Connective Auxin Transport in the Shoot Facilitates Communication between Shoot Apices.
The bulk polar movement of the plant signaling molecule auxin through the stem is a long-recognized but poorly understood phenomenon. Here we show that the highly polar, high conductance polar auxin transport stream (PATS) is only part of a multimodal auxin transport network in the stem. The dynamics of auxin movement through stems are inconsistent with a single polar transport regime and instead suggest widespread low conductance, less polar auxin transport in the stem, which we term connective auxin transport (CAT). The bidirectional movement of auxin between the PATS and the surrounding tissues, mediated by CAT, can explain the complex auxin transport kinetics we observe. We show that the auxin efflux carriers PIN3, PIN4, and PIN7 are major contributors to this auxin transport connectivity and that their activity is important for communication between shoot apices in the regulation of shoot branching. We propose that the PATS provides a long-range, consolidated stream of information throughout the plant, while CAT acts locally, allowing tissues to modulate and be modulated by information in the PATS.


Comparison of ionisation measurements in water and polystyrene for electron beam dosimetry.
For the determination of absorbed dose to water in electron beams, dosimetry protocols advocate ionisation measurements in plastic phantoms instead of water for practical reasons. The chamber readings in polystyrene at the depth of maximum ionisation must be corrected for the difference in physical properties between the two materials. This correction factor was determined for a Farmer 0.6 cm3 graphite-walled chamber in electron beams with mean energies at the phantom surface between 6 and 19 MeV. Experiments with white polystyrene yielded corrections for the measured ionisation ranging from 0.3 to 2.4%. For clear polystyrene, 0.6-1% higher corrections were found. For beams with the same mean energy at the phantom surface, but with different beam-flattening and collimation systems, variations in this correction up to 1.2% were observed. In contrast to recent reports on electrical charge storage in polystyrene due to electron irradiation, our experiments do not show differences in the chamber readings any larger than 0.5%.


Predicting reading comprehension in young children with autism spectrum disorder.
Relationships between early literacy measures (i.e., curriculum-based measurement) and advanced literacy measures (i.e., reading comprehension) were examined in young children with autism spectrum disorders (ASDs). Participants in this study were 167 children between the ages of 4 and 7 years (M = 5 years 8 months), who were assessed at 2 time points during 1 school year. Results indicated that, compared to other measures of early literacy skills, curriculum-based measurements (CBMs) accurately assessed skills in students with ASD. Furthermore, early literacy skills predicted reading comprehension approximately six months later in this sample. The reading development of children with ASD compared to typically developing children appears to be similar in the predictive capacity of decoding skills on later reading skills and dissimilar in the variability and range of skills. CBM tools can provide educators with information about the early reading skills of children with ASD to help address reading and language difficulties seen in this population. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


[Responsibilities of ethics committees].
Increasing numbers of clinical research projects are submitted to ethical committees (institutional review boards) for approval. New therapeutic developments have to be evaluated by these committees to protect patients/volunteers. Thus, the responsibility of ethical committees is increasing. The "Nürnberger Kodex" and the "Declaration of Helsinki" are the background for these evaluations. According to the German drug law the physician is obligated by law to submit the protocol to such a committee. In addition, local state physician authorities require such a procedure. Important considerations during the review process besides ethical aspects are the informed consent, which should be written in an understandable form, and the obligations of the insurance.


Optical implementations of radial basis classifiers.
We describe two optical systems based on the radial basis function approach to pattern classification. An optical-disk-based system for handwritten character recognition is demonstrated. The optical system computes the Euclidean distance between an unknown input and 650 stored patterns at a demonstrated rate of 26,000 pattern comparisons/s. The ultimate performance of this system is limited by optical-disk resolution to 10(11) binary operations/s. An adaptive system is also presented -that facilitates on-line learning and provides additional robustness.


Ultrasound shear wave elastography effectively predicts integrity of ventral hernia repair using acellular dermal matrix augmented with platelet-rich plasma (PRP).
Complications of ventral hernia repair (VHR) may be investigated by computed tomography or ultrasound (US) but neither modality gives a quantifiable metric of repair quality short of identifying hernia recurrence. Platelet-rich plasma (PRP), a growth factor-rich autologous blood product, has been shown to improve incorporation of native tissue with bioprosthetics. In this study, we investigate the effect of PRP on the incorporation and mechanical integrity of a non-crosslinked porcine acellular dermal matrix (pADM) in a rodent model of VHR and the correlative ability of ultrasound shear wave elastography (US-SWE) to assess repair quality. PRP was isolated from whole blood of Lewis rats. Twenty-eight Lewis rats underwent chronic VHR using either pADM alone or augmented with autologous PRP prior to non-invasive imaging assessment and specimen harvest at either 3 or 6 months. US-SWE was performed to estimate the Young's modulus prior to histological assessment and data from PRP-treated rodents were compared to controls. Implanted pADM was easily distinguishable by US-SWE imaging in all cases analyzed in this study. The mean Young's modulus measured was 1.78 times and 2.54 times higher in PRP-treated samples versus control at 3-month and 6-month time points respectively (p < 0.05). At 3 months, qualitative and quantitative histology revealed decreased inflammation and improved incorporation in PRP-treated samples along the implant/abdominal wall interface. At 6 months, the PRP cohort had no hernia recurrence and preserved ADM integrity from immunologic degradation, while all control animals suffered hernia recurrence (4/6) or extreme ADM thinning (2/6). This study confirms both the efficacy of PRP in augmenting VHR using pADM, as well as the reliability of US-SWE to non-invasively predict the quality of VHR. Although further human studies are necessary, this work supports PRP use to improve VHR outcomes and US-SWE potential for bedside non-invasive hernia characterization.


Intramolecular Light-Driven Accumulation of Reduction Equivalents by Proton-Coupled Electron Transfer.
The photochemistry of a molecular pentad composed of a central anthraquinone (AQ) acceptor flanked by two Ru(bpy)32+ photosensitizers and two peripheral triarylamine (TAA) donors was investigated by transient IR and UV-vis spectroscopies in the presence of 0.2 M p-toluenesulfonic acid (TsOH) in deaerated acetonitrile. In ∼15% of all excited pentad molecules, AQ is converted to its hydroquinone form (AQH2) via reversible intramolecular electron transfer from the two TAA units (τ = 65 ps), followed by intermolecular proton transfer from TsOH (τ ≈ 3 ns for the first step). Although the light-driven accumulation of reduction equivalents occurs through a sequence of electron and proton transfer steps, the resulting photoproduct decays via concerted PCET (τ = 4.7 μs) with an H/D kinetic isotope effect of 1.4 ± 0.2. Moreover, the reoxidation of AQH2 seems to take place via a double electron transfer step involving both TAA+ units rather than sequential single electron transfer events. Thus, the overall charge-recombination reaction seems to involve a concerted proton-coupled two-electron oxidation of AQH2. The comparison of experimental data obtained in neat acetonitrile with data from acidic solutions suggests that the inverted driving-force effect can play a crucial role for obtaining long-lived photoproducts resulting from multiphoton, multielectron processes. Our pentad provides the first example of light-driven accumulation of reduction equivalents stabilized by PCET in artificial molecular systems without sacrificial reagents. Our study provides fundamental insight into how light-driven multielectron redox chemistry, for example the reduction of CO2 or the oxidation of H2O, can potentially be performed without sacrificial reagents.


Effect of spinal cord stimulation for chronic complex regional pain syndrome Type I: five-year final follow-up of patients in a randomized controlled trial.
Chronic complex regional pain syndrome-Type I (CRPS-I) is a painful, disabling disorder for which no treatment with proven effect is available. In the present randomized controlled trial, the authors assessed the effectiveness of spinal cord stimulation (SCS) in reducing pain due to CRPS-I at the 5-year follow-up. The authors performed a randomized trial in a 2:1 ratio in which 36 patients with CRPS-I were allocated to receive SCS and physical therapy (PT) and 18 patients to receive PT alone. Twenty-four patients who received SCS+PT also underwent placement of a permanent spinal cord stimulator after successful test stimulation; the remaining 12 patients did not receive a permanent stimulator. The authors assessed pain intensity, global perceived effect, treatment satisfaction, and health-related quality of life. Patients were examined before randomization, before implantation, and every year until 5 years thereafter. Ten patients were excluded from the final analysis. At 5 years posttreatment, SCS+PT produced results similar to those following PT for pain relief and all other measured variables. In a subgroup analysis, the results with regard to global perceived effect (p=0.02) and pain relief (p=0.06) in 20 patients with an implant exceeded those in 13 patients who received PT. Despite the diminishing effectiveness of SCS over time, 95% of patients with an implant would repeat the treatment for the same result.


Degradation of glomerular basement membrane by purified mammalian metalloproteinases.
Neutral metalloproteinases degrade components of the extracellular matrix, including collagen types I-V, fibronectin, laminin and proteoglycan. However, their ability to degrade intact glomerular basement membrane (GBM) has not previously been investigated. Incubation of [3H]GBM (50,000 c.p.m.; pH 7.5; 24 h at 37 degrees C) with purified gelatinase or stromelysin (2 units) resulted in significant GBM degradation: gelatinase, 46 +/- 2.2; stromelysin, 59 +/- 5.8 (means +/- S.E.M.; percentage release of non-sedimentable radioactivity; n = 4). In contrast, 2 units of collagenase released only 5.6 +/- 0.52% (n = 3) of the [3H]GBM radioactivity compared with 2.0 +/- 0.15% (n = 7) released from [3H]GBM incubated alone. Sephadex G-200 gel chromatography of supernatants obtained from incubations of [3H]GBM with either gelatinase or stromelysin confirmed the ability of these enzymes to degrade GBM and revealed both high-(800,000) and relatively low-(less than 20,000) Mr degradation products for both enzymes. GBM degradation by gelatinase and stromelysin was dose-dependent (range 0.02-2.0 units), near maximal between pH 6.0 and 8.6, and was completely inhibited (greater than 95%) by 2 mM-o-phenanthroline. Collagenase (2 units) did not enhance the degradation of GBM by either gelatinase (0.02 or 0.2 unit) or stromelysin (0.02 or 0.2 unit). Our results indicate that metalloproteinase-mediated GBM degradation by neutrophils and glomeruli may be attributable to gelatinase (neutrophils) and/or stromelysin (glomeruli) and suggest an important role for these proteinases in glomerular pathophysiology.


Neural Control of REM Sleep and Motor Atonia: Current Perspectives.
Since the formal discovery of rapid eye movement (REM) sleep in 1953, we have gained a vast amount of knowledge regarding the specific populations of neurons, their connections, and synaptic mechanisms regulating this stage of sleep and its accompanying features. This article discusses REM sleep circuits and their dysfunction, specifically emphasizing recent studies using conditional genetic tools. Sublaterodorsal nucleus (SLD) in the dorsolateral pons, especially the glutamatergic subpopulation in this region (SLDGlut), are shown to be indispensable for REM sleep. These neurons appear to be single REM generators in the rodent brain and may initiate and orchestrate all REM sleep events, including cortical and hippocampal activation and muscle atonia through distinct pathways. However, several cell groups in the brainstem and hypothalamus may influence SLDGlut neuron activity, thereby modulating REM sleep timing, amounts, and architecture. Damage to SLDGlut neurons or their projections involved in muscle atonia leads to REM behavior disorder, whereas the abnormal activation of this pathway during wakefulness may underlie cataplexy in narcolepsy. Despite some opposing views, it has become evident that SLDGlut neurons are the sole generators of REM sleep and its associated characteristics. Further research should prioritize a deeper understanding of their cellular, synaptic, and molecular properties, as well as the mechanisms that trigger their activation during cataplexy and make them susceptible in RBD.


A survey on platforms for big data analytics.
The primary purpose of this paper is to provide an in-depth analysis of different platforms available for performing big data analytics. This paper surveys different hardware platforms available for big data analytics and assesses the advantages and drawbacks of each of these platforms based on various metrics such as scalability, data I/O rate, fault tolerance, real-time processing, data size supported and iterative task support. In addition to the hardware, a detailed description of the software frameworks used within each of these platforms is also discussed along with their strengths and drawbacks. Some of the critical characteristics described here can potentially aid the readers in making an informed decision about the right choice of platforms depending on their computational needs. Using a star ratings table, a rigorous qualitative comparison between different platforms is also discussed for each of the six characteristics that are critical for the algorithms of big data analytics. In order to provide more insights into the effectiveness of each of the platform in the context of big data analytics, specific implementation level details of the widely used k-means clustering algorithm on various platforms are also described in the form pseudocode.


Use of orally administered anhydrous crystalline maltose for relief of dry mouth.
To examine the safety and efficacy of anhydrous crystalline maltose (ACM) for treatment of dry mouth. ACM was delivered orally as a 200-mg lozenge given three times daily over a 12-week (study Alpha) or 24-week (study Omega) period to a total of 22 and 97 subjects, respectively. All participants had prominent complaints of persistent dry mouth associated with primary Sjögren's syndrome. Patients were examined every 4 weeks in study Alpha and every 6 weeks in study Omega. Patients were seen in outpatient clinics at a total of 33 sites within the United States. Unstimulated whole saliva output, a measure of basal salivary gland function, was determined at each visit. Symptoms associated with oral and ocular dryness were assessed at the same time with the use of 100-mm visual analog scales. Safety was assessed by physical examination and laboratory studies. During these clinical trials, a majority of subjects demonstrated an increase in unstimulated whole saliva output and the treatment exhibited an excellent safety profile. The ACM treatment in study Omega led to significant improvement in several subjective measures of oral and ocular comfort. In these two studies, ACM lozenges administered three times daily for 12 or 24 weeks improved salivary output and decreased complaints of dry mouth and eyes. Side effects were minimal, and treatment was without significant adverse events. This safe and simple intervention may provide clinical benefit to individuals with distressing dry mouth symptoms.


Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial.
The prognosis for patients with pancreatic cancer is poor, even after resection with curative intent. Gemcitabine-based chemotherapy is standard treatment for advanced pancreatic cancer, but its effect on survival in the adjuvant setting has not been demonstrated. To analyze whether previously reported improvement in disease-free survival with adjuvant gemcitabine therapy translates into improved overall survival. CONKO-001 (Charité Onkologie 001), a multicenter, open-label, phase 3 randomized trial to evaluate the efficacy and toxicity of gemcitabine in patients with pancreatic cancer after complete tumor resection. Patients with macroscopically completely removed pancreatic cancer entered the study between July 1998 and December 2004 in 88 hospitals in Germany and Austria. Follow-up ended in September 2012. After stratification for tumor stage, nodal status, and resection status, patients were randomly assigned to either adjuvant gemcitabine treatment (1g/m2 d 1, 8, 15, q 4 weeks) for 6 months or to observation alone. The primary end point was disease-free survival. Secondary end points included treatment safety and overall survival, with overall survival defined as the time from date of randomization to death. Patients lost to follow-up were censored on the date of their last follow-up. A total of 368 patients were randomized, and 354 were eligible for intention-to-treat-analysis. By September 2012, 308 patients (87.0% [95% CI, 83.1%-90.1%]) had relapsed and 316 patients (89.3% [95% CI, 85.6%-92.1%]) had died. The median follow-up time was 136 months. The median disease-free survival was 13.4 (95% CI, 11.6-15.3) months in the treatment group compared with 6.7 (95% CI, 6.0-7.5) months in the observation group (hazard ratio, 0.55 [95% CI, 0.44-0.69]; P < .001). Patients randomized to adjuvant gemcitabine treatment had prolonged overall survival compared with those randomized to observation alone (hazard ratio, 0.76 [95% CI, 0.61-0.95]; P = .01), with 5-year overall survival of 20.7% (95% CI, 14.7%-26.6%) vs 10.4% (95% CI, 5.9%-15.0%), respectively, and 10-year overall survival of 12.2% (95% CI, 7.3%-17.2%) vs 7.7% (95% CI, 3.6%-11.8%). Among patients with macroscopic complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall survival as well as disease-free survival. These findings provide strong support for the use of gemcitabine in this setting. isrctn.org Identifier: ISRCTN34802808.


Quantitative, depth-resolved determination of particle motion using multi-exposure, spatial frequency domain laser speckle imaging.
Laser Speckle Imaging (LSI) is a simple, noninvasive technique for rapid imaging of particle motion in scattering media such as biological tissue. LSI is generally used to derive a qualitative index of relative blood flow due to unknown impact from several variables that affect speckle contrast. These variables may include optical absorption and scattering coefficients, multi-layer dynamics including static, non-ergodic regions, and systematic effects such as laser coherence length. In order to account for these effects and move toward quantitative, depth-resolved LSI, we have developed a method that combines Monte Carlo modeling, multi-exposure speckle imaging (MESI), spatial frequency domain imaging (SFDI), and careful instrument calibration. Monte Carlo models were used to generate total and layer-specific fractional momentum transfer distributions. This information was used to predict speckle contrast as a function of exposure time, spatial frequency, layer thickness, and layer dynamics. To verify with experimental data, controlled phantom experiments with characteristic tissue optical properties were performed using a structured light speckle imaging system. Three main geometries were explored: 1) diffusive dynamic layer beneath a static layer, 2) static layer beneath a diffuse dynamic layer, and 3) directed flow (tube) submerged in a dynamic scattering layer. Data fits were performed using the Monte Carlo model, which accurately reconstructed the type of particle flow (diffusive or directed) in each layer, the layer thickness, and absolute flow speeds to within 15% or better.


Differential visceral pain sensitivity and colonic morphology in four common laboratory rat strains.
What is the central question of this study? Does stress sensitivity and susceptibility to inflammation innate to certain rat strains make them vulnerable to bowel dysfunction? What is the main finding and its importance? Of four different rat strains, the Lewis rat, which displays both susceptibility to gastrointestinal inflammation and sensitivity to stress, exhibits the most aberrant gastrointestinal morphology and visceral pain sensitivity. Given the similarities to human functional bowel disorders, such as irritable bowel syndrome, this may make it a good model of this disease. Irritable bowel syndrome is a common, debilitating gastrointestinal (GI) disorder characterized by episodic exacerbations of symptoms such as abdominal pain, bloating and altered bowel habit. Contributory factors for the development of irritable bowel syndrome include genetics, childhood trauma and prior GI infection leading to chronic low-grade inflammation or immune activation. Additional considerations in comprehending the chronic relapsing pattern that typifies irritable bowel syndrome symptoms are the effects of both psychosocial and infection-related stresses. Background stress and immune profiles can influence gut permeability and visceral pain sensitivity. This study examined whether innate susceptibility to inflammation and stress sensitivity in four rat strains is associated with bowel dysfunction. The pain threshold to colorectal distension was assessed in Lewis, Fischer (F344) and spontaneously hypertensive rats and compared with Sprague-Dawley control animals. Colons were subsequently excised and morphologically assessed for total length, goblet cell hyperplasia and muscle and mucosal thickness. Lewis rats displayed visceral hypersensitivity compared with other strains. At a morphological level, the gastrointestinal tract from these rats displayed mucosal goblet cell hyperplasia and alterations in muscle layer thickness. The Lewis rat strain, which is reported to have increased susceptibility to GI inflammation in addition to stress sensitivity, had the most prominent features of physiological and morphological GI dysfunction. These data support the hypothesis that background strain is a key factor in the development and exacerbation of bowel dysfunction in rodent models.


Assessment of nonoccupational exposure to DDT in the tropics and the north: relevance of uptake via inhalation from indoor residual spraying.
People who live in dwellings treated with indoor residual spraying (IRS) of DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] for disease-vector control in the tropics and indigenous populations in the Arctic who consume marine mammals experience high nonoccupational exposure to DDT. Although the use of DDT in IRS is rising, the resulting nonoccupational exposure is poorly characterized. We have provided a comparative assessment of exposure to DDT and its metabolites in the general population of the tropical and northern regions and in highly exposed populations in these regions. We compiled > 600 average or median DDT concentrations from the peer-reviewed literature, representing > 23,000 individual measurements in humans, food, air, soil, and dust. We use Monte Carlo sampling of distributions based on these data to estimate distributions of population- and route-specific uptake. We evaluate our exposure estimates by comparing them with biomonitoring data. DDT concentrations are highest in people living in IRS-treated houses and lowest in the northern general population, differing by a factor of about 60. Inuits and the general population in the tropics have similar concentrations. Inhalation exposure explains most of the difference in concentration between the highly exposed and the general population in the Tropics. Calculated exposure levels are consistent with human biomonitoring data. Nonoccupational inhalation exposure is a relevant exposure pathway for people living in homes treated by IRS of DDT. Continued monitoring of time trends and DDE to DDT ratios in the Tropics and in the North is needed to identify a possible slowdown in concentration decline and the influence of ongoing DDT use.


Use of photoimmunoconjugates to characterize ABCB1 in cancer cells.
Accurate detection of ATP-binding cassette drug transporter ABCB1 expression is imperative for precise identification of drug-resistant tumors. Existing detection methods fail to provide the necessary molecular details regarding the functional state of the transporter. Photo-immunoconjugates are a unique class of antibody-dye conjugates for molecular diagnosis and therapeutic treatment. However, conjugating hydrophobic photosensitizers to hydrophilic antibodies is quite challenging. Here, we devise a photoimmunoconjugate that combines a clinically approved benzoporphyrin derivative (BPD) photosensitizer and the conformational-sensitive UIC2 monoclonal antibody to target functionally active human ABCB1 (i.e., ABCB1 in the inward-open conformation). We show that PEGylation of UIC2 enhances the BPD conjugation efficiency and reduces the amount of non-covalently conjugated BPD molecules by 17%. Size exclusion chromatography effectively separates the different molecular weight species found in the UIC2-BPD sample. The binding of UIC2-BPD to ABCB1 was demonstrated in lipidic nanodiscs and ABCB1-overexpressing triple negative breast cancer (TNBC) cells. UIC2-BPD was found to retain the conformation sensitivity of UIC2, as the addition of ABCB1 modulators increases the antibody reactivity in vitro. Thus, the inherent fluorescence capability of BPD can be used to label ABCB1-overexpressing TNBC cells using UIC2-BPD. Our findings provide insight into conjugation of hydrophobic photosensitizers to conformation-sensitive antibodies to target proteins expressed on the surface of cancer cells.


Diuretics, magnesium, potassium and sodium.
Diuretics increase renal magnesium excretion and, when chronically administered, decrease intracellular magnesium levels. This deficiency reduces active transport of potassium into the cell and intracellular potassium decreases irrespective of serum potassium levels. Potassium supplementation or the co-administration of potassium-sparing diuretics cannot maintain intracellular potassium at normal levels when intracellular magnesium is reduced. The effects of chronic magnesium supplementation have not been adequately studied. Maintenance of the diuretic dose at an effective minimum and curtailing sodium intake when diuretics are chronically prescribed are the simplest and safest manoeuvres which can be undertaken in order to prevent the occurrence of events usually ascribed to hypokalaemia and in fact principally due to low intracellular potassium which is associated with magnesium deficiency.


Cutaneous neonatal neuroblastoma: report of a case.
We herein report a case of neonatal neuroblastoma with cutaneous metastasis. This newborn male was a full-term infant of a G3P3 mother. Asphyxia occurred immediately after birth, though he was revived after intensive medical treatment. Physical examination revealed multiple firm cutaneous nodules distributed over his body. In addition, congenital glaucoma, hepatomegaly, and a soft tissue mass along the right temporal bone were also observed. Laboratory data revealed markedly elevated urinary vanilmandelic acid excretion, leukopenia, thrombocytopenia and an increased level of SGOT and SGPT. A skin biopsy was performed on a cutaneous nodule on the right hip, and the histopathological picture confirmed the diagnosis of neuroblastoma. The patient expired 12 days after birth due to complications caused by his condition.


Implementation study of an analog spiking neural network for assisting cardiac delay prediction in a cardiac resynchronization therapy device.
In this paper, we aim at developing an analog spiking neural network (SNN) for reinforcing the performance of conventional cardiac resynchronization therapy (CRT) devices (also called biventricular pacemakers). Targeting an alternative analog solution in 0.13- μm CMOS technology, this paper proposes an approach to improve cardiac delay predictions in every cardiac period in order to assist the CRT device to provide real-time optimal heartbeats. The primary analog SNN architecture is proposed and its implementation is studied to fulfill the requirement of very low energy consumption. By using the Hebbian learning and reinforcement learning algorithms, the intended adaptive CRT device works with different functional modes. The simulations of both learning algorithms have been carried out, and they were shown to demonstrate the global functionalities. To improve the realism of the system, we introduce various heart behavior models (with constant/variable heart rates) that allow pathologic simulations with/without noise on the signals of the input sensors. The simulations of the global system (pacemaker models coupled with heart models) have been investigated and used to validate the analog spiking neural network implementation.


Aerolysin gene characterization and antimicrobial resistance profile of Aeromonas hydrophila isolated from milkfish (Chanos chanos) in Gresik, Indonesia.
Motile Aeromonas septicemia is a crucial disease in freshwater fish. Aeromonas hydrophila is a disease agent associated with sporadic fish mortality, food safety, and public health. This study aimed to estimate the prevalence and the presence of the aerolysin gene and antimicrobial resistance profile of A. hydrophila isolated from milkfish in Gresik, Indonesia. A total of 153 milkfish gill samples were collected from 16 locations in Gresik and then cultured and identified using biochemical tests. The aerolysin gene was investigated using a polymerase chain reaction, and antimicrobial resistance profiles of the recovered isolates were investigated. Of the 153 examined samples, 35 (22.9%) were confirmed positive for A. hydrophila and 22 (62.9%) presented the aerolysin gene. The recovered isolates were resistant to the following antibiotics: Amoxicillin (62.9%), tetracycline (60%), streptomycin (54.3%), cefotaxime (51.4%), gentamycin (31.4%), kanamycin (28.6%), erythromycin (25.7%), chloramphenicol (20%), and trimethoprim (14.3%). Meanwhile, only ciprofloxacin, nalidixic acid, and imipenem were indicated as susceptible. The presence of the aerolysin gene is vital in determining the virulence of A. hydrophila. The study results indicated a high aerolysin gene prevalence. In addition, this study emphasized antibiotic use monitoring, food safety improvement, and negative impact reduction on human health and the environment.


Political economy of tobacco control in Thailand.
Thailand has some of the world's strongest anti-tobacco legislation. This paper examines the political economy of tobacco control in Thailand, emphasising the identification of forces which have supported and opposed the passage of strong anti-tobacco measures. It argues that while a powerful tobacco control coalition was created in the late 1980s, the gains won by this coalition are now under threat from systematic attempts by transnational tobacco companies to strengthen their share of the Thai cigarette market. The possible privatisation of the Thailand Tobacco Monopoly could threaten the tobacco control cause, but the pro-control alliance is fighting back with a proposed Health Promotion Act which would challenge the tobacco industry with a hypothecated excise tax dedicated to health awareness campaigns.


A quantile count model of water depth constraints on Cape Sable seaside sparrows.
1. A quantile regression model for counts of breeding Cape Sable seaside sparrows Ammodramus maritimus mirabilis (L.) as a function of water depth and previous year abundance was developed based on extensive surveys, 1992-2005, in the Florida Everglades. The quantile count model extends linear quantile regression methods to discrete response variables, providing a flexible alternative to discrete parametric distributional models, e.g. Poisson, negative binomial and their zero-inflated counterparts. 2. Estimates from our multiplicative model demonstrated that negative effects of increasing water depth in breeding habitat on sparrow numbers were dependent on recent occupation history. Upper 10th percentiles of counts (one to three sparrows) decreased with increasing water depth from 0 to 30 cm when sites were not occupied in previous years. However, upper 40th percentiles of counts (one to six sparrows) decreased with increasing water depth for sites occupied in previous years. 3. Greatest decreases (-50% to -83%) in upper quantiles of sparrow counts occurred as water depths increased from 0 to 15 cm when previous year counts were 1, but a small proportion of sites (5-10%) held at least one sparrow even as water depths increased to 20 or 30 cm. 4. A zero-inflated Poisson regression model provided estimates of conditional means that also decreased with increasing water depth but rates of change were lower and decreased with increasing previous year counts compared to the quantile count model. Quantiles computed for the zero-inflated Poisson model enhanced interpretation of this model but had greater lack-of-fit for water depths > 0 cm and previous year counts 1, conditions where the negative effect of water depths were readily apparent and fitted better with the quantile count model.


Physical activity and the progression of coronary artery calcification.
The association of physical activity with the development and progression of coronary artery calcium (CAC) scores has not been studied. This study aimed to evaluate the prospective association between physical activity and CAC scores in apparently healthy adults. Prospective cohort study of men and women free of overt cardiovascular disease who underwent comprehensive health screening examinations between 1 March 2011 and 31 December 2017. Baseline physical activity was measured using the International Physical Activity Questionnaire Short Form (IPAQ-SF) and categorised into three groups (inactive, moderately active and health-enhancing physically active (HEPA)). The primary outcome was the difference in the 5-year change in CAC scores by physical activity category at baseline. We analysed 25 485 participants with at least two CAC score measurements. The proportions of participants who were inactive, moderately active and HEPA were 46.8%, 38.0% and 15.2%, respectively. The estimated adjusted average baseline CAC scores (95% confidence intervals) in participants who were inactive, moderately active and HEPA were 9.45 (8.76, 10.14), 10.20 (9.40, 11.00) and 12.04 (10.81, 13.26). Compared with participants who were inactive, the estimated adjusted 5-year average increases in CAC in moderately active and HEPA participants were 3.20 (0.72, 5.69) and 8.16 (4.80, 11.53). Higher physical activity was association with faster progression of CAC scores both in participants with CAC=0 at baseline and in those with prevalent CAC. We found a positive, graded association between physical activity and the prevalence and the progression of CAC, regardless of baseline CAC scores.


Retinoic acid affects left-right patterning.
Our understanding of the means by which the left-right axis is patterned is not fully understood, although a number of key intermediaries have been recently described. We report here that retinoic acid (RA) excess affects heart situs concomitant with alterations in the expression of genes implicated in the establishment of the left-right axis. Specifically, RA exposure during a specific developmental window evoked bilateral expression of lefty-1, lefty-2, nodal, and pitx-2 in the lateral plate mesoderm. Time course experiments, together with analysis of midline markers, suggest that nascent mesoderm constitutes a predominant RA target involved in this process. These events are likely to underlie the perturbations of heart looping provoked by excess RA and suggest a means by which retinoids influence the early steps in establishment of the left-right embryonic axis.


Assessing the potential of ChatGPT for psychodynamic formulations in psychiatry: An exploratory study.
Although there were several attempts to apply ChatGPT (Generative Pre-Trained Transformer) to medicine, little is known about therapeutic applications in psychiatry. In this exploratory study, we aimed to evaluate the characteristics and appropriateness of the psychodynamic formulations created by ChatGPT. Along with a case selected from the psychoanalytic literature, input prompts were designed to include different levels of background knowledge. These included naïve prompts, keywords created by ChatGPT, keywords created by psychiatrists, and psychodynamic concepts from the literature. The psychodynamic formulations generated from the different prompts were evaluated by five psychiatrists from different institutions. We next conducted further tests in which instructions on the use of different psychodynamic models were added to the input prompts. The models used were ego psychology, self-psychology, and object relations. The results from naïve prompts and psychodynamic concepts were rated as appropriate by most raters. The psychodynamic concept prompt output was rated the highest. Interrater agreement was statistically significant. The results from the tests using instructions in different psychoanalytic theories were also rated as appropriate by most raters. They included key elements of the psychodynamic formulation and suggested interpretations similar to the literature. These findings suggest potential of ChatGPT for use in psychiatry.


Chronic medical conditions mediate the association between depression and cardiovascular disease mortality.
To determine whether chronic medical conditions mediate the association between depression and cardiovascular disease (CVD) mortality. Data analyzed were from 6,394 subjects aged 25-74 years who participated in extensive health examinations in the NHEFS conducted between 1971 and 1975 and follow-up studies to 1992. CVD mortality was the endpoint. Depression predictors were clinically significant depressive symptoms at baseline by the GWB-D, and/or at 1982-1984 by the CES-D ('baseline', 'new', or 'twice' depression). Chronic conditions were prevalent/incident high blood pressure, diabetes, and non-fatal CVD by examination and/or self-report. Mediation effects were assessed by stepwise adjustments of covariates and additive interactions in competing risks regression models (accounting for other mortality causes) and logit models. Baseline, new, and twice depression were significant predictors of CVD mortality in competing-risks models adjusted for demographics (HRs 1.3, 1.4, and 2.0), but effects were progressively weakened and became non-significant after adjustment for lifestyle factors, prevalent and incident medical conditions, respectively. CVD mortality risk was 80% higher for depression plus incident non-fatal CVD than without (HR 4.0 vs. 3.2, additive interaction), and mediation effects of depression via chronic medical conditions (particularly via incident non-fatal CVD) increased the risk by 2-11% in logit models, independent of all covariates. Several levels of evidence suggest that the association between depression and CVD mortality is partially mediated by prevalent/incident chronic medical conditions, as well as unhealthy lifestyle behaviors. Patients presenting with clinically significant depressive symptoms, particularly if persistent, should be assessed for both chronic conditions and lifestyle risk factors.


An integrated approach towards the development of novel antifungal agents containing thiadiazole: synthesis and a combined similarity search, homology modelling, molecular dynamics and molecular docking study.
This study aims to synthesise and characterise novel compounds containing 2-amino-1,3,4-thiadiazole and their acyl derivatives and to investigate antifungal activities. Similarity search, molecular dynamics and molecular docking were also studied to find out a potential target and enlighten the inhibition mechanism. As a first step, 2-amino-1,3,4-thiadiazole derivatives (compounds 3 and 4) were synthesised with high yields (81 and 84%). The target compounds (6a-n and 7a-n) were then synthesised with moderate to high yields (56-87%) by reacting 3 and 4 with various acyl chloride derivatives (5a-n). The synthesized compounds were characterized using the IR, 1H-NMR, 13C-NMR, Mass, X-ray (compound 7n) and elemental analysis techniques. Later, the in vitro antifungal activities of the synthesised compounds were determined. The inhibition zones exhibited by the compounds against the tested fungi, their minimum fungicidal activities, minimum inhibitory concentration and the lethal dose values (LD50) were determined. The compounds exhibited moderate to high levels of activity against all tested pathogens. Finally, in silico modelling was used to enlighten inhibition mechanism using ligand and structure-based methods. As an initial step, similarity search was carried out and the resulting proteins that belong to Homo sapiens were used as reference in sequence similarity search to find the corresponding amino acid sequences in target organisms. Homology modelling was used to construct the protein structure. The stabilised protein structure obtained from molecular dynamics simulation was used in molecular docking. The overall results presented here might be a good starting point for the identification of novel and more active compounds as antifungal agents.


Genomic characterisation of respiratory syncytial virus: a novel system for whole genome sequencing and full-length G and F gene sequences.
To advance our understanding of respiratory syncytial virus (RSV) impact through genomic surveillance, we describe two PCR-based sequencing systems, (i) RSVAB-WGS for generic whole-genome sequencing and (ii) RSVAB-GF, which targets major viral antigens, G and F, and is used as a complement for challenging cases with low viral load. These methods monitor RSV genetic diversity to inform molecular epidemiology, vaccine effectiveness and treatment strategies, contributing also to the standardisation of surveillance in a new era of vaccines.


Recombinant C1-inhibitor: effects on coagulation and fibrinolysis in patients with hereditary angioedema.
Recombinant human C1-inhibitor (rhC1INH; Ruconest®) has been developed for treatment of acute angioedema attacks in patients with hereditary angioedema (HAE) due to heterozygous deficiency of C1INH. Previous reports suggest that administration of plasma-derived C1INH products may be associated with an increased risk for thromboembolic complications. Our aim is to evaluate the effects of rhC1INH on coagulation and fibrinolysis in symptomatic HAE patients. Levels of various coagulation and fibrinolytic parameters were determined in pre- and post-exposure plasma samples from HAE patients included in a randomized clinical trial. Patients were treated with either saline, or 50 or 100 U/kg rhC1INH for an acute angioedema attack. Prior to rhC1INH treatment, the majority of patients had low to normal activated partial thromboplastin times (aPTT) and increased levels of prothrombin fragment 1+2, thrombin-antithrombin complexes, D-dimers and plasmin-antiplasmin complexes, all of which indicate activation of both coagulation and fibrinolysis. Infusion of rhC1INH at doses up to 100 U/kg did not affect these parameters except for a dose-dependent prolongation of aPTT, confirming that rhC1INH is an inhibitor of the contact system, and that F1+2 levels decreased. Coagulation and fibrinolytic systems are activated in HAE patients suffering from an acute angioedema attack. Treatment with rhC1INH at 50 or 100 U/kg had no effect on parameters reflecting activation of these systems except for a significant effect on aPTT, which likely reflects a pharmacodynamic effect of rhC1INH, and a reduction on plasma levels of the prothrombin activation fragment F1+2. We conclude that these results argue against a prothrombotic effect of treatment with this rhC1INH product in HAE patients.


Cooperative induction of apoptosis in NRAS mutant melanoma by inhibition of MEK and ROCK.
No effective targeted therapy is currently available for NRAS mutant melanoma. Experimental MEK inhibition is rather toxic and has only limited efficacy in clinical trials. At least in part, this is caused by the emergence of drug resistance, which is commonly seen for single agent treatment and shortens clinical responses. Therefore, there is a dire need to identify effective companion drug targets for NRAS mutant melanoma. Here, we show that at concentrations where single drugs had little effect, ROCK inhibitors GSK269962A or Fasudil, in combination with either MEK inhibitor GSK1120212 (Trametinib) or ERK inhibitor SCH772984 cooperatively caused proliferation inhibition and cell death in vitro. Simultaneous inhibition of MEK and ROCK caused induction of BimEL , PARP, and Puma, and hence apoptosis. In vivo, MEK and ROCK inhibition suppressed growth of established tumors. Our findings warrant clinical investigation of the effectiveness of combinatorial targeting of MAPK/ERK and ROCK in NRAS mutant melanoma.


Hydrolase controls cellular NAD, sirtuin, and secondary metabolites.
Cellular levels of NAD(+) and NADH are thought to be controlled by de novo and salvage mechanisms, although evidence has not yet indicated that they are regulated by NAD(+) degradation. Here we show that the conserved nudix hydrolase isozyme NdxA hydrolyzes and decreases cellular NAD(+) and NADH in Aspergillus nidulans. The NdxA-deficient fungus accumulated more NAD(+) during the stationary growth phase, indicating that NdxA maintains cellular NAD(+)/NADH homeostasis. The deficient strain also generated less of the secondary metabolites sterigmatocystin and penicillin G and of their gene transcripts than did the wild type. These defects were associated with a reduction in acetylated histone H4 on the gene promoters of aflR and ipnA that are involved in synthesizing secondary metabolites. Thus, NdxA increases acetylation levels of histone H4. We discovered that the novel fungal sirtuin isozyme SirA uses NAD(+) as a cosubstrate to deacetylate the lysine 16 residue of histone H4 on the gene promoter and represses gene expression. The impaired acetylation of histone and secondary metabolite synthesis in the NdxA-deficient strain were restored by eliminating functional SirA, indicating that SirA mediates NdxA-dependent regulation. These results indicated that NdxA controls total levels of NAD(+)/NADH and negatively regulates sirtuin function and chromatin structure.


Mesenchymal stem cell implantation provides short-term clinical improvement and satisfactory cartilage restoration in patients with knee osteoarthritis but the evidence is limited: a systematic review performed by the early-osteoarthritis group of ESSKA-European knee associates section.
Implantation of mesenchymal stem cells (MSCs) is a potential cell-based modality for cartilage repair. Currently, its clinical use largely surrounds focal cartilage defect repair and intra-articular injections in knee osteoarthritis. The MSCs' implantation efficacy as a treatment option for osteoarthritis remains contentious. This systematic review aims to evaluate studies that focused on MSCs implantation in patients with knee OA to provide a summary of this treatment option outcomes. A systematic search was performed in PubMed (Medline), Scopus, Cinahl, and the Cochrane Library. Original studies investigating outcomes of MSCs implantations in patients with knee OA were included. Data on clinical outcomes using subjective scores, radiological outcomes, and second-look arthroscopy gradings were extracted. Nine studies were included in this review. In all included studies, clinical outcome scores revealed significantly improved functionality and better postoperative pain scores at 2-3 years follow-up. Improved cartilage volume and quality at the lesion site was observed in five studies that included a postoperative magnetic resonance imaging assessment and studies that performed second-look arthroscopy. No major complications or tumorigenesis occurred. Outcomes were consistent in both single MSCs implantation and concurrent HTO with MSCs implantation in cases with excessive varus deformity. According to the available literature, MSCs implantation in patients with mild to moderate knee osteoarthritis is safe and provides short-term clinical improvement and satisfactory cartilage restoration, either as a standalone procedure or combined with HTO in cases with axial deformity. However, the evidence is limited due to the high heterogeneity among studies and the insufficient number of studies including a control group and mid-term outcomes. IV.


Extreme contagion in global habitat clearance.
Habitat clearance remains the major cause of biodiversity loss, with consequences for ecosystem services and for people. In response to this, many global conservation schemes direct funds to regions with high rates of recent habitat destruction, though some also emphasize the conservation of remaining large tracts of intact habitat. If the pattern of habitat clearance is highly contagious, the latter approach will help prevent destructive processes gaining a foothold in areas of contiguous intact habitat. Here, we test the strength of spatial contagion in the pattern of habitat clearance. Using a global dataset of land-cover change at 50 x 50 km resolution, we discover that intact habitat areas in grid cells are refractory to clearance only when all neighbouring cells are also intact. The likelihood of loss increases dramatically as soon as habitat is cleared in just one neighbouring cell, and remains high thereafter. This effect is consistent for forests and grassland, across biogeographic realms and over centuries, constituting a coherent global pattern. Our results show that landscapes become vulnerable to wholesale clearance as soon as threatening processes begin to penetrate, so actions to prevent any incursions into large, intact blocks of natural habitat are key to their long-term persistence.


Fuzheng Qingjie granules potentiate the anticancer effect of cyclophosphamide by regulating cellular immune function and inducing apoptosis in Hepatoma 22 tumor-bearing mice.
Fuzheng Qingjie (FZQJ) is a polyherbal Chinese medicine that has previously been implemented as an adjuvant therapy for gastrointestinal cancer. The present study investigated whether FZQJ is able to potentiate the anticancer effect of cyclophosphamide (CTX). Hepatoma 22 tumor-bearing mice were randomly divided into a vehicle group, CTX group, FZQJ group and combination (CTX+FZQJ) group. In addition, untreated mice without H22 cells served as blank controls. Seven days post-treatment, the mice were sacrificed and the tumors were weighed. Blood cells were evaluated using an automatic hemocytometer analyzer and flow cytometer. The expression levels of interleukin (IL)-2 and tumor necrosis factor (TNF)-α were evaluated using a radioimmunoassay. Apoptotic cells were observed using a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Alanine transaminase, aspartate aminotransferase, blood urea nitrogen and creatinine were examined using an automatic biochemical analyzer. The results demonstrated that the tumor inhibitory rate and apoptosis index were higher in the combination group, compared with those in the CTX group. Notably, FZQJ was able to alleviate CTX-induced decreases in the numbers of white blood cells and platelets, CD3+ and CD4+ T lymphocyte subsets, and the concentration of hemoglobin, body weight and thymus index, and increase serum TNF-α and IL-2 levels without overt hepatorenal toxicity. These results suggest that FZQJ granules may enhance the anticancer effect of CTX, in addition to alleviating the side effects.


NEAL: an open-source tool for audio annotation.
Passive acoustic monitoring is used widely in ecology, biodiversity, and conservation studies. Data sets collected via acoustic monitoring are often extremely large and built to be processed automatically using artificial intelligence and machine learning models, which aim to replicate the work of domain experts. These models, being supervised learning algorithms, need to be trained on high quality annotations produced by experts. Since the experts are often resource-limited, a cost-effective process for annotating audio is needed to get maximal use out of the data. We present an open-source interactive audio data annotation tool, NEAL (Nature+Energy Audio Labeller). Built using R and the associated Shiny framework, the tool provides a reactive environment where users can quickly annotate audio files and adjust settings that automatically change the corresponding elements of the user interface. The app has been designed with the goal of having both expert birders and citizen scientists contribute to acoustic annotation projects. The popularity and flexibility of R programming in bioacoustics means that the Shiny app can be modified for other bird labelling data sets, or even to generic audio labelling tasks. We demonstrate the app by labelling data collected from wind farm sites across Ireland.


Development of mouse ova in explanted oviducts: fertilization, cultivation, and transplantation.
The development of fertilized ova in explanted parts of oviducts was studied from 12 to 36 hours after fertilization, and from 36 to 84 hours after fertilization. No egg mortality during cultivation, nor any slowing of development could be detected in either experiment. It may be presumed that the mortality of mouse ova during the period before implantation has no essential effect on the resulting fertility. During cultivation of oviducts for 144 hours, there occurred in most blastocysts herniation of their walls resulting in a formation similar to the blastocyst, and a migration of a disorganized mass of cells, some of which resembled the giant trophoblastic cells. After transplantation of ova fertilized in vitro to recipients, in four cases there occurred nidation and subsequent normal development of the embryo.


Os trigonum syndrome.
Os trigonum syndrome is the result of an overuse injury of the posterior ankle caused by repetitive plantar flexion stress. It is predominantly seen in ballet dancers and soccer players and is primarily a clinical diagnosis of exacerbated posterior ankle pain while dancing on pointe or demi-pointe or while doing push-off maneuvers. Symptoms may improve with rest or activity modification. Imaging studies, including a lateral radiographic view of the ankle in maximal plantar flexion, will typically reveal the os trigonum between the posterior tibial lip and calcaneus. If an os trigonum is absent on radiography, an MRI may reveal scar tissue behind the posterior talus, a condition associated with similar symptoms. Os trigonum syndrome is often associated with pathology of the flexor hallucis longus tendon. Treatment begins with nonsurgical measures. In addition to physical therapy, symptomatic athletes may need surgical excision of os trigonum secondary to unavoidable plantar flexion associated with their sport. This surgery can be performed using open or arthroscopic approaches.


Generation of higher pressure pulses at the surface of piezo-composite materials using electrical pre-strain.
New clinical concepts in lithotripsy demand smaller shock heads. Reducing the size of piezoelectric shock heads requires increasing the surface pressure of each transducer so that the total pressure at the focus remains the same. A new method allowing generation of large surface pressures is described. The hypothesis is that piezoelectric plots in piezo-composite material are more fragile in extension than in compression. For this reason, actuators are mechanically prestressed between two flasks. This method cannot be used for transducers working at high frequencies, such as 0.5 MHz. So we tried to electrically prestrain compressively the piezoelectric material by applying a high-electrical field in the opposite direction of polarization. Three protocols were tested and compared to classically driven transducers. In the first protocol, prestrain is permanently applied, in the second protocol prestrain is applied for 100 micros before the compressive impulse, and in the third protocol prestrain is applied for 100 micros and followed by a bipolar field that allows the material to be repoled between two successive pulses. With the two first protocols, rapid depoling and repoling in the opposite direction was noticed. Only with the last protocol was it possible to increase the maximum surface pressure. This increase was approximately the same whether the material was hard or soft. Using this protocol, aging tests were conducted on three samples of each kind of material, and a pressure of 4 MPa was obtained over 10(6) shocks. This value seems to be enough to develop a piezoelectric shock-wave generator with a diameter of approximately 20 cm instead of the 45-cm commercially available.


Reconstitution of recombinant cytochrome P450 2C10(2C9) and comparison with cytochrome P450 3A4 and other forms: effects of cytochrome P450-P450 and cytochrome P450-b5 interactions.
Tolbutamide methyl hydroxylation and S-warfarin 7-hydroxylation activities were reconstituted in systems containing recombinant human cytochrome P450 (P450 or CYP) 2C10(2C9) and the optimal conditions for the systems were compared with those of bufuralol 1'-hydroxylation by CYP1A1, theophylline 8-hydroxylation by CYP1A2, bufuralol 1'-hydroxylation by CYP2D6, chlorzoxazone 6-hydroxylation by CYP2E1, and testosterone 6 beta-hydroxylation by CYP3A4. CYP2C10 required cytochrome b5 (b5) for optimal rates of tolbutamide and S-warfarin oxidations and b5 could be replaced by apo-b5; apo-b5 and b5 effects on the reconstituted systems have already been reported in systems containing CYP3A4 for the oxidation of testosterone and nifedipine and for the rapid reduction of CYP3A4 by NADPH-P450 reductase (H. Yamazaki et al., 1996, J. Biol. Chem. 271, 27438-27444). Stopped-flow studies, however, suggested that apo-b5 as well as b5 did not cause stimulation of the reduction of CYP2C10 by NADPH-P450 reductase, while the reduction rates were dependent on the substrates in reconstituted systems. Chlorzoxazone 6-hydroxylation by CYP2E1 was stimulated by b5, but not by apo-b5, in reconstituted systems. Neither apo- nor holo-b5 increased bufuralol 1'-hydroxylation activity by CYP1A1 or 2D6 or theophylline 8-hydroxylation by CYP1A2. Interestingly, we found that testosterone 6 beta-hydroxylation by CYP3A4 was stimulated by CYP1A2 (and also by a modified form in which the first 36 residues of the native human protein were removed) and CYP1A1 as well as by b5, and such stimulations were not seen when other P450 proteins (e.g., CYP2C10, 2D6, or 2E1) were added to the reconstituted systems. In contrast, substrate oxidations by CYP2C10 and CYP2E1 were not stimulated by other P450 proteins. The present results suggest that there are differences in optimal conditions for reconstitution of substrate oxidations by various forms of human P450 enzymes, and in some P450-catalyzed reactions protein-protein interactions between P450 and b5 and other P450 proteins are very important in some oxidations catalyzed by CYP2C10, 2E1, and 3A4.


Fluoridated milk for preventing dental caries.
Dental caries remains a major public health problem in most industrialised countries, affecting 60% to 90% of school children and the vast majority of adults. Milk provides a relatively cost-effective vehicle for fluoride in the prevention of dental caries. To determine the effectiveness of fluoridated milk, as a means of delivering fluoride on a community basis, for preventing dental caries. We searched Cochrane Oral Health Group Trials Register (28 April 2005), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2005), MEDLINE (1966 to 17 May 2005), OLDMEDLINE (1950 to 1965), EMBASE (1980 to 2005 week 20), LILACS (1982 to 17 May 2005), BBO (1986 to 17 May 2005), SIGLE (1980 to 17 May2005), Digital Dissertations (1861 to 17 May 2005) and reference lists of relevant articles. Attempts were made to identify both unpublished and ongoing studies. There were no language restrictions. Randomised or quasi-randomised controlled trials (RCTs), with an intervention or follow-up period of at least 3 years, comparing fluoridated milk with non-fluoridated milk. Primary outcome was change in caries experience, as measured by changes in decayed, missing and filled figures on tooth (dmft/DMFT) and surface (dmfs/DMFS). Inclusion decisions, data extraction and quality assessment were carried out independently and in duplicate. Study authors were contacted for additional information where necessary. Two RCTs involving 353 children were included. For permanent teeth, after 3 years there was a significant reduction in the DMFT (78.4%, P < 0.05) between the test and control groups in one trial, but not in the other. The latter study only showed a significant reduction in the DMFT until the fourth (35.5%, P < 0.02) and fifth (31.2%,P < 0.05) years. For primary teeth, again there was a significant reduction in the dmft (31.3%, P< 0.05) between the test and control groups after 3 years in one study, but not in the other. The results could not be pooled because of the difference in concentration of fluoride in the milk. There are insufficient studies with good quality evidence examining the effects of fluoridated milk in preventing dental caries. However, the included studies suggested that fluoridated milk was beneficial to school children, especially their permanent dentition. The data need to be supplemented by further RCTs to provide the highest level of evidence for practice.


Musculocutaneous flap or muscle flap and skin graft?
Six factors must be considered in choosing between muscle only and musculocutaneous flaps for reconstruction of defects: size, bulk, donor deformity, durability, pliability, and sensibility. The choice depends on the location and characteristics of the specific defect. Advantages and disadvantages of each flap in different circumstances are discussed, with emphasis on restoring form and function to the defect while preserving them at the donor site.


The influence of pre-injury behaviour on children's type of accident, type of injury and severity of injury.
To investigate the relationship between children's pre-injury behaviour and accident type (high vs. low risk), injury type (traumatic brain injury (TBI), fractures/dislocations and other injuries) and TBI severity. Cross-sectional comparison of 205 children with TBI aged 6-14 years, with 101 children aged 7-14 years with non-TBI injuries. Pre-injury behavioural data were collected via parental report with the Child Behaviour Checklist. Information on children's accident type and TBI severity was obtained from medical records. The pre-injury behaviour of children involved in high or low risk accidents did not differ. Pre-injury behavioural differences were observed among children with TBI, fractures/dislocations, other injuries and normative samples. The involvement of children in high and low risk accidents differed depending on the severity of TBI. Pre-injury behaviour of children with mild or moderate/severe TBI was similar. Pre-injury behaviour does not appear to influence children's involvement in high vs. low risk accidents or the severity of their TBI. However pre-injury behaviour increases children's differential risk for types of accidental injuries.


[Abdominal ectopic pregnancy].
This review summarises the knowledge of abdominal ectopic pregnancy (AEP), which is a rare condition with higher morbidity and mortalilty than other types of ectopic pregnancies. The condition can be primary, if the pregnancy implants directly on to an abdominal site, or it can be secondary after a tubar abortion. AEP differs from tubal pregnancies by a normal level of human chorionic gonadotropin and rare vaginal bleeding, which causes a diagnostic delay. In an early pregnancy the treatment is laparoscopic removal, but in second and third trimester pregnancies laparotomy is preferred, if possible preceded by MRI for mapping of vascular involvement and location of placenta.


Brachial-ankle pulse wave velocity as a marker of atherosclerotic vascular damage and cardiovascular risk.
The measurement of brachial-ankle pulse wave velocity (baPWV) is simple and applicable for general population studies. The present study was conducted to evaluate the applicability of baPWV for screening cardiovascular risk as well as for use as a marker of the severity of atherosclerotic vascular damage in a general population. baPWV was measured in a cross-sectional study involving two cohorts constituting a total of 10,828 subjects who underwent annual health screening check up examinations (6,716 males and 4,112 females; age 30 to 74 years). The Framingham risk score and Pocock's score were obtained. Multivariate analysis demonstrated that baPWV was associated with both scores, independently from conventional atherosclerotic risk factors. The receiver-operator characteristic curve demonstrated that a baPWV of 14.0 m/s is useful for risk stratification by Framingham score and to discriminate patients with either stroke or coronary heart disease (n=143), but the likelihood ratios were less than 5.0. Logistic regression analysis demonstrated that a baPWV>14.0 m/s is an independent variable for the risk stratification by Framingham score and for the discrimination of patients with atherosclerotic cardiovascular disease. Thus, baPWV has potential as a new marker of cardiovascular risk and may be more useful than other conventional markers; in addition, baPWV is easy to obtain and serves as an indicator of either atherosclerotic cardiovascular risk or severity of atherosclerotic vascular damage; thus it is useful to screen the general population. While the discriminating powers are not sufficiently high, a cutoff value of 14.0 m/s serves to screen subjects, especially in middle-aged ones, of either gender.


Clinical Features and Risk Factors for Gastrointestinal Complications in Dogs Treated Surgically for Thoracolumbar Intervertebral Disc Extrusion.
Gastrointestinal (GI) complications and their clinical implications are poorly characterized in dogs treated surgically for acute thoracolumbar intervertebral disc extrusion (TL-IVDE). The objective of this retrospective study was to characterize GI signs (including vomiting, diarrhea, melena, and hematochezia) in dogs undergoing hemilaminectomy for acute TL-IVDE. One-hundred and sixteen dogs were included. Frequency, type and severity of GI signs during hospitalization, duration of hospitalization and outcome were obtained from the medical record. Potential risk factors for the development of GI signs were explored using univariable and multivariable analyses. Gastrointestinal signs occurred in 55/116 dogs (47%); 22/55 dogs (40%) had one episode and 21/55 (38%) had ≥5 episodes. Diarrhea was the most common (40/55, 73%) while melena was rare (1/55, 2%). GI signs developed in 8/11 dogs (73%) treated perioperatively with both non-steroidal anti-inflammatories and corticosteroids with or without a washout period and in 25/52 dogs (48%) treated prophylactically with proton pump inhibitors. Median hospitalization was 7 days (4-15 days) vs. 5 days (4-11 days) in dogs with or without GI signs, respectively. Duration of hospitalization was associated with development of any GI signs, diarrhea and more severe GI signs (p = 0.001, 0.005, 0.021, respectively). Pre-operative paraplegia with absent pain perception was identified on univariable analysis (p = 0.005) and longer anesthetic duration on multivariable analysis to be associated with development of more severe GI signs (p = 0.047). In dogs undergoing surgery for acute TL-IVDE, GI signs were common and associated with duration of hospitalization and anesthesia. The influence of specific medications and neurologic severity on development of GI signs requires further investigation.


"C"-type viral particles in plasma of cats with feline leukemia.
Linear sucrose-density gradient was used to detect and isolate typical "C"-type viral particles in plasma of cats with spontaneous and experimentally induced leukemia. The density of the agent is similar to known murine leukemia virus (1.15 to 1.17 grams per cubic centimeter). In the electron microscope the virus showed typical "C"-type particle morphology with various maturation stages. The maximum diameter of the mature viral particles in plasma was 115 millimicrons, a diameter slightly larger than budding particles observed in tissue. Leukemia was transmitted with cellular and cell-free inoculum after a 5-week period of latency.


A comparative study of the blockade of calcium-dependent action potentials by verapamil, nifedipine and nimodipine in ventricular muscle.
The electrophysiological and chemical properties of the Ca++-channel blocking drugs verapamil, nifedipine and nimodipine were compared. In avian ventricular muscle depolarized by 25 mM K+-saline, the primary Na+ conductance was inactivated and the peak of action potential varied by 30 mV/10-fold change in extracellular Ca++. A double reciprocal plot of the maximum rate of rise vs. [Ca++]0(-1) yielded a straight line, a result consistent with the surface density hypothesis for the electrogenic permeation of cell membranes by Ca++. Verapamil, nifedipine and nimodipine caused the peak of action potential to deviate significantly from its Ca++-electrode property. Verapamil, but not nifedipine or nimodipine, blocked the Ca++-dependent action potential in a frequency-dependent manner. However, the dihydrophyridines (nifedipine and nimodipine) and verapamil were similar insofar as they inhibited the maximum rate of rise of the Ca++-dependent action potential competitively at concentrations less than or equal to 10(-6) M. These results are consistent with the hypothesis that low concentrations of these drugs inhibit the Ca++-dependent action potential by reducing the secondary inward current which is carried largely by Ca++. At higher concentrations, blockade of the maximum rate of rise by all of the Ca++-channel blocking drugs could not be described as competitive, noncompetitive or uncompetitive. The inability to describe the equilibrium actions of high concentrations of verapamil, nifedipine and nimodipine in such terms may arise from drug effects on membrane currents in addition to secondary inward current.


A strain-specific segment of the RNA-dependent RNA polymerase of grapevine fanleaf virus determines symptoms in Nicotiana species.
Factors involved in symptom expression of viruses from the genus Nepovirus in the family Secoviridae such as grapevine fanleaf virus (GFLV) are poorly characterized. To identify symptom determinants encoded by GFLV, infectious cDNA clones of RNA1 and RNA2 of strain GHu were developed and used alongside existing infectious cDNA clones of strain F13 in a reverse genetics approach. In vitro transcripts of homologous combinations of RNA1 and RNA2 induced systemic infection in Nicotiana benthamiana and Nicotiana clevelandii with identical phenotypes to WT virus strains, i.e. vein clearing and chlorotic spots on N. benthamiana and N. clevelandii for GHu, respectively, and lack of symptoms on both hosts for F13. The use of assorted transcripts mapped symptom determinants on RNA1 of GFLV strain GHu, in particular within the distal 408 nt of the RNA-dependent RNA polymerase (1E(Pol)), as shown by RNA1 transcripts for which coding regions or fragments derived thereof were swapped. Semi-quantitative analyses indicated no significant differences in virus titre between symptomatic and asymptomatic plants infected with various recombinants. Also, unlike the nepovirus tomato ringspot virus, no apparent proteolytic cleavage of GFLV protein 1E(Pol) was detected upon virus infection or transient expression in N. benthamiana. In addition, GFLV protein 1E(Pol) failed to suppress silencing of EGFP in transgenic N. benthamiana expressing EGFP or to enhance GFP expression in patch assays in WT N. benthamiana. Together, our results suggest the existence of strain-specific functional domains, including a symptom determinant module, on the RNA-dependent RNA polymerase of GFLV.


Genome-wide identification, phylogenetic analysis, and expression profiling of polyamine synthesis gene family members in tomato.
Polyamines (PAs), including putrescine (Put), spermidine (Spd), spermine (Spm), and thermospermine (T-Spm), play key roles in plant development, including fruit setting and ripening, morphogenesis, and abiotic/biotic stress. Their functions appear to be intimately related to their synthesis, which occurs via arginine/ornithine decarboxylase (ADC/ODC), Spd synthase (SPDS), Spm synthase (SPMS), and Acaulis5 (ACL5), respectively. Unfortunately, the expression and function of these PA synthesis-relate genes during specific developmental process or under stress have not been fully elucidated. Here, we present the results of a genome-wide analysis of the PA synthesis genes (ADC, ODC, SPDS, SPMS, ACL5) in the tomato (Solanum lycopersicum). In total, 14 PA synthesis-related genes were identified. Further analysis of their structures, conserved domains, phylogenetic trees, predicted subcellular localization, and promoter cis-regulatory elements were analyzed. Furthermore, we also performed experiments to evaluate their tissue expression patterns and under hormone and various stress treatments. To our knowledge, this is the first study to elucidate the mechanisms underlying PA function in this variety of tomato. Taken together, these data provide valuable information for future functional characterization of specific genes in the PA synthesis pathway in this and other plant species. Although additional research is required, the insight gained by this and similar studies can be used to improve our understanding of PA metabolism ultimately leading to more effective and consistent plant cultivation.


Monophenolase and catecholase activity of Aspergillus oryzae catechol oxidase: insights from hybrid QM/MM calculations.
Catechol oxidase from Aspergillus oryzae (AoCO4) can not only catalyze oxidation of o-diphenols to o-quinones, but can also catalyze monooxygenation of small phenolics. To gain insight into the catecholase and monophenolase activities of AoCO4, the reaction mechanism of catechol oxidation was investigated by means of hybrid quantum mechanical/molecular mechanical (QM/MM) calculations. The oxy-form of AoCO4 was found to be a μ-η2:η2 side-on peroxo dicopper(ii) complex, which can undergo a proton coupled electron transfer from the substrate rather than a proton transfer from the nearby Ser302 residue to generate a hydroperoxide. The μ-1,1-OOH Cu2(i,ii) complex is thermodynamically more stable than the μ-η1:η2 hydroperoxide. Moreover, the cleavage of the O-O bond in the μ-1,1-OOH Cu2(i,ii) intermediate has a much lower barrier than that in the μ-η1:η2 hydroperoxide species. In both cases, the O-O bond cleavage is the rate-limiting step, generating the reactive (μ-O˙)(μ-OH) dicopper(ii) complex. In addition, our results demonstrated that the oxidation of catechol to quinone is much more preferred than the hydroxylation reaction. These findings may provide useful information for understanding the reactivity of the Cu2O2 active site of coupled binuclear copper enzymes.


S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability in multiple myeloma.
Multiple Myeloma (MM) is the second most prevalent hematological malignancy and is incurable due to the inevitable development of drug resistance. The methionine adenosyltransferase 2α (MAT2A) is the primary producer of the methyl donor S-adenosylmethionine (SAM) and several studies reported MAT2A deregulation in different solid cancers. As the role of MAT2A in MM is not studied yet, the aim of this study was to clarify the potential role and underlying molecular mechanisms of MAT2A in MM, exploring new therapeutic options to overcome drug resistance. By analyzing publicly available gene expression profiling data, MAT2A was found to be highly expressed in patient-derived myeloma cells compared to normal bone marrow plasma cells (BMPC), correlating with an unfavorable prognosis in relapsed patients. MAT2A inhibition in MM cells led to a reduction in intracellular SAM levels, which resulted in impaired cell viability and proliferation and induction of apoptosis. Further mechanistic investigation demonstrated that MAT2A inhibition inactivated the mTOR-4EBP1 pathway, accompanied with a decrease in protein synthesis. MAT2A targeting in vivo with the small molecule compound FIDAS-5 was able to significantly reduce tumor burden in the 5TGM1 model. Finally, we found that MAT2A inhibition can synergistically enhance the anti-MM effect of the standard-of-care agent bortezomib both on MM cell lines and primary human CD138+ _MM cells. In summary, we demonstrate that MAT2A inhibition reduces MM cell proliferation and survival by inhibiting mTOR-mediated protein synthesis. Moreover, our findings suggest that the MAT2A inhibitor FIDAS-5 could be a novel compound to improve bortezomib-based treatment of MM.


Lung cancer risk associated with selenium status is modified in smoking individuals by Sep15 polymorphism.
Selenium (Se) is a trace element suggested to act chemopreventive in lung cancer. The mechanism by which Se suppresses tumour development may be associated with some of the functions of selenoproteins, including 15 kDa selenoprotein (Sep15). This protein exhibits antioxidant properties and thus may be involved in the process of carcinogenesis. Recently, it has been shown that the genetic polymorphism of Sep15, resulting in different response of the protein to Se, is associated with the risk of breast and head and neck cancers. The aim of the study was to investigate the possible association between lung cancer risk and Sep15 polymorphism in combination with Se status in the Polish population. The study concerned 325 cases and 287 controls. All the participants were smokers. Plasma Se concentration was determined using graphite furnace atomic absorption spectrometry, and Sep15 polymorphism (1125 G/A transition within 3'-untranslated region) was detected with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The adjusted odds ratios (ORs) for lung cancer cases, compared to individuals with Sep15 wild type variant (GG), were: 0.91 (95% CI: 0.64-1.32) for the heterozygous variant (GA) and 0.80 (95% CI: 0.39-1.65) for the homozygous variant (AA). Although plasma Se concentration was statistically lower in lung cancer cases (49.4 +/- 17.4 ng/ml) compared to controls (53.3 +/- 14.0 ng/ml, p < 0.002), the analysis of the joint effect of Sep15 polymorphism and Se status for lung cancer development revealed that lung cancer risk differed between the Se15 genotype groups. An increasing Se concentration was associated with a decreased risk in all individuals; however, at Se concentration above 80 ng/ml, the risk started to increase in individuals possessing the Sep15 1125 GG or GA genotype. It appears that among smoking individuals, those with the Sep15 1125 AA genotype may benefit most from a higher Se intake, whereas in those with the GG or GA genotype, a higher Se status may increase the risk for lung cancer.


Improved treatment of a brain-tumor model. Part 2: Sequential therapy with BCNU and 5-fluorouracil.
A combination chemotherapy regimen for brain tumors was developed, based on investigations of the survival of animals harboring the intracerebral 9L rat brain-tumor model and on analyses of their clonogenic tumor cells. Fischer 344 rats harboring 9L brain tumors were treated with 2-day courses of 5-fluorouracil (5-FU), in order to expose all cycling tumor cells to the drug during DNA synthesis and achieve maximum anti-tumor activity for this cell-cycle-specific anti-metabolite. Although a 74% cell kill was obtained for a total dose of 45 mg/kg or greater, animal life span was not increased over that of untreated tumor-bearing controls. However, when 5-FU (48 to 96 mg/kg total dose over 2 days) was administered after a single LD10 dose of BCNU (13.3 mg/kg), additive cell kill was suggested. In three large series, long-term animal survivors and occasional tumor cures were observed with this drug combination, a result never observed following BCNU alone. Schedule dependency was not apparent. A previously published protocol for treating recurrent malignant gliomas with sequential courses of BCNU and 5-FU was partially planned based upon these initial observations. Anti-tumor activity with the combination of drugs was superior to therapy with BCNU alone. Both animal and human studies confirm that, contrary to presently accepted oncological tenets, a chemotherapeutic agent that kills significant numbers of tumor cells but is clinically ineffective when given alone might, nevertheless, be useful in combination therapy regimens.


Amyloid β accelerates age-related proteome-wide protein insolubility.
Loss of proteostasis is a highly conserved feature of aging across model organisms and typically results in the accumulation of insoluble protein aggregates. Protein insolubility is a central feature of major age-related neurodegenerative diseases, including Alzheimer's Disease (AD), where hundreds of insoluble proteins associate with aggregated amyloid beta (Aβ) in senile plaques. Moreover, proteins that become insoluble during aging in model organisms are capable of accelerating Aβ aggregation in vitro. Despite the connection between aging and AD risk, therapeutic approaches to date have overlooked aging-driven protein insolubility as a contributory factor. Here, using an unbiased proteomics approach, we questioned the relationship between Aβ and age-related protein insolubility. We demonstrate that Aβ expression drives proteome-wide protein insolubility in C. elegans and this insoluble proteome closely resembles the insoluble proteome driven by normal aging, suggesting the possibility of a vicious feedforward cycle of aggregation in the context of AD. Importantly, using human genome-wide association studies (GWAS), we show that the CIP is replete with biological processes implicated not only in neurodegenerative diseases but also across a broad array of chronic, age-related diseases (CARDs). This provides suggestive evidence that age-related loss of proteostasis could play a role in general CARD risk. Finally, we show that the CIP is enriched with proteins that modulate the toxic effects of Aβ and that the gut-derived metabolite, Urolithin A, relieves Aβ toxicity, supporting its use in clinical trials for dementia and other age-related diseases.


Endoscopic Endonasal Transinfraturbinate Approach With Nasoseptal Window for Removal of the Pterygopalatine Fossa Tumor.
Recent advances in endoscopic intranasal technology have allowed for a safe approach to the pterygopalatine fossa lesion. However, we consider that there is still scope of improvement to approach a broader area with better operability and minimal invasiveness. A 51-year-old man underwent endoscopic endonasal surgery due to the recurrence of chordoma at the left pterygopalatine fossa. To access the lower and lateral part of the pterygopalatine fossa, we performed endoscopic endonasal transmaxillary removal via an inferior turbinate incision. During surgery, a wide operative field and good operability could be secured by inserting an endoscope from the right nostril through a window of the nasal septum. Subtotal removal of the tumor was achieved without any complication during the surgery. Endoscopic endonasal transinfraturbinate approach with nasoseptal window was effective in the removal of the pterygopalatine fossa tumor because it is less invasive and provides a good surgical view with better operability.


Evaluation of parental awareness regarding their child's oral hygiene.
To determine parental awareness about their child's oral hygiene and its associated factors. In this cross-sectional study, 396 parents and their 3- to 6-year-old children were selected by randomized cluster sampling from Shiraz kindergartens in 2013. Parents completed a questionnaire on their perception of their child's oral hygiene. The children received a dental examination, and their dental cleaning status was determined using Simplified Debris Index. Parental awareness was determined by comparing parents' perception of their child's oral hygiene with the results of the dental examination. Associations between demographic factors and parental awareness were evaluated. Sixty per cent of the parents were aware of their child's teeth cleaning status. Higher percentage of parents with university degree (P < 0.001) and parents whose child did not have a previous dental visit (P < 0.001) were aware. Also, more aware mothers were employed compared with homemakers (P = 0.002). Children of aware parents had lower dmft (P < 0.001) and better oral hygiene (P = 0.001) than those of unaware parents. Parents who perceived overall oral health status of their child as good (P < 0.001) as well as those who believed that their child did not have any cavities (P < 0.001) were more likely to be aware of their child's teeth cleaning than those who perceived otherwise. Many parents were not aware of their child's oral hygiene. Educational interventions should be provided to young families to increase parental knowledge and skills that help them recognize their child's dental needs. The interventions are more necessary for low socioeconomic parents and for the parents of children with poor oral hygiene.


Single Image based Super Resolution Ultrasound Imaging Using Residual Learning of Wavelet Features.
The generation of super resolution ultrasound images from the low-resolution (LR) brightness mode (B-mode) images acquired by the portable point of care ultrasound systems has been of sufficient interest in the recent past. With the advancements in deep learning, there have been numerous attempts in this direction. However, all the approaches have been concentrated on employing the direct image as the input to the neural network. In this work, a stationary wavelet (SWT) decomposition is employed to extract the features from the input LR image which is passed through a modified residual network and the learned features are combined using the inverse SWT to reconstruct the high resolution (HR) image at a 4× scale factor. The proposed approach when compared to the state-of-the art approaches, results in an improved high resolution reconstruction.Clinical relevance- The proposed approach will enable the generation of high-resolution images from portable ultrasound systems, allowing for easier interpretation and faster diagnostics in primary care settings.


One kilometer (1 km) electric solar wind sail tether produced automatically.
We produced a 1 km continuous piece of multifilament electric solar wind sail tether of μm-diameter aluminum wires using a custom made automatic tether factory. The tether comprising 90,704 bonds between 25 and 50 μm diameter wires is reeled onto a metal reel. The total mass of 1 km tether is 10 g. We reached a production rate of 70 m/24 h and a quality level of 1‰ loose bonds and 2‰ rebonded ones. We thus demonstrated that production of long electric solar wind sail tethers is possible and practical.


Empirical Mode Decomposition Based Measures for Investigating the Progression of Pregnancy from Uterine EMG.
The objective of this study is to analyze the uterine electromyography (uEMG) signals to study the progression of pregnancy under term condition (gestational age > 36 weeks) using EMD-based time-frequency features. uEMG signals are obtained from the multiple public datasets during two conditions, namely T1 (acquired < 26 gestational weeks) and T2 (acquired ≥ 26 gestational weeks). The considered signals are preprocessed. Empirical mode decomposition is applied to decompose the signals and time-frequency features, such as median frequency (MDF), mean frequency (MNF), peak frequency and peak magnitude, are extracted from each intrinsic mode functions and statistically analyzed. The results depict that the obtained time-frequency features are able to distinguish between T1 and T2 conditions. The extracted features, namely MNF and MDF, are observed to decrease from T1 to T2 conditions. These features are found to have higher effect size, confirming the better differentiation between T1 and T2 conditions. It appears that EMD-based time-frequency features can aid in studying the evolving changes in uterine contractions towards labor.


The health, economic and social burden of smoking in Argentina, and the impact of increasing tobacco taxes in a context of illicit trade.
Tobacco tax increases, the most cost-effective measure in reducing consumption, remain underutilized in low and middle-income countries. This study estimates the health and economic burden of smoking in Argentina and forecasts the benefits of tobacco tax hikes, accounting for the potential effects of illicit trade. Using a probabilistic Markov microsimulation model, this study quantifies smoking-related deaths, health events, and societal costs. The model also estimates the health and economic benefits of different increases in the price of cigarettes through taxes. Annually, smoking causes 45,000 deaths and 221,000 health events in Argentina, costing USD 2782 million in direct medical expenses, USD 1470 million in labor productivity loss costs, and USD 1069 million in informal care costs-totaling 1.2% of the national gross domestic product. Even in a scenario that considers illicit trade of tobacco products, a 50% cigarette price increase through taxes could yield USD 8292 million in total economic benefits accumulated over a decade. Consequently, raising tobacco taxes could significantly reduce the health and economic burdens of smoking in Argentina while increasing fiscal revenue.


Role of IL-17A signalling in psoriasis and associated bone loss.
Inflammation is a physiological reaction to tissue injury, pathogen invasion and a natural response to various stress stimuli. Innate and adaptive immune cells are activated and recruited to the site of inflammation to suppress or promote inflammation. The recruitment and activation of immune cells is modulated by cytokines and chemokines, which are regulated by transcription factors, such as AP-1 (Fos/Jun), NF-kB, NFATs and STATs. Moreover, it is now appreciated that chronic inflammation can lead to systemic effects affecting the whole organism by mechanisms which are not well understood.Here we review our recent data obtained from the analyses of psoriasis patient samples as well as from AP-1 (Fos/Jun)-dependent, genetically engineered mouse models. The deletion of two AP-1 factors JunB and c-Jun in an inducible manner in adult mice, specifically in Keratin-5 expressing tissues, leads to a psoriasis-like disease. Importantly, the epidermal proteome of the mutant mice is comparable to psoriasis patient samples. Our analyses revealed that the activation of S100A8/A9-dependent C3 complement as well as a miR-21-dependent TIMP-3/TACE pathway leading to TNF-α shedding, are causally involved in disease development.Epidermal deletion of only JunB in mice leads to chronic skin inflammation with increased levels of pro-inflammatory cytokines and multi-organ involvement. Our recent findings show that chronic skin inflammation induces bone loss through systemic elevated IL-17A signalling. This novel mechanism involves inhibition of osteoblast-mediated bone formation by reduced Wnt signalling with no effect on RANKL-dependent osteoclastic bone resorption. These data have important translational implications; blocking of IL-17A signalling, which is already approved for the treatment of psoriasis, should also be considered to prevent the adverse skeletal consequences of chronic inflammatory diseases.


Screening of Trypanosoma brucei gambiense in domestic livestock and tsetse flies from an insular endemic focus (Luba, Equatorial Guinea).
Sleeping sickness is spread over 36 Sub-Saharan African countries. In West and Central Africa, the disease is caused by Trypanosoma brucei gambiense, which produces a chronic clinical manifestation. The Luba focus (Bioko Island, Equatorial Guinea) has not reported autochthonous sleeping sickness cases since 1995, but given the complexity of the epidemiological cycle, the elimination of the parasite in the environment is difficult to categorically ensure. The aim of this work is to assess, by a molecular approach (Polymerase Chain Reaction, PCR), the possible permanence of T. b. gambiense in the vector (Glossina spp.) and domestic fauna in order to improve our understanding of the epidemiological situation of the disease in an isolated focus considered to be under control. The results obtained show the absence of the parasite in peridomestic livestock but its presence, although at very low rate, in the vector. On the other hand, interesting entomological data highlight that an elevated concentration of tsetse flies was observed in two out of the ten villages considered to be in the focus. These findings demonstrate that even in conditions of apparent control, a complete parasite clearance is difficult to achieve. Further investigations must be focused on animal reservoirs which could allow the parasites to persist without leading to human cases. In Luba, where domestic livestock are scarcer than other foci in mainland Equatorial Guinea, the epidemiological significance of wild fauna should be assessed to establish their role in the maintenance of the infection.


Quality assessment metrics for whole genome gene expression profiling of paraffin embedded samples.
Formalin fixed, paraffin embedded tissues are most commonly used for routine pathology analysis and for long term tissue preservation in the clinical setting. Many institutions have large archives of Formalin fixed, paraffin embedded tissues that provide a unique opportunity for understanding genomic signatures of disease. However, genome-wide expression profiling of Formalin fixed, paraffin embedded samples have been challenging due to RNA degradation. Because of the significant heterogeneity in tissue quality, normalization and analysis of these data presents particular challenges. The distribution of intensity values from archival tissues are inherently noisy and skewed due to differential sample degradation raising two primary concerns; whether a highly skewed array will unduly influence initial normalization of the data and whether outlier arrays can be reliably identified. Two simple extensions of common regression diagnostic measures are introduced that measure the stress an array undergoes during normalization and how much a given array deviates from the remaining arrays post-normalization. These metrics are applied to a study involving 1618 formalin-fixed, paraffin-embedded HER2-positive breast cancer samples from the N9831 adjuvant trial processed with Illumina's cDNA-mediated Annealing Selection extension and Ligation assay. Proper assessment of array quality within a research study is crucial for controlling unwanted variability in the data. The metrics proposed in this paper have direct biological interpretations and can be used to identify arrays that should either be removed from analysis all together or down-weighted to reduce their influence in downstream analyses.


Kubas-type hydrogen storage in V(III) polymers using tri- and tetradentate bridging ligands.
Oxalic acid, oxamide, glycolic acid, and glycolamide were employed as 2-carbon linkers to synthesize a series of one-dimensional V(III) polymers from trismesityl vanadium(III)·THF containing a high concentration of low-valent metal sites that can be exploited for Kubas binding in hydrogen storage. Synthesized materials were characterized by powder X-ray diffraction (PXRD), nitrogen adsorption (BET), X-ray photoelectron spectroscopy (XPS), infrared spectroscopy (IR), Raman spectroscopy, thermogravimetric analysis, and elemental analysis. Because each of these organic linkers possesses a different number of protons and coordinating atoms, the products in each case were expected to have different stoichiometries with respect to the number of mesityl groups eliminated and also a different geometry about the V(III) centers. For example, the oxalate and glycolate polymers contained residual mesityl groups; however, these could be exchanged with hydride via hydrogenolysis. The highest adsorption capacity was recorded on the product of trismesityl vanadium(III)·THF with oxamide (3.49 wt % at 77 K and 85 bar). As suggested by the high enthalpy of adsorption (17.9 kJ/mol H(2)), a substantial degree of performance of the vanadium metal centers was retained at room temperature (25%), corresponding to a gravimetric adsorption of 0.87 wt % at 85 bar, close to the performance of MOF-177 at this temperature and pressure. This is remarkable given the BET surface area of this material is only 9 m(2)/g. A calculation on the basis of thermogravimetric results provides 0.88 hydrogen molecule per vanadium center under these conditions. Raman studies with H(2) and D(2) showed the first unequivocal evidence for Kubas binding on a framework metal in an extended solid, and IR studies demonstrated H(D) exchange of the vanadium hydride with coordinated D(2). These spectroscopic observations are sufficient to assign the rising trends in isosteric heats of hydrogen adsorption observed previously by our group in several classes of materials containing low-valent transition metals to the Kubas interaction.