Physician shadowing: a review of the literature and proposal for guidelines.
Premedical students commonly shadow physicians to gain an understanding of what careers in medicine entail. The authors reviewed the literature to explore (1) whether shadowing achieves this goal consistently and effectively, (2) the ethical issues involved, and (3) other reasons that individuals shadow physicians. The authors searched the MEDLINE database via Ovid for English-language articles published from 1948 to March 2011. Eligible articles described physician shadowing programs and/or assessed the value of physician shadowing independently or in comparison with other educational methods. Of 770 articles identified, 13 articles about physician shadowing programs met inclusion criteria. Two of the 13 programs involved shadowing only, whereas 11 included other educational initiatives. Participants varied; shadowers included students (high school, college, medical school), recent medical school graduates, or international medical graduates. Few studies addressed shadowing by premedical students. Most studies involved programs outside the United States. Shadowing program objectives and characteristics differed. Data reported from focus groups, interviews, and surveys suggest that shadowing experiences generally increased participants' interest in medicine (or a specialty) or improved participants' confidence in transitioning to a new position. Some articles raised ethical and practical concerns related to shadowing. The few shadowing programs described in the literature were heterogeneous and often involved other activities. Further research is warranted; objective outcomes measures would be useful. The authors propose developing guidelines and introducing a code of conduct for premedical students, to enhance the consistency of shadowing experiences and address ethical and practical considerations.


Influenza A Pneumonia Associated with Diffuse Alveolar Hemorrhage. A Case Report and Literature Review.
BACKGROUND Diffuse alveolar hemorrhage (DAH) represents a life-threatening complication for many respiratory infections. We present a case of a patient with influenza A pneumonia associated with DAH. CASE REPORT An 80-year-old female patient was admitted with lethargy, dyspnea, and chest pain. On examination, she was afebrile with bilateral basal inspiratory crackles. Her chest x-ray revealed retro-cardiac infiltrate. Her hospital course was complicated by respiratory failure and septic shock requiring intubation. Nasopharyngeal swabs, rapid testing was positive for influenza A. Bronchoscopy showed diffuse bleeding and bronchoalveolar lavage (BAL) of the left lower lobe showed progressively bloody returns, consistent with DAH. Methylprednisolone 250 mg daily was started, with improvement in oxygenation. Repeat bronchoscopy 2 days later revealed normal mucosa and no further bleeding. The patient's respiratory status and infiltrates improved, but her overall status continued to deteriorate, and she died 2 weeks after admission. CONCLUSIONS High fatality rates have been reported in patients with influenza A viral pneumonia complicated by DAH. Advanced age and the presence of significant co-morbidities might predispose a patient to the development of a more aggressive clinical manifestation of influenza A and also increases the risk of developing DAH. Therefore, clinicians managing patients with influenza A viral pneumonia with this predisposing history should also maintain a high suspicion for DAH. We suggest early BAL for diagnosis and for the evaluation of other infections etiologies. Aggressive supportive care and the use of antiviral agents is recommended. The role of steroids is unclear and can be considered in patients with fulminant disease but might have no outcome benefit.


Aluminum adjuvants elicit fibrin-dependent extracellular traps in vivo.
It has been recognized for nearly 80 years that insoluble aluminum salts are good immunologic adjuvants and that they form long-lived nodules in vivo. Nodule formation has long been presumed to be central for adjuvant activity by providing an antigen depot, but the composition and function of these nodules is poorly understood. We show here that aluminum salt nodules formed within hours of injection and contained the clotting protein fibrinogen. Fibrinogen was critical for nodule formation and required processing to insoluble fibrin by thrombin. DNase treatment partially disrupted the nodules, and the nodules contained histone H3 and citrullinated H3, features consistent with extracellular traps. Although neutrophils were not essential for nodule formation, CD11b(+) cells were implicated. Vaccination of fibrinogen-deficient mice resulted in normal CD4 T-cell and antibody responses and enhanced CD8 T-cell responses, indicating that nodules are not required for aluminum's adjuvant effect. Moreover, the ability of aluminum salts to retain antigen in the body, the well-known depot effect, was unaffected by the absence of nodules. We conclude that aluminum adjuvants form fibrin-dependent nodules in vivo, that these nodules have properties of extracellular traps, and the nodules are not required for aluminum salts to act as adjuvants.


Single molecule magnets: from thin films to nano-patterns.
Single molecule magnets (SMM) are a class of molecules exhibiting magnetic properties similar to those observed in conventional bulk magnets, but of molecular origin. SMMs have been proposed as potential candidates for several technological applications that require highly controlled thin films and patterns. Here we present an overview of the most important approaches for thin film growth and micro(nano)-patterning of SMM, giving special attention to Mn(12) based molecules. We present both conventional approaches to thin film growth (Langmuir-Blodgett, chemical approach, dip and dry, laser evaporation), patterning (micro-contact printing, deposition on patterned surface, moulding of homogeneous films) and new methods specifically developed for SMM (lithographically controlled wetting, lithographically controlled de-mixing).


A first-generation microsatellite-based genetic linkage map of the Siberian jay (Perisoreus infaustus): insights into avian genome evolution.
Genomic resources for the majority of free-living vertebrates of ecological and evolutionary importance are scarce. Therefore, linkage maps with high-density genome coverage are needed for progress in genomics of wild species. The Siberian jay (Perisoreus infaustus; Corvidae) is a passerine bird which has been subject to lots of research in the areas of ecology and evolutionary biology. Knowledge of its genome structure and organization is required to advance our understanding of the genetic basis of ecologically important traits in this species, as well as to provide insights into avian genome evolution. We describe the first genetic linkage map of Siberian jay constructed using 117 microsatellites and a mapping pedigree of 349 animals representing five families from a natural population breeding in western Finland from the years 1975 to 2006. Markers were resolved into nine autosomal and a Z-chromosome-specific linkage group, 10 markers remaining unlinked. The best-position map with the most likely positions of all significantly linked loci had a total sex-average size of 862.8 cM, with an average interval distance of 9.69 cM. The female map covered 988.4 cM, whereas the male map covered only 774 cM. The Z-chromosome linkage group comprised six markers, three pseudoautosomal and three sex-specific loci, and spanned 10.6 cM in females and 48.9 cM in males. Eighty-one of the mapped loci could be ordered on a framework map with odds of >1000:1 covering a total size of 809.6 cM in females and 694.2 cM in males. Significant sex specific distortions towards reduced male recombination rates were revealed in the entire best-position map as well as within two autosomal linkage groups. Comparative mapping between Siberian jay and chicken anchored 22 homologous loci on 6 different linkage groups corresponding to chicken chromosomes Gga1, 2, 3, 4, 5, and Z. Quite a few cases of intra-chromosomal rearrangements within the autosomes and three cases of inter-chromosomal rearrangement between the Siberian jay autosomal linkage groups (LG1, LG2 and LG3) and the chicken sex chromosome GgaZ were observed, suggesting a conserved synteny, but changes in marker order, within autosomes during about 100 million years of avian evolution. The constructed linkage map represents a valuable resource for intraspecific genomics of Siberian jay, as well as for avian comparative genomic studies. Apart from providing novel insights into sex-specific recombination rates and patterns, the described maps - from a previously genomically uncharacterized superfamily (Corvidae) of passerine birds - provide new insights into avian genome evolution. In combination with high-resolution data on quantitative trait variability from the study population, they also provide a foundation for QTL-mapping studies.


Effect of pH on Cleavage of Glycogen by Vaginal Enzymes.
Glycogen expressed by the lower genital tract epithelium is believed to support Lactobacillus growth in vivo, although most genital isolates of Lactobacillus are not able to use glycogen as an energy source in vitro. We recently reported that α-amylase is present in the genital fluid of women and that it breaks down glycogen into small carbohydrates that support growth of lactobacilli. Since the pH of the lower genital tract can be very low, we determined how low pH affects glycogen processing by α-amylase. α-amylase in saliva degraded glycogen similarly at pH 6 and 7, but activity was reduced by 52% at pH 4. The glycogen degrading activity in nine genital samples from seven women showed a similar profile with an average reduction of more than 50% at pH 4. However, two samples collected from one woman at different times had a strikingly different pH profile with increased glycogen degradation at pH 4, 5 and 6 compared to pH 7. This second pH profile did not correlate with levels of human α-acid glucosidase or human intestinal maltase glucoamylase. High-performance anion-exchange chromatography showed that mostly maltose was produced from glycogen by samples with the second pH profile in contrast to genital α-amylase that yielded maltose, maltotriose and maltotetraose. These studies show that at low pH, α-amylase activity is reduced to low but detectable levels, which we speculate helps maintain Lactobacillus growth at a limited but sustained rate. Additionally, some women have a genital enzyme distinct from α-amylase with higher activity at low pH. Further studies are needed to determine the identity and distribution of this second enzyme, and whether its presence influences the makeup of genital microbiota.


Safety evaluation of telbivudine.
Successful treatment of chronic hepatitis B (CHB) often requires long-term oral nucleoside/nucleotide agents which can be associated with viral resistance, patient non-compliance and adverse effects. Telbivudine is one of the more potent options available, with a 6.5- to 6.6-log copies/ml hepatitis B DNA reduction at 12 weeks in an early viral kinetic study, a potency comparable to entecavir. It is also one of the few drugs in the treatment of CHB under FDA pregnancy Category B. The efficacy and safety profile of telbivudine in compensated and decompensated CHB patients compared to other agents are discussed. Viral resistance, characteristic adverse effects including elevation in creatine kinase and peripheral neuropathy in telbivudine treatment are reviewed. Infrequent but significant adverse effects of other nucleoside/nucleotide analogs are highlighted. Readers are provided the latest update on the clinical profile of long-term use of telbivudine. Long-term telbivudine treatment offers effective viral suppression to CHB patients with certain baseline characteristics and on-treatment virologic response. Creatine kinase elevation is not a good predictor of muscle-related adverse effects with nucleoside/nucleotide analogs. But significant myopathy and neuropathy have been reported in a small number of patients receiving telbivudine.


An organic-inorganic broadband photodetector based on a single polyaniline nanowire doped with quantum dots.
The capability to detect light over a broad waveband is highly important for practical optoelectronic applications and has been achieved with photodetectors of one-dimensional inorganic nanomaterials such as Si, ZnO, and GaN. However, achieving high speed responsivity over an entire waveband within such a photodetector remains a challenge. Here we demonstrate a broadband photodetector using a single polyaniline nanowire doped with quantum dots that is highly responsive over a broadband from 350 to 700 nm. The high responsivity is due to the high density of trapping states at the enormous interfaces between polyaniline and quantum dots. The interface trapping can effectively reduce the recombination rate and enhance the efficiency for light detection. Furthermore, a tunable spectral range can be achieved by size-based spectral tuning of quantum dots. The use of organic-inorganic hybrid polyaniline nanowires in broadband photodetection may offer novel functionalities in optoelectronic devices and circuits.


The Sea Peoples, from cuneiform tablets to carbon dating.
The 13(th) century BC witnessed the zenith of the Aegean and Eastern Mediterranean civilizations which declined at the end of the Bronze Age, ∼3200 years ago. Weakening of this ancient flourishing Mediterranean world shifted the political and economic centres of gravity away from the Levant towards Classical Greece and Rome, and led, in the long term, to the emergence of the modern western civilizations. Textual evidence from cuneiform tablets and Egyptian reliefs from the New Kingdom relate that seafaring tribes, the Sea Peoples, were the final catalyst that put the fall of cities and states in motion. However, the lack of a stratified radiocarbon-based archaeology for the Sea People event has led to a floating historical chronology derived from a variety of sources spanning dispersed areas. Here, we report a stratified radiocarbon-based archaeology with anchor points in ancient epigraphic-literary sources, Hittite-Levantine-Egyptian kings and astronomical observations to precisely date the Sea People event. By confronting historical and science-based archaeology, we establish an absolute age range of 1192-1190 BC for terminal destructions and cultural collapse in the northern Levant. This radiocarbon-based archaeology has far-reaching implications for the wider Mediterranean, where an elaborate network of international relations and commercial activities are intertwined with the history of civilizations.


Herpesviruses and Toxoplasma gondii in orbital frontal cortex of psychiatric patients.
Herpes simplex virus (HSV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus-6 (HHV-6) are viruses capable of establishing latency. All of these infect the CNS and have been detected in human postmortem brains. Toxoplasma gondii is a protozoan organism which can reactivate in the brains of previously infected immunocompromised individuals. To screen for the presence of herpesviruses and T. gondii in postmortem orbital frontal brain samples from patients with schizophrenia, affective disorders, and controls, we used nested-polymerase chain reaction (n-PCR)/sequencing. We identified HHV-6B sequences in 2/51 postmortem brain samples but no sequences from other herpesviruses. We did not detect sequences of T. gondii in the postmortem brains. Additional studies including ones directed at the sensitive detection of viral nucleic acids in multiple brain regions should be directed at confirming or excluding a role for viruses and protozoa in the etiology of these disorders.


Anti-inflammatory and wound healing activities of Aloe littoralis in rats.
Aloe littoralis Baker (Asphodelaceae family) is a well known plant in southern parts of Iran. Because of its use in Iranian folk medicine as a wound-healing agent, the present study was carried out to investigate anti-inflammatory and wound healing activities of this plant in Wistar rats. A. littoralis raw mucilaginous gel (ALRMG) and also two gel formulations prepared from the raw mucilaginous gel were used in this study. Gel formulations (12.5% and 100% v/w Aloe mucilage in a carbomer base) were applied topically (500 mg once daily) for 24 days in the thermal wound model. Also Aloe gel formulation (100%) and ALRMG (500 mg daily) were evaluated in incisional wound model. Carrageenan-induced paw edema was used to assess the anti-inflammatory effect of intraperitoneal injection of ALRMG. In burn wound, ALRMG and Aloe formulated gel (100%) showed significant (P<0.05) healing effect. Topical application of ALMRG and Aloe formulated gel (100%) promoted healing rate of incisional wound. In carrageenan test, ALRMG (2.5 and 5 ml/Kg) revealed significant (P<0.05) anti-inflammatory activity. Results showed that A. littoralis is a potential wound-healing and anti-inflammatory agent in rats. Further studies are needed to find out the mechanism of these biological effects and also the active constituents responsible for the effects.


The Clostridium sporulation programs: diversity and preservation of endospore differentiation.
Bacillus and Clostridium organisms initiate the sporulation process when unfavorable conditions are detected. The sporulation process is a carefully orchestrated cascade of events at both the transcriptional and posttranslational levels involving a multitude of sigma factors, transcription factors, proteases, and phosphatases. Like Bacillus genomes, sequenced Clostridium genomes contain genes for all major sporulation-specific transcription and sigma factors (spo0A, sigH, sigF, sigE, sigG, and sigK) that orchestrate the sporulation program. However, recent studies have shown that there are substantial differences in the sporulation programs between the two genera as well as among different Clostridium species. First, in the absence of a Bacillus-like phosphorelay system, activation of Spo0A in Clostridium organisms is carried out by a number of orphan histidine kinases. Second, downstream of Spo0A, the transcriptional and posttranslational regulation of the canonical set of four sporulation-specific sigma factors (σ(F), σ(E), σ(G), and σ(K)) display different patterns, not only compared to Bacillus but also among Clostridium organisms. Finally, recent studies demonstrated that σ(K), the last sigma factor to be activated according to the Bacillus subtilis model, is involved in the very early stages of sporulation in Clostridium acetobutylicum, C. perfringens, and C. botulinum as well as in the very late stages of spore maturation in C. acetobutylicum. Despite profound differences in initiation, propagation, and orchestration of expression of spore morphogenetic components, these findings demonstrate not only the robustness of the endospore sporulation program but also the plasticity of the program to generate different complex phenotypes, some apparently regulated at the epigenetic level.


Effectiveness of a Smartphone App With a Wearable Activity Tracker in Preventing the Recurrence of Mood Disorders: Prospective Case-Control Study.
Smartphones and wearable devices can be used to obtain diverse daily log data related to circadian rhythms. For patients with mood disorders, giving feedback via a smartphone app with appropriate behavioral correction guides could play an important therapeutic role in the real world. We aimed to evaluate the effectiveness of a smartphone app named Circadian Rhythm for Mood (CRM), which was developed to prevent mood episodes based on a machine learning algorithm that uses passive digital phenotype data of circadian rhythm behaviors obtained with a wearable activity tracker. The feedback intervention for the CRM app consisted of a trend report of mood prediction, H-score feedback with behavioral guidance, and an alert system triggered when trending toward a high-risk state. In total, 73 patients with a major mood disorder were recruited and allocated in a nonrandomized fashion into 2 groups: the CRM group (14 patients) and the non-CRM group (59 patients). After the data qualification process, 10 subjects in the CRM group and 33 subjects in the non-CRM group were evaluated over 12 months. Both groups were treated in a similar manner. Patients took their usual medications, wore a wrist-worn activity tracker, and checked their eMoodChart daily. Patients in the CRM group were provided with daily feedback on their mood prediction and health scores based on the algorithm. For the CRM group, warning alerts were given when irregular life patterns were observed. However, these alerts were not given to patients in the non-CRM group. Every 3 months, mood episodes that had occurred in the previous 3 months were assessed based on the completed daily eMoodChart for both groups. The clinical course and prognosis, including mood episodes, were evaluated via face-to-face interviews based on the completed daily eMoodChart. For a 1-year prospective period, the number and duration of mood episodes were compared between the CRM and non-CRM groups using a generalized linear model. The CRM group had 96.7% fewer total depressive episodes (n/year; exp β=0.033, P=.03), 99.5% shorter depressive episodes (total; exp β=0.005, P<.001), 96.1% shorter manic or hypomanic episodes (exp β=0.039, P<.001), 97.4% fewer total mood episodes (exp β=0.026, P=.008), and 98.9% shorter mood episodes (total; exp β=0.011, P<.001) than the non-CRM group. Positive changes in health behaviors due to the alerts and in wearable device adherence rates were observed in the CRM group. The CRM app with a wearable activity tracker was found to be effective in preventing and reducing the recurrence of mood disorders, improving prognosis, and promoting better health behaviors. Patients appeared to develop a regular habit of using the CRM app. ClinicalTrials.gov NCT03088657; https://clinicaltrials.gov/ct2/show/NCT03088657.


Report from the kick-off meeting of the Cochrane Skin Group Core Outcome Set Initiative (CSG-COUSIN).
A major obstacle of evidence-based clinical decision making is the use of nonstandardized, partly untested outcome measurement instruments. Core Outcome Sets (COSs) are currently developed in different medical fields to standardize and improve the selection of outcomes and outcome measurement instruments in clinical trials, in order to pool results of trials or to allow indirect comparison between interventions. A COS is an agreed minimum set of outcomes that should be measured and reported in all clinical trials of a specific disease or trial population. The international, multidisciplinary Cochrane Skin Group Core Outcome Set Initiative (CSG-COUSIN) aims to develop and implement COSs in dermatology, thus making trial evidence comparable and, herewith, more useful for clinical decision making. The inaugural meeting of CSG-COUSIN was held on 17-18 March 2015 in Dresden, Germany, as the exclusive theme of the Annual Cochrane Skin Group Meeting. In total, 29 individuals representing a broad mix of different stakeholder groups, professions, skills and perspectives attended. This report provides a description of existing COS initiatives in dermatology, highlights current methodological challenges in COS development, and presents the concept, aims and structure of CSG-COUSIN.


Effect of cisplatin on proximal convoluted and straight segments of the rat kidney.
The immediate effect of cisplatin on rat proximal tubular function was investigated by two different methods, the lithium clearance method and the occlusion time-transit time method (TT-OT). Within minutes after administration of cisplatin a significant increase in lithium clearance, fractional lithium clearance (CLi/Cin) and e-TT/OT was observed (from 270 +/- 32 to 387 +/- 60 microliters/min/g kidney weight, 0.202 +/- 0.03 to 0.340 +/- 0.06 and 0.415 +/- 0.02 to 0.497 +/- 0.02, respectively). These increases indicate an increased fluid delivery from both the proximal straight segment and the late proximal convoluted tubule after cisplatin administration. Concomitantly absolute proximal reabsorption rate was significantly decreased. Intervention by saline loading (2% of body weight) did not prevent the increase in e-TT/OT, but the increase in CLi/Cin was significantly less than in the control group. This finding suggests that saline loading protects either the pars recta of the proximal tubule or the juxtamedullary nephrons. Thus, cisplatin-induced nephrotoxicity in the rat is initiated by an acute mainly proximal tubular impairment including both pars convoluta and pars recta of the proximal tubule.


Tracheal intubation through laryngeal mask airway CTrach™ with polyvinyl chloride tube: Comparison between two orientations of the tracheal tube.
Higher success rate of intubation is observed with the reverse orientation of polyvinyl chloride (PVC) tracheal tube while intubating through laryngeal mask airway (LMA) Fastrach™. It is not clear whether the same is true during intubation through LMA CTrach™ visualizing the process of intubation. The primary aim of this study was to compare the influence of the PVC tracheal tube orientation on the success rate of intubation while intubating through LMA CTrach™. One-hundred and fifty patients belonging to American Society of Anesthesiologists status I-II, undergoing elective surgery under general anesthesia were randomized to either group normal orientation or group reverse orientation. A maximum of 3 intubation attempts within a span of 3 min was allowed in each group before the change over to the other group. If intubation failed with the other orientation of the tube also, then intubation through LMA CTrach™ was abandoned and intubation done by direct laryngoscopy. The success of intubation, time, maneuvers, postoperative sore throat, and hoarseness were recorded. Tracheal intubation through LMA CTrach™ with PVC tube was successful in 94.5% of patients in group normal orientation and in 98.6% of patients in group reverse orientation. The first attempt success rate was 75.3% and 86.3% in group normal and group reverse orientation, respectively. The incidence of a sore throat was higher in the group normal orientation than in the reverse orientation (31.8% and 26.5%, respectively). Overall success rate of intubation was comparable between the two groups. Though statistically insignificant, the first attempt success rate was higher in group reverse orientation.


Ozone exposure induces respiratory barrier biphasic injury and inflammation controlled by IL-33.
IL-33 plays a critical role in regulation of tissue homeostasis, injury, and repair. Whether IL-33 regulates neutrophil recruitment and functions independently of airways hyperresponsiveness (AHR) in the setting of ozone-induced lung injury and inflammation is unclear. We sought to examine the role of the IL-33/ST2 axis in lung inflammation on acute ozone exposure in mice. ST2- and Il33-deficient, IL-33 citrine reporter, and C57BL/6 (wild-type) mice underwent a single ozone exposure (1 ppm for 1 hour) in all studies. Cell recruitment in lung tissue and the bronchoalveolar space, inflammatory parameters, epithelial barrier damage, and airway hyperresponsiveness (AHR) were determined. We report that a single ozone exposure causes rapid disruption of the epithelial barrier within 1 hour, followed by a second phase of respiratory barrier injury with increased neutrophil recruitment, reactive oxygen species production, AHR, and IL-33 expression in epithelial and myeloid cells in wild-type mice. In the absence of IL-33 or IL-33 receptor/ST2, epithelial cell injury with protein leak and myeloid cell recruitment and inflammation are further increased, whereas the tight junction proteins E-cadherin and zonula occludens 1 and reactive oxygen species expression in neutrophils and AHR are diminished. ST2 neutralization recapitulated the enhanced ozone-induced neutrophilic inflammation. However, myeloid cell depletion using GR-1 antibody reduced ozone-induced lung inflammation, epithelial cell injury, and protein leak, whereas administration of recombinant mouse IL-33 reduced neutrophil recruitment in Il33-deficient mice. Data demonstrate that ozone causes an immediate barrier injury that precedes myeloid cell-mediated inflammatory injury under the control of the IL-33/ST2 axis. Thus IL-33/ST2 signaling is critical for maintenance of intact epithelial barrier and inflammation.


Intramolecular Proton Transfer Controls Protein Structural Changes in Phytochrome.
Phytochromes are biological photoswitches that interconvert between two parent states (Pr and Pfr). The transformation is initiated by photoisomerization of the tetrapyrrole chromophore, followed by a sequence of chromophore and protein structural changes. In the last step, a phytochrome-specific peptide segment (tongue) undergoes a secondary structure change, which in prokaryotic phytochromes is associated with the (de)activation of the output module. The focus of this work is the Pfr-to-Pr photoconversion of the bathy bacteriophytochrome Agp2 in which Pfr is the thermodynamically stable state. Using spectroscopic techniques, we studied the structural and functional consequences of substituting Arg211, Tyr165, His278, and Phe192 close to the biliverdin (BV) chromophore. In Pfr, substitutions of these residues do not affect the BV structure. The characteristic Pfr properties of bathy phytochromes, including the protonated propionic side chain of ring C (propC) of BV, are preserved. However, replacing Arg211 or Tyr165 blocks the photoconversion in the Meta-F state, prior to the secondary structure transition of the tongue and without deprotonation of propC. The Meta-F state of these variants displays low photochemical activity, but electronic excitation causes ultrafast alterations of the hydrogen bond network surrounding the chromophore. In all variants studied here, thermal back conversion from the photoproducts to Pfr is decelerated but substitution of His278 or Phe192 is not critical for the Pfr-to-Pr photoconversion. These variants do not impair deprotonation of propC or the α-helix/β-sheet transformation of the tongue during the Meta-F-to-Pr decay. Thus, we conclude that propC deprotonation is essential for restructuring of the tongue.


Effects of the model's skill level on observational motor learning.
Observation of a model prior to physical practice often facilitates the acquisition of motor skills. The majority of research studies on observational motor learning has used a skilled model for the demonstration. Recent research, however, suggests that observing an unskilled (learning) model may also be effective. The experiment reported here compared motor skill acquisition following observation of a learning model or a skilled model to the performance of subjects who lacked the benefit of observation. The task was to play a computer tracking game. Subjects were tested in pairs. Observers watched either a skilled or a learning model perform 3 trials. The observers then practiced the game for 3 trials. Observation of another 12 trials was followed by 12 more practice trials. Substantial observational learning was found, as both groups of observers performed better than the learning models after both the 3 initial trials of observation and after 12 more observation trials. However, there were no differences due to observing the skilled or the learning model. These findings are discussed in relation to theoretical issues of observational learning.


Oral rehabilitation after treatment for head and neck malignancy.
Advances in the management of oral malignancy have resulted in significant improvements in survival and functional outcome. Ablation of oral tissues and radiotherapy render many patients unable to wear conventional prostheses, and these patients are, thus, candidates for oral rehabilitation with osseointegrated implants. We aim to present outcomes and complications of such treatment over a 14-year period in a single unit. Data were collected for 81 consecutive patients, most of whom had received microvascular free flap reconstruction after surgical ablation of oral squamous cell carcinoma. Three hundred eighty-six implants were placed after a delay of 12 months after surgery. Sixty-five percent of implants were placed in the anterior mandible. Radiotherapy was used in 47% of the patients, and hyperbaric oxygen treatment was routinely used in irradiated subjects during the latter half of the series. Retrospective analysis of implants and prostheses was made by use of case notes, radiographs, and a computerized database. Data are presented for 364 of the 386 implants in 77 of the 81 patients after a median follow-up of 4 years. Two hundred sixty-five (73%) of the implants were in function supporting prostheses, 56 (15%) had been lost, and 43 (12%) were present but not loaded (ie, "sleepers"). Implant loss seemed patient specific and was also correlated with host bone type. Thirteen percent of patients in whom implants were placed in the mandible lost at least one implant, and the equivalent values for the maxilla was 40%. Thirty-six percent of patients in whom implants were placed in bone graft or flap lost at least one implant. The effects of implant manufacture, dimensions, radiotherapy, and hyperbaric oxygen did not reach statistical significance in this series. Cases of a second primary malignancy were noteworthy; however, the impact of recurrence was minimized by the delay between resection and rehabilitation. Of the 42 fixed and 29 removable prostheses fitted, 12 (17%) failed. Implants placed in mandible were reliable, but failure rates in vascularized bone graft and maxilla were higher. Radiotherapy did not seem to prejudice implant survival, and hyperbaric oxygen had no demonstrable benefit in this series. Despite some persistent soft tissue problems and implant loss, most patients reached a successful prosthetic and functional outcome.


Rapid antigen diversification through mitotic recombination in the human malaria parasite Plasmodium falciparum.
Malaria parasites possess the remarkable ability to maintain chronic infections that fail to elicit a protective immune response, characteristics that have stymied vaccine development and cause people living in endemic regions to remain at risk of malaria despite previous exposure to the disease. These traits stem from the tremendous antigenic diversity displayed by parasites circulating in the field. For Plasmodium falciparum, the most virulent of the human malaria parasites, this diversity is exemplified by the variant gene family called var, which encodes the major surface antigen displayed on infected red blood cells (RBCs). This gene family exhibits virtually limitless diversity when var gene repertoires from different parasite isolates are compared. Previous studies indicated that this remarkable genome plasticity results from extensive ectopic recombination between var genes during mitotic replication; however, the molecular mechanisms that direct this process to antigen-encoding loci while the rest of the genome remains relatively stable were not determined. Using targeted DNA double-strand breaks (DSBs) and long-read whole-genome sequencing, we show that a single break within an antigen-encoding region of the genome can result in a cascade of recombination events leading to the generation of multiple chimeric var genes, a process that can greatly accelerate the generation of diversity within this family. We also found that recombinations did not occur randomly, but rather high-probability, specific recombination products were observed repeatedly. These results provide a molecular basis for previously described structured rearrangements that drive diversification of this highly polymorphic gene family.


DNA priming for seasonal influenza vaccine: a phase 1b double-blind randomized clinical trial.
The efficacy of current influenza vaccines is limited in vulnerable populations. DNA vaccines can be produced rapidly, and may offer a potential strategy to improve vaccine immunogenicity, indicated by studies with H5 influenza DNA vaccine prime followed by inactivated vaccine boost. Four sites enrolled healthy adults, randomized to receive 2011/12 seasonal influenza DNA vaccine prime (n=65) or phosphate buffered saline (PBS) (n=66) administered intramuscularly with Biojector. All subjects received the 2012/13 seasonal inactivated influenza vaccine, trivalent (IIV3) 36 weeks after the priming injection. Vaccine safety and tolerability was the primary objective and measurement of antibody response by hemagglutination inhibition (HAI) was the secondary objective. The DNA vaccine prime-IIV3 boost regimen was safe and well tolerated. Significant differences in HAI responses between the DNA vaccine prime and the PBS prime groups were not detected in this study. While DNA priming significantly improved the response to a conventional monovalent H5 vaccine in a previous study, it was not effective in adults using seasonal influenza strains, possibly due to pre-existing immunity to the prime, unmatched prime and boost antigens, or the lengthy 36 week boost interval. Careful optimization of the DNA prime-IIV3 boost regimen as related to antigen matching, interval between vaccinations, and pre-existing immune responses to influenza is likely to be needed in further evaluations of this vaccine strategy. In particular, testing this concept in younger age groups with less prior exposure to seasonal influenza strains may be informative. ClinicalTrials.gov NCT01498718.


Fouling Microbial Communities on Plastics Compared with Wood and Steel: Are They Substrate- or Location-Specific?
Although marine biofouling has been widely studied on different substrates, information on biofouling on plastics in the Arabian Gulf is limited. Substrate- and location-specific effects were investigated by comparing the microbial communities developed on polyethylene terephthalate (PET) and polyethylene (PE) with those on steel and wood, at two locations in the Sea of Oman. Total biomass was lower on PET and PE than on steel and wood. PET had the highest bacterial abundance at both locations, whereas chlorophyll a concentrations did not vary between substrates. MiSeq 16S ribosomal RNA sequencing revealed comparable operational taxonomic unit (OTU) richness on all substrates at one location but lower numbers on PET and PE at the other location. Non-metric multidimensional scaling (NMDS) showed distinct clusters of the bacterial communities based on substrate (analysis of similarity (ANOSIM), R = 0.45-0.97, p < 0.03) and location (ANOSIM, R = 0.56, p < 0.0001). The bacterial genera Microcystis and Hydrogenophaga and the diatoms Licmophora and Mastogloia were specifically detected on plastics. Desulfovibrio and Pseudomonas spp. exhibited their highest abundance on steel and Corynebacterium spp. on wood. Scanning electron microscopy (SEM) revealed fissure formation on PET and PE, indicating physical degradation. The presence of free radicals on PET and carbonyl bonds (C=O) on PE, as revealed by Fourier transform infrared (FTIR) spectroscopy, indicated abiotic degradation while hydroxyl groups and spectral peaks for proteins and polysaccharides on PE indicated biotic degradation. We conclude that fouling microbial communities are not only substrate-specific but also location-specific and microbes developing on plastics could potentially contribute to their degradation in the marine environment.


The origin and nature of stromal osteoclast-like multinucleated giant cells in breast carcinoma: implications for tumour osteolysis and macrophage biology.
The origin and nature of osteoclast-like multinucleated giant cells (OMGCs), in extraskeletal neoplasms, is uncertain. The ultrastructure, antigenic phenotype and function of OMGCsm in a breast carcinoma were studied in order to clarify the relationship between OMGCs, osteoclasts and other cells of the mononuclear phagocyte system (MPS). OMGCs resorbed cortical bone in a manner similar to osteoclasts. However, unlike osteoclasts, OMGCs did not possess a ruffled border or clear zone, and expressed HLA-DR and Fc receptors and CD14, CD16, CD18 and CD11 (p150,95) antigens. In addition, OMGCs failed to respond morphologically to calcitonin and were directly stimulated by parathyroid hormone (PTH) to increase bone resorption. These findings suggest that OMGCs are a specific type of macrophage polykaryon distinct from both osteoclasts and other types of inflammatory polykaryon. Occasional smaller (20-25 microns) macrophage-like cells were also associated with resorption pits. Bone resorption by OMGCs isolated from the breast indicates that a cell of the MPS can be transplanted to a new tissue location and perform a highly specialised function appropriate to an MPS cell of that tissue (i.e. the osteoclast). PTH stimulation of bone resorption by OMGCs suggests that PTH or a PTH-like protein, may be involved in the bone resorption and consequent hypercalcaemia associated with metastatic breast cancer.


Health Care Access and Physical and Behavioral Health Among Undocumented Latinos in California.
This paper provides statewide estimates on health care access and utilization patterns and physical and behavioral health by citizenship and documentation status among Latinos in California. This study used data from the 2011-2015 California Health Interview Survey to examine health care access and utilization and physical and behavioral health among a representative sample of all nonelderly Latino and US-born non-Latino white adults (N=51,386). Multivariable regressions estimated the associations between the dependent measures and citizenship/documentation status among Latinos (US-born, naturalized citizen, green card holder, and undocumented). Adjusted results from multivariable analyses observed worse access and utilization patterns among immigrant Latinos compared with US-born Latinos, with undocumented immigrants using significantly less health care. Undocumented Latinos had lower odds of self-reporting excellent/very good health status compared with US-born Latinos, despite them having lower odds of having several physical and behavioral health outcomes (overweight/obesity, physician-diagnosed hypertension, asthma, self-reported psychological distress, and need for behavioral health services). Among those reporting a need for behavioral health services, access was also worse for undocumented Latinos when compared with US-born Latinos. Patterns of poor health care access and utilization and better physical and behavioral health are observed across the continuum of documentation status, with undocumented immigrants having the worst access and utilization patterns and less disease. Despite fewer reported diagnoses and better mental health, undocumented Latinos reported poorer health status than their US-born counterparts.


Snake Venom as an Effective Tool Against Colorectal Cancer.
Cancer is considered one of the most predominant causes of morbidity and mortality all over the world and colorectal cancer is the most common fatal cancers, triggering the second cancer related death. Despite progress in understanding carcinogenesis and development in chemotherapeutics, there is an essential need to search for improved treatment. More than the half a century, cytotoxic and cytostatic agents have been examined as a potential treatment of cancer, among these agents; remarkable progresses have been reported by the use of the snake venom. Snake venoms are secreting materials of lethal snakes are store in venomous glands. Venoms are composite combinations of various protein, peptides, enzymes, toxins and non proteinaceous secretions. Snake venom possesses immense valuable mixtures of proteins and enzymes. Venoms have potential to combat with the cancerous cells and produce positive effect. Besides the toxicological effects of venoms, several proteins of snake venom e.g. disintegrins, phospholipases A2, metalloproteinases, and L-amino acid oxidases and peptides e.g. bradykinin potentiators, natriuretic, and analgesic peptides have shown potential as pharmaceutical agents, including areas of diagnosis and cancer treatment. In this review we have discussed recent remarkable research that has involved the dynamic snake venoms compounds, having anticancer bustle especially in case of colorectal cancer.


The Baltic Sea: An ecosystem with multiple stressors.
This introductory chapter to our Environment International VSI does not need an abstract and therefore we just include our recommendations below in order to proceed with the resubmission. Future work should examine waterbirds as food web sentinels of multiple stressors as well as Baltic Sea food web dynamics of hazardous substances and how climate change may modify it. Also, future work should aim at further extending the new frameworks developed within BALTHEALTH for energy and contaminant transfer at the population level (Desforges et al., 2018, Cervin et al., 2020/this issue Silva et al., 2020/this issue) and their long term effects on Baltic Sea top predators, such as harbour porpoises, grey seals ringed seals, and white-tailed eagles. Likewise, the risk evaluation conducted for PCB in connection with mercury on Arctic wildlife (Dietz et al., 2019, not a BONUS BALTHEALTH product) could be planned for Baltic Sea molluscs, fish, bird and marine mammals in the future. Finally, future efforts could include stressors not covered by the BONUS BALTHEALTH project, such as food web fluxes, overexploitation, bycatches, eutrophication and underwater noise.


The Psychosocial Impact of Undergoing Prophylactic Total Gastrectomy (PTG) to Manage the Risk of Hereditary Diffuse Gastric Cancer (HDGC).
Individuals identified as at high risk of developing Hereditary Diffuse Gastric Cancer (HDGC) are advised to undergo prophylactic surgery - have their stomach removed - in their early twenties. Research with (older) cancer patients who undergo gastrectomy for curative reasons suggests that gastric resection has a number of physical and psychosocial sequelae. Because it is difficult to extrapolate the findings of studies of older cancer patients to younger healthy patients who are considering prophylactic total gastrectomy (PTG), the aim of this qualitative interview study was to determine the psychosocial implications of undergoing prophylactic surgery to manage genetic risk. Fourteen men and 13 women from the UK's Familial Gastric Cancer study who had undergone PTG were invited to participate in qualitative interviews. Most reported that undergoing surgery and convalescence was easier than anticipated. There was evidence that age affected experiences of PTG, with younger patients tending to report faster recovery times and more transient aftereffects. All saw the benefits of risk reduction as outweighing the costs of surgery. Surgery was described as having a range of physical impacts (disrupted appetite, weight loss, fatigue, GI symptoms) that had related psychological, social and economic implications. Those considering PTG need to be aware that its impact on quality of life is difficult to predict and negative sequelae may be ongoing for some individuals.


An iron-regulated gene required for utilization of aerobactin as an exogenous siderophore in Vibrio parahaemolyticus.
A previous investigation using the Fur titration assay system showed that Vibrio parahaemolyticus possesses a gene encoding a protein homologous to IutA, the outer-membrane receptor for ferric aerobactin in Escherichia coli. In this study, a 5.6 kb DNA region from the V. parahaemolyticus WP1 genome was cloned and two entire genes, iutA and alcD homologues, were identified which are absent from Vibrio cholerae genomic sequences. The V. parahaemolyticus IutA and AlcD proteins share 43 % identity with the Escherichia coli IutA protein and 24 % identity with the Bordetella bronchiseptica AlcD protein of unknown function, respectively. Primer extension analysis revealed that the iutA gene is transcribed in response to low-iron availability from a putative promoter overlapped with a sequence resembling a consensus E. coli Fur-binding sequence. In agreement with the above finding, V. parahaemolyticus effectively utilized exogenously supplied aerobactin for growth under iron-limiting conditions. Moreover, insertional inactivation of iutA impaired growth in the presence of aerobactin and incapacitated the outer-membrane fraction from iron-deficient cells for binding (55)Fe-labelled aerobactin. These results indicate that the V. parahaemolyticus iutA homologue encodes an outer-membrane protein which functions as the receptor for ferric aerobactin. Southern blot analysis revealed that the iutA homologues are widely distributed in clinical and environmental isolates of V. parahaemolyticus. However, additional genes required for ferric aerobactin transport across the inner membrane remain to be clarified.


Effects of circle of Willis anatomic variations on angiographic and clinical outcomes of coiled anterior communicating artery aneurysms.
Anterior communicating artery aneurysms account for one-fourth of all intracranial aneurysms and frequently occur in the context of A1 vessel asymmetry. The purpose of this study was to correlate circle of Willis anatomic variation association to angiographic and clinical outcomes of anterior communicating aneurysm coiling. The Cerecyte Coil Trial provides a subgroup of 124 cases with anterior communicating artery aneurysms after endovascular coiling. One hundred seventeen of 124 anterior communicating artery aneurysms had complete imaging and follow-up for clinical outcome analysis, stability of aneurysm coil packing, and follow-up imaging between 5 and 7 months after treatment. Clinical outcomes were assessed by the mRS at 6 months. Anterior cerebral artery trunk-dominance was seen in 91 of 124 (73%) anterior communicating artery aneurysms and codominance in 33 of 124 (27%) anterior communicating artery aneurysms. There was no significant difference (P > .5) in treatment success at 5-7 months for anterior communicating artery aneurysms between the anterior cerebral artery trunk-dominant (49 of 86, 57%) and anterior cerebral artery trunk-codominant (19 of 31) groups. Angiographic follow-up demonstrates a statistically significant increase in neck remnants and progressive aneurysm sac filling with the A1 dominant configuration (n = 21, 24% at follow-up versus n = 11, 12% at immediate posttreatment, P = .035). There was no statistically significant difference in clinical outcomes between types of anterior cerebral artery trunk configuration (P > .5). Anterior communicating artery aneurysms with anterior cerebral artery trunk-dominant circle of Willis configurations show less angiographic stability at follow-up than those with anterior cerebral artery trunk-codominance similar to other "termination" type aneurysms. This supports the hypothesis that anterior cerebral artery trunk-dominant flow contributes to aneurysm formation, growth, and instability after coiling treatment.


Apolipoprotein E deficiency worsens outcome from global cerebral ischemia in the mouse.
Apolipoprotein E (apoE) has been found relevant in a variety of central nervous system disorders. This experiment examined the effect of endogenous murine apoE on selective neuronal necrosis resulting from a transient forebrain ischemia insult. ApoE deficient (n=16) and wild type (n=17) halothane-anesthetized mice were subjected to severe forebrain ischemia (10 minutes of bilateral carotid occlusion and systemic hypotension). After 3 days' recovery, brain injury was determined histologically. In other apoE-deficient and wild-type mice, regional cerebral blood flow (CBF) was determined by 14C-iodoantipyrine autoradiography 10 minutes before, 5 minutes after onset of, and 30 minutes after reperfusion from 10 minutes of forebrain ischemia. The percentage of dead hippocampal CA1 neurons (mean+/-SD) was greater in the apoE-deficient group (apoE deficient=67+/-30%; wild type=37+/-33%; P=0.011). A similar pattern was observed in the caudoputamen (P=0.002) and neocortex (P=0.014). Cerebral blood flow was similar between groups at each measurement interval. Marked hypoperfusion persisted in both groups at 30 minutes after ischemia. ApoE deficiency worsens ischemic outcome. This is not attributable to effects on CBF. A role of apoE in the cerebral response to global ischemia is consistent with prior reports that murine apoE deficiency increases infarct size resulting from focal cerebral ischemia.


Immunostaining for Met/HGF receptor may be useful to identify malignancies in thyroid lesions classified suspicious at fine-needle aspiration biopsy.
The receptor for hepatocyte growth factor (Met) is not expressed in the normal thyroid but it is overexpressed in most thyroid carcinomas. We evaluated whether Met immunostaining of cytological smears from fine-needle aspiration biopsy (FNAB) may be useful for the preoperative diagnosis of thyroid cancer. Notably, routine cytological examination often fails to distinguish well-differentiated follicular carcinomas and a proportion of papillary carcinomas (low-grade papillary carcinomas and papillary carcinomas follicular variant [FVPTC]) from benign lesions: all these lesions are usually classified as suspicious. We examined 80 thyroid lesions diagnosed as suspicious at cytology that had subsequently undergone surgery. The histologic diagnosis had been: papillary carcinomas (n = 14), FVPTC (n = 11), follicular carcinomas (n = 25), atypical follicular adenomas (n = 5), follicular adenomas (n = 20), and nodular goiters (n = 5). We also studied typical papillary carcinomas (n = 30) and nodular goiters (n = 10), all correctly diagnosed at cytology. In lesions classified suspicious at routine cytology, Met immunostaining was positive in 12 of 14 (85.7%) papillary carcinomas, 8 of 11 (72.7%) FVPTC, 7 of 25 (28%) follicular carcinomas, and 5 of 5 atypical adenomas. In contrast, none of the 25 lesions cytologically suspicious but benign at histology were positive. These data suggest that Met immunostaining of suspicious cytological smears are useful for identifying malignant lesions, especially those with a papillary histotype.


Influence of small mechanical loads of variability of breathing pattern.
The effect of low-level mechanical loading on the variability of the human breathing pattern was examined using a small elastic (E) load (approximately 10 cmH2O/1) and a small flow-resistive (R) load (approximately 3 cmH2O.1(-1).s) to approximately halve and double the normal respiratory mechanical time constant. The pooled responses from six subjects showed 1) E loading increased the mean estimated work rate (W); 2) R loading increased the mean tidal volume (VT), inspiratory duration (TI), and estimated W, and decreased mean breathing frequency (f) and mean inspiratory flow (VT/TI), while reducing the variabilities of f and VT/TI; 3) E loading significantly reduced the frequency of occurrence of large breaths from the control state, whereas the effect of R loading on this phenomenon was smaller and not significant; and 4) R loading tended to increase an E loading to decrease the significant VT:TI rank correlation seen in the nonloaded state. The influence of loading on the distributions of VT and f became apparent in the tendency of breath-by-breath values to cluster closer to the minimum of the W-VA-pattern parameter surface.


Alternative analyses for handling incomplete follow-up in the intention-to-treat analysis: the randomized controlled trial of balloon kyphoplasty versus non-surgical care for vertebral compression fracture (FREE).
Clinical trial participants may be temporarily absent or withdraw from trials, leading to missing data. In intention-to-treat (ITT) analyses, several approaches are used for handling the missing information - complete case (CC) analysis, mixed-effects model (MM) analysis, last observation carried forward (LOCF) and multiple imputation (MI). This report discusses the consequences of applying the CC, LOCF and MI for the ITT analysis of published data (analysed using the MM method) from the Fracture Reduction Evaluation (FREE) trial. The FREE trial was a randomised, non-blinded study comparing balloon kyphoplasty with non-surgical care for the treatment of patients with acute painful vertebral fractures. Patients were randomised to treatment (1:1 ratio), and stratified for gender, fracture aetiology, use of bisphosphonates and use of systemic steroids at the time of enrolment. Six outcome measures - Short-form 36 physical component summary (SF-36 PCS) scale, EuroQol 5-Dimension Questionnaire (EQ-5D), Roland-Morris Disability (RMD) score, back pain, number of days with restricted activity in last 2 weeks, and number of days in bed in last 2 weeks - were analysed using four methods for dealing with missing data: CC, LOCF, MM and MI analyses. There were no missing data in baseline covariates values, and only a few missing baseline values in outcome variables. The overall missing-response level increased during follow-up (1 month: 14.5%; 24 months: 28%), corresponding to a mean of 19% missing data during the entire period. Overall patterns of missing response across time were similar for each treatment group. Almost half of all randomised patients were not available for a CC analysis, a maximum of 4% were not included in the LOCF analysis, and all randomised patients were included in the MM and MI analyses. Improved estimates of treatment effect were observed with LOCF, MM and MI compared with CC; only MM provided improved estimates across all six outcomes considered. The FREE trial results are robust as the alternative methods used for substituting missing data produced similar results. The MM method showed the highest statistical precision suggesting it is the most appropriate method to use for analysing the FREE trial data. This trial is registered with ClinicalTrials.gov (number NCT00211211).


Freerunning circasemilunar spawning rhythm of Fundulus grandis and its temperature compensation.
Gulf killifish, Fundulus grandis, exhibit rhythmic reproductive activities that are synchronized with semilunar tidal fluctuations in their Gulf coast habitat. These cyclic activities, monitored through daily egg collections, persist in the laboratory for as long as four months with periods near the tidal period of 13.7 days. In nature, a specific semilunar spawning phase is maintained with respect to tidal cycles. However, in the laboratory, the phase may gradually advance or delay. These phase changes occur as a result of small differences between the periods of the spawning cycle and concurrent tidal cycle. Changes in the phase of the spawning cycle can be produced after several cycles by exposing fish to different temperatures (21 and 27°C). However, the period of the spawning cycle changes only slightly with temperature. Q10 calculations produce a value not significantly different from 1.0, indicating nearly complete temperature compensation. These results provide evidence for an endogenous circasemilunar cycle that is temperature-compensated and freeruns in the laboratory.


Bayesian reconstruction of natural images from human brain activity.
Recent studies have used fMRI signals from early visual areas to reconstruct simple geometric patterns. Here, we demonstrate a new Bayesian decoder that uses fMRI signals from early and anterior visual areas to reconstruct complex natural images. Our decoder combines three elements: a structural encoding model that characterizes responses in early visual areas, a semantic encoding model that characterizes responses in anterior visual areas, and prior information about the structure and semantic content of natural images. By combining all these elements, the decoder produces reconstructions that accurately reflect both the spatial structure and semantic category of the objects contained in the observed natural image. Our results show that prior information has a substantial effect on the quality of natural image reconstructions. We also demonstrate that much of the variance in the responses of anterior visual areas to complex natural images is explained by the semantic category of the image alone.


Synchronous subarachnoid drop metastases from a pituitary adenoma with multiple recurrences. Case report.
The authors report the case of a 49-year-old man with synchronous drop metastases from a multiply recurrent somatotroph pituitary adenoma. The metastatic lesions were found in the subarachnoid space of the cauda equina and foramen magnum 18 years after the initial diagnosis of the disease. Five transsphenoidal resections had previously failed to cure the sellar tumor. Two of these, performed 4 and 5 years before the patient's current presentation, had been complicated by cerebrospinal fluid rhinorrhea that necessitated lumbar drainage. Resections of the two subarachnoid lesions, separated by 14 months, removed pathologically aggressive pituitary adenomas. There were no signs of local recurrence or subarachnoid dissemination of disease during the postoperative follow-up periods, which lasted 18 and 4 months, respectively. Previous cases of subarachnoid spread of a pituitary adenoma have been associated with multiple intracranial metastases, multiple intraspinal metastases, or widely disseminated disease. This case demonstrates that subarachnoid metastasis of a pituitary adenoma, particularly when it follows multiple operations, is not invariably widely disseminated or associated with a very poor prognosis.


Body Mass Index Mediates the Effects of Low Income on Preschool Children's Executive Control, with Implications for Behavior and Academics.
Children from low-income backgrounds are more likely to have cognitive impairments, academic problems, and obesity. Biological mechanisms for the relationship between adiposity and neurocognitive functioning have been suggested, but the direction of effects is unclear. The relations among income, BMI, and cognitive-behavioral functioning were modeled longitudinally. Children (n = 306) were assessed at 36-39 months (Time 1; T1) and 63-67 months (Time 4; T4) through anthropometry, measures of executive control (EC), delay ability (DA), and questionnaires on academic readiness, social competence, and behavioral adjustment. Income was positively related to T1 EC and DA and negatively related to T1 BMI. T1 BMI was negatively related to T4 EC, after controlling for T1 EC, but was unrelated to changes in DA. Neither T1 EC nor DA was related to changes in BMI. T4 EC predicted greater academic readiness and social competence and lower adjustment problems at T4. T4 BMI was related to higher T4 adjustment problems. There was an indirect effect of income on T4 EC through T1 BMI. There were indirect effects of T1 BMI on academic readiness, social competence, and adjustment through T4 EC. Children who were obese at T1 had a 19% lower rate of growth of EC, compared to nonobese children. BMI mediates the effect of income on children's EC and has negative implications for academic readiness, social competence, and behavioral adjustment. The dual impact of obesity and cognitive-behavioral problems underscores the importance of early identification of and intervention for overweight children which could have neurocognitive and social-emotional benefits. What's New: BMI mediates the effect of income on preschoolers' executive control (EC) and has negative implications for academic readiness and behavioral adjustment. EC and delay ability did not predict changes in BMI. Early identification of, and intervention for, overweight children may have neurocognitive and social-emotional benefits.


Appropriate nutritional management in patients with impaired mastication and those with mild dysphagia: a multicenter study of the usefulness of novel foods processed and softened by enzymes.
Our aim was to investigate the safety of iEAT (a food that is softened by heat and enzyme homogeneous permeation) and iEAT-affected nutrition parameters, e.g., nutrition intake (calculated from the consumption rate in patients with impaired mastication and those with mild dysphagia). A multicenter, randomized, cross-over study of iEAT was conducted in 50 patients (mean age 77.0±11.0 years) with dysphagia due to Occasional aspiration (4 points on the Dysphagia Severity Scale [DSS]) or Oral problems (5 points) randomly assigned to the study diet (iEAT) or its opposite (the modified traditional [control] diet) for 1 week and then switched for 1 week to the opposing diet. Intake of energy, protein, lipid, carbohydrate, and sodium were evaluated along with questionnaire-assessed levels of satisfaction. The mean intake was significantly lower for the study diet, whereas the intakes of energy, protein, carbohydrate on day 1, intake of protein on day 7, and body weight on day 7 were significantly higher for the study diet. We found no between-group differences in hematologic and blood biochemistry parameters, no diet-related adverse events, greater satisfaction with the appearance of the study diet (p<0.001), and comparable levels of satisfaction with ease of eating, ease of swallowing, and taste for both diets. iEAT was provided to patients with mild dysphagia as safely as a blender diet or other diets usually provided at each study site, and can serve as an efficient nutrition source.


Programmable assembly of pressure sensors using pattern-forming bacteria.
Biological systems can generate microstructured materials that combine organic and inorganic components and possess diverse physical and chemical properties. However, these natural processes in materials fabrication are not readily programmable. Here, we use a synthetic-biology approach to assemble patterned materials. We demonstrate programmable fabrication of three-dimensional (3D) materials by printing engineered self-patterning bacteria on permeable membranes that serve as a structural scaffold. Application of gold nanoparticles to the colonies creates hybrid organic-inorganic dome structures. The dynamics of the dome structures' response to pressure is determined by their geometry (colony size, dome height, and pattern), which is easily modified by varying the properties of the membrane (e.g., pore size and hydrophobicity). We generate resettable pressure sensors that process signals in response to varying pressure intensity and duration.


Rosuvastatin-induced arrest in progression of renal disease.
Preclinical and limited clinical data suggest that statins decrease the progressive decline in renal function that occurs in patients with renal disease. Pooled analysis of data obtained from a population of hyperlipidemic patients enrolled in the rosuvastatin (Crestor) clinical development program permitted assessment of its effects on renal function both early and later in the course of treatment. Study participants were initially included in controlled clinical trials that evaluated the lipid-lowering efficacy and safety of rosuvastatin when compared with placebo or other lipid-lowering agents (i.e., atorvastatin, simvastatin, pravastatin, cholestyramine, fenofibrate or extended-release niacin). The median duration of treatment with the various doses of statins in these trials was approximately 8 weeks. Following completion of a controlled clinical trial, patients were permitted to enter an open-label extension trial and received rosuvastatin treatment. These data permitted assessment of renal function in a diverse group of over 10,000 patients who received rosuvastatin in its recommended dose range (5-40 mg) for up to 3.8 years. Mean serum creatinine concentrations were lower when compared with baseline both early and later in the course of rosuvastatin treatment. In contrast, no change in mean serum creatinine was observed with placebo. Mean glomerular filtration rates (GFR) predicted from the Modification of Diet in Renal Disease (MDRD) equation were higher when compared with baseline both early and later in the course of rosuvastatin treatment. No change in GFR was observed in the placebo group. Among patients who received long-term rosuvastatin treatment (> or =96 weeks), GFR was unchanged or tended to increase, rather than decrease, when compared with baseline irrespective of age, gender, hypertensive or diabetic status, level of renal function (GFR > or =60 vs. <60 ml/min/1.73 m(2)) at entry or urine dipstick protein status prior to or during the period of treatment. These findings suggest that rosuvastatin may arrest the progression of renal disease.


Ultrafast excited state dynamics controlling photochemical isomerization of N-methyl-4-[trans-2-(4-pyridyl)ethenyl]pyridinium coordinated to a {Re I(CO)3(2,2'-bipyridine)} chromophore.
Two multifunctional photoactive complexes [Re(Cl)(CO)(3)(MeDpe(+))(2)](2+) and [Re(MeDpe(+))(CO)(3)(bpy)](2+) (MeDpe(+)=N-methyl-4-[trans-2-(4-pyridyl)ethenyl]pyridinium, bpy=2,2'-bipyridine) were synthesized, characterized, and their redox and photonic properties were investigated by cyclic voltammetry; ultraviolet-visible-infrared (UV/Vis/IR) spectroelectrochemistry, stationary UV/Vis and resonance Raman spectroscopy; photolysis; picosecond time-resolved absorption spectroscopy in the visible and infrared regions; and time-resolved resonance Raman spectroscopy. The first reduction step of either complex occurs at about -1.1 V versus Fc/Fc(+) and is localized at MeDpe(+). Reduction alone does not induce a trans-->cis isomerization of MeDpe(+). [Re(Cl)(CO)(3)(MeDpe(+))(2)](2+) is photostable, while [Re(MeDpe(+))(CO)(3)(bpy)](2+) and free MeDpe(+) isomerize under near-UV irradiation. The lowest excited state of [Re(Cl)(CO)(3)(MeDpe(+))(2)](2+) has been identified as the Re(Cl)(CO)(3)-->MeDpe(+ 3)MLCT (MLCT=metal-to-ligand charge transfer), decaying directly to the ground state with lifetimes of approximately 42 (73 %) and approximately 430 ps (27 %). Optical excitation of [Re(MeDpe(+))(CO)(3)(bpy)](2+) leads to population of Re(CO)(3)-->MeDpe(+) and Re(CO)(3)-->bpy (3)MLCT states, from which a MeDpe(+) localized intraligand (3)pipi* excited state ((3)IL) is populated with lifetimes of approximately 0.6 and approximately 10 ps, respectively. The (3)IL state undergoes a approximately 21 ps internal rotation, which eventually produces the cis isomer on a much longer timescale. The different excited-state behavior of the two complexes and the absence of thermodynamically favorable interligand electron transfer in excited [Re(MeDpe(+))(CO)(3)(bpy)](2+) reflect the fine energetic balance between excited states of different orbital origin, which can be tuned by subtle structural variations. The complex [Re(MeDpe(+))(CO)(3)(bpy)](2+) emerges as a prototypical, multifunctional species with complementary redox and photonic behavior.


Tissue Culture as a Source of Replicates in Nonmodel Plants: Variation in Cold Response in Arabidopsis lyrata ssp. petraea.
While genotype-environment interaction is increasingly receiving attention by ecologists and evolutionary biologists, such studies need genetically homogeneous replicates-a challenging hurdle in outcrossing plants. This could be potentially overcome by using tissue culture techniques. However, plants regenerated from tissue culture may show aberrant phenotypes and "somaclonal" variation. Here, we examined somaclonal variation due to tissue culturing using the response to cold treatment of photosynthetic efficiency (chlorophyll fluorescence measurements for Fv/Fm, Fv'/Fm', and ΦPSII, representing maximum efficiency of photosynthesis for dark- and light-adapted leaves, and the actual electron transport operating efficiency, respectively, which are reliable indicators of photoinhibition and damage to the photosynthetic electron transport system). We compared this to variation among half-sibling seedlings from three different families of Arabidopsis lyrata ssp. petraea Somaclonal variation was limited, and we could detect within-family variation in change in chlorophyll fluorescence due to cold shock successfully with the help of tissue-culture derived replicates. Icelandic and Norwegian families exhibited higher chlorophyll fluorescence, suggesting higher performance after cold shock, than a Swedish family. Although the main effect of tissue culture on Fv/Fm, Fv'/Fm', and ΦPSII was small, there were significant interactions between tissue culture and family, suggesting that the effect of tissue culture is genotype-specific. Tissue-cultured plantlets were less affected by cold treatment than seedlings, but to a different extent in each family. These interactive effects, however, were comparable to, or much smaller than the single effect of family. These results suggest that tissue culture is a useful method for obtaining genetically homogenous replicates for studying genotype-environment interaction related to adaptively-relevant phenotypes, such as cold response, in nonmodel outcrossing plants.


Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48(UFD1/NPL4), a ubiquitin-selective chaperone.
The OLE pathway of yeast regulates the level of the ER-bound enzyme Delta9-fatty acid desaturase OLE1, thereby controlling membrane fluidity. A central component of this regulon is the transcription factor SPT23, a homolog of mammalian NF-kappaB. SPT23 is synthesized as an inactive, ER membrane-anchored precursor that is activated by regulated ubiquitin/proteasome-dependent processing (RUP). We now show that SPT23 dimerizes prior to processing and that the processed molecule, p90, retains its ubiquitin modification and initially remains tethered to its unprocessed, membrane-bound SPT23 partner. Subsequently, p90 is liberated from its partner for nuclear targeting by the activity of the chaperone-like CDC48(UFD1/NPL4) complex. Remarkably, this enzyme binds preferentially ubiquitinated substrates, suggesting that CDC48(UFD1/NPL4) is qualified to selectively remove ubiquitin conjugates from protein complexes.


An experimental study of the coloring problem on human subject networks.
Theoretical work suggests that structural properties of naturally occurring networks are important in shaping behavior and dynamics. However, the relationships between structure and behavior are difficult to establish through empirical studies, because the networks in such studies are typically fixed. We studied networks of human subjects attempting to solve the graph or network coloring problem, which models settings in which it is desirable to distinguish one's behavior from that of one's network neighbors. Networks generated by preferential attachment made solving the coloring problem more difficult than did networks based on cyclical structures, and "small worlds" networks were easier still. We also showed that providing more information can have opposite effects on performance, depending on network structure.


Medico-legal and ethical aspects of nasal fractures secondary to assault: do we owe a duty of care to advise patients to have a facial x-ray?
Guidelines advise that x-rays do not contribute to the clinical management of simple nasal fractures. However, in cases of simple nasal fracture secondary to assault, a facial x-ray may provide additional legal evidence should the victim wish to press charges, though there is no published guidance. We examine the ethical and medico-legal issues surrounding this controversial area.


High-Intensity Interval Resistance Training (HIRT) influences resting energy expenditure and respiratory ratio in non-dieting individuals.
The benefits of exercise are well established but one major barrier for many is time. It has been proposed that short period resistance training (RT) could play a role in weight control by increasing resting energy expenditure (REE) but the effects of different kinds of RT has not been widely reported. We tested the acute effects of high-intensity interval resistance training (HIRT) vs. traditional resistance training (TT) on REE and respiratory ratio (RR) at 22 hours post-exercise. In two separate sessions, seventeen trained males carried out HIRT and TT protocols. The HIRT technique consists of: 6 repetitions, 20 seconds rest, 2/3 repetitions, 20 secs rest, 2/3 repetitions with 2'30″ rest between sets, three exercises for a total of 7 sets. TT consisted of eight exercises of 4 sets of 8-12 repetitions with one/two minutes rest with a total amount of 32 sets. We measured basal REE and RR (TT0 and HIRT0) and 22 hours after the training session (TT22 and HIRT22). HIRT showed a greater significant increase (p < 0.001) in REE at 22 hours compared to TT (HIRT22 2362 ± 118 Kcal/d vs TT22 1999 ± 88 Kcal/d). RR at HIRT22 was significantly lower (0.798 ± 0.010) compared to both HIRT0 (0.827 ± 0.006) and TT22 (0.822 ± 0.008). Our data suggest that shorter HIRT sessions may increase REE after exercise to a greater extent than TT and may reduce RR hence improving fat oxidation. The shorter exercise time commitment may help to reduce one major barrier to exercise.


Ketone body metabolism and its defects.
Acetoacetate (AcAc) and 3-hydroxybutyrate (3HB), the two main ketone bodies of humans, are important vectors of energy transport from the liver to extrahepatic tissues, especially during fasting, when glucose supply is low. Blood total ketone body (TKB) levels should be evaluated in the context of clinical history, such as fasting time and ketogenic stresses. Blood TKB should also be evaluated in parallel with blood glucose and free fatty acids (FFA). The FFA/TKB ratio is especially useful for evaluation of ketone body metabolism. Defects in ketogenesis include mitochondrial HMG-CoA synthase (mHS) deficiency and HMG-CoA lyase (HL) deficiency. mHS deficiency should be considered in non-ketotic hypoglycemia if a fatty acid beta-oxidation defect is suspected, but cannot be confirmed. Patients with HL deficiency can develop hypoglycemic crises and neurological symptoms even in adolescents and adults. Succinyl-CoA-3-oxoacid CoA transferase (SCOT) deficiency and beta-ketothiolase (T2) deficiency are two defects in ketolysis. Permanent ketosis is pathognomonic for SCOT deficiency. However, patients with "mild" SCOT mutations may have nonketotic periods. T2-deficient patients with "mild" mutations may have normal blood acylcarnitine profiles even in ketoacidotic crises. T2 deficient patients cannot be detected in a reliable manner by newborn screening using acylcarnitines. We review recent data on clinical presentation, metabolite profiles and the course of these diseases in adults, including in pregnancy.


Identification of a novel acetate-utilizing bacterium belonging to Synergistes group 4 in anaerobic digester sludge.
Major acetate-utilizing bacterial and archaeal populations in methanogenic anaerobic digester sludge were identified and quantified by radioisotope- and stable-isotope-based functional analyses, microautoradiography-fluorescence in situ hybridization (MAR-FISH) and stable-isotope probing of 16S rRNA (RNA-SIP) that can directly link 16S rRNA phylogeny with in situ metabolic function. First, MAR-FISH with (14)C-acetate indicated the significant utilization of acetate by only two major groups, unidentified bacterial cells and Methanosaeta-like filamentous archaeal cells, in the digester sludge. To identify the acetate-utilizing unidentified bacteria, RNA-SIP was conducted with (13)C(6)-glucose and (13)C(3)-propionate as sole carbon source, which were followed by phylogenetic analysis of 16S rRNA. We found that bacteria belonging to Synergistes group 4 were commonly detected in both 16S rRNA clone libraries derived from the sludge incubated with (13)C-glucose and (13)C-propionate. To confirm that this bacterial group can utilize acetate, specific FISH probe targeting for Synergistes group 4 was newly designed and applied to the sludge incubated with (14)C-acetate for MAR-FISH. The MAR-FISH result showed that bacteria belonging to Synergistes group 4 significantly took up acetate and their active population size was comparable to that of Methanosaeta in this sludge. In addition, as bacteria belonging to Synergistes group 4 had high K(m) for acetate and maximum utilization rate, they are more competitive for acetate over Methanosaeta at high acetate concentrations (2.5-10 mM). To our knowledge, it is the first time to report the acetate-utilizing activity of uncultured bacteria belonging to Synergistes group 4 and its competitive significance to acetoclastic methanogen, Methanosaeta.


Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer.
Early indicators of treatment response in metastatic colorectal cancer (mCRC) could conceivably be used to optimize treatment. We explored early changes in circulating tumor DNA (ctDNA) levels as a marker of therapeutic efficacy. This prospective study involved 53 mCRC patients receiving standard first-line chemotherapy. Both ctDNA and CEA were assessed in plasma collected before treatment, 3 days after treatment and before cycle 2. Computed tomography (CT) scans were carried out at baseline and 8-10 weeks and were centrally assessed using RECIST v1.1 criteria. Tumors were sequenced using a panel of 15 genes frequently mutated in mCRC to identify candidate mutations for ctDNA analysis. For each patient, one tumor mutation was selected to assess the presence and the level of ctDNA in plasma samples using a digital genomic assay termed Safe-SeqS. Candidate mutations for ctDNA analysis were identified in 52 (98.1%) of the tumors. These patient-specific candidate tissue mutations were detectable in the cell-free DNA from the plasma of 48 of these 52 patients (concordance 92.3%). Significant reductions in ctDNA (median 5.7-fold; P < 0.001) levels were observed before cycle 2, which correlated with CT responses at 8-10 weeks (odds ratio = 5.25 with a 10-fold ctDNA reduction; P = 0.016). Major reductions (≥10-fold) versus lesser reductions in ctDNA precycle 2 were associated with a trend for increased progression-free survival (median 14.7 versus 8.1 months; HR = 1.87; P = 0.266). ctDNA is detectable in a high proportion of treatment naïve mCRC patients. Early changes in ctDNA during first-line chemotherapy predict the later radiologic response.


Protection from cerebral air emboli with perfluorocarbons in rabbits.
Cerebral air emboli have been implicated in the transient neurological deficits seen in patients after cardiovascular surgery. Since perfluorocarbon emulsions such as FC-43 have greater solubilities for gases compared to plasma, it was decided to investigate their potential in providing protection against transient ischemia produced by such emboli. Forty rabbits were divided into three groups of ten, twenty, and ten. They were anesthetized with acepromazine and ketamine and were given an infusion of either hetastarch or FC-43, 10 ml/kg i.v. In Group I, which received a bolus air injection into the internal carotid artery, survival rates were: 2/5 for the hetastarch group and 5/5 for the FC-43 group (p less than .05). In Group 2, which received an air infusion until the EEG was flat bilaterally, 3/10 hetastarch-treated rabbits survived while 10/10 FC-43-treated rabbits survived for 24 hours (p = .035). In Group 3, analysis of blood viscosity and osmolality over a four hour period following either hetastarch or FC-43 infusion resulted in no significant differences between the two treatments but a significant decrease in both variables after 30 minutes which returned to baseline values at 60 minutes. The results of the study demonstrate a protective effect from cerebral air emboli delivered into the internal carotid artery as either a bolus or slow infusion in rabbits pretreated with a perfluorocarbon emulsion in terms of survivability and recovery from transient neurological deficits.


Occupational risks for adenocarcinoma of the nasal cavity and paranasal sinuses in the German wood industry.
To examine the risk of wood dust and chemical exposures for adenocarcinoma of the nasal cavity and paranasal sinuses (ADCN) among German wood workers. An industry-based case-control study with 86 male ADCN cases and 204 controls was conducted in the German wood-working industries. Cumulative and average wood-dust exposure was quantified with a job-exposure matrix based on wood-dust measurements at recent and historical workplaces. Probabilities of exposure to wood preservatives, stains, varnishes, and formaldehyde were semi-quantitatively rated. Odds ratios and 95% confidence intervals were calculated with logistic regression analysis conditional on age and adjusted for smoking and other factors. For estimating the risks of either wood dust or chemical additives, the authors additionally adjusted for the corresponding co-exposure. ADCN occurred relatively more frequently among wood workers that had ever worked as cabinet makers or joiners (OR 2.96, 95% CI 1.46 to 6.01) than as saw millers (OR 0.15, 95% CI 0.03 to 0.68). Average exposure to inhalable wood dust >/=5 mg/m(3) was associated with a high risk (OR 48.47, 95% CI 13.30 to 176.63) compared to levels below 3.5 mg/m(3). Assuming 40 years of exposure under these concentrations, the corresponding OR was 4.20 (95% CI 1.69 to 10.43). Exposure between 3.5 and 5 mg/m(3) was also found to pose a risk (OR 10.54, 95% CI 3.34 to 33.27). Exposure to pigment stains before 1970 was associated with an increased risk (OR 3.03; 95% CI 1.11 to 8.26). No significant associations were estimated for wood preservatives, varnishes, and formaldehyde. The authors found an elevated ADCN risk for exposure to inhalable wood dust above 3.5 mg/m(3). The rareness of the disease does not allow the exclusion of risk below that concentration. For pigment stains, there is evidence for an association of historical exposure with the development of ADCN in German wood workers.


When proteomics meets structural biology.
Recent progress in proteomics has identified vast arrays of interacting proteins together with knowledge of their post-translational modifications. A key challenge is to integrate this information with homology modelling and structural biology to provide a topological or even an atomic context for these modifications. Mass spectrometry (MS) is ideally placed to bring together these largely independent disciplines, being already established in proteomics and rapidly emerging in structural biology. By using MS-based approaches to probe the subunit stoichiometry of intact complexes, interaction networks and subunit packing can be defined, leading ultimately to 3D models. In this review, we discuss how superimposing proteomics information onto both low-resolution 3D models and high-resolution atomic structures can reveal new insight into function.


A novel laminin E8 cell adhesion site required for lung alveolar formation in vitro.
Basement membrane-adherent type II alveolar cells isolated from lung assemble into lumen-containing cellular spheres which retain the correct polarity and thereby approximate the earliest fetal stage of alveolar morphogenesis. The molecular basis of this process, determined in initial experiments to be attributable mainly to the large heterotrimeric glycoprotein laminin, was probed with laminin proteolytic fragments, antibodies, and synthetic peptides. The carboxy-terminal fragment E8, but not equimolar amounts of fragment P1, blocked alveolar formation. To pursue this observation, we used several anti-E8 antibodies and identified one, prepared against A chain residues 2179-2198 ("SN-peptide") from the first loop of the G domain, as inhibitory. These results were confirmed by use of SN-peptide alone and further defined by trypsin digestion of SN-peptide to the sequence SINNNR. This conserved site promoted divalent cation dependent adhesion of both type II alveolar and HT1080 cells, was inhibitable with equimolar amounts of fragment E8 but not P1, and derives from a form of laminin present in fetal alveolar basement membranes. These studies point to an important novel cell adhesion site in the laminin E8 region with a key role in lung alveolar morphogenesis.


Epidermal growth factor and aging: a signaling molecule reveals a new eye opening function.
Epidermal Growth Factor (EGF) is known for its role in promoting cell division and cellular differentiation in developing animals, but we know surprising little about what EGF does in vivo in mature adult animals. Here I review EGF signaling, emphasizing several recent studies that uncovered an unexpected role for EGF in promoting longevity and healthspan in mature adult C. elegans. EGF, acting through phospholipase Cγ and the IP3 receptor signaling, maintains pharyngeal and body wall muscle function in aging adults, and delays the accumulation of lipofuscin-enriched aging pigments within intestinal cells. EGF also acts through the Ras/ERK pathway to regulate protein homeostasis by promoting the expression of antioxidant genes, stimulating the activity of the Ubiquitin Proteasome System (UPS), and repressing the expression of small heat shock protein chaperones. The effects of EGF signaling on lifespan are largely independent of Insulin/IGF-like Signaling (IIS), as the effects of EGF signaling mutants on lifespan and heathspan are not affected by mutations in the DAF-2 insulin receptor or the DAF-16 FOXO transcription factor. Nevertheless, these two signal pathways have multiple points of overlap, coordination, and cross regulation. I propose that the IIS and EGF signaling pathways respond to environment and to developmental timing, respectively, so as to coordinate the appropriate physiological strategy that cells use to maintain protein homeostasis.


Opportunities and Challenges for Environmental Exposure Assessment in Population-Based Studies.
A growing number and increasing diversity of factors are available for epidemiological studies. These measures provide new avenues for discovery and prevention, yet they also raise many challenges for adoption in epidemiological investigations. Here, we evaluate 1) designs to investigate diseases that consider heterogeneous and multidimensional indicators of exposure and behavior, 2) the implementation of numerous methods to capture indicators of exposure, and 3) the analytical methods required for discovery and validation. We find that case-control studies have provided insights into genetic susceptibility but are insufficient for characterizing complex effects of environmental factors on disease development. Prospective and two-phase designs are required but must balance extended data collection with follow-up of study participants. We discuss innovations in assessments including the microbiome; mass spectrometry and metabolomics; behavioral assessment; dietary, physical activity, and occupational exposure assessment; air pollution monitoring; and global positioning and individual sensors. We claim the the availability of extensive correlated data raises new challenges in disentangling specific exposures that influence cancer risk from among extensive and often correlated exposures. In conclusion, new high-dimensional exposure assessments offer many new opportunities for environmental assessment in cancer development. Cancer Epidemiol Biomarkers Prev; 26(9); 1370-80. ©2017 AACR.


Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation.
The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.


Control of action potential duration alternans in canine cardiac ventricular tissue.
Cardiac electrical alternans, characterized by a beat-to-beat alternation in action potential waveform, is a naturally occurring phenomenon, which can occur at sufficiently fast pacing rates. Its presence has been putatively linked to the onset of cardiac reentry, which is a precursor to ventricular fibrillation. Previous studies have shown that closed-loop alternans control techniques that apply a succession of externally administered cycle perturbations at a single site provide limited spatially-extended alternans elimination in sufficiently large cardiac substrates. However, detailed experimental investigations into the spatial dynamics of alternans control have been restricted to Purkinje fiber studies. A complete understanding of alternans control in the more clinically relevant ventricular tissue is needed. In this paper, we study the spatial dynamics of alternans and alternans control in arterially perfused canine right ventricular preparations using an optical mapping system capable of high-resolution fluorescence imaging. Specifically, we quantify the spatial efficacy of alternans control along 2.5 cm of tissue, focusing on differences in spatial control between different subregions of tissue. We demonstrate effective control of spatially-extended alternans up to 2.0 cm, with control efficacy attenuating as a function of distance. Our results provide a basis for future investigations into electrode-based control interventions of alternans in cardiac tissue.


Mapping and characterization of seed dormancy QTLs using chromosome segment substitution lines in rice.
Seed dormancy--the temporary failure of a viable seed to germinate under favorable conditions--is a complex characteristic influenced by many genes and environmental factors. To detect the genetic factors associated with seed dormancy in rice, we conducted a QTL analysis using chromosome segment substitution lines (CSSLs) derived from a cross between Nona Bokra (strong dormancy) and Koshihikari (weak dormancy). Comparison of the levels of seed dormancy of the CSSLs and their recurrent parent Koshihikari revealed that two chromosomal regions-on the short arms of chromosomes 1 and 6-were involved in the variation in seed dormancy. Further genetic analyses using an F(2) population derived from crosses between the CSSLs and Koshihikari confirmed the allelic differences and the chromosomal locations of three putative QTLs: Sdr6 on chromosome 1 and Sdr9 and Sdr10 on chromosome 6. The Nona Bokra alleles of the three QTLs were associated with decreased germination rate. We discuss the physiological features of the CSSLs and speculate on the possible mechanisms of dormancy in light of the newly detected QTLs.


Fetal alcohol syndrome in adolescents and adults.
Fetal alcohol syndrome is a specific recognizable pattern of malformation. Manifestations in 61 adolescents and adults suffering from alcohol teratogenesis are presented. After puberty, the faces of patients with fetal alcohol syndrome or fetal alcohol effects were not as distinctive. Patients tended to remain short and microcephalic, although their weight was somewhat closer to the mean. The average IQ was 68, but the range of IQ scores widely varied. Average academic functioning was at the second- to fourth-grade levels, with arithmetic deficits most characteristic. Maladaptive behaviors such as poor judgment, distractibility, and difficulty perceiving social cues were common. Family environments were remarkably unstable. Fetal alcohol syndrome is not just a childhood disorder; there is a predictable long-term progression of the disorder into adulthood, in which maladaptive behaviors present the greatest challenge to management.


Handgrip Based Action Information Modulates Attentional Selection: An ERP Study.
Prior work shows that the possibility of action to an object (visual affordance) facilitates attentional deployment. We sought to investigate the neural mechanisms underlying this modulation of attention by examining ERPs to target objects that were either congruently or incongruently gripped for their use in the presence of a congruently or incongruently gripped distractor. Participants responded to the presence or absence of a target object matching a preceding action word with a distractor object presented in the opposite location. Participants were faster in responding to congruently gripped targets compared to incongruently gripped targets. There was a reduced N2pc potential when the target was congruently gripped, and the distractor was incongruently gripped compared to the conditions where targets were incongruently gripped or when the distractor, as well as target, was congruently gripped. The N2pc results indicate that target selection is easier when action information is congruent with an object's use.