Self-assembly of rod-coil-rod block copolymers in a coil-selective solvent: coarse-grained simulation results.

The solution self-assembly of amphiphilic polymers provides a versatile approach to design novel nanostructured materials. Multiblock polymers, particularly those composed of liquid crystalline and coil blocks, are of significant interest due to the potential display of nematic ordering in liquid crystalline domains, offering intriguing optical and mechanical properties. In this study, dissipative particle dynamics is used to investigate the solution self-assembly of rod-coil-rod copolymers in a coil-selective solvent. Extensive molecular simulations were conducted to elucidate the impact of polymer composition, concentration and flexibility on the self-assembly behavior. A quantitative analysis was performed to investigate how polymer conformations varied with changes in composition, concentration, and rigidity. Simulation results show that, at small rod compositions, rod-coil-rod polymers self-assemble into micelles at low concentrations, transitioning to network formation as concentration increases. An increase in rod composition leads to the formation of larger aggregates, resulting in cylindrical micelles and membranes. The results reported here also offer insights into the role of flexibility in shaping the self-assembly behavior of rod-coil-rod triblocks in selective solvents, thus, contributing to a comprehensive understanding of the factors governing the formation of diverse structures in the solution self-assembly of triblock copolymers.

Cost-utility analysis of transitional care services for older inpatients with chronic obstructive pulmonary disease (COPD) in Korea.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with a high readmission rate and poses a significant disease burden. South Korea initiated pilot projects on transitional care services (TCS) to reduce readmissions. However, evidence from cost-effectiveness analyses remains undiscovered. This study aimed to evaluate the cost-effectiveness of TCS in patients with COPD from the healthcare system' perspective. METHOD: A cost-utility analysis was conducted using a Markov model containing six components of possible medical use after discharge. Transition probabilities and medical costs were extracted from the National Health Insurance Service Senior Cohort (NHIS-SC), and utility data were obtained from published literature. Sensitivity analyses were performed to test the robustness of the results. RESULTS: Conducting TCS produced an incremental quality-adjusted life years gain of 0.231, 0.275, 0.296 for those in their 60s, 70s, and 80s, respectively, and cost savings of $225.16, $1668, and $2251.64 for those in their 60s, 70s, and 80s, respectively, per patient over a 10-year time horizon. The deterministic sensitivity analysis indicated that the TCS cost and the cost of readmission by other diseases immensely impact the results. The probabilistic sensitivity analyses showed that the probability that the incremental cost-effectiveness ratio is below $23,050 was over 85%, 93%, and 97% for those in the 60s, 70s, and 80s, respectively. CONCLUSIONS: TCS was the dominant option compared to usual care. However, it is advantageous to the healthcare budget preferentially consider patients aged over 70 years with severe TCS symptoms. In addition, it is essential to include the management of underlying comorbidities in TCS intervention. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), KCT0007937. Registered on 24 November 2022.

Facilitating and barrier factors to the implementation of a transitional care program: a qualitative study of hospital coordinators in South Korea.

BACKGROUND: Transitional care is an integrated service to ensure coordination and continuity of patients' healthcare. Many models are being developed and implemented for this care. This study aims to identify the facilitators and obstacles of project performance through the experiences of the coordinator in charge of the Community Linkage Program for Discharge Patients (CLDP), a representative transitional care program in Korea. METHOD: Forty-one coordinators (nurses and social workers) from 21 hospitals were interviewed using a semi-structured questionnaire, and thematic analysis was performed. RESULT: Three themes were found as factors that facilitate or hinder CLDP: Formation and maintenance of cooperative relationships; Communication and information sharing system for patient care; and interaction among program, regional, and individual capabilities. These themes were similar regardless of the size of the hospitals. CONCLUSION: A well-implemented transitional care model requires a program to prevent duplication and form a cooperative relationship, common computing platform to share patient information between institutions, and institutional assistance to set long-term directions focused on patient needs and support coordinators' capabilities.

Serum CircNIPSNAP3A is Associated with Metabolic Disorders, Atherosclerosis and Severity of Coronary Artery Disease in a Chinese Population.

The relationships of serum circNIPSNAP3A and circHIPK3 with metabolic disorders, atherosclerosis and severity of coronary artery disease (CAD) remain to be clarified. Three hundred and thirty-eight subjects were categorized into normal coronary artery, atherosclerosis and CAD groups. Clinical data including anthropometric indexes, medical history, and physiological and biochemical parameters were collected. Serum circNIPSNAP3A and circHIPK3 were determined by quantitative real-time PCR. CAD severity was evaluated by clinical manifestation, electrocardiogram and coronary angiography. Both CAD and atherosclerosis groups had a higher serum level of circNIPSNAP3A than the normal coronary artery group (P < 0.05 for all). The subjects with a high percentage (> 66th percentile) of circNIPSNAP3A had higher mean levels of triglycerides, uric acid and homocysteine, and lower mean levels of high-density lipoprotein cholesterol and apolipoprotein AI than those with a low percentage (< 33rd percentile) of circNIPSNAP3A. Notably, circNIPSNAP3A is significantly and independently associated with CAD, and subjects with a high percentage of circNIPSNAP3A had more diseased coronary branches and a higher incidence of acute coronary syndrome than those with a low percentage of circNIPSNAP3A. Regarding circHIPK3, subjects with a medium or high percentage of circHIPK3 had a lower mean level of apolipoprotein AI than those with a low percentage of circHIPK3, but no significant differences in the incidence and severity of CAD among the < 33rd, 33rd-66th, and > 66th percentiles of circHIPK3 were detected. Serum circNIPSNAP3A is related to cardiovascular risk factors and CAD severity, and may be a potential prognostic marker and/or therapeutic target for CAD.

Vasomotion in human arteries and their regulations based on ion channel regulations: 10 years study.

Vasomotion is the oscillation of vascular tone which gives rise to flow motion of blood into an organ. As is well known, spontaneous contractile organs such as heart, GI, and genitourinary tract produce rhythmic contraction. It imposes or removes pressure on their vessels alternatively for exchange of many substances. It was first described over 150 years ago, however the physiological mechanism and pathophysiological implications are not well understood. This study aimed to elucidate underlying mechanisms and physiological function of vasomotion in human arteries. Conventional contractile force measurement, immunohistochemistry, and Western blot analysis were employed to study human left gastric artery (HLGA) and uterine arteries (HUA). RESULTS: Circular muscle of HLGA and/or HUA produced sustained tonic contraction by high K+ (50 mM) which was blocked by 2 µM nifedipine. Stepwise stretch and high K+ produced nerve-independent spontaneous contraction (vasomotion) (around 45% of tested tissues). Vasomotion was also produced by application of BayK 8644, 5-HT, prostagrandins, oxytocin. It was blocked by nifedipine (2 µM) and blockers of intracellular Ca2+ stores. Inhibitors of Ca2+ -activated Cl- channels (DIDS and/or niflumic acid) and ATP-sensitive K+ (KATP ) channels inhibited vasomotion reversibly. Metabolic inhibition by sodium cyanide (NaCN) and several neuropeptides also regulated vasomotion in KATP channel-sensitive and -insensitive manner. Finally, we identified TMEM16A Ca2+ -activated Cl- channels and subunits of KATP channels (Kir 6.1/6.2 and sulfonylurea receptor 2B [SUR2B]), and c-Kit positivity by Western blot analysis. We conclude that vasomotion is sensitive to TMEM16A Ca2+ -activated Cl- channels and metabolic changes in human gastric and uterine arteries. Vasomotion might play an important role in the regulation of microcirculation dynamics even in pacemaker-related autonomic contractile organs in humans.

A uniform conditioning regimen of busulfan, fludarabine, and antithymocyte globulin for allogeneic haematopoietic cell transplantation from haploidentical family, matched sibling, or unrelated donors-A single-centre, prospective, explorative study.

In a prospective, explorative study, the donor-source difference of haploidentical family (HF), matched sibling (MS), and unrelated donors (UD) was evaluated for the outcome of haematopoietic cell transplantations (HCT) in 101 patients with acute myeloid leukaemia (AML) in complete remission (CR). To eliminate compounding effects, a uniform conditioning regimen containing antithymocyte globulin (ATG) was used. After transplantation, there was a significantly higher cumulative incidence of acute graft-versus-host disease (GVHD) in HF-HCT patients (49%, 7%, and 16% for HF-, MS- and UD-HCT respectively; p < 0.001). A quarter of acute GVHD cases observed in HF-HCT patients occurred within three days of engraftment and were characterized by diffuse skin rash, fever, weight gain, and hypoalbuminaemia. This peri-engraftment acute GVHD was not observed in MS-HCT or UD-HCT patients. Additionally, a significantly higher proportion of HF-HCT patients achieved complete donor chimaerism in the peripheral mononuclear cells at one month (88%, 46%, and 69% for HF-, MS- and UD-HCT respectively; p = 0.001). There was no significant difference in engraftment, chronic GVHD, leukaemia recurrence, non-relapse mortality, and patient survival. In patients with AML in CR who received HCT using ATG-containing conditioning, stronger donor-patient alloreactivity was observed in HF-HCT, in terms of increased acute GVHD and higher likelihood of complete donor chimaerism.

BacMam Expressing Highly Glycosylated Porcine Interferon Alpha Induces Robust Antiviral and Adjuvant Effects against Foot-and-Mouth Disease Virus in Pigs.

Foot-and-mouth disease (FMD) is an acute contagious disease that affects cloven-hoofed animals and has severe global economic consequences. FMD is most commonly controlled by vaccination. Currently available commercial FMD vaccines contain chemically inactivated whole viruses, which are thought to be slow acting as they are effective only 4 to 7 days following vaccination. Hence, the development of a novel rapid vaccine or alternative measures, such as antiviral agents or the combination of vaccines and antiviral agents for prompt FMD virus (FMDV) outbreak containment, is desirable. Here, we constructed a recombinant baculovirus (BacMam) expressing consensus porcine interferon alpha (IFN-α) that has three additional N-glycosylation sites driven by a cytomegalovirus immediate early (CMV-IE) promoter (Bac-Con3N IFN-α) for protein expression in mammalian cells. Bac-Con3N IFN-α expressing highly glycosylated porcine IFN-α protein increased the duration of antiviral effects. We evaluated the antiviral effects of Bac-Con3N IFN-α in swine cells and mice and observed sustained antiviral effects in pig serum; additionally, Bac-Con3N IFN-α exhibited sustained antiviral effects in vivo as well as adjuvant effects in combination with an inactivated FMD vaccine. Pigs injected with a combination of Bac-Con3N IFN-α and the inactivated FMD vaccine were protected against FMDV at 1, 3, and 7 days postvaccination. Furthermore, we observed that in combination with the inactivated FMD vaccine, Bac-Con3N IFN-α increased neutralizing antibody levels in mice and pigs. Therefore, we suggest that Bac-Con3N IFN-α is a strong potential antiviral and adjuvant candidate for use in combination with inactivated FMD vaccines to protect pigs against FMDV. IMPORTANCE Early inhibition of foot-and-mouth disease (FMD) virus (FMDV) replication in pigs is highly desirable as FMDV transmission and shedding rates are higher in pigs than in cattle. However, commercial FMD vaccines require at least 4 to 7 days postvaccination (dpv) for protection, and animals are vulnerable to heterologous viruses before acquiring high antibody levels after the second vaccination. Therefore, the development of antiviral agents for use in combination with FMD vaccines is essential. We developed a novel antiviral and immunostimulant, Bac-Con3N IFN-α, which is a modified porcine IFN-α-expressing recombinant baculovirus, to improve IFN stability and allow its direct delivery to animals. We present a promising candidate for use in combination with inactivated FMD vaccines as pigs applied to the strategy had early protection against FMDV at 1 to 7 dpv, and their neutralizing antibody levels were higher than those in pigs administered the vaccine only.

Midbody plays an active role in fibroblast-myofibroblast transition by mediating TGF-ß signaling.

The transition of fibroblasts into myofibroblasts is a crucial step in kidney fibrosis. However, the biological processes involved in this transdifferentiation are incompletely understood. In this study, we discovered that the midbody plays a role in the fibroblast-myofibroblast transition by mediating TGF-ß/Smad signaling. Combining bulk RNA-seq, histology, and the western blot of unilateral ureteral obstruction kidneys, we demonstrated that the pathway related to microtubules is implicated in kidney fibrosis, and the blocking of microtubule dynamics by colchicine improved kidney fibrosis. Subsequently, to explore microtubule-based organelles in detail, we cultured NRK-49F (rat kidney fibroblast cell line) and HKC-8 (human proximal tubule cell line) under transforming growth factor-ß1 (TGF-ß1) stimulation, which caused deciliation in both cell lines during epithelial-mesenchymal and fibroblast-myofibroblast transition. We identified another microtubule-based organelle, the midbody, whose formation is promoted by TGF-ß1 in fibroblasts as a result of proliferation in contrast to tubular cells. Notably, TGF-ß receptors were present in the midbody of both cell lines. In TGF-ß1-treated fibroblasts, colchicine or Hedgehog pathway inhibitor 4 impaired the midbody formation, and attenuated the upregulation of canonical TGF-ß/Smad signaling and α-SMA expression. These findings offer novel insight into the midbody as an active organelle involved in fibroblast-myofibroblast transition by mediating TGF-ß/Smad signaling, which could be a potential therapeutic target.

Chain End-Functionalized Dense Polymer Brushes from an Inimer Coating by SI-RAFT.

Polymer brushes with controllable grafting density are grown on an inimer coating bearing Reversible Addition-Fragmentation Chain Transfer polymerization (RAFT) chain transfer agents (CTAs). The inimer coating is cross-linked on the substrate to provide an initiator layer that is stable during exposure to organic solvents at high temperatures. Surface-initiated RAFT is conducted to grow poly(2-vinylpyridine) (P2VP) brushes on the coating at grafting densities approaching the theoretical limits. This methodology allows facile end-group functionalization using an efficient thiol-ene click chemistry. Chain ends were functionalized with low surface energy groups to modulate the location of the untethered chain ends by thermal annealing. At lower grafting densities, the low surface energy groups segregate to the surface upon annealing. This effect is less pronounced at higher grafting densities. Detailed characterization of the brushes at varying grafting densities using X-ray photoelectron spectroscopy (XPS) is presented. In tandem with experiments, Monte Carlo simulations examine the effect of the chain-end group size and selectivity on the conformation of the polymer brush, providing numerical evidence of laterally non-uniform distributions of functional groups at different locations in the brush. Simulations further predict the existence of morphologies with an interlayer formed by spherical micelles rich in functional end groups, demonstrating the possibility of end-group functionalization for synthetic modulation of both brush conformation and chain-end location.

Formulation of chitosan microsphere-based oral vaccine against the scuticociliate parasite Miamiensis avidus: Evaluation of its protective immune potency in olive flounder (Paralichthys olivaceus).

Miamiensis avidus is a parasitic pathogen that causes scuticociliatosis, a severe and often lethal marine infection that affects marine fishes worldwide, including olive flounder (Paralichthys olivaceus) in Korea. This parasite infects all size groups of flounder year-round, causing recurring mortalities and huge economic losses to the Korean flounder industry each year. However, few efforts have been made to implement effective remedial measures to control this parasite. Therefore, our study sought to develop a chitosan microsphere (MS)-encapsulated inactivated vaccine (IMa + chitosan) for oral delivery (adsorbed in feed) to flounder fingerlings and assess its protective efficacy at different modalities via three in vivo experimental trials. Immunisation trial-1 was conducted to determine the effective concentration of chitosan. Our findings indicated that an IMa + chitosan 0.05 % vaccine formulation was safe and effective in providing moderate protection [46.67%-53.3 % relative percent survival (RPS)] against M. avidus intraperitoneal (IP) injection challenge at two weeks post-vaccination (wpv) compared to the IMa + chitosan 0.01 % and IMa + chitosan 0.005 % vaccines (0%-13.3 % RPS) irrespective of the antigen doses. In trial-2, the IMa + chitosan 0.05 % vaccine elicited similar protective immunity (30.8%-57.1 % RPS) in olive flounder against M. avidus at varying antigen doses (high: 2.38 × 106 cells/fish; low: 1.5 × 105 cells/fish), immunisation periods (2 and 5 wpv), and challenge modes (IP injection and immersion). Furthermore, experimental trial-3 validated the use of chitosan MS as an IMa antigen carrier to improve survivability (41.7 % RPS) in the host by significantly (p < 0.05) upregulating specific anti-M. avidus antibody titres in the fish sera and mucus of the group immunised with IMa-containing chitosan MS. In contrast, non-specific immunomodulatory effects (16.7 % RPS and enhanced mucosal antibody titres) were observed in the group treated with chitosan MS without IMa. Therefore, our findings suggested that oral administration of chitosan MS (0.05 %)-encapsulated IMa vaccine is a promising immunisation strategy against M. avidus that can protect the IMa antigen from digestive degradation, facilitates its targeted delivery to the host immune organs, and helps in orchestrating protective immune induction in olive flounder, thus controlling parasite infection.

Deep learning reconstruction in pediatric brain MRI: comparison of image quality with conventional T2-weighted MRI.

INTRODUCTION: Deep learning-based MRI reconstruction has recently been introduced to improve image quality. This study aimed to evaluate the performance of deep learning reconstruction in pediatric brain MRI. METHODS: A total of 107 consecutive children who underwent 3.0 T brain MRI were included in this study. T2-weighted brain MRI was reconstructed using the three different reconstruction modes: deep learning reconstruction, conventional reconstruction with an intensity filter, and original T2 image without a filter. Two pediatric radiologists independently evaluated the following image quality parameters of three reconstructed images on a 5-point scale: overall image quality, image noisiness, sharpness of gray-white matter differentiation, truncation artifact, motion artifact, cerebrospinal fluid and vascular pulsation artifacts, and lesion conspicuity. The subjective image quality parameters were compared among the three reconstruction modes. Quantitative analysis of the signal uniformity using the coefficient of variation was performed for each reconstruction. RESULTS: The overall image quality, noisiness, and gray-white matter sharpness were significantly better with deep learning reconstruction than with conventional or original reconstruction (all P < 0.001). Deep learning reconstruction had significantly fewer truncation artifacts than the other two reconstructions (all P < 0.001). Motion and pulsation artifacts showed no significant differences among the three reconstruction modes. For 36 lesions in 107 patients, lesion conspicuity was better with deep learning reconstruction than original reconstruction. Deep learning reconstruction showed lower signal variation compared to conventional and original reconstructions. CONCLUSION: Deep learning reconstruction can reduce noise and truncation artifacts and improve lesion conspicuity and overall image quality in pediatric T2-weighted brain MRI.

Exploring conformations of comb-like polymers with varying grafting density in dilute solutions.

Comb-like polymers have shown potential as advanced materials for a diverse palette of applications due to the tunability of their polymer architecture. To date, however, it still remains a challenge to understand how the conformational properties of these polymers arise from the interplay of their architectural parameters. In this work, extensive simulations were performed using dissipative particle dynamics to investigate the effect of grafting density, backbone length, and sidechain length on the conformations of comb-like polymers immersed in a good solvent. To quantify the effect of these architectural parameters on polymer conformations, we computed the asphericity, radius of gyration, and backbone and sidechain end-to-end distances. Bond-bond correlation functions and effective Kuhn lengths were computed to quantify the topological stiffness induced by sidechain-sidechain interactions. Simulation results reveal that the effective Kuhn length increases as grafting density and sidechain length increase, in agreement with previous experimental and theoretical studies. This increase in stiffness results in comb-like polymers adopting extended conformations as grafting density and sidechain length increase. Simulation results regarding the radius of gyration of comb-like polymers as a function of grafting density are compared with scaling theory predictions based on a free energy proposed by Morozova and Lodge [ACS Macro Lett. 6, 1274-1279 (2017)] and scaling arguments by Tang et al. [Macromolecules 55, 8668-8675 (2022)].

Mediation effect of pregnancy-induced hypertension on the association between assisted reproductive technology and adverse neonatal outcomes: a population-based study.

BACKGROUND: Assisted reproductive technology (ART) has been widely used in the treatment of infertility, and is associated with adverse maternal and neonatal outcomes. However, the potential pathways by which ART affects adverse neonatal outcomes are unclear. We aimed to investigate the role of pregnancy-induced hypertension (PIH) in the association between ART and adverse neonatal outcomes. METHODS: Adult women (aged ≥ 18 years) with a singleton pregnancy in the National Vital Statistics System (NVSS) 2020 were enrolled in this retrospective cohort study. Study outcomes were adverse neonatal outcomes, including premature birth, low birth weight, and admission to the neonatal intensive care unit (NICU). Logistic regression models were utilized to investigate the association between ART, PIH, and adverse neonatal outcomes, expressed as odds ratio (OR) and 95% confidence interval (CI). The distribution-of-the-product method was used to explore whether there was a mediating effect of PIH between ART and adverse neonatal outcomes, and the 95% CI of the distribution-of-the-product did not contain 0 indicating a mediating effect. RESULTS: This study included 2,824,418 women, of whom 35,020 (1.24%) women used ART, 239,588 (8.48%) women had PIH, and 424,741 (15.04%) neonates had any adverse neonatal outcomes. The use of ART was associated with higher odds of PIH (OR = 1.42; 95%CI: 1.37-1.46) and any adverse neonatal outcomes (OR = 1.47; 95%CI: 1.43-1.51). The distribution-of-the-product was 0.31 (95%CI: 0.28-0.34), and 8.51% of the association between ART and adverse neonatal outcomes was mediated through PIH. Among different adverse neonatal outcomes, PIH mediated 29.17% of the association between ART and low birth weight, 9.37% of the association between ART and premature birth, and 12.20% of the association between ART and NICU admission. The mediating effect of PIH was found in women of different ages (< 35 years and ≥ 35 years) and parities (primipara and multipara). CONCLUSION: This study supports a mediating role for PIH in the association between ART and adverse neonatal outcomes. Further studies are needed to determine the mechanisms by which AR affects PIH so that interventions to reduce PIH can be developed to reduce adverse neonatal outcomes associated with ART.

Ultra-low-dose computed tomography with deep learning reconstruction for craniosynostosis at radiation doses comparable to skull radiographs: a pilot study.

BACKGROUND: Craniofacial computed tomography (CT) is the diagnostic investigation of choice for craniosynostosis, but high radiation dose remains a concern. OBJECTIVE: To evaluate the image quality and diagnostic performance of an ultra-low-dose craniofacial CT protocol with deep learning reconstruction for diagnosis of craniosynostosis. MATERIALS AND METHODS: All children who underwent initial craniofacial CT for suspected craniosynostosis between September 2021 and September 2022 were included in the study. The ultra-low-dose craniofacial CT protocol using 70 kVp, model-based iterative reconstruction and deep learning reconstruction techniques was compared with a routine-dose craniofacial CT protocol. Quantitative analysis of the signal-to-noise ratio and noise was performed. The 3-dimensional (D) volume-rendered images were independently evaluated by two radiologists with regard to surface coarseness, step-off artifacts and overall image quality on a 5-point scale. Sutural patency was assessed for each of six sutures. Radiation dose was compared between the two protocols. RESULTS: Among 29 patients (15 routine-dose CT and 14 ultra-low-dose CT), 23 patients had craniosynostosis. The 3-D volume-rendered images of ultra-low-dose CT without deep learning showed decreased image quality compared to routine-dose CT. The 3-D volume-rendered images of ultra-low-dose CT with deep learning reconstruction showed higher noise level, higher surface coarseness but decreased step-off artifacts, comparable signal-to-noise ratio and overall similar image quality compared to the routine-dose CT images. Diagnostic performance for detecting craniosynostosis at the suture level showed no significant difference between ultra-low-dose CT without deep learning reconstruction, ultra-low-dose CT with deep learning reconstruction and routine-dose CT. The estimated effective radiation dose for the ultra-low-dose CT was 0.05 mSv (range, 0.03-0.06 mSv), a 95% reduction in dose over the routine-dose CT at 1.15 mSv (range, 0.54-1.74 mSv). This radiation dose is comparable to 4-view skull radiography (0.05-0.1 mSv) and lower than previously reported effective dose for craniosynostosis protocols (0.08-3.36 mSv). CONCLUSION: In this pilot study, an ultra-low-dose CT protocol using radiation doses at a level similar to skull radiographs showed preserved diagnostic performance for craniosynostosis, but decreased image quality compared to the routine-dose CT protocol. However, by combining the ultra-low-dose CT protocol with deep learning reconstruction, image quality was improved to a level comparable to the routine-dose CT protocol, without sacrificing diagnostic performance for craniosynostosis.

Ubiquitination Links DNA Damage and Repair Signaling to Cancer Metabolism.

Changes in the DNA damage response (DDR) and cellular metabolism are two important factors that allow cancer cells to proliferate. DDR is a set of events in which DNA damage is recognized, DNA repair factors are recruited to the site of damage, the lesion is repaired, and cellular responses associated with the damage are processed. In cancer, DDR is commonly dysregulated, and the enzymes associated with DDR are prone to changes in ubiquitination. Additionally, cellular metabolism, especially glycolysis, is upregulated in cancer cells, and enzymes in this metabolic pathway are modulated by ubiquitination. The ubiquitin-proteasome system (UPS), particularly E3 ligases, act as a bridge between cellular metabolism and DDR since they regulate the enzymes associated with the two processes. Hence, the E3 ligases with high substrate specificity are considered potential therapeutic targets for treating cancer. A number of small molecule inhibitors designed to target different components of the UPS have been developed, and several have been tested in clinical trials for human use. In this review, we discuss the role of ubiquitination on overall cellular metabolism and DDR and confirm the link between them through the E3 ligases NEDD4, APC/CCDH1, FBXW7, and Pellino1. In addition, we present an overview of the clinically important small molecule inhibitors and implications for their practical use.

Awareness, intentions and attitudes towards planned oocyte cryopreservation among female medical staff.

RESEARCH QUESTION: What are the awareness, intentions and attitudes of female medical staff towards planned oocyte cryopreservation? DESIGN: A cross-sectional survey was conducted during June 2019 among 171 female medical staff at a single tertiary hospital. The self-administered questionnaire consisted of 39 questions. RESULTS: A total of 151 responses (88%) were received from 13 doctors and 138 nurses. The mean age of the respondents was 26.4 years. Fewer than half of the women (47.7%) answered correctly on the age at which female fertility markedly declines. The study demonstrated that 28.5% of respondents considered themselves as 'potential freezers' while 30.5% would not consider the procedure. Potential freezers (58.1% versus 21.7%, P < 0.001) and older age participants (44.2% versus 28.4, P = 0.014) were more interested in consulting about fertility preservation during an obstetrician/gynaecologist (OB/GYN) visit. If respondents were to consider oocyte cryopreservation, they thought that lack of information would be a major obstacle to accepting the procedure (57.6%). Of the respondents, 85.3% believed that oocyte cryopreservation is a woman's right. A strong majority of respondents (96.0%) agreed or were neutral on the statement that all women have the right to receive education on fertility preservation during OB/GYN visits, but none had ever received medical education about fertility preservation, reflecting lack of access to fertility preservation care. CONCLUSIONS: This study indicated that there was widespread awareness about planned oocyte cryopreservation among female medical staff. The majority of participants considered planned oocyte cryopreservation as a woman's right. There appears to be a critical need for proper education about fertility preservation.

Multiple Cognitive and Behavioral Factors Link Association Between Brain Structure and Functional Impairment of Daily Instrumental Activities in Older Adults.

OBJECTIVE: Functional impairment in daily activity is a cornerstone in distinguishing the clinical progression of dementia. Multiple indicators based on neuroimaging and neuropsychological instruments are used to assess the levels of impairment and disease severity; however, it remains unclear how multivariate patterns of predictors uniquely predict the functional ability and how the relative importance of various predictors differs. METHOD: In this study, 881 older adults with subjective cognitive complaints, mild cognitive impairment (MCI), and dementia with Alzheimer's type completed brain structural magnetic resonance imaging (MRI), neuropsychological assessment, and a survey of instrumental activities of daily living (IADL). We utilized the partial least square (PLS) method to identify latent components that are predictive of IADL. RESULTS: The result showed distinct brain components (gray matter density of cerebellar, medial temporal, subcortical, limbic, and default network regions) and cognitive-behavioral components (general cognitive abilities, processing speed, and executive function, episodic memory, and neuropsychiatric symptoms) were predictive of IADL. Subsequent path analysis showed that the effect of brain structural components on IADL was largely mediated by cognitive and behavioral components. When comparing hierarchical regression models, the brain structural measures minimally added the explanatory power of cognitive and behavioral measures on IADL. CONCLUSION: Our finding suggests that cerebellar structure and orbitofrontal cortex, alongside with medial temporal lobe, play an important role in the maintenance of functional status in older adults with or without dementia. Moreover, the significance of brain structural volume affects real-life functional activities via disruptions in multiple cognitive and behavioral functions.

The Association between COMT Val158Met Polymorphism and the Post-Traumatic Stress Disorder Risk: A Meta-Analysis.

BACKGROUND: Genetic factors were suggested to have influence on the development of post-traumatic stress disorder (PTSD). The possible association between catechol-O-methyltransferase (COMT) Val158Met polymorphism and PTSD has been evaluated in several studies. But the results were still controversial. Therefore, we conduct this meta-analysis to address these issues. METHODS: The PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched for eligible studies. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to estimate the association between COMT Val158Met polymorphism and PTSD. RESULTS: Five articles including 6 studies with 893 cases and 968 controls were finally included in the present meta-analysis. The pooled analyses did not demonstrate a significant association between the COMT Val158Met polymorphism and PTSD in any of the selected genetic models: allele model (OR = 1.13, 95% CI: 0.97-1.31), dominant model (OR = 1.17, 95% CI: 0.93-1.46), recessive model (OR = 1.44, 95% CI: 0.78-2.66), and additive model (OR = 1.54, 95% CI: 0.85-2.80). Subgroup analyses suggested that the Hardy-Weinberg equilibrium status of genotype distributions could influence the relationship of COMT Val158Met polymorphism and PTSD. CONCLUSIONS: The present meta-analysis suggested that the COMT Val158Met polymorphism may not be associated with the PTSD risk. Further large-scale and population-representative studies are warranted to evaluate the impact of the COMT Val158Met polymorphism on the risk of PTSD.

Efficacy of Chitosan-PLGA encapsulated trivalent oral vaccine against viral haemorrhagic septicemia virus, Streptococcus parauberis, and Miamiensis avidus in olive flounder (Paralichthys olivaceus).

The present study was conducted to assess the protective efficacy of a trivalent oral vaccine containing chitosan-PLGA encapsulated inactivated viral haemorrhagic septicemia virus (VHSV), Streptococcus parauberis serotype I and Miamiensis avidus antigens, followed by its oral (incorporated in feed) administration to olive flounder (Paralichthys olivaceus) fingerlings for a period of 15-consecutive days. After 35 days of initial vaccination, three separate challenge studies were conducted at the optimal temperature of the targeted pathogens using an intraperitoneal injection route. RPS analysis revealed moderate protection in the immunized group against all the three pathogens viz., VHSV (53.30% RPS), S. parauberis serotype-I (33.30% RPS), and M. avidus (66.75% RPS), as compared to the respective non-vaccinated challenge (NVC) control group. In addition, the immunized fish demonstrated significantly (p < 0.05) higher specific antibody titres in serum and significant (p < 0.05) upregulation in the transcript levels of immune genes of Igs (IgM, IgT, pIgR), TLRs (TLR 2, TLR 7), cytokines (IL-1ß, IL-8) and complement pathway (C3) in the mucosal and systemic tissues than those of NVC control fish, suggesting orchestration of pathogen-specific host immune responses thereby favouring its combativeness against the three pathogens. The expression dynamics of IFN-γ, Mx, caspase 3 genes post VHSV challenge; IFN-γ, TLR 2, caspase 1 genes post S. parauberis serotype I challenge and CD-8α, IL-10, TNF-α genes post M. avidus challenge further substantiates the efficacy of the vaccine in stimulating antiviral, antibacterial and antiparasitic immune responses in the host resulting in their better survival. The findings from the present study reflect that the formulated trivalent oral vaccine incorporating VHSV, S. parauberis serotype I and M. avidus antigens can be a promising prophylactic strategy to prevent the associated disease outbreaks in olive flounder.

Intra-host diversity of drug-resistant cytomegalovirus: A case report of cytomegalovirus infection after allogeneic hematopoietic cell transplantation.

Cytomegalovirus (CMV) is a major infectious agent causing severe complications in allogeneic hematopoietic cell transplantation (HCT) recipients, thereby warranting the need for aggressive preemptive or targeted antiviral therapy. However, prolonged or repeated use of antiviral agents, such as ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV), can result in drug-resistant CMV infection, posing challenges to successful outcomes. Here, we report a case of a patient with acute myeloid leukemia and drug-resistant CMV infection who presented with persistent CMV DNAemia, colitis, pneumonia, and encephalitis. An intra-host diversity of UL97 and UL54 mutations were detected through the genotypic resistance testing conducted on two blood samples (D+199 and D+224) and a cerebrospinal fluid (CSF) specimen (D+260) collected from the patient. UL97 L595W/L595F and L595W mutations were detected in the blood and CSF samples, respectively, that conferred GCV resistance. UL54 F412L mutation detected in all three samples conferred GCV/CDV resistance. However, the V787L mutation of UL54, conferring GCV/FOS resistance, was observed only in the D+224 blood sample. Despite combination therapy with FOS and high dose GCV and adjunctive therapy with leflunomide, the patient died from CMV infection and multiple organ failure on D+279. Further data on resistant mutations and intra-host diversity of CMV should be accumulated to elucidate the antiviral resistance and related outcomes.