Power output of sound-producing muscles in the tree frogs Hyla versicolor and Hyla chrysoscelis.
Sound-producing muscles provide the opportunity of studying the limits of power production at high contractile frequencies. We used the work loop technique to determine the power available from the external oblique muscles in two related species of North American gray tree frog, Hyla chrysoscelis and Hyla versicolor. These trunk muscles contract cyclically, powering high-intensity sound production in anuran amphibians. The external oblique muscles in H. chrysoscelis have an in vivo operating frequency of 40-55 Hz at 20-25 degrees C, whereas in H. versicolor these muscles contract with a frequency of 20-25 Hz at these temperatures. In vivo investigations have shown that these muscles use an asymmetrical sawtooth length trajectory (with a longer shortening phase compared with the lengthening phase) during natural cycles. To study the influence of this particular length trajectory on power output, we subjected the muscles to both sinusoidal and sawtooth length trajectories. In both species, the sawtooth trajectory yielded a significantly higher power output than the sinusoidal length pattern. The maximum power output during sawtooth cycles was similar in both species (54 W kg(-)(1) in H. chrysoscelis and 58 W kg(-)(1) in H. versicolor). These values are impressive, particularly at the operating frequencies and temperatures of the muscle. The sinusoidal length trajectory yielded only 60 % of the total power output compared with the sawtooth trajectory (34 W kg(-)(1) for H. chrysoscelis and 36 W kg(-)(1) for H. versicolor). The optimum cycle frequencies maximizing the power output using a sawtooth length pattern were approximately 44 Hz for H. chrysoscelis and 21 Hz for H. versicolor. These frequencies are close to those used by the two species during calling. Operating at higher frequencies, H. chrysoscelis maximized power at a strain amplitude of only 8 % compared with a value of 12 % in H. versicolor. These strains match those used in vivo during calling. The stimulus timing observed in vivo during calling was also similar to that yielding maximum power at optimal frequency in both species (6 ms and 8 ms before the start of shortening in H. chrysoscelis and H. versicolor, respectively). As expected, twitch duration in H. chrysoscelis is much shorter than that in H. versicolor (23 ms and 37 ms, respectively). There was a less remarkable difference between their maximum shortening velocities (V(max)) of 13.6 L(0 )s(-)(1) in H. chrysoscelis and 11.1 L(0 )s(-)(1) in H. versicolor, where L(0) is muscle length. The force-velocity curves are very flat, which increases power output. At the myofibrillar level, the flat force-velocity curves more than compensate for the lower peak isometric force found in these muscles. The data presented here emphasize the importance of incorporating in vivo variables in designing in vitro studies.


Demographic but not geographic insularity in HIV transmission among young black MSM.
To understand patterns of HIV transmission among young black MSM and others in Mississippi. Phylogenetic analysis of HIV-1 polymerase (pol) sequences from 799 antiretroviral-naive persons newly diagnosed with HIV infection in Mississippi during 2005-2008, 130 (16%) of whom were black MSM aged 16-25 years. We identified phylogenetic clusters and used surveillance data to evaluate demographic attributes and risk factors of all persons in clusters that included black MSM aged 16-25 years. We identified 82 phylogenetic clusters, 21 (26%) of which included HIV strains from at least one young black MSM. Of the 69 persons in these clusters, 59 were black MSM and seven were black men with unknown transmission category; the remaining three were MSM of white or Hispanic race/ethnicity. Of these 21 clusters, 10 included residents of one geographic region of Mississippi, whereas 11 included residents of multiple regions or outside of the state. Phylogenetic clusters involving HIV-infected young black MSM were homogeneous with respect to demographic and risk characteristics, suggesting insularity of this population with respect to HIV transmission, but were geographically heterogeneous. Reducing HIV transmission among young black MSM in Mississippi may require prevention strategies that are tailored to young black MSM and those in their sexual networks, and prevention interventions should be delivered in a manner to reach young black MSM throughout the state. Phylogenetic analysis can be a tool for local jurisdictions to understand the transmission dynamics in their areas.


Application of radioimmunoassay to monitor treatment of human cerebral gliomas with bleomycin entrapped within liposomes.
A radioimmunoassay was assessed for its suitability for monitoring the blood and urinary concentrations of bleomycin entrapped within large unilamellar liposomes in patients receiving therapeutic doses of the drug. Bleomycin entrapped within liposomes was administered by direct intracerebral injection to three patients with grade III to IV cerebral gliomas, twice weekly for up to six weeks. No clinically important toxic effects were observed which could have been attributed to these preparations, although all three patients showed progressive deterioration in their clinical condition. This type of treatment may be more beneficial to patients at an earlier stage of their disease.


Estrogen-induced acute pancreatitis: A case report and literature review.
Estrogens are commonly used in gynecologic area, such as oral contraception, hormone replacement therapy, and in vitro fertilization-embryo transfer. Although estrogen is a common cause of acute drug-induced pancreatitis, there has been paucity of report in Korea. Clinical course of estrogen-induced acute pancreatitis is usually mild to moderate, but fetal case can occur. In addition, there can be a latency from the first administration to the symptom. Therefore, physicians should consider the possibility of the disease when a woman taking estrogen or previous history of taking estrogen presents with acute abdominal pain. Here, we report a case of estrogen-induced acute pancreatitis that occurred during the preparation for embryo transfer.


Evaluation of mechanical and thermal nociception as objective tools to measure painful and nonpainful lameness phases in multiparous sows.
The objective of this study was to quantify pain sensitivity differences using mechanical nociception threshold (MNT) and thermal nociception threshold (TNT) tests when sows were in painful and nonpainful transient lameness phases. A total of 24 mixed parity crossbred sows (220.15 ± 21.23 kg) were utilized for the MNT test, and a total of 12 sows (211.41 ± 20.21 kg) were utilized for the TNT test. On induction day (D0), all sows were anesthetized and injected with Amphotericin B (10mg/mL) in the distal interphalangeal joint space in both claws of one randomly selected hind limb to induce transient lameness. Three days were compared: (1) D-1 (sound phase, defined as 1 d before induction), (2) D+1 (most lame phase, defined as 1 d after induction), and (3) D+6 (resolution phase, defined as 6 d after induction). After completion of the first round, sows were given a 7-d rest period and then the procedures were repeated with lameness induced in the contralateral hind limb. During the MNT test, pressure was applied perpendicularly to 3 landmarks in a randomized sequence for each sow: 1) middle of cannon on the hind limb (cannon), 2) 1 cm above the coronary band on the medial hind claw (medial claw), and 3) 1 cm above the coronary band on the lateral hind claw (lateral claw). During the TNT test, a radiant heat stimulus was directed 1 cm above the coronary band. The data were analyzed using the MIXED procedure in SAS with sow as the experimental unit. Differences were analyzed between sound and lame limbs on each day. For the MNT test, pressure tolerated by the lame limb decreased for every landmark (P < 0.05) when comparing D-1 and D+1. The sound limb tolerated more pressure on D+1 and D+6 than on baseline D-1 (P < 0.05). Thermal stimulation tolerated by the sound limb did not change over the 3 d (P > 0.05). However, the sows tolerated less heat stimulation on their lame limb on D+1 compared to D-1 levels (P < 0.05). Both MNT and TNT tests indicated greater pain sensitivity thresholds when sows were acutely lame.


Classification of phenoptotic phenomena.
Phenoptosis is defined as the programmed death of an organism. In a more detailed formulation of the concept, it is the death of an individual caused by its own actions or by actions of close relatives (and not by accidents or age-independent diseases), which is determined by genes that are favored by natural selection and in certain cases increase the evolvability of organisms. This category of phenomena cannot be justified in terms of individual selection and needs always a justification in terms of supra-individual selection. Four types of phenoptosis are proposed (A, obligatory and rapid; B, obligatory and slow; C, optional; D, indirect). Examples of each type and subtype are given. The classification is discussed in its meaning and implications, and compared with another classification of end life types largely based on the classical concept of senescence.


Genetic and environmental contributions to the association between attention deficit hyperactivity disorder and alcohol dependence in adulthood: A large population-based twin study.
Previous research indicates that attention deficit hyperactivity disorder (ADHD) frequently co-occurs with alcohol dependence; however, the extent to which shared genetic risk factors underpin this association remains unclear. The aim of this study is to investigate the relative importance of genetic, shared, and nonshared environmental factors for the overlap between ADHD and alcohol dependence in adults. Almost 18,000 adult twins aged 20-45 years, from more than 12,000 twin pairs (5,420 complete pairs), from the population-representative Swedish Twin Registry, were included. Self-ratings were used to assess symptoms of ADHD and alcohol dependence. Twin analysis was used to determine the role of additive genetic (A), shared (C), and nonshared environmental (E) factors. As a result, we found a significant association between ADHD and alcohol dependence (odds ratio 3.58; 95% confidence interval, 2.85-4.49). Twin analysis suggested that shared genetic risk factors explained 64% of the overlap between ADHD and alcohol dependence. Nonshared environmental factors accounted for the remaining 36%, whereas the contribution of shared environmental factors was minimal. We found no support for statistically significant sex differences in the overlap between ADHD and alcohol dependence. In conclusion the overlap between ADHD and alcohol dependence in adulthood was largely explained by shared genetic risk factors. This is an important step toward understanding the underlying nature of the risk of alcohol dependence in patients with ADHD and suggests that individuals with ADHD and their family members are important targets for alcohol prevention and treatment. © 2015 Wiley Periodicals, Inc.


Broad Salinity Tolerance as a Refuge from Predation in the Harmful Raphidophyte Alga Heterosigma akashiwo (Raphidophyceae).
The ability of harmful algal species to form dense, nearly monospecific blooms remains an ecological and evolutionary puzzle. We hypothesized that predation interacts with estuarine salinity gradients to promote blooms of Heterosigma akashiwo (Y. Hada) Y. Hada ex Y. Hara et M. Chihara, a cosmopolitan toxic raphidophyte. Specifically, H. akashiwo's broad salinity tolerance appears to provide a refuge from predation that enhances the net growth of H. akashiwo populations through several mechanisms. (1) Contrasting salinity tolerance of predators and prey. Estuarine H. akashiwo isolates from the west coast of North America grew rapidly at salinities as low as six, and distributed throughout experimental salinity gradients to salinities as low as three. In contrast, survival of most protistan predator species was restricted to salinities >15. (2) H. akashiwo physiological and behavioral plasticity. Acclimation to low salinity enhanced H. akashiwo's ability to accumulate and grow in low salinity waters. In addition, the presence of a ciliate predator altered H. akashiwo swimming behavior, promoting accumulation in low-salinity surface layers inhospitable to the ciliate. (3) Negative effects of low salinity on predation processes. Ciliate predation rates decreased sharply at salinities <25 and, for one species, H. akashiwo toxicity increased at low salinities. Taken together, these behaviors and responses imply that blooms can readily initiate in low salinity waters where H. akashiwo would experience decreased predation pressure while maintaining near-maximal growth rates. The salinity structure of a typical estuary would provide this HAB species a unique refuge from predation. Broad salinity tolerance in raphidophytes may have evolved in part as a response to selective pressures associated with predation.


Betaine protects cerebellum from oxidative stress following levodopa and benserazide administration in rats.
The aim of the present study was to evaluate antioxidant and methyl donor effects of betaine in cerebellum following levodopa and benserazide administration in rats. Sprague-Dawley male rats were treated with levodopa (LD), betaine (Bet), levodopa plus betaine (LD/Bet), levodopa plus benserazide (LD/Ben), levodopa plus betaine-benserazide (LD/Bet-Ben), and the controls with vehicle for 10 consecutive days, orally. Treatment of rats with LD and benserazide significantly increased total homocysteine in plasma of the LD/Ben group when compared to the other groups. Lipid peroxidation of cerebellum increased significantly in LD-treated rats when compared to the other groups. In contrast, glutathione peroxidase activity and glutathione content in cerebellum were significantly higher in the betaine-treated rats when compared to the LD and LD/Ben groups. Serum dopamine concentration increased significantly in LD-treated rats in comparison with the LD/Ben group. LD/Bet-treated rats also demonstrated significantly higher dopamine levels when compared to the LD/Ben group. We observed valuable effects of Bet in combination with LD and benserazide, which routinely were used for Parkinson's disease (PD) treatment, in experimentally-induced oxidative stress and hyperhomocysteinemia in rats. Therefore, it seems that Bet is a vital and promising agent regarding PD for future clinical trials in humans.


Membrane currents of identified isolated rat corticotropes and gonadotropes.
Membrane currents of identified, isolated corticotropes and gonadotropes from mammalian anterior pituitary gland have been evaluated. Pituitary gonadotropes and corticotropes were isolated enzymatically and stained in the living state using biotinylated gonadotropin-releasing hormone (Bio-GnRH) or biotinylated corticotropin-releasing hormone (Bio-CRF) followed by avidin fluorescein. Electrophysiological recordings were made with patch-clamp electrodes in the whole-cell clamp configuration. Tetrodotoxin (TTX)-sensitive sodium currents were larger in corticotropes than in gonadotropes. Corticotropes showed two components of calcium currents, a transient low-threshold component and a longer lasting high-threshold component. Small TTX-resistant inward currents were present also in gonadotropes, and both cell types had transient and steady potassium currents.


Identification of the sirohaem biosynthesis pathway in Staphylococcus aureus.
Sirohaem is a modified tetrapyrrole and a key prosthetic group of several enzymes involved in nitrogen and sulfur metabolisms. This work shows that Staphylococcus aureus produces sirohaem through a pathway formed by three independent enzymes. Of the two putative sirohaem synthases encoded in the S. aureus genome and annotated as cysG, one is herein shown to be a uroporphyrinogen III methyltransferase that converts uroporphyrinogen III to precorrin-2, and was renamed as UroM. The second cysG gene encodes a precorrin-2 dehydrogenase that converts precorrin-2 to sirohydrochlorin, and was designated as P2D. The last step was found to be performed by the gene nirR that, in fact, codes for a protein with sirohydrochlorin ferrochelatase activity, labelled as ShfC. Additionally, site-directed mutagenesis studies of S. aureus ShfC revealed that residues H22 and H87, which are predicted by homology modelling to be located at the active site, control the ferrochelatase activity. Within bacteria, sirohaem synthesis may occur via one, two or three enzymes, and we propose to name the correspondent pathways as Types 1, 2 and 3, respectively. A phylogenetic analysis revealed that Type 1 is the most used pathway in Gammaproteobacteria and Streptomycetales, Type 2 predominates in Fibrobacteres and Vibrionales, and Type 3 predominates in Firmicutes of the Bacillales order. Altogether, we concluded that the current distribution of sirohaem pathways within bacteria, which changes at the genus or species level and within taxa, seems to be the result of evolutionary multiple fusion/fission events.


Invasive coronary procedure use and outcomes among veterans with posttraumatic stress disorder: insights from the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program.
Posttraumatic stress disorder (PTSD) is prevalent in the general population and US veterans in particular and is associated with an increased risk of developing coronary artery disease (CAD). We compared the patient characteristics and postprocedural outcomes of veterans with and without PTSD undergoing coronary angiography. This is a multicenter observational study of patients who underwent coronary angiography in Veterans Affairs hospitals nationally from October 2007 to September 2011. We described patient characteristics at angiography, angiographic results, and after coronary angiography, we compared risk-adjusted 1-year rates of all-cause mortality, myocardial infarction (MI), and revascularization by the presence or absence of PTSD. Overall, of 116,488 patients undergoing angiography, 14,918 (12.8%) had PTSD. Compared with those without PTSD, patients with PTSD were younger (median age 61.9 vs 63.7; P < .001), had higher rates of cardiovascular risk factors, and were more likely to have had a prior MI (26.4% vs 24.7%; P < .001). Patients with PTSD were more likely to present for stable angina (22.4% vs 17.0%) or atypical chest pain (58.5% vs 48.6%) and less likely to have obstructive CAD identified at angiography (55.9% vs 62.2%; P < .001). After coronary angiography, PTSD was associated with lower unadjusted 1-year rates of MI (hazard ratio (HR), 0.86; 95% CI [0.75-1.00]; P = 0.04), revascularization (HR, 0.88; 95% CI [0.83-0.93]; P < .001), and all-cause mortality (HR, 0.66; 95% CI [0.60-0.71]; P < .001). After adjustment for cardiovascular risk, PTSD was no longer associated with 1-year rates of MI or revascularization but remained associated with lower 1-year all-cause mortality (HR, 0.91; 95% CI [0.84-0.99]; P = .03). Findings were similar after further adjustment for depression, anxiety, alcohol or substance use disorders, and frequency of outpatient follow-up. Among veterans undergoing coronary angiography in the Veterans Affairs, those with PTSD were more likely to present with elective indications and less likely to have obstructive CAD. After coronary angiography, PTSD was not associated with adverse 1-year outcomes of MI, revascularization, or all-cause mortality.


Chemoembolization of hepatocellular carcinoma: patient status at presentation and outcome over 15 years at a single center.
We report the outcome of the care of 209 patients with hepatocellular carcinoma with a focus on relevant scoring systems for predicting overall survival and time to progression and on changes in presentation status and outcome from 1991 to 2006. Hepatic arterial chemoembolization was performed on 209 patients in 375 sessions. Disease status was evaluated with the Child-Pugh, Okuda, Cancer of the Liver Italian Program, and American Joint Committee on Cancer (AJCC) systems. Changes in status at presentation from 1991 to 2006 and change in overall survival period and time to progression were analyzed. Median and mean overall survival periods for the entire group were 376 and 574 +/- 61 days. Median and mean times to progression were 267 and 409 +/- 54 days. Forty-nine patients underwent liver transplantation a median of 143 days after chemoembolization. The median and mean overall survival times among patients not undergoing transplantations were 466 and 574 +/- 61 days. Okuda score (p < 0.0001) and AJCC stage (p = 0.014) were the best predictors of overall survival and time to progression, respectively. Patients with disease with an Okuda I score and in AJCC stage I or II had median and mean overall survival periods of 667 and 992 +/- 176 days and times to progression of 378 and 589 +/- 110 days. Clinical status at presentation, overall survival period (p = 0.64), and time to progression (p = 0.44) were unchanged from 1991 to 2006. The 30-day mortality was 3.2%. Patients treated with hepatic arterial chemoembolization for HCC in Okuda score I and AJCC stage I or II have more durable survival than previously reported in a U.S. population.


Effect of patient Age on surgical outcomes for Graves' disease: a case-control study of 100 consecutive patients at a high volume thyroid surgical center.
To compare outcomes between children (<18 yrs) and adults undergoing total thyroidectomy for Graves' disease (GD) at a high volume, multidisciplinary thyroid center. Reported complication rates for children undergoing surgery for Graves' disease are worse than for adults. 100 consecutive patients (32 children; 68 adults) who underwent total thyroidectomy for Graves' disease (GD) by a high-volume endocrine surgery team from were compared. The mean patient age was 9.7 yrs (range 3.4-17.9 yrs) in children versus 44.9 yrs (range 18.4-84.2 yrs) in adults. Operative times were longer in children (2.18 ± 0.08 hrs) than in adults (1.66 ± 0.03 hrs) (p = 0.003). Pediatric thyroid specimens averaged 38.6.0 ± 8.9 gm (range: 9-293 gm) and adult thyroid specimens averaged 48.0 ± 6.4 gm (range: 6.6-203 gm) (p = 0.34). Thyroid to body weight ratios were greater in children (0.94 ± 0.11 gm/kg) than adults (0.67 ± 0.8 gm/kg) (p = 0.05). In all patients, the hyperthyroid state resolved after surgery. There was no operative mortality, recurrence, or permanent hypoparathyroidism. Transient post-operative hypocalcemia requiring calcium infusion was greater in children than adults (6/32 vs. 1/68; p = 0.004). Transient recurrent laryngeal nerve dysfunction occurred in two children and in no adults (p = 0.32). Postoperative hematoma occurred in two adults and in no children (p = 0.46). The length of stay was longer for children (1.41 ± 0.12 days) than for adults (1.03 ±0.03 days) (p = 0.004). Surgical management of GD is technically more challenging in children as evidenced by longer operative times. Whereas temporary hypocalcemia occurs more commonly in children than adults, the risks of major complications including disease recurrence, permanent hypoparathyroidism, recurrent laryngeal nerve injury, or neck hematoma were indistinguishable. These data suggest that excellent and equivalent outcomes can be achieved for GD surgery in children and adults when care is rendered by a high volume, endocrine surgery team.


Degradation of methoxylated benzoic acids by a Nocardia from a lignin-rich environment: significance to lignin degradation and effect of chloro substituents.
Strain A81 of Nocardia corallina hydroxylates or demethylates p-anisic acid to p-hydroxybenzoic acid and isovanillic acid. It demethylates veratric acid to a mixture of vanillic and isovanillic acids. These are both demethylated to protocatechuic acid, which undergoes ring cleavage to afford beta-carboxy-cis-cis-muconic acid. The intermediacy of protocatechuic acid in the catabolic pathway of veratric acid was confirmed by blocking ring cleavage with an additional substituent in the ring: 5-chlorovanillic acid was demethylated to 5-chloro-protocatechuic acid, which accumulated. Chloro substituents in the ring of other methoxylated benzoic acids also arrested their normal metabolism by the Nocardia: an ortho-chloro substituent thwarted both demethylation and ring-opening. ortho-Hydroxylation of p-methoxybenzoic acid to isovanillic acid was unaffected by a chlorine ortho to the methoxyl group. Washed whole cells of veratric acid-grown N. corallina A81 produced no detected structural changes in an isolated lignin. The implications of this observation are discussed.


Antibodies to the repetitive epitope of Plasmodium falciparum circumsporozoite protein in a rural Tanzanian community: a longitudinal study of 132 children.
An ELISA employing a novel synthetic peptide consisting of 40 (Asn-Ala-Asn-Pro) repeats of Plasmodium falciparum circumsporozoite protein, (NANP)40, was used to detect antibodies against P. falciparum circumsporozoite protein in 132 children, 1 month to 15 years old, from a rural community (Kikwawila village) of Tanzania, a region where malaria is hyperendemic. The children were surveyed comprehensively over 3 consecutive years for clinical, parasitological, and serological parameters. Entomological data were also gathered for selected households in this village. The following results were obtained: anti-(NANP)40 antibodies increased as a function of age; the majority of children over 10 years showed a stable positivity for such antibodies during the longitudinal study; a negative correlation was observed between the levels of anti-sporozoite antibodies and both spleen enlargement and the presence of parasites in thick smears; no relationship was found between anti-(NANP)40 antibodies and asexual blood stage antibodies; children living in two representative households with comparable indoor resting mosquito densities showed markedly different frequencies of anti-(NANP)40 antibodies, in spite of comparable clinical, parasitological, and serological parameters. Thus, in addition to the exposure to infectious mosquito bites, other (e.g., genetic) factors, may play a role in the ability of certain individuals to mount an antibody response against this immunodominant repetitive epitope. The results presented in this paper confirm that the (NANP)40-ELISA represents a simple, reliable means for the detection of anti-(NANP)40 circumsporozoite protein antibodies and suggest that such antibodies may contribute to the immune protection against malaria in humans.


Muscle contributions to support and progression over a range of walking speeds.
Muscles actuate walking by providing vertical support and forward progression of the mass center. To quantify muscle contributions to vertical support and forward progression (i.e., vertical and fore-aft accelerations of the mass center) over a range of walking speeds, three-dimensional muscle-actuated simulations of gait were generated and analyzed for eight subjects walking overground at very slow, slow, free, and fast speeds. We found that gluteus maximus, gluteus medius, vasti, hamstrings, gastrocnemius, and soleus were the primary contributors to support and progression at all speeds. With the exception of gluteus medius, contributions from these muscles generally increased with walking speed. During very slow and slow walking speeds, vertical support in early stance was primarily provided by a straighter limb, such that skeletal alignment, rather than muscles, provided resistance to gravity. When walking speed increased from slow to free, contributions to support from vasti and soleus increased dramatically. Greater stance-phase knee flexion during free and fast walking speeds caused increased vasti force, which provided support but also slowed progression, while contralateral soleus simultaneously provided increased propulsion. This study provides reference data for muscle contributions to support and progression over a wide range of walking speeds and highlights the importance of walking speed when evaluating muscle function.


Ab initio construction of a eukaryotic transcriptome by massively parallel mRNA sequencing.
Defining the transcriptome, the repertoire of transcribed regions encoded in the genome, is a challenging experimental task. Current approaches, relying on sequencing of ESTs or cDNA libraries, are expensive and labor-intensive. Here, we present a general approach for ab initio discovery of the complete transcriptome of the budding yeast, based only on the unannotated genome sequence and millions of short reads from a single massively parallel sequencing run. Using novel algorithms, we automatically construct a highly accurate transcript catalog. Our approach automatically and fully defines 86% of the genes expressed under the given conditions, and discovers 160 previously undescribed transcription units of 250 bp or longer. It correctly demarcates the 5' and 3' UTR boundaries of 86 and 77% of expressed genes, respectively. The method further identifies 83% of known splice junctions in expressed genes, and discovers 25 previously uncharacterized introns, including 2 cases of condition-dependent intron retention. Our framework is applicable to poorly understood organisms, and can lead to greater understanding of the transcribed elements in an explored genome.


Didymin induces apoptosis by inhibiting N-Myc and upregulating RKIP in neuroblastoma.
Neuroblastomas arise from the neural crest cells and represent the most common solid tumors outside the nervous system in children. The amplification of N-Myc plays a primary role in the pathogenesis of neuroblastomas, whereas acquired mutations of p53 lead to refractory and relapsed cases of neuroblastomas. In this regard, dietary compounds which can target N-Myc and exert anticancer effects independent of p53 status acquire significance in the management of neuroblastomas. Hence, we investigated the anticancer properties of the flavonoid didymin in neuroblastomas. Didymin effectively inhibited proliferation and induced apoptosis irrespective of p53 status in neuroblastomas. Didymin downregulated phosphoinositide 3-kinase, pAkt, Akt, vimentin, and upregulated RKIP levels. Didymin induced G(2)/M arrest along with decreasing the levels of cyclin D1, CDK4, and cyclin B1. Importantly, didymin inhibited N-Myc as confirmed at protein, mRNA, and transcriptional level by promoter-reporter assays. High-performance liquid chromatography analysis of didymin-treated (2 mg/kg b.w.) mice serum revealed effective oral absorption with free didymin concentration of 2.1 μmol/L. Further in vivo mice xenograft studies revealed that didymin-treated (2 mg/kg b.w.) animals had significant reductions in tumors size compared with controls. Didymin strongly inhibited the proliferation (Ki67) and angiogenesis (CD31) markers, as well as N-Myc expression, as revealed by the histopathologic examination of paraffin-embedded section of resected tumors. Collectively, our in vitro and in vivo studies elucidated the anticancer properties and mechanisms of action of a novel, orally active, and palatable flavonoid didymin, which makes it a potential new approach for neuroblastoma therapy (NANT) to target pediatric neuroblastomas.


Sequential blood level monitoring of basiliximab during multisession plasmapheresis in a kidney transplant recipient.
Basiliximab, a chimeric monoclonal antibody against the alpha chain of the interleukin-2 receptor (IL-2R) has been used in renal transplant patients. We monitored sequential blood concentrations of basiliximab in a patient who received a kidney transplant with basiliximab-based immunosuppression together with multiple sessions of plasmapheresis. A 34-year-old man received a living-related kidney transplant with induction immunosuppression including tacrolimus, mycophenolate, methylprednisolone, and basiliximab. Severe antibody-mediated acute rejection lead to a requirement for hemodialysis. Deoxyspergualin was administered for 10 days at a daily dose of 5 mg/kg combined with eight sessions of double filtration plasmapheresis (DFPP). After treatment, the serum creatinine returned to 0.95 mg/dL, and there were no major complications or infections. Sequential basiliximab blood levels of the patient were monitored following transplantation. The serum basiliximab concentration decreased by 72.4% after five consecutive DFPPs, and by 87.6% after eight DFPP sessions. The elimination rate of basiliximab (DeltaBLX) was 6.1% before DFPP, but increased over eight DFPPs to 20.5%. Serum basiliximab concentrations declined to 0.16 microg/mL on day 33, which is below the IL-2R saturation concentration (0.2 microg/mL). Multiple sessions of plasmapheresis using DFPP enhanced the elimination of serum basiliximab at an average elimination rate of 19.1%. In the patient reported on here, the serum basiliximab concentration fell to below the IL-2R saturation level (0.2 microg/mL) within 1 month of living-related kidney transplantation. We recommend that additional basiliximab infusions be considered for cases undergoing more than three plasmapheresis sessions.


[Intergenomic chromosome substitutions in wheat interspecific hybrids and their use in the development of a genetic nomenclature of Triticum timopheevii chromosomes].
The results of analysis of the genome formation in interspecific hybrids of Triticum aestivum with T. timopheevii are reviewed. The spectra of substitutions and rearrangements are shown to depend on the genotypes of the parental forms and on the direction of selection. The frequencies of substitutions of individual T. timopheevii chromosomes significantly vary and reflect the level of their divergence relative to the common wheat chromosomes. Some aspects of classification of the A(t)- and G-genome chromosomes are discussed.


Low mineral intake is associated with high systolic blood pressure in the Third and Fourth National Health and Nutrition Examination Surveys: could we all be right?
Analysis of the first National Health and Nutrition Examination Survey (NHANES) in 1984 revealed that a dietary pattern low in mineral intake, specifically calcium, potassium, and magnesium, was associated with hypertension in American adults. Using more recent survey data from NHANES III and NHANES IV, we re-examined the validity of this relationship. Blood pressure (BP) and nutrient intake data from 10,033 adult participants in NHANES III and 2311 adults in NHANES IV revealed findings similar to those of the earlier analysis, demonstrating that the association between inadequate mineral consumption and higher BP is valid and has persisted over two decades. Exploring this relationship further, we separated untreated hypertensive persons by hypertension type (systolic, diastolic, or both), and observed that the BP effect of low mineral intake was most pronounced in those with only systolic hypertension. We also observed that sodium intake was significantly lower in the systolic hypertension group and significantly higher in the diastolic hypertension group compared with the other groups. The nutrient pattern in the combined hypertension group was similar to that of the normotensive group. These findings may help to explain the inconsistent responses generally observed in dietary intervention studies, and they highlight the possible importance of tailored nutritional recommendations for hypertension based on hypertension category and individual dietary practices. Although randomized controlled trials are needed to characterize further the relationship between nutrient intake and hypertension type, these findings indicate that dietary management of hypertension may be more effective if the focus is on the overall nutritional profile rather than single-nutrient intake as currently recommended for most patients.


Potential effects of UV-B on the chemical environment of marine organisms: a review.
An increase in ultraviolet-B (UV-B) due to depletion of stratospheric ozone may affect growth of marine phytoplankton by altering the chemistry of their environment. Production of bioactive free radicals, photodecomposition of organic matter, and availability of trace metals are likely to be altered by increased UV-B flux. Such changes to the chemical environment may be both deleterious and beneficial to marine phytoplankton. Extracellular free radicals such as OH, Br(2)(-), and CO(3)(-) are predicted to have a negligible impact, but superoxide and its decomposition product hydrogen peroxide may react rapidly with cell surfaces and destroy membrane function and integrity. Increased UV-B will enhance the bioavailability of the redox active trace metals Fe and Cu. Thus, in the Fe-limited high latitude ocean, increased Fe availability may promote phytoplankton production, while in other parts of the ocean increased Cu availability may be toxic. Overall, the interdependent direct and indirect effects of UV-B on phytoplankton may compensate for each other and account for the ability of marine ecosystems to be subjected to widely variable UV-B flux without apparent damage.


Lingering radioactivity at the Bikini and Enewetak Atolls.
We made an assessment of the levels of radionuclides in the ocean waters, seafloor and groundwater at Bikini and Enewetak Atolls where the US conducted nuclear weapons tests in the 1940's and 50's. This included the first estimates of submarine groundwater discharge (SGD) derived from radium isotopes that can be used here to calculate radionuclide fluxes in to the lagoon waters. While there is significant variability between sites and sample types, levels of plutonium (239,240Pu) remain several orders of magnitude higher in lagoon seawater and sediments than what is found in rest of the world's oceans. In contrast, levels of cesium-137 (137Cs) while relatively elevated in brackish groundwater are only slightly higher in the lagoon water relative to North Pacific surface waters. Of special interest was the Runit dome, a nuclear waste repository created in the 1970's within the Enewetak Atoll. Low seawater ratios of 240Pu/239Pu suggest that this area is the source of about half of the Pu in the Enewetak lagoon water column, yet radium isotopes suggest that SGD from below the dome is not a significant Pu source. SGD fluxes of Pu and Cs at Bikini were also relatively low. Thus radioactivity associated with seafloor sediments remains the largest source and long term repository for radioactive contamination. Overall, Bikini and Enewetak Atolls are an ongoing source of Pu and Cs to the North Pacific, but at annual rates that are orders of magnitude smaller than delivered via close-in fallout to the same area.


Microphotoelectrochemical Surface-Enhanced Raman Spectroscopy: Toward Bridging Hot-Electron Transfer with a Molecular Reaction.
The rational design and applications of plasmon-mediated chemical reactions (PMCRs) are fundamentally determined by an understanding of photon-electron-molecule interactions. However, the current understanding of the PMCR of plasmon-decayed hot electron-mediated reactions remains implicit, since there has not been a single measurement of both hot-electron transfer and molecular transformation following photon excitation. Therefore, we invented a method called microphotoelectrochemical surface-enhanced Raman spectroscopy (μPEC-SERS) that uses an ultramicroelectrode (UME) whose dimensions match those of the focused laser spot. This system can simultaneously record the photocurrent (∼picoamps) of hot-electron transfer with a high signal-to-noise ratio and the SERS spectra of a molecular reaction in the same electrode area. The responses of the photocurrent and SERS spectra to laser illumination can correlate the surface reaction activated by hot electrons with the SERS spectral changes. A typical PMCR of p-aminothiophenol (PATP) on a Ag UME was used to illustrate that the correlation of the photocurrent with the spectral changes is capable of revealing the reaction mechanism in terms of the formation of activated oxygenated species. The laser power-, laser wavelength-, and surface roughness-dependent photocurrents link the formation of activated oxygenated species to the hot-electron transfer. Further comparisons of the photocurrent with the conventional electrochemical current of the oxygen reduction reaction indicate that the activated oxygenated species are oxidative in transforming PATP to p,p'-dimercaptoazobenzene, which is supported by a density functional theory (DFT) calculation. Therefore, μPEC-SERS could be a powerful tool for investigating PMCRs and other systems involving photon-electron-molecule interactions.


Protein extracted from Moringa oleifera Lam. Leaves: Bio-evaluation and characterization as suitable plant-based meat-protein alternative.
This study aimed to isolate and characterize moringa leaf protein (MLP) via HPLC and evaluate its consumption's effects through rat model. Four groups of Albino Wistar rats (n = 25 each) along with a control group (n = 25) were acclimatized. The isolated MLP was added to the basal diet (casein; control) in various percentages (25, 50, 75, 100%) for a 21-day experimental period. On three intervals (1st, 11th, 21st days), blood samples were collected and subjected for hematological and biochemical examination (Renal Function Test (RFT), Liver Function Test (LFT)). MLP contained a variety of essential and non-essential amino acids in substantial amounts. The Protein Efficiency Ratio (PER) of 50% MLP-treated group was the highest (1.72) among MLP treatments. Increases in feed intake and weight were observed in treated rats compared to the control. The hematological profile of the rats revealed increases in Hemoglobin (Hb) (7.9-14.0%), White Blood Cell (WBC) (35.9-51.5%), Red Blood Cell (RBC) (17.1-22.2%), Hematocrit (HCT) (13.1-22.9%), and platelets levels (36.5-40.6%) from day 1. Protein isolates decreased liver parameters but resulted in non-significant changes in liver and kidney functions in rats. Further investigation is needed to determine the safe daily intake of MLP.


Northern exposure: nuclear cardiology in the Canadian health care system.
The Canadian health care system may provide valuable insights into the future practice of nuclear cardiology in the United States. Rationing of medical care is not legislated by the Canadian health care system, although resource allocation is required of Canadian physicians and hospital administrators. Canadian nuclear cardiologists and physicians are not restricted in the ordering of diagnostic studies, despite the decreased availability in imaging systems and the centralization of equipment and personnel in Canada. Canadian imaging equipment is, in general, used more with less average idle time per unit. Delays in the performance of nonemergent imaging studies are more common in Canadian imaging laboratories. The number of out-of-hospital nuclear medicine laboratories is not increasing, because of government constraints on licensing and the general requirement that only radiologists or certified nuclear medicine physicians can operate these laboratories. A survey of 71 nuclear cardiology laboratories in the United States and Canada reveal that 21% of all cardiac imaging studies are performed for post-myocardial infarction risk stratification in Canada, compared with only 11% in United States laboratories. Rest and reinjection thallium imaging studies are performed more than twice as often in the United States laboratories. Canadian laboratories perform a higher average number of myocardial perfusion (2123 vs 1789) and ventricular function (773 vs 554) studies as compared with their United States counterparts. No other significant differences in clinical usage patterns were identified. A total of 130,000 nuclear cardiologies were performed in Canada in 1993, with less than 5% growth in the number of Canadian studies projected for 1994. Forty-five percent of Canadian perfusion studies are performed with 99mTc-labeled sestamibi frequently using a 2-day protocol (60%) with electrocardiogram gating (30%). Positron emission tomography (PET) can be performed in only six Canadian cities. Canadian PET centers are government funded, located in university teaching hospitals, and principally used for the purpose of research. Stress echocardiography is not widely performed in Canada because of the heavy clinical volume of standard echocardiographic studies at most hospitals, which reduces the time available for stress echocardiography. No separate billing code is available for stress echocardiography studies in Canada. Canadian cardiologists have accepted the value of rest and stress nuclear studies for the management of their patients and have concluded that it is more time efficient to perform clinical duties in lieu of stress echocardiographic studies. In conclusion, the realities of the Canadian health care system are that universal health care is valuable as long as it is consistent high quality medical care, and that the cost of universal coverage must be borne by the taxpayer using the system. The fact that nuclear cardiology has continued to thrive in the Canadian health care system suggests that future health care modifications in the United States will not exert a significant impact on the practice of nuclear cardiology.


Evidence for sharp increase in the economic damages of extreme natural disasters.
Climate change has increased the frequency and intensity of natural disasters. Does this translate into increased economic damages? To date, empirical assessments of damage trends have been inconclusive. Our study demonstrates a temporal increase in extreme damages, after controlling for a number of factors. We analyze event-level data using quantile regressions to capture patterns in the damage distribution (not just its mean) and find strong evidence of progressive rightward skewing and tail-fattening over time. While the effect of time on averages is hard to detect, effects on extreme damages are large, statistically significant, and growing with increasing percentiles. Our results are consistent with an upwardly curved, convex damage function, which is commonly assumed in climate-economics models. They are also robust to different specifications of control variables and time range considered and indicate that the risk of extreme damages has increased more in temperate areas than in tropical ones. We use simulations to show that underreporting bias in the data does not weaken our inferences; in fact, it may make them overly conservative.


A two-tiered curriculum to improve data management practices for researchers.
Better research data management (RDM) provides the means to analyze data in new ways, effectively build on another researcher's results, and reproduce the results of an experiment. Librarians are recognized by many as a potential resource for assisting researchers in this area, however this potential has not been fully realized in the biomedical research community. While librarians possess the broad skill set needed to support RDM, they often lack specific knowledge and time to develop an appropriate curriculum for their research community. The goal of this project was to develop and pilot educational modules for librarians to learn RDM and a curriculum for them to subsequently use to train their own research communities. We created online modules for librarians that address RDM best practices, resources and regulations, as well as the culture and practice of biomedical research. Data was collected from librarians through questions embedded in the online modules on their self-reported changes in understanding of and comfort level with RDM using a retrospective pre-post design. We also developed a Teaching Toolkit which consists of slides, a script, and an evaluation form for librarians to use to teach an introductory RDM class to researchers at their own institutions. Researchers' satisfaction with the class and intent to use the material they had learned was collected. Actual changes in RDM practices by researchers who attended was assessed with a follow-up survey administered seven months after the class. The online curriculum increased librarians' self-reported understanding of and comfort level with RDM. The Teaching Toolkit, when employed by librarians to teach researchers in person, resulted in improved RDM practices. This two-tiered curriculum provides concise training and a ready-made curriculum that allows working librarians to quickly gain an understanding of RDM, and translate this knowledge to researchers through training at their own institutions.


Aspirin inhibits platelet function independent of the acetylation of cyclo-oxygenase.
Aspirin inhibits platelet function and prevents thrombosis in some clinical situations. This antithrombotic effect is attributed to the irreversible inhibition of platelet thromboxane A2 synthesis, an effect which is achieved by a low dose of aspirin. There is some evidence that higher doses of aspirin may have additional antithrombotic effects. To test this possibility, we measured the effect of high and low dose aspirin on hemostasis in vivo and platelet function ex vivo in the rabbit. Both carotid arteries were isolated. One was replaced with a 2 cm piece of polyethylene tubing and the other was left intact. The prosthetic and intact vessels were then punctured with a needle and the time take for bleeding from each to cease was measured. Aspirin (3 and 100 mg/kg given 1 or 20 hours before hand) had no effect on the bleeding from the intact vessel, but prolonged the bleeding time in the prosthetic vessel in a dose-related manner. Washed platelets obtained from the 100 mg/kg-treated rabbits were less responsive to collagen and thrombin than platelets obtained from the 3 mg/kg-treated rabbits which in turn, were less responsive than control platelets. This additional effect of aspirin on platelet function was not due to the further inhibition of platelet thromboxane A2 release nor to further inhibition of the platelet release phenomenon. It is suggested that the enhanced effect of high dose aspirin on haemostasis from the arterial prosthesis is related to the second platelet inhibiting effect of aspirin.


Body-related concerns and participation in physical education among adolescent students: the mediating role of motivation.
There is a need to understand better factors influencing participation in physical education (PE) and the mechanisms involved. The adolescent years are characterised by increasing levels of body-related concerns. In PE, the body is judged for its physical abilities and subject to social comparisons and body judgements. Grounded in the Self-Determination Theory, this study aimed to explore whether body-related factors were associated with adolescents' involvement in PE and whether types of motivation mediated this relationship. The study involved 2,140 (54.5% girls) secondary students (15-16-year-olds) from Norway participating in the nationally representative "Health Behaviour in School-aged Children (HBSC) study: a WHO collaborative cross-national study." Body-related factors included Body Mass Index (BMI), health complaints, body perception and dietary behaviours. Gender, age, and socioeconomic status (family affluence) were control variables. Motivation for PE was assessed with the Perceived Locus of Causality (PLOCQ) scale measuring three distinct factors: autonomous motivation, controlled motivation and amotivation. PE involvement was self-reported as weekly participation in PE classes and time spent in moderate-to-vigorous physical activity (MVPA) during PE. Gender (girl), family affluence, health complaints, not being on a diet but wanting to lose weight, and body perception (too fat) were negatively associated with weekly PE participation when adjusting for other variables. This association was largely explained by students' autonomous motivation in the case of health complaints and partly in the case of dietary behaviour and body perception. Similar results were observed for MVPA during PE lessons. Additionally, gender was associated with MVPA through amotivation. The study adds new knowledge to the understanding of the relationship between body-related factors and PE, supporting that autonomous motivation is a central mechanism and an avenue for further research. The results should be considered in planning high-quality PE classes and suggest that an autonomous supportive learning climate sensitive to body-related concerns should be a priority to increase adolescent involvement in PE.


Increased cerebral CO(2) reactivity after heparin-mediated extracorporal LDL precipitation (HELP) in patients with coronary heart disease and hyperlipidemia.
There is experimental and clinical evidence that hypercholesterolemia leads to an impairment of endothelial function in coronary and cerebral arteries. Using transcranial Doppler sonography, we examined CO(2) reactivity as a marker of cerebral vasoreactivity in patients with coronary heart disease and hyperlipidemia before and after drastic lowering of LDL cholesterol, lipoprotein(a) [Lp(a)], and fibrinogen levels by heparin-mediated extracorporal LDL precipitation (HELP). CO(2) reactivity was determined in 13 patients with coronary artery disease and hyperlipidemia undergoing regular HELP therapy. Middle cerebral artery mean blood flow velocity (MFV) was detected by transcranial Doppler. CO(2) reactivity was calculated as the percent change of MFV during hypercapnia, induced by ventilation of carbogene (5% CO(2), 95% O(2)), to normocapnia. Patients with extracranial or intracranial stenoses were excluded. Other parameters such as blood viscosity, heart rate, and blood pressure were measured to control hemorheologic and systemic influences on CO(2) reactivity. A single HELP treatment reduced total cholesterol, LDL cholesterol, Lp(a), triglycerides, and fibrinogen levels by >50% (P<0.001). Blood viscosity significantly decreased from 1.24+/-0.04 to 1.07+/-0.02 mPa (P<0.001). Blood pressure, heart rate, and MFV did not change significantly. CO(2) reactivity increased from 22% +/- 21% to 36% +/- 18% (P<0.05). Fast and drastic removal of LDL cholesterol, Lp(a), and fibrinogen from plasma results in an improvement of cerebrovascular reactivity in patients with coronary heart disease and hyperlipidemia. The clinical use of HELP in patients with impaired cerebrovascular reactivity might be promising.


Garlic oil polysulfides: H2S- and O2-independent prooxidants in buffer and antioxidants in cells.
The health benefits of garlic and other organosulfur-containing foods are well recognized and have been attributed to both prooxidant and antioxidant activities. The effects of garlic are surprisingly similar to those of hydrogen sulfide (H2S), which is also known to be released from garlic under certain conditions. However, recent evidence suggests that polysulfides, not H2S, may be the actual mediator of physiological signaling. In this study, we monitored formation of H2S and polysulfides from garlic oil in buffer and in human embryonic kidney (HEK) 293 cells with fluorescent dyes, 7-azido-4-methylcoumarin and SSP4, respectively and redox activity with two redox indicators redox-sensitive green fluorescent protein (roGFP) and DCF. Our results show that H2S release from garlic oil in buffer requires other low-molecular-weight thiols, such as cysteine (Cys) or glutathione (GSH), whereas polysulfides are readily detected in garlic oil alone. Administration of garlic oil to cells rapidly increases intracellular polysulfide but has minimal effects on H2S unless Cys or GSH are also present in the extracellular medium. We also observed that garlic oil and diallyltrisulfide (DATS) potently oxidized roGFP in buffer but did not affect DCF. This appears to be a direct polysulfide-mediated oxidation that does not require a reactive oxygen species intermediate. Conversely, when applied to cells, garlic oil became a significant intracellular reductant independent of extracellular Cys or GSH. This suggests that intracellular metabolism and further processing of the sulfur moieties are necessary to confer antioxidant properties to garlic oil in vivo.


Lactobacillus acidophilus protects tight junctions from aspirin damage in HT-29 cells.
Non-steroidal anti-inflammatory drugs cause enterocyte damage inducing an increase of intestinal permeability. Tight junctions are the key structures in the permeability of the intestinal mucosa. ZO-1 is a tight junction associated protein considered a good marker of their integrity. It has been suggested that probiotics could play a protective role in the intestinal barrier function. We determined, in vitro, whether the heat-killed Lactobacillus acidophilus strain LB (LaLB) with its spent culture supernatant protects tight junctions of HT-29 cells from aspirin (ASA) damage. HT-29 cells were treated with ASA alone or ASA and LaLB with its spent culture supernatant together. Morphological alterations of tight junctions were evaluated by immunofluorescence using an anti-ZO-1 antibody. Moreover, a semiquantitative assay for ZO-1 was performed by Western blot. Immunofluorescence analysis showed a fragmented and granulous ZO-1 staining, after ASA treatment. Using both ASA and LaLB with its spent culture supernatant together, we found a fine continuous linear web at cell-cell contacts similarly to control. Western blot revealed that ASA inhibited ZO-1 expression and LaLB with its spent culture supernatant counteracted this effect. This pilot study shows, for the first time, the protective effect of LaLB with its spent culture supernatant on tight junctions from ASA damage. These results suggest that probiotics could play a role in the prevention of ASA-induced alterations of intestinal permeability.


{beta}-Adrenoceptor gene variation and intermediate physiological traits: prediction of distant phenotype.
Intermediate physiological phenotype is the genetic and environmental influence on functional physiological characteristics with direct prognostic relevance to distant, more complex phenotypes, such as cardiovascular and metabolic disease. Increasingly available and affordable genotyping techniques have created an explosion of information on candidate gene variation and its relationship to intermediate physiological traits. Variation in beta-adrenoceptor genes is an intense focus of investigation because beta-adrenoceptors are: (1) ubiquitous in organ system distribution; (2) integral to a multitude of physiological processes; (3) well described in cardiovascular and metabolic disease; and (4) major pharmacological treatment targets. Furthermore, knowledge of functional gene variants in these receptors predates the description of the human genome. This review highlights the influence of common gene variation in the three beta-adrenoceptor subtypes on intermediate physiological phenotype predictive of cardiovascular disease and obesity. Although further information is needed to replicate this information across populations, this review condenses and summarizes growing trends in specific pleiotropic effects of beta-adrenoceptor polymorphisms and suggests which variants may be predictive of distant phenotype.


Sensitivity to visual prosodic cues in signers and nonsigners.
Three studies are presented in this paper that address how nonsigners perceive the visual prosodic cues in a sign language. In Study 1, adult American nonsigners and users of American Sign Language (ASL) were compared on their sensitivity to the visual cues in ASL Intonational Phrases. In Study 2, hearing, nonsigning American infants were tested using the same stimuli used in Study I to see whether maturity, exposure to gesture, or exposure to sign language is necessary to demonstrate this type of sensitivity. Study 3 addresses nonsigners' and signers' strategies for segmenting Prosodic Words in a sign language. Adult participants from six language groups (3 spoken languages and 3 sign languages) were tested.The results of these three studies indicate that nonsigners have a high degree of sensitivity to sign language prosodic cues at the Intonational Phrase level and the Prosodic Word level; these are attributed to modality or'channel' effects of the visual signal.There are also some differences between signers' and nonsigners' sensitivity; these differences are attributed to language experience or language-particular constraints.This work is useful in understanding the gestural competence of nonsigners and the ways in which this type of competence may contribute to the grammaticalization of these properties in a sign language.


Understanding the reconstitution of the B-cell compartment in bone marrow and blood after treatment for B-cell precursor acute lymphoblastic leukaemia.
A better understanding of the reconstitution of the B-cell compartment during and after treatment in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) will help to assess the immunological status and needs of post-treatment BCP-ALL patients. Using 8-colour flow cytometry and proliferation-assays, we studied the composition and proliferation of both the B-cell precursor (BCP) population in the bone marrow (BM) and mature B-cell population in peripheral blood (PB) during and after BCP-ALL therapy. We found a normal BCP differentiation pattern and a delayed formation of classical CD38dim -naive mature B-cells, natural effector B-cells and memory B-cells in patients after chemotherapy. This B-cell differentiation/maturation pattern was strikingly similar to that during initial B-cell development in healthy infants. Tissue-resident plasma cells appeared to be partly protected from chemotherapy. Also, we found that the fast recovery of naive mature B-cell numbers after chemotherapy was the result of increased de novo BCP generation, rather than enhanced B-cell proliferation in BM or PB. These results indicate that post-treatment BCP-ALL patients will eventually re-establish a B-cell compartment with a composition and B-cell receptor repertoire similar to that in healthy children. Additionally, the formation of a new memory B-cell compartment suggests that revaccination might be beneficial after BCP-ALL therapy.


Preparation of finely dispersed O/W emulsion from fatty acid solubilized in subcritical water.
A novel method for preparing a finely dispersed oil-in-water emulsion is proposed. Octanoic acid dissolved in water at a high temperature of 220 or 230 degrees C at 15 MPa was combined with an aqueous solution of a surfactant and then the mixture was cooled. When a nonionic surfactant, decaglycerol monolaurate (ML-750) or polyoxyethylene sorbitan monolaurate (Tween 20), was used, fine emulsions with a median oil droplet diameter of 100 nm or less were successfully prepared at ML-750 and Tween 20 concentrations of 0.083% (w/v) and 0.042%, respectively, or higher. The diameters were much smaller than those of oil droplets prepared by the conventional homogenization method using a rotor/stator homogenizer. However, an anionic surfactant, sodium dodecyl sulfate, was not adequate for the preparation of such fine emulsions by the proposed method. Although the interfacial tensions between octanoic acid and the surfactant solutions were measured at different temperatures, they were not an indication for selecting a surfactant for the successful preparation of the fine emulsion by the proposed method.


MCRIP1, an ERK substrate, mediates ERK-induced gene silencing during epithelial-mesenchymal transition by regulating the co-repressor CtBP.
The ERK pathway not only upregulates growth-promoting genes, but also downregulates anti-proliferative and tumor-suppressive genes. In particular, ERK signaling contributes to repression of the E-cadherin gene during epithelial-mesenchymal transition (EMT). The CtBP transcriptional co-repressor is also involved in gene silencing of E-cadherin. However, the functional relationship between ERK signaling and CtBP is unknown. Here, we identified an ERK substrate, designated MCRIP1, which bridges ERK signaling and CtBP-mediated gene silencing. CtBP is recruited to promoter elements of target genes by interacting with the DNA-binding transcriptional repressor ZEB1. We found that MCRIP1 binds to CtBP, thereby competitively inhibiting CtBP-ZEB1 interaction. When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications. Our findings reveal a molecular mechanism underlying ERK-induced epigenetic gene silencing during EMT and its dysregulation in cancer.


HDL-cholesterol levels and risk of age-related macular degeneration: a multiethnic genetic study using Mendelian randomization.
Dyslipidemia, particularly high-density lipoprotein cholesterol (HDL-C), has recently been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss. However, epidemiological studies have yielded conflicting results. We investigated the causal role of plasma lipid levels in AMD in multiethnic populations comprising 16 144 advanced AMD cases and 17 832 controls of European descent, together with 2219 cases and 5275 controls of Asian descent, using Mendelian randomization in three models. Model 1 is a conventional meta-analysis which does not account for pleiotropy of instrumental variable (IV) effects. Model 2 is a univariate, inverse variance weighted regression analysis that accounts for potential unbalanced pleiotropy using MR-Egger method. Finally, Model 3 is a multivariate regression analysis that addresses pleiotropy by MR-Egger method and by adjusting for effects on other lipid traits. A 1 standard deviation (SD) higher HDL-cholesterol level was associated with an odds ratio (OR) for AMD of 1.17 (95% confidence interval: 1.07-1.29) in Europeans (P = 6.88 × 10-4) and of 1.58 (1.24-2.00) in Asians (P = 2.92 × 10-4) in Model 3. The corresponding OR estimates were 1.30 (1.09-1.55) in Europeans (P = 3.18 × 10-3) and 1.42 (1.11-1.80) in Asians (P = 4.42 × 10-3) in Model 1, and 1.21 (1.11-1.31) in Europeans (P = 3.12 × 10-5) and 1.51 (1.20-1.91) in Asians (P = 7.61 × 10-4) in Model 2. Conversely, neither LDL-C (Europeans: OR = 0.96, P = 0.272; Asians: OR = 1.02, P = 0.874; Model 3) nor triglyceride levels (Europeans: OR = 0.91, P = 0.102; Asians: OR = 1.06, P = 0.613) were associated with AMD. We also assessed the association between lipid levels and polypoidal choroidal vasculopathy (PCV) in Asians, a subtype of AMD, and found a similar trend for association of PCV with HDL-C levels. Our study shows that high levels of plasma HDL-C are causally associated with an increased risk for advanced AMD in European and Asian populations, implying that strategies reducing HDL-C levels may be useful to prevent and treat AMD.


The Impact of Double Sequential Shock Timing on Outcomes During Refractory Out -of-Hospital Cardiac Arrest.
Animal studies suggest the efficacy of double sequential external defibrillation (DSED) may depend on the interval between the two shocks, or "DSED interval". No human studies have examined this concept. To determine the relationship between DSED interval and termination of ventricular fibrillation (VFT), return of spontaneous circulation (ROSC), survival to hospital discharge, and favourable neurological status (MRS < 2) for patients in refractory VF. We performed a retrospective review of adult (≥18 years) out-of-hospital cardiac arrest between January 2015 and May 2022 with refractory VF who received ≥1 DSED shock. DSED interval was divided into four pre-defined categories. We examined the association between DSED interval and patient outcomes using general estimated equation logistic regression or Fisher's exact test. Among 106 included patients, 303 DSED shocks were delivered (median 2, IQR 1-3). DSED intervals of 75-125 msec (OR 0.39, 95% CI 0.16-0.98), 125-500 msec (OR 0.36, 95% CI 0.16-0.82), and >500 msec (OR 0.27, 95% CI 0.11-0.63) were associated with lower probability of VF termination compared to <75 msec interval. DSED interval of >75 msec was associated with lower probability of ROSC compared to <75 msec interval (OR 0.37, 95% CI 0.14-0.98). No association was noted between DSED interval and survival to hospital discharge or neurologic outcome. Among patients in refractory VF a DSED interval of less than 75 msec was associated with improved rates of VF termination and ROSC. No association was noted between DSED interval and survival to hospital discharge or neurologic outcome.


Organismal climatology: analyzing environmental variability at scales relevant to physiological stress.
Predicting when, where and with what magnitude climate change is likely to affect the fitness, abundance and distribution of organisms and the functioning of ecosystems has emerged as a high priority for scientists and resource managers. However, even in cases where we have detailed knowledge of current species' range boundaries, we often do not understand what, if any, aspects of weather and climate act to set these limits. This shortcoming significantly curtails our capacity to predict potential future range shifts in response to climate change, especially since the factors that set range boundaries under those novel conditions may be different from those that set limits today. We quantitatively examine a nine-year time series of temperature records relevant to the body temperatures of intertidal mussels as measured using biomimetic sensors. Specifically, we explore how a 'climatology' of body temperatures, as opposed to long-term records of habitat-level parameters such as air and water temperatures, can be used to extrapolate meaningful spatial and temporal patterns of physiological stress. Using different metrics that correspond to various aspects of physiological stress (seasonal means, cumulative temperature and the return time of extremes) we show that these potential environmental stressors do not always occur in synchrony with one another. Our analysis also shows that patterns of animal temperature are not well correlated with simple, commonly used metrics such as air temperature. Detailed physiological studies can provide guidance to predicting the effects of global climate change on natural ecosystems but only if we concomitantly record, archive and model environmental signals at appropriate scales.


The nature of coherences in the B820 bacteriochlorophyll dimer revealed by two-dimensional electronic spectroscopy.
Light-harvesting in photosynthesis is determined by the excitonic interactions in disordered antennae and the coupling of collective electronic excitations to fast nuclear motions, producing efficient energy transfer with a complicated interplay between exciton and vibrational coherences. Two-dimensional electronic spectroscopy (2DES) is a powerful tool to study the presence of these coherences in photosynthetic complexes. However, the unambiguous assignment of the nature of the observed coherences is still under debate. In this paper we apply 2DES to an excitonically coupled bacteriochlorophyll dimer, the B820 subunit of the light harvesting complex 1 (LH1-RC) of R. rubrum G9. Fourier analysis of the measured kinetics and modeling of the spectral responses in a complete basis of electronic and vibrational states allow us to distinguish between pure vibrational, mixed exciton-vibrational (vibronic), and predominantly exciton coherences. The mixed coherences have been found in a wide range of oscillation frequencies, whereas exciton coherences give the biggest contributions for the frequencies in the 400-550 cm(-1) range, corresponding to the exciton splitting energy of the B820 dimer. Significant exciton coherences are also present at higher frequencies, i.e., up to 800 cm(-1), which are determined by realizations of the disorder with a large energy gap between the two pigments (which increases the apparent value of the exciton splitting). Although the B820 dimer is a model system, the approach presented here represents a basis for further analyses of more complicated systems, providing a tool for studying the interplay between electronic and vibrational coherences in disordered photosynthetic antennae and reaction centres.


Pre-treatment neutrophil-to-lymphocyte ratio as predictor of adverse outcomes in patients undergoing radical cystectomy for urothelial carcinoma of the bladder.
An elevated neutrophil-to-lymphocyte ratio (NLR) is associated with poor outcome in various tumours. Its prognostic utility in patients with urothelial carcinoma of the bladder (UCB) undergoing radical cystectomy (RC) is yet to be fully elucidated. A cohort of patients undergoing RC for UCB in a tertiary referral centre between 1992 and 2012 was analysed. Neutrophil-to-lymphocyte ratio was computed using complete blood counts performed pre-RC, or before neo-adjuvant chemotherapy where applicable. Time-dependent receiver operating characteristic curves were used to determine the optimal cutoff point for predicting recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). The predictive ability of NLR was assessed using Kaplan-Meier analyses and multivariable Cox proportional hazards models. The likelihood-ratio test was used to determine whether multivariable models were improved by including NLR. The cohort included 424 patients followed for a median of 58.4 months. An NLR of 3 was determined as the optimal cutoff value. Patients with an NLR⩾3.0 had significantly worse survival outcomes (5y-RFS: 53% vs 64%, log-rank P=0.013; 5y-CSS: 57% vs 75%, log-rank P<0.001; 5y-OS: 43% vs 64%, log-rank P<0.001). After adjusting for disease-specific predictors, an NLR ⩾3.0 was significantly associated with worse RFS (HR=1.49; 95% CI=1.12-2.0, P=0.007), CSS (HR=1.88; 95% CI=1.39-2.54, P<0.001) and OS (average HR=1.67; 95% CI=1.17-2.39, P=0.005). The likelihood-ratio test confirmed that prognostic models were improved by including NLR. Neutrophil-to-lymphocyte ratio is an inexpensive prognostic biomarker for patients undergoing RC for UCB. It offers pre-treatment prognostic value in addition to established prognosticators and may be helpful in guiding treatment decisions.


Does health affect portfolio choice?
A number of recent studies find that poor health is empirically associated with a safer portfolio allocation. It is difficult to say, however, whether this relationship is truly causal. Both health status and portfolio choice are influenced by unobserved characteristics such as risk attitudes, impatience, information, and motivation, and these unobserved factors, if not adequately controlled for, can induce significant bias in the estimates of asset demand equations. Using the 1992-2006 waves of the Health and Retirement Study, we investigate how much of the connection between health and portfolio choice is causal and how much is due to the effects of unobserved heterogeneity. Accounting for unobserved heterogeneity with fixed effects and correlated random effects models, we find that health does not appear to significantly affect portfolio choice among single households. For married households, we find a small effect (about 2-3 percentage points) from being in the lowest of five self-reported health categories.


Incorporating Scientific Publishing into an Undergraduate Neuroscience Course: A Case Study Using IMPULSE.
The journal IMPULSE offers undergraduates worldwide the opportunity to publish research and serve as peer reviewers for the submissions of others. Undergraduate faculty have recognized the journal's value in engaging students working in their labs in the publication process. However, integration of scientific publication into an undergraduate laboratory classroom setting has been lacking. We report here on a course at Ursinus College where 20 students taking Molecular Neurobiology were required to submit manuscripts to IMPULSE. The syllabus allowed for the laboratory research to coincide with the background research and writing of the manuscript. Students completed their projects on the impact of drugs on the Daphnia magna nervous system while producing manuscripts ready for submission by week 7 of the course. Findings from a survey completed by the students and perceptions of the faculty member teaching the course indicated that students spent much more time writing, were more focused on completing the assays, completed the assays with larger data sets, were more engaged in learning the scientific concepts and were more thorough with their revisions of the paper knowing that it might be published. Further, the professor found she was more thorough in critiquing students' papers knowing they would be externally reviewed. Incorporating journal submission into the course stimulated an in depth writing experience and allowed for a deeper exploration of the topic than students would have experienced otherwise. This case study provides evidence that IMPULSE can be successfully used as a means of incorporating scientific publication into an undergraduate laboratory science course. This approach to teaching undergraduate neuroscience allows for a larger number of students to have hands-on research and scientific publishing experience than would be possible with the current model of a few students in a faculty member's laboratory. This report illustrates that IMPULSE can be incorporated as an integral part of an academic curriculum with positive outcomes on student engagement and performance.


The effect of a lifestyle intervention on pregnancy and postpartum dietary patterns determined by factor analysis.
Optimizing maternal diet during pregnancy improves maternal and infant health. This study assessed the effect of an antenatal lifestyle intervention for women with overweight or obesity on dietary patterns during pregnancy and post partum. This study is a secondary analysis of a randomized controlled trial in which pregnant women (BMI ≥ 25 kg/m2 ) received lifestyle advice (n = 943) or standard care (n = 924). Dietary pattern analysis was undertaken using factor analysis with comparisons between trial entry and 28 weeks, 36 weeks, and 4 months post partum. The dietary pattern analysis revealed two distinct patterns: "prudent" and "Western." There was a significant difference between groups in the change over time for both patterns (P < 0.001). For the prudent score, the lifestyle group had higher scores at all times after trial entry compared with standard care, while for the Western score, the lifestyle group had a lower score at 28 weeks. The intervention effect differed based on trial entry BMI (P = 0.043) and smoking (P = 0.019), with higher prudent scores for women with obesity compared with overweight and smokers compared with nonsmokers. The provision of an antenatal lifestyle intervention for women with overweight and obesity was associated with an improvement in dietary patterns that persisted post partum. This has important implications for the future consideration of optimal dietary intervention components to include in antenatal lifestyle interventions.


Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies.
Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose-escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137). Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability. Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses. INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.


Knowledge integration in One Health policy formulation, implementation and evaluation.
The One Health concept covers the interrelationship between human, animal and environmental health and requires multistakeholder collaboration across many cultural, disciplinary, institutional and sectoral boundaries. Yet, the implementation of the One Health approach appears hampered by shortcomings in the global framework for health governance. Knowledge integration approaches, at all stages of policy development, could help to address these shortcomings. The identification of key objectives, the resolving of trade-offs and the creation of a common vision and a common direction can be supported by multicriteria analyses. Evidence-based decision-making and transformation of observations into narratives detailing how situations emerge and might unfold in the future can be achieved by systems thinking. Finally, transdisciplinary approaches can be used both to improve the effectiveness of existing systems and to develop novel networks for collective action. To strengthen One Health governance, we propose that knowledge integration becomes a key feature of all stages in the development of related policies. We suggest several ways in which such integration could be promoted.


Comparing the nutrition environment and practices of home- and centre-based child-care facilities.
To assess and compare the nutrition environment and practices (as they relate to pre-schoolers) of centre- and home-based child-care facilities. Using a cross-sectional study design, nineteen child-care facilities (ten centre-based, nine home-based) were assessed for one full day using the Environment and Policy Assessment and Observation (EPAO) tool (consisting of a day-long observation/review of the nutrition environment, practices and related documents). Specifically, eight nutrition-related subscales were considered. Child-care facilities in London, Ontario, Canada. Child-care facilities were recruited through directors at centre-based programmes and the providers of home-based programmes. The mean total nutrition environment EPAO scores for centre- and home-based facilities were 12·3 (sd 1·94) and 10·8 (sd 0·78) out of 20 (where a higher score indicates a more supportive environment with regard to nutrition), respectively. The difference between the total nutrition environment EPAO score for centre- and home-based facilities was approaching significance (P=0·055). For both types of facilities, the highest nutrition subscale score (out of 20) was achieved in the staff behaviours domain (centre mean=17·4; home mean=17·0) and the lowest was in the nutrition training and education domain (centre mean=3·6; home mean=2·0). Additional research is needed to confirm these findings. In order to better support child-care staff and enhance the overall nutrition environment in child care, modifications to food practices could be adopted. Specifically, the nutritional quality of foods/beverages provided to pre-schoolers could be improved, nutrition-related training for child-care staff could be provided, and a nutrition curriculum could be created to educate pre-schoolers about healthy food choices.


Secretion and functional display of fusion proteins through the curli biogenesis pathway.
Curli are functional amyloids expressed as fibres on the surface of Enterobacteriaceae. Contrary to the protein misfolding events associated with pathogenic amyloidosis, curli are the result of a dedicated biosynthetic pathway. A specialized transporter in the outer membrane, CsgG, operates in conjunction with the two accessory proteins CsgE and CsgF to secrete curlin subunits to the extracellular surface, where they nucleate into cross-beta strand fibres. Here we investigate the substrate tolerance of the CsgG transporter and the capability of heterologous sequences to be built into curli fibres. Non-native polypeptides ranging up to at least 260 residues were exported when fused to the curli subunit CsgA. Secretion efficiency depended on the folding properties of the passenger sequences, with substrates exceeding an approximately 2 nm transverse diameter blocking passage through the transport channel. Secretion of smaller passengers was compatible with prior DsbA-mediated disulphide bridge formation in the fusion partner, indicating that CsgG is capable of translocating non-linear polypeptide stretches. Using fusions we further demonstrate the exported or secreted heterologous passenger proteins can attain their native, active fold, establishing curli biogenesis pathway as a platform for the secretion and surface display of small heterologous proteins.


Risk assessment for resistance to fludioxonil in Corynespora cassiicola in Liaoning China.
Cucumber corynespora leaf spot, caused by Corynespora cassiicola, is the primary disease of cucumber leaves in greenhouses in China. Fludioxonil is a phenylpyrrole fungicide that inhibits C. cassiicola growth. We studied the sensitivity of 170 isolates of C. cassiicola to fludioxonil and evaluated resistance risk. All of the isolates were sensitive to fludioxonil. The EC50 values ranged from 0.082 to 0.539 μg/mL with a mean of 0.207 ± 0.0053 μg/mL. Laboratory-created mutants with a high resistance factor to fludioxonil were genetically stable after 10 transfers and showed positive cross-resistance to iprodione and procymidone but not to azoxystrobin, carbendazim, pydiflumetofen, and prochloraz. There was no significant difference in mycelial growth and temperature adaptation between the mutant s and the sensitive isolates, except for pathogenicity and sporulation. The resistant isolates accumulated less glycerol than their parental isolates and were more sensitive to osmotic stress. The histidine kinase activity of the sensitive isolates was significantly inhibited compared to that of the resistant mutants. Sequence alignment of the histidine kinase gene CCos revealed that the mutants RTL4, RXM5, and RFS102 had point mutations at different sites that resulted in amino acid changes at G934E, S739F, and A825P in the CCos protein. The mutant RFS102 had an alanine deletion at site 824. After fludioxonil treatment, CCos expression by RFS20 was significantly lower than that of the parental isolate. Our findings demonstrate that C. cassiicola exhibits moderate resistance to fludioxonil.


Association between dynamic fluctuations in triiodothyronine levels and prognosis among critically ill patients within comprehensive intensive care units.
Decrease in free thyroid hormone T3 (FT3) can be used as an independent prognostic indicator for the risk of death in ICUs. However, FT3 as a predictive marker is hindered by its accuracy. The study introduces the concept of dynamic FT3 data as a means to bolster the value of FT3 as a prognostic tool. Therefore, the aim of this study is to investigate the prognostic value of dynamic FT3 evolution in a comprehensive ICU setting, analyze the consistency between dynamic FT3 changes and variations in disease severity, and explore the feasibility of FT3 as an objective indicator for real-time clinical treatment feedback. Employing a single-center prospective observational study, FT3 measurements were taken on multiple days following enrollment, corresponding clinical data were collected. To investigated the pattern of dynamic changes of FT3,its prognostic significance in forecasting the risk of 28-day mortality, the alignment between dynamic FT3 changes and variations in the Sequential Organ Failure Assessment (SOFA) score. The survival group exhibited higher last FT3 levels compared to the lowest point (p<0.05), while the death group did not show statistically significant differences (p>0.05). The study also identifies the optimal correlation between FT3 and SOFA score at day 5 (optimal correlation coefficient -0.546).The ROC curve for FT3 at day 5 yielded an optimal AUC of 0.88, outperforming the SOFA score. The study categorizes FT3 curve patterns,Kaplan-Meier survival analysis of these patterns highlighted that the descending-type curve was significantly associated with increased risk of death (P<0.001). Additionally, the research explores the consistency between changes in FT3 and SOFA scores. While overall consistency rates were modest, subgroup analyses unveiled that greater disease severity led to higher consistency rates. This study introduces the concept of dynamic FT3 changes to augment its prognostic utility in comprehensive ICU settings. The research identifies day 5 as the optimal time point for predictive efficacy, the descending FT3 curve as indicative of poor prognosis. While overall consistency with SOFA scores is modest, the correlation strengthens with greater disease severity.


Wavelet-based color image compression: exploiting the contrast sensitivity function.
The visual efficiency of an image compression technique depends directly on the amount of visually significant information it retains. By "visually significant" we mean information to which a human observer is most sensitive. The overall sensitivity depends on aspects such as contrast, color, spatial frequency, and so forth. One important aspect is the inverse relationship between contrast sensitivity and spatial frequency. This is described by the contrast sensitivity function (CSF). In compression algorithms the CSF can be exploited to regulate the quantization step-size to minimize the visibility of compression artifacts. Existing CSF implementations for wavelet-based image compression use the same quantization step-size for a large range of spatial frequencies. This is a coarse approximation of the CSF. This paper presents two new techniques that implement the CSF at significantly higher precision, adapting even to local variations of the spatial frequencies within a decomposition subband. The approaches can be used for luminance as well as color images. For color perception three different CSFs describe the sensitivity. The implementation technique is the same for each color band. Implemented into the JPEG2000 compression standard, the new techniques are compared to conventional CSF-schemes. The proposed techniques turn out to be visually more efficient than previously published methods. However, the emphasis of this paper is on how the CSF can be implemented in a precise and locally adaptive way, and not on the superior performance of these techniques.


GSTM1 null genotype in COPD and lung cancer: evidence of a modifier or confounding effect?
Studies over the past two decades have reported associations between GSTM1 (glutathione S-transferase mu 1) null genotype and chronic obstructive pulmonary disease (COPD) or lung cancer. However, a modifier or confounding effect from COPD mediating the GSTM1 association with lung cancer has not been previously explored. This variant was examined in a case-control study of current or former smokers with COPD (n = 669), lung cancer (n = 454), or normal lung function (n = 488). Sex, age, and smoking history were comparable between groups. The GSTM1 null genotype was found to be more frequent in smokers with COPD alone (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.02-1.66, P = 0.031) and lung cancer (OR 1.26, 95% CI 0.96-1.65, P = 0.083) than in matched smokers with normal lung function (62%, 61%, and 56%, respectively). However, when smokers with lung cancer were subgrouped according to the presence of COPD, then the association with all COPD subjects (OR 1.34, 95% CI 1.07-1.70, P = 0.010) and with COPD and lung cancer (OR 1.50, 95% CI 1.06-2.12, P = 0.018) continued to be significant while that with lung cancer only was reduced (OR 1.11, 95% CI 0.78-1.56, P = 0.55). These associations were independent of age, sex, height, lung function, and smoking history. Findings suggest that COPD is an important subphenotype of lung cancer and may underlie previously reported associations with the GSTM1 null genotype.


Changes in muscle activity and perceived exertion during exercises performed on a swiss ball.
The objective of this study was to determine differences in electromyographic (EMG) activity of prime mover and abdominal muscles while performing squats, push ups, and double leg lowering with a swiss ball. Twelve healthy subjects performed the movements. There was no difference between the surface conditions for muscle activity during the squat exercise; however, individuals had lower perceived exertion for the swiss ball squat. Activity of the triceps and abdominals was highest performing push ups on the swiss ball, whereas the activity of rectus abdominus (RA) only increased during double leg lowering on the swiss ball. Perceived exertion was highest for the push up and leg-lowering exercise performed on the swiss ball. Increased RA activity during double leg lowering can be attributed to its role as a hip flexor, whereas the lack of a rotation aspect to the task prevented increased oblique muscle activity. The swiss ball appears to only increase muscle activity during exercises where the unstable surface is the primary base of support.


DeepRTAlign: toward accurate retention time alignment for large cohort mass spectrometry data analysis.
Retention time (RT) alignment is a crucial step in liquid chromatography-mass spectrometry (LC-MS)-based proteomic and metabolomic experiments, especially for large cohort studies. The most popular alignment tools are based on warping function method and direct matching method. However, existing tools can hardly handle monotonic and non-monotonic RT shifts simultaneously. Here, we develop a deep learning-based RT alignment tool, DeepRTAlign, for large cohort LC-MS data analysis. DeepRTAlign has been demonstrated to have improved performances by benchmarking it against current state-of-the-art approaches on multiple real-world and simulated proteomic and metabolomic datasets. The results also show that DeepRTAlign can improve identification sensitivity without compromising quantitative accuracy. Furthermore, using the MS features aligned by DeepRTAlign, we trained and validated a robust classifier to predict the early recurrence of hepatocellular carcinoma. DeepRTAlign provides an advanced solution to RT alignment in large cohort LC-MS studies, which is currently a major bottleneck in proteomics and metabolomics research.


Recrudescence of bovine herpesvirus-5 in experimentally infected calves.
A latent infection of bovine herpesvirus-5 (BHV-5) was established in 4 calves. These calves, plus 2 controls, were given dexamethasone (DM) to reactivate the latent virus. The 4 principal calves developed antibodies to BHV-5 by postinoculation day (PID) 21. Antibody titers increased until PID 42 before decreasing to low levels of PID 75. After the first DM treatment (started on PID 76), an anamnestic antibody response was demonstrated in the 4 principal calves. Calves, 2, 3, and 4 were euthanatized and necropsied at PID 121, and their antibody titers were again decreasing. The virus BHV-5 was not isolated from the tissues by conventional techniques of viral isolation but was isolated from the trigeminal ganglion and spinal cord of calf 3 by explantation techniques. The BHV-5 was isolated, using conventional viral isolation techniques, from a nasal swab sample of calf 1 on PID 91 (15 days after the first DM treatment) and from the thoracic lymph node 6 days after the start of a 2nd DM treatment. Seemingly, BHV-5 may be latently harbored in the nerve tissues or calves and this virus may be reactivated from the upper respiratory tract following subsequent DM treatment.


Insulin-like growth factor I receptor signaling in differentiation of neuronal H19-7 cells.
The type I insulin-like growth factor receptor (IGF-IR) is known to send two seemingly contradictory signals inducing either cell proliferation or cell differentiation, depending on cell type and/or conditions. H19-7 cells are rat hippocampal neuronal cells immortalized by a temperature-sensitive SV40 large T antigen that grow at 34 degrees C in epidermal growth factor or serum but differentiate at 39 degrees C when induced by basic fibroblast growth factor. At 39 degrees C, expression of the human IGF-IR in H19-7 cells induces an insulin-like growth factor (IGF) I-dependent differentiation. We have investigated the domains of the IGF-IR required for differentiation of H19-7 cells. The tyrosine 950 residue and serines 1280-1283 in the COOH terminus of the receptor are required for IGF-I-induced differentiation at 39 degrees C, although they are dispensable for IGF-I-mediated growth at 34 degrees C. Both domains have to be mutated to inactivate the differentiating function. The inability of these mutant receptors to induce differentiation correlates with mitogen-activated protein kinase activation. In contrast, inhibitors of phosphatidylinositol 3'-kinase have no effect on IGF-I-mediated differentiation of H19-7 cells, although they do inhibit the mitogenic response.