n-Type charge transport and mobility of fluorinated perylene bisimide semiconductors.
The intramolecular and intermolecular charge transport parameters are evaluated quantum chemically for three fluorinated derivatives of perylene bisimide (PBI) semiconductors, two of which feature a twisted PBI core. Charge transfer rates are computed within the Marcus-Levich-Jortner formalism including a single effective mode treated quantum mechanically and are injected in a kinetic Monte Carlo scheme to propagate the charge carrier in the crystal and to estimate charge mobilities at room temperature. The relative order of computed mobilities agrees with the observed trend, and the largest mobility is computed for the planar PBI derivative. It is suggested that thermally induced disorder effects should contribute considerably to the observed large mobility of the planar PBI derivative, while a retardation effect induced by the presence of alternating slow and fast jumps along pi-stacked PBI columns is responsible for the lower mobilities of the two twisted derivatives. The computed parameters reveal the subtle interplay between intramolecular and intermolecular contributions to the charge carrier propagation in these organic semiconductors and may guide the design of more efficient architectures.


Combination therapies for hypertension - why we need to look beyond RAS blockers.
Hypertension is the leading cause of mortality and disability worldwide. Despite the proven benefits of blood pressure (BP) reduction, lack of BP pressure control continues to be the most important clinical problem in hypertension management. Areas covered: Factors involved in the lack of BP control and strategies to improve such control have been reviewed, with special focus on the usefulness of combination therapies, those types of combination which include a renin-angiotensin system (RAS) blocker, with diuretics, calcium channel blockers, or both. Expert commentary: Combination therapy is required for BP control in most hypertensive patients. RAS blockers should be included in such combinations, except contraindicated. Diuretics, and especially calcium channel blockers are the drugs of choice for double or triple combinations. Diuretics stimulate RAS and enhance the effect of RAS blockers, while minimizing the undesirable metabolic effects of diuretics. RAS blockers and calcium channel blockers have synergistic protective effects on the vascular wall and have demonstrated to be superior to other types of combinations, thus becoming the preferred initial treatment for most hypertensive patients. The use of single-pill combinations is associated with better treatment adherence, thus facilitating the achievement of adequate BP control.


Feasibility of fecal occult-blood testing for detection of colorectal neoplasia: debits and credits.
A screening program for colorectal cancer and adenomas has been applied to 6,579 mostly asymptomatic men and women age 40 years and older utilizing fecal occult-blood testing followed by investigation of patients with positive slides by air-contrast barium enema and colonoscopy. A control population of 7,325 patients had sigmoidoscopy only and no occult-blood testing. Approximately 1% of the patients had positive slides; most patients had only one or two slides positive. Approximately 50% of patients with positive slides had significant neoplastic lesions, including 23 patients with large adenomas and 7 patients with cancers. Pathological staging of cancers was more favorable in the screened asymptomatic group as compared with the control group. Neoplastic lesions seen on sigmoidoscopy in screened patients who had negative fecal occult-blood tests included 2 cancers and 15 large adenomas. Reasons for false negativity include possible conversion of initially positive slides to negative. Screening for colorectal cancer and adenomas with fecal occult-blood testing appears to be feasible approach with good patient compliance, and manageable rate of positive slides productive of a high percentage of neoplastic lesions. The number of false-positives seems to be low. False negativity has been observed and will require further study.


Smoking and healthcare expenditure reductions associated with the California Tobacco Control Program, 1989 to 2019: A predictive validation.
Previous research used data through 2008 to estimate a model for the effect of the California Tobacco Control Program (CTCP) that used cumulative real per capita tobacco control expenditure to predict smoking behavior (current adult smoking prevalence and mean cigarette consumption per current smoker). Predicted changes in smoking behavior due to the CTCP were used to predict its effect on health care expenditure. This research updates the model using the most recently available data and estimates CTCP program effect through 2019. The data used in the previous research were updated, and the original model specification and a related predictive forecast model were re-estimated. The updated regression estimates were compared to those previously published and used to update estimates of CTCP program effect in 2019 dollars. There was no evidence of structural change in the previously estimated model. The estimated effect of the CTCP program expenditures on adult current smoking prevalence and mean consumption per adult current smoker has remained stable over time. Over the life of the program, one additional dollar per capita of program expenditure was associated with a reduction of current adult smoking prevalence by about 0.05 percentage point and mean annual consumption per adult current smoker by about 2 packs. Using updated estimates, the program prevented 9.45 (SE 1.04) million person-years of smoking and cumulative consumption of 15.7 (SE 3.04) billion packs of cigarettes from 1989 to 2019. The program produced cumulative savings in real healthcare expenditure of $544 (SE $82) billion using the National Income and Product Accounts (NIPA), and $816 (SE $121) billion using the Center for Medicare and Medicaid Services (CMS) measure of medical costs. During this time, the CTCP expenditure was $3.5 billion. A simple predictive model of the effectiveness of the CTCP program remained stable and retains its predictive performance out-of-sample. The updated estimates of program effect suggest that CTCP program has retained its effectiveness over its 31-year life and produced a return on investment of 231 to 1 in direct CMS medical expenditure.


Predictors for repeat self-harm and suicide among older people within 12 months of a self-harm presentation.
A past history of self-harm is a significant risk factor for suicide in older people. The aims of this study are to (i) characterize older people who present with self-harm to emergency departments (EDs); and (ii) determine the predictors for repeat self-harm and suicide. Demographic and clinical data were retrospectively collected on older people (age 65+ years), who presented to seven EDs in New Zealand following an episode of self-harm between 1st July 2010 and 30th June 2013. In addition, 12-month follow-up information on repeat self-harm and suicide was collected. The sample included 339 older people (55.2% female) with an age range of 65-96 years (mean age = 75.0; SD = 7.6). Overdose (68.7%) was the most common method of self-harm. 76.4% of the self-harm cases were classified as suicide attempts. Perceived physical illness (47.8%) and family discord (34.5%) were the most common stressors. 12.7% of older people repeated self-harm and 2.1% died by suicide within 12 months. Older people who had a positive blood alcohol reading (OR = 3.87, 95% Cl = 1.35-11.12, p = 0.012) and were already with mental health services at the index self-harm (OR = 2.73, 95% Cl = 1.20-6.25, p = 0.047) were more likely to repeat self-harm/suicide within 12 months. Older people who self-harm are at very high risk of repeat self-harm and suicide. Screening and assessment for alcohol use disorders should be routinely performed following a self-harm presentation, along with providing structured psychological treatment as an adjunct to pharmacological treatment for depression and interventions to improve the person's resilience resources.


An attempt to explain disordered immunity and hypogammaglobulinemia in B-CLL.
Most CLL cases correspond to proliferation of a B-cell clone characterized by: low amounts of surface Ig (SIg); presence of receptors for mouse red blood cells; expression of a 67 Kd antigenic determinant (CD5) initially described to be a pan-T cell antigen. These peculiar characteristics differentiate the CLL B lymphocyte from B lymphocytes proliferating in other B-cell malignancies. These so-called CD5 + B cells constitute a minority of B cells in adults, although they predominate during foetal life. This latter fact induced a majority of authors to assume that CLL B lymphocytes correspond to proliferation of an immature B-cell clone. However, this hypothesis does not explain the particular high frequency with which hypogammaglobulinemia and autoimmune phenomena directed against blood cell components are found in B-CLL, as well as the difficulty to include CD5 antigen in most differentiation pathways of B-cells. In this work, we shall discuss the available evidence coming from Ly 1-B cells (mouse counterpart of CD5 B cells), indicating that these cells correspond to a separate B lineage. We shall also discuss the evidence for hypogammaglobulinemia being mainly a B cell defect caused by dilution or inhibition of normal CD5 negative B cells and disordered autoimmunity as a consequence of a disturbance of the idiotypic network, which normally antagonizes autoimmune clones.


Effect of the Type and Number of Adverse Childhood Experiences and the Timing of Adverse Experiences on Clinical Outcomes in Individuals with Bipolar Disorder.
: Studies have reported an association between adverse childhood experiences (ACEs) and the clinical outcomes of bipolar disorder (BD). However, these studies have several limitations; therefore, we aimed to clarify the effect of the type and number of ACEs and the timing of adverse experiences on clinical outcomes in patients with BD. We analyzed the data of patients with BD (N = 2675) obtained from the National Institute of Mental Health: Bipolar Disorder Genetic Association Information Network, Translational Genomic Institute-I, and Translational Genomic Institute-II. All patients had been diagnosed using the Diagnostic Interview for Genetic Studies. ACEs were evaluated using the Childhood Life Events Scale (CLES). We analyzed the relationship between childhood trauma and clinical outcome in patients with and without exposure to ACEs. We found that ACEs had a robust negative effect on clinical outcomes, including earlier age at onset, presence of psychotic episodes, suicide attempts, mixed symptoms or episodes, substance misuse comorbidity, and worse life functioning. Specifically, the number of ACEs had the most significant effect on clinical outcomes; however, specific ACEs, such as physical abuse, had a considerable influence. Moreover, post-childhood adverse experiences had a weaker effect on clinical outcomes than ACEs did. There was an association of ACEs with negative clinical outcomes in patients with BD. This indicates the importance of basic and clinical research on ACEs in patients with BD.


The Impact of Hepatic Cirrhosis on Chronic Obstructive Pulmonary Disease in the United States: A Nationwide Analysis.
We aimed to study the impact of Hepatic Cirrhosis (HC) on chronic obstructive pulmonary disease (COPD). Our study is a retrospective cohort study using the 2016-2017 National Readmission Database (NRD). NRD is part of the Healthcare Cost and Utilization Project (HCUP), organized and supported by means of the Agency for Healthcare Research and Quality (AHRQ). Patients were included if they were 18 years or older and had a principal diagnosis of COPD based on International Classification of Diseases, Tenth Revision (ICD-10- CM) codes and had a secondary diagnosis of HC. A total of 505,004 patients were included in the study with a diagnosis of COPD, 6196 (1.23%) of whom had HC. HC was found to be more common amongst male patients between the ages of 50 and 65 years. Medicare beneficiaries with high comorbidity burden, lower socioeconomic status, and those who received treatment in a large urban teaching hospital also had higher rates of HC. Patients with HC and COPD correlated to an increase of in-hospital mortality (adjusted odds ratio (aOR: 2.21, p<0.001) and 30-day hospital readmission rate (aOR: 1.23, p<0.001) compared with patients without HC. The in-hospital mortality rate was higher during readmission compared with index admissions (5.01% versus 2.16%; p<0.001). In addition, HC was associated with higher morbidity including prolonged mechanical ventilation (aOR: 1.39, p<0.001), resource utilization with prolong length of stay (LOS) (adjusted mean difference (aMD: 0.51, p<0.001), higher total hospitalization charges (aMD: 4967, p<0.001), and costs (aMD: 1200, p<0.001). Both patient groups had similar odds of being intubated (aOR: 1.18, p-0.13), tracheostomy (aOR: 0.81, p-069) and bronchoscopy rates (aOR: 1.27, p-0.36). The most common causes of hospital readmission were found to be COPD with acute exacerbation (19.7%), sepsis, unspecified organism (6.0%, acute and chronic respiratory failure with hypoxia (4.2%), acute on chronic systolic heart failure (3.9%), and hepatic failure, unspecified coma (3.1%). Various autonomous prognosticators of readmission were sex (particularly female), alcohol dependence, LOS greater than 7 days, lower comorbidity burden, and discharge to short term hospital or against medical advice. On the other hand, males, patients without a history of alcohol dependence, greater comorbidity burden, and LOS fewer than 3 days, were less likely to be readmitted. We found that HC is related to higher in-hospital mortality, LOS, increased mechanical ventilation, resource utilization with prolonged LOS, hospital costs, odds of intubation, and tracheostomy and bronchoscopy rates. Our study aims to shed light on the impact of HC on COPD in hopes to improve future management.


Paucibacillary primary dapsone resistance--a case report.
A Case of primary paucibacillary Dapsone resistance was presented. Its clinical suspicion and diagnosis are stressed. Emergence of dapsone resistance and its implications are shortly reviewed. A short note on its prevention is discussed. Literature is briefly reviewed.


Protection against allergies: Microbes, immunity, and the farming effect.
The prevalence of asthma and other allergic diseases has rapidly increased in "Westernized" countries over recent decades. This rapid increase suggests the involvement of environmental factors, behavioral changes or lifestyle, rather than genetic drift. It has become increasingly clear that the microbiome plays a key role in educating the host immune system and, thus, regulation of disease susceptibility. This review will focus on recent advances uncovering immunological and microbial mechanisms that protect against allergies, in particular, within the context of a farming environment. A whole body of epidemiological data disclosed the nature of the protective exposures in a farm. Current evidence points toward an important role of the host microbiome in setting an immunological equilibrium that determines progression toward, or protection against allergic diseases. Conclusive mechanistic insights on how microbial exposures prevent from developing allergic diseases in humans are still lacking but findings from experimental models reveal plausible immunological mechanisms. Gathering further knowledge on these mechanisms and confirming their relevance in humans is of great importance to develop preventive strategies for children at risk of developing allergies.


Biological clockwork underlying adaptive rhythmic movements.
Owing to the complexity of neuronal circuits, precise mathematical descriptions of brain functions remain an elusive ambition. A more modest focus of many neuroscientists, central pattern generators, are more tractable neuronal circuits specialized to generate rhythmic movements, including locomotion. The relative simplicity and well-defined motor functions of these circuits provide an opportunity for uncovering fundamental principles of neuronal information processing. Here we present the culmination of mathematical analysis that captures the adaptive behaviors emerging from interactions between a central pattern generator, the body, and the physical environment during locomotion. The biologically realistic model describes the undulatory motions of swimming leeches with quantitative accuracy and, without further parameter tuning, predicts the sweeping changes in oscillation patterns of leeches undulating in air or swimming in high-viscosity fluid. The study demonstrates that central pattern generators are capable of adapting oscillations to the environment through sensory feedback, but without guidance from the brain.


Click-PEGylation - A mobility shift approach to assess the redox state of cysteines in candidate proteins.
The redox state of cysteine thiols is critical for protein function. Whereas cysteines play an important role in the maintenance of protein structure through the formation of internal disulfides, their nucleophilic thiol groups can become oxidatively modified in response to diverse redox challenges and thereby function in signalling and antioxidant defences. These oxidative modifications occur in response to a range of agents and stimuli, and can lead to the existence of multiple redox states for a given protein. To assess the role(s) of a protein in redox signalling and antioxidant defence, it is thus vital to be able to assess which of the multiple thiol redox states are present and to investigate how these alter under different conditions. While this can be done by a range of mass spectrometric-based methods, these are time-consuming, costly, and best suited to study abundant proteins or to perform an unbiased proteomic screen. One approach that can facilitate a targeted assessment of candidate proteins, as well as proteins that are low in abundance or proteomically challenging, is by electrophoretic mobility shift assays. Redox-modified cysteine residues are selectively tagged with a large group, such as a polyethylene glycol (PEG) polymer, and then the proteins are separated by electrophoresis followed by immunoblotting, which allows the inference of redox changes based on band shifts. However, the applicability of this method has been impaired by the difficulty of cleanly modifying protein thiols by large PEG reagents. To establish a more robust method for redox-selective PEGylation, we have utilised a Click chemistry approach, where free thiol groups are first labelled with a reagent modified to contain an alkyne moiety, which is subsequently Click-reacted with a PEG molecule containing a complementary azide function. This strategy can be adapted to study reversibly reduced or oxidised cysteines. Separation of the thiol labelling step from the PEG conjugation greatly facilitates the fidelity and flexibility of this approach. Here we show how the Click-PEGylation technique can be used to interrogate the redox state of proteins.


Increasing the public health effectiveness of fluoridated salt.
This paper aims at assessing the public health potential of salt fluoridation schemes. There is now solid evidence which shows that the cariostatic effectiveness of universal salt fluoridation is equivalent to that of water fluoridation in both the permanent and primary dentition. In countries of continental Europe, only domestic salt is fluoridated, and its consistent use may be expected to warrant a 30% reduction of caries prevalence. However, the effectiveness in the population at large is lower because only part of the population uses the fluoridated domestic salt. Under these conditions, it must be assumed that the effectiveness is further reduced because families in low S-E strata use fluoridated salt (FS) less frequently than those in the higher S-E strata who are known to use preventive methods like toothbrushing twice a day with a fluoride dentifrice more regularly. Model calculations tend to show that in Germany, where FS has reached a market share of 60%, the overall effectiveness is 14% instead of 30%. For France with a market share of 30% of the fluoridated domestic salt, model calculations lead to an overall effectiveness of 8%. In order to obtain a substantial decline of caries in the entire population, it is important to aim for a high market share of the FS of 80%, or preferably 90%. This goal can be reached with a relatively small budget. The task of health ministries would be to promote the switch from unfluoridated salt to FS; however, such promotion is often withheld by health ministries. It is possible, through modest price increases of salt, to finance effective campaigns inducing the majority of the population to use the fluoridated variety. On a world wide scale, fluoridation of salt has established itself as an efficient public health measure. It may be particularly beneficial for developing countries because it is by far the cheapest method and it is compatible with the use of fluoridated toothpastes.


Comparison of laryngeal mask airway and endotracheal intubation in gynecological cancer operation.
Endotracheal intubation (ETI) and laryngeal mask airway (LMA) in terms of hemodynamics and reaction were compared. A total of 54 general anesthesia patients were randomized into two groups with 27 cases in each group. Acceleration index (ACI), cardiac index (CI), cardiac output (CO), left cardiac work (LCW), systemic circulation resistance (SVR), mean arterial pressure (MAP), heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded at 12 time-points: before surgery (T0), start effect (T1), lost consciousness (T2), before ETI or LMA (T3), 1 min (T4), 3 min (T5), 5 min (T6) after ETI or LMA, the beginning of surgery (T7), 30 min (T8), 1 hour (T9) after surgery, the end of surgery (T10) and extubation (T11). In each group these indexes went down and rose up gently during surgery except for T4 (intubation) and T11 (extubation) in ETI. These indexes reached the highest at T11 (extubation). This is due to the stimulus on mucosa and muscle of root of tongue, throat and epiglottis from the windpipe. The stimulus excites sympathetic nerve and increases the release of catecholamine. As a result, the heart beats faster and blood pressure rises. However, the range in the LMA group is smaller especially at T4 and T11. This is most likely due to LMA not stimulating the trachea. SVR, MAP, HR, SBP and DBP were lower in LMA with statistical significance in some time-points. The other indexes such as ACI, CI, CO and LCW were significantly higher in LMA (P<0.05). These results indicated that LMA can be suitable for use in general anesthesia for less stimulation. The airway with LMA in patients undergoing gynecological cancer operation is better than ETI in keeping stable hemodynamics and producing less anesthetic complications with smooth recovery from general anesthesia.


Analysis of direct-acting antiviral-resistant hepatitis C virus haplotype diversity by single-molecule and long-read sequencing.
The method of analyzing individual resistant hepatitis C virus (HCV) by a combination of haplotyping and resistance-associated substitution (RAS) has not been fully elucidated because conventional sequencing has only yielded short and fragmented viral genomes. We performed haplotype analysis of HCV mutations in 12 asunaprevir/daclatasvir treatment-failure cases using the Oxford Nanopore sequencer. This enabled single-molecule long-read sequencing using rolling circle amplification (RCA) for correction of the sequencing error. RCA of the circularized reverse-transcription polymerase chain reaction products successfully produced DNA longer than 30 kilobase pairs (kb) containing multiple tandem repeats of a target 3 kb HCV genome. The long-read sequencing of these RCA products could determine the original sequence of the target single molecule as the consensus nucleotide sequence of the tandem repeats and revealed the presence of multiple viral haplotypes with the combination of various mutations in each host. In addition to already known signature RASs, such as NS3-D168 and NS5A-L31/Y93, there were various RASs specific to a different haplotype after treatment failure. The distribution of viral haplotype changed over time; some haplotypes disappeared without acquiring resistant mutations, and other haplotypes, which were not observed before treatment, appeared after treatment. Conclusion: The combination of various mutations other than the known signature RAS was suggested to influence the kinetics of individual HCV quasispecies in the direct-acting antiviral treatment. HCV haplotype dynamic analysis will provide novel information on the role of HCV diversity within the host, which will be useful for elucidating the pathological mechanism of HCV-related diseases.


Evidence for a circulating ergostatic factor: studies on parabiotic rats.
The effect of electrolytic ventromedial hypothalamic lesions or forced overfeeding through gastric cannulas was studied in parabiotic rats. In one experiment a ventromedial hypothalamic lesion in one member of the parabiotic union was associated with an increased fatness in the lesioned rat and a decrease in fat pad weight and a rise in body density (loss of fat) of the unlesioned animal. In the other two experiments a high fat or high carbohydrate diet was tube fed to one member of a parabiotic union. The average preinfusion intake per rat was 56 kcal/day. When 90 kcal/day were given through the intragastric cannula, oral intake of calories for the two animals fell to approximately 44 kcal/day. Body fat of the non-tube-fed animal was less than in the tube-fed controls. These studies suggest the presence of an ergostatic (energy stabilizing) factor that enters and is transported in the blood with passage from one animal to another.


Advances in percutaneous interventional therapies: the tricuspid valve.
Tricuspid regurgitation (TR) is a prevalent valve condition, with an estimated 1.6 million people in the USA living with moderate or greater severity. Functional TR, which predominantly develops due to left-sided heart disease, is the predominant condition affecting the tricuspid valve in the Western world and severe TR is associated with substantial morbidity and mortality. In part, due to a prolonged latency period with insidious symptoms, patients are often referred for surgery at advanced stages, with associated increased or prohibitive surgical risk. In addition, surgical treatment can result in high rates of recurrence. Therefore, there is an unmet need for percutaneous therapies that may provide a relatively low-risk treatment option. There are several devices with early human feasibility data available that will be reviewed in this article.


Effect of barium in porcelain on bonding strength of titanium-porcelain system.
The bonding strength to titanium, thermal expansion, and bending strength of glassy porcelain containing barium of 5, 10, and 15 mass% were estimated and compared with those of barium-free porcelain, to estimate the effect of barium content on bonding strength to titanium. The three different glassy porcelains containing barium were made by melting at 950 degrees C. The bonding strength of a commercial porcelain to titanium increased with the addition of barium. Bending strength and thermal expansion were not affected by the barium content. Therefore, the addition of barium to porcelain is effective for strengthening the bonding of porcelain to titanium.


Impact of cancer therapy on survival.
Survival rates improved significantly for 28,036 lymphoma and leukemia patients studied between 1950 and 1973. Nine cancers reviewed demonstrated increased one, three and five year survival rates. Greatest improvement was acute lymphocytic leukemia survival. Least improvement was for chronic granulocytic leukemia. Analyses of age-specific trends in U.S. cancer mortality since 1960 indicates death rates decreased 20% for all ages up to 45 years. This included 70% of the population, but less than 10% of all cancer deaths. Age groups over 55 experienced an 8% increase in cancer mortality. Accurate determination of national cancer incidence trends is not presently possible. Available data, representing approximately 15 million population, indicate that cancer incidence rates increased between 1960 and 1973. Age-specific trend analyses indicate unusual divergences. For the group 15 to 29-years-old, incidence increased 28% in 13 years and there was a concomitant decrease of 20% in mortality.


Is extrahepatic biliary atresia related to viral infections?
Extrahepatic biliary atresia is characterized by obliteration or absence of the extrahepatic bile ducts in very young infants and ultimately lead to liver cirrhosis and failure. The cause of this disease is currently unknown. There are several hypotheses for the development of extrahepatic biliary atresia. Failure of development or canalization of extrahepatic biliary tree is the unconfirmed old theory. Perinatal insults like viral infections have been suspected as possible etiologies including reovirus type 3, cytomegalovirus and rotavirus, although none of them has been concluded as playing a significant role in the pathogenesis of this disease. By using cultured murine extrahepatic biliary epithelial cell, a virally-induced, immune mediated extrahepatic biliary epithelial cell injury has been demonstrated in our recent work, which may be implicated in the pathogenesis of extrahepatic biliary atresia. Further studies are needed to develop a curative treatment for this serious disorder in the future.


Designing the shape evolution of SnSe2 nanosheets and their optoelectronic properties.
Layered chalcogenide materials (LCMs) are emerging materials in recent years for their great potential in applications of electronics and optoelectronics. As a member of LCMs, SnSe2, an n-type semiconductor with a band gap of ∼1.0 eV, is of great value to explore. In this paper, we develop a facile CVD method, for the first time, to synthesize diverse shaped SnSe2 and square SnSe nanosheets (NSs) on SiO2/Si substrates. To the best of our knowledge, the thickness of as-grown SnSe2 is among the thinnest ones synthesized by CVD methods on various substrates. What's more, photodetectors are fabricated to investigate the optoelectronic properties of SnSe2. The on/off ratio of photoswitches reaches 100 under the illumination of an 800 nm laser. This work will pave a new pathway to synthesize LCM nanostructures, shed light on the shape evolution during the growth process and expand the candidates for high performance optoelectronic devices.


Optical observation of the C, 3ssigma(g)F3, and 3ppi(u)G3 3Pi(u) states of N2.
High-resolution laser-based one extreme-ultraviolet (EUV)+one UV two-photon ionization spectroscopy and EUV photoabsorption spectroscopy have been employed to study spin-forbidden (3)Pi(u)-X (1)Sigma(g) (+)(v,0) transitions in (14)N(2) and (15)N(2). Levels of the C (3)Pi(u) valence and 3ssigma(g)F(3) and 3ppi(u)G(3) (3)Pi(u) Rydberg states are characterized, either through their direct optical observation, or, indirectly, through their perturbative effects on the (1)Pi(u) and (1)Sigma(u) (+) states, which are accessible in dipole-allowed transitions. Optical observation of the G(3)-X(0,0) and (1,0) transitions is reported for the first time, together with evidence for six new vibrational levels of the C state. Following the recent observation of the F(3)-X(0,0) transition at rotational resolution [J. P. Sprengers et al., J. Chem. Phys. 123, 144315 (2005)], the F(3)(v=1) level is found to be responsible for a local perturbation in the rotational predissociation pattern of the b(') (1)Sigma(u) (+)(v=4) state. Despite their somewhat fragmentary nature, these new observations provide a valuable database on the (3)Pi(u) states of N(2) and their interactions which will help elucidate the predissociation mechanisms for the nitrogen molecule.


Hypoxia-induced carbonic anhydrase mediated dorsal horn neuron activation and induction of neuropathic pain.
Neuropathic pain, such as that seen in diabetes mellitus, results in part from central sensitisation in the dorsal horn. However, the mechanisms responsible for such sensitisation remain unclear. There is evidence that disturbances in the integrity of the spinal vascular network can be causative factors in the development of neuropathic pain. Here we show that reduced blood flow and vascularity of the dorsal horn leads to the onset of neuropathic pain. Using rodent models (type 1 diabetes and an inducible endothelial-specific vascular endothelial growth factor receptor 2 knockout mouse) that result in degeneration of the endothelium in the dorsal horn, we show that spinal cord vasculopathy results in nociceptive behavioural hypersensitivity. This also results in increased hypoxia in dorsal horn neurons, depicted by increased expression of hypoxia markers such as hypoxia inducible factor 1α, glucose transporter 3, and carbonic anhydrase 7. Furthermore, inducing hypoxia through intrathecal delivery of dimethyloxalylglycine leads to the activation of dorsal horn neurons as well as mechanical and thermal hypersensitivity. This shows that hypoxic signalling induced by reduced vascularity results in increased hypersensitivity and pain. Inhibition of carbonic anhydrase activity, through intraperitoneal injection of acetazolamide, inhibited hypoxia-induced pain behaviours. This investigation demonstrates that induction of a hypoxic microenvironment in the dorsal horn, as occurs in diabetes, is an integral process by which neurons are activated to initiate neuropathic pain states. This leads to the conjecture that reversing hypoxia by improving spinal cord microvascular blood flow could reverse or prevent neuropathic pain.


Diffraction properties of periodic lattices under free electron laser radiation.
In this Letter, we report the pioneering use of free electron laser radiation for the investigation of periodic crystalline structures. The diffraction properties of silver behenate single nanocrystals (5.8 nm periodicity) with the dimensions of 20 nm x 20 nm x 20 microm and as powder with grain sizes smaller than 200 nm were investigated with 8 nm free electron laser radiation in single-shot modus with 30 fs long free electron laser pulses. This work emphasizes the possibility of using soft x-ray free electron laser radiation for these crystallographic studies on a nanometer scale.


Technical Difficulties: Teaching Critical Philosophical Orientations toward Technology.
Issue: Technological innovation is accelerating, creating less time to reflect on the impact new technologies will have on the medical profession. Modern technologies are becoming increasingly embedded in routine medical practice with far-reaching impacts on the patient-physician relationship and the very essence of the health professions. These impacts are often difficult to predict and can create unintended consequences for medical education. This article is driven by a main question: How do we prepare trainees to critically assess technologies that we cannot foresee and effectively use technology to support equitable and compassionate care? Evidence: We translate insights from the philosophy of technology into a proposal for integrating critical technical consciousness in medical curricula. We identify three areas required to develop critical consciousness with regard to emerging technologies. The first area is technical literacy, which involves not just knowing how to use technology, but also understanding its limitations and appropriate contexts for use. The second area is the ability to assess the social impact of technology. This practice requires understanding that while technification creates new possibilities it can also have adverse, unintended consequences. The third area is critical reflection on the relationship between 'the human' and 'the technical' as it relates to the values of the medical profession and professional identity formation. Human and technology are two sides of the same coin; therefore, thinking critically about technology also forces us to think about what we consider 'the human side of medicine'. Implications: Critical technical consciousness can be fostered through an educational program underpinned by the recognition that, although technological innovation can create new possibilities for healing, technology is never neutral. Rather, it is imperative to emphasize that technology is interwoven with the social fabric that is essential to healing. Like medication, technology can be both potion and poison.


Epstein-Barr virus infection in renal transplant recipients. Effects of antithymocyte globulin and interferon.
We studied Epstein-Barr (EB) virus excretion and antibody in 41 renal transplant recipients enrolled in a placebo-controlled trial of human leukocyte interferon. Half the patients were also treated with antithymocyte globulin. Epstein-Barr virus excretion occurred more often in recipients of cadaver kidneys (P = 0.03) and those receiving antithymocyte globulin (P = 0.04) and less often in patients given interferon (P = 0.08). Antibody to viral capsid antigen increased fourfold or more in 12 of 22 patients treated with antithymocyte globulin and in none of the non-antithymocyte globulin-treated group (P = 0.0002). Antibody to the restricted component of early antigen rose fourfold or more in eight patients and appeared related to the occurrence of syndromes similar to those attributed to cytomegalovirus in transplant recipients. We conclude that increasing immunosuppression augments the rate of EB virus reactivation and that EB virus may be an important pathogen in heretofore ill-defined syndromes.


Body Gaze as a Marker of Sexual Objectification: A New Scale for Pervasive Gaze and Gaze Provocation Behaviors in Heterosexual Women and Men.
Body gaze behavior is assumed to be a key feature of sexual objectification. However, there are few self-report gaze measures available and none capturing behavior which seeks to invite body gaze from others. Across two studies, we used existing self-report instruments and measurement of eye movements to validate a new self-report scale to measure pervasive body gaze behavior and body gaze provocation behavior in heterosexual women and men. In Study 1, participants (N = 1021) completed a survey with newly created items related to pervasive body gaze and body gaze provocation behavior. Participants also completed preexisting measures of body attitudes, sexual assault attitudes, pornography use, and relationship status. Exploratory and confirmatory factor analyses across independent samples suggested a 12-item scale for men and women to separately measure pervasive body gaze (5 items) and body gaze provocation (7 items) toward the opposite sex. The two scales yielded excellent internal consistency estimates (.86-.89) and promising convergent validity via positive correlations with body and sexual attitudes. In Study 2, a subsample (N = 167) of participants from Study 1 completed an eye-tracking task to capture their gaze behavior toward matched images of partially and fully dressed female and male subjects. Men exhibited body-biased gaze behavior toward all the female imagery, whereas women exhibited head-biased gaze behavior toward fully clothed male imagery. Importantly, self-reported body gaze correlated positively with some aspects of objectively measured body gaze behavior. Both scales showed good test-retest reliability and were positively correlated with sexual assault attitudes.


Sunken Eye Induced by Superior Orbital Wall Defect After Craniofacial Surgery.
Enophthalmos after a ventriculo-peritoneal (V-P) shunt placement is very rare. Previous defects of the orbital wall with intracranial hypotension can cause enophthalmos after V-P shunting. The authors present 2 patients of enophthalmos with orbital wall defects resulting from anterior clinoidectomy that was performed during previous aneurysmal surgery. Both patients received a V-P shunt for hydrocephalus after subarachnoid hemorrhage. Although the hydrocephalus was improved by V-P shunts in both patients, sunken eyes were observed. The patients received reconstructive surgery of the superior orbital wall using titanium mesh and recovered after surgery without any neurological deficits. Here, the authors present 2 patients of enophthalmos with orbital wall defects treated by orbital wall reconstruction.


Right- and left-handed three-helix proteins. II. Similarity and differences in mechanical unfolding of proteins.
Here, we study mechanical properties of eight 3-helix proteins (four right-handed and four left-handed ones), which are similar in size under stretching at a constant speed and at a constant force on the atomic level using molecular dynamics simulations. The analysis of 256 trajectories from molecular dynamics simulations with explicit water showed that the right-handed three-helix domains are more mechanically resistant than the left-handed domains. Such results are observed at different extension velocities studied (192 trajectories obtained at the following conditions: v = 0.1, 0.05, and 0.01 Å ps(-1) , T = 300 K) and under constant stretching force (64 trajectories, F = 800 pN, T = 300 K). We can explain this by the fact, at least in part, that the right-handed domains have a larger number of contacts per residue and the radius of cross section than the left-handed domains.


Survival in a neonate with complete urorectal septum malformation sequence after fetal vesico-amniotic shunting for a prominently dilated cloaca.
Complete urorectal septum malformation sequence (URSMS) is usually a lethal anomaly that is characterized by urethral obstruction, imperforate anus, ambiguous genitalia, renal agenesis or dysplasia, and mullerian duct maldevelopment. This anomaly is thought to be caused by the cessation of urorectal septum migration toward the caudal cloacal membrane. Teratogenic factors or a genetic abnormality is postulated as the etiology. To date, only 4 patients with URSMS have survived the neonatal period; however, 2 of these infants died before the age of 1 year. We report the survival in a case with complete URSMS who had moderate pulmonary hypoplasia and preserved left renal function. The cloacal remnant was dilated more than expected because the wall of the muscle layer was torn, perhaps in early fetal life, and timely placement of vesico-amniotic shunts prevented severe pulmonary hypoplasia caused by oligohydramnios.


An Optical Actuator Based on Gold-Nanoparticle-Containing Temperature-Memory Semicrystalline Polymers.
Photoresponsive actuators based on semicrystalline poly(ethylene-co-vinyl acetate) (EVA) loaded with small amounts of gold nanoparticles (AuNPs) are described. Upon absorption of light (532 nm), the heat released by the AuNPs raises the temperature in the irradiated region to Tlight to melt crystallites with lower melting temperatures (Tm <Tlight ), resulting in a contraction force on the sample sustained by the crystalline skeleton domains with Tm >Tlight . Once the light is turned off, the recrystallization of oriented chains in the actuation domains upon cooling gives rise to an expansion force. We show that the photoinduced contraction force, Tlight , and the speed for reaching Tlight can readily be adjusted, which makes EVA/AuNP a robust, fast optical actuation system tunable in both speed and magnitude. The material design can easily be extended to other temperature-memory semicrystalline polymers in combination with various light-absorbing and heat-generating additives.


[Roles of autocrine soluble fibronectin on the maintenance of cell shape of osteosarcoma MG-63 cells].
To investigate the roles of autocrine soluble FN of MG-63 cells in cell shape maintaining. Human osteosarcoma MG-63 cells (1 × 10(4); cells/cm(2);) were routinely cultured in MEM medium+10% fetal bovine serum (FBS) for 24 h and then the medium was replaced by fresh medium(the group without autocrine soluble FN), conditional medium of collected after 24 h of MG-63 cells (the group containing autocrine soluble FN ) and fresh medium with 20 microg/mL FN( the group with plasma FN) after 24 h, and the cell morphology was observed using phase contrast microscope; The concentrations of soluble FN in fresh and conditional medium were detected; Microfilament and insoluble FN changes of MG-63 cells were investigated. The concentration of soluble FN in conditional medium is much higher than that in the fresh medium (P<0.01). Fresh medium will result in the cell shape changing from spindle to round for 0.5 h. The cell began to spread for 1 h, and the cell shape recovered for 2 h; Conditioned medium has no significant effects on cell shape. Addition of FN (20 mg/L) to fresh medium could inhibit the cell shape change induced by fresh medium. Microfilament and insoluble FN were disorganized by fresh medium. These results indicated that autocrine soluble FN of osteosarcoma MG-63 cells may be involved in cell shape maintaining.


Magnetocaloric effect in magnetic nanoparticle systems: how to choose the best magnetic material?
Magnetic nanoparticles with controlled magnetocaloric properties are a good candidate to lower the temperature of nanosized systems: they are easy to manipulate and to distribute into different geometries, as wires or planes. Using a Monte Carlo technique we study the entropy change and refrigerant capacity of an assembly of fine magnetic particles as a function of their anisotropy and magnetization, key-parameters of the magnetic behavior of the system. We focus our attention on the anisotropy energy/dipolar energy ratio by means of the related parameter c0 = 2K/M(S)2, where K is the anisotropy constant and M(S) is the saturation magnetization of the nanoparticles. Making to vary the value of co parameter by choosing different K-M(S) combinations, allows us to discuss how the magnetocaloric response of an assembly of magnetic nanoparticles may be tuned by an appropriate choice of the magnetic material composition.


Thromboxane A2 induces leukotriene B4 synthesis that in turn mediates neutrophil diapedesis via CD 18 activation.
Previous studies have indicated that thromboxane (Tx) and leukotriene (LT) B4 act synergistically to induce neutrophil (PMN) adhesion in the microvasculature. This study explores the ability of Tx to induce LTB4 synthesis, which then leads to activation of PMN and endothelial adhesion receptors. Tx-mimic (U46619, 1 microgram/ml) was administered into abraded skin chambers placed on the backs of rabbits (n = 6). After 3 hr LTB4 was synthesized in the blister fluid at 385 pg/ml, a value higher than levels in saline-treated blisters, 10 pg/ml (P less than 0.05). The LTB4 generation following Tx-mimic was correlated (P less than 0.05, r = 0.70) with neutrophil diapedesis. These averaged 645 PMN/mm3, values higher than saline values of 20 PMN/mm3 (P less than 0.05). Intravenous (iv) treatment of other rabbits (n = 4) with the lipoxygenase inhibitor diethylcarbamazine at 60 mg/kg, followed by 40 mg/kg/hr, prevented Tx-mimic-induced LTB4 synthesis (10 pg/ml) and diapedesis (19 PMN/mm3) (both P less than 0.05). Intravenous treatment of yet other rabbits (n = 4) with the anti-CD 18 monoclonal antibody R 15.7 at 1 mg/kg abolished Tx-induced diapedesis (3 PMN/mm3) (P less than 0.05). In contrast, local administration of 3 ng of the protein synthesis inhibitor actinomycin D, to prevent expression of endothelial adhesion proteins, limited TNF- but not Tx-induced diapedesis. The data indicate that Tx-induced diapedesis is mediated by the generation of LTB4 and the activation of neutrophil CD 18 but not endothelial adhesion proteins.


Intravenous adenosine activates diffuse nociceptive inhibitory controls in humans.
Experimentally induced pain can be attenuated by concomitant heterotopic nociceptive stimuli (counterirritation). Animal data indicate that this stems from supraspinal "diffuse noxious inhibitory controls" (DNICs) triggered by C and Aδ fibers. In humans, only noxious stimuli induce counterirritation. This points at C fibers, but the effects of pharmacologically stimulating C fibers have not been studied. Intravenous adenosine activates pulmonary C fibers and induces dyspnea. This study tests the hypothesis that putative activation of pulmonary C fibers by adenosine would trigger DNICs in humans and induce counterirritation. Twelve healthy volunteers were included (with valid results available in 9) and studied according to a double-blind, randomized, cross-over design (intravenous adenosine, 140 μg·kg(-1)·min(-1), during 5 min vs. placebo). We measured ventilatory variables and end-tidal CO2 tension, dyspnea intensity by visual analog scale, and the intensity of putative chest pain. The primary outcome was the amplitude of the RIII component of the nociceptive flexor reflex recorded by biceps femoris electromyogram in response to painful electrical sural nerve stimulation (RIII), taken as a substitute for pain perception. Placebo did not induce any significant effect. Adenosine induced dyspnea, hyperpnea, tachycardia, and significant RIII inhibition (24 ± 8% at the 4th min, P < 0.0001). The temporal dynamics of adenosine-induced dyspnea and RIII inhibition differed (immediate onset followed by a slow decrease for dyspnea, slower onset for RIII inhibition). Intravenous adenosine in normal humans induces counterirritation, fueling the notion that C-fiber stimulation trigger DNICs in humans. The temporal dissociation between adenosine-induced dyspnea and RIII inhibition suggests that C fibers other than pulmonary ones might be involved.


Bronchial dilatation in patients with HIV infection: CT assessment and correlation with pulmonary function tests and findings at bronchoalveolar lavage.
Symptoms of airway disease occur in patients infected with HIV, and bronchiectasis has been reported in patients with AIDS. We evaluated thin-section thoracic CT scans in HIV-positive individuals for bronchial dilatation and correlated imaging findings with pulmonary function abnormalities and findings at bronchoalveolar lavage (BAL). Sixty-one subjects, 50 of whom were HIV-positive and 11 of whom were HIV-negative, underwent thin-section CT, BAL, and pulmonary function tests. Two radiologists evaluated the CT scans on two separate occasions for bronchial dilatation in each lobe. BAL and pulmonary function test data in the subjects with bronchial dilatation were compared with such data in subjects with normal bronchi seen on CT scans. Eighteen of the 50 HIV-positive subjects and none of the HIV-negative subjects had bronchial dilatation revealed by CT. Subjects with bronchial dilatation revealed by CT had significantly higher BAL neutrophil counts (p = .014) and significantly lower diffusing capacity (p = .003) than did subjects with normal bronchi revealed by CT. Bronchial dilatation is commonly revealed by CT scans of HIV-positive individuals. The association of elevated levels of BAL neutrophils and decreased diffusing capacity with bronchial dilatation that we found in this study suggests that the neutrophil may be associated with airway damage and lung destruction in patients who are infected with HIV.


Locoregional therapies in cholangiocarcinoma.
Cholangiocarcinoma is a rare and aggressive malignancy of the biliary tract. Complete surgical resection can be curative, but the majority of patients are diagnosed with advanced disease and usually die within a year of diagnosis. Most deaths are attributable to local disease progression rather than distant metastases, supporting the use of locoregional therapies. There is evidence that locoregional therapies can provide local tumor control resulting in increased survival while avoiding some of the side effects of systemic treatments, increasing potential treatment options for patients who may be unsuitable for systemic palliative treatments. This review considers the evidence for locoregional therapies in cholangiocarcinoma, which can be classified into endoscopic, vascular, percutaneous and radiation oncological therapies. Current guidelines do not recommend the routine use of locoregional therapies due to a lack of prospective data, but the results of ongoing trials are likely to increase the evidence base and impact on clinical practice.


Clinical Features of Nivolumab-Induced Thyroiditis: A Case Series Study.
The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in immune checkpoint therapy for cancer. It consists of the PD-1 receptor and its two ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Nivolumab is an anti-PD-1 monoclonal antibody approved for malignant melanoma, advanced non-small cell lung cancer, and advanced renal cell carcinoma in Japan. Thyrotoxicosis and hypothyroidism have both been reported in international Phase 3 studies and national post-marketing surveillance of nivolumab in Japan. This study analyzed five consecutive cases with thyroid dysfunction associated with nivolumab therapy. Second, it examined the mRNA and protein expressions of PD-L1 and PD-L2 by reverse transcription polymerase chain reaction and Western blotting. All patients were diagnosed with painless thyroiditis. Thyrotoxicosis developed within four weeks from the first administration of nivolumab and normalized within four weeks of onset in three of the five patients. Hypothyroidism after transient thyrotoxicosis developed in two patients, and preexisting hypothyroidism persisted in one patient. The other two patients were treated with glucocorticoids and discontinued nivolumab therapy for comorbid adverse events. One did not develop hypothyroidism, and the other developed mild, transient hypothyroidism. In addition, it was verified that normal thyroid tissue expresses PD-L1 and PD-L2 mRNA and those proteins. In the present cases, nivolumab-induced thyrotoxicosis seemed to be associated with painless thyroiditis, while no patient with Graves' disease was observed. A transient and rapid course with subsequent hypothyroidism was observed in nivolumab-induced thyroiditis. In addition, it was verified that PD-L1 and PD-L2 are expressed in normal thyroid tissue. This suggests that nivolumab therapy reduces immune tolerance, even in normal thyroid tissue, and leads to the development of thyroiditis. Treating thyrotoxicosis with only supportive care and considering levothyroxine replacement therapy once subsequent hypothyroidism occurs is proposed. Further investigations are required to confirm whether glucocorticoid therapy and discontinuation of nivolumab therapy prevent subsequent hypothyroidism.


Origins and population genetics of weedy red rice in the USA.
Weedy red rice (Oryza sativa spontonea) is a persistent and problematic weed of rice culture worldwide. A major hypothesis for the mechanism of production of this weed in South and Southeast Asia is hybridization between cultivated rice (Oryza sativa) and wild rice (Oryza rufipogon). However, weedy red rice can often be found outside the range of O. rufipogon leaving questions on the origin and process behind weedy rice infestations. In the USA, weedy red rice was first documented as early as 1846 and has continued to affect rice production areas. In this study, we attempt to identify the origin and population structure of weedy red rice sampled from the USA using both DNA sequence data from a neutral nuclear locus as well as microsatellite genotype data. Results suggest that two major accessions of weedy rice exist, strawhull and blackhull, and these forms may both hybridize with the cultivated rice of the USA, O. sativa japonica. Using population assignment of multilocus genotype signatures with principal component analysis and structure, an Asian origin is supported for US weedy rice. Additionally, hybridization between strawhull and blackhull varieties was inferred and may present the opportunity for the production of new weedy forms in the future.


Current Trends in the Management of Temporomandibular Joint Dysfunction: A Review.
The temporomandibular joint (TMJ) is a synovial bi-condylar joint with 3 degrees of freedom. One-third of the adult population reportedly suffers from temporomandibular joint dysfunction (TMD). Females are more commonly affected than males. Almost 50% of TMD patients do not require any intervention, and the symptoms are self-limiting within one year after the onset; however, 75-80% of adults suffering from TMD require medical intervention and it takes up to three years for the complete remission of the symptoms. The clinical features of TMD are clenching, clicking, and locking of the jaw, and occlusion due to faulty posture. Based on the diagnostic criteria for temporomandibular disorder (DC/TMD) criteria proposed in the year 2014, the classification of TMD is done based on axis I and axis II diagnoses. This review aims to provide an overview of TMD and examine available treatment strategies for TMD. Various conservative treatment methods have been proven to be effective, including self-care strategies, dental treatment strategies, pharmacological treatment, physical therapy modalities, manual mobilization, electrotherapy and dry needling, relaxation techniques, intra-articular injections, cognitive behavioral therapy, and surgical corrections.


The Whiteness of Bones: Sceletopoeia and the Human Body in Early Modern Europe.
In Western Europe between 1500 and 1700 the human skeleton became an object: a scientific object, a natural object, an artistic object, an artisanal object, independent of its bodily origins yet retaining a troubling moral status. The act of making a skeleton created a scientific object that also had aesthetic value, with qualities of authenticity, accuracy, and whiteness. Beginning with Vesalius, many anatomists included instructions on how to make a skeleton in their anatomical texts, and many more taught their students how to do this. Skeletons became central to anatomical instruction, both for medicine and for art. By the end of the seventeenth century, skeletons increasingly were found in cabinets and collections, and their aesthetic qualities, particularly their whiteness, became critical. However, the emotional and moral impacts of making skeletons remained unspoken.


LC-MS analysis combined with principal component analysis and soft independent modelling by class analogy for a better detection of changes in N-glycosylation profiles of therapeutic glycoproteins.
Therapeutic proteins are among the top selling drugs in the pharmaceutical industry. More than 60 % of the approved therapeutic proteins are glycosylated. Nowadays, it is well accepted that changes in glycosylation may affect the safety and the efficacy of the therapeutic proteins. For this reason, it is important to characterize both the protein and the glycan structures. In this study, analytical and data processing methods were developed ensuring an easier characterization of glycoprofiles. N-glycans were (i) enzymatically released using peptide-N-glycosidase F (PNGase F), (ii) reduced, and (iii) analyzed by hydrophilic interaction liquid chromatography coupled to a high-resolution mass spectrometer (HILIC-HRMS). Glycosylation changes were analyzed in human plasma immunoglobulin G samples which had previously been artificially modified by adding other glycoproteins (such as ribonuclease B and fetuin) or by digesting with enzyme (neuraminidase). Principal component analysis (PCA) and classification through soft independent modelling by class analogy (SIMCA) were used to detect minor glycosylation changes. Using HILIC-MS-PCA/SIMCA approach, it was possible to detect small changes in N-glycosylation, which had not been detected directly from the extracted-ion chromatograms, which is current technique to detect N-glycosylation changes in batch-to-batch analysis. The HILIC-MS-PCA/SIMCA approach is highly sensitive approach due to the sensitivity of MS and appropriate data processing approaches. It could help in assessing the changes in glycosylation, controlling batch-to-batch consistency, and establishing acceptance limits according to the glycosylation changes, ensuring safety and efficacy. Graphical abstract N-glycosylation characterization using LC-MS-PCA approach.


The H,K-ATPase beta subunit as a model to study the role of N-glycosylation in membrane trafficking and apical sorting.
The role of N-glycosylation in trafficking of an apical membrane protein, the gastric H,K-ATPase beta subunit linked to yellow fluorescent protein, was analyzed in polarized LLC-PK1 cells by confocal microscopy and surface-specific biotinylation. Deletion of the N-glycosylation sites at N1, N3, N5, and N7 but not at N2, N4, and N6 significantly slowed endoplasmic reticulum-to-Golgi trafficking, impaired apical sorting, and enhanced endocytosis from the apical membrane, resulting in decreased apical expression. Golgi mannosidase inhibition to prevent carbohydrate chain branching and elongation resulted in faster internalization and degradation of the beta subunit, indicating that terminal glycosylation is important for stabilization of the protein in the apical membrane and protection of internalized protein from targeting to the degradation pathway. The decrease in the apical content of the beta subunit was less with mannosidase inhibition compared with that found in the N1, N3, N5, and N7 site mutants, suggesting that the core region sugars are more important than the terminal sugars for apical sorting.


Functional glycine receptors are expressed by postnatal nestin-positive neural stem/progenitor cells.
Multipotent neural stem and progenitor cells (NS/PCs) are well-established cell subpopulations occurring in the developing, and also in the mature mammalian nervous systems. Trophic and transcription factors are currently the main signals known to influence the development and the commitment of NS/PCs and their progeny. However, recent studies suggest that neurotransmitters could also contribute to neural development. In that respect, rodent-cultured embryonic NS/PCs have been reported to express functional neurotransmitter receptors. No similar investigation has, however, been made in postnatal and/or in adult rodent brain stem cells. In this study, using RT-PCR and immunocytochemical methods, we show that alpha(1)-, alpha(2)- and beta-subunit mRNAs and alpha-subunit proteins of the glycine ionotropic receptor are expressed by 80.5 +/- 0.9% of postnatal rat striatum-derived, nestin-positive cells within cultured neurospheres. Whole-cell patch-clamp experiments further demonstrated that glycine triggers in 33.5% of these cells currents that can be reversibly blocked by strychnine and picrotoxin. This demonstrates that NS/PCs express functional glycine receptors, the consequence(s) of their activation remaining unknown.


Racial and Ethnic Health Disparities Among People With Intellectual and Developmental Disabilities.
Racial and ethnic health disparities are a pervasive public health problem. Emerging research finds similar health disparities among people with intellectual and developmental disabilities (IDD) compared to nondisabled adults. However, few studies have examined racial and ethnic health disparities among adults with IDD. Using national data, we examined racial and ethnic disparities in health status among adults with IDD, and investigated differences in health status between adults with IDD and nondisabled adults within each racial and ethnic group. We found that Latino and Black adults with IDD had worse health outcomes compared to White adults with IDD, and Latino and Black adults with IDD had worse health outcomes than nondisabled adults from the same racial and ethnic group.


Neuroactive molecules and growth factors modulate cytoskeletal protein expression during astroglial cell proliferation and differentiation in culture.
Steroid hormones and neurotrophic factors regulate astroglial cell survival, proliferation, and differentiation in culture. The present study examines the interaction between glucocorticoids and growth factors (GFs) on cytoskeletal proteins and extracellular signal-regulated kinase 2 (ERK2) expression in stressed astroglial cultures at 25 days in vitro, according to the following experimental condition. Pretreatment with basic fibroblast growth factor alone or in combination with dexamethasone 10(-9) M for 48 hr induced an enhancement of glial fibrillary acidic protein, vimetin, and ERK2 expression. Treatment with "progression" GFs alone and in the last 12 hr significantly increased the above-mentioned markers' expression. The present study shows that glucocorticoids may cooperate with GFs or may abrogate their effects, depending on the experimental culture conditions used as well as the exposure time and the types of GFs added. Our findings provide evidence of interactive dialogue between GFs and neurosteroids in cultured astrocytes. This may have implications in the therapeutic approach to neurologic disorders associated with astrogliosis.


Common polymorphisms in the promoter of the visfatin gene (PBEF1) influence plasma insulin levels in a French-Canadian population.
The adipokine visfatin (PBEF1) exhibits insulin-mimetic effects and correlates strongly with visceral adiposity. We sequenced visfatin gene exons and 1,480 bp of the promoter in 23 individuals, including 18 individuals from the Quebec Family Study (QFS) with varying degrees of abdominal visceral fat, assessed by computed tomography, and 5 individuals from the Saguenay-Lac-Saint-Jean region of Québec. We identified a synonymous polymorphism in exon 7 (SER301SER) but no nonsynonymous mutations. We observed an additional 10 polymorphisms, including 5 intronic, 4 within the promoter, and 1 within the 3' untranslated region. Further promoter sequencing (816 bp) identified five additional single nucleotide polymorphisms (SNPs) in the QFS population. To investigate the role of visfatin gene variants in obesity-related phenotypes, we genotyped a total of 13 SNPs in the promoter region of the gene. From these, we analyzed the seven common SNPs in the QFS sample (918 participants from 208 families). A significant association was found between two SNPs (rs9770242 and rs1319501), in perfect linkage disequilibrium, and fasting insulin levels (P = 0.002). These SNPs were also associated with fasting glucose (P <or= 0.02). In addition, a more distal SNP (rs7789066) was significantly associated with the apolipoprotein B component of VLDL (P = 0.012).


Medical Termination of Pregnancy Act of India: Treading the Path between Practical and Ethical Reproductive Justice.
One of the most important facets of reproductive freedom and justice is the right to abortion. For centuries, the debate on legalisation and regulation of abortion has caused ethical dilemmas with proponents for both sides of the argument. India, a developing nation, with a wide spectrum of cultures, traditions, socio-economic statuses and religious beliefs, would be expected to be grappling with this problem. However, India since the 1970s made a clear stance on the matter of abortion. Respecting the right to personal liberty, reproductive freedom of women and upholding the importance of women's health, Medical Termination Pregnancy (MTP) has been legal in India since 1971. We look at the laws governing MTP in India, the practical and ethical considerations, the recent amendments in these laws and the road ahead.


Content of fluorine in vegetables and fruits from an industrial area.
Content of fluorine in vegetables and fruits from allotments situated in an industrial area as well as in an agricultural area without industrial emissions was determined. The fluorine determination was made by means of a potentiometric method with application of an ion-selective electrode. Statistically significant differences between the fluorine content in vegetables and fruits from an area contaminated with the emissions of fluorine compounds and the fluorine content in vegetables and fruits from the control area were found. Significant differences between the fluorine content in above- and under-ground parts of some vegetables were stated. The greatest fluorine content appeared in parsley haulm and in black currants.


Different metabolic adaptation of heart and skeletal muscles to moderate-intensity treadmill training in the rat.
The effect was investigated of treadmill training of moderate intensity on the fatty acid-binding protein (FABP) content in relation to parameters of oxidative and glycolytic metabolism. To this end, the cytoplasmic FABP content and the activity of beta-hydroxyacyl-coenzyme A dehydrogenase (HAD), citrate synthase (CS), and 6-phosphofructokinase (PFK) were measured in heart, fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscles (SOL) of male Wistar rats. To investigate the influence of the amount of training (defined as the product of exercise duration, intensity and frequency), two training groups were created that differed in training frequency (HF, high frequency 5 days x week(-1), n = 9; LF, low frequency 2 days x week(-1), n = 9; the exercise being 20 m x min(-1) for 2 h with no gradient, over 6 weeks) and compared with SC, sedentary controls (n = 7). In heart muscle, the cytoplasmic FABP content was 34% higher in HF than in SC but was the same as in LF. The CS and HAD activities were no different in the three groups, suggesting that the capacity to oxidize fatty acids (FA) was not affected by training. The PFK activity was higher (43%) in HF, suggesting a shift towards carbohydrate utilization. The FABP content and HAD activity did not change in SOL and EDL after training whereas the CS activity increased (27%) in SOL and decreased (21%) in EDL in both training groups. In addition, PFK activity in EDL was much higher (113%) in the HF than in SC group. The HF training was associated with a fine-tuning of FA availability and use in heart muscle, and with a more efficient energy production. It is suggested therefore that cytoplasmic FABP could be an early marker of muscle adaptation to training in heart but not in skeletal muscle. The training reinforced the metabolic profile of the skeletal muscles, in particular that of the fast-twitch glycolytic muscle. We concluded that a large amount of training is needed when the effect on both oxidative and glycolytic parameters is to be studied.


[Sacrococcygeal teratoma of newborn infants; a report of two cases].
Two cases of sacrococcygeal teratoma in female infants are reported. Case 1. A newborn baby with a hemispheric mass on her hip underwent surgery 3 days after birth and the lesion proved to be an immature teratoma. The serum AFP level was very high but became normal one month after the operation. The child also had agenesis of the corpus callosum and arachnoid cysts in right middle fossa. She died after developing shunt infection. Case 2. A newborn baby with a mature teratoma was operated on the day following birth. The tumor was subtotally removed, and there has been no recurrence after 6 months. Sacrococcygeal teratoma in female infants is often associated with agenesis of the corpus callosum and arachnoid cysts. They tend to develop almost at the same time as the teratoma. It is often difficult to determine whether the infant should be treated by chemotherapy or not if the teratoma is immature, especially when it has been totally removed, the serum AFP is normal, and the tumor is pathologically of a low grade.


Transcriptional regulation of the 230-kDa bullous pemphigoid antigen gene expression by interferon regulatory factor 1 and interferon regulatory factor 2 in normal human epidermal keratinocytes.
Interferon regulatory factors (IRFs) are a family of transcriptional factors induced by interferon-gamma (IFN-gamma). Recent studies have indicated that the deregulation of IRF system in keratinocytes is responsible, at least in part, for aberrant proliferation and the differentiation of the psoriatic epidermis. Previously, we reported that the expression of 230-kDa bullous pemphigoid antigen (BPAG1) gene, which is strictly restricted to basal keratinocytes, is transcriptionally suppressed by IFN-gamma, but the contribution of IRFs in such suppression is still unclear. In this study, we investigated the role of IRFs in the regulation of BPAG1 gene expression. Computer analysis identified IRF1 and IRF2 consensus sequences between -135 and -123 on BPAG1 promoter region. Transient transfection studies with BPAG1 promoter-luciferase reporter gene plasmids and IRF1 and IRF2 expression plasmids revealed that IRF1 and IRF2 directly down-regulated BPAG1 gene transcription in cultured normal human epidermal keratinocytes. Several sets of gel retardation assays with the BPAG1-IRF binding sequence as a probe indicated that IRF1 and IRF2 could bind to the BPAG1-IRF sequence, but some other protein(s), which was induced by IFN-gamma stimulation and possessed binding activity to IRF consensus sequence, showed preferential binding to the BPAG1-IRF sequence. Our results suggest that IFN-gamma-IRF system is involved in BPAG1 gene regulation in type-1 helper T-cell inflammatory skin conditions, such as psoriasis vulgaris.


Altered endometrial oestrogen-responsiveness and recurrent reproductive failure.
Recurrent reproductive failure (RRF) encompasses recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL). These highly prevalent, distressing conditions have many unanswered questions regarding aetiology and management. Oestrogen receptor beta (ERβ) is the predominant oestrogen receptor expressed in the vascular endothelium of the endometrium during the window of implantation (WOI). The establishment of normal endometrial receptivity is integrally associated with progesterone receptor (PR). Therefore, we aimed to investigate whether women with RRF have clinical, type-specific endometrial aberrations of ERβ, PR and Ki-67 expression during the WOI. Thirty-eight endometrial biopsies were collected; 29 RRF (10 RIF, 9 recurrent loss of early pregnancy (RLEP) and 10 recurrent fetal loss (RFL)) and 9 fertile controls (FC). Within RIF, RLEP and RFL groups, the perivascular compartment showed significantly lower levels of ERβ vs FC (P = 0.02, P = 0.03 and P = 0.01, respectively). Vascular endothelium also displayed significantly lower levels of ERβ within RIF and RFL cohorts vs FC (P = 0.03 and P = 0.003). The expression of Ki-67 was significantly lower within vascular endothelium of all RRF; RIF (P = 0.02), RLEP (P = 0.02) and RFL (P <0.01). PR was significantly reduced (P <0.001) in the perivascular area of women with RIF. These findings provide novel insights into biological correlates of clinical subtypes of RRF. The endometrium of women with RRF display significantly altered levels of ERβ, PR and Ki-67 during the WOI, furthering our understanding of the defective endometrial phenotype of women suffering from RRF, with possible impaired glandular function, angiogenesis and decidualisation. Recurrent reproductive failure (RRF) refers to a group of devastating conditions with many unanswered questions regarding their causes and treatment options. The lining of the womb, the endometrium, is primed and suitable for successful embryo implantation for a short time during the menstrual cycle; the window of implantation (WOI). Oestrogen is a key hormone that plays an important role in regulating the endometrium and its effects are exerted via two oestrogen receptor subtypes. Oestrogen receptor beta (ERβ) is the main oestrogen receptor present during the WOI. Progesterone receptor allows the other main hormone, progesterone, to influence the endometrial activity and Ki-67 reflects the proliferative activity of the cells within the endometrium. We investigated the expression of these markers in endometrial samples collected from women with RRF and proven fertility. We found that the endometrium of women with RRF has significantly lower levels of ERβ and Ki-67 during the WOI, possibly leading to unsuccessful pregnancies.


γ-Oryzanol suppresses COX-2 expression by inhibiting reactive oxygen species-mediated Erk1/2 and Egr-1 signaling in LPS-stimulated RAW264.7 macrophages.
Cyclooxygenase (COX)-2 produces prostanoids, which contribute to inflammatory responses. Nuclear factor (NF)-κB is a key transcription factor mediating COX-2 expression. γ-Oryzanol is an active component in rice bran oil, which inhibits lipopolysaccharide (LPS)-mediated COX-2 expression by inhibiting NF-κB. However, the inhibition of COX-2 expression by γ-oryzanol independently of NF-κB is poorly understood. We found that LPS upregulated Egr-1 expression at the transcriptional level. Forced expression of Egr-1 trans-activated the Cox-2 promoter independently of NF-κB. In contrast, silencing of Egr-1 abrogated LPS-mediated COX-2 expression. LPS produced reactive oxygen species (ROS), which, in turn, induced Egr-1 expression via the Erk1/2 MAPK pathway. ROS scavenging activity of γ-oryzanol suppressed Egr-1 expression by inhibiting the Erk1/2 MAPK pathway. Our results suggest that γ-oryzanol inhibits LPS-mediated COX-2 expression by suppressing Erk1/2-mediated Egr-1 expression. This study supports that γ-oryzanol may be useful for ameliorating LPS-mediated inflammatory responses.


Development of a whole-cell biocatalyst/biosensor by display of multiple heterologous proteins on the Escherichia coli cell surface for the detoxification and detection of organophosphates.
This paper reports the codisplay of organophosphorus hydrolase (OPH) and methyl parathion hydrolase (MPH)-green fluorescent protein (GFP) fusion on the cell surface of Escherichia coli using the truncated ice nucleation protein (INPNC) and Lpp-OmpA as the anchoring motifs. The surface localization of both OPH and MPH-GFP was demonstrated by cell fractionation, Western blot analysis, protease accessibility experiment, and immunofluorescence microscopy. Anchorage of the foreign proteins on the outer membrane neither inhibits cell growth nor affects cell viability. The recombinant strain can be used as a whole-cell biocatalyst and showed a broader substrate range than strains expressing either OPH or MPH. A mixture of six organophosphorus pesticides (OPs) (0.2 mM each) could be degraded completely within 5 h. The broader substrate specificity in combination with the rapid degradation rate makes the recombinant strain a promising candidate for detoxification of OPs. The fluorescence of surface-displayed GFP is very sensitive to environmental pH change. Because hydrolysis of OPs by OPH or MPH generates protons, the recombinant E. coli could be used as a whole-cell biosensor for the rapid detection of OPs by evaluating fluorescence changes as a function of OP concentrations.


Hydroxynaphthaldehyde phosphate derivatives as potent covalent Schiff base inhibitors of fructose-1,6-bisphosphate aldolase.
Interactions of phosphate derivatives of 2,6-dihydroxynaphthalene (NA-P(2)) and 1,6-dihydroxy-2-naphthaldehyde (HNA-P, phosphate at position 6) with fructose-1,6-bisphosphate aldolase from rabbit muscle were analyzed by enzyme kinetics, difference spectroscopy, site-directed mutagenesis, mass spectrometry, and molecular dynamics. Enzyme activity was competitively inhibited by NA-P(2), whereas HNA-P exhibited slow-binding inhibition with an overall inhibition constant of approximately 24 nM. HNA-P inactivation was very slowly reversed with t(1/2) approximately 10 days. Mass spectrometry and spectrophotometric absorption indicated that HNA-P inactivation occurs by Schiff base formation. Rates of enzyme inactivation and Schiff base formation by HNA-P were identical and corresponded to approximately 4 HNA-P molecules bound par aldolase tetramer at maximal inhibition. Site-directed mutagenesis of conserved active site lysine residues 107, 146, and 229 and Asp-33 indicated that Schiff base formation by HNA-P involved Lys-107 and was promoted by Lys-146. Titration of Lys-107 by pyridoxal 5-phosphate yielded a microscopic pK(a) approximately 8 for Lys-107, corroborating a role as nucleophile at pH 7.6. Site-directed mutagenesis of Ser-271, an active site residue that binds the C(1)-phosphate of dihydroxyacetone phosphate, diminished HNA-P binding and enabled modeling of HNA-P in the active site. Molecular dynamics showed persistent HNA-P phosphate interactions with the C(1)-phosphate binding site in the noncovalent adduct. The naphthaldehyde hydroxyl, ortho to the HNA-P aldehyde, was essential for promoting carbinolamine precursor formation by intramolecular catalysis. The simulations indicate a slow rate of enzyme inactivation due to competitive inhibition by the phenate form of HNA-P, infrequent nucleophilic attack in the phenol form, and significant conformational barrier to bond formation as well as electrostatic destabilization of protonated ketimine intermediates. Solvent accessibility by Lys-107 Nz was reduced in the covalent Schiff base complex, and in those instances where water molecules interacted with Lys-107 in the simulations, Schiff base hydrolysis was not mechanistically favorable. The findings at the molecular level corroborate the observed mechanism of slow-binding tight inhibition by HNA-P of muscle aldolase and should serve as a blueprint for future aldolase inhibitor design.


Absence of transformation of beta-muricholic acid by human microflora implanted in the digestive tracts of germfree male rats.
Germfree rats biosynthetize cholic and beta-muricholic acids. The latter does not exist in humans. Germfree rats were given human fecal suspensions. These rats degraded cholic acid into deoxycholic acid but failed to metabolize beta-muricholic acid.


HER3/ErbB3, an emerging cancer therapeutic target.
HER3 is a member of the HER (EGFR/ErbB) receptor family consisting of four closely related type 1 transmembrane receptors (EGFR, HER2, HER3, and HER4). HER receptors are part of a complex signaling network intertwined with the Ras/Raf/MAPK, PI3K/AKT, JAK/STAT, and PKC signaling pathways. Aberrant activation of the HER receptors and downstream signaling molecules tips the balance on cellular events, leading to various types of cancers. Monoclonal antibodies (mAbs) and small molecule inhibitors targeting EGFR and HER2 tyrosine kinase activities exhibit clinical benefits in the treatment of several types of cancers, but their clinical efficacy is limited by the occurrence of drug resistance. HER3 is the preferred dimerization partner of HER2 and it is well established that HER3 plays an important role in drug resistance to EGFR- and HER2-targeting therapies. Since HER3 has limited kinase activity, mAbs are being explored to target HER3 for cancer therapy. Currently, approximately a dozen of anti-HER3 mAbs are at different stages of clinical development. However, the lack of established biomarkers has made it more challenging to stratify cancer patients to whom HER3-targeting therapies can be more effective. In this review, we focus on the validation of HER3 as a cancer drug target, the recent development in biomarker discovery for anti-HER3 therapies, and the progress made in the clinical development of HER3-targeting mAbs.


No evidence of reaction time slowing in autism spectrum disorder.
A total of 32 studies comprising 238 simple reaction time and choice reaction time conditions were examined in individuals with autism spectrum disorder (n = 964) and controls (n = 1032). A Brinley plot/multiple regression analysis was performed on mean reaction times, regressing autism spectrum disorder performance onto the control performance as a way to examine any generalized simple reaction time/choice reaction time slowing exhibited by the autism spectrum disorder group. The resulting regression equation was Y (autism spectrum disorder) = 0.99 × (control) + 87.93, which accounted for 92.3% of the variance. These results suggest that there are little if any simple reaction time/choice reaction time slowing in this sample of individual with autism spectrum disorder, in comparison with controls. While many cognitive and information processing domains are compromised in autism spectrum disorder, it appears that simple reaction time/choice reaction time remain relatively unaffected in autism spectrum disorder.


Breast cancer in Western Australia in 1989: III. Accuracy of FNA cytology in diagnosis.
A population-based study of all cases of breast cancer diagnosed in Western Australia (WA) in 1989 revealed 701 cases of cancer in 692 women. Three hundred and ninety-six (56.5%) of these cancers had fine needle aspiration (FNA) cytology. Forty-three cases were managed non-surgically, on the basis of an FNA diagnosis and without histologic follow up. Of the cases with histological follow-up, 73% received an unequivocal diagnosis of malignancy by FNA, and abnormal cells (atypical, suspicious or malignant diagnoses) were reported in 94.2%. Of the cases, 3.2% were reported as benign and in 2.6% the samples taken were unsatisfactory. There were no false positive cytological diagnoses of malignancy. This study is the first to examine the results of FNA diagnosis of breast cancer from a medical community as a whole, rather than for individual or specialist units; the accuracy of diagnosis was similar for different pathology practices including public and private sector laboratories. Lower absolute sensitivity (the proportion of cases given an unequivocal diagnosis of malignancy) was seen in very small and very large tumours, pure duct carcinoma in situ (DCIS), and invasive lobular carcinoma. False negative rates (the proportion of cases given a benign cytological diagnosis) were very low for all laboratories (0-4.5%) and for all types of carcinoma, and the proportion of unsatisfactory samples was exceptionally low for all laboratories (0-4.5%). The overall figures for accuracy are similar to those reported from other centres in Australasia and overseas, and confirm the effective use of FNA cytology throughout the clinical and pathology community in WA.


Target and resistance-related proteins of recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand on myeloma cell lines.
Recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand (rmhTRAIL) has become a potential therapeutic drug for multiple myeloma (MM). However, the exact targets and resistance mechanisms of rmhTRAIL on MM cells remain to be elucidated. The present study aimed to investigate the target and resistance-related proteins of rmhTRAIL on myeloma cell lines. A TRAIL-sensitive myeloma cell line, RPMI 8226, and a TRAIL-resistance one, U266, were chosen and the differentially expressed proteins between the two cell lines were analyzed prior and subsequent to rmhTRAIL administration by a liquid chromatography-tandem mass spectrometry method. The results showed that following TRAIL treatment, 6 apoptosis-related proteins, calpain small subunit 1 (CPNS1), peflin (PEF1), B-cell receptor-associated protein 31 (BAP31), apoptosis-associated speck-like protein containing CARD (ASC), BAG family molecular chaperone regulator 2 (BAG2) and chromobox protein homolog 3 (CBX3), were upregulated in RPMI 8226 cells while no change was identified in the U266 cells. Furthermore, small ubiquitin-related modifier 1 and several other ubiquitin proteasome pathway (UPP)-related proteins expressed higher levels in TRAIL-resistant cells U266 compared to the RPMI-8226 cells prior and subsequent to rmhTRAIL treatment. These results suggested that CPNS1, PEF1, BAP31, ASC, BAG2 and CBX3 were possibly target proteins of rmhTRAIL on RPMI 8226 cells, while UPP may have a vital role in mediating TRAIL-resistance in U266 cells.


Lack of Evidence for Transovarial Transmission of the Lyme Disease Spirochete Borrelia mayonii by Infected Female Ixodes scapularis (Acari: Ixodidae) Ticks.
The recently described Lyme disease spirochete Borrelia mayonii is associated with human illness in the Upper Midwest of the United States. Experimental laboratory studies and field observations on natural infection indicate that B. mayonii is maintained by horizontal transmission between tick vectors and vertebrate reservoirs. While maintaining a colony of Ixodes scapularis Say (Acari: Ixodidae) ticks infected with the B. mayonii type strain (MN14-1420), we had an opportunity to examine whether infected females may pass this spirochete transovarially to their offspring. We found no evidence of B. mayonii infection in subsets of larvae originating from 18 infected I. scapularis females (grand total of 810 larvae tested), or in mice exposed to larval feeding.


Parental employment status and neural-tube defects and folic acid/multivitamin supplementation in Hungary.
To study the role of parental employment status as indicator of socio-economic status (SES) in the origin of neural-tube defect (NTD) and in the use of periconceptional folic acid/multivitamin supplementation. One thousand two hundred and two cases with neural-tube defects, 38,151 population controls without any defects and 22,475 patient controls with other defects were compared in the population-based data set of the Hungarian case-control surveillance of congenital abnormalities, 1980-1996. The proportion of professionals was lower, while the proportion of semi- and unskilled workers was higher in the neural-tube defect group compared with the population control group. However, the comparison of neural-tube defect and patient control groups showed a lower socio-economic status in the patient control group. In addition, the socio-economic status of fathers in the neural-tube defect group seemed to be better than in the population and patient control groups. The higher periconceptional folic acid supplementation and the higher use of multivitamins during pregnancy occurred in the professional and managerial categories in all the three study groups. The occurrence of neural-tube defect shows a slight socio-economic dependence in the mothers at the comparison with population control group, however, patient control group had the lowest socio-economic status. The higher maternal education goes together with a higher proportion of periconceptional folic acid supplementation.


Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma.
Patients with locally advanced and metastatic urothelial carcinoma have a low survival rate (median 15.7 months, 13.1-17.8), with only a 23% response rate to monotherapy treatment with anti-PDL1 checkpoint immunotherapy. To identify new therapeutic targets, we profiled the immune regulatory signatures during murine cancer development using the BBN carcinogen and identified an increase in the expression of the T cell inhibitory protein B7-H4 (VTCN1, B7S1, B7X). B7-H4 expression temporally correlated with decreased lymphocyte infiltration. While the increase in B7-H4 expression within the bladder by CD11b+ monocytes is shared with human cancers, B7-H4 expression has not been previously identified in other murine cancer models. Higher expression of B7-H4 was associated with worse survival in muscle-invasive bladder cancer in humans, and increased B7-H4 expression was identified in luminal and luminal-papillary subtypes of bladder cancer. Evaluation of B7-H4 by single-cell RNA-Seq and immune mass cytometry of human bladder tumors found that B7-H4 is expressed in both the epithelium of urothelial carcinoma and CD68+ macrophages within the tumor. To investigate the function of B7-H4, treatment of human monocyte and T cell co-cultures with a B7-H4 blocking antibody resulted in enhanced IFN-γ secretion by CD4+ and CD8+ T cells. Additionally, anti-B7-H4 antibody treatment of BBN-carcinogen bladder cancers resulted in decreased tumor size, increased CD8+ T cell infiltration within the bladder, and a complimentary decrease in tumor-infiltrating T regulatory cells (Tregs). Furthermore, treatment with a combination of anti-PD-1 and anti-B7-H4 antibodies resulted in a significant reduction in tumor stage, a reduction in tumor size, and an increased level of tumor necrosis. These findings suggest that antibodies targeting B7-H4 may be a viable strategy for bladder cancers unresponsive to PD-1 checkpoint inhibitors.


COVID-19 fear-induced anorexia nervosa and obsessive-compulsive disorder leading to fatal megaloblastic anemia: Lethal psychological complication of the pandemic.
We report a young female having severe pallor and breathlessness on presentation, being diagnosed as a case of megaloblastic anemia, which was confirmed on bone marrow biopsy. On detailed history taking, she was revealed to have anorexia nervosa precipitated due to extreme fear of COVID-19 along with obsessive-compulsive disorder. Thus, a psychiatric disorder presenting due to simple phobia of COVID-19 can also have a fatal outcome in the young. Therefore, psychiatric health needs urgent attention by physicians, governments, and policymakers across the globe to prevent the surge of mental illness during the ongoing pandemic.


Identifying the assembly pathway of cyanophage inside the marine bacterium using electron cryo-tomography.
Advances in electron cryo-tomography open up a new avenue to visualize the 3-D internal structure of a single bacterium before and after its infection by bacteriophages in its native environment, without using chemical fixatives, fluorescent dyes or negative stains. Such direct observation reveals the presence of assembly intermediates of the bacteriophage and thus allows us to map out the maturation pathway of the bacteriophage inside its host.


Leptin resistance during pregnancy is also exerted at the periphery.
Pregnancy is a physiological state with a great demand of energy and nutrients in mammals and is characterized by hyperphagia, increase in fat mass, hyperleptinemia, and central resistance to leptin. In order to evaluate whether pregnancy is also a state of leptin resistance at the periphery, we studied the response to leptin in the liver and subcutaneous adipose tissue (SAT). We demonstrated reduced levels of phosphoryalated signal transducer and activator of transcription 3 (p-STAT3) and phosphorylated protein kinase B (p-AKT) after intravenous leptin in both tissues in mid-term pregnant rats (G13) and a restored response in late pregnancy (G18). As underlying mechanisms of the peripheral leptin resistance of mid-gestation we found decreased leptin receptor b (LepRb) mRNA levels and increased content of suppressor of cytokine signaling 3 (SOCS3). Furthermore, we demonstrated that in G13 rats the main lipogenic molecules and activity (sterol regulatory element binding transcription protein 1 (SREBP-1) and fatty acid synthase (FAS)) were elevated in the liver and SAT, and the molecules involved in β-oxidation (peroxisome proliferator activated receptor α (PPARα) and carnitine palmitoyltransferase 1 (CPT-1)) were reduced, as it happens in early pregnancy. In G18, the opposite pattern is observed. This probably reflects that in G13 the peripheral resistance to the hyperleptinemia might help maintaining the lipogenic metabolism of early pregnancy. In contrast, the recovery of the response to leptin in late pregnancy would favor a catabolic metabolism. Finally, using a pseudogestation model we showed that progesterone and prolactin are not involved in the gestational peripheral leptin resistance. In conclusion, during mid-pregnancy a state of leptin resistance is also exerted at the periphery, and is probably involved in the characteristic lipid regulation of this physiological state.


Direct enthalpy measurements of the calcium-dependent interaction of annexins V and VI with phospholipid vesicles.
Annexins V and VI are two members of the annexin protein family, each of which associate with phospholipid vesicles in a calcium-dependent manner. They may be important intracellular calcium response elements. Titration calorimetry and spectroscopic techniques showed striking features of these interactions. For annexin V and VI, the total heat release from calcium-dependent binding to bilayer vesicles composed of phosphatidylserine/phosphatidylcholine was -25 and -38 kcal/mol, respectively. The enthalpy of association (delta Hassoc) for the respective protein-calcium interactions was about -11 and -5 kcal/mol. The delta Hassoc for the annexin VI-vesicle interaction was largely independent of the headgroup of the anionic phospholipid and of the pH from 7.1 to 8.4. Use of phosphatidylethanolamine as the neutral phospholipid resulted in a slightly more negative delta Hassoc. Enthalpy was either independent of vesicle size (annexin V) or showed a slightly more negative value for large vesicles (annexin VI). The delta Hassoc for annexin VI-membrane interaction was not constant during protein titration but became more exothermic with higher protein density on the membrane. This behavior was surprising because the equilibrium constant showed negative cooperativity with respect to protein density [Bazzi, M. D., & Nelsestuen, G. L. (1991) Biochemistry 30, 7970-7977]. Apparently, entropy changes occurred which were large and negative, thereby compensating for the increasingly negative enthalpy but decreasing affinity as protein density was increased. In fact, the exothermic process coincided more closely with a change in the intrinsic tryptophan fluorescence of annexin VI than with actual protein-membrane binding. Circular dichroism detected very small changes in protein secondary structure during these events. The observed delta Hassoc for annexin-membrane interaction appeared to involve contributions from the membrane as well as from the protein. Annexin-membrane binding may exert large effects on the membrane that could serve a regulatory capacity in the cell.