Objective Obesity is known to be associated with cardiovascular compromise and is a major risk factor for the development of hypertensive disorders in pregnancy. The aim of this study was to investigate the effect of obesity on the maternal cardiovascular system. Design This was a prospective, observational, longitudinal study. Setting A tertiary centre in London Population Pregnant women with booking body mass index (BMI) ≥ 30kg/m2 (n=64) were compared to pregnant women with normal booking BMI (20-24.9kg/m2) (n=14). Methods Two-dimensional trans-thoracic echocardiography. Main outcomes Longitudinal difference in blood pressure, cardiac geometry and cardiac function between the groups. Results In women with obesity, the blood pressure, heart rate and cardiac output were higher and peripheral vascular resistance was lower (p<0.01 for all) compared to normal BMI women. Women with obesity had altered cardiac geometry with higher left ventricular end diastolic diameter, relative wall thickness and left ventricular mass (p<0.001 for all comparisons). There was also evidence of impaired diastolic indices in the obese group with lower E/A ratio, TDI E’ lateral and medial and higher left atrial volume (p<0.01 for all). Finally, women with obesity had reduced longitudinal function between the second and third trimester of pregnancy indicating possible early cardiac dysfunction in this group. Conclusions Obesity is associated with maternal hyperdynamic circulation, altered cardiac geometry and suboptimal diastolic function compared to normal BMI pregnant women; this may contribute to the increased risk of complications in obese pregnant women. Funding UK charities: Borne and CW+

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Background: In developed countries, retinoblastoma is curable in more than 95% of cases, whereas in low-income countries, mortality remains high, especially when the diagnosis is made late or the treatment is discontinued. The aim of this work was to determine the factors associated with adherence to the treatment of retinoblastoma in the Ivory Coast and the Democratic Republic of Congo (DRC). Procedure: A retrospective cohort study was carried out. Data were collected from patient folders and follow-up records of parents. Results: A total of 175 children with retinoblastoma were registered from January 2013 to December 2015. Seventy-six children (43%) were 5 years old and above. Care costs were covered by families in 86.9% of cases. Chemotherapy refusal was recorded in 39 cases (22.3%), and enucleation refusal was recorded in 79 cases (45.1%). After 36 months of follow-up, we recorded 16.6% deaths, 27.4% treatment dropouts, and 18.3% loss to follow-up after treatment. The commonest cause for enucleation refusal was fear of infirmity, while chemotherapy refusal and absconding treatment were due to financial constraints. Conclusion: Poor adherence to retinoblastoma management was due to financial constraints, and a lack of knowledge of the disease and its treatment. Family psychosocial support is needed to improve this condition.

Background and Purpose Vancomycin is one of the most common antibiotics administered in the hospital setting, yet acute kidney injury is a major limiting factor. Common combinations of antibiotics with vancomycin have been reported to worsen and improve vancomycin-induced kidney injury. We aimed to study the impact of flucloxacillin and imipenem-cilastatin on kidney injury when combined with vancomycin in our translational rat model. Experimental Approach Male Sprague-Dawley rats received allometrically scaled (1) vancomycin (2) flucloxacillin, (3) vancomycin+flucloxacillin, (4) vancomycin+imipenem-cilastatin, or (5) saline for 4 days. Vancomycin was administered intravenously and flucloxacillin or imipenem-cilastatin were administered intraperitoneally. Kidney injury was evaluated via drug accumulation and urinary biomarkers including urinary output, kidney injury molecule-1 (KIM-1), clusterin, and osteopontin. Relationships between vancomycin accumulation in the kidney and urinary kidney injury biomarkers were explored. Key Results Urinary output increased every study day for vancomycin+flucloxacillin; whereas in the vancomycin group it was elevated after the first dose only. In the vancomycin+flucloxacillin group, urinary KIM-1/24h increased on all days compared to vancomycin. In the vancomycin+imipenem-cilastatin group, urinary KIM-1/24h was decreased on days 1 and 2 compared to vancomycin. Similar trends were observed for clusterin. More vancomycin accumulated in the kidney with vancomycin+flucloxacillin compared to vancomycin and vancomycin+imipenem-cilastatin. The accumulation of vancomycin in the kidney tissue correlated with increasing urinary KIM-1 (4-parameter Hill Slope, R2=0.7985). Conclusion and Implications Vancomycin+flucloxacillin caused more kidney injury compared to vancomycin alone and vancomycin+imipenem-cilastatin in a translational rat model as determined by multiple kidney injury biomarkers. The combination of vancomycin+imipenem-cilastatin was nephroprotective.

Lower extremity weakness with reversible or medical etiologies is sometimes overlooked in the elderly patient. There are various causes of increased falls and weakness in the elderly population. Some causes of increased falls vision disturbances, impaired balance due to otolith dysfunction, arthritic-related immobility, and lower extremity neuropathy.

Aim: To evaluate drug–drug interaction (DDI) between tacrolimus (TAC) and different formulations of voriconazole (VRCZ) in adults and pediatrics with different ages. Method: Physiologically based pharmacokinetics (PBPK) models were used to evaluate DDI between oral TAC and different formulations of VRCZ (oral and intravenous (IV) formulations) in adults and pediatrics with different age groups. Both single dose and multiple dose administration were assessed. Multiple dosage regimens were maintained for 7 days. Result: A higher IV dose might lead to a great increase in area under the plasma concentration-time curve (AUC) and maximum concentrations (Cmax) of TAC in both adults and pediatrics. Besides, compared with IV administration, these two PK values of TAC increased more when combined with VRCZ orally. The ratio of two PK values increased with the age growth in pediatrics. And it increased progressively to adult values at the age of 3-8 years. Tacrolimus liposolubility was the most significant parameter on the DDI between TAC and VRCZ. Conclusion: In pediatric population, VRCZ had a less impact on PK of TAC than that in adults. The DDI progressed gradually as the age advances in pediatrics and finally equal to adults. Oral VRCZ increased PK parameters of tacrolimus even more than IV administration. Personalized dosage adjustment should be considered in clinical practice when co-administrated with VRCZ, especially in adults or in oral formulation.

Title : Comment on: [Lost at Sea in Search of a Diagnosis: A Case of Unexplained Bleeding]Subtitle : Scurvy from chemotherapy-induced adverse effects in an adolescent oncology patientAuthors : Michelle Toker, BS and Benedict Wu, DO, PhDAffiliation : Division of Dermatology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USACorresponding author :Michelle TokerAlbert Einstein College of Medicine, Montefiore Medical CenterEmail: michelle.toker@einsteinmed.eduTelephone: 516-946-4726Funding and support : NoneConflicts of Interest : NoneManuscript word count : 452Reference count : 6Figure count : 1Table count : 0Key words : chemotherapy, oncology, pediatrics, nutritional deficiency, vitamin C deficiency, scurvyDear Editor,The brief report published by Amos et al in 2016 shed light on the occurrence of scurvy in pediatric and adolescent patients with dietary restrictions.1 Indeed, patients with neurodevelopmental conditions are most commonly associated with the risk of developing scurvy; other at-risk patients include those with gastrointestinal disorders, alcoholism, and psychiatric conditions.2, 3 We aim to expand upon the situations when scurvy should be considered by presenting a case of an adolescent male diagnosed with scurvy secondary to the adverse effects of his chemotherapy.A 19-year-old male with a 10-month history of high-risk pre-B-cell acute lymphoblastic leukemia was consulted by the dermatology service for a new diffuse rash present for four days. He was recently enrolled in a phase 3 randomized trial of inotuzumab ozogamicin and was receiving methotrexate and vincristine. The chemotherapy regimen induced severe dizziness, nausea, and vomiting refractory to anti-emetic medications. His aversion to chemotherapy was so strong that it caused him to feel nauseated between treatment sessions. He also endorsed painful oral and pharyngeal sores that made it difficult to tolerate a regular diet. In addition to oropharyngeal pain, he experienced marked arthralgia and fatigue, which he also attributed to the chemotherapy. Additionally, the patient reported that vincristine reduced his taste sensation, which led to a poor appetite. These adverse symptoms culminated in a loss of 6.7 kg (9.1%) in less than one month.Physical examination revealed peri-follicular purpura on the back (Fig 1A), face, and bilateral upper and lower extremities. Upon closer inspection, we noted prominent corkscrew (spiral and curly appearance) hairs (Fig 1B). The lower mucosal lip had superficial erosions with scalloped-borders and fine petechiae (Fig 1C). Laboratory evaluation revealed pancytopenia with a platelet count of 42 k/UL and low serum levels of vitamin C (<0.1 mg/dL), potassium (3.4 mEq/L), magnesium (1.1 mg/dL), and albumin (2.8 g/dL). Serum vitamin A (35 mcg/dL) levels were within normal limits. The patient was diagnosed with scurvy due to poor food intake from his chemotherapy-induced nausea, emesis, and mucositis. It was thought that acidic foods, such as citrus, exacerbated the mucosal erosions, which caused him to avoid vitamin C-rich foods.Scurvy, caused by a prolonged L-ascorbic acid (vitamin C) deficiency, may manifest as pathognomonic corkscrew hairs with petechiae, gingival pain and bleeding, vascular fragility, arthralgias, fatigue, and numerous gastrointestinal symptoms.4,5, 6 Although vitamin C deficiency was an indirect result of his chemotherapy, scurvy, by itself, may have aggravated his symptoms, thereby creating a vicious cycle of poor oral intake. Our case highlights the complex relationship between chemotherapy-induced mucocutaneous adverse effects, a limited diet, and vitamin C deficiency. We recommend clinicians to consider scurvy in oncology patients, with or without thrombocytopenia, presenting with peri-follicular purpura and corkscrew hairs.Ethics Statement: Informed patient consent was obtained for publication of the case details and photographs.

Monkeypox infections in the US and across the world have been rising in the past few months. Most of these infections have been found to be transmitted among men who have sex with men (MSM). Our case report discusses the rare presentation of a patient with monkeypox along with multiple comorbidities, including AIDS, late latent syphilis, acute hepatitis C, and asymptomatic and scrotal and penile cellulitis secondary to MRSA. Further, our case report raises discussion on the need for further research to identify the effect of monkeypox vaccine on symptomatic patients who are immunocompromised.

In this work we studied the effect of Yellow Fever Virus (YFV) infection on mitochondrial network dynamics (MD). Using the A549 cell line as a model, we examined MD during YFV infection at day 1 post-infection (dpi), when only some cells are infected, and at day 3, when viral infection has spread. Although we did not detect significant differences in total mitochondrial mass using flow cytometry, confocal and MiNA image analysis at 1 dpi showed that YFV increased the number of individual structures, networks, and branches compared with mock-infected cells. In contrast, no differences were observed at 3 dpi. Using two different mitotimer plasmids, the results showed that YFV slightly increased mitochondrial biogenesis and mitophagy at 1 dpi. Confocal studies of Parkin 2 and F1-ATPase colocalization supported these results. Treatment of cells with CCCP, a reversible ionophore that triggers mitochondrial fragmentation, increased the number of individual structures and networks one day later and had opposite effects at three days after treatment. Treatment also decreased viral titers in cell supernatants. On the other hand, treatment of cells with Mdivi-1, an inhibitor of mitochondrial fission that leads to mitochondrial elongation, increased the number of individual structures one day later and decreased the number of individual structures, networks, and branches at three days after treatment, with no change in viral titers. As expected, YFV infection increased IFN-I transcription and PKR expression, but these levels were also modulated by the drugs CCCP and Mdivi-1. Our results suggest that YFV infection induces early changes at MD that affect viral replication and open new strategies for developing new treatments.

Background & Aims: Linear ubiquitin chain assembly complex (LUBAC) has been reported to participate in cancer progression, but its role in hepatocellular carcinoma (HCC) remains unknown. This study aimed to investigate the functions and potential tumorigenic mechanisms of LUBAC components in HBV-associated HCC. Methods: The expression of LUBAC components ( RBCK1, RNF31, and Sharpin) and Met1-linked ubiquitination (M1-Ubi) and their correlation with prognosis were detected. The biological functions of RBCK1 in HBV-associated HCC were investigated in vitro and in vivo. The regulation of RBCK1 on the HBx protein expression was analyzed by cycloheximide chase assays, coimmunoprecipitation, and ubiquitin assays. Results: We found that the expression of LUBAC components and M1-Ubi was significantly upregulated in HCC and correlated with poor prognosis. Interestingly, subgroup analysis revealed that RBCK1, not RNF31 or Sharpin, was exclusively overexpressed in HBV-associated HCC compared to non-HBV-associated HCC. Upregulated RBCK1 expression was associated with larger tumor size, higher AFP level, and poor prognosis in HBV-associated HCC cohort. Functionally, RBCK1-knockdown suppressed cell growth and migration, and also inhibited the progression of xenografted tumors in HBV-associated HCC mouse model. Mechanistically, RBCK1 interacted with HBx to promote its stabilization by increasing M1-Ubi ubiquitination and reducing K48-linked ubiquitination. Furthermore, clinical analysis confirmed a positive correlation between RBCK1 and HBx, and the co-expression of which predicted poor prognosis for HCC patients. Conclusion: RBCK1 is an oncogenic gene to promote tumor progression and may serve as a potential target for HBV-associated HCC.

Among the electrode materials for supercapacitors (SCs), metal-organic framework (MOFs) is attracting huge research interest as a new type of energy storage electrode materia. However, due to their poor conductivity and stability, the practical application of original MOFs in the field of energy storage has been greatly hindered. Here, we demonstrate a special core-shell structure, which the synergistic action of NiCo2O4 and Ni-MOF forms a tight conductive network that speeds up electron transport and larger specific surface area, more active sites were obtained and mechanical stability that indicates its outstanding long life. The test results show that it has a high specific capacity of 4.23 F cm-2 at 5 mA cm-2, and the capacity retention rate is maintained at 97.5% after 8000 cycles. In addition, the assembled hybrid SCs device, using NiCo2O4@Ni-MOF and activated carbon (AC) as anode and cathode, has a high specific capacity of 3.21 F cm-2 at 5 mA cm-2 and excellent cycling performance (83.8% retention over 8000 cycles at 10 mA cm-2). Our work demonstrates the possibility of using novel structured Ni-MOF-based hybrid arrays as electrodes for SCs with enhanced electrochemical performance compared to Ni-MOF and NiCo2O4, providing a reliable prospect for flexible energy storage devices.

Deprescribing is an essential component of safe prescribing, especially for people with higher levels of polypharmacy. Identifying individuals prepared to consider medicine changes may facilitate deprescribing-orientated reviews. We aimed to explore the relationship between revised patient attitudes towards deprescribing (rPATD) scores and medication changes in older people prescribed ≥15 medicines. A secondary analysis of rPATD scores and prescription data from a cluster randomised controlled trial of a GP-delivered, deprescribing-orientated medication review was conducted. The association between number of medicines stopped, started and changed and baseline rPATD scores was assessed using Poisson regression adjusting for patient age, gender, study group allocation, baseline number of medicines and effects of clustering. Participants (n=404) had a mean age of 76.4 years and were prescribed a mean of 17.1 medicines at baseline. Willingness to stop a medicine was associated with higher rates of both deprescribing (IRR: 1.40; 95%CI: 1.06-1.84) and initiating medicines (IRR: 1.43; 95%CI: 1.09-1.88). Satisfaction with current medicines was associated with a lower rate of deprescribing (IRR: 0.69; 95%CI: 0.57-0.85). The rPATD questionnaire could be used as part of a deprescribing intervention to identify participants who may be prepared to engage in deprescribing, enabling more efficient use of clinician time during complex consultations.

Background: Leukemia is a malignancy of white blood cells in which acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) are most common in children. With The 5-year survival rate has increased 87% in 2005, the treatment of ALL also aims to improve quality of life. 1,2,3 There was no research in Palembang about factors affecting the quality of life in children with ALL before. Objective: The purpose of this study was to identify the factors that influence the quality of life of ALL children. Methods: A cross-sectional design observational analytic study was used to analyze the relationship between the quality of life of one-hundred twelve patients who participated in Hemato-oncology division and the Growth and Development-Social Pediatric (GaDSOP) division of RSUP dr. Mohammad Hoesin Palembang from September 2021–August 2022 with PedsQL TM. Results: The proportion of poor quality of life based on parental reports was 32.2% and 20.8% based on children’s reports. Despite only 24.1% that lived in the urban and female proportion only 34.8%, from multivariate analysis, according to the reports from parents and children, female living in the urban with malnutrition and sleep disorders was 93.21% and 99.28% more at risk of experiencing poor life quality respectively. Conclusion: Factors that influence poor life quality in this research according to parents were gender, place of residence, malnutrition, and sleep disturbances whereas according to children were gender, sleep disturbances, movement, and activity disorders.

A safety-critical system is a system in which the software malfunctioning could result in death, injury, or damage to the environment. Addressing safety concerns early on at the architecture design level is critical to guide the subsequent life cycle activities to ensure that the eventual system is reliable. A fundamental approach to address safety at the design level is the adoption of architectural tactics. It is crucial for safety-critical systems to correctly implement the constraints as defined by the selected safety tactics. This article proposes a systematic approach for assessing the adequacy of test suites of safety-critical systems based on these architectural safety tactics. We use a case study to evaluate the effectiveness of our approach using fault-injection techniques. Our study shows that this systematic approach is feasible and effective for test suite assessment of safety-critical systems.

Background Healthcare workers (HCWs) have suffered considerable morbidity and mortality during the COVID-19 pandemic. Few studies have evaluated Coronavac vaccine effectiveness (VE), particularly in eastern Europe, where the vaccine has been widely used. Methods We conducted a prospective cohort study among HCWs in seven hospitals in Baku, Azerbaijan between May 17 to December 1, 2021, to evaluate primary series (two-dose) CoronaVac VE against symptomatic SARS-CoV-2 infection. Participants completed weekly symptom questionnaires, provided nasal swabs for SARS-CoV-2 RT-PCR testing when symptomatic, and provided serology samples at enrolment that were tested for anti-spike and anti-nucleocapsid antibodies. We estimated VE as (1 – hazard ratio)*100 using a Cox proportional hazards model with vaccination status as a time-varying covariate. Results We enrolled 1582 HCWs. At enrolment, 1040 (66%) had received two doses of CoronaVac; 421 (27%) were unvaccinated. During the study period, 72 PCR-positive SARS-CoV-2 infections occurred; 36/39 (92%) sequenced samples were classified as delta variant. The adjusted primary series VE against COVID-19 illness was 29% (95% CI:-51%;67%). For the delta-predominant period, adjusted primary series VE was 19% (95% CI:-81%;64%). For the entire analysis period, adjusted primary series VE was 39% (95% CI:-40%;73%) for HCW vaccinated within 14–149 days, and 19% (95%CI:-81;63) for those vaccinated ≥150 days. Conclusions During a delta-predominant period in Azerbaijan, point estimates suggest that primary series CoronaVac protected nearly 1 in 3 HCWs against COVID-19, but this finding was not statistically significant. Our findings underscore the need to consider booster doses in individuals who have received primary series CoronaVac.

Background and Purpose: Allograft rejection and corneal endothelial dysfunction are the two leading causes of corneal transplantation failure, but the underlying pathogenesis remains largely uncertain. Experimental Approaches: Using murine orthotopic corneal transplantation model, we analyzed the cellular senescence of allografts at early stage after transplantation through senescence-associated β-galactosidase (SA-β-Gal) staining, real-time PCR and western blot. Genetic approach, adoptive transfer experiment, primary mouse corneal fibroblasts (MCF) culture platform, exosome purification, and various experimental readouts were performed to investigate the pathogenic roles of transplantation stress-induced senescence in driving corneal allograft rejection and the underlying mechanism. Key Results: We showed that the surgery injury evoked corneal senescence-like phenotype at early stage after age-matched transplantation, characterized by more accumulation of SA-β-Gal positive cells in corneal endothelium and stroma, and elevated senescence marker p16INK4a (CDKN2A) and p21 (CDKN1A). Through genetic approach and adoptive transfer experiment, we revealed that stress-induced senescence promoted corneal immune rejection. Mechanistically, stress-induced senescence drove the escalated alloimmune responses through senescence-associated secretory phenotype (SASP) and exosomes. Targeting senescent cell using senolytic approach significantly blocked ocular alloresponse and subsequent immune rejection. Conclusion and Implications: These findings highlighted transplantation stress-induced senescence as pathogenic driver for corneal allograft rejection, further suggesting senolytic therapy as a novel option against corneal transplantation rejection and perhaps other organ transplantation rejection.

Possible structural variation of a bio-based dimethacrylate derived from oleic acid and ethylene glycol is discussed as well as sources to obtain the starting material for manufacturing of this monomer. Furthermore, aspects influencing the transfer of a newly developed product or further scientific result to application are included into the discussion as well focusing to manufacturing processes and development of a new product for the market.

Objective: To investigate the etiology and the clinical characteristics of community-acquired pneumonia (CAP) among children requiring bronchoalveolar lavage and analyze the impact of spreading of COVID-19 on the pathogens and clinical manifestations. Study design: Children <14 years old hospitalized with CAP requiring bronchoalveolar lavage were enrolled between February 2019 to January 2020 and August 2021 to July 2022. Multiplex reverse transcription polymerase chain reaction (mRT-PCR) was used for pathogen detection. The demographic and clinical characteristics were compared between different type pathogen infection groups and between before and during COVID-19 pandemic. Results: Among 1487 children studied, ≥1 pathogen was detected in 1363 (91.66%) children and co-infection was detected in 79 (5.31%) children. M.pneumoniae, Adenovirus and Human Rhinovirus were the most frequently detected pathogens. During the COVID-19 pandemic, it was found that the proportion of children under 3 years was appreciably reduced and the proportion of children over 7 years was appreciably increased. The frequency of virus and co-infection was decreased except for that of atypical bacteria. The results of clinical manifestations, CT scan and fiberoptic bronchoscopy showed significant difference with different pathogen infection and the lung inflammation of the enrolled children were relatively mild compared to those before the COVID-19 pandemic. Conclusions: M.pneumoniae infection might be the greatest pediatric disease burden leading to CAP in northern China. Wearing masks and social distancing in public places could effectively reduce the transmission of respiratory viruses, but could not reduce the infection rate of M.pneumoniae. In addition, precautions could significantly reduced the lung inflammation compared with those before the pandemic.

Climate change is projected to increase mean temperatures as well as the frequency and intensity of extreme heat events. These changes are anticipated to alter the behavior of animals as they seek to thermoregulate in extreme heat. An important area of research is understanding how mutualistic interactions between animals and plants, such as pollination, will be affected by the cascading effects of extreme heat on animal foraging behavior. In this study, we used an experimental and observational approach to quantify the effects of extreme heat on hummingbird foraging preferences for nectar sources in shady versus sunny microsites. We also quantified pollen deposition using artificial stigmas at these sites to quantify any cascading effects on plant reproduction. We hypothesized that hummingbirds would respond to extreme heat by preferentially foraging in shady microsites. We found little support for this hypothesis, instead finding that hummingbirds preferred to forage in sunny microsites regardless of ambient temperature. We found that in sunny microsites on hot days pollen deposition was slightly higher than in all other microsite and ambient temperature interactions, though it was only near-significant.

Background and Purpose: Epimedii Folium is a traditional herb widely-utilized in China. Recently, our study discovered that Epimedin B (EB), as a high-content, low-toxicity flavonoid compound in Epimedii Folium extract, strongly showed melanogenesis and tyrosinase activation effect. However, there are no studies of EB in pigment synthesis and regulation mechanism. This study aims to evaluate the pigmentation effect of EB and elucidate the melanogenic mechanism. Experimental Approach: Melanin contents in melanoma cells, primary human melanocytes, human skin tissues, and intracellular melanosomes changes were determined to evaluate the melanogenic effect of EB. The influence of TYRs expression was determined by RNA sequencing and mRNA/proteins changes. The tyrosinase activity were tested on mushroom tyrosinase, depigmented models of melanoma cells, zebrafishes and C57BL/6 mice. The stability of TYRs were investigated by monobenzone-induced TYRs degradation on melanoma cells, skin tissues and C57BL/6 mice, analyzed by cellular ubiquitin, chaperone co-expression, and endoplasmic reticulum/ proteasome co-localization assays. Key Results: EB increased TYRs expression through MITF-mediated pathways, then to promote melanosome number and maturation for melanogenesis. Additionally, EB exerted repigmentation through activating tyrosinase activity in multiple tyrosinase inhibitive models. Furthermore, EB could protect monobenzone-induced TYRs degradation and repigmentation in vitro and in vivo, enhance TYRs stability via inhibiting misfolded tyrosinase, TYR-related protein 1 formation, retention in endoplasmic reticulum, and ubiquitin-proteasome system. Conclusion and Implications: These data conclude that EB can target TYRs from expression, catalytic activity and stability approaches to exhibit pigmentation function, which might provide a novel rational strategy for hypopigmentation in pharmaceutical and cosmetic industries.

Aims: The sympathetic nervous system regulates numerous aspects of mitochondrial function in the heart through activation of adrenergic receptors (ARs) on cardiomyocytes. Mounting evidence suggests that α1-ARs, particularly the α1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic β-AR activation by shared endogenous ligands. The mechanisms through which α1A-ARs exert their cardioprotective effects remain unclear. Here we tested the hypothesis that α1A-ARs adaptively regulate cardiomyocyte oxidative metabolism in the uninjured and infarcted heart. Methods: We used an α1A-AR knockout mouse (α1A-KO) to characterize the effects of α1A-AR genetic deletion on mitochondrial function and metabolism in the uninjured mouse heart using high resolution respirometry, substrate-specific electron transport chain (ETC) enzyme assays, transmission electron microscopy (TEM) and proteomics. We then compared the effects of α1A- and β-AR agonist treatment on mitochondrial function in uninjured mice and mice subjected to experimental myocardial infarction. Results: We found that isolated cardiac mitochondria from α1A-KO mice had deficits in fatty acid-dependent respiration and ETC enzyme activity. TEM revealed abnormalities of mitochondrial morphology characteristic of these functional deficits. The selective α1A-AR agonist A61603 enhanced oxidative metabolism in isolated cardiac mitochondria. The β-AR agonist isoproterenol enhanced oxidative stress in vitro and this adverse effect was mitigated by A61603. A61603 enhanced ETC Complex I activity and protected contractile function following myocardial infarction. Conclusions: Collectively, these novel findings position α1A-ARs as critical regulators of cardiomyocyte metabolism in the basal state and suggest that metabolic mechanisms may underlie the protective effects of α1A-AR activation in the failing heart.

Cerebral hemorrhage is an extremely rare complication of CLIPPERS. We report a patient who developed CLIPPERS in his 50s and was responding to glucocorticoid therapy developed cerebellar space-occupying hemorrhage with high glucose metabolism in bilateral cerebellar hemispheres during hospitalization.

This report aims to emphasize the importance of preoperative assessment for cardiac surgery planning. A 40-year-old female diagnosed with severe mitral and tricuspid valves regurgitation. CT chest showed a porcelain aorta. She underwent MV replacement and tricuspid valve repair on a beating heart without an aortic cross-clamp.

DNA glycosylases protect genetic fidelity during DNA replication by removing potentially mutagenic chemically damaged DNA bases. Bacterial Lhr proteins are well-characterized DNA repair helicases that are fused to additional 600-700 amino acids of unknown function, but with structural homology to SecB chaperones and AlkZ DNA glycosylases. Here we identify that E. coli Lhr is a uracil-DNA glycosylase that depends on an active site aspartic acid residue. We show that the Lhr DNA helicase activity is functionally independent of the uracil-DNA glycosylase activity, but that the helicase domains are required for fully active uracil DNA glycosylase activity. Consistent with uracil DNA glycosylase activity, deletion of lhr from the E. coli chromosome sensitized cells to oxidative stress that triggers cytosine deamination to uracil. The ability of Lhr to translocate single-stranded DNA and remove uracil bases suggests a surveillance role to seek and remove potentially mutagenic base changes during replication stress.