Route towards sustainable smart sensors: ferroelectric polyvinylidene fluoride-based materials and their integration in flexible electronics.
With the advent of the Internet of Everything (IoE) era, our civilization and future generations will employ an unimaginable complex array of electronics and sensors in daily life. Ferroelectric polymers represent a core group of materials supporting the fast development of IoE, and their functionality, straightforward processing and unmatched versatility make them prime candidates for integration in multifaceted devices. Since they are highly selective, highly responsive, highly scalable, self-powering and compatible with flexible and stretchable substrates, they can be easily integrated with various electronics into numerous stand-alone objects and even into skin as sensors for monitoring diverse mechanical, thermal and vital parameters. They can also be used in combination with other sensor materials for harvesting waste energy from mechanical and thermal sources, for data storage and for actuation. This article reviews the up-to-date accomplishments in the ferroelectric polymer field, with focus on materials involving polyvinylidene fluoride (PVDF), and also discussed both their current advancement and future growth in the development of sustainable systems.


Comprehensive simulation platform for a metamaterial imaging system.
Recently, a frequency-diverse, metamaterial-based aperture has been introduced in the context of microwave and millimeter wave imaging. The generic form of the aperture is that of a parallel plate waveguide, in which complementary metamaterial elements patterned into the upper plate couple energy from the waveguide mode to the scene. To reliably predict the imaging performance of such an aperture prior to fabrication and experiments, it is necessary to have an accurate forward model that predicts radiation from the aperture, a model for scattering from an arbitrary target in the scene, and a set of image reconstruction approaches that allow scene estimation from an arbitrary set of measurements. Here, we introduce a forward model in which the metamaterial elements are approximated as polarizable magnetic dipoles, excited by the fields propagating within the waveguide. The dipoles used in the model can have arbitrarily assigned polarizability characteristics. Alternatively, fields measured from actual metamaterial samples can be decomposed into a set of effective dipole radiators, allowing the performance of actual samples to be quantitatively modeled and compared with simulated apertures. To confirm the validity of our model, we simulate measurements and scene reconstructions with a virtual multiaperture imaging system operating in the K-band spectrum (18-26.5 GHz) and compare its performance with an experimental system.


Changes in the Distribution of Pectin in Root Border Cells Under Aluminum Stress.
Root border cells (RBCs) surround the root apices in most plant species and are involved in the production of root exudates. We tested the relationship between pectin content in root tips and aluminum (Al) tolerance by comparing these parameters in wild-type (WT) and sensitive-to-Al-rhizotoxicity (star1) mutant rice plants. Staining for demethylesterified pectin decreased after Al treatment in the WT. A high level of pectin was observed in RBCs of the root tips. The level of total pectin was increased by about 50% compared with the control. In the Al-sensitive star1 mutant, Al treatment decreased root elongation and pectin content, especially in RBCs. In addition, almost no Al accumulation was observed in the control, whereas more Al was accumulated in the RBCs of STAR1 roots. These results show that the amount of pectin influences Al tolerance; that Al accumulation in rice roots is reduced by the distribution of pectin in root-tip RBCs; and that these reactions occur in the field around the RBCs, including the surrounding mucilage. Al accumulation in rice roots is reduced by the distribution of pectin in root tips, and pectin in the root cell walls contributes to the acquisition of Al tolerance in rice by regulating its distribution. The release of Al-binding mucilage by RBCs could play a role in protecting root tips from Al-induced cellular damage.


Glycogen availability does not affect the TCA cycle or TAN pools during prolonged, fatiguing exercise.
The hypothesis that fatigue during prolonged exercise arises from insufficient intramuscular glycogen, which limits tricarboxylic acid cycle (TCA) activity due to reduced TCA cycle intermediates (TCAI), was tested in this experiment. Seven endurance-trained men cycled at approximately 70% of peak O(2) uptake (Vo(2 peak)) until exhaustion with low (LG) or high (HG) preexercise intramuscular glycogen content. Muscle glycogen content was lower (P < 0.05) at fatigue than at rest in both trials. However, the increase in the sum of four measured TCAI (>70% of the total TCAI pool) from rest to 15 min of exercise was not different between trials, and TCAI content was similar after 103 +/- 15 min of exercise (2.62 +/- 0.31 and 2.59 +/- 0.28 mmol/kg dry wt for LG and HG, respectively), which was the point of volitional fatigue during LG. Subjects cycled for an additional 52 +/- 9 min during HG, and although glycogen was markedly reduced (P < 0.05) during this period, no further change in the TCAI pool was observed, thus demonstrating a clear dissociation between exercise duration and the size of the TCAI pool. Neither the total adenine nucleotide pool (TAN = ATP + ADP + AMP) nor IMP was altered compared with rest in either trial, whereas creatine phosphate levels were not different when values measured at fatigue were compared with those measured after 15 min of exercise. These data demonstrate that altered glycogen availability neither compromises TCAI pool expansion nor affects the TAN pool or creatine phosphate or IMP content during prolonged exercise to fatigue. Therefore, our data do not support the concept that a decrease in muscle TCAI during prolonged exercise in humans compromises aerobic energy provision or is the cause of fatigue.


11β-Hydroxysteroid Dehydrogenase Type II is a Potential Target for Prevention of Colorectal Tumorigenesis.
Colorectal cancer (CRC) is a leading cause of cancer death, yet primary prevention remains the best approach to reducing overall morbidity and mortality. There is a clear molecular link between cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) production and CRC progression. Although selective COX-2 inhibitors as well as non-steroidal anti-inflammatory drugs (NSAIDs) reduce the number and sizes of colonic adenomas, increased cardiovascular risks of selective COX-2 inhibitors and increased gastrointestinal side-effects of NSAIDs limit their use in chemoprevention of CRC. Glucocorticoids induce apoptosis and are endogenous, potent COX-2 inhibitors. Glucocorticoids have been used for the treatment of hematologic malignancies, but not for solid tumors due to adverse side-effects such as immunosuppression and osteoporosis. In tissues, glucocorticoid actions are down-regulated by t y p e 2 1 1 β-hydroxysteroid dehydrogenase (11βHSD2), and inhibition of 11βHSD2 activity will elevate intracellular active glucocorticoid to levels that effectively suppress COX-2 expression. Both COX-2 and 11βHSD2 increase in Apc+/min mouse intestinal adenomas and human colonic adenomas and either pharmacologic or genetic 11βHSD2 inhibition leads to decreases in COX-2-mediated PGE2 production in tumors and prevents adenoma formation, tumor growth, and metastasis. 11βHSD2 inhibition may represent a novel approach for CRC chemoprevention by increasing tumor cell intracellular glucocorticoid activity, which in turn inhibits tumor growth by suppressing the COX-2-derived PGE2 pathway, as well as other pathways, without potential side-effects relating to chronic application of COX-2 inhibitors, NSAIDs and glucocorticoids.


Cellular fatty acids as chemotaxonomic markers of the genera Anabaena, Aphanizomenon, Microcystis, Nostoc and Planktothrix (cyanobacteria).
The cellular fatty acid content of 22 cyanobacterial strains belonging to the genera Anabaena, Aphanizomenon, Calothrix, Cylindrospermum, Nostoc, Microcystis and Planktothrix were analysed. The identities of the major peaks were confirmed by MS. Correspondence analysis of the data revealed three distinct groups formed by the Microcystis strains, the Nostoc/Planktothrix strains and the Anabaena/Aphanizomenon/Cylindrospermum strains. The Calothrix strain did not cluster with the other heterocystous cyanobacteria, supporting its morphological classification separate from the Nostocaceae family. The presence of large amounts of the fatty acids 18:30omega6,9,12c and 18:0 iso distinguished the Microcystis strains from the other cyanobacteria studied. The high content of 16:1omega7c grouped the Nostoc strains with the Planktothrix strains. A free-living strain of Nostoc contained 16:1omegao5c and 16: 1omega7c (about 1: 1), separating it from the symbiotic Nostoc strain and the Planktothrix strains. the strains of Anabaena, Aphanizomenon and Cylindrospermum grouped tightly and were characterized by the presence of 16:1omega9c and 16:0 anteiso fatty acids. Correspondence analysis of Anabaena, Aphanizomenon and Cylindrospermum showed that all hepatotoxic Anabaena strains grouped together, whereas the non-toxic and neurotoxic Anabaena strains grouped with the non-toxic Aphanizomenon strains.


Magnetic field exposure and long-term survival among children with leukaemia.
We examined the association between magnetic field (MF) exposure and survival among children with acute lymphoblastic leukaemia (ALL) treated at 51 Pediatric Oncology Group centres between 1996 and 2001. Of 1672 potentially eligible children under treatment, 482 (29%) participated and personal 24-h MF measurements were obtained from 412 participants. A total of 386 children with ALL and 361 with B-precursor ALL were included in the analysis of event-free survival (time from diagnosis to first treatment failure, relapse, secondary malignancy, or death) and overall survival. After adjustment for risk group and socioeconomic status, the event-free survival hazard ratio (HR) for children with measurements >/=0.3 muT was 1.9 (95% confidence interval (CI) 0.8, 4.9), compared to <0.1 muT. For survival, elevated HRs were found for children exposed to >/=0.3 muT (multivariate HR=4.5, 95% CI 1.5-13.8) but based on only four deaths among 19 children. While risk was increased among children with exposures above 0.3 muT, the small numbers limited inferences for this finding.


Body mass index, tumor characteristics, and prognosis following diagnosis of early-stage breast cancer in a mammographically screened population.
Many studies suggest increased body mass index (BMI) is associated with worse breast cancer outcomes, but few account for variability in screening, access to treatment, and tumor differences. We examined the association between BMI and risk of breast cancer recurrence, breast cancer-specific mortality, and all-cause mortality, and evaluated whether tumor characteristics differ by BMI among a mammographically screened population with access to treatment. Using a retrospective cohort study design, we followed 485 women aged ≥40 years diagnosed with stage I/II breast cancer within 24 months of a screening mammogram occurring between 1988 and 1993 for 10-year outcomes. BMI before diagnosis was categorized as normal (<25 kg/m(2)), overweight (25-29.9 kg/m(2)), and obese (≥30 kg/m(2)). Tumor marker expression was assessed via immunohistochemistry using tissue collected before adjuvant treatment. Medical records were abstracted to identify treatment, recurrence, and mortality. We used Cox proportional hazards to separately model the hazard ratios (HR) of our three outcomes by BMI while adjusting for age, stage, and tamoxifen use. Relative to normal-weight women, obese women experienced increased risk of recurrence (HR 2.43; 95 % CI 1.34-4.41) and breast cancer death (HR 2.41; 95 % CI 1.00-5.81) within 10 years of diagnosis. There was no association between BMI and all-cause mortality. Obese women had significantly faster growing tumors, as measured by Ki-67. Our findings add to the growing evidence that obesity may contribute to poorer breast cancer outcomes, and also suggest that increased tumor proliferation among obese women is a pathway that explains part of their excess risk of adverse outcomes.


Identification and characterization of a novel anti-inflammatory lipid isolated from Mycobacterium vaccae, a soil-derived bacterium with immunoregulatory and stress resilience properties.
Mycobacterium vaccae (NCTC 11659) is an environmental saprophytic bacterium with anti-inflammatory, immunoregulatory, and stress resilience properties. Previous studies have shown that whole, heat-killed preparations of M. vaccae prevent allergic airway inflammation in a murine model of allergic asthma. Recent studies also demonstrate that immunization with M. vaccae prevents stress-induced exaggeration of proinflammatory cytokine secretion from mesenteric lymph node cells stimulated ex vivo, prevents stress-induced exaggeration of chemically induced colitis in a model of inflammatory bowel disease, and prevents stress-induced anxiety-like defensive behavioral responses. Furthermore, immunization with M. vaccae induces anti-inflammatory responses in the brain and prevents stress-induced exaggeration of microglial priming. However, the molecular mechanisms underlying anti-inflammatory effects of M. vaccae are not known. Our objective was to identify and characterize novel anti-inflammatory molecules from M. vaccae NCTC 11659. We have purified and identified a unique anti-inflammatory triglyceride, 1,2,3-tri [Z-10-hexadecenoyl] glycerol, from M. vaccae and evaluated its effects in freshly isolated murine peritoneal macrophages. The free fatty acid form of 1,2,3-tri [Z-10-hexadecenoyl] glycerol, 10(Z)-hexadecenoic acid, decreased lipopolysaccharide-stimulated secretion of the proinflammatory cytokine IL-6 ex vivo. Meanwhile, next-generation RNA sequencing revealed that pretreatment with 10(Z)-hexadecenoic acid upregulated genes associated with peroxisome proliferator-activated receptor alpha (PPARα) signaling in lipopolysaccharide-stimulated macrophages, in association with a broad transcriptional repression of inflammatory markers. We confirmed using luciferase-based transfection assays that 10(Z)-hexadecenoic acid activated PPARα signaling, but not PPARγ, PPARδ, or retinoic acid receptor (RAR) α signaling. The effects of 10(Z)-hexadecenoic acid on lipopolysaccharide-stimulated secretion of IL-6 were prevented by PPARα antagonists and absent in PPARα-deficient mice. Future studies should evaluate the effects of 10(Z)-hexadecenoic acid on stress-induced exaggeration of peripheral inflammatory signaling, central neuroinflammatory signaling, and anxiety- and fear-related defensive behavioral responses.


Attitudes in the general population towards hemi-craniectomy for middle cerebral artery (MCA) infarction. A population-based survey.
Decompressive hemicraniectomy reduces mortality after space-occupying MCA infarction. Data on the general public's opinion toward interventions that can save lives but leave the survivors impaired are lacking. In this population-based epidemiological study in a German city, we surveyed 312 adults in a telephone interview. Here, we presented a scenario of a space-occupying MCA infarct. We evaluated probands' attitude toward decompressive surgery in general, and toward outcome scenarios according to Rankin scale (RS) definitions. 312 persons (157 women, 52 ± 20 years) were interviewed. 58 persons had difficulty comprehending the proposed scenario, most of them being of advanced age (79 ± 5 years). From the remaining 254 responders 5 (2%) persons favoured surgical intervention, 149 (58%) were undecided, and 100 (39%) were opposed to surgery. The number of individuals opting for surgery rose in scenarios with a better outcome: If very severe impairment was anticipated (RS 5), only 3 (1%) persons favored surgery. With severe (RS 4), moderate (RS3), and slight impairment (RS2) the numbers were at 16 (6%), 60 (24%), and 161 (63%), respectively. We found no association with age, sex, religion, education, self-estimated health status, or marital status. Explaining complex medical situations to laypersons poses a major problem, particularly to those of old age. Only a minority favors life-saving medical interventions if survival is associated with deficits of unpredictable degree. The majority of persons does not favor intervention even if only moderate impairment is anticipated. Decompressive surgery may in fact be against the values of many individuals.


Identification of stem cells during prepubertal spermatogenesis via monitoring of nucleostemin promoter activity.
The nucleostemin (NS) gene encodes a nucleolar protein found at high levels in several types of stem cells and tumor cell lines. The function of NS is unclear but it may play a critical role in S-phase entry by stem/progenitor cells. Here we characterize NS expression in murine male germ cells. Although NS protein was highly expressed in the nucleoli of all primordial germ cells, only a limited number of gonocytes showed NS expression in neonatal testes. In adult testes, NS protein was expressed at high levels in the nucleoli of spermatogonia and primary spermatocytes but at only low levels in round spermatids. To evaluate the properties of cells expressing high levels of NS, we generated transgenic reporter mice expressing green fluorescent protein (GFP) under the control of the NS promoter (NS-GFP Tg mice). In adult NS-GFP Tg testes, GFP and endogenous NS protein expression were correlated in spermatogonia and spermatocytes but GFP was also ectopically expressed in elongated spermatids and sperm. In testes of NS-GFP Tg embryos, neonates, and 10-day-old pups, however, GFP expression closely coincided with endogenous NS expression in developing germ cells. In contrast to a previous report, our results support the existence in neonatal testes of spermatogonial stem cells with long-term repopulating capacity. Furthermore, our data show that NS expression does not correlate with cell-cycle status during prepuberty, and that strong NS expression is essential for the maintenance of germline stem cell proliferation capacity. We conclude that NS is a marker of undifferentiated status in the germ cell lineage during prepubertal spermatogenesis.


Estimated economic impact of vaccinations in 73 low- and middle-income countries, 2001-2020.
To estimate the economic impact likely to be achieved by efforts to vaccinate against 10 vaccine-preventable diseases between 2001 and 2020 in 73 low- and middle-income countries largely supported by Gavi, the Vaccine Alliance. We used health impact models to estimate the economic impact of achieving forecasted coverages for vaccination against Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, rotavirus, rubella, Streptococcus pneumoniae and yellow fever. In comparison with no vaccination, we modelled the costs - expressed in 2010 United States dollars (US$) - of averted treatment, transportation costs, productivity losses of caregivers and productivity losses due to disability and death. We used the value-of-a-life-year method to estimate the broader economic and social value of living longer, in better health, as a result of immunization. We estimated that, in the 73 countries, vaccinations given between 2001 and 2020 will avert over 20 million deaths and save US$ 350 billion in cost of illness. The deaths and disability prevented by vaccinations given during the two decades will result in estimated lifelong productivity gains totalling US$ 330 billion and US$ 9 billion, respectively. Over the lifetimes of the vaccinated cohorts, the same vaccinations will save an estimated US$ 5 billion in treatment costs. The broader economic and social value of these vaccinations is estimated at US$ 820 billion. By preventing significant costs and potentially increasing economic productivity among some of the world's poorest countries, the impact of immunization goes well beyond health.


Innovations that reach the patient: early health technology assessment and improving the chances of coverage and implementation.
With growing concerns for the sustainability of the financial burden that health care-and especially cancer services-poses on the national budgets, the role of health economic analyses in coverage decisions is likely to grow. One of the strategies for the biomedical research field-also in oncology research-to foster coverage and health system implementation, is to anticipate this new role and to involve health technology assessment techniques earlier in various stages of translational research. In this article, we elaborate on the early involvement of health technology assessment in translational research and the concept of Coverage with Evidence Development in The Netherlands Cancer Institute and give two case examples that are currently ongoing: (1) tumour infiltrating lymphocytes therapy for metastatic melanoma; and (2) high-dose chemotherapy for BRCA1-like subgroup in triple-negative breast cancer. We conclude with recommendations for institutional policy.


Downregulation of CLDN7 due to promoter hypermethylation is associated with human clear cell renal cell carcinoma progression and poor prognosis.
Metastasis is the primary cause of death in renal cell carcinoma (RCC). Loss of cell-to-cell adhesion, including tight junctions (TJs) is the initial step in the process of metastasis. Claudin-7 (CLDN7) is a major component of TJs. However, the clinical significance and its regulation of kidney tumorigenesis remain poorly understood. A total of 120 fresh clear cell RCC (ccRCC) specimens and 144 primary RCC and adjacent nonmalignant renal paraffin specimens were obtained from Department of Urology, Peking University First Hospital. Expression of CLDN7 in ccRCC tissues and cell lines were determined using bioinformatic data mining, quantitative real-time PCR (qRT-PCR), Western blotting and immunostaining. The clinical significance of CLDN7 expression and promoter DNA methylation status was analyzed in ccRCC patients from Peking University First Hospital and The Cancer Genome Atlas. Additionally, the methylation specific-PCR, bisulfite genomic sequencing and demethylation analysis of CLDN7 were performed. Biological functions of CLDN7 were investigated by examining cell proliferation using MTS assays and EdU incorporation assays, cell migration by in vitro wound healing assays and transwell migration assays, cell invasion by transwell invasion assays, and cell apoptosis by flow cytometry. Mouse model experiments were performed to confirm the effects of CLDN7 on tumor growth and metastasis in vivo. The molecular mechanism of CLDN7 function was investigated using gene-set enrichment analysis (GSEA) and high-throughput cDNA sequencing (RNA-Seq) and confirmed by qRT-PCR, Western blot and immunostaining in vitro and in vivo. Our findings revealed that CLDN7 is frequently downregulated via hypermethylation of its promoter in ccRCC. CLDN7 can help predict aggressive tumor status and poor prognosis in ccRCC patients. Interestingly, hypermethylation of the CLDN7 promoter was related to advanced ccRCC status and poor prognosis. Moreover, overexpression of CLDN7 induced cell apoptosis, suppressed proliferation, migration and invasion abilities of ccRCC cells both in vitro and in vivo. Additionally, GSEA and RNA-Seq results showed that CLDN7 had negative effects in cancer-associated signaling pathways and (epithelial-mesenchymal transition) EMT-related pathways. These results were validated by qRT-PCR, Western blot and immunostaining. We have demonstrated a previously undescribed role of CLDN7 as a ccRCC suppressor and suggest that loss of CLDN7 potentiates EMT and tumor progression. CLDN7 may serve as a functional tumor suppressor in tumor progression and a potential biomarker and target in patients with ccRCC.


Drug quality analysis through high performance liquid chromatography of isometamidium chloride hydrochloride and diminazene diaceturate purchased from official and unofficial sources in Northern Togo.
Trypanocidal drugs remain the most accessible and thus commonly used means of controlling tsetse transmitted animal African trypanosomosis. In Togo, trypanocides are sold on official as well as unofficial markets, but the quality of these trypanocides is undocumented so a drug quality assessment study was conducted from May 2013 to June 2014. Trypanocides supplied by European, Indian and Chinese pharmaceutical companies and sold on official and unofficial markets in Togo were purchased. In total fifty-two trypanocides were obtained, 24 of these samples from official markets and 28 from unofficial markets made up of a total of 36 diminazene diaceturate and 16 isometamidium chloride hydrochloride samples. The samples were analysed in the reference laboratory of the OIE (World Organisation for Animal Health), Laboratory for the Control of Veterinary Medicines (LACOMEV) in Dakar which uses galenic testing and high performance liquid chromatography (HPLC) testing as standard reference analysis methods. The results revealed a high proportion of trypanocides of sub-standard quality on the Togolese market: 40% were non-compliant to these quality reference standards. All of the HPLC non-compliant samples contained lower amounts of active ingredient compared to the concentration specified on the packaging. Non-compliance was higher in samples from the unofficial (53.57%) than from the official markets (25%; p=0.04).The main drug manufacturers, mostly of French origin in the study area, supply quality drugs through the official legal distribution circuit. Products of other origins mostly found on illegal markets present a significantly lower quality.


Identification of recurrent chromosomal aberrations in germ cell tumors of neonates and infants using genomewide array-based comparative genomic hybridization.
Human germ cell tumors (GCTs) of neonates and infants comprise a heterogeneous group of neoplasms, including teratomas and yolk sac tumors with distinct clinical and epidemiologic features. As yet, little is known about the cytogenetic constitution of these tumors. We applied the recently developed genomewide array-based comparative genomic hybridization (array CGH) technology to 24 GCTs derived from patients under the age of 5 years. In addition, we included seven tumors derived from children and adolescents older than 5 years. In the series from those under the age of 5 years, most teratomas displayed normal profiles, except for some minor recurrent aberrations. In contrast, the yolk sac tumors displayed recurrent losses of 1p35-pter and gains of 3p21-pter and of 20q13. In the GCTs of patients older than 5 years, the main recurrent anomalies included gains of 12p and of whole chromosomes 7 and 8. In addition, gains of the 1q32-qter region and losses of the 6q24-qter and 18q21-qter regions were frequent in GCTs of varied histology, independent of age. We concluded that array CGH is a highly suitable method for identifying recurrent chromosomal anomalies in GCTs of neonates and infants. The recurrent anomalies observed point to chromosomal regions that may harbor novel diagnostic/prognostic identifiers and genes relevant to the development of these neoplasms.


The Postural Tachycardia Syndrome (POTS): pathophysiology, diagnosis & management.
Postural tachycardia syndrome (POTS), characterized by orthostatic tachycardia in the absence of orthostatic hypotension, has been the focus of increasing clinical interest over the last 15 years 1. Patients with POTS complain of symptoms of tachycardia, exercise intolerance, lightheadedness, extreme fatigue, headache and mental clouding. Patients with POTS demonstrate a heart rate increase of >or=30 bpm with prolonged standing (5-30 minutes), often have high levels of upright plasma norepinephrine (reflecting sympathetic nervous system activation), and many patients have a low blood volume. POTS can be associated with a high degree of functional disability. Therapies aimed at correcting the hypovolemia and the autonomic imbalance may help relieve the severity of the symptoms. This review outlines the present understanding of the pathophysiology, diagnosis, and management of POTS.


Role of Reverse Divalent Cation Diffusion in Forward Osmosis Biofouling.
We investigated the role of reverse divalent cation diffusion in forward osmosis (FO) biofouling. FO biofouling by Pseudomonas aeruginosa was simulated using pristine and chlorine-treated thin-film composite polyamide membranes with either MgCl2 or CaCl2 draw solution. We related FO biofouling behavior-water flux decline, biofilm architecture, and biofilm composition-to reverse cation diffusion. Experimental results demonstrated that reverse calcium diffusion led to significantly more severe water flux decline in comparison with reverse magnesium permeation. Unlike magnesium, reverse calcium permeation dramatically altered the biofilm architecture and composition, where extracellular polymeric substances (EPS) formed a thicker, denser, and more stable biofilm. We propose that FO biofouling was enhanced by complexation of calcium ions to bacterial EPS. This hypothesis was confirmed by dynamic and static light scattering measurements using extracted bacterial EPS with the addition of either MgCl2 or CaCl2 solution. We observed a dramatic increase in the hydrodynamic radius of bacterial EPS with the addition of CaCl2, but no change was observed after addition of MgCl2. Static light scattering revealed that the radius of gyration of bacterial EPS with addition of CaCl2 was 20 times larger than that with the addition of MgCl2. These observations were further confirmed by transmission electron microscopy imaging, where bacterial EPS in the presence of calcium ions was globular, while that with magnesium ions was rod-shaped.


Biochanin A Reduces Inflammatory Injury and Neuronal Apoptosis following Subarachnoid Hemorrhage via Suppression of the TLRs/TIRAP/MyD88/NF-κB Pathway.
Inflammatory injury and neuronal apoptosis participate in the period of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Suppression of inflammation has recently been shown to reduce neuronal death and neurobehavioral dysfunction post SAH. Biochanin A (BCA), a natural bioactive isoflavonoid, has been confirmed to emerge the anti-inflammatory pharmacological function. This original study was aimed at evaluating and identifying the neuroprotective role of BCA and the underlying molecular mechanism in an experimental Sprague-Dawley rat SAH model. Neurobehavioral function was evaluated via the modified water maze test and modified Garcia neurologic score system. Thus, we confirmed that BCA markedly decreased the activated level of TLRs/TIRAP/MyD88/NF-κB pathway and the production of cytokines. BCA also significantly ameliorated neuronal apoptosis which correlated with the improvement of neurobehavioral dysfunction post SAH. These results indicated that BCA may provide neuroprotection against EBI through the inhibition of inflammatory injury and neuronal apoptosis partially via the TLRs/TIRAP/MyD88/NF-κB signal pathway.


Post-treatment surveillance in a large cohort of patients with colon cancer.
To determine how patients complied with different components of guideline-recommended post-treatment surveillance in a large nationwide population-based cohort of patients with colon cancer. Retrospective cohort study. We used the linked Surveillance, Epidemiology, and End Results-Medicare database to identify patients 66 years or older diagnosed as having stage I to stage III colon adenocarcinoma between January 2000 and June 2002 with a follow-up duration of at least 3.5 years. After tumor resection, patients who completed at least 2 office visits per year for 3 years, at least 2 carcinoembryonic antigen tests per year (in the first and second years of follow-up), and at least 1 colonoscopy within 3 years were defined as meeting the recommended post-treatment care. We identified 7348 patients, with a median follow-up duration of 59 months. Adherence to post-treatment surveillance was 83.9% for office visits, 29.4% for carcinoembryonic antigen tests, and 74.3% for colonoscopy. Younger age at diagnosis, white race/ethnicity, married status, advanced tumor stage, fewer comorbidities, and chemotherapy use were significantly associated with guideline adherence. Adherence to colon cancer posttreatment surveillance was low, although proportions of patients complying with office visits and colonoscopy were reasonably high. Underlying reasons for noncompliance, which varied by type of service, may need further investigation.


Ethanol wet-bonding technique sensitivity assessed by AFM.
In ethanol wet bonding, water is replaced by ethanol to maintain dehydrated collagen matrices in an extended state to facilitate resin infiltration. Since short ethanol dehydration protocols may be ineffective, this study tested the null hypothesis that there are no differences in ethanol dehydration protocols for maintaining the surface roughness, fibril diameter, and interfibrillar spaces of acid-etched dentin. Polished human dentin surfaces were etched with phosphoric acid and water-rinsed. Tested protocols were: (1) water-rinse (control); (2) 100% ethanol-rinse (1-min); (3) 100% ethanol-rinse (5-min); and (4) progressive ethanol replacement (50-100%). Surface roughness, fibril diameter, and interfibrillar spaces were determined with atomic force microscopy and analyzed by one-way analysis of variance and the Student-Newman-Keuls test (α = 0.05). Dentin roughness and fibril diameter significantly decreased when 100% ethanol (1-5 min) was used for rinsing (p < 0.001). Absolute ethanol produced collapse and shrinkage of collagen fibrils. Ascending ethanol concentrations did not collapse the matrix and shrank the fibrils less than absolute ethanol-rinses.


Mixing is required for uniform reconstitution of filter-dried protein antigens in a single-injection vaccine formulation.
Ambient temperature filter dried vaccine formulations have been proposed to simultaneously achieve thermostability and offer a ready-to-use immunisation device that combines reconstitution and injection. Vaccine concentration should be uniform at the point of injection, but the uniformity following direct reconstitution of filter-dried vaccines has not been reported. We present here a study of vaccine mixing and release following dissolution of filter-dried model protein and toxoid antigens within a single syringe, filter and needle unit. Release was better for filters made from glass than cellulose. Without additional mixing, uniformity was poor and only 41% of input protein was released from protein filter-dried onto glass fiber. In contrast, adding a simple glass bead and mixing by inversion, 100% release antigen solution was achieved, with uniform concentration at exit from the needle throughout a simulated injection. Adsorption onto alum adjuvant had no detectable effect on vaccine dissolution and mixing. The uniformity and yield of low doses of diphtheria and tetanus toxoid was also improved by mixing, albeit with a lower yield of 60-68%. We conclude that uniformity and mixing should be studied to ensure safety and efficacy of directly reconstituted filter-dried vaccine formulations.


Two-photon imaging of lymphocyte motility and antigen response in intact lymph node.
Lymphocyte motility is vital for trafficking within lymphoid organs and for initiating contact with antigen-presenting cells. Visualization of these processes has previously been limited to in vitro systems. We describe the use of two-photon laser microscopy to image the dynamic behavior of individual living lymphocytes deep within intact lymph nodes. In their native environment, T cells achieved peak velocities of more than 25 micrometers per minute, displaying a motility coefficient that is five to six times that of B cells. Antigenic challenge changed T cell trajectories from random walks to "swarms" and stable clusters. Real-time two-photon imaging reveals lymphocyte behaviors that are fundamental to the initiation of the immune response.


Talking about parental substance abuse with children: eight families' experiences of Beardslee's family intervention.
Many children are affected by parental substance use disorder. Beardslee's family intervention (BFI) is a family-based psycho-educative method for children of mentally ill parents, used in psychiatric practise in several Nordic countries. The method has also been used to some extent when a parent suffers from substance use disorder. The aim of the study was to explore the family members' experiences of the BFI when a parent has a diagnosis of substance use disorder, to gain new knowledge about the process of the BFI in this area. Ten children and 14 parents were interviewed about their experiences 6 months after a BFI. The interviews were analyzed by qualitative content analysis. The children's psychological symptoms were measured by the Strengths and Difficulties Questionnaire at baseline and after 6 months. Increased openness about the substance use disorder in the families was a recurrent theme throughout the material and a central issue reported in the children's experiences. The children had a high level of psychological symptoms according to the SDQ at baseline, but the majority of them felt that the BFI made a positive difference in their families and for themselves. The parents reported improved wellbeing of their children. Positive experienced effects for children and parents are reported in families with parental substance use disorder, with possible connection to use of BFI. The present study suggests that Beardslee's family intervention is applicable as a preventive method for children in families with a parent suffering from substance use disorder.


Effects of weak microwave fields amplitude modulated at ELF on EEG of symmetric brain areas in rats.
Averaged electroencephalogram (EEG) frequency spectra were studied in eight unanesthetized and unmyorelaxed adult male rats with chronically implanted carbon electrodes in symmetrical somesthetic areas when a weak (0.1-0.2 mW/cm) microwave (MW, 945 MHz) field, amplitude-modulated at extremely low frequency (ELF) (4 Hz), was applied. Intermittent (1 min "On," 1 min "Off") field exposure (10-min duration) was used. Hemispheric asymmetry in frequency spectra (averaged data for 10 or 1 min) of an ongoing EEG was characterized by a power decrease in the 1.5-3 Hz range on the left hemisphere and by a power decrease in the 10-14 and 20-30 Hz ranges on the right hemisphere. No differences between control and exposure experiments were shown under these routines of data averaging. Significant elevations of EEG asymmetry in 10-14 Hz range were observed during the first 20 s after four from five onsets of the MW field, when averaged spectra were obtained for every 10 s. Under neither control nor pre- and postexposure conditions was this effect observed. These results are discussed with respect to interaction of MW fields with the EEG generators.


Effect of Hepatitis B Virus X Gene on the Expression Level of p53 Gene using Hep G2 Cell Line.
The HBV-X (HBX) protein is believed to contribute to the development of HCC. However, the molecular mechanisms involved in HBX- mediated hepatocarcinogenesis remain obscure. In this study, the effect of hepatitis B virus X gene and its protein product HBxAg on expression of p53 gene in Hep G2 cell line was investigated. Viral DNA extracted from HBV-positive serum and HBX gene region was amplified using polymerase chain reaction (PCR). Then, PCR product was cloned into the pcDNA3 vector. After confirmation of cloning, the recombinant plasmid pcDNA3-X was transfected into HepG2 cell line using lipid-mediated DNA-transfection procedure. SDS-PAGE and western blotting methods were used to identify expression of HBX protein. Relative quantification was used to analyze the p53gene expression using the 2-(ΔΔ Ct) method. Recombinant plasmid pcDNA3-HBX was confirmed by restriction endonucleases digestion and colony-PCR. The results of SDS-PAGE and western blot assays showed that HBX gene could be expressed in Hep G2 cell line. There was no significant difference between the expression levels of p53 compared with GAPDH gene as housekeeping gene (p < 0.05). There was no significant difference in the protein levels between the transfected cells with X gene containing HBX130 and HBX131 double mu-tations and p53 gene. It is necessary to do more studies on Hepatitis B virus to understand the role of HBX on the development of liver cancer and its function on p53 tumor suppressor protein.


Asymmetric synthesis of dihydrocoumarins via the organocatalytic hetero-Diels-Alder reaction of ortho-quinone methides.
Enantioselective organocatalytic inverse-electron-demand hetero-Diels-Alder reactions of in situ generated ortho-quinone methides with azlactones have been developed. This strategy could generate various chiral dihydrocoumarins bearing a quaternary amino acid moiety in high yields (up to 94%) and stereoselectivities (up to 99 : 1 e.r., >20 : 1 dr) in the presence of a chiral phosphoric acid catalyst. The useful transformation and mechanistic study of this process are also presented.


Multiband wavelength-division demultiplexing with a cascaded substrate-mode grating structure.
A multiband wavelength-division-demultiplexing (WDDM) structure, which incorporates cascaded substrate-mode holograms, is presented. The method can be used to design a WDDM device that consists of two or more layers of fundamental units (i.e., substrate-mode holograms). The fundamental unit is based on a diffracted grating and a substrate that include angular dispersion, wavelength bandwidth, and total internal reflection, which can be used to separate optical signals of different wavelengths. We have designed and built a multiband WDDM device, incorporating cascaded substrate-mode holograms in dichromated gelatin.


Dynamic autoregulation of cutaneous circulation: differential control in glabrous versus nonglabrous skin.
The purpose of this project was to test the hypothesis that, independent of neural control, glabrous and nonglabrous cutaneous vasculature is capable of autoregulating blood flow. In 10 subjects, spectral and transfer function analyses of arterial pressure and skin blood flow (laser-Doppler flowmetry) from glabrous (palm) and nonglabrous (forearm) regions were performed under three conditions: baseline, ganglionic blockade via intravenous trimethaphan administration, and trimethaphan plus oscillatory lower body negative pressure (LBNP; -5 to -10 mmHg) from 0.05 to 0.07 Hz. Oscillatory LBNP was applied to regenerate mean arterial pressure variability that was abolished by ganglionic blockade. Ganglionic blockade was verified by an absence of a heart rate response to a Valsalva maneuver. Spectral power and transfer function gain between blood pressure and skin blood flow were calculated in this oscillatory frequency range (0.05-0.07 Hz). Within this frequency range, ganglionic blockade significantly decreased spectral power of blood flow in both the forearm and palm, whereas regeneration of arterial blood pressure oscillations significantly increased spectral power of forearm blood flow but not palm blood flow. During oscillatory LBNP, transfer function gain between blood pressure and skin blood flow was significantly elevated at the forearm (0.28 +/- 0.03 to 0.53 +/- 0.02 flux units/mmHg; P < 0.05) but was reduced at the palm (4.7 +/- 0.5 to 1.2 +/- 0.1 flux units/mmHg; P < 0.05). These data show that independent of neural control of blood flow, glabrous skin has the ability to buffer blood pressure oscillations and demonstrates a degree of dynamic autoregulation. Conversely, these data suggest that nonglabrous skin has diminished dynamic autoregulatory capabilities.


Combining whole-school and targeted programs for the reduction of bullying victimization: A randomized, effectiveness trial.
Despite the extensive evaluation of school-based interventions for bullying, victimization remains a significant problem in schools. Bullying victimization is significantly predicted by contextual (school-related) factors. As a consequence whole-school programs have been commonly used to prevent and reduce bullying victimization. Evidence also points to individual risk factors (such as emotional distress) in predicting victimization, yet programs to prevent bullying victimization by changing these individual risks are far less developed. Few studies have approximated "real-world" implementation conditions in their trials. The current effectiveness trial evaluated the combination of a whole-school program designed to prevent bullying perpetration and victimization together with a targeted intervention for at-risk students, teaching them individual and dyadic strategies to reduce their anxiety and manage victimization, allowing schools some latitude to implement programs as they typically would. Students from Grades 3 and 4 (N = 8,732) across 135 schools were randomly assigned to one of four conditions: combined intervention; whole-school intervention only; individual intervention only; and care as usual. Victimization decreased significantly and similarly across all four conditions at 12 and 24 months following baseline. Similar reductions and failure to discriminate conditions were found on other key constructs: anxiety; bullying perpetration; and depression. Possible reasons for the failure to demonstrate victimization prevention differences and lessons learned from this large, effectiveness trial are considered.


Estimation of sparse nonnegative sources from noisy overcomplete mixtures using MAP.
In this letter, we propose a new algorithm for estimating sparse nonnegative sources from a set of noisy linear mixtures. In particular, we consider difficult situations with high noise levels and more sources than sensors (underdetermined case). We show that when sources are very sparse in time and overlapped at some locations, they can be recovered even with very low signal-to-noise ratio, and by using many fewer sensors than sources. A theoretical analysis based on Bayesian estimation tools is included showing strong connections with algorithms in related areas of research such as ICA, NMF, FOCUSS, and sparse representation of data with overcomplete dictionaries. Our algorithm uses a Bayesian approach by modeling sparse signals through mixed-state random variables. This new model for priors imposes l(0) norm-based sparsity. We start our analysis for the case of nonoverlapped sources (1-sparse), which allows us to simplify the search of the posterior maximum avoiding a combinatorial search. General algorithms for overlapped cases, such as 2-sparse and k-sparse sources, are derived by using the algorithm for 1-sparse signals recursively. Additionally, a combination of our MAP algorithm with the NN-KSVD algorithm is proposed for estimating the mixing matrix and the sources simultaneously in a real blind fashion. A complete set of simulation results is included showing the performance of our algorithm.


Quaternary Pavonites A1+xSn2-xBi5+xS10 (A+ = Li+, Na+): Site Occupancy Disorder Defines Electronic Structure.
The field of mineralogy represents an area of untapped potential for the synthetic chemist, as there are numerous structure types that can be utilized to form analogues of mineral structures with useful optoelectronic properties. In this work, we describe the synthesis and characterization of two novel quaternary sulfides A1+xSn2-xBi5+xS10 (A = Li+, Na+). Though not natural minerals themselves, both compounds adopt the pavonite structure, which crystallizes in the C2/m space group and consists of two connected, alternating defect rock-salt slabs of varying thicknesses to create a three-dimensional lattice. Despite their commonalities in structure, their crystallography is noticeably different, as both structures have a heavy degree of site occupancy disorder that affects the actual positions of the atoms. The differences in site occupancy alter their electronic structures, with band gap values of 0.31(2) eV and 0.07(2) eV for the lithium and sodium analogues, respectively. LiSn2Bi5S10 exhibits ultralow thermal conductivity of 0.62 W m-1 K-1 at 723 K, and this result is corroborated by phonon dispersion calculations. This structure type is a promising host candidate for future thermoelectric materials investigation, as these materials have narrow band gaps and intrinsically low thermal conductivities.


Phosphorylation of Arabidopsis transketolase at Ser428 provides a potential paradigm for the metabolic control of chloroplast carbon metabolism.
Calcium is an important second messenger in eukaryotic cells that regulates many different cellular processes. To elucidate calcium regulation in chloroplasts, we identified the targets of calcium-dependent phosphorylation within the stromal proteome. A 73 kDa protein was identified as one of the most dominant proteins undergoing phosphorylation in a calcium-dependent manner in the stromal extracts of both Arabidopsis and Pisum. It was identified as TKL (transketolase), an essential enzyme of both the Calvin-Benson-Bassham cycle and the oxidative pentose phosphate pathway. Calcium-dependent phosphorylation of both Arabidopsis isoforms (AtTKL1 and AtTKL2) could be confirmed in vitro using recombinant proteins. The phosphorylation is catalysed by a stroma-localized protein kinase, which cannot utilize GTP. Phosphorylation of AtTKL1, the dominant isoform in most tissues, occurs at a serine residue that is conserved in TKLs of vascular plants. By contrast, an aspartate residue is present in this position in cyanobacteria, algae and mosses. Characterization of a phosphomimetic mutant (S428D) indicated that Ser428 phosphorylation exerts significant effects on the enzyme's substrate saturation kinetics at specific physiological pH values. The results of the present study point to a role for TKL phosphorylation in the regulation of carbon allocation.


Low physical activity among adolescents in practical education.
The aim of this study was to investigate physical activity levels and factors related to physical activity among 16-year-old girls and boys in secondary school practical and theoretical programs. An additional aim was to identify factors contributing to differences in physical activity patterns between the educational programs. Sixteen-year-old students in the first year of secondary school in Sweden (n=585) were systematically selected and 93% agreed to complete a questionnaire. Compared with students in theoretical programs, those in practical programs spent less time and energy per day in physical activity. Girls in practical programs were the least physically active, and boys in theoretical programs the most physically active students. Statistical analysis showed that, among students in practical programs, the influence of educational program on physical activity level was explained by lower socio-economic level, less parental support, lower perceived health level, and negative attitudes toward outdoor physical activities. These data suggest that promotion of physical activity should focus on students, especially girls, in practical programs. Because the difference in physical activity levels between educational programs was partly an effect of less positive parental influence, school-based programs may be especially influential in increasing physical activity levels among secondary school students.


Gastroesophageal reflux disease prevalence in the city of Sivas.
Epidemiological data of gastroesophageal reflux disease from Turkey is scarce. For this reason, we aimed to determine the gastroesophageal reflux disease prevalence in our region and to compare it with both the Western part of Turkey and with other countries in the world. We used a previously validated reflux questionnaire and applied it to a random sample of 1345 subjects stratified by socio-economic status, who were older than 20 years and were living in the city center of Sivas. The questionnaire was conducted by medical students who were attending Public Health internship. We estimated a prevalence rate of 19.3% for gastroesophageal reflux disease, defined as heartburn and/or acid regurgitation at least once a week or more frequent. We found a significant association of gastroesophageal reflux disease with age, obesity, lying down within two hours after meals, and being under stress within the last one year, but not with smoking. Comorbid diseases associated with gastroesophageal reflux disease presence included recurrent pharyngitis, chronic cough, asthma, diabetes mellitus, hypertension, and chronic obstructive pulmonary disease, but not coronary heart disease. 50.8% of our subjects had visited a physician for gastroesophageal reflux disease symptoms. The most common drug they used was proton pump inhibitors. The prevalence of gastroesophageal reflux disease in a city of the Middle Anatolian region of Turkey was similar to that in developed countries and also to the results of another study performed in the Western part of Turkey. Further studies are needed to elucidate the role of environmental factors in the development of gastroesophageal reflux disease.


Spanish National Hip Fracture Registry (RNFC): analysis of its first annual report and international comparison with other established registries.
Hip fracture registries have helped improve quality of care and reduce variability, and several audits exist worldwide. The results of the Spanish National Hip Fracture Registry are presented and compared with 13 other national registries, highlighting similarities and differences to define areas of improvement, particularly surgical delay and early mobilization. Hip fracture audits have been useful for monitoring current practice and defining areas in need of improvement. Most established registries are from Northern Europe. We present the results from the first annual report of the Spanish Hip Fracture Registry (RNFC) and compare them with other publically available audit reports. Comparison of the results from Spain with the most recent reports from another ten established hip fracture registries highlights the differences in audit characteristics, casemix, management, and outcomes. Of the patients treated in 54 hospitals, 7.208 were included in the registry between January and October 2017. Compared with other registries, the RNFC included patients ≥ 75 years old; in general, they were older, more likely to be female, had a worse prefracture ambulation status, and were more likely to have extracapsular fractures. A larger proportion was treated with intramedullary nails than in other countries, and spinal anesthesia was most commonly used. With a mean of 75.7 h, Spain had by far the longest surgical delay, and the lowest proportion of patients mobilized on the first postoperative day (58.5%). Consequently, development of pressure ulcers was high, but length of stay, mortality, and discharge to home remained in the range of other audits. National hip fracture registries have proved effective in changing clinical practice and our understanding of patients with this condition. Such registries tend to be based on an internationally recognized common dataset which would make comparisons between national registries possible, but variations such as age inclusion criteria and follow-up are becoming evident across the world. This variation should be avoided if we are to maximize the comparability of registry results and help different countries learn from each other's practice. The results reported in the Spanish RNFC, compared with those of other countries, highlight the differences between countries and detect areas of improvement, particularly surgical delay and early mobilization.


Multimodal distribution of human cold pain thresholds.
It is assumed that different pain phenotypes are based on varying molecular pathomechanisms. Distinct ion channels seem to be associated with the perception of cold pain, in particular TRPM8 and TRPA1 have been highlighted previously. The present study analyzed the distribution of cold pain thresholds with focus at describing the multimodality based on the hypothesis that it reflects a contribution of distinct ion channels. Cold pain thresholds (CPT) were available from 329 healthy volunteers (aged 18 - 37 years; 159 men) enrolled in previous studies. The distribution of the pooled and log-transformed threshold data was described using a kernel density estimation (Pareto Density Estimation (PDE)) and subsequently, the log data was modeled as a mixture of Gaussian distributions using the expectation maximization (EM) algorithm to optimize the fit. CPTs were clearly multi-modally distributed. Fitting a Gaussian Mixture Model (GMM) to the log-transformed threshold data revealed that the best fit is obtained when applying a three-model distribution pattern. The modes of the identified three Gaussian distributions, retransformed from the log domain to the mean stimulation temperatures at which the subjects had indicated pain thresholds, were obtained at 23.7 °C, 13.2 °C and 1.5 °C for Gaussian #1, #2 and #3, respectively. The localization of the first and second Gaussians was interpreted as reflecting the contribution of two different cold sensors. From the calculated localization of the modes of the first two Gaussians, the hypothesis of an involvement of TRPM8, sensing temperatures from 25 - 24 °C, and TRPA1, sensing cold from 17 °C can be derived. In that case, subjects belonging to either Gaussian would possess a dominance of the one or the other receptor at the skin area where the cold stimuli had been applied. The findings therefore support a suitability of complex analytical approaches to detect mechanistically determined patterns from pain phenotype data.


Management of giant paraesophageal hernia.
A retrospective review was performed of 51 patients operated on for giant paraesophageal hiatal hernia to compare the transthoracic and transabdominal approaches and to assess the value of a concomitant fundoplication. Operative repair was performed using open transthoracic, transabdominal, and thoracoabdominal approaches. Laparoscopic techniques were used in one patient. Fundoplication was performed in 45 patients. There was no operative mortality, but early postoperative complications occurred in 29% of patients. The presence of commonly associated symptoms was used to derive preoperative and postoperative symptom scores. Follow-up was available in 48 patients. Excellent results were reported in 69% of patients and 17% had good results. The symptom score improved significantly regardless of the operative approach selected or whether a fundoplication was performed. We conclude that outcome after open paraesophageal hiatal hernia repair is satisfactory in most patients, irrespective of the route chosen or techniques used for repair.


Dosimetric and geometric evaluation of a hybrid strategy of offline adaptive planning and online image guidance for prostate cancer radiotherapy.
For prostate cancer patients, online image-guided (IG) radiotherapy has been widely used in clinic to correct the translational inter-fractional motion at each treatment fraction. For uncertainties that cannot be corrected online, such as rotation and deformation of the target volume, margins are still required to be added to the clinical target volume (CTV) for the treatment planning. Offline adaptive radiotherapy has been implemented to optimize the treatment for each individual patient based on the measurements at early stages of treatment process. It has been shown that offline adaptive radiotherapy can effectively reduce the required margin. Recently a hybrid strategy of offline adaptive replanning and online IG was proposed and the geometric evaluation was performed. It was found that the planning margins can further be reduced by 1-2 mm compared to online IG only strategy. The purpose of this study was to investigate the dosimetric benefits of such a hybrid strategy on the target and organs at risk. A total of 420 repeated helical computed tomography scans from 28 patients were included in the study. Both low-risk patients (LRP, CTV = prostate) and intermediate-risk patients (IRP, CTV = prostate + seminal vesicles, SV) were included in the simulation. Two registration methods, based on center-of-mass shift of prostate only and prostate plus SV, were performed for IRP. The intensity-modulated radiotherapy was used in the simulation. Criteria on both cumulative and fractional doses were evaluated. Furthermore, the geometric evaluation was extended to investigate the optimal number of fractions necessary to construct the internal target volume (ITV) for the hybrid strategy. The dosimetric margin improvement was smaller than its geometric counterpart and was in the range of 0-1 mm. The optimal number of fractions necessary for the ITV construction is 2 for LRPs and 3-4 for IRPs in a hypofractionation protocol. A new cumulative index of target volume was proposed for the evaluation of adaptive radiotherapy strategies, and it was found that it had the advantages over other indices in evaluating different adaptive radiotherapy strategies.


Oxidative Stress and Spontaneous Reperfusion of Infarct-Related Artery in Patients With ST-Segment Elevation Myocardial Infarction.
In the pathogenesis of atherosclerosis, oxidative stress plays a major role in plaque instability, rupture, and erosion, which subsequently leads to thrombus formation and causes total infarct-related artery (IRA) occlusion. We investigated the relationship between spontaneous reperfusion (SR) of IRA and oxidative stress in patients with anterior ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. A total of 341 consecutive patients with anterior STEMI were prospectively included in the present study. Patients were divided into 2 groups according to their thrombolysis in myocardial infarction (TIMI) flow grade: SR group (66 patients, TIMI flow 3) and non-SR group (275 patients, TIMI flow 0-2). On multivariate logistic regression analysis, oxidative stress index (β = 0.868, 95% confidence interval [CI] = 0.806-0.934, P < .001), neutrophil to lymphocyte ratio, uric acid, mean platelet volume, Killip 2 to 4 class, and initial SYNTAX score were independently associated with SR. Oxidative stress as well as inflammation may play a pivotal role in the pathogenesis of SR in patients with STEMI.


The lupus family registry and repository.
The Lupus Family Registry and Repository (LFRR) was established with the goal of assembling and distributing materials and data from families with one or more living members diagnosed with SLE, in order to address SLE genetics. In the present article, we describe the problems and solutions of the registry design and biometric data gathering; the protocols implemented to guarantee data quality and protection of participant privacy and consent; and the establishment of a local and international network of collaborators. At the same time, we illustrate how the LFRR has enabled progress in lupus genetics research, answering old scientific questions while laying out new challenges in the elucidation of the biologic mechanisms that underlie disease pathogenesis. Trained staff ascertain SLE cases, unaffected family members and population-based controls, proceeding in compliance with the relevant laws and standards; participant consent and privacy are central to the LFRR's effort. Data, DNA, serum, plasma, peripheral blood and transformed B-cell lines are collected and stored, and subject to strict quality control and safety measures. Coded data and materials derived from the registry are available for approved scientific users. The LFRR has contributed to the discovery of most of the 37 genetic associations now known to contribute to lupus through 104 publications. The LFRR contains 2618 lupus cases from 1954 pedigrees that are being studied by 76 approved users and their collaborators. The registry includes difficult to obtain populations, such as multiplex pedigrees, minority patients and affected males, and constitutes the largest collection of lupus pedigrees in the world. The LFRR is a useful resource for the discovery and characterization of genetic associations in SLE.


Can IGF-I polymorphism affect power and endurance athletic performance?
Insulin-like growth factor-I (IGF-I) plays a key role in exercise-associated muscle growth and development. The regulatory region of the promoter of the IGF-I gene is labile, but changes in this region were studied mostly in the elderly and in relation to pathological states. C-1245T (rs35767) is a genetic variation in the promoter region of the IGF-I gene. The minor allele T was found to be associated with higher circulating IGF-I levels, and possibly with increased muscle mass. The aim of the current study was to analyze the frequency distribution of C-1245T SNP in athletic and nonathletic Israeli populations. One hundred and sixty-five athletes (78 endurance-type athletes, and 87 power-type athletes) and 159 nonathletic healthy individuals participated in the current study. Genomic DNA was extracted from peripheral EDTA treated anti-coagulated blood using a standard protocol. Genotyping of the IGF1 C-1245T polymorphism was performed using polymerase chain reaction (PCR). We found that the endurance and power athletes' allele and genotype frequencies were significantly different from those of the control group. Only 4.8% of the athletes were TT carriers, but none of the controls carried this genotype. The T allele was found to be more frequent in the top-level power athletes (international and Olympic level) compared to national level athletes, but such a difference was not found in endurance athletes. Our findings suggest a possible contribution for the relatively rare IGF-I TT genotype to endurance performance, and in particular to power sport excellence in Israeli athletes.


A novel route towards water-soluble luminescent iridium(iii) complexes via a hydroxy-bridged dinuclear precursor.
The synthesis and photophysical characterization of a new family of luminescent water-soluble ionic iridium(iii) complexes of the general formula [(ppy)2Ir(bpy)]X are reported. The Ir(iii) complexes incorporate a cyclometalated 2-phenylpyridine (ppy), the ancillary ligand 2,2'-bipyridyl (bpy) and different counterions (X- = EtO-, OH-, EtOCH2CO2-, MeOCH2CO2-). These complexes were obtained starting from the cyclometalated Ir(iii) chloro-bridged dimer [(ppy)2Ir(μ-Cl)]2, for the first time synthesized through a new microwave assisted synthetic procedure, and subsequently converted into the corresponding hydroxy-bridged dimer [(ppy)2Ir(μ-OH)]2. The latter was eventually used as a sole reagent for the synthesis of all the reported complexes by simply varying the nature of the reaction solvent from water to alcohols and glycol ethers. This study demonstrates the versatility of the [(ppy)2Ir(μ-OH)]2 complex as a precursor to water soluble ionic Ir(iii) complexes. Indeed, [(ppy)2Ir(μ-OH)]2 has shown its peculiar chemical reactivity due to both a strong base character and an unexpected oxidative ability towards the alcoholic function of glycol ethers. All the synthesized complexes exhibit, in water solution, an orange emission centred at 606 nm. Moreover, all complexes display the ability to give rise to gel phases in water upon increasing their concentration, and the photophysical study evidenced the various interactions governing the gelification process. The water-solubility of these new luminescent Ir(iii) complexes makes them potentially useful in bio-related systems.


Reciprocal interactions of the SMA and cingulate cortex sustain premovement activity for voluntary actions.
Voluntary action is one of the core functions of the human brain, and is accompanied by the well known readiness potential or Bereitschaftspotential. A network of cortical areas is responsible for the motor preparation process, including the anterior mid-cingulate cortex (aMCC) and the SMA. However, the relationship between activity in these regions during movement preparation and the readiness potential is poorly understood. We examined this relationship by integrating simultaneously acquired EEG and fMRI through computational modeling. We first observed that global field power of premovement neural activity showed a specific correlation with BOLD responses in the aMCC. We then used dynamic causal modeling to infer premovement interactions between these regions and their relationship to the premovement neural activity underlying the readiness potential. These analyses suggest that SMA and aMCC have strong reciprocal connections that act to sustain each other's activity, and that this interaction is mediated during movement preparation according to the readiness potential amplitude, as reflected in global cortical field power. Our study suggests that the reciprocal connections between SMA and aMCC are important to maintain the sustained activity of the readiness potential before movement and lead to a weak system instability at movement onset. We suggest that the effective connectivity of this network underlies its functional role in the preparation of self-generated actions.


Cellular composition and organization of the subventricular zone and rostral migratory stream in the adult and neonatal common marmoset brain.
The adult subventricular zone (SVZ) of the lateral ventricle contains neural stem cells. In rodents, these cells generate neuroblasts that migrate as chains toward the olfactory bulb along the rostral migratory stream (RMS). The neural-stem-cell niche at the ventricular wall is conserved in various animal species, including primates. However, it is unclear how the SVZ and RMS organization in nonhuman primates relates to that of rodents and humans. Here we studied the SVZ and RMS of the adult and neonatal common marmoset (Callithrix jacchus), a New World primate used widely in neuroscience, by electron microscopy, and immunohistochemical detection of cell-type-specific markers. The marmoset SVZ contained cells similar to type B, C, and A cells of the rodent SVZ in their marker expression and morphology. The adult marmoset SVZ had a three-layer organization, as in the human brain, with ependymal, hypocellular, and astrocyte-ribbon layers. However, the hypocellular layer was very thin or absent in the adult-anterior and neonatal SVZ. Anti-PSA-NCAM staining of the anterior SVZ in whole-mount ventricular wall preparations of adult marmosets revealed an extensive network of elongated cell aggregates similar to the neuroblast chains in rodents. Time-lapse recordings of marmoset SVZ explants cultured in Matrigel showed the neuroblasts migrating in chains, like rodent type A cells. These results suggest that some features of neurogenesis and neuronal migration in the SVZ are common to marmosets, humans, and rodents. This basic description of the adult and neonatal marmoset SVZ will be useful for future studies on adult neurogenesis in primates.


Effects of residue and antioxidant on thermo-optical properties of biodiesel.
Thermal lens (TL) spectrometry was applied to soybean biodiesel samples, in order to assess the behavior of their thermo-optical properties during the preparation before and after the washing process. The study was based on the thermal diffusivity parameter, which is highly sensitive and is related to the chemical composition of the sample. The results showed a difference of approximately 20% between the initial (unwashed) and the final (washed) steps of biodiesel production. This behavior indicates that the residue of the biodiesel production influences the thermal diffusivity value. Consequently, TL spectrometry can be a useful methodology for certifying the quality of biodiesel during production.


Molecular imaging of angiogenesis in nascent Vx-2 rabbit tumors using a novel alpha(nu)beta3-targeted nanoparticle and 1.5 tesla magnetic resonance imaging.
Early noninvasive detection and characterization of solid tumors and their supporting neovasculature is a fundamental prerequisite for effective therapeutic intervention, particularly antiangiogenic treatment regimens. Emerging molecular imaging techniques now allow recognition of early biochemical, physiological, and anatomical changes before manifestation of gross pathological changes. Although new tumor, vascular, extracellular matrix, and lymphatic biomarkers continue to be discovered, the alpha(nu)beta(3)-integrin remains an attractive biochemical epitope that is highly expressed on activated neovascular endothelial cells and essentially absent on mature quiescent cells. In this study, we report the first in vivo use of a magnetic resonance (MR) molecular imaging nanoparticle to sensitively detect and spatially characterize neovascularity induced by implantation of the rabbit Vx-2 tumor using a common clinical field strength (1.5T). New Zealand White rabbits (2 kg) 12 days after implantation of fresh Vx-2 tumors (2 x 2 x 2 mm(3)) were randomized into one of three treatment groups: (a) alpha(nu)beta(3)-targeted, paramagnetic formulation; (b) nontargeted, paramagnetic formulation; and (c) alpha(nu)beta(3)-targeted nonparamagnetic nanoparticles followed by (2 h) the alpha(nu)beta(3)-targeted, paramagnetic formulation to competitively block magnetic resonance imaging (MRI) signal enhancement. After i.v. systemic injection (0.5 ml of nanoparticles/kg), dynamic T(1)-weighted MRI was used to spatially and temporally determine nanoparticle deposition in the tumor and adjacent tissues, including skeletal muscle. At 2-h postinjection, alpha(nu)beta(3)-targeted paramagnetic nanoparticles increased MRI signal by 126% in asymmetrically distributed regions primarily in the periphery of the tumor. Similar increases in MR contrast were also observed within the walls of some vessels proximate to the tumor. Despite their relatively large size, nanoparticles penetrated into the leaky tumor neovasculature but did not appreciably migrate into the interstitium, leading to a 56% increase in MR signal at 2 h. Pretargeting of the alpha(nu)beta(3)-integrin with nonparamagnetic nanoparticles competitively blocked the specific binding of alpha(nu)beta(3)-targeted paramagnetic nanoparticles, decreasing the MR signal enhancement (50%) to a level attributable to local extravasation. The MR signal of adjacent hindlimb muscle or contralateral control tissues was unchanged by either the alpha(nu)beta(3)-targeted or control paramagnetic agents. Immunohistochemistry of alpha(nu)beta(3)-integrin corroborated the extent and asymmetric distribution of neovascularity observed by MRI. These studies demonstrate the potential of this targeted molecular imaging agent to detect and characterize (both biochemically and morphologically) early angiogenesis induced by minute solid tumors with a clinical 1.5 Tesla MRI scanner, facilitating the localization of nascent cancers or metastases, as well as providing tools to phenotypically categorize and segment patient populations for therapy and to longitudinally follow the effectiveness of antitumor treatment regimens.


Involved-field radiation therapy for selected cases of recurrent ovarian cancer.
In our institutional experience, involved-field radiation therapy (IFRT) yields favorable outcomes in patients with recurrent epithelial ovarian cancer (EOC). This retrospective study aimed to investigate the clinical benefits of IFRT in this patient population. Among patients treated with IFRT for recurrent EOC between 2010 and 2017, 61 patients with 90 treatments were included. IFRT encompassed all treatable lesions identified via imaging studies with 10-15-mm margins. Prescribed doses were ≥45 Gy (equivalent dose in 2 Gy/fraction). Patients were followed up for a median of 19.0 (Interquartile range, 8.6-34.9) months after IFRT. The 2-year in-field control, progression-free survival, and overall survival (OS) rates were 42.7%, 24.2%, and 78.9%, respectively. Fifty-three IFRT sessions (58.9%) were followed by systemic chemotherapy, and the median chemotherapy-free interval (CFI) was 10.5 (95% confidence interval=7.3-13.7) months. A higher carbohydrate antigen-125 (CA-125) level correlated with a worse 2-year OS (69.2% vs. 91.0%; p=0.001) and shorter median CFI (4.7 vs. 11.9 months; p<0.001). Twenty-eight (31.1%) of 90 treatments yielded a long-term CFI >12 months. For patients with a normal CA-125 level and/or platinum-sensitive tumor, IFRT prolonged CFI regardless of pre-existing carcinomatosis, gross tumor volume, and number of treatment sites. Our early experience demonstrates the safety and feasibility of IFRT as an effective salvage therapy and enables a "chemotherapy holiday" in selected recurrent EOC settings. The CA-125 value before IFRT (within normal range) and/or platinum sensitivity could be used as selection criteria for IFRT.


The Aspergillus fumigatus cell wall integrity signaling pathway: drug target, compensatory pathways, and virulence.
Aspergillus fumigatus is the most important airborne fungal pathogen, causing severe infections with invasive growth in immunocompromised patients. The fungal cell wall (CW) prevents the cell from lysing and protects the fungus against environmental stress conditions. Because it is absent in humans and because of its essentiality, the fungal CW is a promising target for antifungal drugs. Nowadays, compounds acting on the CW, i.e., echinocandin derivatives, are used to treat A. fumigatus infections. However, studies demonstrating the clinical effectiveness of echinocandins in comparison with antifungals currently recommended for first-line treatment of invasive aspergillosis are still lacking. Therefore, it is important to elucidate CW biosynthesis pathways and their signal transduction cascades, which potentially compensate the inhibition caused by CW- perturbing compounds. Like in other fungi, the central core of the cell wall integrity (CWI) signaling pathway in A. fumigatus is composed of three mitogen activated protein kinases. Deletion of these genes resulted in severely enhanced sensitivity of the mutants against CW-disturbing compounds and in drastic alterations of the fungal morphology. Additionally, several cross-talk interactions between the CWI pathways and other signaling pathways are emerging, raising the question about their role in the CW compensatory mechanisms. In this review we focused on recent advances in understanding the CWI signaling pathway in A. fumigatus and its role during drug stress response and virulence.


Temporal super-resolution microscopy using a hue-encoded shutter.
Limited time-resolution in microscopy is an obstacle to many biological studies. Despite recent advances in hardware, digital cameras have limited operation modes that constrain frame-rate, integration time, and color sensing patterns. In this paper, we propose an approach to extend the temporal resolution of a conventional digital color camera by leveraging a multi-color illumination source. Our method allows for the imaging of single-hue objects at an increased frame-rate by trading spectral for temporal information (while retaining the ability to measure base hue). It also allows rapid switching to standard RGB acquisition. We evaluated the feasibility and performance of our method via experiments with mobile resolution targets. We observed a time-resolution increase by a factor 2.8 with a three-fold increase in temporal sampling rate. We further illustrate the use of our method to image the beating heart of a zebrafish larva, allowing the display of color or fast grayscale images. Our method is particularly well-suited to extend the capabilities of imaging systems where the flexibility of rapidly switching between high frame rate and color imaging are necessary.


Painful engrams: Oscillatory correlates of working memory for phasic nociceptive laser stimuli.
Research suggests that working memory (WM) is impaired in chronic pain. Yet, information on how potentially noxious stimuli are maintained in memory is limited in patients as well as in healthy people. We recorded electroencephalography (EEG) in healthy volunteers during a modified delayed match-to-sample task where maintenance in memory of relevant attributes of nociceptive laser stimuli was essential for subsequent cued-discrimination. Participants performed in high and low load conditions (i.e. three vs. two stimuli to keep in WM). Modulation of EEG oscillations in the beta band during the retention interval and in the alpha band during the pre-retention interval reflected performance in the WM task. Importantly, both a non-verbal and a verbal neuropsychological WM test predicted oscillatory modulations. Moreover, these two neuropsychological tests and self-reported personality measures predicted the performance in the nociceptive WM task. Results demonstrate (i) that beta and alpha EEG oscillations can represent WM for nociceptive stimuli; (ii) the association between neuropsychological measures of WM and the brain representation of phasic nociceptive painful stimuli; and (iii) that personality factors can predict memory for nociceptive stimuli at the behavioural level. Altogether, our findings offer a promising approach for investigating cortical correlates of nociceptive memory in clinical pain conditions.


Comparative performance information plays no role in the referral behaviour of GPs.
Comparative performance information (CPI) about the quality of hospital care is information used to identify high-quality hospitals and providers. As the gatekeeper to secondary care, the general practitioner (GP) can use CPI to reflect on the pros and cons of the available options with the patient and choose a provider best fitted to the patient's needs. We investigated how GPs view their role in using CPI to choose providers and support patients. We used a mixed-method, sequential, exploratory design to conduct explorative interviews with 15 GPs about their referral routines, methods of referral consideration, patient involvement, and the role of CPI. Then we quantified the qualitative results by sending a survey questionnaire to 81 GPs affiliated with a representative national research network. Seventy GPs (86% response rate) filled out the questionnaire. Most GPs did not know where to find CPI (87%) and had never searched for it (94%). The GPs reported that they were not motivated to use CPI due to doubts about its role as support information, uncertainty about the effect of using CPI, lack of faith in better outcomes, and uncertainty about CPI content and validity. Nonetheless, most GPs believed that patients would like to be informed about quality-of-care differences (62%), and about half the GPs discussed quality-of-care differences with their patients (46%), though these discussions were not based on CPI. Decisions about referrals to hospital care are not based on CPI exchanges during GP consultations. As a gatekeeper, the GP is in a good position to guide patients through the enormous amount of quality information that is available. Nevertheless, it is unclear how and whether the GP's role in using information about quality of care in the referral process can grow, as patients hardly ever initiate a discussion based on CPI, though they seem to be increasingly more critical about differences in quality of care. Future research should address the conditions needed to support GPs' ability and willingness to use CPI to guide their patients in the referral process.


Experimental evidence for the origin of ductal-type adenocarcinoma from the islets of Langerhans.
To investigate the role of the islets of Langerhans in pancreatic carcinogenesis, freshly isolated islets from male Syrian hamsters were transplanted into the right submandibular glands of 50 female hamsters that were or were not pre-treated with streptozotocin. Thyroid gland fragments, cellulose powder, and immortal hamster pancreatic ductal cells were injected into the left submandibular gland of the same hamsters. All recipient hamsters were then treated with the potent pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine weekly at a dose of 40 mg/kg of body weight for 3 weeks. Between 3 and 8 weeks later, 18 of 75 (24%) hamsters developed large ductal-type adenocarcinomas in the submandibular gland region, where islets were transplanted, but none developed tumors in the left submandibular gland. In 9 of 18 hamsters, tumors were multiple so that a total of 31 cancers were found. Eleven of these carcinomas were in the vicinity of transplanted islets, eight of which showed intra-insular ductular or cyst formation as seen in the pancreas of hamsters during pancreatic carcinogenesis. The formation of ductular structures within islets was also demonstrated in vitro. Some tumor cells in the vicinity of these islets were reactive with anti-insulin. Y chromosome message was found by polymerase chain reaction analysis in one of the three tumors examined. Also, like the induced pancreatic tumors, all three submandibular gland tumors that were examined had the mutation of the c-Ki-ras oncogene at codon 12 and all tumors expressed blood group A antigen. These and other findings strongly suggest that some components of islets, most probably stem cells, are the origin of ductal-type adenocarcinomas in this model.


Bound-to-continuum absorption with tunneling in type-II nanostructures: a multiband source-radiation approach.
We convert calculations of the bound-to-continuum absorption in type-II semiconductor quantum wells into an equivalent source-radiation problem under the effective-mass approximation with band mixing. Perfectly matched layers corresponding to the eight-band Luttinger-Kohn Hamiltonian are introduced to incorporate the effect of quasi-bound states in open regions. In this way, the interplay between quantum tunneling and optical transitions is fully taken into account. From resulted lineshapes of the Fano resonance, we can evaluate tunneling rates of these metastable states and related absorption strengths relative to those of the continuum. The approach here is useful in estimations of carrier extraction rates from type-II nanostructures for photovoltaic applications.


Effects of a 98% solution of glycerol or sterilization with ethylene oxide on FeLV in bone allografts and effects on bone incorporation of allografts in cats.
To compare virucidal effects and bone incorporation properties of cortical bone allografts transplanted into specific-pathogen-free (SPF) cats. Allografts consisted of untreated bone from a SPF cat (negative-control group) and bone from 5 FeLV-infected cats that was subjected to sterilization with ethylene oxide (ETO), preservation with glycerol, or no treatment (positive-control group). Bones from the aforementioned groups and twenty 8-week-old SPF cats (5 cats/group) implanted with an allograft from 1 of the aforementioned groups. After implantation, blood samples were collected weekly to monitor FeLV p27 antigen and antibody titers. Quantification of FeLV provirus was performed on blood samples at weeks 0, 4, and 8 and donor bone samples at time of implantation. Cats were euthanatized 8 weeks after transplantation, and graft sites were evaluated. All results for negative-control cats were negative. All ETO group cats had negative results for antigen and provirus in blood, whereas 1 cat had a low antibody titer. Although 3 ETO-treated allografts were positive for provirus, the DNA appeared denatured. One cat in the glycerol group had positive results for all tests in blood samples. All glycerol-preserved allografts were positive when tested for provirus. All results for positive-control group cats were positive. Differences in incorporation of bone grafts were not observed. Glycerol preservation of FeLV-infected bone allografts did not eliminate transmission of retrovirus to recipients. In contrast, ETO sterilization appeared to denature DNA and prevent infection. Treatments did not affect incorporation of bone grafts in young cats.


Effect of sodium chloride on the structure and stability of spider silk's N-terminal protein domain.
A spider's ability to store silk protein solutions at high concentration is believed to be related to the protein's terminal domains. It has been suggested that a shift in salt concentration and pH can have a significant influence on the assembly process. Based on experimental data, a model has been proposed in which the N-terminal domain exists as a monomer during storage and assembles into a homodimer upon spinning. Here we perform a systematic computational study using atomistic, coarse-grained and well-tempered metadynamics simulation to understand how the NaCl concentration in the solution affects the N-terminal domain of the silk protein. Our results show that a high salt concentration, as found during storage, weakens key salt bridges between the monomers, inducing a loss in bond energy by 28.6% in a single salt bridge. As a result dimer formation is less likely as 35.5% less energy is required to unfold the dimer by mechanical force. Conversely, homodimer formation appears to be more likely at low salt concentrations as the salt bridge stays at the lower energy state. The link between salt concentration, structure and stability of the N-terminal domain provides a possible mechanism that prevents premature fiber formation during storage.


Mutant huntingtin impairs immune cell migration in Huntington disease.
In Huntington disease (HD), immune cells are activated before symptoms arise; however, it is unclear how the expression of mutant huntingtin (htt) compromises the normal functions of immune cells. Here we report that primary microglia from early postnatal HD mice were profoundly impaired in their migration to chemotactic stimuli, and expression of a mutant htt fragment in microglial cell lines was sufficient to reproduce these deficits. Microglia expressing mutant htt had a retarded response to a laser-induced brain injury in vivo. Leukocyte recruitment was defective upon induction of peritonitis in HD mice at early disease stages and was normalized upon genetic deletion of mutant htt in immune cells. Migration was also strongly impaired in peripheral immune cells from pre-manifest human HD patients. Defective actin remodeling in immune cells expressing mutant htt likely contributed to their migration deficit. Our results suggest that these functional changes may contribute to immune dysfunction and neurodegeneration in HD, and may have implications for other polyglutamine expansion diseases in which mutant proteins are ubiquitously expressed.


Dynamics of sheet nacre formation in bivalves.
Formation of nacre (mother-of-pearl) is a biomineralization process of fundamental scientific as well as industrial importance. However, the dynamics of the formation process is still not understood. Here, we use scanning electron microscopy and high spatial resolution ion microprobe depth-profiling to image the full three-dimensional distribution of organic materials around individual tablets in the top-most layer of forming nacre in bivalves. Nacre formation proceeds by lateral, symmetric growth of individual tablets mediated by a growth-ring rich in organics, in which aragonite crystallizes from amorphous precursors. The pivotal role in nacre formation played by the growth-ring structure documented in this study adds further complexity to a highly dynamical biomineralization process.


Information Transfer in Gonadotropin-releasing Hormone (GnRH) Signaling: EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK)-MEDIATED FEEDBACK LOOPS CONTROL HORMONE SENSING.
Cell signaling pathways are noisy communication channels, and statistical measures derived from information theory can be used to quantify the information they transfer. Here we use single cell signaling measures to calculate mutual information as a measure of information transfer via gonadotropin-releasing hormone (GnRH) receptors (GnRHR) to extracellular signal-regulated kinase (ERK) or nuclear factor of activated T-cells (NFAT). This revealed mutual information values <1 bit, implying that individual GnRH-responsive cells cannot unambiguously differentiate even two equally probable input concentrations. Addressing possible mechanisms for mitigation of information loss, we focused on the ERK pathway and developed a stochastic activation model incorporating negative feedback and constitutive activity. Model simulations revealed interplay between fast (min) and slow (min-h) negative feedback loops with maximal information transfer at intermediate feedback levels. Consistent with this, experiments revealed that reducing negative feedback (by expressing catalytically inactive ERK2) and increasing negative feedback (by Egr1-driven expression of dual-specificity phosphatase 5 (DUSP5)) both reduced information transfer from GnRHR to ERK. It was also reduced by blocking protein synthesis (to prevent GnRH from increasing DUSP expression) but did not differ for different GnRHRs that do or do not undergo rapid homologous desensitization. Thus, the first statistical measures of information transfer via these receptors reveals that individual cells are unreliable sensors of GnRH concentration and that this reliability is maximal at intermediate levels of ERK-mediated negative feedback but is not influenced by receptor desensitization.


Supramodal Theta, Gamma, and Sustained Fields Predict Modality-specific Modulations of Alpha and Beta Oscillations during Visual and Tactile Working Memory.
Flexible control over currently relevant sensory representations is an essential feature of primate cognition. We investigated the neurophysiological bases of such flexible control in humans during an intermodal working memory task in which participants retained visual or tactile sequences. Using magnetoencephalography, we first show that working memory retention engages early visual and somatosensory areas, as reflected in the sustained load-dependent suppression of alpha and beta oscillations. Next, we identify three components that are also load dependent but modality independent: medial prefrontal theta synchronization, frontoparietal gamma synchronization, and sustained parietal event-related fields. Critically, these domain-general components predict (across trials and within load conditions) the modality-specific suppression of alpha and beta oscillations, with largely unique contributions per component. Thus, working memory engages multiple complementary frontoparietal components that have discernible neuronal dynamics and that flexibly modulate retention-related activity in sensory areas in a manner that tracks the current contents of working memory.


Are there acyl-homoserine lactones within mammalian intestines?
Many Proteobacteria are capable of quorum sensing using N-acyl-homoserine lactone (acyl-HSL) signaling molecules that are synthesized by LuxI or LuxM homologs and detected by transcription factors of the LuxR family. Most quorum-sensing species have at least one LuxR and one LuxI homolog. However, members of the Escherichia, Salmonella, Klebsiella, and Enterobacter genera possess only a single LuxR homolog, SdiA, and no acyl-HSL synthase. The most obvious hypothesis is that these organisms are eavesdropping on acyl-HSL production within the complex microbial communities of the mammalian intestinal tract. However, there is currently no evidence of acyl-HSLs being produced within normal intestinal communities. A few intestinal pathogens, including Yersinia enterocolitica, do produce acyl-HSLs, and Salmonella can detect them during infection. Therefore, a more refined hypothesis is that SdiA orthologs are used for eavesdropping on other quorum-sensing pathogens in the host. However, the lack of acyl-HSL signaling among the normal intestinal residents is a surprising finding given the complexity of intestinal communities. In this review, we examine the evidence for and against the possibility of acyl-HSL signaling molecules in the mammalian intestine and discuss the possibility that related signaling molecules might be present and awaiting discovery.


YtqI from Bacillus subtilis has both oligoribonuclease and pAp-phosphatase activity.
Oligoribonuclease is the only RNase in Escherichia coli that is able to degrade RNA oligonucleotides five residues and shorter in length. Firmicutes including Bacillus subtilis do not have an Oligoribonuclease (Orn) homologous protein and it is not yet understood which proteins accomplish the equivalent function in these organisms. We had previously identified oligoribonucleases Orn from E. coli and its human homolog Sfn in a screen for proteins that are regulated by 3'-phosphoadenosine 5'-phosphate (pAp). Here, we identify YtqI as a potential functional analog of Orn through its interaction with pAp. YtqI degrades RNA oligonucleotides in vitro with preference for 3-mers. In addition, YtqI has pAp-phosphatase activity in vitro. In agreement with these data, YtqI is able to complement both orn and cysQ mutants in E. coli. An ytqI mutant in B. subtilis shows impairment of growth in the absence of cysteine, a phenotype resembling that of a cysQ mutant in E. coli. Phylogenetic distribution of YtqI, Orn and CysQ supports bifunctionality of YtqI.


Improvement in retinal image quality with dynamic correction of the eye's aberrations.
We measured the improvement in retinal image quality provided by correcting the temporal variation in the eye's wave aberration with a closed-loop adaptive optics system. This system samples the eye's wave aberration at rates up to 30 Hz. Correction of the eye's aberrations can be completed in 0.25-0.5 seconds, resulting in residual rms wave-front errors as low as 0.1 microns for 6.8 mm pupils. Real-time wave-front measurements were used to determine how effectively the spatial and temporal components of the eye's wave aberration were corrected. The system provides dynamic correction of fluctuations in Zernike modes up to 5 th order with temporal frequency components up to 0.8 Hz. Temporal performance is in good agreement with predictions based on theory. Correction of the temporal variation in the eye's wave aberration increases the Strehl ratio of the point spread function nearly 3 times, and increases the contrast of images of cone photoreceptors by 33% compared with images taken with only static correction of the eye's higher order aberrations.