Pre-clinical Comparison of a High-Definition 3-Dimensional Exoscope and an Operating Microscope: A Prospective Randomized Crossover Study.
The high-definition 3D operating exoscope is a new tool for surgical visualization and magnification that was designed to replace the operating microscope. However, the paucity of studies that have prospectively compared the two systems has made it difficult to draw clear recommendations. The purpose of this study was to compare the operating exoscope and the operating microscope in first-time users in a pre-clinical setting. Twenty-eight consecutive medical students were prospectively enrolled and randomized in a crossover design. Each student performed four exercises that required basic microsurgical skills. A tailored questionnaire (Comparison Assessment Tool) was used to subjectively compare the two systems using a 5-point Likert scale. The time needed to perform each task was recorded. A post-intervention cross-sectional survey was conducted to assess the overall quality of the trial session. The operating exoscope was preferred over the operating microscope by most of the students in all items of the Comparison Assessment Tool, particularly with regard to "focusing" and "image quality" (n = 25, 92.6%). A significant difference between groups was found in two exercises that were easier to perform with the operating exoscope. Most of the students considered the overall quality of the evaluation experience to be "very good" (n = 25, 92.6%). The exoscope allows first-time users to better perform basic microsurgical tasks in a simulated clinical scenario compared to the operating microscope. Further prospective comparative studies will be needed to validate our preliminary findings in an actual clinical scenario.


Current strategies and possible perspectives of ultrasonic risk stratification of ischemic stroke in internal carotid artery disease.
Atherosclerotic alterations of the internal carotid artery frequently result in ischemic stroke. However, it remains unclear which specific factor mainly causes an increased risk of stroke. Constant improvements of the diagnostic possibilities of ultrasonic examinations provide increasingly profound insight into plaque alterations. If "risk plaque" could be reliably identified, the therapeutic decision for either medical or surgical treatment could be made more rationally. In this review, we summarize current developments in the ultrasound imaging of atherosclerotic changes in carotid artery disease with special emphasis on technical aspects and the rationale of contrast imaging of plaque vascularization. Methodological limitations and possible future applications are discussed.


Late paternity and stillbirth risk.
The role of paternal ageing on the incidence of some genetic diseases in offspring depends on the hypothesis that spontaneous mutations accumulate due to continuous cell divisions during spermatogenesis. We examined the effect of paternal age on the complex multifactorial character, stillbirth. In 3,619,647 Italian singletons born in 1990-1996 we evaluated stillbirth risk as a function of paternal ageing by means of multiple logistic regression models, which included maternal age and family education, as categorical covariates and interactions. The categorical risk was estimated for mothers and fathers beyond threshold ages of 35 and 40 years, respectively. Stillbirth risk increases with paternal ageing in mothers > or =30 years old, and maternal age and family education modify the impact. In families with low education, the risk accounts for odds ratio (OR) 1.015 [95% confidence interval (CI) 1.01-1.02] in mothers aged 30-34 years, and for OR 1.032 (95% CI 1.02-1.04) in mothers aged > or =35 years; in families with higher education the risk accounts for OR 1.008 (95% CI 1.00-1.02) and OR 1.025 (95% CI 1.01-1.04), respectively, in mothers aged 30-34 and > or =35 years. In these latter families, for mothers aged <35 and fathers > or =40 years the risk accounts for OR 1.12 (95% CI 1.00-1.25). The effect of paternal ageing on stillbirth risk is revealed in mothers aged > or =30 years and is modified by family education. In mothers aged 30-34 years from families with high education, the increase imputable to paternal ageing might be indicative of a genetic component.


How intracellular bacteria survive: surface modifications that promote resistance to host innate immune responses.
Bacterial pathogens regulate the expression of virulence factors in response to environmental signals. In the case of salmonellae, many virulence factors are regulated via PhoP/PhoQ, a two-component signal transduction system that is repressed by magnesium and calcium in vitro. PhoP/PhoQ-activated genes promote intracellular survival within macrophages, whereas PhoP-repressed genes promote entrance into epithelial cells and macrophages by macropinocytosis and stimulate epithelial cell cytokine production. PhoP-activated genes include those that alter the cell envelope through structural alterations of lipopolysaccharide and lipid A, the bioactive component of lipopolysaccharide. PhoP-activated changes in the bacterial envelope likely promote intracellular survival by increasing resistance to host cationic antimicrobial peptides and decreasing host cell cytokine production.


Intraocular pressure changes following topical ocular hypotensive medications washout.
To review the changes in intraocular pressure (IOP) following topical hypotensive medications washout in patients with primary open angle glaucoma (POAG), ocular hypertension (OHT) and uveitic glaucoma (UG)/OHT. The study included 120 patients with POAG, OHT and UG recruited from prospective clinical trials between February 2013 and July 2017. We excluded 20 eyes with IOP of ≤21 mm Hg, 11 eyes with previous incisional surgery and 17 eyes with incomplete data. UG eyes with active inflammation and on steroid treatment were excluded. Participants underwent a 1-month washout period from topical ocular hypotensive medications before IOP phasing. Comparisons were made between pre/post-washout IOP, and highest-recorded (peak) and post-washout IOP. A total of 110 eyes with POAG, 33 eyes with OHT and 43 eyes with UG were included for analysis. The mean pre-washout IOP was 18.1±3.3 mm Hg in POAG, 18.8±3.3 mm Hg in OHT and 17.9±8.8 mm Hg in UG; the mean post-washout IOP was 26.6±4.8 mm Hg, 26.4±3.9 mm Hg, 23.1±10.1 mm Hg in POAG, OHT and UG, respectively. The mean increase in IOP after washout was significantly lower in UG compared with POAG and OHT eyes (p=0.01). The percentage of eyes with post-washout IOP <22 mm Hg was 12.7% in POAG, 6.1% in OHT and 51.2% in UG. Active inflammation and steroid treatment contributes to elevated IOP in uveitis. Therefore, IOP may revert to normal once inflammation subsides. We recommend ocular hypotensive treatment washout to be considered in UG eyes that have IOP under control in the absence of recurrence of uveitis.


Intentional Discontinuation of Psychostimulants Used to Treat ADHD in Youth: A Review and Analysis.
Objectives: This paper reviews the literature on intentional discontinuation of psychostimulants in ADHD to summarize what is known about clinical course of controlled discontinuation and guide practitioners who are considering stopping these medications for youth with ADHD. Methods: A systematic search was executed in Cochrane CENTRAL, EMBASE, Psychinfo, and MEDLINE databases to identify all articles that addressed the topic of deprescribing of psychotropic medications in children and adolescents. Keywords and search strings were developed using "PICO" framework, involving Population of interest (<18 y.o.), Intervention ("discontinuation," "deprescribing," and synonyms), Comparator (continuation of specific medications), and Outcomes. Ten reviewers conducted the initial screen via a single reviewer system. Articles that met a set of three inclusionary criteria were selected for full text review and identification as specific to discontinuation of stimulants in ADHD. Results: The literature review identified 35 articles specifically addressing intentional deprescribing, discontinuation, tapering, or withdrawal of stimulants for children and adolescents with ADHD. In addition to providing broad support for the efficacy of stimulants to treat ADHD and reduce negative outcomes, there is a distinct population of children and adolescents with ADHD who do not relapse or deteriorate when taken off medications for ADHD. The majority of articles addressed either the re-emergence of ADHD symptoms or side effects, both desired and adverse, following discontinuation of stimulants. While confirming the ability of stimulants to treat ADHD in youth, our results support periodic consideration of trials of stopping medications to determine continued need. Conclusions: This systematic review summarizes the literature on deprescribing stimulants for ADHD in children and adolescents. Further research is needed to determine the optimal duration of treatment, identify patients that may benefit from medication discontinuation, and inform evidence-based guidelines for discontinuation when appropriate. More research is needed to understand and define the subgroup of youth who may succeed with stimulant discontinuation.


Increased apoptosis induction in CD4+ CD25+ Foxp3+ T cells contributes to enhanced disease activity in patients with rheumatoid arthritis through IL-10 regulation.
Abnormality in the number and function of regulatory T cells (Tregs) has been linked to initiation and progression in patients with Rheumatoid Arthritis (RA). This study aims to demonstrate the apoptosis status of regulatory T cells (Tregs) and its correlation with clinical activity of RA patients and the effect of interleukin-10 (IL-10) on Tregs apoptosis in RA. Apoptosis rates and its related molecules including Fas, Bcl-2, Caspase-3 and Caspase-8 were examined using flow cytometry. The correlation between the apoptosis level of Tregs and clinical activity parameters including ESR (erythrocyte sedimentation rate), CPR (C reactive protein), RF (Rheumatoid Factor) and DAS28 (Disease activity score 28) was analysed. PBMCs isolated from RA patients were cultured with IL-10 or anti-IL-10, and the apoptosis frequency of Tregs was then analyzed. The frequency of Tregs in active RA patients was decreased, and Fas, Caspase-3 and Caspase-8 expression on Tregs was much higher compared with the healthy subjects. The expression of anti-apoptotic protein, Bcl-2 on Tregs did not display significant changes between active RA patients and healthy subjects. There was a significantly positive correlation between the levels of apoptosis rates and Caspase-3 expression in Tregs and DAS28 of active RA patients. The apoptosis rates of Tregs in RA patients decreased or increased, respectively, following treatment with IL-10 or anti-IL-10 antibody in vitro. Apoptosis pathways are defective in Treg cells from RA patients with active disease. IL-10 treatment can modulate apoptosis in Tregs via extrinsic (type I) pathway, which may lead to restoration of the Tregs towards that of controlling autoimmune reaction in RA patients.


Expression of NF-κB, CD68 and CD105 in carotid atherosclerotic plaque.
Atherosclerotic plaque vulnerability is associated with cerebrovascular events in patients with carotid atherosclerosis. The aim of this study was to investigate the expression of inflammatory factors in carotid artherosclerotic plaques in order to explore its clinical significance in patients with carotid stenosis. Forty three patients with carotid stenosis were divided into symptomatic group (n=24) and asymptomatic group (n=19) based on clinical manifestation. All patients were treated with selective standard carotid endarterectomy (CEA); the carotid atherosclerotic plaques were removed surgically and studied pathologically to investigate the expression of nuclear factor-kappa κ (NF-κB), CD68 and CD105. The plaques were grouped into stable and unstable plaques based on thickness of the fibrous cap and the area of lipid-rich core in the plaques. The proportion of unstable plaques were significantly higher in symptomatic group than in asymptomatic group (70.8% vs. 63.2%, P=0.026). Results of immunohistochemisty staining showed that the expression of NF-κB, CD68 and CD105 in unstable plaques was higher than stable plaques (P<0.001). The association of the higher expression of these factors with instability of carotid plaque needs to be clarified in future study.


Frequency encoding for simultaneous display of multimodality images.
An original method for simultaneous display of functional and anatomic images, based on frequency encoding (FE), merges color PET with T1-weighted MR brain images, and grayscale PET with multispectral color MR images. A comparison with two other methods reported in the literature for image fusion (averaging and intensity modulation techniques) was performed. For FE, the Fourier transform of the merged image was obtained summing the low frequencies of the PET image and the high frequencies of the MR image. For image averaging, the merged image was obtained as a weighted average of the intensities of the two images to be merged. For intensity modulation, the red, green and blue components of the color image were multiplied on a pixel-by-pixel basis by the grayscale image. A comparison of the performances of the three techniques was made by three independent observers assessing the conspicuity of specific MRI and PET information in the merged images. For evaluation purposes, images from seven patients and a computer-simulated MRI/PET phantom were used. Data were compared with a chi-square test applied to ranks. For the depiction of MRI and PET information when merging color PET and T1-weighted MR images, FE was rated superior to intensity modulation and averaging techniques in a significant number of comparisons. For merging grayscale PET with multispectral color MR images, FE and intensity modulation were rated superior to image averaging in terms of both MRI and PET information. The data suggest that improved simultaneous evaluation of MRI and PET information can be achieved with a method based on FE.


APE1/Ref-1 interacts with NPM1 within nucleoli and plays a role in the rRNA quality control process.
APE1/Ref-1 (hereafter, APE1), a DNA repair enzyme and a transcriptional coactivator, is a vital protein in mammals. Its role in controlling cell growth and the molecular mechanisms that fine-tune its different cellular functions are still not known. By an unbiased proteomic approach, we have identified and characterized several novel APE1 partners which, unexpectedly, include a number of proteins involved in ribosome biogenesis and RNA processing. In particular, a novel interaction between nucleophosmin (NPM1) and APE1 was characterized. We observed that the 33 N-terminal residues of APE1 are required for stable interaction with the NPM1 oligomerization domain. As a consequence of the interaction with NPM1 and RNA, APE1 is localized within the nucleolus and this localization depends on cell cycle and active rRNA transcription. NPM1 stimulates APE1 endonuclease activity on abasic double-stranded DNA (dsDNA) but decreases APE1 endonuclease activity on abasic single-stranded RNA (ssRNA) by masking the N-terminal region of APE1 required for stable RNA binding. In APE1-knocked-down cells, pre-rRNA synthesis and rRNA processing were not affected but inability to remove 8-hydroxyguanine-containing rRNA upon oxidative stress, impaired translation, lower intracellular protein content, and decreased cell growth rate were found. Our data demonstrate that APE1 affects cell growth by directly acting on RNA quality control mechanisms, thus affecting gene expression through posttranscriptional mechanisms.


Interaction of Bacteriophages with the Immune System: Induction of Bacteriophage-Specific Antibodies.
In all cases when a bacteriophage makes a direct contact with a mammalian organism, it may challenge the mammalian immunological system. Its major consequence is the production of antibodies specific to the bacteriophage, particularly IgM, IgG, and IgA as the typical response. Here we present protocols applicable in studies of the ability of bacteriophage to induce specific antibodies; immunization to whole virions or to isolated phage proteins has been included. The protocols have been divided into three parts: purification, immunization, and detection (enzyme-linked immunosorbent assay, ELISA).


Spatio-temporal influences at the neural level of object recognition.
In late 1988, Miyashita published work reporting recordings of single cells in the inferotemporal cortex of the macaque monkey (Miyashita 1988 Nature 335 817-20). He described the responses of neurons to a sequence of random fractal pattern images, and how many of the neurons tested were seen to respond strongly to a subset of the images on the basis of sequence presentation order, i.e. appearance in time, rather than their spatial similarity. In this work, I describe a local Hebb-like learning rule which in conjunction with a simple feedforward neural architecture is capable of replicating the type of temporal-order association apparent in the cells from which he made recordings. The paper also advances reasons for requiring such learning by describing its possible role in establishing transformation invariant representations of objects.


Growth of mammalian cells at high oxygen concentrations.
Oxygen, although essential to the growth of mammalian cells in vitro and in vivo, has been widely reported to be toxic at concentrations at or above the oxygen concentration in culture medium equilibrated with air (approximately 200 microM). We were therefore surprised to note that a diploid human B-cell line (TK6) was able to proliferate normally while exposed to 380 microM-oxygen. This observation was extended to Vero (African Green monkey kidney) cells, and Sp2/0-derived murine transfectomas producing antibody. Using an experimental system with a high capacity for oxygen transfer, we determined the growth rates of the three cell lines at controlled oxygen concentrations ranging from 80 microM to 910 microM. Each of these cell types was able to grow normally at oxygen concentrations up to 360-380 microM. At oxygen concentrations above 380 microM, a significant increase in the apparent doubling times of the cells was observed. No adverse effect of oxygen on TK6 cell survival was seen for concentrations ranging from 60 microM to 410 microM. We conclude that exponential growth at nearly maximum growth rates was observed for Sp2/0-derived cells, TK6, and Vero cells at constant oxygen concentrations up to 400 microM (twice air saturation). These findings have substantial implications for process control in the production of cells and cell-derived materials. The intrinsic oxygen transfer rate of any cell culture vessel can be increased severalfold by raising the oxygen gas concentration.(ABSTRACT TRUNCATED AT 250 WORDS)


Carfilzomib, Lenalidomide, and Dexamethasone Followed by Lenalidomide Maintenance for Prevention of Symptomatic Multiple Myeloma in Patients With High-risk Smoldering Myeloma: A Phase 2 Nonrandomized Controlled Trial.
High-risk smoldering myeloma has a 5-year risk of progression to symptomatic multiple myeloma of approximately 75%. Treatment with lenalidomide decreases the risk of progression; however, novel triplet regimens are superior, and earlier disease may be more treatment sensitive. To evaluate the use of carfilzomib, lenalidomide, and dexamethasone (KRd) with lenalidomide maintenance therapy as early intervention in high-risk smoldering myeloma and to determine the rates of minimal residual disease (MRD)-negative complete response (CR). In this single-arm, single-center, phase 2 nonrandomized controlled trial, responses were evaluated at every cycle during KRd treatment and every 3 cycles subsequently. Bone marrow biopsies and imaging were performed by cycle 8 and then annually. The study enrolled patients from May 29, 2012, to July 23, 2020, at the National Institutes of Health Clinical Center, a highly specialized tertiary cancer center. Patient key eligibility criteria included a diagnosis of high-risk smoldering myeloma based on the Mayo Clinic, Spanish, and/or Rajkumar, Mateos, and Landgren criteria. Patients received eight 4-week cycles of intravenous carfilzomib 36 mg/m2 (first 2 doses, 20 mg/m2), dexamethasone (20 mg, cycles 1-4; 10 mg, cycles 5-8 twice weekly), and lenalidomide 25 mg (days 1-21) followed by twenty-four 28-day cycles of maintenance lenalidomide 10 mg (days 1-21). Stem cell harvest and storage were optional. The primary outcome was the MRD-negative CR rate. Key secondary outcomes included duration of MRD-negative CR and progression to multiple myeloma. A total of 54 patients (median age, 59 years [range, 40-79 years]; 30 men [55.6%]; and 2 Asian [3.7%], 15 Black [27.8%], 1 Hispanic [1.9%], and 36 White [66.7%] patients) were enrolled, with a median potential follow-up time of 31.9 months (range, 6.7-102.9 months). The MRD-negative CR rate was 70.4% (95% CI, 56.4%-82.0%), with a median sustained duration of 5.5 years (95% CI, 3.7 years to not estimable). The 8-year probability of being free from progression to multiple myeloma was 91.2% (95% CI, 67.4%-97.9%), and no deaths occurred. Nonhematologic grade 3 adverse events occurred in 21 patients (38.9%) and included thromboembolism, rash, and lung infection, with no grade 4 events. Results of this phase 2 nonrandomized controlled trial suggest that treatment of high-risk smoldering myeloma with novel triplet regimens, such as KRd and lenalidomide maintenance therapy, may alter the natural history of smoldering myeloma by significantly delaying development of end-organ disease. Randomized clinical trials are needed to confirm this favorable benefit-to-risk profile. ClinicalTrials.gov Identifier: NCT01572480.


Occurrence of abdominal bulging and hernia after open partial nephrectomy: a retrospective cohort study.
Abdominal bulging and incisional hernia are known sequelae after open partial nephrectomy (OPN) via a flank incision. Precise rates are not known. The aims of this study were to determine the rates of bulging and hernia after OPN, and to examine potential risk factors. A retrospective review was undertaken of 197 consecutive patients operated on with OPN via a flank incision between 2004 and 2014. After exclusion, 184 patients remained. Medical records and radiological images from the preoperative work-up, and follow-up after surgery at 3, 12 and 24 months, were reviewed. A visible bulge was noted in 36 of the 184 patients at clinical examination. Only 20 cases (12%) remained at the last follow-up. Radiological changes interpreted as a bulge were initially seen in 50 patients, while only 35 (19%) remained at the last radiological examination. Clinical incisional hernia was reported in five patients (3%), and radiological hernia was seen in 10 patients (5%). Patients who developed a hernia had a higher body mass index (30 vs 26 kg/m2, p = 0.02). Other demographic variables showed no significant correlation. Bulging is a common sequela after flank incision. The rate of incisional hernia after flank incision is comparable to rates after other forms of abdominal surgery. Further studies are required to evaluate the psychological and physiological effects of bulging, the pain and weakness caused, and the cosmetic embarrassment suffered by the patient.


Tracking hydrogen/deuterium exchange at glycan sites in glycoproteins by mass spectrometry.
Hydrogen/deuterium exchange coupled to mass spectrometry (HDX-MS) has emerged as a technique for studying glycoproteins, which are often refractory to classical methods. Glycan chains are generally assumed to exchange protons very rapidly, making them invisible to this technique. Here, we show that under conditions commonly used for HDX-MS, acetamido groups within glycan chains retain a significant amount of deuterium. Using mono- and polysaccharide standards along with glycopeptides from a panel of glycoproteins, we demonstrate that N-acetyl hexosamines, along with modified Asn side chains, are responsible for this effect. Model compounds for sialic acid also displayed similar exchange kinetics, but terminal sialic acids in the context of an entire glycan chain did not contribute to deuterium retention. Furthermore, the presence of sialic acid appears to enhance the exchange rate of the nearby N-acetyl glucosamines. The ability to detect deuterium exchange at the glycan level opens the possibility of applying HDX-MS to monitor glycan interactions and dynamics.


Isolation and characterization of NUC70, a cytoplasmic, hematopoietic apoptotic endonuclease.
Endonucleolytic DNA fragmentation is the common end point and the prevailing indicator of apoptosis. We have identified a 70-kDa endonuclease (NUC70) that is activated in drug-induced apoptosis of human hematopoietic cells. We purified NUC70 to homogeneity and generated a rabbit polyclonal antibody to distinguish it from previously identified nucleases. Biochemical characterization of isolated NUC70 demonstrates that it is Ca2+/Mg2+-dependent and active over a pH range of 6-8. When incubated with isolated HeLa nuclei, NUC70 was capable of generating internucleosomal DNA fragmentation. This endonucleolytic activity was inhibited by Zn2+, aurintricarboxylic acid, N-ethylmaleimide, spermine, and iodoacetamide. Western immunoblots using the anti-NUC70 antibody and DNA-SDS-polyacrylamide gel electrophoresis assays indicate that NUC70 expression and activity is restricted to human hematopoietic cells. No such activity was detected in human epithelial cell lines or murine hematopoietic cells. We also observed no difference in levels of NUC70 expression between apoptotic and nonapoptotic cells, suggesting that activation of NUC70 may be by posttranslational modification. We demonstrate that NUC70 activity is diminished in cells pretreated with the caspase inhibitors z-DEVD-fmk, z-VAD-fmk, and Z-CH2-Asp-DCB. Time course studies of cytoplasmic and nuclear endonuclease activities during apoptosis show that NUC70 is a cytoplasmic endonuclease that is translocated to the nucleus after the initiation of apoptosis. We confirmed this with immunostaining studies using anti-NUC70 antibody. These results demonstrate that NUC70 is an endogenous cytoplasmic endonuclease that is activated during apoptosis in a caspase-dependent mechanism.


Impurity in buffer substances mimics the effects of ATP on soluble 5'-nucleotidase.
An impurity, probably an anion, present in some batches of the buffer substances 4-(2-hydroxyethyl) piperazine-1-ethanesulfonic acid (HEPES), 2-morpholinoethane sulfonic acid (Mes) and piperazine-1,4-bis(2-ethane sulfonic acid (Pipes), activates the soluble 5'-nucleotidase from rat kidney. The affinity of the enzyme for 5'-IMP and the Vmax were both increased by the unidentified activator. ATP and 2,3-diphosphoglycerate, known activators of the soluble 5'-nucleotidase, had no effect if the incubation media were buffered with batches containing high concentrations of the activating impurity. These results suggest that the impurity interacts with the soluble 5'-nucleotidase at the same site as ATP and 2,3-diphosphoglycerate, however with a much higher affinity than these two compounds. It is possible that the same impurity might interfere with other proteins for which ATP is a substrate or a ligand.


Molecular regulation of autophagosome formation.
Macroautophagy, hereafter autophagy, is a degradative process conserved among eukaryotes, which is essential to maintain cellular homeostasis. Defects in autophagy lead to numerous human diseases, including various types of cancer and neurodegenerative disorders. The hallmark of autophagy is the de novo formation of autophagosomes, which are double-membrane vesicles that sequester and deliver cytoplasmic materials to lysosomes/vacuoles for degradation. The mechanism of autophagosome biogenesis entered a molecular era with the identification of autophagy-related (ATG) proteins. Although there are many unanswered questions and aspects that have raised some controversies, enormous advances have been done in our understanding of the process of autophagy in recent years. In this review, we describe the current knowledge about the molecular regulation of autophagosome formation, with a particular focus on budding yeast and mammalian cells.


Effect of drinking arsenic-contaminated water in children.
Chronic arsenic toxicity due to drinking of arsenic-contaminated water has been a major environmental health hazard throughout the world including India. Although a lot of information is available on health effects due to chronic arsenic toxicity in adults, knowledge of such effect on children is scanty. A review of the available literature has been made to highlight the problem in children. Scientific publications on health effects of chronic arsenic toxicity in children with special reference to psychological issues are reviewed. The prevalence of skin abnormalities such as pigmentation change and keratosis, the diagnostic signs of chronic arsenic toxicity, vary in various arsenic-exposed children population in different regions of the world. The occurrence of chronic lung disease including pulmonary interstitial fibrosis has been described in arsenic-exposed children in Chile. Affection of intellectual function has also been reported to occur in arsenic-exposed children studied in Thailand, Bangladesh, and India. Methylation patterns of arsenic in children aggregate in families and are correlated in siblings, providing evidence of a genetic basis for the variation in arsenic methylation. Chronic arsenic toxicity due to drinking of arsenic-contaminated water causes significant morbidity in children resulting in skin lesions, lung disease, and defect in intellectual function.


The effect of ethanol and alcoholic beverages on gastric emptying of solid meals in humans.
The systematic study of the effect of pure ethanol, alcoholic beverages, and their non-alcoholic components on gastric emptying of solid meals in humans. 16 fasting healthy male subjects received once weekly 300 ml of the following solutions in random order: 4 and 10% (v/v) ethanol, beer, red wine, 5.5 and 11.4% (w/v) glucose, and water. The test solutions were given either together with a low caloric (270 kcal, n = 8) or a high caloric (740 kcal, n = 8) solid meal. Ultrasonography of the antrum was used to determine gastric emptying. Gastric half emptying time (t(1/2) ) of the high caloric solid meal with water was 131.3 +/- 7 min. The ingestion of 4 and 10% (v/v) ethanol (158.8 +/- 9.3 and 165.6 +/- 6.2 min, respectively), beer (163.1 +/- 11 min), and red wine (186.3 +/- 8.4 min) resulted in a significantly longer t(1/2) than water. The lag phases after 4 and 10% (v/v) ethanol, beer, and red wine were not significantly different from that of water (48.1 +/- 6.5 min). Compared with water, the ingestion of 5.5 and 11.4% (w/v) glucose resulted in a significantly longer t(1/2) (153.8 +/- 5 and 168.1 +/- 14.4 min, respectively) by increasing the duration of the lag phase. The high caloric meals resulted in a 2-fold prolongation of t(1/2) when compared with the low caloric meals. The effect of the solutions on the gastric emptying times, however, was similar for both test meals. (i) Ethanol in low concentrations of 4 and 10% (v/v) prolongs gastric emptying of solid meals; this inhibitory effect is not dose-dependent. (ii) Alcoholic beverages (beer and red wine) also result in a prolongation of gastric emptying. The inhibitory effect of red wine, but not of beer, is more pronounced than that of the corresponding ethanol concentration and amount. (iii) The inhibitory effect of ethanol and alcoholic beverages is mainly induced by a prolongation of the gastric emptying phase (without affecting the lag phase), whereas 5.5 and 11.4% (w/v) glucose prolong the lag phase in a dose-dependent manner. (iv) The inhibitory effect of ethanol, beer, and red wine on gastric emptying does not depend on the caloric content of the meal.


Sorption of PBDE in low-density polyethylene film: implications for bioavailability of BDE-209.
The coefficients of partitioning (K(pew) ) between low-density polyethylene (LDPE) film (50-µm thickness) and water for 23 polybrominated diphenyl ether (PBDE) congeners were determined based on a regression analysis of sorption kinetics over an extended exposure period (up to 365 d). A curvilinear relationship between log K(pew) and log K(OW) (octanol-water partition coefficient) was obtained for the target BDE congeners with the turning point at log K(OW) approximately 8. Previously obtained dietary uptake efficiencies of BDE congeners in common carp (Cyprinus carpio) were also found to relate curvilinearly to log K(OW) . In addition, field-measured relative abundances of BDE-209 compiled from previous investigations conducted in the Pearl River Delta of South China were significantly (p < 0.001) higher in abiotic samples (n = 79 from 11 matrices) than in biotic samples (n = 73 from 12 matrices), suggesting the likelihood for reduced bioavailability of BDE-209 in certain biota. Finally, a molecular-scale analysis indicated that the curvilinear relationship between log K(pew) and log K(OW) can be attributed to the energy barrier that a molecule has to overcome as it attempts to diffuse into the LDPE structure, which can become significant for larger molecules. Similarly, the reduced bioavailability of BDE-209 in many biological species can be regarded as a reflection of the magnitude of molecular interactions between cell membranes and BDE-209.


Netrin1 Produced by Neural Progenitors, Not Floor Plate Cells, Is Required for Axon Guidance in the Spinal Cord.
Netrin1 has been proposed to act from the floor plate (FP) as a long-range diffusible chemoattractant for commissural axons in the embryonic spinal cord. However, netrin1 mRNA and protein are also present in neural progenitors within the ventricular zone (VZ), raising the question of which source of netrin1 promotes ventrally directed axon growth. Here, we use genetic approaches in mice to selectively remove netrin from different regions of the spinal cord. Our analyses show that the FP is not the source of netrin1 directing axons to the ventral midline, while local VZ-supplied netrin1 is required for this step. Furthermore, rather than being present in a gradient, netrin1 protein accumulates on the pial surface adjacent to the path of commissural axon extension. Thus, netrin1 does not act as a long-range secreted chemoattractant for commissural spinal axons but instead promotes ventrally directed axon outgrowth by haptotaxis, i.e., directed growth along an adhesive surface.


The use of writing groups to facilitate adaptation after stroke.
This is a report on a pilot study of small writing groups to assist in long-term adaptation after stroke onset. 26 stroke survivors participated in a small group experience to write a short essay to be published about their recovery. The sample consisted of middle-aged, well-educated participants who were several years post stroke and were self-selected by interest and experience in writing. The sample was evenly divided between men and women, and minority racial groups were adequately represented. Essays were published on a website and clustered in themes about coping with recovery and personal growth/changes in self-concept. The group experience was well received by participants. Objective measures showed a trend toward improvement in positive identity and no significant change in depression or well-being. Significant differences found between subgroups (improved vs. declined; aphasia vs. no aphasia) are discussed. Anecdotal observations of the group process and implications for practice and further research are provided.


The effects of probiotics and synbiotic supplementation on glucose and insulin metabolism in adults with prediabetes: a double-blind randomized clinical trial.
Probiotics and/or prebiotics could be a promising approach to improve metabolic disorders by favorably modifying the gut microbial composition. To assess the effects of probiotics and synbiotic on glycemic indices in prediabetic individuals who are at risk of type 2 diabetes and its complications. In a double-blind, randomized, placebo-controlled parallel-group clinical trial, 120 prediabetic adults participated and were randomly allocated to receive either probiotics or synbiotic or placebo supplements for 24 weeks. Anthropometric measurements, food record, physical activity and glycemic biomarkers including glycated hemoglobin (HbA1C), fasting plasma glucose (FPG), fasting insulin levels (FIL), homoeostasis model assessment for insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and β-cell function (HOMA-B) were assessed at baseline and repeated at 12 and 24 weeks and compared within and between three groups using repeated measure ANOVA. Compared with the placebo, synbiotic supplementation resulted in a higher significant reduction in FPG (- 6.5 ± 1.6 vs. - 0.82 ± 1.7 mg/dL, P = 0.01), FIL (- 2.6 ± 0.9 vs. - 0.8 ± 0.8 µIU/mL, P = 0.028), and HOMA-IR (- 0.86 ± 0.3 vs. - 0.16 ± 0.25, P = 0.007), and a significant elevation in the QUICKI (+ 0.01 ± 0.003 vs. + 0.003 ± 0.002, P = 0.006). In addition, significant decreases in HbA1C was seen following the supplementation of probiotics and synbiotic compared with the placebo (- 0.12 ± 0.06 and - 0.14 ± 0.05 vs. +0.07 ± 0.06%, P = 0.005 and 0.008, respectively). HOMA-B was not found to be different between or within the three groups. Glycemic improvement by probiotics and particularly synbiotic supplements in prediabetic individuals has been supported by current study. However, further studies are required for optimal recommendations in this important area of patient treatment. Iranian Registry of Clinical Trials: IRCT201511032321N2, Date registered February 27, 2016.


In vivo and in vitro acquisition of resistance to voriconazole by Candida krusei.
Candida krusei is an important agent of opportunistic infections that often displays resistance to several antifungals. We describe here the in vivo acquisition of resistance to voriconazole (VRC) by C. krusei isolates recovered from a leukemia patient during a long period of VRC therapy. In order to mimic the in vivo development of VRC resistance, a susceptible C. krusei isolate was exposed daily to 1 μg/ml of VRC in vitro. Interestingly, after 5 days of exposure to VRC, a MIC of 4 μg/ml was achieved; this value remained constant after 25 additional days of treatment with VRC and also after 30 consecutive days of incubation in VRC-free medium. Our objective was to determine the associated molecular resistance mechanisms, such as expression of efflux pump genes and ERG11 gene mutations, among the resistant strains. Synergistic effects between the efflux blocker tacrolimus (FK506) and VRC were found in all of the resistant strains. Moreover, ABC1 gene expression increased over time in both the in vivo- and in vitro-induced resistant strains, in contrast to the ABC2 and ERG11 genes, whose expression was invariably lower and constant. ERG11 gene sequencing showed two different types of mutations, i.e., heterozygosity at T1389T/C, corresponding to synonymous mutations, in C. krusei strains and a missense mutation at position T418C, resulting in a change from Tyr to His, among resistant C. krusei clinical isolates. This study highlights the relevance of ATP-dependent efflux pump (namely, Abc1p) activity in VRC resistance and describes new mutations in the ERG11 gene among resistant C. krusei clinical isolates.


Disseminated intravascular coagulation (DIC). Immunohistochemical study of fibrin-related materials (FRMs) in renal tissues.
Renal tissues of 208 autopsied cases were examined. Malignant neoplasm with hematological malignancies often accompanied DIC. Tissue sections were stained with hematoxylin and eosin and Mallory's phosphotungstic acid hematoxylin (PTAH), and were applied for immunoperoxidase method (IP), using antisera against human fibrinogen, FDP-D and FDP-E. Histologically in 80 cases (38%) fibrin or fibrinogen related materials (FRMs) were observed in the glomerular capillary or the intratubular area or in both. FRMs were PTAH or IP positive or both in 23 of the 26 cases (88%) clinically diagnosed as DIC. In the remaining three cases anticoagulants probably interfered with FRMs observation. This study showed the PTAH stain was nonspecific and insensitive to FRMs, and that IP was necessary for a pathological diagnosis of DIC. The presence of FRMs in the renal tubuli is an important finding in confirming DIC. DIC may be present histologically in the absence of clinical DIC symptoms.


[Radioimmunoassay of progesterone in peripheral and placental blood of pregnant rabbits and guinea pigs].
Radioimmunoassay of progesterone in systemic and placental blood of pregnant rabbits and guinea pigs. 1. The level of progesterone in pregnant rabbits and guinea pigs serum was measured directly (without extraction) using a RadioImmunoAssay (RIA). 2. Hormonal concentrations in systemic blood were shown to increase with gestational age, being at their highest half-way through pregnancy (16.03 +/- 2.63 ng/ml for rabbits; 319.01 +/- 42.10 ng/ml for guinea pigs) and decreasing at the end of the pregnancy. 3. Progesterone was not detectable in rabbit placental blood, whereas a high level of this hormone was found in guinea pig placental blood, which increased with gestational age. From the 28th to the 56th post-coital day, the level increased from 143.22 +/- 13.15 to 283.30 +/- 36.84 ng/ml. 4. The method used enables to measure correctly progesterone concentrations in rabbit and guinea pig serum without extraction.


Controlling collective dynamics in complex minority-game resource-allocation systems.
Resource allocation takes place in various kinds of real-world complex systems, such as traffic systems, social services institutions or organizations, or even ecosystems. The fundamental principle underlying complex resource-allocation dynamics is Boolean interactions associated with minority games, as resources are generally limited and agents tend to choose the least used resource based on available information. A common but harmful dynamical behavior in resource-allocation systems is herding, where there are time intervals during which a large majority of the agents compete for a few resources, leaving many other resources unused. Accompanying the herd behavior is thus strong fluctuations with time in the number of resources being used. In this paper, we articulate and establish that an intuitive control strategy, namely pinning control, is effective at harnessing the herding dynamics. In particular, by fixing the choices of resources for a few agents while leaving the majority of the agents free, herding can be eliminated completely. Our investigation is systematic in that we consider random and targeted pinning and a variety of network topologies, and we carry out a comprehensive analysis in the framework of mean-field theory to understand the working of control. The basic philosophy is then that, when a few agents waive their freedom to choose resources by receiving sufficient incentives, the majority of the agents benefit in that they will make fair, efficient, and effective use of the available resources. Our work represents a basic and general framework to address the fundamental issue of fluctuations in complex dynamical systems with significant applications to social, economical, and political systems.


Design and methods for a randomized clinical trial treating comorbid obesity and major depressive disorder.
Obesity is often comorbid with depression and individuals with this comorbidity fare worse in behavioral weight loss treatment. Treating depression directly prior to behavioral weight loss treatment might bolster weight loss outcomes in this population, but this has not yet been tested in a randomized clinical trial. This randomized clinical trial will examine whether behavior therapy for depression administered prior to standard weight loss treatment produces greater weight loss than standard weight loss treatment alone. Obese women with major depressive disorder (N = 174) will be recruited from primary care clinics and the community and randomly assigned to one of the two treatment conditions. Treatment will last 2 years, and will include a 6-month intensive treatment phase followed by an 18-month maintenance phase. Follow-up assessment will occur at 6-months and 1- and 2 years following randomization. The primary outcome is weight loss. The study was designed to provide 90% power for detecting a weight change difference between conditions of 3.1 kg (standard deviation of 5.5 kg) at 1-year assuming a 25% rate of loss to follow-up. Secondary outcomes include depression, physical activity, dietary intake, psychosocial variables and cardiovascular risk factors. Potential mediators (e.g., adherence, depression, physical activity and caloric intake) of the intervention effect on weight change will also be examined. Treating depression before administering intensive health behavior interventions could potentially boost the impact on both mental and physical health outcomes. NCT00572520.


Working across boundaries to improve health outcomes: a case study of a housing support and outreach service for homeless people living with HIV.
This paper reports the findings of an evaluation of the 'Housing Support, Outreach and Referral' service developed to support people living with HIV who were homeless or at risk of homelessness. The service was set up as part of the Supporting People Health Pilot programme established to demonstrate the policy links between housing support services and health and social care services by encouraging the development of integrated services. The paper considers the role of housing support in improving people's health, and considers the challenges of working across housing, health and social care boundaries. The evaluation of the health pilot employed two main sources of data collection: quarterly project evaluation reports, which collected process data as well as reporting progress against aims and objectives, and semi-structured interviews with professionals from all key stakeholder groups and agencies, and with people who used services. Over the course of 15 months, 56 referrals were received of which 27 were accepted. Fifteen people received tenancy support of whom 12 were helped to access temporary accommodation. At the end of the 15 months, all of the tenancies had been maintained. In addition, 18 people registered with a general practitioner and 13 registered with an HIV clinic. Interviews with professionals emphasised the importance of the local joint working context, the involvement of the voluntary sector and the role of the support workers as factors that accounted for these outcomes. Those using services placed most emphasis on the flexibility of the support worker role. Importantly, interviews with professionals and those using services suggest that the role of support worker incorporates two dimensions--those of networker/navigator as well as advocate--and that both dimensions are important in determining the effectiveness of the service.


Design and analysis of a tunable synchronized oscillator.
The use of in silico simulations as a basis for designing artificial biological systems (and experiments to characterize them) is one of the tangible differences between Synthetic Biology and "classical" Genetic Engineering. To this end, synthetic biologists have adopted approaches originating from the traditionally non-biological fields of Nonlinear Dynamics and Systems & Control Theory. However, due to the complex molecular interactions affecting the emergent properties of biological systems, mechanistic descriptions of even the simplest genetic circuits (transcriptional feedback oscillators, bi-stable switches) produced by these methods tend to be either oversimplified, or numerically intractable. More comprehensive and realistic models can be approximated by constructing "toy" genetic circuits that provide the experimenter with some degree of control over the transcriptional dynamics, and allow for experimental set-ups that generate reliable data reflecting the intracellular biochemical state in real time. To this end, we designed two genetic circuits (basic and tunable) capable of exhibiting synchronized oscillatory green fluorescent protein (GFP) expression in small populations of Escherichia coli cells. The functionality of the basic circuit was verified microscopically. High-level visualizations of computational simulations were analyzed to determine whether the reliability and utility of a synchronized transcriptional oscillator could be enhanced by the introduction of chemically inducible repressors. Synchronized oscillations in GFP expression were repeatedly observed in chemically linked sub-populations of cells. Computational simulations predicted that the introduction of independently inducible repressors substantially broaden the range of conditions under which oscillations could occur, in addition to allowing the frequency of the oscillation to be tuned. The genetic circuits described here may prove to be valuable research tools for the study of synchronized transcriptional feedback loops under a variety of conditions and experimental set-ups. We further demonstrate the benefit of using abstract visualizations to discover subtle non-linear trends in complex dynamic models with large parameter spaces.


Gaseous isotope separation using solar wind phenomena.
A large evacuated drum-like chamber fitted with supersonic nozzles in the center, with the chamber and the nozzles corotating, can separate gaseous fluids according to their molecular weights. The principle of separation is essentially the same as that of the solar wind propagation, in which components of the plasma fluid are separated due to their difference in the time-of-flight. The process can inherently be very efficient, serving as a pump as well as a separator, and producing well over 10(5) separative work units (kg/year) for the hydrogen/deuterium mixture at high-velocity flows.


A selective ultrahigh responding high temperature ethanol sensor using TiO2 nanoparticles.
In this research work, the sensitivity of TiO2 nanoparticles towards C2H5OH, H2 and CH4 gases was investigated. The morphology and phase content of the particles was preserved during sensing tests by prior heat treatment of the samples at temperatures as high as 750 °C and 1000 °C. Field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM) and X-ray diffraction (XRD) analysis were employed to characterize the size, morphology and phase content of the particles. For sensor fabrication, a film of TiO2 was printed on a Au interdigitated alumina substrate. The sensing temperature was varied from 450 °C to 650 °C with varying concentrations of target gases. Results show that the sensor has ultrahigh response towards ethanol (C2H5OH) compared to hydrogen (H2) and methane (CH4). The optimum sensing temperature was found to be 600 °C. The response and recovery times of the sensor are 3 min and 15 min, respectively, for 20 ppm C2H5OH at the optimum operating temperature of 600 °C. It is proposed that the catalytic action of TiO2 with C2H5OH is the reason for the ultrahigh response of the sensor.


Role of articulatory motor networks in perceptual categorization of speech signals: a 7T fMRI study.
Speech and language processing involve complex interactions between cortical areas necessary for articulatory movements and auditory perception and a range of areas through which these are connected and interact. Despite their fundamental importance, the precise mechanisms underlying these processes are not fully elucidated. We measured BOLD signals from normal hearing participants using high-field 7 Tesla fMRI with 1-mm isotropic voxel resolution. The subjects performed 2 speech perception tasks (discrimination and classification) and a speech production task during the scan. By employing univariate and multivariate pattern analyses, we identified the neural signatures associated with speech production and perception. The left precentral, premotor, and inferior frontal cortex regions showed significant activations that correlated with phoneme category variability during perceptual discrimination tasks. In addition, the perceived sound categories could be decoded from signals in a region of interest defined based on activation related to production task. The results support the hypothesis that articulatory motor networks in the left hemisphere, typically associated with speech production, may also play a critical role in the perceptual categorization of syllables. The study provides valuable insights into the intricate neural mechanisms that underlie speech processing.


[Efficacy of pitavastatin on HDL-cholesterol].
Epidemiological studies have shown that low HDL predicts cardiovascular risk just as much as elevated LDL cholesterol levels. However, today we know that HDL functionality is more important than HDL levels. As a group effect, statins increase HDL levels. They are also thought to increase functional HDL. Pitavastatin is a new statin with a different structure, shown to increase HDL levels more than other statins as well as functionality. Studies have shown that plaque regression occurs with pitavastatin. These findings provide the expectation that it will also decrease cardiovascular events.


Electron density characterization by use of a broadband x-ray-compatible wave-front sensor.
The use of a Hartmann wave-front sensor to accurately measure the line-integrated electron density gradients formed in laser-produced and z-pinch plasma experiments is examined. This wave-front sensor may be used with a soft-x-ray laser as well as with incoherent line emission at multikilovolt x-ray energies. This diagnostic is significantly easier to use than interferometery and moiré deflectometry, both of which have been demonstrated with soft-x-ray lasers. This scheme is experimentally demonstrated in the visible region by use of a Shack-Hartmann wave-front sensor and a liquid-crystal spatial light modulator to simulate a phase profile that could occur when an x-ray probe passes through a plasma. The merits of using a Hartmann sensor include a wide dynamic range, broadband or low-coherence-length light capability, high x-ray efficiency, two-dimensional gradient determination, multiplexing capability, and experimental simplicity. Hartmann sensors could also be utilized for wavelength testing of extreme-ultraviolet lithography components and x-ray phase imaging of biological specimens.


Evidence for the involvement of the GABAergic, but not serotonergic transmission in the anxiolytic-like effect of bisabolol in the mouse elevated plus maze.
Bisabolol (α-(-)-bisabolol) is a sesquiterpene which is a part of the essential oil of a variety of plants, but its common source is German chamomile. Several bioactivities including anti-inflammatory, anti-nociceptive, and anti-tumor effects were attributed to bisabolol. However, the neuropharmacological properties of bisabolol have not yet been reported. The present study evaluated behavioral effects of bisabolol using elevated plus maze (EPM), open field test (OFT), and rotarod test. Moreover, this study also examined whether the 5-HT1A and GABAA-benzodiazepine receptor systems are involved in the anxiolytic-like effects of bisabolol. After acute intraperitoneal treatment with bisabolol at the doses of 0.5, 1, 2, 5, and 10 mg/kg, OFT, EPM, and rotarod were utilized for investigating behavioral effects. Flumazenil, a benzodiazepine receptor antagonist, and WAY-100635, a 5-HT1A receptor antagonist, were used to determine the action mechanism in the EPM. Bisabolol especially at the dose of 1 mg/kg was effective in increasing the total number of entries and time spent in the open arms of EPM while number of rearing and grooming in OFT was decreased in comparison to the control. In the rotarod, permanence time was decreased in the mice treated with the high doses of bisabolol. Pretreatment with flumazenil, but not WAY-100635, was able to reverse the effect of bisabolol 1 mg/kg in the EPM, indicating that the anxiolytic-like activity of bisabolol occurs via the GABAergic but not serotonergic transmission. The present study supports the idea that bisabolol may mediate its anxiolytic-like and sedative mechanisms involving GABAA receptors.


[Fever of unknown origin in internal medicine. The experience of Spanish authors over 20 years].
The diseases responsible of fever of unknown origin (FUO) have changed in the last years. With the object of study the etiologic spectrum and diagnostic attitude in the FUO in a national level in the last 25 years, we has revised 14 articles of FUO realized in Internal Medicine published from 1970 to 1995, without aids patients. We use MEDLINE and Indice Médico Español to search the publications about FUO. In 14 articles, 914 cases of FUO was evaluated, the infection was the principal cause (41.2%), followed by tumor (19.2%) and collagenoses/vasculitis (13.7%). In the infection group, the disease more frequent was the tuberculosis (134/377) (35.5%) follow by brucellosis (15.6%) y abscesses (11.6%). Half of malignancy group was due to lymphoma. Systemic lupus erythematous, polyarteritis nodosa and temporal arteritis were caused of FUO in 28.8%, 21.6% y 20% of collagenoses/vasculitis group. In the miscellaneous group emphasized granulomatous diseases (38.8%) (including sarcoidosis, idiopathic granulomatous hepatitis and chronic granulomatous disease). The improve of diagnostic procedures has conditioned a change of spectrum of the diseases, with a decrease of infectious causes (as brucellosis or salmonellosis) and increase or neoplasia and collagenoses/vasculitis (except lupus).


CIRCADIAN CLOCK-ASSOCIATED1 Controls Resistance to Aphids by Altering Indole Glucosinolate Production.
CIRCADIAN CLOCK-ASSOCIATED1 (CCA1), a well-known central circadian clock regulator, coordinates plant responses to environmental challenges. Its daily rhythmic expression in Arabidopsis (Arabidopsis thaliana) confers host resistance to the caterpillar Trichoplusia ni However, it is unclear whether CCA1 plays a role in defense against phloem sap-feeding aphids. In this study, we showed that green peach aphid (Myzus persicae) displayed an intrinsic circadian feeding rhythm. Under constant light, wild-type Columbia-0 (Col-0) Arabidopsis plants coentrained with aphids in the same light/dark cycles exhibited greater antixenotic activity than plants preentrained in the opposite cycle from the aphids. Consistently, circadian mutants cca1-1, cca1-11, lhy-21, ztl-1, ztl-4, and lux-2 suffered more severe damage than Col-0 plants when infested by aphids, suggesting that the Arabidopsis circadian clock plays a defensive role. However, the arrhythmic CCA1 overexpression line (CCA1-OX) displayed strong antixenotic and antibiotic activities despite its loss of circadian regulation. Aphids feeding on CCA1-OX plants exhibited lower reproduction and smaller body size and weight than those on Col-0. Apparently, CCA1 regulates both clock-dependent and -independent defense responses. Systematic investigation based on bioinformatics analyses indicated that resistance to aphids in CCA1-OX plants was due primarily to heightened basal indole glucosinolate levels. Interestingly, aphid feeding induced alternatively spliced intron-retaining CCA1a/b transcripts, which are normally expressed at low levels, whereas expression of the major fully spliced CCA1 transcript remained largely unchanged. We hypothesize that posttranscriptional modulation of CCA1 expression upon aphid infestation maximizes the potential of circadian-mediated defense and stress tolerance while ensuring normal plant development.


Neurosurgical gram-negative bacillary ventriculitis and meningitis: a retrospective study evaluating the efficacy of intraventricular gentamicin therapy in 31 consecutive cases.
Gram-negative bacillary (GNB) ventriculitis and meningitis are rare but serious complications after neurosurgery. Prospective studies on antibiotic treatment for these infections are lacking, and retrospective reports are sparse. At our hospital in Uppsala, Sweden, meropenem has been recommended as empirical therapy since 1996, with the addition of intraventricular gentamicin in cases that do not respond satisfactorily to treatment. In this study, we retrospectively compare the efficacy of combination treatment with intraventricular gentamicin to that of systemic antibiotics alone. In addition, we report our experience of meropenem for the treatment of GNB ventriculomeningitis. Adult consecutive patients with gram-negative bacteria isolated from cerebrospinal fluid during a 10-year period and with postneurosurgical GNB ventriculitis or meningitis were included retrospectively. Data were abstracted from the medical records. Thirty-one patients with neurosurgical GNB ventriculitis or meningitis and follow-up for 3 months were identified. The main intravenous therapies were meropenem (n = 24), cefotaxime (n = 3), ceftazidime (n = 2), imipenem (n = 1), and trimethoprim-sulfamethoxazole (n = 1). Thirteen patients were given combination treatment with appropriate intraventricular gentamicin. These patients had a higher cure rate and a lower relapse rate than did those treated with intravenous antibiotics alone (P = .03). Relapse occurred in 0 of 13 patients treated intraventricularly and in 6 of 18 patients treated with systemic antibiotics alone. The mortality rate was 19%; 3 patients in each group died, but in no case was death considered to be attributable to meningitis. Our results support combination treatment with intraventricular gentamicin for postneurosurgical GNB ventriculomeningitis. Meropenem seems to be an effective and safe alternative for the systemic antibiotic treatment of these neurointensive care infections.


Continued competency: the experience of the California Dental Association.
The California Dental Association has developed a program--Quality Improvement through Lifelong Learning or QUIL3--that enables a dentist to privately and confidentially determine whether he or she meets current clinical practice standards and has the requisite knowledge to practice dentistry competently. Using the concept of continuous quality improvement (CQI), this innovative program was two years in development and attempts to positively and proactively address issues associated with dental performance. QUIL3 is an initial step.


Identification of the major functional proteins of prokaryotic lipid droplets.
Storage of cellular triacylglycerols (TAGs) in lipid droplets (LDs) has been linked to the progression of many metabolic diseases in humans, and to the development of biofuels from plants and microorganisms. However, the biogenesis and dynamics of LDs are poorly understood. Compared with other organisms, bacteria seem to be a better model system for studying LD biology, because they are relatively simple and are highly efficient in converting biomass to TAG. We obtained highly purified LDs from Rhodococcus sp. RHA1, a bacterium that can produce TAG from many carbon sources, and then comprehensively characterized the LD proteome. Of the 228 LD-associated proteins identified, two major proteins, ro02104 and PspA, constituted about 15% of the total LD protein. The structure predicted for ro02104 resembles that of apolipoproteins, the structural proteins of plasma lipoproteins in mammals. Deletion of ro02104 resulted in the formation of supersized LDs, indicating that ro02104 plays a critical role in cellular LD dynamics. The putative α helix of the ro02104 LD-targeting domain (amino acids 83-146) is also similar to that of apolipoproteins. We report the identification of 228 proteins in the proteome of prokaryotic LDs, identify a putative structural protein of this organelle, and suggest that apolipoproteins may have an evolutionarily conserved role in the storage and trafficking of neutral lipids.


Analyses of Thinopyrum bessarabicum, T. elongatum, and T. junceum chromosomes using EST-SSR markers.
Wild Thinopyrum grasses are important gene pools for forage and cereal crops. Knowledge of their chromosome organizations is pivotal for efficient utilization of this important gene pool in germplasm enhancement programs. Expressed sequence tags derived simple sequence repeat (EST-SSR) markers for Thinopyrum bessarabicum, T. elongatum, and T. junceum chromosomes were identified among amplicons produced from three series of wheat-Thinopyrum addition lines using 193 primer pairs designed from the Leymus EST unigenes. The homology of T. junceum chromosomes in 13 wheat addition lines was tentatively established to reveal that homologous groups 3, 4, 5, 6, and 7 were represented by HD3515, HD3505, AJDAj11, AJDAj1, and HD3508, whereas groups 1 and 2 were represented by AJADj7-AJDAj9 and AJDAj2-AJDAj4, respectively. AJDAj5 and AJDAj6 had complexly reconstituted T. junceum chromosomes that might have resulted from fusion or translocations of large chromosomal segments from two or more chromosomes, that is (1+5) and (2+5+1), respectively. The identified EST-SSR markers will be useful in comparative gene mapping, chromosome tracing, taxonomic studies, gene introgression, and cultivar identification.


A click mediated route to a novel fluorescent pyridino-extended calix[4]pyrrole sensor: synthesis and binding studies.
A novel fluorescent aryl-extended phenoxycalix[4]pyrrole ditopic sensor with enhanced cation recognition properties was efficiently synthesized via click chemistry and characterized through both molecular fluorescence and nuclear magnetic resonance spectroscopy. Results demonstrate the selectivity of this fluorescent sensor for fluoride when taking into account its interaction with anions, while its cation binding properties showed selectivity for iron, and its sensing properties for several cations in dimethylsulfoxide. This work introduces a new ditopic receptor able to complex major environmentally relevant species and depicts the importance of click chemistry in the introduction of new tetra-chromophoric calix[4]pyrrole binding platforms with specific photophysical properties.


Use of rectal tissue for reconstruction of an anogenital cleft in a juvenile dog with recurrent rectal prolapse.
A 4-month-old 4.2 kg sexually intact female mixed-breed dog was evaluated for rectal and vesicular tenesmus, intermittent rectal prolapse, fecal incontinence, and an anogenital cleft. Rectal prolapse and an anogenital cleft were confirmed on physical examination. Results of a CBC and serum biochemical analysis were within respective reference ranges, and abdominal ultrasonography revealed no abnormalities. Urinalysis revealed evidence of a urinary tract infection. An H-perineoplasty was performed and the prolapse was reduced. The repair partially dehisced and was repaired (with concurrent reduction of a recurrent rectal prolapse) but dehisced again. There was limited tissue available for additional reconstruction. In another surgical procedure, the rectum was allowed to prolapse, the most dorsal 40% of the prolapsed rectal tissue was resected, and the rectal tissue margin and skin in this region were apposed. The remaining rectal tissue flap was folded ventrally, and the lateral margins of the aborad aspect were sutured to the dorsolateral vestibular mucosa. In a subsequent surgery, 2.5 to 3 cm of the rectal tissue flap was excised. The remainder was used to create ventral margins for the rectum and vestibular mucosa. The perineal skin between the anus and dorsal vulvar commissure was closed. The patient experienced mild cutaneous partial dehiscence of the repair that healed by second intention. Over an 18-month follow-up period, some fecal incontinence persisted, but straining resolved and urinary tract infection did not recur. For the dog of this report, the use of rectal mucosa in surgical repair of an anogenital cleft provided an acceptable clinical outcome.


Adaptive Langevin sampler for separation of t-distribution modelled astrophysical maps.
We propose to model the image differentials of astrophysical source maps by Student's t-distribution and to use them in the Bayesian source separation method as priors. We introduce an efficient Markov Chain Monte Carlo (MCMC) sampling scheme to unmix the astrophysical sources and describe the derivation details. In this scheme, we use the Langevin stochastic equation for transitions, which enables parallel drawing of random samples from the posterior, and reduces the computation time significantly (by two orders of magnitude). In addition, Student's t-distribution parameters are updated throughout the iterations. The results on astrophysical source separation are assessed with two performance criteria defined in the pixel and the frequency domains.


A less invasive method for orthotopic injection of breast cancer cells into the mouse mammary gland.
Breast cancer is the most common type of cancer diagnosed in women, and the second most common cause of cancer-related deaths in women in North America. The use of laboratory mice in research is an essential tool for the study of breast cancer biology and for pre-clinical therapeutic development. While subcutaneous flank injections of cancer cells are widely used for studying breast cancer biology and for exploring novel therapies, orthotopic xenografting of tumors into the mouse mammary gland allow for the study of breast cancers in a biologically relevant microenvironment. In this study we report a modification of the method of orthotopic injections of cancer cells into the mouse mammary gland which greatly reduces the effects of surgery in mice including decreased wound size, procedure time and anesthesia. It also removes the risk of accidentally puncturing the peritoneal cavity. Consequently post-operative animal handling and stress are significantly reduced. All of these advantages are present without compromising procedure success rate. Therefore, this modification makes orthotopic mammary gland injection a more efficient procedure and greatly improves animal welfare.


Activin A marks a novel progenitor cell population during fracture healing and reveals a therapeutic strategy.
Insufficient bone fracture repair represents a major clinical and societal burden and novel strategies are needed to address it. Our data reveal that the TGF-β superfamily member Activin A became very abundant during mouse and human bone fracture healing but was minimally detectable in intact bones. Single cell RNA-sequencing revealed that the Activin A-encoding gene Inhba was highly expressed in a unique, highly proliferative progenitor cell (PPC) population with a myofibroblast character that quickly emerged after fracture and represented the center of a developmental trajectory bifurcation producing cartilage and bone cells within callus. Systemic administration of neutralizing Activin A antibody inhibited bone healing. In contrast, a single recombinant Activin A implantation at fracture site in young and aged mice boosted: PPC numbers; phosphorylated SMAD2 signaling levels; and bone repair and mechanical properties in endochondral and intramembranous healing models. Activin A directly stimulated myofibroblastic differentiation, chondrogenesis and osteogenesis in periosteal mesenchymal progenitor culture. Our data identify a distinct population of Activin A-expressing PPCs central to fracture healing and establish Activin A as a potential new therapeutic tool.


Estimates for the partial differential-Neumann problem for pseudoconvex domains in C of finite type.
We outline results obtained for the partial differential-Neumann problem for an arbitrary pseudoconvex domain in C(2) of finite type. We obtain an approximation to the Neumann operator. A number of sharp estimates for the solution of partial differentialu = f are a consequence; one of these is an extension of the L(1) estimate of Henkin and Skoda used to characterize the zero sets of functions of the Nevanlinna class.


Automatic calculation of the nine equivalents of nursing manpower use score (NEMS) using a patient data management system.
The most recent approach to estimate nursing resources consumption has led to the generation of the Nine Equivalents of Nursing Manpower use Score (NEMS). The objective of this prospective study was to establish a completely automatically generated calculation of the NEMS using a patient data management system (PDMS) database and to validate this approach by comparing the results with those of the conventional manual method. Prospective study. Operative intensive care unit of a university hospital. Patients admitted to the ICU between 24 July 2002 and 22 August 2002. Patients under the age of 16 years, and patients undergoing cardiovascular surgery or with burn injuries were excluded. None. The NEMS of all patients was calculated automatically with a PDMS and manually by a physician in parallel. The results of the two methods were compared using the Bland and Altman approach, the interclass correlation coefficient (ICC), and the kappa-statistic. On 20 consecutive working days, the NEMS was calculated in 204 cases. The Bland Altman analysis did not show significant differences in NEMS scoring between the two methods. The ICC (95% confidence intervals) 0.87 (0.84-0.90) revealed a high inter-rater agreement between the PDMS and the physician. The kappa-statistic showed good results (kappa>0.55) for all NEMS items apart from the item "supplementary ventilatory care". This study demonstrates that automatical calculation of the NEMS is possible with high accuracy by means of a PDMS. This may lead to a decrease in consumption of nursing resources.


Comparison of Topical 5-Fluorouracil and Interferon Alfa-2b as Primary Treatment Modalities for Ocular Surface Squamous Neoplasia.
To compare the efficacy of topical 5-fluorouracil 1% (5FU) and interferon alfa-2b 1 MIU/mL (IFN) eye drops as primary treatment modalities for ocular surface squamous neoplasia (OSSN). Retrospective, comparative, interventional case series. Fifty-four patients who received 5FU and 48 patients who received IFN as primary therapy for OSSN were included. Primary outcome measures were the frequency of clinical resolution and time to OSSN recurrence by treatment modality. Secondary outcome was the frequency of side effects with each therapy. The mean age of patients was 68 years. More Hispanics were treated with 5FU. In a univariable analysis, frequency of OSSN resolution was higher with 5FU (96.3%, n = 52) than with IFN (81.3%, n = 39), P = .01. In a multivariable analysis, treatment modality did not remain a significant predictor of resolution. In patients whose OSSN resolved, time to resolution was similar with both agents, (5FU mean 6.6 months, standard deviation (SD) 4.5 vs IFN mean 5.5 months, SD 2.9, P = .17). Of the 52 eyes whose OSSN resolved with 5FU, 11.5% of lesions (n = 6) recurred, whereas of the 39 eyes whose OSSN resolved with IFN, 5.1% of lesions (n = 2) recurred, P = .46. Kaplan-Meier survival curves of OSSN recurrence were similar between groups (log-rank = 0.16). One-year recurrence rates were 11.4% with 5FU and 4.5% with IFN. Eyelid edema (P = .04) and tearing (P = .02) were more significant with 5FU. This is the first direct comparison study between 5FU and IFN eye drops as primary treatment modalities for OSSN. Both modalities resulted in a high frequency of tumor resolution and low recurrence rates and are effective treatment options for OSSN.


A Case-Mix System for Children and Youth With Developmental Disabilities.
Limited funding across health and social service programs presents a challenge regarding how to best match resources to the needs of the population. There is increasing consensus that differences in individual characteristics and care needs should be reflected in variations in service costs, which has led to the development of case-mix systems. The present study sought to develop a new approach to allocate resources among children and youth with intellectual and developmental disabilities (IDD) as part of a system-wide Medicaid payment reform initiative in Arkansas. To develop the system, assessment data collected using the interRAI Child and Youth Mental Health-Developmental Disability instrument was matched to paid service claims. The sample consisted of 346 children and youth with developmental disabilities in the home setting. Using automatic interactions detection, individuals were sorted into unique, clinically relevant groups (ie, based on similar resource use) and a standardized relative measure of the cost of services provided to each group was calculated. The resulting case-mix system has 8 distinct, final groups and explains 30% of the variance in per diem costs. Our analyses indicate that this case-mix classification system could provide the foundation for a future prospective payment system that is centered around stability and equitability in the allocation of limited resources within this vulnerable population.


Partial xenon coagulation of net in histoplasmic choroiditis.
Ten patients with ocular histoplasmosis (photocoagulated 17 times) were retrospectively selected, in what was considered an unbiased manner, for examination of their response to partial xenon photocoagulation of their neovascular nets. Of the 17 photocoagulations, the part of the neovascular net not coagulated remained the same in 7, was stimulated in 5, and suppressed in 5. This distribution was not statistically different from a control group receiving corticosteroids alone. A direct relation of suppression of the uncoagulated part of the net with the distance of this coagulation from the fovea was demonstrated.


THE EXPOSOME IN HUMAN EVOLUTION: FROM DUST TO DIESEL.
Global exposures to air pollution and cigarette smoke are novel in human evolutionary history and are associated with about 16 million premature deaths per year. We investigate the history of the human exposome for relationships between novel environmental toxins and genetic changes during human evolution in six phases. Phase I: With increased walking on savannas, early human ancestors inhaled crustal dust, fecal aerosols, and spores; carrion scavenging introduced new infectious pathogens. Phase II: Domestic fire exposed early Homo to novel toxins from smoke and cooking. Phases III and IV: Neolithic to preindustrial Homo sapiens incurred infectious pathogens from domestic animals and dense communities with limited sanitation. Phase V: Industrialization introduced novel toxins from fossil fuels, industrial chemicals, and tobacco at the same time infectious pathogens were diminishing. Thereby, pathogen-driven causes of mortality were replaced by chronic diseases driven by sterile inflammogens, exogenous and endogenous. Phase VI: Considers future health during global warming with increased air pollution and infections. We hypothesize that adaptation to some ancient toxins persists in genetic variations associated with inflammation and longevity.


Mapping of quantitative trait loci for mycoplasma and tetanus antibodies and interferon-gamma in a porcine F(2) Duroc x Pietrain resource population.
The aim of the present study was to detect quantitative trait loci (QTL) for innate and adaptive immunity in pigs. For this purpose, a Duroc x Pietrain F(2) resource population (DUPI) with 319 offspring was used to map QTL for the immune traits blood antibodies and interferon-gamma using 122 microsatellites covering all autosomes. Antibodies response to Mycoplasma hyopneumoniae and tetanus toxoid vaccine and the interferon-gamma (IFNG) serum concentration were measured at three different time points and were used as phenotypes. The differences of antibodies and interferon concentration between different time points were also used for the linkage mapping. Line-cross and imprinting QTL analysis, including two-QTL, were performed using QTL Express. A total of 30 QTL (12, 6, and 12 for mycoplasma, tetanus antibody, and IFNG, respectively) were identified at the 5% chromosome-wide-level significant, of which 28 were detected by line-cross and 2 by imprinting model. In addition, two QTL were identified on chromosome 5 using the two-QTL approach where both loci were in repulsion phase. Most QTL were detected on pig chromosomes 2, 5, 11, and 18. Antibodies were increased over time and immune traits were found to be affected by sex, litter size, parity, and month of birth. The results demonstrated that antibody and IFNG concentration are influenced by multiple chromosomal areas. The flanking markers of the QTL identified for IFNG on SSC5 did incorporate the position of the porcine IFNG gene. The detected QTL will allow further research in these QTL regions for candidate genes and their utilization in selection to improve the immune response and disease resistance in pig.


Diagnostic Value of Prenatal MR Imaging in the Detection of Brain Malformations in Fetuses before the 26th Week of Gestational Age.
In several countries, laws and regulations allow abortion for medical reasons within 24-25 weeks of gestational age. We investigated the diagnostic value of prenatal MR imaging for brain malformations within 25 weeks of gestational age. We retrospectively included fetuses within 25 weeks of gestational age who had undergone both prenatal and postnatal MR imaging of the brain between 2002 and 2014. Two senior pediatric neuroradiologists evaluated prenatal MR imaging examinations blinded to postnatal MR imaging findings. With postnatal MR imaging used as the reference standard, we calculated the sensitivity, specificity, positive predictive value, and negative predictive value of the prenatal MR imaging in detecting brain malformations. One-hundred nine fetuses (median gestational age at prenatal MR imaging: 22 weeks; range, 21-25 weeks) were included in this study. According to the reference standard, 111 malformations were detected. Prenatal MR imaging failed to detect correctly 11 of the 111 malformations: 3 midline malformations, 5 disorders of cortical development, 2 posterior fossa anomalies, and 1 vascular malformation. Prenatal MR imaging misdiagnosed 3 findings as pathologic in the posterior fossa. The diagnostic value of prenatal MR imaging between 21 and 25 weeks' gestational age is very high, with limitations of sensitivity regarding the detection of disorders of cortical development.


Social engagement and disability in a community population of older adults: the New Haven EPESE.
This paper examines the effect of social engagement on disability among community-dwelling older adults in 1982-1991. Data were collected from the New Haven, Connecticut, site of the Established Populations for Epidemiologic Studies of the Elderly. Baseline social engagement was measured by using 11 items related to social and productive activity. Disability data consisted of a six-item measure of activities of daily living, a three-item measure of gross mobility, and a four-item measure of basic physical functions. Nine waves of yearly disability data were analyzed by using generalized estimating equations models. After adjustment for age, gender, race, and physical activity, significant cross-sectional associations (p's < 0.001) were found between social engagement and all three measures of disability, with more socially engaged older adults reporting less disability. Social engagement also showed small, but negative interaction effects with follow-up-time outcomes (p's < 0.01), indicating that the protective effect of social engagement decreased slightly during follow-up. Results suggest a strong, but not necessarily causal association of social engagement with disability. Promotion of social engagement may still be important for the prevention of disability.


Saikosaponin D: A potential therapeutic drug for osteoarthritis.
Osteoarthritis is a degenerative joint disease. Currently, no effective therapeutic exists for osteoarthritis in the clinic setting. Inflammatory response and autophagy are key players in the occurrence and prognosis of osteoarthritis. In recent years, the regulation of inflammation and autophagy signal pathway has been touted as a potential treatment course for osteoarthritis. Saikosaponin D has anti-inflammatory and induces autophagy effects via inhibiting the nuclear transcription factor-κB, mTOR signaling pathways. Here in the report, we analyze and summarize recent evidences pertaining to the relationship between Saikosaponin and osteoarthritis. Published studies were scoured for in research databases, such as PubMed and Scopus with the keywords Saikosaponin and osteoarthritis. Phosphatidylinositol 3-kinase (PI3k)/Akt/mTOR signaling pathway is an important autophagy modulator, and can regulate chondrocytic autophagy, inflammation, and apoptosis. Saikosaponin D alleviates inflammation and regulates autophagy by inhibiting the PI3k/Akt/mTOR signaling pathway. Saikosaponin D could be a potential therapeutic drug for osteoarthritis.


Eye-tracking-based assessment of cognitive function in low-resource settings.
Early development of neurocognitive functions in infants can be compromised by poverty, malnutrition and lack of adequate stimulation. Optimal management of neurodevelopmental problems in infants requires assessment tools that can be used early in life, and are objective and applicable across economic, cultural and educational settings. The present study examined the feasibility of infrared eye tracking as a novel and highly automated technique for assessing visual-orienting and sequence-learning abilities as well as attention to facial expressions in young (9-month-old) infants. Techniques piloted in a high-resource laboratory setting in Finland (N=39) were subsequently field-tested in a community health centre in rural Malawi (N=40). Parents' perception of the acceptability of the method (Finland 95%, Malawi 92%) and percentages of infants completing the whole eye-tracking test (Finland 95%, Malawi 90%) were high, and percentages of valid test trials (Finland 69-85%, Malawi 68-73%) satisfactory at both sites. Test completion rates were slightly higher for eye tracking (90%) than traditional observational tests (87%) in Malawi. The predicted response pattern indicative of specific cognitive function was replicated in Malawi, but Malawian infants exhibited lower response rates and slower processing speed across tasks. High test completion rates and the replication of the predicted test patterns in a novel environment in Malawi support the feasibility of eye tracking as a technique for assessing infant development in low-resource setting. Further research is needed to the test-retest stability and predictive validity of the eye-tracking scores in low-income settings.


Micro-scale and meso-scale architectural cues cooperate and compete to direct aligned tissue formation.
Tissue and biomaterial microenvironments provide architectural cues that direct important cell behaviors including cell shape, alignment, migration, and resulting tissue formation. These architectural features may be presented to cells across multiple length scales, from nanometers to millimeters in size. In this study, we examined how architectural cues at two distinctly different length scales, "micro-scale" cues on the order of ∼1-2 μm, and "meso-scale" cues several orders of magnitude larger (>100 μm), interact to direct aligned neo-tissue formation. Utilizing a micro-photopatterning (μPP) model system to precisely arrange cell-adhesive patterns, we examined the effects of substrate architecture at these length scales on human mesenchymal stem cell (hMSC) organization, gene expression, and fibrillar collagen deposition. Both micro- and meso-scale architectures directed cell alignment and resulting tissue organization, and when combined, meso cues could enhance or compete against micro-scale cues. As meso boundary aspect ratios were increased, meso-scale cues overrode micro-scale cues and controlled tissue alignment, with a characteristic critical width (∼500 μm) similar to boundary dimensions that exist in vivo in highly aligned tissues. Meso-scale cues acted via both lateral confinement (in a cell-density-dependent manner) and by permitting end-to-end cell arrangements that yielded greater fibrillar collagen deposition. Despite large differences in fibrillar collagen content and organization between μPP architectural conditions, these changes did not correspond with changes in gene expression of key matrix or tendon-related genes. These findings highlight the complex interplay between geometric cues at multiple length scales and may have implications for tissue engineering strategies, where scaffold designs that incorporate cues at multiple length scales could improve neo-tissue organization and resulting functional outcomes.


Role of tumor cell glycoproteins immunologically related to glycoproteins Ib and IIb/IIIa in tumor cell-platelet and tumor cell-matrix interactions.
A panel of monoclonal and polyclonal antibodies raised against human platelet GpIb or the GpIIb/IIIa complex were used to detect immunologically related molecules on two cell lines derived from human solid tumors. Human cervical carcinoma (MS751) and human colon carcinoma (clone A) expressed molecules immunologically related to platelet GpIb and GpIIb/IIIa complex. These molecules were localized to their plasma membranes by immunofluorescence and immunocytochemistry. The immunologically related GpIb was evenly distributed on the tumor cell membrane with occasional areas of aggregates, whereas the immunologically related GpIIb/IIIa had a pronounced punctate distribution of aggregates in prefixed cells. When MS751 or clone A cells were pretreated with antibodies against platelet GpIb and/or the GpIIb/IIIa complex, their ability to induce platelet aggregation was significantly inhibited. In addition, when tumor cells were pretreated with antibodies against the platelet IIb/IIIa complex, adherence to fibronectin-coated plates was also significantly inhibited. These results suggest a role for these immunologically related tumor cell glycoproteins in tumor cell-host cell (i.e., platelet, endothelial cells) interactions, tumor cell interactions with components of the subendothelial matrix, and subsequent tumor metastasis.


Chemotherapy of atherosclerosis.
Clinical and experimental studies have provided an increasing amount of evidence that atherosclerosis is preventable and that regression is feasible. Although the elimination of risk factors would be a form of primary prevention such is hardly feasible in our modern industrial age. Thus the combination of elimination or at least decrease in risk factors and a direct treatment of the arterial wall should help to bring about this prevention and regression. Metabolic changes and/or dysfunction of the vessel wall particularly endothelial cells has been given increasing attention. Energy and cyclic nucleotide metabolism in endothelial cells have been studied in the initiation, progression and regression of atherosclerosis. Several compounds were found to exert beneficial effects on metabolism in the endothelial cells and clinical favorable effects have been documented. Chemotherapy for the treatment of "endotheliopathy" and atherosclerosis will not doubt be the object of intensive studies.


Differences in coordination between dominant and non-dominant hands in tele-operation.
The intuitive tele-operation of industrial robot arms is necessary for the teaching of autonomous movement. We developed a novel interface, namely the iFeel Desktop Haptic Device, for operating robots intuitively. However, when a user uses two interfaces with two hands, there are differences in coordination between the dominant and non-dominant hands. In this paper, we investigated the differences in coordination between dominant and non-dominant hands using two devices for the development of cooperative control. In an experiment, when the participants manipulated the two interfaces to operate a virtual tracking system, we measured the tracking error in each degree of freedom (i.e., X, Y, Z, pitch, yaw, and roll directions). The results show that there were significant differences between the dominant and non-dominant hands for movement in the X, Y, Z, and pitch directions. We conclude that the operations that involve more body parts have a greater difference between dominant and non-dominant hands.


Host Transcriptional Response of Sclerotinia sclerotiorum Induced by the Mycoparasite Coniothyrium minitans.
Mycoparasite Coniothyrium minitans parasitizes specifically the mycelia or sclerotia of Sclerotinia sclerotiorum, a worldwidely spread plant fungal pathogen causing serious diseases on crops. The interaction of C. minitans with S. sclerotiorum remains reciprocal and complex and little is known, especially on the side of the host (S. sclerotiorum). In this study, the early transcriptional response of S. sclerotiorum to the mycoparasitism by C. minitans was explored and the differentially expressed genes (DEGs) were analyzed. Based on GO ontology, KEGG pathway and fungal categories database, 887 up-regulated DEGs were enriched in the growth related function (i.e., rRNA processing, ribosome biogenesis, binding and transport), while the 546 down-regulated DEGs were enriched in the stress-related functions (i.e., oxidoreductase, response to stress and heat and the chorismate biosynthetic process). The expression of shikimate pathway and the biosynthesis of phenylalanine involving genes was significantly suppressed. Furthermore, 581 unenriched DEGs were explored in the parasitizing process and were mapped on the Pfam domains of redox enzymes, Alpha/Beta hydrolase, haloacid dehalogenase, and other universal conserved domain containing proteins. Thirty-two DEGs encoding candidate effectors, with 16 up-regulated and 16 down-regulated, were observed with diverse function. SS1G_11912 (encoding SsNEP2) was significantly up-regulated and may function in the parasitism. The involving of the shikimate pathway of phenylalanine biosynthesis and effector candidates were discussed. The results provide a basal understand on the interaction of S. sclerotiorum and C. minitans.


The Construction of Bone Metastasis-Specific Prognostic Model and Co-expressed Network of Alternative Splicing in Breast Cancer.
Breast cancer (BRCA) ranks among the top most common female malignancies and was regarded as incurable when combined with bone and distant metastasis. Alternative splicing events (ASEs) together with splicing factors (SFs) were considered responsible for the development and progression of tumors. Datasets including RNA sequencing and ASEs of BRCA samples were achieved from TCGA and TCGASpliceSeq databases. Then, a survival model was built including 15 overall-survival-associated splicing events (OS-SEs) by Cox regression and Lasso regression. The co-expressed SFs of each bone-and-distant-metastasis-related OS-SE were discovered by Pearson correlation analysis. Additionally, Gene Set Variation Analysis (GSVA) was performed to identify the downstream mechanisms of the key OS-SEs. Finally, the results were validated in different online platforms. A reliable survival model was established (the area under ROC = 0.856), and CIRBP was found co-expressed with FAM110B (R = 0.320, P < 0.001) associated with the fatty acid metabolism pathway. Aberrant SF, CIRBP, regulated a specific ASE, exon skip (ES) of FAM110B, during which the fatty acid metabolism pathway played an essential part in tumorigenesis and prognosis of BRCA.


Physical Activity Assessed by Wrist and Thigh Worn Accelerometry and Associations with Cardiometabolic Health.
Physical activity is increasingly being captured by accelerometers worn on different body locations. The aim of this study was to examine the associations between physical activity volume (average acceleration), intensity (intensity gradient) and cardiometabolic health when assessed by a thigh-worn and wrist-worn accelerometer. A sample of 659 office workers wore an Axivity AX3 on the non-dominant wrist and an activPAL3 micro on the right thigh concurrently for 24 h a day for 8 days. An average acceleration (proxy for physical activity volume) and intensity gradient (intensity distribution) were calculated from both devices using the open-source raw accelerometer processing software GGIR. Clustered cardiometabolic risk (CMR) was calculated using markers of cardiometabolic health, including waist circumference, triglycerides, HDL-cholesterol, mean arterial pressure and fasting glucose. Linear regression analysis assessed the associations between physical activity volume and intensity gradient with cardiometabolic health. Physical activity volume derived from the thigh-worn activPAL and the wrist-worn Axivity were beneficially associated with CMR and the majority of individual health markers, but associations only remained significant after adjusting for physical activity intensity in the thigh-worn activPAL. Physical activity intensity was associated with CMR score and individual health markers when derived from the wrist-worn Axivity, and these associations were independent of volume. Associations between cardiometabolic health and physical activity volume were similarly captured by the thigh-worn activPAL and the wrist-worn Axivity. However, only the wrist-worn Axivity captured aspects of the intensity distribution associated with cardiometabolic health. This may relate to the reduced range of accelerations detected by the thigh-worn activPAL.


Conformation switching of clathrin light chain regulates clathrin lattice assembly.
Clathrin-coated vesicle formation is responsible for membrane traffic to and from the endocytic pathway during receptor-mediated endocytosis and organelle biogenesis, influencing how cells relate to their environment. Generating these vesicles involves self-assembly of clathrin molecules into a latticed coat on membranes that recruits receptors and organizes protein machinery necessary for budding. Here we define a molecular mechanism regulating clathrin lattice formation by obtaining structural information from co-crystals of clathrin subunits. Low resolution X-ray diffraction data (7.9-9.0 A) was analyzed using a combination of molecular replacement with an energy-minimized model and noncrystallographic symmetry averaging. Resulting topological information revealed two conformations of the regulatory clathrin light chain bound to clathrin heavy chain. Based on protein domain positions, mutagenesis, and biochemical assays, we identify an electrostatic interaction between the clathrin subunits that allows the observed conformational variation in clathrin light chains to alter the conformation of the clathrin heavy chain and thereby regulates assembly.