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Ubiquitin (Ub) is a post-translational modification that largely controls proteostasis through mechanisms spanning transcription, translation, and notably, protein degradation. Ub conjugation occurs through a hierarchical cascade of three enzyme classes (E1, E2, and E3s) involving >1000 proteins that regulate the ubiquitination of proteins. The E2 Ub-conjugating enzymes are the midpoint, yet their cellular roles remain under-characterized, partly due to a lack of inhibitors. For example, the cellular roles of the promiscuous E2 UBE2D/UBCH5 are not well described. Here, we develop a highly selective, multivalent, engineered protein inhibitor for the UBE2D family that simultaneously targets the RING- and backside-binding sites. In HeLa cells, these inhibitors phenocopy knockdown of UBE2D by reducing the IC 50 to cisplatin and whole-cell proteomics reveal an increased abundance of ~20% of the identified proteins, consistent with reduced Ub degradation and proteotoxic stress. These precision tools will enable new studies probing UBE2D's central role in proteome management.

Aim: In this study, we assessed the use of advanced pharmacological behavior management techniques (BMTs) among pediatric dentists in Saudi Arabia and the barriers to their clinical application., Materials and Methods: This cross-sectional study used a self-administered electronic survey that targeted members of the Saudi Society of Pediatric Dentistry. The questionnaire included questions on five techniques of advanced and pharmacological behavior management recommended by the American Academy of Pediatric Dentistry. Descriptive statistics, frequency, Chi-square test, and Fisher's exact test were used to present the outcomes and independent variables., Results: A total of 57 pediatric dentists completed the survey. Nitrous oxide (N 2 O) sedation, general anesthesia (GA), and protective stabilization were used regularly by pediatric dentists in 70.2%, 68.4%, and 56.1% of the participants, respectively. A few participants reported using oral (14.0%) or intravenous (IV) sedation (10.5%) regularly. The most common barriers to using these techniques were either dentists' discomfort or the non-availability of the equipment/drugs., Conclusions: The most common method used by pediatric dentists was N 2 O inhalation sedation, followed by GA and protective stabilization. The participants' use of pharmacological BMTs, including IV and oral sedation, was relatively low., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of International Society of Preventive and Community Dentistry.)

Purpose: A comprehensive operative report for cancer surgery is crucial for accurate disease staging, risk stratification, and therapy escalation/de-escalation, which affects the outcome. Narrative operative reports may fail to include some critical findings. Furthermore, standardized operative reports can form the basis of a local registry, which is often lacking in limited-resource settings (LRSs). In adult literature, synoptic operative reports (SOR) contain more key findings than narrative operative reports. In the LRSs, where the capacity of diagnostic pathology services is typically suboptimal, the value of a thorough operative report is even greater. The aim of this study was to develop a SOR template to help standardize childhood cancer surgery reporting in LRSs., Methods: Twenty-three experts in pediatric cancer with extensive experience practicing in LRSs were invited to participate in a modified Delphi procedure. SOR domains for pediatric oncology surgery were drafted based on a literature search and then modified based on experts' opinions. The experts anonymously answered multiple rounds of online questionnaires until all domains and subdomains reached a consensus, which was predefined as 70% agreement., Results: Sixteen experts participated in the study, and two rounds of the survey were completed. Twenty-one domains were considered relevant, including demographics, diagnosis, primary site, preoperative disease stage, previous tumor biopsy or surgery, preoperative tumor rupture, neoadjuvant therapy, surgical access, type of resection, completeness of resection, tumor margin assessment, locoregional tumor extension, organ resection, intraoperative tumor spillage, vascular involvement, lymph node sampling, estimated blood loss, intraoperative complications and interventions to address them, specimen names, and specimen orientation., Conclusion: We developed a SOR template for pediatric oncology surgery in LRSs. Consensus for all 21 domains and associated subdomains was achieved using a modified Delphi procedure., (© 2023 Wiley Periodicals LLC.)

The present study explores the concept of reenactment of known and unknown war trauma that may be unfamiliar to the readers while also opening up new discourses of understanding and empathy through the lens of Cathy Caruth's trauma theory by focusing on the novel A Land of Permanent Goodbyes by Atia Abawi. War fiction, such as Abawi's novel, highlights the concept of psychological trauma as a double wound (known as "outsiders" and unknown as "insiders") through the textual analysis and characterization of characters by presenting their haunting pasts, present lives, and losses concerning traumatic events. The present study also recounts what the trauma of the unknown means to war-torn survivors by focusing on "trauma as double wounds" from three aspects: cause, effects, and recuperation. Finally, the study concludes with a new paradigm in which trauma is portrayed as a healer rather than a wound., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ahmad, Bukhari, Khan, Ashraf and Kanwal.)

The premise of this study is to look at the intergenerational transferal of language and racial trauma of Asian immigrants in general and Korean-American immigrants in particular to a western country, the United States of America. This study investigates trauma from a psychological standpoint, based on Chang-Rae Lee's novel Native Speaker. In describing a marker of citizenship, the novel's title also points to who is the native language speaker and who is a native of a country, and why one who is not may be excluded. The Korean immigrants' vulnerability to the English language and racial differences highlights their status as minority "others," and they suffer from transgenerational trauma. As a result of transgenerational traumatic effects, Henry (the protagonist) has various traumatic side effects such as dysphasia, aphasia, and parasomnia and finally leaves no stone unturned to recuperate from trauma. The Trauma of the Unspeakable theory by Michelle Balaev is used in this article to show how trauma affects people's minds., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ahmad, Nawaz, Bukhari, Nadeem and Hussain.)

Objective: Eosinophilic esophagitis (EoE) is a Th2 disease that presently is diagnosed and followed by clinical symptoms in the presence of endoscopic biopsies documenting elevated esophageal eosinophilia. To simplify clinical care, multiple studies have attempted to identify a disease specific serologic marker. None have been successful. The goal of this study was to employ custom designed Luminex multiplex bead assays to identify a reliable serologic marker for EoE., Methods: Luminex assays were employed to measure serum levels of 11 analytes associated with EoE (IL-5, lL13, periostin, eotaxin-3, thymic stromal lymphopoietin, and immunoglobulins) in a cohort of pediatric patients consisting of active EoE (n=30), EoE in remission (n=13), and controls (n=34)., Results: No analyte was found to be elevated or depressed in active EoE compared to the other groups. Additionally, among the cohort with active EoE, none of the 11 analytes correlated with peak esophageal eosinophilia, endoscopic features of EoE quantitatively defined by an EoE validated endoscopic reference score (EREFS), or esophageal thickness as determined by endosonography., Conclusion: This is the largest prospective survey of heterogeneous markers studied in a consecutive cohort to determine whether they could diagnose or follow EoE. Although none were identified in this cohort, Luminex provides a rapid, economical tool to simultaneously screen multiple sera for proteins that are increased or decreased in disease states., (© 2022 by the Association of Clinical Scientists, Inc.)

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a significant global health emergency with new variants in some cases evading current therapies and approved vaccines. COVID-19 presents with a broad spectrum of acute and long-term manifestations. Severe COVID-19 is characterized by dysregulated cytokine release profile, dysfunctional immune responses, and hypercoagulation with a high risk of progression to multi-organ failure and death. Unraveling the fundamental immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and design of more effective therapeutic interventions for individuals at the highest risk of severe outcomes. Caspases are expressed in both immune and non-immune cells and mediate inflammation and cell death, including apoptosis and pyroptosis. Here we review accumulating evidence defining the importance of the expression and activity of caspase family members following SARS-CoV-2 infection and disease. Research suggests SARS-CoV-2 infection is linked to the function of multiple caspases, both mechanistically in vitro as well as in observational studies of individuals with severe COVID-19, which may further the impact on disease severity. We also highlight immunological mechanisms that occur in severe COVID-19 pathology upstream and downstream of activated caspase pathways, including innate recognition receptor signaling, inflammasomes, and other multiprotein complex assembly, inflammatory mediators IL-1β and IL-18, and apoptotic and pyroptotic cell death. Finally, we illuminate discriminate and indiscriminate caspase inhibitors that have been identified for clinical use that could emerge as potential therapeutic interventions that may benefit clinical efforts to prevent or ameliorate severe COVID-19., Competing Interests: Author OA was employed by company Amerimmune. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Premeaux, Yeung, Bukhari, Bowler, Alpan, Gupta and Ndhlovu.)

Background: COVID-19 can present with lymphopenia and extraordinary complex multiorgan pathologies that can trigger long-term sequela., Aims: Given that inflammasome products, like caspase-1, play a role in the pathophysiology of a number of co-morbid conditions, we investigated caspases across the spectrum of COVID-19 disease., Materials & Methods: We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. Non-COVID-19 subject presenting with various comorbid conditions served as controls., Results: Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in T cells, neutrophils, dendritic cells, and eosinophils compared with controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared with unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed upregulated caspase-1activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7levels in red blood cells from COVID-19 patients compared with controls that was reduced following caspase inhibition., Discussion: Our preliminary results suggest an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed., Conclusion: Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)