Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia.
Therapeutic hypothermia represents a brain-protective strategy for multiple emergency situations, such as stroke or traumatic injury. Neurotensin (NT), which exerts its effects through activation of two G protein-coupled receptors, namely NTS1 and NTS2, induces a strong and long-lasting decrease in core body temperature after its central administration. Growing evidence demonstrates that NTS1 is the receptor subtype mediating the hypothermic action of NT. As such, potent NTS1 agonists designed on the basis of the minimal C-terminal NT(8-13) bioactive fragment have been shown to produce mild hypothermia and exert neuroprotective effects under various clinically relevant conditions. The high susceptibility of NT(8-13) to protease degradation (half-life <2 min) represents, however, a serious limitation for its use in pharmacological therapy. In light of this, we report here a structure-activity relationship study in which pairs of NT(8-13) analogs have been developed, based on the incorporation of a reduced Lys8-Lys9 bond. To further stabilize the peptide bonds, a panel of backbone modifications was also inserted along the peptide sequence, including Sip10, D-Trp11, Dmt11, Tle12, and TMSAla13. Our results revealed that the combination of appropriate chemical modifications leads to compounds exhibiting improved resistance to proteolytic cleavages (>24 h; 16). Among them, the NT(8-13) analogs harboring the reduced amine bond combined with the unnatural amino acids TMSAla13 (4) and Sip10 (6) or the di-substitution Lys11 - TMSAla13 (12), D-Trp11-TMSAla13 (14), and Dmt11-Tle12 (16) produced sustained hypothermic effects (-3°C for at least 1 h). Importantly, we observed that hypothermia was mainly driven by the increased stability of the NT(8-13) derivatives, instead of the high binding-affinity at NTS1. Altogether, these results reveal the importance of the reduced amine bond in optimizing the metabolic properties of the NT(8-13) peptide and support the development of stable NTS1 agonists as first drug candidate in neuroprotective hypothermia.


Oscillatory phase dynamics in neural entrainment underpin illusory percepts of time.
Neural oscillatory dynamics are a candidate mechanism to steer perception of time and temporal rate change. While oscillator models of time perception are strongly supported by behavioral evidence, a direct link to neural oscillations and oscillatory entrainment has not yet been provided. In addition, it has thus far remained unaddressed how context-induced illusory percepts of time are coded for in oscillator models of time perception. To investigate these questions, we used magnetoencephalography and examined the neural oscillatory dynamics that underpin pitch-induced illusory percepts of temporal rate change. Human participants listened to frequency-modulated sounds that varied over time in both modulation rate and pitch, and judged the direction of rate change (decrease vs increase). Our results demonstrate distinct neural mechanisms of rate perception: Modulation rate changes directly affected listeners' rate percept as well as the exact frequency of the neural oscillation. However, pitch-induced illusory rate changes were unrelated to the exact frequency of the neural responses. The rate change illusion was instead linked to changes in neural phase patterns, which allowed for single-trial decoding of percepts. That is, illusory underestimations or overestimations of perceived rate change were tightly coupled to increased intertrial phase coherence and changes in cerebro-acoustic phase lag. The results provide insight on how illusory percepts of time are coded for by neural oscillatory dynamics.


Interferon-gamma increases IL-6 production in human glioblastoma cell lines.
Various immunotherapeutical approaches are presently evaluated for their efficacy to eradicate glioma cells. Complicating the concepts, these tumors secrete cytokines which modulate the immune response. We analyzed the influence of interferon gamma (IFN-gamma) on the cytokine production and IFN-gamma receptor expression in T98G and U87-MG human glioma cells. The IFN-gamma receptors were own-regulated after IFN-gamma treatment. Secretion of interleukin-6 (IL-6) protein was elevated by factors of 6.4 in T98G cells and 5.2 in U87-MG. Other cytokines were increased as well, but less constantly: IL-8, and VEGF were elevated significantly only in T98G, but not in U87-MG. Increases of IL-1 beta, IL-1 alpha and TGF beta-2 were only detectable at the mRNA level. TNF was not detectable in any of the cell lines, and TGF-beta, alpha FGF and HG were not influenced by IFN-gamma. IL-6 produced by glioma cells in response to IFN-gamma might support immune eradication of glioma cells.


Retinoic acid modifies mesodermal patterning in early Xenopus embryos.
Treatment of early Xenopus embryos with retinoic acid (RA) produces a concentration-dependent series of defects in anterior axial structures that range from small deletions to embryos lacking heads. The graded series of axial defects obtained after RA administration to early embryos appears to result, in part, from actions of RA on embryonic mesoderm. RA modifies the differentiation of anterior dorsal mesoderm from animal cap ectoderm induced by mesoderm-inducing peptide growth factors (PGFs). Concentrations of RA that suppress anterior dorsal mesoderm result in the differentiation of mesoderm of more posterior or ventral character. The suppression of anterior dorsal mesoderm may account for the absence of anterior neural ectoderm after RA treatment. Although RA changes the character of mesoderm, it does not seem to affect mesodermal induction by PGFs or the levels of Xhox3 mRNA induced in the mesoderm by PGFs. RA therefore appears to affect steps downstream from those involved in the initial induction of mesoderm. In experiments to examine the possible physiological role of RA in early Xenopus development, dorsal and ventral ectoderm were found to respond differently to identical concentrations of PGFs. One potential basis for this heterogeneity is the existence of a localized inhibitor, possibly RA, in the early Xenopus embryo. RA could therefore contribute to axial patterning by inhibiting the development of mesoderm of different character induced by PGFs.


Power spectrum analysis with least-squares fitting: amplitude bias and its elimination, with application to optical tweezers and atomic force microscope cantilevers.
Optical tweezers and atomic force microscope (AFM) cantilevers are often calibrated by fitting their experimental power spectra of Brownian motion. We demonstrate here that if this is done with typical weighted least-squares methods, the result is a bias of relative size between -2/n and +1/n on the value of the fitted diffusion coefficient. Here, n is the number of power spectra averaged over, so typical calibrations contain 10%-20% bias. Both the sign and the size of the bias depend on the weighting scheme applied. Hence, so do length-scale calibrations based on the diffusion coefficient. The fitted value for the characteristic frequency is not affected by this bias. For the AFM then, force measurements are not affected provided an independent length-scale calibration is available. For optical tweezers there is no such luck, since the spring constant is found as the ratio of the characteristic frequency and the diffusion coefficient. We give analytical results for the weight-dependent bias for the wide class of systems whose dynamics is described by a linear (integro)differential equation with additive noise, white or colored. Examples are optical tweezers with hydrodynamic self-interaction and aliasing, calibration of Ornstein-Uhlenbeck models in finance, models for cell migration in biology, etc. Because the bias takes the form of a simple multiplicative factor on the fitted amplitude (e.g. the diffusion coefficient), it is straightforward to remove and the user will need minimal modifications to his or her favorite least-squares fitting programs. Results are demonstrated and illustrated using synthetic data, so we can compare fits with known true values. We also fit some commonly occurring power spectra once-and-for-all in the sense that we give their parameter values and associated error bars as explicit functions of experimental power-spectral values.


Association of gustatory dysfunction and Alzheimer's disease: a systematic review and meta-analysis.
Chemosensory dysfunction has been reported to be involved in the pathogenesis of Alzheimer's disease (AD). Compared with olfaction, gustatory dysfunction in AD has not been evaluated in depth. We reviewed previously published studies regarding gustatory dysfunction in patients with AD compared with healthy controls. A systematic review was conducted by searching the MEDLINE, Cochrane Library, Embase, and PubMed databases covering publications from January 2000 to February 2023. The search was performed using the keyword "Alzheimer* AND (gustatory OR taste OR gustation)." Only studies that performed gustatory function testing and compared the results between patients with AD and healthy controls were included. A random-effects meta-analysis was performed. Twelve articles were finally included, and various gustatory tests including taste strips, the taste disk test, taste solutions, and subjective questionnaires were applied. Overall gustatory function based on the taste strip test was significantly decreased in patients with AD compared with controls in two out of three papers. The overall gustatory function of patients with AD was significantly decreased in all studies based on the taste disk and taste solution tests. We also found that the sweet taste test showed low heterogeneity across all the included studies, and there was low publication bias. In studies using subjective questionnaires, gustatory function was not significantly different between patients with AD and healthy controls in the meta-analysis. Based on these studies, gustatory dysfunction diagnosed by gustatory function testing was closely related to AD. However, the results of subjective questionnaires were not significantly different between patients with AD and healthy controls in the current meta-analysis. As the number of studies and enrolled subjects was limited and unified gustatory function testing was lacking, further studies are needed to confirm this relationship.


Orthostatic hypertension with nephroptosis and aortitis disease.
A 53-year-old woman with nephroptosis and aortitis disease was found also to have orthostatic hypertension. When standing, she had high renin levels and normal catecholamine values, with a reduced baroreflex sensitivity. This orthostatic hypertension largely may be due to an activation of the renin system caused by nephroptosis and partly due to a reduced baroreflex sensitivity caused by aortitis. Captopril and propranolol hydrochloride were effective for the treatment of hypertension.


Modified expansion sphincter pharyngoplasty for treatment of children with obstructive sleep apnea.
Lateral pharyngeal wall collapse has been implicated in the pathogenesis of obstructive sleep apnea (OSA). Modified expansion sphincter pharyngoplasty (ESP) is a simple procedure and can be considered in the surgical management of children with severe OSA. To describe a modified ESP addressing lateral pharyngeal muscle wall collapse in the treatment of children with OSA. Retrospective review of the medical records of children with OSA and lateral pharyngeal muscle wall collapse who underwent modified ESP and children who had tonsillectomy and adenoidectomy (TA) for OSA between 2008 and 2013 at a tertiary care children's hospital. Modified ESP. The primary outcome measure was the rate of cure, which was defined as an apnea-hypopnea index (AHI) lower than 1. Other outcomes were differences in preoperative and postoperative AHI, minimum saturation of peripheral oxygen, and percentage of total sleep study time with oxygen saturation less than 90%. Twenty-five children who had modified ESP and 25 AHI-matched children who had TA for severe OSA were identified. The postoperative AHI was lower than the preoperative AHI in both groups. Preoperative AHI was similar between modified ESP and TA groups. The mean (SD) postoperative AHI of the modified ESP group (2.4 [3.9]) was lower than that of the TA group (6.2 [6.0]) (P < .001). Cure rates for the modified ESP group (AHI <1, 64%; AHI <2, 72%; and AHI <5, 80%) were greater than those for the TA group (AHI <1, 8%; AHI <2, 44%; and AHI <5, 60%). Modified ESP provided objective clinical improvement of OSA in children with severe OSA and lateral pharyngeal wall collapse and might serve as an effective alternative to TA for treatment of OSA.


Adsorption of colloidal iron by bacteria.
The adsorption of iron from a positive-iron sol by species of seven bacterial genera was examined by electron microscopy. All species precipitated the iron from the sol, and the bacterial cells became encrusted with iron. This was related to iron deposition in surface water supplies.


Survival Outcomes After Heart Transplantation: Does Recipient Sex Matter?
Currently, women represent <25% of heart transplant recipients. Reasons for this female underrepresentation have been attributed to selection and referral bias and potentially poorer outcomes in female recipients. The aim of this study was to compare long-term posttransplant survival between men and women, when matched for recipient and donor characteristics. Using the International Society for Heart and Lung Transplantation Registry, we performed descriptive analyses and estimated overall freedom from posttransplant death stratified by sex using Kaplan-Meier survival methods. Male and female recipients were matched according to the Index for Mortality Prediction After Cardiac Transplantation and Donor Risk Index score using 1:1 propensity score matching. The study cohort comprised 34 198 heart transplant recipients (76.3% men, 23.7% women) between 2004 and 2014. Compared with men, women were more likely younger (51 [39-59] versus 55 [46-61] years; P<0.001) and had a different distribution of heart failure etiology (P<0.001). In general, the prevalence of comorbidities was lower in women than in men. Women were less likely to have diabetes mellitus (19.1% versus 26.2%; P<0.001), hypertension (40.7% versus 47.9%; P<0.001), peripheral vascular disease (2.4% versus 3.3%; P=0.002), tobacco use (36.5% versus 52.3%; P<0.001), and prior cardiovascular surgery (38.6% versus 50.7%; P<0.001). Women were more likely to have a history of malignancy (10.5% versus 5.3%; P<0.001), require intravenous inotropes (41.4% versus 37.2%; P<0.001), and were less likely supported by an intra-aortic balloon pump (3.3% versus 3.8%; P=0.03) or durable ventricular assist device (22% versus 31.5%; P<0.001). Transplanted male recipients had a higher Index for Mortality Prediction After Cardiac Transplantation score (5 [2-7] versus 4 [1-6]; P<0.001). When male and female heart transplant recipients were matched for recipient and donor characteristics, there was no significant survival difference (P=0.57). Overall survival does not differ between men and women after cardiac transplantation. Women who survive to heart transplantation appear to have lower risk features than male recipients but receive hearts from higher risk donors.


Characterization of LORF11, a unique gene common to the three Marek's disease virus serotypes.
The unique open reading frame 11 (LORF11) of Marek's disease virus (MDV) is present in all three serotypes of MDV and is located in the unique long region of the MDV genome. In the serotype 1 Md5 genome, LORF11 comprises 2711 nucleotides and encodes a predicted protein of 903 amino acids. In order to study the biological function of LORF11 we deleted it from the MDV cosmid A6 by using the RecA-assisted restriction endonuclease cleavage method. The recombinant cosmid, A6DeltaLORF11, was transfected into duck embryo fibroblasts (DEF) in conjunction with parental SN5, P89, SN16, and B40 cosmid clones. Recombinant rMd5DeltaLORF11 plaques were evident at 12-13 days after transfection. Polymerase chain reaction amplification of DEF cells infected with rMd5DeltaLORF11 viruses confirmed the deletion of a 2.57-kb fragment resulting in a 296-bp fragment. Three rMd5DeltaLORF11 mutants were generated and their biological functions were studied in vitro and in vivo. In vitro growth characteristics of rMd5DeltaLORF11 viruses were similar to those of parental rMd5, indicating that LORF11 is not essential for replication in vitro. In vivo studies of rMd5DeltaLORF11 mutants showed that they were impaired in viral replication in the lymphoid organs and had 100x lower viremia than chickens infected with the parental rMd5 virus. Furthermore, rMd5-infected chickens horizontally transmitted the virus to contact controls whereas no horizontal transmission occurred in rMd5DeltaLORF11-infected chickens. Three independent deletion mutants were tested and showed the same phenotypes, so it is unlikely that the observed phenotype is because of any random mutation in the genome. Therefore the LORF11 gene of MDV is essential for normal virus replication in chickens and deletion of LORF11 renders an attenuated virus.


Alprazolam reduces stress hyperglycemia in ob/ob mice.
We have shown that the C57BL/6J ob/ob (obese) mouse, a commonly used model of type II diabetes mellitus, is not in fact consistently hyperglycemic except when exposed to environmental stress. In an attempt to modify stress hyperglycemia in this animal, we administered either a 5 mg/kg dose of the benzodiazepine alprazolam or vehicle (propylene glycol) intraperitoneally to both obese mice and their lean littermates prior to a rest and a stress period. Alprazolam modified the hyperglycemic effect of stress only in the obese mice. Alprazolam significantly reduced plasma corticosterone in obese animals at rest and following stress. In addition, alprazolam significantly increased plasma insulin in all animals at rest and following stress. These data suggest a possible role for benzodiazepines in the modification of stress hyperglycemia in type II diabetes mellitus.


Maternal depression and inflammation during pregnancy.
Maternal depression during pregnancy increases the risk for adverse developmental outcomes in children. However, the underpinning biological mechanisms remain unknown. We tested whether depression was associated with levels of and change in the inflammatory state during pregnancy, if early pregnancy overweight/obesity or diabetes/hypertensive pregnancy disorders accounted for/mediated these effects, and if depression added to the inflammation that typically accompanies these conditions. We analyzed plasma high-sensitivity C-reactive protein (hsCRP) and glycoprotein acetyls at three consecutive stages during pregnancy, derived history of depression diagnoses before pregnancy from Care Register for Healthcare (HILMO) (N = 375) and self-reports (N = 347) and depressive symptoms during pregnancy using the Center for Epidemiological Studies Depression Scale completed concurrently to blood samplings (N = 295). Data on early pregnancy body mass index (BMI) and diabetes/hypertensive pregnancy disorders came from medical records. Higher overall hsCRP levels, but not change, during pregnancy were predicted by history of depression diagnosis before pregnancy [HILMO: mean difference (MD) = 0.69 standard deviation (s.d.) units; 95% confidence interval (CI) 0.26-1.11, self-report: MD = 0.56 s.d.; 95% CI 0.17-0.94] and higher depressive symptoms during pregnancy (0.06 s.d. per s.d. increase; 95% CI 0.00-0.13). History of depression diagnosis before pregnancy also predicted higher overall glycoprotein acetyls (HILMO: MD = 0.52 s.d.; 95% CI 0.12-0.93). These associations were not explained by diabetes/hypertensive disorders, but were accounted for and mediated by early pregnancy BMI. Furthermore, in obese women, overall hsCRP levels increased as depressive symptoms during pregnancy increased (p = 0.006 for interaction). Depression is associated with a proinflammatory state during pregnancy. These associations are mediated by early pregnancy BMI, and depressive symptoms during pregnancy aggravate the inflammation related to obesity.


Absence of pathological changes following intravenous methamphetamine and intra-arterial iothalamate meglumine.
Eleven Rhesus monkeys received injections of intravenous methamphetamine hydrochloride (Desoxyn) and/or intra-arterial 60% iothalamate meglumine (Conray) according to a schedule previously reported to produce marked radiological and pathological changes in the cerebral vasculature of the Rhesus monkey. While radiological changes consistent with impaired cerebral circulation were observed, they could not be correlated directly with the administration of intravenous methamphetamine because of the trauma and variability of the technique utilized. Moreover, significant pathological changes could not be found in animals given intravenous methamphetamine alone, intra-arterial iothalamate meglumine alone, or both drugs together. This was true for both drug naive and drug experienced monkeys. These results suggest: (1) radiological changes consistent with decreased cerebral blood flow are not necessarily pathognomonic for reported morphological lesions, and (2) further investigation is required to determine the specific factors necessary to cause the previously reported changes.


Evaluation of a dementia training workshop for health and social care staff in rural Scotland.
This short project report presents an evaluation of a training workshop for health and social-care staff working in one of the most rural areas in Scotland. The objective was to explore the learning needs and outcomes of training participants delivering services to people with dementia in a rural area. The training workshop encouraged health and social-care staff to discuss key challenges they experienced in their dementia care practice, as well as providing information on dementia care, services and rural dementia research. In a post-training evaluation, despite barriers to implementing learning, participants rated their satisfaction with the workshop as high overall. Further training needs identified included: how to recognise dementia, what the diagnostic process entails, and the management of challenging behaviour. Health and social-care staff in rural areas of Scotland require further training on specific issues related to dementia to enable them to be confident in in the diagnostic process and delivery of post-diagnostic dementia services.


Handling and protecting your flexible ureteroscope: how to maximise scope usage.
Flexible ureteroscopy is an important therapeutic and diagnostic procedure and has seen rapid rise in its utilisation in recent years. There have been numerous developments in flexible ureteroscope (fURS) technology but scope fragility, and the associated high maintenance costs, remains a concern. A comprehensive Medline search for related publications from the last 20 years was undertaken to identify common causes of fURS damage and ascertain practices to minimise this. Flexible ureteroscopy can be due to intraoperative causes (loss of the deflection mechanism, damage to the working channel due and fibreoptic bundle injury) and non-operative damage which occur during cleaning, sterilisation and handling of the fURS. The review summarises the available literature to help highlight common mechanisms of scope damage, and outlines evidence-based measures to reduce the risk of damage and maximise durability. Scope fragility remains a problem with significant associated cost implications. In a culture of rising fURS use and reducing re-imbursement for endourologists, prolonging the longevity of the fURS is imperative for maintaining profitability. There are simple and inexpensive practices which can be immediately adopted to maximise fURS use and reduce the need for repairs.


Evaluating the impact of a pre-rotation workshop on student preparation for clinical advanced pharmacy practice experiences.
This pilot study was designed to evaluate the impact of a pre-rotation workshop (PRW) on pharmacy students' clinical skills and preparation for clinical Advanced Pharmacy Practice Experiences (APPE) involving direct patient care. Randomized controlled trial of an educational intervention with Institutional Review Board approval. PRW activities designed to simulate rotation activities around five competencies, patient charts, medication histories, SOAP notes, patient presentations, and professionalism. Endpoints were evaluated using clinical rotation preceptors' evaluation of performance and students' performance on objective structured clinical exams (OSCE). Eight fourth-year students and eight GPA matched controls (20% of the total class) were selected to voluntarily participate. The PRW demonstrated a positive impact on students' clinical skills and preparation for rotations by improving OSCE performance. However, no significant differences were found between groups when comparing preceptor evaluations of skills on rotations. These results are limited by the small sample size, potential OSCE "test-wiseness" effects, lack of OSCE evaluator blinding to study groups, potential case specificity effects due to the limited number of cases used on the OSCE and possible lack of sensitivity of the rotation evaluation tool to capture true differences among the experimental and control group participants. The PRW was successful at advancing students' clinical skills and preparation for rotations and may be considered as a tool to help bridge didactic to clinical experiences in the Pharm.D. curriculum.


Mechanism of irreversible inhibition of O2 evolution in photosystem II by Tris(hydroxymethyl)aminomethane.
The dark reaction of tris(hydroxymethyl)aminomethane (Tris) with the O2-evolving center of photosystem II (PSII) in the S1 state causes irreversible inhibition of O2 evolution. Similar inhibition is observed for several other amines: NH3, CH3NH2, (CH3)2NH, ethanolamine, and 2-amino-2-ethyl-1,3-propanediol. In PSII membranes, both depleted of the 17- and 23-kDa polypeptides and undepleted, the rate of reaction of Tris depends inversely upon the Cl- concentration. However, the rate of reaction of Tris is about 2-fold greater with PSII membranes depleted of the 17- and 23-kDa polypeptides than with undepleted PSII membranes. We have used low-temperature electron paramagnetic resonance (EPR) spectroscopy to study the effect of Tris on the oxidation state of the Mn complex in the O2-evolving center, to monitor the electron-donation reactions in Tris-treated samples, and to observe any loss of the Mn complex (forming Mn2+ ions) after Tris treatment. We find that Tris treatment causes loss of electron-donation ability from the Mn complex at the same rate as inhibition of O2 evolution and that Mn2+ ions are released. We conclude that Tris reduces the Mn complex to labile Mn2+ ions, without generating any kinetically stable, partially reduced intermediates, and that the reaction occurs at the Cl(-)-sensitive site previously characterized in studies of the reversible inhibition of O2 evolution by amines.


Epstein-Barr virus lytic transactivator Zta enhances chemotactic activity through induction of interleukin-8 in nasopharyngeal carcinoma cells.
Epstein-Barr virus (EBV)-associated, undifferentiated type of nasopharyngeal carcinoma (NPC) is characterized by intensive leukocyte infiltration. Interaction between the infiltrating cells and the tumor cells has been considered crucial for NPC development. Recruitment of the infiltrates can be directed by certain chemokines present in the NPC tissues. It is unknown whether and how EBV lytic infection regulates expression of the chemokines. Using an antibody array, we first found that several chemokines secreted from EBV-infected NPC cells are increased upon EBV reactivation into the lytic cycle, and interleukin-8 (IL-8) is the chemokine upregulated most significantly and consistently. Further studies showed that the EBV lytic transactivator Zta is a potent inducer of IL-8 in NPC cells, augmenting secreted and intracellular IL-8 proteins, as well as IL-8 RNA. Zta upregulates Egr-1, a cellular transcription factor that has been involved in upregulation of IL-8, but the Zta-induced IL-8 expression is independent of Egr-1. The ability of Zta to transactivate the IL-8 promoter is important for the induction of IL-8, and we have identified two Zta-responsive elements in the promoter. Zta can bind to these two elements in vitro and can also be recruited to the IL-8 promoter in vivo. DNA-binding-defective Zta mutants can neither activate the IL-8 promoter nor induce IL-8 production. In addition, Zta-expressing NPC cells exert enhanced chemotactic activity that is mainly mediated by IL-8. Since IL-8 may contribute to not only leukocyte infiltration but also multiple oncogenic processes, the present study provides a potential link between EBV lytic infection and pathogenesis of NPC.


Effects of OKY 1581 on bronchoconstrictor responses to arachidonic acid and PGH2.
The influence of OKY 1581, a thromboxane synthase inhibitor, on airway responses to arachidonic acid and endoperoxide, [prostaglandin (PG) H2], were investigated in anesthetized, paralyzed, mechanically ventilated cats. Intravenous injections of arachidonic acid and PGH2 caused dose-related increases in transpulmonary pressure and lung resistance and decreases in dynamic and static compliance. OKY 1581 significantly decreased airway responses to arachidonic acid but not to PGH2. Sodium meclofenamate, a cyclooxygenase inhibitor, abolished airway responses to arachidonic acid but had no effect on airway responses to PGH2. OKY 1581 or meclofenamate has no effect on airway responses to PGF2 alpha, PGD2, or U 46619, a thromboxane mimic. In microsomal fractions from the lung, OKY 1581 inhibited thromboxane formation without decreasing prostacyclin synthesis or cyclooxygenase activity. These studies show that OKY 1581 is a selective thromboxane synthesis inhibitor in the cat lung and suggest that a substantial part of the bronchoconstrictor response to arachidonic acid is due to thromboxane A2 formation. Moreover, the present data suggest that airway responses to endogenously released and exogenous PGH2 are mediated differently and that a significant part of the response to exogenous PGH2 may be due to activation of an endoperoxide/thromboxane receptor, since responses to PGH2 are blocked by the thromboxane receptor antagonist SQ 29548.


Defining the critical period for neocortical neurogenesis after pediatric brain injury.
Pediatric traumatic brain injury (TBI) is a significant and underappreciated societal problem. Whereas many TBI studies have evaluated the mechanisms of cell death after TBI, fewer studies have evaluated the extent to which regeneration is occurring. Here we used a cryoinjury model to damage the somatosensory cortex of rats at postnatal day 6 (P6), P10 and P21. We evaluated the production of new neocortical neurons using a combination of 5-bromo-2-deoxyuridine (BrdU) labeling combined with staining for doublecortin (DCX). BrdU+/DCX+ bipolar cells were observed adjacent to the neocortical lesion, with their processes oriented perpendicular to the pial surface. As the animals aged, both the overall proliferative response as well as the production of neocortical neuroblasts diminished, with P6 animals responding most robustly, P10 animals less strongly, and P21 animals showing a very modest proliferative response and virtually no evidence of neocortical neurogenesis. When BrdU was administered at increasingly delayed intervals after the injury at P6, there was a clear difference in the number of new neuroblasts produced as a function of age, with the greatest number of new neocortical neurons produced between 4 and 7 days after the injury. These studies demonstrate that the immature brain has the capacity to produce neocortical neurons after traumatic injury, but this capacity diminishes as the brain continues to develop. Furthermore, in contrast to moderate hypoxic/ischemic brain damage in the P6 rat, where neurogenesis persists for at least 2 months, the response to cryoinjury is quite different as the neurogenic response diminishes over time.


Modulating effect of adenosine on the hypertensive response to physostigmine.
The purpose of this work was to study the neuromodulatory role of adenosine on the hypertensive response to physostigmine in the rat. It was found that increasing doses of adenosine, injected intravenously, produced a biphasic blood pressure response, consisting of an initial and short-lasting hypotension, followed by a prolonged hypertension. The hypertensive phase of this response was significantly depressed or even abolished by phentolamine, whereas the hypotensive phase was depressed but not abolished by atropine. If injected intravenously, but immediately before physostigmine, adenosine produced a potentiation of the blood pressure response to physostigmine. This was even more evident if adenosine was injected directly into the carotid artery immediately before the intravenous injection of physostigmine. Neither aminophylline nor 8-phenyltheophylline affected this potentiating action of adenosine. This finding might indicate that this potentiating action does not involve the already known adenosine receptors, or that this action is realized through some other type of receptors and mechanisms not sensitive to xanthine derivatives. It is concluded that adenosine might have a general modulating presynaptic effect on various transmitting processes, including those which take place in the central nervous system during the hypertensive response to physostigmine in the rat.


The attitude towards Medical Device-Related Pressure Injuries Questionnaire: a Turkish validity and reliability study.
The attitudes of nurses should be measured using valid and reliable tools to develop effective nursing care strategies for the prevention of medical device-related pressure injuries and to organize necessary training programs. This study was planned to conduct the Turkish validity and reliability study of the Attitude towards Medical Device-Related Pressure Ulcers/Injuries Questionnaire (MDRPU/I Questionnaire (the English-language version)) in nurses. This methodological study included 134 nurses working in hospitals of different sizes and characteristics (public hospitals, training and research hospitals, and university hospitals) in Turkey. The validity and reliability of the Attitude Towards Medical Device-Related Pressure Injuries (MDRPI Questionnaire (the Turkish-language version)) Questionnaire were tested using language validity, content validity, face validity, construct validity, and reliability analyses. The final version of the questionnaire had a content validity index of 98.03%, sufficient construct validity, and a Cronbach α value of 0.92 for the total questionnaire. The Turkish version of the MDRPI Questionnaire is valid, reliable, and suitable for measuring the attitudes of nurses in Turkey toward the prevention and care of medical device-related pressure injuries.


Antimicrobial Peptide-Peptoid Hybrids with and without Membrane Disruption.
Among synthetic analogues of antimicrobial peptides (AMPs) under investigation to address antimicrobial resistance, peptoids (N-alkylated oligoglycines) have been reported to act both by membrane disruption and on intracellular targets. Here we gradually introduced peptoid units into the membrane-disruptive undecapeptide KKLLKLLKLLL to test a possible transition toward intracellular targeting. We found that selected hybrids containing up to five peptoid units retained the parent AMP's α-helical folding, membrane disruption, and antimicrobial effects against Gram-negative bacteria including multidrug-resistant (MDR) strains of Pseudomonas aeruginosa and Klebsiella pneumoniae while showing reduced hemolysis and cell toxicities. Furthermore, some hybrids containing as few as three peptoid units as well as the full peptoid lost folding, membrane disruption, hemolysis, and cytotoxicity but displayed strong antibacterial activity under dilute medium conditions typical for proline-rich antimicrobial peptides (PrAMPs), pointing to intracellular targeting. These findings parallel previous reports that partially helical amphiphilic peptoids are privileged oligomers for antibiotic development.


Commensals Serve as Natural Barriers to Mammalian Cells during Acanthamoeba castellanii Invasion.
Acanthamoeba castellanii is a free-living, pathogenic ameba found in the soil and water. It invades the body through ulcerated skin, the nasal passages, and eyes and can cause blinding keratitis and granulomatous encephalitis. However, the mechanisms underlying the opportunistic pathogenesis of A. castellanii remain unclear. In this study, we observed that commensal bacteria significantly reduced the cytotoxicity of the ameba on mammalian cells. This effect occurred in the presence of both Gram-positive and Gram-negative commensals. Additionally, commensals mitigated the disruption of cell junctions. Ex vivo experiments on mouse eyeballs further showed that the commensals protected the corneal epithelial layer. Together, these findings indicate that A. castellanii is pathogenic to individuals with a dysbiosis of the microbiota at infection sites, further highlighting the role of commensals as a natural barrier during parasite invasion. IMPORTANCE Acanthamoeba castellanii, an opportunistic protozoan widely present in the environment, can cause Acanthamoeba keratitis and encephalitis in humans. However, only a few reports describe how the ameba acts as an opportunistic pathogen. Our study showed that the normal microbiota interfered with the cytotoxicity of Acanthamoeba, persevered during Acanthamoeba invasion, and reduced corneal epithelium peeling in the mouse eyeball model. This suggests that commensals may act as a natural barrier against Acanthamoeba invasion. In future, individuals who suffer from Acanthamoeba keratitis should be examined for microbiota absence or dysbiosis to reduce the incidence of Acanthamoeba infection in clinical settings.


Discrimination against international medical graduates in the United States residency program selection process.
Available evidence suggests that international medical graduates have improved the availability of U.S. health care while maintaining academic standards. We wondered whether studies had been conducted to address how international graduates were treated in the post-graduate selection process compared to U.S. graduates. We conducted a Medline search for research on the selection process. Two studies provide strong evidence that psychiatry and family practice programs respond to identical requests for applications at least 80% more often for U.S. medical graduates than for international graduates. In a third study, a survey of surgical program directors, over 70% perceived that there was discrimination against international graduates in the selection process. There is sufficient evidence to support action against discrimination in the selection process. Medical organizations should publish explicit proscriptions of discrimination against international medical graduates (as the American Psychiatric Association has done) and promote them in diversity statements. They should develop uniform and transparent policies for program directors to use to select applicants that minimize the possibility of non-academic discrimination, and the accreditation organization should monitor whether it is occurring. Whether there should be protectionism for U.S. graduates or whether post-graduate medical education should be an unfettered meritocracy needs to be openly discussed by medicine and society.


Cost-Effectiveness of Peginterferon Beta-1a and Alemtuzumab in Relapsing-Remitting Multiple Sclerosis.
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, affecting 2.5 million people globally and 400,000 people in the United States. While no cure exists for MS, the goal is to manage the disease using disease-modifying therapies (DMTs), which have been shown to slow disease progression and prevent relapses. Relapsing-remitting MS (RRMS) is the most common form of MS at the time of diagnosis. Peginterferon beta-1a (PEG) and alemtuzumab (ALT) were recently approved and have demonstrated good clinical outcomes, including reduced relapse rates in clinical trials. High costs associated with these DMTs necessitates cost-effectiveness analyses to understand their overall value in RRMS management. To assess the cost-effectiveness of (a) Model 1: PEG relative to intramuscular interferon beta-1a (IM IFN), subcutaneous interferon beta-1b (SC IFN), glatiramer acetate 20 mg per mL (GA), fingolimod (FIN), natalizumab (NAT), and dimethyl fumarate (DMF), and (b) Model 2: ALT relative to subcutaneous interferon beta-1a 44 μg (IFN beta-1a 44 μg). Both analyses were conducted from a U.S. third-party payer perspective. Two static decision models were used to compare the cost-effectiveness of PEG and ALT over a 1-year and a 2-year time horizon, respectively. Model inputs were drug acquisition costs (wholesale acquisition cost from RED BOOK); drug administration and monitoring costs (package inserts and Centers for Medicare & Medicaid Services 2015 Physician Fee Schedule); relapse rates and relapse rate reduction (clinical trials); and cost of managing relapses (published literature). All costs were adjusted to 2015 U.S. dollars using the medical care component of the Consumer Price Index. Outcomes measured were total cost of therapy per patient, cost per relapse avoided, and incremental cost-effectiveness ratios (ICERs) calculated as cost per relapse avoided. Sensitivity analysis was conducted to test model robustness given the uncertainty of model inputs and study assumptions. Model 1 results showed that PEG dominated IM IFN and GA, compared with SC IFN; PEG had an ICER of $1,978,000 per relapse avoided. Compared with FIN, NAT, and DMF, PEG was less expensive and less effective. Model 2 showed that ALT had an ICER of $25,276 per relapse avoided relative to IFN beta-1a 44 μg. In patients with RRMS, PEG is a viable alternative when compared with the DMTs in our model. Deciding whether to choose PEG over other DMTs would depend on multiple factors. On the other hand, ALT had an ICER of $25,276 cost per relapse avoided relative to IFN beta-1a 44 μg. The study results will assist payers in evaluating different medication choices for effective therapy. No outside funding supported this study. Kamal has received research funding from Novartis Pharmaceuticals and the College of Psychiatric and Neurologic Pharmacists and also serves as a consultant for the Lynx Group. Dashputre and Pawar report no conflicts of interest. Study concept and design were primarily contributed by Dashputre, along with Kamal and Pawar. Dashputre took the lead in data collection, along with Kamal, and data analysis was performed by Dashputre, Kamal, and Pawar. The manuscript was written and revised primarily by Dashputre, along with Kamal and Pawar.


An optimized method for histological detection of dopaminergic neurons in Drosophila melanogaster.
Parkinson's disease (PD) affects >1 million Americans and is marked by the loss of dopaminergic neurons in the substantia nigra. PD has been linked to two causative factors: genetic risks (hereditary PD) and environmental toxins (idiopathic PD). In recent years, considerable effort has been devoted to the development of a Drosophila model of human PD that might be useful for examining the cellular mechanisms of PD pathology by genetic screening. In 2000, Feany and Bender reported a Drosophila model of PD in which transgenic flies expressing human mutant alpha-synuclein exhibited shortened life spans, dopaminergic losses, Parkinsonian behaviors, and Lewy bodies in surviving dopaminergic neurons. Since then, a number of studies have been published that validate the model or build on it; conversely, a number report an inability to replicate the results and suggest that most protocols for dopaminergic histology underreport the actual numbers of dopaminergic neurons in the insect brain. Here we report the optimization of dopaminergic histology in Drosophila and identification of new dopaminergic neurons, show the remarkable dendritic complexity of these neurons, and provide an updated count of these neurons in adult brains. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.


Optimizing synaptic conductance calculation for network simulations.
High computational requirements in realistic neuronal network simulations have led to attempts to realize implementation efficiencies while maintaining as much realism as possible. Since the number of synapses in a network will generally far exceed the number of neurons, simulation of synaptic activation may be a large proportion of total processing time. We present a consolidating algorithm based on a recent biophysically-inspired simplified Markov model of the synapse. Use of a single lumped state variable to represent a large number of converging synaptic inputs results in substantial speed-ups.


Electroconvulsive therapy and suicide risk.
For major psychiatric disorders in which suicidality is often a symptom, electroconvulsive therapy (ECT) is an established, highly effective treatment. In fact, suicidal risk may be an indication for the use of ECT to treat those disorders. The authors present new data and review clinical experience that indicate that ECT often exerts a profound short-term beneficial effect on suicidality. Little, if any, evidence supports a long-term positive effect of ECT on suicide rates, especially if diagnostically heterogeneous groups are considered. However, patients may have been assigned ECT precisely because they were suicidal and, hence, these reports may represent underestimates. As a whole, the published reports are weakened by methodological shortcomings, such as lack of controls, weak design, and possible cohort effects. In fact, most studies were designed to examine the impact of ECT on mortality rates in general, and all but one study found reductions in overall mortality, the source of which remains undetermined.


Impact of light conditions on reading ability following multifocal pseudophakic corrections.
To examine the impact of light intensity and temperature on reading performance following bilateral pseudophakic multifocal presbyopic correction. This is a prospective clinic-based trial conducted at the Department of Ophthalmology in the University Hospital of Alexandroupolis, Greece. Three groups of patients were formed (G1: patients with bilateral bifocal implantation, G2: patients with bilateral trifocal implantation, and control group: patients with bilateral pseudophakic monofocal implantation). Reading ability was quantified with the Greek version of MNREAD chart with minimal reading speed at 80 words/min for the following light intensities (25, 50, and 75 Foot-Candles [FC]) and temperatures (3,000, 4,000, and 6,000 K). Preferred light conditions for reading were assessed, as well. ClinicalTrials.gov Identifier: NCT03226561. Control group demonstrated significantly lower reading ability at all light combinations with maximal ability at 75 FC and 6,000 K (0.58±0.18 logMAR). Bifocal group presented a light-dependent reading ability that ranged from 0.45±0.08 logMAR (25 FC and 3,000 K) to 0.40±0.11 logMAR (75 FC and 4,000 or 6,000 K). Trifocal participants presented the best reading ability that was light intensity-independent; however, their performance was reduced at 6,000 K. G1 and G2 preferred primarily intermediate light temperature, while control participants preferred cold light temperature. Multifocal pseudophakic corrections improve reading ability; however, they present variable efficacy according to the light conditions.


Bubble rupture & viability of red blood cells under resonant acoustic standing waves.
The presentation of a novel prospective treatment for scenarios where bubble presence in the bloodstream poses a clinical risk. The method relies on generating resonant acoustic standing waves within a limb to non-invasively accelerate the dissolution of bubbles present in the bloodstream via bubble rupture. Additionally, a preliminary assessment of the effects of the resonant acoustic waves and bubble rupture events on red blood cell viability is provided. Two semicircular piezoelectric (PZT) transducers electrically connected to each other were assembled around a small-girth segment of a rear thigh removed from a swine specimen. When driven at the frequency of electric resonance, this swine thigh and PZT transducer arrangement generates resonant acoustic standing waves within the swine thigh. Consequently, mechanical resonance of the system was non-invasively established by monitoring the electric response of the PZT to the applied frequency. The resonant acoustic field generated was used for the detection and rupture of bubbles that travel through a simulated blood vessel installed across the swine thigh. Two sets of experiments were carried out using this methodology, one with the artificial blood vessel filled with saline solution and one with defibrinated sheep blood. For the latter case, a preliminary hematologic assessment was done with red blood cell counts. Resonant acoustic standing waves effectively rupture bubbles of 300μm to 900μm within a simplified swine thigh model. The average dissolved gas content was 44% due to resonant acoustic waves at powers above 20W. No significant effect on red blood cell counts was observed.


High burden of invasive beta-haemolytic streptococcal infections in Fiji.
We undertook a 5-year retrospective study of group A streptococcal (GAS) bacteraemia in Fiji, supplemented by a 9-month detailed retrospective study of beta-haemolytic streptococcal (BHS) infections. The all-age incidence of GAS bacteraemia over 5 years was 11.6/100,000. Indigenous Fijians were 4.7 times more likely to present with invasive BHS disease than people of other ethnicities, and 6.4 times more likely than Indo-Fijians. The case-fatality rate for invasive BHS infections was 28%. emm-typing was performed on 23 isolates: 17 different emm-types were found, and the emm-type profile was different from that found in industrialized nations. These data support the contentions that elevated rates of invasive BHS and GAS infections are widespread in developing countries, and that the profile of invasive organisms in these settings reflects a wide diversity of emm-types and a paucity of types typically found in industrialized countries.


Optimizing an Acceptance and Commitment Therapy Microintervention Via a Mobile App With Two Cohorts: Protocol for Micro-Randomized Trials.
Given gaps in the treatment of mental health, brief adaptive interventions have become a public health imperative. Transdiagnostic interventions may be particularly appropriate given high rates of medical comorbidity and the broader reach of transdiagnostic therapies. One such approach utilized herein is acceptance and commitment therapy (ACT), which is focused on increasing engagement with values, awareness, and openness to internal experiences. ACT theory posits that experiential avoidance is at the center of human suffering, regardless of diagnosis, and, as such, seeks to reduce unworkable experiential avoidance. Our objective is to provide the rationale and protocol for examining the safety, feasibility, and effectiveness of optimizing an ACT-based intervention via a mobile app among two disparate samples, which differ in sociodemographic characteristics and symptom profiles. Twice each day, participants are prompted via a mobile app to complete assessments of mood and activity and are then randomly assigned to an ACT-based intervention or not. These interventions are questions regarding engagement with values, awareness, and openness to internal experiences. Participant responses are recorded. Analyses will examine completion of assessments, change in symptoms from baseline assessment, and proximal change in mood and activity. A primary outcome of interest is proximal change in activity (eg, form and function of behavior and energy consumed by avoidance and values-based behavior) following interventions as a function of time, symptoms, and behavior, where we hypothesize that participants will focus more energy on values-based behaviors. Analyses will be conducted using a weighted and centered least squares approach. Two samples will run concurrently to assess the capacity of optimizing mobile ACT in populations that differ widely in their clinical presentation and sociodemographic characteristics: individuals with bipolar disorder (n=30) and distressed first-generation college students (n=50). Recruitment began on September 10, 2019, for the bipolar sample and on October 5, 2019, for the college sample. Participation in the study began on October 18, 2019. This study examines an ACT-based intervention among two disparate samples. Should ACT demonstrate feasibility and preliminary effectiveness in each sample, a large randomized controlled trial applying ACT across diagnoses and demographics would be indicated. The public health implications of such an approach may be far-reaching. ClinicalTrials.gov NCT04098497; https://clinicaltrials.gov/ct2/show/NCT04098497; ClinicalTrials.gov NCT04081662; https://clinicaltrials.gov/ct2/show/NCT04081662. DERR1-10.2196/17086.


Radiation treatment monitoring with DCE-US in CWR22 prostate tumor xenografts.
Longitudinal monitoring of potential radiotherapy treatment effects can be determined by dynamic contrast-enhanced ultrasound (DCE-US). To assess functional parameters by means of DCE-US in a murine subcutaneous model of human prostate cancer, and their relationship to dose deposition and time-frame after treatment. A special focus has been placed to evaluate the vascular heterogeneity of the tumor and on the most suitable data analysis approach that reflects this heterogeneity. In vivo DCE-US was acquired 24 h and 48 h after radiation treatment with a single dose of 7.5 Gy and 10 Gy, respectively. Tumor vasculature was characterized pixelwise using the Brix pharmacokinetic analysis of the time-intensity curves. Longitudinal changes were detected ( P < 0.001) at 24 h and 48 h after treatment. At 48 h, the eliminating rate constant of the contrast agent from the plasma, kel, was correlated ( P ≤ 0.05) positively with microvessel density (MVD; rτ = 0.7) and negatively with necrosis (rτ = -0.6) for the treated group. Furthermore, Akep, a parameter related to transcapillary transport properties, was also correlated to MVD (rτ = 0.6, P ≤ 0.05). DCE-US has been shown to detect vascular changes at a very early stage after radiotherapy, which is a great advantage since DCE-US is non-invasive, available at most hospitals, and is low in cost compared to other techniques used in clinical practice.


Clients and Oncogenic Roles of Molecular Chaperone gp96/grp94.
As an endoplasmic reticulum heat shock protein (HSP) 90 paralogue, glycoprotein (gp) 96 possesses immunological properties by chaperoning antigenic peptides for activation of T cells. Genetic studies in the last decade have unveiled that gp96 is also an essential master chaperone for multiple receptors and secreting proteins including Toll-like receptors (TLRs), integrins, the Wnt coreceptor, Low Density Lipoprotein Receptor-Related Protein 6 (LRP6), the latent TGFβ docking receptor, Glycoprotein A Repetitions Predominant (GARP), Glycoprotein (GP) Ib and insulin-like growth factors (IGF). Clinically, elevated expression of gp96 in a variety of cancers correlates with the advanced stage and poor survival of cancer patients. Recent preclinical studies have also uncovered that gp96 expression is closely linked to cancer progression in multiple myeloma, hepatocellular carcinoma, breast cancer and inflammation-associated colon cancer. Thus, gp96 is an attractive therapeutic target for cancer treatment. The chaperone function of gp96 depends on its ATPase domain, which is structurally distinct from other HSP90 members, and thus favors the design of highly selective gp96-targeted inhibitors against cancer. We herein discuss the strategically important oncogenic clients of gp96 and their underlying biology. The roles of cell-intrinsic gp96 in T cell biology are also discussed, in part because it offers another opportunity of cancer therapy by manipulating levels of gp96 in T cells to enhance host immune defense.


Vestibular evoked myogenic potential in noise-induced hearing loss.
Noise affects one's hearing as well as balance mechanism. The hearing mechanism of the noise-exposed individuals has been extensively studied. However, in view of the poor research focus on the sacculo-collic reflexes, especially in this study area, the present study was undertaken to examine the vestibular evoked myogenic potentials (VEMP) in subjects with noise-induced hearing loss (NIHL). A total of 30 subjects (55 ears) with NIHL participated in the present study within the age range of 30-40 years. VEMP recordings were done at 99 dBnHL using IHS instrument. The results indicated that as the average pure tone hearing threshold increased, the VEMP latencies were prolonged and peak to peak amplitude was reduced in NIHL subjects. Out of the 55 ears, VEMP was absent in 16 (29.0%) ears. The latency was prolonged and the peak to peak amplitude was reduced in 19 (34.6%) ears. VEMP results were normal in 20 (36.4%) ears. Therefore, VEMP was abnormal or absent in 67% of NIHL subjects in the present study. Hence it can be concluded that the possibility of vestibular dysfunction, specially the saccular pathway, is high in individuals with NIHL. VEMP, a non-invasive and user friendly procedure, can be employed in these individuals to assess sacculo-collic reflex.


Blue emitting organic semiconductors under high pressure: status and outlook.
This review describes essential optical and emerging structural experiments that use high GPa range hydrostatic pressure to probe physical phenomena in blue-emitting organic semiconductors including π-conjugated polyfluorene and related compounds. The work emphasizes molecular structure and intermolecular self-organization that typically determine transport and optical emission in π-conjugated oligomers and polymers. In this context, hydrostatic pressure through diamond anvil cells has proven to be an elegant tool to control structure and interactions without chemical intervention. This has been highlighted by high pressure optical spectroscopy whilst analogous x-ray diffraction experiments remain less frequent. By focusing on a class of blue-emitting π-conjugated polymers, polyfluorenes, this article reviews optical spectroscopic studies under hydrostatic pressure, addressing the impact of molecular and intermolecular interactions on optical excitations, electron-phonon interaction, and changes in backbone conformations. This picture is connected to the optical high pressure studies of other π-conjugated systems and emerging x-ray scattering experiments from polyfluorenes which provides a structure-property map of pressure-driven intra- and interchain interactions. Key obstacles to obtain further advances are identified and experimental methods to resolve them are suggested.


Cooperative slit and netrin signaling in contralateralization of the mouse trigeminothalamic pathway.
Ascending somatosensory pathways are crossed pathways representing each side of the body in the contralateral neocortex. The principal sensory nucleus of the trigeminal nerve (PrV) relays the facial sensations to the contralateral somatosensory cortex via the ventrobasal thalamus. In the companion article (Kivrak and Erzurumlu [2012] J. Comp. Neurol. 12-0013) we described the normal development of the trigeminal lemniscal pathway in the mouse. In this study we investigated the role of midline axon navigation signals, the netrin and slit proteins. In situ hybridization assays revealed that both netrin and slit mRNAs are expressed along the midline facing the PrV axons and their receptors are expressed in developing PrV neurons. In wild-type mouse embryos, PrV axons cross the midline and take a sharp rostral turn heading toward the contralateral thalamus. Examination of trigeminal lemniscal axons in dcc knockout mice revealed absence of midline crossing between E11 and E15. However, a few axons crossed the midline at E17 and reached the contralateral thalamus, resulting in a bilateral PrV lemniscal pathway at P0. We also found that slit1, -2 or -3 single or double knockout mice have impaired development of the trigeminal-lemniscal pathway. These include axon stalling along the midline, running within the midline, and recrossing of axons back to the site of origin. Collectively, our studies indicate a cooperative role for netrin and slit proteins in midline attraction and crossing behavior of the ascending facial somatosensory projections during development.


[Clinical picture of central nervous system lesions in hematosarcoma].
A description of 21 patients suffering from lympho- and reticulosarcomas with metastatic affections of the cerebral and spinal meninges (20 patients) and an intracerebral solitary tumour (one patient) is presented. In 17 cases the diagnosis was confirmed on autopsy. The neurological picture was similar to the clinical picture of basal (7 patients) or cerebrospinal (9 patients) meningitis. Isolated spinal lesions were infrequent (4 patients). The cerebrospinal liquor showed, as a rule, a protein-cellular dissociation; in individual cases a high blastic pleocytosis was observed. A favourable effect on the disease course was produced by methotrexate which was injected endolumbarly.


Adiponectin is a candidate biomarker of lower extremity bone density in men with chronic spinal cord injury.
Adipose tissue is a major regulator of bone metabolism and in the general population obesity is associated with greater bone mineral density (BMD). However, bone-fat interactions are multifactorial, and may involve pathways that influence both bone formation and resorption with competing effects on the skeleton. One such pathway involves adipocyte production of adipokines that regulate bone metabolism. In this study we determined the association between BMD, walking status, and circulating adipokines (adiponectin and leptin) in 149 men with chronic spinal cord injury (SCI). Although adipokine levels did not vary significantly based on walking status, there was a significant inverse association between adiponectin and BMD in wheelchair users independent of body composition. We found no association between adiponectin and BMD in the walkers and no association between leptin and BMD in either group. These findings suggest that for subjects with chronic SCI, walking may mitigate the effect of adiponectin mediated bone loss. For wheelchair users, adipose-derived adiponectin may contribute to SCI-induced osteoporosis because the osteoprotective benefits of obesity appear to require mechanical loading during ambulation.


Differential and overlapping targets of the transcriptional regulators NRF1, NRF2, and NRF3 in human cells.
The nuclear factor (erythroid 2)-like (NRF) transcription factors are a subset of cap'n'collar transcriptional regulators. They consist of three members, NRF1, NRF2, and NRF3, that regulate the expression of genes containing antioxidant-response elements (AREs) in their promoter regions. Although all NRF members regulate ARE-containing genes, each is associated with distinct roles. A comprehensive study of differential and overlapping DNA-binding and transcriptional activities of the NRFs has not yet been conducted. Here, we performed chromatin immunoprecipitation (ChIP)-exo sequencing, an approach that combines ChIP with exonuclease treatment to pinpoint regulatory elements in DNA with high precision, in conjunction with RNA-sequencing to define the transcriptional targets of each NRF member. Our approach, done in three U2OS cell lines, identified 31 genes that were regulated by all three NRF members, 27 that were regulated similarly by all three, and four genes that were differentially regulated by at least one NRF member. We also found genes that were up- or down-regulated by only one NRF member, with 84, 84, and 22 genes that were regulated by NRF1, NRF2, and NRF3, respectively. Analysis of the ARE motifs identified in ChIP peaks revealed that NRF2 prefers binding to AREs flanked by GC-rich regions and that NRF1 prefers AT-rich flanking regions. Thus, sequence preference, likely in combination with upstream signaling events, determines NRF member activation under specific cellular contexts. Our analysis provides a comprehensive description of differential and overlapping gene regulation by the transcriptional regulators NRF1, NRF2, and NRF3.


Evolution of the apicoplast and its hosts: from heterotrophy to autotrophy and back again.
The photosynthetic origin of apicomplexan parasites was proposed upon the discovery of a reduced non-photosynthetic plastid termed the apicoplast in their cells. Although it is clear that the apicoplast has evolved through a secondary endosymbiosis, its particular origin within the red or green plastid lineage remains controversial. The recent discovery of Chromera velia, the closest known photosynthetic relative to apicomplexan parasites, sheds new light on the evolutionary history of alveolate plastids. Here we review our knowledge on the evolutionary history of Apicomplexa and particularly their plastids, with a focus on the pathway by which they evolved from free-living heterotrophs through photoautotrophs to omnipresent obligatory intracellular parasites. New sequences from C. velia (histones H2A, H2B; GAPDH, TufA) and phylogenetic analyses are also presented and discussed here.


Six distinct nuclear factors interact with the 75-base-pair repeat of the Moloney murine leukemia virus enhancer.
Binding sites for six distinct nuclear factors on the 75-base-pair repeat of the Moloney murine leukemia virus enhancer have been identified by an electrophoretic mobility shift assay combined with methylation interference. Three of these factors, found in WEHI 231 nuclear extracts, which we have named LVa, LVb, and LVc (for leukemia virus factors a, b, and c) have not been previously identified. Nuclear factors that bind to the conserved simian virus 40 corelike motif, the NF-1 motif, and the glucocorticoid response element were also detected. Testing of multiple cell lines showed that most factors appeared ubiquitous, except that the NF-1 binding factor was found neither in nuclear extracts from MEL cells nor in the embryonal carcinoma cell lines PCC4 and F9, and core-binding factor was relatively depleted from MEL and F9 nuclear extracts.


The effect of the Breast and Cervical Cancer Prevention and Treatment Act on Medicaid disenrollment.
The Breast and Cervical Cancer Prevention and Treatment Act (BCCPTA) of 2000 created a new Medicaid option that allowed states to expand coverage to previously uninsured low-income women screened by certain public providers and found in need of treatment for those cancers. States also had the flexibility to allow any provider to screen for this new eligibility category and BCCPTA women were made eligible for all Medicaid services for the duration of their treatment. We have assessed the effect of this new program on the disenrollment patterns of women with breast/cervical cancer versus those with control cancers pre- and post-BCCPTA in Georgia. The post-BCCPTA period analyzed here was one in which Georgia BCCPTA women could self-report that they were in active treatment and, hence, still eligible. The Georgia Comprehensive Cancer Registry (1999-2004) was linked to Medicaid enrollment files (1998-2005) to identify female Medicaid enrollees aged under 65 and enrolled in Medicaid at or after being diagnosed with breast (n = 2,265), cervical (n = 439) or one of five control cancers (n = 700). The rate of disenrollment (per 100 person-months) was computed for each cancer group pre- versus post-BCCPTA. We employed difference-in-differences analysis to adjust for any temporal changes other than BCCPTA that could affected the disenrollment rate of women with both the treatment (breast/cervical) and control cancers. We used a parametric hazard model with a Weibull distribution to analyze the odds of disenrollment. The unadjusted disenrollment rate declined 50% for women with breast and cervical cancers, whereas it increased over 30% for those with control cancers, pre- versus post-BCCPTA. The direction and magnitude of these results held after adjusting for socio-demographics and area characteristics that could affect disenrollment rates. Georgia BCCPTA has the potential to improve continuity of care for women with breast and cervical cancers because they experience more stable coverage and simpler recertification process under this new eligibility category.


Respiratory viruses associated with community-acquired pneumonia in children: matched case-control study.
Community-acquired pneumonia (CAP) is the leading cause of death in children worldwide and a substantial proportion of childhood CAP is caused by viruses. A better understanding of the role of virus infections in this condition is needed to improve clinical management and preventive measures. The aim of the study was therefore to assess the association between specific respiratory viruses and childhood CAP. A case-control study was conducted during 3 years in Stockholm, Sweden. Cases were children aged ≤5 years with radiological CAP. Healthy controls were consecutively enrolled at child health units during routine visits and matched to cases on age and calendar time. Nasopharyngeal aspirates were obtained and analysed by real-time PCR for 15 viruses. Multivariate conditional logistic regression was used to account for coinfections with other viruses and baseline characteristics. A total of 121 cases, of which 93 cases met the WHO criteria for radiological pneumonia, and 240 controls were included in the study. Viruses were detected in 81% of the cases (n=98) and 56% of the controls (n=134). Influenza virus, metapneumovirus and respiratory syncytial virus were detected in 60% of cases and were significantly associated with CAP with ORs >10. There was no association with parainfluenza virus, human enterovirus or rhinovirus and coronavirus and bocavirus were negatively associated with CAP. Our study indicates viral CAP is an underestimated disease and points out hMPV as a new important target for the prevention of childhood CAP.


Role of Single Nucleotide Variants in FSHR, GNRHR, ESR2 and LHCGR Genes in Adolescents with Polycystic Ovary Syndrome.
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting up to 16.6% of reproductive-age women. PCOS symptoms in adolescents comprise oligomenorrhoea/amenorrhoea and biochemical and/or clinical hyperandrogenism. Long-term health risks of PCOS patients include infertility, metabolic syndrome, type 2 diabetes and cardiovascular disease. Genetic factors have been proven to play a role in development of the syndrome and its symptoms. To investigate single nucleotide variants (SNVs) in the GNRHR, ESR2, LHCGR and FSHR genes in adolescent patients with PCOS and their association with PCOS symptoms. We conducted a cross-sectional study comprising of 152 adolescents: 63 patients with PCOS, 22 patients at risk of developing PCOS and 67 healthy controls. Participants were recruited from out-patients attending a gynaecologist at the Children's Clinical University Hospital, Riga, Latvia, between January 2017 and December 2020. Genomic DNA was extracted from whole blood, and SNVs in the GNRHR, ESR2, LHCGR and FSHR genes were genotyped. The distributions of SNV genotypes were compared among the three groups and genotype-phenotype associations within the PCOS group were evaluated. No statistically significant differences were found in the distributions of genotypes for GNRHR (rs104893837), ESR2 (rs4986938), LHCGR (rs2293275) and FSHR (rs6166, rs6165, rs2349415) among PCOS patients, risk patients and healthy controls. Within the PCOS group, ESR2 rs4986938 minor allele homozygous patients had a significantly higher level of total testosterone than major allele homozygous patients and heterozygous patients. A significantly higher total testosterone level was also observed in PCOS patients carrying the LHCGR rs2293275 minor allele compared with major allele homozygous patients. The SNVs ESR2 rs4986938 and LHCGR rs2293275 play a role in the phenotypic characteristics of PCOS. To fully uncover their influence on the development of PCOS and its symptoms, further studies of larger cohorts and a follow up of this study sample through to adulthood are required. Furthermore, studies of adolescent PCOS patients conducted prior to the latest European Society of Human Reproduction and Embryology (ESHRE) criteria (2018) should be re-evaluated as the study groups might include risk patients according to these updated criteria, thereby potentially significantly impacting the published results.


5'-flanking and intragenic sequences confer androgenic and developmental regulation of mouse aldose reductase-like gene in vas deferens and adrenal in transgenic mice.
The MVDP (mouse vas deferens protein) gene, which encodes an aldose reductase-like enzyme, is mainly expressed in vas deferens epithelium and adrenal cortex. Vas deferens MVDP gene transcription was known to be under androgenic control, we now have evidence for androgen and probable ACTH responsiveness of the MVDP gene in the adrenal. To analyze the role of potential regulatory regions in hormonal, developmental, and tissue-specific aspects of MVDP regulation, we generated transgenic mice harboring MVDP-CAT fusion genes. The constructs carried either -1.8 or -0.5 kb 5'-flanking sequence attached to the chloramphenicol acetyltransferase gene in presence or absence of a 3.5-kb intragenic fragment in a downstream position. We show that at least two regions ensure proper gene regulation in vivo. The first, located within the 1.8-kb promoter fragment, directs tissue specificity; positive elements necessary for vas deferens and adrenal expression lay within positions -1804 to -510 and -510 to +41, respectively. The second, located within the 3.5-kb intragenic fragment spanning intron 1 to intron 2, increases percentage of expressing lines and behaves as a vas deferens-specific enhancer. Hormonal and developmental control of transgenes closely parallel endogenous gene regulation. Androgen and ACTH responsiveness in adrenals is conferred by 0.5-kb promoter, whereas in vas deferens, full androgenic response of the 1.8-kb promoter required the 3.5-kb intragenic fragment. Thus, vas deferens and adrenals use distinct cis-acting elements to direct and regulate the expression of the MVDP gene.


Risk of advanced proximal neoplasms in asymptomatic adults according to the distal colorectal findings.
The clinical significance of a distal colorectal polyp is uncertain. We determined the risk of advanced proximal neoplasia, defined as a polyp with villous features, a polyp with high-grade dysplasia, or cancer, among persons with distal hyperplastic or neoplastic polyps as compared with the risk among persons with no distal polyps. We analyzed data from 1994 consecutive asymptomatic adults (age, 50 years or older) who underwent colonoscopic screening for the first time between September 1995 and December 1998 as part of a program sponsored by an employer. The location and histologic features of all polyps were recorded. Colonoscopy to the level of the cecum was completed in 97.0 percent of the patients. Sixty-one patients (3.1 percent) had advanced lesions in the distal colon, including 5 with cancer, and 50 (2.5 percent) had advanced proximal lesions, including 7 with cancer. Twenty-three patients with advanced proximal neoplasms (46 percent) had no distal polyps. The prevalence of advanced proximal neoplasia among patients with no distal polyps was 1.5 percent (23 cases among 1564 persons; 95 percent confidence interval, 0.9 to 2.1 percent). Among patients with distal hyperplastic polyps, those with distal tubular adenomas, and those with advanced distal polyps, the prevalence of advanced proximal neoplasia was 4.0 percent (8 cases among 201 patients), 7.1 percent (12 cases among 168 patients), and 11.5 percent (7 cases among 61 patients), respectively. The relative risk of advanced proximal neoplasia, adjusted for age and sex, was 2.6 for patients with distal hyperplastic polyps, 4.0 for those with distal tubular adenomas, and 6.7 for those with advanced distal polyps, as compared with patients who had no distal polyps. Older age and male sex were associated with an increased risk of advanced proximal neoplasia (relative risk, 1.3 for every five years of age and 3.3 for male sex). Asymptomatic persons 50 years of age or older who have polyps in the distal colon are more likely to have advanced proximal neoplasia than are persons without distal polyps. However, if colonoscopic screening is performed only in persons with distal polyps, about half the cases of advanced proximal neoplasia will not be detected.


[Pain and corneal pathology].
Since the development of photorefractive keratectomy, ophtalmologists are concerned by the mechanisms of corneal pain in order to prevent and reduce it. Corneal epithelium and anterior stroma are widely innervated by nasociliary fibers form ophtalmologic nerve (V). Receptors react to a chemical, mechanical and thermal stimulation by an acute and precisely located pain. This pain is developed by release of inflammatory mediators and neuro transmitters. Pain is different regarding the pathology and the treatment: photorefractive keratectomy, Acanthamoeba keratitis, Mooren's ulcer. Topical non steroidal antiinflammatory drugs have a specific role in controlling corneal pain.


Guideline for the treatment of haemophilia in South Africa.
This guideline has been prepared by the authors for and on behalf of the Medical and Scientific Advisory Council (MASAC) of the South African Haemophilia Foundation to facilitate the appropriate management of individuals with haemophilia in South Africa. Individuals with haemophilia and their physicians should be advised by a Comprehensive Haemophilia Treatment Centre. Strategies that help to prevent bleeds include regular exercise to strengthen muscles, protect joints and improve fitness; maintaining a healthy body weight to avoid extra stress on joints; and avoiding contact sports. Acute bleeds should be treated early, ideally within 2 hours of onset. Patients with mild or moderate haemophilia A may be treated with desmopressin. Bleeding in patients with severe haemophilia A without inhibitors should be treated with factor VIII concentrate. Bleeding in patients with haemophilia B without inhibitors should be treated with factor IX replacement. Tranexamic acid can be used for mucous membrane bleeding in surgical or dental procedures. Bleeds in patients with inhibitors must be managed in consultation with a haemophilia treatment centre. Major bleeding episodes are large muscle or joint bleeds, bleeds resulting from severe injury, or bleeds that affect the central nervous system; gastrointestinal system; neck or throat; hip or iliopsoas; or the forearm compartment. These bleeds may cause death or musculoskeletal deformities, and advice on their treatment should be sought from a haemophilia treatment centre physician. Appropriate factor replacement therapy must be started urgently for major bleeds, and hospitalisation is usually required to maintain adequate factor levels.


Essential Oils as an Alternative to Pyrethroids' Resistance against Anopheles Species Complex Giles (Diptera: Culicidae).
Widespread resistance of Anopheles sp. populations to pyrethroid insecticides has led to the search for sustainable alternatives in the plant kingdom. Among many botanicals, there is great interest in essential oils and their constituents. Many researchers have explored essential oils (EOs) to determine their toxicity and identify repellent molecules that are effective against Anopheles populations. Essential oils are volatile and fragrant substances with an oily consistency typically produced by plants. They contain a variety of volatile molecules such as terpenes and terpenoids, phenol-derived aromatic components and aliphatic components at quite different concentrations with a significant insecticide potential, essentially as ovicidal, larvicidal, adulticidal, repellency, antifeedant, growth and reproduction inhibitors. The current review provides a summary of chemical composition of EOs, their toxicity at different developmental stages (eggs, larvae and adults), their repellent effects against Anopheles populations, for which there is little information available until now. An overview of antagonist and synergistic phenomena between secondary metabolites, the mode of action as well as microencapsulation technologies are also given in this review. Finally, the potential use of EOs as an alternative to current insecticides has been discussed.


Mid-infrared guided optics: a perspective for astronomical instruments.
Research activities during the last decade have shown the strong potential of photonic devices to greatly simplify ground based and space borne astronomical instruments and to improve their performance. We focus specifically on the mid-infrared wavelength regime (about 5-20 microm), a spectral range offering access to warm objects (about 300 K) and to spectral features that can be interpreted as signatures for biological activity (e.g. water, ozone, carbon dioxide). We review the relevant research activities aiming at the development of single-mode guided optics and the corresponding manufacturing technologies. We evaluate the experimentally achieved performance and compare it with the performance requirements for applications in various fields of astronomy. Our goal is to show a perspective for future astronomical instruments based on mid-infrared photonic devices.


Videotape preparation of patients before hip replacement surgery reduces stress.
Elective surgery represents a considerable source of stress for the patient. Many attempts have been made to prepare patients before surgery with the aim of reducing stress and improving outcome. This study used a novel approach to fulfill this aim by showing a videotape of a patient undergoing total hip replacement surgery, covering the time period from hospital admission to discharge, that strictly keeps to the patient's perspective. Before elective total hip replacement surgery, 100 patients were randomly assigned to a control group or a preparation group; the latter group was shown the videotape on the evening before surgery. Anxiety and pain were evaluated daily for 5 days, beginning with the preoperative day, by means of the State-Trait Anxiety Inventory and a visual analog scale. Intraoperative heart rate and blood pressure, as well as postoperative intake of analgesics and sedatives, were recorded. Urinary levels of cortisol, epinephrine, and norepinephrine were determined in 12-hour samples collected at night for 5 nights, beginning with the preoperative night. Compared with the control group, the preparation group showed significantly less anxiety on the morning before surgery and the mornings of the first 2 postoperative days, and significantly fewer of them had an intraoperative systolic blood pressure increase of more than 15%. The pain ratings did not differ significantly between the two groups, but the prepared patients needed less analgesic medication after surgery. Prepared patients had significantly lower cortisol excretion during the preoperative night and the first 2 postoperative nights. Excretion of catecholamines did not differ significantly between groups. We conclude that use of the videotape decreased anxiety and stress, measured in terms of urinary cortisol excretion and intraoperative systolic blood pressure increase, in patients undergoing hip replacement surgery and prepared them to cope better with postoperative pain.


Outcomes and patient perspectives following implementation of tiered opioid prescription guidelines in gynecologic surgery.
To report the impact of implementing standardized guidelines for opioid prescriptions after gynecologic surgery and describe patient perspectives before and after implementation for those undergoing laparotomy for ovarian cancer. Patients undergoing gynecologic surgery between October 2017 and May 2018 were prescribed opioids at discharge using tiered guidelines; prescriptions were compared to consecutive historical controls (March 2017-October 2017). A subset of ovarian cancer laparotomy patients were surveyed regarding postoperative opioid consumption and patient experience. A total of 620 women in the tiered guideline cohort were compared with 599 historical controls. Following implementation, 95.8% of prescriptions met guidelines. Median milligram morphine equivalents (MME) prescribed decreased from 150 to 75 (p ≤ 0.001) with no change in opioid refills (7.7 vs 6.9%, p = 0.62). In surveyed ovarian cancer patients, 100% of tiered guideline patients and 92% of historical controls felt satisfied with pain control (p = 0.24), despite a 50% reduction in prescribed MME and 14.6% receiving no opioids at discharge (p = 0.002). The median (IQR) MME consumed after discharge was 15 (0, 75) in tiered guideline patients vs. 24 (0, 135) in historical controls, and 38.2% and 42.4% consumed no opioids, respectively. Mean time between surgery and opioid use cessation was <1 week in both groups; patients' perceptions of opioid prescription appropriateness did not change (p = 0.49). More than 75% of patients kept their remaining opioids rather than dispose of them. Reducing prescribed opioids after gynecologic surgery using tiered guidelines did not increase opioid refills or worsen patients' perceptions of postoperative pain. Even after laparotomy, very little opioids were required over a short duration after dismissal. Infrequent disposal of leftover opioids highlights the need to avoid over-prescribing.


Fetal intestinal oxygen consumption at various levels of oxygenation.
In seven chronically catheterized fetal lambs, blood flow and oxygen consumption (VO2) in the combined small and large intestines were determined at various oxygen concentrations in fetal arterial blood (CaO2). Intestinal blood flow (Qi) was measured with the radioactive-microsphere technique; intestinal oxygen delivery (DO2 = Qi X CaO2), VO2 [Qi X C(a-v)O2, where oxygen extraction [C(a-v)O2/CaO2] were computed with the Fick equation. Compared with normally oxygenated fetuses (CaO2 greater than 6.6 ml/dl), moderately hypoxemic fetuses (CaO2 = 4.4-6.6 ml/dl) had decreased intestinal DO2, increased oxygen extraction, and no change in intestinal VO2, Qi, or mesenteric-venous pH and base excess. During severe fetal hypoxemia (CaO2 less than 4.4 ml/dl), DO2 decreased further while oxygen extraction increased substantially. Intestinal VO2 dropped, however, because the rise in oxygen extraction could no longer completely compensate for the reduced DO2. With severe hypoxemia, Qi and mesenteric-venous pH and base excess also fell. These data indicate that the fetal intestinal tract is able to meet its oxygen needs during hypoxemia until a critically low level of oxygenation is reached. Below this level intestinal oxygenation becomes inadequate, and anaerobic metabolism ensures.


[Chlamydia trachomatis--pattern of testing and prevalence among young women].
The purpose of this study was to explore pattern of testing and prevalence of C trachomatis among 16 to 19 year old Norwegian high school girls. The study subjects were 827 girls who participated in a study of oral contraceptives prescribed by public health nurses. The first consultation was an interview about sexual behaviour and other characteristics. The participants were encouraged to test for C trachomatis with their general practitioners. We explored characteristics of those tested and predictors of genital C trachomatis infection. Half of the study population was tested, either before (21%) or during the study period (26%). Girls with risk factors such as change of partner over the last six months, older partner or no regular partner were more likely to be tested than girls with no change of partner or a regular same-age partner. One out of four girls with high-risk behaviour (> or =3 partners) was never tested. The prevalence of infection at first test was 9%. The risk for having a positive test result was three times higher for single girls than for girls with a regular same-age partner. Too few young girls were tested for C trachomatis. Encouragement from public health providers had low influence on the pattern of testing. Alternative strategies such as implementation of do-it-yourself tests by urine or vulvovaginal sampling procedures have to be provided as a low-threshold service.


How and When? Metacognition and Solution Timing Characterize an "Aha" Experience of Object Recognition in Hidden Figures.
The metacognitive feelings of an "aha!" experience are key to comprehending human subjective experience. However, behavioral characteristics of this introspective cognition are not well known. An aha experience sometimes occurs when one gains a solution abruptly in problem solving, a subjective experience that subserves the conscious perception of an insight. We experimentally induced an aha experience in a hidden object recognition task, and analyzed whether this aha experience was associated with metacognitive judgments and behavioral features. We used an adaptation of Mooney images, i.e., morphing between a grayscale image and its binarised image in 100 steps, to investigate the phenomenology associated with insight: aha experience, confidence, suddenness, and pleasure. Here we show that insight solutions are more accurate than non-insight solutions. As metacognitive judgments, participants' confidence in the correctness of their solution is higher in insight than non-insight problem solving. Intensities of the aha feeling are positively correlated with subjective rating scores of both suddenness and pleasure, features that show marked signs of unexpected positive emotions. The strength of the aha experience is also positively correlated with response times from the onset of presentation until finding the solution, or with task difficulty only if the solution confidence is high enough. Our findings provide metacognitive and temporal conditions for an aha experience, characterizing features distinct from those supporting non-aha experience.


Green synthesis and synergistic catalytic effect ofAg/reduced graphene oxide nanocomposite.
A nanocomposite of silver nanoparticles and reduced graphene oxide (Ag/rGO) has been developed as a catalyst for the reduction of 4-nitrophenol (4-NP) to 4-aminophenol (4-AP) with sodium borohydride, owing to the larger specific surface area and synergistic effect of rGO. A facile and rapid microwave-assisted green route has been used for the uniform deposition of Ag nanoparticles and the reduction of graphene oxide simultaneously with l-arginine as the reducing agent. The resulting Ag/rGO nanocomposite contained about 51 wt% of Ag, and the Ag nanoparticles deposited on the surface of rGO had a mean diameter of 8.6 ± 3.5 nm. Also, the Ag/rGO nanocomposite exhibited excellent catalytic activity and stability toward the reduction of 4-NP to 4-AP with sodium borohydride. The reduction reaction obeyed the pseudo-first-order kinetics. The rate constants increased not only with the increase of temperature and catalyst amount but also with the increase of initial 4-NP concentration, revealing that the support rGO could enhance the catalytic activity via a synergistic effect. A mechanism for the catalytic reduction of 4-NP with NaBH4 by Ag/rGO nanocomposite via both the liquid-phase and solid-phase routes has been suggested.


Role of caspase activation in butyrate-induced terminal differentiation of HT29 colon carcinoma cells.
Colon epithelial cells have a defined life span and undergo terminal differentiation as they mature and migrate to the luminal surface. The differentiation process can be induced in cultured colon cancer cells by sodium butyrate, which induces expression of various differentiation markers followed subsequently by cell death. In the present study, HT29 colorectal carcinoma cells were shown to undergo butyrate-induced caspase activation that was mainly produced through a mitochondrial pathway. Inhibition of caspase activation, either by peptide pan caspase inhibitor Z-VAD-FMK, by caspase 9 inhibitor Z-LEHD-FMK, or by overexpression of Bcl-XL, also inhibited the expression of differentiation markers. These findings suggest (a) that terminal differentiation of HT29 colon carcinoma cells is tightly linked to caspase activation and (b) that increased expression of anti-apoptotic members of the Bcl-2 family of proteins, as well as other inhibitors of caspase activation, has the potential to inhibit terminal differentiation and thereby may contribute to the progression of colon cancer.


Role of purinergic signaling pathways in the adaptogenic-like activity of methyl jasmonate in rats exposed to unpredictable chronic mild stress.
Objectives Purinergic signaling pathway has been implicated in maladaptation of animals subjected to chronic stress. Previous studies have shown that methyl jasmonate (MJ) exhibited adaptogenic properties in mice exposed to unpredictable chronic mild stress (UCMS) via antioxidant and neuroprotective-related mechanisms. Methods This study evaluated the role of purinergic system in adaptogenic-like activity of MJ. Male Wistar rats were treated intraperitoneally with vehicle (10 mL/kg) or MJ (25, 50, or 100 mg/kg) 30 min prior exposure to UCMS. Thereafter, rats were assessed for swimming endurance in forced swim test (FST) and post-swimming motor coordination on beam walk test (BWT) apparatus. The rats' brains were processed for adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine deaminase, and arginase quantification. Hematological parameters, cholesterol, triglyceride, creatinine, and urea nitrogen were also determined. Results MJ prolonged swimming endurance time and reversed stress-induced post-swimming motor dysfunction. The altered hematological parameters induced by UCMS in rats were significantly (p<0.05) attenuated by MJ. MJ also reversed UCMS-induced alterations of total cholesterol, triglyceride, creatinine, and urea nitrogen levels. MJ averted UCMS-induced alterations in purinergic system by decreasing ATP and ADP hydrolysis, adenosine deaminase, and arginase activities in rats' brains. Conclusions Overall, these findings further suggest that MJ has adaptogenic-like activity in rats exposed to UCMS, which may be related to modulation of the purinergic signaling pathway.


miR-4999-5p Predicts Colorectal Cancer Survival Outcome and Reprograms Glucose Metabolism by Targeting PRKAA2.
Colorectal cancer (CRC) is the third most common cancer, and the second leading cause of cancer death worldwide. Dysregulation of microRNAs has been shown to modulate glucose metabolic reprogramming in CRC. However, the functional role of miR-4999-5p in the CRC glucose metabolic shift has not been characterized. The levels of miR-4999-5p and PRKAA2 were evaluated by RT-qPCR. Univariate and multivariate survival analyses were conducted to evaluate the prognostic value of miR-4999-5p. Cell proliferation was assessed using the CCK-8 and colony formation assays. Extracellular acidification rate, glucose uptake, cellular glucose-6-phosphate level, and lactate production were evaluated to assess the effects of miR-4999-5p on CRC glycolysis. Dual-luciferase reporter assay was conducted to investigate the direct interaction between miR-4999-5p and PRKAA2. Mouse xenograft models were established to assess the functions of miR-4999-5p in vivo. miR-4999-5p was highly expressed in CRC tissues and cell lines. In addition, miR-4999-5p was associated with tumor differentiation and TNM stage, and elevated expression of miR-4999-5p was an independent predictor of poorer overall survival. Furthermore, miR-4999-5p promoted cell proliferation and glycolysis in CRC. miR-4999-5p targeted PRKAA2 to exert its tumor-promoting functions, and PRKAA2 knockdown rescued decreased cell proliferation and glycolysis in miR-4999-5p-silenced CRC cells. In vivo experiments showed that miR-4999-5p promoted CRC growth. miR-4999-5p facilitated cell growth and glucose metabolic reprogramming through direct targeting of PRKAA2. Our results showed that miR-4999-5p may be a novel prognostic marker and therapeutic target for CRC.