Dangerous Liaisons: Caspase-11 and Reactive Oxygen Species Crosstalk in Pathogen Elimination.
Recently, the focus of murine caspase-11 and human orthologs caspase-4, -5 research has been on their novel function to induce noncanonical inflammasome activation in direct response to Gram-negative bacterial infection. On the other hand, a new role in anti-bacterial autophagy has been attributed to caspase-11, -4 and -5, which currently stands largely unexplored. In this review, we connect lately emerged evidence that suggests these caspases have a key role in anti-bacterial autophagy and discuss the growing implications of a danger molecule--extracellular ATP--and NADPH oxidase-mediated ROS generation as novel inducers of human caspase-4, -5 signaling during infection. We also highlight the adeptness of persistent pathogens like Porphyromonas gingivalis, a Gram-negative anaerobe and successful colonizer of oral mucosa, to potentially interfere with the activated caspase-4 pathway and autophagy. While, the ability of caspase-4, -5 to promote autophagolysosomal fusion is not well understood, the abundance of caspase-4 in skin and other mucosal epithelial cells implies an important role for caspase-4 in mucosal defense, supporting the view that caspase-4, -5 may play a non-redundant part in innate immunity. Thus, this review will join the currently disconnected cutting-edge research thereby proposing a working model for regulation of caspase-4, -5 in pathogen elimination via cellular-trafficking.


Children intoxicated by alcohol in Nottingham and Glasgow, 1973-84.
The circumstances of ingestion, clinical course, and long term sequelae were examined retrospectively in 143 children (108 boys, 35 girls) admitted with acute alcohol intoxication in Glasgow and Nottingham over the 12 years 1973-84. Fifty three of the children were aged less than 7 years and 90 were aged 7-14. Twelve of the children were hypoglycaemic on arrival at hospital. Trauma related to intoxication occurred in 14 cases, and nine boys became drunk under duress, which in four cases was associated with sexual abuse.


Investigation of the interactions between methylene blue and intramolecular G-quadruplexes: an explicit distinction in electrochemical behavior.
G-quadruplex sequences exist in eukaryotic organisms and prokaryotes, and the investigation of the interactions between G-quadruplexes and small molecule ligands is important for gene therapy, biosensor fabrication, fluorescence imaging and so on. Here, we investigated the behaviour of methylene blue (MB), an electroactive molecule, in the presence of different intramolecular G-quadruplexes by an electrochemical method using a miniaturized electrochemical device based on its intrinsic electrochemical properties. Although the effects of MB on different intramolecular G-quadruplex structures are not obvious by circular dichroism spectroscopy, distinct differences in the binding affinities of MB with different intramolecular G-quadruplexes were quickly and easily observed by an electrochemical technique. At the same time, for the human telomerase G-rich sequence (HT), the diffusion current of MB changed sensitively under different ionic conditions due to the formation of different conformations of HT, which indicated that our electrochemical method has the potential to study the influence of metal ions on the conformations of the G-quadruplexes with simplicity, rapid response and low cost. From all these, a new stacking mechanism and rule were obtained, which were also validated by docking studies and isothermal titration calorimetry (ITC).


Input polarization-independent polarization-sensitive optical coherence tomography using a depolarizer.
Polarization-sensitive optical coherence tomography is gaining attention because of its ability to diagnose certain pathological conditions at an early stage. The majority of polarization-sensitive optical coherence tomography systems require a polarization controller and a polarizer to obtain the optimal polarization state of the light at the sample. Such systems are prone to misalignment since any movement of the optical fiber normally coupled to the light source will change the polarization state of the incident beam. We propose and demonstrate an input polarization-independent polarization-sensitive optical coherence tomography system using a depolarizer that works for any input polarization state of the light source. The change in the optical power at the sample for arbitrary input polarized light for the standard polarization-sensitive optical coherence tomography system was found to be approximately 84% compared to 9% for our proposed method. The developed system was used to measure the retardance and optical axis orientation of a quarter-wave plate and the obtained values matched closely to the expectation. To further demonstrate the capability of measuring the birefringent properties of biological samples, we also imaged the nail bed. We believe that the proposed system is a robust polarization-sensitive optical coherence tomography system and that it will improve the diagnostic capabilities in clinical settings.


Heterogeneity of horizontal cells in the chicken retina.
Despite numerous reports that different markers are expressed by horizontal cells in the avian retina, it remains unknown whether different types of horizontal cells can be defined by differences in their immunocytochemical profiles. The purpose of this study was to rectify this deficiency. We identified horizontal cells by indirect immunofluorescence with antibodies to calretinin, trkA, GABA, Prox1, AP2alpha, Pax6, islet1, and Lim1 + 2. We found two major groups of horizontal cells, those that express trkA and those that express calretinin. The trkA-immunoreactive (-IR) horizontal cells had small, round somata and robust, bulbous dendritic endings, whereas calretinin-IR horizontal cells had large, polygonal cell bodies and fine, diffuse dendritic endings, both contacting the calbindin-IR pedicles of double cones. Weak gamma-aminobutyric acid (GABA) immunoreactivity was observed only in a few of the trkA-IR horizontal cells, whereas the overlap of calretinin and GABA immunoreactivities was 100%. The majority of trkA-IR horizontal cells expressed islet1, and the majority of calretinin-IR horizontal cells expressed Lim1 + 2, AP2alpha, and Pax6. Islet1 immunoreactivity was observed in a small fraction of calretinin-IR/non-trkA-IR cells. In agreement with previous reports, we detected Prox1 immunoreactivity in all types of horizontal cells. These immunolabeling profiles suggest that there are four immunochemically distinct subtypes of horizontal cells in the postnatal chick retina, which may match the four types that have been observed in Golgi-impregnated pigeon and turtle retinas.


[The pharmacological therapy of glomerulonephritis].
Clinical and experimental studies have markedly expanded our understanding of the causes of renal disease. Although they have not resulted in comparable therapeutic advances, new lines of treatment have emerged which cannot be underestimated. The prognosis of lipoid nephrosis has been substantially modified. The treatment of membranous glomerulonephropathy with steroids and immunosuppressive drugs may modify the course of the disease, at least in a subset of patients with decreased and deteriorating renal function. Encouraging results have been reported after the use of inhibitors of platelet aggregation in mesangiocapillary glomerulonephritis. We have demonstrated that a receptor antagonist of thromboxane can significantly influence the renal functional parameters in patients with lupus nephritis. ACE-inhibitors, cyclosporine and NSAID's have proved useful in reducing nephrotic proteinuria. Lipid lowering agents are able to ameliorate the glomerular lesions in experimental models of renal injuries. Since systemic hypertension may initiate the development of renal disease or accelerate loss of function in the kidney in which parenchymal disease is already established, controlling hypertension by any effective means helps to slow the progression of renal failure. Preliminary reports have suggested that there may be advantages to using ACE-inhibitors and/or calcium entry blockers.


Dynamic determination of the functional state in photolyase and the implication for cryptochrome.
The flavin adenine dinucleotide cofactor has an unusual bent configuration in photolyase and cryptochrome, and such a folded structure may have a functional role in initial photochemistry. Using femtosecond spectroscopy, we report here our systematic characterization of cyclic intramolecular electron transfer (ET) dynamics between the flavin and adenine moieties of flavin adenine dinucleotide in four redox forms of the oxidized, neutral, and anionic semiquinone, and anionic hydroquinone states. By comparing wild-type and mutant enzymes, we have determined that the excited neutral oxidized and semiquinone states absorb an electron from the adenine moiety in 19 and 135 ps, whereas the excited anionic semiquinone and hydroquinone states donate an electron to the adenine moiety in 12 ps and 2 ns, respectively. All back ET dynamics occur ultrafast within 100 ps. These four ET dynamics dictate that only the anionic hydroquinone flavin can be the functional state in photolyase due to the slower ET dynamics (2 ns) with the adenine moiety and a faster ET dynamics (250 ps) with the substrate, whereas the intervening adenine moiety mediates electron tunneling for repair of damaged DNA. Assuming ET as the universal mechanism for photolyase and cryptochrome, these results imply anionic flavin as the more attractive form of the cofactor in the active state in cryptochrome to induce charge relocation to cause an electrostatic variation in the active site and then lead to a local conformation change to initiate signaling.


Sumatriptan alleviates pain in patients with trigeminal neuralgia.
Arterial compression of the trigeminal root may lead to trigeminal neuralgia. 5-HT1B/1D receptor agonists may inhibit vasodilation and inflammation near the irritated trigeminal root. A recent study showed attenuation of mechanical allodynia by a 5-HT1A receptor agonist in a rat model of trigeminal neuralgia. The present study examined the effectiveness of a 5-HT1A/1B/1D receptor agonist, sumatriptan, on pain relief in patients with trigeminal neuralgia. The study was conducted in 15 patients with idiopathic trigeminal neuralgia. The patients had been suffering from painful paroxysms for at least 1 month. Each patient was injected with 1 mL of saline subcutaneously (placebo), followed 15 minutes later with subcutaneous sumatriptan (3 mg in 1 mL saline). This was followed the next day by oral sumatriptan (50 mg twice daily) for 1 week. The visual analog scale did not change after saline, but significantly decreased after subcutaneous sumatriptan. Both 1 week after oral sumatriptan and 1 week after discontinuation of the drug, visual analog scale scores resulted in a significant decrease from the baseline. Adverse events after subcutaneous sumatriptan occurred in 4 patients: fatigue in 4 and nausea in 2. Side effects from the oral medication appeared in 4 patients: fatigue in 2, nausea in 1 and chest discomfort in 1. These side effects subsided soon after discontinuation of sumatriptan. Our results indicate that subcutaneous injection followed by oral administration of sumatriptan produces prompt and continuous analgesia in patients with trigeminal neuralgia.


COVID-19: a retrospective cohort study with focus on the over-80s and hospital-onset disease.
Data from the UK COVID-19 outbreak are emerging, and there are ongoing concerns about a disproportionate effect on ethnic minorities. There is very limited information on COVID-19 in the over-80s, and the rates of hospital-onset infections are unknown. This was a retrospective cohort study from electronic case records of the first 450 patients admitted to our hospital with PCR-confirmed COVID-19, 77% of the total inpatient caseload to date. Demographic, clinical and biochemical data were extracted. The primary endpoint was death during the index hospital admission. The characteristics of all patients, those over 80 years of age and those with hospital-onset COVID-19 were examined. The median (IQR) age was 72 (56, 83), with 150 (33%) over 80 years old and 60% male. Presenting clinical and biochemical features were consistent with those reported elsewhere. The ethnic breakdown of patients admitted was similar to that of our underlying local population. Inpatient mortality was high at 38%. Patients over 80 presented earlier in their disease course and were significantly less likely to present with the typical features of cough, breathlessness and fever. Cardiac co-morbidity and markers of cardiac dysfunction were more common, but not those of bacterial infection. Mortality was significantly higher in this group (60% vs 28%, p < 0.001). Thirty-one (7%) patients acquired COVID-19 having continuously been in hospital for a median of 20 (14, 36) days. The peak of hospital-onset infections occurred at the same time as the overall peak of admitted infections. Despite being older and more frail than those with community-onset infection, their outcomes were no worse. Inpatient mortality was high, especially among the over-80s, who are more likely to present atypically. The ethnic composition of our caseload was similar to the underlying population. While a significant number of patients acquired COVID-19 while already in hospital, their outcomes were no worse.


An innovative study design with intermittent dosing to generate a GLP-regulatory package in preclinical species for long lasting molecule M5717, inhibitor of Plasmodium eukaryotic translation elongation factor 2.
M5717 is a novel drug inhibiting synthesis of elongation factor 2 (PeEF2) in Plasmodium species, showing potent anti-malarial activity in preclinical studies. Traditional daily-dosing animal experiments estimating maximum safe starting dose for a first-in-human study ('no observed adverse effect level'; NOAEL) were unsuccessful due to the long pharmacokinetic half-life of M5717, causing significant drug accumulation and high exposure. This study describes an innovative strategy to produce a GLP-certified toxicology package and estimate NOAEL for long-lasting molecules like M5717. Simulated pharmacokinetic/toxicokinetic profiles were used to design the dosing schedule for preclinical safety studies and to determine the 14-day total exposure. Animals (rats/dogs) were administered various doses of M5717 using an intermittent dosing schedule allowing partial drug elimination and alleviation of toxicity during off-treatment days to maintain a minimal parasitical concentration (MPC) of 10 ng/mL; subsequently animals were monitored for toxicity and mortality. Results showed good correlation to the modelled data used to design the dosing regimen and required MPC was reached for M5717 in study animals and could be used to calculate NOAEL. This fit-for-purpose study design allowed for maintaining clinically relevant exposure to M5717, whilst minimizing toxicity-causing compound accumulation, an aspect unaddressed by traditional NOAEL-estimating experiments. This is the first time that a compound-specific, species-specific, kinetic model-based approach to preclinical study design for regulatory toxicology studies has been described and applied to an antimalarial drug candidate with long pharmacokinetic half-life. It has potential for application to other drugs with long half-lives, supporting their clinical development.


Interferon regulatory factor 1 (IRF-1) and IRF-2 expression in breast cancer tissue microarrays.
Interferon-gamma (IFN-gamma) is a pleiotropic cytokine with potent antitumor effects, both in vitro and in vivo. The antitumor activity of IFN-gamma is mediated in part through IFN regulatory factor-1 (IRF-1) and may be blocked by IRF-2. To test our hypothesis that some tumors escape the antitumor effects of IFN-gamma by cellular changes reflected in IRF-1 and IRF-2 expression, we examined IRF-1 and IRF-2 expression in tissue microarrays (TMA) containing 187 specimens of clinically defined invasive breast carcinoma. TMAs (Cooperative Breast Cancer Tissue Resource [CBCTR], National Cancer Institute [NCI]) were stained and then scored by three evaluators blinded to the patients' clinical status. After final scoring, the CBCTR provided the available clinical data for each patient. Whether sorted by carcinoma type or for all data together, statistical analysis showed a significant positive correlation between IRF-1 and IRF-2 expression (p = 0.01) and a negative correlation between IRF-1 expression and tumor grade (p = 0.005). IRF-1 expression is consistent with its role as a tumor suppressor; high-grade breast carcinomas were less likely to maintain expression of IRF-1, a finding consistent with a role for IRF-1 as a tumor suppressor. Further, tumors maintained expression of IRF-2 if there was coincident expression of IRF-1. These data support a model in which alterations of the expression of intracellular effectors of IFN-gamma signaling may diminish the immune-mediated tumor control mechanisms of IFN-gamma.


Biocatalytic Membrane Based on Polydopamine Coating: A Platform for Studying Immobilization Mechanisms.
Application of biocatalytic membrane is promising in food, pharmaceutical, and water treatment industries, whereas enzyme immobilization is the key step of biocatalytic membrane preparation. Thus, how to minimize the negative effect of immobilization on enzyme performance is required to answer. In this work, we proposed a platform for biocatalytic membrane preparation and immobilization mechanism investigation based on polydopamine (PDA) coating, which was demonstrated by immobilizing five commonly used enzymes (laccase, glucose oxidase, lipase, pepsin, and dextranase) on three commercially available membranes via three immobilization mechanisms (electrostatic attraction, covalent bonding, and hydrophobic adsorption), respectively. By examining the enzyme loading, activity, and kinetics under different immobilization mechanisms, we found that except for dextranase, enzyme immobilization via electrostatic attraction retained the most activity, whereas covalent bonding and hydrophobic adsorption were detrimental to enzyme conformation. Enzyme immobilization via covalent bonding ensured a high enzyme loading, and hydrophobic adsorption was only suitable for lipase and dextranase immobilization. Moreover, the properties of functional groups around the enzyme active center should be considered for the selection of suitable immobilization strategy (i.e., avoid covering the active center by membrane carrier). This work not only established a versatile platform for biocatalytic membrane preparation but also provided a novel methodology to evaluate the effect of immobilization mechanisms on enzyme performance.


Self-heating allows athermal laser diode wavelength control using a thermally insulating sub-mount over a 70 °C range.
The wavelength of a single frequency quantum dot distributed feedback (DFB) laser operating in the O-band is athermalised over a 74 °C ambient temperature range. Two techniques are presented, one utilising the laser self-heating for tuning control, the other using a resistive heater. Both techniques show greatly improved power efficiency over conventional wavelength control schemes, and both demonstrate wavelength stability of better than 0.1 nm (17.5 GHz) without mode hops over the entire temperature range. The use of a high operating temperature quantum dot laser together with an innovative submount design to increase the thermal impedance of the device enables the improved use of the laser self-heating for wavelength tuning. The submount design entails the laser being suspended over an air gap with the use of glass supports, preventing heat from escaping from the diode.


[35S]thiosulphate oxidation by rat liver mitochondria in the presence of glutathione.
1. Rat liver mitochondria incubated in oxygen with glutathione and [(35)S]-thiosulphate produced labelled sulphate. 2. Inner-labelled thiosulphate (S.(35)SO(3))(2-) was converted into [(35)S]sulphate more rapidly than outer-labelled thiosulphate ((35)S.SO(3))(2-). 3. Thiosulphate labelled in both sulphur atoms was formed during ((35)S.SO(3))(2-) oxidation; the outer sulphur atom before oxidation to sulphate was incorporated into the inner position. 4. A thiosulphate cycle in the metabolic pathway of sulphate formation in animal tissues is discussed.


Association of folic acid, vitamin B12, and intelligence scores in epileptic children.
Epilepsy is a serious childhood disease associated with cognitive impairment. Our aim was to investigate the possible association of serum folic acid, vitamin B12, and intelligence scores in epileptic children. A group of 30 children with established diagnosis of idiopathic epilepsy for at least one year as well as another group of 30 nonepileptic healthy children as the control group were recruited for analysis. Cognitive performance was assessed by a battery of psychological tests that covers verbal and nonverbal intelligence. Serum B12 level was significantly lower in patients than the control group (264.17 ± 58.07, 450.55 ± 134.9, respectively). No significant difference was detected between patients and the control group regarding serum folic acid level. Verbal, performance, and total IQ were significantly lower in patients than the control group (83.2 ± 3.08 vs. 95.8 ± 6.22, 78.4 ± 10.68 vs. 91.3 ± 2.45, and 180.6 ± 6.58 vs. 93.5 ± 3.02, respectively). However, no significant correlation was detected in folic acid, vitamin B 12, and cognitive scores. Epileptic children were five times more at risk of having low IQ (verbal, performance, and total) < 85 than the control group (OR = 4.754, 95% CI 13.047-1031.316, p = .000). In conclusion, children with epilepsy might be at higher risk for cognitive dysfunction than normal children. No significant association was detected between cognitive performance and either folic acid or vitamin B12 in epileptic children receiving sodium valproate. Supplementation of those vitamins should be restricted to those with documented deficiency.


Epstein-Barr virus-host cell interactions: an epigenetic dialog?
Here, we wish to highlight the genetic exchange and epigenetic interactions between Epstein-Barr virus (EBV) and its host. EBV is associated with diverse lymphoid and epithelial malignancies. Their molecular pathogenesis is accompanied by epigenetic alterations which are distinct for each of them. While lymphoblastoid cell lines derived from B cells transformed by EBV in vitro are characterized by a massive demethylation and euchromatinization of the viral and cellular genomes, the primarily malignant lymphoid tumor Burkitt's lymphoma and the epithelial tumors nasopharyngeal carcinoma and EBV-associated gastric carcinoma are characterized by hypermethylation of a multitude of cellular tumor suppressor gene loci and of the viral genomes. In some cases, the viral latency and oncoproteins including the latent membrane proteins LMP1 and LMP2A and several nuclear antigens affect the level of cellular DNA methyltransferases or interact with the histone modifying machinery. Specific molecular mechanisms of the epigenetic dialog between virus and host cell remain to be elucidated.


Pathophysiology and management of pulmonary infections in cystic fibrosis.
This comprehensive State of the Art review summarizes the current published knowledge base regarding the pathophysiology and microbiology of pulmonary disease in cystic fibrosis (CF). The molecular basis of CF lung disease including the impact of defective cystic fibrosis transmembrane regulator (CFTR) protein function on airway physiology, mucociliary clearance, and establishment of Pseudomonas aeruginosa infection is described. An extensive review of the microbiology of CF lung disease with particular reference to infection with P. aeruginosa is provided. Other pathogens commonly associated with CF lung disease including Staphylococcal aureus, Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans and atypical mycobacteria are also described. Clinical presentation and assessment of CF lung disease including diagnostic microbiology and other measures of pulmonary health are reviewed. Current recommendations for management of CF lung disease are provided. An extensive review of antipseudomonal therapies in the settings of treatment for early P. aeruginosa infection, maintenance for patients with chronic P. aeruginosa infection, and treatment of exacerbation in pulmonary symptoms, as well as antibiotic therapies for other CF respiratory pathogens, are included. In addition, the article discusses infection control policies, therapies to optimize airway clearance and reduce inflammation, and potential future therapies.


The "VH1-like" dual-specificity protein tyrosine phosphatases.
The number of dual-specificity protein tyrosine phosphatases has grown considerably in the last few years, and thus it would be helpful to organize these novel enzymes. The simple term "VH1-like" or "dual-specificity" phosphatase does not adequately reflect the different subclasses within this new and important phosphatase subfamily. In this article, we review the salient features of dual-specificity phosphatases and propose a novel classification scheme of these enzymes based on their structural motifs. Classification of dual-specificity phosphatases based on their motifs should serve as a useful organizational framework for bringing together this now large subgroup of phosphatases. Moreover, this classification scheme may hold predictive value, since some of these motifs may hold the key to new, undiscovered functional properties.


Hippocampal sulcus remnant: potential cause of change in signal intensity in the hippocampus.
A small area of changed signal intensity in the hippocampus is often seen on magnetic resonance (MR) images of the brain in patients without specific clinical signs or symptoms. To ascertain its cause by means of histologic examination, this finding was evaluated retrospectively in 109 patients and correlated with findings in two human brain specimens. This area of change was typically round or curvilinear and 1-2 mm in diameter. Its location was between the hippocampus and dentate gyrus. The signal intensity was the same as that of cerebrospinal fluid (CSF) with all MR sequences used. The incidence of change in signal intensity was greater in elderly patients. Correlation with histologic findings showed that this area of change, a dilated perivascular space, was the residual cavity of the hippocampal sulcus. Whenever an area of CSF-like signal intensity has this shape and topographic features, the possibility of anatomic variation should be considered before the change in signal intensity is diagnosed as brain injury.


Investigating weathering in light diesel oils using comprehensive two-dimensional gas chromatography-High resolution mass spectrometry and pixel-based analysis: Possibilities and limitations.
Petroleum-derived fuels are chronically spilled in urbanized areas, affecting the environment and the population's health. Forensic investigations of oil spills aim to find the responsible source of the spills. Weathering processes (dissolution, evaporation, photo-oxidation and biodegradation) change the chemical composition of the spills and hamper the matching of spill-source pairs, especially for light diesel oils (i.e. n-C9 - n-C20) in which the source diesels can be very similar due to the refining process and only compounds resistant to short- or middle-term weathering are present. In this study, comprehensive two-dimensional gas chromatography - high resolution mass spectrometry (GC × GC - HRMS) and pixel-based analysis were combined for: i) improve the identification of very similar diesel oils, and ii) identify weathering-resistant compounds that can also distinguish samples from different sources. Diesel oils from two sources that have been exposed to different degrees of evaporation, photo-oxidation and biodegradation in a laboratory setup. The study revealed the tentatively identified octanoic acid methyl ester and n-nonaldehyde were more resistance to evaporation than hydrocarbons < n-C15. Furthermore, the hydrocarbons > n-C17 could be used for source-apportionment of all the diesel oils susceptible to evaporation and photo-oxidation, but only pristane and phytane were also more resistant to biodegradation. Naphthenes, bicyclic sesquiterpanes and adamantanes were more resistant to only photo-oxidation and biodegradation. GC × GC - HRMS enhanced the separation of the highly similar naphthenes in the diesel oils; however, the diagnostic power for forensic spill investigations was still similar to 1D GC - HRMS.


Use of psychological decompression in military operational environments.
This article reviews the use of psychological decompression as applied to troops returning from active service in operational theaters. Definitions of the term are considered and a brief history is given. Current policies and practices are described and the question of mandatory decompression is considered. Finally, the evidence base for the efficacy of decompression is examined and some conclusions are drawn. This article highlights variations in the definition and practice of decompression and its use. Although there is, as yet, no evidence that decompression works, there is also no evidence to the contrary. Given the lack of knowledge as to the balance of risks and benefits of decompression and the absence of any definitive evidence that decompression is associated with improved mental health outcomes or that lack of decompression is associated with the reverse, it is argued that the use of decompression should remain a matter for discretion.


Trackplot: A flexible toolkit for combinatorial analysis of genomic data.
Here, we introduce Trackplot, a Python package for generating publication-quality visualization by a programmable and interactive web-based approach. Compared to the existing versions of programs generating sashimi plots, Trackplot offers a versatile platform for visually interpreting genomic data from a wide variety of sources, including gene annotation with functional domain mapping, isoform expression, isoform structures identified by scRNA-seq and long-read sequencing, as well as chromatin accessibility and architecture without any preprocessing, and also offers a broad degree of flexibility for formats of output files that satisfy the requirements of major journals. The Trackplot package is an open-source software which is freely available on Bioconda (https://anaconda.org/bioconda/trackplot), Docker (https://hub.docker.com/r/ygidtu/trackplot), PyPI (https://pypi.org/project/trackplot/) and GitHub (https://github.com/ygidtu/trackplot), and a built-in web server for local deployment is also provided.


Racing to help: racial bias in high emergency helping situations.
The present work explored the influence of emergency severity on racial bias in helping behavior. Three studies placed participants in staged emergencies and measured differences in the speed and quantity of help offered to Black and White victims. Consistent with predictions, as the level of emergency increased, the speed and quality of help White participants offered to Black victims relative to White victims decreased. In line with the authors' predictions based on an integration of aversive racism theory and the arousal: cost-reward perspective on prosocial behavior, severe emergencies with Black victims elicited high levels of aversion from White helpers, and these high levels of aversion were directly related to the slower help offered to Black victims but not to White victims (Study 1). In addition, the bias was related to White individuals' interpretation of the emergency as less severe and themselves as less responsible to help Black victims rather than White victims (Studies 2 and 3). Study 3 also illustrated that emergency racial bias is unique to White individuals' responses to Black victims and not evinced by Black helpers.


Bilateral leg movements during sleep: detailing their structure and features in normal controls and in patients with restless legs syndrome.
The aim of this study was to analyze statistically the number of single leg movements (LMs) forming bilateral LMs during sleep, along with their combined duration, to eventually provide evidence-based data for the adjustment of the current scoring rules defining bilateral LMs. Polysomnographic recordings of 111 untreated patients with RLS with a median age of 56.0 years, along with 42 normal controls with a mean age of 60.0 years, were included. In each recording, we identified all LMs that were considered as bilateral when two or more LMs were overlapping or the onset of the following movement was <0.5 second after the offset of the preceding LM. The remaining LMs were classified as monolateral. A series of parameters were computed for both bilateral and monolateral LMs. The duration of monolateral LMs in RLS patients was significantly longer than that of normal controls. For bilateral LMs, the maximum number of single LMs forming a bilateral movement and the maximum duration were slightly higher in RLS patients; however, the distribution of the number of individual LMs forming a single bilateral LM was similar. Only 0.12% and 0.27% of bilateral LMs consisted of >4 individual movements, and only 0.16% and 1.90% of bilateral LMs were >15 seconds in RLS patients and healthy controls, respectively. Our results strongly suggest that bilateral LMs during sleep should be constituted by no more than four individual LMs and should have a maximum duration of 15 seconds.


Artificial grammar learning meets formal language theory: an overview.
Formal language theory (FLT), part of the broader mathematical theory of computation, provides a systematic terminology and set of conventions for describing rules and the structures they generate, along with a rich body of discoveries and theorems concerning generative rule systems. Despite its name, FLT is not limited to human language, but is equally applicable to computer programs, music, visual patterns, animal vocalizations, RNA structure and even dance. In the last decade, this theory has been profitably used to frame hypotheses and to design brain imaging and animal-learning experiments, mostly using the 'artificial grammar-learning' paradigm. We offer a brief, non-technical introduction to FLT and then a more detailed analysis of empirical research based on this theory. We suggest that progress has been hampered by a pervasive conflation of distinct issues, including hierarchy, dependency, complexity and recursion. We offer clarifications of several relevant hypotheses and the experimental designs necessary to test them. We finally review the recent brain imaging literature, using formal languages, identifying areas of convergence and outstanding debates. We conclude that FLT has much to offer scientists who are interested in rigorous empirical investigations of human cognition from a neuroscientific and comparative perspective.


Direct amidation of esters with nitroarenes.
Esters are one of the most common functional groups in natural and synthetic products, and the one-step conversion of the ester group into other functional groups is an attractive strategy in organic synthesis. Direct amidation of esters is particularly appealing due to the omnipresence of the amide moiety in biomolecules, fine chemicals, and drug candidates. However, efficient methods for direct amidation of unactivated esters are still lacking. Here we report nickel-catalysed reductive coupling of unactivated esters with nitroarenes to furnish in one step a wide range of amides bearing functional groups relevant to the development of drugs and agrochemicals. The method has been used to expedite the syntheses of bio-active molecules and natural products, as well as their post-synthetic modifications. Preliminary mechanistic study indicates a reaction pathway distinct from conventional amidation methods using anilines as nitrogen sources. The work provides a novel and efficient method for amide synthesis.


Effects of Directional Change on Postural Adjustments during the Sit-to-walk Task.
[Purpose] The purpose of this study was to clarify the effects of directional change on postural adjustments during the sit-to-walk (STW) task. [Subjects] Fifteen healthy young men participated in this study. [Methods] Subjects were required to stand up from a chair and walk toward a target. The first step was limited to the right limb only. Three conditions of target direction (straight, ipsilateral and contralateral) were set. For the ipsilateral and contralateral conditions, the target was placed at an angle 45° clockwise and 45° counterclockwise from straight ahead, respectively. Trials were recorded by a motion capture system and force plates. The forward momentum of the body, time of events, center of pressure (COP) and center of gravity (COG) displacement were measured and compared between conditions. [Results] In the contralateral condition, the fluidity index was significantly lower than that in the straight condition. In the contralateral condition, COP displacement toward the swing limb was larger than in the other conditions. [Conclusion] The present results indicate that a directional change during the STW task affects fluidity and postural adjustments. When the STW direction was changed to diagonal, the lateral component of postural control became more important.


PGC-1alpha integrates insulin signaling, mitochondrial regulation, and bioenergetic function in skeletal muscle.
The pathophysiology underlying mitochondrial dysfunction in insulin-resistant skeletal muscle is incompletely characterized. To further delineate this we investigated the interaction between insulin signaling, mitochondrial regulation, and function in C2C12 myotubes and in skeletal muscle. In myotubes elevated insulin and glucose disrupt insulin signaling, mitochondrial biogenesis, and mitochondrial bioenergetics. The insulin-sensitizing thiazolidinedione pioglitazone restores these perturbations in parallel with induction of the mitochondrial biogenesis regulator PGC-1alpha. Overexpression of PGC-1alpha rescues insulin signaling and mitochondrial bioenergetics, and its silencing concordantly disrupts insulin signaling and mitochondrial bioenergetics. In primary skeletal myoblasts pioglitazone also up-regulates PGC-1alpha expression and restores the insulin-resistant mitochondrial bioenergetic profile. In parallel, pioglitazone up-regulates PGC-1alpha in db/db mouse skeletal muscle. Interestingly, the small interfering RNA knockdown of the insulin receptor in C2C12 myotubes down-regulates PGC-1alpha and attenuates mitochondrial bioenergetics. Concordantly, mitochondrial bioenergetics are blunted in insulin receptor knock-out mouse-derived skeletal myoblasts. Taken together these data demonstrate that elevated glucose and insulin impairs and pioglitazone restores skeletal myotube insulin signaling, mitochondrial regulation, and bioenergetics. Pioglitazone functions in part via the induction of PGC-1alpha. Moreover, PGC-1alpha is identified as a bidirectional regulatory link integrating insulin-signaling and mitochondrial homeostasis in skeletal muscle.


Prevalent bee venom genes evolved before the aculeate stinger and eusociality.
Venoms, which have evolved numerous times in animals, are ideal models of convergent trait evolution. However, detailed genomic studies of toxin-encoding genes exist for only a few animal groups. The hyper-diverse hymenopteran insects are the most speciose venomous clade, but investigation of the origin of their venom genes has been largely neglected. Utilizing a combination of genomic and proteo-transcriptomic data, we investigated the origin of 11 toxin genes in 29 published and 3 new hymenopteran genomes and compiled an up-to-date list of prevalent bee venom proteins. Observed patterns indicate that bee venom genes predominantly originate through single gene co-option with gene duplication contributing to subsequent diversification. Most Hymenoptera venom genes are shared by all members of the clade and only melittin and the new venom protein family anthophilin1 appear unique to the bee lineage. Most venom proteins thus predate the mega-radiation of hymenopterans and the evolution of the aculeate stinger.


Limb Regeneration and Interference Competition Consequences on Foraging Efficiency of Coccinella undecimpunctata and Hippodamia variegata (Coccinellidae: Coleoptera) to Their Prey, Aphis craccivora (Hemiptera: Aphididae).
Regeneration of limbs lost during development has been recorded in a large number of species of hexapoda including many Coccinellids. Although regeneration has obvious survival and fitness benefits, it has also been demonstrated to impose costs on development, reproduction, and behavior. To investigate consequences of regeneration on foraging behavior, Coccinella undecimpunctata L. and Hippodamia variegata (Goeze) larvae were treated to remove one limb, allowed to pupate and regenerate and then prey searching ability assessed. Different densities of adults were placed in Petri dishes with aphid prey and consumption assessed over a 24-h period. Amputation/regeneration, predator species, and predator density significantly affected the total number of aphids consumed. Aphid consumption rates and predation efficiency of both regenerated and control beetles significantly increased as predator density increased. Although there were significant differences in consumption between ablated/regenerated and control C. undecimpunctata at each predator densities, H. variegata did not. Further, mutual interference was significantly higher for regenerated compared with control C. undecimpunctata but not so for H. variegata. This is the first demonstration of an effect of ablation/regeneration on foraging behavior of C. undecimpunctata and suggests that H. variegata demonstrates an adaptive phenotypic response to limb regeneration. Coccinellids are widely used as biological agents and these findings concerning the impact of variation in predator density have clear implications for the management of predator-prey ratios in order to maximize efficiency of pest consumption.


Impaired replication elongation in Tetrahymena mutants deficient in histone H3 Lys 27 monomethylation.
Replication of nuclear DNA occurs in the context of chromatin and is influenced by histone modifications. In the ciliate Tetrahymena thermophila, we identified TXR1, encoding a histone methyltransferase. TXR1 deletion resulted in severe DNA replication stress, manifested by the accumulation of ssDNA, production of aberrant replication intermediates, and activation of robust DNA damage responses. Paired-end Illumina sequencing of ssDNA revealed intergenic regions, including replication origins, as hot spots for replication stress in ΔTXR1 cells. ΔTXR1 cells showed a deficiency in histone H3 Lys 27 monomethylation (H3K27me1), while ΔEZL2 cells, deleting a Drosophila E(z) homolog, were deficient in H3K27 di- and trimethylation, with no detectable replication stress. A point mutation in histone H3 at Lys 27 (H3 K27Q) mirrored the phenotype of ΔTXR1, corroborating H3K27me1 as a key player in DNA replication. Additionally, we demonstrated interactions between TXR1 and proliferating cell nuclear antigen (PCNA). These findings support a conserved pathway through which H3K27me1 facilitates replication elongation.


Synthesis of 2-Vinylindole-3-Acetic Acid Derivatives via Cyanide-Catalyzed Imino-Stetter Reaction.
A new method for the synthesis of 2-vinylindole-3-acetic acid derivatives from aldimines, which are derived from 2-aminocinnamic acid derivatives and α,β-unsaturated aldehydes, via a cyanide-catalyzed imino-Stetter reaction is described. Various types of 2-aminocinnamic acid derivatives and α,β-unsaturated aldehydes could be used in this protocol, and the desired 2-vinyl substituted indole-3-acetic acid derivatives were obtained in high yields. This cyanide-catalyzed imino-Stetter reaction was further extended to the preparation of indole-3-acetic acid derivatives bearing a carboxylic acid functionality at the 2-position, using aldimines obtained from glyoxylates and 2-aminocinnamic acid derivatives.


Worry as a risk factor for mental and somatic diseases. A research on home-cared cancer patients family caregivers.
Cancer patients family caregivers are exposed to several physical and emotional distress. Many recent reviews have provided strong evidence linking negative affective states and dispositions to disease. Moreover, several recent studies suggested that perseverative cognition, as manifested in worry, plays a role in nearly all anxiety disorders and is a crucial factor in somatic health as well. In this study, we tested a group of family caregivers since we wanted to find out whether worry might act directly on psychological and somatic diseases. The sample consists of 107 family caregivers. Participants completed a battery of self-report questionnaires including the Caregiver Burden Inventory, the Penn State Worry Questionnaire, the Psychophysiological Questionnaire and the Beck Depression Inventory. They underwent tests at the moment of oncological home-care request. The study has revealed that there is a significant positive correlation between worry measures and mental and physical health of the participants. In fact, the tendency to perseverative cognition resulted as a powerful and solid predictor of physical symptomatology (R = 0.5, beta = 0.67, p < 0.001) and depression level (R = 0.46, beta = 0.52, p < 0.000001). Worry plays an important role in psychological and physical health and it is a counterproductive attempt at constructive mental problem solving. These results have great practical and operative value. Interventions improving caregiver's ability to cope with stress situations are likely to result in more positive benefits for cancer patients: in fact, if we promote the caregiver's physical and emotional well-being, he or she can provide the best care possible to the patient.


Concepts of CNS plasticity in the context of brain damage and repair.
How effectively the brain can respond to injury and undergo structural repair has become one of the most exciting areas of contemporary basic and translational neuroscience research. Although there are no clinical treatments yet available to enhance repair of the damaged brain, there are a number of potential therapies being investigated. New drugs are designed to provide some degree of neuroprotection by preventing injured or vulnerable nerve cells from dying, or they are given in the hope of stimulating regenerative processes that could lead to the restoration or the formation of new connections that were lost because of the injury. The developments in pharmacology are based primarily upon understanding the molecular mechanisms of drug actions at the level of the genome or with respect to cellular metabolism. Although there is a substantial interest in the pharmacology of brain repair, there seems to be less concern with the various theories of central nervous system plasticity, organization, and reorganization after an injury. This review discusses some of the older and current ideas and theories that have been presented over the years to explain recovery of function. We then provide an overview of what is being done in the laboratory to develop new and safe drugs for the treatment of traumatic brain injuries.


Structure of the plant photosystem I supercomplex at 2.6 Å resolution.
Four elaborate membrane complexes carry out the light reaction of oxygenic photosynthesis. Photosystem I (PSI) is one of two large reaction centres responsible for converting light photons into the chemical energy needed to sustain life. In the thylakoid membranes of plants, PSI is found together with its integral light-harvesting antenna, light-harvesting complex I (LHCI), in a membrane supercomplex containing hundreds of light-harvesting pigments. Here, we report the crystal structure of plant PSI-LHCI at 2.6 Å resolution. The structure reveals the configuration of PsaK, a core subunit important for state transitions in plants, a conserved network of water molecules surrounding the electron transfer centres and an elaborate structure of lipids bridging PSI and its LHCI antenna. We discuss the implications of the structure for energy transfer and the evolution of PSI.


Thermal Condensation of Glycine and Alanine on Metal Ferrite Surface: Primitive Peptide Bond Formation Scenario.
The amino acid condensation reaction on a heterogeneous mineral surface has been regarded as one of the important pathways for peptide bond formation. Keeping this in view, we have studied the oligomerization of the simple amino acids, glycine and alanine, on nickel ferrite (NiFe₂O₄), cobalt ferrite (CoFe₂O₄), copper ferrite (CuFe₂O₄), zinc ferrite (ZnFe₂O₄), and manganese ferrite (MnFe₂O₄) nanoparticles surfaces, in the temperature range from 50-120 °C for 1-35 days, without applying any wetting/drying cycles. Among the metal ferrites tested for their catalytic activity, NiFe₂O₄ produced the highest yield of products by oligomerizing glycine to the trimer level and alanine to the dimer level, whereas MnFe₂O₄ was the least efficient catalyst, producing the lowest yield of products, as well as shorter oligomers of amino acids under the same set of experimental conditions. It produced primarily diketopiperazine (Ala) with a trace amount of alanine dimer from alanine condensation, while glycine was oligomerized to the dimer level. The trend in product formation is in accordance with the surface area of the minerals used. A temperature as low as 50 °C can even favor peptide bond formation in the present study, which is important in the sense that the condensation process is highly feasible without any sort of localized heat that may originate from volcanoes or hydrothermal vents. However, at a high temperature of 120 °C, anhydrides of glycine and alanine formation are favored, while the optimum temperature for the highest yield of product formation was found to be 90 °C.


An omni-directional model of injury risk in planar crashes with application for autonomous vehicles.
Objective: Automated driving systems (ADS) are actively being deployed within the driving fleet. ADS are designed to safely navigate roadways, which entails an expectation of encountering varying degrees of potential conflict with other road users. The ADS design and evaluation process benefits from estimating injury severity probabilities for collisions that may occur. Current regression models in the literature are typically bespoke analyses involving targeted principal directions of force (PDOFs) and occupant positions. It is preferable to rely on injury severity models derived from a single source to provide a continuous function of risk for all planar collisions, while also accounting for specific vehicle and occupant characteristics. The novel feature of the proposed models is continuous, parametric injury risk surfaces that encompass the full spectrum of available United States field data.Methods: We used years 2001-2015 of the National Automotive Sampling System, Crashworthiness Data System (NASS-CDS) and years 2017-2019 of the Crash Investigation Sampling System (CISS) to estimate injury risk at the maximum abbreviated injury scale (MAIS) 3 and higher (3+) and 5 and higher (5+) levels for all adult occupants traveling in 2002 or newer passenger vehicles which were less than 10 years old at the time of the crash. The models account for occupant, vehicle, and crash characteristics. Interactions with vulnerable road users (e.g., pedestrian, bicyclist) were not considered.Results: We present statistical models suitable to predict injury in all non-rollover crashes at the maximum MAIS3+ and 5+ levels, and show that these models can be comparable to similar single scenario (e.g., frontal) crash models. We discuss challenges with imputing missing field data, and discuss handling of covariates that may not be known at the time of the crash.Conclusions: Collision severity assessment is a vital component of the ADS design process. We developed a novel injury risk function that can assess occupant injury risks across the spectrum of foreseeable planar collisions. These models can provide insight on potential outcomes of counterfactual simulations, injury risk and crashworthiness considerations for human driven vehicles, and provide an evaluation tool that can be applied in ADS safety impact evaluation.


Carotenoids in Microalgae.
Carotenoids are a class of isoprenoids synthesized by all photosynthetic organisms as well as by some non-photosynthetic bacteria and fungi with broad applications in food, feed and cosmetics, and also in the nutraceutical and pharmaceutical industries. Microalgae represent an important source of high-value products, which include carotenoids, among others. Carotenoids play key roles in light harvesting and energy transfer during photosynthesis and in the protection of the photosynthetic apparatus against photooxidative damage. Carotenoids are generally divided into carotenes and xanthophyls, but accumulation in microalgae can also be classified as primary (essential for survival) and secondary (by exposure to specific stimuli).In this chapter, we outline the high value carotenoids produced by commercially important microalgae, their production pathways, the improved production rates that can be achieved by genetic engineering as well as their biotechnological applications.


Psychiatric consultation to elderly medical inpatients in a general hospital.
To determine the reasons for referral of elderly medical inpatients for psychiatric consultation and the appropriateness of such referrals. To determine whether the provision of a consultation service is associated with increases in referral rates over time. One hundred consecutive referrals seen over an 18-week period were included in the study and data on reason for referral, ICD-10 diagnosis and recommended interventions gathered prospectively. Rates of referral were calculated and compared with a similar study performed in the same location five years previously. In this location the most frequent reason for referral was for assessment of depressive symptoms (47%). Referrals were generally appropriate and there was a high degree of concordance between reason for referral and psychiatric diagnosis, particularly for depressive symptoms. There was a moderate (22%) increase in referral rates in the five years since the previous study. Concordance rates between reason for referral and psychiatric diagnosis had improved considerably during this period, particularly for depressive symptoms. Referral rates for psychogeriatric consultation increase over time. Referrals are generally appropriate, and recognition of depressive illness improves. Psychiatric illness may still be under-recognised and increasing workload may indicate a need for more refined models of service delivery.


Spatial Distribution of Sand Fly Vectors and Eco-Epidemiology of Cutaneous Leishmaniasis Transmission in Colombia.
Leishmania is transmitted by Phlebotominae insects that maintain the enzootic cycle by circulating between sylvatic and domestic mammals; humans enter the cycles as accidental hosts due to the vector's search for blood source. In Colombia, leishmaniasis is an endemic disease and 95% of all cases are cutaneous (CL), these cases have been reported in several regions of the country where the intervention of sylvatic areas by the introduction of agriculture seem to have an impact on the rearrangement of new transmission cycles. Our study aimed to update vector species distribution in the country and to analyze the relationship between vectors' distribution, climate, land use and CL prevalence. A database with geographic information was assembled, and ecological niche modeling was performed to explore the potential distribution of each of the 21 species of medical importance in Colombia, using thirteen bioclimatic variables, three topographic and three principal components derived from NDVI. Binary models for each species were obtained and related to both land use coverage, and a CL prevalence map with available epidemiological data. Finally, maps of species potential distribution were summed to define potential species richness in the country. In total, 673 single records were obtained with Lutzomyia gomezi, Lutzomyia longipalpis, Psychodopygus panamensis, Psathyromyia shannoni and Pintomyia evansi the species with the highest number of records. Eighteen species had significant models, considering the area under the curve and the jackknife results: L. gomezi and P. panamensis had the widest potential distribution. All sand fly species except for Nyssomyia antunesi are mainly distributed in regions with rates of prevalence between 0.33 to 101.35 cases per 100,000 inhabitants and 76% of collection data points fall into transformed ecosystems. Distribution ranges of sand flies with medical importance in Colombia correspond predominantly to disturbed areas, where the original land coverage is missing therefore increasing the domiciliation potential. We highlight the importance of the use of distribution maps as a tool for the development of strategies for prevention and control of diseases.


Multiplexed, high-throughput measurements of cell contraction and endothelial barrier function.
Vascular leakage, protein exudation, and edema formation are events commonly triggered by inflammation and facilitated by gaps that form between adjacent endothelial cells (ECs) of the vasculature. In such paracellular gap formation, the role of EC contraction is widely implicated, and even therapeutically targeted. However, related measurement approaches remain slow, tedious, and complex to perform. Here, we have developed a multiplexed, high-throughput screen to simultaneously quantify paracellular gaps, EC contractile forces, and to visualize F-actin stress fibers, and VE-cadherin. As proof-of-principle, we examined barrier-protective mechanisms of the Rho-associated kinase inhibitor, Y-27632, and the canonical agonist of the Tie2 receptor, Angiopoietin-1 (Angpt-1). Y-27632 reduced EC contraction and actin stress fiber formation, whereas Angpt-1 did not. Yet both agents reduced thrombin-, LPS-, and TNFα-induced paracellular gap formation. This unexpected result suggests that Angpt-1 can achieve barrier defense without reducing EC contraction, a mechanism that has not been previously described. This insight was enabled by the multiplex nature of the force-based platform. The high-throughput format we describe should accelerate both mechanistic studies and the screening of pharmacological modulators of endothelial barrier function.


Prenatal Exposure to Multiple Endocrine-Disrupting Chemicals and Childhood BMI Trajectories in the INMA Cohort Study.
Prenatal exposure to endocrine-disrupting chemicals (EDCs) may disrupt normal fetal and postnatal growth. Studies have mainly focused on individual aspects of growth at specific time points using single chemical exposure models. However, humans are exposed to multiple EDCs simultaneously, and growth is a dynamic process. The objective of this study was to evaluate the associations between prenatal exposure to EDCs and children's body mass index (BMI) growth trajectories using single exposure and mixture modeling approaches. Using data from the INfancia y Medio Ambiente (INMA) Spanish birth cohort (n=1,911), prenatal exposure to persistent chemicals [hexachlorobenzene (HCB), 4-4'-dichlorodiphenyldichloroethylene (DDE), polychlorinated biphenyls (PCB-138, -150, and -180), 4 perfluoroalkyl substances (PFAS)] and nonpersistent chemicals (8 phthalate metabolites, 7 phenols) was assessed using blood and spot urine concentrations. BMI growth trajectories were calculated from birth to 9 years of age using latent class growth analysis. Multinomial regression was used to assess associations for single exposures, and Bayesian weighted quantile sum (BWQS) regression was used to evaluate the EDC mixture's association with child growth trajectories. In single exposure models exposure to HCB, DDE, PCBs, and perfluorononanoic acid (PFNA) were associated with increased risk of belonging to a trajectory of lower birth size followed by accelerated BMI gain by 19%-32%, compared with a trajectory of average birth size and subsequent slower BMI gain [e.g., relative risk ratio (RRR) per doubling in DDE concentration=1.19 (95% CI: 1.05, 1.35); RRR for PFNA=1.32 (95% CI: 1.05, 1.66)]. HCB and DDE exposure were also associated with higher probability of belonging to a trajectory of higher birth size and accelerated BMI gain. Results from the BWQS regression showed the mixture was positively associated with increased odds of belonging to a BMI trajectory of lower birth size and accelerated BMI gain (odds ratio per 1-quantile increase of the mixture=1.70; credible interval: 1.03, 2.61), with HCB, DDE, and PCBs contributing the most. This study provides evidence that prenatal EDC exposure, particularly persistent EDCs, may lead to BMI trajectories in childhood characterized by accelerated BMI gain. Given that accelerated growth is linked to a higher disease risk in later life, continued research is important. https://doi.org/10.1289/EHP11103.


The Association of Joint Pain and Dipeptidyl Peptidase-4 Inhibitor Use Among U.S. Adults With Type-2 Diabetes Mellitus.
The purpose of this study was to examine the association of dipeptidyl peptidase-4 inhibitors (DPP4Is) with joint pain in adults with type 2 diabetes mellitus (T2DM). This was a retrospective cross-sectional study design, pooling data from the 2012 and 2014 Medical Expenditure Panel Survey. The sample consisted of 4,559 T2DM patients older than 40 years with (n = 3,224) or without joint pain (n = 1,335). Chi-square test and logistic regression were used to describe association of DPP4I use with joint pain. Among adults with T2DM, 70.7% reported physician-diagnosed joint pain. There were no significant differences in DPP4I use among those with and without joint pain (7.8% vs 6.3%). Even after adjusting for other factors that may affect DPP4I use, there was not a statistically significant difference in DPP4I use among adults with T2DM with and without joint pain (AOR = 1.04; 95% CI, 0.74-1.48). Adults with public health insurance (AOR = 1.76; 95% CI, 1.01-3.04), with prescription insurance (AOR = 1.76; 95% CI, 1.02-3.03), and with a heart disease (AOR = 1.59; 95% CI, 1.18-2.15). DPP4I use was not affected by the presence of joint pain.


Morphological measurements on filamentous microorganisms by fully automatic image analysis.
Characterization of mycelial morphology is important for physiological and engineering studies of filamentous fermentations, and in the design and operation of such fermentations. Image analysis has been developed as a method for this characterization, and has been shown to be faster and generally more accurate than previous methods. A fully automatic system has been developed, in which speed is gained, but with loss of accuracy in some cases. The method has been tested on Streptomyces clavuligerus and Penicillium chrysogenum P1 batch fermentations. It has also been tested on a fed-batch Penicillium chrysogenum P2 fermentation, in which the medium contained solid ingredients. Fully automatic image analysis for morphological characterization of filamentous microorganisms is an important development which will make practical many engineering and physiological studies of such fermentations that have so far not been completely satisfactory.


The 1-Tosylpentan-3-one Protects against 6-Hydroxydopamine-Induced Neurotoxicity.
Previous studies have demonstrated that the marine compound austrasulfone, isolated from the soft coral Cladiella australis, exerts a neuroprotective effect. The intermediate product in the synthesis of austrasulfone, dihydroaustrasulfone alcohol, attenuates several inflammatory responses. The present study uses in vitro and in vivo methods to investigate the neuroprotective effect of dihydroaustrasulfone alcohol-modified 1-tosylpentan-3-one (1T3O). Results from in vitro experiments show that 1T3O effectively inhibits 6-hydroxydopamine-induced (6-OHDA-induced) activation of both p38 mitogen-activated protein kinase (MAPK) and caspase-3 in SH-SY5Y cells; and enhances nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression via phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling. Hoechst staining and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining results reveal that 1T3O significantly inhibits 6-OHDA-induced apoptosis. In addition, the addition of an Akt or HO-1 inhibitor decreases the protective effect of 1T3O. Thus, we hypothesize that the anti-apoptotic activity of 1T3O in neuronal cells is mediated through the regulation of the Akt and HO-1 signaling pathways. In vivo experiments show that 1T3O can reverse 6-OHDA-induced reduction in locomotor behavior ability in zebrafish larvae, and inhibit 6-OHDA-induced tumor necrosis factor-alpha (TNF-α) increase at the same time. According to our in vitro and in vivo results, we consider that 1T3O exerts its anti-apoptotic activities at SH-SY5Y cells after 6-OHDA challenges, probably via the regulation of anti-oxidative signaling pathways. Therefore, this compound may be a promising therapeutic agent for neurodegenerations.


Navigating and negotiating information and support: Experiences of first-time mothers.
To examine how first-time mothers in Nova Scotia identified and prioritised their own postpartum needs and where they went for information and support, inclusive of informal or formal programmes and services, social media, family and friends. The early postpartum period is an exciting, yet stressful life experience for first-time mothers. Mothers have often turned to families, friends and healthcare professionals for support and information; however, these social networks look differently today due to changes in institutional policies and postpartum healthcare practices, as well as the emergence of online resources and networks. There is currently limited understanding of how online resources have shifted mothers social networking practices and the degree to which programmes and resources are currently meeting the needs of mothers and families. Data were collected through focus group interviews in rural and urban Nova Scotia communities (n = 19) and online electronic interviews (n = 18). Data were analysed using feminist poststructuralism and discourse analysis to understand issues of inclusion and health equity for mothers and how relations of power were negotiated by first-time mothers in their search for support and information. Most participants were savvy as they critiqued, compared, navigated and negotiated advice and information from various sources, including health professionals, family, friends and online forums. However, they unanimously wanted face-to-face support with other mothers and healthcare professionals. Participants enacted their agency to critically analyse information and support to ensure it matched their own beliefs, values and practices. It is important to understand first-time mothers' practices and need for face-to-face support, as well as a need for further research with more diverse or marginalised demographics of mothers.


Epigenetic Mechanism of 5-HT/NE/DA Triple Reuptake Inhibitor on Adult Depression Susceptibility in Early Stress Mice.
Major depressive disorder (MDD) is a chronic, remitting and debilitating disease and the etiology of MDD is highly complicated that involves genetic and environmental interactions. Despite many pharmacotherapeutic options, many patients remain poorly treated and the development of effective treatments remains a high priority in the field. LPM570065 is a potent 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) triple reuptake inhibitor and both preclinical and clinical results demonstrate significant efficacy against MDD. This study extends previous findings to examine the effects and underlying mechanisms of LPM570065 on stress vulnerability using a "two-hit" stress mouse model. The "two-hit" stress model used adult mice that had experienced early life maternal separation (MS) stress for social defeat stress (SDS) and then they were evaluated in three behavioral assays: sucrose preference test, tail suspension test and forced swimming test. For the mechanistic studies, methylation-specific differentially expressed genes in mouse hippocampal tissue and ventral tegmental area (VTA) were analyzed by whole-genome transcriptome analysis along with next-generation bisulfite sequencing analysis, followed by RT-PCR and pyrophosphate sequencing to confirm gene expression and methylation. LPM570065 significantly reversed depressive-like behaviors in the mice in the sucrose preference test, the tail suspension test, and the forced swimming test. Morphologically, LPM570065 increased the density of dendritic spines in hippocampal CA1 neurons. Hypermethylation and downregulation of oxytocin receptor (Oxtr) in the hippocampal tissues along with increased protein expression of Dnmt1 and Dnmt3a in mice that experienced the "two-hit" stress compared to those that only experienced adulthood social defeat stress, and LPM570065 could reverse these changes. Combined, these results suggest that methylation specificity of the gene Oxtr in the hippocampus may play an important role in early life stress-induced susceptibility to depression and that the5-HT/NE/DA triple reuptake inhibitor LPM570065 may reduce depression susceptibility via the reversal of the methylation of the gene Oxtr.


Probiotics as a Tool to Biosynthesize Metallic Nanoparticles: Research Reports and Patents Survey.
Probiotics are the live microbes that exert beneficial effects on the health of the host cell, creating novel nanoformulations via probiotic bacteria, thus gaining tremendous momentum recently. The probiotic bacteria are being employed in synthesizing or more specifically biosynthesizing several nanoparticles like metallic as well as non-metallic nanoparticles. Biosynthesis of metallic nanoparticles is currently the focus of research nowadays due to several applications. Research inputs have led to the exploration of probiotic bacteria in biosynthesizing novel metallic nanoparticles. The present review explores various research and patent reports on metallic nanoparticles biosynthesized using probiotic bacteria. Through the sites, www.freepatentsonline.com and www.uspto.gov/patft, patents have been retrieved including US patents, EP and WIPO patents. Various reports and patents have revealed that probiotic bacteria can effectively produce metallic nanoparticles. These nanoparticles have found applications in cosmetics, pharmaceutics, medicine and biotechnology. Areas of future research can include the exploration of formulation aspects of metallic nanoparticles of iron, zinc, tellurium and synthesis of these particles using yeast, fungi, plant extracts and several biomaterials. Use of probiotic bacteria in synthesizing metallic nanoparticles is an effective biosynthetic approach. However, the technique needs wider exploration for newer metallic/nonmetallic/metalloid NPs for therapeutic applications.


Single-molecule fluorescence microscopy review: shedding new light on old problems.
Fluorescence microscopy is an invaluable tool in the biosciences, a genuine workhorse technique offering exceptional contrast in conjunction with high specificity of labelling with relatively minimal perturbation to biological samples compared with many competing biophysical techniques. Improvements in detector and dye technologies coupled to advances in image analysis methods have fuelled recent development towards single-molecule fluorescence microscopy, which can utilize light microscopy tools to enable the faithful detection and analysis of single fluorescent molecules used as reporter tags in biological samples. For example, the discovery of GFP, initiating the so-called 'green revolution', has pushed experimental tools in the biosciences to a completely new level of functional imaging of living samples, culminating in single fluorescent protein molecule detection. Today, fluorescence microscopy is an indispensable tool in single-molecule investigations, providing a high signal-to-noise ratio for visualization while still retaining the key features in the physiological context of native biological systems. In this review, we discuss some of the recent discoveries in the life sciences which have been enabled using single-molecule fluorescence microscopy, paying particular attention to the so-called 'super-resolution' fluorescence microscopy techniques in live cells, which are at the cutting-edge of these methods. In particular, how these tools can reveal new insights into long-standing puzzles in biology: old problems, which have been impossible to tackle using other more traditional tools until the emergence of new single-molecule fluorescence microscopy techniques.


Occlusal development between primary and mixed dentitions: a 5-year longitudinal study.
The purpose of this study was to evaluate the variations in occlusal relationships and the influence of dental arch type and primate spaces on the development of primary and mixed dentition, including molar-canine relationship and anterior crowding, over a 5-year period. One hundred twenty-eight children were examined in schools in Nova Friburgo, Rio de Janeiro, Brazil. There was a straight terminal plane development (ie, from mesial step to Class I and III, and from distal step to Class II). It was noted that a Class I canine relationship observed in the primary dentition was maintained in 91% of the cases during the mixed dentition presenting type 1 arch and primate spaces, whereas a Class III relationship developed into Class I. There was a modification in the negative overbite followed by mild to severe relationship and then by a moderate one in the mixed dentition, with a discrete increase in overjet compared to the primary dentition. It was verified a greater prevalence of Baume arch type I and primate spaces. As for the molar relation, there were no significant changes in the development from primary to mixed dentition, according to dental arch type and primate spaces. Lower arch crowding, however, was found in 29% of the children, even in the presence of arch type I and primate spaces. The occlusal relationships in the mixed dentition were influenced and followed a pattern determined by the primary dentition. Arch type I and primate spaces favor both development of Class I malocclusion and the absence of upper arch crowding, although they do not appear to affect the molar relationship and lower arch crowding.


Punicalagin, a PTP1B inhibitor, induces M2c phenotype polarization via up-regulation of HO-1 in murine macrophages.
Current data have shown that punicalagin (PUN), an ellagitannin isolated from pomegranate, possesses anti-inflammatory and anti-oxidant properties; however, its direct targets have not yet been reported. This is the first report that PTP1B serves as a direct target of PUN, with IC50 value of 1.04μM. Results from NPOI further showed that the Kon and Koff of PUN-PTP1B complex were 3.38e2M-1s-1 and 4.13e-3s-1, respectively. The active site Arg24 of PTP1B was identified as a key binding site of PUN by computation simulation and point mutation. Moreover, inhibition of PTP1B by PUN promoted an M2c-like macrophage polarization and enhanced anti-inflammatory cytokines expression, including IL-10 and M-CSF. Based on gene expression profile, we elucidated that PUN treatment significantly up-regulated 275 genes and down-regulated 1059 genes. M1-like macrophage marker genes, such as Tlr4, Irf1/2, Hmgb1, and Stat1 were down-regulated, while M2 marker genes, including Tmem171, Gpr35, Csf1, Il1rn, Cebpb, Fos, Vegfα, Slc11a1, and Bhlhe40 were up-regulated in PUN-treated macrophages. Hmox-1, a gene encoding HO-1 protein, was preferentially expressed with 16-fold change. Inhibition of HO-1 obviously restored PUN-induced M2 polarization and IL-10 secretion. In addition, phosphorylation of both Akt and STAT3 contributed to PUN-induced HO-1 expression. This study provided new insights into the mechanisms of PUN-mediated anti-inflammatory and anti-oxidant activities and provided new therapeutic strategies for inflammatory diseases.


Ethical Dilemmas at the Beginning and End of Life: A Needs-Based, Experience-Informed, Small-Group, Case-Based Curriculum for Pediatric Residents.
Pediatric residents are faced with ethical dilemmas in beginning- and end-of-life situations throughout their training. These situations are innately challenging, yet despite recommendations that residents receive training in ethics and end-of-life domains, they continue to report the need for additional training. To address these concerns, we developed an interactive and reflective palliative care and medical ethics curriculum including sessions focusing on ethical dilemmas at the beginning and end of life. This module includes a trio of case-based, small-group discussions on artificial nutrition and hydration, futility, and ethical considerations in neonatology. Content was developed based on a needs assessment, input from local experts, and previously published material. Trainees completed assessments of comfort and understanding before and after each session. The module was attended and assessed by an average of 27 trainees per session, including residents and medical students. Knowledge of ethical considerations improved after individual sessions, with 86% of trainees reporting understanding ethical considerations involved in the decision to withdraw or withhold medically provided nutrition and hydration and 67% of trainees reporting understanding the use of the term futility. Trainee comfort in providing counseling or recommendations regarding specific ethical issues demonstrated a trend toward improvement but did not reach statistical significance. We successfully implemented this innovative module, which increased trainees' comfort with end-of-life care and ethical conflicts. Future studies should focus on the trainees' ability to implement these skills in clinical practice.


How does environmental regulation affect carbon productivity? The role of green technology progress and pollution transfer.
This empirical study examines the impact of environmental regulations on carbon productivity under varying conditions using panel data from Chinese provinces from 2011 to 2019. Prior research has reported inconsistent results regarding the relationships between these variables. We developed a spatial Durbin model (SDM) and tested the non-linear effects of environmental regulation on carbon productivity from a spatial linkage perspective. The results demonstrate a U-shaped curve representing the local-neighborhood effect of environmental regulations on carbon productivity. This curve is further dissected into two components: the average direct effect (ADE) and the average indirect effect (AIE). Furthermore, the findings indicate that green technology progress and pollution transfer act as moderating factors in shaping the U-shaped curve. Green technological progress has steepened the U-shape curve, whereas pollution transfer has flattened it. Based on these findings, we propose three recommendations for the formulation of environmental regulation policies.


Maternal determinants of neonatal immune response to ovalbumin: effect of breast feeding on development of anti-ovalbumin antibody in the neonate.
Inbred Brown-Norway female rats were immunized intraperitoneally with ovalbumin (OVA) or sham-immunized 14 days before and 10 days after mating. In subsequent studies with OVA, babies fed by immunized mothers, regardless of whether they were born from immunized or sham-immunized mothers, showed suppression of IgG, IgM and IgE anti-OVA responses. In additional studies, these babies developed OX-8-positive but W3/25-negative phenotypic suppressor T-cells specific for anti-OVA antibody production. However, these regulatory cells did not react with OVA itself when tested for in vitro proliferative response to OVA. Subsequent immunization of the neonates with OVA appeared to abrogate suppression of IgG and IgM antibody responses. However, maternally induced suppression of IgE persisted and was not influenced by subsequent immunization.


Epigenetics and environment: a complex relationship.
The epigenomes of higher organisms constantly change over time. Many of these epigenetic changes are necessary to direct normal cellular development and differentiation in the developing organism. However, developmental abnormalities may occur in response to inappropriate epigenetic signaling that occurs secondarily to still poorly understood causes. In addition to genetic and stochastic influences on epigenetic processes, epigenetic variation can arise as a consequence of environmental factors. Here we review the effects of such environmental factors on the epigenomes of higher organisms. We discuss the possible impact of epigenetic changes on physiological and pathophysiological processes, depending in part on whether these changes occur during embryonic development or adulthood.


The prevalence of comorbid anxiety in schizophrenia, schizoaffective disorder and bipolar disorder.
The aim of this study to determine the prevalence of anxiety disorders in publically treated psychiatric inpatients with a DSM-IV diagnosis of schizophrenia, schizoaffective disorder or bipolar disorder. Using the Structured Clinical Interview for DSM-III-R (SCID), 100 consecutive inpatients with a psychotic disorder were examined for the presence or absence of an anxiety disorder. Questionnaire measures of phobias, obsessive-compulsive and general anxiety symptoms were also applied. The prevalences of social phobia (17%), obsessive-compulsive disorder (13%) and generalised anxiety disorder in schizophrenia were relatively high, as were prevalences of obsessive-compulsive (30%) and panic disorder (15%) in bipolar disorder. The proportion of subjects with an anxiety disorder (43-45%) was almost identical across the three psychoses, with some evidence of gender differences. Although self-ratings of overall psychiatric symptoms were significantly elevated in those with anxiety disorders, hospital admission rates were not. Almost none of those with anxiety disorders were being treated for them, primarily because the severity of the acute psychotic illness required full diagnostic and therapeutic attention. Patients were generally discharged as soon as their psychotic episode was resolved, with little recognition of the presence of an anxiety disorder. Given that anxiety disorders are relatively responsive to treatment, greater awareness of their comorbidity with psychosis should yield worthwhile clinical benefits.


Erythrocyte phospholipid molecular species and fatty acids of Down syndrome children compared with non-affected siblings.
The majority of children with Down syndrome (DS) develop Alzheimer's disease (AD) at an early age. Although long-chain n-3 fatty acids (FA) are protective of neurodegeneration, little is known about the FA status in DS. In the present study, we aimed to investigate whether children with DS presented altered plasma and erythrocyte membrane phospholipids (PL) FA composition, when compared with their non-affected siblings. Venous blood samples were analysed for plasma and erythrocyte membrane FA composition by TLC followed by GC techniques. Lipid molecular species were determined by electrospray ionisation/tandem MS (ESI-MS/MS). FA analysis measured by standard GC showed an increased concentration of MUFA and a decreased concentration of plasmalogens in major PL fractions, but there were no differences in the concentrations of arachidonic acid or DHA. However, as identified by ESI-MS/MS, children with DS had increased levels of the following erythrocyte PL molecular species: 16 : 0-16 : 0, 16 : 0-18 : 1 and 16 : 0-18 : 2n-6, with reduced levels of 16 : 0-20 : 4n-6 species. Children with DS presented significantly higher levels of MUFA in both plasma and erythrocyte membrane, as well as higher levels of saturated and monounsaturated molecular species. Of interest was the almost double proportion of 16 : 0-18 : 2n-6 and nearly half the proportion of 16 : 0-20 : 4n-6 of choline phosphoacylglycerol species in children with DS compared with their non-affected siblings. These significant differences were only revealed by ESI-MS/MS and were not observed in the GC analysis. Further investigations are needed to explore molecular mechanisms and to test the association between the pathophysiology of DS and the risk of AD.


Campylobacter-like organisms and Candida in peptic ulcers and similar lesions of the upper gastrointestinal tract: a study of 247 cases.
Campylobacter-like organisms were detected by light microscopy in association with 57 of 102 (56%) of gastric ulcers, all the gastric erosions associated with gastritis, three of five (60%) of gastric erosions without gastritis, five of 13 (39%) of mild superficial gastritis and two of 36 (6%) of normal gastric mucosa. They were also seen in four of 20 (20%) of duodenal ulcers, but not in duodenal erosions with duodenitis or normal duodenal biopsy specimens. They were seen in association with 12 of 64 (19%) of cases of Barrett's oesophagus. Moniliasis was seen in nine of 78 (12%) of the gastric ulcers in which campylobacter-like organisms were found, and the incidence of moniliasis was three of 15 (20%) in association with duodenal ulcers when ulcer debris was present in biopsy material, and in association with six of 25 (24%) of cases of Barrett's oesophagus. These findings do not support the hypothesis that campylobacter-like organisms cause inflammatory and ulcerative lesions of the upper gastrointestinal tract.


The radiologic demonstration of early changes in ulcerative colitis by double contrast technique.
The double contrast technique can be applied safely to the investigation of patients with suspected inflammatory bowel disease. The early changes of mucosal hyperemia and edema can be detected when the colon has been adequately cleansed. The extent and distribution of disease can be mapped with precision. This is of considerable importance in the differential diagnosis between ulcerative and granulomatous colitis and in the choice of appropriate treatment. Even in early stages of the disease there is a high correlation between the radiographic abnormalities and the endoscopic findings.


Acquired thermotolerance and heat shock proteins in thermophiles from the three phylogenetic domains.
Thermophilic organisms from each of the three phylogenetic domains (Bacteria, Archaea, and Eucarya) acquired thermotolerance after heat shock. Bacillus caldolyticus grown at 60 degrees C and heat shocked at 69 degrees C for 10 min showed thermotolerance at 74 degrees C, Sulfolobus shibatae grown at 70 degrees C and heat shocked at 88 degrees C for 60 min showed thermotolerance at 95 degrees C, and Thermomyces lanuginosus grown at 50 degrees C and heat shocked at 55 degrees C for 60 min showed thermotolerance at 58 degrees C. Determinations of protein synthesis during heat shock revealed differences in the dominant heat shock proteins for each species. For B. caldolyticus, a 70-kDa protein dominated while for S. shibatae, a 55-kDa protein dominated and for T. lanuginosus, 31- to 33-kDa proteins dominated. Reagents that disrupted normal protein synthesis during heat shock prevented the enhanced thermotolerance.


Intra-Household Decision-Making and their Effects on Women Dietary Diversity: Evidence from Ethiopia.
This paper attempts to analyze the status of women in household decision-making processes and their effects on dietary diversity in Ethiopia. The results indicate that men and women do not have equal decision-making authority within a household when it comes, particularly to decisions on food crop production, proportion of produced crop consumed at home and to be sold out in the market, and income generating activities. The results show variations in minimum dietary diversity for women across regions in Ethiopia. Therefore, more emphasis needed to empower women to improve their benefit from agricultural production and other income generating activities in Ethiopia.


A 5', 8-cyclo-2'-deoxypurine lesion induces trinucleotide repeat deletion via a unique lesion bypass by DNA polymerase β.
5',8-cyclo-2'-deoxypurines (cdPus) are common forms of oxidized DNA lesions resulting from endogenous and environmental oxidative stress such as ionizing radiation. The lesions can only be repaired by nucleotide excision repair with a low efficiency. This results in their accumulation in the genome that leads to stalling of the replication DNA polymerases and poor lesion bypass by translesion DNA polymerases. Trinucleotide repeats (TNRs) consist of tandem repeats of Gs and As and therefore are hotspots of cdPus. In this study, we provided the first evidence that both (5'R)- and (5'S)-5',8-cyclo-2'-deoxyadenosine (cdA) in a CAG repeat tract caused CTG repeat deletion exclusively during DNA lagging strand maturation and base excision repair. We found that a cdA induced the formation of a CAG loop in the template strand, which was skipped over by DNA polymerase β (pol β) lesion bypass synthesis. This subsequently resulted in the formation of a long flap that was efficiently cleaved by flap endonuclease 1, thereby leading to repeat deletion. Our study indicates that accumulation of cdPus in the human genome can lead to TNR instability via a unique lesion bypass by pol β.


[Rapamycin in the treatment of cardiac rhabdomyoma associated with tuberous sclerosis complex].
To assess the efficacy and safety of mammalian target of rapamycin (mTOR) inhibitor rapamycin in treatment of children with cardiac rhabdomyoma, associated with tuberous sclerosis complex (TSC). The clinical data of children with cardiac rhabdomyomas, who had received a diagnosis of TSC previously, were collected between September 2011 and November 2015 from Pediatric Department of the People's Liberation Army General Hospital.Patients in line with the inclusion criteria received long-term treatment with sirolimus.The starting doses of sirolimus was 1 mg/ (m(2)·d), and the plasma concentration was maintained at 5-10 μg/L.The size and number of cardiac rhabdomyomas were analyzed after treatment with rapamycin, and the efficacy and safety were assessed. The Wilcoxon test was used to analyze data. All the 51 children met the inclusion and exclusion criteria, including 30 males and 21 females.The median age for rapamycin treatment was 15.0 months (7.0-35.0 months). Tumors disappeared in 26 (51%) children, decreased by more than 50%(including 50%) in 15 (29%) children, decreased by less than 50% in 5 (12%) children, and had no change or progressed in 4 (8%) children.The number of tumors decreased by 77(72%). The median maximum diameter of tumor was 8.7 (5.9-11.3) mm before treatment, 0.0 (0.0-4.0) mm after treatment, and the median decrease of tumor size were 6.7 (3.9-10.0) mm (Z=-8.817, P<0.01). The median disappearance time was 3.26 (2.92-5.37) months.Among different age groups, after treatment by rapamycin, the rate of tumor's disappearance was 50% (12/24) in 0-1 years group.Tumors disappeared in 10 of 16 patients in >1-3 years group and in 4 of 11 patients in >3 years group.The rate of tumor's disappearance was the highest after 3 months of treatment as compared with 6 and 12 months of treatment.Ten children had adverse event that was related to rapamycin.Canker sore was reported in one child and dyslipidemia was reported in 9 children. Rapamycin is efficacious and well tolerate in treatment of cardiac rhabdomyomas associate with TSC, and lead to a reduction in tumor size and number, in addition, significantly shorten the duration of cardiac rhabdomyoma.


Research progress on photoelectrochemical sensors for contamination analysis in agricultural fields.
The establishment of rapid and efficient contamination detection methods in agricultural fields is of great significance for safeguarding agricultural production and human health, and for ensuring the healthy development of agricultural industries. As a booming analytical method, photoelectrochemical (PEC) sensors, which combine the advantages of electrochemical analysis and optical analysis, have received increasing research attention. Due to the complete separation of the excitation source (light) and the detection signal (current), the background signal of PEC sensors is greatly decreased, and their sensitivity is high. This review aims to cover the advances in PEC sensors for contamination analysis in agricultural fields over the past 5 years, including the analysis of heavy metals, antibiotics, pesticides, and toxins. The future prospects in this field are also discussed.


Immunological and structural conservation of mammalian skeletal muscle glycosylphosphatidylinositol-linked ADP-ribosyltransferases.
NAD:arginine ADP-ribosyltransferases catalyze the ADP-ribosylation of arginine residues in proteins. Coding region nucleic acid and deduced amino acid sequences of a human skeletal muscle ADP-ribosyltransferase cDNA were, respectively, 80.8% and 81.3% identical to those of the rabbit skeletal muscle transferase. A human transferase-specific cDNA probe detected major mRNA of 1.2 kb (mouse and rat), 3.0 kb (rabbit), 3.8 kb (monkey), and 5.7 kb (human) upon Northern analysis. Polyclonal anti-rabbit ADP-ribosyltransferase antibodies reacted with 36,000 M(r) proteins in partially purified transferase preparations from bovine, dog, and rabbit heart muscle and a 40,000 M(r) protein from human skeletal muscle. The human muscle ADP-ribosyltransferase cDNA, like the previously cloned rabbit muscle transferase, predicts predominantly hydrophobic amino- and carboxy-terminal amino acid sequences, which is characteristic of glycosylphosphatidylinositol (GPI)-anchored proteins. On immunoblots of partially purified rabbit and human skeletal muscle ADP-ribosyltransferases, anti-cross-reacting determinant antibodies detected at 36,000 and 40,000 M(r), respectively, phosphatidylinositol-specific, phospholipase C-sensitive, GPI-anchored proteins. These data are consistent with the conclusion that GPI-anchored skeletal and cardiac muscle ADP-ribosyltransferases are conserved across mammalian species.


Bleeding from peristomal varices: a complication of portal hypertension.
Peristomal varices are a recognised complication of stomas in the presence of portal hypertension. There has been a progression of treatment options described in the literature, including the transjugular intrahepatic portosystemic shunt (TIPS). The use of TIPS, a percutaneous procedure allowing connection between the portal and systemic circulations within the liver, is a well-recognised method of treating the complications of portal hypertension. This report presents a case of peristomal varices successfully treated with TIPS and subsequently reviews the literature relating to its management.


Inactivation and sublethal injury kinetics of Staphylococcus aureus in broth at low temperature storage.
Low temperatures are widely used to ensure food quality and safety. However, sublethally injured Staphylococcus aureus is an important microbiological safety concern in low temperature food. The objective of this study was to develop predictive inactivation kinetic models for the inactivation and sublethal injury of S. aureus in broth at different temperatures (4 to -18°C) and time points. S. aureus was diluted in tryptic soy broth plus 0.6% (wt/vol) yeast extract (TSBYE) to obtain approximately 10(8) CFU/ml and was stored separately at 4, -3, -11, and -18°C. After specific time points within 96 days, survival of S. aureus was determined on TSBYE and TSBYE agar plus 10% NaCl for enumeration of the total viable and noninjured cell numbers, respectively. Linear, Weibull, and modified Gompertz models were applied to determine survival curve regression. The combination of low temperature and time resulted in S. aureus inactivation, although the cells were able to survive in this sublethal state. Storage temperature was the critical parameter in survival of S. aureus. The modified Weibull model successfully described a second model of noninjured S. aureus cell survival at different low temperatures, whereas only the linear model was able to fit the total viable cells. The predictive model may be used to estimate the level of S. aureus contamination in food at low storage temperatures and times, and it provides new insight into the sublethally injured survival state of S. aureus in low temperature food.


One-Pot Microwave-Assisted Synthesis of Carbon Dots and in vivo and in vitro Antimicrobial Photodynamic Applications.
Carbon-based photosensitizers are more attractive than the other ones based on their low cost, high stability, broadband of light absorption, tunable emission spectra, high quantum yield, water solubility, high resistance to metabolic degradation, and selective delivery. These properties allow multiple applications in the field of biology and medicine. The present study evaluated in vitro and in vivo the antimicrobial photodynamic effect of a one-pot microwave produced C-DOTS based on citric acid. The in vitro assays assessed the effectiveness of illuminated C-DOTS (C-DOTS + light) against Staphylococcus aureus suspension and biofilm. The concentrations of 6.9 and 13.8 mg/mL of C-DOTS and light doses of 20 and 40 J/cm2 were able to reduce significantly the microorganisms. Based on these parameters and results, the in vivo experiments were conducted in mice, evaluating this treatment on wounds contaminated with S. aureus. The viability test showed that C-DOTS-mediated photodynamic inactivation reduced 104 log of the bacteria present on the skin lesions. These results, altogether, showed that antibacterial photodynamic therapy using C-DOTS is a promising and viable treatment for Gram-positive bacteria-infected wounds.