Production of authentic SARS-CoV M(pro) with enhanced activity: application as a novel tag-cleavage endopeptidase for protein overproduction.
The viral proteases have proven to be the most selective and useful for removing the fusion tags in fusion protein expression systems. As a key enzyme in the viral life-cycle, the main protease (M(pro)) is most attractive for drug design targeting the SARS coronavirus (SARS-CoV), the etiological agent responsible for the outbreak of severe acute respiratory syndrome (SARS) in 2003. In this study, SARS-CoV M(pro) was used to specifically remove the GST tag in a new fusion protein expression system. We report a new method to produce wild-type (WT) SARS-CoV M(pro) with authentic N and C termini, and compare the activity of WT protease with those of three different types of SARS-CoV M(pro) with additional residues at the N or C terminus. Our results show that additional residues at the N terminus, but not at the C terminus, of M(pro) are detrimental to enzyme activity. To explain this, the crystal structures of WT SARS-CoV M(pro) and its complex with a Michael acceptor inhibitor were determined to 1.6 Angstroms and 1.95 Angstroms resolution respectively. These crystal structures reveal that the first residue of this protease is important for sustaining the substrate-binding pocket and inhibitor binding. This study suggests that SARS-CoV M(pro) could serve as a new tag-cleavage endopeptidase for protein overproduction, and the WT SARS-CoV M(pro) is more appropriate for mechanistic characterization and inhibitor design.


Prevalence and risk factors of brucellosis among veterinary health care professionals.
The study describes prevalence, clinical symptoms and risk factors for brucellosis in personnel engaged in veterinary health care in Karnataka, India. A total of 1050 sera samples were collected from animal handlers, veterinarians, veterinary students, para-veterinarians and persons engaged in artificial insemination of animals. The sera samples were tested for brucellosis by Rose Bengal plate test (RBPT), serum agglutination test (SAT), IgG and IgM indirect ELISA and PCR. Age, sex, clinical symptoms and risk factors were recorded in structured questionnaire. Of the 1050 samples tested, 6.76, 6.38, 3.90, 2.67 and 2.0% were positive by IgG ELISA, RBPT, SAT, IgM ELISA and PCR, respectively and overall prevalence recorded was 7.04%. The prominent clinical symptoms observed were intermittent fever (71.62%) followed by joint pain and body aches. A high degree of suspicion, awareness and multimodal diagnostic approach is suggested for early diagnosis, treatment and disease follow up.


Dynamic characteristics of silver nanoparticles in physiological fluids: toxicological implications.
The field of nanotoxicology has made tremendous progress identifying novel and potentially adverse biological effects following nanomaterial (NM) exposure. However, one facet yet to be satisfactorily explored is how a physiological environment modifies NM physicochemical properties, thus introducing novel complexities associated with solid phase material exposures. In this study, artificial alveolar, lysosomal, and interstitial fluids were used to identify environmental-specific modulations to the properties and behavior of hydrocarbon-coated (Ag-HC) and polysaccharide-coated (Ag-PS) silver NMs. As inhalation is a common route of exposure, an alveolar macrophage cell model with deposition dosages representing approximately 2.5 months and 10 years of occupational exposure (0.5 and 25 ng/mL, respectively) were employed. Following dispersion in the artificial fluids, the Ag-HC and Ag-PS NMs demonstrated significant alterations to morphology, aggregation patterns, and particle reactivity. However, the Ag-PS also demonstrated a loss of particle coating, which elicited increased cytotoxicity, phagocytosis, and inflammation not associated with the original Ag-PS. This study demonstrated that in a physiological system NMs undergo considerable modulation, introducing a scenario where the toxicity of NMs may increase over time due to internal bioconditions. These findings highlight the critical influence that the dynamic and insoluble nature of NMs have on bioeffects and the importance of characterizing this behavior.


Cultural beliefs and domestic violence.
The role of cultural beliefs in domestic violence is examined within the context of the identification of more culturally viable options for women who are operating within diverse cultural frameworks and experiencing domestic violence worldwide. Domestic violence advocacy efforts are encouraged to incorporate more culturally informed strategies that complement the worldviews and cultural traditions of women from different backgrounds. The need for a more culturally sensitive definition of domestic violence that is inclusive of a range of domestic violence across cultures and also enhances communication among victims is identified. Points of relevant cultural reference are discussed and a cultural cost-benefit analysis is recommended for culturally relevant domestic violence research and program implementation.


Electronic and optical characterization of 2D Ti2C and Nb2C (MXene) thin films.
Two-dimensional (2D) transition metal carbides and/or nitrides (MXenes) are a new class of 2D materials, with extensive opportunities for property tailoring due to the numerous possibilities for varying chemistries and surface terminations. Here, Ti2AlC and Nb2AlC MAX phase epitaxial thin films were deposited on sapphire substrates by physical vapor deposition. The films were then etched in LiF/HCl solutions, yielding Li-intercalated, 2D Ti2CT z and Nb2CT z films, whose terminations, transport and optical properties were characterized. The former exhibits metallic conductivity, with weak localization below 50 K. In contrast, the Nb-based film exhibits an increase in resistivity with decreasing temperature from RT down to 40 K consistent with variable range hopping transport. The optical properties of both films were determined from spectroscopic ellipsometry in the 0.75 to 3.50 eV range. The results for Ti2CT z films confirm the metallic behavior. In contrast, no evidence of metallic behavior is observed for the Nb2CT z film. The present work therefore demonstrates that one fruitful approach to alter the electronic and optical properties of MXenes is to change the nature of the transition metal.


'Form is easy, meaning is hard' revisited: (re) characterizing the strengths and weaknesses of language in children with autism spectrum disorder.
Children with autism spectrum disorder (ASD) demonstrate impairments in social interaction and communication, and in repetitive/stereotypical behaviors. The degree to which children with ASD also manifest impairments in structural language-such as lexicon and grammar-is currently quite controversial. We reframe this controversy in terms of Naigles' (Naigles, Cognition 2002, 86: 157-199) 'form is easy, meaning is hard' thesis, and propose that the social difficulties of children with ASD will lead the meaning-related components of their language to be relatively more impaired than the form-related components. Our review of the extant literature supports this proposal, with studies (1) reporting that children with ASD demonstrate significant challenges in the areas of pragmatics and lexical/semantic organization and (2) highlighting their good performance on grammatical assessments ranging from wh-questions to reflexive pronouns. Studies on children with ASD who might have a co-morbid grammatical impairment are discussed in light of the absence of relevant lexical-semantic data from the same children. Most importantly, we present direct comparisons of assessments of lexical/semantic organization and grammatical knowledge from the same children from our laboratory, all of which find more children at a given age demonstrating grammatical knowledge than semantic organization. We conclude with a call for additional research in which in-depth grammatical knowledge and detailed semantic organization are assessed in the same children. WIREs Cogn Sci 2017, 8:e1438. doi: 10.1002/wcs.1438 This article is categorized under: Linguistics > Language Acquisition Linguistics > Language in Mind and Brain Neuroscience > Development.


High-order scheme for the source-sink term in a one-dimensional water temperature model.
The source-sink term in water temperature models represents the net heat absorbed or released by a water system. This term is very important because it accounts for solar radiation that can significantly affect water temperature, especially in lakes. However, existing numerical methods for discretizing the source-sink term are very simplistic, causing significant deviations between simulation results and measured data. To address this problem, we present a numerical method specific to the source-sink term. A vertical one-dimensional heat conduction equation was chosen to describe water temperature changes. A two-step operator-splitting method was adopted as the numerical solution. In the first step, using the undetermined coefficient method, a high-order scheme was adopted for discretizing the source-sink term. In the second step, the diffusion term was discretized using the Crank-Nicolson scheme. The effectiveness and capability of the numerical method was assessed by performing numerical tests. Then, the proposed numerical method was applied to a simulation of Guozheng Lake (located in central China). The modeling results were in an excellent agreement with measured data.


Systemic antiatherosclerotic treatment for the peripheral arterial occlusive disease patient.
Symptomatic and asymptomatic peripheral arterial occlusive disease (PAD) is indicative of widespread atherosclerosis. The major threat is from cardiovascular ischaemic events; thus, an important therapeutic goal is to modify atherosclerotic risk factors. Data from several large drug trials indicate that patients with PAD may gain as much, if not more, benefit from aggressive secondary prevention than those with other manifestations of atherothrombosis. In fact, the level of care for patients with PAD is lower as compared with those with ischaemic heart disease, although PAD is defined to be a coronary artery risk equivalent. This paper reviews observational data and generalisation from trials in patients with other manifestations of cardiovascular disease that support the importance of treating key risk factors such as smoking, diabetes, hypertension and hyperlipidaemia in PAD patients.


Methods: Aortic wall deformation assessment by ultrafast ultrasound imaging: Application to bicuspid aortic valve associated aortopathy.
Purpose: Aortic maximal rate of systolic distention (MRSD) is a prognosis factor of ascending aorta dilatation with magnetic resonance imaging. Its calculation requires precise continuous tracking of the aortic diameter over the cardiac cycle, which is not feasible by focused ultrasound. We aimed to develop an automatic aortic acquisition using ultrafast ultrasound imaging (UUI) to provide access to the aortic MRSD. Methods: A phased array probe and developed sequences at 2000 frames/s were used. A created interface automatically tracked the anterior and posterior aortic walls over the cardiac cycle. Tissue Doppler allowed a precise estimation of the walls' movements. MRSD was the maximum derivative of the aortic diameter curve over time. To assess its feasibility, 34 patients with bicuspid aortic valve (BAV) and 31 controls were consecutively included to evaluate the BAV-associated aortopathy at the sinus of Valsalva, the tubular ascending aorta, and the aortic arch. Results: UUI acquisitions and the dedicated interface allow tracking of the aortic diameter and calculating the MRSD for the BAV patients and controls (mean age of 34 vs. 43 years, p = 0.120). A trend toward lower deformation in the different aortic segments was observed, as expected. Still, only the MRSD with UUI was significantly different at the sinus of Valsalva in this small series: (0.61 .103.s-1 [0.37-0.72] for BAV patients vs. 0.92 .103.s-1 [0.72-1.02] for controls, p = 0.025). Conclusion: Aortic deformation evaluated with UUI deserves attention with a simple and automated measurement technique that could assess the segmental aortic injury associated with BAV.


Mechanistic insights into the dual inhibition strategy for checking Leishmaniasis.
Leishmaniasis (1) is an endemic disease mainly caused by the protozoan Leishmania donovani (Ld). Polyamines have been identified as essential organic compounds for the growth and survival of Ld. These are synthesized in Ld by polyamine synthesis pathway comprising of many enzymes such as ornithine decarboxylase (ODC), spermidine synthase (SS), and S-adenosylmethionine decarboxylase. Inhibition of these enzymes in Ld offers a viable prospect to check its growth and development. In the present work, we used computational approaches to search natural inhibitors against ODC and SS enzymes. We predicted three-dimensional structures of ODC and SS using comparative modeling and molecular dynamics (MD) simulations. Thousands of natural compounds were virtually screened against target proteins using high throughput approach. MD simulations were then performed to examine molecular interactions between the screened compounds and functional residues of the active sites of the enzymes. Herein, we report two natural compounds of dual inhibitory nature active against the two crucial enzymes of polyamine pathway of Ld. These dual inhibitors have the potential to evolve as lead molecules in the development of antileishmanial drugs. (1)These authors contributed equally.


Inhibition of ischaemic tolerance in the gerbil hippocampus by quercetin and anti-heat shock protein-70 antibody.
To clarify the role of heat shock protein-70 (HSP70) in ischaemic tolerance following pretreatment with sublethal cerebral ischaemia, we examined whether the induction of tolerance in the gerbil hippocampus is inhibited by quercetin, an inhibitor of HSP70 expression, or anti-HSP70 antibody. A 3 min period of forebrain ischaemia was induced following pretreatment with 2 min of ischaemia and 3 days of reperfusion. Quercetin or anti-HSP70 antibody was continuously infused into the left lateral ventricle using an implanted osmotic minipump started 3 h after or 2 h before the first ischaemia. The animals were killed 4 days after the second ischaemia for histological observations. Both agents produced no neuronal damage in the brain following a single 2 min period of ischaemia. The neuronal density of the CA1 hippocampus in animals subjected to treatment with quercetin and anti-HSP70 antibody was significantly lower than vehicle-treated animals but were significantly higher than animals with a single 3 min period of ischaemia. Thus, the present study showed that quercetin and anti-HSP70 antibody prevent the induction of ischaemic tolerance. The result suggests that HSP70 expression, at least in part, plays a role in the induction of ischaemic tolerance.


Zinc in Multiple Sclerosis: A Systematic Review and Meta-Analysis.
In the last 35 years, zinc (Zn) has been examined for its potential role in the disease multiple sclerosis (MS). This review gives an overview of the possible role of Zn in the pathogenesis of MS as well as a meta-analysis of studies having measured Zn in serum or plasma in patients with MS. Searching the databases PubMed and EMBASE as well as going through reference lists in included articles 24 studies were found measuring Zn in patients with MS. Of these, 13 met inclusion criteria and were included in the meta-analysis. The result of the meta-analysis shows a reduction in serum or plasma Zn levels in patients with MS with a 95% CI of [-3.66, -0.93] and a p value of .001 for the difference in Zn concentration in μM. One of six studies measuring cerebrospinal fluid, Zn levels found a significant increase in patients with MS with controls. The studies measuring whole blood and erythrocyte Zn levels found up to several times higher levels of Zn in patients with MS compared with healthy controls with decreasing levels during attacks in relapsing-remitting MS patients. Future studies measuring serum or plasma Zn are encouraged to analyze their data through homogenous MS patient subgroups on especially age, sex, and disease subtype since the difference in serum or plasma Zn in these subgroups have been found to be significantly different. It is hypothesized that local alterations of Zn may be actively involved in the pathogenesis of MS.


Structure and dynamics of an RNA tetraloop: a joint molecular dynamics and NMR study.
Molecular dynamics simulations of the RNA tetraloop 5'-CGCUUUUGCG-3' with high melting temperature and significant conformational heterogeneity in explicit water solvent are presented and compared to NMR studies. The NMR data allow for a detailed test of the theoretical model, including the quality of the force field and the conformational sampling. Due to the conformational heterogeneity of the tetraloop, high temperature (350 K) and locally enhanced sampling simulations need to be invoked. The Amber98 force field leads to a good overall agreement with experimental data. Based on NMR data and a principal component analysis of the 350 K trajectory, the dynamic structure of the tetraloop is revealed. The principal component free energy surface exhibits four minima, which correspond to well-defined conformational structures that differ mainly by their base stacking in the loop region. No correlation between the motion of the sugar rings and the stacking dynamics of the loop bases is found.


Strategies toward protecting group-free glycosylation through selective activation of the anomeric center.
Glycosylation is an immensely important biological process and one that is highly controlled and very efficient in nature. However, in a chemical laboratory the process is much more challenging and usually requires the extensive use of protecting groups to squelch reactivity at undesired reactive moieties. Nonetheless, by taking advantage of the differential reactivity of the anomeric center, a selective activation at this position is possible. As a result, protecting group-free strategies to effect glycosylations are available thanks to the tremendous efforts of many research groups. In this review, we showcase the methods available for the selective activation of the anomeric center on the glycosyl donor and the mechanisms by which the glycosylation reactions take place to illustrate the power these techniques.


Men have eating disorders too: an analysis of online narratives posted by men with eating disorders on YouTube.
Eating Disorders (ED) among men are still surrounded by stigma and gender stereotypes, with a common misconception that ED are an exclusively female condition. This study employed a gender-sensitive approach to uncover males' critical needs for effective treatment and recovery. We qualitatively analyzed a sample of twenty-five videos posted on YouTube by men with ED, presenting personal stories of recovery and recovery in-progress. Through thematic analysis of the narratives, we identified three common factors increasing disordered eating behaviors in men: 1) bullying, 2) drive for muscularity, and 3) self-regulation. In addition, we found three major themes related to barriers preventing men from help-seeking: 1) shame and stigma, 2) lack of knowledge and information, and 3) low level of perceived doctor-patient communication. The findings of this study can contribute to the conceptualization of future interventions and recovery programs designed to prevent and treat ED in men.


The TORC1/2 inhibitor TAK228 sensitizes atypical teratoid rhabdoid tumors to cisplatin-induced cytotoxicity.
Atypical teratoid/rhabdoid tumors (AT/RTs) are deadly pediatric brain tumors driven by LIN28. Mammalian target of rapamycin (mTOR) is activated in many deadly, drug-resistant cancers and governs important cellular functions such as metabolism and survival. LIN28 regulates mTOR in normal cells. We therefore hypothesized that mTOR is activated downstream of LIN28 in AT/RT, and the brain-penetrating mTOR complex 1 and 2 (mTORC1/2) kinase inhibitor TAK228 would reduce AT/RT tumorigenicity. Activation of mTOR in AT/RT was determined by measuring pS6 and pAKT (Ser473) by immunohistochemistry on tissue microarray of 18 primary AT/RT tumors. In vitro growth assays (BrdU and MTS), death assays (CC3, c-PARP by western blot), and survival curves of AT/RT orthotopic xenograft models were used to measure the efficacy of TAK228 alone and in combination with cisplatin. Lentiviral short hairpin RNA-mediated knockdown of LIN28A led to decreased mTOR activation. Primary human AT/RT had high levels of pS6 and pAKT (Ser473) in 21% and 87% of tumors by immunohistochemistry. TAK228 slowed cell growth, induced apoptosis in vitro, and nearly doubled median survival of orthotopic xenograft models of AT/RT. TAK228 combined with cisplatin synergistically slowed cell growth and enhanced cisplatin-induced apoptosis. Suppression of AKT sensitized cells to cisplatin-induced apoptosis and forced activation of AKT protected cells. Combined treatment with TAK228 and cisplatin significantly extended survival of orthotopic xenograft models of AT/RT compared with each drug alone. TAK228 has efficacy in AT/RT as a single agent and synergizes with conventional chemotherapies by sensitizing tumors to cisplatin-induced apoptosis. These results suggest TAK228 may be an effective new treatment for AT/RT.


Light-Sensitive Material Structure-Electrical Performance Relationship for Optical Memory Transistors Incorporating Photochromic Dihetarylethenes.
Photoswitchable organic field-effect transistors (OFETs) with embedded photochromic materials are considered as a promising platform for development of organic optical memory devices. Unfortunately, the operational mechanism of these devices and guidelines for selection of light-sensitive materials are still poorly explored. In the present work, a series of photochromic dihetarylethenes with a cyclopentenone bridge moiety were investigated as a dielectric/semiconductor interlayer in the structure of photoswitchable OFETs. It was shown that the electrical performance and stability of the devices can be tuned by variation of the substituents in the structure of the photochromic material. In particular, it was found that dihetarylethenes with donor substituents demonstrated the best light-induced switching effects (wider memory windows and higher switching coefficients) in the devices. The operation mechanism of the light-triggered memory devices was proposed based on the differential in situ Fourier transform infrared (FTIR) spectroscopy data and regression analysis of the threshold voltage-programming time experimental dependencies. The established relationships will facilitate further rational design of new photochromic materials, thus paving a way to fast and durable organic optical memories and memory transistors (memristors).


We are not alone: a case for the human microbiome in extra intestinal diseases.
"Dysbiosis" in the gut microbiome has been implicated in auto-immune diseases, in inflammatory diseases, in some cancers and mental disorders. The challenge is to unravel the cellular and molecular basis of dysbiosis so as to understand the disease manifestation. Next generation sequencing and genome enabled technologies have led to the establishment of the composition of gut microbiomes and established that "dysbiosis" is the cause of several diseases. In a few cases the cellular and molecular changes accompanying dysbiosis have been investigated and correlated with the disease. Gut microbiome studies have indicated that Christensenella minuta controls obesity in mice, Faecalibacterium prausnitzii protects mice against intestinal inflammation and Akkermansia muciniphila reverses obesity and insulin resistance by secreting endocannabinoids. In mice polysaccharide antigen A on the surface of Bacteroides fragilis, reduces inflammation. Such experiments provide the link between the gut microbiome and human health but implicating dysbiosis with extra-intestinal diseases like arthritis, muscular dystrophy, vaginosis, fibromyalgia, some cancers and mental disorders appears to be more challenging. The relevance of gut microbiome to the eye appears to be very remote. But considering that the eye is the site of inflammatory diseases like uveitis, scleritis, Mooren's corneal ulcer etc. it is possible that these diseases are also influenced by dysbiosis. In mice signals from the gut microbiota activate retina specific T cells that are involved in autoimmune uveitis. Such information would open up new strategies for therapy where the emphasis would be on restoring the diversity in the gut by antibiotic or specific drug use, specific microbe introduction, probiotic use and fecal transplant therapy. The ocular surface microbiome may also be responsible for eye diseases in man but such studies are lacking. Microbiome of the healthy cornea and conjunctiva have been identified. But whether the ocular microbiome exhibits dysbiosis with disease? Whether ocular microbiome is influenced by the gut microbiome? What mediates the cross-talk between the gut and ocular microbiomes? These are questions that need to be addressed to understand idiopathic infections of the eye. Evaluating diseases remote from the gut would unfold the mysteries of the microbiome.


Antioxidant capacity of crude extracts from clones of banana and plane species.
Banana and plane are the most important fruits in world trade, behind citric plants. In this work we studied the antioxidant capacity of banana and plane varieties of fruits obtained from interspecies crossed varieties of Musa acuminata and Musa balbisiana, named Harton plane, Cavendish banana, and Manzano banana. With this purpose we evaluated banana and plane crude extracts using the ferrous ion oxidation with xylenol orange method, the thiobarbituric acid method, determination of antioxidant activity, and effect on superoxide anion and hydroxyl radical and the radicals generated by ultraviolet light. The experiments showed that all extracts have the capacity to decrease the concentrations of lipid hydroperoxides and malondialdehyde, produced in the lipid peroxidation process, in a manner comparable to that of other widely studied antioxidants like melatonin and vitamin E. Moreover, all extracts had the capacity to inhibit the generation of superoxide anion, hydroxyl radical, and the radicals generated by ultraviolet light. When antioxidant activity was calculated, a value was found that was equivalent to a concentration of uric acid between 0.20 and 0.30 mM at the highest concentration of extract used, with uric acid being a potent antioxidant at 1 mM.


Rare deleterious variants in GRHL3 are associated with human spina bifida.
Neural tube defects, including spina bifida, are among the most common birth defects caused by failure of neural tube closure during development. They have a complex etiology involving largely undetermined environmental and genetic factors. Previous studies in mouse models have implicated the transcription factor Grhl3 as an important factor in the pathogenesis of spina bifida. In the present study, we conducted a resequencing analysis of GRHL3 in a cohort of 233 familial and sporadic cases of spina bifida. We identified two novel truncating variants: one homozygous frameshift variant, p.Asp16Aspfs*10, in two affected siblings and one heterozygous intronic splicing variant, p.Ala318Glyfs*26. We also identified five missense variants, one of which was demonstrated to reduce the activation of gene targets in a luciferase reporter assay. With the previously identified p.Arg391Cys variant, eight variants were found in GRHL3. Comparison of the variant rate between our cohort and the ExAC database identified a significant enrichment of deleterious variants in GRHL3 in the whole gene and the transactivation region in spina bifida patients. These data provide strong evidence for a role of GRHL3 as a predisposing factor to spina bifida and will help dissect the complex etiology and pathogenic mechanisms of these malformations.


Using computed tomography enterography to evaluate patients with Crohn's disease: what impact does examiner experience have on the reproducibility of the method?
To assess the impact that examiner experience has on the reproducibility and accuracy of computed tomography (CT) enterography in the detection of radiological signs in patients with Crohn's disease. This was a retrospective, cross-sectional observational study involving the analysis of CT enterography scans of 20 patients with Crohn's disease. The exams were analyzed independently by two radiologists in their last year of residence (duo I) and by two abdominal imaging specialists (duo II). The interobserver agreement of each pair of examiners in identifying the main radiological signs was calculated with the kappa test. The accuracy of the examiners with less experience was quantified by using the consensus among three experienced examiners as a reference. Duo I and duo II obtained a similar interobserver agreement, with a moderate to good correlation, for mural hyperenhancement, parietal thickening, mural stratification, fat densification, and comb sign (kappa: 0.45-0.64). The less experienced examiners showed an accuracy > 80% for all signs, except for lymph nodes and fistula, for which it ranged from 60% to 75%. Less experienced examiners have a tendency to present a level of interobserver agreement similar to that of experienced examiners in evaluating Crohn's disease through CT enterography, as well as showing satisfactory accuracy in identifying most radiological signs of the disease.


Conformational study of human serum albumin in pre-denaturation temperatures by differential scanning calorimetry, circular dichroism and UV spectroscopy.
Thermal conformational changes of human serum albumin (HSA) in phosphate buffer, 10 mM at pH = 7 are investigated using differential scanning calorimetric (DSC), circular dichroism (CD) and UV spectroscopic methods. The results indicate that temperature increment from 25 degrees C to 55 degrees C induces reversible conformational changes in the structure of HSA. Conformational change of HSA are shown to be a three-step process. Interestingly, melting temperature of the last domain is equal to the maximum value of fever in pathological conditions, i.e. 42 degrees C. These conformational alterations are accompanied by a mild alteration of secondary structures. Study of HSA-SDS (sodium dodecyl sulphate) interaction at 45 degrees C and 35 degrees C reveals that SDS affects the HSA structure at least in three steps: the first two steps result in more stabilization and compactness of HSA structure, while the last one induces the unfolding of HSA. Since HSA has a more affinity for SDS at 45 degrees C compared to 35 degrees C, It is suggested that the net negative charge of HSA is decreased in fever, which results in the decrease of HSA-associated cations and plasma osmolarity, and consequently, heat removal via the increase in urine volume.


Human placenta-derived mesenchymal stem cell administration protects against acute lung injury in a mouse model.
This study aims to investigate the effect of placenta-derived mesenchymal stem cells (PMSCs) administration on tissue repair following acute lung injury (ALI). PMSCs were transplanted intravenously to a mouse model of lipopolysaccharide-induced ALI. The therapeutic effects were determined by evaluating several indicators, including pathology; the wet/dry ratio of the lungs; blood gas analysis; the total protein content, cell numbers, and the activity of myeloperoxidase (MPO) in bronchial alveolar lavage fluid (BALF); and the levels of anti-inflammatory and proinflammatory cytokines in serum and BALF. To investigate the underlying mechanism, PMSC-derived exosomes were used for ALI treatment. Administration of PMSCs improved the degree of lung injury, reduced inflammation, increased the expression levels of anti-inflammatory cytokines, and protected lung function. As expected, the effects of PMSC-derived exosomes in the ALI model were similar to those of PMSCs, both in terms of improved lung function and reduced inflammation. These findings suggest that PMSCs have ameliorating effects on ALI that are potentially mediated via their secreted exosomes.


Brg1 is required to maintain colorectal cancer stem cells.
Tumor cells capable of self-renewal and continuous production of progeny cells are called tumor stem cells (TSCs) and are considered to be potential therapeutic targets. However, the mechanisms underlying the survival and function of TSCs are not fully understood. We previously reported that chromatin remodeling regulator Brg1 is essential for intestinal stem cells in mice and Dclk1 is an intestinal TSC marker. In this study, we investigated the role of Brg1 in Dclk1+ intestinal tumor cells for the maintenance of intestinal tumors in mice. Specific ablation of Brg1 in Dclk1+ intestinal tumor cells reduced intestinal tumors in ApcMin mice, and continuous ablation of Brg1 maintained the reduction of intestinal tumors. Lineage tracing in the context of Brg1 ablation in Dclk1+ intestinal tumor cells revealed that Brg1-null Dclk1+ intestinal tumor cells did not give rise to their descendent tumor cells, indicating that Brg1 is essential for the self-renewal of Dclk1+ intestinal tumor cells. Five days after Brg1 ablation, we observed increased apoptosis in Dclk1+ tumor cells. Furthermore, Brg1 was crucial for the stemness of intestinal tumor cells in a spheroid culture system. BRG1 knockdown also impaired cell proliferation and increased apoptosis in human colorectal cancer (CRC) cells. Microarray analysis revealed that apoptosis-related genes were upregulated and stem cell-related genes were downregulated in human CRC cells by BRG1 suppression. Consistently, high BRG1 expression correlated with poor disease-specific survival in human CRC patients. These data indicate that Brg1 plays a crucial role in intestinal TSCs in mice by inhibiting apoptosis and is critical for cell survival and stem cell features in human CRC cells. Thus, BRG1 represents a new therapeutic target for human CRC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


CT-guided celiac ganglion block with alcohol.
Celiac ganglion block has been performed without radiologic guidance by surgeons or anesthetists since it was first described by Kappis [1] in 1914. Radiographic guidance for celiac block was first reported in the 1950s [2], and more recently, radiologists have used CT to guide needle placement [3-5]. With CT guidance, more directed positioning of the needle is possible, allowing alcohol to be deposited in the specific ganglion areas. This article reviews our collective experience with CT-guided celiac ganglion block.


[Antimicrobial activity of ceftolozane/tazobactam against Enterobacteriaceae and Pseudomonas aeruginosa in the Czech Republic in 2016].
Ceftolozane/tazobactam is an antibiotic effective against Gram-negative bacteria(including Pseudomonas aeruginosa).The study aimed at determining the effectiveness of the novel antibiotic in the Czech Republic. The effectiveness of the antibiotic was studied in 16 Czech laboratories in 822 Enterobacteriaceae isolates (including AmpC and ESBL producers) and P. aeruginosa causing complicated intraabdominal or urinary tract infections. Minimum inhibitory concentrations were determined using the Etest. With the exception of Citrobacter freundii and Enterobacter cloacae, ceftozolane/tazobactam proved to be very effective against Enterobacteriaceae; no P. aeruginosa strain was resistant to the antibiotic. The results confirmed good activity of ceftozolane/tazobactam in vitro against Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis) and P. aeruginosa in the Czech Republic.


Novel Management Options for Adult Patients With Progressive Acute Lymphoblastic Leukemia: A Case-Study Compendium.
Acute lymphoblastic leukemia (ALL) is a heterogeneous hematologic malignancy characterized by highly proliferative immature lymphoid cells in the bone marrow and peripheral blood. In adults, ALL accounts for approximately 20% of all adult leukemias. ALL carries a poor prognosis in adults. The 5-year overall survival is 24% in patients ages 40 to 59 years and 18% in patients ages 60 to 69 years. ALL can be grouped into different categories according to its cell lineage (B cell or T cell), the presence or absence of the Philadelphia chromosome, and various cytogenetic and molecular classifications. A main goal of treatment is to allow the patient to achieve a complete remission and to consolidate this remission with either a maintenance regimen or an allogeneic stem cell transplant. Although the overall rate of complete remission following frontline therapy for newly diagnosed ALL is high, the majority of patients experience a disease relapse. In general, the duration of initial complete remission impacts the patient's prognosis and response to further therapies. Subsequent treatments must balance the goal of achieving a remission with the need for the patient to maintain or improve quality of life. Recently approved agents, such as blinatumomab and vincristine sulfate liposome injection, offer the promise of a second remission that can serve as a bridge to allogeneic stem cell transplant while still maintaining quality of life. A novel approach using adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cells is associated with extremely robust responses.


Affective Responses to Acute Bouts of Aerobic Exercise, Mindfulness Meditation, and Combinations of Exercise and Meditation: A Randomized Controlled Intervention.
Single bouts of aerobic exercise and meditation have been shown to induce positive affect. In a novel experimental paradigm, we sought to examine the effects of an acute bout of aerobic exercise and meditation, as well as exercise and meditation combined on affect among young adults. Participants ( N = 110, mean age = 21.4 years) were randomly assigned to walk, meditate, walk then meditate, meditate then walk, or to sit (inactive control). All walking and meditation bouts were 10 minutes in duration. Participants' affect was monitored before and after the intervention using the Exercise Induced Feelings Inventory. Significant group × time interaction effects were observed for three Exercise Induced Feelings Inventory subscales, including revitalization ( p < .001), tranquility ( p = .02), and exhaustion ( p = .03); the group × time interaction for Exercise Induced Feelings Inventory positive engagement was nonsignificant ( p = .16). A single bout of brisk walking or meditation, as well as a combination of walking and meditation, may positively influence affect. There is some evidence to suggest that affective benefits may be greater following meditation or a combination of meditation and walking, when compared with walking alone.


Thai Water Lily Extract Induces B16 Melanoma Cell Apoptosis and Inhibits Cellular Invasion Through the Role of Cellular Oxidants
Melanoma is a cancer that is associated with a high capacity of invasion. Oxidative stress is recognized as cancer growth and progression. The phytochemical pigments of natural products show either anti-oxidant or pro-oxidant activity from the redox system. In addition, the phytophenolics also prevent cancer cell proliferation and progression. Objective: This study aims to investigate the effects of Thai water lily on cell apoptosis and cellular invasion through the role of cellular oxidants in B16 melanoma cells. Methods: The cytotoxicity and cell apoptosis of Thai water lily extract treating B16 cells were performed by using the MTT and Annexin V/PI-flow cytometry methods, respectively. In addition, cellular oxidants and cancer cell invasion were also obtained by using DCFH-DA and Boyden chamber assays, respectively. Results: Thai water lily, Nymphaea stellate extract was shown to be markedly toxic to B16 melanoma cells with IC50 = 814 μg/ml. The extract at 800 and 1,000 μg/ml demonstrated pro-oxidant activity relating to the cell apoptosis. The low concentrations of the extract at 200 and 400 μg/ml showed the anti-oxidant function associated with the inhibitory effect of melanoma cell invasion. Conclusion: Thai water lily extract may play an important role in bioactive work as a chemo preventive agent on the modulation of cellular oxidative stress-induced apoptosis and suppressed cancer cell invasion.


Semla: a versatile toolkit for spatially resolved transcriptomics analysis and visualization.
Spatially resolved transcriptomics technologies generate gene expression data with retained positional information from a tissue section, often accompanied by a corresponding histological image. Computational tools should make it effortless to incorporate spatial information into data analyses and present analysis results in their histological context. Here, we present semla, an R package for processing, analysis, and visualization of spatially resolved transcriptomics data generated by the Visium platform, that includes interactive web applications for data exploration and tissue annotation. The R package semla is available on GitHub (https://github.com/ludvigla/semla), under the MIT License, and deposited on Zenodo (https://doi.org/10.5281/zenodo.8321645). Documentation and tutorials with detailed descriptions of usage can be found at https://ludvigla.github.io/semla/.


A Low Noise Amplifier for Neural Spike Recording Interfaces.
This paper presents a Low Noise Amplifier (LNA) for neural spike recording applications. The proposed topology, based on a capacitive feedback network using a two-stage OTA, efficiently solves the triple trade-off between power, area and noise. Additionally, this work introduces a novel transistor-level synthesis methodology for LNAs tailored for the minimization of their noise efficiency factor under area and noise constraints. The proposed LNA has been implemented in a 130 nm CMOS technology and occupies 0.053 mm-sq. Experimental results show that the LNA offers a noise efficiency factor of 2.16 and an input referred noise of 3.8 μVrms for 1.2 V power supply. It provides a gain of 46 dB over a nominal bandwidth of 192 Hz-7.4 kHz and consumes 1.92 μW. The performance of the proposed LNA has been validated through in vivo experiments with animal models.


[Stability of Soil Aggregates at Different Altitudes in Qinling Mountains and Its Coupling Relationship with Soil Enzyme Activities].
To explore changes in soil aggregate stability along an elevation gradient, and its regulating factors, soil samples were taken from the 0-10 cm surface layer at 3 different elevations on Taibai Mountain. We measured and analyzed the distribution of soil aggregates, physical and chemical properties, microbial biomass, and extracellular enzymes. The results showed that: ① the soil aggregates from the 3 elevations had mean weight diameters (MWD) of 2.17 mm, 1.83 mm, and 1.82 mm (increasing elevation), and geometric mean diameters (GMD) of 1.66 mm, 1.39 mm, and 1.32 mm, respectively. ② The change in soil aggregate stability along an elevation gradient was regulated by extracellular enzymes in the soil, in particular, the LAP in soil meso-aggregate and the BG in soil micro-aggregate. ③ Microorganisms can alleviate the N limitation at high elevations by adjusting the relative production of extracellular enzymes and altering nutrient utilization efficiency, which also changes soil aggregate stability along an elevation gradient. The results of this study have important scientific significance for soil quality evaluation and ecological environment protection in Taibai Mountain.


Accuracy of 18-F FDG PET/CT to detect bone marrow clearance in patients with peripheral T-cell lymphoma - tissue remains the issue.
Staging of peripheral T-cell non-Hodgkin lymphoma (PTCL) is determined by 18-F FDG PET scan and bone marrow biopsy. This study addressed the accuracy of PET at detecting bone marrow (BM) involvement at restaging in patients with known involvement pretreatment. We identified patients with biopsy proven BM PTCL at diagnosis and concomitant BM and PET at the end of therapy. Pre-treatment PET demonstrated 50% (8/16) had a false-negative PET scan of the BM. After induction, repeat biopsy revealed 62.5% (10/16) with BM involvement. Of these 10, two had a positive PET; eight were false negative by PET. Of the six patients with a negative posttherapy BM biopsy, four were PET negative and two false positive. The sensitivity of PET at end of treatment was 20% (2/10) with a specificity of 66.7% (4/6). PET/CT is not an accurate predictor of BM involvement in patients with known PTCL in the marrow.


Polyarthritis and Psoriasiform Skin Lesions following Pembrolizumab Therapy.
A notable feature of immune checkpoint inhibitor (ICI) therapy in oncology patients is its association with increased frequency of immune related adverse reactions, directly associated with their unique mechanism of action. These adverse events are of great interest to rheumatologists, as not only do they commonly require immunosuppressive therapeutic intervention, but can also aid in unveiling important immunopathogenetic pathways that underlie autoimmune phenomena. Herein we describe a case of psoriasiform skin lesions and polyarthritis in a patient receiving ICI for lung cancer.


Role of benzodiazepines in the treatment of anxiety disorders in 2014.
This article aims at determining the place of benzodiazepines in the current treatment of anxiety disorders in opposition to antidepressants, neuroleptics and anticonvulsants. Belgium and France are the only two European countries which prescribe the most benzodiazepines despite the dissuasion of the international guidelines (NICE) issued in the nineties concerning the high risk of dependance of these molecules. What about the respect of these guidelines and the use of benzodiazepines in general practice in 2014? Review of the literature with the following key words "anxiety disorder, benzodiazepines, anxiolytic, treatment" in the international database of PubMed, Medline, PsycINFO, PsycARTICLES and consulting of various reference books. No class of molecules could measure up to benzodiazepines until now, neither from the point of view of efficiency, nor from the point of view of cost-efficiency. This is why the guidelines (NICE) discourage the few available alternatives in the general practice. International figures from Belgium and France show a continuous increase in the use of benzodiazepines in the treatment of anxiety disorders, even after the nineties. Given the fact that benzodiazepines differ from one another at the level of their action profile (graphical representation in "stars") and are therefore able to relieve several symptoms simultaneously, these molecules still respond nowadays to many expectations of the clinical practitioners. The divergence between the guidelines and the practice confirm the irreplaceability of benzodiazepines at the present time. Nevertheless, the expectation of new molecules with fewer side effects should be investigated in further research.


The Natural-CCD Algorithm, a Novel Method to Solve the Inverse Kinematics of Hyper-redundant and Soft Robots.
This article presents a new method to solve the inverse kinematics problem of hyper-redundant and soft manipulators. From an engineering perspective, this kind of robots are underdetermined systems. Therefore, they exhibit an infinite number of solutions for the inverse kinematics problem, and to choose the best one can be a great challenge. A new algorithm based on the cyclic coordinate descent (CCD) and named as natural-CCD is proposed to solve this issue. It takes its name as a result of generating very harmonious robot movements and trajectories that also appear in nature, such as the golden spiral. In addition, it has been applied to perform continuous trajectories, to develop whole-body movements, to analyze motion planning in complex environments, and to study fault tolerance, even for both prismatic and rotational joints. The proposed algorithm is very simple, precise, and computationally efficient. It works for robots either in two or three spatial dimensions and handles a large amount of degrees-of-freedom. Because of this, it is aimed to break down barriers between discrete hyper-redundant and continuum soft robots.


Early differentiation and volatile accretion recorded in deep-mantle neon and xenon.
The isotopes (129)Xe, produced from the radioactive decay of extinct (129)I, and (136)Xe, produced from extinct (244)Pu and extant (238)U, have provided important constraints on early mantle outgassing and volatile loss from Earth. The low ratios of radiogenic to non-radiogenic xenon ((129)Xe/(130)Xe) in ocean island basalts (OIBs) compared with mid-ocean-ridge basalts (MORBs) have been used as evidence for the existence of a relatively undegassed primitive deep-mantle reservoir. However, the low (129)Xe/(130)Xe ratios in OIBs have also been attributed to mixing between subducted atmospheric Xe and MORB Xe, which obviates the need for a less degassed deep-mantle reservoir. Here I present new noble gas (He, Ne, Ar, Xe) measurements from an Icelandic OIB that reveal differences in elemental abundances and (20)Ne/(22)Ne ratios between the Iceland mantle plume and the MORB source. These observations show that the lower (129)Xe/(130)Xe ratios in OIBs are due to a lower I/Xe ratio in the OIB mantle source and cannot be explained solely by mixing atmospheric Xe with MORB-type Xe. Because (129)I became extinct about 100 million years after the formation of the Solar System, OIB and MORB mantle sources must have differentiated by 4.45 billion years ago and subsequent mixing must have been limited. The Iceland plume source also has a higher proportion of Pu- to U-derived fission Xe, requiring the plume source to be less degassed than MORBs, a conclusion that is independent of noble gas concentrations and the partitioning behaviour of the noble gases with respect to their radiogenic parents. Overall, these results show that Earth's mantle accreted volatiles from at least two separate sources and that neither the Moon-forming impact nor 4.45 billion years of mantle convection has erased the signature of Earth's heterogeneous accretion and early differentiation.


Immunomodulatory activities of Centella asiatica and Rhinacanthus nasutus extracts.
Centella asiatica (CA) and Rhinacanthus nasutus (RN )have been used for treatment of various illnesses, but the mechanisms of action remain largely unknown. This study focused on the influence of CA and RN extracts on cell-mediated and humoral immune responses. In human peripheral blood mononuclear cells (PBMCs), CA (water extract) and RN (water and ethanol extracts) significantly increased proliferation and the production of IL-2 and TNF-alpha. In contrast, an ethanol extract of CA inhibited human PBMC mitogenesis and the production of IL-2 and TNF-alpha. BALB/c mice treated with CA extracts (100 mg/kg bw) showed higher responses to both primary and secondary antibodies against BSA when compared with non-treated group. Only the secondary antibody response was increased in RN extract-treated mice. The present study revealed immunomodulating activity of CA and RN extracts with regard to both non-specific cellular and humoral immune responses. The data available to date suggest that they may have chemopreventive or anticancer potential.


[Trans-acting short interfering RNAs].
RNA is now considered a key factor in the regulation of gene expression. There are several classes of small regulatory RNAs in plants, functioning in posttranscriptional gene silencing (PTGS) or epigenetic DNA modification. Trans-acting short interfering RNAs (tasiRNAs) form a class of small regulatory RNAs which has been distinguished only recently. To date, five genes encoding tasiRNAs have been identified in Arabidopsis thaliana. TasiRNAs derive from non-coding RNA precursors which are initially targeted for cleavage by a miRNA. Cleavage products are then converted into dsRNAs by a RNA dependent RNA polymerase and sequentially cleaved into 21-nt tasiRNAs. Like the majority of plant miRNAs, tasiRNAs regulate gene expression at the posttranscriptional level, guiding cleavage of ARF and PPR transcripts. Here, we briefly present tasiRNAs and speculate whether they form a homogeneous class of siRNAs.


Effects of organic matter on crystallization of struvite in biologically treated swine wastewater.
A sustainable way to recover phosphorus (P) in swine wastewater involves a preliminary step of P dissolution followed by the separation of particulate organic matter (OM). The next two steps are firstly the precipitation of struvite crystals done by adding a crystallization reagent (magnesia) and secondly the filtration of the crystals. To develop the process successfully at an industrial scale, the control of the mechanisms of precipitation is the key point in order to obtain high value-added products, that is, big struvite crystals easy to harvest and handle. Experiments with process parameters optimized previously in a synthetic swine wastewater were performed on real swine wastewater to assess the role of the OM on struvite crystallization. After 24 h, with a pH increase to 6.8 only, 90% of the initial P was precipitated and 60% was precipitated as struvite. 80% of the solid recovered was in the fraction > 100 µm. The other forms recovered were brushite, amorphous calcium phosphate, NaCl, KCl and OM. The influence of OM on struvite precipitation in acidified swine wastewater was negative on the reaction kinetics but positive on the size of the struvite crystals. The presence of colloidal particles increased the size of the struvite crystals but slowed down the kinetics due to the viscosity induced by the repulsive force of the colloids. The maximum size of single struvite crystals (200 µm) was observed with the presence of particulate OM.


[Radiculopathy and the organization of health services: applicability verification of a technic for analyzing time factors in diagnostic procedures].
The PERT is a SPR (Reticular Programation System) based on statistic-mathematic models. Since some years they are applied to productive processes to increase the efficiency and effectiveness. They all have a same base structure which is the net that is composed by the logical succession of the event and the activity which has the part of the project. Determining the minimum time (to), the maximum one (tp) and the more frequent time (tm) of each activity and applying the statistic method PERT, one gets the probable duration (te) of every activity and the critical path of the net is placed in evidence. This is formed by the chain of those activities whose duration determines the total duration of the project. The Authors have desired to verify the applicability of SPR even to the "medical industry" and, more precisely, to the diagnostic process for the verification of radiculoneuropathy. Such pathology affects a large part of the active population. The diagnostic process in this case comprises besides an accurate neurological and clinical examination of the patient, also the x-ray exam, the electromyography, the Computed Tomography (CT) and the Magnetic Resonance Imaging (MR) exam. These last two investigations gives an increase of diagnostic accuracy. With the collaboration of the physicians of the diagnostic Service, the Authors have measured in every step of the diagnostic procedure the waiting time of 48 patients with low back pain. Applying the PERT method, it has been possible to put in evidence in the net the critical activities. They are such that their duration time determines the probable duration of the whole diagnostic process. Such duration in this case it corresponds to 91 days with a standard deviation of 33 days. The delay of any critical activity causes a lealy of the whole route. This delay influences negatively on the patient's health. Besides it determines an economic damage to the system because a relation cost/time exists. The systems of reticular programmation have as objective not only the one of improving the programmation and the control of the processes, but also the attainment of an optimum cost/time ratio, varying in a way that the total cost of the realization of the process is minimum. They represent a useful criterion to direct Quality Assurance (Q.A) in the local political sanitary context, within the bounds of organization of technical - scientific quality. An accurate application of the Q.A. should modify besides the duration of the critical activities.


Characterization of the receptors for axon guidance factor netrin-4 and identification of the binding domains.
Netrins are a family of secreted protein related to laminin and act as tropic cues directing axon growth and cell migration during neural development. Netrin-4 is a novel member of netrin family recently identified in the vertebrate with neuritis elongation promoting activity; however, the receptors for netrin-4 are still unknown. To better understand the function and signal transduction pathway of netrin-4, the potential receptors for netrin-4 were studied in this paper. The netrin-4 protein was prepared by introducing a eukaryotic expression vector with a secretable alkaline phosphatase tag (AP4) into COS7 cells to allow the expression of AP4-netrin4 fusion protein. Axon guidance activity of netrin-4 was confirmed by using the cortical explants. After incubation with cultured primary cortical neurons, the neurons were distinctly labeled by the AP4-coupled netrin-4 ligands. In contrast, the binding activity of AP4-netrin4 to neurons could be completely competed by the exogenously expressed netrin-4 protein without AP4 tag, indicating specificity of netrin-4 binding to the potential receptors. Moreover, netrin-4 could also bind to CHO cells transfected with the plasmids expressing two known receptors for netrin-1, Deleted in Colorectal Cancer (DCC) and UNC5 homolog 1 (UNC5H1) respectively. As there are three domains in netrin-4, we further tried to narrow down the region containing binding sites with the receptors. Interestingly, only the N-terminal domain (LNT) could bind to DCC and UNC5H1. A further ligand-receptor binding analysis showed that both the N- and the C-terminal domain (NCT) but not the EGF-like (EGFL) domain of netrin-4 could bind to the surface of cultured primary neurons, indicating the existence of novel receptors for netrin-4. After competed by netrin-4, we confirmed that the binding of AP tagged netrin-4 domains to neurons were also netrin-4 dependent. The binding activity of the N-terminal domain of netrin-4 is about 3-fold higher than that for the C-terminal domain. In summary, our data here indicated that the two known receptors for netrin-1, DCC and UNC5H1, are also receptors for netrin-4, while only LNT but not EGFL and NCT is the key domain for specific binding. In addition, there are novel receptors for netrin-4, where both LNT and NCT but not EGFL are key domains for binding.


Molecular diagnosis of ATP-binding cassette transporter-related diseases.
ATP-binding cassette (ABC) transporters are involved in a variety of physiologic processes such as xenobiotic defense, lipid metabolism, ion homeostasis and immune functions. A large number of ABC proteins have been causatively linked to rare and common human genetic diseases including familial high-density lipoprotein deficiency, retinopathies, cystic fibrosis, diabetes and cardiomyopathies. Furthermore, genetic variations in ABC transporter genes and dysregulated expression patterns of these molecules significantly contribute to drug resistance in human cancer cells and alter the pharmacokinetic properties of a variety of drugs. In order to analyze DNA sequence alterations or define disease-associated mRNA expression patterns of the complete ABC transporter superfamily, novel high-throughput molecular methods such as quantitative real-time PCR and DNA microarray analysis are emerging. The aim of this review is to provide an overview and to present some examples of human ABC transporters involved in monogenic diseases, cancer and pharmacogenetics. Methodologic aspects of molecular diagnostics applied to analyze genetic variations, mRNA and protein expression levels and functional characteristics of ABC transporters are discussed.


One of the two cytoplasmic actin isoforms in Drosophila is essential.
Actin is a highly conserved protein found in all eukaryotic organisms. Most organisms have multiple cytoplasmic actin genes that encode isoforms with slightly different amino acid sequences. These different isoforms are coexpressed in many cell types. Why organisms have multiple very similar cytoplasmic actin genes is unclear. We have addressed this question with the cytoplasmic actins in Drosophila, Act5C, and Act42A. These isoforms differ by only two amino acids and both genes are expressed in all cells at all times during development. We identified P element insertions in the Act5C gene that resulted in a lethal phenotype. The lethal phenotype is rescued by a transgene with a genomic fragment that includes Act5C regulatory and amino acid coding sequences. A hybrid transgene containing the protein coding sequence for the Act42A isoform, under the control of the regulatory regions of the Act5C gene, also rescues the lethality of the Act5C mutants. Furthermore, flies that carry only one copy each of Act5C and Act42A are viable. These results suggest the amino acid differences between these two cytoplasmic actin isoforms are not important for function and the need for increased gene dosage to provide more actin is not likely to explain the existence of multiple genes. Instead, our results suggest that regulated expression of Act5C is essential to the fly.


Negative pressure wound therapy: Where are we in 2022?
The use of negative pressure wound therapy (NPWT) continues to be an important tool for surgeons. As the use and general acceptance of NPWT have grown, so have the indications for its use. These indications have expanded to include soft tissue defects in trauma, infection, surgical wound management, and soft tissue grafting procedures. Many adjuvants have been engineered into newer generations of NPWT devices such as wound instillation of fluid or antibiotics allowing surgeons to further optimize the wound healing environment or aid in the eradication of infection. This review discusses the recent relevant literature on the proposed mechanisms of action, available adjuvants, and the required components needed to safely apply NPWT. The supporting evidence for the use of NPWT in traumatic extremity injuries, infection control, and wound care is also reviewed. Although NPWT has a low rate of complication, the surgeon should be aware of the potential risks associated with its use. Furthermore, the expanding indications for the use of NPWT are explored, and areas for future innovation and research are discussed.


IL-18 (IFN-gamma-inducing factor) regulates early cytokine production in, and promotes resolution of, bacterial infection in mice.
IL-12-induced IFN-gamma production is essential for clearance of Yersinia enterocolitica infection. Similar to IL-12, the recently described cytokine IL-18 (IFN-gamma-inducing factor) is produced by macrophages and induces IFN-gamma production in spleen cells. Therefore, we have investigated the role of IL-18 in Yersinia infection of mice. Heat-killed yersinia-triggered IL-18-promoted IFN-gamma production of splenocytes was predominantly dependent on endogenous IL-12 production, whereas IL-12-promoted IFN-gamma production was not IL-18 dependent. IL-18-induced IFN-gamma production was to a higher degree dependent on IFN-gammaR-mediated mechanisms and in synergism with IL-2 resulted in at least fivefold higher IFN-gamma levels as compared with the combination of IL-12 plus IL-2. Analysis of the effect of IL-18 on IL-12 production of LPS-stimulated peritoneal macrophages revealed that IL-18 decreased LPS-induced IL-12 production, indicating that IL-18 might be involved in negative regulation of IL-12 production. In vivo studies revealed that Yersinia-resistant C57BL/6 mice expressed fourfold higher IL-18 mRNA levels than did susceptible BALB/c mice. Administration of anti-IL-18 Abs caused a 100- to 1000-fold increase in bacterial counts in the spleen of infected mice but did not change IFN-gamma production levels. Taken together, our data demonstrate that IL-18 is involved in regulation of cytokine production during the early phase of bacterial infections as well as in clearance of Yersinia infection.


Kinetic control of surface patterning by laser-induced photochemical deposition in liquid solutions. II. Experimental investigations.
We experimentally analyze the real-time formation of periodic surface patterning resulting from laser-driven photochemical deposition in liquid solutions. Using photochemical deposition of chromium hydroxide layers driven by a continuous Ar+ laser wave in a potassium chromate solution, we analyze the kinetic formation of three different types of patterning: dot array, periodic line writing, and holographic grating formed by interfering beams. Results are also presented for both flat and curved substrates. In each case, the deposit growth laws are measured and they show the emergence of scaling regimes that are predicted by our model [Phys. Rev. E 69, 051605 (2004)]]. Data taken from literature are also confronted to the model. The observed agreement suggests that a unified picture of the processes involved for photodeposition driven by a one-photon absorption can be devised, whatever the initial photosensitive medium is. This kinetic control of photodeposition, associated to the versatility in monitoring the geometry of laser/medium interaction and the flexibility in deposited materials by various photochemical reactions, offers a valuable level of development in substrate patterning for lithographic or holographic applications.


The potential role of serum extracellular vesicle derived small RNAs in AML research as non-invasive biomarker.
Extracellular vesicles (EV) are cell-derived vesicles released by all cells in health and disease. Accordingly, EVs are also released by cells in acute myeloid leukemia (AML), a hematologic malignancy characterized by uncontrolled growth of immature myeloid cells, and these EVs likely carry markers and molecular cargo reflecting the malignant transformation occurring in diseased cells. Monitoring antileukemic or proleukemic processes during disease development and treatment is essential. Therefore, EVs and EV-derived microRNA (miRNA) from AML samples were explored as biomarkers to distinguish disease-related patterns ex vivo or in vivo. EVs were purified from serum of healthy (H) volunteers and AML patients by immunoaffinity. EV surface protein profiles were analyzed by multiplex bead-based flow cytometry (MBFCM) and total RNA was isolated from EVs prior to miRNA profiling via small RNA sequencing. MBFCM revealed different surface protein patterns in H versus AML EVs. miRNA analysis showed individual as well as highly dysregulated patterns in H and AML samples. In this study, we provide a proof-of-concept for the discriminative potential of EV derived miRNA profiles as biomarkers in H versus AML samples.


Readiness to accept Western standard of beauty and body satisfaction among Muslim girls with and without hijab.
The purpose of this paper was to determine whether there is a difference in the readiness to accept Western standards of beauty in which thinness is an ideal of beauty and attractiveness, as well in body and appearance satisfaction between Muslim adolescent girls attending madrassa and dressing in accordance with tradition, that is to say wearing hijab, and Muslim adolescent girls who do not wear hijab and who follow contemporary Western-influenced fashion trends. Both of these groups were also compared to a non-Muslim group of adolescent girls. The sample consisted of 75 Muslim adolescent girls with hijab, 75 Muslim adolescent girls without hijab and 75 Orthodox adolescent girls. The following instruments were used: the Eating Attitudes Test (EAT-26), the Sociocultural Attitudes towards Appearance Questionnaire (SATAQ-3) and the Contour Drawing Rating Scale (CDRS). The highest level of body satisfaction (despite this group having the highest body weight in the sample) was evident among Muslim adolescent girls attending madrassa and wearing hijab. They also showed significantly less pressure to attain the Western thin-ideal standards of beauty than adolescent girls who accept Western way of dressing. Research results indicate a significant role of socio-cultural factors in one's attitude towards the body image, but also opens the question of the role of religion as a protective factor when it comes to the body and appearance attitude among Muslim women who wear hijab.


The Diverse AAA+ Machines that Repair Inhibited Rubisco Active Sites.
Gaseous carbon dioxide enters the biosphere almost exclusively via the active site of the enzyme ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco). This highly conserved catalyst has an almost universal propensity to non-productively interact with its substrate ribulose 1,5-bisphosphate, leading to the formation of dead-end inhibited complexes. In diverse autotrophic organisms this tendency has been counteracted by the recruitment of dedicated AAA+ (ATPases associated with various cellular activities) proteins that all use the energy of ATP hydrolysis to remodel inhibited Rubisco active sites leading to release of the inhibitor. Three evolutionarily distinct classes of these Rubisco activases (Rcas) have been discovered so far. Green and red-type Rca are mostly found in photosynthetic eukaryotes of the green and red plastid lineage respectively, whereas CbbQO is associated with chemoautotrophic bacteria. Ongoing mechanistic studies are elucidating how the various motors are utilizing both similar and contrasting strategies to ultimately perform their common function of cracking the inhibited Rubisco active site. The best studied mechanism utilized by red-type Rca appears to involve transient threading of the Rubisco large subunit C-terminal peptide, reminiscent of the action performed by Clp proteases. As well as providing a fascinating example of convergent molecular evolution, Rca proteins can be considered promising crop-improvement targets. Approaches aiming to replace Rubisco in plants with improved enzymes will need to ensure the presence of a compatible Rca protein. The thermolability of the Rca protein found in crop plants provides an opportunity to fortify photosynthesis against high temperature stress. Photosynthesis also appears to be limited by Rca when light conditions are fluctuating. Synthetic biology strategies aiming to enhance the autotrophic CO2 fixation machinery will need to take into consideration the requirement for Rubisco activases as well as their properties.


Prevalence and Predictors of Dietary and Nutritional Supplement Use in the Australian Army: A Cross-Sectional Survey.
Dietary supplements (DSs) and nutritional supplements (NSs) can enhance performance, recovery or training adaptations, however, some substances, dosages, and usage protocols are unsafe. Knowledge of the type and extent of use within populations enables strategies to be formulated to promote safe and effective use (where needed) and to avoid adverse side effects. The purpose of this study was to understand DS and NS use by active-duty Australian soldiers. Surveys were distributed by e-mail and hard copy to eligible participants (n = 23,195). Respondents (males n = 1833; females n = 296) comprised 9.3% of the total population. Use of ≥1 DSs/week was reported by 76.4% of males and 86.8% of females, and use of ≥1 NSs/week was reported by 21.7% of males and 20.9% of females. The most commonly used supplements were protein or amino acids (55.6%), multivitamins and minerals (38.2%), other DSs (37.8%), individual vitamins and minerals (33.0%), and combination products (32.8%). Logistic regression revealed the number of DSs respondents used simultaneously was significantly different between males and females, age groups, BMI ranges, and body weight actions. Engagement in special operations was a significant predictor of the use of any DS, individual vitamin and minerals and multivitamin and minerals. Approximately 16% of regular DS users reported experiencing one or more side effects, with the most common being palpitations (10.6%), tingling or numbness in the face, fingers, arms, or legs (5.5%), tremors or shaking (2.9%), flushing (2.3%), headache (2.0%), abdominal pain (1.6%), anxiety (1.4%), and dizziness or confusion (0.9%). The results revealed more prevalent use of several categories of DSs and NSs among some subgroups. Ongoing surveillance of DS and NS use is important for tracking trends in use over time and gauging the effectiveness of any strategies employed to enhance the quality of supplement use.


Clinical impact of multimodal treatment including chemoradiotherapy, conversion surgery and postoperative chemotherapy for borderline resectable and unresectable locally advanced pancreatic cancer without disease progression after gemcitabine plus nab-paclitaxel.
The purpose of this study was to investigate treatment outcomes of chemoradiotherapy (CRT) using S-1 with or without conversion surgery after gemcitabine plus nab-paclitaxel (GnP) for borderline resectable (BR) and unresectable locally advanced (UR-LA) pancreatic cancer. From 2016 to 2020, patients without disease progression after GnP for BR or UR-LA pancreatic cancer underwent CRT with S-1. If distant metastasis was not detected after CRT, conversion surgery and oral administration of S-1 as postoperative adjuvant chemotherapy for at least 6 months was performed. Forty patients were included in the present study. The median number of cycles of GnP was 6. Surgery was performed after CRT in 25 patients. The median progression-free survival (PFS) and overall survival (OS) periods from the start of radiotherapy were 24.6 and 27.4 months, respectively. The OS periods from the start of radiotherapy in patients who underwent conversion surgery and those who did not undergo conversion surgery were 41.3 and 16.8 months, respectively. The PFS periods from the start of radiotherapy in patients who underwent surgery and those who did not undergo surgery were 28.3 and 8.6 months, respectively. Patients who were able to receive S-1 after conversion surgery for more than 6 months had better OS than those who were not (p = 0.039), although there was no significant difference of PFS (p = 0.365). In BR/UR-LA pancreatic cancer without disease progression after GnP, multimodal treatment including CRT, conversion surgery and the scheduled postoperative chemotherapy may be effective.


Comparison of a tubular pulsatile pump and a volumetric pump for continuous venovenous renal replacement therapy in a pediatric animal model.
We compare the efficacy of a tubular pulsatile pump and a conventional volumetric pump (IVAC 571), connected to a neonatal hemofiltration circuit with an FH22 filter, for continuous renal replacement therapy in 54 Maryland pigs weighing 8-16 kg. Three different flow rates (30 ml/min in 12 cases, 15 ml/min in 22 cases, and 5 ml/min in 20 cases) were used over a 2-hour period. Hemofiltration and hemodiafiltration were performed, and measurements of ultrafiltrate flow, circuit pressures, heart rate, blood pressure, temperature, urea, creatinine, total proteins, Na, K, Cl, hematocrit, and hemolysis parameters (aspartate transaminase, lactic dehydrogenase, haptoglobin, indirect bilirubin, free hemoglobin) were made. There were no differences in ultrafiltrate flow between the two pumps. Ultrafiltrate volume was significantly higher with higher flows (p < 0.01). The technique was well tolerated by all pigs. When each blood flow was analyzed separately, cross-filter pressure drop was significantly higher in the volumetric pump than in the tubular pulsatile pump (p < 0.05). No significant differences in heart rate, blood pressure, or analytical determinations were seen between the two pumps. We conclude that pulsatile and volumetric pumps can be uses as an alternative to roller pumps for continuous venovenous renal replacement therapy in neonates and infants.


Minimally invasive left-sided esophagectomy (MILO): a novel approach for locally advanced tumors of the gastroesophageal junction.
Recent national audit has shown that levels of minimally invasive esophagectomy for cancer have increased to around 45% in the UK. The hybrid approach is the most common, with a laparoscopic abdominal phase and an open thoracic dissection. A number of centers have now adopted a two-phase Ivor-Lewis minimally invasive esophagectomy using a laparoscopic abdominal phase, followed by a thoracoscopic chest phase with a mini-thoracotomy to extract the specimen. The two-phase nature of the procedure lengthens the operative time and makes returning to the abdominal cavity difficult. The thoracotomy incision can also be painful and may reduce respiratory function post operatively. This report describes a novel single-phase minimally invasive left-sided technique with a mini-laparotomy for specimen extraction. This method offers excellent hiatal exposure, avoids a thoracotomy, and shortens the procedure time. Minimally invasive left-sided esophagectomy is a new useful approach for tumors located at the gastroesophageal junction.


Gamma-radiation synthesis and properties of superparamagnetic CS-ZnSe:Mn nanocrystals for biological labeling.
Chitosan coated ZnSe:Mn (CS-ZnSe:Mn) nanocrystals were successfully synthesized in aqueous system through a gamma-radiation route at room temperature under ambient pressure. The structure and properties of nanocrystals were investigated with transmission electron microscope (TEM), fourier transform infrared spectrometer (FT-IR), ultraviolet-visible (UV-vis) spectrometer, photoluminescence emission (PL) spectra, X-ray Diffraction (XRD) and energy dispersion spectrum (EDS). Results showed that the diameter of these nanocrystals was about 4 nm with narrow size distribution. With the increase of doped Mn2+ concentration, strong emission peak at 610 nm was observed besides the weak emission peak at 425 nm since the non-radiative transition of 4T1(4G)-6A1(6S) level, resulting the transfer of fluorescence color from blue to orange. Moreover, analysis of SQUID magnetometer indicated that the nanocrystals were superparamagnetic with a saturation magnetization of 1.7 emu/g and a Curie-Weiss temperature of 14-15 K. Hep G2 cells were incubated in solution of nanocrystals and results showed that the synthesized nanocrystals could stain cytoplasm but could not enter into nucleus.


Perceived competence and actual level of knowledge of diabetes mellitus among nurses.
Staff nurses were surveyed on their perceived and actual level of knowledge of diabetes mellitus. Staff nurses (n = 32) employed at a rural 62-bed acute care hospital in the southeastern United States constituted a convenience sample. The Diabetes Self-Report Tool was used to assess staff nurses' perceptions of knowledge of diabetes mellitus. Using a Likert-type scale a mean score of 88% was obtained concerning perceived knowledge. The Diabetes Basic Knowledge Test was used to measure the actual level of knowledge of diabetes mellitus. A mean score of 75% was obtained on the Diabetes Basic Knowledge Test. Nurses' perception of knowledge was not related to actual knowledge scores. Study findings raise questions for the nurse involved in staff development concerning the adequacy of nursing competency validation in the area of diabetes management.


Unpredicted but It Exists: Trigonal Sc2Ru with a Significant Metal-Metal Charge Transfer.
The Sc2Ru compound, obtained by high-temperature synthesis, was found to crystallize in a new trigonal hP45 structure type [space group P3̅m1; a = 9.3583(9) Å and c = 11.285(1) Å]: Ru@Sc8 cubes, Ru@Sc12 icosahedra, and uncommon Ru@Sc10 sphenocoronae are the building blocks of a unique motif tiling the whole crystal space. According to density functional theory studies, Sc2Ru is a metallic compound characterized by multicenter interactions: a significant charge transfer occurs from Sc to Ru, indicating an unexpectedly strong ionic character of the interactions between the two transition metals. Energy calculations support our experimental results in terms of stability of this compound, contributing to the recurrent discussion on the limits of the high-throughput first-principles calculations for metallic materials design.


Patient-reported denials, appeals, and complaints: associations with overall plan ratings.
To assess whether Medicare patients' reports of denied care, appeals/complaints, and satisfactory resolution were associated with ratings of their health plan or care. Retrospective analysis of 2010 Medicare Advantage Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey data. Multivariate linear regression of data from 154,766 respondents (61.1% response rate) tested the association of beneficiary ratings of plan and care with beneficiary reports of denied care, appeals, complaints, and complaint resolution, adjusting for beneficiary demographics. Beneficiaries who reported being denied needed care rated their plans and care significantly less positively, by 17.2 points (on a 100-point scale) and 9.1 points, respectively. Filing an appeal was not statistically significantly associated with further lower ratings. Beneficiaries who filed a complaint that was satisfactorily resolved gave slightly lower ratings of plans (-3.4 points) and care (-2.5 points) than those not filing a complaint (P <.001 for all results). Lower ratings from patients reporting complaints and denied care may notably affect the overall 0-10 CAHPS ratings of Medicare Advantage plans. Our results suggest that beneficiaries may attribute the actions that lead to complaints or denials to plans more than to the care they received. Successful complaint resolution and utilization management review might eliminate most deficits associated with complaints and denied care, consistent with the service recovery paradox. High rates of complaints and denied care might identify areas that need improved utilization management review, customer service, and quality improvement. Among those reporting being denied care, filing an appeal was not associated with lower patient ratings of plan or care.


A Successful Strategy to Integrate Sex and Gender Medicine into a Newly Developed Medical Curriculum.
A new modular, outcome-based, interdisciplinary curriculum was introduced for undergraduate medical education at one of the largest European medical faculties. A key stated institutional goal was to systematically integrate sex and gender medicine and gender perspectives into the curriculum in order to foster adequate gender-related knowledge and skills for future doctors concerning the etiology, pathogenesis, clinical presentation, diagnosis, treatment, and research of diseases. A change agent was integrated directly into the curriculum development team to facilitate interactions with all key players of the curricular development process. The gender change agent established a supporting organizational framework of all stakeholders, and developed a 10-step approach including identification, selection, placing relevant sex and gender medicine-related issues in the curricular planning sessions, counseling of faculty members, and monitoring of the integration achieved. With this approach, quantitatively sex and gender medicine-related content was widely integrated throughout all teaching and learning formats and from early basic science to later clinical modules (94 lectures, 33 seminars, and 16 practical courses). Gender perspectives involve 5% of the learning objectives and represent an integral part of the assessment program. Qualitatively, the relevance of gender (sociocultural) differences was combined with sex (biological) differences in disease manifestation throughout the curriculum. The appointment of a change agent facilitates the development of systematic approaches that can be a key and serve as practice models to successfully integrate new overarching curricular perspectives and dimensions--in this case sex and gender medicine--into a new medical curriculum.


"Trophoblast islands of the chorionic connective tissue" (TICCT): a novel placental histologic feature.
We found isolated or clustered trophoblasts in the chorionic connective tissue of the extraplacental membranes, and defined this novel histologic feature as the "trophoblast islands of the chorionic connective tissue" (TICCT). This study was conducted to determine the clinical significance of TICCT. Immunohistochemistry for cytokeratin-7 was performed on the chorioamniotic membranes (N = 2155) obtained from singleton pregnancies of 1199 uncomplicated term and 956 preterm deliveries. The study groups comprised 1236 African-American and 919 Hispanic women. Gestational age ranged from 24(+0) weeks to 41(+6) weeks. Multiple logistic regression analysis was performed to investigate the magnitude of association between patient characteristics and the presence of TICCT. The likelihood of TICCT was significantly associated with advancing gestational age both in term (OR: 1.29, 95% CI: 1.16-1.45, p < 0.001) and preterm deliveries (OR: 1.19, 95% CI: 1.07-1.32, p = 0.001) . Hispanic women were less likely than African-American women to have TICCT across gestation in term (OR: 0.23, 95% CI: 0.18-0.31, p < 0.001) and preterm pregnancies (OR: 0.41, 95% CI: 0.29-0.58, p < 0.001). Women with a female fetus were significantly more likely to have TICCT than women with a male fetus, in both term (OR: 1.64, 95% CI: 1.28-2.11, p < 0.001) and preterm gestations (OR: 2.04, 95% CI: 1.46-2.85, p < 0.001). TICCT was 40% less frequent in the presence of chronic placental inflammation [term (OR: 0.60, 95% CI: 0.45-0.81, p = 0.001) and preterm gestations (OR: 0.58, 95% CI: 0.40-0.84, p = 0.003)] and in parous women at term (OR: 0.60, 95% CI: 0.44-0.81, p = 0.001). Our findings suggest that the duration of pregnancy, fetal sex, and parity may influence the behavior of extravillous trophoblast and placental mesenchymal cells.


Urinary tract infections: evaluation and treatment.
Urinary tract infections (UTI) are the second most common bacterial infection in children after those of the respiratory tract. These infections are important in view of their acute morbidity and the long-term risk of renal scarring. Occurrence of UTI below two years of age, delay in starting treatment and presence of vesicoureteric reflux or obstruction are the chief risk factors associated with renal scarring. The classical features of UTI are absent in young children, who often present with few signs or symptoms other than fever. Since the diagnosis of UTI warrants a thorough evaluation subsequently, empiric treatment based on symptoms or urinalysis alone should be avoided. Therapy with appropriate antibiotics is started only after obtaining a urine culture. The distinction between upper and lower urinary tract infections is difficult and the choice of therapy guided by the patient's age and severity of clinical manifestations. All children with UTI should be investigated to identify those with an underlying urinary tract anomaly.


Paroxetine treatment of mood and anxiety disorders in children and adolescents.
This article provides an overview of the use of paroxetine in the treatment of mood and anxiety disorders in children and adolescents. Although not currently approved for use in patients younger than 18 years of age, the efficacy and safety of paroxetine have been studied in several pediatric mood and anxiety disorders. The epidemiology, diagnosis, and course of major depression, obsessive-compulsive disorder, social anxiety disorder, and panic disorder are discussed briefly. Current available data on the safety and efficacy of paroxetine based on double-blind, placebo-controlled trials and open-label studies for the treatment of mood and anxiety disorders in children and adolescents are reviewed. Clinical guidelines for the use of paroxetine in children and adolescents and recommendations regarding future directions of study are discussed.


Patterns of care and outcome for patients with glioblastoma diagnosed during 2008-2010 in Spain.
To assess management patterns and outcome in patients with glioblastoma multiforme (GBM) treated during 2008-2010 in Spain. Retrospective analysis of clinical, therapeutic, and survival data collected through filled questionnaires from patients with histologically confirmed GBM diagnosed in 19 Spanish hospitals. We identified 834 patients (23% aged >70 years). Surgical resection was achieved in 66% of patients, although the extent of surgery was confirmed by postoperative MRI in only 41%. There were major postoperative complications in 14% of patients, and age was the only independent predictor (Odds ratio [OR], 1.03; 95% confidence interval [CI],1.01-1.05; P = .006). After surgery, 57% received radiotherapy (RT) with concomitant and adjuvant temozolomide, 21% received other regimens, and 22% were not further treated. In patients treated with surgical resection, RT, and chemotherapy (n = 396), initiation of RT ≤42 days was associated with longer progression-free survival (hazard ratio [HR], 0.8; 95% CI, 0.64-0.99; P = .042) but not with overall survival (HR, 0.79; 95% CI, 0.62-1.00; P = .055). Only 32% of patients older than 70 years received RT with concomitant and adjuvant temozolomide. The median survival in this group was 10.8 months (95% CI, 6.8-14.9 months), compared with 17.0 months (95% CI, 15.5-18.4 months; P = .034) among younger patients with GBM treated with the same regimen. In a community setting, 57% of all patients with GBM and only 32% of older patients received RT with concomitant and adjuvant temozolomide. In patients with surgical resection who were eligible for chemoradiation, initiation of RT ≤42 days was associated with better progression-free survival.


Charge pair interactions stabilizing ferredoxin-ferredoxin reductase complexes. Identification by complementary site-specific mutations.
Ferredoxin reductase (Fd-reductase) supplies electrons to mitochondrial steroid hydroxylase cytochrome P450 enzymes via a [2Fe-2S] ferredoxin. Chemical labeling studies with bovine Fd-reductase have implicated Lys-243 as important in binding to bovine ferredoxin (Hamamoto, I., Kazutaka, K., Tanaka, S., and Ichikawa, Y. (1988) Biochim. Biophys. Acta 953, 207-213). We have used site-directed mutagenesis to examine the role of charged residues in this region of human Fd-reductase in ferredoxin binding. Mutant proteins were expressed in Escherichia coli and were assayed for activity by ferredoxin-mediated electron transfer to cytochrome c. Replacement of Lys-242 (homologous to Lys-243 in bovine Fd-reductase) with Gln and replacement of Arg-241 with Ser had little effect (2.7- and 3.6-fold increased Km, respectively). In contrast, mutants at positions 239 and 243 (R239S and R243Q) exhibited markedly lower affinity for ferredoxin (17.5- and 1,600-fold increased Km, respectively). Studies were also carried out with two ferredoxin charge mutants shown previously to have lowered affinity for Fd-reductase (Coghlan, V. M., and Vickery, L. E. (1991) J. Biol. Chem. 266, 18606-18612). Comparisons of the binding of ferredoxin mutants D76N and D79N to Fd-reductase mutants R239S and R243Q suggest that Arg-239 and Arg-243 of Fd-reductase each interact directly with both Asp-76 and Asp-79 of ferredoxin during formation of the complex between the two proteins. These results support the hypothesis that specific electrostatic interactions involving this region are important in stabilizing the ferredoxin-Fd-reductase complex.


Migraine pain associated with middle cerebral artery dilatation: reversal by sumatriptan.
The combination of measurements of regional cerebral blood flow (rCBF) and blood velocity in the middle cerebral arteries (MCA) by transcranial doppler sonography was used to investigate cerebrovascular involvement in migraine. Ten migraine patients with unilateral headache were studied during an attack and when they had been free of attacks for 5 days (non-attack). On both occasions they were given as intravenous infusion of sumatriptan (2 mg), a 5-HT1-like receptor agonist, which relieved the symptoms within 30 min without affecting rCBF. The MCA velocity was normal on both sides on the non-attack day and on the unaffected side during the attack. However, during the attack the MCA velocity on the headache side was significantly lower than that on the non-headache side (45 vs 61 cm/s:mean difference 16.3 [95% confidence interval 10.3-22.3]; p = 0.02). The MCA velocity on the headache side returned to normal after treatment with sumatriptan and recovery. Since rCBF in the MCA supply territory was unaffected, the lower velocity can be explained only by dilatation of the MCA. The mean MCA diameter increase was estimated to be 20%. Thus, headache was associated with intracranial large arterial dilatation on the headache side. Sumatriptan predominantly had effects on the distended artery, which suggests that the 5-HT receptor system has a role in the pathogenesis of migraine.


The breadth of the Mexican Transition Zone as defined by its flowering plant generic flora.
Biogeographic regions are defined by taxa with similar distribution patterns. Flowering plants have been widely used to propose biogeographic regionalization schemes because of shared historical or ecological factors that determine their distribution. The Mexican Transition Zone represents the boundary between the Nearctic and Neotropical kingdoms; however, there is no general agreement about the limits and extent of this region. Despite the significance of its role in the history of Mexican biota, no study involving a set of relevant plant taxa validates the magnitude of the Mexican Transition Zone. This work attempts to determine the proportion of flowering plant families and genera that characterize the biogeographic kingdoms and the Mexican Transition Zone. Through identification of distinctive genera it is shown that the Mexican Transition Zone includes the mountains of Mexico, from Oaxaca northwards. The results provide a broad view of the distribution patterns of the flora of Mexico and allow the evaluation of relationships and floristic affinities.


When is Solitude Maladaptive for Adolescents? A Comprehensive Study of Sociability and Characteristics of Solitude.
Research examining the link between solitude and psychosocial adjustment among adolescents has lacked a comprehensive, person-centered examination of differential patterns of both solitude and sociability. The current study surveyed 1071 adolescents (Mage = 12.48, SD = 1.71, 49.86% female, age range = 10-16 years). Using latent-profile analysis, four groups were identified with differential patterns of characteristics of solitude (i.e., enjoyment, motivations, preference, frequency) and sociability. Results indicated that worse psychosocial adjustment across time points was associated with membership in the PFS-NonSociable group (characterized by high enjoyment, preference, and frequency of solitude; low sociability) compared to all other groups. Findings suggest that solitude for adolescents appears to be linked to worse psychosocial adjustment only if accompanied by a lack of sociability.


Dynamical exchanges in facilitated models of supercooled liquids.
We investigate statistics of dynamical exchange events in coarse-grained models of supercooled liquids in spatial dimensions d=1, 2, and 3. The models, based upon the concept of dynamical facilitation, capture generic features of statistics of exchange times and persistence times. Here, distributions for both times are related and calculated for cases of strong and fragile glass formers over a range of temperatures. Exchange-time distributions are shown to be particularly sensitive to the model parameters and dimensions, and exhibit more structured and richer behavior than persistence-time distributions. Mean exchange times are shown to be Arrhenius, regardless of models and spatial dimensions. Specifically, tx approximately c-2, with c being the excitation concentration. Different dynamical exchange processes are identified and characterized from the underlying trajectories. We discuss experimental possibilities to test some of our theoretical findings.


Chronic obstructive pulmonary disease. Major objectives of management.
The successful management of chronic obstructive pulmonary disease (COPD) depends on achieving three major goals: reduction of airflow obstruction, prevention or management of complications, and improvement in the patient's quality of life. Exercise training is effective in improving the patient's performance; breathing training and education regarding smoking cessation and use of a peak flow meter are also vital to management. Some COPD patients may be suitable candidates for long-term oxygen therapy.


[The chemical constituents of Goniothalamus howii Merr].
Two new compounds were isolated from the chloroform soluble fraction of ethanolic extract of bark of Goniothalamus howii Merr. On the basis of their chemical properties and spectral data (MS, UV, IR, 1H and 13CNMR) they were identified as 6S (1R-hydroxy-2R-cinnamyloxyphenethyl) 5, 6-dihydro-5S-hydroxy-2-pyrone named Howiinol A and 6S-(1S, 2R-epoxyphenethyl-5S-cinnamyloxy) 5, 6-dihydro-2-pyrone named Howiinin A. Howiinol A showed significant antitumor activities toward human tumor cell in vitro and in vivo and less toxic.


Life in the Year 6000 by Santiago Ramón y Cajal: A Translation of an Unpublished "Vacation Story".
In 2006, Laura Otis provided the first English translation of five short stories written by the Spanish artist, neuroscientist, and histologist Santiago Ramón y Cajal. These stories, originally published in 1905 by Cajal under the pseudonym "Dr. Bacteria," are called "Cuentos de vacaciones: narraciones seudocientíficas" or "Vacation Stories: Pseudoscientific Tales." In 1973, a version of Cajal's manuscript "La vida en el año 6000" (Life in the year 6000) was revealed. It had remained in manuscript form since the mid-1880s and appears to be a draft of one of Cajal's unpublished "Cuentos de vacaciones." The present work is a translation of this manuscript, which is archived in the Cajal Institute in Madrid. It details the protagonist's observations, especially regarding advances in science and medicine, when he suddenly awakes in the year 6000 AD.