Multiscale Morphology of Nanoporous Copper Made from Intermetallic Phases.
Many application-relevant properties of nanoporous metals critically depend on their multiscale architecture. For example, the intrinsically high step-edge density of curved surfaces at the nanoscale provides highly reactive sites for catalysis, whereas the macroscale pore and grain morphology determines the macroscopic properties, such as mass transport, electrical conductivity, or mechanical properties. In this work, we systematically study the effects of alloy composition and dealloying conditions on the multiscale morphology of nanoporous copper (np-Cu) made from various commercial Zn-Cu precursor alloys. Using a combination of X-ray diffraction, electron backscatter diffraction, and focused ion beam cross-sectional analysis, our results reveal that the macroscopic grain structure of the starting alloy surprisingly survives the dealloying process, despite a change in crystal structure from body-centered cubic (Zn-Cu starting alloy) to face-centered cubic (Cu). The nanoscale structure can be controlled by the acid used for dealloying with HCl leading to a larger and more faceted ligament morphology compared to that of H3PO4. Anhydrous ethanol dehydrogenation was used as a probe reaction to test the effect of the nanoscale ligament morphology on the apparent activation energy of the reaction.


Efficacy and safety of the recombinant human growth hormone in short children born small for gestational age: A randomized, multicentre, comparative phase III trial.
Growth hormone (GH) treatment is known to be effective in increasing stature in children with a short stature born small for gestational age (SGA). This multicentre, randomized, open-label, comparative, phase III study aimed to evaluate the efficacy and safety of Growtropin-II (recombinant human GH) and to demonstrate that the growth-promoting effect of Growtropin-II is not inferior to that of Genotropin in children with SGA (NCT ID: NCT02770157). Seventy five children who met the inclusion criteria were randomized into 3 groups in a ratio of 2:2:1 (the study group [Growtropin-II, n = 30], control group [Genotropin, n = 30], and 26-week non-treatment group [n = 15]). The study and control groups received subcutaneous injections of Growtropin-II and Genotropin, respectively for 52 weeks, whereas the non-treatment group underwent a non-treatment observation period during weeks 0 to 26 and a dosing period during weeks 27 to 52 and additional dosing till week 78 only in re-consenting children. No significant differences in demographic and baseline characteristics between the groups were observed. The mean ± standard deviation change difference in annualized height velocity (aHV) (study group - control group) was 0.65 ±2.12 cm/year (95% confidence interval [CI], -0.53 to 1.83), whereas the lower limit for the 2-sided 95% CI was -0.53 cm/year. Regarding safety, treatment-emergent adverse events (TEAEs) occurred in 53.33% children in the study group and 43.33% children in the control group; the difference in the incidence of TEAEs between the 2 treatment groups was not statistically significant (P = .4383). A total of 17 serious adverse events (SAEs) occurred in 13.33% children in the treatment groups, and no significant difference in incidence between groups (P = .7065) was seen. Two cases of adverse drug reaction (ADR) occurred in 2 children (3.33%): 1 ADR (injection site swelling or pain) occurred in 1 child (3.33%) each in the study and control groups. This study demonstrates that the change in aHV from the baseline till 52 weeks with Growtropin-II treatment is non-inferior to that with Genotropin treatment in children with short stature born SGA. Growtropin-II is well-tolerated, and its safety profile is comparable with that of Genotropin over a 1-year course of treatment.


From plant to cancer drug: lessons learned from the discovery of taxol.
Many researchers in the natural product sciences dream of discovering a successful drug. For almost all of us, this dream will never be realized. Among the heroes of our past, though, there is a team whose efforts led to the discovery of not one but two new drugs. Dr Monroe Wall and Dr Mansukh Wani isolated and solved the structures for taxol and camptothecin, plant-based compounds that continue to play a critical role in cancer therapy today. Since the 1960s and 1970s when Wall, Wani and collaborators did their seminal work, there have been tremendous technological advances in the natural product sciences. With access to most sophisticated technology, it might be expected that the rate of discovery of new drugs from plants and other sources would have sped up. However, this has not come to pass. Why is this? Is it that the promise of new drug candidates from plant-based sources has been exhausted? Has our fascination with new technologies and with the promise of the genomics revolution caused us to stop investing effort and resources in the practices that are proven to yield success? With this Viewpoint, we share the story of taxol's discovery, highlighting critical challenges that were overcome and considering their relevance to botanical natural products drug discovery today. We hope that consideration of lessons learned from the past will help fuel success by researchers currently studying plants with the goal of discovering promising therapeutic leads.


Quantitative Assessment of Trunk Muscles Involvement in Patients with Myotonic Dystrophy Type 1 Using a Whole Body Muscle Magnetic Resonance Imaging.
The aim of this study was to analyze the pattern of trunk muscles involvement through a muscle MRI, in relation to the clinical data of patients diagnosed with myotonic dystrophy type 1 (DM1). Patients with DM1 who visited the neurology department were enrolled (n = 19). In all patients, the fatty degeneration of the muscle MRI in the lower cervical, upper thoracic, middle thoracic, and lumbosacral spine extensor muscle group and trunk flexor muscle group was evaluated. Clinical data, including CTG repeats, spinal deformity were analyzed to find the correlations with the fatty degeneration of trunk muscles in the muscle MRI. All DM1 patients who presented with very mild to severe functional status showed T1-weghted high intensity signals in the upper-thoracic spine extensor muscle group. The sum MRI score of the spine extensor muscle group showed a significant correlation with the 6-min walking test, and Cobb's angle. DM1 frequently affects the trunk muscles, even in the early stage of disease progression, regardless of disease severity or age of onset. Among the para-vertebral muscles, the selective involvement of spine extensor muscles may explain the cause of spinal deformities, which mirrors the functional status of DM1.


Critical role of diacylglycerol- and phospholipid-regulated protein kinase C epsilon in induction of low-density lipoprotein receptor transcription in response to depletion of cholesterol.
Induction of low-density lipoprotein (LDL) receptor transcription in response to depletion of cellular sterols in animal cells is well established. The intracellular signal or signals involved in regulating this process, however, remain unknown. Using a specific inhibitor of protein kinase C (PKC), calphostin C, we show the requirement of this kinase in the induction process in human hepatoma HepG2 cells. Overexpression of PKC epsilon, but not PKC alpha, -gamma, -delta, or -zeta was found to dramatically induce (approximately 18-fold) LDL receptor promoter activity. Interestingly, PKC epsilon-mediated induction was found to be sterol resistant. To further establish that PKC epsilon is involved in the sterol regulation of LDL receptor gene transcription, endogenous PKC epsilon was specifically inhibited by transfection with antisense PKC epsilon phosphorothionate oligonucleotides. Antisense treatment decreased endogenous PKC epsilon protein levels and completely blocked induction of LDL receptor transcription following sterol depletion. PKC epsilon-induced LDL receptor transcription is independent of the extracellular signal-regulated kinase 1 and 2 (p42/44(MAPK)) cascade, because the MEK-1/2 inhibitor, PD98059 did not inhibit, even though it blocked p42/44(MAPK) activation. Finally, photoaffinity labeling studies showed an isoform-specific interaction between PKC epsilon and sterols, suggesting that sterols may directly modulate its function by hampering binding of activators. This was confirmed by PKC activity assays. Altogether, these results define a novel signaling pathway leading to induction of LDL receptor transcription following sterol depletion, and a model is proposed to account for a new function for PKC epsilon as part of a sterol-sensitive signal transduction pathway in hepatic cells.


Beta, Delta, and Omicron, Deadliest Among SARS-CoV-2 Variants: A Computational Repurposing Approach.
SARS-CoV-2 has been highly susceptible to mutations since its emergence in Wuhan, China, and its subsequent propagation due to containing an RNA as its genome. The emergence of variants with improved transmissibility still poses a grave threat to global health. The spike protein mutation is mainly responsible for higher transmissibility and risk severity. This study retrieved SARS-CoV-2 variants structural and nonstructural proteins (NSPs) sequences from several geographic locations, including Africa, Asia, Europe, Oceania, and North and South America. First, multiple sequence alignments with BioEdit and protein homology modeling were performed using the SWISS Model. Then the structure visualization and structural analysis were performed by superimposing against the Wuhan sequence by Pymol to retrieve the RMSD values. Sequence alignment revealed familiar, uncommon regional among variants and, interestingly, a few unique mutations in Beta, Delta, and Omicron. Structural analysis of such unique mutations revealed that they caused structural deviations in Beta, Delta, and Omicron spike proteins. In addition, these variants were more severe in terms of hospitalization, sickness, and higher mortality, which have a substantial relationship with the structural deviations because of those unique mutations. Such evidence provides insight into the SARS-CoV-2 spike protein vulnerability toward mutation and their structural and functional deviations, particularly in Beta, Delta, and Omicron, which might be the cause of their broader coverage. This knowledge can help us with regional vaccine strain selection, virus pathogenicity testing, diagnosis, and treatment with more specific vaccines.


Proposed new anthropometric indices of childhood undernutrition.
The three conventional anthropometric indicators of childhood undernutrition are stunting (low height-for-age), underweight (low weight-for-age) and wasting (low weight-for-height). Recently a new composite index, namely the Composite Index of Anthropometric Failure (CIAF) has been proposed and utilised to study childhood undernutrition. In this paper, we have attempted to construct three new indices of undernutrition, relative to the CIAF. These three indices are: Stunting Index (SI) = Stunting / CIAF, Underweight Index (UI) = Underweight / CIAF and Wasting Index (WI) = Wasting / CIAF. Furthermore, we have calculated and compared these indices using our dataset as well as other existing datasets. Using our dataset, the sex-combined values of SI, UI and WI were 0.364, 0.866 and 0.684, respectively. The corresponding values among boys were 0.364, 0.866 and 0.729. Among girls, they were 0.380, 0.866 and 0.641, respectively. When applied to the all India dataset, the values of SI, UI and WI were 0.756, 0.788 and 0.266, respectively. Similar values (SI = 0.723, UI = 0.681, WI = 0.294) were observed when they were computed on data available from Coimbatore, South India. In conclusion, we suggest that these three new indices provide additional information on the prevalence of different forms of undernutrition relative to the total level of undernutrition in a particular population.


An evaluation of intensive intervention for students with persistent reading difficulties.
To evaluate the effects of an intensive tertiary reading intervention, 27 students with severe reading difficulties and disabilities, 14 of whom had demonstrated an inadequate response to 1-2 tiers of prior reading instruction, received a 16-week intervention package involving decoding and fluency skills. The decoding intervention was provided for 2 hours per day for 8 weeks and was based on the Phono-Graphix program. The fluency intervention followed the decoding intervention and involved 1 hour of daily instruction for 8 weeks based on the Read Naturally program. The 16-week intervention resulted in significant improvement in reading decoding, fluency, and comprehension. Although individual responses to the intervention were variable, 12 of the 27 students showed a significant response to these interventions. Students who had participated in previous Tier 1 plus Tier 2 interventions but remained impaired had a stronger response to intervention in the current study than students who had previously participated only in Tier 1 intervention and students who had not received prior intervention outside of special education.


Epitaxial Growth of Ternary Topological Insulator Bi2 Te2 Se 2D Crystals on Mica.
Nanostructures of ternary topological insulator (TI) Bi2 Te2 Se are, in principle, advantageous to the manifestation of topologically nontrivial surface states, due to significantly enhanced surface-to-volume ratio compared with its bulk crystals counterparts. Herein, the synthesis of 2D Bi2 Te2 Se crystals on mica via the van der Waals epitaxy method is explored and systematically the growth behaviors during the synthesis process are investigated. Accordingly, 2D Bi2 Te2 Se crystals with domain size up to 50 µm large and thickness down to 2 nm are obtained. A pronounced weak antilocalization effect is clearly observed in the 2D Bi2 Te2 Se crystals at 2 K. The method for epitaxial growth of 2D ternary Bi2 Te2 Se crystals may inspire materials engineering toward enhanced manifestation of the subtle surface states of TIs and thereby facilitate their potential applications in next-generation spintronics.


P045 Prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with inflammatory bowel disease (IBD) in a Brazilian public healthcare clinic.
Inflammatory Bowel Disease (IBD) is an inflammatory and chronic disease, as well as non-alcoholic fatty liver disease (NAFLD). Current literature has shown that IBD patients are at high risk for NAFLD. In those patients, the pathogenesis of NAFLD may be more complex and related to multifactor causes, such as gut dysbiosis, unhealthy nutritional behavior, body composition and systemic inflammation. There is an increase in NAFLD's incidence in the general population, otherwise, there are few studies evaluating NAFLD prevalence in IBD patients. So, this study aimed to evaluate prevalence of NAFLD and identify the clinical factors associated with the presence of NAFLD in patients with IBD. This cross-sectional, descriptive, observational study included 71 IBD patients from an IBD public outpatient in São Paulo State, Brazil. Laboratory evaluation and clinical data were collected. The presence of NAFLD was evaluated by ultrasonography. The exclusion criteria were as follows: pre-existing liver disease, history of alcohol intake >20g/day for women and >30g/day for men, and glucocorticoids treatment >20mg/day. Statistical analysis: descriptive statistics and association tests. 71 patients were included, of which 34 (47.89%) were Crohn´s disease (CD) and 37 (52.11%) ulcerative colitis (UC). Median age was 45.32±13.59 years, 63.38% were female, 69.1% Caucasian, 7.04% smokers. The time from diagnosis was 12.55 ± 8.01 years. Regarding the characteristics of the diseases, 42.42% of patients with CD have ileocolonic involvement, 50% penetrating disease and 39.4% perianal involvement. In relation to patients with UC, most patients have pancolitis (72.22%). Mostly, the patients were in clinical (63.89%) and endoscopic (52.86%) remission. Regarding medical treatment, the most used drugs were biological therapy (79.41%) and azathioprine (52.94%) in CD, and mesalazine (45.95%), azathioprine (40.54%) and biological therapy (40.54%) in UC. The NAFLD group consists of 32 (45.07%) patients: 40.63% had mild steatosis; 40.63% moderate and 18.65% intense NAFLD. Development of NAFLD vs no NAFLD was associated with body mass index (29.49 ± 3.93 vs 24.32 ± 3.85, p < 0.0001), and laboratory biomarkers, such as C-reactive protein (1.99 ± 4.39 vs 0.87 ± 0.52, p = 0.0061), AST (29.72 ± 16.64 vs 23.46 ± 5.31, p = 0.0226), ALT (24.92 ± 14.22 vs 17.92 ± 6.57, p = 0.0099), albumin (4.1 ± 0.37 vs 4.36 ± 0.32, p = 0.0415), fasting glucose (95.5 ± 14.01 vs 84.36 ± 13.01, p = 0.0251) and blood insulin (18.41 ± 11.88 vs 6.4 ± 4.26, p = 0.0054). Also, the NAFLD group had higher prevalence of systemic arterial hypertension (31.25% vs 10.26%, p = 0.0369). When comparing patients with the presence or absence of NAFLD, there was no difference between the groups regarding time since diagnosis (p = 0.9684), previous surgery (p = 0.5908), Montreal classification, clinical activity assessed by CDAI (p = 0.2258), clinical activity assessed by the Mayo score (p = 0.4935), endoscopic activity (p = 0.0599), histological activity (p = 1.0), or medical treatment. Development of NAFLD is a frequent occurrence in patients with IBD. NAFLD group had higher levels of body mass index, C-reactive protein, AST, ALT, fasting glucose and blood insulin, which are also associated with metabolic syndrome. Early diagnosis and appropriate nutritional orientation are necessary to prevent NAFLD related complications.


An observer for an occluded reaction-diffusion system with spatially varying parameters.
Spatially dependent parameters of a two-component chaotic reaction-diffusion partial differential equation (PDE) model describing ocean ecology are observed by sampling a single species. We estimate the model parameters and the other species in the system by autosynchronization, where quantities of interest are evolved according to misfit between model and observations, to only partially observed data. Our motivating example comes from oceanic ecology as viewed by remote sensing data, but where noisy occluded data are realized in the form of cloud cover. We demonstrate a method to learn a large-scale coupled synchronizing system that represents the spatio-temporal dynamics and apply a network approach to analyze manifold stability.


Profiling isoflavonoids found in legume root extracts using capillary electrophoresis.
Legumes such as alfalfa (Medicago sativa L.), barrel medic (Medicago truncatula), white sweet clover (Melilotus alba) and fenugreek (Trigonella graecum), normally accumulate (-)-medicarpin and its malonated glucose conjugate as natural inhibitors of fungal pathogens. These plants also accumulate the biosynthetic precursor formononetin as well as the malonated glycoside. We were interested in developing a robust high-throughput method to quantitate the levels of these two isoflavonoids, both free and conjugated, in legume root extracts, for use in screening for mutant plants accumulating altered levels of these compounds. Capillary electrophoresis was examined as an alternative to current high-performance liquid chromatography (HPLC) methods to generate isoflavonoid profiles. The developed assay used micellar electrokinetic capillary chromatography (MEKC) to provide the required selectivity in complex root extracts. The addition of 1,2-hexanediol to the sodium dodecyl sulfate (SDS) electrolyte provided improved resolution of adjacent isoflavonoids. We examined the role of several factors including sample preparation, buffer composition, buffer pH, and organic component in the injected sample. The use of capillaries with longer path lengths were also examined to increase sensitivity. A comparison of results obtained using MEKC and HPLC showed good correlation in the relative amounts of the isoflavonoids studied.


Cost-effective trauma implant selection: AAOS exhibit selection.
Today's increasingly complex health-care landscape requires that physicians take an active role in minimizing health-care costs and expenditures. Judicious choice of implants, a fracture-driven treatment algorithm, capitation models, use of generic fracture implants, and reuse of external fixation constructs all represent mechanisms that can result in substantial savings. In some health-care environments, these cost savings programs may be directly linked to physician reimbursement in the form of gainsharing plans. Evidence-based critical evaluations of implant usage patterns are necessary to help control implant-related health-care spending but are lacking in the current literature. Physicians need to acknowledge their influence and responsibility in this realm and assume an active role to help reduce costs.


Effects of unilateral stereotactic posterior striatotomy on harmaline-induced tremor in rats.
Although long known and the most prevalent movement disorder, pathophysiology of essential tremor (ET) remains controversial. The most accepted hypothesis is that it is caused by a dysfunction of the olivocerebellar system. Vilela Filho et al. [2001; Stereotact Funct Neurosurg 77:149-150], however, reported a patient with unilateral hand ET that was completely relieved after a stroke restricted to the contralateral posterior putamen and suggested that ET could be the clinical manifestation of posterior putamen hyperactivity. The present study was designed to evaluate this hypothesis in the most often used model of ET, harmaline-induced tremor in rats. Fifty-four male Wistar rats were randomly distributed into three groups: experimental (EG), surgical control (SCG), and pharmacological control (PCG) groups. EG animals underwent stereotactic unilateral posterior striatotomy. SCG rats underwent sham lesion at the same target. PCG served exclusively as controls for harmaline effects. All animals received, postoperatively, intraperitoneal harmaline, and the induced tremor was video-recorded for later evaluation by a blind observer. Thirteen animals were excluded from the study. Limb tremor was reduced ipsilaterally to the operation in 20 of 21 rats of EG and in two of nine of SCG, being asymmetric in one of 10 of PCG rats. Comparisons between EG × SCG and EG × PCG were statistically significant, but not between SCG × PCG. Limb tremor reduction was greater in anterior than in posterior paws. Lateral lesions yielded better results than medial lesions. These results suggest that the posterior striatum is involved with harmaline-induced tremor in rats and support the hypothesis presented.


Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain.
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), has caused a global pandemic in only 3 months. In addition to major respiratory distress, characteristic neurological manifestations are also described, indicating that SARS-CoV-2 may be an underestimated opportunistic pathogen of the brain. Based on previous studies of neuroinvasive human respiratory coronaviruses, it is proposed that after physical contact with the nasal mucosa, laryngopharynx, trachea, lower respiratory tract, alveoli epithelium, or gastrointestinal mucosa, SARS-CoV-2 can induce intrinsic and innate immune responses in the host involving increased cytokine release, tissue damage, and high neurosusceptibility to COVID-19, especially in the hypoxic conditions caused by lung injury. In some immune-compromised individuals, the virus may invade the brain through multiple routes, such as the vasculature and peripheral nerves. Therefore, in addition to drug treatments, such as pharmaceuticals and traditional Chinese medicine, non-pharmaceutical precautions, including facemasks and hand hygiene, are critically important.


Stressful experiences in childhood and chronic back pain in the general population.
To determine if stressful experiences in childhood are associated with an increased risk of chronic back problems later in life. We conducted a prospective cohort study in the Canadian household population. Study participants were respondents to the first 3 cycles of the National Population Health Survey in Canada who were 18 years of age or older at baseline (n = 9552). Cases of chronic back pain during a 4-year follow-up period were ascertained with an interviewer-administered questionnaire. Stressful experiences in childhood were measured by an index consisting of 7 questions. In multivariate analyses, the risk of back pain was 1.17 (95% confidence interval 0.97-1.41) for 1 stressful event and 1.49 (95% confidence interval 1.21-1.84) for 2 or more events. The effect was consistent across subgroups defined by gender, socioeconomic status, and health status. Specific events associated with an increased risk included fearful experiences, prolonged hospitalization, and parental unemployment. Our study shows that persons reporting multiple stressful experiences in childhood are at increased risk of developing chronic back problems.


Global Hypomethylation (LINE-1) and Gene-Specific Hypermethylation (GSTP1) on Initial Negative Prostate Biopsy as Markers of Prostate Cancer on a Rebiopsy.
Men at risk of missed prostate cancer on a negative biopsy often undergo a rebiopsy. We evaluated whether global hypomethylation, measured through LINE-1 methylation, and GSTP1 hypermethylation on a negative biopsy are associated with subsequent prostate cancer diagnosis. We performed a case-control study nested in an unselected series of 737 men who received at least two prostate biopsies at least three months apart at the Molinette Hospital (Turin, Italy). Two pathology wards were included for replication purposes. The study included 67 cases and 62 controls in Ward 1 and 62 cases and 66 controls in Ward 2. We used pyrosequencing to analyze LINE-1 and GSTP1 methylation in the negative biopsies. Odds ratios (OR) of prostate cancer diagnosis were estimated using conditional logistic regression. After mutual adjustment, GSTP1 hypermethylation was associated with an OR of prostate cancer diagnosis of 5.1 (95% confidence interval: 1.7-14.9) in Ward 1 and 2.0 (0.8-5.3) in Ward 2, whereas an association was suggested only for low LINE-1 methylation levels (<70% vs. 70%-74%) with an OR of 2.1 (0.5-9.1) in Ward 1 and 1.6 (0.4-6.1) in Ward 2. When the two wards were combined the association was stronger for tumors with Gleason score ≥ 4+3 [GSTP1 hypermethylation: 9.2 (2.0-43.1); LINE-1 (<70% vs. 70%-74%): 9.2 (1.4-59.3)]. GSTP-1 alone improved the predictive capability of the model (P = 0.007). GSTP1 hypermethylation on a negative biopsy is associated with the risk of prostate cancer on a rebiopsy, especially of high-grade prostate cancer. Consistent results were found only for extremely low LINE-1 methylation levels.


Collagen scaffolds populated with human marrow stromal cells reduce lesion volume and improve functional outcome after traumatic brain injury.
Traumatic brain injury (TBI) causes extensive loss of cerebral parenchyma; however, no strategy for reconstruction has been clinically effective. Our group and others have used human marrow stromal cells (hMSCs) to treat rats subjected to TBI and found no significant changes in the lesion volume, although functional outcome was improved significantly. To identify new ways of delivering hMSCs into the injured brain and to maximize the therapeutic benefits of hMSC treatment, we investigated the use of collagen scaffolds implanted with hMSCs as a cell delivery system for treatment of TBI. Collagen scaffolds populated with 3 x 10(6) hMSCs were transplanted into the lesion cavity of the injured cortex 4 days after TBI, and the rats were euthanized 35 days after TBI. We measured sensorimotor function and spatial learning using an array of function tests, and the brain tissue was processed for histopathology analysis. The data show that scaffolds populated by hMSCs improve spatial learning and sensorimotor function, reduce the lesion volume, and foster the migration of hMSCs into the lesion boundary zone after TBI in rats. hMSC-populated scaffolds may be a new way to reconstruct the injured brain and improve neurological function after TBI.


FixJ-regulated genes evolved through promoter duplication in Sinorhizobium meliloti.
The FixLJ two-component system of Sinorhizobium meliloti is a global regulator, turning on nitrogen-fixation genes in microaerobiosis. Up to now, nifA and fixK were the only genes known to be directly regulated by FixJ. We used a genomic SELEX approach in order to isolate new FixJ targets in the genome. This led to the identification of 22 FixJ binding sites, including the known sites in the fixK1 and fixK2 promoters. FixJ binding sites are unevenly distributed among the three replicons constituting the S. meliloti genome: a majority are carried either by pSymA or by a short chromosomal region of non-chromosomal origin. Thus FixJ binding sites appear to be preferentially associated with the pSymA replicon, which carries the fixJ gene. Functional analysis of FixJ targets led to the discovery of two new FixJ-regulated genes, smc03253 and proB2. This FixJ-dependent regulation appears to be mediated by a duplication of the whole fixK promoter region, including the beginning of the fixK gene. Similar duplications were previously reported for the nifH promoter. By systematic comparison of all promoter regions we found 17 such duplications throughout the genome, indicating that promoter duplication is a common mechanism for the evolution of regulatory pathways in S. meliloti.


Reexamining the role of the accessory plasmid pAtC58 in the virulence of Agrobacterium tumefaciens strain C58.
Isogenic strains of Agrobacterium tumefaciens carrying pTiC58, pAtC58, or both were constructed and assayed semiquantitatively and quantitatively for virulence and vir gene expression to study the effect of the large 542-kb accessory plasmid, pAtC58, on virulence. Earlier studies indicate that the att (attachment) genes of A. tumefaciens are crucial in the ability of this soil phytopathogen to infect susceptible host plants. Mutations in many att genes, notably attR and attD, rendered the strain avirulent. These genes are located on pAtC58. Previous work also has shown that derivatives of the wild-type strain C58 cured of pAtC58 are virulent as determined by qualitative virulence assays and, hence, pAtC58 was described as nonessential for virulence. We show here that the absence of pAtC58 in pTiC58-containing strains results in reduced virulence but that disruption of the attR gene does not result in avirulence or a reduction in virulence. Our studies indicate that pAtC58 has a positive effect on vir gene induction as revealed by immunoblot analysis of Vir proteins and expression of a PvirB::lacZ fusion.


Simultaneous determination of five common additives in insulating mineral oils by high-performance liquid chromatography with ultraviolet and coulometric detection.
Dielectric mineral oils are used to impregnate power transformers and large electrical apparatus, acting as both liquid insulation and heat dissipation media. Antioxidants and passivators are frequently added to mineral oils to enhance oxidation stability and reduce the electrostatic charging tendency, respectively. Since existing standard test methods only allow analysis of individual additives, new approaches are needed for the detection of mixtures. For the first time we investigate and discuss the performance of analytical methods, which require or do not require extraction as sample pretreatment, for the simultaneous reversed-phase high-performance liquid chromatography determination of passivators (benzotriazole, Irgamet(®) 39) and antioxidants (N-phenyl-1-naphtylamine, 2,6-di-tert-butylphenol, 2,6-di-tert-butyl-p-cresol), chosen for their presence in marketed oils. Quick easy, cheap, effective, rugged and safe and solid phase extractions were evaluated as sample pretreatments. Direct sample-injection was also studied. Ultraviolet spectrophotometry and direct-current coulometry detection were explored. As less prone to additive concentrations variability, the direct-injection high-performance liquid chromatography with ultraviolet and coulometric detection method was validated through comparison with Standard Method IEC 60666 and through an ASTM interlaboratory proficiency test. Obtained detection limits are (mg kg(-1) ): benzotriazole (2.8), Irgamet(®) 39 (13.8), N-phenyl-1-naphtylamine (11.9), 2,6-di-tert-butylphenol (13.1), 2,6-di-tert-butyl-p-cresol (10.2). Simultaneous determination of selected additives was possible both in unused and used oils, with good precision and accuracy.


International workshop: islet transplantation without borders enabling islet transplantation in Greece with international collaboration and innovative technology.
Recently, initiatives have been undertaken to establish an islet transplantation program in Athens, Greece. A major hurdle is the high cost associated with the establishment and maintenance of a clinical-grade islet manufacturing center. A collaboration was established with the University Hospitals of Geneva, Switzerland, to enable remote islet cell manufacturing with an established and validated fully operational team. However, remote islet manufacturing requires shipment of the pancreas from the procurement to the islet manufacturing site (in this case from anywhere in Greece to Geneva) and then shipment of the islets from the manufacturing site to the transplant site (from Geneva to Athens). To address challenges related to cold ischemia time of the pancreas and shipment time of islets, a collaboration was initiated with the University of Arizona, Tucson, USA. An international workshop was held in Athens, December 2011, to mark the start of this collaborative project. Experts in the field presented in three main sessions: (i) islet transplantation: state-of-the-art and the "network approach"; (ii) technical aspects of clinical islet transplantation and outcomes; and (iii) islet manufacturing - from the donated pancreas to the islet product. This manuscript presents a summary of the workshop.


svBreak: A New Approach for the Detection of Structural Variant Breakpoints Based on Convolutional Neural Network.
Structural variation (SV) is an important type of genome variation and confers susceptibility to human cancer diseases. Systematic analysis of SVs has become a crucial step for the exploration of mechanisms and precision diagnosis of cancers. The central point is how to accurately detect SV breakpoints by using next-generation sequencing (NGS) data. Due to the cooccurrence of multiple types of SVs in the human genome and the intrinsic complexity of SVs, the discrimination of SV breakpoint types is a challenging task. In this paper, we propose a convolutional neural network- (CNN-) based approach, called svBreak, for the detection and discrimination of common types of SV breakpoints. The principle of svBreak is that it extracts a set of SV-related features for each genome site from the sequencing reads aligned to the reference genome and establishes a data matrix where each row represents one site and each column represents one feature and then adopts a CNN model to analyze such data matrix for the prediction of SV breakpoints. The performance of the proposed approach is tested via simulation studies and application to a real sequencing sample. The experimental results demonstrate the merits of the proposed approach when compared with existing methods. Thus, svBreak can be expected to be a supplementary approach in the field of SV analysis in human tumor genomes.


Landscape review of global real-world data sources for studying medication use in pregnancy and lactation that support regulatory decision making.
Most pregnant people take at least one medication during gestation or while breastfeeding, however data are lacking on the safety of medication use in these populations. We conducted a landscape review of real-world data sources specific to medication use in pregnancy and breastfeeding populations that have met, or have potential to meet, health authorities' requirements for post-authorization safety studies. A 2-phase approach identified data sources from literature, publicly available registers of non-interventional post-authorization studies of pregnant women, existing database inventories, and emerging data sources known to the authors. Required key attributes were assessed according to current regulatory guidance, resulting in selection of 49 suitable data sources. All global regions were represented, with North America (37%) and Europe (33%) most common; 12% of the data sources included pregnancy information from low-to middle-income countries. Administrative healthcare claims (25%) and electronic healthcare records (21%) comprised the largest types of data sources. Across data sources, 53% were managed by national or regional governments, 27% by industry, and 20% by academic institutions. Maternal age, diagnoses, prenatal care, and reproductive history were available in most, whereas fewer included demographic data (e.g., race/ethnicity). Breastfeeding data were collected in 37% of the final data sources. We conducted a systematic approach to data source evaluation of pregnancy and breastfeeding to be used as a resource for investigators to consider when designing pregnancy-related research studies to satisfy regulatory requirements.


Effects of late referral to a nephrologist in patients with chronic renal failure.
We lack information about the role of late diagnosis of end-stage renal disease (ESRD), late nephrological referral and its impact on biochemical variables and first hospitalization in East Anatolia, Turkey. For a total of 101 ESRD patients, dialysis was initiated between January 1998 and December 2002 at the Yuzuncu Yil University Hospital. Early referral (ER) and late referral (LR) were defined as the time of first referral or admission to a nephrologist greater or less than 12 weeks, respectively, before initiation of haemodialysis (HD). The need for urgent dialysis was less among the early referral cases compared with the late referral cases (P = 0.03). Patients with LR started dialysis with lower levels of haemoglobin (8.6 vs 9.5 g/dL, P < 0.05) bicarbonate (16 vs 12 mEq/lt, P < 0.03) and albumin (2.9 vs 3.29 mg/dL, P < 0.02) and with higher serum levels of blood urea nitrogen (173 vs 95 mg/dL, P < 0.001), creatinine (10 vs 7.9 mg/dL, P < 0.001) and potassium (5.3 vs 4.8, P < 0.04). Hospitalization duration beginning at dialysis was significantly longer in the LR group (27.3 +/- 24) compared with the ER group (13.4 +/- 7.5, P < 0.001). When the groups were compared in terms of distance between the patients home and hospital, there were significantly more patients living far away from hospital (i.e. >100 km) in the LR group compared with the ER (P < 0.0001) group. Early referral to a nephrology unit and/or early diagnosis of ESRD results in better biochemical variables, shorter first hospitalization length and a higher percentage of elective construction of AVF and the availability to start with an alternative dialysis modality (i.e. CAPD).


Tuning the Photocatalytic Activity of Graphitic Carbon Nitride by Plasma-Based Surface Modification.
In this study, we demonstrate that plasma treatment can be a facile and environmentally friendly approach to perform surface modification of graphitic carbon nitride (g-CN), leading to a remarkable modulation on its photocatalytic activity. The bulk properties of g-CN, including the particle size, structure, composition, and electronic band structures, have no changes after being treated by oxygen or nitrogen plasma; however, its surface composition and specific surface area exhibit remarkable differences corresponding to an oxygen functionalization induced by the plasma post-treatment. The introduced oxygen functional groups play a key role in reducing the recombination rate of the photoexcited charge carries. As a consequence, the oxygen-plasma-treated sample shows a much superior photocatalytic activity, which is about 4.2 times higher than that of the pristine g-CN for the degradation of rhodamine B (RhB) under visible light irradiation, while the activity of nitrogen-plasma-treated sample exhibits a slight decrease. Furthermore, both of the plasma-treated samples are found to possess impressive photocatalytic stabilities. Our results suggest that plasma treatment could be a conventional strategy to perform surface modification of g-CN in forms of both powders and thin films, which holds broad interest not only for developing g-CN-based high-performance photocatalysts but also for constructing photoelectrochemical cells and photoelectronic devices with improved energy conversion efficiencies.


Rare congenital bleeding disorders.
The rare congenital bleeding disorders are a heterogeneous group of diseases which include deficiencies of fibrinogen, prothrombin and factors V, V + VIII, VII, X, XI and XIII. They are usually transmitted as autosomal recessive disorders, and the prevalence of the severe forms ranges from one case in 500,000 for factor VII up to one in 2,000,000 for factor XIII in the general population. Patients with rare congenital bleeding disorders may have a broad spectrum of clinical symptoms, ranging from mucocutaneous bleeding to life-threatening haemorrhages, such as those occurring in the central nervous system. The treatment of these disorders is based principally on the replacement of the deficient factor using, when available, specific plasma-derived or recombinant products. The aim of this narrative review is to summarise current knowledge about these rare bleeding conditions.


Tubulointerstitial fibrosis can sensitize the kidney to subsequent glomerular injury.
Chronic glomerular injury is associated with eventual development of tubulointerstitial fibrosis. Here we aimed to assess whether, and how, mild chronic tubulointerstitial injury affects glomeruli. For this, we generated mice expressing different toxin receptors, one on their proximal tubular epithelial cells (diphtheria toxin receptor [DTR]) and the other only on podocytes (human CD25 [IL-2R] driven by the nephrin promoter [Nep25]), allowing serial induction of tubule-specific and glomerular (podocyte)-specific injury, respectively. Six weeks after diphtheria toxin injection, mild interstitial fibrosis was found in Nep25+/DTR+, but not in Nep25+/DTR- mice. However, atubular glomeruli and neuronal nitric oxide synthase, a mediator of tubuloglomerular feedback, were higher in Nep25+/DTR+ than in DTR- mice and these atubular glomeruli had less podocyte density as assessed by WT-1 biomarker expression. Peritubular capillary density, hypoxia-inducible factor-1 and -2, and cyclooxygenase 2 expression were similar at week six in the two groups. At week seven, all mice were given the immunotoxin LMB-2, which binds to CD25 to induce podocyte injury. Ten days later, proteinuria, podocyte injury, and glomerulosclerosis were more severe in Nep25+/DTR+ than Nep25+/DTR- mice with more severe sclerosis in the tubule-connected glomeruli. This supports the concept that even mild preexisting tubulointerstitial injury sensitizes glomeruli to subsequent podocyte-specific injury. Thus, increased atubular glomeruli and abnormal tubuloglomerular feedback significantly contribute to the crosstalk between the tubulointerstitium and glomeruli.


Structure activity study of carbonic anhydrase IX: Selective inhibition with ureido-substituted benzenesulfonamides.
Ureido-substituted benzenesulfonamides (USBs) show great promise as selective and potent inhibitors for human carbonic anhydrase hCA IX and XII, with one such compound (SLC-0111/U-F) currently in clinical trials (clinical trials.gov, NCT02215850). In this study, the crystal structures of both hCA II (off-target) and an hCA IX-mimic (target) in complex with selected USBs (U-CH3, U-F, and U-NO2), at resolutions of 1.9 Å or better, are presented, and demonstrate differences in the binding modes within the two isoforms. The presence of residue Phe 131 in hCA II causes steric hindrance (U-CH3, 1765 nM; U-F, 960 nM; U-NO2, 15 nM) whereas in hCA IX (U-CH3, 7 nM; U-F, 45 nM; U-NO2, 1 nM) and hCA XII (U-CH3, 6 nM; U-F, 4 nM; U-NO2, 6 nM), 131 is a Val and Ala, respectively, allows for more favorable binding. Our results provide insight into the mechanism of USB selective inhibition and useful information for structural design and drug development, including synthesis of hybrid USB compounds with improved physiochemical properties.


Comparison of microtia reconstructive surgery with autograft versus homograft.
Microtia is a congenital abnormality with low incidence but considerable morbidities. Reconstruction of the microtia deformity is a complex and difficult process that requires a proper planning. The primary technique of reconstruction employs patient's own rib cartilage. Irradiated homograft cartilages previously have been used in facial reconstruction but its application in microtia surgery has not been reported yet. This study is designed to compare the results of autograft versus homograft auriculoplasty. Between 1992 - 2002, 23 patients underwent auricular reconstructive surgery by the senior author in our department. Autograft implantation was performed in one stage but homograft auriculoplasty was done in two stages. Auricular deformity was right-sided in 13, left-sided in 8, and bilateral in 2 cases. Implanted graft was autograft in 9 patients and homograft in 14 patients. During mean follow-up of 4 years, cartilage graft resorption was detected in two cases, one in autograft and one in homograft group (P > 0.05). No postoperative infection was observed. Status of postauricular sulcus was optimal in 85.7% of homograft and 77.8% of autograft groups (P > 0.05). The satisfaction score of the patients and/or parents was excellent in 66.7% of autograft and 92.9% of homograft groups (P < 0.01). Based on better satisfaction score, equivalent aesthetic appearance, and absence of complications such as scaring and pain on the chest wall, homograft auriculoplasty is an appropriate option for reconstructive surgery in patients with microtia.


Non-coding RNAs in Natural Killer/T-Cell Lymphoma.
Natural killer/T-cell lymphoma (NKTCL) is a rare and aggressive subtype of non-Hodgkin's lymphoma that is associated with a poor outcome. Non-coding RNAs (ncRNAs), which account for 98% of human RNAs, lack the function of encoding proteins but instead have the important function of regulating gene expression, including transcription, translation, RNA splicing, editing, and turnover. However, the roles and mechanisms of aberrantly expressed ncRNAs in NKTCL are not fully clear. Aberrant expressions of microRNA (miRNAs) affect the PI3K/AKT signaling pathways (miRNA-21, miRNA-155, miRNA-150, miRNA-142, miRNA-494), NF-κB (miRNA-146a, miRNA-155) and cell cycle signaling pathways to regulate cell function. Moreover, Epstein-Barr virus (EBV) encoded miRNAs and EBV oncoprotein LMP-1 regulated the expression of cellular genes that induce invasion, metastasis, cell cycle progression and cellular transformation. In addition, NKTCL-associated Long non-coding RNA (lncRNA) ZFAS1 regulated certain pathways and lncRNA MALAT1 acted as a predictive marker. This review article provides an overview of ncRNAs associated with NKTCL, summarizes the function of significantly differentially expressed hotspot non-coding RNAs that contribute to the pathogenesis, diagnoses, treatment and prognosis of NKTCL and discusses the relevance of these ncRNAs to clinical practice.


Insilico analysis of marine indole alkaloids for design of adenosine A2A receptor antagonist.
Neurological disease is the disease associated with most of geriatric population in the world. The diseases like Alzheimer's disease and Parkinson's disease are associated with the change in the life style in current era. Treatment of these diseases normally focused on the agents which can able to manipulate the neurotransmitter release, so it is associated with severe side effects. Adenosine receptors are the upcoming targets for the inflammatory as well as neurological diseases as agents like istradefylline are in the clinical use. Marine natural products are the rich source of the valuable drug like substances, number marine alkaloids are known for their ability to pass blood brain barrier (BBB) which is major hurdle in the neurological drug discovery. Here, we report the virtual screening of some marine alkaloids for adenosine 2 receptor binding potential. Results indicated topsentin C, 6'-debromohamacanthin, 6-hydroxydiscodermindole and discodermindole are having excellent binding affinity towards the adenosine 2A receptor than other selected alkaloids.Communicated by Ramaswamy H. Sarma.


Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial.
Emerging evidence suggests that stem cells and progenitor cells derived from bone marrow can be used to improve cardiac function in patients after acute myocardial infarction. In this randomised trial, we aimed to assess whether intracoronary transfer of autologous bone-marrow cells could improve global left-ventricular ejection fraction (LVEF) at 6 months' follow-up. After successful percutaneous coronary intervention (PCI) for acute ST-segment elevation myocardial infarction, 60 patients were randomly assigned to either a control group (n=30) that received optimum postinfarction medical treatment, or a bone-marrow-cell group (n=30) that received optimum medical treatment and intracoronary transfer of autologous bone-marrow cells 4.8 days (SD 1.3) after PCI. Primary endpoint was global left-ventricular ejection fraction (LVEF) change from baseline to 6 months' follow-up, as determined by cardiac MRI. Image analyses were done by two investigators blinded for treatment assignment. Analysis was per protocol. Global LVEF at baseline (determined 3.5 days [SD 1.5] after PCI) was 51.3 (9.3%) in controls and 50.0 (10.0%) in the bone-marrow cell group (p=0.59). After 6 months, mean global LVEF had increased by 0.7 percentage points in the control group and 6.7 percentage points in the bone-marrow-cell group (p=0.0026). Transfer of bone-marrow cells enhanced left-ventricular systolic function primarily in myocardial segments adjacent to the infarcted area. Cell transfer did not increase the risk of adverse clinical events, in-stent restenosis, or proarrhythmic effects. Intracoronary transfer of autologous bone-marrow-cells promotes improvement of left-ventricular systolic function in patients after acute myocardial infarction.


The Babesia divergens Asia Lineage Is Maintained through Enzootic Cycles between Ixodes persulcatus and Sika Deer in Hokkaido, Japan.
Parasites of the Babesiadivergens Asia lineage, which are closely related to B. divergens in Europe and Babesia sp. strain MO1 in the United States, were recently reported in sika deer (Cervus nippon) in eastern Japan. To identify the tick vector(s) for this parasite, we conducted a field survey in Hokkaido, Japan, where the infection rate in sika deer is the highest in the country. A specific PCR system which detects and discriminates between lineages within B. divergens and between those lineages and Babesia venatorum showed that Ixodes persulcatus (11/822), but not sympatric Ixodes ovatus (0/595) or Haemaphysalis sp. (0/163) ticks, carried B. divergens Asia lineage. Genomic DNA was archived from salivary glands of partially engorged I. persulcatus females and three isolates of B. divergens Asia lineage were newly described. The 18S rRNA gene sequence of the isolates formed the Asia lineage cluster with those previously described in sika deer isolates. One salivary gland also contained parasites of Babesia microti U.S. lineage, which were subsequently isolated in a hamster in vivoB. venatorum (strain Etb5) was also detected in one I. persulcatus tick. The 18S rRNA sequence of Etb5 was 99.7% identical to that of B. venatorum (AY046575) and was phylogenetically positioned in a taxon composed of B. venatorum isolates from Europe, China, and Russia. The geographical distribution of I. persulcatus is consistent with that of B. divergens in sika deer in Japan. These results suggest that I. persulcatus is a principal vector for B. divergens in Japan and Eurasia, where I. persulcatus is predominantly distributed.IMPORTANCE The Babesiadivergens Asia lineage of parasites closely related to B. divergens in Europe and Babesia sp. MO1 in the United States was recently reported in Cervus nippon in eastern Japan. In this study, specific PCR for the Asia lineage identified 11 positives in 822 host-seeking Ixodes persulcatus ticks, a principal vector for many tick-borne disease agents. Gene sequences of three isolates obtained from DNA in salivary glands of female ticks were identical to each other and to those in C. nippon We also demonstrate the coinfection of B. divergens Asia lineage with Babesia microti U.S. lineage in a tick salivary gland and, furthermore, isolated the latter in a hamster. These results suggest that I. persulcatus is the principal vector for B. divergens as well as for B. microti, and both parasites may be occasionally cotransmitted by I. persulcatus This report will be important for public health, since infection may occur through transfusion.


Cell Membrane Repair Assay Using a Two-photon Laser Microscope.
Numerous pathophysiological insults can cause damage to cell membranes and, when coupled with innate defects in cell membrane repair or integrity, can result in disease. Understanding the underlying molecular mechanisms surrounding cell membrane repair is, therefore, an important objective to the development of novel therapeutic strategies for diseases associated with dysfunctional cell membrane dynamics. Many in vitro and in vivo studies aimed at understanding cell membrane resealing in various disease contexts utilize two-photon laser ablation as a standard for determining functional outcomes following experimental treatments. In this assay, cell membranes are subjected to wounding with a two-photon laser, which causes the cell membrane to rupture and fluorescent dye to infiltrate the cell. The intensity of fluorescence within the cell can then be monitored to quantify the cell's ability to reseal itself. There are several alternative methods for assessing cell membrane response to injury, as well as great variation in the two-photon laser wounding approach itself, therefore, a single, unified model of cell wounding would beneficially serve to decrease the variation between these methodologies. In this article, we outline a simple two-photon laser wounding protocol for assessing cell membrane repair in vitro in both healthy and dysferlinopathy patient fibroblast cells transfected with or without a full-length dysferlin plasmid.


Role of 3D SPACE sequence and susceptibility weighted imaging in the evaluation of hydrocephalus and treatment-oriented refined classification of hydrocephalus.
The aim of our study was to evaluate the diagnostic utility of three-dimensional sampling perfection with application optimized contrast using different flip angle evolution (3D SPACE) sequence and Susceptibility Weighted Imaging (SWI) in hydrocephalus and to propose a refined definition and classification of hydrocephalus with relevance to the selection of treatment option. A prospective study of 109 patients with hydrocephalus was performed with magnetic resonance imaging (MRI) brain using standardized institutional sequences along with additional sequences 3D SPACE and SWI. The images were independently read by two senior neuroradiologists and the etiopathogenesis of hydrocephalus was arrived by consensus. With conventional sequences, 46 out of 109 patients of hydrocephalus were diagnosed as obstructive of which 21 patients showed direct signs of obstruction and 25 showed indirect signs. In the remaining 63 patients of communicating hydrocephalus, cause could not be found out in 41 patients. Whereas with 3D SPACE sequence, 88 patients were diagnosed as obstructive hydrocephalus in which all of them showed direct signs of obstruction and 21 patients were diagnosed as communicating hydrocephalus. By including SWI, we found out hemorrhage causing intraventricular obstruction in three patients and hemorrhage at various sites in 24 other patients. With these findings, we have classified the hydrocephalus into communicating and noncommunicating, with latter divided into intraventricular and extraventricular obstruction, which is very well pertaining to the selection of surgical option. We strongly suggest to include 3D SPACE and SWI sequences in the set of routine MRI sequences, as they are powerful diagnostic tools and offer complementary information regarding the precise evaluation of the etiopathogenesis of hydrocephalus and have an effective impact in selecting the mode of management.


Respiratory viruses associated with severe mechanically ventilated pneumonia in children.
The burden of pneumonia, especially that caused by respiratory viruses, is markedly high in the pediatric age group. This study aimed to assess viral agents causing severe pneumonia among mechanically ventilated patients. Nonbronchoscopic bronchoalveolar lavage was performed for pediatric patients having severe pneumonia indicated for mechanical ventilation to be tested with a multiplex PCR immediate diagnosis of their etiologic pathogen. Among the 75 patients recruited, viral agents were detected in 73.4% of cases. Rhinovirus and respiratory syncytial virus (RSV) were the most common viruses detected in 32.1% and 29.5%, respectively. The rate of viral infection showed a clear increased incidence in the winter season. The mortality rate among viral-associated severe pneumonia reached 56.36%. Odds of mortality increased threefolds in presence of comorbid conditions and 10-folds with congenital heart disease. The study demonstrated the neglected importance of rhinovirus besides RSV in causing severe critical pneumonia in the pediatric age.


[Perforation of the ileum due to tuberculosis].
The paper presents a 26-year old female patient who was operated two times due to complications of ileal tuberculosis. The first operation was caused by intestinal perforation and the second by external fistula. Diagnosis of tuberculosis was established owing to microscopical examination of specimens.


COVID-19 Outbreak Among Three Affiliated Homeless Service Sites - King County, Washington, 2020.
On March 30, 2020, Public Health - Seattle and King County (PHSKC) was notified of a confirmed case of coronavirus disease 2019 (COVID-19) in a resident of a homeless shelter and day center (shelter A). Residents from two other homeless shelters (B and C) used shelter A's day center services. Testing for SARS-CoV-2, the virus that causes COVID-19, was offered to available residents and staff members at the three shelters during March 30-April 1, 2020. Among the 181 persons tested, 19 (10.5%) had positive test results (15 residents and four staff members). On April 1, PHSKC and CDC collaborated to conduct site assessments and symptom screening, isolate ill residents and staff members, reinforce infection prevention and control practices, provide face masks, and advise on sheltering-in-place. Repeat testing was offered April 7-8 to all residents and staff members who were not tested initially or who had negative test results. Among the 118 persons tested in the second round of testing, 18 (15.3%) had positive test results (16 residents and two staff members). In addition to the 31 residents and six staff members identified through testing at the shelters, two additional cases in residents were identified during separate symptom screening events, and four were identified after two residents and two staff members independently sought health care. In total, COVID-19 was diagnosed in 35 of 195 (18%) residents and eight of 38 (21%) staff members who received testing at the shelter or were evaluated elsewhere. COVID-19 can spread quickly in homeless shelters; rapid interventions including testing and isolation to identify cases and minimize transmission are necessary. CDC recommends that homeless service providers implement appropriate infection control practices, apply physical distancing measures including ensuring resident's heads are at least 6 feet (2 meters) apart while sleeping, and promote use of cloth face coverings among all residents (1).


Ultrafast Imaging of Cardiomyocyte Contractions by Combining Scanning Ion Conductance Microscopy with a Microelectrode Array.
Beating cardiomyocytes undergo fast morphodynamics during the contraction-relaxation cycle. However, imaging these morphodynamics with a high spatial and temporal resolution is difficult, owing to a lack of suitable techniques. Here, we combine scanning ion conductance microscopy (SICM) with a microelectrode array (MEA) to image the three-dimensional (3D) topography of cardiomyocytes during a contraction-relaxation cycle with 1 μm spatial and 1 ms time resolution. We record the vertical motion of cardiomyocytes at many locations across a cell by SICM and synchronize these data using the simultaneously recorded action potential by the MEA as a time reference. This allows us to reconstruct the time-resolved 3D morphology of cardiomyocytes during a full contraction-relaxation cycle with a raw data rate of 200 μs/frame and to generate spatially resolved images of contractile parameters (maximum displacement, time delay, asymmetry factor). We use the MEA-SICM setup to visualize the effect of blebbistatin, a myosin II inhibitor, on the morphodynamics of contractions. Further, we find an upper limit of 0.02% for cell volume changes during an action potential. The results show that MEA-SICM provides an ultrafast imaging platform for investigating the functional interplay of cardiomyocyte electrophysiology and mechanics.


Patient-related outcomes five years after coronary artery bypass graft surgery.
For five years, we prospectively studied 353 consecutive patients undergoing first-time coronary artery bypass graft surgery (CABG) for stable angina in the North of England. Angina was present before surgery in nearly all patients, in 20% 3 months after surgery, and in 48% after 60 months. The Nottingham Health Profile, showed a significant improvement in perceived health status (PHS) 12 and 60 months after surgery compared with preoperation. However, PHS at 60 months was worse than at 12 months in the dimensions 'pain' and 'physical mobility' in part 1, and in 'looking after the home' and 'taking holidays' in part 2. Employment rates were 36%, 34% and 21%, before, and 12 and 60 months after surgery, respectively. Working at 12 and 60 months was associated with age below retirement age, work preoperation and absence of angina, and at 12 months also with male gender and waiting time < 6 months. This study describes everyday clinical practice. The significant improvement in angina symptoms and PHS after CABG persists for at least 5 years. However, only one third of patients in this geographical area return to work, and this is not solely dependent on clinical symptoms.


Cell surface proteins of wholeXenopus embryos identified by radioiodination.
We have examined the proteins ofXenopus whole oocytes and embryos that are accessible to surface iodination. These cell surface proteins appear to undergo stagespecific modulation during development. The most pronounced changes were observed between oocytes and the 32-cell stage when the number of labelled proteins doubled, and between early and late gastrula when the complexity declined by two thirds. The simplification of the pattern during gastrulation may reflect changes in cell position as endodermal cells move inside leaving ectodermal cells at the external surface. The lectin binding patterns for NP-40 solubilized proteins extracted from oocytes and embryos also changed in a stage-dependent manner. Con A and WGA recognized a complex pattern of glycoproteins containing glucose and mannose residues. In contrast, SAB and RCA binding to galactose residues recognized far fewer glycoproteins. Many of the observed changes occurred during cleavage stages before embryonic gene transcription is initiated and may be due to post-translational modifications.


Integrative taxonomy of Hemimycale (Hymedesmiidae: Poecilosclerida: Demospongiae) from Southeastern Brazil, with the description of two new species.
Two new species of Hemimycale from Southeastern Brazil are described in this study with the use of morphological and molecular data. Hemimycale oxeata sp. nov. is orange salmon colored in life and has unique oxeote like tornote spicules in addition to the typical (subtylo-)strongyles of the genus. Hemimycale ceadensis sp. nov. is reddish orange in life and has raised, tiny pore sieves, and subtylostrongyles with asymmetrical ends and raphides as microscleres. The diagnosis of the genus Hemimycale was slightly modified for the inclusion of the new species. Maximum-Likelihood analyses of 18S rRNA and COI sequences resulted in the clustering of both new species with the type species of the genus, thus confirming our morphological identification. The value of anatomical characters of pore sieves for diagnosing species and the genus is discussed. A key for species identification is also furnished.


Optimization of a fermented soy product formulation with a kefir culture and fiber using a simplex-centroid mixture design.
The objective of this work was to optimize a fermented soy product formulation with kefir and soy, oat and wheat fibers and to evaluate the fiber and product characteristics. A simplex-centroid mixture design was used for the optimization. Soymilk, soy, oat and wheat fiber mixtures, sucrose and anti-foaming agent were used for the formulation, followed by thermal treatment, cooling and the addition of flavoring. Fermentation was performed at 25 °C with a kefir culture until a pH of 4.5 was obtained. The products were cooled, homogenized and stored for analysis. From the mathematical models and variables response surface and desirability an optimal fermented product was formulated containing 3% (w/w) soy fiber. Compared with the other formulations, soy fermented product with 3% soy fiber had the best acidity, viscosity, syneresis, firmness and Lactococcus lactis count.


Towards reliable identification of male Dicerura: descriptions of three new and seven poorly known species in the Palearctic region (Diptera: Cecidomyiidae, Porricondylinae).
The taxonomy of Dicerura Kieffer, 1898, a genus of Porricondylinae now comprising 32 species in the Holarctic region, is revised. Three new species are described based on morphological characters of male adults: D. jakovlevi Jaschhof Spungis sp. nov. (from Finland), D. penttineni Jaschhof Spungis sp. nov. (Finland), and D. yezoensis Jaschhof Spungis sp. nov. (Japan). Dicerura padi Mamaev, 1975 syn. nov. is revealed to be a junior synonym of D. furculata Mamaev, 1968. Seven species, whose original descriptions are from a present-day perspective inadequate for the purpose of identification, are redescribed: D. barbata Mamaev, 1966; D. formosa Mamaev, 1998; D. foliicola Mamaev, 1968; D. furculata; D. iridis (Kaltenbach, 1873); D. stipator Mamaev, 1972; and D. unidentata Spungis, 1987. A key to males of Palearctic Dicerura is provided. New faunistic records are presented for D. barbata; D. complicata Spungis, 1987; D. dentata Spungis, 1979; D. formosa; D. fungicola (Mamaev, 1964); D. mixta Spungis, 1987; and D. unidentata. Male genitalic characters are shown to be useful to a certain extent for structuring the species diversity found within the genus Dicerura. The following groups of species are defined: iridis group (with nine species), dentata group (six species), fungicola group (four species), and formosa group (four species). Six of the species whose morphology is adequately known cannot be grouped within the proposed scheme, indicating the need for further character analysis and continuing search for yet undiscovered species that are assumed to exist in large numbers.


RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair.
Protein ubiquitylation and sumoylation play key roles in regulating cellular responses to DNA double-strand breaks (DSBs). Here, we show that human RNF4, a small ubiquitin-like modifier (SUMO)-targeted ubiquitin E3 ligase, is recruited to DSBs in a manner requiring its SUMO interaction motifs, the SUMO E3 ligases PIAS1 and PIAS4, and various DSB-responsive proteins. Furthermore, we reveal that RNF4 depletion impairs ubiquitin adduct formation at DSB sites and causes persistent histone H2AX phosphorylation (γH2AX) associated with defective DSB repair, hypersensitivity toward DSB-inducing agents, and delayed recovery from radiation-induced cell cycle arrest. We establish that RNF4 regulates turnover of the DSB-responsive factors MDC1 and replication protein A (RPA) at DNA damage sites and that RNF4-depleted cells fail to effectively replace RPA by the homologous recombination factors BRCA2 and RAD51 on resected DNA. Consistent with previous data showing that RNF4 targets proteins to the proteasome, we show that the proteasome component PSMD4 is recruited to DNA damage sites in a manner requiring its ubiquitin-interacting domains, RNF4 and RNF8. Finally, we establish that PSMD4 binds MDC1 and RPA1 in a DNA damage-induced, RNF4-dependent manner and that PSMD4 depletion cause MDC1 and γH2AX persistence in irradiated cells. RNF4 thus operates as a DSB response factor at the crossroads between the SUMO and ubiquitin systems.


Isolated central nervous system relapse of acute lymphoblastic leukemia.
Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer and may exhibit central nervous system (CNS) involvement. Advances in chemotherapy and effective CNS prophylaxis have significantly decreased the incidence of CNS relapse of ALL to 5-10%. Here, we report the case of a patient with isolated CNS relapse of standard risk group pre-B-cell type ALL in an 11-year-old girl, relapsed 3 years after successful completion of chemotherapy. An 11-year-old girl visited our hospital complaining of headache, dizziness, vomiting, and visual field defects. Neurological examination revealed left-side homonymous hemianopsia. Brain magnetic resonance imaging showed a large irregular dural-based sulcal hematoma in the right parietal and occipital lobes. Surgery to remove the hematoma revealed the existence of hematopoietic malignancy after pathologic evaluation. Bone marrow biopsy was subsequently performed but showed no evidence of malignancy.


Additives for Superconformal Gold Feature Filling.
An overview of the effect of additives on Au electrodeposition from Na3Au(SO3)2 based electrolytes is presented with an emphasis on filling of fully metallized recessed surface features such as trenches and vias. The impact of heavy metals additives Tl+, Pb2+, and Bi3+ is reviewed and accompanied by a brief survey of the effects of Sb3+, Te4+, SeCN-, 3-mercapto-1-propanesulfonic acid (MPS) and polyethyleneimine (PEI) additions. The addition of Tl+, Pb2+, Bi3+ or Sb3+ accelerates the kinetics of Au(SO3)2 3- reduction to Au, as manifest in hysteretic voltammetry and rising chronoamperometric transients, and yields bright specular deposits. Gold deposition with Pb2+ addition exhibits superconformal filling in sub-micrometer trenches while Bi3+ addition induces a more extreme bottom-up filling, but Tl+ and Sb3+ additions yield essentially conformal deposition for the conditions examined. Modest acceleration and hysteresis observed with Te4+ addition reflect roughening due to limited nucleation, 3D growth and delayed coalescence, rather than catalysis, and are associated with conformal feature filling. Unlike the other additives, SeCN-, MPS and PEI inhibit the deposition kinetics. Breakdown of suppression during deposition in micrometer size trenches is biased toward recessed surfaces where the flux of suppressor is constrained, yielding localized deposition and superconformal filling.


Acute severe methotrexate toxicity in patients with psoriasis: a case series and discussion.
Methotrexate (MTX) is considered a relatively safe drug when prescribed at low-dose regimens not exceeding 25 mg/week. Severe acute toxicity is rare and presents with mucositis, cutaneous ulceration and pancytopenia. Most cases occur as the result of inadvertent overdosing due to erroneously taking the drug daily. However, concomitant factors such as older age, co-medication and renal failure may increase the drug's toxicity. We report four consecutive cases of acute MTX toxicity in patients with psoriasis vulgaris. In three patients, MTX was erroneously taken daily for 2-4 weeks. All three patients recovered following MTX withdrawal and intensive treatment. The fourth patient was taking 7.5 mg weekly MTX as prescribed, but had concomitant factors and died. Although low-dose MTX appears to be a safe medication, acute MTX toxicity can be a life-threatening emergency. Greater awareness of possible MTX toxicity is still needed for its prevention, early diagnosis and management.


Subdiaphragmatic bronchogenic cysts: Case series and literature review.
Bronchogenic cysts are congenital malformations caused by aberrant foregut budding. They major occur in the thorax, with subdiaphragmatic cases being uncommon. Here, we present a series of 19 patients diagnosed with subdiaphragmatic bronchogenic cysts histopathologically at a single institution in China from 2012 to 2021. A literature review was also conducted by searching the PubMed database using keywords related to "bronchogenic cysts" and "subdiaphragmatic," yielding 107 cases. Taken together, the 126 cases had a median age of 41.0 years (interquartile range, 30.0-51.0 years) and 62 of them were male (49.2%). The cysts were most commonly detected in the left adrenal region (36.2%), followed by the pancreatic region (11.5%) and gastric cardia/lesser curvature of the stomach (9.2%). All patients except two underwent surgery for a definite diagnosis, symptom alleviation, and (or) malignancy prevention. Most patients recovered fast and were discharged from the hospital within 1 week after surgery, and the surgical complications were infrequent. The prognosis was generally favorable, as no recurrence was reported during the follow-up as long as 77 months.


Variations in Neurodevelopmental Outcomes in Children with Prenatal SSRI Antidepressant Exposure.
Mood disorders and treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy are common and both pose neurodevelopmental risks. This often makes the decision to treat prenatal depression with pharmacotherapy (i.e., antidepressants) challenging for clinicians and mothers. SSRIs block the reuptake of the neurotransmitter serotonin (5HT) and given its developmental role, it is not inconceivable that early changes in 5HT signaling could have an impact on early brain development. Identifying long-term neurodevelopmental effects of prenatal SSRI exposure is challenging in humans due to difficulties in distinguishing the effect of the drug from mother's mood during pregnancy and everyday environment in which the child lives, all of which contribute to shaping emotional, cognitive, and social development long after birth. In this review, we focus on the long-term neurobehavioral effects in childhood illustrating wide variations in outcomes revealing that some, but not all children appear to be affected by prenatal SSRI exposure. Emerging research reports findings that are beginning to distinguish the impact of genetic factors and the environment from prenatal medication exposure. Future research is needed to identify genetic, maternal, and environmental factors that put some children at developmental risk and others who may even benefit from maternal SSRI treatment. Birth Defects Research 109:909-923, 2017.© 2017 Wiley Periodicals, Inc.


"Cap" sequences in poly(A)-rich RNA from dry wheat embryos.
Although template-active RNA in dry seeds and embryos has attracted widespread interest, there have been no published reports about 5'-terminal "capping" sequences in such RNA. Boro[3H]hydride labeling of periodate-oxidized termini and high performance liquid chromatography of cap oligonucleotides have been used to compare terminal sequences in poly(A)-rich RNA from dry and germinating embryos. As is the case in germinating embryos, poly(A)-rich RNA from dry embryos contains only "type 0" cap sequences, i.e., m7G(5')ppp(5')N, in which m7G is the 7-methylguanosine cap and N is any of the classical ribonucleosides: adenosine (A), guanosine (G), cytidine (C),a nd uridine (U). Striking differences between the cell-free translational capacities of bulk messenger RNA (mRNA) populations from dry and germinating embryos are not reflected in signal differences in their proportions of "type 0" cap structures: in general, there is approximately 40% m7G(5')ppp(5')A, with roughly equivalent amounts of m7G(5')ppp(5')G and m7G(5')ppp(5')C accounting for most of the remaining sequences. The findings with mRNA from dry plant embryos serve to emphasize interesting differences between patterns of methylation in the capped and uncapped RNA molecules in higher plants and animals; the differences have not been previously noted in the literature and are the subject of brief comment in this paper.


State-dependent spike and local field synchronization between motor cortex and substantia nigra in hemiparkinsonian rats.
Excessive beta frequency oscillatory and synchronized activity has been reported in the basal ganglia of parkinsonian patients and animal models of the disease. To gain insight into processes underlying this activity, this study explores relationships between oscillatory activity in motor cortex and basal ganglia output in behaving rats after dopamine cell lesion. During inattentive rest, 7 d after lesion, increases in motor cortex-substantia nigra pars reticulata (SNpr) coherence emerged in the 8-25 Hz range, with significant increases in local field potential (LFP) power in SNpr but not motor cortex. In contrast, during treadmill walking, marked increases in both motor cortex and SNpr LFP power, as well as coherence, emerged in the 25-40 Hz band with a peak frequency at 30-35 Hz. Spike-triggered waveform averages showed that 77% of SNpr neurons, 77% of putative cortical interneurons, and 44% of putative pyramidal neurons were significantly phase-locked to the increased cortical LFP activity in the 25-40 Hz range. Although the mean lag between cortical and SNpr LFPs fluctuated around zero, SNpr neurons phase-locked to cortical LFP oscillations fired, on average, 17 ms after synchronized spiking in motor cortex. High coherence between LFP oscillations in cortex and SNpr supports the view that cortical activity facilitates entrainment and synchronization of activity in basal ganglia after loss of dopamine. However, the dramatic increases in cortical power and relative timing of phase-locked spiking in these areas suggest that additional processes help shape the frequency-specific tuning of the basal ganglia-thalamocortical network during ongoing motor activity.


Strain rate effect on the failure properties of tendons.
The purpose of this study is to evaluate the effect of strain rate on the failure properties of tendons. Seventy-five chicken flexor digitorum profundus (FDP) tendons were tensile tested at 15 strain rates, ranging from 0.05 to 150 per cent/s. Results showed that strain rate had little effect on the shape of the stress-strain curve. No significant change was observed in the toe region, while the slope of the linear region increased with the increase in strain rate. Generally, the ultimate tensile strength (UTS) and elastic modulus increased significantly as strain rate increased (p < 0.01), while no significant change in strain at UTS (p > 0.01) was observed. It was found the change in failure properties of tendons was not significant, with small change in strain rate.


Role of ethical beliefs and attitudes of dental students in providing care for HIV/AIDS patients.
Dental care has remained as an unmet need for people living with HIV/AIDS (PLWHAs). Dental students are considered as future healthcare workforce and having beliefs which are discriminating may have negative attitudes towards providing care to these individuals (Azodo et al., 2010). The study aimed to assess the ethical beliefs and attitudes of dental students towards PLWHAs for providing care. It is a descriptive correlational and cross sectional study. Nine public and private dental schools in Malaysia participated in the study. Data was collected using a validated self-administered questionnaire. A total of 481 dental students participated in this study, yielding response rate of 78%. Majority of the participants (74%) believed that patients' HIV status should be disclosed to patients' sexual partner without permission. Approximately 60% of the participants reported that rooms/beds of HIV patients should be clearly marked. Regarding patient disease status 28% of the students reported that it is appropriate to test a patient for HIV/AIDS without patient's permission. Only Fifty five percent of the students expressed the willingness to treat HIV patients and 49% reported to held fear of getting infected while treating patients with HIV/AIDS. Sixty four percent of the participants reported to be more comfortable giving care to non-HIV patients than HIV-positive patients. Dental students' ethical beliefs about HIV/AIDS were not consistent with the ethical principles as stated in the code of ethics and they held negative attitudes towards PLWHAs. Ethical beliefs were found to be a determinant that may influence future attitudes of these students towards individuals with HIV/AIDS when providing care.


The Kidney Awareness Registry and Education (KARE) study: protocol of a randomized controlled trial to enhance provider and patient engagement with chronic kidney disease.
Chronic kidney disease (CKD) is common and is associated with excess mortality and morbidity. Better management could slow progression of disease, prevent metabolic complications, and reduce cardiovascular outcomes. Low patient awareness of CKD and ineffective patient-provider communication can impede such efforts. We developed provider and patient-directed interventions that harness health information technology to enhance provider recognition of CKD and delivery of guideline concordant care and augment patient understanding and engagement in CKD care. We report the design and protocol of the Kidney Awareness Registry and Education (KARE) Study, a 2x2 factorial randomized controlled trial that examines the impact of a multi-level intervention on health outcomes among low-income English, Spanish and Cantonese-speaking patients with CKD in a safety net system. The intervention includes: (1) implementation of a primary care electronic CKD registry that notifies practice teams of patients' CKD status and employs a patient profile and quarterly feedback to encourage provision of guideline-concordant care at point-of-care and via outreach; and (2) a language-concordant, culturally-sensitive self-management support program that consists of automated telephone modules, provision of low-literacy written patient-educational materials and telephone health coaching. The primary outcomes of the trial are changes in systolic blood pressure (BP) and the proportion of patients with BP control (≤ 140/90 mmHg) after one year. Secondary outcomes include patient understanding of CKD, participation in healthy behaviors, and practice team delivery of guideline-concordant CKD care. Results from the KARE study will provide data on the feasibility, effectiveness, and acceptability of technology-based interventions that support primary care efforts at improving health outcomes among vulnerable patients with CKD. ClinicalTrials.gov, number: NCT01530958.


Acute asthma in a children's emergency room: a clinical audit and management guideline proposal.
Adequate asthma control in children includes optimal medical management of acute exacerbations of the disorder. Asthma guidelines provide critical information and serve as quick reference decision-support material for clinicians. This clinical audit aimed at evaluating emergency management of acute asthma as well as proposing for use a management protocol, with the view of improving quality of care. This is a retrospective audit of the management of acute asthma over 18 months (October 2000-April 2002) Relevant data related to diagnostic and therapeutic procedures in thirty asthmatics were extracted and examined. There were 20 males and 10 females (M:F ratio 2:1). Mean age (range) was 5.9 years (10 months-12.5 years) and mean (range) duration of symptoms prior to presentation was 1.9 days (2 hours-8 days). Trigger factors, current medications, clinical and functional indices of severity of acute asthma were not documented in 73.3%, 93.3% and 96.7% cases respectively. Diagnostic labels used in 28 (93.3%) did not reflect the acute nature or severity of the acute episode. Although nebulized salbutamol and oral corticosteroids were used for 80.0% of cases, aminophylline was frequently prescribed in addition. Discharge medications and instructions, including follow up in the respiratory clinic were not given in 21 (70.0%) and 28 (93.3%) cases respectively. This audit noted that the overall management of acute asthma in the emergency room and the documentation of crucial information vital in the acute and long-term care of asthmatics were inadequate. We propose and recommend for use in the Children's Emergency Room, acute asthma management guideline and protocol-based asthma paper records as well as computerization of patient records.


Discovery of an excellent IR absorbent with a broad working waveband: Cs(x)WO3 nanorods.
Cs(0.32)WO(3) nanorods, synthesized by a designed water controlled-release process, exhibited strong absorption of light in a wide waveband of 800-15,000 nm, quick conversion of photo-energy to local heat and excellent heat rays cutoff character.


Batch Mode TD($\lambda$ ) for Controlling Partially Observable Gene Regulatory Networks.
External control of gene regulatory networks (GRNs) has received much attention in recent years. The aim is to find a series of actions to apply to a gene regulation system making it avoid its diseased states. In this work, we propose a novel method for controlling partially observable GRNs combining batch mode reinforcement learning (Batch RL) and TD() algorithms. Unlike the existing studies inferring a computational model from gene expression data, and obtaining a control policy over the constructed model, our idea is to interpret the time series gene expression data as a sequence of observations that the system produced, and obtain an approximate stochastic policy directly from the gene expression data without estimation of the internal states of the partially observable environment. Thereby, we get rid of the most time consuming phases of the existing studies, inferring a model and running the model for the control. Results show that our method is able to provide control solutions for regulation systems of several thousands of genes only in seconds, whereas existing studies cannot solve control problems of even a few dozens of genes. Results also show that our approximate stochastic policies are almost as good as the policies generated by the existing studies.


Elevated transferrin receptor content in human prostate cancer cell lines assessed in vitro and in vivo.
Transferrin receptors (TfR) were measured in benign and malignant prostatic cells by performing Scatchard analysis following the administration of 125I-transferrin. Established human prostate cancer cell lines (PC-3 and DU-145) as well as biologically aggressive variants (PC-3 ASC and PC-3 DES) were shown to possess significant levels of high affinity TfR when assessed in vitro. In contrast, TfR content was negligible in cultured stromal cell fractions derived from human benign prostatic hyperplasia (BPH) specimens. Scatchard analysis was also performed on in vivo derived prostatic tissues: tumors resulting from the subcutaneous xenografting of PC-3 ASC cells into athymic, nude mice and fresh BPH surgical specimens. These tissues were dissociated and their stromal and epithelial components separated. TfR were only detected in the epithelial component of both malignant and benign epithelial cells. PC-3 ASC tumor cells exhibited TfR levels comparable to their in vitro expression and these levels were 10-fold greater than in the BPH cells. These findings suggest that elevated TfRs may serve as another useful marker of the transformed phenotype within human prostate tumor systems.


Improved Prognostic Precision in Uveal Melanoma through a Combined Score of Clinical Stage and Molecular Prognostication.
Prognosis of uveal melanoma (UM) is assessed using clinical staging or molecular testing. Two modalities often used for prognostication are the American Joint Committee on Cancer (AJCC) staging and a tumor gene expression profile (GEP), the outcomes of which are often discordant. This article discusses a total risk score created to combine the discordant information from both sources. A retrospective case series was conducted of all patients presenting with UM over 6 years to 2 referral centers. Each tumor was classified using the AJCC and the GEP. A total risk score was calculated for each patient using results from both AJCC and GEP. Kaplan-Meier analysis of metastasis-free survival was used to compare groups. A total of 294 patients were included in the study. Kaplan-Meier estimates showed significant curve separation between individual AJCC and GEP risk groups. The combined total risk score provided an accurate estimate of prognosis that incorporated results from both AJCC and GEP. Clinical staging and molecular prognostication of UM can be discordant. There is important information provided by each system that is not provided by the other. The total risk score provides a simple method to combine information from both AJCC stage and the GEP class in order to provide patients and care teams with a more complete understanding of metastatic risk.


The dynamics of technological change in medicine.
This paper contrasts a dynamic and interactive view of technological change with the linear model of medical innovation that is still so deeply ingrained in many policy discussions. In particular, it focuses on the role of feedback mechanisms between the users and the developers of medical technology and the demand and supply forces (including competition among medical specialties) determining this feedback. It explores three distinct mechanisms by which technological change may contribute to rising health care spending: intensity of use of existing technology, introduction of new technologies, and expanded application of these new technologies.


Data Normalization of Urine miRNA Profiling from Head and Neck Cancer Patients Treated with Cisplatin.
The microRNA (miRNA) expression profile by qRT-PCR depends directly on the most appropriate normalization strategy adopted; however, currently there is no universally adequate reference gene. Therefore, this study aimed to determine, considering RNA-Seq results, the most adequate endogenous normalizer for use in the relative quantification of urine miRNAs from head and neck cancer patients, treated with cisplatin chemoradiotherapy. The massive sequencing was performed to identify the miRNAs differentially expressed between the group with cisplatin nephrotoxicity (n = 6) and the one without (n = 6). The candidate endogen normalizer was chosen according to four criteria: (1) the miRNA must be expressed in most samples; (2) the miRNA must have a fold change value between 0.99 and 1.01; (3) the miRNA must have a p-value ≥ 0.98; and (4) the miRNA must not be commented on by the final GeneGlobe (Qiagen, Hilden, Germany) analysis. Four miRNAs met all the criteria (hsa-miR-363-5p, hsa-miR-875-5p, hsa-miR-4302, and hsa-miR-6749-5p) and were selected for validation by qRT-PCR in a cohort of 49 patients (including the 12 sequencing participants). Only hsa-miR-875-5p was shown to be an adequate normalizer for the experimental condition under investigation, as it exhibited invariant expression between the two groups.


[The medical faculty of the Wittenberg University 1502-1817 - the stats of research].
This essay provides an overview of the scientific literature regarding the history of the Faculty of Medicine at the University of Wittenberg, Germany. The University of Wittenberg was the domain, where Martin Luther and Philipp Melanchton worked; in the 16th century it was one of the greatest universities of the Holy Roman Empire. There has been a controversial discussion on the history of the Faculty of Medicine since the mid-19th century. Since the 1980s, it is an accepted and studied field of research on its own. The various publications on the topic can be subdivided into three specific areas: 1. Reformation and medicine, 2. biographic works on professors of medicine, and 3. historical works regarding social and librarian fields of research. The results of those works can be interpreted and merged in view of the Faculty of Medicine. However, for a revalidation of the faculty's role within an European scientific scene further scrutiny of sources is needed.


High-speed gradient parallel liquid chromatography/tandem mass spectrometry with fully automated sample preparation for bioanalysis: 30 seconds per sample from plasma.
In this work, a high-throughput and high-performance bioanalytical system is described that is capable of extracting and analyzing 1152 plasma samples within 10 hours. A Zymark track robot system interfaced with a Tecan Genesis liquid handler was used for simultaneous solid-phase extraction of four 96-well plates in a fully automated fashion. The extracted plasma samples were injected onto four parallel monolithic columns for separation via a four-injector autosampler. The use of monolithic columns allowed for fast and well-resolved separations at a considerably higher flow rate without generating significant column backpressure. This resulted in a total chromatographic run cycle time of 2 min on each 4.6 x 100 mm column using gradient elution. The effluent from the four columns was directed to a triple quadrupole mass spectrometer equipped with an indexed four-probe electrospray ionization source (Micromass MUX interface). Hence, sample extraction, separation, and detection were all performed in a four-channel parallel format that resulted in an overall throughput of about 30 s per sample from plasma. The performance of this system was evaluated by extracting and by analyzing twelve 96-well plates (1152) of human plasma samples spiked with oxazepam at different concentrations. The relative standard deviation (RSD) of analyte sensitivity (slope of calibration curve) across the four channels and across the 12 plates was 5.2 and 6.8%, respectively. An average extraction recovery of 77.6% with a RSD of 7.7% and an average matrix effect of 0.95 with a RSD of 5.2% were achieved using these generic extraction and separation conditions. The good separation efficiency provided by this system allowed for rapid method development of an assay quantifying the drug candidate and its close structural analog metabolite. The method was cross-validated with a conventional liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay.


The skin conductance orienting response to semantic stimuli: significance can be independent of arousal.
The characteristics of stimuli that elicit skin conductance responses (SCRs) have been conceptualized in varied ways, with strong emphasis on the significance or arousing quality of stimuli. Our goal was to determine whether "significance" can be shown to have an effect on SCRs independent of "arousal," using words as stimuli. Ratings of words indicated that significance is partially independent of arousal. In Study 1, SCRs from 43 participants during presentation of 20 significant, nonarousing words with a negative valence that were either depression related or potentially self-referent and 20 nonsignificant words matched on valence and arousal showed a main effect of significance. In Study 2 (N=44), significant, nonarousing words were sampled more broadly to examine the effects of self-reference and valence. Significance, rather than just negativity or self-reference, elicited SCRs independently of arousal. SCRs to significant words may reflect cognitive and attentional processes that, in turn, might prove useful for the assessment of the cognitive aspects of anxiety.


AFM study of the elastin-like biopolymer poly(ValGlyGlyValGly).
In this paper, we report an AFM study on the supramolecular structures adopted by the synthetic polypentapeptide poly(ValGlyGlyValGly), whose monomeric sequence is an abundant, simple building block of elastin. The polypeptide was analyzed by deposition from both methanolic and aqueous suspensions, showing different behaviors. In methanol, the polypeptide is able to evolve, in a time-dependent way, from layers to ribbons to beaded filaments. When the equilibrium is reached, the formation of well-defined dendritic structures is also observed. This restructuring of the polypentapeptide seems to be reminiscent of a sort of Rayleigh instability. When deposited from aqueous suspensions, the polypeptide self-assembles either in fibrillar networks or in amyloid-like patterns, both of them being found in elastin or elastin-related polypeptides. As a general finding, poly(ValGlyGlyValGly) seems to constitute an excellent mimetic of the supramolecular properties of native elastin.