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Aim This retrospective study was conducted to assess the relationship between renal functional parameters and histolopathological findings in patients with renal amyloidosis. Methods A total of 40 patients with biopsy-proven renal amyloidosis, which was diagnosed at the Department of Pathology, Hanyang University Hospital, between 1986 and 2010, were investigated. Renal biopsy specimens were evaluated in various histochemical and immunohistochemical stains using light, immunofluorescence and electron microscopes, and renal function was determined by estimated glomerular filtration rate (eGFR) (ml/min/1.73m(2)) using the method proposed by the Modification of Diet in Renal Disease study. Glomerular amyloid deposits were classified into four groups: none, mild, segmental and diffuse types. The vascular, tubular and interstitial deposits were subdivided into the negative and positive groups. Results In simple regression analysis, 24-hour protein excretion, serum blood urea nitrogen and eGFR were found to significantly correlate with the increased extent of glomerular amyloid deposit. In multiple regression analysis, a decrease in eGFR was significantly associated with an increase in glomerular amyloid deposits (p=0.024), but there was no significant correlation with an increase in 24-hour protein excretion and blood urea nitrogen (p=0.119 and 0.184, respectively). Conclusion The results of this study demonstrate that the increased extent of glomerular amyloid deposits may be associated with the decline of GFR in patients with renal amyloidosis. [ABSTRACT FROM AUTHOR]

Electrochemical CO 2 reduction reaction (CO 2 RR) occurring at the electrode/electrolyte interface is sensitive to both the potential and concentration polarization. Compared to static electrolysis at a fixed potential, pulsed electrolysis with alternating anodic and cathodic potentials is an intriguing approach that not only reconstructs the surface structure, but also regulates the local pH and mass transport from the electrolyte side in the immediate vicinity of the cathode. Herein, via a combined online mass spectrometry investigation with sub-second temporal resolution and 1-dimensional diffusion profile simulations, we reveal that heightened surface CO 2 concentration promotes CO 2 RR over H 2 evolution for both polycrystalline Ag and Cu electrodes after anodic pulses. Moreover, mild oxidative pulses generate a roughened surface topology with under-coordinated Ag or Cu sites, delivering the best CO 2 -to-CO and CO 2 -to-C 2+ performance, respectively. Surface-enhanced infrared absorption spectroscopy elucidates the potential dependence of *CO and *OCHO species on Ag as well as the gradually improved *CO consumption rate over under-coordinated Cu after oxidative pulses, directly correlating apparent CO 2 RR selectivity with dynamic interfacial chemistry at the molecular level., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Neuroendocrine tumor (NET) is a rare malignant tumor, notably small cell lung cancer (SCLC), a type of lung neuroendocrine tumor, which has a survival rate of less than 7%. Although various biomarkers including CHGA (Chromogranin A), INSM1 (Insulinoma-associated protein 1), and SYP (Synaptophysin) are extensively used for the diagnostic testing of NET, their diverse specificities and sensitivities are acknowledged as limitations. Here, we demonstrate that RepID (Replication initiation determinant protein), a component of CRL4 (Cullin-RING ubiquitin E3 ligase 4), holds promise as a biomarker for identifying NET and SCLC. Analysis of the Cancer Cell Line Encyclopedia (CCLE) via the CellMinerCDB portal reveals a high correlation between RepID transcript levels and mRNA expression of NE signature genes. Additionally, RepID protein is highly expressed in SCLC patient tissues and a subset of SCLC cell lines. Viability analysis following treatment with pevonedistat and SZL-P1-41 in SCLC cell lines and human SCLC-organoid models indicates that RepID expression determines the sensitivity to CRL-targeting anti-cancer drugs. These findings suggest that RepID represents a novel biomarker for NET and SCLC, and insights from RepID research in these cancers could lead to innovative therapeutic strategies., Competing Interests: Declarations Competing interests The authors declare no competing interests. Consent for publication Not applicable., (© 2024. The Author(s).)

Parkinson's disease (PD) is a complex neurodegenerative disorder marked by the gradual deterioration of dopaminergic neurons, especially in the substantia nigra pars compacta (SNc). Dysregulation of the transcription factor FoxO1 is associated with various neurodegenerative conditions, including Alzheimer's disease and PD, though the specific mechanisms involved are not fully understood. This study explores the effects of α-Synuclein preformed fibrils (PFF) on BV-2 microglial cells, focusing on changes in molecular characteristics and their impact on neuronal degeneration. Our results demonstrate that PFF treatment significantly increases FoxO1 mRNA (p = 0.0443) and protein (p = 0.0216) levels, leading to its nuclear translocation (p = 0.0142) and enhanced expression of genes involved in the detoxification of reactive oxygen species (ROS), such as Catalase (Cat, p = 0.0249) and superoxide dismutase 2 (Sod2, p = 0.0313). Furthermore, we observed that PFF treatment elevates mitochondrial ROS levels. However, cells lacking FoxO1 or treated with FoxO1 inhibitors showed increased vulnerability to PFF-induced ROS, attributed to reduced expression of ROS detoxifying enzymes Cat and Sod2 (p < 0.0001). Besides enhancing ROS production, inhibiting FoxO1 also heightens neurotoxicity induced by PFF treatment in microglia-conditioned medium (p < 0.0001). Conversely, treatment with N-acetylcysteine or bacterial superoxide dismutase A mitigated the ROS increase induced by PFF (p < 0.0001). These findings suggest the essential role of FoxO1 in regulating ROS levels, which helps alleviate pathology in PFF-induced PD models. Our study provides insights into the genetic mechanisms of PD and suggests potential pathways for developing novel therapeutic strategies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To evaluate the usefulness of a cranial implantable chemoport, the H-port, as an alternative to the Ommaya reservoir for intraventricular chemotherapy/cerebrospinal fluid (CSF) access in patients with leptomeningeal metastasis (LM)., Methods: One hundred fifty-two consecutive patients with a diagnosis of LM and who underwent H-port installation between 2015 and 2021 were evaluated. Adverse events associated with installation and intraventricular chemotherapy, and the rate of increased intracranial pressure (ICP) control via the port were evaluated for safety and efficacy. These indices were compared with published data of Ommaya (n=89), from our institution., Results: Time-to-install and installation-related complications of intracranial hemorrhage (n=2) and catheter malposition (n=5) were not significantly different between the two groups. Intraventricular chemotherapy-related complications of CSF leakage occurred more frequently in the Ommaya than in the H-port group (13/89 vs. 3/152, respectively, p<0.001). Intracranial hemorrhage during chemotherapy occurred only in the Ommaya group (n=4). The CSF infection rate was not statistically different between groups (14/152 vs. 12/89, respectively). The ICP control rate according to reservoir type revealed a significantly higher ICP control rate with the H-port (40/67), compared with the Ommaya result (12/58, p<0.001). Analyzing the ICP control rate based on the CSF drainage method, continuous extraventricular drainage (implemented only with the H-port), found a significantly higher ICP control rate than with intermittent CSF drainage (33/40 vs. 6/56, respectively, p<0.0001)., Conclusion: The H-port for intraventricular chemotherapy in patients with LM was superior for ICP control; it had equal or lower complication rates than the Ommaya reservoir.

Background: GBA1 mutations are the most common genetic risk factor for development of Parkinson's disease (PD). The loss of catalytic activity in GBA1, as well as the reduction of the GBA1 protein in certain cellular compartment, may increase disease progression. However, the mechanisms underlying cellular dysfunction caused by GBA1 deficiency are still mostly unknown., Objective: In this study, we focus on the genetic interaction between GBA1 deficiency and PD-causing genes, such as DJ-1, in mitochondrial dysfunction., Methods: GBA1 knockout (KO) SH-SY5Y cells were used to assess DJ-1 functions against oxidative stress in vitro. The levels of cellular reactive oxygen species were monitored with MitoSOX reagent. The expression of the PARK7 gene was analyzed using the quantitative real-time PCR (qRT-PCR). To understand the mechanism underlying DJ-1 upregulation in GBA1 KO cells, we assess ROS levels, antioxidant protein, and cell viability in GBA1 KO cells with treatment of ROS inhibitor N-acetyl-cysteine or miglustat, which is an inhibitor of glucosylceramide synthase. Dopaminergic degeneration was assessed from Gba1 L444P heterozygous mice mated with Park7 knockout mice., Results: We find that DJ-1 is significantly upregulated in GBA1 KO cells. Elevated levels of DJ-1 are attributed to the transcriptional expression of PARK7 mRNA, but not the inhibition of DJ-1 protein degradation. Because DJ-1 expression is highly linked to oxidative stress, we observe cellular reactive oxygen species (ROS) in GBA1 KO cells. Moreover, several antioxidant gene expressions and protein levels are increased in GBA1 KO cells. To this end, GBA1 KO cells are more susceptible to H 2 O 2 -induced cell death. Importantly, there is a significant reduction in dopaminergic neurons in the midbrain from Gba1 L444P heterozygous mice mated with Park7 knockout mice, followed by mild motor dysfunction., Conclusion: Taken together, our results suggest that DJ-1 upregulation due to GBA1 deficiency has a protective role against oxidative stress. It may be supposed that mutations or malfunctions in the DJ-1 protein may have disadvantages in the survival of dopaminergic neurons in the brains of patients harboring GBA1 mutations., (© 2024. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Background/objectives: Obesity is a major cause of metabolic disorders; to prevent obesity, research is ongoing to develop natural and safe ingredients with few adverse effects. In this study, we determined the anti-obesity effects of Rosa multiflora root extract (KWFD-H01) in 3T3-L1 adipocytes and Sprague-Dawley (SD) rats., Materials/methods: The anti-obesity effects of KWFD-H01in 3T3-L1 adipocytes and SD rats were examined using various assays, including Oil Red O staining, gene expression analyses, protein expression analyses, and blood biochemical analyses., Results: KWFD-H01 reduced intracellular lipid accumulation and inhibited the mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ), cytidine-cytidine-adenosine-adenosine-thymidine (CCAAT)/enhancer binding proteins (C/EBPα), sterol regulatory element-binding transcription factor 1 (SREBP-1c), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) in 3T3-L1 cells. KWFD-H01 also reduced body weight, weight gain, and the levels of triglycerides, total and LDL-cholesterol, glucose, and leptin, while increasing high-density lipoprotein-cholesterol and adiponectin in SD rats. PPARγ, C/EBPα, SREBP-1c, ACC, and FAS protein expression was inhibited in the epididymal fat of SD rats., Conclusion: Overall, these results confirm the anti-obesity effects of KWFD-H01 in 3T3-L1 adipocytes and SD rats, indicating their potential as baseline data for developing functional health foods or pharmaceuticals to control obesity., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interests., (©2024 The Korean Nutrition Society and the Korean Society of Community Nutrition.)

Obesity is one of the major risk factors for metabolic diseases worldwide. This study examined the effects of YC-1102, an extract derived from the roots of Rosa multiflora , on 3T3-L1 preadipocytes and high-fat diet (HFD)-induced obese mice. In vivo experiments involved the oral administration of YC-1102 (100, 150, and 200 mg/kg body weight) daily to mice for eight weeks. YC-1102 was found to downregulate the expressions of PPARγ and C/EBPα during adipogenesis, inhibiting adipocyte differentiation and upregulating the expression of PGC-1α for energy metabolism to enhance mitochondrial biogenesis and fatty acid oxidation. It has been shown that daily administration of YC-1102 to mice receiving a HFD prevented an increase in body weight and the accumulation of body fat. YC-1102 administration also reduced TG, TC, and LDL cholesterol levels, as well as glucose and leptin levels, and increased adiponectin levels, thus effectively inhibiting the metabolism of lipids. YC-1102-treated mice showed significant reductions in the mRNA expression of PPARγ and C/EBPα . The levels of PGC-1α involved in energy metabolism increased significantly in the YC-1102-treated mice when compared to the HFD-treated mice. According to the findings of this study, YC-1102 has a dual mechanism that reduces transcription factors that promote the differentiation of adipocytes and increases transcription factors that promote energy consumption.

Background: The occurrence of delayed graft function (DGF) significantly enhances the possibility of both acute and chronic rejection of the transplanted organ, thereby reducing patient quality of life and survival rates. To prevent and manage oliguria in renal transplant patients, loop diuretics are presently commonly used. In our study, we assessed the possible impact of furosemide on the incidence of DGF among kidney transplant recipients., Methods: A review of medical records was conducted to examine demographic characteristics and kidney transplant outcomes in an adult (older than 18 years old) population. The primary objective was to determine the incidence of delayed graft function (DGF), whereas the secondary objective was to compare the creatinine levels and estimated glomerular filtration rate (eGFR) at day 30 and day 90 post-transplantation in patients who were administered furosemide vs those who were not., Results: This study included 330 patients who underwent kidney transplantation. Furosemide was administered to 169 (51.3%), whereas 161(48.7%) patients did not receive continued dose of diuretic postoperatively. The rate of DGF was significantly higher in patients who received furosemide than in those who did not (furosemide 44% vs 4%; P < .001). The eGFR was lower in the furosemide group compared to the no furosemide group at day 30 (56 ± 24 vs 71 ± 24 mL/min/1.73 m 2 , P < .001) and day 90 (66 ± 27 vs 78 ± 25 mL/min/1.73 m 2 , P < .001)., Conclusions: Our results show that there is no benefit in treating an oliguric AKI with furosemide. Administration of furosemide, especially in high doses, may increase the risk of toxicity, delay dialysis, and increase the length of stay., Competing Interests: Declaration of competing interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Few drug dosing recommendations for patients receiving home hemodialysis (HHD) have been published which has hindered the adoption of HHD. HHD regimens vary widely and differ considerably from conventional, thrice weekly, in-center hemodialysis in terms of treatment frequency, duration and blood and dialysate flow rates. Consequently, vancomycin and daptomycin clearances in HHD are also likely to be different, consequently HHD dosing regimens must be developed to ensure efficacy and minimize toxicity when these antibiotics are used. Many HHD regimens are used clinically, this study modeled ten common HHD regimens and determined optimal vancomycin and daptomycin dosing for each HHD regimen., Methods: Monte Carlo simulations using pharmacokinetic data derived from the literature and demographic data from a large HHD program treating patients with end stage kidney disease were incorporated into a one-compartment pharmacokinetic model. Virtual vancomycin and daptomycin doses were administered post-HHD and drug exposures were determined in 5,000 virtual patients receiving ten different HHD regimens. Serum concentration monitoring with subsequent dose changes was incorporated into the vancomycin models. Pharmacodynamic target attainment rates were determined for each studied dose. The lowest possible doses that met predefined targets in virtual patients were chosen as optimal doses., Results: HHD frequency, total dialysate volumes and HHD durations influenced drug exposure and led to different dosing regimens to meet targets. Antibiotic dosing regimens were identified that could meet targets for 3- and 7-h HHD regimens occurring every other day or 4-5 days/week. HHD regimens with 3-day interdialytic periods required higher doses prior to the 3-day period. The addition of vancomycin serum concentration monitoring allowed for calculation of necessary dosing changes which increased the number of virtual subjects meeting pharmacodynamic targets., Conclusions: Doses of vancomycin and daptomycin that will meet desired pharmacodynamic targets in HHD are dependent on patient and HHD-specific factors. Doses used in conventional thrice weekly hemodialysis are unlikely to meet treatment goals. The antibiotic regimens paired with the HHD parameters studied in this analysis are likely to meet goals but require clinical validation., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Megakaryocytes (MKs) are platelet precursors, which arise from hematopoietic stem cells (HSCs). While MK lineage commitment and differentiation are accompanied by changes in gene expression, many factors that modulate megakaryopoiesis remain to be uncovered. Replication initiation determinant protein (RepID) which has multiple histone-code reader including bromodomain, cryptic Tudor domain and WD40 domains and Cullin 4-RING E3 ubiquitin ligase complex (CRL4) recruited to chromatin mediated by RepID have potential roles in gene expression changes via epigenetic regulations. We aimed to investigate whether RepID-CRL4 participates in transcriptional changes required for MK differentiation., Methods: The PCR array was performed using cDNAs derived from RepID-proficient or RepID-deficient K562 erythroleukemia cell lines. Correlation between RepID and DAB2 expression was examined in the Cancer Cell Line Encyclopedia (CCLE) through the CellMinerCDB portal. The acceleration of MK differentiation in RepID-deficient K562 cells was determined by estimating cell sizes as well as counting multinucleated cells known as MK phenotypes, and by qRT-PCR analysis to validate transcripts of MK markers using phorbol 12-myristate 13-acetate (PMA)-mediated MK differentiation condition. Interaction between CRL4 and histone methylation modifying enzymes were investigated using BioGRID database, immunoprecipitation and proximity ligation assay. Alterations of expression and chromatin binding affinities of RepID, CRL4 and histone methylation modifying enzymes were investigated using subcellular fractionation followed by immunoblotting. RepID-CRL4-JARID1A-based epigenetic changes on DAB2 promoter were analyzed by chromatin-immunoprecipitation and qPCR analysis., Results: RepID-deficient K562 cells highly expressing MK markers showed accelerated MKs differentiation exhibiting increases in cell size, lobulated nuclei together with reaching maximum levels of MK marker expression earlier than RepID-proficient K562 cells. Recovery of WD40 domain-containing RepID constructs in RepID-deficient background repressed DAB2 expression. CRL4A formed complex with histone H3K4 demethylase JARID1A in soluble nucleus and loaded to the DAB2 promoter in a RepID-dependent manner during proliferation condition. RepID, CRL4A, and JARID1A were dissociated from the chromatin during MK differentiation, leading to euchromatinization of the DAB2 promoter., Conclusion: This study uncovered a role for the RepID-CRL4A-JARID1A pathway in the regulation of gene expression for MK differentiation, which can form the basis for the new therapeutic approaches to induce platelet production. Video Abstract., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Intravenous β-lactam antibiotics remain a cornerstone in the management of bacterial infections due to their broad spectrum of activity and excellent tolerability. β-lactams are well established to display time-dependent bactericidal activity, where reductions in bacterial burden are directly associated with the time that free drug concentrations remain above the minimum inhibitory concentration (MIC) of the pathogen during the dosing interval. In an effort to take advantage of these bactericidal characteristics, prolonged (extended and continuous) infusions (PIs) can be applied during the administration of intravenous β-lactams to increase time above the MIC. PI dosing regimens have been implemented worldwide, but implementation is inconsistent. We report consensus therapeutic recommendations for the use of PI β-lactams developed by an expert international panel with representation from clinical pharmacy and medicine. This consensus guideline provides recommendations regarding pharmacokinetic and pharmacodynamic targets, therapeutic drug-monitoring considerations, and the use of PI β-lactam therapy in the following patient populations: severely ill and nonseverely ill adult patients, pediatric patients, and obese patients. These recommendations provide the first consensus guidance for the use of β-lactam therapy administered as PIs and have been reviewed and endorsed by the American College of Clinical Pharmacy (ACCP), the British Society for Antimicrobial Chemotherapy (BSAC), the Cystic Fibrosis Foundation (CFF), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Diseases Society of America (IDSA), the Society of Critical Care Medicine (SCCM), and the Society of Infectious Diseases Pharmacists (SIDP)., (© 2023 The Authors. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

MB-102 is a novel fluorescent tracer agent that is exclusively removed from the body by glomerular filtration. This agent can be detected transdermally to provide a real-time measurement of glomerular filtration rate at the point-of-care and is currently in clinical studies for such. MB-102 clearance during continuous renal replacement therapy (CRRT) is unknown. Its plasma protein binding (~0%), molecular weight (~372 Da) and volume of distribution (15-20 L) suggest that it may be removed by renal replacement therapies. To determine the disposition of MB-102 during CRRT, an in vitro study assessing the transmembrane clearance (CL TM ) and adsorptive clearance of MB-102 was conducted. A validated in vitro bovine blood continuous hemofiltration (HF) and continuous hemodialysis (HD) models were performed using two types of hemodiafilters to evaluate CL TM of MB-102. For HF, three different ultrafiltration rates were evaluated. For HD, four different dialysate flow rates were evaluated. Urea was used as a control. No MB-102 adsorption to the CRRT apparatus or either of hemodiafilters was observed. MB-102 is readily removed by HF and HD. Dialysate and ultrafiltrate flow rates directly influence MB-102 CLTM. Hence MB-102 CLTM should be measurable for critically ill patients receiving CRRT., Competing Interests: Disclosure: The authors have no conflict of interest to report., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASAIO.)

The concept of truth is at the core of science, journalism, law, and many other pillars of modern society. Yet, given the imprecision of natural language, deciding what information should count as true is no easy task, even with access to the ground truth. How do people decide whether a given claim of fact qualifies as true or false? Across two studies (N = 1181; 16,248 observations), participants saw claims of fact alongside the ground truth about those claims. Participants classified each claim as true or false. Although participants knew precisely how accurate the claims were, participants classified claims as false more often when they judged the information source to be intending to deceive (versus inform) their audience, and classified claims as true more often when they judged the information source to be intending to provide an approximate (versus precise) account. These results suggest that, even if people have access to the same set of facts, they might disagree about the truth of claims if they attribute discrepant intentions to information sources. Such findings may shed light on the robust and persistent disagreements over claims of fact that have arisen in the "post-truth era"., (© 2023. The Author(s).)

Objective. Although pharmacists improve outcomes in the care of patients with kidney diseases and current guidelines advocate multidisciplinary care, pharmacist nephrology training is not well described. This study seeks to characterize required and elective coursework within US Doctor of Pharmacy curricula. This information will be valuable in identification and evaluation of educational gaps for pharmacists as best practices in the education and care of kidney diseases for pharmacists are established. Methods. This prospective, cross-sectional, descriptive study assessed current practices and trends in education on kidney diseases within Doctor of Pharmacy curricula at accredited programs in the United States through an electronic survey. Results. Forty-three percent (N=61) of all ACPE-accredited pharmacy institutions were represented in the survey. Content on kidney diseases was found to be taught in both required and elective coursework, and one-third of responding institutions offered advanced pharmacy practice experiences focused on kidney diseases. Variation was found in the amount of time allotted for the teaching of kidney diseases topics in pharmacy curricula and the types of experiential training offered. Six respondents reported offering postgraduate education that focused on kidney diseases. Most respondents were clinical faculty who had completed residency training and board certification. Conclusion. Given the complex interplay between kidney diseases and other health conditions, the increasing incidence and prevalence of kidney diseases, and the potential expansion of pharmacists' roles in the care of patients with kidney diseases, a review of current Doctor of Pharmacy curricula is necessary to guide any future optimization efforts to ensure practice-ready pharmacists., (© 2023 American Association of Colleges of Pharmacy.)

Human acetyltransferases MOZ and MORF are implicated in chromosomal translocations associated with aggressive leukemias. Oncogenic translocations involve the far amino terminus of MOZ/MORF, the function of which remains unclear. Here, we identified and characterized two structured winged helix (WH) domains, WH1 and WH2, in MORF and MOZ. WHs bind DNA in a cooperative manner, with WH1 specifically recognizing unmethylated CpG sequences. Structural and genomic analyses show that the DNA binding function of WHs targets MORF/MOZ to gene promoters, stimulating transcription and H3K23 acetylation, and WH1 recruits oncogenic fusions to HOXA genes that trigger leukemogenesis. Cryo-EM, NMR, mass spectrometry and mutagenesis studies provide mechanistic insight into the DNA-binding mechanism, which includes the association of WH1 with the CpG-containing linker DNA and binding of WH2 to the dyad of the nucleosome. The discovery of WHs in MORF and MOZ and their DNA binding functions could open an avenue in developing therapeutics to treat diseases associated with aberrant MOZ/MORF acetyltransferase activities., (© 2023. The Author(s).)

Cullin-RING E3 ubiquitin ligases (CRLs) spatiotemporally regulate the proteasomal degradation of numerous cellular proteins involved in cell cycle control, DNA replication, and maintenance of genome stability. Activation of CRLs is controlled via neddylation by NEDD8-activating, -conjugating, and -attaching enzymes to the C-terminus of scaffold cullins (CULs), whereas the COP9 signalosome (CSN) inactivates CRLs via deneddylation. Here, we show that the deneddylation rate of each CUL is differentially modulated. Dose- or time-dependent treatment with pevonedistat, a small molecule inhibitor of NEDD8-activating enzyme (NAE), rapidly inhibits neddylation in most CULs, including CUL1, CUL3, CUL4A/B, and CUL5, whereas the deneddylation of CUL2 is slowly increased. We revealed that the different deneddylation speeds of each CUL depend on its binding strength with CSN5, the catalytic core of the CSN complex. Immunoprecipitation analysis revealed that CUL2 has a lower binding affinity for CSN5 than other CULs. Consistently, released cells treated with CSN5 inhibitor showed that CUL2 was slowly converted to the deneddylated form compared to the rapid deneddylation of other CULs. These findings provide mechanistic insights into the different dynamics of CULs in neddylation-deneddylation conversion., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cullin-RING ubiquitin E3 ligase (CRLs) composed of four components including cullin scaffolds, adaptors, substrate receptors, and RING proteins mediates the ubiquitination of approximately 20% of cellular proteins that are involved in numerous biological processes. While CRLs deregulation contributes to the pathogenesis of many diseases, including cancer, how CRLs deregulation occurs is yet to be fully investigated. Here, we demonstrate that components of CRL3 and its transcriptional regulators are possible prognosis marker of neuroendocrine (NE) cancer. Analysis of Cancer Cell Line Encyclopedia (CCLE) through the CellMinerCDB portal revealed that expression of CRL3 scaffold Cullin 3 (CUL3) highly correlates with NE signature, and CUL3 silencing inhibited NE cancer proliferation. Moreover, subset of 151 BTB (Bric-a-brac, Tramtrack, Broad complex) domain-containing proteins that have dual roles as substrate receptors and adaptor subunits in CRL3, as well as the expression of transcription factors (TFs) that control the transcription of BTB genes were upregulated in NE cancer. Analysis using published ChIP-sequencing data in small cell lung cancer (SCLC), including NE or non-NE SCLC verified that gene promoter of candidates which show high correlation with NE signature enriched H3K27Ac. These observations suggest that CRL3 is a master regulator of NE cancer and knowledge of specifically regulated CRL3 genes in NE cancer may accelerate new therapeutic approaches., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The SARS-CoV-2 envelope (E) protein hijacks human BRD4 (bromodomain and extra-terminal domain protein 4). Here, we describe a protocol to characterize the interaction of the acetylated E protein with BRD4 in vivo. We detail steps to use NMR spectroscopy to map the binding interface and include steps to monitor the effect of BRD4 inhibitors in SARS-CoV-2-infected human lung bronchial epithelial cells. This approach could be applied to study interactions involving other viral and human proteins. For complete details on the use and execution of this protocol, please refer to Vann et al. (2022). 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Non-receptor tyrosine kinase, c-Abl plays a role in the pathogenesis of several neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Here, we found that TDP-43, which was one of the main proteins comprising pathological deposits in amyotrophic lateral sclerosis (ALS), is a novel substrate for c-Abl. The phosphorylation of tyrosine 43 of TDP-43 by c-Abl led to increased TDP-43 levels in the cytoplasm and increased the formation of G3BP1-positive stress granules in SH-SY5Y cells. The kinase-dead mutant of c-Abl had no effect on the cytoplasmic localization of TDP-43. The expression of phosphor-mimetic mutant Y43E of TDP-43 in primary cortical neurons accumulated the neurite granule. Furthermore, the phosphorylation of TDP-43 at tyrosine 43 by c-Abl promoted the aggregation of TDP-43 and increased neuronal cell death in primary cortical neurons, but not in c-Abl-deficient primary cortical neurons. Identification of c-Abl as the kinase of TDP43 provides new insight into the pathogenesis of ALS.

Introduction: The average body weight is smaller in Asian patients compared with Western patients, but influence of body weight in antibiotic dosing is unknown. This study was to predict the optimal ceftazidime, cefepime, meropenem, piperacillin/tazobactam doses in Asian patients undergoing continuous venovenous hemofiltration (CVVH)., Methods: Monte Carlo simulations (MCS) were performed using published Asian demographics and pharmacokinetics parameters in 5000 virtual patients at three CVVH effluent rates (Qeff; 20, 30, 40 mL/kg/h). Various dosing regimens were assessed for the probability of target attainments using 60% fT > 1 × MIC or 4xMIC and neurotoxicity risk at 48-h using suggested neurotoxicity thresholds., Results: Ceftazidime 1 g q12h, meropenem 1 g q12h, and piperacillin/tazobactam 3.375 g q6h were optimal for all Qeff settings against fT > 1 × MIC. Cefepime 2 g q24h and 2 g q12h were optimal at 20 and 30-40 mL/kg/h respectively. For the aggressive PD target (4 × MIC), optimal ceftazidime regimens were 1.25 g q8h (20-30 mL/kg/h) and 1.5 g q8h (40 mL/kg/h). Cefepime 2 g q8h and meropenem 1 g q8h were optimal at all Qeff settings. No simulated piperacillin doses attained the aggressive PD target. Increased neurotoxicity risk was predicted with ceftazidime and cefepime doses attaining the efficacy., Conclusion: MCS enabled the prediction of optimal β-lactam dosing regimens for Asian patients receiving CVVH at varying Qeff. Clinical validation is warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Upon the growing concern over a massive infodemic and politicization of health issues during the COVID-19 pandemic, this study investigated how individuals' use of partisan media and Trump briefings, along with other information sources, predicts risk preventive behaviors. Drawing on the Extended Parallel Process Model (EPPM), our survey analysis ( n = 1,106) revealed that those obtaining COVID-19 information from conservative media and Trump briefings were less likely to believe that COVID-19 is a serious threat (perceived threat) and that recommended preventive behaviors are effective and feasible (perceived efficacy). These beliefs, in turn, resulted in their decreased intentions to adopt risk preventative behaviors. In contrast, those who got COVID-19 information from liberal media, health organizations' briefings, and traditional media reported heightened threat and efficacy perception, which, in turn, led to their willingness to take risk preventive actions.

Much of the research on nursing informatics competence has been conducted in a Western context. Thus, this study aimed to develop the Korean Nursing Informatics Competence Assessment Scale for clinical nurses and to evaluate its validity and reliability. A total of 52 items were derived based on the hybrid model. After a content validity test by six experts and item evaluation by 20 nurses, the scale was revised to include 35 items. For this study, 214 nurses completed the nursing informatics competence assessment scale to verify the scale's reliability and validity. Confirmatory factor analysis revealed five factors composed of 20 items; the fit index of the derived model was good. A positive correlation between scores on the nursing informatics competence scale and the patient safety competence scale ( r = .66, P < .001) was found for the criterion-related validity test. Cronbach's α was .91, indicating that the instrument is reliable and stable. Overall, this study provides preliminary evidence for the validity and reliability of the Korean nursing informatics competence assessment scale to evaluate clinical nurses. This study contributes to the understanding and improvement of nursing informatics competence by providing a reliable scale for assessing clinical nursing practice., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Emerging new variants of SARS-CoV-2 and inevitable acquired drug resistance call for the continued search of new pharmacological targets to fight the potentially fatal infection. Here, we describe the mechanisms by which the E protein of SARS-CoV-2 hijacks the human transcriptional regulator BRD4. We found that SARS-CoV-2 E is acetylated in vivo and co-immunoprecipitates with BRD4 in human cells. Bromodomains (BDs) of BRD4 bind to the C-terminus of the E protein, acetylated by human acetyltransferase p300, whereas the ET domain of BRD4 recognizes the unmodified motif of the E protein. Inhibitors of BRD4 BDs, JQ1 or OTX015, decrease SARS-CoV-2 infectivity in lung bronchial epithelial cells, indicating that the acetyllysine binding function of BDs is necessary for the virus fitness and that BRD4 represents a potential anti-COVID-19 target. Our findings provide insight into molecular mechanisms that contribute to SARS-CoV-2 pathogenesis and shed light on a new strategy to block SARS-CoV-2 infection., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The duration and impact of the COVID-19 pandemic depends in a large part on individual and societal actions which is influenced by the quality and salience of the information to which they are exposed. Unfortunately, COVID-19 misinformation has proliferated. To date, no systematic efforts have been made to evaluate interventions that mitigate COVID-19-related misinformation. We plan to conduct a scoping review that seeks to fill several of the gaps in the current knowledge of interventions that mitigate COVID-19-related misinformation., Methods: A scoping review focusing on interventions that mitigate COVID-19 misinformation will be conducted. We will search (from January 2020 onwards) MEDLINE, EMBASE, CINAHL, PsycINFO, Web of Science Core Collection, Africa-Wide Information, Global Health, WHO Global Literature on Coronavirus Disease Database, WHO Global Index Medicus, and Sociological Abstracts. Gray literature will be identified using Disaster Lit, Google Scholar, Open Science Framework, governmental websites, and preprint servers (e.g., EuropePMC, PsyArXiv, MedRxiv, JMIR Preprints). Study selection will conform to Joanna Briggs Institute Reviewers' Manual 2020 Methodology for JBI Scoping Reviews. Only English language, original studies will be considered for inclusion. Two reviewers will independently screen all citations, full-text articles, and abstract data. A narrative summary of findings will be conducted. Data analysis will involve quantitative (e.g., frequencies) and qualitative (e.g., content and thematic analysis) methods., Discussion: Original research is urgently needed to design interventions to mitigate COVID-19 misinformation. The planned scoping review will help to address this gap., Systematic Review Registrations: Systematic Review Registration: Open Science Framework (osf/io/etw9d)., (© 2022. The Author(s).)

During routine genome duplication, many potential replication origins remain inactive or 'dormant'. Such origin dormancy is achieved, in part, by an interaction with the metabolic sensor SIRT1 deacetylase. We report here that dormant origins are a group of consistent, pre-determined genomic sequences that are distinguished from baseline (i.e. ordinarily active) origins by their preferential association with two phospho-isoforms of the helicase component MCM2. During normal unperturbed cell growth, baseline origins, but not dormant origins, associate with a form of MCM2 that is phosphorylated by DBF4-dependent kinase (DDK) on serine 139 (pS139-MCM2). This association facilitates the initiation of DNA replication from baseline origins. Concomitantly, SIRT1 inhibits Ataxia Telangiectasia and Rad3-related (ATR)-kinase-mediated phosphorylation of MCM2 on serine 108 (pS108-MCM2) by deacetylating the ATR-interacting protein DNA topoisomerase II binding protein 1 (TOPBP1), thereby preventing ATR recruitment to chromatin. In cells devoid of SIRT1 activity, or challenged by replication stress, this inhibition is circumvented, enabling ATR-mediated S108-MCM2 phosphorylation. In turn, pS108-MCM2 enables DDK-mediated phosphorylation on S139-MCM2 and facilitates replication initiation at dormant origins. These observations suggest that replication origin dormancy and activation are regulated by distinct post-translational MCM modifications that reflect a balance between SIRT1 activity and ATR signaling., (Published by Oxford University Press on behalf of Nucleic Acids Research 2022.)

One critical lesson learned from public opinion research about climate change is that the cost of politicization is disastrous. Although the literature has shown the dire consequences of politicized science issues, few have examined how such politicization is possibly triggered by political leaders in a seemingly nonpartisan science topic. Using two experiments (total n = 1,249), this article demonstrates how political cues over scientific expertise shape individuals' beliefs in the vaccine and autism debate. The results indicate that Republicans tend to follow President Trump compared to scientists in the subject matter. On the other hand, Democrats follow scientists but are not influenced by Trump. The implications of political encroachment into health and science are discussed.

What Is Known and Objective: Tertiary drug information resources are frequently consulted for the optimal antimicrobial dosing in intermittent hemodialysis (IHD) patients. Yet, significant discrepancy may exist in dosing recommendations between resources. This study was to evaluate the consistency of antimicrobial dosing recommendations in IHD among four different drug information resources and the relevance of referenced pharmacokinetic studies., Methods: Dosing recommendations of 29 commonly prescribed antimicrobials in IHD patients were collected from Micromedex, LexiComp, Clinical Pharmacology and Drug Prescribing in Renal Impairment to compare dosing categorization and the total daily dose (TDD). Significant dosing discrepancies were defined as ≥30% difference. Referenced pharmacokinetic studies were evaluated for their relevance in current practice, using sample size, hemodialyzer types, the use of optimal pharmacodynamic targets and the consideration of different interdialytic dosing periods., Results and Discussion: A significant variation was found both in dosing categorization and recommended doses between resources. Seventeen drugs were compared for TDD with significant dosing discrepancy in 8 drugs. Among 42 referenced pharmacokinetic studies, 40 were evaluated. Mean patient numbers of pharmacokinetic studies were 13 ranging from 3 to 70. Sixty per cent of studies utilized contemporary hemodialyzers (e.g., high-flux and/or high efficiency). The optimal pharmacodynamic targets and the impact of different interdialytic intervals were assessed only in 27.5% and 7.5% respectively., What Is New and Conclusion: Inconsistent antimicrobial dosing recommendations for IHD patients exist among four well-established resources. Many referenced pharmacokinetic studies utilized outdated or less pharmacodynamically relevant study methods. Newer studies are warranted to reflect contemporary dialysis practice and assess its impact on optimal antimicrobial dosing., (© 2021 John Wiley & Sons Ltd.)

Background: Open online forums like Reddit provide an opportunity to quantitatively examine COVID-19 vaccine perceptions early in the vaccine timeline. We examine COVID-19 misinformation on Reddit following vaccine scientific announcements, in the initial phases of the vaccine timeline., Methods: We collected all posts on Reddit (reddit.com) from January 1 2020 - December 14 2020 (n=266,840) that contained both COVID-19 and vaccine-related keywords. We used topic modeling to understand changes in word prevalence within topics after the release of vaccine trial data. Social network analysis was also conducted to determine the relationship between Reddit communities (subreddits) that shared COVID-19 vaccine posts, and the movement of posts between subreddits., Results: There was an association between a Pfizer press release reporting 90% efficacy and increased discussion on vaccine misinformation. We observed an association between Johnson and Johnson temporarily halting its vaccine trials and reduced misinformation. We found that information skeptical of vaccination was first posted in a subreddit (r/Coronavirus) which favored accurate information and then reposted in subreddits associated with antivaccine beliefs and conspiracy theories (e.g. conspiracy, NoNewNormal)., Conclusions: Our findings can inform the development of interventions where individuals determine the accuracy of vaccine information, and communications campaigns to improve COVID-19 vaccine perceptions, early in the vaccine timeline. Such efforts can increase individual- and population-level awareness of accurate and scientifically sound information regarding vaccines and thereby improve attitudes about vaccines, especially in the early phases of vaccine roll-out. Further research is needed to understand how social media can contribute to COVID-19 vaccination services., (© 2022. The Author(s).)

Background: Many inpatients become anxious or frightened about scheduled treatment processes, and medical staff do not have sufficient time to provide emotional support. The recent advancement of information and communications technology (ICT) and the use of artificial intelligence (AI), including robots, in the health care field is being put to the test., Objective: This study aimed to develop a bedside robot system to deliver information and provide emotional support to inpatients and to evaluate the usability and perceptions of the developed robot., Methods: The first stage was accomplished by deriving essential functions from the results of user demand surveys on robots and by implementing a prototype by mapping each essential function to the robot's hardware and software. For the second stage, the robot was assessed for usability and perceptions in a simulation center, a hospital-like environment, by 10 nurses, 10 inpatients, and family caregivers. Usability and perception were evaluated using the think-aloud method, a survey, and individual interviews., Results: Based on the usability evaluation, the perceived usefulness, ease of use, and satisfaction were 5.28 ± 1.27 points, 5.42 ± 1.55 points, and 5.27 ± 1.46 points out of 7, respectively. It was found that overall, the robot was positively perceived by participants. As a result of the qualitative data analysis, the participants perceived the robot as an object that had the positive effect of providing emotional support through communication., Conclusions: The bedside robot in this study, which incorporated human-robot interaction (HRI) technology, is an alternative suited to the new normal era that will contribute to ensuring that patients have more self-directed hospital stays as well as emotional support through information delivery and communication.

(1) Purpose of this study: To determine whether patient weight influences the probability of target attainment (PTA) over 72 h of initial therapy with beta-lactam (cefepime, ceftazidime, piperacillin/tazobactam) and carbapenem (imipenem, ertapenem, meropenem) antibiotics in the critical care setting. This is the first paper to address the question of whether patient size affects antibiotic PTA in the ICU. (2) Methods: We performed a post hoc analysis of Monte Carlo simulations conducted in virtual critically ill patients receiving antibiotics and continuous renal replacement therapy. The PTA was calculated for each antibiotic on the following pharmacodynamic (PD) targets: (a) were above the target organism's minimum inhibitory concentration (≥%fT≥1×MIC), (b) were above four times the MIC (≥%fT≥4×MIC), and (c) were always above the MIC (≥100%fT≥MIC) for the first 72 h of antibiotic therapy. The PTA was analyzed in patient weight quartiles [Q1 (lightest)-Q4 (heaviest)]. Optimal doses were defined as the lowest dose achieving ≥90% PTA. (3) Results: The PTA for fT≥1×MIC led to similarly high rates regardless of weight quartiles. Yet, patient weight influenced the PTA for higher PD targets (100%fT≥MIC and fT≥4×MIC) with commonly used beta-lactams and carbapenems. Reaching the optimal PTA was more difficult with a PD target of 100%fT≥MIC compared to fT≥4×MIC. (4) Conclusions: The Monte Carlo simulations showed patients in lower weight quartiles tended to achieve higher antibiotic pharmacodynamic target attainment compared to heavier patients.

Acute kidney injury (AKI) is a common complication in critically ill patients, which is associated with increased in-hospital mortality. Delivering effective antibiotics to treat patients with sepsis receiving continuous renal replacement therapy (RRT) is complicated by variability in pharmacokinetics, dialysis delivery, lack of primary literature, and therapeutic drug monitoring. Pharmacokinetic alterations include changes in absorption, distribution, protein binding (PB), metabolism, and renal elimination. Drug absorption may be significantly changed due to alterations in gastric pH, perfusion, gastrointestinal motility, and intestinal atrophy. Volume of distribution for hydrophilic drugs may be increased due to volume overload. Estimation of renal clearance is challenged by the effective delivery of RRT. Drug characteristics such as PB, volume of distribution, and molecular weight impact removal of the drug by RRT. The totality of these alterations leads to reduced exposure. Despite our best knowledge, therapeutic drug monitoring of patients receiving continuous RRT demonstrates wide variability in antimicrobial concentrations, highlighting the need for expanded monitoring of all drugs. This review article will focus on changes in drug pharmacokinetics in AKI and dosing considerations to attain antibiotic pharmacodynamic targets in critically ill patients receiving continuous RRT., (© 2021 Wiley Periodicals LLC.)

(1) Purpose of this study: determination of adsorption and transmembrane clearances (CL TM ) of imipenem and relebactam in ex vivo continuous hemofiltration (CH) and continuous hemodialysis (CHD) models. These clearances were incorporated into a Monte Carlo Simulation (MCS), to develop drug dosing recommendations for critically ill patients requiring continuous renal replacement therapy (CRRT); (2) Methods: A validated ex vivo bovine blood CH and CHD model using two hemodiafilters. Imipenem/relebactam and urea CL TM at different ultrafiltrate/dialysate flow rates were evaluated in both CH and CHD. MCS was performed to determine dose recommendations for patients receiving CRRT; (3) Results: Neither imipenem nor relebactam adsorbed to the CRRT apparatus. The CL TM of imipenem, relebactam, and urea approximated the effluent rates (ultrafiltrate/dialysate flow rates). The types of hemodiafilter and effluent rates did not influence CL TM except in a dialysis flow rate of 1 L/h and 6 L/h in the CHD with relebactam ( p < 0.05). Imipenem and relebactam 200 mg/100 mg every 6 h were sufficient to meet the standard time above the MIC pharmacodynamic targets in the modeled CRRT regimen of 25 kg/mL/h. (4) Conclusions: Imipenem and relebactam are not removed by adsorption to the CRRT apparatus, but readily cross the hemodiafilter membrane in CH and CHD. Dosage adjustment of imipenem/relebactam is likely required for critically ill patients receiving CRRT.

The cell cycle is modulated by ubiquitin ligases, including CRL4, which facilitate degradation of the chromatin-bound substrates involved in DNA replication and chromosome segregation. One of the members of the CRL4 complex, RepID (DCAF14/PHIP), recognizes kinetochore-localizing BUB3, known as the CRL4 substrate, and recruits CRL4 to the chromatin/chromosome using the WD40 domain. Here, we show that the RepID WD40 domain provides different platforms to CRL4 and BUB3. Deletion of the H-box or exon 8 located in the RepID WD40 domain compromises the interaction between RepID and CRL4, whereas BUB3 interacts with the exon 1-2 region. Moreover, deletion mutants of other exons in the WD40 domain lost chromatin binding affinity. Structure prediction revealed that the RepID WD40 domain has two beta-propeller folds, linked by loops, which are possibly crucial for chromatin binding. These findings provide mechanistic insights into the space occupancy of the RepID WD40 domain to form a complex with CRL4, BUB3, or chromatin., Competing Interests: Declaration of competing interest The authors have no potential conflict of interest to declare in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Angiotensin-converting enzyme inhibitors (ACEi) are frequently used antihypertensive medications with additional advantages such as reducing proteinuria and cardiovascular events. ACEi are commonly held at least 24 hours before a therapeutic plasma exchange (TPE) to reduce possibility of adverse events (AEs) including adverse drug reactions (ADR). The objective of this study was to determine if ACEi use increases the risk of ADR in patients receiving TPE with a conventional centrifuge-based apheresis system. This is a retrospective chart review study (n = 252; 52% male). Binary logistic regression was used to analyze the association of ACEi use and AEs. Of 171 patients who had AE during TPE, only 38 patients were taking ACEi. There was no significant association between ACEi use and AEs after adjustments (odds ratio = 0.885, 95% confidence interval: 0.468, 1.674). Our results suggest that risk of AEs is not higher in patients taking ACEi receiving TPE using a centrifuge-based machine. Randomized controlled prospective trials may be needed to further investigate this matter., (© 2020 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Deciphering how DCAFs (DDB1-CUL4 Associated Factors) modulate a broad spectrum of cellular processes, including cell cycle progression and maintenance of genomic integrity is critical to better understand cellular homeostasis and diseases. Cells contain more than 100 DCAFs that associate with the Cullin-Ring Ubiquitin Ligase 4 (CRL4) complex that target specific protein substrates for degradation. DCAFs are thought to act as substrate receptors that dictate the specificity of the ubiquitination machinery ("catalytic DCAFs"). However, recent studies have suggested that some DCAFs might play a different role by targeting CRL4 complexes to distinct cellular compartments ("structural DCAFs"). Once localized to their correct cellular domains, these CRLs dissociate from the structural DCAFs prior to their association with other, substrate-specific catalytic DCAFs. Thus, we propose that DCAF switches can provide a mechanistic basis for the degradation of proteins that regulate cell growth and proliferation at precise points in space and time., (© 2021 Wiley Periodicals LLC.)

Safeguards against excess DNA replication are often dysregulated in cancer, and driving cancer cells towards over-replication is a promising therapeutic strategy. We determined DNA synthesis patterns in cancer cells undergoing partial genome re-replication due to perturbed regulatory interactions (re-replicating cells). These cells exhibited slow replication, increased frequency of replication initiation events, and a skewed initiation pattern that preferentially reactivated early-replicating origins. Unlike in cells exposed to replication stress, which activated a novel group of hitherto unutilized (dormant) replication origins, the preferred re-replicating origins arose from the same pool of potential origins as those activated during normal growth. Mechanistically, the skewed initiation pattern reflected a disproportionate distribution of pre-replication complexes on distinct regions of licensed chromatin prior to replication. This distinct pattern suggests that circumventing the strong inhibitory interactions that normally prevent excess DNA synthesis can occur via at least two pathways, each activating a distinct set of replication origins.

Background: This study aimed to investigate the needs of medical users of telemedicine robots to encourage international cooperation and development. Introduction: As the use of telemedicine expands, it is necessary to develop new systems, including robots, which consider the perceived needs of end users to ensure quality of care and positive user experience. Materials and Methods: A survey of medical staff was conducted at a hospital in Vietnam to investigate users' needs for a telemedicine robot system. Results: A total of 117 medical staff participated in the survey, comprising 74 nurses and 43 doctors. The most preferred type of robot was the humanoid type, female version, and the preferred mobility type was walking. The most requested functions were "heart rate measurement," "recognition and avoidance of obstacles," "oxygen saturation measurement," "Transmitting Medical Information," and "wireless system." In addition, the most important considerations in developing a robot system were "cleaning the robot to prevent infection," followed by "convenience of operation." Discussion: The results of this study largely supported those of similar previous studies. However, some differences may reflect the cultural variation or differences in the level of medical development across contexts. Conclusion: To apply robotic systems to help develop telemedicine internationally, it is essential to develop a robot that reflects actual users' needs. If relevant matters such as legal issues are considered and addressed, an appropriate robotic telemedicine system can be successfully developed. Consequently, telemedicine can improve the quality of local medical care, strengthen practitioner capacity, and improve outcomes.