Neonatal Risk in Children of Women With Congenital Heart Disease: A Cohort Study With Focus on Socioeconomic Status.
Background We hypothesized that women with congenital heart disease (CHD) are at increased risk of giving birth preterm, including very and moderately preterm and giving birth to infants small for gestational age (SGA). We aimed to investigate this in a nation-wide study with focus on the potential modifying effect of socioeconomic status. Methods and Results We performed a cohort study using Danish nation-wide registers between 1997 and 2014. The exposure, maternal CHD, was subdivided into simple, moderate and complex based on severity of defects. Outcomes were preterm birth and SGA. Cox regression was used to estimate hazard ratios (HR). A total of 933 149 births including 3745 births among women with CHD were studied. The risk of giving birth preterm and SGA were higher among women with CHD as compared with women without CHD; for example, adjusted hazard ratios of preterm birth according to severity: simple 1.33 (95% CI, 1.11-1.59), moderate 1.45 (95% CI, 1.14-1.83) and complex 3.26 (95% CI, 2.41-4.40). Same pattern was seen for very and moderately preterm births and SGA. Education was a strong predictor of both preterm birth and SGA but did not modify the association between maternal congenital heart disease and preterm birth (P=0.38) or SGA (P=0.99). Conclusions Women with CHD were at increased risk of preterm birth both, moderately and very preterm, as well as giving birth to infants SGA. Education was a strong predictor of both preterm birth and SGA but the association between CHD and risk of preterm birth and SGA was independent of educational level.


[Pharyngeal musculature and obstructive sleep apnea syndromes].
An analysis of the way the pharyngeal musculature modulates the caliber of the pharynx is important to better understand and treat obstructive sleep apnea syndromes. The caliber of the pharynx at the soft palate depends on the action of the tensor veli, the palatoglossus, the palatopharyngeus and the uvula muscles. At the ligual level, the action of the genioglossus and the geniohyoideus predominate. These different muscle groups contract in co-ordination before the diaphragm contracts. Their activity is diminished and disorganized during sleep. These muscles appears to have a histological composition adapted to short-duration intense contractions making them vulnerable to fatigue. In apneic patients, these muscles are solicited constantly. Muscular lesions related to overwork have been suggested. The histological composition of these muscles is modified in apneic patients compared with non-apneic subjects (increased number of type IIa fibres), the expression of an adaptive process. The degree of adaptation varies depending of the pharyngeal level considered. Similar to their reflex stimulation, the response of these pharyngeal muscles to increased resistance is probably greatest at the soft palate level. Greater solicitation of palatine muscles associated with their greater vulnerability to fatigue could explain why obstruction is particularly important at this level. A study of the mechanical and histological properties of the pharyngeal musculature is required for a better understanding of the occlusive mechanisms of the upper airways and must be undertaken before initiating therapeutic stimulation of these muscles.


Mentoring Nontenured Track Nursing Faculty: A Systematic Review.
The purpose of this systematic review was to evaluate the effectiveness of mentoring strategies for nursing faculty progression and productivity in the nontenure track at institutions of higher education. Sixty articles were included in the review. Findings revealed that nontenure track nursing faculty require planned programs and mentoring strategies unique to their role and abilities. Schools of nursing can improve on faculty progression, scholarship, and career growth by providing structured mentoring activity.


Evaluation of a new lithium dosage-prediction technique.
The accuracy of a lithium dosage prediction technique was studied retrospectively. The dosage-prediction technique evaluated is based on lithium body clearance. The medical records of 71 psychiatric patients (30 men, 41 women) were reviewed. Age, sex, height, weight, serum creatinine, and one-compartment intravenous dosage equations were used. The lithium dose that would produce steady-state concentrations equal to those actually attained clinically was calculated. Forty-five (64%) of the predictions were within one capsule/day of the actual dose. There were 42 episodes (59%) of underprediction and 10(14%) of overprediction by one or more capsules per day. Underprediction occurred significantly more often in women than in men (31/41 versus 11/30). Predictions differed from actual doses by three or more capsules per day in 10 cases, nine of which were underpredictions. These patients did not differ significantly from the rest of the study group in age, sex, weight, serum creatinine, creatinine clearance, concurrent medical problems, or other medications. This lithium dosage prediction technique may be reliable, rapid, and inexpensive, but further refinement and prospective evaluation are necessary.


An empirical model for electrostatic interactions in proteins incorporating multiple geometry-dependent dielectric constants.
Here we introduce an electrostatic model that treats the complexity of electrostatic interactions in a heterogeneous protein environment by using multiple parameters that take into account variations in protein geometry, local structure, and the type of interacting residues. The optimal values for these parameters were obtained by fitting the model to a large dataset of 260 experimentally determined pK(a) values distributed over 41 proteins. We obtain fits between the calculated and observed values that are significantly better than the null model. The model performs well on the groups that exhibit large pK(a) shifts from solution values in response to the protein environment and compares favorably with other, successful continuum models. The empirically determined values of the parameters correlate well with experimentally observed contributions of hydrogen bonds and ion pairs as well as theoretically predicted magnitudes of charge-charge and charge-polar interactions. The magnitudes of the dielectric constants assigned to different regions of the protein rank according to the strength of the relaxation effects expected for the core, boundary, and surface. The electrostatic interactions in this model are pairwise decomposable and can be calculated rapidly. This model is therefore well suited for the large computations required for simulating protein properties and especially for prediction of mutations for protein design.


Common channel length predicts outcomes of biliopancreatic diversion alone and with the duodenal switch surgery.
The optimal common channel (CC) length for malabsorptive weight loss surgeries is unknown even though these surgeries were developed in the 1970s (biliopancreatic diversion [BPD]) and the 1990s (biliopancreatic diversion with a duodenal switch [BPD DS]). We hypothesized that the length of the CC correlates with a successful weight loss result. We evaluated 3 groups of patients based on the length of the CC whose duration of follow-up evaluation was at least 1 year. We reviewed all patients who had either an open BPD (5 patients) or a BPD DS (119 patients) from August 1998 to October 2003, for which D.B.M. was the participating surgeon. Group I comprised 15 patients: their preoperative body mass index (BMI) was 53.9 kg/m(2); 73.3% of patients had a BMI more than 50, and the CC length was 150 cm. Group II comprised 76 patients: their preoperative BMI was 54.25 kg/m(2); 73.3% of patients had a BMI more than 50, and the CC length was 100 cm. Group III comprised 33 patients: their preoperative BMI was 60.1 kg/m(2); 84% of patients had a BMI more than 50, and the CC length was 80 to 90 cm. The mean weight loss in group I was 45 kg (44% mean excess weight loss). The mean weight loss in groups II and III was 55.8 and 61.5 kg, respectively (a 57% and 54.8% mean excess weight loss, respectively) (all P < .05 by analysis of variance). A weight loss of greater than 50% of excess body weight occurred in 40% of patients in group I versus 63% of patients in groups II and III combined (P < .01 by chi(2)). The length of the CC contributes significantly to successful excess weight loss in BPD and BPD DS patients. In general, the length of the CC should not exceed 100 cm.


Maize histone H2B-mCherry: a new fluorescent chromatin marker for somatic and meiotic chromosome research.
Cytological studies of fluorescent proteins are rapidly yielding insights into chromatin structure and dynamics. Here we describe the production and cytological characterization of new transgenic maize lines expressing a fluorescent histone fusion protein, H2B-mCherry. The transgene is expressed under the control of the maize ubiquitin1 promoter, including its first exon and intron. Polymerase chain reaction-based genotyping and root-tip microscopy showed that most of the lines carrying the transgene also expressed it, producing bright uniform staining of nuclei. Further, plants showing expression in root tips at the seedling stage also showed expression during meiosis, late in the life cycle. Detailed high-resolution three-dimensional imaging of cells and nuclei from various somatic and meiotic cell types showed that H2B-mCherry produced remarkably clear images of chromatin and chromosome fiber morphology, as seen in somatic, male meiotic prophase, and early microgametophyte cells. H2B-mCherry also yielded distinct nucleolus staining and was shown to be compatible with fluorescence in situ hybridization. We found several instances where H2B-mCherry was superior to DAPI as a generalized chromatin stain. Our study establishes these histone H2B-mCherry lines as new biological reagents for visualizing chromatin structure, chromosome morphology, and nuclear dynamics in fixed and living cells in a model plant genetic system.


The role of the media in the amplification of a contested health risk: Rubber granulate on sport fields.
This study aims to increase insights into the potential role of the media in the amplification and attenuation of modern risks in society, by studying the dynamics and contents of the newspaper coverage about the potential health risk posed by rubber granulate in the Netherlands. We thematically analysed 153 national newspaper articles about the risks posed by rubber granulate between September 2016 and February 2017. Our results suggest that newspaper coverage might have contributed to heightened public risk perceptions by presenting the negligible health risk as uncertain, focusing on controversy between authorities and experts, describing responses such as concerns, commotion, and adopted risk mitigation measures by members of the public, and by providing insufficient contextualization on whether hazardous substances in rubber granulate pose a threat to health. The risks posed by rubber granulate is one of the many modern risks that has become subject to heated and mediated public discussions. Our results provide in-depth insights into important content elements in media coverage during such discussions and the impact of these elements on public perceptions. Public health institutes and other authorities might be able to mitigate the amplification of risks through media coverage by means of appropriate preparedness and response.


Neuropeptide Y is produced by adipose tissue macrophages and regulates obesity-induced inflammation.
Neuropeptide Y (NPY) is induced in peripheral tissues such as adipose tissue with obesity. The mechanism and function of NPY induction in fat are unclear. Given the evidence that NPY can modulate inflammation, we examined the hypothesis that NPY regulates the function of adipose tissue macrophages (ATMs) in response to dietary obesity in mice. NPY was induced by dietary obesity in the stromal vascular cells of visceral fat depots from mice. Surprisingly, the induction of Npy was limited to purified ATMs from obese mice. Significant basal production of NPY was observed in cultured bone marrow derived macrophage and dendritic cells (DCs) and was increased with LPS stimulation. In vitro, addition of NPY to myeloid cells had minimal effects on their activation profiles. NPY receptor inhibition promoted DC maturation and the production of IL-6 and TNFα suggesting an anti-inflammatory function for NPY signaling in DCs. Consistent with this, NPY injection into lean mice decreased the quantity of M1-like CD11c(+) ATMs and suppressed Ly6c(hi) monocytes. BM chimeras generated from Npy(-/-) donors demonstrated that hematopoietic NPY contributes to the obesity-induced induction of Npy in fat. In addition, loss of Npy expression from hematopoietic cells led to an increase in CD11c(+) ATMs in visceral fat with high fat diet feeding. Overall, our studies suggest that NPY is produced by a range of myeloid cells and that obesity activates the production of NPY in adipose tissue macrophages with autocrine and paracrine effects.


Low-cost high-resolution fast spin-echo MR of acoustic schwannoma: an alternative to enhanced conventional spin-echo MR?
To determine whether unenhanced high-resolution T2-weighted fast spin-echo MR imaging provides an acceptable and less expensive alternative to contrast-enhanced conventional T1-weighted spin-echo MR techniques in the diagnosis of acoustic schwannoma. We reviewed in a blinded fashion the records of 25 patients with pathologically documented acoustic schwannoma and of 25 control subjects, all of whom had undergone both enhanced conventional spin-echo MR imaging and unenhanced fast spin-echo MR imaging of the cerebellopontine angle/internal auditory canal region. The patients were imaged with the use of a quadrature head receiver coil for the conventional spin-echo sequences and dual 3-inch phased-array receiver coils for the fast spin-echo sequences. The size of the acoustic schwannomas ranged from 2 to 40 mm in maximum dimension. The mean maximum diameter was 12 mm, and 12 neoplasms were less than 10 mm in diameter. Acoustic schwannoma was correctly diagnosed on 98% of the fast spin-echo images and on 100% of the enhanced conventional spin-echo images. Statistical analysis of the data using the kappa coefficient demonstrated agreement beyond chance between these two imaging techniques for the diagnosis of acoustic schwannoma. There is no statistically significant difference in the sensitivity and specificity of unenhanced high-resolution fast spin-echo imaging and enhance T1-weighted conventional spin-echo imaging in the detection of acoustic schwannoma. We believe that the unenhanced high-resolution fast spin-echo technique provides a cost-effective method for the diagnosis of acoustic schwannoma.


Descriptive epidemiology of blood pressure in a rural adult population in Northern Ghana.
There are limited data on blood pressure (BP) levels in rural populations in sub-Saharan Africa. This is a cause for concern considering high BP contributes to a substantial public health burden in this population. Blood pressure levels were measured in a representative rural sample from Kassena-Nankana District of Northern Ghana, West Africa, and associations with anthropometric indices, age, sex, and time of BP measurement were assessed. This cross-sectional survey was made on a random sample drawn from a population register and included 207 males and 367 females aged between 18 and 65 years. Data collection consisted of anthropometric and blood pressure measurements after questionnaire interviews. Household salt consumption was also measured in 20 randomly selected households. Overall prevalence of casual high BP was 19.3% (111/574). Age-adjusted mean (standard deviation) systolic BPs (SBPs) and diastolic BPs (DBPs) were 124.25 (18.67) and 69.92 (12.09) mmHg in males and 122.07 (22.01) and 72.11 (12.35) mmHg in females. Mean body mass index (BMI) was 21.78 (3.09) kg/m2; 21.13 (2.27) for males and 22.15 (3.41) kg/m2 for females (p > 0.05). Blood pressures increased with age, 4 and 3 mmHg per decade for SBP and DBP, respectively (p < 0.000). Regression analyses showed that SBP was significantly associated with age, BMI, waist circumference and time of BP measurement (p < 0.000). In multiple regression analyses, age and BMI were independently associated with SBP and DBP in women (p < 0.001). Time of BP measurement was independently associated with SBP but only in men (p < 0.001). There was no increase in BMI with age. Repeat measurements in 89 subjects yielded a regression dilution factor of 0.57 for SBP. Salt consumption per individual was estimated as equivalent to 12.5 g of pure salt/day. Average BPs are not notably high in this predominantly lean rural West African population. Blood pressures do, however, increase as expected with age and BMI. Population-wide approaches need to be developed, appropriate to the level of medical provision, in order to address vascular disease risks resulting from higher than optimal BPs. These should include programs to reduce salt consumption.


Gene expression of tyrosine hydroxylase and neuropeptide Y in prevertebral ganglia of renal hypertensive rats.
The gene expression of tyrosine hydroxylase (TH) and neuropeptide Y (NPY) was studied in prevertebral ganglia and adrenal glands of adult male rats during the development of renal hypertension (removal of 1 kidney/constriction of other kidney). Only tissues from rats with arterial pressures significantly elevated by day 3 were compared with those from controls. At 4 or 5 days after renal surgery, superior cervical ganglia, celiac-mesenteric plexus, adrenal glands, and stellate ganglia were surgically removed from nonfixed rats for Northern blot analysis or from perfusion-fixed rats for in situ hybridization. In all tissues, levels of TH mRNA were decreased in hypertensive rats; cells with decreased levels were scattered throughout each tissue. In contrast, levels of NPY mRNA were unchanged in hypertensive rats compared with controls. Changes in TH mRNA levels suggest that the developing phase of renal hypertension is associated with a decrease in sympathetic outflow to the periphery. In contrast, the failure of NPY mRNA levels to change suggests a different regulatory mechanism for NPY expression or a different role for NPY in sympathetic neurotransmission.


Retrospective real-world pilot data on transcranial pulse stimulation in mild to severe Alzheimer's patients.
Transcranial pulse stimulation (TPS) is a non-invasive neuromodulation therapy that uses short, repetitive shockwaves through a neuro-navigated device. Current research suggests that these pulses lead to a wide range of vascular, metabolic, and neurotrophic changes. This relatively new CE-marked treatment provided first promising results in a clinical pilot study for improving cognition in mild-to-moderate Alzheimer's. Data from other centers is lacking, so here we analyzed safety and pilot real-world short-term results of TPS from the first center in Germany. To gain information about effects in different stages, patients with not only mild but also moderate-to-severe Alzheimer's were analyzed. A total of 11 patients were retrospectively examined for cognitive and emotional function before and after the first stimulation series. The effect was assessed using several neuropsychological tests [Alzheimer's Disease Assessment Scale (ADAS), including the ADAS cognitive score (ADAS Cog) and ADAS affective scores, Mini-Mental Status Examination (MMSE), and Montreal Cognitive Assessment (MoCA)] including in comparison between the groups of mild-to-severe patients. Moreover, subjective improvement of symptom severity, potential effects on depressive symptoms, and side effects were analyzed using Numeric Rating Scales (NRS). Side effects were rare (in 4% of sessions) with moderate subjective severity and only transient. Patients significantly improved in the ADAS and ADAS Cog, while there was no significant effect in MMSE and MoCA. Patients' self-reported symptom severity improved significantly. The depressive symptoms measured in an ADAS subscale also improved significantly. Statistical data analyses revealed no significant correlation of clinical improvement with baseline symptom severity. TPS might be a safe and promising add-on therapy for Alzheimer's, even for moderate-to-severe patients. More research on long-term effects in patients as well as studies with sham control groups is needed. Moreover, translational research on the mechanisms of action and effects on cerebral network physiology will be needed to understand this new neuromodulation technique.


Lipid Compositions in Escherichia coli and Bacillus subtilis During Growth as Determined by MALDI-TOF and TOF/TOF Mass Spectrometry.
Lipids in Escherichia coli and Bacillus subtilis were analyzed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry and TOF/TOF tandem mass spectrometry. Lipids were extracted from bacterial cells using an equal volume mixture of dichloromethane, ethanol, and water, which formed a biphasic system with the lipids in the organic layer. The resulting mass spectra of the extracts from both bacteria showed a series of peaks corresponding to sodiated phospholipids - primarily phosphatidylethanolamines (PE) and phosphatidylglycerols (PG). The relative amounts of the phospholipids and the fatty acid compositions inferred from the spectra were in good agreement with previously reported values from GC/MS and thin-layer chromatography studies. E. coli and B. subtilis were easily differentiated by dissimilarities in the composition and relative amounts of the phospholipids present as well as by the presence of lysyl-phosphatidylglycerol and diglucosyl diglycerides solely in the B. subtilis mass spectra. Changes in lipid content in the bacteria during their growth phases were also monitored. In E. coli, the spectra indicated an increase in the amount of the unique C(cy-17) fatty acid (in which the fatty acid chain contains a cyclopropane ring) formed during exponential growth. During stationary growth, the spectra indicated an increase in the amount of saturated fatty acids. In B. subtilis, the phospholipid composition remained relatively unchanged during exponential growth, but the amount of PG slightly decreased while the amount of PE slightly increased during stationary growth. No significant changes were observed for the lysyl-phosphatidylglycerols or glycolipids during the exponential or stationary growth phases.


Pregnancy and pre-existing heart disease.
Heart disease is encountered in nearly 1% of pregnancies, and the incidence is increasing. This is likely due to advances in cardiac management over the past 25 years, particularly advances in cardiac surgery and drugs, which have allowed more women with congenital and other abnormalities not only to survive to reach the age of child-bearing but also to carry a pregnancy to term successfully. Cardiac diseases of particular importance include stenotic valvular lesions, cyanotic disorders, and lesions accompanied by pulmonary hypertension. These abnormalities are associated with increased fetal and maternal morbidity and mortality, and therefore require very close monitoring during pregnancy. The physician also should be familiar with the more common cardiac disorders seen in pregnancy, be familiar with cardiovascular drugs and their potential effects on the pregnant patient and fetus, and be aware of cardiac disorders which are relative and absolute contraindications to pregnancy due to high rates of maternal mortality.


Effects of Hylan G-F 20 supplementation on cartilage preservation detected by magnetic resonance imaging in osteoarthritis of the knee: a two-year single-blind clinical trial.
Although viscosupplementation is an effective symptomatic treatment for knee osteoarthritis (OA), the effect of longer term administration on articular cartilage has not been fully explored. We examined the effect of viscosupplementation with Hylan G-F 20 on knee cartilage over 2 years in patients with knee OA. In this prospective, single-blind, parallel control group pilot study, 78 patients with symptomatic knee OA (Kellgren-Lawrence grade II and III) were assigned to either intervention group (n = 39 receiving 4 courses of 3 × 2.0 ml of intra-articular Hylan G-F 20 injections at 6 month intervals) or control group (n = 39 receiving usual care for knee OA without injections). Magnetic resonance imaging of the study knee was performed at baseline, 12 and 24 months. Cartilage volume and defects were assessed using validated methods. Fifty-five subjects (71%) completed 24 month follow up. Over 24 months, the intervention group had a reduced annual percentage rate of medial and lateral tibial cartilage volume loss (mean ± SD, -0.3 ± 2.7% and -1.4 ± 4.3%) compared with the control group (2.3 ± 2.6% and 1.4 ± 2.6%, P = 0.001 and 0.005 for difference, respectively). The intervention group also showed reduced cartilage defect score increment in the medial tibiofemoral compartment (0.1 ± 1.3) compared with the control group (0.8 ± 1.5, P = 0.05). Six monthly intra-articular injections of Hylan G-F 20 administered to patients with symptomatic knee OA have a beneficial effect on knee cartilage preservation measured by both cartilage volume and cartilage defects. Hylan G-F 20 warrants further evaluation in larger clinical trials as a possible disease-modifying agent in the treatment of knee OA. The study was registered with ClinicalTrials.gov (NCT00393393).


Variability of the polymerase gene (NS5B) in hepatitis C virus-infected women.
There are limited data on diversity within the hepatitis C virus polymerase (NS5B). In concordance with its key functional role during the life cycle, NS5B intrapatient variability was low. Moreover, differences between NS5B nonsynonymous (dN) and synonymous (dS) mutation rates (dN - dS) were positively correlated with CD4 cell count, while nonsynonymous mutations were strongly correlated with reduced replication in vivo.


Effectiveness and cost of two stair-climbing interventions-less is more.
The current study compared two interventions for promotion of stair climbing in the workplace, an information-based intervention at a health information day and an environmental intervention (point-of-choice prompts), for their effectiveness in changing stair climbing and cost per employee. Interrupted time-series design. Four buildings on a university campus. Employees at a university in the United Kingdom. Two stair-climbing interventions were compared: (1) a stand providing information on stair climbing at a health information day and (2) point-of-choice prompts (posters). Observers recorded employees' gender and method of ascent (n = 4279). The cost of the two interventions was calculated. Logistic regression. There was no significant difference between baseline (47.9% stair climbing) and the Workplace Wellbeing Day (48.8% stair climbing), whereas the prompts increased stair climbing (52.6% stair climbing). The health information day and point-of-choice prompts cost $773.96 and $31.38, respectively. The stand at the health information day was more expensive than the point-of-choice prompts and was inferior in promoting stair climbing. It is likely that the stand was unable to encourage stair climbing because only 3.2% of targeted employees visited the stand. In contrast, the point-of-choice prompts were potentially visible to all employees using the buildings and hence better for disseminating the stair climbing message to the target audience.


Making sense out of jargon: a neurolinguistic and computational account of jargon aphasia.
To identify the cognitive and neuroanatomic bases of neologistic jargon aphasia with spared comprehension and production of written words. Detailed analysis of performance across experiments of naming, reading, writing, repetition, and word/picture matching by a 68-year-old woman (J.B.N.) served to identify which cognitive mechanisms underlying naming and word comprehension were impaired. J.B.N.'s impairments were then simulated by selectively "lesioning" a computer model of word production that has semantic, word form, and subword phonologic levels of representation (described by Dell in 1986). In comprehension experiments, J.B.N. made far more errors with spoken word input than with written word or picture input (chi-square = 40-59; df = 1; p < 0.0001) despite intact auditory discrimination. In naming experiments (with picture, definition, or tactile input), J.B.N. made far more errors in spoken output relative to written output (chi-square = 14-56; df = 1; p < 0.0001). These selective impairments of spoken word processing were simulated by reducing connection strength between word-level and subword-level phonologic units but maintaining full connection strength between word-level and semantic units in Dell's model. The simulation yielded a distribution of error types that was nearly identical to that of J.B.N., and her CT and MRI scans showed a small subarachnoid hemorrhage in the left sylvian fissure without infarct. Cerebral angiogram showed focal vasospasm in sylvian branches of the left middle cerebral artery. Focal left perisylvian dysfunction can result in a highly selective "disconnection" between word-level and subword-level phonologic representations manifest as neologistic jargon aphasia with intact understanding and production of written words.


Model-independent tests of cosmic gravity.
Gravitation governs the expansion and fate of the universe, and the growth of large-scale structure within it, but has not been tested in detail on these cosmic scales. The observed acceleration of the expansion may provide signs of gravitational laws beyond general relativity (GR). Since the form of any such extension is not clear, from either theory or data, we adopt a model-independent approach to parametrizing deviations to the Einstein framework. We explore the phase space dynamics of two key post-GR functions and derive a classification scheme, and an absolute criterion on accuracy necessary for distinguishing classes of gravity models. Future surveys will be able to constrain the post-GR functions' amplitudes and forms to the required precision, and hence reveal new aspects of gravitation.


Multiphasic Continuous-Flow Reactors for Handling Gaseous Reagents in Organic Synthesis: Enhancing Efficiency and Safety in Chemical Processes.
The use of reactive gaseous reagents for the production of active pharmaceutical ingredients (APIs) remains a scientific challenge due to safety and efficiency limitations. The implementation of continuous-flow reactors has resulted in rapid development of gas-handling technology because of several advantages such as increased interfacial area, improved mass- and heat transfer, and seamless scale-up. This technology enables shorter and more atom-economic synthesis routes for the production of pharmaceutical compounds. Herein, we provide an overview of the development of gas-handling continuous-flow technology as well as the use of gases in functionalization of APIs.


Cholinergic suppression of visual responses in primate V1 is mediated by GABAergic inhibition.
Acetylcholine (ACh) has been implicated in selective attention. To understand the local circuit action of ACh, we iontophoresed cholinergic agonists into the primate primary visual cortex (V1) while presenting optimal visual stimuli. Consistent with our previous anatomical studies showing that GABAergic neurons in V1 express ACh receptors to a greater extent than do excitatory neurons, we observed suppressed visual responses in 36% of recorded neurons outside V1's primary thalamorecipient layer (4c). This suppression is blocked by the GABA(A) receptor antagonist gabazine. Within layer 4c, ACh release produces a response gain enhancement (Disney AA, Aoki C, Hawken MJ. Neuron 56: 701-713, 2007); elsewhere, ACh suppresses response gain by strengthening inhibition. Our finding contrasts with the observation that the dominant mechanism of suppression in the neocortex of rats is reduced glutamate release. We propose that in primates, distinct cholinergic receptor subtypes are recruited on specific cell types and in specific lamina to yield opposing modulatory effects that together increase neurons' responsiveness to optimal stimuli without changing tuning width.


Decreased systolic function and inadequate hypertrophy in large and small breed dogs with chronic mitral valve insufficiency.
Systolic dysfunction associated with chronic mitral valve insufficiency (CMVI) has been demonstrated in experimental animal models and large breed (LB) dogs but has been reported as an uncommon finding in small breed (SB) dogs with naturally occurring disease. It has been suggested the myocardial failure could be, in part, because of an insufficient increase in left ventricular mass. To test if SB and LB dogs with CMVI and moderate heart failure have systolic dysfunction and if they have adequate eccentric hypertrophy. Data from 38 SB and 18 LB dogs affected with CMVI were compared retrospectively with results from 2 groups of normal dogs (17 SB and 32 LB). Systolic function was investigated echocardiographically by using percentage fractional shortening (FS), the ratio between observed and expected end-systolic diameter (ESD/ESDe), and end-systolic volume index (ESVI). Left ventricular hypertrophy was estimated by using the ratio between the thickness of the left ventricular free wall and the radius in diastole (h/R). Both affected SB and LB dogs had a significantly increased FS and ESVI (FS% SB 45.6 + 8.04 versus 40.06 + 8.9, P < .05; FS% LB 33.64 + 8.61 versus 27.3 + 7.3 P < .05; ESVI SB 30.0 +/- 2.3 mL/m2 versus 21.18 +/- 13.9 mL/m2, P < .05; ESVI LB 83.22 +/- 43.84 mL/m2 versus 36.43 +/- 13.30 mL/m2 versus P < .001). The h/R in affected animals was decreased (0.53 +/- 0.11 versus 0.41 +/- 0.12, P < .05 SB; 0.47 +/- 0.11 versus 0.38 +/- 0.09, P < .05, LB). Data from this study indicate that dogs with moderate heart failure caused by CMVI have systolic dysfunction. Inadequate hypertrophy of the left ventricle may be, in part, responsible for this finding.


Isolation and characterization of americanin, a specific inhibitor of thrombin, from the salivary glands of the lone star tick Amblyomma americanum (L.).
A thrombin (EC 220.127.116.11) inhibitor (americanin) was isolated from the salivary glands of the lone star tick Amblyomma americanum (L.) using reversed-phase chromatography and anion-exchange chromatography. Americanin did not inhibit any other protease tested, including factor Xa, plasmin, trypsin, chymotrypsin, elastase, papain, pepsin, and carboxypeptidase. The inhibition of thrombin by americanin decreased dramatically with dilution of the reaction mixture including thrombin, its substrate, and americanin. When thrombin assays were performed in the presence of americanin, the reaction curve showed a time-dependent inhibition. Significant inhibition was observed when americanin concentration was approximately equal to that of thrombin, with a Ki of 0.073 nM. The results suggest that americanin is a specific, reversible, competitive, slow, tight-binding inhibitor of thrombin.


Newly Diagnosed Crohn's Disease Treated with Standard Care or Enteral Nutrition: Psychological Outcomes over 6 Months.
Impaired health-related quality of life and higher rates of anxiety and depression are observed in patients with Crohn's disease. This single center study aimed to describe and compare longitudinal psychological outcomes of newly diagnosed Crohn's disease patients treated with standard care or enteral nutrition to induce remission. Two separate cohorts of patients were recruited from one center and treated with standard care (n = 22) or enteral nutrition (n = 18) to induce disease remission. Disease activity, quality of life, anxiety, and depression were -assessed at diagnosis and month 6. At baseline, quality of life (n = 40) was not correlated with disease activity; symptoms of anxiety and depression were present in 15 (38%) and 5 (13%) of the 40 patients, respectively. Significant improvements in quality of life (p < 0.0001) and anxiety scores (p = 0.002) were observed after 2 weeks of exclusive enteral nutrition, and at month 6 significant improvements in all psychological outcomes were observed. At month 6, patients who received standard care had a significant improvement in quality of life (p = 0.004), but not in anxiety or depression scores, and there were no differences in psychological outcomes between the treatment groups. Overall, 34/40 (85%) patients were in clinical remission at month 6, and a clinically significant quality of life score was achieved by 31/40 (78%). Patient health-related quality of life and symptoms of anxiety and depression improved as disease activity improved, and 6 months after diagnosis psychological outcomes were similar in patients treated with standard care or enteral nutrition to initially induce remission.


Inflammasome activation restricts Legionella pneumophila replication in primary microglial cells through flagellin detection.
Microglial cells constitute the first line of defense of the central nervous system (CNS) against microbial invasion. Pathogens are detected thanks to an array of innate immune receptors termed pattern recognition receptors (PRRs). PRRs have been thoroughly characterized in bone marrow-derived macrophages, but the PRRs repertoire and functionality in microglial cells remain largely unknown. Microglial cells express various Toll-like Receptors and the Nod1/2 receptors. Recently, a novel innate immune signalling pathway, the inflammasome pathway has been uncovered. Inflammasome activation leads to caspase-1 activation, release of the proinflammatory cytokines, IL-1β and IL-18 and cell death in a process termed pyroptosis. One inflammasome receptor, NLRP3, has been characterized in microglial cells and associated with response to infections and in the initiation of neuro-degeneration in an Alzheimer's disease model. Legionella pneumophila (L.pneumophila) is a flagellated bacterium replicating within macrophages. In bone marrow-derived macrophages, L. pneumophila is detected in a flagellin-dependent manner by the Naip5-NLRC4 (Ipaf) inflammasome pathway. In this study, we decided to use L. pneumophila to investigate the presence and the functionality of this inflammasome in primary murine microglial cells. We show that microglial cells detect L. pneumophila infection in a flagellin-dependent manner leading to caspase-1-mediated bacterial growth restriction, infected cell death and secretion of the proinflammatory cytokines IL-1β and IL18. Overall, our data demonstrate that microglial cells have a functional Naip5-NLRC4 inflammasome likely to be important to monitor and clear CNS infections by flagellated bacteria.


Nitric oxide reactivity of fluorophore coordinated carboxylate-bridged diiron(II) and dicobalt(II) complexes.
The synthesis, structural characterization, and NO reactivity of carboxylate-bridged dimetallic complexes were investigated. The diiron(II) complex [Fe(2)(mu-O(2)CAr(Tol))(4)(Ds-pip)(2)] (1), where O(2)CAr(Tol) = 2,6-di(p-tolyl)benzoate and Ds-pip = dansyl-piperazine, was prepared and determined by X-ray crystallography to have a paddlewheel geometry. This complex reacts with NO within 1 min with a concomitant 4-fold increase in fluorescence emission intensity ascribed to displacement of Ds-pip. Although the diiron complex reacts with NO, as revealed by infrared spectroscopic studies, its sensitivity to dioxygen renders it unsuitable as an atmospheric NO sensor. The air-stable dicobalt(II) analogue was also synthesized and its reactivity investigated. In solution, the dicobalt(II) complex exists as an equilibrium between paddlewheel [Co(2)(mu-O(2)CAr(Tol))(4)(Ds-pip)(2)] (2) and windmill [Co(2)(mu-O(2)CAr(Tol))(2)(O(2)CAr(Tol))(2)(Ds-pip)(2)] (3) geometric isomers. Conditions for crystallizing pure samples of each of these isomers are described. Reaction of 2 with excess NO proceeds by reductive nitrosylation giving [Co(mu-O(2)CAr(Tol))(2)(NO)(4)] (5), which is accompanied by release of the Ds-pip fluorophore that is N-nitrosated in the process. This reaction affords an overall 9.6-fold increase in fluorescence emission intensity, further demonstrating the potential utility of ligand dissociation as a strategy for designing fluorescence-based sensors to detect nitric oxide in a variety of contexts.


[Radiotherapy of the tonsillar region. Analysis of prognostic factors].
We report our personal experience with the treatment of tonsillar cancers at the Otorhinolaryngology-Radiotherapy Department of Umberto I Hospital, Mestre, Italy. The results were analyzed by tumor site and stage, lymph node involvement, treatment type and patient age. January, 1987, through December, 1995, we treated a hundred and 25 patients with carcinoma of the tonsil and tonsillar region. Most patients were men (M:F = 4:1), with a mean age of 61.9 years (range: 38-87). The lesions were staged at physical examination, chest radiography, bone scintigraphy. US of the liver and neck, CT and/or MRI of the tonsillar region and neck. Eleven patients were in stage I (8.8%), 26 in stage II (20.8%), 31 in stage III (24.8%) and 57 in stage IV (45.6%). Forty-one patients were submitted to tonsillectomy and more/less massive neck dissection: surgery was not radical-in 14 of them. All patients received gamma-photon radiotherapy with a cobalt unit: the minimum dose was 50 Gy after radical surgery and 60 Gy for exclusive irradiation and after nonradical surgery. The hemiblock field technique was always used with the conventional fractionation (2 Gy/day. 1 fraction/day, 5 fractions/week); the treatment was planned with the Theraplan V05-B method on CT scans. When the tolerance dose was reached, the spinal cord was shielded and the dose compensated with 9 MeV electrons. The treatment was discontinued only when needed, and never for more than 7-10 days. The overall 5-year survival and the 5-year disease-free survival rates were 28% and 45%, respectively; the overall 5-year cause-specific survival rate was 39%. Disease-free survival was 81% in stage I, 52.7% in stage II, 44.2% in stage III and 35.8% in stage IV (p = .005). The 5-year disease-free survival for the patients receiving surgery and irradiation was 62.1%, versus 38.3% for irradiation alone; the rate was 37.6% when neck nodes were involved (N+). One hundred and two patients achieved complete remission (CR), while the other 23 had partial remission (PR). Twenty-eight CR patients recurred; the most common cause of death was failure in primary tumor local control. There were no complications during or after treatment. Secondary lesions were found in 13 patients (10.1%). Irradiation alone yields fairly good results in early tonsil carcinoma, while the surgery-irradiation combination should be preferred in large tumors. Better results are expected from kinetic and conformal irradiation techniques with 3D calculations on CT and MR images, which should permit to deliver high doses to strictly targeted areas and to reduce side-effects. Other improvements are expected from new combination therapies.


Acute postoperative swelling after hand surgery: an exploratory, double-blind, randomised study with paracetamol, naproxen, and placebo.
A model using volumetry to evaluate the effect of drugs on acute postoperative swelling after operations for primary Dupuytren's contracture (DC) and carpal tunnel syndrome (CTS) was established and validated. The temperature of the saline and time of measurement during the day influenced the volumetric readings. The error of measurement after volumetry of unoperated and operated hands after operations for DC was 0.7% and 0.6%, respectively. Naproxen (500 mg twice a day), paracetamol (1000 mg four times a day), or placebo were given postoperatively for three days to 35 patients after DC and 42 patients after CTS in a randomised, placebo-controlled study. Hand volume was measured preoperatively and 72 hours after surgery. There was a difference in swelling (p = 0.009) indicating different degree of development of swelling 72 hours postoperatively between the DC and CTS placebo groups, which invalidated pooling of the data. After operations for DC naproxen was slightly but not significantly superior to paracetamol and placebo, with paracetamol numerically superior to placebo. The power of the study, caused by the limited number of patients included, does not permit this difference to reach significance. Operations for CTS caused so little swelling that comparisons were invalidated. Naproxen treatment, irrespective of type of operation, did not require rescue analgesics, while two patients after CTS treated with paracetamol did. Two and six placebo-treated patients required rescue drugs after operations for DC and CTS, respectively. We conclude that naproxen might have a clinical relevant effect on swelling when used on minor surgery in the hand, unlike paracetamol. Naproxen might be a useful analgesic during the immediate postoperative phase.


Current Advances, Research Needs and Gaps in Mycotoxins Biomonitoring under the HBM4EU-Lessons Learned and Future Trends.
Mycotoxins are natural metabolites produced by fungi that contaminate food and feed worldwide. They can pose a threat to human and animal health, mainly causing chronic effects, e.g., immunotoxic and carcinogenic. Due to climate change, an increase in European population exposure to mycotoxins is expected to occur, raising public health concerns. This urges us to assess the current human exposure to mycotoxins in Europe to allow monitoring exposure and prevent future health impacts. The mycotoxins deoxynivalenol (DON) and fumonisin B1 (FB1) were considered as priority substances to be studied within the European Human Biomonitoring Initiative (HBM4EU) to generate knowledge on internal exposure and their potential health impacts. Several policy questions were addressed concerning hazard characterization, exposure and risk assessment. The present article presents the current advances attained under the HBM4EU, research needs and gaps. Overall, the knowledge on the European population risk from exposure to DON was improved by using new harmonised data and a newly derived reference value. In addition, mechanistic information on FB1 was, for the first time, organized into an adverse outcome pathway for a congenital anomaly. It is expected that this knowledge will support policy making and contribute to driving new Human Biomonitoring (HBM) studies on mycotoxin exposure in Europe.


Immunological effects of reduced mucosal integrity in the early life of BALB/c mice.
Certain stimuli at the gut barrier may be necessary in early life to establish a proper balance of immune tolerance. We evaluated a compromised barrier in juvenile mice in relation to microbiota and local and systemic immunity. BALB/c mice were treated with a low dose of dextran sulfate sodium (DSS) with or without ampicillin and lipopolysaccharide (LPS) to clarify the importance of microbial antigens and interaction between microbial-associated patterns and toll-like receptors. The barrier breach resulted in increased plasma LPS, which was highest in mice treated simultaneously with ampicillin. Adding LPS in the food reduced its levels in plasma. Regulatory T cells were acutely increased in mesenteric lymph nodes (MLN) and spleen during DSS treatment regardless of simultaneous ampicillin treatment. In contrast, NK T and NK cells decreased in MLN and in spleen. This acute DSS effect was reflected in fold changes of haptoglobin and Il1a in colon, and this was also more pronounced in mice simultaneously treated with ampicillin. On day 1 post-treatment, major upregulations of Ifng, Foxp3, Il1b, Il2, and Il6 genes in colon were only observed in the mice simultaneously treated with ampicillin. A two-fold upregulation of colonic Foxp3 and Il1a was evident 25 days post-treatment. DSS skewed the microbiota in favor of Gram negative phyla. Therefore, increased permeability induced tolerogenic immunity independent of microbiota, and this was enhanced by LPS stimulation.


Host genetic variants in the pathogenesis of hepatitis C.
Direct-acting antiviral drugs (DAAs) are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment decisions in a clinical setting with cost restrictions. Genetic host factors are hereby essential to implement an individualized treatment concept. In recent years results on different genetic variants have been published with a strong association with therapy response, fibrosis and treatment-related side effects. Polymorphisms of the IL28B gene were identified as accurate predictors for therapy response and spontaneous clearance of HCV infection and are already used for diagnostic decisions. For RBV-induced side effects, such as hemolytic anemia, associations to genetic variants of inosine triphosphatase (ITPA) were described and different SLC28 transporters for RBV-uptake have been successfully analyzed. Fibrosis progression has been associated with variants of Vitamin D receptor (VDR) and ABCB11 (bile salt export pump). Cirrhotic patients especially have a high treatment risk and low therapy response, so that personalized antiviral treatment is mandatory. This review focuses on different host genetic variants in the pathogenesis of Hepatitis C at the beginning of a new area of treatment.


Glycerol is metabolized in a complex and strain-dependent manner in Enterococcus faecalis.
Enterococcus faecalis is equipped with two pathways of glycerol dissimilation. Glycerol can either first be phosphorylated by glycerol kinase and then oxidized by glycerol-3-phosphate oxidase (the glpK pathway) or first be oxidized by glycerol dehydrogenase and then phosphorylated by dihydroxyacetone kinase (the dhaK pathway). Both pathways lead to the formation of dihydroxyacetone phosphate, an intermediate of glycolysis. It was assumed that the glpK pathway operates during aerobiosis and that the dhaK pathway operates under anaerobic conditions. Because this had not been analyzed by a genetic study, we constructed mutants of strain JH2-2 affected in both pathways. The growth of these mutants on glycerol under aerobic and anaerobic conditions was monitored. In contrast to the former model, results strongly suggest that glycerol is catabolized simultaneously by both pathways in the E. faecalis JH2-2 strain in the presence of oxygen. In accordance with the former model, glycerol is metabolized by the dhaK pathway under anaerobic conditions. Comparison of different E. faecalis isolates revealed an impressive diversity of growth behaviors on glycerol. Analysis by BLAST searching and real-time reverse transcriptase PCR revealed that this diversity is based not on different gene contents but rather on differences in gene expression. Some strains used preferentially the glpK pathway whereas others probably exclusively the dhaK pathway under aerobic conditions. Our results demonstrate that the species E. faecalis cannot be represented by only one model of aerobic glycerol catabolism.


Solvent effect on the competition between weak and strong interactions in phenol solutions studied by near-infrared spectroscopy and DFT calculations.
Near-infrared (NIR) spectra of phenol in a series of non-aromatic and aromatic solvents were recorded to study the competition between various types of solute-solute and solute-solvent interactions. Depending on the phenol concentration, the free OH and OH involved in the OH⋯OH interactions in the dimers and higher associates are present in cyclohexane solutions. On the other hand, free OH does not appear in Cl-containing solvents since at a low phenol content the OH groups participate in the OH⋯Cl interactions. In CCl4 and tetrachloroethylene this interaction is weak, while in chlorobenzene the strength of this interaction is higher. In the aromatic solvents the solute-solute OH⋯OH interactions compete with the solute-solvent OH⋯π and aromatic CH⋯OH ones. Consequently, the degree of self-association of phenol in aromatic solvents is smaller than that in non-aromatic ones. The strength of the OH⋯π interactions increases with growing electron-donating ability of the substituents in the benzene derivatives. This observation obtained from the NIR spectra is in line with the results of the theoretical calculations (DFT). A clear correlation appears between the number of methyl groups in aromatic solvents and the population of the free OH groups. The methyl groups are steric hindrances and impede the formation of the OH⋯OH and OH⋯π interactions. Our results suggest the presence of aromatic CH⋯OH solute-solvent interactions, not observed in previous studies. NIR spectroscopy appears to be a powerful tool for exploration of free and weakly-bonded OH groups.


Histone H3 globular domain acetylation identifies a new class of enhancers.
Histone acetylation is generally associated with active chromatin, but most studies have focused on the acetylation of histone tails. Various histone H3 and H4 tail acetylations mark the promoters of active genes. These modifications include acetylation of histone H3 at lysine 27 (H3K27ac), which blocks Polycomb-mediated trimethylation of H3K27 (H3K27me3). H3K27ac is also widely used to identify active enhancers, and the assumption has been that profiling H3K27ac is a comprehensive way of cataloguing the set of active enhancers in mammalian cell types. Here we show that acetylation of lysine residues in the globular domain of histone H3 (lysine 64 (H3K64ac) and lysine 122 (H3K122ac)) marks active gene promoters and also a subset of active enhancers. Moreover, we find a new class of active functional enhancers that is marked by H3K122ac but lacks H3K27ac. This work suggests that, to identify enhancers, a more comprehensive analysis of histone acetylation is required than has previously been considered.


Evolutionary constraints in high-dimensional trait sets.
Genetic variation for individual traits is typically abundant, but for some multivariate combinations it is very low, suggesting that evolutionary limits might be generated by the geometric distribution of genetic variance. To test this prediction, we artificially selected along all eight genetic eigenvectors of a set of eight quantitative traits in Drosophila serrata. After six generations of 50% truncation selection, at least one replicate population of all treatments responded to selection, allowing us to reject a null genetic subspace as a cause of evolutionary constraint in this system. However, while all three replicate populations of the first five selection treatments displayed a significant response, the remaining three, characterized by low genetic variance in their selection indexes in the base population, displayed inconsistent responses to selection. The observation that only four of the nine replicate populations evolved in response to the direct selection applied to them in these low genetic variance treatments, led us to conclude that a nearly null subspace did limit evolution. Dimensions associated with low genetic variance are often found in multivariate analyses of standing genetic variance in morphological traits, suggesting that the nearly null genetic subspace may be a common mechanism of evolutionary constraint in nature.


Rational design of new class of BH3-mimetics as inhibitors of the Bcl-xL protein.
The Bcl-2 family of proteins plays an important role in the intrinsic pathway of cell apoptosis. Overexpression of pro-survival members of this family of proteins is often associated with the development of many types of cancer and confers resistance against conventional therapeutic treatments. Accordingly, antagonism of its protective function has emerged as an encouraging anticancer strategy. In the present work, we use a pharmacophore for describing interaction between the BH3 domain of different pro-apoptotic members and the pro-survival protein Bcl-x(L) in order to identify new lead compounds. In the strategy followed in the present work, the pharmacophore was derived from molecular dynamics studies of different Bcl-x(L)/BH3 complexes. This pharmacophore was later used as query for 3D database screening. Hits obtained from the search were computationally assessed, and a subset proposed for in vitro testing. Two of the 15 compounds assayed were found able to disrupt the Bcl-x(L)/Bak(BH3) complex with IC(50) values in the lower micromolar range. Finally, docking studies were performed to explore the binding mode of these compounds to Bcl-x(L) for further modifications.


Reduced CA2-CA3 Hippocampal Subfield Volume Is Related to Depression and Normalized by l-DOPA in Newly Diagnosed Parkinson's Disease.
Hippocampal dysfunctions may play an important role in the non-motor aspects of Parkinson's disease (PD), including depressive and cognitive symptoms. Fine structural alterations of the hippocampus and their relationship with symptoms and medication effects are unknown in newly diagnosed PD. We measured the volume of hippocampal subfields in 35 drug-naïve, newly diagnosed PD patients without cognitive impairment and 30 matched healthy control individuals. Assessments were performed when the patients did not receive medications and after a 24-week period of l-DOPA treatment. We obtained a T1-weighted 3D magnetization-prepared rapid acquisition gradient echo image at each assessment. FreeSurfer v6.0 was used for image analysis. Results revealed a selectively decreased CA2-CA3 volume in non-medicated PD patients, which was normalized after the 24-week treatment period. Higher depressive symptoms were associated with smaller CA2-CA3 volumes. These results indicate that the CA2-CA3 subfield is structurally affected in the earliest stage of PD in the absence of cognitive impairment. This structural anomaly, normalized by l-DOPA, is related to depressive non-motor symptoms.


Dihydrocapsaicin Inhibits Epithelial Cell Transformation through Targeting Amino Acid Signaling and c-Fos Expression.
Chili peppers are one of the most widely consumed spices worldwide. However, research on the health benefits of chili peppers and some of its constituents has raised controversy as to whether chili pepper compounds possess cancer-promoting or cancer-preventive effects. While ample studies have been carried out to examine the effect of capsaicin in carcinogenesis, the chemopreventive effect of other major components in chili pepper, including dihydrocapsaicin, capsiate, and capsanthin, is relatively unclear. Herein, we investigated the inhibitory effect of chili pepper components on malignant cell transformation. Among the tested chili pepper compounds, dihydrocapsaicin displayed the strongest inhibitory activity against epidermal growth factor (EGF)-induced neoplastic transformation. Dihydrocapsaicin specifically suppressed EGF-induced phosphorylations of the p70S6K1-S6 pathway and the expression of c-Fos. A reduction in c-Fos levels by dihydrocapsaicin led to a concomitant downregulation of AP-1 activation. Further analysis of the molecular mechanism responsible for the dihydrocapsaicin-mediated decrease in phospho-p70S6K1, revealed that dihydrocapsaicin can block amino acid-dependent mechanistic targets of rapamycin complex 1 (mTORC1)-p70S6K1-S6 signal activation. Additionally, dihydrocapsaicin was able to selectively augment amino acid deprivation-induced cell death in mTORC1-hyperactive cells. Collectively, dihydrocapsaicin exerted chemopreventive effects through inhibiting amino acid signaling and c-Fos pathways and, thus, might be a promising cancer preventive natural agent.


ASSOCIATIONS OF IL-6 -174G>C AND IL-10 -1082A>G POLYMORPHISMS WITH SUSCEPTIBILITY TO CELIAC DISEASE: EVIDENCE FROM A META-ANALYSIS AND LITERATURE REVIEW.
There has been little evidence to suggest that the IL-6 -174G>C and IL-10 -1082A>G polymorphisms are significantly associated with susceptibility to celiac disease. Thus, we performed the present meta-analysis to explore the potential association between these polymorphisms and celiac disease risk. Eligible studies were searched in PubMed, Medline, Embase, Web of Science and CNKI database up to April 20, 2019. Odds ratios with 95% confidence interval were calculated to assess the potential associations. Moreover, we performed the heterogeneity, sensitivity, and publication bias tests to clarify and validate the pooled results. Overall, nine case-control studies involving five studies with 737 cases and 1,338 control on IL-6 -174G>C polymorphism and four studies with 923 cases and 864 controls on IL-10 -1082A>G polymorphism were selected. The pooled ORs showed that the IL-6 -174G>C and IL-10 -1082A>G polymorphisms were not significantly associated with increased risk of celiac disease under all five genetic models. There was no publication bias. To the best of our knowledge, this is the first meta-analysis summarizing all of the available studies on the association of IL-6 -174G>C and IL-10 -1082A>G polymorphisms with celiac disease. Our results suggest that the IL-6 -174G>C and IL-10 -1082A>G polymorphisms may not be associated with increased risk of celiac disease. Moreover, large and well-designed studies are needed to fully describe the association of IL-6 -174G>C and IL-10 -1082A>G polymorphisms with celiac disease.


A new methodology for studying vortex dynamics based on point-contact spectroscopy.
Vortex dynamics has attracted tremendous attention for both fundamental physics and applications of type-II superconductors. However, methods to detect local vortex motion or vortex jump with high sensitivity are still scarce. Here, we fabricated soft point contacts on the clean layered superconductor 2H-NbSe2, which are demonstrated to contain multiple parallel micro-constrictions by scanning electronic microscopy. Andreev reflection spectroscopy was then studied in detail for the contacts. Differential conductance taken at fixed bias voltages was discovered to vary spontaneously over time in various magnetic fields perpendicular to the sample surface. The conductance variations become invisible when the field is zero or large enough, or parallel to the sample surface, which can be identified as the immediate consequence of vortex motion across a finite number of micro-constrictions. These results demonstrate point contact Andreev reflection spectroscopy to be a new potential way with a high time resolution to study the vortex dynamics in type-II superconductors.


Mutations induced by gamma-irradiation of M13 bacteriophages containing single-stranded DNA.
Oxygenated suspensions of M13 bacteriophages, containing single-stranded M13mp10 DNA, were gamma-irradiated followed by infection of E. coli cells. Mutants in the mutational target sequence, which consists of the lac promoter /operator region, the lacZ alpha gene, and a 144 bp inframe insert in the lacZ alpha gene, were selected and characterized. Except for three one-base deletions, all of the 51 mutations characterized were base substitutions. All base substitutions appeared to involve guanines and cytosines and none affect adenines and thymines. Since most of the known repair systems do not act on single-stranded DNA, the conclusion can be drawn that radiation induces under these conditions only mutagenic damages on guanine and cytosine. Although all possible G- and C-transversions and transitions were found, there is a strong preference for G-->C and G-->T transversions (21 and 25% of all base substitutions, respectively) and C-->T transitions (48% of all base substitutions). These results indicate, that the G/C-->C/G and G/C-->T/A transversions, found after irradiation of double-stranded M13 DNA, are mainly due to radiation guanine products, whereas cytosine damage is mainly responsible for G/C-->A/T transitions.


Case-control diagnosis and Bayesian inference in common viral infections.
The predictive values of symptoms and signs for given diseases are often unknown. The fact that a high proportion of individuals with a certain disease may have a specific group of symptoms (the case-control approach) does not necessarily mean that the specific group of symptoms will allow one reliably to diagnose the disease. This study, utilizing a population based data set for common acute infections, shows that descriptions of common viral illnesses found in medical textbooks that associate illnesses with symptoms do not allow one to predict reliably isolation of the supposed causal organism. Positive predictive value of groups of symptoms for specific viral infections did not exceed 11 percent in this study. However, the data closely fitted the Bayesian statistical model often proposed for such decision making by physicians.


Pattern of congenital neck masses in a Kenyan paediatric population.
The distribution of congenital neck masses varies between countries and is important in diagnosis and treatment modalities. Data from Africa is scarce, and altogether absent from Kenya. To describe the pattern of congenital masses in a Kenyan paediatric population. SET UP: Kenyatta National Hospital, Nairobi Kenya. Prospective descriptive cross-sectional. Children aged 15 years and below with neck masses who presented to various surgical clinics and wards at the Kenyatta National Hospital between December 2006 and April 2007 were included in the study. They were examined for age, gender, type and location of the neck mass. Mode of investigation and final diagnosis were recorded. Data was analyzed by using statistical package for social sciences. Descriptive statistics were applied to determine means, frequencies and modes. Ninety-five percent confidence interval was used and p value of 0.05 taken as significant. Data are presented in form of tables. Two hundred and thirty-five children (129 male) with neck masses were examined. Fifty-one (22%) of these masses were congenital. Thyroglossal duct cysts were the most common (29%) followed by cystic hygromas (21%) and branchial cleft cysts (20%). Fifty-one percent of the masses were present at birth. The midline was the most common location (31.4%) followed by anterior border of sternocleidomastoid (27.5%) and submandibular region (19.6%). Ultrasound was the commonest diagnostic investigation. Congenital defects constitute an important differential diagnosis for paediatric neck masses in Kenya. Thyroglossal duct cysts, cystic hygromas and branchial cleft cysts are the most prevalent occurring most commonly in the midline and anterior border of sternocleidomastoid muscle. An understanding of the distribution of these masses improves diagnosis, preoperative decision making and their overall management.


Reduction of Hypothalamic Endoplasmic Reticulum Stress Activates Browning of White Fat and Ameliorates Obesity.
The chaperone GRP78/BiP (glucose-regulated protein 78 kDa/binding immunoglobulin protein) modulates protein folding in reply to cellular insults that lead to endoplasmic reticulum (ER) stress. This study investigated the role of hypothalamic GRP78 on energy balance, with particular interest in thermogenesis and browning of white adipose tissue (WAT). For this purpose, we used diet-induced obese rats and rats administered thapsigargin, and by combining metabolic, histologic, physiologic, pharmacologic, thermographic, and molecular techniques, we studied the effect of genetic manipulation of hypothalamic GRP78. Our data showed that rats fed a high-fat diet or that were centrally administered thapsigargin displayed hypothalamic ER stress, whereas genetic overexpression of GRP78 specifically in the ventromedial nucleus of the hypothalamus was sufficient to alleviate ER stress and to revert the obese and metabolic phenotype. Those effects were independent of feeding and leptin but were related to increased thermogenic activation of brown adipose tissue and induction of browning in WAT and could be reversed by antagonism of β3 adrenergic receptors. This evidence indicates that modulation of hypothalamic GRP78 activity may be a potential strategy against obesity and associated comorbidities.


Bacterial alpha-glucan phosphorylases.
Although glycogen and other alpha-1,4-D-glucan storage polysaccharides are present in many bacteria, only few glucan phosphorylases from bacteria have been identified and characterised on the protein or gene level. All bacterial phosphorylases follow the same catalytic mechanisms as their plant and vertebrate counterparts, but differ considerably in terms of their substrate specificity and regulation. The catalytic domains are highly conserved while the regulatory sites are only poorly conserved. The degree of conservation between bacterial and mammalian phosphorylases is comparable to that of other non-mammalian and mammalian alpha-glucan phosphorylases. Only for maltodextrin phosphorylase from E. coli the physiological role of the enzyme in the utilisation of maltodextrins is known in detail; that of all other phosphorylases remains still unclear. Roles in regulation of endogenous glycogen metabolism in periods of starvation, and sporulation, stress response or quick adaptation to changing environments are imaginable.


Feeling voices.
Two experiments investigated deaf individuals' ability to discriminate between same-sex talkers based on vibrotactile stimulation alone. Nineteen participants made same/different judgments on pairs of utterances presented to the lower back through voice coils embedded in a conforming chair. Discrimination of stimuli matched for F0, duration, and perceived magnitude was successful for pairs of spoken sentences in Experiment 1 (median percent correct = 83%) and pairs of vowel utterances in Experiment 2 (median percent correct = 75%). Greater difference in spectral tilt between "different" pairs strongly predicted their discriminability in both experiments. The current findings support the hypothesis that discrimination of complex vibrotactile stimuli involves the cortical integration of spectral information filtered through frequency-tuned skin receptors.


[Asthma and allergy due to carmine dye].
Cochineal carmine, or simply carmine (E120), is a red colouring that is obtained from the dried bodies of the female insect Dactylopius coccus Costa (the cochineal insect). We have evaluated the prevalence of sensitization and asthma caused by carmine in a factory using natural colouring, following the diagnosis of two workers with occupational asthma. The accumulated incidence of sensitization and occupational asthma due to carmine in this factory are 48.1% and 18.5% respectively, figures that make the introduction of preventive measures obligatory. Occupational asthma caused by inhaling carmine should be considered as a further example of the capacity of certain protein particles of arthropods (in this case cochineal insects) to act as aeroallergens. Carmine should be added to the list of agents capable of producing occupational asthma, whose mechanism, according to our studies, would be immunological mediated by IgE antibodies in the face of diverse allergens of high molecular weight, which can vary from patient to patient. Nonetheless, given the existence of different components in carmine, it cannot be ruled out that substances of low molecular weight, such as carminic acid, might act as haptenes. Besides, since we are dealing with a colouring that is widely used as a food additive, as a pharmaceutical excipient and in the composition of numerous cosmetics, it is not surprising that allergic reactions can appear both through ingestion and through direct cutaneous contact. We find ourselves facing a new example of an allergen that can act through both inhalation and digestion, giving rise to an allergolical syndrome that can show itself clinically with expressions of both respiratory allergy and alimentary allergy.


Nature-Inspired, Graphene-Wrapped 3D MoS2 Ultrathin Microflower Architecture as a High-Performance Anode Material for Sodium-Ion Batteries.
In response to the increasing concern for energy management, molybdenum disulfide (MoS2) has been extensively researched as an attractive anode material for sodium-ion batteries (SIBs). The proficient cycling durability and good rate performance of SIBs are the two key parameters that determine their potential for practical use. In this study, nature-inspired three-dimensional (3D) MoS2 ultrathin marigold flower-like microstructures were prepared by a controlled hydrothermal method. These microscale flowers are constructed by arbitrarily arranged but closely interconnected two-dimensional ultrathin MoS2 nanosheets. The as-prepared MoS2 microflowers (MFs) have then been chemically wrapped by layered graphene sheets to form the bonded 3D hybrid MoS2-G networks. TEM, SEM, XRD, XPS, and Raman characterizations were used to study the morphology, crystallization, chemical compositions, and wrapping contact between MoS2 and graphene. The ultrathin nature of MoS2 in 3D MFs and graphene wrapping provide strong electrical conductive channels and conductive networks in an electrode. Benefitting from the 2 nm ultrathin crystalline MoS2 sheets, chemically bonded graphene, defect-induced sodium storage active sites, and 3D interstitial spaces, the prepared electrode exhibited an outstanding specific capacity (606 mA h g-1 at 200 mA g-1), remarkable rate performance (345 mA h g-1 at 1600 mA g-1), and long cycle life (over 100 cycles with tremendous Coulombic efficiencies beyond 100%). The proposed synthesis strategy and 3D design developed in the present study reveal a unique way to fabricate promising anode materials for SIBs.


Inhibitory Control in Young Healthy Adults - a tDCS Study.
Inhibitory control plays a role in the behavior selection and detection of conflicts. Defects in inhibitory control are an integral part of many neuropsychiatric disorders and the possibilities of influencing it are the subject of active study. Studies have shown and confirmed the activation of the dorsolateral prefrontal cortex (DLPFC) during the Stroop task and other tests involving response inhibition. Non-invasive brain stimulation is an emerging and actively developing group of methods used in cognitive research. In the present study, we used non-invasive, painless, and delicate transcranial direct stimulation (tDCS) for the study of inhibitory control, and to explore the effect of impulsivity on response inhibition ability in young healthy participants. We conducted a cross-over study with cross-hemispheric application of 2 mA tDCS with electrodes placed on the right - cathode, and left - anode - DLPFC. Participants performed a classic Stroop test before and after stimulation. Impulsivity was measured via the personal impulsiveness questionnaire. There was no significant difference in interference score alteration between active and sham stimulations, anodal and sham tDCS both induced slight improvement in Stroop test results. Individual impulsivity in healthy participants showed no influence on their results. Our study adds to the picture and helps to deepen knowledge about the impact of different stimulation parameters on cognitive functions.


Integrative group psychotherapy for patients with somatic symptom disorder: A randomized controlled trial.
The study aimed to determine whether specific integrative group psychotherapy (IGPT), based on CBT, combined with techniques of psychodynamic therapy and mindful body and emotional awareness is more effective than non-specific supportive group psychotherapy (SGPT) and treatment as usual (TAU) alone. A total of 120 SSD patients were randomly assigned to IGPT, SGPT or TAU groups. Both IGPT and SGPT showed significantly lower SSD-12 scores at the 4, 8, and 12-week follow-ups compared to TAU. No significant differences were observed between IGPT and SGPT at any follow-up point. These findings highlight the potential benefits of group psychotherapy in SSD treatment.


Activity of cefixime against Helicobacter pylori and affinities for the penicillin-binding proteins.
Cefixime induced the formation of rounded cells from the spiral bacillary form of Helicobacter pylori at the MIC or less. Three main penicillin-binding proteins, called A, B and C, were separated from H. pylori. Cefixime had the strongest affinity to penicillin-binding protein B. The binding of cefixime to this protein may induce the formation of rounded H. pylori cells.


Metabolism of myo-inositol during sporulation of myo-inositol-requiring Saccharomyces cerevisiae.
We investigated the sporulation properties of a series of diploid Saccharomyces cerevisiae strains homozygous for inositol auxotrophic markers. The strains required different amounts of inositol for the completion of sporulation. Shift experiments revealed two phases of inositol requirement during sporulation which coincided with the two phases of lipid synthesis found by earlier workers. Phase I was at the beginning and during premeiotic deoxyribonucleic acid synthesis; phase II immediately preceded the appearance of mature asci. Of the inositol taken up by sporulating cells, 90% was incorporated into inositol phospholipids. By two-dimensional thin-layer chromatography, eight compounds were resolved, one of which was sporulation specific. The majority of the inositol phospholipids were, however, identical to those found in vegetatively growing cells. In the absence of inositol, the cells did not sporulate but, after a certain time, were unable to return to vegetative growth. These nonsporulating cells did, however, incorporate acetate into lipids and double their deoxyribonucleic acid content in the premeiotic phase. We believe that it is this lack of coordination of biosynthetic events which causes inositol-less death on sporulation media without inositol.


[Homocysteine and neuropsychiatric disorders].
The author presents an overview of the current literature on homocysteine as a risk factor for neuropsychiatric disorders. The databases MEDLINE, Current Contents and EMBASE were searched (between 1966 and 2002) for English language publications with the key words 'Homocysteine' and 'Stroke'; 'Alzheimer Disease'; 'Cognitive Impairment'; 'Epilepsy'; 'Depression'; or 'Parkinson's disease'. Individual articles were hand searched for relevant cross-references. It is biologically plausible that high homocysteine levels may cause brain injury and neuropsychiatric disorders. Homocysteine is proatherogenic and prothrombotic, thereby increasing the risk of cerebrovascular disease, and may have a direct neurotoxic effect. Evidence for homocysteine as a risk factor for cerebral microvascular disease is conflicting but warrants further study. Cross-sectional and some longitudinal studies support increased prevalence of stroke and vascular dementia in hyperhomocysteinemic individuals. The evidence of increased neurodegeneration is accumulating. The relationship with depression is still tentative, as it is with epilepsy. Currently, treatment studies are necessary to place the evidence on a stronger footing, and maybe high-risk patients should be screened for hyperhomocysteinemia and this should be treated with folic acid. More research evidence is necessary before population screening can be recommended.


[Action of extract and oil neem in the control of Rhipicephalus (Boophilus) microplus (Canestrini, 1887) (Acari: Ixodidae) in laboratory].
Organic plant extracts and emulsified oil of Azadirachta indica A. Juss (Meliaceae) (neem) were studied to evaluate its effects in control of engorged females of Rhipicephalus (Boophilus) microplus (Canestrini, 1887) in the laboratory. Hexane and alcoholic organic extracts, 2% (weight/volume) were used in tests of immersion for 5 minutes, prepared with seeds, solubilized in dimethylsulfoxide (DMSO) to 1%. The experiment was entirely randomized, consisting of 6 treatments and 5 replicates, each represented by 5 ticks. Control groups consisted of untreated females. Based on the results of this work, we can indicate that the seed extract (hexanic fraction) and óleo emulsionável I¹ concentration to 2% have significant adjuvant potential to control the cattle tick, because, cause the mortality in the first days after the treatment and interfere in the reproduction, showing to be an alternative to acaricides normally used.


A randomized study of the efficacy and safety of 0.1% cyclosporine A cationic emulsion in treatment of moderate to severe dry eye.
The SICCANOVE study aimed to compare the efficacy and safety of 0.1% cyclosporine A cationic emulsion (CsA CE) versus vehicle in patients with moderate to severe dry eye disease (DED). In this multicenter, double-masked, parallel-group, controlled study, patients were randomized (1:1) to receive CsA CE (Ikervis®) or vehicle for 6 months. The co-primary efficacy endpoints at month 6 were mean change from baseline in corneal fluorescein staining (CFS; modified Oxford scale) and in global ocular discomfort (visual analogue scale [VAS]). The mean change in CFS from baseline to month 6 (CsA CE: n = 241; vehicle: n = 248) was significantly greater with CsA CE than with vehicle (-1.05 ± 0.98 and -0.82 ± 0.94, respectively; p = 0.009). Ocular discomfort improved similarly in both groups; however, the percentage of patients with ≥25% improvement in VAS was significantly higher with CsA CE (50.2%) than with vehicle (41.9%; p = 0.048). In a post hoc analysis of patients with severe ocular surface damage (CFS score 4) at baseline (CsA CE: n = 43; vehicle: n = 42), the percentage of patients with improvements of ≥2 grades in CFS score and ≥30% in Ocular Surface Disease Index score was significantly greater with CsA CE (p = 0.003). Treatment compliance and ocular tolerability were satisfactory and as expected for CsA use. Cyclosporine A CE was well-tolerated and effectively improved signs and symptoms in patients with moderate to severe DED over 6 months, especially in patients with severe disease, who are at risk of irreversible corneal damage.


Transmission of Mycobacterium orygis (M. tuberculosis complex species) from a tuberculosis patient to a dairy cow in New Zealand.
Mycobacterium orygis, previously called the oryx bacillus, is a member of the Mycobacterium tuberculosis complex and has been reported only recently as a cause of human tuberculosis in patients of South Asian origin. We present the first case documenting the transmission of this organism from a human to a cow.


Bixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner.
Mechanical ventilation (MV) is a therapeutic intervention widely used in the clinic to assist patients that have difficulty breathing due to lung edema, trauma, or general anesthesia. However, MV causes ventilator-induced lung injury (VILI), a condition characterized by increased permeability of the alveolar-capillary barrier that results in edema, hemorrhage, and neutrophil infiltration, leading to exacerbated lung inflammation and oxidative stress. This study explored the feasibility of using bixin, a canonical NRF2 inducer identified during the current study, to ameliorate lung damage in a murine VILI model. In vitro, bixin was found to activate the NRF2 signaling pathway through blockage of ubiquitylation and degradation of NRF2 in a KEAP1-C151 dependent manner; intraperitoneal (IP) injection of bixin led to pulmonary upregulation of the NRF2 response in vivo. Remarkably, IP administration of bixin restored normal lung morphology and attenuated inflammatory response and oxidative DNA damage following MV. This observed beneficial effect of bixin derived from induction of the NRF2 cytoprotective response since it was only observed in Nrf2(+/+) but not in Nrf2(-/-) mice. This is the first study providing proof-of-concept that NRF2 activators can be developed into pharmacological agents for clinical use to prevent patients from lung injury during MV treatment.


Hilbert-Space Fragmentation from Strict Confinement.
We study one-dimensional spin-1/2 models in which strict confinement of Ising domain walls leads to the fragmentation of Hilbert space into exponentially many disconnected subspaces. Whereas most previous works emphasize dipole moment conservation as an essential ingredient for such fragmentation, we instead require two commuting U(1) conserved quantities associated with the total domain-wall number and the total magnetization. The latter arises naturally from the confinement of domain walls. Remarkably, while some connected components of the Hilbert space thermalize, others are integrable by Bethe ansatz. We further demonstrate how this Hilbert-space fragmentation pattern arises perturbatively in the confining limit of Z_{2} gauge theory coupled to fermionic matter, leading to a hierarchy of timescales for motion of the fermions. This model can be realized experimentally in two complementary settings.


[Microbiological identification and in vitro sensitivity of Candida isolates from the oral cavity of HIV-positive individuals].
Oropharyngeal candidiasis is the most common fungal infection among patients infected with the human immunodeficiency virus. It can be treated with either systemic or topical antifungal agents, which are indicated empirically on the basis of clinical data. The objective of this study was to determine the frequency of yeast in mouthwashes from HIV-positive patients, compare the results between patients presenting different states of immunodeficiency, and investigate the susceptibility profile of the species isolated in relation to antifungal agents, with the aim of evaluating whether the treatments used in clinical practice are able to reach the majority of the species identified. Yeasts were isolated from 58% of the mouthwash samples collected. Candida albicans was the most (93%) frequent species. Resistance or dose-dependent susceptibility in relation to the antifungal agent tested was registered in approximately 17% of the samples. The significant variability of responses suggests that there are limitations regarding the effectiveness of the empirical therapies instituted.


Biological and therapeutic significance of tissue transglutaminase in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers world-wide with an estimated annual incidence and mortality rates of approximately 6,500 cases in the UK, over 40,000 cases in Europe, 19,000 cases in Japan and over 30,000 cases in the United States. Difficulty to diagnose the disease at an early stage, rapid progression and intrinsic resistance to currently available therapies are major factors that contribute to poor disease outcome in these patients (overall 5 years survival, <3%). Identification of cancer cell-encoded genes that contribute to the development of intrinsic resistance and metastatic spread of the PDA tumors, may yield immediate clinical benefits in terms of revealing new therapeutic targets for effective treatment of the disease. This article discusses the significance of tissue-type transglutaminase (TG2) whose expression is elevated in the majority of PDA tumors and cell lines. Based on the published data and the results discussed in this review, TG2 appears to be a promising target for containment and treatment of this formidable disease.


The Impact of the Inoculation of Phosphate-Solubilizing Bacteria Pantoea agglomerans on Phosphorus Availability and Bacterial Community Dynamics of a Semi-Arid Soil.
The bacterial genus Pantoea has been widely evaluated as promising bacteria to increase phosphorus (P) availability in soil. The aim of this study was to characterize the phosphate solubilizing (PS) activity of a Pantoea agglomerans strain and to evaluate the impact of its application in a semi-arid soil on phosphate availability and structure of the bacterial communities as a whole. An incubation experiment under close-to-natural soil environmental conditions was conducted for 15 days at 30 °C. High-throughput sequencing of the bacterial 16S rRNA gene was used to characterize and to compare the bacterial community structure of P. agglomerans-inoculated soil with non-inoculated control. Furthermore, a qPCR-based method was developed for detection and quantification of the functional genes related to the expression of mineral phosphate solubilization (MPS) phenotype in P. agglomerans. The results showed that in vitro solubilization of Ca3(PO4)2 by P. agglomerans strain was very efficient (980 mg/L), and it was associated with a drop in pH due to the secretion of gluconic acid; these changes were concomitant with the detection of gdh and pqqC genes. Moreover, P. agglomerans inoculum application significantly increased the content of available P in semi-arid soil by 69%. Metagenomic analyses showed that P. agglomerans treatment modified the overall edaphic bacterial community, significantly impacting its structure and composition. In particular, during P. agglomerans inoculation the relative abundance of bacteria belonging to Firmicutes (mainly Bacilli class) significantly increased, whereas the abundance of Actinobacteria together with Acidobacteria and Chloroflexi phyla decreased. Furthermore, genera known for their phosphate solubilizing activity, such as Aneurinibacillus, Lysinibacillus, Enterococcus, and Pontibacter, were exclusively detected in P. agglomerans-treated soil. Pearson's correlation analysis revealed that changes in soil bacterial community composition were closely affected by soil characteristics, such as pH and available P. This study explores the effect of the inoculation of P. agglomerans on the bacterial community structure of a semi-arid soil. The effectiveness in improving the phosphate availability and modification in soil bacterial community suggested that P. agglomerans represent a promising environmental-friendly biofertilizer in arid and semi-arid ecosystems.


Short-term supplementation with active hexose correlated compound improves the antibody response to influenza B vaccine.
Administration of bioactive nutritional supplements near or at the time of immunization has been a recent approach to stimulate human immune response to vaccination. Active hexose correlated compound (AHCC), a mushroom extract, has been shown to protect mice against lethal primary influenza infection. Moreover, when AHCC was administered pre-vaccination in mice, they showed improved protection from lethal avian flu infection when compared to mice vaccinated alone. In this study, we hypothesized that AHCC will also improve the immune responses of healthy individuals to influenza vaccine. A randomized controlled study was performed with 30 healthy adults to evaluate the effects of AHCC supplementation on the immune response to the 2009-2010 seasonal influenza vaccine. Blood was drawn pre-vaccination and 3 wk post-vaccination. Immediately post-vaccination, the AHCC group began supplementation with AHCC (3 g/d). Flow cytometric analysis of lymphocyte subpopulations revealed that AHCC supplementation increased NKT cells (P < .1), and CD8 T cells (P < .05) post-vaccination compared to controls. Analysis of antibody production 3 weeks post-vaccination revealed that AHCC supplementation significantly improved protective antibody titers to influenza B, while the improvement was not significant in the control group. Overall, our study showed that AHCC supplementation improved some lymphocyte percentages and influenza B antibody titers over the control. Future studies are required to determine the kinetics of AHCC supplementation to improve the overall response to influenza vaccination.


Low-dose radiation differentially regulates protein acetylation and histone deacetylase expression in human coronary artery endothelial cells.
Ionizing radiation induces cardiovascular disease, the endothelium being the main target. The exact mechanism of the damage is unclear but the involvement of multiple signaling pathways is probable. Reversible lysine acetylation is a posttranslational protein modification that regulates activity across a broad range of signaling pathways. The aim of this study was to determine if a low radiation dose results in acetylome alteration in endothelial cells. Human coronary artery endothelial cell line was irradiated with Cs-137 gamma-rays (0.5 Gy) and proteomics analysis was performed using enriched acetylated peptides and all peptides. Data were validated using immunoblotting, deacetylase activity assay, and RhoA activity assay. Nearly a hundred proteins were found to have an altered acetylation status 24 h after irradiation, primarily due to an overall decrease in acetylation. The expression of specific deacetylases was significantly increased, coinciding with an enhancement in global deacetylase activity. Proteins changed in their acetylation status belonged to several pathways including protein synthesis, cytoskeleton-related processes, protein folding and calcium signaling. The predicted changes in the RhoA/actin cytoskeleton pathway were validated by immunoassay. This study shows that protein acetylation is an important mediator of radiation responses in human cardiac coronary endothelial cells. Increased knowledge of the endothelial response to radiation is crucial for the development of normal tissue-sparing modalities during radiation therapy.


Optimization of time series features to estimate brain age in children from electroencephalography.
Functional brain age measures in children, derived from the electroencephalogram (EEG), offer direct and objective measures in assessing neurodevelopmental status. Here we explored the effectiveness of 32 preselected 'handcrafted' EEG features in predicting brain age in children. These features were benchmarked against a large library of highly comparative multivariate time series features (>7000 features). Results showed that age predictors based on handcrafted EEG features consistently outperformed a generic set of time series features. These findings suggest that optimization of brain age estimation in children benefits from careful preselection of EEG features that are related to age and neurodevelopmental trajectory. This approach shows potential for clinical translation in the future.Clinical Relevance-Handcrafted EEG features provide an accurate functional neurodevelopmental biomarker that tracks brain function maturity in children.


Significance of a common epitope of plant and animal endomembranes.
A rat monoclonal antibody that was raised against a common epitope on bean (Phaseolus vulgaris) endomembranes has been shown to cross-react with microsomal polypeptides from a number of plant and animal species. Immunoblotting has shown that the epitope is present on a large subset of polypeptides on microsomes of five animal species. The antigenic site appears to be accessible on intact bean membranes since it is readily digested by trypsin. The epitope is probably not derived post-translationally since the same Mr range is immunoprecipitated from polypeptides newly synthesized in vivo and in vitro. The polypeptides in bean appear to be regulated independently, one of Mr 58,000, in particular, was highly induced by treatment of suspension cultures with fungal elicitor. Preincubation of membranes enriched with endoplasmic reticulum and Golgi apparatus with the antibody blocks transfer of radioactivity from one compartment to the other in vitro. The common antigenic site could possibly be concerned in recognition or some fusion event during membrane trafficking within the cell.


Higher-order spatial correlation coefficients of ultrasonic backscattering signals using partial cross-correlation analysis.
The spatial correlation properties of ultrasonic backscattering signals in random media have important implications. For example, they can be used for microstructural characterization and flaw detection in engineering materials. However, the traditional spatial correlation coefficient (SCC) is only a leading order quantity that does not capture the true spatial correlations of random media. This is caused by neglecting confounding variables such as non-zero means or other non-zero odd-order moments. Here, the SCC is generalized from zeroth- to general-order through partial cross-correlation analysis. A series of indicators are defined to quantify the SCC curve at zero time lag, and the maximum time shift curve, which are both functions of lateral separation between two sensor positions. A stainless-steel specimen and a focused ultrasonic transducer are used to verify the method. Scattering measurements show that the higher-order SCC can consistently capture spatial correlations whereas the zeroth-order SCC is inadequate. The zeroth-order SCC is shown to predict a step size that can be more than six times too large. Thus, the present method can provide better understanding of statistical correlations and conditions to measure uncorrelated backscattering signals.


Physiotherapy for patients on extracorporeal membrane oxygenation support: How, When, and Who. An international EuroELSO survey.
Extracorporeal membrane oxygenation (ECMO) continues to play an essential role in organ support in cardiogenic shock or acute respiratory distress syndrome and bridging to transplantation. The main purpose of the present survey was to define which clinical and organizational practices are adopted for the administration of physiotherapy in adult patients undergoing ECMO support worldwide. This international survey was conceived in November 2021. The survey launch was announced at the 10th EuroELSO (European ELSO chapter) Congress, London, May 2022. The survey returned 32 questionnaires from 29 centers across 14 countries. 17 centers (53.1%) had more than 30 intensive care unit beds available and most (46.8%) were able to care for five to 10 patients on extracorporeal life support simultaneously. The predominant physiotherapist-to-patient ratio was 1:>5 (37.5%); physiotherapy was available 5/7 days and 7/7 days by 31.2% and 25% respectively. Respiratory physiotherapy was not defined by a specific protocol in most centers (46.8%) while 31.2% declared that the treatment commences less than 12 h after sedation is stopped/reduced. Mostly, early physiotherapy in non-cooperative ventilated patients was provided within the first 48 h (68.6%) and consisted of as passive range of motion, in-bed positioning, and splinting. Postural passages and sitting were provided to patients and walking was included in those advanced motor activities which are part of the treatment. Physiotherapy in patients on ECLS is feasible, however substantial variability exists between centers with a trend of delivering not protocolized and understaffed rehabilitation practices.