The status of maternal and newborn health care services in Zanzibar.
It is estimated that 287,000 women worldwide die annually from pregnancy and childbirth-related conditions, and 6.9 million under-five children die each year, of which about 3 million are newborns. Most of these deaths occur in sub-Saharan Africa. The maternal health situation in Tanzania mainland and Zanzibar is similar to other sub-Saharan countries. This study assessed the availability, accessibility and quality of emergency obstetric care services and essential resources available for maternal and child health services in Zanzibar. From October and November 2012, a cross-sectional health facility survey was conducted in 79 health facilities in Zanzibar. The health facility tools developed by the Averting Maternal Death and Disability program were adapted for local use. Only 7.6 % of the health facilities qualified as functioning basic EmONC (Emergency Obstetric and Neonatal Care) facilities and 9 % were comprehensive EmONC facilities. Twenty-eight percent were partially performing basic EmONC and the remaining 55.7 % were not providing EmONC. Neonatal resuscitation was performed in 80 % of the hospitals and only 17.4 % of the other health facilities that were surveyed. Based on World Health Organisation (WHO) criteria, the study revealed a gap of 20 % for minimum provision of EmONC facilities per 500,000 population. The met need at national level (proportion of women with major direct obstetric complications treated in a health facility providing EmONC) was only 33.1 % in the 12 months preceding the survey. The study found that there was limited availability of human resources in all visited health facilities, particularly for the higher cadres, as per Zanzibar minimum staff requirements. There is a need to strengthen human resource capacity at primary health facilities through training of health care providers to improve EmONC services, as well as provision of necessary equipment and supplies to reduce workload at the higher referral health facilities and increase geographic access.


Limited DNase I nicking as a probe of gene conformation.
We have extended the use of pancreatic DNase I as a probe of chromatin structure by exploring the accessibility of an active gene to the introduction of the first single-stranded nick. We show by a target analysis that the beta-globin gene is about 25-fold more sensitive to single-site nicking than is an average sequence in the chicken erythrocyte nucleus or the nontranscribed albumin gene. The sites of initial DNase I nicking are shown to cluster within the transcribed sequence of the beta-globin gene.


A sequence-based method to predict the impact of regulatory variants using random forest.
Most disease-associated variants identified by genome-wide association studies (GWAS) exist in noncoding regions. In spite of the common agreement that such variants may disrupt biological functions of their hosting regulatory elements, it remains a great challenge to characterize the risk of a genetic variant within the implicated genome sequence. Therefore, it is essential to develop an effective computational model that is not only capable of predicting the potential risk of a genetic variant but also valid in interpreting how the function of the genome is affected with the occurrence of the variant. We developed a method named kmerForest that used a random forest classifier with k-mer counts to predict accessible chromatin regions purely based on DNA sequences. We demonstrated that our method outperforms existing methods in distinguishing known accessible chromatin regions from random genomic sequences. Furthermore, the performance of our method can further be improved with the incorporation of sequence conservation features. Based on this model, we assessed importance of the k-mer features by a series of permutation experiments, and we characterized the risk of a single nucleotide polymorphism (SNP) on the function of the genome using the difference between the importance of the k-mer features affected by the occurrence of the SNP. We conducted a series of experiments and showed that our model can well discriminate between pathogenic and normal SNPs. Particularly, our model correctly prioritized SNPs that are proved to be enriched for the binding sites of FOXA1 in breast cancer cell lines from previous studies. We presented a novel method to interpret functional genetic variants purely base on DNA sequences. The proposed k-mer based score offers an effective means of measuring the impact of SNPs on the function of the genome, and thus shedding light on the identification of genetic risk factors underlying complex traits and diseases.


May-Thurner syndrome: an often overlooked cause for refractory venous leg ulcers.
We report a 53-year-old female patient presenting with a refractory venous leg ulcer and unremarkable findings in the doppler Ultrasound venous mapping of the leg veins. Further comprehensive diagnostics demonstrated an underlying May-Thurner syndrome. After resolution of the primary mechanical obstruction, rapid wound healing in the following 3 weeks was documented. Iliac vein compression syndrome, commonly known as May-Thurner syndrome, is a distinguishable anatomical variant that results from an external compression over the left iliac vein exerted by the overriding adjacent right common iliac artery. It is mostly seen among young, healthy female patients and can easily be under-diagnosed. Lower extremities duplex ultrasonography remains the gold standard in diagnosing venous insufficiency, but it should not solely depend on it. Instead, clinicians should consider other possibilities, assessing the patency within the truncal veins, which in turn might contribute to the venous insufficiency along the lower limbs. An active early diagnostic approach can prevent significant overall morbidity and help patients to ease back into their daily-life activities. Therefore, it is recommended that all patients with suspected venous insufficiency and normal lower limbs duplex findings should undergo further evaluation of the truncal venous system pattern. May-Thurner syndrome, along with other causes of iliac veins compression, should be considered in the differential diagnosis in unclear persistent cases of unilateral venous symptoms.


An inpatient study of the effects of buprenorphine on cigarette smoking in men concurrently dependent on cocaine and opioids.
The effect of sublingual buprenorphine on cigarette smoking was examined in 23 adult men with DSM III-R diagnosis of concurrent opiate and cocaine dependence. After admission to a clinical research ward, subjects were detoxified with methadone (10-50 mg/day), then were drug-free for 6 days before random assignment to either 4 or 8 mg/day of buprenorphine. Gradually increasing daily sublingual doses of buprenorphine were administered for 5 days, then subjects were maintained on 4 or 8 mg/day of buprenorphine for 12 days. Each subject's preferred brand of cigarettes was available ad libitum throughout the study. Five responses (FR 5) on a key were required to earn each cigarette. The time and number of cigarettes were recorded by an automated cigarette dispenser. Subjects acquired significantly more cigarettes during the buprenorphine induction and maintenance phases (25.5+/-2.0) than during the drug-free phase (18.5+/-1.8; p<0.0002). During buprenorphine induction, the number of cigarettes acquired was positively correlated with increasing doses of buprenorphine (p<0.001) and the inter-cigarette interval was significantly shorter during buprenorphine maintenance than during drug-free conditions (p<0.001). These data showed that daily administration of the partial mu opioid agonist buprenorphine was associated with increased smoking in men concurrently dependent on opiates and cocaine. These findings are consistent with previous reports of opioid-cigarette interactions.


Husk Tomato (Physalis ixocarpa Brot.) Waste as a Promising Source of Pectin: Extraction and Physicochemical Characterization.
Husk tomato (Physalis ixocarpa Brot. var. Rendidora) waste was evaluated as a source of specialized pectin, and pectin extracted from this waste was characterized physicochemically. Fruit was blanched for 10 or 15 min and extracted in 0.1 N HCl for 15 to 25 min. Extracted pectin was subjected to physicochemical analysis. For all extraction conditions, the percentage of anhydrogalacturonic acid exceeded 60%, indicating that husk tomato was a good source of pectin. The degree of esterification of pectin molecules was 63% to 91%. The amount of extracted pectin decreased with increasing extraction time. The apparent viscosity of husk tomato pectin showed the characteristic behavior of pseudoplastic fluids. Neutral sugars were identified, and the amounts of 6 sugars (fucose, rhamnose, arabinose, galactose, glucose, and xylose) were quantified. Sugars identified in husk tomato pectin and present in the Rhamnogalacturonan I region, arabinose, galactose, and rhamnose suggest a highly branched structure, which will influence its future applications. Molecular weight values were 542 to 699 kDa, exceeding molecular weight values reported for commercial citrus pectins from 134 to 480 kDa. The extraction process significantly (P < 0.05) influenced the physicochemical properties of pectin. Up to 19.8% from the total amount of pectin in the husk tomato was extracted by 10 min of blanching and 20 min of a more heat treatment. Our findings indicate that husk tomato can be a good alternative source of pectin having highly distinctive physicochemical characteristics.


Novel Random Triblock Copolymers for Sustained Delivery of Macromolecules for the Treatment of Ocular Diseases.
The objective of this study is to design, develop, and synthesize novel random triblock (RTB) copolymers for sustained delivery of macromolecules. RTB copolymers have not been utilized for the delivery of macromolecules for ocular diseases. RTB copolymers comprising of polyethylene glycol, glycolide, and ɛ-caprolactone blocks were synthesized and assessed for their molecular weights and purity using 1H-NMR spectroscopy, gel permeation chromatography, FTIR (functionality), and XRD (crystallinity). No toxicity was observed when ocular cell lines were treated with RTB copolymers. These materials were applied for encapsulation of peptides and proteins (catalase, IgG, BSA, IgG Fab fragment, lysozyme, insulin, and octreotide) in nanoparticles. Particle size ranged from 202.41 ± 2.45 to 300.1 ± 3.11 nm depending on the molecular size and geometry of proteins/peptides. Polydispersity indices were between 0.26 ± 0.02 and 0.46 ± 0.07 respectively. Percentage entrapment efficiency and drug loading ranged from 83.44 ± 2.24 to 45.35 ± 5.53 and 21.56 ± 0.46 to 13.08 ± 1.35 respectively depending on molecular weights of peptides or proteins. A sustained in vitro release of macromolecule was observed over 3-month period. These results suggest that RTB copolymers may be suitable for sustained delivery systems for various macromolecules for different diseases including ocular diseases.


[Phenothiazine derivatives, chlorpromazine and triflupromazine, produce different effects on sympathetic nerve activity in urethane-anesthetized rabbits].
This study was designed to evaluate effects of chlorpromazine (CPZ) or triflupromazine (TPZ) on renal sympathetic nerve activity and hemodynamics in urethane-anesthetized rabbits. Thirty-five rabbits were divided into the following two groups: CPZ group (N = 10) and TPZ group (N = 25), challenged by an intravenous injection of either CPZ (0.4 mg.kg-1) or TPZ (0.2 mg.kg-1), respectively. Each experimental group was further divided into the following groups. CPZ group was divided into CPZ-INTACT group of animals with neuraxis intact (N = 6) and CPZ-SAD group of animals with combined denervation of the carotid sinus and aortic nerves (N = 4). TPZ group was divided into TPZ-INTACT group of rabbits with neuraxis intact (N = 8), TPZ-VAGOTOMY group of only cervical vagotomy (N = 6), TPZ-SADV group with combined denervation of the carotid sinus and aortic nerves with cervical vagotomy (N = 5) and TPZ-VI group with right cervical vagotomy but having the intact left vagus (N = 6). In the last group, right afferent vagal nerve activity was measured simultaneously. Mean blood pressure, central venous pressure, heart rate and renal sympathetic nerve activity were measured at the same time. In the CPZ-INTACT group, the agent caused a decrease in mean blood pressure and significant increases in sympathetic nerve activity and heart rate, but no significant change in central venous pressure. This increase in sympathetic nerve activity and heart rate disappeared in the SAD animals in spite of hypotension. Animals of the TPZ-INTACT group showed an abrupt decrease in sympathetic nerve activity in response to hypotension, but did not exhibit a remarkable change in heart rate and central venous pressure. However, in contrast, animals with severed cervical vagi showed a sympathetic augmentation after the TPZ injection. These sympathetic changes were abolished in the SADV animals. In the TPZ-VI group, TPZ elicited a decline in sympathetic nerve activity similar to that observed in INTACT animals, but afferent vagal nerve activity increaed simultaneously with sympathetic depression. These results indicate that a reflex increase in sympathetic nerve activity which occurred during hypotension after CPZ injection may have been mediated by the arterial baroreceptor reflex and that a sympathetic reduction after TPZ administration may have resulted from a reciprocal interaction between an excitation through the sino-aortic nerves and an inhibition via the vagal nerves.


More equal societies have less mental illness: what should therapists do on Monday morning?
Therapists seeing poor clients may ask if countries with greater income equality have less mental illness. If so, how should therapists respond? A review of epidemiological studies, theories of inequality and democratic reform movements in psychiatry and psychology leads to four arguments. (1) Increasing income equality improves the health of societies. (2) An elite opposes greater equality, partly by persuading the majority to consent to the existing order. (3) Therapists may inadvertently help in this persuasive effort. (4) However, therapists in democratic traditions create systems of care that support movements for greater income equality.


Biliary immunoreactive trypsin in man.
Small, but significant amounts of immunoreactive trypsin/trypsinogen (IRT) are excreted in bile, obtained via percutaneous transhepatic catheter in patients with complete distal bile duct obstruction, and thus uncontaminated with pancreatic juice. The major serum proteolytic enzyme inhibitors alpha 2-macroglobulin and alpha 1-antitrypsin are also present in very small amounts in bile. The bile-to-serum ratios of these inhibitors are much lower (approximately two orders of magnitude) than that for IRT. The role of these inhibitors and their relative importance in biliary proteolytic enzyme inhibition is unknown.


Myeloid leukemias express a broad spectrum of VEGF receptors including neuropilin-1 (NRP-1) and NRP-2.
Vascular endothelial growth factor (VEGF) is produced in neoplastic cells in various myeloid neoplasms and may act as an autocrine growth-regulator. We have examined the expression of five VEGF receptors (VEGR1/Flt-1, VEGFR2/KDR, Flt-4, neuropilin-1 = NRP-1, NRP-2) in leukemic cells obtained from patients with acute myeloid leukemia (n = 28), chronic myeloid leukemia (n = 14), chronic eosinophilic leukemia (n = 3), chronic myelomonocytic leukemia (n = 9), or mast cell leukemia/systemic mastocytosis (n = 3) as well as in respective cell lines. Expression of VEGFR mRNA was analyzed by RT-PCR, and expression of VEGFR protein by immunocytochemistry. In most patients, leukemic cells expressed NRP-1 mRNA and NRP-2 mRNA independent of the type of disease. By contrast, transcripts for Flt-1, KDR, and Flt-4 were expressed variably without a clear correlation to the type of leukemia. Expression of VEGF receptors was also demonstrable at the protein level in all cases tested. In conclusion, neoplastic cells in myeloid leukemias frequently express VEGFR including NRP-1 and NRP-2.


Integrative Western and Traditional Chinese Medicine service model for low back pain.
Low back pain (LBP) is a common, costly, and debilitating condition that creates a heavy socioeconomic burden on the global health care systems. In Western Medicine (WM), the treatment goals are to relieve pain, reduce disability, and enhance rehabilitation. In Traditional Chinese Medicine (TCM), acupuncture is frequently used to rebalance the vital energy "Qi". Whilst numerous literatures are available from WM and TCM in the management of LBP, the value of an integrative WMTCM therapy remains unknown. This article aims to introduce an integrative WM-TCM service model for LBP, which is now available at the Hong Kong Institute of Integrative Medicine, the Chinese University of Hong Kong.


[Potentials and limits of conventional differential diagnosis of the endometrium].
The reproducible identification of various histological types of the endometrium is of special interest for many reasons. The controversy in endometrial classification and terminology led us to study the algorithm of conventional endometrial diagnosing. This study is to examine the significance of historical morphologic parameters for differential diagnosis by semiquantitative or binary recording and computer-assisted evaluation. The results are based on cross-tables and cluster-analysis. The statistical test showed that most of the historical parameters were neither adequate for reclassification nor exclusion of historical typing of the endometrium. An objective and reproducible classification of endometrial changes by using binary parameters can only be achieved for specific histological types of normal endometrium and several types of hyperplastic endometrium. The dedifferentiated carcinoma is a diagnosis "per exclusionem ", since nearly all of the binary parameters cannot be analysed. The individual borderline lesions cannot be differentiated from each other by descriptive parameters. They cannot even be distinguished from the highly differentiated endometrial carcinomas. This kind of differential diagnosis is obviously not based on conventional formalistic criteria but on nonquantifiable empirical data. This might be a reason for the above mentioned controversy in endometrial diagnosis and terminology.


Nintedanib plus Docetaxel after Immune Checkpoint Inhibitor Failure in Patients with Advanced Non-Small-Cell Lung Cancer: A Case Series.
Advances in the treatment of non-small-cell lung cancers (NSCLCs) lacking an actionable driver mutation have included the approval of immunotherapies, such as monotherapy or in combination with chemotherapy. However, limited evidence exists to guide clinical decision-making after progression with immunotherapy. The vascular endothelial growth factor (VEGF) signaling pathway promotes tumor angiogenesis and the development of an immunosuppressive tumor microenvironment (TME). Anti-VEGF treatment is postulated to favor an immunosupportive TME through an "angio-immunogenic switch." Nintedanib, an anti-VEGF receptor treatment, is approved in the EU and other countries, in combination with docetaxel for the treatment of locally advanced, metastatic, or locally recurrent adenocarcinoma NSCLC after failure of first-line chemotherapy. We present a case series from 5 patients treated with nintedanib plus docetaxel, after chemotherapy and immunotherapy, during routine clinical practice in Austria and Hungary. Four patients were treated with nintedanib plus docetaxel as a second- or third-line treatment after chemotherapy and immunotherapy, and a fifth patient received immunotherapy before and after nintedanib plus docetaxel. Although these patients would typically have a poor prognosis, each achieved a partial response with nintedanib plus docetaxel, with response duration from 8 months to over 30 months. Adverse events were manageable. The fifth patient case shows that nintedanib does not preclude later-line immunotherapy or chemotherapy, supporting the angio-immunogenic switch hypothesis. Overall, the case studies indicate that nintedanib plus docetaxel is an effective and well tolerated treatment, after sequential or combined chemo-immunotherapy for advanced NSCLC, and is compatible with a rechallenge with immunotherapy.


Impact of functional status and medical comorbidities on tracheostomy decannulation in pediatric patients.
To determine if medical or functional factors influence the ability of a pediatric patient with a tracheostomy to tolerate decannulation. Retrospective evaluation of patients at a tertiary Children's Hospital undergoing evaluation with capped tracheostomy polysomnogram (cPSG) for possible tracheostomy decannulation. Charts were reviewed for demographic information, functional status, cPSG characteristics, and success or failure of decannulation. Statistical analysis was performed to determine which patient factors were predictive of successful decannulation. A total of 139 sleep studies were analyzed in 104 unique children followed for at least 1 year after a cPSG was performed to determine readiness for decannulation. At 1 year after most recent PSG, 79.8% of children were decannulated. There was no significant association between any single comorbid condition and the ability to decannulate. There was no association between individual or total functional status score and successful decannulation. Patients with at least 3 comorbid conditions investigated and a total functional score less than 7 were less likely to be decannulated successfully than other patients (71% vs. 93%, p= 0.04). Functional status and comorbid conditions do not independently predict successful decannulation. Regular multi-disciplinary team reevaluation is indicated in patients with lower functional status, as removal of tracheostomy tube may be successfully accomplished.


The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR-ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents.
Chronic myeloid leukaemia is typically characterised by the presence of dysregulated BCR-ABL tyrosine kinase activity, which is central to the oncogenic feature of being resistant to a wide range of cytotoxic agents. We have investigated whether the inhibition of this tyrosine kinase by the novel compound STI571 (formerly CGP57148B) would render K562, KU812 cell lines and chronic myeloid leukaemia-progenitor cells sensitive to induction of cell kill. Proliferation assays showed STI571 to be an effective cytotoxic agent in chronic myeloid leukaemia-derived cell lines (IC(50) on day 5 of 4.6 microg ml(-1) and 3.4 microg ml(-1) for K562 and KU812 respectively) and in leukaemic blast cells (per cent viability on day 3 at 4 microg ml(-1): 55.5+/-8.7 vs 96.4+/-3.7%). STI571 also appeared to specifically target bcr-abl expressing cells, as results from colony forming assays using the surviving cell fraction from STI571-treated peripheral CD34(+) chronic myeloid leukaemia blast cells, indicated a reduction in the expansion of colonies of myeloid lineage, but no effect on normal colony formation. Our data also showed synergy between STI571 and other anti-leukaemic agents; as an example, there were significant increases in per cent cell kill in cell lines cultured with both STI571 and etoposide compared to the two alone (per cent cell kill on day 3: 73.7+/-11.3 vs 44.5+/-8.7 and 17.8+/-7.0% in cultures with STI571 and etoposide alone respectively; P<0.001). This study confirms the central oncogenic role of BCR-ABL in the pathogenesis of chronic myeloid leukaemia, and highlights the role of targeting this tyrosine kinase as a useful tool in the clinical management of the disease.


Cortical and subcortical localization of response to pain in man using positron emission tomography.
A quantitative study of the regional cerebral responses to non-painful and painful thermal stimuli in six normal volunteers has been done by monitoring serial measurements of regional blood flow measured by positron emission tomography (PET). In comparison to a baseline of warm stimulation no statistically significant changes in blood flow were seen in relation to increasing non-painful heat. However, highly significant increases in blood flow were seen in response to painful heat in comparison to non-painful heat. These changes were in the contralateral cingulate cortex, thalamus and lenticular nucleus. These findings are discussed in relation to previous physiological observations of responses to nociceptive stimuli in man and primates.


Comparison of angle, shape, and position of articular processes in Dobermans and Great Danes with and without cervical spondylomyelopathy.
Cervical spondylomyelopathy (CSM), also known as wobbler syndrome, affects mainly large and giant-breed dogs, causing compression of the cervical spinal cord and/or nerve roots. Structural and dynamic components seem to play a role in the development of CSM; however, pathogenesis is not yet fully understood. Physiologic and pathologic movements of the cervical spine depend on the morphology and morphometry of articular processes, as well as on intervertebral discs and vertebral column ligaments. Moreover, the characteristics of the articular processes affect motion and stability of the vertebral column. The goal of this study was to investigate the angle, shape, and position of the articular surfaces within the articular processes and compare them between Doberman Pinschers and Great Danes with and without cervical spondylomyelopathy. Magnetic resonance images were obtained for 60 dogs: 15 clinically normal Dobermans (Dob-N), 15 CSM-affected Dobermans (Dob-CSM), 15 clinically normal Great Danes (GD-N), and 15 CSM-affected Great Danes (GD-CSM). Angle, shape, and position (lateral distance) of the articular surfaces from the articular processes were analyzed from C2-3 to C7-T1. Results indicate that the mean angle was different between Dob-CSM and GD-CSM at C4-5, C5-6, and C6-7, and between GD-N and GD-CSM at C6-7. There were differences between Dob-N and GD-N, and between Dob-CSM and GD-CSM for the lateral distance at most locations, except C2-3. Compared with Great Danes, Dobermans generally had a greater proportion of concave caudal surfaces at C4-5, C5-6, and C6-7. Concave articular surfaces have been associated with greater axial rotation. This may explain the high proportion of disc-associated CSM in Dobermans compared to Great Danes. The differences between breeds suggest they may have different motion patterns in the caudal cervical vertebral column. Considering that no differences in angle, shape, or position of the articular surfaces within the articular processes were found between normal and CSM-affected dogs, their relevance appears to have a secondary role in the pathogenesis of CSM.


Acanthopanax senticosus attenuates inflammation in lipopolysaccharide-induced acute lung injury by inhibiting the NF-κB pathway.
The dried roots of the plant Acanthopanax senticosus (AS) are used in traditional Oriental medicine and reportedly possess anti-inflammatory properties in vitro. However, whether AS has the same anti-inflammatory effect in vivo and the underlying mechanisms of this action remain unknown. In this study, we pretreated a mouse model of lipopolysaccharide-induced acute lung injury with AS and found that the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and neutrophils in bronchoalveolar lavage fluid were reduced and that inflammation in lung tissues was attenuated. To determine the mechanisms of these actions, we next assessed the effects of AS on the activation of the nuclear factor (NF)-kB pathway. We found that AS decreased the level of NF-kB and the DNA-binding activity of NF-kB. In summary, we found that AS attenuated the levels of TNF-α and IL-6 in the lung tissue of a mouse model of acute lung injury by inhibiting the NF-kB pathway.


Perturbation theory corrections to the two-particle reduced density matrix variational method.
In the variational 2-particle-reduced-density-matrix (2-RDM) method, the ground-state energy is minimized with respect to the 2-particle reduced density matrix, constrained by N-representability conditions. Consider the N-electron Hamiltonian H(lambda) as a function of the parameter lambda where we recover the Fock Hamiltonian at lambda=0 and we recover the fully correlated Hamiltonian at lambda=1. We explore using the accuracy of perturbation theory at small lambda to correct the 2-RDM variational energies at lambda=1 where the Hamiltonian represents correlated atoms and molecules. A key assumption in the correction is that the 2-RDM method will capture a fairly constant percentage of the correlation energy for lambda in (0,1] because the nonperturbative 2-RDM approach depends more significantly upon the nature rather than the strength of the two-body Hamiltonian interaction. For a variety of molecules we observe that this correction improves the 2-RDM energies in the equilibrium bonding region, while the 2-RDM energies at stretched or nearly dissociated geometries, already highly accurate, are not significantly changed. At equilibrium geometries the corrected 2-RDM energies are similar in accuracy to those from coupled-cluster singles and doubles (CCSD), but at nonequilibrium geometries the 2-RDM energies are often dramatically more accurate as shown in the bond stretching and dissociation data for water and nitrogen.


Precise dosage of an endogenous mutagen in the immune system.
Four decades ago, it was hypothesized that lymphocytes mutate the immunoglobulin loci at a rate much greater than the spontaneous rate. Over time this Ig somatic hypermutation became the prime example of in vivo, site-directed mutagenesis. But recent studies have demonstrated that this is not necessarily the case, and that hypermutation occurs not only at the Ig locus but also at various locations throughout the genome. Here, we propose that hypermutation can be genome-wide with minimal injury, if a sufficient mutation rate is coupled with strong clonal selection.


Role of the LuxR family transcriptional regulator Lpg2524 in the survival of Legionella pneumophila in water.
The water-borne Gram-negative bacterium Legionella pneumophila (Lp) is the causative agent of Legionnaires' disease. Lp is typically transmitted to humans from water systems, where it grows inside amoebae. Survival of Lp in water is central to its transmission to humans. A transcriptomic study previously identified many genes induced by Lp in water. One such gene, lpg2524, encodes a putative LuxR family transcriptional regulator. It was hypothesized that this gene could be involved in the survival of Lp in water. Deletion of lpg2524 does not affect the growth of Lp in rich medium, in the amoeba Acanthamoeba castellanii, or in human macrophage-like THP-1 cells, showing that Lpg2524 is not required for growth in vitro and in vivo. Nevertheless, deletion of lpg2524 results in a faster colony-forming unit (CFU) reduction in an artificial freshwater medium, Fraquil, indicating that Lpg2524 is important for Lp to survive in water. Overexpression of Lpg2524 also results in a survival defect, suggesting that a precise level of this transcriptional regulator is essential for its function. However, our result shows that Lpg2524 is dispensable for survival in water when Lp is at a high cell density (109 CFU/mL), suggesting that its regulon is regulated by another regulator activated at high cell density.


Modular tripodal receptors for the hydrosulfide (HS-) anion.
Hydrogen sulfide (H2S) is an endogenously-produced gasotransmitter and is predominantly speciated as HS- at physiological pH. Despite this importance, reversible binding of HS- to synthetic receptors remains rare and confined to highly-engineered receptor systems. Here we demonstrate the generality of reversible HS- binding in a family of tren-based receptors.


Future prospects of anticytokine therapy in chronic heart failure.
Several lines of evidence suggest that chronic heart failure is a state of chronic inflammation. Indeed, various pro-inflammatory markers, including the cytokines TNF-alpha, and interleukin 6 and 1, are activated in the course of the disease. In chronic heart failure, these substances are frequently induced even before the classical neurohormones angiotensin II and noradrenaline. Although the recently published anti-TNF-alpha trials with etanercept and infliximab have called the beneficial effects of targeting single cytokines into question, the overactive immune system remains a promising target for therapeutic interventions, which aim at slowing down disease progression. Broader approaches are required. These comprise targeting bacterial lipopolysaccharide (endotoxin) that enters the circulation through the oedematous gut wall, immune modulation therapy with patient-derived whole blood exposed to oxidative stress, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (the so-called statins) and a number of other substances including pentoxifylline and thalidomide.


Anti-Influenza Virus (H5N1) Activity Screening on the Phloroglucinols from Rhizomes of Dryopteris crassirhizoma.
For screening the active phloroglucinols on influenza virus (H5N1) from Dryopteris crassirhizoma NaKai, a database was established including twenty-three phloroglucinols that had been isolated from Dryopteris crassirhizoma. Their inhibitory effect on the neuraminidase (NA) of influenza virus H5N1 was screened by molecular docking. As a result, three candidates were selected. The rhizomes of D. crassirhizoma were subjected to isolation and purification processes to obtain the inhibitor candidates. Thirteen phloroglucinols were obtained, including three selected candidates and two new phloroglucinols. The five phloroglucinols were investigated for their inhibitory activity on NA in vitro. The results showed that dryocrassin ABBA and filixic acid ABA exhibited inhibitory effects on NA with IC50 as 18.59 ± 4.53 and 29.57 ± 2.48 μM, respectively, and the other three phloroglucinols showed moderate inhibitory activity. Moreover, the anti-influenza virus (H5N1) activity and cytotoxicity of dryocrassin ABBA and filixic acid ABA were tested on Madin-Darby canine kidney (MDCK) cells with the cell counting kit-8 (CCK8) method. The results confirmed that dryocrassin ABBA exhibited an inhibitory activity with low cytotoxicity (TC50 > 400 μM) against influenza virus (H5N1) which will have to be investigated in further detail. In conclusion, phloroglucinols from D. crassirhizoma were shown to have anti-influenza virus activity, and especially dryocrassin ABBA, one of the phloroglucinols, may have the potential to control influenza virus (H5N1) infection.


Healthy knees have a highly variable patellofemoral alignment: a systematic review.
There is still lack of knowledge regarding the variability of patellofemoral alignment in healthy, non-osteoarthritic knees, without patellofemoral instability. Therefore, a systematic review of the existing literature was performed to evaluate the variability of patellofemoral alignment. Patellofemoral alignment of the knee was defined by the following parameters: sulcus angle (SA), femoral trochlear depth (FTD), patellar tilt angle (PTA), lateral patellofemoral angle (LPFA), lateral femoral trochlear inclination (LFTI) and tibial tubercle-trochlear groove distance (TT-TG). The electronic databases MEDLINE and EMBASE were searched from database inception to search date (January 11, 2019) and screened for relevant studies. The PRISMA guidelines were followed. Articles reporting PF alignment measurements of healthy knees in patients between 15 years and 47 years were included. A total of 15 studies met the inclusion criteria. The studies reported mean values and standard deviations for the SA between 118.7° ± 7 and 168°; for the FTD between 3.4 mm ± 1.1 and 7.1 mm ± 1.8; for the PTA between 0.7° ± 4.99 and 17.05° ± 4.3; for the LPFA between 6.26° ± 4.1 and 11.1° ± 4.0; for the LFTI between 16.3° ± 2.8 and 22.1° ± 1.9; and for the TT-TG between 9.8 mm ± 4.6 and 17.3 mm ± 5.3. Patellofemoral alignment in the healthy knee is extremely variable. A more precise knowledge of the complex relationship between the patella and the trochlea may help to better diagnose PF disorders and eventually help in selecting the correct therapy. Furthermore, standardised imaging protocols and measurement techniques for patellofemoral parameters are needed. III.


Genetically encoded iron-associated proteins as MRI reporters for molecular and cellular imaging.
All cell imaging applications rely on some form of specific cell labeling to achieve visualization of cells contributing to disease or cell therapy. The purpose of this review article is to summarize the published data on genetically encoded iron-based imaging reporters. The article overviews regulation of iron homeostasis as well as genetically encoded iron-associated molecular probes and their applications for noninvasive magnetic resonance imaging (MRI) of transplanted cells. Longitudinal repetitive MRI of therapeutic cells is extremely important for providing key functional endpoints and insight into mechanisms of action. Future directions in molecular imaging and techniques for improving sensitivity, specificity and safety of in vivo reporter gene imaging are discussed. WIREs Nanomed Nanobiotechnol 2018, 10:e1482. doi: 10.1002/wnan.1482 This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.


Picosecond sulfur K-edge X-ray absorption spectroscopy with applications to excited state proton transfer.
Picosecond X-ray absorption (XA) spectroscopy at the S K-edge (∼2.4 keV) is demonstrated and used to monitor excited state dynamics in a small organosulfur molecule (2-Thiopyridone, 2TP) following optical excitation. Multiple studies have reported that the thione (2TP) is converted into the thiol (2-Mercaptopyridine, 2MP) following photoexcitation. However, the timescale and photochemical pathway of this reaction remain uncertain. In this work, time-resolved XA spectroscopy at the S K-edge is used to monitor the formation and decay of two transient species following 400 nm excitation of 2TP dissolved in acetonitrile. The first transient species forms within the instrument response time (70 ps) and decays within 6 ns. The second transient species forms on a timescale of ∼400 ps and decays on a 15 ns timescale. Time-dependent density functional theory is used to identify the first and second transient species as the lowest-lying triplet states of 2TP and 2MP, respectively. This study demonstrates transient S K-edge XA spectroscopy as a sensitive and viable probe of time-evolving charge dynamics near sulfur sites in small molecules with future applications towards studying complex biological and material systems.


Mechanism of Formation of the Nonstandard Product in the Prenyltransferase Reaction of the G115T Mutant of FtmPT1: A Case of Reaction Dynamics Calling the Shots?
FtmPT1 is a fungal indole prenyltransferase that affords Tryprostatin B from Brevianamide F and dimethylallyl pyrophosphate; however, when a single residue in the active site is mutated (Gly115Thr), a novel five-membered ring compound is obtained as the major product with Tryprostatin B as the minor product. Herein, we describe detailed studies of the catalysis of the Gly115Thr mutant of FtmPT1 with a focus on the observed regioselectivity of the reaction. We employ one- and two-dimensional potential of mean force simulations to explore the catalytic mechanism, along with molecular dynamics simulations exploring the reaction dynamics of the prenyl transfer reaction. Single-point electronic structure calculations were also used to explore the performance of the self-consistent charge density functional tight-binding method to model specific reaction steps. Importantly, we observe that the two reaction pathways have comparable activation parameters and propose that the origin of the novel product is predicated, at least in part, on the topology of the potential energy surface as revealed by reaction dynamics studies.


High spatial resolution, low-noise Brillouin dynamic gratings reflectometry based on digital pulse compression.
Digital pulse compression was used to enhance the performance of optical time-domain reflectometry, employing Brillouin dynamic gratings (BDGs) in polarization-maintaining fibers. The fundamental and unique issues in BDG field-reflection are addressed, and rules for proper selection of the coding and detection techniques are formulated. While coding in BDG applications generally requires coherent processing of the reflection, conditions are established for use of direct detection. A 256-bit Golay complementary unipolar probe code is used to demonstrate an eightfold signal-to-noise ratio enhancement in the measurement of the Brillouin gain spectrum (BGS), with a spatial resolution of 2 cm and a full-BGS acquisition rate of 133⅓ kHz, resulting in an equivalent reduction in the estimation error of small Brillouin frequency shifts.


Construction of 3D bioprinting of HAP/collagen scaffold in gelation bath for bone tissue engineering.
Reconstruction of bone defects remains a clinical challenge, and 3D bioprinting is a fabrication technology to treat it via tissue engineering. Collagen is currently the most popular cell scaffold for tissue engineering; however, a shortage of printability and low mechanical strength limited its application via 3D bioprinting. In the study, aiding with a gelatin support bath, a collagen-based scaffold was fabricated via 3D printing, where hydroxyapatite (HAP) and bone marrow mesenchymal stem cells (BMSCs) were added to mimic the composition of bone. The results showed that the blend of HAP and collagen showed suitable rheological performance for 3D extrusion printing and enhanced the composite scaffold's strength. The gelatin support bath could effectively support the HAP/collagen scaffold's dimension with designed patterns at room temperature. BMSCs in/on the scaffold kept living and proliferating, and there was a high alkaline phosphate expression. The printed collagen-based scaffold with biocompatibility, mechanical properties and bioactivity provides a new way for bone tissue engineering via 3D bioprinting.


The use of concentrated multiple reflection ATR spectroscopy in the analysis of nail polish as forensic evidence.
Multiple reflection ATR spectroscopy is a technique used in cases where additional sensitivity is required over that provided by single reflection. Normally, multiple reflection equipment requires significantly more sample in order to adequately cover a larger sampling area. These larger sample amounts may not be available in forensic investigations. In this work, the capabilities of a concentrated multiple reflection ATR (CMRATR) accessory, in which all reflections are confined to a very small area, are demonstrated. Liquid solution sample sizes of only 5 to 15 μl are required. The accessory is used with an evaporative technique which further enhances sensitivity by concentrating the solute in close contact onto the ATR sampling surface. The technique along with a multivariate statistical analysis is used to discriminate visually similar nail polish samples made by different manufacturers.


A quantitative analysis of knee joint kinematics during the sidestep cutting maneuver. Implications for non-contact anterior cruciate ligament injury.
This study accurately quantifies the knee joint kinematics associated with sidestep cutting maneuvers in vivo. These data were subsequently evaluated to determine the relationship between sidestep cutting and non-contact anterior cruciate ligament (ACL) injury. Sixteen male subjects, proficient in the sidestep cutting maneuver, had knee joint kinematic data recorded during the stance phase of straight line running and sidestep cutting. Cutting speeds (5.5 msec-1 to 7.0 msec-1) and angles (30 degrees to 55 degrees) were chosen to reflect the sporting context. All subjects underwent medical screening prior to testing to ensure data represented joint biomechanics of healthy, ACL intact individuals. The temporal three dimensional positions of externally mounted (skin) markers were submitted to a custom software package (JTMOTION), which described in clinically meaningful terms, movements for the three rotational degrees of freedom at the knee joint. While mean patterns of motion for the three clinical knee rotations compared favorably between running and cutting data, sidestepping induced significantly (p < 0.01) greater maximum knee joint rotations during stance. Knee joint rotational ranges were also found to be significantly (p < 0.01) larger during cutting when compared to running. Increases in knee joint kinematics during cutting however, were not of a great enough magnitude to alone elicit spontaneous non-contact ACL injury, falling well within "safe" ranges of knee motion. Significant increases in inter-trial variability for the three rotations were observed in some subjects for sidestepping compared to running. It was concluded that a lack of consistency in knee joint biomechanics between cutting maneuvers increased the risk of ACL injury with the performance of an abnormal and potentially hazardous sidestep being more likely. The risk of non-contact ACL injury during cutting maneuvers was suggested to increase further when an individual displayed these "atypical" joint biomechanics in conjunction with specific joint structures, levels of experience and conditioning, and ligament morphologies.


Reclassification of risk of malignancy with Percepta Genomic Sequencing Classifier following nondiagnostic bronchoscopy.
Bronchoscopic sampling of pulmonary lesions suspicious for lung cancer is frequently nondiagnostic. A genomic sequencing classifier utilizing bronchial brushings obtained at the time of the bronchoscopy has been shown to provide an accurate reclassification of the risk of malignancy (ROM) based on pre-procedure risk. Our objectives for this study were to determine the frequency with which the classifier up- or down-classifies risk in regular clinical practice and to model the potential clinical utility of that reclassification. This observational study retrospectively assessed data from four clinical sites that regularly use the genomic classifier in the bronchoscopic evaluation of indeterminate lesions. Demographics and pre-bronchoscopy ROM were recorded. The frequency of up- and down-classification was calculated. Modeling based on reclassification rates and the performance characteristics of the classifier was performed to demonstrate the potential clinical utility of the result. 86 patients who underwent classifier testing following a nondiagnostic bronchoscopy were included. 45% of patients with high ROM prior to bronchoscopy were reclassified very high-risk. 38% of patients with intermediate ROM were up-or down-classified. 56% of patients with low ROM were reclassified to very low-risk. Overall, 42% of patients had a change in classification. 35% of the study cohort could potentially have avoided additional unnecessary procedures with subsequent guideline-adherent management. The classifier can guide decision-making following a nondiagnostic bronchoscopy, reclassifying risk in a significant percentage of cases. Use of the classifier should allow more patients with early-stage cancer to proceed directly to curative therapy while helping more patients with benign disease avoid further unnecessary procedures.


Indigenously produced biochar retains fertility in sandy soil through unique microbial diversity sustenance: a step toward the circular economy.
Agricultural productivity in the arid hot desert climate of UAE is limited by the unavailability of water, high temperature, and salt stresses. Growing enough food under abiotic stresses and decreasing reliance on imports in an era of global warming are a challenge. Biochar with high water and nutrient retention capacity and acid neutralization activity is an attractive soil conditioner. This study investigates the microbial community in the arid soil of Dubai under shade house conditions irrigated with saline water and the shift in the microbial community, following 1 year of amendment with indigenously prepared biochar from date palm waste. Amplicon sequencing was used to elucidate changes in bacterial, archaeal, and fungal community structures in response to long-term biochar amendment. Samples were collected from quinoa fields receiving standard NPK doses and from fields receiving 20 and 30 tons ha-1 of biochar, in addition to NPK for 1 year. Water holding capacity, pH, electrical conductivity, calcium, magnesium, chloride, potassium, sodium, phosphorus, total carbon, organic matter, and total nitrogen in the soil from biochar-treated and untreated controls were determined. The results show that soil amendment with biochar helps retain archaeal and bacterial diversity. Analysis of differentially abundant bacterial and fungal genera indicates enrichment of plant growth-promoting microorganisms. Interestingly, many of the abundant genera are known to tolerate salt stress, and some observed genera were of marine origin. Biochar application improved the mineral status and organic matter content of the soil. Various physicochemical properties of soil receiving 30 tons ha-1 of biochar improved significantly over the control soil. This study strongly suggests that biochar helps retain soil fertility through the enrichment of plant growth-promoting microorganisms.


[Effects of lysyl oxidase down-regulation on invasion, migration and E-cadherin protein expression of hypoxic lung cancer cells].
To observe the effects of lysyl oxidase (LOX) down-regulation on invasion, migration and epithelial-mesenchymal transition phenotype molecule E-cadherin protein expression, induced by hypoxia in lung cancer NCI-H460 cells. Small interfering RNA against human LOX gene (LOX siRNA) was used to transfect lung cancer cells under normoxia (19%O2). After a 24 h incubation, the cells were plated for 24 h in hypoxic incubator (0.5%O2). Real-time polymerase chain reaction (PCR) was performed to detect the LOX mRNA expression. The protein levels of LOX and E-cadherin were determined by Western blot. And invasion and migration capacities were detected by transwell chamber. Compared with NCI-H460 cells under normoxia (set to 1), hypoxia increased to the levels of LOX mRNA and protein expression up to 26.04 ± 1.78 and 5.57 ± 1.27 respectively (both P < 0.05). Compared with control siRNA group (set to 1), LOX mRNA and protein expression after LOX siRNA transfection were 0.24 ± 0.03 and 0.29 ± 0.03 respectively, cellular invasive and migratory capacities were 0.57 ± 0.03 and 0.49 ± 0.02 respectively, the protein expression of E-cadherin was 2.17 ± 0.21 (all P < 0.05). LOX down-regulation reduces invasion and migration potentials of hypoxic human lung cancer cell and potentiates the protein expression of E-cadherin.


A System Review and Meta-Analysis of Canaloplasty Outcomes in Glaucoma Treatment in Comparison with Trabeculectomy.
Purpose. This system review studied the efficiency and safety of canaloplasty (CP) and compared the outcomes between CP and trabeculectomy (TE). Methods. Literatures were searched in PubMed and EMBASE. The meta-analysis was conducted on the postoperative outcomes in CP and then on the differences of outcomes between CP and TE. Results. In the meta-analysis, IOP decreased by 9.94 (95% CI 8.42 to 11.45) mmHg with an average AGM reduction of 2.11 (95% CI 1.80 to 2.42) one year after CP. The IOP reduction was significantly higher after TE than after CP, with an average difference of 3.61 (95% CI 1.69 to 5.53) mmHg at 12 months postoperationally. For complications, the incidence of hyphema was significantly higher in CP and the Descemet membrane detachment was just reported in CP, with an incidence of 3%. However, the incidence was significantly lower in CP of hypotony and of choroidal effusion/detachment. Meanwhile, suprachoroidal hemorrhage and bleb needling were only reported in TE. Conclusions. CP was less effective in IOP reduction than TE, but CP was able to achieve similar postoperative success rates and reduce the number of AGMs likewise. CP was also associated with lower incidence of complications. More high-quality researches are needed in the future to verify our findings in this system review.


Crocin Suppresses Colorectal Cancer Cell Proliferation by Regulating miR-143/145 and KRAS/RREB1 Pathways.
As a chemoprevention agent, crocin effectively decreases the risk of human cancers, including colorectal cancer (CRC). However, the mechanism underlying the anti-cancer effects of crocin is not entirely explained. Considering that in this study, we investigated the crocin effect on miR-143/145 and related signaling pathways in CRC cells. HCT-116 and HT-29 CRC cells were treated with different concentrations of crocin and then were subjected to MTT and qRT-PCR assays to investigate cell viability and miR-143/miR-145, KRAS, and RREB1 expression, respectively. Also, western blotting was performed to evaluate gene expression at protein levels. Our results showed that treating CRC cells with crocin decreases cell viability by upregulating miR-143/145 expression and reducing KRAS and RREB1 expression dose-dependently. These effects on gene expression in CRC cells were reversed by removing crocin from the media after 48 h. Furthermore, western blotting results exhibited that crocin significantly reduced the protein expression of KRAS and RREB1. Also, it was found that treatment of CRC cells by crocin led to the inactivation of AKT by decreasing its phosphorylation. This study suggests that crocin may inhibit CRC cell proliferation by modulating KRAS, REEB1, and AKT signaling pathways mediated through miR-143/145 upregulation.


Comparative analysis of the conserved functions of Arabidopsis DRL1 and yeast KTI12.
Patterning of the polar axis during the early leaf developmental stage is established by cell-to-cell communication between the shoot apical meristem (SAM) and the leaf primordia. In a previous study, we showed that the DRL1 gene, which encodes a homolog of the Elongator-associated protein KTI12 of yeast, acts as a positive regulator of adaxial leaf patterning and shoot meristem activity. To determine the evolutionally conserved functions of DRL1, we performed a comparison of the deduced amino acid sequence of DRL1 and its yeast homolog, KTI12, and found that while overall homology was low, well-conserved domains were presented. DRL1 contained two conserved plant-specific domains. Expression of the DRL1 gene in a yeast KTI12-deficient yeast mutant suppressed the growth retardation phenotype, but did not rescue the caffeine sensitivity, indicating that the role of Arabidopsis Elongator-associated protein is partially conserved with yeast KTI12, but may have changed between yeast and plants in response to caffeine during the course of evolution. In addition, elevated expression of DRL1 gene triggered zymocin sensitivity, while overexpression of KTI12 maintained zymocin resistance, indicating that the function of Arabidopsis DRL1 may not overlap with yeast KTI12 with regards to toxin sensitivity. In this study, expression analysis showed that class-I KNOX genes were downregulated in the shoot apex, and that YAB and KAN were upregulated in leaves of the Arabidopsis drl1-101 mutant. Our results provide insight into the communication network between the SAM and leaf primordia required for the establishment of leaf polarity by mediating histone acetylation or through other mechanisms.


Target and Mechanism of the Xihuang Pill Based on Network Pharmacology for Lung Squamous Cell Carcinoma.
Lung squamous cell carcinoma (LUSC) accounts for 30% of non-small-cell lung cancers (NSCLC), and an effective pharmacological treatment for LUSC isn't yet available. The Xihuang Pill is a potent Chinese medicinal preparation widely prescribed for the management of LUSC. The study intended to use the network-pharmacology method to ascertain the effective active ingredients, targets of action, and cellular-signal transduction involved in the prevention and treatment of LUSC when using the Xihuang Pill and to identify the mechanism of action of the pills against LUSC, to provide a more adequate scientific basis for subsequent studies. The research team performed a genetic study. The study took place at Shanghai. The research team: (1) created the feature sets, for both the LUSC and normal features, using the Cancer Genome Atlas' (TCGA's) LUSC dataset; (2) performed a weighted correlation network analysis (WGCNA) of the differentially expressed genes (DEGs) using the R package WGCNA; (3) searched for the chemical components of the Xihuang Pill using the Traditional Chinese Medicine Systematic Pharmacology Database and Analysis Platform (TCMSP) and the Herb Group Identification Platform, and (4) selected the novel the Matthews correlation coefficient (MCC) algorithm to screen the hub genes. The study found 8713 DEGs between the LUSC and normal groups. The top ten, important, downregulated genes included: (1) advanced glycosylation end product (AGER), (2) chitinase, acidic pseudogene 2 (CHIAP2), (3) CD300 molecule like family member G (CD300LG), (4) solute carrier family 6 member 4 (SLC6A4), (5) carboxypeptidase B2 (CPB2), (6) claudin 18 (CLDN18), (7) gamma-glutamyltransferase light chain 1 (GGTLC1), (8) gastrokine 2 (GKN2), (9) progastricsin (PGC), and (10) pulmonary surfactant-associated protein C (SFTPC). The top 10 upregulated genes included: (1) cancer susceptibility 9 (CASC9), (2) homeobox C13 (HOXC13), (3) keratin 6a (KRT6A), (4) desmoglein 3 (DSG3), (5) keratin 16 (KRT16), (6) forkhead box E1 (FOXE1), (7) preferentially expressed antigen in melanoma (PRAME), (8) calmodulin-like protein 3 (CALML3), (9) KRT68, and (10) aldo-keto reductase family 1 member B10 (AKR1B10). The study found 41 active ingredients and 843 targets for the Xihuang Pill. The PPI network included 10 hub genes, including cyclin dependent kinase 1 (CDK1), cyclin B1 (CCNB1), cyclin B2 (CCNB2), polo-like kinase 1 (PLK1), aurora kinase B (AURKB), baculoviral IAP repeat containing 5 (BIRC5), cyclin A2 (CCNA2), aurora kinase A (AURKA), centrosome-associated protein E (CENPE), and threonine tyrosine kinase (TTK), which were the principal target genes at the core of the gene-pathway network for the drug compound to central-target relationship. The enrichment analyses used the overlapping genes and the 10 hub genes and found 390 biological processes (BPs), 25 molecular functions (MFs), 43 cellular components (CCs), and 10 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The main enrichment occurred in the regulation of protein serine-threonine kinase activity, mitotic nuclear division, progesterone-mediated oocyte maturation, and the cell cycle. The study found the targets and relevant pathways of the hub genes of Xihuang Pill using biological analysis and molecular docking and demonstrated the interactions of critical chemical compounds with the hub's targeted genes were. More research is necessary to further determine whether the Xihuang Pill can improve LUSC patients' survival rate by regulation of those genes.


Electrophysiology of subject-verb agreement mediated by speakers' gender.
An important property of speech is that it explicitly conveys features of a speaker's identity such as age or gender. This event-related potential (ERP) study examined the effects of social information provided by a speaker's gender, i.e., the conceptual representation of gender, on subject-verb agreement. Despite numerous studies on agreement, little is known about syntactic computations generated by speaker characteristics extracted from the acoustic signal. Slovak is well suited to investigate this issue because it is a morphologically rich language in which agreement involves features for number, case, and gender. Grammaticality of a sentence can be evaluated by checking a speaker's gender as conveyed by his/her voice. We examined how conceptual information about speaker gender, which is not syntactic but rather social and pragmatic in nature, is interpreted for the computation of agreement patterns. ERP responses to verbs disagreeing with the speaker's gender (e.g., a sentence including a masculine verbal inflection spoken by a female person 'the neighbors were upset because I (∗)stoleMASC plums') elicited a larger early posterior negativity compared to correct sentences. When the agreement was purely syntactic and did not depend on the speaker's gender, a disagreement between a formally marked subject and the verb inflection (e.g., the womanFEM (∗)stoleMASC plums) resulted in a larger P600 preceded by a larger anterior negativity compared to the control sentences. This result is in line with proposals according to which the recruitment of non-syntactic information such as the gender of the speaker results in N400-like effects, while formally marked syntactic features lead to structural integration as reflected in a LAN/P600 complex.


Patient-Specific Tailored Intervention Improves INR Time in Therapeutic Range and INR Variability in Heart Failure Patients.
Many patients with heart failure need anticoagulants, including warfarin. Good control is particularly challenging in heart failure patients, with <60% of international normalized ratio (INR) measurements in the therapeutic range, thereby increasing the risk of complications. This study aimed to evaluate the effect of a patient-specific tailored intervention on anticoagulation control in patients with heart failure. Patients with heart failure taking warfarin therapy (n = 145) were randomized to either standard care or a 1-time intervention assessing potential risk factors for lability of INR, in which they received patient-specific instructions. Time in therapeutic range (TTR) using Rosendaal's linear model was assessed 3 months before and after the intervention. The patient-tailored intervention significantly increased anticoagulation control. The median TTR levels before intervention were suboptimal in the interventional and control groups (53% vs 45%, P = .14). After intervention the median TTR increased significantly in the interventional group compared with the control group (80% [interquartile range, 62%-93%] vs 44% [29%-61%], P <.0001). The intervention resulted in a significant improvement in the interventional group before versus after intervention (53% vs 80%, P <.0001) but not in the control group (45% vs 44%, P = .95). The percentage of patients with a TTR ≥60%, considered therapeutic, was substantially higher in the interventional group: 79% versus 25% (P <.0001). The INR variability (standard deviation of each patient's INR measurements) decreased significantly in the interventional group, from 0.53 to 0.32 (P <.0001) after intervention but not in the control group. Patient-specific tailored intervention significantly improves anticoagulation therapy in patients with heart failure.


Environmental persistence assessment of heterocyclic polyaromatic hydrocarbons - Ultimate and primary biodegradability using adapted and non-adapted microbial communities.
Heterocyclic polyaromatic hydrocarbons (heterocyclic PAHs) are of increasing concern and their environmental and human health impacts should be assessed due to their widespread presence and potential persistence in the environment. This study investigated the ultimate and primary biodegradability of ten heterocyclic PAHs, nine of which were found to be non-readily biodegradable. To generate a microbial community capable of degrading such compounds, a bacterial inoculum isolated from the effluent of a wastewater treatment plant (WWTP) was adapted to a mixture of heterocyclic PAHs for one year. Throughout the adaptation process, bacterial samples were collected at different stages to conduct primary biodegradation, ultimate biodegradation, and inoculum toxicity tests. Interestingly, after one year of adaptation, the community developed the ability to mineralize carbazole, but in the same time showed an increasing sensitivity to the toxic effects of benzo[c]carbazole. In two consecutive primary biodegradation experiments, degradation of four heterocycles was observed, while no biodegradation was detected for five compounds in any of the tests. Furthermore, the findings of this work were compared with predictions from in silico models regarding biodegradation timeframe and sorption, and it was found that the models were partially successful in describing these processes. The results of study provide valuable insights into the persistence of a representative group of heterocyclic PAHs in aquatic environments, which contributes to the hazard assessment of this particular class of substances.


Addition of heteroaromatics to alkylidenecyclopropanes catalyzed by palladium.
The reaction of heteroaromatics, such as furans, thiophenes, thiazoles, and pyrroles, with alkylidenecyclopropanes proceeded smoothly in the presence of palladium catalysts, producing the corresponding alpha-allylated products in good to high yields. For example, the reaction of 3-butylpentylidenecyclopropane (1a) with 2-methylfuran (2a), ethyl 2-thiophenecarboxylate (4a), 2-isobutylthiazole (6a), and 1-methylpyrrole (11b) gave the alpha-allylated products in 70%, 66%, 77%, and 30% yield, respectively. The reaction proceeded predominantly through distal bond cleavage. The order of reactivity of heteroaromatics toward 1a is as follows: furan > thiophene approximately thiazole (5-position) > thiazole (2-position) approximately pyrrole. This methodology provides a means for introducing an allylic group to various kinds of heteroaromatics under mild conditions.


Managing Opioid Withdrawal for Hospital Patients in Custody.
Dr. Brown, a hospitalist, admits Mark, a patient transferred from a local jail for management of cellulitis. The patient, who was taken into custody two days prior to hospital admission, has a history of intravenous heroin use. Mark explains that he had been prescribed buprenorphine-naloxone maintenance therapy for opioid use disorder for several years prior to being arrested and had not used other opioids during that time. As a policy, the jail where Mark is detained does not prescribe opioid agonists, and his maintenance therapy was stopped upon his arrival there. Dr. Brown discovers that Mark is diaphoretic and appears distressed. Mark's symptoms suggest to Dr. Brown that, in addition to having cellulitis, Mark is actively withdrawing from opioids. Mark tells Dr. Brown that he has felt "horrible" since his buprenorphine-naloxone therapy was stopped and that he now has intense cravings for opioids. He asks Dr. Brown to help alleviate the withdrawal symptoms. Dr. Brown, who is accustomed to treating opioid withdrawal with opioid replacement therapy, wonders if she should initiate ORT for Mark while he is in the hospital.


Time-Frequency Analysis of Photopic Negative Response in CRVO Patients.
The PhNR is driven by retinal ganglion cells (RGCs). Therefore, the function of RGCs could be objectively evaluated by analyzing the PhNR. The aim of this article is to determine the effect of central retinal vein occlusion (CRVO) on PhNR and RGCs performances. Seventeen patients with CRVO were included. Full-field photopic ERGs, including PhNR, were recorded and compared with the fellow normal eyes. ERG signals were analyzed based on the standard time-domain analyses of the PhNR as well as a continuous wavelet transform (CWT) to extract time-frequency components that correspond to the PhNR using MATLAB. We obtained the main frequencies and their occurrence time from CWT. All a-wave, b-wave, and PhNR amplitudes of CRVO eyes showed a significant reduction compared to those of the fellow eyes (P < .01, P < .001, and P < .001, respectively). The peak times of a-wave, b-wave, and PhNR were increased significantly in the CRVO eyes (P = .04, P = .04, and P = .003, respectively). The dominant f3 frequency, which corresponds to the PhNR in CRVO patients, showed a more significant decrease (P < .001) compared to other dominant frequencies (f0, f1, and f2). The occurrence time of f3 (t3) was significantly higher in the CRVO eyes (P < .001). Time-domain of the PhNR was also affected in CRVO patients (P < .001). CWT allows quantifications of ERG responses, especially for PhNR. The PhNR was severely affected in CRVO eyes implicating loss of RGCs. CWT might demonstrate the severity of CRVO more precisely and identify diagnostically significant changes of ERG waveforms that are not resolved when the analysis is only limited to the time-domain measurements.


Replacing revolving door: a collaborative approach to treating individuals in crisis.
The Crisis Assessment and Psychiatric Emergency Services (CAPES) unit was designed to improve the quality of psychiatric treatment, contain costs, and provide relief to overburdened psychiatric inpatient and emergency services in Delaware. This innovative program is the result of collaboration between public and private agencies to treat individuals in crisis. The myriad factors that contributed to a broken system and instigated Delaware's search for a solution are discussed in this article. The CAPES unit has resulted in improved communication among providers, decreased committal rates, better linkage to appropriate levels of care, increased safety, and improved coordination of services. Clinical implications for nursing practice include providing more holistic care in a safer environment.


Reduction of coronary events with aspirin in older patients with prior myocardial infarction treated with and without statins.
In an observational prospective study of 1,410 patients (mean age, 81 +/- 9 years) with prior myocardial infarction, no contraindications to aspirin, and a serum low-density lipoprotein cholesterol level of 125 mg/dL or higher, 832 (59%) were treated with aspirin. At the 36-month follow-up evaluation, the incidence of new coronary events was 52% in persons treated with aspirin versus 70% in those who were not treated with aspirin (P < 0.0001). The stepwise Cox regression model showed that significant independent predictors of new coronary events were age (risk ratio, 1.05 for each 1-year increase), current cigarette smoking (risk ratio, 2.7), hypertension (risk ratio, 1.7), diabetes mellitus (risk ratio, 2.2), initial serum low-density lipoprotein cholesterol level (risk ratio, 1.01 for each 1-mg/dL increase), initial serum high-density lipoprotein cholesterol level (risk ratio, 0.96 for each 1-mg/dL increase), use of statins (risk ratio, 0.46), and use of aspirin (risk ratio, 0.48).


Compound Structure-Independent Activity Prediction in High-Dimensional Target Space.
Profiling of compound libraries against arrays of targets has become an important approach in pharmaceutical research. The prediction of multi-target compound activities also represents an attractive task for machine learning with potential for drug discovery applications. Herein, we have explored activity prediction in high-dimensional target space. Different types of models were derived to predict multi-target activities. The models included naïve Bayesian (NB) and support vector machine (SVM) classifiers based upon compound structure information and NB models derived on the basis of activity profiles, without considering compound structure. Because the latter approach can be applied to incomplete training data and principally depends on the feature independence assumption, SVM modeling was not applicable in this case. Furthermore, iterative hybrid NB models making use of both activity profiles and compound structure information were built. In high-dimensional target space, NB models utilizing activity profile data were found to yield more accurate activity predictions than structure-based NB and SVM models or hybrid models. An in-depth analysis of activity profile-based models revealed the presence of correlation effects across different targets and rationalized prediction accuracy. Taken together, the results indicate that activity profile information can be effectively used to predict the activity of test compounds against novel targets.


Systemic lupus erythematosus with presentation as vertigo and vertical nystagmus: report of one case.
An 11-year-old boy suffered from fever, headache, severe vertigo and unsteady gait. Physical examination showed bilateral vertical nystagmus, mild corneal reflex delay of the right eye and asymmetric facial expression. Laboratory data showed leukopenia, high ESR and normal CSF study. Brain CT showed diffuse brain edema. Electronystagmography showed upbeat nystagmus and central vertigo. EEG revealed diffuse slow wave and mild to moderate cortical dysfunction. MRI of the head showed focal abnormal signal intensity at the ventral portion of the medulla oblongata on both sides. Under suspicion of enteroviral encephalitis, mannitol and IVIG were given. The virological profiles were negative, ANA 1:640 nucleolar type, low complements and proteinuria. Anti-ds DNA was elevated and anti-ribosomal-P antibodies were positive. Under impression of SLE with CNS involvement, betamethasone was given. Fever, nystagmus and ataxia subsided gradually. Steroid was tapered and imuran was added. The following laboratory data were normal. In his past history, the patient was diagnosed Kikuchi disease. The manifestations of SLE were rare initial presentations as vertigo or vertical nystagmus. We present a case with review of literature and conclusion that physicians should keep in mind the possibility of SLE if patients present with unspecific neurological symptoms and concomitant systemic symptoms.


DMPP attenuates lipopolysaccharide-induced lung injury by inhibiting glycocalyx degradation through activation of the cholinergic anti-inflammatory pathway.
The study aimed to investigate the therapeutic potential of 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), an agonist of nicotinic acetylcholine receptor (nAChR), in treating acute lung injury (ALI) induced by lipopolysaccharide (LPS). A murine ALI model was developed utilizing intraperitoneal injection of LPS. We evaluated the therapeutic efficacy of DMPP treatment in LPS-induced lung injury using various approaches, including pathohistological evaluation, appraisal of pulmonary edema, and measurement of inflammatory cytokine levels and their associated pathways within lung tissues. The gene chip data of LPS-induced acute lung injury mice were retrieved from the Gene Expression Omnibus (GEO) database for gene differential expression analysis and Gene Set Enrichment Analysis (GSEA) analysis. The impact of DMPP on glycocalyx shedding was assessed by measuring the expression levels of syndecan-1 (SDC-1) and matrix metalloproteinase-9 (MMP-9). DMPP treatment significantly improved pathomorphological changes and pathological lung injury scores in the LPS-induced ALI mouse model. The genes expressed differentially in the LPS-induced ALI group in GSE2411 were found to be involved in multiple processes, including the NF-κB signaling pathway, NOD-like receptor signaling pathway, Toll-like receptor signaling pathway, as well as the JAK-STAT signaling pathway. DMPP treatment effectively downregulated pro-inflammatory cytokines, suppressed the NF-κB signaling pathway, and effectively restrained the LPS-induced upregulation of MMP-9 and shedding of syndecan-1, thereby contributing to the preservation of endothelial glycocalyx and attenuation of endothelial barrier dysfunction. The administration of DMPP has been shown to confer protection against LPS-induced acute lung injury via a cholinergic anti-inflammatory pathway, which effectively inhibits endothelial glycocalyx degradation.


Could preventive intranasal interferon lower the morbidity in children prone to respiratory illness?
Recent studies have demonstrated that rhinovirus infections can be prevented in the family setting through use of intranasal interferon sprays which are commenced when another family member develops a cold. One hundred and twenty-seven children aged 4-9 years who had been hospitalized during their first year of life for severe infections caused by respiratory syncytial virus were studied virologically and epidemiologically during a seven-month period which included the winter months. The hypothesis was that a significant part of their respiratory morbidity would be preventable by a contact prophylaxis approach using intranasal interferon. However, the findings suggest that a preventive approach of this kind would not substantially reduce the burden of respiratory illness in these children because: the target children themselves more often introduced illness into the family than did other household members; rhinovirus infections preventable by interferon were associated with little lower respiratory morbidity; and rhinoviruses were minor contributors to the total respiratory illness burden in these respiratory illness-prone children.


Temporal Association between Influenza Vaccination Coverage and Ambulatory Antibiotic Use in Children.
In this population-based retrospective cohort study, increased influenza vaccination coverage was temporally associated with a reduction in ambulatory antibiotic use in children. After adjustment for yearly vaccine effectiveness, antibiotic prescription rate declined by 3/1000 person-months for each 1% increase in influenza vaccination coverage between 2012 and 2017 in South Carolina (P < 0.001).


h-Analysis and data-parallel physics-informed neural networks.
We explore the data-parallel acceleration of physics-informed machine learning (PIML) schemes, with a focus on physics-informed neural networks (PINNs) for multiple graphics processing units (GPUs) architectures. In order to develop scale-robust and high-throughput PIML models for sophisticated applications which may require a large number of training points (e.g., involving complex and high-dimensional domains, non-linear operators or multi-physics), we detail a novel protocol based on h-analysis and data-parallel acceleration through the Horovod training framework. The protocol is backed by new convergence bounds for the generalization error and the train-test gap. We show that the acceleration is straightforward to implement, does not compromise training, and proves to be highly efficient and controllable, paving the way towards generic scale-robust PIML. Extensive numerical experiments with increasing complexity illustrate its robustness and consistency, offering a wide range of possibilities for real-world simulations.


Quantitative analysis of trimethobenzamide hydrochloride by ion-pair column chromatography and semiquantitative analysis of 3,4,5-trimethoxybenzoic acid by thin-layer chromatography.
An ion-pair column chromatographic/UV spectrophotometric method for assaying trimethobenzamide hydrochloride in capsules and injections is presented, as well as a method for the detection of 3,4,5- trimethoxybenzoic acid in trimethobenzamide hydrochloride bulk drug and dosage forms. Results obtained by the USP XX, Pharmacopeial Forum, and ion-pair column assay procedures are compared, and results of a collaborative study of the proposed assay and impurity detection methods are presented.


[Drinking in different periods of a day of primary and middle school students in four cities of China].
To investigate intake of water in different periods of a day of primary and middle school students in Beijing, Shanghai, Guangzhou and Chengdu of China. A total of 5914 primary and middle school students from Beijing, Shanghai, Guangzhou and Chengdu were recruited using multiple-stage random sampling method from September to October 2011. Among them, 5868 students completed the survey. The information of amounts and types of drinking in 8 time periods, morning, afternoon, night as well as in meal and non-meal time in 24 hours of a day was recorded by subjects for seven consecutive days using a quantitative measurement. This information was analyzed by different periods. The amount of drinking water among 8 periods of a day was (99 ± 101), (130 ± 106), (191 ± 155), (96 ± 107), (246 ± 172), (90 ± 101), (188 ± 135) and (50 ± 81) ml, respectively for before breakfast, during breakfast, after breakfast, during lunch, after lunch, during dinner, after dinner, and midnight (F = 1679.77, P < 0.01). Based on three periods of a day, the amount of drinking water in the morning (420 ± 242) ml was the statistically significantly most, followed by afternoon (341 ± 199) ml, and the least in the evening (327 ± 195) ml (F = 325.23, P < 0.01). The distribution trend of plain water in three periods was the same as total drinking water, with (270 ± 209), (250 ± 179) and (224 ± 177) ml, respectively (F = 84.89, P < 0.01) ; but beverage consumption was the most in the morning(151 ± 133) ml, then in the evening (103 ± 122) ml, and the least in the afternoon (91 ± 199) ml (F = 373.56, P < 0.01). The daily plain water consumption in meal time was (316 ± 247) ml, while it in non-meal time was (773 ± 445) ml with statistically significant difference (Z = 65.2, P < 0.01). There was no significant difference in meal time between plain water (165 ± 194) ml and beverage (151 ± 152) ml (Z = 0.59, P = 0.56) whilst plain water (579 ± 408) ml in non-meal time was significantly higher than beverages (194 ± 204) ml (Z = 64.5, P < 0.01). The amount of drinking water of primary and middle school students in different periods of a day was different in four cities of China.


A case report of the orbit, ocular association and the lung in granulomatosis with polyangiitis: A diagnostic challenge.
Granulomatosis with polyangiitis (GPA) is a systemic form of vasculitis that involves small to medium sized vessels and is associated with high morbidity and mortality. GPA presents a continuous and difficult clinical diagnostic concern, due to the rarity of the disease and the diversity of the manifestations. This case report discusses the unusual symptoms presented by a particular patient, discusses these manifestations and explains how the final diagnosis was identified as GPA. A 40-year old Chinese woman was initially referred to the present institution for a progressive worsening pain, redness and gradual decrease in visual acuity in the eyes over the past 7-year period. Previous therapeutic interventions included noncompliant topical and intravenous dexamethasone for 6 years. A pre-operative examination conducted in a differing hospital to search for the presence of an orbital mass, resulted in the identification of an asymptomatic space-occupying lesion in the right middle lung, which was surgically removed in March 2015. A total of four weeks later, surgery was then applied to remove a left orbital mass, in the same hospital. A total of three months later, the patient was diagnosed with peripheral ulcerative keratitis associated with GPA, at the present institution. The corneal lesions were then treated bilaterally with cryotherapy and oral prednisone and cyclophosphamide were administered. Following surgery, the condition of the eyes appeared to be stable. A total of seven months later, the redness and pain of the right eye recurred, followed by a deep lamellar keratoplasty for the treatment of necrotizing scleritis. The condition of the two eyes was subsequently observed to be stable during the nine month follow-up. The present case study reviews various points to consider in a rare, complicated and potentially blinding case of GPA. GPA must therefore be considered in the differential diagnosis of further inflammatory conditions and tumors. Early diagnosis and an appropriate interdisciplinary approach to management, are required to decrease recurrence and morbidity in patients with GPA-mediated inflammatory ocular disease.


A Doorway Detection and Direction (3Ds) System for Social Robots via a Monocular Camera.
In this paper, we propose a novel algorithm to detect a door and its orientation in indoor settings from the view of a social robot equipped with only a monocular camera. The challenge is to achieve this goal with only a 2D image from a monocular camera. The proposed system is designed through the integration of several modules, each of which serves a special purpose. The detection of the door is addressed by training a convolutional neural network (CNN) model on a new dataset for Social Robot Indoor Navigation (SRIN). The direction of the door (from the robot's observation) is achieved by three other modules: Depth module, Pixel-Selection module, and Pixel2Angle module, respectively. We include simulation results and real-time experiments to demonstrate the performance of the algorithm. The outcome of this study could be beneficial in any robotic navigation system for indoor environments.


Clinical cardiac regenerative studies in children.
Although the incidence of pediatric heart failure is low, the mortality is relatively high, with severe clinical symptoms requiring repeated hospitalization or intensive care treatment in the surviving patients. Cardiac biopsy specimens have revealed a higher number of resident human cardiac progenitor cells, with greater proliferation and differentiation capacity, in the neonatal period as compared with adults, demonstrating the regeneration potential of the young heart, with rising interest in cardiac regeneration therapy in critically ill pediatric patients. We review here the available literature data, searching the MEDLINE, Google Scholar and EMBASE database for completed, and www.clinicaltrials.gov homepage for ongoing studies involving pediatric cardiac regeneration reports. Because of difficulties conducting randomized blinded clinical trials in pediatric patients, mostly case reports or cohort studies with a limited number of individuals have been published in the field of pediatric regenerative cardiology. The majority of pediatric autologous cell transplantations into the cardiac tissue have been performed in critically ill children with severe or terminal heart failure. Congenital heart disease, myocarditis, and idiopathic hypertrophic or dilated cardiomyopathy leading to congestive heart failure are some possible areas of interest for pediatric cardiac regeneration therapy. Autologous bone marrow mononuclear cells, progenitor cells, or cardiospheres have been applied either intracoronary or percutaneously intramyocardially in severely ill children, leading to a reported clinical benefit of cell-based cardiac therapies. In conclusion, compassionate use of autologous stem cell administration has led to at least short-term improvement in heart function and clinical stability in the majority of the critically ill pediatric patients.


Continuous pericapsular nerve group (PENG) block through an elastomeric infusion system, associated with the lateral cutaneous nerve block of the thigh for total hip arthroplasty.
Orthopaedic surgeries can lead to pain that is difficult to treat, sometimes requiring prolonged hospitalisation. Peripheral nerve blocks stand out as an efficient strategy within the context of multimodal analgesia. The hypothesis is that continuous pericapsular nerve group block, when combined with lateral femoral cutaneous nerve block, can provide excellent analgesic coverage for hip surgeries. Continuous infusion systems can prolong analgesia, minimising opioid consumption, adverse effects and providing faster recovery. We describe a case of efficient analgesia, in which a catheter was positioned between the iliopsoas muscle plane and the iliopubic eminence for total hip arthroplasty.


The sound and the fury: Late positive potential is sensitive to sound affect.
Emotion is an emergent construct of multiple distinct neural processes. EEG is uniquely sensitive to real-time neural computations, and thus is a promising tool to study the construction of emotion. This series of studies aimed to probe the mechanistic contribution of the late positive potential (LPP) to multimodal emotion perception. Experiment 1 revealed that LPP amplitudes for visual images, sounds, and visual images paired with sounds were larger for negatively rated stimuli than for neutrally rated stimuli. Experiment 2 manipulated this audiovisual enhancement by altering the valence pairings with congruent (e.g., positive audio + positive visual) or conflicting emotional pairs (e.g., positive audio + negative visual). Negative visual stimuli evoked larger early LPP amplitudes than positive visual stimuli, regardless of sound pairing. However, time frequency analyses revealed significant midfrontal theta-band power differences for conflicting over congruent stimuli pairs, suggesting very early (∼500 ms) realization of thematic fidelity violations. Interestingly, late LPP modulations were reflective of the opposite pattern of congruency, whereby congruent over conflicting pairs had larger LPP amplitudes. Together, these findings suggest that enhanced parietal activity for affective valence is modality independent and sensitive to complex affective processes. Furthermore, these findings suggest that altered neural activities for affective visual stimuli are enhanced by concurrent affective sounds, paving the way toward an understanding of the construction of multimodal affective experience.


A case of verrucous perforating collagenoma in a toddler.
Verrucous perforating collagenoma is an extremely rare variant of acquired perforating dermatosis that has been seldom described in literature. We present the case of an 18-month-old boy who presented with an erythematous plaque with a central keratotic plug on the leg. Histopathology revealed transepidermal elimination of collagen, consistent with a diagnosis of verrucous perforating collagenoma.


[Neurological presentation of non-Hodgkin lymphoma: a diagnostic problem].
In two patients, men aged 69 and 38 years, neurological signs were the first presenting symptoms of systemic non-Hodgkin's lymphoma (NHL). This presentation is uncommon. The patients had focal neurological deficit and elevated serum lactate dehydrogenase (LDH) activity. Neurological manifestations of NHL may be caused by extradural lymphoma or by diffuse leptomeningeal metastasis (meningitis lymphomatosa). A third patient, a woman of 48, had a third form of nervous system involvement, primary cerebral NHL, which is not a metastatic sequel to systemic NHL. Primary neurological presentation of NHL may be difficult to diagnose, particularly in case of prior treatment with corticosteroids.


Development and validation of a multiplex real-time PCR for detection of Clostridium chauvoei and Clostridium septicum.
Clostridium chauvoei is the causative agent of blackleg in cattle and sheep. The clinical symptoms of this severe disease are very similar to that of malignant edema (Clostridium septicum), infections of other Clostridium species belonging to the gas edema complex, and anthrax (Bacillus anthracis). C. chauvoei and C. septicum are closely related taxa and share many phenotypic properties hampering diagnosis by using traditional microbiological methods. Thus, there is a need for a fast and reliable identification method for specific detection of both species in clinical samples. The multiplex real-time PCR assay presented here is based on the detection of the spo0A gene and enables the simultaneous identification of C. chauvoei and C. septicum. The assay design includes an amplification control DNA template for the recognition of PCR-inhibitors. Assay validation was performed using a collection of 29 C. chauvoei, 38 C. septicum strains and 26 strains of other Clostridium species. Furthermore, the real-time PCR assay was successfully tested on tissue samples from 19 clinical blackleg cases. The assay allowed the reliable detection of one picogram DNA which represents approximate 239 genome equivalents.


Benefits of risk-adapted and mould-specific antifungal prophylaxis in childhood leukaemia.
Fluconazole is one of the most commonly used drugs for antifungal prophylaxis in childhood leukaemia. However, its interaction with vincristine may induce neuropathy and the emergence of antifungal drug resistance contributes to substantial mortality caused by invasive fungal infections (IFIs). In a retrospective single-centre study, we compared tolerability and outcome of different antifungal prophylaxis strategies in 198 children with acute leukaemia (median age 5·3 years). Until 2010, antifungal prophylaxis with fluconazole was offered to most of the patients and thereafter was replaced by liposomal amphotericin-B (L-AMB) and restricted to high-risk patients only. Vincristine-induced neurotoxicity was significantly reduced under L-AMB, as the percentage of patients with severe constipation decreased (15·4% vs. 3·7%, before vs. after 31 December·2010, P = 0·01) and stool frequency increased by up to 38% in polyene-treated patients (P = 0·005). Before 2011, 10 patients developed confirmed IFIs, most of them were infected with Aspergillus species. After risk adaption in 2011, IFIs were completely prevented (P = 0·007). L-AMB prophylaxis is beneficial in childhood leukaemia patients, as it offers effective antifungal activity with improved tolerability as compared to fluconazole. The potential impact of our risk-adapted antifungal treatment should be included in current prophylaxis guidelines for childhood leukaemia.


Attention-Based Multi-Source Domain Adaptation.
Multi-source domain adaptation (MSDA) aims to transfer knowledge from multi-source domains to one target domain. Inspired by single-source domain adaptation, existing methods solve MSDA by aligning the data distributions between the target domain and each source domain. However, aligning the target domain with the dissimilar source domain would harm the representation learning. To address the above issue, an intuitive motivation of MSDA is using the attention mechanism to enhance the positive effects of the similar domains, and suppress the negative effects of the dissimilar domains. Therefore, we propose Attention-Based Multi-Source Domain Adaptation (ABMSDA) by considering the domain correlations to alleviate the effects caused by dissimilar domains. To obtain the domain correlations between source and target domains, ABMSDA firstly trains a domain recognition model to calculate the probability that the target images belong to each source domain. Based on the domain correlations, Weighted Moment Distance (WMD) is proposed to pay more attention on the source domains with higher similarities. Furthermore, Attentive Classification Loss (ACL) is developed to constrain that the feature extractor can generate the alignment and discriminative visual representations. The evaluations on two benchmarks demonstrate the effectiveness of the proposed model, e.g., an average of 6.1% improvement on the challenging DomainNet dataset.


Bayesian method for gene detection and mapping, using a case and control design and DNA pooling.
Association mapping studies aim to determine the genetic basis of a trait. A common experimental design uses a sample of unrelated individuals classified into 2 groups, for example cases and controls. If the trait has a complex genetic basis, consisting of many quantitative trait loci (QTLs), each group needs to be large. Each group must be genotyped at marker loci covering the region of interest; for dense coverage of a large candidate region, or a whole-genome scan, the number of markers will be very large. The total amount of genotyping required for such a study is formidable. A laboratory effort efficient technique called DNA pooling could reduce the amount of genotyping required, but the data generated are less informative and require novel methods for efficient analysis. In this paper, a Bayesian statistical analysis of the classic model of McPeek and Strahs is proposed. In contrast to previous work on this model, I assume that data are collected using DNA pooling, so individual genotypes are not directly observed, and also account for experimental errors. A complete analysis can be performed using analytical integration, a propagation algorithm for a hidden Markov model, and quadrature. The method developed here is both statistically and computationally efficient. It allows simultaneous detection and mapping of a QTL, in a large-scale association mapping study, using data from pooled DNA. The method is shown to perform well on data sets simulated under a realistic coalescent-with-recombination model, and is shown to outperform classical single-point methods. The method is illustrated on data consisting of 27 markers in an 880-kb region around the CYP2D6 gene.


Cheminformatics Research at the Unilever Centre for Molecular Science Informatics Cambridge.
The Centre for Molecular Informatics, formerly Unilever Centre for Molecular Science Informatics (UCMSI), at the University of Cambridge is a world-leading driving force in the field of cheminformatics. Since its opening in 2000 more than 300 scientific articles have fundamentally changed the field of molecular informatics. The Centre has been a key player in promoting open chemical data and semantic access. Though mainly focussing on basic research, close collaborations with industrial partners ensured real world feedback and access to high quality molecular data. A variety of tools and standard protocols have been developed and are ubiquitous in the daily practice of cheminformatics. Here, we present a retrospective of cheminformatics research performed at the UCMSI, thereby highlighting historical and recent trends in the field as well as indicating future directions.