Diminished Neuronal ESCRT-0 Function Exacerbates AMPA Receptor Derangement and Accelerates Prion-Induced Neurodegeneration.

Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in exosomes, yet how prions impact proteostatic pathways is unclear. We found that prion-affected human and mouse brain showed a marked reduction in Hrs and STAM1 (ESCRT-0), which route ubiquitinated membrane proteins from early endosomes into MVBs. To determine how the reduction in ESCRT-0 impacts prion conversion and cellular toxicity in vivo, we prion-challenged conditional knockout mice (male and female) having Hrs deleted from neurons, astrocytes, or microglia. The neuronal, but not astrocytic or microglial, Hrs-depleted mice showed a shortened survival and an acceleration in synaptic derangements, including an accumulation of ubiquitinated proteins, deregulation of phosphorylated AMPA and metabotropic glutamate receptors, and profoundly altered synaptic structure, all of which occurred later in the prion-infected control mice. Finally, we found that neuronal Hrs (nHrs) depletion increased surface levels of the cellular prion protein, PrPC, which may contribute to the rapidly advancing disease through neurotoxic signaling. Taken together, the reduced Hrs in the prion-affected brain hampers ubiquitinated protein clearance at the synapse, exacerbates postsynaptic glutamate receptor deregulation, and accelerates neurodegeneration.SIGNIFICANCE STATEMENT Prion diseases are rapidly progressive neurodegenerative disorders characterized by prion aggregate spread through the central nervous system. Early disease features include ubiquitinated protein accumulation and synapse loss. Here, we investigate how prion aggregates alter ubiquitinated protein clearance pathways (ESCRT) in mouse and human prion-infected brain, discovering a marked reduction in Hrs. Using a prion-infection mouse model with neuronal Hrs (nHrs) depleted, we show that low neuronal Hrs is detrimental and markedly shortens survival time while accelerating synaptic derangements, including ubiquitinated protein accumulation, indicating that Hrs loss exacerbates prion disease progression. Additionally, Hrs depletion increases the surface distribution of prion protein (PrPC), linked to aggregate-induced neurotoxic signaling, suggesting that Hrs loss in prion disease accelerates disease through enhancing PrPC-mediated neurotoxic signaling.

Acute kidney injury in bortezomib-treated patients with multiple myeloma.

BACKGROUND: The nephrotoxicity of bortezomib, a proteasome inhibitor, has not yet been elucidated, although tumor lysis syndrome (TLS) associated with multiple myeloma (MM) has been reported to increase after introduction of the drug. This study compared the incidence and risk factors for acute kidney injury (AKI) and TLS in patients with MM after bortezomib-based chemotherapy to investigate drug-related nephrotoxicity. METHODS: From 2006 to 2017, 276 patients who underwent a first cycle of bortezomib-based chemotherapy for MM were identified in a single tertiary hospital. Laboratory TLS was defined according to the Cairo-Bishop definition. Development of AKI was assessed by AKI Network criteria within 7 days of the first chemotherapy. RESULTS: The median (interquartile range) age was 65 (56-72) years, and baseline estimated glomerular filtration rate (eGFR) was 61.3 (34.1-89.1) mL/min/1.73 m2. The incidences of AKI and laboratory TLS were 17% (n = 47) and 13% (n = 36), respectively. Ten (3.6%) subjects met both AKI and TLS criteria. Multivariate analyses showed that lower eGFR category [30-59, odds ratio (OR) 3.005 (95% confidence interval 1.163-7.976); 15-29, OR 4.225 (1.183-15.000); <15, OR 16.154 (3.831-70.920) vs ≥60, P < .001], lower serum albumin level [per 1 increase, OR 0.479 (0.256-0.871), P = .018], renal amyloidosis [OR 13.039 (4.108-44.041), P < .001] and use of acyclovir during bortezomib treatment [OR 3.689 (1.133-14.469), P = .042] were predictors of AKI. MM stages and ß-2-microglobulin were not associated with increased risk of AKI. Regarding laboratory TLS, MM stage and ß-2-microglobulin were higher in those with TLS than in others. In multivariate analyses, ß-2-microglobulin level [OR 1.204 (1.005-1.461), P = .038] and absence of high-risk chromosome abnormalities [OR 0.143 (0.022-0.588), P = .016] were associated with higher risk of TLS. CONCLUSIONS: Development of AKI was often observed in the absence of TLS in patients with MM after treatment with bortezomib. In addition, the risk factors for AKI and TLS varied widely. These findings indicate the potential nephrotoxicity of bortezomib irrespective of TLS in patients with decreased kidney function.

Asymmetric Synthesis of γ-Hydroxy Pinacolboronates through Copper-Catalyzed Enantioselective Hydroboration of α,ß-Unsaturated Aldehydes.

We report a copper-catalyzed enantioselective hydroboration of α,ß-unsaturated aldehydes with pinacolborane. α,ß-Unsaturated aldehydes were converted to the corresponding γ-pinacolboronate alcohols in good yields and enantioselectivities through consecutive hydroboration of the C═O and C═C bonds. This process provides simple access to the hydroborated product of allylic alcohols, and the resulting γ-pinacolboronate alcohols could be utilized in various transformations.

Copper-Catalyzed Enantioselective Hydroboration of Unactivated 1,1-Disubstituted Alkenes.

We report an efficient and highly enantioselective hydroboration of aliphatic 1,1-disubstituted alkenes with pinacolborane using a phosphine-Cu catalyst. The method allows facile preparation of enantiomerically enriched ß-chiral alkyl pinacolboronates from a range of 1,1-disubstituted alkenes with high enantioselectivity up to 99% ee. Unprecedented enantiodiscrimination between the geminal alkyl substituents was observed with functional group compatibility in the hydroboration. Furthermore, a catalyst loading as low as 1 mol % furnished the desired product without a decrease in yield or selectivity, demonstrating its efficiency in gram scale synthesis.

De novo hepatitis B virus infection after pediatric liver transplantations with hepatitis B core antibody-positive donors: a single-center 20-yr experience.

DNHB is common in countries with high prevalence of hepatitis B, and therefore, contracting hepatitis B after LT with HBcAb(+) grafts is a major concern. We studied DNHB in 247 children (aged <18 yr) who underwent LT from 1994 to 2013. Sixty-six of 247 recipients received HBcAb(+) donor grafts. The incidence of DNHB was 5.7% (14 of 247 children) and that in HBcAb(+) donor grafts was 19.7% (13 of 66 children). The incidence of DNHB without LAM prophylaxis was 31.3% (nine of 29 children), while that with prophylaxis was 10.8% (four of 37 children). LAM prophylaxis negatively correlated with DNHB by Cox regression analysis (p = 0.028, odds ratio = 0.258). Among 13 DNHB patients with HBcAb(+) donor grafts, eight recovered from DNHB and four showed the emergence of LAM resistance. There was no DNHB-related graft failure. This study showed that HBcAb(+) donor graft was associated with development of DNHB, and use of LAM prophylaxis decreased the incidence of DNHB with HBcAb(+) graft.

Improved outcomes in liver transplantation in children with acute liver failure.

OBJECTIVE: The aim of our study was to review the experiences of a living donor-dominant transplantation program for children with acute liver failure (ALF). METHODS: Data were derived from the retrospective chart review of 50 children with ALF in a major liver center in the Republic of Korea. RESULTS: A total of 50 children with ALF underwent 47 (94%) primary living donor liver transplantations and 3 (6%) cadaveric liver transplantations. The cumulative survival rates of the grafts at 1 and 5 years were 81.9% and 79.2%, respectively. The overall retransplantation rate was 12%. The cumulative survival rates of these patients at 1 and 5 years were all 87.9%. Most incidents of mortality followed the failure of the preceding graft. We observed no mortalities among donors. Based on multivariate analysis, children who had pretransplant thrombocytopenia or had to use the molecular adsorbent recycling system preoperatively were related to the graft loss. Age younger than 2 years and a hyperacute onset (within 7 days) of hepatic encephalopathy were associated with pretransplant thrombocytopenia. CONCLUSIONS: Living donor-dominant transplantation program in the present study demonstrates tolerable achievements in terms of clinical outcomes of recipients and donors; however, putative factors, such as pretransplant thrombocytopenia, seem to play unclear roles in a poor prognosis following transplantation.

Demineralized Dentin Matrix Incorporated with rhBMP-2 Composite Graft for Treating Medication-Related Osteonecrosis of the Jaw.

Medication-Related Osteonecrosis of the Jaw (MRONJ) is characterized by bone exposure in the oral and maxillofacial region for more than eight weeks in patients treated with anti-resorptive agents, immunosuppressants, or anti-angiogenic agents, without prior radiation therapy or metastatic disease to the jaws. Conservative treatments can control infection in mild cases, but surgical intervention is necessary for patients with severe symptoms. A 78-year-old female with a history of bisphosphonate treatment for osteoporosis presented with persistent pain, swelling, and malodor following implant placement in the upper right maxilla. SPECT/CT imaging revealed a high-risk hot spot in the right maxillary region. BIS-guided surgery using the Qray pen-C was performed, selectively removing red fluorescent bone tissue. The defect was grafted with HuBT incorporated with rhBMP-2. Postoperative follow-ups at 4, 7, and 14 months showed successful bone healing, transforming into a corticocancellous complex, and implant placement without MRONJ recurrence. Allogeneic demineralized dentin matrix (DDM) incorporated with rhBMP-2 demonstrates effective bone healing and implant placement following BIS-guided MRONJ surgery. This case supports the use of DDM/rhBMP-2 for tissue regeneration in MRONJ treatment, enabling successful prosthetic restoration without recurrence.

Determination of work function of graphene under a metal electrode and its role in contact resistance.

Although the work function of graphene under a given metal electrode is critical information for the realization of high-performance graphene-based electronic devices, relatively little relevant research has been carried out to date. In this work, the work function values of graphene under various metals are accurately measured for the first time through a detailed analysis of the capacitance-voltage (C-V) characteristics of a metal-graphene-oxide-semiconductor (MGOS) capacitor structure. In contrast to the high work function of exposed graphene of 4.89-5.16 eV, the work function of graphene under a metal electrode varies depending on the metal species. With a Cr/Au or Ni contact, the work function of graphene is pinned to that of the contacted metal, whereas with a Pd or Au contact the work function assumes a value of ∼4.62 eV regardless of the work function of the contact metal. A study of the gate voltage dependence on the contact resistance shows that the latter case provides lower contact resistance.

Codon Pair Deoptimization (CPD)-Attenuated PRRSV-1 Vaccination Exhibit Immunity to Virulent PRRSV Challenge in Pigs.

Commercially used porcine respiratory and reproductive syndrome (PRRS) modified live virus (MLV) vaccines provide limited protection with heterologous viruses, can revert back to a virulent form and they tend to recombine with circulating wild-type strains. Codon pair deoptimization (CPD) is an advanced method to attenuate a virus that overcomes the disadvantages of MLV vaccines and is effective in various virus vaccine models. The CPD vaccine against PRRSV-2 was successfully tested in our previous study. The co-existence of PRRSV-1 and -2 in the same herd demands protective immunity against both viruses. In this study, live attenuated PRRSV-1 was constructed by recoding 22 base pairs in the ORF7 gene of the E38 strain. The efficacy and safety of the CPD live attenuated vaccine E38-ORF7 CPD to protect against virulent PRRSV-1 were evaluated. Viral load, and respiratory and lung lesion scores were significantly reduced in animals vaccinated with E38-ORF7 CPD. Vaccinated animals were seropositive by 14 days post-vaccination with an increased level of interferon-γ secreting cells. In conclusion, the codon-pair-deoptimized vaccine was easily attenuated and displayed protective immunity against virulent heterologous PRRSV-1.

Evaluation and Determination of a Suitable Passage Number of Codon Pair Deoptimized PRRSV-1 Vaccine Candidate in Pigs.

Porcine reproductive and respiratory syndrome virus (PRRSV) is major economic problem given its effects on swine health and productivity. Therefore, we evaluated the genetic stability of a codon pair de-optimized (CPD) PRRSV, E38-ORF7 CPD, as well as the master seed passage threshold that elicited an effective immune response in pigs against heterologous virus challenge. The genetic stability and immune response of every 10th passage (out of 40) of E38-ORF7 CPD was analyzed through whole genome sequencing and inoculation in 3-week-old pigs. E38-ORF7 CPD passages were limited to 20 based on the full-length mutation analysis and animal test results. After 20 passages, the virus could not induce antibodies to provide effective immunity and mutations accumulated in the gene, which differed from the CPD gene, presenting a reason for low infectivity. Conclusively, the optimal passage number of E38-ORF7 CPD is 20. As a vaccine, this may help overcome the highly diverse PRRSV infection with substantially enhanced genetic stability.

Molecular Characterization of Porcine Reproductive and Respiratory Syndrome Virus in Korea from 2018 to 2022.

Porcine reproductive and respiratory syndrome (PRRS) is an endemic disease in the Republic of Korea. Surveillance of PRRS virus (PRRSV) types is critical to tailor control measures. This study collected 5062 serum and tissue samples between 2018 and 2022. Open reading frame 5 (ORF5) sequences suggest that subgroup A (42%) was predominant, followed by lineage 1 (21%), lineage 5 (14%), lineage Korea C (LKC) (9%), lineage Korea B (LKB) (6%), and subtype 1C (5%). Highly virulent lineages 1 (NADC30/34/MN184) and 8 were also detected. These viruses typically mutate or recombine with other viruses. ORF5 and non-structural protein 2 (NSP2) deletion patterns were less variable in the PRRSV-1. Several strains belonging to PRRSV-2 showed differences in NSP2 deletion and ORF5 sequences. Similar vaccine-like isolates to the PRRSV-1 subtype 1C and PRRSV-2 lineage 5 were also found. The virus is evolving independently in the field and has eluded vaccine protection. The current vaccine that is used in Korea offers only modest or limited heterologous protection. Ongoing surveillance to identify the current virus strain in circulation is necessary to design a vaccine. A systemic immunization program with region-specific vaccinations and stringent biosecurity measures is required to reduce PRRSV infections in the Republic of Korea.

Graphene gate electrode for MOS structure-based electronic devices.

We demonstrate that the use of a monolayer graphene as a gate electrode on top of a high-κ gate dielectric eliminates mechanical-stress-induced-gate dielectric degradation, resulting in a quantum leap of gate dielectric reliability. The high work function of hole-doped graphene also helps reduce the quantum mechanical tunneling current from the gate electrode. This concept is applied to nonvolatile Flash memory devices, whose performance is critically affected by the quality of the gate dielectric. Charge-trap flash (CTF) memory with a graphene gate electrode shows superior data retention and program/erase performance that current CTF devices cannot achieve. The findings of this study can lead to new applications of graphene, not only for Flash memory devices but also for other high-performance and mass-producible electronic devices based on MOS structure which is the mainstream of the electronic device industry.

Investigation of interaction between graphene and dielectrics.

The properties of micromechanically exfoliated graphene on different oxide dielectrics--SiO(2), Al(2)O(3), and HfO(2)--are investigated by Raman spectroscopy and AFM measurement. The pristine graphene has stronger adhesion and a higher hole concentration when the dielectric constant of the underlying oxide is higher. It is found that annealing under a high vacuum significantly enhances the adhesion between graphene and the oxides and causes a shift of the Raman G and 2D bands to a higher wavelength. The high vacuum annealing also causes an increase in carrier concentration of up to ten times with a corresponding Fermi level shift of approximately 0.65 eV for graphene on HfO(2). On the other hand, the high vacuum annealing of graphene on SiO(2) induces a biaxial compressive stress as high as 4 GPa on graphene. The results provide understanding on the interaction of graphene and oxides, which is essential for successful realization of graphene-based electronic devices.

Characteristics and trends in the incidence of inflammatory bowel disease in Korean children: a single-center experience.

BACKGROUND: Inflammatory bowel disease (IBD) is rare in Asian children and few reports on pediatric IBD have appeared. AIMS: We, therefore, investigated the incidence trends and clinical characteristics of pediatric IBD in Korea. METHODS: We enrolled 48 children with Crohn's disease (CD) and 14 children with ulcerative colitis (UC) from 1996 to 2007. Trends in annual enrollment and clinical characteristics were retrospectively evaluated by medical record review. RESULTS: During the 12 years of observation, the number of new enrollments gradually increased. CD showed male predominance (33 boys, 15 girls), but more females presented with UC (4 boys, 10 girls). A relevant family history was observed in 3 (4.9%) of the 61 unrelated families. The most common presenting symptom was abdominal pain (67%) in CD and hematochezia (93%) in UC. Growth delay was observed in 10% of CD patients, but not in any of the UC patients. In CD, colonic involvement occurred in 87% of patients, ileal involvement in 87%, and both the small bowel and colon were affected in 75%. With UC, pancolitis occurred in 43% of patients, left-sided colitis in 36%, and proctitis in 21%, including all three patients with appendiceal orifice inflammation. The most frequent disease behavior was inflammatory in 85% of patients, but perianal fistula was noted in 50% of CD patients. CONCLUSION: This study showed that the incidence of pediatric IBD has been rapidly increasing in Korea in recent years. Relevant family history is less prevalent and phenotypic expression differs from what is seen in Western countries.

The Mediating Effect of Childcare Teachers' Resilience on the Relationship between Social Support in the Workplace and Their Self-Care.

(1) Background: The purpose of this study is to examine the relationship between social support in the workplace for childcare teachers, resilience, and self-care. This study explores the inner mechanism that helps to strengthen self-care of childcare teachers, which enables teachers to provide quality care to children and promote their own wellbeing. (2) Methods: The survey was conducted from September to October 2018 for childcare teachers in Seoul and Gyeonggi Province using convenience sampling. Out of 550 questionnaires, 491 were returned, with 466 used for the analysis, excluding those with incomplete responses. The collected data were analyzed using descriptive statistics, correlation analysis, and mediation analysis. (3) Results: There were significant correlations between all variables. The mediation analysis showed a complete mediation of resilience. (4) Conclusion: Childcare teachers first have to take good care of themselves in order to perform well as a childcare professional. Educational materials and counseling programs tailored for childcare teachers need to be developed for better self-care and building greater resilience. Materials for directors of daycare centers, as well as teachers stressing the importance of social support for each other, will help childcare teachers' effective functioning in their professional and personal life. Prevention and intervention programs for self-care will eventually help lower the costs of healthcare in society.

Early decongestive therapy versus high-flow nasal cannula for the prevention of adverse clinical events in patients with acute cardiogenic pulmonary edema.

BACKGROUND: Few studies have investigated the role of decongestive therapy and high-flow nasal cannula (HFNC) in preventing reintubation and in-hospital mortality in patients with acute cardiogenic pulmonary edema (ACPE). METHODS: Data from patients with ACPE who were weaned from mechanical ventilation in the cardiac intensive care unit between January 2013 and December 2017 were retrospectively evaluated. All patients were treated with HFNC or conventional oxygen therapy (COT), such as a nasal cannula or venturi mask, immediately after extubation. Decongestive therapy (intravenous furosemide infusion) was administered at the discretion of the attending physician. RESULTS: Of 212 patients treated during the study period, 47 were excluded due to recent open-heart surgery and two, due to insufficient clinical data. The remaining 163 patients had a mean age of 67.4±14.3 years, and 92 (56.4%) were male; 44 patients received HFNC, and 119 COT. Mean weight loss within 72 hours of extubation was -0.86±2.03 kg. A total of 38 patients (23.3%) required reintubation, 21 of whom (12.9%) required reintubation within 72 hours of extubation. In-hospital mortality occurred in 16 patients (9.8%). Multivariate analysis showed that weight increase within 72 hours of extubation was independent determinants of reintubation (OR =1.7; 95% CI: 1.2-2.2; P<0.001) and in-hospital mortality (OR =1.5; 95% CI: 1.1-2.1; P=0.005). The use of HFNC was not associated with reintubation or in-hospital mortality. CONCLUSIONS: Our findings indicate that early weight loss resulted in reduced reintubation and in-hospital mortality in patients with ACPE. However, HFNC and COT did not differ in the prevention of reintubation and in-hospital mortality. Therefore, aggressive decongestive therapy, rather than HFNC, should be considered early after extubation.

Improved Drain Current Saturation and Voltage Gain in Graphene-on-Silicon Field Effect Transistors.

Graphene devices for radio frequency (RF) applications are of great interest due to their excellent carrier mobility and saturation velocity. However, the insufficient current saturation in graphene field effect transistors (FETs) is a barrier preventing enhancements of the maximum oscillation frequency and voltage gain, both of which should be improved for RF transistors. Achieving a high output resistance is therefore a crucial step for graphene to be utilized in RF applications. In the present study, we report high output resistances and voltage gains in graphene-on-silicon (GoS) FETs. This is achieved by utilizing bare silicon as a supporting substrate without an insulating layer under the graphene. The GoSFETs exhibit a maximum output resistance of 2.5 MΩ∙µm, maximum intrinsic voltage gain of 28 dB, and maximum voltage gain of 9 dB. This method opens a new route to overcome the limitations of conventional graphene-on-insulator (GoI) FETs and subsequently brings graphene electronics closer to practical usage.

Nutritional status and growth in Korean children with Crohn's disease: a single-center study.

BACKGROUND/AIMS: Malnutrition and growth retardation are important issues in treating pediatric Crohn's disease (CD). Thus, we aimed to investigate the prevalence of various nutritional and growth parameters at the time of diagnosis in Korean children with CD. METHODS: Seventy-one children (<18 years) were enrolled. We analyzed the Z-scores of height-for-age (HAZ), weight-for-height (WHZ), body mass index for age (BMIZ), bone mineral density for age (BMDZ), and the biochemical markers measured at the time of diagnosis. RESULTS: At diagnosis, HAZ <-2 was observed in three patients (4%), WHZ <-2 in 20 patients (28%), BMIZ <-2 in 19 patients (27%), and BMDZ <-2 in 11 patients (18%). The HAZ was significantly lower in females and patients with extraintestinal manifestations, and the WHZ and BMIZ were significantly lower in patients with stricturing and penetrating disease. Subnormal serum levels were highly prevalent for hemoglobin, albumin, iron, ferritin, calcium, magnesium, folate, vitamin B12, and zinc. There was a significant correlation between nutritional status, growth retardation, and disease activity. CONCLUSIONS: Abnormal nutritional status was highly prevalent in Korean children with CD at the time of diagnosis and was associated with the extent, behavior, and activity of the disease.

Liver transplantation in a child with acute liver failure resulting from drug rash with eosinophilia and systemic symptoms syndrome.

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is characterized by a severe idiosyncratic reaction including rash and fever, often with associated hepatitis, arthralgias, lymph node enlargement, or hematologic abnormalities. The mortality rate is approximately 10%, primarily owing to liver failure with massive or multiple disseminated focal necrosis. Here, we report a case of a 14-year-old girl treated with vancomycin because of a wound infection by methicillin-resistant Staphylococcus aureus, who presented with non-specific symptoms, which progressed to acute liver failure, displaying the hallmarks of DRESS syndrome. With the presence of aggravated hepatic encephalopathy and azotemia, the patient was refractory to medical treatments, she received a living-donor liver transplantation, and a cure was achieved without any sign of recurrence. Vancomycin can be a cause of DRESS syndrome. A high index of suspicion and rapid diagnosis are necessary not to miss this potentially lethal disease.