Potassium channel KIR4.1-specific antibodies in children with acquired demyelinating CNS disease.
A serum antibody against the inward rectifying potassium channel KIR4.1 (KIR4.1-IgG) was recently discovered, which is found in almost half of adult patients with multiple sclerosis. We investigated the prevalence of KIR4.1-IgG in children with acquired demyelinating disease (ADD) of the CNS. We also compared antibody responses to KIR4.1 and myelin oligodendrocyte glycoproteins (MOGs), another potential autoantigen in childhood ADDs. We measured KIR4.1-IgG by ELISA in children with ADD (n = 47), other neurologic disease (n = 22), and autoimmune disease (n = 22), and in healthy controls (HCs) (n = 18). One hundred six samples were also measured by capture ELISA. Binding of KIR4.1-IgG human subcortical white matter was analyzed by immunofluorescence. Anti-MOG antibodies were measured using a cell-based assay. KIR4.1-IgG titers were significantly higher in children with ADD compared with all control groups by ELISA and capture ELISA (p < 0.0001, p < 0.0001). Overall, 27 of 47 patients with ADD (57.45%) but none of the 62 with other neurologic disease or autoimmune disease or the HCs (0%) were KIR4.1-IgG antibody positive by ELISA. Sera containing KIR4.1-IgG stained glial cells in brain tissue sections. No correlation among KIR4.1-IgG, age, or MOG-IgG was observed in the ADD group. Serum antibodies to KIR4.1 are found in the majority of children with ADD but not in children with other diseases or in HCs. These findings suggest that KIR4.1 is an important target of autoantibodies in childhood ADD.


Intermolecular associations determine the dynamics of the circadian KaiABC oscillator.
Three proteins from cyanobacteria (KaiA, KaiB, and KaiC) can reconstitute circadian oscillations in vitro. At least three molecular properties oscillate during this reaction, namely rhythmic phosphorylation of KaiC, ATP hydrolytic activity of KaiC, and assembly/disassembly of intermolecular complexes among KaiA, KaiB, and KaiC. We found that the intermolecular associations determine key dynamic properties of this in vitro oscillator. For example, mutations within KaiB that alter the rates of binding of KaiB to KaiC also predictably modulate the period of the oscillator. Moreover, we show that KaiA can bind stably to complexes of KaiB and hyperphosphorylated KaiC. Modeling simulations indicate that the function of this binding of KaiA to the KaiB*KaiC complex is to inactivate KaiA's activity, thereby promoting the dephosphorylation phase of the reaction. Therefore, we report here dynamics of interaction of KaiA and KaiB with KaiC that determine the period and amplitude of this in vitro oscillator.


Iterative Segmentation from Limited Training Data: Applications to Congenital Heart Disease.
We propose a new iterative segmentation model which can be accurately learned from a small dataset. A common approach is to train a model to directly segment an image, requiring a large collection of manually annotated images to capture the anatomical variability in a cohort. In contrast, we develop a segmentation model that recursively evolves a segmentation in several steps, and implement it as a recurrent neural network. We learn model parameters by optimizing the intermediate steps of the evolution in addition to the final segmentation. To this end, we train our segmentation propagation model by presenting incomplete and/or inaccurate input segmentations paired with a recommended next step. Our work aims to alleviate challenges in segmenting heart structures from cardiac MRI for patients with congenital heart disease (CHD), which encompasses a range of morphological deformations and topological changes. We demonstrate the advantages of this approach on a dataset of 20 images from CHD patients, learning a model that accurately segments individual heart chambers and great vessels. Compared to direct segmentation, the iterative method yields more accurate segmentation for patients with the most severe CHD malformations.


Tuberculosis infection and stillbirth in Ethiopia-A prospective cohort study.
Tuberculosis is among the leading causes of death among infectious diseases. Regions with a high incidence of tuberculosis, such as sub-Saharan Africa, are disproportionately burdened by stillbirth and other pregnancy complications. Active tuberculosis increases the risk of pregnancy complications, but the association between latent tuberculosis infection (LTBI) and pregnancy outcomes is unknown. We explored the effect of latent tuberculosis infection on the risk of stillbirth in women attending antenatal care clinics in Ethiopia, a country with >170 000 annual cases of active tuberculosis. Pregnant women were enrolled from antenatal care at three health facilities in Adama, Ethiopia, during 2015-2018, with assessment for previous and current active tuberculosis and testing for LTBI using QuantiFERON-TB-GOLD-PLUS. Proportions of stillbirth (≥ 20 weeks of gestation) and neonatal death (< 29 days of birth) were compared with respect to categories of maternal tuberculosis infection (tuberculosis-uninfected, LTBI, previous-, and current active tuberculosis). Multivariable logistic regression was performed for stillbirth. Among 1463 participants enrolled, the median age was 25 years, 10.2% were HIV-positive, 34.6% were primigravidae, and the median gestational age at inclusion was 18 weeks. Four (0.3%) were diagnosed with active tuberculosis during pregnancy, 68 (4.6%) reported previous treatment for active tuberculosis, 470 (32.1%) had LTBI, and 921 (63.0%) were tuberculosis-uninfected. Stillbirth was more frequent in participants with LTBI compared to tuberculosis-uninfected participants, although not reaching statistical significance (19/470, 4.0% vs 25/921, 2.7%, adjusted [for age, gravidity and HIV serostatus] odds ratio 1.38, 95% confidence interval 0.73-2.57, p = 0.30). Rates of neonatal death (5/470, 1.1% vs 10/921, 1.1%) were similar between these categories. Latent tuberculosis infection was not significantly associated with stillbirth or neonatal death in this cohort. Studies based on larger cohorts and with details on causes of stillbirth, as well as other pregnancy outcomes, are needed to further investigate this issue.


Analysis of pin force distributions of halo orthoses.
The halo orthosis is a medical device used to immobilize the cervical spine when an injury to the region is sustained. This device consists of a halo vest, support rods, a ring, and four pins that contact the skull. A major problem experienced with the halo is pin loosening. In our previous research, we were able to model the halo orthosis as a mechanism and use kinematic principles to analyze the constraint characteristics. Using the Grubler/Kutzbach equation (a well accepted method of characterizing constraint systems), we were able to show that the halo orthosis is over-constrained which could be a possible source of pin loosening. We now present preliminary data that will show decreasing axial pin force and observed geometry changes that occur at each pin site. Biomechanical tests were performed on two cadaver skulls using a tensile loading machine that simulated the forces exerted by a patient. We were able to observe the changes in axial forces at each of the pins using load cells as cyclic transverse forces were applied. Our results show a force reduction over time at each pin site. We also discovered that the effects of creep are significant and potentially contribute to pin loosening.


Silicate Microfiber Scaffolds Support the Formation and Expansion of the Cortical Neuronal Layer of Cerebral Organoids With a Sheet-Like Configuration.
Cerebral organoids (COs) are derived from human-induced pluripotent stem cells in vitro and mimic the features of the human fetal brain. The development of COs is largely dependent on "self-organization" mechanisms, in which differentiating cells committed to cortical cells autonomously organize into the cerebral cortex-like tissue. However, extrinsic manipulation of their morphology, including size and thickness, remains challenging. In this study, we discovered that silicate microfiber scaffolds could support the formation of cortical neuronal layers and successfully generated cortical neuronal layers, which are 9 times thicker than conventional COs, in 70 days. These cortical neurons in the silicate microfiber layer were differentiated in a fetal brain-like lamination pattern. While these cellular characteristics such as cortical neurons and neural stem/progenitor cells were like those of conventional COs, the cortical neuronal layers were greatly thickened in sheet-like configuration. Moreover, the cortical neurons in the scaffolds showed spontaneous electrical activity. We concluded that silicate microfiber scaffolds support the formation of the cortical neuronal layers of COs without disturbing self-organization-driven corticogenesis. The extrinsic manipulation of the formation of the cortical neuronal layers of COs may be useful for the research of developmental mechanisms or pathogenesis of the human cerebral cortex, particularly for the development of regenerative therapy and bioengineering.


Leyomiomatosis peritonealis disseminata associated with ovarian endometriosis in a patient submitted to hysteroscopic myomectomy.
To describe laparoscopic management of a case of leyomiomatosis peritonealis disseminata associated with ovarian endometriosis. Surgical video article. Academic hospital. We present a case of a 30-year-old woman referred to our clinic for abdominal and pelvic pain and dyspareunia. A hysteroscopic myomectomy was reported as previous surgical history. At ultrasound examination, a left ovarian cyst of 4 cm suspected for typical endometrioma and a mild hydroureteronephrosis of left kidney were revealed. The patient was scheduled for laparoscopic surgery. During laparoscopy, multiple nodules were found simulating widespread metastases involving colon, small bowel, omentum, right diaphragmatic dome, gastric surface, vesico-uterine area and abdominal peritoneum. Several biopsies and a peritoneal washing were performed, suspecting a peritoneal carcinomatosis. The histological frozen section examination revealed a possible benign disease, requiring further immunohistochemical study that diagnosed leiomyomatosis peritonealis. A second laparoscopy was then performed after one month. Enucleation of the left ovarian endometriotic cyst with classic stripping technique was performed. The left ureter was compressed by a fibrotic nodule of 5 cm that was isolated and removed. Operating time was 80 minutes. The postoperative course was uneventful and the patient was discharged on postoperative day 2. Description of a case of leiomyomatosis peritonealis disseminata in a patient with no previous history of intra-abdominal morcellation. The removal of the left ovarian endometriotic cyst and the periureteral nodule was successfully performed. The patient reported good health conditions without hydroureteronephrosis at six months follow up visit. Leiomyomatosis peritonealis disseminata is a rare clinical disorder characterized by proliferation of nodules, consisted by smooth muscle cells. The association of this condition with endometriosis has been described in other studies. Despite several medical therapies have been proposed (chemotherapy, aromatase inhibitor, gonadotropin-releasing hormone agonist), surgical excision remains a good option, frequently performed for symptoms palliation. Laparoscopic approach might be considered the procedure of choice in case of symptomatic women with leiomyomatosis peritonealis disseminata.


Three-dimensional parallelization of microfluidic droplet generators for a litre per hour volume production of single emulsions.
This paper looks at the design, fabrication and characterization of stackable microfluidic emulsion generators, with coefficients of variation as low as ~6% and with production rates as high as ~1 L h(-1). This work reports the highest throughput reported in the literature for a microfluidic device with simultaneous operation of liquid-liquid droplet generators. The device was achieved by stacking several layers of 128 flow-focusing droplet generators, organized in a circular array. These layers are interconnected via through-holes and fed with designated fractal distribution networks. The proposed layers were milled on poly(methylmethacrylate) (PMMA) sheets and the stack was thermo-compression bonded to create a three-dimensional device with a high density of generators and an integrated hydraulic manifold. The effect of stacking multiple layers was studied and the results show that fabrication accuracy has a greater impact on the dispersity of the emulsion than the addition of more layers to the stack. Particle crystallization of drugs was also demonstrated as a possible application of this technology in industry.


From a circle to a sphere: the ultrasound imaging of ovarian follicle with 2D and 3D technology.
Ultrasound follicular count (antral follicle count, AFC) is a necessary tool for measuring ovarian reserve, whereby the estimated number of follicles responsive to FSH can predict the number of oocytes retrieved in IVF cycles and may be the basis for individualized ovarian stimulation therapy. Advances in the ultrasound technology have recently lead to the improvement in resolution and quality of the image. Moreover the automatic measurements of follicular diameter by using some specific 3D software seems associated to several advantages when compared to the 2D technique. Examination time is reduced because the ultrasound scan data are stored and can be analyzed in detail at a later time. These data can be reconstructed in any plane, regardless of the original scan plane facilitating the detailed analysis. Another advantage is that this new technique reduces the operator's influence on scan interpretation and objectivity; therefore, interobserver variability is reduced. Using follicular volume obtained with sono AVC as the measure of follicular growth combined with volume-based criteria for the hCG triggering may in the future improve the treatment outcome compared to that achieved with conventional monitoring with follicular diameter. Better knowledge in this area could be helpful to optimize IVF outcome, by refining ovarian stimulation protocols and obtain high quality oocytes.


Amino-terminal precursor sequence modulates canine distemper virus fusion protein function.
The fusion (F) proteins of most paramyxoviruses are classical type I glycoproteins with a short hydrophobic leader sequence closely following the translation initiation codon. The predicted reading frame of the canine distemper virus (CDV) F protein is more complex, with a short hydrophobic sequence beginning 115 codons downstream of the first AUG. To verify if the sequence between the first AUG and the hydrophobic region is translated, we produced a specific antiserum that indeed detected a short-lived F protein precursor that we named PreF(0). A peptide resulting from PreF(0) cleavage was identified and named Pre, and its half-life was measured to be about 30 min. PreF(0) cleavage was completed before proteolytic activation of F(0) into its F(1) and F(2) subunits by furin. To test the hypothesis that the Pre peptide may influence protein activity, we compared the function of F proteins synthesized with that peptide to that of F proteins synthesized with a shorter amino-terminal signal sequence. F proteins synthesized with the Pre peptide were more stable and less active. Thus, the Pre peptide modulates the function of the CDV F protein. Interestingly, a distinct two-hit activation process has been recently described for human respiratory syncytial virus, another paramyxovirus.


FHR-1 Binds to C-Reactive Protein and Enhances Rather than Inhibits Complement Activation.
Factor H-related protein (FHR) 1 is one of the five human FHRs that share sequence and structural homology with the alternative pathway complement inhibitor FH. Genetic studies on disease associations and functional analyses indicate that FHR-1 enhances complement activation by competitive inhibition of FH binding to some surfaces and immune proteins. We have recently shown that FHR-1 binds to pentraxin 3. In this study, our aim was to investigate whether FHR-1 binds to another pentraxin, C-reactive protein (CRP), analyze the functional relevance of this interaction, and study the role of FHR-1 in complement activation and regulation. FHR-1 did not bind to native, pentameric CRP, but it bound strongly to monomeric CRP via its C-terminal domains. FHR-1 at high concentration competed with FH for CRP binding, indicating possible complement deregulation also on this ligand. FHR-1 did not inhibit regulation of solid-phase C3 convertase by FH and did not inhibit terminal complement complex formation induced by zymosan. On the contrary, by binding C3b, FHR-1 allowed C3 convertase formation and thereby enhanced complement activation. FHR-1/CRP interactions increased complement activation via the classical and alternative pathways on surfaces such as the extracellular matrix and necrotic cells. Altogether, these results identify CRP as a ligand for FHR-1 and suggest that FHR-1 enhances, rather than inhibits, complement activation, which may explain the protective effect of FHR-1 deficiency in age-related macular degeneration.


Expression of enzymatically active adenovirus DNA polymerase from cloned DNA requires sequences upstream of the main open reading frame.
Replication of human adenovirus (Ad) DNA requires three virus-encoded proteins that are coordinately transcribed from a single promoter at early times after infection. The mRNAs for two of these proteins, the preterminal protein (pTP) and the Ad DNA polymerase (Ad Pol), share several exons, including one encoded near Ad genome coordinate 39. Plasmids containing the putative exons that encode Ad Pol mRNA were constructed to determine if enzymatically active Ad Pol protein could be synthesized. An Ad Pol of 140 kDa was detected by immunoprecipitation with specific antibody and its enzymatic activity was confirmed by complementation of Ad DNA replication in vitro. In addition to an Ad2 DNA fragment from 24.7 to 9.2 map units which contains an open reading frame for a protein of 120 kDa, the HindIII-J fragment that encodes the exon at genome coordinate 39 can be shown to be essential for production of full-length (140 kDa), enzymatically active Ad Pol.


Surface replacement is comparable to primary total hip arthroplasty.
Conversion of a failed surface hip replacement to a conventional total hip arthroplasty is reportedly a straightforward procedure with excellent results. We compared perioperative parameters, complications, and clinical as well as radiographic outcomes of 39 hemi and total hip resurfacing conversions with conventional THAs. The hips were matched by diagnosis, gender, age, body mass index, preoperative Harris hip score, and followup time to a cohort of primary conventional THAs performed during the same time period by the same surgeon. The mean operative time was longer (by 19 minutes) for the conversions, but other perioperative parameters were similar. At a mean followup of 45 months (range, 24-63 months), the mean Harris hip scores were similar in the two groups (92 points versus 94 points for the conversion and conventional hips, respectively). Thirty-eight of 39 stems were well-aligned and appeared osseointegrated. When a resurfaced hip fails, conversion to conventional THA has similar early clinical and radiographic outcomes to primary conventional THA. Level III, therapeutic (retrospective comparative study). See the Guidelines for Authors for a complete description of levels of evidence.


Evolution and spread of Venezuelan equine encephalitis complex alphavirus in the Americas.
Venezuelan equine encephalitis (VEE) complex alphaviruses are important re-emerging arboviruses that cause life-threatening disease in equids during epizootics as well as spillover human infections. We conducted a comprehensive analysis of VEE complex alphaviruses by sequencing the genomes of 94 strains and performing phylogenetic analyses of 130 isolates using complete open reading frames for the nonstructural and structural polyproteins. Our analyses confirmed purifying selection as a major mechanism influencing the evolution of these viruses as well as a confounding factor in molecular clock dating of ancestors. Times to most recent common ancestors (tMRCAs) could be robustly estimated only for the more recently diverged subtypes; the tMRCA of the ID/IAB/IC/II and IE clades of VEE virus (VEEV) were estimated at ca. 149-973 years ago. Evolution of the IE subtype has been characterized by a significant evolutionary shift from the rest of the VEEV complex, with an increase in structural protein substitutions that are unique to this group, possibly reflecting adaptation to its unique enzootic mosquito vector Culex (Melanoconion) taeniopus. Our inferred tree topologies suggest that VEEV is maintained primarily in situ, with only occasional spread to neighboring countries, probably reflecting the limited mobility of rodent hosts and mosquito vectors.


Salivary Cortisol Levels Predict Therapeutic Response to a Sleep-Promoting Method in Children with Postural Tachycardia Syndrome.
To determine the value of salivary cortisol concentrations in predicting the efficacy of sleep-promoting treatment in children with postural tachycardia syndrome (POTS). This prospective study involved 40 children with POTS and 20 healthy children (controls). POTS was diagnosed using the head-up or head-up tilt test. Patients with POTS received a sleep-promoting treatment: >8 hours of sleep every night and a midday nap in an appropriate environment; no drinking water or exercising before bedtime; and urination before bedtime. The Pittsburgh Sleep Quality Index was used to evaluate sleep quality, and symptom scores were used to assess POTS severity. Salivary samples were collected upon awakening, 30 minutes after awakening, at 12:00 p.m., 4:00 p.m., and 8:00 p.m., and at bedtime before treatment. Enzyme-linked immunosorbent assay was used to measure salivary cortisol concentrations. Cortisol concentrations were significantly higher in patients with POTS than in the controls at all time points (P < .05 for all). PSQI scores were significantly higher in patients with POTS (7.2 ± 3.0) than in the controls (1.35 ± 1.39; t = -10.370, P <.001). Salivary cortisol concentrations at awakening were significantly higher in responders than in nonresponders (4.83 ± 0.73 vs 4.05 ± 0.79 ng/mL, t = -3.197, P = .003). The area under the receiver operating characteristic curve was 75.8%, (95% CI 59.3%-92%). Cut-off at-awakening salivary cortisol concentrations of >4.1 ng/mL yielded 83.3% sensitivity and 68.7% specificity in predicting therapeutic efficacy. At-awakening salivary cortisol concentrations may predict the efficacy of sleep-promoting treatment in patients with POTS.


[The surgical treatment of deep burns in the course of the 1st week after the trauma].
Results of treatment of 252 patients with burns, to 138 of whom an early necrectomy in terms from several hours to 7 days was conducted, are adduced. Surgical concept of discrimination of the excised deep burn wounds of III and IV degrees according to the depth of affection, using the organ-preserving tactics in dependence of functional state and the cutaneous and fascial wound coverage safety, was proposed. The operative treatment tactics choice depending on indications and contraindications for securing of successful treatment of deep burns was discussed.


Hypothalamic control of hepatic lipid metabolism via the autonomic nervous system.
Our body is well designed to store energy in times of nutrient excess, and release energy in times of food deprivation. This adaptation to the external environment is achieved by humoral factors and the autonomic nervous system. Claude Bernard, in the 19th century, showed the importance of the autonomic nervous system in the control of glucose metabolism. In the 20th century, the discovery of insulin and the development of techniques to measure hormone concentrations shifted the focus from the neural control of metabolism to the secretion of hormones, thus functionally "decapitating" the body. Just before the end of the 20th century, starting with the discovery of leptin in 1994, the control of energy metabolism went back to our heads. Since the start of 21st century, numerous studies have reported the involvement of hypothalamic pathways in the control of hepatic insulin sensitivity and glucose production. The autonomic nervous system is, therefore, acknowledged to be one of the important determinants of liver metabolism and a possible treatment target. In this chapter, we review research to date on the hypothalamic control of hepatic lipid metabolism.


Indications for fertility preservation not included in the 2017 Japan Society of Clinical Oncology Guideline for Fertility Preservation in Pediatric, Adolescent, and Young Adult Patients treated with gonadal toxicity, including benign diseases.
In recent years, local governments in Japan have established a public financial support system for fertility preservation in pediatric, adolescent, and young adult cancer patients. Fertility preservation has become popular for patients with cancers included in the gonadal toxicity risk classification of the 2017 edition of the Guideline for Fertility Preservation in Children, Adolescents and Young Adult Cancer Patients from the Japan Society of Clinical Oncology. However, patients with cancer and non-cancer diseases that are not included in the Guideline's gonadal toxicity risk classification also often receive treatment that may affect fertility, but they are often denied the opportunity of fertility preservation because no public financial support is available for diseases not listed in the Guideline. The national research project proposes including these diseases in the indications and treatment for fertility preservation. Therefore, we cooperated with the Japan Society for Fertility Preservation and the Ministry of Health, Labour and Welfare research group to solicit opinions from experts in each therapeutic area and reviewed the literature and overseas guidelines. This paper summarizes the findings of the project. We believe that it will be an important source of information for clinicians treating patients who need fertility preservation but note that the appropriateness of fertility preservation for the disorders listed in this report needs to be continuously reviewed as medical care advances.


Alone you go faster, together you go farther.
The metastatic process is an extraordinarily complex step-by-step procedure, characterized by many analogies with migratory patterns of humans or animals across our planet. The ongoing interrogation of circulating tumor cells (CTCs), caught in the act of spreading from one location to another, is revealing distinct behaviors including biological, physical, and mechanical features that impact on their likelihood to form metastasis. In this viewpoint, I will discuss some of these findings and provide a perspective on the metastatic journey, open questions and opportunities to exploit some of the most recent discoveries for the development of antimetastasis medicines.


Admission screening form and osteoporosis educational appointment: a novel fracture liaison service system for identifying osteoporosis patients and facilitating medication initiation.
Our FLS team aimed to ensure that patients admitted to the orthopedic department were promptly initiated for medication and identify and initiate medication for patients admitted to other departments. Our innovative FLS system along with admission screening and osteoporosis education have proven effective in identifying patients with osteoporosis and initiating medication. The fracture liaison service (FLS) plays a crucial role in the secondary prevention of fragility fractures by involving various medical professionals. Our FLS team had two goals for preventing primary and secondary fractures: ensuring that patients admitted to the orthopedic department were promptly initiated on medication and identifying and initiating medication for patients admitted to other departments. From April 2020 to March 2023, we analyzed the number of dual-energy X-ray absorptiometry (DEXA) scans performed, the DEXA rate among patients with proximal femoral fractures, and the rate of medication initiation each year. Our hospital implemented the FLS system in April 2022. It is a unique system utilizing admission screening form and osteoporosis educational appointments conducted by rehabilitation staff to initiate medication for orthopedic and non-orthopedic patients. The average monthly number of DEXA scans increased significantly, with 47.7 in 2020, 57.0 in 2021, and 90.8 in 2022. The DEXA rate among proximal femoral fracture patients increased from 23.3% in 2020 to 88.1% in 2021 and 100% in 2022. The rate of treatment initiation also increased remarkably, from 21.7% in 2020, to 68.7% in 2021, reaching 97.8% in 2022. We performed 504 interventions, resulting in 251 patients diagnosed with osteoporosis, of whom 134 (56 from non-orthopedic departments) successfully started medication. Our innovative FLS system, incorporating an admission screening form and osteoporosis educational appointments, proved effective in identifying patients with osteoporosis and facilitating medication initiation, which will prevent both primary and secondary fractures.


Neuroimaging evidence for the direct role of auditory scene analysis in object perception.
Auditory Scene Analysis (ASA) refers to the grouping of acoustic signals into auditory objects. Previously, we have shown that perceived musicality of auditory sequences varies with high-level organizational features. Here, we explore the neural mechanisms mediating ASA and auditory object perception. Participants performed musicality judgments on randomly generated pure-tone sequences and manipulated versions of each sequence containing low-level changes (amplitude; timbre). Low-level manipulations affected auditory object perception as evidenced by changes in musicality ratings. fMRI was used to measure neural activation to sequences rated most and least musical, and the altered versions of each sequence. Next, we generated two partially overlapping networks: (i) a music processing network (music localizer) and (ii) an ASA network (base sequences vs. ASA manipulated sequences). Using Representational Similarity Analysis, we correlated the functional profiles of each ROI to a model generated from behavioral musicality ratings as well as models corresponding to low-level feature processing and music perception. Within overlapping regions, areas near primary auditory cortex correlated with low-level ASA models, whereas right IPS was correlated with musicality ratings. Shared neural mechanisms that correlate with behavior and underlie both ASA and music perception suggests that low-level features of auditory stimuli play a role in auditory object perception.


Mutations in the non-coding RNU4ATAC gene affect the homeostasis and function of the Integrator complex.
Various genetic diseases associated with microcephaly and developmental defects are due to pathogenic variants in the U4atac small nuclear RNA (snRNA), a component of the minor spliceosome essential for the removal of U12-type introns from eukaryotic mRNAs. While it has been shown that a few RNU4ATAC mutations result in impaired binding of essential protein components, the molecular defects of the vast majority of variants are still unknown. Here, we used lymphoblastoid cells derived from RNU4ATAC compound heterozygous (g.108_126del;g.111G>A) twin patients with MOPD1 phenotypes to analyze the molecular consequences of the mutations on small nuclear ribonucleoproteins (snRNPs) formation and on splicing. We found that the U4atac108_126del mutant is unstable and that the U4atac111G>A mutant as well as the minor di- and tri-snRNPs are present at reduced levels. Our results also reveal the existence of 3'-extended snRNA transcripts in patients' cells. Moreover, we show that the mutant cells have alterations in splicing of INTS7 and INTS10 minor introns, contain lower levels of the INTS7 and INTS10 proteins and display changes in the assembly of Integrator subunits. Altogether, our results show that compound heterozygous g.108_126del;g.111G>A mutations induce splicing defects and affect the homeostasis and function of the Integrator complex.


Context-specific gene regulations in cancer gene expression data.
Learning or inferring networks of genomic regulation specific to a cellular state, such as a subtype of tumor, can yield insight above and beyond that resulting from network-learning techniques which do not acknowledge the adaptive nature of the cellular system. In this study we show that Cellular Context Mining, which is based on a mathematical model of contextual genomic regulation, produces gene regulatory networks (GRNs) from steady-state expression microarray data which are specific to the varying cellular contexts hidden in the data; we show that these GRNs not only model gene interactions, but that they are also readily annotated with context-specific genomic information. We propose that these context-specific GRNs provide advantages over other techniques, such as clustering and Bayesian networks, when applied to gene expression data of cancer patients.


PASSCLAIM - Diet-related cardiovascular disease.
Cardiovascular disease (CVD) has a multifactorial aetiology and many potential risk markers are known. As it was not feasible to discuss all markers and their possible interactions in relation to all aspects of CVD, selections had to be made in this paper. In the context of claims and functional foods, emphasis was placed on those aetiological processes and risk markers that have been shown previously to be modified by diet: lipid and lipoprotein metabolism, haemostatic function, oxidative damage, homocysteine metabolism, and blood pressure. Except for methodological and biological characteristics of these biomarkers, their relationships with the risk of CVD are discussed. For LDL and HDL cholesterol, fasting triacylglycerol, homocysteine, and blood pressure well-validated, easy applicable, and generally accepted biomarkers exist. For haemostatic function and oxidative damage validation of markers with respect to CVD or intermediate clinical markers is recommended. For diet-related CVD, however, the ultimate question is whether changes in the biomarker are truly related to changes in risk. Only for LDL cholesterol and blood pressure does consensus exist among scientists for a possible application as enhanced function claims. For HDL, triacylglycerol, and homocysteine, and in particular for haemostatic function and oxidative damage, however, formal proof is lacking that diet-induced changes in these biomarkers alter the risk of CVD. At the same time, it should be emphasised that CVD is multifactorial. Therefore it does not seem justified that a change in one particular biomarker is enough evidence to substantiate a claim. There are examples of food components or drugs that one biomarker is changed in a favourable way, but at the same time another biomarker is changed in an unfavourable way. Therefore, studies to further validate generic predictors for the CVD risk should be initiated.


Risk Factors Associated with Trastuzumab-induced Cardiotoxicity in Patients with Human Epidermal Growth Factor Receptor 2-positive Breast Cancer.
Although trastuzumab is a highly effective and selective targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, the drug-induced cardiotoxicity may confine its usefulness in patients. To explore risk factors associated with the development of cardiotoxicity in patients with HER2-positive breast cancer. A retrospective review of medical records and chart review for all patients with breast cancer treated with trastuzumab was conducted at King Abdulaziz Medical City and King Abdullah Specialized Children Hospital in Riyadh, Kingdom of Saudi Arabia, between October 2015 and February 2018. Patients with declined left ventricular ejection fraction, either with or without cardiac symptoms, were recognized as those with cardiotoxicity due to trastuzumab administration. A total of 146 patients were included in the study with an average age of 52.7 (standard deviation = 12.2) years. Thirty-two (21.9%) patients developed cardiotoxicity. However, only 24 (16.4%) were symptomatic with an apparent heart failure but it did not necessitate interruption of trastuzumab therapy. The majority of patients had prior underlying cardiovascular diseases. This study identified unilateral tumor site (62.5%), breast surgery (37.5%), and concomitant taxane chemotherapy (62.5%) as the main risk factors associated with significant increase in cardiotoxicity in patients with breast cancer (with P values of 0.0269, 0.0482, and 0.0225, respectively). The majority of patients (more than 90%) developed cardiotoxicity after completion of chemotherapy. However, recruiting a larger sample size should be warranted to confirm or negate these findings.


Basaloid large cell lung carcinoma presenting concurrently with metastatic uveal tumor.
A 51-year-old man complaining of cough, hemoptysis, and decreased visual acuity was admitted to our hospital. Chest radiography revealed a left hilar mass and pleural effusion in the left hemithorax. In his ophtalmological examination, there was total retinal detachment in the left eye. Ultrasonographic examination and orbital magnetic resonance imaging (MRI) were reported as choroidal metastasis. A computed tomography (CT) confirmed the mass in the left hilum and multiple mass lesions consistent with metastasis in the liver and in the body of 12th thoracic vertebra. Bronchoscopic biopsies revealed large cell carcinoma with basaloid features. He died after 4 months with rapid progression of the disease in spite of combined chemotherapy. Although primary lung cancer with concurrent eye metastasis is an uncommon entity, it should always be kept in mind for patients with ocular symptoms.


New trends in tailoring active sites in zeolite-based catalysts.
This review addresses the recent developments and trends in tailoring the nature and local properties of active sites in zeolite-based catalysts, with a special focus on novel extra-large pore, layered (2D), nanocrystalline, and hierarchical (mesoporous) zeolites with enhanced pore accessibility. In the first part of the review, we discuss the latest achievements in the bottom-up (direct synthesis) and top-down (post-synthesis) approaches for isomorphous substitution in zeolites enabling control over the type (Brønsted, Lewis, or both), amount, strength, and location of acid sites. The benefits in catalysis provided by such zeolites with tuned acidity and improved accessibility are shown for different acid-catalyzed reactions involving bulky molecules, as in the synthesis of fine chemicals and biomass transformations. The incorporation of metal species of different sizes (increasing from single atoms to clusters and to nanoparticles) in zeolites allows expanding the set of reactions catalyzed by these materials. The main preparation strategies for designing metal-zeolite catalysts, especially those offering control over the size of the metal species, and their catalytic behaviour in industrially relevant and emerging sustainable catalytic processes are dealt with in the second part of the review. Particular attention is paid to the stabilization of size-controlled small metal clusters and nanoparticles through their encapsulation in the voids of zeolite frameworks as well as to the dynamic behaviour of the metal species under reactive environments with important implications in catalysis. The need for using advanced operando spectroscopic and imaging tools to unveil the precise nature and functioning of the active sites in working zeolites is emphasized. The information gathered in this review is expected to provide guidance for developing more efficient zeolite-based catalysts for existing and new applications.


Conformational differences in Mycobacterium tuberculosis catalase-peroxidase KatG and its S315T mutant revealed by resonance Raman spectroscopy.
KatG from Mycobacterium tuberculosis is a heme-containing catalase-peroxidase, which belongs to the class I peroxidases and is important for activation of the prodrug isoniazid (INH), a front-line antituberculosis drug. In many clinical isolates, resistance to INH has been linked to mutations on the katG gene, and the most prevalent mutation, S315T, suggests that modification of the heme pocket has occurred. Electronic absorption and resonance Raman spectra of ferric wild-type (WT) KatG and its INH-resistant mutant KatG(S315T) at different pH values and their complexes with INH and benzohydroxamic acid (BHA) are reported. At neutral pH, a quantum mechanically mixed spin state (QS) is revealed, which coexists with five-coordinate and six-coordinate high-spin hemes in WT KatG. The QS heme is the major species in KatG(S315T). Addition of either INH or BHA to KatG induces only minor changes in the resonance Raman spectra, indicating that both compounds do not directly interact with the heme iron. New vibrational modes are observed at 430, 473, and 521 cm(-1), and these modes are indicative of a change in conformation in the KatG heme pocket. The intensity of these modes and the relative population of the QS heme are stable in KatG(S315T) but not in the WT enzyme. This indicates that there are differences in heme pocket stability between WT KatG and KatG(S315T). We will discuss the stabilization of the QS heme and propose a model for the inhibition of INH oxidation by KatG(S315T).


The AvrE superfamily: ancestral type III effectors involved in suppression of pathogen-associated molecular pattern-triggered immunity.
The AvrE superfamily of type III effectors (T3Es) is widespread among type III-dependent phytobacteria and plays a crucial role during bacterial pathogenesis. Members of the AvrE superfamily are vertically inherited core effectors, indicating an ancestral acquisition of these effectors in bacterial plant pathogens. AvrE-T3Es contribute significantly to virulence by suppressing pathogen-associated molecular pattern (PAMP)-triggered immunity. They inhibit salicylic acid-mediated plant defences, interfere with vesicular trafficking and promote bacterial growth in planta. AvrE-T3Es elicit cell death in both host and non-host plants independent of any known plant resistance protein, suggesting an original interaction with the plant immune system. Recent studies in yeast have indicated that they activate protein phosphatase 2A and inhibit serine palmitoyl transferase, the first enzyme of the sphingolipid biosynthesis pathway. In this review, we describe the current picture that has emerged from studies of the different members of this fascinating large family.


CFTR gene transfer reduces the binding of Pseudomonas aeruginosa to cystic fibrosis respiratory epithelium.
Much of the morbidity and mortality seen in cystic fibrosis (CF) is related to chronic infection of the respiratory tract with Pseudomonas aeruginosa. Some studies have attributed the strong relationship between CF and Pseudomonas colonization to the presence of increased numbers of specific cell-surface receptors, although other work suggests that this relates to the presence of mucus. Several groups are now assessing the use of gene transfer as a novel form of treatment for CF. We have examined whether P. aeruginosa binding to freshly obtained CF respiratory epithelial cells is increased, and have studied the effects of transfer of the CF transmembrane conductance regulator (CFTR) gene on this attachment. Binding of P. aeruginosa to noncultured nasal epithelial cells from both CF patients (n = 31) and healthy controls (n = 15) was studied with scanning electron microscopy. Binding was also assessed for CF cells following transfection with CFTR/liposome complexes. Epifluorescence microscopy was used to assess the effects of gene transfer on chloride fluxes. Adherence of P. aeruginosa directly to the cell surface of CF airway epithelium was significantly (P < 0.001) increased over that in non-CF controls. Liposome-mediated CFTR gene transfer resulted in a significant (P < 0.01) reduction in the numbers of bacteria bound to ciliated epithelial cells. Fluorescence microscopy confirmed correction of the basic chloride defect. Thus, in CF, the absence of normal CFTR results in increased binding of P. aeruginosa to respiratory epithelial cells. This abnormality can be corrected in vitro by restoration of CFTR function. This has important implications both for the pathogenesis of CF and for the future application and assessment of gene therapy for this disease.


Comparison of globin RNA processing methods for genome-wide transcriptome analysis from whole blood.
Whole blood is likely to become the prime tissue to detect biomarkers using gene expression analyses. In this study, we assessed whether whole-blood or globin-reduced RNA provides the most robust and sensitive results to detect small gene expression changes, for example, in response to hormone therapy (HT) exposure. Each sample (n = 12) was processed according to three different protocols: no globin reduction, globin reduction using peptide nucleic acids (PNAs) and globin reduction using magnetic beads in the GlobinClear kit from Ambion. Both globin reduction approaches using Ambion kit and PNAs were efficient at reducing globin RNA. However, globin reduction using Ambion kit also lowered the remaining cRNA. Samples processed with PNAs gave an intermediary profile closest to the no globin reduction group, with a slight increase in sensitivity of transcript detection and decrease in variability, but a loss of reproducibility. Globin RNA processing method in blood transcriptome analyses should be optimized for each microarray platform to be used. In our study, globin reduction was not found to be beneficial using the Applied Biosystems microarray system (AB1700).


Time-dependent density-functional approach for biological chromophores: the case of the green fluorescent protein.
We performed first-principles calculations of the optical response of the green fluorescent protein (GFP) within a combined quantum-mechanical molecular-mechanics and time-dependent density-functional theory approach. The computed spectra are in excellent agreement with experiments assuming the presence of two, protonated and deprotonated, forms of the photoreceptor in a approximately 4:1 ratio, which supports the conformation model of photodynamics in GFP. Furthermore, we discuss charge transfer, isomerization, and environment effects. The present approach allows for systematic studies of excited-state electron-ion dynamics in biological systems.


Distal pancreatectomy for resectable adenocarcinoma of the body and tail of the pancreas.
The study goal was to analyze outcome after distal pancreatectomy for three subtypes of adenocarcinoma to determine the role of en bloc resection in surgical management. A secondary aim was to identify those clinicopathologic factors correlating with survival in an analysis limited to ductal adenocarcinoma. Medical records of consecutive patients undergoing distal pancreatectomy for adenocarcinoma between 1987 and 2003 were reviewed. A comparative analysis was undertaken of the safety and outcome of patients undergoing standard and en bloc resections. Clinicopathologic factors for patients undergoing distal pancreatectomy for ductal adenocarcinoma were subjected to both univariate and multivariate survival analyses. Ninety-three patients underwent resection for ductal adenocarcinoma (66, 71%), mucinous cystadenocarcinoma (18, 19%), or adenocarcinoma associated with intraductal papillary mucinous neoplasm (IPMN) (9, 10%). En bloc resection was required in 33 (35%) patients. There was no operative mortality. Median survival was 15.5 months, 30.2 months, and 50.7 months for ductal adenocarcinoma, mucinous cystadenocarcinoma, and adenocarcinoma associated with IPMN, respectively. Patients undergoing en bloc resection had a higher overall complication rate, required more transfusions and more intensive care unit admissions, and had a higher rate of positive margins; however, there were no deaths. For ductal adenocarcinoma, tumor size greater than 3.5 cm, age greater than 60 years, and stage were factors that correlated with survival on a univariate analysis. None were significant on multivariate analysis. Four patients with ductal adenocarcinoma were actual 5-year survivors. While en bloc resections are associated with a higher rate of complications, the majority are self-limited and mortality is low. Resection, including adjacent organs, should be performed when appropriate. Long-term survival for patients with cystadenocarcinoma or IPMN-associated adenocarcinoma can be anticipated. While rare, long-term survival for patients with ductal adenocarcinoma after distal pancreatectomy can be achieved.


Medication compliance and persistence: terminology and definitions.
The aim of the study is to provide guidance regarding the meaning and use of the terms "compliance" and "persistence" as they relate to the study of medication use. A literature review and debate on appropriate terminology and definitions were carried out. Medication compliance and medication persistence are two different constructs. Medication compliance (synonym: adherence) refers to the degree or extent of conformity to the recommendations about day-to-day treatment by the provider with respect to the timing, dosage, and frequency. It may be defined as "the extent to which a patient acts in accordance with the prescribed interval, and dose of a dosing regimen." Medication persistence refers to the act of continuing the treatment for the prescribed duration. It may be defined as "the duration of time from initiation to discontinuation of therapy." No overarching term combines these two distinct constructs. Providing specific definitions for compliance and persistence is important for sound quantitative expressions of patients' drug dosing histories and their explanatory power for clinical and economic events. Adoption of these definitions by health outcomes researchers will provide a consistent framework and lexicon for research.


Once-Daily Oral Sarecycline 1.5 mg/kg/day Is Effective for Moderate to Severe Acne Vulgaris: Results from Two Identically Designed, Phase 3, Randomized, Double-Blind Clinical Trials.
Side effects may limit the use of current tetracycline-class antibiotics for acne. Evaluate the efficacy and safety of once-daily sarecycline, a novel, narrow-spectrum tetracycline-class antibiotic, in moderate to severe acne. Patients 9-45 years with moderate to severe facial acne (Investigator's Global Assessment [IGA] score ≥ 3, 20-50 inflammatory and ≤ 100 noninflammatory lesions, and ≤ 2 nodules) were randomized 1:1 to sarecycline 1.5 mg/kg/day or placebo for 12 weeks in identically designed phase 3 studies (SC1401 and SC1402). In SC1401 (sarecycline n=483, placebo n=485) and SC1402 (sarecycline n=519, placebo n=515), at week 12, IGA success (≥ 2-grade improvement and score 0 [clear] or 1 [almost clear]) rates were 21.9% and 22.6% (sarecycline), respectively, versus 10.5% and 15.3% (placebo; P less than 0.0001 and P equals 0.0038). Onset of efficacy in inflammatory lesions occurred by the first visit (week 3), with mean percentage reduction in inflammatory lesions at week 12 in SC1401 and SC1402 of -51.8% and -49.9% (sarecycline), respectively, versus -35.1% and -35.4% (placebo; P less than 0.0001). Onset of efficacy for absolute reduction of noninflammatory lesion count occurred at week 6 in SC1401 (P less than 0.05) and week 9 in SC1402 (P less than 0.01). In SC1401, the most common TEAEs (in ≥ 2% of either sarecycline or placebo group) were nausea (4.6% [sarecycline]; 2.5% [placebo]), nasopharyngitis (3.1%; 1.7%), headache (2.7%; 2.7%), and vomiting (2.1%; 1.4%) and, in SC1402, nasopharyngitis (2.5%; 2.9%) and headache (2.9%; 4.9%). Most were not considered treatment-related. Vestibular (dizziness, tinnitus, vertigo) and phototoxic (sunburn, photosensitivity) TEAEs both occurred in ≤ 1% of sarecycline patients. Gastrointestinal TEAE rates for sarecycline were low. Among females, vulvovaginal candidiasis (SC1401: 1.1% [sarecycline] and 0 [placebo]; SC1402: 0.3% and 0) and mycotic infection (0.7% and 0; 1.0% and 0) rates were low. The narrow-spectrum antibiotic sarecycline was safe, well tolerated, and effective for moderate to severe acne, with low rates of side effects common with tetracycline antibiotics. J Drugs Dermatol. 2018;17(9):987-996.


Clustering the autisms using glutamate synapse protein interaction networks from cortical and hippocampal tissue of seven mouse models.
Autism spectrum disorders (ASDs) are a heterogeneous group of behaviorally defined disorders and are associated with hundreds of rare genetic mutations and several environmental risk factors. Mouse models of specific risk factors have been successful in identifying molecular mechanisms associated with a given factor. However, comparisons among different models to elucidate underlying common pathways or to define clusters of biologically relevant disease subtypes have been complicated by different methodological approaches or different brain regions examined by the labs that developed each model. Here, we use a novel proteomic technique, quantitative multiplex co-immunoprecipitation or QMI, to make a series of identical measurements of a synaptic protein interaction network in seven different animal models. We aim to identify molecular disruptions that are common to multiple models. QMI was performed on 92 hippocampal and cortical samples taken from seven mouse models of ASD: Shank3B, Shank3Δex4-9, Ube3a2xTG, TSC2, FMR1, and CNTNAP2 mutants, as well as E12.5 VPA (maternal valproic acid injection on day 12.5 post-conception). The QMI panel targeted a network of 16 interacting, ASD-linked, synaptic proteins, probing 240 potential co-associations. A custom non-parametric statistical test was used to call significant differences between ASD models and littermate controls, and Hierarchical Clustering by Principal Components was used to cluster the models using mean log2 fold change values. Each model displayed a unique set of disrupted interactions, but some interactions were disrupted in multiple models. These tended to be interactions that are known to change with synaptic activity. Clustering revealed potential relationships among models and suggested deficits in AKT signaling in Ube3a2xTG mice, which were confirmed by phospho-western blots. These data highlight the great heterogeneity among models, but suggest that high-dimensional measures of a synaptic protein network may allow differentiation of subtypes of ASD with shared molecular pathology.


Effects of alpha-difluoromethylornithine and 5-fluorouracil on the proliferation of a human colon adenocarcinoma cell line.
Because alpha-difluoromethylornithine (DFMO) reduces the incidence of experimental colon cancers, inhibits the growth of human lung cancer cells and human leukemia cells in culture, and in combination with methylglyoxal (bis)guanylhydrazone induces remission in children with leukemia, its effectiveness against a human colon adenocarcinoma cell line (Colo 205) was tested alone and in combination with 5-fluorouracil (5-FU). Both DFMO (2 X 10(-4) M) and 5-FU (10(-6) M) inhibited Colo 205 cell proliferation. Above 5 X 10(-4) M DFMO (p less than 0.001) and at 10(-4) M 5-FU (p less than 0.001), Colo 205 growth was completely inhibited. Although DFMO did not sensitize Colo 205 cells to a noninhibitory concentration of 5-FU, the effectiveness of inhibitory concentrations of 5-FU and DFMO in reducing Colo 205 cell growth was additive. DFMO (2 X 10(-4) M) caused 89 to 93% inhibition of ornithine decarboxylase activity (p less than 0.001) and reduced levels of putrescine (93%; p less than 0.01) and spermidine (57%; p less than 0.02). Growth rate and the intracellular putrescine and spermidine contents were restored by 10(-6) M putrescine. DFMO could be an effective chemotherapeutic agent against human colonic cancer because of its effects at such unusually low concentrations in vitro.


DNA Dendrons as Agents for Intracellular Delivery.
Herein, a method for synthesizing and utilizing DNA dendrons to deliver biomolecules to living cells is reported. Inspired by high-density nucleic acid nanostructures, such as spherical nucleic acids, we hypothesized that small clusters of nucleic acids, in the form of DNA dendrons, could be conjugated to biomolecules and facilitate their cellular uptake. We show that DNA dendrons are internalized by 90% of dendritic cells after just 1 h of treatment, with a >20-fold increase in DNA delivery per cell compared with their linear counterparts. This effect is due to the interaction of the DNA dendrons with scavenger receptor-A on cell surfaces, which results in their rapid endocytosis. Moreover, when conjugated to peptides at a single attachment site, dendrons enhance the cellular delivery and activity of both the model ovalbumin 1 peptide and the therapeutically relevant thymosin alpha 1 peptide. These findings show that high-density, multivalent DNA ligands play a significant role in dictating cellular uptake of biomolecules and consequently will expand the scope of deliverable biomolecules to cells. Indeed, DNA dendrons are poised to become agents for the cellular delivery of many molecular and nanoscale materials.


Isolated subcutaneous implantation of a borderline ovarian tumor: A case report and review of the literature.
Laparoscopy-related tumor implantations of gynecological malignancies into the subcutaneous tissue are rarely diagnosed. We report an interesting case of a 46-year-old female who presented with an abdominal subcutaneous metastasis of a borderline ovarian tumor. The patient received a laparoscopic unilateral adnexectomy for a solid-cystic tumor of the right ovary. Histopathological workup showed a papillary borderline tumor of mucinous type. Nine days later she underwent a hysterectomy, left adnexectomy, appendectomy and omentectomy. Exploration of the peritoneum revealed no intraperitoneal implants. Further exploration showed a non-invasive implant of a borderline tumor in the subcutaneous tissue above the fascia that had no contact to the peritoneum. It is hypothesized that tumor cells may have been implanted during a previous laparoscopy, the most recent of which had been fourteen years prior to her current presentation. Various risk factors for port-site malignancies have been identified. Tumor manipulation and extraction of tumor tissue without a protective bag may contribute to development of trocar-site metastasis.


Survival in an extreme habitat: the roles of behaviour and energy limitation.
Extreme habitats challenge animals with highly adverse conditions, like extreme temperatures or toxic substances. In this paper, we report of a fish (Poecilia mexicana) inhabiting a limestone cave in Mexico. Several springs inside the cave are rich in toxic H(2)S. We demonstrate that a behavioural adaptation, aquatic surface respiration (ASR), allows for the survival of P. mexicana in this extreme, sulphidic habitat. Without the possibility to perform ASR, the survival rate of P. mexicana was low even at comparatively low H(2)S concentrations. Furthermore, we show that food limitation affects the survival of P. mexicana pointing to energetically costly physiological adaptations to detoxify H(2)S.


The Fes/Fer non-receptor tyrosine kinase cooperates with Src42A to regulate dorsal closure in Drosophila.
Fes/Fer non-receptor tyrosine kinases regulate cell adhesion and cytoskeletal reorganisation through the modification of adherens junctions. Unregulated Fes/Fer kinase activity has been shown to lead to tumours in vivo. Here, we show that Drosophila Fer localises to adherens junctions in the dorsal epidermis and regulates a major morphological event, dorsal closure. Mutations in Src42A cause defects in dorsal closure similar to those seen in dfer mutant embryos. Furthermore, Src42A mutations enhance the dfer mutant phenotype, suggesting that Src42A and DFer act in the same cellular process. We show that DFer is required for the formation of the actin cable in leading edge cells and for normal rates of dorsal closure. We have isolated a gain-of-function mutation in dfer (dfergof) that expresses an N-terminally fused form of the protein, similar to oncogenic forms of vertebrate Fer. dfergof blocks dorsal closure and causes axon misrouting. We find that in dfer loss-of-function mutants beta-catenin is hypophosphorylated, whereas in dfergof beta-catenin is hyperphosphorylated. Phosphorylated beta-catenin is removed from adherens junctions and degraded, thus implicating DFer in the regulation of adherens junctions.


Heme-Oxygenase-1 Attenuates Oxidative Functions of Antigen Presenting Cells and Promotes Regulatory T Cell Differentiation during Fasciola hepatica Infection.
Fasciola hepatica is a fluke that infects livestock and humans causing fasciolosis, a zoonotic disease of increasing importance due to its worldwide distribution and high economic losses. The parasite regulates the host immune system by inducing a strong Th2 and regulatory T (Treg) cell immune response through mechanisms that might involve the expression or activity of heme-oxygenase-1 (HO-1), the rate-limiting enzyme in the catabolism of free heme that also has immunoregulatory and antioxidant properties. In this paper, we show that F. hepatica-infected mice upregulate HO-1 on peritoneal antigen-presenting cells (APC), which produce decreased levels of both reactive oxygen and nitrogen species (ROS/RNS). The presence of these cells was associated with increased levels of regulatory T cells (Tregs). Blocking the IL-10 receptor (IL-10R) during parasite infection demonstrated that the presence of splenic Tregs and peritoneal APC expressing HO-1 were both dependent on IL-10 activity. Furthermore, IL-10R neutralization as well as pharmacological treatment with the HO-1 inhibitor SnPP protected mice from parasite infection and allowed peritoneal APC to produce significantly higher ROS/RNS levels than those detected in cells from infected control mice. Finally, parasite infection carried out in gp91phox knockout mice with inactive NADPH oxidase was associated with decreased levels of peritoneal HO-1+ cells and splenic Tregs, and partially protected mice from the hepatic damage induced by the parasite, revealing the complexity of the molecular mechanisms involving ROS production that participate in the complex pathology induced by this helminth. Altogether, these results contribute to the elucidation of the immunoregulatory and antioxidant role of HO-1 induced by F. hepatica in the host, providing alternative checkpoints that might control fasciolosis.


An improved approximation for the spatial impulse response of a rectangular transducer.
One common approximation for a field point located in the far field of the transducer is to trapezoidally-shaped function to approximate the true spatial impulse response. A quadrilaterally shaped function is proposed here. The quadrilaterally shaped function also includes the trapezoidally shaped function as a special case. This paper shows that the quadrilateral approximation applied in the specifically defined field location is superior to the trapezoidal approximation for the true spatial impulse response function when the transducer elements have the aspect ratio of approximately 10, typical of those found in 1.5 D arrays.


A risk-based evaluation of onsite, non-potable reuse systems developed in compliance with conventional water quality measures.
Water quality standards (WQSs) based on water quality measures (e.g., fecal indicator bacteria (FIB)) have been used by regulatory agencies to assess onsite, non-potable water reuse systems. A risk-based approach, based on quantitative microbial risk assessment, was developed to define treatment requirements that achieve benchmark levels of risk. This work compared these approaches using the predicted annual infection risks for non-potable reuse systems that comply with WQSs along with the benchmark risk levels achieved by the risk-based systems. The systems include a recirculating synthetic sand filter or an aerobic membrane bioreactor (MBR) combined with disinfection. The greywater MBR system had predicted risks in the range of the selected benchmark levels. However, wastewater reuse with systems that comply with WQSs had uncertain and potentially high predicted risks (i.e., >10-2 infections per person per year) in residential applications, due to exposures to viruses and protozoa. The predicted risks illustrate that WQSs based on FIB treatment performance do not ensure adequate treatment removal of viruses and protozoa. We present risk-based log10 pathogen reduction targets for intermediate-sized non-potable systems, which are 0.5 log10 less than those previously proposed for district-sized systems. Still, pathogen treatment performance data are required to better manage non-potable reuse risk.


The increasing importance of herbicides in worldwide crop production.
Herbicide use is increasingly being adopted around the world. Many developing countries (India, China, Bangladesh) are facing shortages of workers to hand weed fields as millions of people move from rural to urban areas. In these countries, herbicides are far cheaper and more readily available than labor for hand weeding. History shows that in industrializing countries in the past, including the United States, Germany, Japan and South Korea, the same phenomenon has occurred-as workers have left agriculture, herbicides have been adopted. It is inevitable that herbicide use will increase in sub-Saharan Africa, not only because millions of people are leaving rural areas, creating shortages of hand weeders, but also because of the need to increase crop yields. Hand weeding has never been a very efficient method of weed control-often performed too late and not frequently enough. Uncontrolled weeds have been a major cause of low crop yields in sub-Saharan Africa for a long time. In many parts of the world, herbicides are being increasingly used to replace tillage in order to improve environmental conditions. In comparison with tillage, herbicide use reduces erosion, fuel use, greenhouse gas emissions and nutrient run-off and conserves water.


Characterization of Toxoplasma gondii subtelomeric-like regions: identification of a long-range compositional bias that is also associated with gene-poor regions.
Chromosome ends are composed of telomeric repeats and subtelomeric regions, which are patchworks of genes interspersed with repeated elements. Although chromosome ends display similar arrangements in different species, their sequences are highly divergent. In addition, these regions display a particular nucleosomal composition and bind specific factors, therefore producing a special kind of heterochromatin. Using data from currently available draft genomes we have characterized these putative Telomeric Associated Sequences in Toxoplasma gondii. An all-vs-all pairwise comparison of T. gondii assembled chromosomes revealed the presence of conserved regions of ∼ 30 Kb located near the ends of 9 of the 14 chromosomes of the genome of the ME49 strain. Sequence similarity among these regions is ∼ 70%, and they are also highly conserved in the GT1 and VEG strains. However, they are unique to Toxoplasma with no detectable similarity in other Apicomplexan parasites. The internal structure of these sequences consists of 3 repetitive regions separated by high-complexity sequences without annotated genes, except for a gene from the Toxoplasma Specific Family. ChIP-qPCR experiments showed that nucleosomes associated to these sequences are enriched in histone H4 monomethylated at K20 (H4K20me1), and the histone variant H2A.X, suggesting that they are silenced sequences (heterochromatin). A detailed characterization of the base composition of these sequences, led us to identify a strong long-range compositional bias, which was similar to that observed in other genomic silenced fragments such as those containing centromeric sequences, and was negatively correlated to gene density. We identified and characterized a region present in most Toxoplasma assembled chromosomes. Based on their location, sequence features, and nucleosomal markers we propose that these might be part of subtelomeric regions of T. gondii. The identified regions display a unique trinucleotide compositional bias, which is shared (despite the lack of any detectable sequence similarity) with other silenced sequences, such as those making up the chromosome centromeres. We also identified other genomic regions with this compositional bias (but no detectable sequence similarity) that might be functionally similar.


Perceived risk for Type 2 diabetes in participants in a stepwise population-screening programme.
To determine the risk perception of Type 2 diabetes in participants in a stepwise population-screening programme. This study was carried out within the framework of a stepwise Type 2 diabetes population screening in the general (age 50-75 years) Dutch population. Main outcome measures were perceived risk of having diabetes and perceived seriousness of diabetes, based on a self-report questionnaire, completed before being informed about the diagnosis (Type 2 diabetes yes/no) of the screening procedure. Among 7736 participants, the risk perception of 217 screening-detected participants was compared with 4435 with a low-risk profile for undiagnosed Type 2 diabetes. Of 7736 participants, 43.5% could not give an estimate of their risk of having diabetes, 31.2% estimated their risk to be 0% and 25.3% estimated their risk to be 10% or higher. Compared with 4435 participants with an objectively low risk profile, 217 screening-detected participants were more likely to answer 'I do not know' (52.4% vs. 40.1%, P < 0.001), perceived their risk less often to be 0% (19.3% vs. 34.7%, P < 0.001), and slightly more often perceived their risk to be 10% or higher (28.3% vs. 25.2%, P < 0.001). Overall, more than half of the total population, including both participants with a low risk profile and the screening-detected participants, perceived diabetes as a (very) serious disease. Higher age, obesity and taking anti-hypertensive drugs did not translate into a higher perceived risk. Among screening-detected participants the seriousness of Type 2 diabetes was generally acknowledged, whilst the perceived risk of having Type 2 diabetes was low, despite the presence of risk factors.


Volume of resection in patients treated with breast conservation for ductal carcinoma in situ.
The optimal treatment of ductal carcinoma in situ (DCIS) is one of the most controversial issues in the management of breast cancer. Identification of factors that affect the risk of local recurrence is very important as the incidence of DCIS increases and the use of breast conservation becomes more widespread. Because the extent of resection may affect the relapse rate, we hypothesized that larger volumes of resection (VR) may account for the lower local recurrence rates we have previously found in elderly patients. Between 1978 and 1990, 173 cases of histologically confirmed DCIS were treated at MSKCC with breast conservation therapy. Of these, complete VR data were available for 126 cases. The VRs thus obtained were divided into two groups, <60 cm3 and > or =60 cm3, and were evaluated for correlating factors. The patients were divided into three groups by age at diagnosis: younger than 40 years, 40 to 69 years, and 70 years or older. The eldest group had a significantly greater proportion of large VRs (30%) as compared to the middle group (11%) and the youngest group (9%) (P=.03, chi2). Although not statistically significant, the large VR group had a lower 6-year actuarial local recurrence rate (5.6%) than did the small VR group (21.3%) (P=.16, log-rank test). This trend was observed even though adjuvant radiotherapy was used less often in patients who had large VRs. Breast conservation surgery for DCIS in elderly patients is more likely to employ a large VR. This may explain, at least in part, the observation that elderly patients have a lower local recurrence rate.


Isolation and characterization of cysK mutants of Escherichia coli K12.
cysK mutants, deficient in O-acetylserine sulphydrylase A [O-acetyl-L-serine acetate-lyase (adding hydrogen-sulphide); EC 220.127.116.11], were isolated as strains resistant to selenite or giving a black colour reaction on bismuth citrate indicator medium. All were resistant to the inhibitor I,2,4-triazole. Four independent mutants were found which possessed lowered levels of O-acetylserine sulphydrylase activity and also partially constitutive levels of NADPH-sulphite reductase [hydrogen-sulphide: NADP+ oxidoreductase; EC I.8.I.2]. Strains containing both a cysE mutation and a cysK mutation lacked the constitutive levels of NADPH-sulphite reductase showing that these levels were due to the in vivo concentration of the inducer, O-acetylserine. The cysK locus was found to be 81% cotransducible with the ptsI gene.


Pathogenesis of infection induced by an adenovirus isolated from a goat.
To determine the pathogenic potential of an adenovirus isolated from a goat. 14 colostrum-deprived, isolation-reared goat kids approximately 3 weeks old. Kids were inoculated with either cell culture fluid containing adenovirus (n = 10) or uninfected cell culture fluid (n = 4): 2 ml transtracheally and 1 ml/nostril. Clinical signs of disease and rectal temperature were recorded daily; nasal secretion and fecal specimens were collected daily. Control kids were necropsied, 2/d, on postinoculation days (PID) 5 and 10. Virus-inoculated kids were necropsied on PID 3, 5, 7, 10, and 28. After necropsy, lung, liver, kidney, and brain specimens were aseptically collected for virus isolation attempts. Tracheal fluid was collected on sterile cotton swabs. Turbinate, trachea, lung, mediastinal lymph node, liver, kidney, duodenum, jejunum, ileum, mesenteric lymph node, colon, and brain specimens were collected for histologic evaluation. Kids developed mild-to-moderate clinical respiratory tract infection. Virus was recovered consistently from nasal secretion and sporadically from fecal specimens. Grossly, there were multiple areas of atelectasis and hyperemia, principally in the cranioventral portion of the lungs. Microscopically, there was detachment and sloughing of foci of epithelial cells of the terminal bronchioles and alveoli. In kids necropsied late in the disease, these changes were accompanied by hyperplasia of type-II epithelial cells. Viral inclusions were not an obvious feature, but a few cells contained probable inclusions. The caprine adenovirus reported here is capable of inducing respiratory tract disease and lesions in the lungs of young kids.


Clinical evaluation of two different techniques for the removal of fluorosis stains.
Dental fluorosis or mottled enamel manifest itself as a brown, gray or black discolourations on the external enamel surfaces of the permanent teeth. The causative factor has been found to be the ingestion of fluorine in the drinking water more than 1 pp.m. In its most severe form the enamel discolouration provide a very displeasing appearance. Many times friends and relatives tease the patient that these stains are associated with smoking and/or poor oral hygiene. Such unwarranted, lose and inflicting personal remarks leads an individual into a severe psychological depression. A clinical study was under taken with its aims and objectives to evaluate the efficaciousness of 18% hydrochloric acid with pumice and McInnes solution with pumice in fighting the various forms of fluorosis stains and also observe and record their actions and reactions with the patients and the vitalities of the treated teeth.


Novel Research Strategies of Benzimidazole Derivatives: A Review.
Benzimidazole plays an important role in the medicinal chemistry and drug discovery with many pharmacological activities which have made an indispensable anchor for discovery of novel therapeutic agents. Substitution of benzimidazole nucleus is an important synthetic strategy in the drug discovery process. Therapeutic properties of the benzimidazole related drugs have encouraged the medicinal chemists to synthesize novel therapeutic agents. Therefore, it is required to couple the latest information with the earliest information to understand the current status of benzimidazole nucleus in drug discovery. In the present review, benzimidazole derivatives with different pharmacological activities are described on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for the development of SAR on benzimidazoles for each activity. This article aims to review the work reported, chemistry and pharmacological activities of benzimidazole derivatives during past years.


Core Data Elements in Acute Myeloid Leukemia: A Unified Medical Language System-Based Semantic Analysis and Experts' Review.
For cancer domains such as acute myeloid leukemia (AML), a large set of data elements is obtained from different institutions with heterogeneous data definitions within one patient course. The lack of clinical data harmonization impedes cross-institutional electronic data exchange and future meta-analyses. This study aimed to identify and harmonize a semantic core of common data elements (CDEs) in clinical routine and research documentation, based on a systematic metadata analysis of existing documentation models. Lists of relevant data items were collected and reviewed by hematologists from two university hospitals regarding routine documentation and several case report forms of clinical trials for AML. In addition, existing registries and international recommendations were included. Data items were coded to medical concepts via the Unified Medical Language System (UMLS) by a physician and reviewed by another physician. On the basis of the coded concepts, the data sources were analyzed for concept overlaps and identification of most frequent concepts. The most frequent concepts were then implemented as data elements in the standardized format of the Operational Data Model by the Clinical Data Interchange Standards Consortium. A total of 3265 medical concepts were identified, of which 1414 were unique. Among the 1414 unique medical concepts, the 50 most frequent ones cover 26.98% of all concept occurrences within the collected AML documentation. The top 100 concepts represent 39.48% of all concepts' occurrences. Implementation of CDEs is available on a European research infrastructure and can be downloaded in different formats for reuse in different electronic data capture systems. Information management is a complex process for research-intense disease entities as AML that is associated with a large set of lab-based diagnostics and different treatment options. Our systematic UMLS-based analysis revealed the existence of a core data set and an exemplary reusable implementation for harmonized data capture is available on an established metadata repository.


The natural history of pediatric-onset IBD-unclassified and prediction of Crohn's disease reclassification: a 27-year study.
A definitive diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) in patients who were initially diagnosed as inflammatory bowel disease-unclassified (IBDU) remains challenging. Our aims were to describe the natural history of pediatric-onset IBDU patients during prolonged period of follow up and to identify associated predictors for CD reclassification among them. In this retrospective single center study, out of 723 patients with pediatric onset IBD, we identified 53 patients (7.3%) diagnosed with IBDU at the Schneider Children's Medical Center of Israel between 1986 and 2013. Potential predictors for CD reclassification including age at diagnosis, gender, clinical manifestations, disease extent and laboratory findings were assessed. The median follow-up was 6.8 (± 6.7) years. Reclassification to CD was observed in 24/53 (45%) of patients. The median interval from diagnosis to CD reclassification was 9.4 years. In 58% of these patients, CD reclassification occurred within 5 years from diagnosis. Multivariate Cox models showed that familial history of CD and hypoalbuminemia at diagnosis were significantly associated with CD reclassification (HR 11.3, p = .02 and HR 5.3, p = .03, respectively). All other assessed clinical, laboratory and endoscopic parameters did not serve as predictors for CD reclassification later on. In our cohort, a substantial high proportion of pediatric onset IBDU patients were later re-diagnosed as CD. Only a family history of CD and hypoalbuminemia could predict reclassification among IBDU patients.


Cerebrospinal fluid dynamics correlate with neurogenic claudication in lumbar spinal stenosis.
Neurogenic claudication is a typical manifestation of lumbar spinal stenosis (LSS). However, its pathophysiology is still unclear. The severity of clinical symptoms has been shown not to correlate with the degree of structural stenosis. Altered cerebrospinal fluid (CSF) flow has been suggested as one of the causative factors of LSS. The objectives of this study were to compare CSF dynamics at the lumbosacral level between patients with LSS and healthy controls and to investigate whether CSF dynamics parameters explain symptom severity in LSS. Phase-contrast magnetic resonance imaging (PC-MRI) was conducted to measure CSF dynamics in 18 healthy controls and 9 patients with LSS. Cephalic peak, caudal peak, and peak-to-peak CSF velocities were evaluated at the lumbosacral level in the patients and controls. The power of CSF dynamics parameters to predict symptom severity was determined using a linear regression analysis adjusted for demographic and structural variables. Significantly attenuated CSF flow velocity was observed in the patients compared with the controls. The cephalic peak, caudal peak, and peak-to-peak velocities at the lumbar level were greater in the controls than in the patients (p<0.001). The predictive power increased most when the peak-to-peak velocity was added (adjusted R2 = 0.410) to the model with age, body mass index, and the minimum anterior-posterior diameter (adjusted R2 = 0.306), and the peak-to-peak velocity was the only statistically significant variable. CSF dynamics variables showed an association with the severity of LSS symptoms, independent of structural stenosis. PC-MRI can help to further our understanding of the pathophysiology of neurogenic claudication and support the diagnosis of LSS.


Diabetic neuropathies.
There is a family of diabetic neuropathies that mimic the entire spectrum of peripheral neuropathies. Distal sensory neuropathy is the most common. In small-fibre neuropathy, autonomic failure and loss of sense of pain and temperature are prominent. Painfulness is seen in a number of diabetic neuropathies. The asymmetric neuropathies are distinctive and are probably caused by a combination of microvascular and immune-mediated mechanisms. The pathogenesis of diabetic neuropathy is probably multifactorial. Hyperglycaemia is central to any pathogenic scheme whereby nerve blood flow is reduced by an effect on microvessels mediated by perturbations such as oxidative stress, reduction of nitric oxide, prostaglandins and an increase in endothelin. It may also affect nerve fibres directly. Recent clinical trials have clearly demonstrated the importance of strict glycaemic control. There is also support for essential fatty acids, antioxidants and aldose reductase inhibitors. Treatment of diabetic neuropathy is focused on improving glycaemic control and treatment of symptoms. The precise role of other modalities of treatment of diabetic neuropathy remain to be firmly established.


Rhodium nanoparticles stabilized by ferrocenyl-phosphine ligands: synthesis and catalytic styrene hydrogenation.
A series of ferrocenylphosphine-stabilized rhodium nanoparticles has been prepared in one pot from the organometallic [Rh(η3-C3H5)3] precursor. This complex has been decomposed by hydrogen treatment (3 bar) in dichloromethane in the presence of five different ferrocene-based phosphine ligands. Very small rhodium nanoparticles in the size range of 1.1-1.7 nm have been obtained. These nanoparticles have shown activity in a model catalytic reaction, namely the hydrogenation of styrene. These results evidence that the metal surface is not blocked despite the steric bulk of the stabilizing ligands. Moreover, certain selectivity has been observed depending on the ligand employed. To the best of our knowledge, such a type of compound has not yet been used for stabilizing metal nanoparticles and our findings highlight the interest to do so.


Association between electronic health records and health care utilization.
The federal government is investing approximately $20 billion in electronic health records (EHRs), in part to address escalating health care costs. However, empirical evidence that provider use of EHRs decreases health care costs is limited. To determine any association between EHRs and health care utilization. We conducted a cohort study (2008-2009) in the Hudson Valley, a multi-payer, multiprovider community in New York State. We included 328 primary care physicians in predominantly small practices (median practice size four primary care physicians), who were caring for 223,772 patients. Data from an independent practice association was used to determine adoption of EHRs. Claims data aggregated across five commercial health plans was used to characterize seven types of health care utilization: primary care visits, specialist visits, radiology tests, laboratory tests, emergency department visits, hospital admissions, and readmissions. We used negative binomial regression to determine associations between EHR adoption and each utilization outcome, adjusting for ten physician characteristics. Approximately half (48%) of the physicians were using paper records and half (52%) were using EHRs. For every 100 patients seen by physicians using EHRs, there were 14 fewer specialist visits (adjusted p < 0.01) and 9 fewer radiology tests (adjusted p = 0.01). There were no significant differences in rates of primary care visits, laboratory tests, emergency department visits, hospitalizations or readmissions. Patients of primary care providers who used EHRs were less likely to have specialist visits and radiology tests than patients of primary care providers who did not use EHRs.


A droplet microfluidics platform for rapid microalgal growth and oil production analysis.
Microalgae have emerged as a promising source for producing future renewable biofuels. Developing better microalgal strains with faster growth and higher oil production rates is one of the major routes towards economically viable microalgal biofuel production. In this work, we present a droplet microfluidics-based microalgae analysis platform capable of measuring growth and oil content of various microalgal strains with single-cell resolution in a high-throughput manner. The platform allows for encapsulating a single microalgal cell into a water-in-oil emulsion droplet and tracking the growth and division of the encapsulated cell over time, followed by on-chip oil quantification. The key feature of the developed platform is its capability to fluorescently stain microalgae within microdroplets for oil content quantification. The performance of the developed platform was characterized using the unicellular microalga Chlamydomonas reinhardtii and the colonial microalga Botryococcus braunii. The application of the platform in quantifying growth and oil accumulation was successfully confirmed using C. reinhardtii under different culture conditions, namely nitrogen-replete and nitrogen-limited conditions. These results demonstrate the capability of this platform as a rapid screening tool that can be applied to a wide range of microalgal strains for analyzing growth and oil accumulation characteristics relevant to biofuel strain selection and development. Biotechnol. Bioeng. 2016;113: 1691-1701. © 2016 Wiley Periodicals, Inc.


Challenges in elevated CO2 experiments on forests.
Current forest Free Air CO(2) Enrichment (FACE) experiments are reaching completion. Therefore, it is time to define the scientific goals and priorities of future experimental facilities. In this opinion article, we discuss the following three overarching issues (i) What are the most urgent scientific questions and how can they be addressed? (ii) What forest ecosystems should be investigated? (iii) Which other climate change factors should be coupled with elevated CO(2) concentrations in future experiments to better predict the effects of climate change? Plantations and natural forests can have conflicting purposes for high productivity and environmental protection. However, in both cases the assessment of carbon balance and how this will be affected by elevated CO(2) concentrations and the interacting climate change factors is the most pressing priority for future experiments.


Evaluation of Sensible Heat Flux and Evapotranspiration Estimates Using a Surface Layer Scintillometer and a Large Weighing Lysimeter.
Accurate estimates of actual crop evapotranspiration (ET) are important for optimal irrigation water management, especially in arid and semi-arid regions. Common ET sensing methods include Bowen Ratio, Eddy Covariance (EC), and scintillometers. Large weighing lysimeters are considered the ultimate standard for measurement of ET, however, they are expensive to install and maintain. Although EC and scintillometers are less costly and relatively portable, EC has known energy balance closure discrepancies. Previous scintillometer studies used EC for ground-truthing, but no studies considered weighing lysimeters. In this study, a Surface Layer Scintillometer (SLS) was evaluated for accuracy in determining ET as well as sensible and latent heat fluxes, as compared to a large weighing lysimeter in Bushland, TX. The SLS was installed over irrigated grain sorghum (Sorghum bicolor (L.) Moench) for the period 29 July-17 August 2015 and over grain corn (Zea mays L.) for the period 23 June-2 October 2016. Results showed poor correlation for sensible heat flux, but much better correlation with ET, with r² values of 0.83 and 0.87 for hourly and daily ET, respectively. The accuracy of the SLS was comparable to other ET sensing instruments with an RMSE of 0.13 mm·h-1 (31%) for hourly ET; however, summing hourly values to a daily time step reduced the ET error to 14% (0.75 mm·d-1). This level of accuracy indicates that potential exists for the SLS to be used in some water management applications. As few studies have been conducted to evaluate the SLS for ET estimation, or in combination with lysimetric data, further evaluations would be beneficial to investigate the applicability of the SLS in water resources management.


[Shared Mental Health Care: New approaches to collaboration between mental health and primary care providers.].
Over the last five years, increasing attention has been paid to ways of improving collaboration between mental health and primary care services (shared mental health care). This reflects a growing recognition of the significant role that family physicians already play in handling mental health problems of Canadians in almost every community across the country and the need to improve the working relationships between mental health and primary care services. This paper reviews the impact of these factors and looks at how the concept of shared care has evolved in Canada. It describes initiatives taking place across the country, focusing in detail on one program in Hamilton, Ontario, that has brought counsellors and psychiatrists into primary care settings for the last eight years. It looks at lessons that can be learned from this approach, the opportunities it offers and its applicability to other communities.


Identification of SNP loci and candidate genes related to four important fatty acid composition in Brassica napus using genome wide association study.
Rapeseed oil (canola, Brassica napus L.) is an important healthy vegetable oil throughout the world, the nutritional and economical value of which largely depends on its seed fatty acid composition. In this study, based on 201,187 SNP markers developed from the SLAF-seq (specific locus amplified fragment sequencing), a genome wide association study of four important fatty acid content traits (erucic acid, oleic acid, linoleic acid and linolenic acid) in a panel of 300 inbred lines of rapeseed in two environments (JXAU and JXRIS) was carried out. A total of 148 SNP loci significantly associated with these traits were detected by MLM model analysis respectively, and 30 SNP loci on A08 and C03 chromosomes were detected in three traits of erucic acid, oleic acid and linoleic acid contents simultaneously. Furthermore, 108 highly favorable alleles for increasing oleic acid and linoleic acid content, also for decreasing erucic acid content simultaneously were observed. By a basic local alignment search tool (BLAST) search with in a distance of 100 Kb around these significantly SNP-trait associations, we identified 20 orthologs of the functional candidate genes related to fatty acid biosynthesis, including the known vital fatty acid biosynthesis genes of BnaA.FAE1 and BnaC. FAE1 on the A08 and C03 chromosomes, and other potential candidate genes involving in the fatty acid biosynthesis pathway, such as the orthologs genes of FAD2, LACS09, KCS17, CER4, TT16 and ACBP5. This study lays a basis for uncovering the genetic variations and the improvement of fatty acid composition in B. napus.


Difference in neural response to social exclusion observation and subsequent altruism between adolescents and adults.
Empathy and prosocial behaviors toward peers promote successful social development and creation of significant long-term relationships, but surprisingly little is known about the maturation of these skills during the period of adolescence. As the majority of studies have used questionnaires or pain observation paradigms, it remains unknown whether the empathic response of adolescents differs from that of adults in a paradigm that is closer to everyday life. In the current study, fMRI was used to examine the neural correlates of social exclusion observation and subsequent prosocial behavior in 20 adolescents (aged 12-17 years) and 20 adults (aged 22-30 years) while playing a ball-tossing game with what they believed to be real individuals. Observing someone being excluded compared to observing equal inclusion of all players elicited a significantly higher activation of the IFG (pars triangularis) in adults compared to adolescents. When given the opportunity to directly help the excluded player during the game, adolescents showed significantly less prosocial behavior than adults, which was underpinned by a significantly lower activity in the right temporoparietal junction, medial/dorsomedial prefrontal cortex and fusiform face area. These findings might indicate that adolescents have a lower propensity to take the victim's perspective and share his or her distress when witnessing social exclusion, which leads to a lower altruistic motivation to help. The factors that could generate what can be interpreted as a downward modulation of empathy during adolescence are discussed.


Caenorhabditis elegans SMA-10/LRIG is a conserved transmembrane protein that enhances bone morphogenetic protein signaling.
Bone morphogenetic protein (BMP) pathways control an array of developmental and homeostatic events, and must themselves be exquisitely controlled. Here, we identify Caenorhabditis elegans SMA-10 as a positive extracellular regulator of BMP-like receptor signaling. SMA-10 acts genetically in a BMP-like (Sma/Mab) pathway between the ligand DBL-1 and its receptors SMA-6 and DAF-4. We cloned sma-10 and show that it has fifteen leucine-rich repeats and three immunoglobulin-like domains, hallmarks of an LRIG subfamily of transmembrane proteins. SMA-10 is required in the hypodermis, where the core Sma/Mab signaling components function. We demonstrate functional conservation of LRIGs by rescuing sma-10(lf) animals with the Drosophila ortholog lambik, showing that SMA-10 physically binds the DBL-1 receptors SMA-6 and DAF-4 and enhances signaling in vitro. This interaction is evolutionarily conserved, evidenced by LRIG1 binding to vertebrate receptors. We propose a new role for LRIG family members: the positive regulation of BMP signaling by binding both Type I and Type II receptors.