Digestion, milk production, milk composition, and blood composition of dairy cows fed formaldehyde treated flaxseed or sunflower seed.
Forty midlactation Holstein cows averaging 635 kg of body weight (SE = 8) were allotted at wk 25 of lactation to ten groups of four cows blocked for similar calving dates to determine the effects of formaldehyde treatment of flaxseed and sunflower seed on fatty acid composition of blood and milk, milk yield, feed intake, and apparent digestibility. Cows were fed a total mixed diet based on grass silage and supplements for ad libitum intake over a 10-wk period. Cows within each block were assigned to one of the four isonitrogenous supplements based on either untreated whole flaxseed, formaldehyde-treated whole flaxseed, untreated whole sunflower seed, or formaldehyde-treated whole sunflower seed. Cows fed whole flaxseed compared with sunflower seed maintained greater dry matter (DM) intake (20.3 vs. 18.9 kg/d). Intake of DM, expressed as a percentage of body weight, was increased by adding formaldehyde to oilseeds (3.24 vs. 2.98%). Milk production was similar for cows fed flaxseed and those fed sunflower. Formaldehyde treatment of flaxseed and sunflower seed increased milk production by an average of 2.65 kg/d. Efficiency of fat-corrected milk yield per kilogram of DM intake was increased by formaldehyde treatment (1.31 vs. 1.21), and it was greater with sunflower seed than with flaxseed (1.33 vs.1.21). Protein concentration in milk was greater for cows fed flaxseed (3.38%) compared with those fed sunflower seed (3.21%) and formaldehyde had no effect. Apparent digestibility of DM was not affected by type of seed but it was greater for cows fed formaldehyde-treated seeds. Cows fed formaldehyde-treated flaxseed had the greatest apparent digestibilities of acid detergent and neutral detergent fiber compared with those fed the other diets. Apparent digestibilities of fatty acids were greater for sunflower seed than for flaxseed-based diets. In general, formaldehyde treatment had limited effect on milk fatty acid composition, suggesting that formaldehyde was not very effective in protecting polyunsaturated fatty acids against ruminal biohydrogenation. Feeding flaxseed resulted in the lowest omega 6 to omega 3 fatty acid ratio. The data suggest that both flaxseed and sunflower seed are acceptable fat sources for midlactating cows and that flaxseed increases milk protein percentage compared to sunflower seed.


Hot Hole Collection and Photoelectrochemical CO2 Reduction with Plasmonic Au/p-GaN Photocathodes.
Harvesting nonequilibrium hot carriers from plasmonic-metal nanostructures offers unique opportunities for driving photochemical reactions at the nanoscale. Despite numerous examples of hot electron-driven processes, the realization of plasmonic systems capable of harvesting hot holes from metal nanostructures has eluded the nascent field of plasmonic photocatalysis. Here, we fabricate gold/p-type gallium nitride (Au/p-GaN) Schottky junctions tailored for photoelectrochemical studies of plasmon-induced hot-hole capture and conversion. Despite the presence of an interfacial Schottky barrier to hot-hole injection of more than 1 eV across the Au/p-GaN heterojunction, plasmonic Au/p-GaN photocathodes exhibit photoelectrochemical properties consistent with the injection of hot holes from Au nanoparticles into p-GaN upon plasmon excitation. The photocurrent action spectrum of the plasmonic photocathodes faithfully follows the surface plasmon resonance absorption spectrum of the Au nanoparticles and open-circuit voltage studies demonstrate a sustained photovoltage during plasmon excitation. Comparison with Ohmic Au/p-NiO heterojunctions confirms that the vast majority of hot holes generated via interband transitions in Au are sufficiently hot to inject above the 1.1 eV interfacial Schottky barrier at the Au/p-GaN heterojunction. We further investigated plasmon-driven photoelectrochemical CO2 reduction with the Au/p-GaN photocathodes and observed improved selectivity for CO production over H2 evolution in aqueous electrolytes. Taken together, our results offer experimental validation of photoexcited hot holes more than 1 eV below the Au Fermi level and demonstrate a photoelectrochemical platform for harvesting hot carriers to drive solar-to-fuel energy conversion.


A factorial randomised controlled trial of decision analysis and an information video plus leaflet for newly diagnosed hypertensive patients.
There is a lack of evidence regarding the value of tools designed to aid decision making in patients with newly diagnosed hypertension. To evaluate two interventions for assisting newly diagnosed hypertensive patients in the decision whether to start drug therapy for reducing blood pressure. Factorial randomised controlled trial. Twenty-one general practices in south-west England, UK. Adults aged 32 to 80 years with newly diagnosed hypertension were randomised to receive either: (a) computerised utility assessment interview with individualized risk assessment and decision analysis; or (b) information video and leaflet about high blood pressure; or (c) both interventions; or (d) neither intervention. Outcome measures were decisional conflict, knowledge, state anxiety, intentions regarding starting treatment, and actual treatment decision. Of 217 patients randomised, 212 (98%) were analysed at the primary follow-up (mean age = 59 years, 49% female). Decision analysis patients had lower decisional conflict than those who did not receive this intervention (27.6 versus 38.9, 95% confidence interval [CI] for adjusted difference = -13.0 to -5.8, P < 0.001), greater knowledge about hypertension (73% versus 67%, adjusted 95% CI = 2% to 9%, P = 0.003) and no evidence of increased state anxiety (34.8 versus 36.8, adjusted 95% CI = -5.6 to 0.1, P = 0.055). Video/leaflet patients had lower decisional conflict than corresponding controls (30.3 versus 36.8, adjusted 95% CI = -7.4 to -0.6, P = 0.021), greater knowledge (75% versus 65%, adjusted 95% CI = 6% to 13%, P < 0.001) and no evidence of increased state anxiety (35.7 versus 36.1, adjusted 95% CI = -3.9 to 1.7, P = 0.46). There were no differences between either of the interventions and their respective controls in the proportion of patients prescribed antihypertensive medication (67%). This trial demonstrates that, among patients facing a real treatment decision, interventions to inform patients about hypertension and to clarify patients' values concerning outcomes of treatment are effective in reducing decisional conflict and increasing patient knowledge, while not resulting in any increases in state anxiety.


Aggregate Effects of Intraocular Pressure and Cup-to-Disc Ratio Genetic Variants on Glaucoma in a Multiethnic Asian Population.
High intraocular pressure (IOP) and large vertical cup-to-disc ratio (VCDR) are important risk factors of glaucoma. Recent genome-wide association studies have discovered several genetic variants associated with IOP and VCDR. In this study, we examined the aggregate effects of these IOP-, VCDR-associated variants on glaucoma. Case-control genetic association study. A total of 6881 participants, including 194 glaucoma and 158 primary open-angle glaucoma (POAG) cases in the Singapore Epidemiology of Eye Diseases Study. We first identified IOP and VCDR risk single nucleotide polymorphisms (SNPs) that were located in previously discovered IOP, VCDR genetic loci and showed strongest associations with IOP and VCDR in our study. We then constructed multi-locus IOP-, VCDR-specific genetic risk scores (GRSs) for each individual by summing the number of risk alleles for each SNP weighted by the respective effect estimates on glaucoma. Associations between tertiles of IOP- and VCDR-specific GRSs with glaucoma and POAG were determined using logistic regression analyses. Discriminating ability of the GRSs was determined by the area under receiver operating characteristic curve (AUC). Odds ratios on glaucoma. Participants in the top tertile of IOP-specific GRS were 2.00 (95% CI, 1.32-3.03, P = 1.1×10(-3)) and 2.50 times (95% CI, 1.54-4.02, P = 2.0×10(-4)) likely to have glaucoma and POAG, respectively, compared with those in the bottom. Participants in the top tertile of VCDR-specific GRS were 2.09 (95% CI, 1.43-3.07, P = 1.6×10(-4)) and 2.31 times (95% CI, 1.50-3.55, P = 1.4×10(-4)) likely to have glaucoma and POAG, respectively. Participants with both GRSs in the top tertile were 5.54 (95% CI, 2.57-11.93, P = 1.1×10(-5)) and 7.77 times (95% CI, 3.03-19.93, P = 2.0×10(-5)) likely to have glaucoma and POAG, respectively, compared with participants with both GRSs in bottom tertiles. The GRSs improved AUC for glaucoma modestly when added to traditional factors (AUC difference = 0.03, P = 0.06). Higher IOP-, VCDR-specific GRSs were associated with greater risk of glaucoma. Participants with both GRSs in the top tertiles had a 5.5-fold increased risk of glaucoma compared with those in the bottom tertiles. These findings may provide insights into the genetic pathogenesis of glaucoma.


Advances in Genetic and Molecular Understanding of Alzheimer's Disease.
Alzheimer's disease (AD) has become a common disease of the elderly for which no cure currently exists. After over 30 years of intensive research, we have gained extensive knowledge of the genetic and molecular factors involved and their interplay in disease. These findings suggest that different subgroups of AD may exist. Not only are we starting to treat autosomal dominant cases differently from sporadic cases, but we could be observing different underlying pathological mechanisms related to the amyloid cascade hypothesis, immune dysfunction, and a tau-dependent pathology. Genetic, molecular, and, more recently, multi-omic evidence support each of these scenarios, which are highly interconnected but can also point to the different subgroups of AD. The identification of the pathologic triggers and order of events in the disease processes are key to the design of treatments and therapies. Prevention and treatment of AD cannot be attempted using a single approach; different therapeutic strategies at specific disease stages may be appropriate. For successful prevention and treatment, biomarker assays must be designed so that patients can be more accurately monitored at specific points during the course of the disease and potential treatment. In addition, to advance the development of therapeutic drugs, models that better mimic the complexity of the human brain are needed; there have been several advances in this arena. Here, we review significant, recent developments in genetics, omics, and molecular studies that have contributed to the understanding of this disease. We also discuss the implications that these contributions have on medicine.


Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated Cardiovascular Toxicities.
Despite the increasing prevalence of therapies utilizing immune checkpoint inhibitors (ICIs), the associated cardiovascular complications have been poorly reported. Given the fatality of ICI-related complications, especially myocarditis, optimal risk stratification to predict major adverse cardio- and cerebrovascular events (MACCEs) in patients receiving ICIs is mandatory. We collected clinical data from patients receiving ICIs, and the primary outcomes were MACCEs, including myocarditis, heart failure, and ischemic stroke. Other systemic immune responses relating to ICIs were also recorded. The median follow-up duration was 3 years. Among 580 patients, the incidence of MACCEs was 3.9%. Older patients, male patients, and patients with lung cancer, liver cirrhosis, or diabetes had higher risks of MACCEs. There was no significant difference between the use of PD-1/PD-L1 inhibitors or CTLA inhibitors in terms of developing cardiovascular toxicities. The development of ICI-related MACCEs was associated with worse survival. Notably, after re-review by specialists, three patients eventually diagnosed with ICI-related myocarditis had not previously been identified. Only one was treated with pulse steroids, and none survived. The most common concomitant extracardiac immune-related adverse events were myositis/dermatitis, endocrine toxicity and hepatitis. Collectively, ICIs may lead to severe cardiovascular toxicities and require more attention. Early identification, proper diagnosis, and prompt treatment are pivotal for improving survival.


Contact tracing strategies in heterogeneous populations.
Contact tracing is a well-established disease control measure that seeks to uncover cases by following chains of infection. This paper examines mathematical models of both single-step and iterative contact tracing schemes and analyses the ability of these procedures to trace core groups and the sensitivity of the intervention to the timescale of tracing. An iterative tracing process is shown to be particularly effective at uncovering high-risk individuals, and thus it provides a powerful public health tool. Further targeting of tracing effort is considered. When the population exhibits like-with-like (assortative) mixing the required effort for eradication can be significantly reduced by preferentially tracing the contacts of high-risk individuals; in populations where individuals have reliable information about their contacts, further gains in efficiency can be realized. Contact tracing is, therefore, potentially an even more potent tool than its present usage suggests.


AiRDose: Developing and Validating an Augmented Reality Smartphone Application for Weight Estimation and Dosing in Children.
Inaccurate weight estimation is a contributing factor to medical error in pediatric emergencies, especially in the prehospital setting. Current American Heart Association guidelines recommend the use of length-based weight estimation tools such as the Broselow tape. We developed the AiRDose smartphone application that uses augmented reality to provide length-based weight estimates, as well as medication dosing, defibrillation energy, and equipment sizing recommendations; AiRDose was programmed to use Broselow conversions to obtain these estimates. The primary objective was to compare the length estimated by AiRDose with the actual length obtained by the standard tape measure. The secondary objectives were to compare the estimated weights and critical medication doses from AiRDose with current established methods. In this prospective validation study, lengths and estimated weights were obtained for children presenting to 2 emergency departments using AiRDose, Broselow, and a standard tape measure; actual weight was recorded from the patient chart. Using the AiRDose estimated weights, hypothetical doses of epinephrine and lorazepam were calculated and compared with doses recommended via Broselow and to actual weight-based doses. Spearman rank correlation coefficients were calculated. We defined an acceptable difference of 20% between AiRDose and standard measurements as clinically relevant. Five hundred forty-nine children (mean age, 4.8 years; standard deviation [SD], 2.9 years) were recruited. There were 99.6% of AiRDose lengths within a 20% difference of tape-measure lengths. There was a significant correlation between AiRDose and tape-measure length measurements (r = 0.989, P < 0.0001), and between AiRDose and Broselow weights (r = 0.983, P < 0.0001) and AiRDose and actual weights (r = 0.886, P < 0.0001). AiRDose lorazepam and epinephrine doses correlated significantly with Broselow lorazepam (r = 0.963, P < 0.0001) and epinephrine (r = 0.966, P < 0.0001) doses. Anthropometric estimates and medication dose recommendations provided by AiRDose strongly correlate with established techniques. Further study will establish the feasibility of using AiRDose to accurately obtain weight estimates and medication doses for pediatric patients in the prehospital setting.


Does the Use of Peripheral Immune-Related Markers Indicate Whether to Administer Pazopanib, Trabectedin, or Eribulin to Advanced Soft Tissue Sarcoma Patients?
Pazopanib, trabectedin, and eribulin are administered for the treatment of soft tissue sarcomas (STSs); however, there is little consensus on which agent should be preferentially used in a clinical setting. This study assessed whether peripheral immune-related markers served as a useful reference when selecting pazopanib, trabectedin, or eribulin. This study included 63 patients who were administered pazopanib, trabectedin, or eribulin for advanced STSs between March 2015 and December 2020. Patients were divided into three groups based on the first drug administered among these three drugs. Differences in overall survival (OS) or progression-free survival (PFS) among the three groups were analyzed. OS showed no significant differences among the drugs administered first. For patients with low neutrophil-to-lymphocyte ratio (NLR), the OS of patients administered pazopanib as the first choice was shorter than the others (hazard ratio [HR] = 9.53, 95% confidence interval [CI] = 1.94-18.13, p = 0.0018). In the low platelet-to-lymphocyte ratio (PLR) subgroup, the OS of the patients administered eribulin for the first choice was longer than that of the others (HR = 0.32, 95%CI = 0.10-0.98, p = 0.046). Therefore, NLR and PLR might be used as prognostic indicators to dictate whether STS patients receive pazopanib, trabectedin, or eribulin.


Strengthening self-regulation and reducing poverty to prevent adolescent depression and anxiety: Rationale, approach and methods of the ALIVE interdisciplinary research collaboration in Colombia, Nepal and South Africa.
Depression and anxiety are the leading contributors to the global burden of disease among young people, accounting for over a third (34.8%) of years lived with disability. Yet there is limited evidence for interventions that prevent adolescent depression and anxiety in low- and middle-income countries (LMICs), where 90% of adolescents live. This article introduces the 'Improving Adolescent mentaL health by reducing the Impact of poVErty (ALIVE)' study, its conceptual framework, objectives, methods and expected outcomes. The aim of the ALIVE study is to develop and pilot-test an intervention that combines poverty reduction with strengthening self-regulation to prevent depression and anxiety among adolescents living in urban poverty in Colombia, Nepal and South Africa. This aim will be achieved by addressing four objectives: (1) develop a conceptual framework that identifies the causal mechanisms linking poverty, self-regulation and depression and anxiety; (2) develop a multi-component selective prevention intervention targeting self-regulation and poverty among adolescents at high risk of developing depression or anxiety; (3) adapt and validate instruments to measure incidence of depression and anxiety, mediators and implementation parameters of the prevention intervention; and (4) undertake a four-arm pilot cluster randomised controlled trial to assess the feasibility, acceptability and cost of the selective prevention intervention in the three study sites. The contributions of this study include the active engagement and participation of adolescents in the research process; a focus on the causal mechanisms of the intervention; building an evidence base for prevention interventions in LMICs; and the use of an interdisciplinary approach. By developing and evaluating an intervention that addresses multidimensional poverty and self-regulation, ALIVE can make contributions to evidence on the integration of mental health into broader development policy and practice.


Theta modulation in the medial and the lateral entorhinal cortices.
Hippocampal neurons show a strong modulation by theta frequency oscillations. This modulation is thought to be important not only for temporal encoding and decoding of information in the hippocampal system, but also for temporal ordering of neuronal activities on timescales at which physiological mechanisms of synaptic plasticity operate. The medial entorhinal cortex (MEC), one of the two major cortical inputs to the hippocampus, is known to show theta modulation. Here, we show that the local field potentials (LFPs) in the other major cortical input to the hippocampus, the lateral entorhinal cortex (LEC), show weaker theta oscillations than those shown in the MEC. Neurons in LEC also show weaker theta modulation than that of neurons in MEC. These findings suggest that LEC inputs are integrated into hippocampal representations in a qualitatively different manner than the MEC inputs. Furthermore, MEC grid cells increase the scale of their periodic spatial firing patterns along the dorsoventral axis, corresponding to the increasing size of place fields along the septotemporal axis of the hippocampus. We show here a corresponding gradient in the tendency of MEC neural firing to skip alternate theta cycles. We propose a simple model based on interference of delta oscillations with theta oscillations to explain this behavior.


Substitution of warthog NF-κB motifs into RELA of domestic pigs is not sufficient to confer resilience to African swine fever virus.
African swine fever virus (ASFV) causes a lethal, haemorrhagic disease in domestic swine that threatens pig production across the globe. Unlike domestic pigs, warthogs, which are wildlife hosts of the virus, do not succumb to the lethal effects of infection. There are three amino acid differences between the sequence of the warthog and domestic pig RELA protein; a subunit of the NF-κB transcription factor that plays a key role in regulating the immune response to infections. Domestic pigs with all 3 or 2 of the amino acids from the warthog RELA orthologue have been generated by gene editing. To assess if these variations confer resilience to ASF we established an intranasal challenge model with a moderately virulent ASFV. No difference in clinical, virological or pathological parameters were observed in domestic pigs with the 2 amino acid substitution. Domestic pigs with all 3 amino acids found in warthog RELA were not resilient to ASF but a delay in onset of clinical signs and less viral DNA in blood samples and nasal secretions was observed in some animals. Inclusion of these and additional warthog genetic traits into domestic pigs may be one way to assist in combating the devastating impact of ASFV.


Efficacy of a novel herbal formulation for weight loss demonstrated in a 16-week randomized, double-blind, placebo-controlled clinical trial with healthy overweight adults.
To re-evaluate the weight loss efficacy of LI85008F in healthy overweight adults via a 16-week randomized, double-blind, placebo-controlled clinical study. One hundred and forty overweight participants (body mass index [BMI] 27-29.9 kg/m2 , 29.3% male; ages 21-50 years) were randomized into placebo (n =70) and LI85008F (n =70) groups. The participants received either 900 mg/d of LI85008F in two divided doses or two identical placebo capsules. In addition, participants were counselled to follow an ~1800 kcal/d diet and to engage in walking for 30 min, 5 d/wk throughout the study. At the end of the trial period, the LI85008F supplemented group showed significant reductions in body weight (5.36 ± 1.769 vs. 0.87 ± 1.381 kg; P < 0.0001) and BMI (2.05 ± 0.693 vs. 0.34 ± 0.559 kg/m2 ; P < 0.0001), compared with placebo. Significant reductions in waist and hip circumferences, and a 2.08-fold reduction of waist/hip ratio, were noted in the LI85008F supplemented group. LI85008F supplementation also resulted in significant improvements in lipid profiles, compared with the placebo; low-density lipoprotein (LDL) cholesterol decreased, while high-density lipoprotein (HDL) cholesterol increased, resulting in a significantly improved LDL/HDL ratio. No major adverse events were reported by the participants during the study. The unique herbal extract blend LI85008F, combined with modest calorie restriction and physical activity, is well tolerated, safe, and effective for weight management in overweight men and women.


Consequences of long-term inflammation. The natural history of asthma.
Although asthma is classically defined as reversible airflow obstruction, and often remits in younger subjects with milder disease, the natural history of asthma is that various degrees of airflow obstruction may persist and, in the long-term, asthma may become moderately to fully irreversible. Severe, irreversible airflow obstruction may develop despite apparently appropriate therapy and in the absence of other risk factors, such as smoking and environmental insults. All studies of subjects with persisting asthma show increased decline in lung function compared with normal subjects. Persistent abnormal physiology is reflected both in reduced airflow rates and in increased airway responsiveness. The cellular and molecular mechanisms of airway remodeling are described elsewhere in this issue. Questions not yet clearly answered are the reasons for these persistent abnormalities in some asthmatics, and which subjects are most at risk. Factors that adversely impact the outcome as adults identified relatively consistently among many longitudinal studies of the natural history of asthma include: Female gender. Environmental tobacco smoke exposure in childhood. Personal tobacco smoking in adolescence and adulthood. Age of onset of symptoms. Severity of childhood asthma. Duration of asthma. Severity of lung function abnormality in childhood. Bronchodilator reversibility. Degree of airway hyperresponsiveness. Delay in initiating anti-inflammatory therapy. Remission among adult asthmatics is uncommon, but is associated with better initial lung function, young age, male gender, and lesser degrees of airway responsiveness. The role of atopy remains controversial. Conversely, risk factors for death from asthma include older age, smoking, atopy, impaired lung function, and moderate to high reversibility. Treatment can improve lung function, reduce airway responsiveness, and improve quality of life. The overall effect of treatment on the natural history of the disease is not yet clear, despite significant short-term improvements from effective anti-inflammatory therapy.


Alteration of redox status and fatty acid profile in gills from the green crab (Carcinus aestuarii) following dimethoate exposure.
Dimethoate is a broad-spectrum organophosphate insecticide and acaricide. Through various pathways, such as runoff and drift, dimethoate can reach marine environment, and easily impact common organisms in coastal areas, close to agriculture lands, namely crustaceans. The purpose of this study was to investigate the potential effects of dimethoate exposure (50, 100, and 200 μg/l), for 1 day, on a wide range of markers of oxidative stress and neurotransmission impairment, as well as fatty acids composition and histopathological aspect in the gills of the green crab Carcinus aestuarii. A significant increase in n-3 polyunsaturated fatty acids series, namely the eicosapentaenoic acid (C20: 5n3) and its precursor alpha-linolenic acid (C 18: 3n3) in dimethoate-treated crabs was recorded. Concerning n-6 polyunsaturated fatty acids, we noted a high reduction in arachidonic acid (C20:4n-6) levels. Dimethoate exposure increased the levels of hydrogen peroxide, malondialdehyde, lipid hydroperoxides, protein carbonyl, and caused the advanced oxidation of protein products along with enzymatic and non-enzymatic antioxidant-related markers. Acetylcholinesterase activity was highly inhibited following exposure to dimethoate in a concentration-dependent manner. Finally, deleterious histopathological changes with several abnormalities were noted in exposed animals confirming our biochemical findings. The present study offered unique insights to establish a relationship between redox status and alterations in fatty acid composition, allowing a better understanding of dimethoate-triggered toxicity.


Insights about echinostomiasis by paleomolecular diagnosis.
Echinostomiasis is a zoonosis caused by intestinal trematodes and transmitted by the ingestion of mollusks, crustaceans, fish, amphibians, and reptiles, either raw or poorly cooked. Today human infection is endemic in Southeast Asia and the Far East, but has been reported more recently in other regions of the world. Interestingly eggs identified as Echinostoma sp. were found in coprolites from a mummified body human in Brazil, dated 560 ± 40 BP (before present). However, the specific diagnosis based on morphology of the eggs has not been resolved at the species level. As a follow-up to the previous finding, the current study now aims to standardize the methodology for molecular diagnosis and apply it to the coprolite, using current Echinostoma paraensei-positive feces as the reference, and also the same fecal material dried in a stove as an experimental coprolite model. Isolated eggs of E. paraensei and adult worm were included to verify the sensibility and as positive control, respectively. An adult worm of E. luisreyi was used for comparison. PCR using primers in-house for ITS1 region (126 bp) and cox1 (123 bp) of Echinostoma spp. and subsequent nucleotide sequencing were performed. This is the first molecular paleoparasitological diagnosis for echinostomiasis. The methodology was able to amplify specific DNA fragments for the genus Echinostoma sp. in all samples: adult worm, feces, and a single egg of the parasite, in both the experimental coprolite and archaeological sample. Additionally we observed that ancient DNA can also be retrieved without rehydrating the material. The nucleotide sequences from E. paraensei and E. luisreyi are very similar in the fragment analyzed that difficult the differentiation these species, but DNA sequence analysis recovered in the parasite found in the mummy showed more similarity with the species E. paraensei.


COP1 mediates dark-specific degradation of microtubule-associated protein WDL3 in regulating Arabidopsis hypocotyl elongation.
CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), a well-known E3 ubiquitin ligase, functions as a central regulator of plant growth and photomorphogenic development in plants, including hypocotyl elongation. It has been well-established that, in darkness, COP1 targets many photomorphogenesis-promoting factors for ubiquitination and degradation in the nucleus. However, increasing evidence has shown that a proportion of COP1 is also localized outside the nucleus in dark-grown seedlings, but the physiological function of this localization remains largely unclear. In this study, we demonstrate that COP1 directly targets and mediates the degradation of WAVE-DAMPENED 2-LIKE 3 (WDL3) protein, a member of the microtubule-associated protein (MAP) WVD2/WDL family involved in regulating hypocotyl cell elongation of Arabidopsis seedlings. We show that COP1 interacts with WDL3 in vivo in a dark-dependent manner at cortical microtubules. Moreover, our data indicate that COP1 directly ubiquitinates WDL3 in vitro and that WDL3 protein is degraded in WT seedlings but is abundant in the cop1 mutant in the dark. Consistently, introduction of the wdl3 mutation weakened, whereas overexpression of WDL3 enhanced, the short-hypocotyl phenotype of cop1 mutant in darkness. Together, this study reveals a function of COP1 in regulating the protein turnover of a cytosol-localized MAP in etiolated hypocotyls, thus providing insights into COP1-mediated degradation of downstream factors to control seedling photomorphogenesis.


T cell receptor transfection shows non-HLA-restricted recognition of nickel by CD8+ human T cells to be mediated by alphabeta T cell receptors.
CD8+ T cells have been assigned a prominent role in allergic contact dermatitis, including nickel allergy; however, human nickel-reactive T cells of the CD8+ phenotype have largely escaped detailed investigation. Here we characterize two quite unusual nickel-specific cytotoxic T cell clones isolated from the peripheral blood of two nickel-sensitized patients. These clones mediate nickel-specific cytolysis of many human cell lines, independent of the expression of HLA class I, CD1, or HLA class II molecules. Lysis is mediated by the alphabeta T cell receptors and involves the perforin, but not the Fas/Fas ligand pathway. Both antigen receptors lack sequence homology to each other as well as to typical natural killer T cell receptors. A transfectant expressing the rearranged alphabeta T cell receptor derived from one of the T cell clones unequivocally demonstrates that the T cell receptor itself is necessary and sufficient to confer HLA-independent nickel specificity. The independent isolation of these clones from two individuals points to an important role of such cells in the pathology of nickel contact dermatitis.


Obinutuzumab for the treatment of indolent lymphoma.
Obinutuzumab is a humanized, type II anti-CD20 monoclonal antibody designed for strong induction of direct cell death and antibody-dependent cell-mediated cytotoxicity. The Phase III GADOLIN trial tested the clinical efficacy of obinutuzumab plus bendamustine followed by obinutuzumab monotherapy in rituximab-refractory indolent non-Hodgkin lymphoma versus treatment with bendamustine alone. It demonstrated significantly longer progression-free survival for the obinutuzumab-containing regimen in this difficult to treat patient group. Based on the results of this trial, US FDA approval was most recently granted for obinutuzumab in the treatment of follicular lymphoma that has relapsed after or was refractory to a rituximab-containing regimen. This article summarizes the available data on chemistry, pharmacokinetics, clinical efficacy and safety of obinutuzumab in the treatment of indolent non-Hodgkin lymphoma.


sTREM2 is associated with attenuated tau aggregate accumulation in the presence of amyloid-β pathology.
Triggering Receptor Expressed on Myeloid Cell 2 (TREM2) plays a crucial role in the transition of microglia from a state of homeostasis to a state associated with the disease. Mutations in TREM2 are strongly linked with a higher risk of developing neurodegenerative diseases, including Alzheimer's disease. There have been contradictory findings regarding the potential detrimental or protective effects of microglial activation and TREM2-related microglial responses in Alzheimer's disease. Although previous studies reported increased CSF soluble TREM2 (sTREM2) in different clinical stages of Alzheimer's disease, the exact association between Alzheimer's disease hallmarks such as amyloid-beta and tau pathology remains unclear. In the present study, I aimed to investigate the association between TREM2-related microglial responses and tau accumulation in the presence and absence of amyloid-beta pathology in order to give a better view of the role of microglial activation in Alzheimer's disease development. Imaging data of 178 non-demented participants including 107 amyloid-beta-negative participants, 71 amyloid-beta-positive were recruited from Alzheimer's disease Neuroimaging Initiative. The CSF sTREM2 was used as an in vivo indicator of microglial responses associated with TREM2. Furthermore, I used longitudinal tau-PET and resting-state functional MRI connectomes in order to investigate the association of TREM2-related microglial activation and tau spreading through functional connections. A higher level of sTREM2 was associated with slower tau aggregate accumulation in non-demented amyloid-beta-positive. Furthermore, measuring the tau spreading through inter-connected regions using functional MRI connectomes confirms that the TREM2-related microglial activity might be a protective factor against tau pathology in brain tissue. These findings demonstrate that in individuals with initial amyloid-beta abnormalities, TREM2-related microglial activation is linked to reduced regional accumulation of tau aggregates and also, spreading across inter-connected brain regions, as evaluated through functional MRI connectomes during the early stages of Alzheimer's disease.


Regulatory steps in the initiation of protein synthesis.
Regulation of protein synthesis is being exerted at different levels with a different extent of attenuation. The major control module seems to work by the inactivation of the elF-2 recycling which enables the cell to shift down from a high rate of initiation to a low rate. Certain events in the cell cycle like mitosis do show such a drastic change in initiation rate. It is suggested that modifications of elF-2 by phosphorylation of the alpha-subunit by different protein-kinases is the basis for such a control mechanism. Already two protein kinases of this type have been described, the hemin-regulated inhibitor and the ds-RNA activated inhibitor from interferon-treated cells. On the other hand modifications of the beta-subunit by other metabolic events, for instance low NADH/NAD+ ratio, can as yet not be excluded. Other conditions like amino acid starvation, serum deprivation, heat-shock and virus-infection seem to evoke quite different strategies. In some cases it has been demonstrated that inactivation of mRNA binding factors as elF-4B and elF-4E, favour the translation of low-dependence, i.e. low secondary structure, messengers. It shall be worthwhile to establish whether the mRNA's with such low degree of secondary structure encoded proteins that are aimed at the survival of the cell under extreme metabolic or stress conditions. Much more work on the structure and nucleotide sequences of the leader sequence is needed to prove these hypothetical points.


Alkyl esters of L-ascorbic acid: Stability, surface behaviour and interaction with phospholipid monolayers.
L-ascorbic acid alkyl esters (ASCn) are molecules of pharmaceutical interest for their amphiphilic nature and proposed antioxidant power. In contrast to L-ascorbic acid, ASC(n) with different acyl chain lengths behaved stably upon oxidation and a tautomeric isomerization was observed. In Langmuir films, when the ascorbic ring has a negative charge, ASC14 and ASC16 form stable monolayers, contrary to ASC10 and ASC12. ASC16 films showed transition from liquid-expanded (LE) to liquid-condensed phase, whereas ASC14 showed only an LE phase. When ASCn are mainly neutral, ASC14 showed phase transition from LE to a crystalline phase, as previously reported for ASC16. The two-dimensional domains displayed crystal-like shapes with anisotropic optical activity when interacting with the polarized light under Brewster angle microscopy. The compounds with the longer acyl chain (ASC16, ASC14 and ASC12) exhibited good surface activity, forming Gibbs monolayers. They also were able to penetrate into phospholipid monolayers up to a critical point of 45-50 mN/m. The 1-palmitoyl-2-oleoylphosphatidylcholine/ASCn films showed LC and/or crystalline domains only for ASC16. This study provides valuable evidence regarding the stability and surface properties of this drug family, and casts light into the differential interaction of these drugs with lipid membranes, which is important for understanding its differential pharmacological activity.


The neural development of conditional reasoning in children: Different mechanisms for assessing the logical validity and likelihood of conclusions.
Scientific and mathematical thinking relies on the ability to evaluate whether conclusions drawn from conditional (if-then) arguments are logically valid. Yet, the neural development of this ability -- termed deductive reasoning -- is largely unknown. Here we aimed to identify the neural mechanisms that underlie the emergence of deductive reasoning with conditional rules in children. We further tested whether these mechanisms have their roots in the neural mechanisms involved in judging the likelihood of conclusions. In a functional Magnetic Resonance Imaging (fMRI) scanner, 8- to 13-year-olds were presented with causal conditional problems such as "If a baby is hungry then he will start crying; The baby is crying; Is the baby hungry?". In Validity trials, children were asked to indicate whether the conclusion followed out of necessity from the premises. In Likelihood trials, they indicated the degree of likelihood of the conclusion. We found that children who made accurate judgments of logical validity (as compared to those who did not) exhibited enhanced activity in left and medial frontal regions. In contrast, differences in likelihood ratings between children were related to differences of activity in right frontal and bilateral parietal regions. There was no overlap between the brain regions underlying validity and likelihood judgments. Therefore, our results suggest that the ability to evaluate the logical validity of conditional arguments emerges from brain mechanisms that qualitatively differ from those involved in evaluating the likelihood of these arguments in children.


Acne vulgaris.
Acne vulgaris is one of the most common dermatological diseases, and caused by a combination of pathogenetic factors including follicular hyperkeratosis, seborrhea, colonization with Propionibacteriumacnes and inflammatory phenomena. Various medical treatments address these causative factors, but they are not always well tolerated. In the last decades, there has been increased interest in laser and light-based treatments. These optical devices mainly target Propionibacteriumacnes by activating porphyrins produced by the bacterium, whereas some treatments directly lead to the destruction of sebaceous glands. Photodynamic therapy can enhance these effects through the prior application of a photosensitizing agent. Many laser and light-based treatments have shown excellent clinical results in the reduction of inflammatory acne lesions and improved acne severity. Although relapses are frequent, results can be improved by combination therapy with conventional medical treatments. Data of randomized controlled studies or studies with a split-face design are contradictory and difficult to compare. Furthermore, the cost of the treatments is often a limiting factor. In summary, some optical devices are an important additional tool in the treatment of patients with mainly inflammatory acne where conventional treatments are not well tolerated.


A Drosophila heat shock response represents an exception rather than a rule amongst Diptera species.
Heat shock protein 70 (Hsp70) is the major player that underlies adaptive response to hyperthermia in all organisms studied to date. We investigated patterns of Hsp70 expression in larvae of dipteran species collected from natural populations of species belonging to four families from different evolutionary lineages of the order Diptera: Stratiomyidae, Tabanidae, Chironomidae and Ceratopogonidae. All investigated species showed a Hsp70 expression pattern that was different from the pattern in Drosophila. In contrast to Drosophila, all of the species in the families studied were characterized by high constitutive levels of Hsp70, which was more stable than that in Drosophila. When Stratiomyidae Hsp70 proteins were expressed in Drosophila cells, they became as short-lived as the endogenous Hsp70. Interestingly, three species of Ceratopogonidae and a cold-water species of Chironomidae exhibited high constitutive levels of Hsp70 mRNA and high basal levels of Hsp70. Furthermore, two species of Tabanidae were characterized by significant constitutive levels of Hsp70 and highly stable Hsp70 mRNA. In most cases, heat-resistant species were characterized by a higher basal level of Hsp70 than more thermosensitive species. These data suggest that different trends were realized during the evolution of the molecular mechanisms underlying the regulation of the responses of Hsp70 genes to temperature fluctuations in the studied families.


Molecular cloning and expression analysis of the sucrose transporter gene family from Theobroma cacao L.
In this study, we performed cloning and expression analysis of six putative sucrose transporter genes, designated TcSUT1, TcSUT2, TcSUT3, TcSUT4, TcSUT5 and TcSUT6, from the cacao genotype 'TAS-R8'. The combination of cDNA and genomic DNA sequences revealed that the cacao SUT genes contained exon numbers ranging from 1 to 14. The average molecular mass of all six deduced proteins was approximately 56 kDa (range 52 to 66 kDa). All six proteins were predicted to exhibit typical features of sucrose transporters with 12 trans-membrane spanning domains. Phylogenetic analysis revealed that TcSUT2 and TcSUT4 belonged to Group 2 SUT and Group 4 SUT, respectively, and the other TcSUT proteins were belonging to Group 1 SUT. Real-time PCR was conducted to investigate the expression pattern of each member of the SUT family in cacao. Our experiment showed that TcSUT1 was expressed dominantly in pods and that, TcSUT3 and TcSUT4 were highly expressed in both pods and in bark with phloem. Within pods, TcSUT1 and TcSUT4 were expressed more in the seed coat and seed from the pod enlargement stage to the ripening stage. TcSUT5 expression sharply increased to its highest expression level in the seed coat during the ripening stage. Expression pattern analysis indicated that TcSUT genes may be associated with photoassimilate transport into developing seeds and may, therefore, have an impact on seed production.


Cerebral Microangiopathy in Leukoencephalopathy With Cerebral Calcifications and Cysts: A Pathological Description.
Leukoencephalopathy with calcifications and cysts (LCC) is a neurological syndrome recently associated with pathogenic variants in SNORD118. We report autopsy neuropathological findings from an individual with genetically confirmed LCC. Histologic studies included staining of formalin-fixed paraffin-embedded tissue sections by hematoxylin and eosin, elastic van Gieson, and luxol fast blue. Immunohistochemistry stains against glial fibrillary acidic protein, proteolipid protein, phosphorylated neurofilament, CD31, alpha-interferon, LN3, and inflammatory markers were performed. Gross examination revealed dark tan/gray appearing white matter with widespread calcifications. Microscopy revealed a diffuse destructive process due to a vasculopathy with secondary ischemic lesions and mineralization. The vasculopathy involved clustered small vessels, resembling vascular malformations, and sporadic lymphocytic infiltration of vessel walls. The white matter was also diffusely abnormal, with concurrent loss of myelin and axons, tissue rarefaction with multifocal cystic degeneration, and the presence of foamy macrophages, secondary calcifications, and astrogliosis. The midbrain, pons, and cerebellum were diffusely involved. It is not understood why variants in SNORD118 result in a disorder that predominantly causes neurological disease and significantly disrupts the cerebral vasculature. Clinical and radiological benefit was recently reported in an LCC patient treated with Bevacizumab; it is important that these patients are rapidly diagnosed and trial of this treatment modality is considered in appropriate circumstances.


Stroke rehabilitation therapy in a patient with a cardiac pacemaker for chronic atrial fibrillation.
A 65-year-old man was implanted with an artificial pacemaker for chronic bradycardic atrial fibrillation associated with hypertensive heart disease. Five years after the pacemaker implantation, he suffered from a cerebral embolism. Approximately 4.5 months after the ictus, he was transferred to the rehabilitation ward. He had flaccid left hemiplegia and severe disuse syndrome. He could not sit and could tilt his head up for only two minutes because of severe orthostatic hypotension. By modulating the rate-responsive mode of the pacemaker every 2-4 weeks, we were able to rehabilitate the patient. Thus, the patient could sit in a wheelchair for more than three hours. This case emphasizes the importance of examining the mode and function of a previously implanted artificial pacemaker. In accord with varying rehabilitation programs and gradual improvement in a patient's physical activities, periodic modulation of a programmable pacemaker can lead to a better functional outcome during rehabilitation therapy.


Planning for coronary angioplasty: guidelines for training and continuing competence. British Cardiac Society (BCS) and British Cardiovascular Intervention Society (BCIS) working group on interventional cardiology.
The following recommendations are made: 1 Existing centres undertaking angioplasty should increase their activity, and the target figure of 400 PTCA procedures per million of the United Kingdom population should be achieved by the end of 1996-97, or immediately thereafter. 2 Angioplasty centres should be appropriately equipped to undertake PTCA safely and effectively and provide a reliable emergency service. They should have a minimum of two trained PTCA operators jointly undertaking a minimum of 200 procedures per year at that centre, and have regular meetings to share experience. 3 Angioplasty operators should ensure that where the need arises patients undergoing PTCA can receive immediate attention from a trained operator at any time until discharge from hospital. 4 Trained operators should undertake at least 1-2 PTCA procedures per week (> 60 procedures per year) to maintain competence, and those undertaking so few procedures should increase their activity over the next three years to more than 100 a year. 5 Trainers should have performed at least 500 procedures before formally training others and should undertake a minimum of 125 procedures a year to maintain accreditation as a trainer. 6 Surgical cover for PTCA procedures should be mandatory and on site cover remains the strongly preferred option. Where surgical cover is provided off site, this should be at a centre less than 30 minutes away by road. Whether provided on or off-site it should be possible to establish cardiopulmonary bypass within 90 minutes of the decision being made to refer the patient for surgery. 7 All operators and interventional centres should audit their activity and results, review these data locally with colleagues, and provide regular audit returns to the national database run by BCIS. This will allow future recommendations concerning standards to take more account of risk stratification and actual outcomes, and not place such emphasis merely on volumes of activity. 8 These recommendations should be reviewed in three years.


Latency-Associated Transcript-Derived MicroRNAs in Herpes Simplex Virus Type 1 Target SMAD3 and SMAD4 in TGF-β/Smad Signaling Pathway.
During its latent infection, hepatic stellate cell (HSV-1) produces only a micro RNA (miRNA) precursor called latency-associated transcript (LAT), which encodes six distinct miRNAs. Recent studies have suggested that some of these miRNAs could target cellular mRNAs. One of the key cell signaling pathways that can be affected by HSV-1 is the TGF-β/Smad pathway. Herein, we investigated the potential role of the LAT as well as three LAT-derived miRNAs in targeting SMAD3 and SMAD4, as two main mediators in TGF-β/Smad. The selection of LAT-derived miRNAs was based on the search results obtained from an online miRNA prediction tool. HEK293T cells were transfected with each miRNA-expressing lentivector and with the construct-expressing LAT. To survey the effect of LAT on the expression of pro-fibrotic markers, we transfected LX-2 cells with LAT construct. The impact of viral miRNA overexpression on SMADs and fibrotic markers was measured by quantitative PCR and luciferase assays. Among the LAT-derived miRNAs, miR-H2, miR-H3, and miR-H4 were selected for the study. Our results demonstrated that while miR-H2 binds to both SMAD mRNAs, miR-H3 and miR-H4 inhibit only the expression of the SMAD4 and SMAD3, respectively. Transfection of the LX-2 with LAT also decreased pro-fibrotic genes expression. Our findings display that LAT negatively regulates TGF-β/Smad through targeting SMAD3 and SMAD4 by its miRNAs. These viral miRNAs can also contribute to the development of therapeutic interventions in diseases for which prevention or treatment can be achieved through targeting TGF-β pathway.


Detection of tumor messenger RNA in the serum of patients with malignant melanoma.
Serum RNases are known to be elevated in patients with cancer. Consequently, it is not clear whether human mRNA with sufficient integrity as to permit reverse transcription-PCR (RT-PCR) amplification is detectable in serum. We examined serum from six patients with malignant melanoma for human tyrosinase mRNA using RT-PCR. Serum from 20 normal volunteers served as controls. Tyrosinase mRNA could be demonstrated in serum from four of the six melanoma patients with detection by gel electrophoresis and confirmation by blotting amplified product to a tyrosinase-specific probe. The serum remained tyrosinase mRNA positive, even if passed through a 0.45 microm filter prior to RNA extraction, indicating that the mRNA was extracellular at the time of extraction. Tyrosinase mRNA could not be detected in any control serum (0 of 20 individuals). The presence and integrity of amplifiable RNA was confirmed in all serum specimens (patients and controls) by RT-PCR amplification of c-abl mRNA. Amplifiable RNA could be demonstrated regardless of whether serum was freshly drawn or stored frozen for several years. We conclude that human mRNA can be extracted and amplified from serum. The ability to amplify tumor mRNA from serum may have important utility in cancer diagnostics and monitoring.


Factors relating to intelligence in treated cases of spina bifida cystica.
Analysis of results on 83 survivors of spina bifida cystica showed the following: (1) in the seven children who had had central nervous system (CNS) infection, intelligence was impaired, six being severely retarded. (2) In the nine children who did not suffer CNS infection or require a shunt, intelligence was normal. The need for a shunt was related to radiological appearance (craniolacunae) and to the sensory level at birth. (3) In the 67 children who did not suffer CNS infection but did require a shunt, intelligence was related to sensory level found at birth and to thickness of the pallium measured within four weeks of birth. Their intelligence did not relate to the occipitofrontal circumference at birth, or to its increase before the insertion of the shunt. Intelligence did not relate to the function of the shunt at the time of assessment or to the number of times it had been revised.


Brave new world?
Recent developments in biology and medicine are raising new problems in the prevention and treatment of birth defects, and in research on these diseases. The problems include immediate issues such as genetic counseling, abortion for birth defects, the withholding of complex treatments from individuals in some situations, screening for genetic and other diseases, artificial insemination, and fertilization in vitro. Other problems, such as the dysgenic effects of modern medicine and the possibilities of cloning and gene therapy, are more remote. Each of these issues should be considered on its own merits and by its immediate and remote consequences rather than by a priori absolute criteria. Ways must be found to deal with these issues in a manner acceptable to most human beings. Open discussions and freedom from coercion are the best guarantees for ultimate success. The ethical human brain is the highest accomplishment of biologic evolution. By harmonizing our scientific, cultural, and ethical capabilities, the potentially achievable results can place us at the threshold of a new era of better health and less human suffering.


Analyses of the proteomes of the leaf, hypocotyl, and root of young soybean seedlings.
The functions of organs in young soybean seedling were determined by means of proteomic analysis. Extracts from leaves, hypocotyls, and roots were separated by two-dimensional polyacrylamide gel electrophoresis, and the proteins were identified by mass spectrometry and protein sequencing. The identified proteins were categorized into various groups according to their function. The leaf was abundant in proteins associated with energy production (50.0%), the hypocotyl was rich in defense proteins (31.8%), and the root contained defense-related proteins (16.7%) and destination and storage proteins (26.7%). Stem 31-kDa glycoprotein, 20 kDa chaperonin, 50S ribosomal protein, and trypsin inhibitor were common to all three tissues. The sequence information obtained from the soybean proteome should be helpful in predicting the functions of unknown proteins.


Learning context shapes bimanual control strategy and generalization of novel dynamics.
Bimanual movements are fundamental components of everyday actions, yet the underlying mechanisms coordinating adaptation of the two hands remain unclear. Although previous studies highlighted the contextual effect of kinematics of both arms on internal model formation, we do not know how the sensorimotor control system associates the learned memory with the experienced states in bimanual movements. More specifically, can, and if so, how, does the sensorimotor control system combine multiple states from different effectors to create and adapt a motor memory? Here, we tested motor memory formation in two groups with a novel paradigm requiring the encoding of the kinematics of the right hand to produce the appropriate predictive force on the left hand. While one group was provided with training movements in which this association was evident, the other group was trained on conditions in which this association was ambiguous. After adaptation, we tested the encoding of the learned motor memory by measuring the generalization to new movement combinations. While both groups adapted to the novel dynamics, the evident group showed a weighted encoding of the learned motor memory based on movements of the other (right) hand, whereas the ambiguous group exhibited mainly same (left) hand encoding in bimanual trials. Despite these differences, both groups demonstrated partial generalization to unimanual movements of the left hand. Our results show that motor memories can be encoded depending on the motion of other limbs, but that the training conditions strongly shape the encoding of the motor memory formation and determine the generalization to novel contexts.


How pervasive is the Hirshfeld partitioning?
One can partition the molecular density into its atomic contributions by minimizing the divergence of the atom-in-molecule densities from their corresponding reference pro-atomic densities, subject to the constraint that the sum of the atom-in-molecule densities is the total molecular density. We expose conditions on the divergence measure that are necessary, and sufficient, to recover the popular Hirshfeld partitioning. Specifically, among all local measures of the divergence between two probability distribution functions, the Hirshfeld partitioning is obtained only for f-divergences.


Genetic analysis of growth, visual scores, height, and carcass traits in Nelore cattle.
Covariance components were estimated for growth traits (BW, birth weight; WW, weaning weight; YW, yearling weight), visual scores (BQ, breed quality; CS, conformation; MS, muscling; NS, navel; PS, finishing precocity), hip height (HH), and carcass traits (BF, backfat thickness; LMA, longissimus muscle area) measured at yearling. Genetic gains were obtained and validation models on direct and maternal effects for BW and WW were fitted. Genetic correlations of growth traits with CS, PS, MS, and HH ranged from 0.20 ± 0.01 to 0.94 ± 0.01 and were positive and low with NS (0.11 ± 0.01 to 0.20 ± 0.01) and favorable with BQ (0.14 ± 0.02 to 0.37 ± 0.02). Null to moderate genetic correlations were obtained between growth and carcass traits. Genetic gains were positive and significant, except for BW. An increase of 0.76 and 0.72 kg is expected for BW and WW, respectively, per unit increase in estimated breeding value (EBV) for direct effect and an additional 0.74 and 1.43, respectively, kg per unit increase in EBV for the maternal effect. Monitoring genetic gains for HH and NS is relevant to maintain an adequate body size and a navel morphological correction, if necessary. Simultaneous selection for growth, morphological, and carcass traits in line with improve maternal performance is a feasible strategy to increase herd productivity.


Ameliorating Effects of Ginger on Isoproterenol-Induced Acute Myocardial Infarction in Rats and its Impact on Cardiac Nitric Oxide.
Myocardial infarction is a major heart disease and is considered a significant reason for mortality and morbidity around the world. The model of Isoproterenol (ISO)-induced myocardial infarction provides a supported method for investigating the impacts of numerous possible cardioprotective bioactive substances. Nitric Oxide (NO) could react with reactive oxygen intermediates and free radicals to create harmful species. For several years, researchers have investigated the use of herbs and natural products as antioxidants to protect the body's organs against toxins and drug metabolites. However, studies on the antioxidant effects of ginger against cardiotoxicity induced by drugs and toxic agents remain insufficient, especially its effects on NO. This study aimed to investigate the possible antioxidant and protective role of ginger in ISO-induced acute myocardial infarction in experimental rats. Special emphasis was given to the impact of ginger on NO levels. Forty adult male albino rats were used in this study. The animals were randomly divided into four equal groups. Group I served as control and received a normal mouse diet. Group II received ginger extract orally, Group III received normal diet for eight weeks, followed by ISO administration subcutaneously to induce myocardial infarction, Group IV received ginger extracts, followed by ISO. The results of this study illustrated ginger's protective role against ISO-induced acute myocardial infarction. This role is mainly due to ginger's antioxidant and anti-inflammatory properties. We assume that sufficient intake of ginger by individuals who are regularly exposed to ISO would be beneficial in overcoming the cardiotoxicity of ISO. The effects of ginger may take place through inhibition of NOS enzymes, which needs further immunohistochemical and biochemical studies to reveal the underlying different mechanisms of the effects of ginger at the molecular and structural levels.


The inverse association between serum 25-hydroxyvitamin D and mortality may be modified by vitamin A status and use of vitamin A supplements.
Low serum 25-hydroxyvitamin D [25(OH)D] levels have been associated with higher risk of many diseases that affect mortality, including cardiovascular disease (CVD) and cancer. The inverse association between serum 25(OH)D and mortality may be modified by excess circulating vitamin A, due to interactions of vitamin A at the level of the vitamin D nuclear receptor. In this prospective cohort study, we investigated whether the association of 25(OH)D with all-cause, cancer, and CVD mortality was modified by circulating vitamin A or preformed vitamin A intake from supplements. We analyzed 15,998 adults in the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. Mortality data for all-cause (n = 3890), cancer (n = 844), and CVD mortality (n = 1715) were assessed through December 2006. Serum 25(OH)D was measured using a radioimmunoassay kit, vitamin A biomarkers were measured by HPLC, and information on supplement use was obtained by self-report. Multivariable hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were estimated by proportional hazards regression. Serum 25(OH)D was significantly inversely associated with all-cause mortality (HR 0.93, 95% CI 0.89, 0.97, per 10 ng/mL increase) and also with CVD mortality and mortality due to non-cancer/non-cardiovascular causes, but not with cancer mortality. The observed inverse associations remained statistically significant only among participants with serum retinyl esters <7.0 μg/dL. High intake (>5000 IU/day) of preformed vitamin A from supplements attenuated the inverse association of 25(OH)D with overall mortality. The observed interactions were not statistically significant. 25(OH)D was inversely associated with overall mortality, CVD mortality, and mortality due to non-cancer/non-CVD causes, but not with cancer mortality. A possible interaction between vitamin A exposure and 25(OH)D concentration appears to be associated with an attenuation of the inverse association between risk of death and quartile of 25(OH)D concentration.


Probiotics enhance pancreatic glutathione biosynthesis and reduce oxidative stress in experimental acute pancreatitis.
Factors determining severity of acute pancreatitis (AP) are poorly understood. Oxidative stress causes acinar cell injury and contributes to the severity, whereas prophylactic probiotics ameliorate experimental pancreatitis. Our objective was to study how probiotics affect oxidative stress, inflammation, and acinar cell injury during the early phase of AP. Fifty-three male Sprague-Dawley rats were randomly allocated into groups: 1) control, 2) sham procedure, 3) AP with no treatment, 4) AP with probiotics, and 5) AP with placebo. AP was induced under general anesthesia by intraductal glycodeoxycholate infusion (15 mM) and intravenous cerulein (5 microg.kg(-1).h(-1), for 6 h). Daily probiotics or placebo were administered intragastrically, starting 5 days prior to AP. After cerulein infusion, pancreas samples were collected for analysis including lipid peroxidation, glutathione, glutamate-cysteine-ligase activity, histological grading of pancreatic injury, and NF-kappaB activation. The severity of pancreatic injury correlated to oxidative damage (r = 0.9) and was ameliorated by probiotics (1.5 vs. placebo 5.5; P = 0.014). AP-induced NF-kappaB activation was reduced by probiotics (0.20 vs. placebo 0.53 OD(450nm)/mg nuclear protein; P < 0.001). Probiotics attenuated AP-induced lipid peroxidation (0.25 vs. placebo 0.51 pmol malondialdehyde/mg protein; P < 0.001). Not only was AP-induced glutathione depletion prevented (8.81 vs. placebo 4.1 micromol/mg protein, P < 0.001), probiotic pretreatment even increased glutathione compared with sham rats (8.81 vs. sham 6.18 miccromol/mg protein, P < 0.001). Biosynthesis of glutathione (glutamate-cysteine-ligase activity) was enhanced in probiotic-pretreated animals. Probiotics enhanced the biosynthesis of glutathione, which may have reduced activation of inflammation and acinar cell injury and ameliorated experimental AP, via a reduction in oxidative stress.


Is an antibacterial adhesive system more effective than cavity disinfectants?
To compare the antibacterial activity of an adhesive system containing an antibacterial monomer MDPB, Clearfil Protect Bond with three different cavity disinfectants, chlorhexidine gluconate-based Consepsis, benzalkonium chloride-based Tubulicid Red and 3% hydrogen peroxide. Materials were tested using agar well technique and a tooth cavity model. The test materials were filled in the agar wells of plates inoculated with Streptococcus mutans. After 48 hours of incubation, the zones of inhibitions were measured in millimeters. For the tooth cavity model test, cylindrical cavities were prepared in the flat occlusal dentin of human extracted molars. The teeth were left in a broth culture of Streptococcus mutans at 37 degrees C for 72 hours allowing bacteria to invade. Teeth were then randomly assigned into five groups of five teeth (10 cavity preparations) each. In the first four groups test materials were applied into the cavities following the manufacturer's instructions and the cavities in the fifth group were left untreated for control. The teeth were kept in saline for 72 hours. Standard amounts of dentin chips were obtained from the cavity walls and the number of bacteria recovered was counted. The results were analyzed by ANOVA, Dunnett C and Bonferroni tests. For the agar well technique, Clearfil Protect Bond primer exhibited greater inhibition zones than all three cavity disinfectants (P< 0.05). When tested by the cavity method, the application of Clearfil Protect Bond system resulted in significantly less bacterial recovery than all disinfectants (P< 0.05). For both microbiological methods, there were no significant differences between the antibacterial activities of Consepsis and Tubulicid Red (P> 0.05). They were superior to hydrogen peroxide in the cavity test method (P< 0.05).


Is the planum temporale surface area a marker of hemispheric or regional language lateralization?
We investigated the association between the left planum temporale (PT) surface area or asymmetry and the hemispheric or regional functional asymmetries during language production and perception tasks in 287 healthy adults (BIL&GIN) who were matched for sex and handedness. The measurements of the PT surface area were performed after manually delineating the region using brain magnetic resonance images (MRI) and considering the Heschl's gyrus (HG) duplication pattern; the measurements either included (PTtot) or did not include (PTpost) the second gyrus. A region encompassing both the PT and HG (HGPT) was also studied. Regardless of the ROI measured, 80% of the sample had a positive left minus right PT asymmetry. We first tested whether the PTtot, PTpost and HGPT surface areas in the left or right hemispheres or PT asymmetries differed in groups of individuals varying in language lateralization by assessing their hemispheric index during a sentence production minus word list production task. We then investigated the association between these different measures of the PT anatomy and the regional asymmetries measured during the task. Regardless of the anatomical definition used, we observed no correlations between the left surface areas or asymmetries and the hemispheric or regional functional asymmetries during the language production task. We then performed a similar analysis using the same sample measuring language functional lateralization during speech listening tasks (i.e., listening to sentences and lists of words). Although the hemispheric lateralization during speech listening was not correlated with the left PTtot, PTpost or HGPT surface areas or the PT asymmetries, significant positive correlations were observed between the asymmetries in these regions and the regional functional asymmetries measured in areas adjacent to the end of the Sylvian fissure while participants listened to the word lists or sentences. The PT asymmetry thus appears to be associated with the local functional asymmetries in auditory areas but is not a marker of inter-individual variability in language dominance.


Metabolic vulnerability disposes retinal ganglion cell axons to dysfunction in a model of glaucomatous degeneration.
We tested the hypothesis that glaucoma disrupts electrophysiological conduction properties and axon function in optic nerve as a function of intraocular pressure (IOP) levels and age in the DBA/2J mouse model of glaucoma. The amplitude and the integral of electrical signals evoked along the axons decreased considerably by 6 months of age as a function of increasing IOP levels. At young ages, raised IOP was directly associated with increased vulnerability to metabolic challenge. Changes in the physiological function of the optic nerves were accentuated with aging, leading to loss of compound action potential in an entire population of fibers: small, slow conducting axons. This loss was accompanied with loss of small fiber axon counts and declining metabolic reserve by demonstrating IOP-dependent ATP decrease in mouse optic nerves. These data shed light on a novel potential mechanism of glaucoma pathology whereby increased IOP and declining metabolic capacity lead to axon liability and eventually dysfunction and loss.


Locations of amino acids in brain slices from the rat. Tetrodotoxin-sensitive release of amino acids.
1. Amino acids, particularly glutamate, gamma-aminobutyrate, aspartate and glycine, were released from rat brain slices on incubation with protoveratrine (especially in a Ca(2+)-deficient medium) or with ouabain or in the absence of glucose. Release was partially or wholly suppressed by tetrodotoxin. 2. Tetrodotoxin did not affect the release of glutamine under various incubation conditions, nor did protoveratrine accelerate it. 3. Protoveratrine caused an increased rate of formation of glutamine in incubated brain slices. 4. Increased K(+) in the incubation medium caused release of gamma-aminobutyrate, the process being partly suppressed by tetrodotoxin. 5. Incubation of brain slices in a glucose-free medium led to increased production of aspartate and to diminished tissue contents of glutamates, glutamine and glycine. 6. Use of tetrodotoxin to suppress the release of amino acids from neurons in slices caused by the joint action of protoveratrine and ouabain (the latter being added to diminish reuptake of amino acids), it was shown that the major pools of glutamate, aspartate, glycine, serine and probably gamma-aminobutyrate are in the neurons. 7. The major pool of glutamine lies not in the neurons but in the glia. 8. The tricarboxylic cycle inhibitors, fluoroacetate and malonate, exerted different effects on amino acid contents in, and on amino acid release from, brain slices incubated in the presence of protoveratrine. Fluoroacetate (3mm) diminished the content of glutamine, increased that of glutamate and gamma-aminobutyrate and did not affect respiration. Malonate (2mm) diminished aspartate and gamma-aminobutyrate content, suppressed respiration and did not affect glutamine content. It is suggested that malonate acts mainly on the neurons, and that fluoroacetate acts mainly on the glia, at the concentrations quoted. 9. Glutamine was more effective than glutamate as a precursor of gamma-aminobutyrate. 10. It is suggested that glutamate released from neurons is partly taken up by glia and converted there into glutamine. This is returned to the neurons where it is hydrolysed and converted into glutamate and gamma-aminobutyrate.


Low-Cost EEG Multi-Subject Recording Platform for the Assessment of Students' Attention and the Estimation of Academic Performance in Secondary School.
The level of student attention in class greatly affects their academic performance. Teachers typically rely on visual inspection to react to students' attention in time, but this subjective method leads to inconsistencies across classes. Online education exacerbates the issue as students can turn off cameras and microphones to keep their own privacy. To address this, we present a novel, low-cost EEG-based platform for assessing students' attention and estimating their academic performance. In a study involving 34 secondary school students (aged 14 to 16), participants watched an academic video and answered evaluation questions while their EEG activity was recorded using a commercial headset. The results demonstrate a significant correlation (0.53, p-value = 0.003) between the power spectral density (PSD) of the EEG beta band (12-30 Hz) and students' academic performance. Additionally, there was a notable difference in PSD-beta between high and low academic performers. These findings encourage the use of PSD-beta for the immediate and objective assessment of both the student attention and the subsequent academic performance. The platform offers valuable and objective feedback to teachers, enhancing the effectiveness of both face-to-face and online teaching and learning environments.


Monophosphoryl lipid A induces protection against LPS in medullary thick ascending limb through a TLR4-TRIF-PI3K signaling pathway.
Monophosphoryl lipid A (MPLA) is a detoxified derivative of LPS that induces tolerance to LPS and augments host resistance to bacterial infections. Previously, we demonstrated that LPS inhibits [Formula: see text] absorption in the medullary thick ascending limb (MTAL) through a basolateral Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-ERK pathway. Here we examined whether pretreatment with MPLA would attenuate LPS inhibition. MTALs from rats were perfused in vitro with MPLA (1 µg/ml) in bath and lumen or bath alone for 2 h, and then LPS was added to (and MPLA removed from) the bath solution. Pretreatment with MPLA eliminated LPS-induced inhibition of [Formula: see text] absorption. In MTALs pretreated with MPLA plus a phosphatidylinositol 3-kinase (PI3K) or Akt inhibitor, LPS decreased [Formula: see text] absorption. MPLA increased Akt phosphorylation in dissected MTALs. The Akt activation was eliminated by a PI3K inhibitor and in MTALs from TLR4-/- or Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF)-/- mice. The effect of MPLA to prevent LPS inhibition of [Formula: see text] absorption also was TRIF dependent. Pretreatment with MPLA prevented LPS-induced ERK activation; this effect was dependent on PI3K. MPLA alone had no effect on [Formula: see text] absorption, and MPLA pretreatment did not prevent ERK-mediated inhibition of [Formula: see text] absorption by aldosterone, consistent with MPLA's low toxicity profile. These results demonstrate that pretreatment with MPLA prevents the effect of LPS to inhibit [Formula: see text] absorption in the MTAL. This protective effect is mediated directly through MPLA stimulation of a TLR4-TRIF-PI3K-Akt pathway that prevents LPS-induced ERK activation. These studies identify detoxified TLR4-based immunomodulators as novel potential therapeutic agents to prevent or treat renal tubule dysfunction in response to bacterial infections.


Inherited demyelinating peripheral neuropathies: relating myelin packing abnormalities to P0 molecular defects.
P0-glycoprotein, the major integral membrane protein of peripheral nerve myelin, is thought to mediate myelination and membrane interactions via its extracellular domain (P0-ED). Molecular modeling of P0-ED has suggested which of its amino acid side-chains may be involved in heterophilic and homophilic adhesions. We previously showed that some of these amino acids are the same ones that are substituted or deleted due to mutations in the human gene for P0 (MPZ), which correlate with certain cases of demyelinating motor and sensory peripheral neuropathies. In the current study, high magnification electron microscopy was used to examine the myelin membrane packing in sural nerve biopsies from patients with MPZ mutations. We found that there were distinguishable ultrastructural phenotypes that could be explained by the alterations in P0-ED. These phenotypes, which were not observed in a control nerve, included widening or irregularity of the extracellular apposition alone (delta Ser34; Arg69Cys), widening at both the extracellular and cytoplasmic appositions (Arg69His), the presence of focal bridges in the widened extracellular space (Arg69His), and a diminished (Arg69Cys) or absence (Arg69His) of staining of the double intraperiod line. Our study, which suggests that the altered P0 is incorporated into the myelin sheath, provides a unique basis for further molecular/ultrastructural correlations between P0-ED structure and myelination irregularities.


Killip classification in patients with acute coronary syndrome: insight from a multicenter registry.
The purpose of this study was to assess the prognostic value of the Killip classification at the presentation in patients with acute coronary syndrome (ACS). In 2007 and over 5 months, 6704 consecutive patients with ACS were enrolled in the Gulf Registry of Acute Coronary Events. Patients were categorized according to Killip classification at presentation (Classes I, II, III, and IV). Patients' characteristics and in-hospital outcomes were analyzed. High Killip classes were defined in 22% of patients. In comparison to Killip Class I, patients with higher Killip class had greater prevalence of cardiovascular risk factors, presented late, were less likely to have angina, and were less likely to receive antiplatelet, statins, and β-blockers. Classes II, III, and IV were associated with higher adjusted odds of death in ST-elevation myocardial infarction (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.25-3.69; OR 6.1, 95% CI 3.41-10.86; and OR 28, 95% CI 15.24-54.70, respectively) and non-ST-elevation acute coronary syndrome (adjusted OR 2.4, 95% CI 1.24-4.82; OR 3.2,95% 1.49-7.02; and OR 9.8, 95% CI 3.79-25.57, respectively). In conclusion, across ACS, patients with higher Killip class had worse clinical profile and were less likely to be treated with evidence-based therapy. High Killip class was independent predictors of mortality in ST-elevation myocardial infarction and non-ST-elevation acute coronary syndrome. Physician in the emergency department should be aware of the importance of clinical examination in the risk stratification in patients presenting with ACS.


Stereotactic Ablative Radiotherapy Uncertainties: Delineation, Setup and Motion.
Stereotactic ablative radiotherapy (SAbR), also known as stereotactic body radiation therapy, is biologically distinct from conventionally fractionated radiotherapy in that it is ablative, causing functional incapacitation of targeted tissue including margins added to avoid errors. In striking contrast, small 1.8-2Gy daily doses associated with historical fractionated radiotherapy cause more modest injury more likely to be repaired by normal tissue than tumor. Strategic plans to deal with uncertainties in tumor location, motion during treatment, dose deposition and heterogeneity effects, and tolerance require a novel approach for SAbR very different from what has been dogma for conventionally fractionated treatments. In essence, the targets must be kept absolutely as small as prudently possible without missing tumor deposits. Given the potency and clinical potential of SAbR, a more sophisticated and rigorous approach to uncertainties and margins is warranted.


A method to reconstruct intra-fractional liver motion in rotational radiotherapy using linear fiducial markers.
Complex intra-fractional motion and deformation of the liver significantly impacts the accuracy of delivered dose in radiotherapy. It limits margin reduction, dose escalation and normal tissue sparing. A critical component of motion management is to accurately reconstruct tumor motion. In this study, we developed a six degrees of freedom projection marker matching method (6-DoF PM3) to reconstruct translational and rotational liver tumor motion in a rotational treatment delivery, such as volumetric modulated arc therapy (VMAT). Specifically, we modeled the use of two gold markers implanted in a linear form. The four endpoints of the two gold linear markers were used as tracking surrogates. During delivery, kV x-ray projection images were acquired. A method was developed to automatically identify the 2D marker-endpoints on the projection images. 3D marker positions were determined by solving an optimization problem with the objective function penalizing the distance from the reconstructed 3D position of each fiducial marker endpoint to the corresponding straight line defined by the kV x-ray projection of the endpoints. We performed a series of tests to evaluate different components of the method. For 2D marker endpoints identification, 99.9% of the marker endpoints were identified with an error [Formula: see text] (1 pixel) along both u and v directions. For 3D reconstruction of motion in simulation studies, error of rotational angle was [Formula: see text]° without considering the 2D marker identification error. The rotational angle error was relatively sensitive to the accuracy of 2D marker identification. When the 2D error raised from 0.22 mm to 0.776 mm, the error of 3D rotational angle increased from 0.5° to 2.5°. In the experimental end-to-end tests, the mean root-mean square error of the 3D reconstructed marker positions was 0.75 mm and the mean error of rotational angle was within 1.7°. Our method can accurately determine intra-fractional liver tumor motion in rotational radiotherapy using kV projections of only two linear fiducial markers.


Frailty and invasive mechanical ventilation: association with outcomes, extubation failure, and tracheostomy.
Invasive mechanical ventilation is a common form of life support provided to critically ill patients. Frailty is an emerging prognostic factor for poor outcome in the Intensive Care Unit (ICU); however, its association with adverse outcomes following invasive mechanical ventilation is unknown. We sought to evaluate the association between frailty, defined by the Clinical Frailty Scale (CFS), and outcomes of ICU patients receiving invasive mechanical ventilation. We performed a retrospective analysis (2011-2016) of a prospectively collected registry from two hospitals of consecutive ICU patients ≥ 18 years of age receiving invasive mechanical ventilation. CFS scores were based on recorded pre-admission function at the time of hospital admission. The primary outcome was hospital mortality. Secondary outcomes included discharge to long-term care, extubation failure at time of first liberation attempt, and tracheostomy. We included 8110 patients, and 2529 (31.2%) had frailty (CFS ≥ 5). Frailty was associated with increased odds of hospital death (adjusted odds ratio [aOR]: 1.24 [95% confidence interval [CI] 1.10-1.40) and discharge to long-term care (aOR 1.21 [95% CI 1.13-1.35]). As compared to patients without frailty, patients with frailty had increased odds of extubation failure (aOR 1.17 [95% CI 1.04-1.37]), hospital death following extubation failure (aOR 1.18 [95% CI 1.07-1.28]), tracheostomy (aOR 1.17 [95% CI 1.01-1.36]), and hospital death following tracheostomy (aOR 1.14 [95% CI 1.03-1.25]). The presence of frailty among patients receiving mechanical ventilation is associated with increased odds of hospital mortality, discharge to long-term care, extubation failure, and need for tracheostomy.


[Philosophy of medicine by Ferdynand Karol Dworzaczek].
This paper is devoted to person of Ferdynand Karol Dworzaczek who should be seen as the first Polish physician and philosopher interested in philosophy of medicine. Well educated, with deep interest in theory and practical side of medicine he became first in Poland and very first in Europe to point the importance of philosophical thinking in medicine. His first lecture on this subject--Preface to Philosophy of Medicine, given in Warsaw in 1856, was in fact first lecture in this field ever given in Poland. Year later he published his main work tilted About Philosophy of Medicine in which we can find the core of Dworzaczek's philosophical view on the subject of medicine. His philosophy of medicine could be described as idealistic, with very strong deterministic impact, deeply anchored in religion. Understandably it had to be in opposition to materialism an mechanistic conception of life. For Dworzaczek the nature of life has dualistic character; it has its spiritual and biological significance in the same time, so spirit dominates and shapes biological function of every organism. It can be said, that Dworzaczek's philosophy of medicine was influenced in the first place by Plato and Hippocrates. It had also connection with medical conceptions of Paracelsus and van Helmont. However it was not original and fresh, Dworzaczek's philosophy was important and real background for polish school of philosophy of medicine, which flourished in second half of 19th century. By that Dworzaczek should be traded as father of Polish philosophy of medicine.


The effects of hydrophobic mismatch between phosphatidylcholine bilayers and transmembrane alpha-helical peptides depend on the nature of interfacially exposed aromatic and charged residues.
In this study, we investigated the extent to which different aromatic and positively charged side chains, which often flank transmembrane segments of proteins, can influence lipid-peptide interactions. Model systems consisting of phosphatidylcholine and hydrophobic alpha-helical peptides with different flanking residues were investigated. The peptides were incorporated in relatively thick and in relatively thin lipid bilayers to create a peptide-bilayer hydrophobic mismatch, and the compensating effects on lipid structure were analyzed. When relatively long with respect to the thickness of the bilayer, the peptides that are flanked by the aromatic side chains, Trp, Tyr, and Phe, all induce a significant ordering of the lipid acyl chains, while the peptides flanked by the charged residues Lys, Arg, and His do not. However, when the peptides are relatively short with respect to the thickness of the bilayer, their effect on lipid organization does not depend primarily on their aromatic or charged character. Peptides flanked by Trp, Tyr, Lys, or (at low pH) His residues are effective in inducing mismatch-relieving cubic and inverted hexagonal phases, while analogues flanked by Phe, Arg, or (at neutral pH) His residues cannot induce an inverted hexagonal phase. The different responses to mismatch might reflect the different interfacial affinities of the residues that were investigated.


Allogeneic carrier-specific enhancement of hapten-specific secondary B-cell responses.
We have analyzed the capacity of carrier-specific T cells to enhance the immune response of hapten-specific secondary B cells which do not share genes in the H-2 complex with the T cells. For this analysis we have used the in vitro splenic focus technique which allows assessment of monoclonal responses of B cells isolated in splenic fragment cultures of irradiated reconstituted carrier primed mice. A previous report from this laboratory demonstrated that syngeny in the I region of the H-2 complex was necessary between collaborating hapten-specific primary (nonimmune) B cells and carrier-specific T cells for responses yielding IgG1 but not IgM antibody. These findings lead up to postulate that the expression of I-region gene products on the surface of primary B cells and I-region syngeny with collaborating carrier-specific T cells were essential elements in the triggering events leading to IgG1 synthesis by primary B cells. The results presented in the present report indicate that, unlike primary B cells, the majority of secondary B cells can be stimulated to produce IgG1 antibody in carrier-primed allogeneic recipients. Although the enhancement of secondary IgG1 responses is slightly greater with syngeneic T cells, the allogeneic collaborative interaction requires both carrier priming of recipient mice and stimulation with the homologous hapten-carrier complex and thus appears to be specific. These findings clearly discriminate secondary from primary B cells and indicate that the mechanism of stimulation of secondary B cells to yield IgG1-producing clones differs fundamentally from the stimulation of primary B cells in that the requisite for I-region syngeny is obviated.


Motiliproteus coralliicola sp. nov., a bacterium isolated from coral.
A Gram-stain-negative, non-spore-forming, aerobic, motile, ovoid or rod-shaped bacterium, designated strain C34T, was isolated from a Porites species coral on Weizhou Island, China. Optimal growth occurred in 4 % NaCl (w/v), at 30 °C and pH 8. The only detected respiratory quinone was Q-8. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, two unidentified ninhydrin-positive lipids, one ninhydrin-positive unidentified phospholipid and two unidentified polar lipids. The genome DNA G+C content was 56.7 mol%. The major cellular fatty acids were C16 : 1ω7c/iso-C15 : 0 2-OH, C16 : 0, C18 : 1ω7c/ω6c, C18 : 0 and iso-C11 : 0 3-OH. Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain C34T forms a stable cluster with Motiliproteus sediminis CICC 10858T (with the highest sequence similarity of 95.7 %). Strain C34T was also physiologically and chemical taxonomically similar to M. sediminis CICC 10858T, although they could be distinguished by colony colour on 2216E agar, the flagellum position and the diphosphatidylglycerol content in the cellular polar lipid. Thus, strain C34T is suggested to represent a new species in the genus Motiliproteus, for which the name Motiliproteus coralliicola is proposed. The type strain is C34T (=MCCC 1K03462T=KCTC 62319T).


Penicillinase from Bacillus licheniformis: nucleotide sequence of the gene and implications for the biosynthesis of a secretory protein in a Gram-positive bacterium.
The gene for the penicillinase from B. licheniformis has been cloned in a functional stat on a 1.5 kb DNA fragment and its nucleotide sequence has been determined. A sequence of 307 amino acid residues is infered for the penicillinase precursor. Of these 34 amino acids precede the sequence of the secreted form of the enzyme. This peptide extension shows the features of a signal for secretion and also provides the hydrophobic anchor for the membrane-bound form of the enzyme.


Perioperative hemodynamic goal-directed therapy and mortality: a systematic review and meta-analysis with meta-regression.
Recent data found that perioperative goal directed therapy (GDT) was effective only in higher control mortality rates (>20%) with a relatively high heterogeneity that limited the strength of evidence. The aim of the present meta-analysis was to clearly understand which high risk patients may benefit of GDT. Systematic review of randomized controlled trials with meta-analyses, including a meta-regression technique. MEDLINE, EMBASE, and The Cochrane Library databases were searched (1980-January 2015). Trials enrolling adult surgical patients and comparing the effects of GDT versus standard hemodynamic therapy were considered. The primary outcome measure was mortality. Data synthesis was obtained by using Odds Ratio (OR) with 95% confidence interval (CI) by random-effects model. Fifty eight studies met the inclusion criteria (8171 participants). Pooled OR for mortality was 0.70 (95% CI 0.56-0.88, P=0.002, no statistical heterogeneity). GDT significantly reduced mortality when it is >10% in control group (OR 0.43, 95% CI 0.30-0.61, P<0.00001). The meta-regression model showed that the cut off of 10% of mortality rate in control group significantly differentiates 43 studies from the other 15, with a regression coefficient b of -0.033 and a P value of 0.0001. The significant effect of GDT was driven by high risk of bias studies (OR 0.48, 95% CI 0.34-0.67, P<0.0001). The present meta-analysis, adopting the meta-regression technique, suggests that GDT significantly reduces mortality even when the event control rate is >10%.


Brachial arterial changes in response to wrist occlusion in normotensive and hypertensive men.
Diameter, blood velocity, and flow of the brachial artery and vascular resistance of the brachial circulation were evaluated with a pulsed Doppler velocimeter before and after wrist occlusion in 8 younger and 8 older normotensive subjects and in 11 younger and 11 older hypertensive patients. Before occlusion, no differences existed between younger and older normotensives. However, in hypertensives, systolic peak velocity was higher in younger than in older hypertensives (P less than 0.001) and correlated to age in the overall patients (r = -0.57, P less than 0.01). Occlusion decreased velocity and flow and increased vascular resistance in all groups, but the change in resistance was not correlated with the base-line resistance. During occlusion, no differences existed between younger and older normotensives. However, in hypertensives mean and systolic peak velocity was higher (P less than 0.01), and vascular resistance was lower (P less than 0.01) in younger than in older patients. In hypertensive patients, during occlusion mean and systolic peak velocity were negatively correlated to age (r = -0.72, P less than 0.001; r = -0.59, P less than 0.01), and vascular resistance was positively related to age (r = +0.66, P less than 0.001). Thus wrist occlusion modified the brachial circulation in normotensive and hypertensive populations but revealed age-related differences only in hypertensive patients, suggesting a combined effect of age and hypertension on the muscle vascular bed.


Water-soluble variant of human Lynx1 induces cell cycle arrest and apoptosis in lung cancer cells via modulation of α7 nicotinic acetylcholine receptors.
Lynx1 is the first three-finger prototoxin found in the mammalian central nervous system. It is a GPI-anchored protein modulating nicotinic acetylcholine receptors (nAChRs) in the brain. Besides the brain, the Lynx1 protein was found in the lung and kidney. Endogenous Lynx1 controls the nicotine-induced up-regulation of the expression of α7 type nAChRs in lung adenocarcinoma A549 cells as well as the cell growth. Here, we analyzed the Lynx1 expression in the set of human epithelial cells. The Lynx1 expression both at the mRNA and protein level was detected in normal oral keratinocytes, and lung, colon, epidermal, and breast cancer cells, but not in embryonic kidney cells. Co-localization of Lynx1 with α7-nAChRs was revealed in a cell membrane for lung adenocarcinoma A549 and colon carcinoma HT-29 cells, but not for breast adenocarcinoma MCF-7 and epidermoid carcinoma A431 cells. The recombinant water-soluble variant of Lynx1 without a GPI-anchor (ws-Lynx1) inhibited the growth of A549 cells causing cell cycle arrest via modulation of α7-nAChRs and activation of different intracellular signaling cascades, including PKC/IP3, MAP/ERK, p38, and JNK pathways. A549 cells treatment with ws-Lynx1 resulted in phosphorylation of the proapoptotic tumor suppressor protein p53 and different kinases participated in the regulation of gene transcription, cell growth, adhesion, and differentiation. Externalization of phosphatidylserine, an early apoptosis marker, observed by flow cytometry, confirmed the induction of apoptosis in A549 cells upon the ws-Lynx1 treatment. Our data revealed the ability of ws-Lynx1 to regulate homeostasis of epithelial cancer cells.