How parental smartphone addiction affects adolescent smartphone addiction: The effect of the parent-child relationship and parental bonding.
Adolescent smartphone addiction (ASA) has fueled concerns worldwide regarding the negative health effects. This study aimed to examine whether parental smartphone addiction (PSA) affected ASA, and evaluated the mediating role of the parent-child relationship and the moderating role of parental bonding in the effect from PSA to ASA, among a Chinese sample of parent-child pairs. A large-scale cross-sectional survey was conducted among 10- to 15-year-old students and their parents. ASA and PSA were assessed by Mobile Phone Addiction Index (MPAI). The parent-child relationship was evaluated by Child-Parent Relationship Scale-Short Form (CPRS-SF), and parental bonding was estimated by Parental Bonding Instrument (PBI). Conditional process model was used to examine the relationship between PSA and ASA, as well as the mediating effect of parent-child relationship and the moderating effect of parental bonding. A total of 9515 adolescents and their parents completed the online survey. PSA significantly positively predicted ASA (B = 0.488, p < 0.001). The parent-child relationship negatively mediated the association from PSA to ASA (B = -0.321, p < 0.001). Parental overprotection moderated the indirect path from PSA to ASA through the parent-child relationship (B = -0.016, p < 0.001), but parental care had not any moderation (B = -0.005, p > 0.05). Specifically, parental overprotection had a positive moderating effect on the second half mediation path. The indirect effect of PSA on ASA through parent-child relationship was greater in higher overprotection than in lower. Cross-sectional study of self-administrated questionnaires. Adolescents had a higher tendency toward smartphone addiction when their parents excessively used smartphones. The findings highlighted the essential role of parent-child relationship and parental bonding in the association from PSA to ASA.


Intrinsic difference between phenyl hexyl- and octadecyl-bonded silicas in the solute retention selectivity in reversed-phase liquid chromatography with aqueous mobile phase.
For choosing an optimal column for a particular separation by reversed-phase liquid chromatography (RPLC), it is essential to quantitatively understand the effects of the chemical structure of hydrophobic bonded layer derived onto silica particles on the distribution equilibrium of a solute compound at the interface between the aqueous mobile phase and the packing material. However, there is still a lack of understanding of the solute distribution equilibrium in RPLC separation due to the complexities of the chemistry at the interface between the mobile phase and the bonded layer. We successfully determined the distribution coefficients of various organic compounds concerning to their accumulation onto the water/bonded layer interface and into the bonded layer from bulk water using surface-bubble-modulated liquid chromatography with octadecyl- and phenyl hexyl-bonded silica columns. The water/phenyl hexyl-bonded layer interface accumulates organic compounds much less than the water/octadecyl-bonded layer interface due to its lower interfacial tension, and this result suggests that phenyl hexyl group orient their benzene ring facing toward water. On the other hand, aromatic moiety of phenyl hexyl group enhances partitioning of the organic compounds into the bonded layer. Experimental findings in the present work demonstrated that the water/bonded layer interface and the bonded layer itself have independent contributions to the solute distribution and the water/phenyl hexyl-bonded layer interface shows quite different solute retention selectivity from the water/octadecyl-bonded layer interface.


Drosophila MAGE controls neural precursor proliferation in postembryonic neurogenesis.
Necdin, a member of the MAGE family, is expressed abundantly in postmitotic neurons and is required for their differentiation and survival. In mammals, the MAGE family consists of more than 30 genes, whereas only one MAGE gene exists in the genome of nonmammalian vertebrates such as zebrafish and chicken. These nonmammalian MAGE genes are expressed in developing nervous system, and the primary structures of the encoded proteins resemble those of necdin-like MAGE proteins. Fruit fly Drosophila also carries a single necdin-like MAGE gene, which is highly expressed in neural stem cells (neuroblasts) during nervous system development. In the present study, we investigated the function of MAGE in Drosophila neurogenesis in vivo using an RNA interference (RNAi) -mediated gene knockdown system. Ubiquitous knockdown of Drosophila MAGE by double-stranded RNA injection into embryos was lethal at early stages of organogenesis. MAGE was then knocked down in developing mushroom bodies by RNAi-mediated gene silencing using the OK107-GAL4 driver. MAGE RNAi increased the population of proliferative neural precursors in larval mushroom bodies. At the pupal stage, RNAi-mediated MAGE knockdown led to a significant enlargement of the mushroom bodies as a result of increased neuronal population, presumably by accelerating the asymmetric division of neural stem cells. MAGE RNAi mushroom bodies of adult flies showed neurodegenerative changes such as vacuolation and nuclear DNA breaks, implying that supernumerary neurons undergo apoptosis during postpupal development. These results suggest that evolutionally conserved necdin-like MAGE is involved in both neural stem cell proliferation and neuronal survival during nervous system development.


Breast Cancer Resistance Protein Abundance, but Not mRNA Expression, Correlates With Estrone-3-Sulfate Transport in Caco-2.
Transporter mRNA and protein expression data are used to extrapolate in vitro transporter kinetics to in vivo drug disposition predictions. Breast cancer resistance protein (BCRP) possesses broad substrate specificity; therefore, understanding BCRP expression-activity relationships are necessary for the translation to in vivo. Bidirectional transport of estrone-3-sulfate (E-3-S), a BCRP probe, was evaluated with respect to relative BCRP mRNA expression and absolute protein abundance in 10- and 29-day cultured Caco-2 cells. BCRP mRNA expression was quantified by real-time PCR against a housekeeper gene, Cyclophilin A. The BCRP protein abundance in total membrane fractions was quantified by targeted proteomics, and [(3)H]-E-3-S bidirectional transport was determined in the presence or absence of Ko143, a potent BCRP inhibitor. BCRP mRNA expression was 1.5-fold higher in 29- versus 10-day cultured cells (n = 3), whereas a 2.4-fold lower (p < 0.001) BCRP protein abundance was observed in 29- versus 10-day cultured cells (1.28 ± 0.33 and 3.06 ± 0.22 fmol/μg protein, n = 6, respectively). This correlated to a 2.45-fold lower (p < 0.01) efflux ratio for E-3-S in 29- versus 10-day cultured cells (8.97 ± 2.51 and 3.32 ± 0.66, n = 6, respectively). Caco-2 cell BCRP protein abundance, but not mRNA levels, correlates with BCRP activity, suggesting that extrapolation strategies incorporating BCRP protein abundance-activity relationships may be more successful.


Generation of induced pluripotent stem cell line, ZJUCHi002-A, from Charcot-Marie-Tooth disease type 2A (CMT2A) patient with a mutation of c.752C>T in MFN2.
The human induced pluripotent stem cell (iPSC) line ZJUCHi002-A was established from renal epithelial cells present in urine (urinary cells) collected from an 8-year-old Charcot-Marie-Tooth disease type 2A (CMT2A) patient carrying point mutation in MFN2 (c.752C > T). Urinary cells were reprogrammed by retrovirus vectors containing reprogramming factors: OCT4, SOX2, KLF4 and c-MYC. The pluripotency, capacity of differentiation into 3 germ layers, silence of reprogramming factors and normal karyotype were all confirmed in this study.


Serotonin-immunoreactive neurons in the brain of Manduca sexta during larval development and larval-pupal metamorphosis.
The developing serotonergic system of the tobacco hornworm, Manduca sexta, has been studied immunocytochemically in whole mount preparations of brain-retrocerebral complexes. The distribution of serotonin-immunoreactive cell bodies, fibers and terminal fields has been analysed during larval and larval-pupal development using a specific rabbit antiserum against serotonin-hemocyanin conjugates. The serotonergic system was conserved from the fourth to the fifth larval stadium, with minimal changes occurring until the onset of pupal development. At this time, alterations in the distribution of serotonin-immunoreactive cells and processes were observed, including the apparent disappearance of some cell bodies and terminals. Nevertheless, the overall appearance of this system in the pupal brain was not significantly different from that in the larva. The larval pattern was characterized by eight bilateral groups of cell bodies which sent thick bridges of fibers across the midline, a feature strikingly similar to the serotonergic system in vertebrate embryos. In addition, three bilateral immunoreactive fields of arborization were observed around and ventral to these cell groups, together with regions of serotonin immunoreactivity in the medial and lateral protocerebral lobes. The central body, larval antennal centers, larval accessory lobes, and the tritocerebrum were also immunoreactive. Fibrous networks of serotonergic processes were usually observed around nerves emanating from the brain, including the connectives from the brain to the corpus cardiacum and corpus allatum. Smaller varicosities were observed in the interior of these neurohemal and glandular organs, and a network of 5-HT fibers was occasionally found around the corpus cardiacum and corpus allatum. The possible relationship of serotonin to cerebral neuroendocrine functions during the postembryonic development of M. sexta is discussed.


Diffuse alveolar hemorrhage with nivolumab monotherapy.
We describe a 60 year old man who developed respiratory insufficiency after treatment with 2 rounds of nivolumab monotherapy. Imaging revealed subtle ground glass infiltrates which progressed to diffuse opacities and consolidation. The patient was treated with high dose corticosteroids, empiric antimicrobial therapy and infliximab. Bronchoscopy with lavage revealed negative cultures and progressive bloody aliquots of fluid consistent with diffuse alveolar hemorrhage. The patient succumbed to respiratory failure. An autopsy study confirmed extensive alveolar hemorrhage. Our reports highlights clinical and diagnostic findings with immunotherapy-induced pneumonitis.


Pet dogs as reservoir of oxacillin and vancomycin-resistant Staphylococcus spp.
The aim of this study was to verify the bacterial resistance profile and detect the presence of mecA gene in Staphylococcus spp. isolated from the nasal microbiota of domiciled dogs. For this purpose 100 nasal swabs from 100 domiciled dogs were collected from the central area of the city of Umuarama (PR), along with a questionnaire answered by their owners. After the isolation all Staphylococcus spp. isolates were submitted to the diffusion disc test by the Kirby-Bauer method, and only oxacillin-resistant samples were submitted to the PCR technique to search for the mecA gene and the results were then submitted to statistical analysis to verify possible risk variables. The 100 Staphylococcus spp. and coagulase negative, among which 41 isolates were resistant to oxacillin, no samples were positive for the mecA gene presence, however, 12 resistant to vancomycin were found. It can be concluded that the domiciled dogs are carriers of Staphylococcus spp. multiresistant, being these a possible source of human contamination.


Xinbao Pill attenuated chronic heart failure by suppressing the ubiquitination of β-adrenergic receptors.
Xinbao Pill (XBP) is extensively used in the adjuvant treatment of chronic heart failure in China. However, the pharmacological effect and underlying mechanism on CHF remains unclear. Our research was performed to investigate the cardioprotective effect of XBP against CHF and uncover the potential mechanism. Male Sprague-Dawley (SD) rats were subjected to the left anterior descending (LAD) artery ligation for 8 weeks and were treated with different doses of XBP (from the 4th week to the end). Cardiac function and morphology assessment were performed by using M-mode echocardiography, H&E and Masson staining. Western blotting analysis, co-immunoprecipitation (IP) assays, siRNA transfection were used to evaluate the mechanism of XBP. XBP improved cardiac function and alleviated cardiac fibrosis in LAD-induced chronic heart failure rats. Meanwhile, XBP protected cardiomyocytes against oxygen-glucose deprivation (OGD) injury in AC16 cells and H9c2 cells. Additionally, XBP could increase the expression of β1-AR and β2-AR and inhibit their ubiquitanation. Further mechanism study showed that XBP upregulated USP18 expression, while silence of USP18 attenuated the cardioprotective effect of XBP and the increase of β1-AR by XBP. Moreover, XBP increased MDM2 and β-arrestin2, and disrupted the interaction between Nedd4 and β2-AR. After using the inhibitor of MDM2, SP141, the cardioprotective effect of XBP and the inhibitory effect on the ubiquitanation of β2-AR were also blocked. Our study firstly revealed that XBP improved cardiac function against CHF through suppressing USP18 and MDM2/β-arrestin2/Nedd4-mediated the ubiquitination of β1-AR and β2-AR.


Aortic Leaflet Stresses Are Substantially Lower Using Pulmonary Visceral Pleura Than Pericardial Tissue.
Background: Porcine heart and bovine pericardium valves, which are collagen-based with relatively little elastin, have been broadly utilized to construct bioprosthetic heart valves (BHVs). With a larger proportion of elastin, the pulmonary visceral pleura (PVP) has greater elasticity and could potentially serve as an advantageous biomaterial for the construction/repair of BHVs. The question of how the aortic valve's performance is affected by its bending rigidity has not been well studied. Methods: Based on the stress-strain relationships of the pericardium and PVP determined by planar uni-axial tests, a three-dimensional (3D) computational fluid-structure interaction (FSI) framework is employed to numerically investigate the aortic valve's performance by considering three different cases with Young's modulus as follows: E = 375 , 750 , and 1500 kPa, respectively. Results: The stroke volumes are 112, 99.6, and 91.4 ml as Young's modulus increases from 375 to 750 and 1500 kPa, respectively. Peak geometric opening area (GOA) values are 2.3, 2.2, and 2.0 cm2 for E = 375 , 750, and 1500 kPa, respectively. The maximum value of the aortic leaflet stress is about 271 kPa for E = 375 kPa, and it increases to about 383 and 540 kPa for E = 750 and 1500 kPa in the belly region at the peak systole, while it reduces from 550 kPa to 450 and 400 kPa for E = 375 , 750, and 1500 kPa, respectively, at the instant of peak "water-hammer". Conclusion: A more compliant PVP aortic leaflet valve with a smaller Young's modulus, E , has a higher cardiac output, larger GOA, and lower hemodynamic resistance. Most importantly, the aortic leaflet stresses are substantially lower in the belly region within the higher compliance PVP aortic valve tissue during the systole phase, even though some stress increase is also found during the fast-closing phase due to the "water-hammer" effect similar to that in the pericardial tissue. Future clinical studies will be conducted to test the hypothesis that the PVP-based valve leaflets with higher compliance will have lower fatigue or calcification rates due to the overall lower stress.


Influence of Aeration Pipe Length on Oxygen Mass Transfer Efficiency in Terms of Bubble Motion Flow Field.
Improving the gas-liquid mass transfer efficiency in microporous aeration technology is the key to strengthening the restoration effect of black and odorous water bodies. However, the effect of bubble motion characteristics on oxygen mass transfer has not been systematically studied, which limits the efficient and economical application of microporous aeration remediation technology in black and odorous water. The influence under different aeration pipe lengths was analyzed for oxygen mass transfer and bubble movement in microporous aeration technology. The aeration pipe length (0.1-0.5 m) was positively correlated (R = 1.000, R = 0.997) with the number of bubbles and the specific surface area of bubbles and negatively correlated with the time-average velocity of bubbles and Sauter average diameter (R = -0.999, R = -0.997). Moreover, the increase in pipe length weakened the disturbance intensity of plume to water body. The results of oxygen mass transfer showed that the oxygen mass transfer coefficient (K L a) and oxygen utilization rate (E A) increased (K L a from 1.96 to 4.57 h-1, E A from 6.47 to 15.07%) with the increase of pipe length, which was significantly positively correlated (R = 0.985, R = 0.969) with the number of bubbles and bubble specific surface area (S b). This study provided theoretical parameters for the mechanism of oxygen mass transfer during microporous aeration.


A fragmented form of annexin A1 is secreted from C2C12 myotubes by electric pulse-induced contraction.
The main function of annexin A1 (ANXA1), a member of the annexin superfamily, is to bind to cellular membranes in a Ca(2+)-dependent manner. In skeletal muscle, ANXA1 is thought to be involved in the repair of damaged membrane tissue and in the migration of muscle cells. We hypothesized that ANXA1 is one of the myokines secreted during muscle contractions to accelerate the repair of cell damage after contraction. Here we performed cell contractions by electric pulse stimulation; the results revealed that a fragmented form of ANXA1 was cleaved by calpain and selectively secreted from skeletal muscle cells by contraction. We therefore realized that muscle-contraction-induced calpain-dependent ANXA1 fragmentation has a wound-healing effect on damaged cells. This suggested that not the intact form but rather fragmented ANXA1 is a contraction-induced myokine.


The protein inhibitor of adenosine 3':5'-monophosphate-dependent protein kinases. Isolation and characterization of three isoinhibitors.
The protein inhibitor of adenosine 3':5 monophosphate-dependent protein-kinases has been purified from rabbit skeletal muscle by affinity chromatography on Sepharose-bound catalytic subunit of the kinase (Demaille et al. (1977) Biochemistry 16, 3080-3086). The inhibitory material can be separated into three species A, B and C either by polyacrylamide gel electrophoresis or by anion-exchange on DEAE-cellulose. However, the isoinhibitors display the same molecular weight and isoelectric point, and the same absence of acid-stable covalently bound phosphate. Their amino acid compositions are strikingly similar and their NH2-terminus are blocked. Also, their COOH-terminus appear to be very close to one another when studied by carboxypeptidase Y digestion. Their major difference lies in their inhibitory properties which are significantly weaker in inhibitor C (Ki = 0.87 nM) than in A and B (Ki = 0.18 and 0.23 nM, respectively). This is the first report on the existence of various forms of the protein-kinase inhibitor that exhibit different inhibitory properties and may play a role in the regulation of the protein-kinase system.


Crosslinked gelatin nanofibres: preparation, characterisation and in vitro studies using glial-like cells.
Gelatin (GL) nanofibrous matrices mimicking the complex biological structure of the natural extracellular matrix (ECM) were prepared from aqueous solutions by electrospinning technique. GL nanofibres with a diameter size of around 300nm were obtained optimising the process and solution parameters. To increase the GL stability in aqueous environment γ-glycidoxypropyltrimethoxysilane (GPTMS) was used as GL crosslinker. GPTMS crosslinking did not modify the nanofibrous matrix morphology: fibre diameter and membrane pores size were 327±45 nm and 1.64±0.37 μm, respectively. The produced GPTMS crosslinked GL nanofibres (GL/GPTMS_NF) were found to support the in vitro adhesion, proliferation and survival of neonatal olfactory bulb ensheating cells (NOBECs).


Autoantibodies to pancreatic islet cells in canine diabetes mellitus.
Indirect immunofluorescence on normal canine pancreatic tissue fixed in Bouin's solution was used to detect islet cell antibodies in dogs with diabetes mellitus, other endocrine diseases, and pancreatitis. 18 of 25 dogs with diabetes mellitus alone, 2 of 8 dogs with diabetes mellitus and concurrent pancreatitis, and 2 of 2 dogs with diabetes mellitus and concurrent pancreatic exocrine insufficiency were positive for autoantibody. 2 of 12 dogs with hypoadrenocorticism, 3 of 6 dogs with hyperadrenocorticism, 6 of 28 dogs with hypothyroidism and one of 19 dogs with pancreatitis alone were also antibody positive. None of 20 healthy dogs or 20 dogs with disorders other than those of the pancreas or endocrine organs were antibody positive. Islet cell antibodies were demonstrated in dogs with diabetes mellitus and other endocrine disorders. The possibility of autoimmune involvement in the development of diabetes mellitus in the dog should be considered.


Chemical design of radioiodinated probes with a metabolizable linkage for target-selective imaging of systemic amyloidosis.
Systemic amyloidosis is a rare disease caused by the deposition of amyloid fibrils in various organs. Amyloid-targeted radiopharmaceuticals have been developed and applied to diagnose systemic amyloidosis peripherally; however, high-contrast imaging has not been achieved because of the high background signals in normal organs. To overcome this problem, we designed an amyloid-targeted radioiodinated probe 1 with a metabolizable linkage (ester bond) to release of radiolabeled metabolites (m-iodohippuric acid) in normal organs that could be rapidly excreted in the urine. Compound 1 was synthesized by conjugating 2-(4-(methylamino)phenyl)benzo[d]thiazol-6-ol, an amyloid-targeting compound, with m-iodohippuric acid. [125I]1 was synthesized via iododestannylation using a tributyltin precursor. Mouse models of amyloid A (AA) amyloidosis, a type of systemic amyloidosis, were prepared by administering amyloid-enhancing factor to mice and used for in vitro autoradiography using organ sections and in vivo evaluation. [125I]1 was obtained with a radiochemical yield of 59% and radiochemical purity of over 95%. An in vitro autoradiographic study demonstrated that [125I]1 specifically binds to amyloid in the splenic tissue. Upon administration to normal mice, [125I]1 was distributed to organs throughout the body, followed by the rapid excretion of radioactivity in the urine as m-[125I]iodohippuric acid. Furthermore, ex vivo autoradiography showed that [125I]1 bound to the amyloid formed around the follicles in the spleens of AA amyloidosis model mice. These results suggest that the interposition of a metabolizable linkage between an amyloid-targeting moiety and a radiolabeled hippuric acid would be useful in the design of radiopharmaceuticals for high-contrast imaging of systemic amyloidosis.


Editor's Choice - Severe Bleeding Risks of Direct Oral Anticoagulants in the Prevention and Treatment of Venous Thromboembolism: A Network Meta-Analysis of Randomised Controlled Trials.
The aim of this study was to determine the severe bleeding safety of direct oral anticoagulants (DOACs) for the prevention and treatment of venous thromboembolism (VTE). PubMed, EMBASE, Web of Science, and the Cochrane Library databases were searched up to 6 January 2021. The incidence of severe bleeding (major, gastrointestinal [GI], intracranial, and fatal) was investigated. Using frequentist network meta-analysis, interventions that were not compared directly could be compared indirectly by the 95% confidence interval (CI), making the search results more intuitive. Based on surface under the cumulative ranking curves (SUCRA), the relative ranking probability of each group was generated. Thirty-one randomised controlled trials (76 641 patients) were included. For the treatment of VTE, the risk of major bleeding with apixaban was significantly lower than dabigatran (odds ratio [OR] 2.10, 95% CI 1.07 - 4.12) and edoxaban (OR 2.64, 95% CI 1.36 - 5.15). The safety of the drugs was ranked from highest to lowest as follows: major bleeding: apixaban (SUCRA 98.0), rivaroxaban (SUCRA 69.6), dabigatran (SUCRA 50.7), edoxaban (SUCRA 26.5), and vitamin K antagonists (VKAs; SUCRA 5.1); GI bleeding: apixaban (SUCRA 80.7), rivaroxaban (SUCRA 66.8), edoxaban (SUCRA 62.3), VKAs (SUCRA 34.4), and dabigatran (SUCRA 5.8); intracranial bleeding: rivaroxaban (SUCRA 74.4), edoxaban (SUCRA 70.4), dabigatran (SUCRA 58.2), apixaban (SUCRA 44.4), and VKAs (SUCRA 5.6); fatal bleeding: edoxaban (SUCRA 82.7), rivaroxaban (SUCRA 59.2), dabigatran (SUCRA 48.6), apixaban (SUCRA 43.0), and VKAs (SUCRA 16.3). For the prevention of VTE, the risk of major bleeding with apixaban was significantly lower than rivaroxaban (OR 2.14, 95% CI 1.02 - 4.52). Among the four types of bleeding, apixaban had the lowest bleeding risk among DOACs (major bleeding: SUCRA 81.6; GI bleeding: SUCRA 75.4; intracranial bleeding: SUCRA 64.1; fatal bleeding: SUCRA 73.6). For the treatment of VTE, in terms of major bleeding and GI bleeding, apixaban had the lowest bleeding risk; in terms of intracranial bleeding, rivaroxaban had the lowest bleeding risk; in terms of fatal bleeding, edoxaban had the lowest bleeding risk. For the prevention of VTE, apixaban had the lowest bleeding risk.


Performance on the Verbal Naming Test among healthy, community-dwelling older adults.
Objective: The Verbal Naming Test (VNT) is a nonvisual measure of word finding with stimuli chosen based on rare frequency of usage in spoken English. The purpose of the current study was to evaluate the psychometric properties of the VNT and test the feasibility of telephone administration. In addition, regression-based normative data were obtained for the VNT as well as other measures.Method: Eighty-one community-dwelling older adults 61-92 years old (mean = 74.19 years) completed the VNT, the Naming subtests of the Neuropsychological Assessment Battery (NAB), the WIAT-III Sentence Repetition subtest, and the Montreal Cognitive Assessment (MoCA).Results: As evidence of construct validity, the VNT had large correlations with the NAB Naming test and medium correlations with the MoCA and WIAT-III Sentence Repetition test. Cronbach's alpha in this sample was 0.621. Age, education, and gender were entered into linear regression equations and regression-based normative equations are presented. Lastly, administration of the VNT over the telephone was found to be feasible.Conclusions: The VNT is a valid measure of naming among community-dwelling older adults. Regression-based normative data for the measure will enable its use in the neuropsychological assessment of naming with a wide range of older adults.


Associations Between General Vaccine Hesitancy and Healthcare Access Among Arkansans.
Vaccines provide protection against numerous diseases that can cause serious illness and death. However, vaccine hesitancy threatens to undermine progress in reducing preventable diseases and illness. Vaccine hesitancy has been shown to vary by sociodemographic characteristics. However, studies examining associations between healthcare access and vaccine hesitancy are lacking. Using a statewide random sample of Arkansas adults, we examined the relationship between general vaccine hesitancy and healthcare access. From July 12 to 30, 2021, participants were contacted by landlines and cellular phones using random digit dialing. A total of 1500 Arkansas adults were surveyed. Black/African American and Hispanic/Latinx adults were oversampled to ensure adequate representation. The survey had a cooperation rate of 20%. The dependent variable was an ordinal measure of general vaccine hesitancy. Age, gender, race, education, relationship status, and rural/urban residence were included in the model. Healthcare access was measured across four domains: (1) health insurance coverage; (2) having a primary care provider (PCP); (3) forgoing care due to cost; and (4) time since last routine checkup. The relationship between general vaccine hesitancy and healthcare access was modeled using ordinal logistic regression, controlling for sociodemographic characteristics. Mean age was 48.5 years, 51.1% were women, 28% reported a race other than White, and 36.3% held a bachelor's degree or higher. Those with a PCP and those with health insurance had approximately two-thirds the odds of being more hesitant ([OR=0.63, CI=0.47, 0.84] and [OR=0.68; CI=0.49, 0.94]) than those without a PCP and those without health insurance. Participants reporting a routine checkup in the last 2 years were almost half as likely to be more hesitant than those reporting a checkup more than 2 years prior (OR=0.58; CI=0.43, 0.79). Results suggest improving access to health insurance, PCPs, and routine preventative care services may be critical to reducing vaccine hesitancy.


The effect of gaze direction on sound localization in brain-injured and normal adults.
This study examined the effects of eye position on sound localization in normal and brain lesion subjects. On the assumption that cerebral lesions may disrupt the representation of or attention to auditory space in the contralesional hemispace, we predicted that subjects with brain lesions would be less accurate in localizing sounds in the contralesional hemispace. In Experiment 1 we showed that gazing to the midline subjects with brain lesions were indeed impaired in localizing sounds in the contralesional hemispace. On the assumption that spatial attention is deployed at the site to which gaze is directed, we predicted that sound localization would be better on the side to which subjects directed their gaze. In Experiment 2, brain lesion subjects performed significantly better in the contralesional hemispace when they directed gaze to that hemispace. This improvement was accompanied by deterioration of performance in the ipsilesional hemispace. When subjects directed gaze to the ipsilesional hemispace, performance in the contralesional hemispace was further impaired. The effect of gaze was also observed in normal subjects in Experiments 2 and 3, independently of response mode (verbal versus pointing responses). These findings are consistent with the hypothesis that sound location may be mapped in eye-centered coordinates and that directing gaze to one hemispace reduces attentional allocation to the other hemispace.


Foot-sole reflex receptive fields for human withdrawal reflexes in symmetrical standing position.
Human withdrawal-reflex receptive fields were assessed in 10 healthy subjects during standing with even support on both legs. Two electrical-stimulus intensities (1.2 and 2.2 times the pain threshold, PTh) were used. The painful stimuli were delivered in random order to 12 positions distributed over the foot sole. Tibialis anterior (TA), soleus (SO), vastus lateralis (VL), semitendinosus (ST), and iliopsoas (IL) reflexes were recorded. Further, the vertical force was recorded and the center or pressure (CoP) was assessed in the frontal and sagittal planes on both legs. Reflexes were observed at both intensities with the strongest reflexes at the high intensity. Around the ankle joint, SO reflexes dominated, which is in contrast to previous observations for subjects sitting. An unloading of the limb was found on the stimulated leg associated with a simultaneous loading of the contralateral leg. The shift in load was most pronounced for stimulation of the heel. The flexors ST and IL also had strong reflexes with reflex patterns correlated to the pattern of unloading. The shift in vertical force was accomplished by a move of the CoP in the anterior direction on the stimulated limb (contraction of SO), which simultaneously caused a small movement of the CoP in the lateral direction. In the present standing conditions, the ankle extensor played a dominant role in the withdrawal pattern in contrast to previous studies during sitting, relaxed conditions.


A common variant on chromosome 9p21 affects the risk of early-onset coronary artery disease.
Background Two single nucleotide polymorphisms (SNPs, rs10757278 and rs2383207) on chromosome 9p21 have been proved to be associated with myocardial infarction. We investigated whether these two genetic markers are determinants of early-onset coronary artery disease. Methods and results A total of 444 consecutive patients were studied including 212 cases with coronary stenosis >or=50% or previous myocardial infarction and 232 controls without documented coronary artery disease. Ligase detection reaction was performed to detect two SNPs. After adjustment of clinical parameters, significant associations were identified for the rs2383207 and rs10757278 SNPs, with A/G and G/G genetypes at rs10757278 and G/G genetype carriers at rs2383207 having a higher risk of early-onset coronary artery disease than carriers of A/A genotype (odds ratio [OR] 2.207, 95% CI: 1.069-4.394, P = 0.028; OR 3.051, 95% CI: 1.086-8.567, P = 0.004; OR 2.964, 95% CI: 1.063-8.265, P = 0.038, respectively). There were no associations between rs10757278 and rs2383207 genotypes and the severity of coronary artery disease (both P > 0.05). Conclusions The rs10757278 and rs2383207 variants are determinants for early-onset coronary artery disease. These markers may help the identification of patients at increased risk for early-onset coronary artery disease.


Novel clinical scoring system to identify patients with pneumothorax with suspicion for Birt-Hogg-Dubé syndrome.
Birt-Hogg-Dubé syndrome (BHDS) is a rare hereditary disease that presents with multiple lung cysts and pneumothorax (PTX). Although some reports propose that findings from chest computed tomography enable one to distinguish BHDS from primary spontaneous pneumothorax (PSP), it is still unclear whether clinical features are useful for identifying patients with suspicion of BHDS from those with PTX. We retrospectively reviewed the medical records of patients with PTX who underwent video-assisted thoracoscopic surgery at Nissan Tamagawa Hospital from January 2012 to December 2015. We identified a total of 1141 patients with PTX, including 54 with BHDS and 517 with PSP. Among them, logistic regression analysis segregated five features that were significantly associated with BHDS: familial history of PTX, past history of bilateral PTX, age at the first episode of PTX (≥25 years old (y.o.)), body mass index (≥18.5) and gender (female). We assigned scores of 3, 3, 2, 2 and 1 to the five features, respectively, to establish a system with a calculated score from 0 to 11. The cut-off value of a calculated score ≥ 4 yielded the highest sensitivity of 93% and specificity of 86%. Receiver operating characteristic (ROC) analysis showed the area under the curve reflecting an accuracy of this diagnostic test as 0.953. BHDS has several clinical features distinct from PSP. Our scoring system consists of only five clinical variables that are easily evaluated and efficiently separate BHDS patients from those who have PTX without relying on an imaging study. Further prospective study is needed to confirm our findings.


Activation of p38 MAPK and expression of TGF-β1 in rat colon enterocytes after whole body γ-irradiation.
To examine the p38 mitogen-activated protein kinase (p38) phosphorylation and transforming growth factor beta 1 (TGF-β1) expression in rat colon enterocytes after irradiation and their contribution to pathology of intestinal radiation disease. Male Wistar rats were irradiated with whole body γ-radiation of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 Gy ((60)Co, 1.44 Gy.min(-1)). Samples were taken 4 and 24 h after irradiation, immunohistochemically stained, then p38 phosphorylation and TGF-β1 expression were measured in apical and cryptal enterocytes using computer image analysis. In selected groups, morphometric parameters, mitosis and apoptosis were evaluated. P38 phosphorylation integrated optical density (IOD)-based levels increased 2.4-fold (p ≤ 0.01) and 3.6 to 22.8-fold (p ≤ 0.001) in apical enterocytes 4 h after 0.5 Gy and 24 h after 3-10 Gy, respectively. TGF-β1 IOD-based expression increased 3.3- to 6.9-fold (p ≤ 0.001) and 1.6- to 4.9-fold (p ≤ 0.001) in apical cells 4 h after 0.5-2, 4, 5 Gy and 24 h after 6-10 Gy, respectively. No changes were observed in crypts. We found a chronological and dose-dependent order of p38 activation and TGF-β1 expression in apical enterocytes. Transient up-regulation of p38 and TGF-β1 signalling observed 4 h after low-dose irradiation may participate in molecular mechanisms creating cellular over-expression in apical compartment, while persistent patterns measured 24 h after high-dose irradiation might provide protection of remaining cells in order to maintain tissue integrity.


FLT3 mutations in normal karyotype acute myeloid leukemia in first complete remission treated with autologous peripheral blood stem cell transplantation.
We retrospectively analysed the significance of FLT3 mutations in patients with acute myeloid leukemia (AML) having a normal karyotype, who were treated with high-dose chemotherapy and autologous peripheral blood stem cell transplantation (auto-PBSCT). In all, 34 patients with normal karyotype AML in first complete remission receiving high-dose chemotherapy and auto-PBSCT were analysed based on the presence or absence of FLT3/ITDs and FLT3/D835. They were 16 males and 18 females and with a median age of 41.5 years. FLT3/ITDs were detected in eight of 34 patients (23.5 %), and FLT3 D835 mutations in two of 34 patients (5.9%). White blood cell count (P=0.0087), serum concentration of lactate dehydrogenase (P=0.005), and percentages of peripheral blood (P=0.0131) and bone marrow (BM) blasts (P=0.0312) were significantly higher in patients showing the FLT3 mutations. Overall survival (OS) and disease-free survival (DFS) were similar between patients with or without FLT3 mutations (5 year DFS, 67.5 vs 68.55%, P=0.819; 5 year OS, 64.81 vs 78.88%, P=0.4457, by the log-rank test). FLT3 mutations demonstrate no further prognostic impact in patients with normal karyotype AML in first CR treated with high-dose chemotherapy and auto-PBSCT. Myeloablative chemotherapy supported by auto-PBSCT may overcome any poor prognostic implications of FLT3 mutations.


Diagnostic precision of endoanal MRI in the detection of anal sphincter pathology: a meta-analysis.
This study aims to evaluate the diagnostic precision of endoanal magnetic resonance imaging in identifying anal sphincter injury and/or atrophy when compared with either endoanal ultrasound or surgical diagnosis. Quantitative meta-analysis was performed on nine studies, comparing endoanal MRI with endoanal ultrasound or surgical diagnosis in 157 patients. Sensitivity, specificity, and diagnostic odds ratio were calculated for each study. Summary receiver operating characteristic curves (SROC) and subgroup analysis were undertaken. The overall sensitivity and specificity of endoanal MRI for external sphincter injury was 0.78 (95%CI: 0.66-0.84) and 0.66 (95%CI: 0.51-0.79), respectively. For internal sphincter injury detection, this was 0.63 (95%CI: 0.50-0.74) and 0.71 (95%CI: 0.60-0.81), respectively. For detection of atrophy, this was 0.86 (95%CI: 0.71-0.95) and 0.82 (95%CI: 0.65-0.93), respectively. The area under the SROC curve and diagnostic odds ratio were 0.84 (SE = 0.07) and 6.14 (95%CI: 2.17-17.4) for external sphincter injury, 0.79 (SE = 0.07) and 4.60 (95%CI: 1.75-12.15) for internal sphincter injury, and 0.92 (SE = 0.08) and 21.49 (95%CI: 2.87-160.64) for sphincter atrophy. Endoanal MRI was sensitive and specific for the detection of external sphincter injury and especially sphincter atrophy. It may be useful as an alternative to endoanal ultrasound in patients presenting with fecal incontinence, although further clinical studies are needed to identify its best application in clinical practice.


A Pilot Study of Perceptual-Motor Training for Peripheral Prisms.
Peripheral prisms (p-prisms) shift peripheral portions of the visual field of one eye, providing visual field expansion for patients with hemianopia. However, patients rarely show adaption to the shift, incorrectly localizing objects viewed within the p-prisms. A pilot evaluation of a novel computerized perceptual-motor training program aiming to promote p-prism adaption was conducted. Thirteen patients with hemianopia fitted with 57Δ oblique p-prisms completed the training protocol. They attended six 1-hour visits reaching and touching peripheral checkerboard stimuli presented over videos of driving scenes while fixating a central target. Performance was measured at each visit and after 3 months. There was a significant reduction in touch error (P = 0.01) for p-prism zone stimuli from pretraining median of 16.6° (IQR 12.1°-19.6°) to 2.7° ( IQR 1.0°-8.5°) at the end of training. P-prism zone reaction times did not change significantly with training (P > 0.05). P-prism zone detection improved significantly (P = 0.01) from a pretraining median 70% (IQR 50%-88%) to 95% at the end of training (IQR 73%-98%). Three months after training improvements had regressed but performance was still better than pretraining. Improved pointing accuracy for stimuli detected in prism-expanded vision of patients with hemianopia wearing 57Δ oblique p-prisms is possible and training appears to further improve detection. This is the first use of this novel software to train adaptation of visual direction in patients with hemianopia wearing peripheral prisms.


Knowledge, attitudes, and behavior of occupational physicians related to burn cases: a cross-sectional survey in Turkey.
The primary care of victims of burns at the workplace is provided by occupational physicians. In Turkey, the routine practice is to certify physicians for work in occupational medicine. The aim was to evaluate the knowledge, attitudes, and behavior of occupational physicians regarding burn cases. A total of 510 occupational physicians working in Ankara were surveyed by mail, and 101 (19.8%) physicians responded. Most of these physicians (n=67, 66.3%) had encountered burn cases within the prior year. The most frequent type of burn was scalds (n=55, 54.5%) followed by thermal burns (n=37, 36.6%). Of the respondents, 22 (21.8%) knew the most appropriate classification of burns. Regarding first-aid treatments prior to triage, only 4% chose the valid items. The mean rate of favourable attitudes of the participants toward first aid of different types of burn injuries was 70.8%. Only 31.7% of the physicians surveyed used up-to-date first-aid modalities. We conclude that Turkish occupational physicians have inadequate knowledge and inappropriate attitudes toward the first aid and primary care of burn victims. With the vital support of the Burn and Fire Disaster Institute at Başkent University, nationwide educational policies could be improved and assessed.


TV pattern evoked cortical responses without and with film mixing.
To obtain measurable TV pattern evoked cortical responses of children, the alpha-rhythm of the EEG must be suppressed. In our study, mixing pattern stimuli and film proved to be an effective way of doing this.


Senescent cells form nuclear foci that contain the 26S proteasome.
The proteasome plays a central role in intracellular protein degradation. Age-dependent decline in proteasome activity is associated with cellular senescence and organismal aging; however, the mechanism by which the proteasome plays a role in senescent cells remains elusive. Here, we show that nuclear foci that contain the proteasome and exhibit liquid-like properties are formed in senescent cells. The formation of senescence-associated nuclear proteasome foci (SANPs) is dependent on ubiquitination and RAD23B, similar to previously known nuclear proteasome foci, but also requires proteasome activity. RAD23B knockdown suppresses SANP formation and increases mitochondrial activity, leading to reactive oxygen species production without affecting other senescence traits such as cell-cycle arrest and cell morphology. These findings suggest that SANPs are an important feature of senescent cells and uncover a mechanism by which the proteasome plays a role in senescent cells.


AMPK Promotes Autophagy by Facilitating Mitochondrial Fission.
AMPK senses decreased cellular energy levels, triggering mitochondrial autophagy or mitophagy through activating ULK1 and inhibiting mTORC1. In a recent report, Toyama et al. (2016) show that activated AMPK phosphorylation of MFF is critical for mitochondrial fission. Unphosphorylatable MFF mutants block mitophagy, connecting AMPK to mitochondrial fission and to mitophagy.


Dissociation of anorectic and affective responses to epinephrine and glucose in rats.
The purpose of this study was to determine whether the anorexia following epinephrine and glucose IP injections is due to the activation of mechanisms of satiety. Epinephrine (100 micrograms.kg-1) and glucose (4 g.kg-1) were injected IP in rats. In control sessions for epinephrine test, rats received IP saline, and IM epinephrine. In control sessions for the glucose test, rats received IP NaCl, isoosmotic to the glucose solution. Food intake or taste reactivity to a sucrose solution was recorded after these treatments. Epinephrine and glucose decreased food intake by 75% (p < 0.001), and 49% (p < 0.01), compared to their controls. No change of taste reactivity responses was observed with any of these treatments. Twelve-hour fasting did not modify the general taste reactivity responses when compared to the responses evoked in rats fed ad lib. These results might be explained by the fact that anorexia could be obtained by a suppression of hunger without the activation of the mechanisms of satiety. This in turn would imply a possible dissociation between the signals and physiological pathways normally involved in hunger and satiety.


Immunolocalization of detergent-susceptible nucleoplasmic lamin A/C foci by a novel monoclonal antibody.
The A-type lamins are localized in the interior of the nucleus as well as on the nuclear periphery. In this study, we have characterized a monoclonal antibody LA-2F9 produced against recombinant rat lamin A which stains a subpopulation of various cell types in a pattern of small nucleoplasmic foci that are unusually susceptible to mild detergent/salt extraction. The specific reactivity of mAb LA-2F9 towards lamins was confirmed by immunoblotting of HeLa and C3H10T(1/2) whole cell lysates and nuclear lysates. The epitope for LA-2F9 was narrowed down to amino acid residues 268-278 (SAKLDNARQSA). To check whether the appearance of lamin foci was cell-cycle-dependent, C3H10T(1/2) cells were serum-starved and then refed to trigger cells to enter the G(1) phase of the cell-cycle. The intensity of staining increased 3.5-fold within 6 h of refeeding, when the maximum number of cells were labeled with LA-2F9. We also checked whether the LA-2F9 foci colocalized with nuclear proteins known to be distributed in small foci such as hnRNPs, snRNPs, SC-35, and p80 coilin, but did not find evidence of colocalization. Our studies suggest that LA-2F9 has a novel and specific reactivity towards detergent-susceptible lower order lamin structures that are likely to be assembly intermediates.


A two-dimensional NMR study of the antimicrobial peptide magainin 2.
Using two-dimensional NMR spectroscopy, a complete 1H resonance assignment has been obtained for the peptide magainin 2 recently isolated from Xenopus laevis. It is demonstrated that this peptide adopts an alpha-helical structure with amphiphilic character when dissolved in a mixture of trifluoroethanol (TFE) and H2O. The transition to the alpha-helical conformation occurs at very low concentrations of TFE.


Understanding the landscape of web-based medical misinformation about vaccination.
Given the high rates of vaccine hesitancy, web-based medical misinformation about vaccination is a serious issue. We sought to understand the nature of Google searches leading to medical misinformation about vaccination, and guided by fuzzy-trace theory, the characteristics of misinformation pages related to comprehension, inference-making, and medical decision-making. We collected data from web pages presenting vaccination information. We assessed whether web pages presented medical misinformation, had an overarching gist, used narrative, and employed emotional appeals. We used Search Engine Optimization tools to determine the number of backlinks from other web pages, monthly Google traffic, and Google Keywords. We used Coh-Metrix to measure readability and Gist Inference Scores (GIS). For medical misinformation web pages, Google traffic and backlinks were heavily skewed with means of 138.8 visitors/month and 805 backlinks per page. Medical misinformation pages were significantly more likely than other vaccine pages to have backlinks from other pages, and significantly less likely to receive at least one visitor from Google searches per month. The top Google searches leading to medical misinformation were "the truth about vaccinations," "dangers of vaccination," and "pro con vaccines." Most frequently, pages challenged vaccine safety, with 32.7% having an overarching gist, 7.7% presenting narratives, and 17.3% making emotional appeals. Emotional appeals were significantly more common with medical misinformation than other high-traffic vaccination pages. Misinformation pages had a mean readability grade level of 11.5, and a mean GIS of - 0.234. Low GIS scores are a likely barrier to understanding gist, and are the "Achilles' heel" of misinformation pages.


Attachment, recalled parental rearing, and ADHD symptoms predict emotion processing and alexithymia in adults with ADHD.
The aim of the aricle is to study the relationship between attachment, parental rearing behavior, and (infant and current) ADHD symptoms with emotion processing and alexithymia in adults with ADHD. Attachment, parental behavior, and ADHD variables were tested for predictive value regarding emotion processing and alexithymia in the total sample, the pooled ADHD groups (with inattentive type and combined type, each with n = 26) and a control group (n = 26). Comparisons were performed between the pooled ADHD groups and the control group, and between the ADHD subtype groups regarding all emotion processing and alexithymia, and attachment-related measures. Emotion processing/alexithymia parameters were mainly predicted by early or current attachment-related features, and, to a lesser extent, by childhood or current ADHD symptoms, primarily in the ADHD groups. The findings suggest partly specific and possibly causal relationships between attachment-related features and current emotion processing/alexithymia in adults with ADHD. The results confirm the necessity for further study of the multiple interactions between infant and parental ADHD symptoms, aversive parenting, and attachment with respect to emotional functioning in adult ADHD.


Piezoelectric Osteotomies in Dorsal Preservation Rhinoplasty.
Dorsal preservation rhinoplasty requires precise management of the osseocartilaginous vault. Ultrasonic piezo instruments offer several advantages compared with traditional tools such as hand saws, rasps, and osteotomes. As always, an understanding of the dynamics of manipulation of the vault, anatomy, and proper technique are paramount and are reviewed herein.


Pacemaker leads and cardiac perforation.
This case series highlights the rare but potentially life threatening complication of ventricular perforation caused by pacemaker leads and discusses appropriate investigations and management strategies.


Characterization of jejunal absorption and apical efflux of ropivacaine, lidocaine and bupivacaine in the rat using in situ and in vitro absorption models.
The purpose of this study was to characterize the rat jejunal passive transport and the possible active efflux of three local anaesthetics, ropivacaine, lidocaine and bupivacaine using two different absorption models, the in situ single-pass intestinal perfusion and the in vitro Ussing chamber model, as well as P-glycoprotein (Pgp)-mediated calcein transport inhibition in Caco-2 cells. Concentration and pH dependence, efflux inhibition by verapamil and digoxin and bi-directional permeability studies were performed to investigate the potential involvement of efflux carriers in the intestinal absorption of the local anaesthetics. In the jejunal perfusion the permeability of these agents appeared to be high, predicting complete intestinal absorption (>90%). There was no effect of the Pgp inhibitors on net absorption for any of the local anaesthetics in the two absorption models. However, in the Ussing chamber at an equal pH of 7.4 at mucosal and serosal sides, the observed jejunal permeability ratios (S-M)/(M-S), of 2.3, 1.8 and 3.0 for ropivacaine, lidocaine and bupivacaine, respectively, indicated at least some involvement of carrier-mediated intestinal secretion. This idea was supported in the calcein AM Pgp transport assay in which two of the tested local anaesthetic agents affected cellular calcein retention. As anticipated for these agents, the mucosal pH conditions were shown to largely affect the gut permeability. The jejunal permeabilities of the local anaesthetics as measured in the two absorption models fitted well in a model comparison that incorporated the permeabilities of six other structurally unrelated drugs. In conclusion, the jejunal permeability of ropivacaine, lidocaine and bupivacaine was high and although evidence was obtained for carrier-mediated intestinal efflux this process appeared not to have a significant influence on the rate and extent of in vivo intestinal absorption. Rather, passive diffusion of these agents seems to be the major mechanism for the intestinal absorption.


3D organization of regulatory elements for transcriptional regulation in Arabidopsis.
Although spatial organization of compartments and topologically associating domains at large scale is relatively well studied, the spatial organization of regulatory elements at fine scale is poorly understood in plants. Here we perform high-resolution chromatin interaction analysis using paired-end tag sequencing approach. We map chromatin interactions tethered with RNA polymerase II and associated with heterochromatic, transcriptionally active, and Polycomb-repressive histone modifications in Arabidopsis. Analysis of the regulatory repertoire shows that distal active cis-regulatory elements are linked to their target genes through long-range chromatin interactions with increased expression of the target genes, while poised cis-regulatory elements are linked to their target genes through long-range chromatin interactions with depressed expression of the target genes. Furthermore, we demonstrate that transcription factor MYC2 is critical for chromatin spatial organization, and propose that MYC2 occupancy and MYC2-mediated chromatin interactions coordinately facilitate transcription within the framework of 3D chromatin architecture. Analysis of functionally related gene-defined chromatin connectivity networks reveals that genes implicated in flowering-time control are functionally compartmentalized into separate subdomains via their spatial activity in the leaf or shoot apical meristem, linking active mark- or Polycomb-repressive mark-associated chromatin conformation to coordinated gene expression. The results reveal that the regulation of gene transcription in Arabidopsis is not only by linear juxtaposition, but also by long-range chromatin interactions. Our study uncovers the fine scale genome organization of Arabidopsis and the potential roles of such organization in orchestrating transcription and development.


Targeting ER stress/PKA/GSK-3β/β-catenin pathway as a potential novel strategy for hepatitis C virus-infected patients.
Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). The HCC risk, while decreased compared with active HCV infection, persists in HCV-cured patients by direct-acting antiviral agents (DAA). We previously demonstrated that Wnt/β-catenin signaling remained activated after DAA-mediated HCV eradication. Developing therapeutic strategies to both eradicate HCV and reverse Wnt/β-catenin signaling is needed. Cell-based HCV long term infection was established. Chronically HCV infected cells were treated with DAA, protein kinase A (PKA) inhibitor H89 and endoplasmic reticulum (ER) stress inhibitor tauroursodeoxycholic acid (TUDCA). Western blotting analysis and fluorescence microscopy were performed to determine HCV levels and component levels involved in ER stress/PKA/glycogen synthase kinase-3β (GSK-3β)/β-catenin pathway. Meanwhile, the effects of H89 and TUDCA were determined on HCV infection. Both chronic HCV infection and replicon-induced Wnt/β-catenin signaling remained activated after HCV and replicon eradication by DAA. HCV infection activated PKA activity and PKA/GSK-3β-mediated Wnt/β-catenin signaling. Inhibition of PKA with H89 both repressed HCV and replicon replication and reversed PKA/GSK-3β-mediated Wnt/β-catenin signaling in both chronic HCV infection and replicon. Both chronic HCV infection and replicon induced ER stress. Inhibition of ER stress with TUDCA both repressed HCV and replicon replication and reversed ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling. Inhibition of either PKA or ER stress both inhibited extracellular HCV infection. Targeting ER stress/PKA/GSK-3β-dependent Wnt/β-catenin signaling with PKA inhibitor could be a novel therapeutic strategy for HCV-infected patients to overcomes the issue of remaining activated Wnt/β-catenin signaling by DAA treatment. Video Abstract.


The influence of matrix properties on growth and morphogenesis of human pancreatic ductal epithelial cells in 3D.
A highly tunable synthetic biomimetic hydrogel platform was developed to study the growth and morphogenesis of pancreatic ductal epithelial cells (PDEC) under the influence of a myriad of instructive cues. A PDEC line, PANC-1, was used as a model system to illustrate the importance of matrix compositions on cell fate determination. PANC-1 is an immortalized ductal epithelial cell line widely used in the study of pancreatic tumor cell behaviors. PANC-1 cells are also increasingly explored as a potential cell source for endocrine differentiation. Thus far, most studies related to PANC-1, among other PDEC lines, are performed on 2D culture surfaces. Here, we evaluated the effect of matrix compositions on PANC-1 cell growth and morphogenesis in 3D. Specifically, PANC-1 cells were encapsulated in PEG-based hydrogels prepared by step-growth thiol-ene photopolymerization. It was found that thiol-ene hydrogels provided a cytocompatible environment for encapsulation and 3D culture of PANC-1 cells. In contrast to a monolayer morphology on 2D culture surfaces, PANC-1 cells formed clusters in 3D thiol-ene hydrogels within 4 days of culture. After culturing for 10 days, however, the growth and structures of these clusters were significantly impacted by gel matrix properties, including sensitivity of the matrix to proteases, stiffness of the matrix, and ECM-mimetic motifs. The use of matrix metalloproteinase (MMP) sensitive linker or the immobilization of fibronectin-derived RGDS ligand in the matrix promoted PANC-1 cell growth and encouraged them to adopt ductal cyst-like structures. On the other hand, the encapsulated cells formed smaller and more compact aggregates in non-MMP responsive gels. The incorporation of laminin-derived YIGSR peptide did not enhance cell growth and caused the cells to form compact aggregates. Immobilized YIGSR also enhanced the expression of epithelial cell markers including β-catenin and E-cadherin. These studies have established PEG-peptide hydrogels formed by thiol-ene photo-click reaction as a suitable platform for studying and manipulating pancreatic epithelial cell growth and morphogenesis in 3D.


Inhibition of platelet aggregation by S-(1,2-dicarboxyethyl)glutathione, intrinsic tripeptide in liver, heart, and lens.
S-(1,2-Dicarboxyethyl)glutathione (DCE-GS) found in animal tissues or baker's yeast showed strong inhibitory effects on blood coagulation and platelet aggregation. The inhibitory effect of blood coagulation was almost the same as those of EDTA, oxalate, and citrate. DCE-GS did not show chelating activity. As for ADP- or thrombin-induced platelet aggregations, DCE-GS exerted a potent effect on the secondary aggregation, while it was less active in the primary aggregation. DCE-GS gave a distinct lag period in the time course of the secondary aggregation induced by collagen and inhibited most strongly the aggregation induced by arachidonic acid compared with those elicited by ADP, thrombin, and collagen. The peptide, however, did not inhibit the platelet aggregation induced by 12-O-tetradecanoylphorbol-13-acetate. Although both DCE-GS and EDTA inhibited the platelet aggregation which was triggered by ADP, their inhibitory manners were entirely different.


A "do-it-yourself" array biosensor.
We have developed an array biosensor for the simultaneous detection of multiple targets in multiple samples within 15-30 min. The biosensor is based on a planar waveguide, a modified microscope slide, with a pattern of small (mm2) sensing regions. The waveguide is illuminated by launching the emission of a 635 nm diode laser into the proximal end of the slide via a line generator. The evanescent field excites fluorophores bound in the sensing region and the emitted fluorescence is measured using a Peltier-cooled CCD camera. Assays can be performed on the waveguide in multichannel flow chambers and then interrogated using the detection system described here. This biosensor can detect many different targets, including proteins, toxins, cells, virus, and explosives with detection limits rivaling those of the ELISA detection system.


DIP2C polymorphisms are implicated in susceptibility and clinical phenotypes of autism spectrum disorder.
Disco-interacting protein 2 C (DIP2C) has recently been reported as a new susceptibility gene for autism spectrum disorder (ASD) in a genome-wide association study. We evaluated associations between single nucleotide polymorphisms (SNPs) of DIP2C and ASD susceptibility in a case-control study (715 ASD cases and 728 controls) from Chinese Han. We identified a significant association between SNPs (rs3740304, rs2288681, rs7088729, rs4242757, rs10795060, and rs10904083) and ASD susceptibility. Of note, rs3740304, rs2288681, and rs7088729 are positively associated with ASD under inheritance models; moreover, haplotypes with any two marker SNPs (rs3740304 [G], rs2288681 [C], rs7088729 [T], rs4242757 [C], rs10795060 [G], and rs10904083 [A]) are also significantly associated with ASD. Additionally, rs10795060 and rs10904083 are associated with "visual reaction" phenotypes of ASD. DIP2C polymorphisms sort out the susceptibility and clinical phenotypes of autism spectrum disorder.


Abatement of NO3-N concentration in agricultural waters by narrow buffer strips.
The performance of narrow buffer strips in abating the NO3-N concentrations in the water coming from cropland was tested in an experiment carried out on the low plains of the Veneto Region (northeast Italy). The buffer was composed of a 5-m wide grass strip and a 1-m wide row of trees. Maize and wheat were cultivated in the neighbouring field during the monitoring period (December 1997-June 1999). Four experimental conditions were monitored, deriving from a combination of two levels of crop N fertilisation and two sizes of buffer trees. The narrow buffer was very effective in abating NO3-N concentrations, allowing water to be discharged with a concentration always below 2 ppm. Its zone of influence might be bigger than its simple width. The abatement was also efficient during winter. Tree size showed no evident effect on the reduction of the concentration.


Surgical resection and liver transplantation for hepatocellular carcinoma.
With a better understanding of the natural history of hepatocellular carcinoma (HCC) and the improvement in imaging, locoregional therapies, surgical techniques, and postoperative care, patients with HCC are now managed by a multidisciplinary team. Partial hepatic resection can be curative in patients developing HCC in the setting of normal liver parenchyma and in patients with early cirrhosis but well-preserved hepatic synthetic function. Liver transplantation offers the best long-term survival and lowest incidence of tumor recurrence in select patients with HCC and underlying cirrhosis. This article discusses the role of surgical resection and liver transplantation in the management of HCC.


The Role of Targeted HIV Screening in the Emergency Department: A Scoping Review.
Human immunodeficiency virus (HIV) infection continues to expand worldwide, and a significant proportion of infection is still undiagnosed. Recent studies have addressed the impact and feasibility of 'opt-out' HIV screening in Emergency Departments (EDs) in urban settings at high HIV prevalence, whereas little is known about the yield of implementing 'targeted' HIV testing, especially in low-prevalence areas. The present study undertakes a scoping review of research carried out on the implementation of targeted HIV screening of adult in EDs to determine the impact, feasibility and acceptability of HIV testing in different HIV prevalence settings. Online databases (EMBASE, MEDLINE) were used to identify papers published between 2000 to 2020. A three-concept search was employed with HIV (HIV, Human immunodeficiency virus infection, HIV infections), targeted testing (Target, screening or testing) and emergency medicine (Emergency Service, emergency ward, A&E, accident and emergency or Emergency Department) (28th February 2020). Only full-text articles written in English, French, Spanish or Italian and using impact and/or feasibility and/or acceptability of the program as primary or secondary outcomes were analysed. The search provided 416 articles. Of these, 12 met inclusion criteria and were included in the final review. Most of the included studies were carried out in the United States (n=8; 67%) and in areas of high HIV prevalence (n=11; 92%). Three (20%) were randomized control studies. While the rate of newly diagnosed HIV cases varied widely (0.03-2.2%), likely due to methodological heterogeneity between studies, the linkage of new HIV diagnosis was often high (80-100%) and median CD4+ cell count was always greater than 200 cells per microliter. Targeted HIV screening was found to be cost-effective (out of 2 studies) and well accepted by participants (out 2 studies). Targeted HIV screening at the ED can be impactful, feasible and well accepted, but often requires extra funding and staff. Most previous work has focused on areas of high disease prevalence.


Variation in immuno-reproductive milieu of testis in Clarias magur from pre-spawning to spawning phase: An indication towards non-canonical role of immune elements in testes.
Immune mechanisms are major players in ensuring the normal functioning of testicular functions. However, apart from their role in active defence against pathogens, prior studies have also suggested a possibility for reproduction-related (non-immune) functions of certain immune elements. This study employs a comparative transcriptomics approach followed by network analysis for tracking the variation in the immuno-reproductive milieu of Clarias magur testis in spawning versus pre-spawning phase. The results show a significant modulation of both reproduction and immune-relevant genes in spawning versus pre-spawning phase. The functional enrichment of the upregulated reproduction-relevant gene network also shows immune-related biological processes which indicates a probability of involvement of these candidates in spermatogenesis-related events for switching from pre-spawning to spawning phase. The upregulated immune network is highly dense with 40 hubs, 10 cluster sub-networks and 142 functionally enriched pathways in comparison to its downregulated counterpart with only 5 hubs, 1 cluster and 1 enriched pathway. These findings indicate that the synchronisation in modulation of both reproductive and immune-related factors is critical for progression of testicular events guiding the switch from pre-spawning to spawning phase. The reproductive phase-dependent variation in plasma sex steroid levels and the selected genes for quantitative PCR also corroborated this hypothesis. The study also serves as a preliminary screening step for probable immune candidates that may be involved in reproductive functions of testis in addition to defence.


Structure of herbivore communities in two oak (Quercus spp.) hybrid zones.
We examined patterns of density and species diversity for leaf-mining Lepidopterans and gall-forming Hymenopterans in two oak (Quercus spp.) hybrid zones: Quercus depressipes x Q. rugosa and Q. emoryi x Q. coccolobifolia. In both species complexes, hybrid hosts typically supported significantly lower densities and species diversity of parasites than did parental types. This contradicts the findings of Whitham (1989) that suggested that hybrid hosts may act as parasite sinks both in ecological and evolutionary time. We discuss features of hybrid zones that are likely to influence patterns of herbivory.


Experience of wrong-site tooth extraction among Nigerian dentists.
To report the experience of wrong-site tooth extraction among Nigerian dentists. A self-administered questionnaire was distributed among a cross-section of Nigerian dentists. Information requested included personal experience on wrong-site tooth/teeth extraction and its after-effect, possible reasons for wrong-site tooth extraction and documentation of the event in patients' case. Respondents were also asked if they were aware of any colleagues who had previously experienced wrong-site tooth extraction and possible legal implication of the event, and if they aware of the universal protocol for preventing wrong site, wrong procedure, and wrong person surgery. Twenty-two (13%) of the respondents reported having extracted a wrong tooth. The event occurred within 5 years after graduation in most cases. Most respondents (53.6%) informed the patient immediately after the event. Only 68% of the respondents documented the event in patient's case record. Most common reasons for wrong-site tooth extraction were heavy workload, presence of multiple condemned teeth and miscommunication between dentists. Fifty-five percent of respondents were aware of a colleague who had extracted a wrong tooth. The most probable legal implication of wrong-site tooth extraction according to the respondents was litigation by the patient. Only 25% of dentists were aware of a universal protocol for preventing wrong-site surgery. Wrong tooth/teeth extraction is not an uncommon event in the studied environment. The need to be familiar with universal protocol on wrong-site surgery and its legal implications are highlighted.


Efficacy of benzoxazinorifamycins in a mouse model of Chlamydia pneumoniae lung infection.
The efficacy of rifalazil and other benzoxazinorifamycins was tested in a mouse model of lung infection against Chlamydia pneumoniae. Rifalazil and six related new chemical entities all showed efficacy after one dose per day for 3 days at either 3 or 1 mg/kg of body weight.


Persistence of habituation deficits after neurological recovery from severe thiamine deprivation.
Rats were fed a thiamine-deficient diet for 4 weeks and injected daily with pyrithiamine during the last two weeks of the diet. This regime induced severe neurological anomalies such as ataxia, loss of righting reflex and visual place reflex, and finally full tonic-clonic seizures. These symptoms are reminiscent of the clinical Wernicke-Korsakoff syndrome. Injection of thiamine dramatically reversed these symptoms within one or two hours as seen in Wernicke patients. Six weeks later these rats showed a marked deficit in habituation of exploratory behavior and of the auditory orienting response. To what extent this chronic deficit in habituation contributes to the cognitive dysfunctions seen in Wernicke-Korsakoff patients is discussed. Histological examination of the brains of 6 of the rats revealed a heterogeneous pattern of damage to the brainstem, including mamillary bodies and several thalamic nuclei, reminiscent of that seen in Korsakoff patients. In addition there were many dark abnormal cells in limited fields of hippocampus neocortex and thalamus in almost all animals.


Neuroticism and sudden cardiac death: a prospective cohort study from UK biobank.
There is a paucity of evidence on the risk of sudden cardiac death (SCD) according to the degree of neuroticism. We sought to evaluate the association between neuroticism and the long-term risk of SCD. From the UK Biobank nationwide prospective cohort, participants free from previous SCD, ventricular arrhythmias, implantable cardioverter-defibrillator (ICD) insertion, depression, schizophrenia, and bipolar disorder were selected. The 12-item scale of neuroticism measurement (neuroticism score) was categorized into high (≥ 3) and low (< 3) groups. The primary outcome was SCD including ventricular fibrillation (VF) at median 12.6 years of follow-up. The outcomes were compared between the groups using multivariable Cox regression and inverse probability of treatment weighting (IPTW). A total of 377,563 participants (aged 56.5 ± 8.1, 53.1% women) were analyzed. The high neuroticism score group had a significantly lower risk of SCD (adjusted hazard ratio [aHR] = 0.87, 95% confidence interval [CI] 0.79-0.96, P = 0.007; IPTW-adjusted HR [IPTW-HR] 0.87 [0.77-0.97], P = 0.016) than the low neuroticism score group. The effect of a high neuroticism score on the decreased risk of SCD was more prominent in women (IPTW-HR 0.71 [0.56-0.89], P = 0.003) than in men (IPTW-HR 0.93 [0.82-1.07], P = 0.305, P-for-interaction = 0.043). Sex differences were observed among independent predictors for incident SCD, emphasizing the protective role of a high neuroticism score and moderate-to-vigorous physical activity only in women. A high neuroticism score was significantly associated with a lower risk of SCD, particularly in women. Efforts to unveil the causal and mechanistic relationship between personality phenotypes and the risk of SCD should be continued.


"Never Land": Where do imaginary worlds come from?
We assume "Imaginary worlds" to be unreal and unfamiliar: high fantasy. I argue they are real and familiar to authors because they comprise memory elements, which blend experience, knowledge, beliefs and pre-occupations. These "bits and pieces" from memories can generate a world, which readers experience as pure imagination. I illustrate using J.M. Barrie's "Never Land" and J.R.R. Tolkien's "Middle-Earth."


Spinal cord cavernoma resection using a fiber-optic CO2 laser.
Spinal cord cavernomas are rare, and progressive growth can lead to neurologic deterioration. Complete microsurgical resection using the OmniGuide® fiber-optic CO2 laser is safe, precise, and can prevent further neurological deterioration. We describe the process, risks, and benefits associated with this approach. Once the cavernoma is isolated, the CO2 laser enables the surgeon to incise and photocoagulate with the same instrument, increasing the accuracy and potentially reducing the procedure's duration. The spinal cord and surrounding tissue are protected from the laser by cerebrospinal fluid and cottonoid pledges. The fiber-optic CO2 laser is safe and effective when resecting spinal cord cavernomas. Personal experience, coupled with recent literature, brings us to this conclusion.


[The distribution of nerve endings in the human cervical nerve roots].
To find out the distribution of nerve endings in the dural sheath of cervical nerve roots and to study the mechanism of cervical radicular pain. 2069 20 microm serial sections were made from 39 cervical root-dorsal root ganglion specimens obtained from 18 postmortems. By using optical microscope and Suzuki silver impregnation method and Klüver-Brrera method, we examined the morphology, quantity and distribution of the nerve ending in the nerve sheath of the root, dorsal root ganglion (DRG) and the spinal nerve of these sections. There were several kinds of nerve endings such as free nerve endings in the nerve sheath of the root, the dorsal root ganglion, and the spinal nerve. Free nerve endings were distributed in the proximal and distal portions of DRG sheath more extensive than that in other parts of the dural root-sheaths. The free nerve endings in the dural root-sheaths especially those in the DRG sheath are thought to play an important role in cervical radicular pain.


An experimental evaluation of the influence of water depth and bottom color on the Common kingfisher's foraging performance.
To investigate how depth and bottom color affect prey selectivity in Common kingfisher (Alcedo atthis), we developed several experimental procedures using captive birds. We used 20 young kingfishers to test depth (25 or 50cm) and color (natural gravel or white) effects on foraging behavior. Live freshwater fish were used as target prey. To assess differences resulting from the natural behavior of different fish, we chose bottom-dwelling [Ebro barbel (Barbus graellsii)] and open-water benthopelagic species [Ebro nase (Parachondrostoma miegii) and Pyrenean minnow (Phoxinus bigerri)]. The number of attempts and captures, as well as the effects of hunger and experience, were assessed relative to feeding behavior. The effect of fish behavior, as observed in grouped vs. isolated fish, on the kingfisher's performance was also tested. The results showed a significant effect of depth, with more attacks and greater success in shallow waters. No significant differences in catch success between natural- and white-colored bottoms were observed. Hunger had no effect on fishing success, but experience had a positive effect in shallow waters and on white bottoms. Both bottom- and open-water species were consumed equally. Kingfishers preyed more often upon grouped prey than upon isolated prey, although capture success did not vary between the two cases. Our results suggest that kingfishers prey upon the most accessible types of prey.


fMR-adaptation reveals a distributed representation of inanimate objects and places in human visual cortex.
The way information about objects is represented in visual cortex remains controversial. It is unclear, for example, whether information is processed in modules, specialized for different categories of objects or whether information is represented in a distributed fashion across a large network of overlapping visual areas. In this study, we used fMR-adaptation to investigate the extent to which 'specialized' regions of visual cortex are involved in representing information about inanimate objects and places. We found adaptation in the object-selective lateral occipital complex (LOC) following repeated presentations of the same inanimate object. However, we also found fMR-adaptation to inanimate objects in fusiform face area (FFA) and the parahippocampal place area (PPA). Furthermore, this adaptation was not affected by changes in the size of the stimulus. In the second part of the experiment, we found adaptation to repeated images of places in the place-selective PPA, which was both size- and viewpoint-invariant. fMR-adaptation to repeated images of places was also observed in the LOC, but not in the FFA. These results suggest that the representation of inanimate objects and places is not restricted to those regions showing maximal responses to these particular categories of objects, but is distributed across human visual cortex and can include 'face-selective' regions such as the FFA.


Streptozocin/5-fluorouracil chemotherapy is associated with durable response in patients with advanced pancreatic neuroendocrine tumours.
The role of systemic chemotherapy for pancreatic neuroendocrine tumours (pNET) is controversially discussed. Objective response rates (RR) reported for streptozocin (STZ)-based chemotherapy are variable and novel targeted drugs have recently been approved. However, the sequence of treatment remains unclear. We aimed to evaluate the efficacy of STZ plus 5-fluorouracil (STZ/5-FU) in a large pNET cohort. Data from 96 pNET patients treated with STZ/5-FU were analysed retrospectively. Endpoints of the study were RR, time to tumour progression (TTP) and overall survival (OS). Mean age of patients at the start of chemotherapy was 57.6years (range, 32.1-80.4). STZ/5-FU was the 1st line treatment in 56.3%. 11.5% had G1, 79.2% G2 and 6.3% G3 neoplasms. Baseline progression was evident in 74%. Objective response rate was 42.7%. 40.6% of patients showed stable disease as best response while 16.7% showed progressive disease. Treatment was discontinued due to toxicity in 16 patients. Median TTP and OS were 19.4 (95% confidence interval (CI), 13.6-25.2) and 54.8months (95% CI, 34.7-74.9), respectively. In Cox regression analysis, Ki67>15% was the only negative prognostic factor for TTP (hazard ratio (HR), 3.3; P<0.001), confirmed by multivariate analysis (HR, 6.7; P=0.001). STZ/5-FU was associated with considerable RR. Treatment was associated with durable TTP especially in patients with Ki67-index of ⩽15%. These findings along with good tolerability strengthen the value of this two-drug chemotherapy for the management of unresectable pNET.


Intravenous contrast medium accentuates the severity of acute necrotizing pancreatitis in the rat.
Contrast-enhanced computed tomography (CECT) is used to show areas of decreased pancreatic perfusion in severe acute pancreatitis (AP). To evaluate possible adverse effects of the contrast medium (CM) on the course of AP, the impact of intravenous CM in AP of graded severity in the rat was studied. Pancreatitis of three levels of severity was induced in Sprague-Dawley rats with intravenous cerulein hyperstimulation plus time- and pressure-controlled intraductal infusion of saline or glycodeoxycholic acid. At 7 hours, control and pancreatitis animals received intravenous ionic CM, nonionic CM, or saline. The principal outcome measures were 24-hour survival, trypsinogen activation peptides (TAP) in ascites, and histological acinar necrosis score. There was no measurable effect of CM on the index features in control animals or animals with mild or moderate AP. In severe AP, CM caused a significant increase in mortality, ascites TAP, and necrosis score. Intravenous CM increases pancreatic injury when administered early in the course of severe experimental AP. Because CM may convert borderline ischemia to irreversible necrosis, CECT performed early in pancreatitis to show poor perfusion and predict areas of necrosis may depict a self-fulfilling prophecy. Early CECT should be reconsidered and perhaps avoided.


Resistance characterization of ledipasvir and velpatasvir in hepatitis C virus genotype 4.
HCV genotype 4 (GT4) has often been overlooked in drug development, even though it infects ~20 million people worldwide. Ledipasvir/sofosbuvir and sofosbuvir/velpatasvir were highly efficacious in GT4 HCV-infected patients from GS-US-337-1119 and GS-US-342-1138. Here, we characterize the resistance profile of ledipasvir (LDV) and velpatasvir (VEL) in patients with GT4 HCV infection. NS5A deep-sequencing was performed for 454 patients infected with HCV GT4 at baseline, including 44 patients enrolled in GS-US-337-1119 and 116 patients enrolled in GS-US-342-1138, and at relapse for patients with virologic failure. LDV and VEL susceptibilities of 56 patient isolates were determined. In GS-US-337-1119, SVR12 rates were 100% for all subtypes except 4b and 4r. Phenotypic assessment of 56 HCV NS5A patient isolates from various GT4 subtypes indicated that LDV had high potency for the common subtypes 4a/d, and subtypes 4c/f/k/l/m/n/o/p/r/t despite the presence of resistance-associated substitutions (RASs). For the rare GT4b, LDV median EC50 was higher, but with a broad range of individual values. Importantly, all GT4b isolates tested had 2-4 NS5A RASs, some including Y93H. Similarly, the 2 GT4r infected patients who had virologic relapse had rare triple RASs. Reversion of these substitutions to the consensus residue significantly increased LDV susceptibility. In GS-US-342-1138, all patients achieved SVR12, regardless of their subtype or presence of RASs. In vitro data confirmed that VEL is potent against all GT4 isolates tested. LDV and VEL are potent antiviral drugs, estimated to be effective against >95% and >99%, respectively, of GT4 HCV isolates.


Phosphorylation of keratin polypeptides.
The phosphorylation of keratin polypeptides was examined in calf snout epidermis. When slices of epidermis were incubated in the medium containing 32Pi, the radioactivity was incorporated into several proteins. The predominant phosphorylated proteins migrated in SDS-polyacrylamide gels with apparent molecular weights between 49000 and 69000 and coincided with keratin polypeptides. The extent of keratin phosphorylation was not altered in the presence of dibutyryl cyclic AMP or reagents which elevate intracellular cyclic AMP. When homogenates of epidermis were incubated with [gamma-32P]ATP, keratin polypeptides were the predominant species phosphorylated as was also observed in epidermal slices. The presence of cyclic AMP or heat-stable inhibitor of cyclic AMP-dependent protein kinase in the reaction mixture did not affect the phosphorylation of keratin polypeptides, although the phosphorylation of exogenously-added histone was stimulated and inhibited, respectively, by these additions. Keratin polypeptides extracted from calf snout epidermis by 8 M urea were phosphorylated by incubation with [gamma-32P]ATP and cyclic AMP-dependent protein kinase from calf snout epidermis or bovine heart. No proteins were phosphorylated without the addition of the enzymes. The presence of cyclic AMP in the reaction mixture stimulated the keratin phosphorylation, and further addition of heat-stable protein kinase inhibitor reduced this stimulation.


Activity analysis of neural networks.
In a series of articles (Leung et al., 1973, 1974; Ogŭztöreli, 1972, 1975, 1978, 1979; Stein et al., 1974) we have investigated some of the physiologically significant properties of a general neural model. In these papers the nature of the oscillations occuring in the model has been briefly analyzed by omitting the effects of the discrete time-lags in the interaction of neurons, although these time-lags were incoporated in the general model. In the present work we investigate the effects of the time-lags on the oscillations which are intrinsic to the neural model, depending on the structural parameters such as external inputs, interaction coefficients, self-inhibition, self-excitation and self-adaptation coefficients. The numerical solution of the neural model, the computation of the steady-state solutions and the natural modes of the oscillations around the steady-state solutions are described.


Uptake and degradation of 125I-labelled high density lipoproteins in rat liver cells in vivo and in vitro.
1. The uptake of 125I-labelled high density lipoproteins (HDL) in various organs of the rat was determined after an intravenous injection. The uptake of 125I-labelled polyvinylpyrrolidone in the same organs was determined in order to assess uptake by fluid endocytosis. The uptake/organ was highest for the liver. The adrenals showed the highest uptake/unit weight of the organs studied. The liver, the kidneys and the spleen showed comparable values for uptake/g of tissue. The uptake of 125I-labelled HDL exceeded by far that of 125I-labelled polyvinylpyrrolidone in the liver, the kidneys, the spleen and the adrenals, indicating that the uptake of 125I-labelled HDL was mediated by adsorptive endocytosis. 2. The in vivo uptake of 125I-labelled HDL was determined in purified hepatocytes and non-parenchymal cells prepared by collagenase perfusion of livers from animals after intravenous injections of 125I-labelled HDL. When expressed per cell, the hepatocytes and the non-parenchymal liver cells took up about the same amount of 125I-labelled HDL. 3. The in vitro uptake and degradation of 125I-labelled HDL in isolated rat hepatocytes was studied. The uptake at increasing concentrations of 125I-labelled HDL was saturable indicating uptake mediated through binding sites. 125I-labelled HDL were easily degraded by contaminating proteases from the perfusate. 4. Subcellular fractionation by isopycnic centrifugation indicated that the accumulation of 125I-labelled HDL did not take place in the lysosomes, but rather on the plasma membrane and possibly in the endosomes (phagosomes). 5. 125I-labelled HDL were internalized into the cells and degraded in the lysosomes. Leupetin and chloroquine, inhibitors of the lysosomal function effectively inhibited the formation of 125I-labelled acid-soluble radioactivity by the cells. Chloroquine, but not the protease inhibitor leupeptin, reduced the hydrolysis of the cholesteryl ester moiety of HDL.


Different functional connectivity modes of the right fronto-insular cortex in akinetic-rigid and tremor-dominant Parkinson's disease.
Patients with akinetic-rigid Parkinson's disease (AR-PD) are more prone to cognitive decline and depressive symptoms than tremor-dominant PD (TD-PD) patients. The right fronto-insular cortex (rFIC), as a key node of salience network, plays a critical role in the switching between central executive network and default mode network. In this study, we explored the functional connectivity mode of rFIC with triple-brain networks, namely default mode network, salience network, and central executive network, in two motor subtypes of PD. We recruited 44 PD patients (including the TD-PD group and AR-PD group) and 18 age-matched healthy controls (HCs). We performed functional connectivity (FC) analysis of resting-state functional MRI. Compared with TD-PD, decreased FC were found in the right insular cortex and bilateral anterior cingulate gyrus in AR-PD. Compared with HCs, decreased FC in the bilateral insula, the anterior cingulate gyrus, the precentral gyrus, and the right medial frontal gyrus were found; therein, the FC value of rFIC-precentral gyrus was positively correlated with the Unified Parkinson's Disease Rating Scale-II score in AR-PD (p = 0.0482, r = 0.4162). While TD-PD showed decreased FC in the left insula as well as bilateral anterior cingulate gyrus when compared with HCs, and the FC value of the rFIC-left insula was positively correlated with its Hamilton Depression Rating Scale score (p = 0.02, r = 0.50). The functional connectivity mode of rFIC in AR-PD differed from that in TD-PD. The decreased rFIC FC with the other nodes of salience network might be a potential indicator for AR-PD patients prone to develop cognitive decline and depressive symptoms.


Association between short-term exposure to PM2.5 and nasal microbiota dysbiosis, inflammation and oxidative stress: A panel study of healthy young adults.
Fine particulate matter (PM2.5) is the primary environmental stressor and a significant threat to public health. However, the effect of PM2.5 exposure on human nasal microbiota and its pathophysiological implication remain less understood. This study aimed to explore the associations of PM2.5 exposure with indices of nasal microbiota and biomarkers of nasal inflammation and oxidative stress. We conducted a panel study with 75 students in Xinxiang, Henan Province, China, from September to December 2017. Biomarkers of nasal inflammation and oxidative stress including interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α), 8-epi-prostaglandin F2 alpha (8-epi-PGF2α) and indices of nasal microbiota diversity and phenotypes were measured. Linear mixed-effect models and bioinformatic analyses were performed to assess the association of PM2.5 concentrations with the abovementioned biomarkers and indices. It was found that per 1 μg/m3 increase in PM2.5 was associated with increments of 13.15% (95 % CI: 5.53-20.76 %) and 78.98 % (95 % CI: 21.61-136.36 %) in TNF-α on lag2 and lag02. Indices of microbial diversity and phenotypes including equitability, Shannon index, biofilm forming, and oxidative stress tolerant decreased to different extent with the increment in PM2.5. Notably, thirteen differential microbes in Clostridia, Bacilli, and Gammaproteobacteria classes were recognized as keystone taxa and eight of them were associated with TNF-α, IL-6, or 8-epi-PGF2α. Moreover, environmental adaptation was the most critical functional pathway of nasal microbiota associated with PM2.5 exposure. In summary, short-term exposure to PM2.5 is associated with nasal inflammation, microbiota diversity reduction, and the microbiota phenotype alterations.


The High-Quality Complete Genome Sequence of the Opportunistic Fungal Pathogen Candida vulturna CBS 14366T.
Candida vulturna is a new member of the Candida haemulonii species complex that recently received much attention as it includes the emerging multidrug-resistant pathogen Candida auris. Here, we describe the high-quality genome sequence of C. vulturna type strain CBS 14366T to cover all genomes of pathogenic C. haemulonii species complex members.


Identification of novel adenosine A(2A) receptor antagonists by virtual screening.
Virtual screening was performed against experimentally enabled homology models of the adenosine A(2A) receptor, identifying a diverse range of ligand efficient antagonists (hit rate 9%). By use of ligand docking and Biophysical Mapping (BPM), hits 1 and 5 were optimized to potent and selective lead molecules (11-13 from 5, pK(I) = 7.5-8.5, 13- to >100-fold selective versus adenosine A(1); 14-16 from 1, pK(I) = 7.9-9.0, 19- to 59-fold selective).


Occurrence and exposure assessment of polychlorinated biphenyls and organochlorine pesticides from homemade baby food in Korea.
Data on the residue levels of persistent organic pollutants (POPs) in baby food samples are scarce. This is the first study to explore current contamination status and exposure assessment of organochlorines (OCs), including polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), in baby food from Korea. In this study, the concentrations of OCs were determined in homemade baby food samples (n=100) collected from 6-, 9-, 12- and 15-month-old infant groups. The average concentrations of PCBs, dichloro-diphenyl-trichloroethanes (DDTs), hexachlorocyclohexanes (HCHs) and chlordanes (CHLs) in baby food samples were 37.5, 96.6, 26.0, and 13.2 pg/g fresh weight, respectively. The major compounds were CBs 28, 153, 52, and 33 for PCBs and p,p'-DDE, p,p'-DDT and β-HCH for OCPs. The contribution of DDTs to the total OC concentrations increased from 30% (6-month-old infants) to 67% (15-month-old infants) with increasing infant age, while the concentrations of PCBs, HCHs and CHLs gradually decreased with increasing infant age, suggesting that highest priority for risk reduction of DDTs. The estimated daily intakes (EDIs) of OCs in Korean infants from baby food consumption were lower than the thresholds proposed by the United States Environmental Protection Agency and Health Canada, implying limited potential health risks. However, considering simultaneous exposure from baby food and breast milk consumption, chlordanes and heptachlor epoxide posed potential health risks. Considering the importance of early development and the vulnerability of infants, it is essential to perform systematic monitoring and management programs of OCs in baby food for risk reduction in Korean infants.


Gd-DTPA-enhanced MR in thoracic disc herniations.
The Gd-DTPA-enhanced magnetic resonance findings in two patients with herniated thoracic intervertebral discs are reported. The first patient was a 56-year-old woman with a small subligamentous T6-7 disc herniation, slightly lateralized to the right. The second patient was a 51-year-old man with a central and right posterolateral disc herniation, including a large calcified fragment, at the T8-9 level. The nonenhanced MR examination revealed the presence of an extradural mass lesion in both patients, impinging upon the dural sac and compressing and displacing the spinal cord posteriorly. The lesion was slightly hypointense on both T1- and T2-weighted spin echo sequences. Following intravenous injection of Gd-DTPA in a dosage of 0.1 mmol/kg body weight, enhancement of the posterior longitudinal ligament was noted and triangular areas of contrast uptake were seen to occur in the epidural space above and below the herniated disc. At surgery, they were found to correspond to dilated and congested epidural veins.


Dark band artifact in transcranial MR-guided focused ultrasound: Mechanism and mitigation with passive crossed wire antennas.
Current FDA-approved transcranial MR-guided focused ultrasound (tcMRgFUS) transducers cause a curved dark band in 3 T brain images that runs through midbrain targets of ablative treatments for essential tremor and other applications, and signal is reduced by at least 25% elsewhere in the brain. This limits the set of scans that can be performed to guide and assess the effects of treatment. An electromagnetic simulation study was performed to elucidate the mechanisms causing the dark band. Based on the results, a pair of passive antennas in a "propeller-beanie" configuration were designed to manipulate the reflected waves to avoid signal cancellation within the brain. The antennas were optimized and validated with in-vivo experiments and hydrophone measurements. The simulation study revealed that the dark band is caused by RF waves reflected from the transducer's ground plane, which cancel with incoming waves from the scanner's body coil. The passive antennas shifted the dark band out of the brain and increased transmit efficiency in the center of brain 2.3 times while improving field homogeneity by 50%. They also increased receive sensitivity and SNR in anatomic and temperature imaging. They caused no detectable distortion in hydrophone-measured focal pressure profiles. The conductive ground planes and coupling media used in tcMRgFUS and other piezoelectric FUS transducers interact with a 3 T scanner's RF fields to reduce transmit efficiency and SNR. For tcMRgFUS scenario, "propeller beanie" passive reflecting antennas alleviated these effects. This could make a broader set of imaging sequences available to guide tcMRgFUS treatment.