F5) is a valid, reliable and clinically feasible patient-reported outcome measure (PROM) for the measurement of RA foot disease activity. Further validation of the RADAI-F5 against musculoskeletal ultrasonography (MSUS) for foot disease activity is necessary before clinical implementation. The aim of this study was to examine the construct validity of the RADAI-F5 in relationship to MSUS and clinical examination.

Methods
Participants with RA completed the RADAI-F5. MSUS was used to evaluate disease activity (synovial hypertrophy/synovitis/tenosynovitis/bursitis) and joint damage (erosion) using greyscale (GS) and power Doppler (PD) at 16 regions in each foot, including joints and soft tissues. These same regions were examined clinically for swelling and tenderness. The construct validity of the RADAI-F5 was assessed using correlation coefficients and a priori-specified hypotheses for the strength of associations.

Results
Of 60 participants, 48 were female, with a mean (s.d.) age of 62.6 (9.96) years and median disease duration of 15.49 (interquartile range 6–20.5) years. Theoretically consistent associations confirming construct validity [95% CI] were observed between the RADAI-F5 and MSUS GS (0.76 [0.57, 0.82]; strong), MSUS PD (0.55 [0.35, 0.71]; moderate), MSUS-detected erosions (0.41 [0.18, 0.61]; moderate), clinical tenderness (0.52 [0.31, 0.68]; moderate) and clinical swelling (0.36 [0.13, 0.55]; weak).

Conclusion
Moderate to strong correlations between RADAI-F5 and MSUS demonstrate the good measurement properties of this instrument. With greater confidence in the utility of the RADAI-F5, clinical use of this new instrument as an adjunct to the disease activity score for 28 joints (DAS-28) could help to identify RA patients at risk for poor functional and radiological outcomes.
CaP-coated Zn-Mn-Li alloys regulate osseointegration via influencing macrophage polarization in the osteogenic environment
Authors: Qiang Huifen , Hou Caiyao , Zhang Yujue , Luo Xin , Li Jun , Meng Chunxiu , Liu Kun , Lv Zhaoyong , Chen Ximeng , Liu Fengzhen 
Published: May 2023

Abstract
Immune response is an important factor in determining the fate of bone replacement materials, in which macrophages play an important role. It is a new idea to design biomaterials with immunomodulatory function to reduce inflammation and promote bone integration by regulating macrophages polarization. In this work, the immunomodulatory properties of CaP Zn-Mn-Li alloys and the specific mechanism of action were investigated. We found that the CaP Zn0.8Mn0.1Li alloy promoted the polarization of macrophages toward M2 and reduced inflammation, which could effectively upregulate osteogenesis-related factors and promote new bone formation, indicating the important role of macrophages polarization in biomaterial induction of osteogenesis. In vivo studies further demonstrated that CaP Zn0.8Mn0.1Li alloy could stimulate osteogenesis better than other Zn-Mn-Li alloys implantations by regulating macrophages polarization and reducing inflammation. In addition, transcriptome results showed that CaP Zn0.8Mn0.1Li played an important regulatory role in the life process of macrophages, activating Toll-like receptor signaling pathway, which participated in the activation and attenuation of inflammation, and accelerated bone integration. Thus, by preparing CaP coatings on the surface of Zn-Mn-Li alloys and combining the bioactive ingredient with controlled release, the biomaterial will be imbibed with beneficial immunomodulatory properties that promote bone integration.
Quantifying the impact of PFOA exposure on B-cell development and antibody production
Authors: Taylor Krystal D , Woodlief Tracey L , Ahmed Aya , Hu Qing , Duncker Patrick C , DeWitt Jamie C 
Published: May 2023

Abstract
Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals; the vast majority are environmentally and biologically persistent, and some have demonstrated toxicity, including cancer, effects on metabolism, endocrine disruption, and immune dysfunction. Suppression of T-cell-dependent antibody responses (TDAR) has been observed in numerous studies of PFAS but mechanisms remain elusive. Evidence from our work suggests that B cells and how they use energy are impacted by PFAS exposure. We hypothesize that a well-studied and immunotoxic PFAS, perfluorooctanoic acid (PFOA), alters B-cell subclasses and markers of their metabolism. Adult male and female C57BL/6 mice were given PFOA (0 or 7.5 mg/kg) via gavage for 15 days, a duration and dose sufficient to suppress the TDAR. After dosing and immunization of subgroups, spleens were prepared to quantify B-cell subsets. Flow cytometric analysis revealed decreased numbers of plasmablasts, follicular, naïve, and overall B-cell subclasses in female PFOA-exposed groups. Male PFOA-exposed groups had a significant increase in follicular B cells and other subsets had decreases, including in the overall number of B cells. Twenty-four hours after naïve B-cell isolation and ex vivo activation, metabolic measurements revealed a 5-fold increase in metabolic markers in response to stimulation in PFOA-exposed groups compared with controls. These findings suggest that B-cell development and survival may be hindered by PFOA exposure, but that activation of the remaining B cells was not. Based on these findings, PFOA-mediated suppression of the primary IgM antibody response results changes to specific subsets of B cells.
An overview of myelodysplastic syndromes
Authors: Pontrelli Gina , Loscalzo Carina , L'Eplattenier Mark 
Published: May 2023

ABSTRACT
Myelodysplastic syndromes (MDS) can present as a cytopenia—often as unexplained anemia. Because MDS can progress to acute myelogenous leukemia, primary care providers should be aware of the signs and symptoms, which are associated with the corresponding cytopenia that patients experience and may include fatigue, infection, easy bruising, and bleeding. Treatment options center on managing related cytopenias. The only cure, stem cell transplant, is not readily available.