Evaluating Computational Shortcuts in Supercell-Based Phonon Calculations of Molecular Crystals: The Instructive Case of Naphthalene.
Phonons crucially impact a variety of properties of organic semiconductor materials. For instance, charge- and heat transport depend on low-frequency phonons, while for other properties, such as the free energy, especially high-frequency phonons count. For all these quantities one needs to know the entire phonon band structure, whose simulation becomes exceedingly expensive for more complex systems when using methods like dispersion-corrected density functional theory (DFT). Therefore, in the present contribution we evaluate the performance of more approximate methodologies, including density functional tight binding (DFTB) and a pool of force fields (FF) of varying complexity and sophistication. Beyond merely comparing phonon band structures, we also critically evaluate to what extent derived quantities, like temperature-dependent heat capacities, mean squared thermal displacements, and temperature-dependent free energies are impacted by shortcomings in the description of the phonon bands. As a benchmark system, we choose (deuterated) naphthalene, as the only organic semiconductor material for which to date experimental phonon band structures are available in the literature. Overall, the best performance among the approximate methodologies is observed for a system-specifically parametrized second-generation force field. Interestingly, in the low-frequency regime also force fields with a rather simplistic model for the bonding interactions (like the General Amber Force Field) perform rather well. As far as the tested DFTB parametrization is concerned, we obtain a significant underestimation of the unit-cell volume resulting in a pronounced overestimation of the phonon energies in the low-frequency region. This cannot be mended by relying on the DFT-calculated unit cell, since with this unit cell the DFTB phonon frequencies significantly underestimate the experiments.


Analgesia and functional outcome after total knee arthroplasty: periarticular infiltration vs continuous femoral nerve block.
Capacity to ambulate represents an important milestone in the recovery process after total knee arthroplasty (TKA). The purpose of this study was to determine the analgesic effect of two analgesic techniques and their impact on functional walking capacity as a measure of surgical recovery. Forty ASA II-III subjects undergoing TKA were enrolled in a randomized, double-blind, single-centre study receiving 48 h postoperative analgesia with either periarticular infiltration of local anaesthetic (Group I) or continuous femoral nerve block (Group F). Breakthrough pain relief was achieved with patient-controlled analgesia (PCA) morphine. The main outcome was postoperative morphine consumption. Early (postoperative days 1-3) and late (6 weeks) functional walking capacity (2 and 6 min walk tests, 2MWT and 6MWT, respectively), degree of physical activity (CHAMPS), health-related quality of life (SF-12), and clinical indicators of knee function (WOMAC, Knee Society evaluation, and range of motion) were measured. Patients in Group F used the PCA less (P=0.02) to achieve adequate analgesia. Postoperative 2MWT was similar in both groups (P=0.27). Six weeks after surgery, recovery of 6MWT, physical activity, and knee function were significantly improved in Group F (P<0.05). Preoperative walking capacity, physical activity and early total walking time were the independent predictors of early recovery. Distance and time spent walking were the predictors of functional walking exercise capacity at 6 weeks after surgery. Femoral block is associated with lower opioid consumption and a better recovery at 6 weeks than periarticular infiltration. Early postoperative activity measures (2MWT and walking time) were proved to be possible indicators of knee function recovery at 6 weeks after surgery.


Sample size for estimation of direct effects in path analysis of corn.
The objective of this study was to assess the sample size required for estimating the direct effects of explanatory variables on the grain yield of corn in the combinations formed by three types of hybrids x two harvests x nine scenarios of explanatory variables x two types of path analyses x four levels of accuracy. A total of 6340 plants were evaluated (361, 373, and 416 plants from single-, triple-, and double-cross hybrids in the 2008/2009 harvest, respectively, and 1777, 1693, and 1720 plants from single-, triple-, and double-cross hybrids in the 2009/2010 harvest, respectively). Eleven explanatory variables were measured in each plant: plant height, ear insertion height, ear weight, number of grain rows per ear, ear length and diameter, cob weight and diameter, 100-grain mass, number of grains per ear, grain length and, the main variable, grain yield. Thus, nine scenarios were planned (scenarios 1, 2, 3, 4, 5, 6, 7, 8, and 9 with 0, 1, 2, 3, 4, 5, 6, 7, and 8 explanatory variables excluded, respectively) and two types of path analyses conducted (traditional and ridge path analyses). The sample size required for estimating the direct effect of each explanatory variable on grain yield was assessed using resampling with replacement at four accuracy levels [95% confidence interval ranges (95%CI) of 0.15, 0.25, 0.35, and 0.45]. The use of the ninth scenario of path analysis is recommended regardless of hybrid and harvest given the smaller sample size required compared to the previous scenarios. To estimate direct effects with the maximum 95%CI of 0.25, 10 to 530 plants are required depending on the type of hybrid, harvest, scenario, type of path analyses, and explanatory variables. To estimate the direct effects in the ninth scenario with a maximum 95%CI of 0.25, 120 plants suffice regardless of the type of hybrid, harvest, or type of path analyses.


Effects and Moderators of a Short Theory of Mind Intervention for Children with Autism Spectrum Disorder: A Randomized Controlled Trial.
Limited perspective taking or "Theory of Mind" (ToM) abilities are a core deficit of autism, and many interventions are aimed to improve ToM abilities. In this study, we investigated the effectiveness of a ToM treatment for children with autism spectrum disorders (ASD) and, for the first time, the moderating roles of social interaction style (SIS) and disruptive behavior (DB), to determine which children are most likely to respond to this intervention. The trial protocol is registered at www.trialregister.nl, trial number 2327 and published before the data collection was finished (www.trialsjournal.com). Children with autism aged 7-12 years (n = 97) were randomized over a waitlist control or a treatment condition. Outcome measures included ToM and emotion understanding, parent and teacher questionnaires on children's social skills, ToM-related social behavior, and autistic traits. Six-month follow-up parent reported data were collected for the treatment group. The treatment had a positive effect on ToM understanding, parent-reported ToM behavior, and autistic traits, but not on parent or teacher-reported social behavior. Passive SIS was associated with diminished treatment effects on autistic traits, but DB was unrelated to outcomes. The ToM intervention improved conceptual social understanding and ToM-related behavior of children with ASD. However, broader application of learned skills to other domains of functioning was limited. Individual differences with regard to treatment response are discussed.


Utilization of insecticide treated nets among pregnant women in Enugu, South Eastern Nigeria.
The goal of roll back malaria partnership is to achieve universal coverage for all populations at risk using appropriate interventions for prevention and case management. The objective of this study is to determine the use of insecticide treated nets (ITNs) and other anti-vector measures among pregnant women in an area hyper-endemic for malaria. Questionnaires were administered to a cross-section of 832 consecutive pregnant women attending antenatal care in three hospitals in Enugu, Nigeria that have high client flow for maternity services. Data collected were analyzed using descriptive and inferential statistics by means of the Statistical Package for Social Sciences (SPSS) version 16. P-value of less than 0.05 was considered statistically significant. The mean age of the women was 33.2 ± 2.9 (range: 15-45) years. Three hundred and fifty nine (43.1%) women owned insecticide treated nets (ITNs), however 325(90.5%) slept under the nets during the index pregnancies; equivalent to 39.1% utilization rate among the 832 women studied. Out of the 325 (39.1%) women that used ITNs; 236 (28.4%) used it singly, while 89 (10.7%) used it in combination with other anti-vector measures. Educational status and social class of the women had strong association with the use of ITNs (P < 0.0001). Women who used ITNs were significantly less likely to have acute malaria, anaemia and babies with low birth weight than women who did not use ITNs (P < 0.05). The use of ITNs is poor among pregnant women in Enugu, but associated with favorable maternal and feto-neonatal outcome. Future measures to increase its use should consider improvement in educational level and social class of our women.


Hypoxia-induced activation of HIF-1: role of HIF-1alpha-Hsp90 interaction.
The protein chaperone heat shock protein 90 (Hsp90) is a major regulator of different transcription factors such as MyoD, a basic helix loop helix (bHLH) protein, and the bHLH-Per-aryl hydrocarbon nuclear translocator (ARNT)-Sim (PAS) factors Sim and aryl hydrocarbon receptor (Ahr). The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), involved in the response to hypoxia, also belongs to the bHLH-PAS family. This work was aimed to investigate the putative role of Hsp90 in HIF-1 activation by hypoxia. Using a EGFP-HIF-1alpha fusion protein, co-immunoprecipitation experiments evidenced that the chimeric protein expressed in COS-7 cells interacts with Hsp90 in normoxia but not in hypoxia. We also demonstrated that Hsp90 interacts with the bHLH-PAS domain of HIF-1alpha. Moreover, Hsp90 is not co-translocated with HIF-1alpha into the nucleus. At last, we showed that Hsp90 activity is essential for HIF-1 activation in hypoxia since it is inhibited in the presence of geldanamycin. These results indicate that Hsp90 is a major regulator in HIF-1alpha activation.


Pollutants increase song complexity and the volume of the brain area HVC in a songbird.
Environmental pollutants which alter endocrine function are now known to decrease vertebrate reproductive success. There is considerable evidence for endocrine disruption from aquatic ecosystems, but knowledge is lacking with regard to the interface between terrestrial and aquatic ecosystems. Here, we show for the first time that birds foraging on invertebrates contaminated with environmental pollutants, show marked changes in both brain and behaviour. We found that male European starlings (Sturnus vulgaris) exposed to environmentally relevant levels of synthetic and natural estrogen mimics developed longer and more complex songs compared to control males, a sexually selected trait important in attracting females for reproduction. Moreover, females preferred the song of males which had higher pollutant exposure, despite the fact that experimentally dosed males showed reduced immune function. We also show that the key brain area controlling male song complexity (HVC) is significantly enlarged in the contaminated birds. This is the first evidence that environmental pollutants not only affect, but paradoxically enhance a signal of male quality such as song. Our data suggest that female starlings would bias their choice towards exposed males, with possible consequences at the population level. As the starling is a migratory species, our results suggest that transglobal effects of pollutants on terrestrial vertebrate physiology and reproduction could occur in birds.


The effect of marker placement around the elbow on calculated elbow extension during bowling in cricket.
The elbow extension angle during bowling in cricket may be calculated from the positions of markers attached around the shoulder, elbow and wrist using an automated laboratory-based motion analysis system. The effects of two elbow-marker sets were compared. In the first, a pair of markers was placed medially and laterally close to the condyles while in the second a triad of markers was placed on the back of the upper arm close to the elbow. The root mean square (RMS) difference in elbow extension angle between the two methods at four key instants was 8° for 12 fast bowlers and 4° for 12 spin bowlers. When evaluated against video estimates of the elbow extension angle for the fast bowlers, the elbow extension angle calculated using the pair method had an RMS error of 2° while the triad method had an RMS error of 8°. The corresponding errors for the spin bowlers were 3° and 5°, respectively. It is thought that the greater errors associated with the triad is a consequence of soft tissue movement in this dynamic activity. This is consistent with the finding of greater error for the fast bowlers compared with the spin bowlers.


Therapeutic considerations of L-glutamine: a review of the literature.
The most abundant amino acid in the bloodstream, L-glutamine fulfills a number of biochemical needs. It operates as a nitrogen shuttle, taking up excess ammonia and forming urea. It can contribute to the production of other amino acids, glucose, nucleotides, protein, and glutathione. Glutamine is primarily formed and stored in skeletal muscle and lungs, and is the principal metabolic fuel for small intestine enterocytes, lymphocytes, macrophages, and fibroblasts. Supplemental use of glutamine, either in oral, enteral, or parenteral form, increases intestinal villous height, stimulates gut mucosal cellular proliferation, and maintains mucosal integrity. It also prevents intestinal hyperpermeability and bacterial translocation, which may be involved in sepsis and the development of multiple organ failure. L-glutamine use has been found to be of great importance in the treatment of trauma and surgery patients, and has been shown to decrease the incidence of infection in these patients. Cancer patients often develop muscle glutamine depletion, due to uptake by tumors and chronic protein catabolism. Glutamine may be helpful in offsetting this depletion; however, it may also stimulate the growth of some tumors. The use of glutamine with cancer chemotherapy and radiotherapy seems to prevent gut and oral toxic side-effects, and may even increase the effectiveness of some chemotherapy drugs.


The importance of coastal gorgonians in the blue carbon budget.
Terrestrial (trees, shrubs) and marine (seaweeds and seagrasses) organisms act as carbon (C) sinks, but the role of benthic suspension feeders in this regard has been largely neglected so far. Gorgonians are one of the most conspicuous inhabitants of marine animal forests (mainly composed of sessile filter feeders); their seston capture rates influence benthic-pelagic coupling processes and they act as C sinks immobilizing carbon in their long-living structures. Three gorgonian species (Paramuricea clavata, Eunicella singularis and Leptogorgia sarmentosa) were studied coupling data of population size structure, biomass and spatial distribution in a NW Mediterranean area (Cap de Creus, Spain) with feeding, respiration and growth rates. In the study area, we calculated that P. clavata sequestered 0.73 ± 0.71 g C m-2 year-1, E. singularis 0.73 ± 0.89 g C m-2 year-1 and L. sarmentosa 0.03 ± 0.02 g C m-2 year-1. To our knowledge, this is the first attempt to calculate the importance as C sinks of gorgonian species that we consider as a starting point to estimate the importance of marine animal forests in C sequestration, and to ensure appropriate management and protection especially in areas and at depths where they are concentrated.


A long trend of sexually transmitted diseases before and after the COVID-19 pandemic in China (2010-21).
The longer ongoing benefits of coronavirus disease 2019 (COVID-19) non-pharmaceutical interventions (NPIs) for sexually transmitted diseases (STDs) in China are still unclear. We aimed to explore the changes in five STDs (AIDS, hepatitis B, hepatitis C, gonorrhoea, and syphilis) before, during, and after the COVID-19 pandemic in mainland China, from 2010 to 2021. The number of the monthly reported cases of the five STDs were extracted from the website to construct the Joinpoint regression and autoregressive integrated moving average (ARIMA) models. Eight indicators reflecting NPIs were chosen from the COVID-19 Government Response Tracker system. The STDs and eight indicators were used to establish the Multivariable generalised linear model (GLM) to calculate the incidence rate ratios (IRRs). With the exception of hepatitis B, the other four STDs (AIDS, hepatitis C, gonorrhoea, and syphilis) had a positive average annual percent change over the past 12years. All the ARIMA models had passed the Ljung-Box test, and the predicted data fit well with the data from 2010 to 2019. All five STDs were significantly reduced in 2020 compared with 2019, with significant estimated IRRs ranging from 0.88 to 0.92. In the GLM, using data for the years 2020 (February-December) and 2021, the IRRs were not significant after adjusting for the eight indicators in multivariate analysis. Our study demonstrated that the incidence of the five STDs decreased rapidly during the COVID-19 pandemic in 2020. A recovery of STDs in 2021 was found to occur compared with that in 2020, but the rising trend disappeared after adjusting for the NPIs. Our study demonstrated that NPIs have an effect on STDs, but the relaxation of NPI usage might lead to a resurgence.


[Efficacy of remote gamma-therapy in patients with juvenile angiofibroma of the base of the skull].
The results of radiation therapy of 48 patients with juvenile nasopharyngeal angiofibroma were analysed. It was found that radiation therapy can produce 80% stable remissions in postoperative recurrence or unresectable tumor. The response did not depend on primary size of the tumor and was better in a total dose over 35 Gy and in children over 14 years of age. Long-term side effects were minimal and did not deteriorate quality of life.


Integrity of Organic Foods and Their Suppliers: Fraud Vulnerability Across Chains.
Organic foods are frequently targeted by fraudsters. Examination of underlying factors helps to reduce fraud vulnerability and to prevent fraud. In this study, the fraud vulnerability of five actors from each of four chains were examined using the SSAFE food fraud vulnerability assessment tool: the organic banana, egg, olive oil and pork supply chains. The organic chains appeared slightly less vulnerable than conventional chains due to fewer opportunities for fraud and the more adequate controls being present. On the other hand, organic chains were associated with enhanced vulnerability resulting from cultural and behavioral drivers. Generally, actors in the organic olive oil and pork chains were more vulnerable than those from the banana and egg chains. However, high risk actors were not limited to particular chains. Across the whole group of actors in organic chains, three groups in terms of cultural/behavioral drivers were distinguished: a low vulnerability group, a group facing more external threats and a group presenting fraud vulnerability in general and in particular from within their own company. Ethical business culture and criminal history scores of businesses correlated significantly. This implies that the climate in a company is an important factor to consider when estimating the exposure of businesses to food fraud.


Benefits of Exercise on Influenza or Pneumonia in Older Adults: A Systematic Review.
A coronavirus pandemic has recently become one of the greatest threats the world is facing. Older adults are under a high risk of infection because of weaker immune systems. Therefore, the purpose of this review is to summarize the recent scientific evidence that outlines the effects of exercise on influenza or pneumonia in older adults. An electronic literature search was conducted using the WEB OF SCIENCE, SCIENCEDIRECT and GOOGLE SCHOLAR databases using the following keywords, "Exercise," "Older adult," "Influenza," and "Pneumonia." Any randomized control trials, cross-sectional and observational studies that related to this topic were all included. Twenty studies met the eligibility criteria for this review. Thirteen randomized control trials investigated the effects of exercise on the immune responses to influenza or pneumonia vaccination: seven trials employed moderate aerobic exercise, three employed resistance exercise, and the remaining three used Asian martial arts or special home-based exercises. Five cross-sectional and two observational studies examined the associations between exercise/physical condition and influenza/pneumonia. Most of the current studies suggested that prolonged moderate aerobic exercise may help to reduce the risk of influenza-related infection and improve the immune responses to influenza or pneumonia vaccination in older adults. In addition, training in traditional Asian martial arts was also found to be beneficial. Future research should focus on the different effects of moderate and vigorous exercise on influenza-related diseases.


Transcriptional and Post-Translational Regulation of Junctional Adhesion Molecule-B (JAM-B) in Leukocytes under Inflammatory Stimuli.
Junctional adhesion molecules (JAMs; comprising JAM-A, -B and -C) act as receptors for viruses, mediate cell permeability, facilitate leukocyte migration during sterile and non-sterile inflammation and are important for the maintenance of epithelial barrier integrity. As such, they are implicated in the development of both communicable and non-communicable chronic diseases. Here, we investigated the expression and regulation of JAM-B in leukocytes under pathogen- and host-derived inflammatory stimuli using immunoassays, qPCR and pharmacological inhibitors of inflammatory signalling pathways. We show that JAM-B is expressed at both the mRNA and protein level in leukocytes. JAM-B protein is localised to the cytoplasm, Golgi apparatus and in the nucleus around ring-shaped structures. We also provide evidence that JAM-B nuclear localisation occurs via the classical importin-α/β pathway, which is likely mediated through JAM-B protein nuclear localisation signals (NLS) and export signals (NES). In addition, we provide evidence that under both pathogen- and host-derived inflammatory stimuli, JAM-B transcription is regulated via the NF-κB-dependent pathways, whereas at the post-translational level JAM-B is regulated by ubiquitin-proteosome pathways. Anaphase-promoting ubiquitin ligase complex (APC/C) and herpes simplex virus-associated ubiquitin-specific protease (HAUSP/USP) were identified as candidates for JAM-B ubiquitination and de-ubiquitination, respectively. The expression and regulation of JAM-B in leukocytes reported here is a novel observation and contrasts with previous reports. The data reported here suggest that JAM-B expression in leukocytes is under the control of common inflammatory pathways.


Proline iminopeptidase gene from Xanthomonas campestris pv. citri.
The pip gene coding for the proline iminopeptidase (Pip) of Xanthomonas campestris pv. citri was cloned in an Escherichia coli leuB strain using a selective medium containing the dipeptide D-Ala-L-Leu as the sole source of L-leucine. Nucleotide sequencing of this gene revealed a 939 bp open reading frame encoding a 312 amino acid protein (35 126 Da). The deduced amino acid sequence showed 47% identity with the Pip from Neisseria gonorrhoeae. A lacZ-pip fusion gene was overexpressed in E. coli under the control of the Plac promoter. The Pip of X. campestris hydrolysed L-prolyl-p-nitroanilide with the highest efficiency, but was also able to hydrolyse L-alanyl-p-nitroanilide and D-alanyl-p-nitroanilide. The molecular mass of Pip was found to be 35 kDa by SDS-PAGE and 120 kDa by gel filtration, suggesting that the active enzyme is a multimer.


Reduced membrane cholesterol limits pulmonary endothelial Ca2+ entry after chronic hypoxia.
Chronic hypoxia (CH)-induced pulmonary hypertension is associated with diminished production of endothelium-derived Ca2+-dependent vasodilators such as nitric oxide. Interestingly, ATP-induced endothelial Ca2+ entry as well as membrane cholesterol (Chol) are decreased in pulmonary arteries from CH rats (4 wk, barometric pressure = 380 Torr) compared with normoxic controls. Store-operated Ca2+ entry (SOCE) and depolarization-induced Ca2+ entry are major components of the response to ATP and are similarly decreased after CH. We hypothesized that membrane Chol facilitates both SOCE and depolarization-induced pulmonary endothelial Ca2+ entry and that CH attenuates these responses by decreasing membrane Chol. To test these hypotheses, we administered Chol or epicholesterol (Epichol) to acutely isolated pulmonary arterial endothelial cells (PAECs) from control and CH rats to either supplement or replace native Chol, respectively. The efficacy of membrane Chol manipulation was confirmed by filipin staining. Epichol greatly reduced ATP-induced Ca2+ influx in PAECs from control rats. Whereas Epichol similarly blunted endothelial SOCE in PAECs from both groups, Chol supplementation restored diminished SOCE in PAECs from CH rats while having no effect in controls. Similar effects of Chol manipulation on PAEC Ca2+ influx were observed in response to a depolarizing stimulus of KCl. Furthermore, KCl-induced Ca2+ entry was inhibited by the T-type Ca2+ channel antagonist mibefradil but not the L-type Ca2+ channel inhibitor diltiazem. We conclude that PAEC membrane Chol is required for ATP-induced Ca2+ entry and its two components, SOCE and depolarization-induced Ca2+ entry, and that reduced Ca2+ entry after CH may be due to loss of this key regulator.NEW & NOTEWORTHY This research is the first to examine the direct role of membrane cholesterol in regulating pulmonary endothelial agonist-induced Ca2+ entry and its components. The results provide a potential mechanism by which chronic hypoxia impairs pulmonary endothelial Ca2+ influx, which may contribute to pulmonary hypertension.


Roles for auxin, cytokinin, and strigolactone in regulating shoot branching.
Many processes have been described in the control of shoot branching. Apical dominance is defined as the control exerted by the shoot tip on the outgrowth of axillary buds, whereas correlative inhibition includes the suppression of growth by other growing buds or shoots. The level, signaling, and/or flow of the plant hormone auxin in stems and buds is thought to be involved in these processes. In addition, RAMOSUS (RMS) branching genes in pea (Pisum sativum) control the synthesis and perception of a long-distance inhibitory branching signal produced in the stem and roots, a strigolactone or product. Auxin treatment affects the expression of RMS genes, but it is unclear whether the RMS network can regulate branching independently of auxin. Here, we explore whether apical dominance and correlative inhibition show independent or additive effects in rms mutant plants. Bud outgrowth and branch lengths are enhanced in decapitated and stem-girdled rms mutants compared with intact control plants. This may relate to an RMS-independent induction of axillary bud outgrowth by these treatments. Correlative inhibition was also apparent in rms mutant plants, again indicating an RMS-independent component. Treatments giving reductions in RMS1 and RMS5 gene expression, auxin transport, and auxin level in the main stem were not always sufficient to promote bud outgrowth. We suggest that this may relate to a failure to induce the expression of cytokinin biosynthesis genes, which always correlated with bud outgrowth in our treatments. We present a new model that accounts for apical dominance, correlative inhibition, RMS gene action, and auxin and cytokinin and their interactions in controlling the progression of buds through different control points from dormancy to sustained growth.


Treatment of infantile spasms.
The treatment of infantile spasms is challenging, especially in the context of the following: (1) a severe phenotype with high morbidity and mortality; (2) the urgency of diagnosis and successful early response to therapy; and (3) the paucity of effective, safe, and well-tolerated therapies. Even after initially successful treatment, relapse risk is substantial and the most effective therapies pose considerable risk with long-term administration. In evaluating any treatment for infantile spasms, the key short-term outcome measure is freedom from both epileptic spasms and hypsarrhythmia. In contrast, the most important long-term outcomes are enduring seizure-freedom and measures of intellectual performance in later childhood and adulthood. First-line treatment options-namely hormonal therapy and vigabatrin-display moderate to high efficacy but also exhibit substantial side-effect burdens. Data on efficacy and safety of each class of therapy, as well as the combination of these therapies, are reviewed in detail. Specific hormonal therapies (adrenocorticotropic hormone and various corticosteroids) are contrasted. Those etiologies that prompt specific therapies are reviewed briefly, as are an array of second-line therapies supported by less-compelling data. The ketogenic diet is discussed in greater detail, with a focus on the limitations of numerous available studies that generally suggest that it is efficacious. Special discussion is allocated to cannabidiol-the investigational therapy that has received the most attention, and which is already in use in the form of various artisanal cannabis extracts. Finally, a treatment algorithm reflecting the concepts and controversies discussed in this review is presented.


Anti-COVID-19, Anti-Inflammatory, and Anti-Osteoarthritis Activities of Sesamin from Sesamum indicum L.
During the COVID-19 (coronavirus disease 2019) outbreak, many people were infected, and the symptoms may persist for several weeks or months for recovering patients. This is also known as "long COVID" and includes symptoms such as fatigue, joint pain, muscle pain, et cetera. The COVID-19 virus may trigger hyper-inflammation associated with cytokine levels in the body. COVID-19 can trigger inflammation in the joints, which can lead to osteoarthritis (OA), while long-term COVID-19 symptoms may lead to joint damage and other inflammation problems. According to several studies, sesame has potent anti-inflammatory properties due to its major constituent, sesamin. This study examined sesamin's anti-inflammatory, anti-osteoarthritis, and anti-COVID-19 effects. Moreover, in vivo and in vitro assays were used to determine sesamin's anti-inflammatory activity against the RAW264.7 and SW1353 cell lines. Sesamin had a dose-dependent effect (20 mg/kg) in a monoiodoacetic acid (MIA)-induced osteoarthritis rat model. Sesamin reduced paw swelling and joint discomfort. In addition, the findings indicated that sesamin suppressed the expression of iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2) in the RAW264.7 cell line within the concentration range of 6.25-50 μM. Furthermore, sesamin also had a suppressive effect on MMP (matrix metalloproteinase) expression in chondrocytes and the SW1353 cell line within the same concentration range of 6.25-50 μM. To examine the anti-viral activity, an in silico analysis was performed to evaluate sesamin's binding affinity with SARS-CoV-2 RdRp (severe acute respiratory syndrome coronavirus 2 RNA-dependent RNA polymerase) and human ACE2 (angiotensin-converting enzyme 2). Compared to the controls, sesamin exhibited strong binding affinities towards SARS-CoV-2 RdRp and human ACE2. Furthermore, sesamin had a higher binding affinity for the ACE2 target protein. This study suggests that sesamin shows potential anti-SARS-CoV-2 activity for drug development.


ReScribe: An Unrestrained Tool Combining Multiplex Recombineering and Minimal-PAM ScCas9 for Genome Recoding Pseudomonas putida.
Genome recoding enables incorporating new functions into the DNA of microorganisms. By reassigning codons to noncanonical amino acids, the generation of new-to-nature proteins offers countless opportunities for bioproduction and biocontainment in industrial chassis. A key bottleneck in genome recoding efforts, however, is the low efficiency of recombineering, which hinders large-scale applications at acceptable speed and cost. To relieve this bottleneck, we developed ReScribe, a highly optimized recombineering tool enhanced by CRISPR-Cas9-mediated counterselection built upon the minimal PAM 5'-NNG-3' of the Streptococcus canis Cas9 (ScCas9). As a proof of concept, we used ReScribe to generate a minimally recoded strain of the industrial chassis Pseudomonas putida by replacing TAG stop codons (functioning as PAMs) of essential metabolic genes with the synonymous TAA. We showed that ReScribe enables nearly 100% engineering efficiency of multiple loci in P. putida, opening promising avenues for genome editing and applications thereof in this bacterium and beyond.


Synchrotron microbeam irradiation induces neutrophil infiltration, thrombocyte attachment and selective vascular damage in vivo.
Our goal was the visualizing the vascular damage and acute inflammatory response to micro- and minibeam irradiation in vivo. Microbeam (MRT) and minibeam radiation therapies (MBRT) are tumor treatment approaches of potential clinical relevance, both consisting of parallel X-ray beams and allowing the delivery of thousands of Grays within tumors. We compared the effects of microbeams (25-100 μm wide) and minibeams (200-800 μm wide) on vasculature, inflammation and surrounding tissue changes during zebrafish caudal fin regeneration in vivo. Microbeam irradiation triggered an acute inflammatory response restricted to the regenerating tissue. Six hours post irradiation (6 hpi), it was infiltrated by neutrophils and fli1a(+) thrombocytes adhered to the cell wall locally in the beam path. The mature tissue was not affected by microbeam irradiation. In contrast, minibeam irradiation efficiently damaged the immature tissue at 6 hpi and damaged both the mature and immature tissue at 48 hpi. We demonstrate that vascular damage, inflammatory processes and cellular toxicity depend on the beam width and the stage of tissue maturation. Minibeam irradiation did not differentiate between mature and immature tissue. In contrast, all irradiation-induced effects of the microbeams were restricted to the rapidly growing immature tissue, indicating that microbeam irradiation could be a promising tumor treatment tool.


Environmental conditions that influence toxin biosynthesis in cyanobacteria.
Over the past 15 years, the genetic basis for production of many cyanobacterial bioactive compounds has been described. This knowledge has enabled investigations into the environmental factors that regulate the production of these toxins at the molecular level. Such molecular or systems level studies are also likely to reveal the physiological role of the toxin and contribute to effective water resource management. This review focuses on the environmental regulation of some of the most relevant cyanotoxins, namely the microcystins, nodularin, cylindrospermopsin, saxitoxins, anatoxins and jamaicamides.


Association between Low Urban Neighborhood Greenness and Hypertensive Disorders of Pregnancy.
Urban neighborhood greenness is associated with greater cardiovascular health in the general population, and with better pregnancy and neonatal outcomes. Hypertension in pregnancy is a leading cause of maternal mortality and long-term cardiovascular morbidity and mortality in women. We sought to examine the association between greenness and hypertensive disorders of pregnancy. This study is a secondary analysis of a prospective cohort study of 1,943 women who received prenatal care from December 2013 to December 2016 at a single, urban, and tertiary academic medical center in Philadelphia, PA. Greenness measure was quantified via residential tree canopy cover within circumferential buffers of 100- and 500-meter radii around participants' homes. Associations between greenness and hypertensive disorders of pregnancy (defined as gestational hypertension or preeclampsia) were estimated by using multilevel logistic regression accounting for maternal sociodemographic information (race-ethnicity, insurance status, and age) medical history (diabetes, body mass index, smoking history, and parity), neighborhood deprivation index, and including 1,225 Philadelphia residents for whom key exposure and outcome data were available. At baseline, the participants' mean (SD) age was 27.5 (5.9) years, (range: 14-44 years). The majority of participants were non-Hispanic Black (857, 70.2%). Participants with less residential tree canopy cover were significantly more likely to have hypertensive disorders of pregnancy. The multivariable-adjusted odds ratio of hypertensive disorders of pregnancy among participants with less than 10% compared with those with greater than 30% tree canopy cover was 2.14 (95% confidence interval [CI]: 1.11-4.15) within 100-meter buffer. In our cohort, greenness was associated with lower hypertensive disorders of pregnancy odds. Our findings add to evidence that greenness may confer health benefits and warrant further investigations in identifying whether there is a causal pathway through which greenness may be protective against hypertensive disorders of pregnancy. · Low residential tree canopy is associated with increased risk of hypertensive disorders of pregnancy. · 100-meter buffers are most sensitive in identifying associations between tree canopy and HDP risk. · The role of greenness against hypertensive disorders of pregnancy should be further studied experimentally.


Hepatic glycogen in humans. I. Direct formation after oral and intravenous glucose or after a 24-h fast.
The formation of hepatic glycogen by the direct pathway is assessed in humans 1) after a 12-h fast and oral loading (100 g) or 2) intravenous infusion (90 g) and 3) after a 24-h fast and the same oral glucose load. The methodology used is based on the double tracer method. [3-3H]glucose is infused at a constant rate for the determination of the metabolic clearance of glucose. [1-14C]glucose is administered with the glucose load. One hour after absorption or the intravenous glucose infusion is terminated, a glucagon infusion is initiated to mobilize the glycogen labeled with [1-14C]glucose and formed during the absorptive period. At this time a third tracer, [6-3H]glucose, is administered to measure glucose clearance. It was found that after the 12-h fast and oral glucose loading 7.2 +/- 1.1 g of hepatic glycogen appears to be formed directly from glucose compared with 8.4 +/- 1.0 g after the same load and a 24-h fast and 8.5 +/- 0.4 g after a 12-h fast and an equivalent intravenous glucose infusion. When the amount of label ([14C]glucose) mobilized that was not corrected for metabolic recycling was calculated, the data suggested that the amount of glycogen formed by gluconeogenic pathways was probably at least equal to that formed by direct uptake. It was also approximately 60% greater after a 24-h fast. It can be concluded that the amount of hepatic glycogen formed directly from glucose during glucose loading is not significantly altered by the route of entry or the extension of the fasting period to 24 h. The data suggest, however, that gluconeogenetic formation of glycogen increases with fasting.


Endosidin1 defines a compartment involved in endocytosis of the brassinosteroid receptor BRI1 and the auxin transporters PIN2 and AUX1.
Although it is known that proteins are delivered to and recycled from the plasma membrane (PM) via endosomes, the nature of the compartments and pathways responsible for cargo and vesicle sorting and cellular signaling is poorly understood. To define and dissect specific recycling pathways, chemical effectors of proteins involved in vesicle trafficking, especially through endosomes, would be invaluable. Thus, we identified chemicals affecting essential steps in PM/endosome trafficking, using the intensely localized PM transport at the tips of germinating pollen tubes. The basic mechanisms of this localized growth are likely similar to those of non-tip growing cells in seedlings. The compound endosidin 1 (ES1) interfered selectively with endocytosis in seedlings, providing a unique tool to dissect recycling pathways. ES1 treatment induced the rapid agglomeration of the auxin translocators PIN2 and AUX1 and the brassinosteroid receptor BRI1 into distinct endomembrane compartments termed "endosidin bodies"; however, the markers PIN1, PIN7, and other PM proteins were unaffected. Endosidin bodies were defined by the syntaxin SYP61 and the V-ATPase subunit VHA-a1, two trans-Golgi network (TGN)/endosomal proteins. Interestingly, brassinosteroid (BR)-induced gene expression was inhibited by ES1 and treated seedlings displayed a brassinolide (BL)-insensitive phenotype similar to a bri1 loss-of-function mutant. No effect was detected in auxin signaling. Thus, PIN2, AUX1, and BRI1 use interactive pathways involving an early SYP61/VHA-a1 endosomal compartment.


Survey of Hospital Employees' Personal Preparedness and Willingness to Work Following a Disaster.
Little is known about the personal readiness of hospital staff for disasters. As many as 30% of hospital staff say that they plan not to report for work during a large-scale disaster. We sought to understand the personal disaster preparedness for hospital staff. Surveys were distributed to the staff of a large academic tertiary-care hospital by either a paper-based version distributed through the departmental safety coordinators or a Web-based version distributed through employee e-mail services, depending on employee familiarity with and access to computer services. Surveys assessed the demographic variables and characteristics of personal readiness for disaster. Of the individuals who accessed the survey, 1334 (95.9%) enrolled in it. Women made up 75% of the respondents, with a mean age of 43 years. Respondents had worked at the hospital an average of 9 years, with the majority (90%) being full-time employees. Most households (93%) reported ≤4 members, 6% supported a person with special medical needs, and 17% were headed by a single parent. A small number (24%) of respondents reported an established meeting place for reuniting households during a disaster. Many reported stockpiling a 3-day supply of food (86%) and a 3-day supply of water (51%). Eighteen percent of respondents were not aware of workplace evacuation plans. Most respondents were willing to report to work for natural disasters (eg, tornado, snowstorm; all categories >65%), but fewer respondents were willing to report during events such as an influenza epidemic (54%), a biological outbreak (41%), a chemical exposure, (40%), or a radiation exposure (39%). Multivariate analysis revealed being female, having a child in the household younger than 6 years old, and having a child in school lowered the likelihood of being willing to report to work in two or more event types, whereas pet ownership, being a clinical healthcare worker, and being familiar with the work emergency plan increased the likelihood. Despite being employed at the same facility for a prolonged period, employees reported being willing to report for work at a low rate in a variety of disasters. Subjects reported suboptimal personal preparedness for disaster, which may further limit the number of staff who will report for work. Hospitals should promote personal disaster preparedness for staff and explore staffing models with an understanding of reduced staff availability during disasters.


Psychiatric disorders, depression and quality of life in patients with psychogenic non-epileptic seizures and drug resistant epilepsy living in Argentina.
Psychiatric disorders are frequently found in both patients with PNES and DRE, making the differential diagnosis even more complex. The aim of this study was to analyze and compare psychiatric aspects and the quality of life in patients with psychogenic non-epileptic seizures (PNES) and drug resistant epilepsy (DRE). Patients admitted to video-electroencephalograpy (VEEG) unit with confirmed PNES and DRE were included. Demographical characteristics, psychiatric diagnosis according to SCID I and II of DSM IV, pharmacological treatment, general functioning measured with GAF (Global assessment of functionality), quality of life (QoL) using QlesQSF (Quality of Life Enjoyment and Satisfaction Questionnaire Short Form) and depression severity using BDI II (Beck depression inventory), were compared between the groups. Non-parametric tests, chi square test, and logistic regression were used for statistical analysis. 148 patients consecutively admitted to VEEG were included (DRE n = 97; PNES n = 51). Somatization disorder (RR: 13.02, 95% CI: 1.23-137.39, p = 0.03) and a history of trauma (RR: 8.66, 95% CI: 3.21-23.31, p = 0.001) were associated with PNES. The QlesQ score and the GAF score were lower with a higher prevalence of suicide attempts in the PNES group (p < 0.01). A negative correlation was observed between the severity of depression and the quality of life (DRE r = - 0.28, p = 0.013; PNES r = - 0.59, p = 0.001). Higher psychiatric comorbidity with poorer QoL were found in PNES patients compared to DRE. However, depression comorbidity negatively affected the QoL in both groups. Future studies based on illness perception will be orientated to complete this analysis.


Drug Combinations with HDAC Inhibitors in Antitumor Therapy.
The treatment of tumor cells with HDAC inhibitors (HDACi) induces a range of effects including apoptosis, cell cycle arrest, differentiation and senescence, modulation of immune response, and altered angiogenesis. The single-agent activities of several HDACi have been tested in preclinical and clinical studies and are currently the subject of ongoing clinical trials. Although HDACi have been shown to be effective as a single agent against a defined subset of hematological tumors, less convincing results have been found in the treatment of solid tumors. Since current clinical trials of single-agent HDACi showed limited efficacy, in this review we focus on drug combinations including HDACi with conventional chemotherapeutic agents and novel targeted agents. Particular emphasis has been devoted to combinations effective in solid tumors and to combinations between HDACi and immunotherapies. An outline of novel combination strategies, including a new generation of more potent and specific HDACi (e.g., compounds with adamantine and noradamantane as scaffolds) as well as chemical hybrid molecules, has been provided. The paradoxical role of HDACs as tumor suppressors in developing tumors and as therapeutic targets in established neoplasms has also been considered.


Are there any remarkable effects of prenatal exposure to food colourings on neurobehaviour and learning process in rat offspring?
Artificial food colourings and additives (AFCAs) have long been discussed to have adverse effects on cognition and behaviour in children. In this study, our aim was to assess the probable side effects of prenatal exposure to colouring food additives on neurobehaviour and spatial learning process. We administered 'no observable adverse effect levels' (NOAELs) of common used AFCAs as a mixture (erythrosine, Ponceau 4R, Allura Red AC, Sunset yellow FCF, tartrazine, Amaranth, Brilliant Blue, Azorubine and Indigotine) to female rats before and during gestation and tested their effects on spatial working memory and behaviour in their offspring. Effects of AFCAs on spatial working memory were evaluated by Morris water maze, behavioural and locomotor effects by open-field and forced-swim tests. Prenatal exposure to commonly used AFCAs had no adverse effects on spatial working memory; however, assessment of interaction of sex and AFCAs on 'latency to locate the visible platform', which was used as a measure of motivation, showed a significant interaction (P < 0.05) on female rats. In addition, AFCAs caused an increase in anxiolytic like effect in the open-field test (P < 0.05) and an increase in mobility time (P < 0.05) in the forced-swim test. We also detected a significant interaction of sex and AFCAs on forced-swim test parameters (P < 0.05). These findings indicated that prenatal exposure to NOAELs of AFCAs resulted in implicit adverse effects that caused an increase in motility and a decrease in motivation and anxiety in offspring in sex-related manner.


Optimizing test procedures for estimating daily methane and carbon dioxide emissions in cattle using short-term breath measures.
Respiration chambers are considered the reference method for quantifying the daily CH production rate (MPR) and CO production rate (CPR) of cattle; however, they are expensive, labor intensive, cannot be used in the production environment, and can be used to assess only a limited number of animals. Alternative methods are now available, including those that provide multiple short-term measures of CH and CO, such as the GreenFeed Emission Monitoring (GEM) system. This study was conducted to provide information for optimizing test procedures for estimating MPR and CPR of cattle from multiple short-term CH and CO records. Data on 495 Angus steers on a 70-d ad libitum feedlot diet with 46,657 CH and CO records and on 121 Angus heifers on a 15-d ad libitum roughage diet with 7,927 CH and CO records were used. Mean (SD) age and BW were 554 d (SD 92) and 506 kg (SD 73), respectively, for the steers and 372 d (SD 28) and 348 kg (SD 37), respectively, for the heifers. The 2 data sets were analyzed separately but using the same procedures to examine the reduction in variance as more records are added and to evaluate the level of precision with 2 vs. 3 min as the minimum GEM visit duration for a valid record. The moving averages procedure as well as the repeated measures procedure were used to calculate variances for both CH and CO, starting with 5 records and progressively increasing to a maximum of 80 records. For both CH and CO and in both data sets, there was a sharp reduction in the variances obtained by both procedures as more records were added. However, there was no substantial reduction in the variance after 30 records had been added. Inclusion of records with a minimum of 2-min GEM visit duration resulted in reduction in precision relative to a minimum of 3 min, as indicated by significantly ( < 0.05) more heterogeneous variances for all cases except CH4 in steers. In addition, more records were required to achieve the same level of precision relative to data with minimum GEM visit durations of 3 min. For example, in the steers, 72% reduction in initial variance was achieved with 30 records for both CH and CO when minimum GEM visit duration was 3 min, relative to 45 records when data with a minimum visit duration of 2 min were included. It is concluded from this study that when using records of multiple short-term breath measures of CH or CO for the computation of an animal's MPR or CPR, a minimum of 30 records, each record obtained from a minimum GEM visit duration of 3 min, are required.


High-dose enoxaparin in the treatment of abdominal angiostrongyliasis in Swiss mice.
Abdominal angiostrongyliasis (AA) is caused by Angiostrongylus costaricensis, which inhabits mesenteric arteries. There is no drug treatment for AA, and since intestinal infarction due to thrombi is one of the main complications of the disease, the use of anticoagulants may be a treatment option. Thus, we aimed to assess the effect of high doses of enoxaparin on the prevention of ischaemic intestinal lesions and on the survival of mice infected with A. costaricensis. Twenty-four mice were infected with L3 of A. costaricensis and divided equally into two groups: Group 1, control treated with placebo, and Group 2, treated daily with enoxaparin (2.5 mg/kg) for 50 days. All mice were subjected to necropsy and histological analysis. The results from gross and microscopic assessments showed no variation in the prevalence of lesions between the groups. An analysis was also performed among survivors and non-survivors, showing that animals that died often presented lesions, such as granulation tissue in the serosa, and intestinal infarction and adhesion. The mortality rate did not vary between the enoxaparin-treated and control groups. Thus, we showed that high doses of enoxaparin have no protective effect against AA, as the survival rates and lesions of mice did not vary between the treated and control groups. Considering that the use of prophylactic doses was also shown to be ineffective in a previous study, we do not recommend the use of enoxaparin for AA treatment.


Genome Sequences of Community Carriage Strains of Staphylococcus aureus from Yuma, Arizona.
Staphylococcus aureus exists as a pathogen and commensal. Individuals with asymptomatic carriage serve as a reservoir for transmission and are at increased risk of infecting themselves. In order to characterize the genomic diversity of S. aureus circulating in the community, we sequenced 166 genomes collected from individuals in Yuma, AZ.


Human activities recognition with RGB-Depth camera using HMM.
Fall detection remains today an open issue for improving elderly people security. It is all the more pertinent today when more and more elderly people stay longer and longer at home. In this paper, we propose a method to detect fall using a system made up of RGB-Depth cameras. The major benefit of our approach is its low cost and the fact that the system is easy to distribute and install. In few words, the method is based on the detection in real time of the center of mass of any mobile object or person accurately determining its position in the 3D space and its velocity. We demonstrate in this paper that this information is adequate and robust enough for labeling the activity of a person among 8 possible situations. An evaluation has been conducted within a real smart environment with 26 subjects which were performing any of the eight activities (sitting, walking, going up, squatting, lying on a couch, falling, bending and lying down). Seven out of these eight activities were correctly detected among which falling which was detected without false positives.


Is over-use of proton pump inhibitors fuelling the current epidemic of Clostridium difficile-associated diarrhoea?
Many developed countries have seen an increase in cases of Clostridium difficile-associated diarrhoea (CDAD) in recent years. This has occurred despite heightened awareness of the risks of broad-spectrum antibiotics, overall reduction in antibiotic use and increased focus on hospital hygiene. Some of the increase is due to the introduction of new hypervirulent strains, but it predates the description of these. The epidemic coincides with increased use of proton pump inhibitors (PPIs), much of which is inappropriate according to UK and other national guidelines. Gastric acid is a key host defence against other gastrointestinal infections and epidemiological and animal studies have demonstrated a positive association between incident CDAD and PPI use. An association with recurrence of CDAD after initially successful treatment has also been found. Vegetative C. difficile cells are rapidly killed at normal gastric pH, but survive at the pH found in patients taking PPI. It has recently been shown that vegetative organisms survive long enough on moist surfaces for transmission between patients to occur. We conclude that restricting PPI use to patients with an appropriate indication would reduce unnecessary expenditure on these agents, and might be an additional means of controlling the current epidemic of CDAD.


S100A7 (Psoriasin), highly expressed in ductal carcinoma in situ (DCIS), is regulated by IFN-gamma in mammary epithelial cells.
The aim of the present work was to explore signal transduction pathways used in the regulation of S100A7 (psoriasin). Members of the S100 gene family participate in many important cellular functions. Psoriasin, S100A8 (calgranulin A) and S100A9 (calgranulin B) are expressed in ductal carcinoma in situ (DCIS), as well as in the hyperproliferative skin disease, psoriasis. In the latter condition, a disturbance in the STAT pathway has recently been reported. This pathway is implicated in the regulation of IFN-gamma, widely recognized as a key cytokine in psoriasis. IFN-gamma also exerts anti-tumor action in a number of tumor cell types, including breast cancer. We therefore examined the effect of IFN-gamma and STAT-signaling on the psoriasin expression. We established a TAC2 mouse mammary epithelial cell line with tetracycline-inducible psoriasin expression (Tet-Off). Viability in cell culture was estimated using MTS assay. Protein and gene expression were evaluated by Western blotting and quantitative real-time PCR. Statistical analyses were assessed using a one-tailed, paired t-test. We report the downregulation of psoriasin by IFN-gamma in the MDA-MB-468 breast cancer cell line, as well as the downregulation of psoriasin induced by anoikis in cell lines derived from different epithelial tissues. In contrast, IFN-gamma had no suppressive effect on calgranulin A or calgranulin B. IFN-gamma is an important activator of the STAT1 pathway and we confirmed an active signaling pathway in the cell lines that responded to IFN-gamma treatment. In contrast, in the SUM190 breast carcinoma cell line, IFN-gamma did not suppress the expression of endogenous psoriasin. Moreover, a reduced phosphorylation of the STAT1 protein was observed. We showed that IFN-gamma treatment and the inhibition of the transcription factor NFkappaB had a synergistic effect on psoriasin levels. Finally, in TAC2 cells with tetracycline-induced psoriasin expression, we observed the increased viability of psoriasin-expressing cells after IFN-gamma treatment. Our data support the possibility that psoriasin expression is transcriptionally suppressed by IFN-gamma and that this effect is likely to be mediated by the activation of the STAT1 signaling pathway. The increased viability of psoriasin-expressing cells after IFN-gamma exposure suggests that psoriasin expression leads to the development of an apoptosis-resistant phenotype.


[Epidemiologic parameters of mentally ill patients subjected to mandatory treatment].
Criminally insanes form a special group of mentally ill patients. This paper investigated some psychiatric, criminological and social aspects of the above mentioned group of patients. The author summarized the data of 114 patients whom he treated in the Forensic Mental Institute at least for two months between 1st February 1997 and 31th January 2002. And these data of mandatory treated patients were compared with that of offenders being sentenced because of a violent crime. The reason of why the majority of criminally insanes ran counter to the law was that they committed or attempted homicide, while violent offenders rather committed rowdyism, bodily injury and robbery. Concerning the victims of crimes the subgroups of male and female mandatory treated insanes showed similarity to the groups of male and female offenders committed violent crime, respectively. Namely males committed crime against their non-family members, while in the majority of cases females attacked their family members. The pecularities of mandatory treated insanes are the following. The majority of those were single and had been treated in a psychiatric department before mandatory treatment started, but only the minority of those attempted suicide. It was not a negligible subgroup of criminal insanes whose illness was diagnosed after they had committed the crime. The question emerges whether in these cases a latent development of disease or an initial delict should be taken into consideration. The initiation of a national, comparative survey is necessary, which on the one hand would help in psychiatric prevention, on the other hand the scientific investigation of criminalization of mentally ill patients would promote the elimination of prejudice saying that mentally ill patients commit violent crimes more frequently than their normal counterparts.


Late-life Onset Mania After Varenicline Use: A Case Report.
Late-life onset manic attacks generally occur secondary to general medical conditions or drug use. Varenicline is an α4β2 nicotinic acetylcholine receptor partial agonist, used for the cessation of smoking. In this case report, we present a 67-year-old male patient with a new-onset manic episode following varenicline treatment. The patient's manic symptoms started on the seventh day of varenicline treatment. His symptoms started on the 7th day of treatment. He was admitted to the psychiatric outpatient clinic since his symptoms did not improve despite discontinuing varenicline treatment. In the initial mental status examination, he scored 35/60 on the Young Mania Rating Scale (YMRS). On the twenty-fifth day of the hospitalization, the patient was discharged since his YMRS score improved (5/60). Varenicline may cause manic episodes in patients with bipolar disorder and in healthy individuals. An increasing number of serious psychiatric disorders are being reported due to varenicline treatment. Mental state examination before and during varenicline treatment seems necessary.


Effect of digitoxin on vaginal epithelial differentiation in the Balb/c mouse.
Vaginal epithelial differentiation (VED) in the mouse and the human is the replacement of columnar by squamous epithelium in the vagina. This occurs in humans in late first and second trimesters of pregnancy and in mice after birth. In both diethylstilbestrol (DES) exposure during the process is associated with persistence of columnar epithelium and later reproductive tract tumor. Cardiac glycosides are estrogenic in both species. The concern: could cardiac glycosides produce similar effects to those seen after DES? Digitoxin was administered to Balb/c neonates at increasing doses. VED occurred by 10 days in three low-dose groups. Cardiotoxic mortality precluded study at higher doses. Therefore digitoxin did not affect VED.


A deletion in the simian virus 40 large T antigen impairs lytic replication in monkey cells in vivo but enhances DNA replication in vitro: new complementation function of T antigen.
We describe a new complementation function within the simian virus 40 (SV40) A gene. This function is required for viral DNA replication and virus production in vivo but, surprisingly, does not affect any of the intrinsic enzymatic functions of T antigen directly required for in vitro DNA replication. Other well-characterized SV40 T-antigen mutants, whether expressed stably from integrated genomes or in cotransfection experiments, complement these mutants for in vivo DNA replication and plaque formation. These new SV40 mutants were isolated and cloned from human cells which stably carry the viral DNA. The alteration in the large-T-antigen gene was shown by marker rescue and nucleotide sequence analysis to be a deletion of 322 bp spanning the splice-donor site of the first exon, creating a 14-amino-acid deletion in the large T antigen. The mutant gene was expressed in H293 human cells from an adenovirus vector, and the protein was purified by immunoaffinity chromatography. The mutant protein directs greater levels of DNA replication in vitro than does the wild-type protein. Moreover, the mutant protein reduces the lag time for in vitro DNA synthesis and can be diluted to lower levels than wild-type T antigen and still promote good replication, which is in clear contrast to the in vivo situation. These biochemical features of the protein are independent of the source of the cellular replication factors (i.e., HeLa, H293, COS 7, or CV1 cells) and the cells from which the T antigens were purified. The mutant T antigen does not transform Rat-2 cells. Several different models which might reconcile the differences observed in vivo and in vitro are outlined. We propose that the function of T antigen affected prepares cells for SV40 replication by activation of a limiting cellular replication factor. Furthermore, a link between the induction of a cellular replication factor and transformation by SV40 is discussed.


TL1A induces TCR independent IL-6 and TNF-α production and growth of PLZF⁺ leukocytes.
An elevated level of the cytokine TL1A is known to be associated with several autoimmune diseases, e.g. rheumatoid arthritis and inflammatory bowel disease. However, the mode of action of TL1A remains elusive. In this study, we investigated the role of TL1A in a pro-inflammatory setting, using human leukocytes purified from healthy donors. We show that TL1A, together with IL-12, IL-15 and IL-18, directly induces the production of IL-6 and TNF-α from leukocytes. Interestingly, TL1A-induced IL-6 was not produced by CD14⁺ monocytes. We further show that the produced IL-6 is fully functional, as measured by its ability to signal through the IL-6 receptor, and that the induction of IL-6 is independent of TCR stimulation. Furthermore, the transcription factor PLZF was induced in stimulated cells. These results offer a substantial explanation for the role of TL1A, since TNF-α and IL-6 are directly responsible for much of the inflammatory state in many autoimmune diseases. Our study suggests that TL1A is a possible target for the treatment of autoimmune diseases.


A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II).
The aim of this study was to evaluate the efficacy and tolerability of quetiapine and paroxetine monotherapy for major depression in bipolar disorder. 740 patients (478 bipolar I, 262 bipolar II) with major depressive episodes (DSM-IV) were randomly assigned to quetiapine 300 mg/d (n = 245), quetiapine 600 mg/d (n = 247), paroxetine 20 mg/d (n = 122), or placebo (n = 126) for 8 weeks. The primary end point was the change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The study was conducted from May 2005 to May 2007. Mean MADRS score change from baseline at 8 weeks was -16.19 for quetiapine 300 mg, -16.31 for quetiapine 600 mg, -13.76 for paroxetine, and -12.60 for placebo (P < .001 for both quetiapine doses, P = .313 for paroxetine, vs placebo). Quetiapine-treated (both doses), but not paroxetine-treated, patients showed significantly greater improvements (P < or = .05) in most secondary outcomes measures at week 8 versus the placebo group. Paroxetine significantly improved Hamilton Anxiety Rating Scale scores versus placebo (P < .05) but not MADRS or Hamilton Depression Rating Scale (HDRS) scores. Both quetiapine doses were associated with greater improvements than paroxetine for MADRS and HDRS scores. The most common adverse events were dry mouth, somnolence, sedation, and dizziness with quetiapine (both doses) and dry mouth, sedation, headache, insomnia, and nausea with paroxetine. The incidence of treatment-emergent mania/hypomania was lower with quetiapine compared with paroxetine and placebo. Quetiapine (300 or 600 mg/d), but not paroxetine, was more effective than placebo for treating acute depressive episodes in bipolar I and II disorder. Quetiapine treatment was generally well tolerated. clinicaltrials.gov Identifier: NCT00119652.


Markers of malnutrition after intestinal transplantation: the role of IGF-1 and calprotectin.
The objective of this study is to valuate two biomarkers that may guide nutritional assessment during follow up after intestinal transplantation. We performed a retrospective study on prospectively collected data of insulin-like growth factor-1 (IGF-1) and effluent calprotectin in patients undergoing intestinal transplantation. Optimal nutritional status (ONS) was defined by using the Malnutrition Universal Screening Tool (MUST). IGF-1 and calprotectin were correlated with ONS by Pearson correlation. Eighteen cadaveric intestinal transplants were performed over 1,650 days (median follow up 425 days, range 29-1,650 days). Mean IGF-1 and calprotectin were significantly associated with independent nutrition. Seven patients became malnourished on one or more occasions. During malnutrition the mean IGF-1 was 22 ± 14 ng/ml and calprotectin 1,597 ± 1,055 mcg/g. Mean weight during episodes of malnutrition changed from 64.77 ± 8.76 kg to 59.05 ± 8.5 kg (-8.9 ± 1.25%). Both IGF-1 and calprotectin negatively correlated with ONS (Pearson's r, -0.612, p = 0.014). Patients broadly aligned with three groups: nutritionally replete (normal IGF-1 and normal calprotectin), nutritionally equivocal (normal or low normal IGF-1 and high calprotectin), and malnourished (low IGF-1 and high calprotectin). Patients with low IGF-1 and high calprotectin may have a benign clinical presentation. However it is in their interests to have parenteral nutrition restarted pending further investigation.


Cost-effectiveness of Intensive Blood Pressure Management.
Among high-risk patients with hypertension, targeting a systolic blood pressure of 120 mm Hg reduces cardiovascular morbidity and mortality compared with a higher target. However, intensive blood pressure management incurs additional costs from treatment and from adverse events. To evaluate the incremental cost-effectiveness of intensive blood pressure management compared with standard management. This cost-effectiveness analysis conducted from September 2015 to August 2016 used a Markov cohort model to estimate cost-effectiveness of intensive blood pressure management among 68-year-old high-risk adults with hypertension but not diabetes. We used the Systolic Blood Pressure Intervention Trial (SPRINT) to estimate treatment effects and adverse event rates. We used Centers for Disease Control and Prevention Life Tables to project age- and cause-specific mortality, calibrated to rates reported in SPRINT. We also used population-based observational data to model development of heart failure, myocardial infarction, stroke, and subsequent mortality. Costs were based on published sources, Medicare data, and the National Inpatient Sample. Treatment of hypertension to a systolic blood pressure goal of 120 mm Hg (intensive management) or 140 mm Hg (standard management). Lifetime costs and quality-adjusted life-years (QALYs), discounted at 3% annually. Standard management yielded 9.6 QALYs and accrued $155 261 in lifetime costs, while intensive management yielded 10.5 QALYs and accrued $176 584 in costs. Intensive blood pressure management cost $23 777 per QALY gained. In a sensitivity analysis, serious adverse events would need to occur at 3 times the rate observed in SPRINT and be 3 times more common in the intensive management arm to prefer standard management. Intensive blood pressure management is cost-effective at typical thresholds for value in health care and remains so even with substantially higher adverse event rates.


Function coupling of otoferlin with GAD65 acts to modulate GABAergic activity.
Otoferlin, an integral membrane protein implicated in a late stage of exocytosis, has been reported to play a critical role in hearing although the underlying mechanisms remain elusive. However, its widespread tissue distribution infers a more ubiquitous role in synaptic vesicle trafficking. Glutamate, an excitatory neurotransmitter, is converted to its inhibitory counterpart, γ-aminobutyric acid (GABA), by L-glutamic acid decarboxylase (GAD), which exists in soluble (GAD67) and membrane-bound (GAD65) forms. For the first time, we have revealed a close association between otoferlin and GAD65 in both HEK293 and neuronal cells, including SH-SY5Y neuroblastoma and primary rat hippocampus cells, showing a direct interaction between GAD65 and otoferlin's C2 domains. In primary rat hippocampus cells, otoferlin and GAD65 co-localized in a punctate pattern within the cell body, as well as in the axon along the path of vesicular traffic. Significantly, GABA is virtually abolished in otoferlin-knockdown neuronal cells whereas otoferlin overexpression markedly increases endogenous GABA. GABA attenuation in otoferlin-knockdown primary cells is correlated with diminished L-type calcium current. This previously unknown and close correlation demonstrates that otoferlin, through GAD65, modulates GABAergic activity. The discovery of otoferlin-GAD65 functional coupling provides a new avenue for understanding the molecular mechanism by which otoferlin functions in neurological pathways.


Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling.
The hexosamine biosynthetic pathway (HBP) plays critical roles in nutrient sensing, stress response, and cell growth. However, its contribution to cardiac hypertrophic growth and heart failure remains incompletely understood. Here, we show that the HBP is induced in cardiomyocytes during hypertrophic growth. Overexpression of Gfat1 (glutamine:fructose-6-phosphate amidotransferase 1), the rate-limiting enzyme of HBP, promotes cardiomyocyte growth. On the other hand, Gfat1 inhibition significantly blunts phenylephrine-induced hypertrophic growth in cultured cardiomyocytes. Moreover, cardiac-specific overexpression of Gfat1 exacerbates pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Conversely, deletion of Gfat1 in cardiomyocytes attenuates pathological cardiac remodeling in response to pressure overload. Mechanistically, persistent upregulation of the HBP triggers decompensated hypertrophy through activation of mTOR while Gfat1 deficiency shows cardioprotection and a concomitant decrease in mTOR activity. Taken together, our results reveal that chronic upregulation of the HBP under hemodynamic stress induces pathological cardiac hypertrophy and heart failure through persistent activation of mTOR.


The Effects of Diets Enriched in Monounsaturated Oleic Acid on the Management and Prevention of Obesity: a Systematic Review of Human Intervention Studies.
Obesity is associated with an increased risk of several major noncommunicable diseases, and is an important public health concern globally. Dietary fat content is a major contributor to the increase in global obesity rates. Changes in dietary habits, such as the quality of fatty acids in the diet, are proposed to prevent obesity and its metabolic complications. In recent years, a number of studies have found that oleic acid (OA), the most common MUFA in daily nutrition, has protective effects against human disease. Importantly, there is emerging evidence indicating the beneficial effects of OA in regulating body weight. Accordingly, the objective of this systematic review was to investigate the effects of diets enriched in monounsaturated OA on the management and prevention of obesity, emphasizing possible mechanisms of action of OA in energy homeostasis. Searches were performed in PubMed/MEDLINE, ScienceDirect, Scopus, ProQuest, and Google Scholar databases for clinical trials that examined the effects of diets rich in OA on obesity. Of 821 full-text articles assessed, 28 clinical trials were included in the present study. According to the studies examined in this review, diets enriched in OA can influence fat balance, body weight, and possibly energy expenditure. Importantly, abdominal fat and central obesity can be reduced following consumption of high-OA-containing meals. Mechanistically, OA-rich diets can be involved in the regulation of food intake, body mass, and energy expenditure by stimulating AMP-activated protein kinase signaling. Other proposed mechanisms include the prevention of the nucleotide-binding oligomerization domain-like receptor 3/caspase-1 inflammasome pathway, the induction of oleoylethanolamide synthesis, and possibly the downregulation of stearoyl-CoA desaturase 1 activity. In summary, current findings lend support to advice not restricting consumption of OA-rich meals so as to maintain a healthy body weight.


A tetravalent dengue nanoparticle stimulates antibody production in mice.
Dengue is a major public health problem worldwide, especially in the tropical and subtropical regions of the world. Infection with a single Dengue virus (DENV) serotype causes a mild, self-limiting febrile illness called dengue fever. However, a subset of patients experiencing secondary infection with a different serotype progresses to the severe form of the disease, dengue hemorrhagic fever/dengue shock syndrome. Currently, there are no licensed vaccines or antiviral drugs to prevent or treat dengue infections. Biodegradable nanoparticles coated with proteins represent a promising method for in vivo delivery of vaccines. Here, we used a murine model to evaluate the IgG production after administration of inactivated DENV corresponding to all four serotypes adsorbed to bovine serum albumin nanoparticles. This formulation induced a production of anti-DENV IgG antibodies (p < 0.001). However, plaque reduction neutralization assays with the four DENV serotypes revealed that these antibodies have no neutralizing activity in the dilutions tested. Our results show that while the nanoparticle system induces humoral responses against DENV, further investigation with different DENV antigens will be required to improve immunogenicity, epitope specicity, and functional activity to make this platform a viable option for DENV vaccines.


One and the same androgen for all? Towards designer androgens.
The introduction of designer oestrogens as a treatment modality in hormone replacement in women has invited to consider the concept of compounds with selective androgenic effects for male hormone replacement therapy. The full spectrum of the actions of testosterone may not be necessary of even undesired for certain indications for testosterone treatment. To define for what indications certain androgenic properties are desired and undesired more insight in basic androgen (patho)physiology is required. There is convincing evidence that aromatization of androgenic compounds to oestrogens might be an advantage for maintenance of bone mass and it might also mitigate negative effects of androgens on biochemical parameters of cardiovascular risks; the potentially negative effects of oestrogens on prostate pathology in ageing men needs further elucidation. While the role of dihydro-testosterone (DHT) for the male sexual differentiation and for pubertal sexual maturation is evident, its role in mature and ageing males seems less significant or may even be harmful. It is, however, of note that a negative effect of DHT on prostate pathophysiology is certainly not proven. For male contraception a progestational agent with strong androgenic properties might be an asset. For most of the androgenic actions the critical levels of androgens are not well established. The latter is relevant since the large amount of androgen molecules required for its biological actions (as compared to oestrogens) is an impediment in androgen replacement modalities. There may be room for more biopotent androgens since delivery of large amounts of androgen molecules to the circulation poses problems for treatment modalities.


Comparison of the ligand binding properties of two homologous rat apocellular retinol-binding proteins expressed in Escherichia coli.
Cellular retinol-binding protein (CRBP) and cellular retinol-binding protein II (CRBP II) are 132-residue cytosolic proteins which have 56% amino acid sequence identity and bind all-trans-retinol as their endogenous ligand. They belong to a family of cytoplasmic proteins which have evolved to bind distinct hydrophobic ligands. Their patterns of tissue-specific and developmental regulation are distinct. We have compared the ligand binding properties of rat apo-CRBP and apo-CRBP II that have been expressed in Escherichia coli. Several observations indicate that the E. coli-derived apoproteins are structurally similar to the native rat proteins: they co-migrate on isoelectric focusing gels; and when complexed with all-trans-retinol, their absorption and excitation/emission spectra are nearly identical to those of the authentic rat holoproteins. Comparative lifetime and acrylamide quenching studies suggest that there are differences in the conformations of apo-CRBP and apo-CRBP II. The interaction of E. coli-derived apo-CRBP and apo-CRBP II with a variety of retinoids was analyzed using spectroscopic techniques. Both apoproteins formed high affinity complexes with all-trans-retinol (K'd approximately 10 nM). In direct binding assays, all-trans-retinal bound to both apoproteins (K'd approximately 50 nM for CRBP; K'd approximately 90 nM for CRBP II). However, all-trans-retinal could displace all-trans-retinol bound to CRBP II but not to CRBP. These observations suggests that there is a specific yet distinct interaction between these two proteins and all-trans-retinal. Apo-CRBP and apo-CRBP II did not demonstrate significant binding to either retinoic acid or methyl retinoate, an uncharged derivative of all-trans-retinoic acid. This indicates that the carboxymethyl group of methyl retinoate cannot be sterically accommodated in their binding pockets and that failure to bind retinoic acid probably is not simply due to the negative charge of its C-15 carboxylate group. Finally, neither all-trans-retinol nor retinoic acid bound to E. coli-derived rat intestinal fatty acid-binding protein, a homologous protein whose tertiary structure is known. Together, the data suggest that these three family members have acquired unique functional capabilities.


Renal parenchymal damage after percutaneous nephrolithotomy with one-stage tract dilation technique: a randomized clinical trial.
To compare the effects of one-stage vs gradual dilation techniques during percutaneous nephrolithotomy (PCNL) on postoperative renal scar formation and overall renal function. Of 152 adult patients who underwent surgery during the study period, 48 were randomized into two groups. In group 1 (n=19), gradual tract dilation with Alken metallic dilators was used, and in group 2 (n=29), one-stage tract dilation was used. We compared patient demographics, intraoperative and preoperative parameters, postoperative overall renal function, and renal scar formation on the target renal pole. Access time (P=0.001; 95% confidence interval [CI]: 3.19-6.30) and radiation exposure during access (P=0.03; 95% CI: 0.03-0.66) were significantly shorter in group 2. In group 1, the decrease in mean technetium-99m dimercaptosuccinic acid (99m-Tc DMSA) uptake from 44.1±20.1% to 43.4±19.6% 4 weeks postoperatively (-0.7%±0.5%; P=0.27; 95% CI: -0.56-1.93) was not significant. In group 2, however, there was a significant decrease in post-PCNL 99m-Tc DMSA uptake 2 (-2.4±0.3%, from 50.1±13.5% to 47.7±13.8%; P=0.001; 95% CI: 1.13-3.66). Four weeks after surgery, new scar formation or progression of the preoperative scar at the site of access were seen in 14 of 29 (48.3%) patients who were treated with one-stage dilation whereas only 2 of 19 (11.0%) patients who were treated with gradual dilation developed new scarring at the access site (P=0.007). Although the one-stage tract dilation technique reduced radiation exposure and access time, in the short term, it may cause more parenchymal damage than the gradual dilation technique.


Strongly exchange coupled inverse ferrimagnetic soft/hard, Mn(x)Fe(3-x)O4/Fe(x)Mn(3-x)O4, core/shell heterostructured nanoparticles.
Inverted soft/hard, in contrast to conventional hard/soft, bi-magnetic core/shell nanoparticles of Mn(x)Fe(3-x)O(4)/Fe(x)Mn(3-x)O(4) with two different core sizes (7.5 and 11.5 nm) and fixed shell thickness (∼0.6 nm) have been synthesized. The structural characterization suggests that the particles have an interface with a graded composition. The magnetic characterization confirms the inverted soft/hard structure and evidences a strong exchange coupling between the core and the shell. Moreover, larger soft core sizes exhibit smaller coercivities and loop shifts, but larger blocking temperatures, as expected from spring-magnet or graded anisotropy structures. The results indicate that, similar to thin film systems, the magnetic properties of soft/hard core/shell nanoparticles can be fine tuned to match specific applications.


[Child malnutrition, infrastructure and income in Mexico].
Explain the variation in child malnutrition (CM), understood as low height for age (0 to 5 years old) for the period 1999-2006. State estimations of child malnutrition and several indicators of subjacent probable causes of CM were employed, such as poverty indices, state product per capita, women scholar attainment and access to health and the sewage system. Panel data regression analysis with fixed and random effects were used to analyze the data. The results indicate that the lack to access to health and sewage systems and poverty worsen CM, whereas women education helps to diminish CM. The study shows that infrastructure variables explain a significant part of the recent variation in DI across Mexican states, and that economic growth is not a sufficient condition to diminish DI.


Multivariate analysis of long-term results after an axillobifemoral and aortobifemoral bypass in patients with aortoiliac occlusive disease.
Controversy still remains regarding the long-term results and indications for axillofemoral bypass (AxFB). A comparison of axillobifemoral bypass (AxBFB) and aortobifemoral bypass (ABFB) was thus conducted to determine whether AxFB is an acceptable alternative vascular procedure to anatomic bypass for high-risk patients. Sixty-three patients who underwent a total of 25 AxBFBs and 38 ABFBs for aortoiliac occlusive disease were reviewed retrospectively, and both univariate and multivarate analyses were perfomed. The overall survival was 82.8% at five years. A univariate analysis revealed significantly lower survival rates for patients with limb-threatening ischemia, coronary disease, and cerebrovascular disease. A multivariate analysis disclosed no significant factors influencing survival rates. The overall primary patency was 79.8% at five years. The primary patency rates for AxBFB (67.7% at five years) were significantly lower than for ABFB (88.5% at five years) based on a univariate analysis (p=0.0045). In addition, the secondary patency rates for AxBFB (80.3% at five years) were significantly lower than for ABFB (96.5% at five years, p=0.0025). A multivariate analysis disclosed significantly lower primary patency rates for grafts with a higher angiographic outflow score and simultaneous infrainguinal reconstructive procedures, but the differences between AxBFB and ABFB were not significant. The survival and primary patency for the AxBFB group were both inferior to the ABFB group, however a multivarate analysis disclosed no significant differences between the two groups. Poor femoral run-off and the presence of synchronous infrainguinal reconstructive procedures significantly affected graft patency, and these factors modulated the patency of AxBFB. AxFB for aortoiliac occlusive disease is therefore considered to be an acceptable procedure in appropriately selected patients.


The competition between cathodic oxygen and ozone reduction and its role in dictating the reaction mechanisms of an electro-peroxone process.
Previous studies indicate that effective generation of hydrogen peroxide (H2O2) from cathodic oxygen (O2) reduction is critical for the improved water treatment performance (e.g., enhanced pollutant degradation and reduced bromate formation) during the electro-peroxone (E-peroxone) process (a combined process of electrolysis and ozonation). However, undesired reactions (e.g., O3, H2O2, and H2O reductions) may occur in competition with O2 reduction at the cathode. To get a better understanding of how these side reactions would affect the process, this study investigated the cathodic reaction mechanisms during electrolysis with O2/O3 gas mixture sparging using various electrochemical techniques (e.g., linear sweep voltammetry and stepped-current chronopotentiometry). Results show that when a carbon brush cathode was used during electrolysis with O2/O3 sparging, H2O and H2O2 reductions were usually negligible cathodic reactions. However, O3 can be preferentially reduced at much more positive potentials (ca. 0.9 V vs. SCE) than O2 (ca. -0.1 V vs. SCE) at the carbon cathode. Therefore, cathodic O2 reduction was inhibited when the process was operated under current limited conditions for cathodic O3 reduction. The inhibition of O2 reduction prevented the desired E-peroxone process (cathodic O2 reduction to H2O2 and ensuing reaction of H2O2 with O3 to OH) from occurring. In contrast, when cathodic O3 reduction was limited by O3 mass transfer to the cathode, cathodic O2 reduction to H2O2 could occur, thus enabling the E-peroxone process to enhance pollutant degradation and mineralization. Many process and water parameters (applied current, ozone dose, and reactivity of water constituents with O3) can cause fundamental changes in the cathodic reaction mechanisms, thus profoundly influencing water treatment performance during the E-peroxone process. To exploit the benefits of H2O2 in water treatment, reaction conditions should be carefully controlled to promote cathodic O2 reduction during the E-peroxone process.


Towards a Miniaturized 3D Receiver WPT System for Capsule Endoscopy.
The optimization, manufacturing, and performance characterization of a miniaturized 3D receiver (RX)-based wireless power transfer (WPT) system fed by a multi-transmitter (multi-TX) array is presented in this study for applications in capsule endoscopy (CE). The 200 mm outer diameter, 35 μm thick printed spiral TX coils of 2.8 g weight, is manufactured on a flexible substrate to enable bendability and portability of the transmitters by the patients. The 8.9 mm diameter-4.8 mm long, miniaturized 3D RX-includes a 4 mm diameter ferrite road to increase power transfer efficiency (PTE) and is dimensionally compatible for insertion into current endoscopic capsules. The multi-TX is activated using a custom-made high-efficiency dual class-E power amplifier operated in subnominal condition. A resulting link and system PTE of 1% and 0.7%, respectively, inside a phantom tissue is demonstrated for the proposed 3D WPT system. The specific absorption rate (SAR) is simulated using the HFSSTM software (15.0) at 0.66 W/kg at 1 MHz operation frequency, which is below the IEEE guidelines for tissue safety. The maximum variation in temperature was also measured as 1.9 °C for the typical duration of the capsule's travel in the gastrointestinal tract to demonstrate the patients' tissues safety.


Comparison of the role of 5' terminal sequences of alfalfa mosaic virus RNAs 1, 2, and 3 in viral RNA replication.
The 5' untranslated regions (UTRs) of the genomic RNAs 1, 2, and 3 of alfalfa mosaic virus (AMV) are 100, 54, and 345 nucleotides (nt) long, respectively, and lack extensive sequence similarity to each other. RNA 3 encodes the movement protein P3 and the coat protein and can be replicated in transgenic tobacco plants expressing the replicase proteins P1 and P2 (P12 plants). 5' Cis-acting sequences involved in RNA 3 replication have been shown to be confined to the 5' UTR. When the 5' UTR of RNA 3 was replaced by the 5' UTRs of RNAs 1 or 2, the recombinant RNA was not infectious to P12 plants. Also, when the P3 gene in RNA 3 was put under the control of a subgenomic promoter and the 5' UTR of this RNA was replaced by 5' terminal RNA 1 sequences of 103 to 860 nt long or RNA 2 sequences of 57 to 612 nt long, no accumulation of the hybrid RNAs was observed. Deletion of the 5' 22 nucleotides of RNA 3 resulted in the accumulation of a major progeny that lacked the 5' 79 nt. However, when the 5' 22 nucleotides of RNA 3 were replaced by the complete 5' UTR of RNA 1 or 5' sequences of RNAs 1, 2, or 3 with a length of 5 to 15 nt, accumulation of the full-length mutant RNAs was observed. The effect of mutations in the 5' viral sequences of 5 to 15 nt was analyzed. It is concluded that although elements within nucleotides 80-345 of the 5' UTR of RNA 3 are sufficient for replication, a specific sequence of 3 to 5 nt is required to target the replicase to an initiation site corresponding to the 5' end of the RNA.


NEUBOrg: Artificially Induced Pluripotent Stem Cell-Derived Brain Organoid to Model and Study Genetics of Alzheimer's Disease Progression.
Alzheimer's disease (AD) is the most common type of neurodegenerative diseases. There are over 44 million people living with the disease worldwide. While there are currently no effective treatments for AD, induced pluripotent stem cell-derived brain organoids have the potential to provide a better understanding of Alzheimer's pathogenesis. Nevertheless, developing brain organoid models is expensive, time consuming and often does not reflect disease progression. Using accurate and inexpensive computer simulations of human brain organoids can overcome the current limitations. Induced whole brain organoids (aiWBO) will greatly expand our ability to model AD and can guide wet lab research. In this study, we have successfully developed and validated artificially induced a whole brain organoid platform (NEUBOrg) using our previously validated machine learning platform, DeepNEU (v6.1). Using NEUBorg platform, we have generated aiWBO simulations of AD and provided a novel approach to test genetic risk factors associated with AD progression and pathogenesis.


Early-Life Exposure to Perfluoroalkyl Substances and Childhood Metabolic Function.
Perfluoroalkyl substances (PFASs) are synthetic chemicals that may persist in the environment and in humans. There is a possible association between early-life PFAS exposure and metabolic dysfunction in later life, but data are limited. We studied 665 mother-child pairs in Project Viva, a Boston, Massachusetts-area cohort recruited 1999-2002. We quantified concentrations of PFASs [perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), perfluorohexane sulfonate (PFHxS), and perfluorodecanoate (PFDeA)] in maternal plasma collected at the first prenatal visit (median, 9.6 weeks gestation) and in child plasma from the mid-childhood research visit (median, 7.7 years). We assessed leptin, adiponectin, and homeostatic model assessment of insulin resistance (HOMA-IR) in mid-childhood. We fit covariate-adjusted linear regression models and conducted stratified analyses by child sex. Children with higher PFAS concentrations had lower HOMA-IR [e.g., -10.1% (95% CI: -17.3, -2.3) per interquartile range increment in PFOA]. This inverse association between child PFAS and HOMA-IR was more pronounced in females [e.g., PFOA: -15.6% (95% CI: -25.4, -4.6) vs. -6.1% (95% CI: -16.2, 5.2) for males]. Child PFAS plasma concentrations were not associated with leptin or adiponectin. Prenatal PFAS plasma concentrations were not associated with leptin, adiponectin, or HOMA-IR in offspring. We found no evidence for an adverse effect of early-life PFAS exposure on metabolic function in mid-childhood. In fact, children with higher PFAS concentrations had lower insulin resistance. Citation: Fleisch AF, Rifas-Shiman SL, Mora AM, Calafat AM, Ye X, Luttmann-Gibson H, Gillman MW, Oken E, Sagiv SK. 2017. Early-life exposure to perfluoroalkyl substances and childhood metabolic function. Environ Health Perspect 125:481-487; http://dx.doi.org/10.1289/EHP303.


Network Pharmacology-Based Analysis of Xiao-Xu-Ming Decoction on the Treatment of Alzheimer's Disease.
Alzheimer's disease (AD) has become a worldwide disease that is harmful to human health and brings a heavy economic burden to healthcare system. Xiao-Xu-Ming Decoction (XXMD) has been widely used to treat stroke and other neurological diseases for more than 1000 years in China. However, the synergistic mechanism of the constituents in XXMD for the potential treatment of AD is still unclear. Therefore, the present study aimed to predict the potential targets and uncover the material basis of XXMD for the potential treatment of AD. A network pharmacology-based method, which combined data collection, drug-likeness filtering and absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties filtering, target prediction and network analysis, was used to decipher the effect and potential targets of XXMD for the treatment of AD. Then, the acetylcholinesterase (AChE) inhibitory assay was used to screen the potential active constituents in XXMD for the treatment of AD, and the molecular docking was furtherly used to identify the binding ability of active constituents with AD-related target of AChE. Finally, three in vitro cell models were applied to evaluate the neuroprotective effects of potential lead compounds in XXMD. Through the China Natural Products Database, Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database, Traditional Chinese Medicine (TCM)-Database @Taiwan and literature, a total of 1481 compounds in XXMD were finally collected. After ADME/T properties filtering, 908 compounds were used for the further study. Based on the prediction data, the constituents in XXMD formula could interact with 41 AD-related targets. Among them, cyclooxygenase-2 (COX-2), estrogen receptor α (ERα) and AChE were the major targets. The constituents in XXMD were found to have the potential to treat AD through multiple AD-related targets. 62 constituents in it were found to interact with more than or equal to 10 AD-related targets. The prediction results were further validated by in vitro biology experiment, resulting in several potential anti-AD multitarget-directed ligands (MTDLs), including two AChE inhibitors with the IC50 values ranging from 4.83 to 10.22 μM. Moreover, fanchinoline was furtherly found to prevent SH-SY5Y cells from the cytotoxicities induced by sodium nitroprusside, sodium dithionate and potassium chloride. In conclusion, XXMD was found to have the potential to treat AD by targeting multiple AD-related targets and canonical pathways. Fangchinoline and dauricine might be the potential lead compounds in XXMD for the treatment of AD.