Calcium channel blockers in the treatment of hypertension.
Physicians need to weigh the efficacy, adverse effects and cost of first-line antihypertensive agents. Calcium channel blockers lower blood pressure, improve coronary blood flow and depress cardiac contractility by relaxing smooth muscle and cardiac muscle. They have beneficial or neutral effects in hypertensive patients with angina, asthma, chronic obstructive pulmonary disease, postural hypotension, peripheral vascular disease, depression, sexual dysfunction, diabetes and hyperlipidemia. The major adverse effect of some calcium channel blockers is that they may worsen congestive heart failure in some patients. Because calcium channel blockers are metabolized in the liver, the dosage must be lowered in the elderly and in patients with hepatic disease. Diltiazem, verapamil and nifedipine represent prototypes of the three classes of calcium channel blockers, each with slightly different effects.


Strategies of adaptation of Staphylococcus epidermidis to hospital and community: amplification and diversification of SCCmec.
Staphylococcus epidermidis is a harmless commensal, but it can become a human pathogen, mainly in the hospital environment. In order to clarify strategies used by these bacteria to adapt to the hospital environment, we compared the population structure and staphylococcal cassette chromosome mec (SCCmec) content of S. epidermidis from the community and hospital. S. epidermidis were collected from nasal swabs of both healthy military draftees (192 isolates) and patients (94 isolates) recovered in the same time period and geographical region. S. epidermidis were characterized by PFGE, multilocus sequence typing and SCCmec typing. Clonal complex 5 was predominant in the hospital (100%) and the community (58%), but some clonal types were specific to each environment and others were found in both (C/H clones). The methicillin-resistant S. epidermidis (MRSE) colonization rate in the community was very low (7%) when compared with the hospital (30%; P < 0.05). Community-associated MRSE carried mostly SCCmec IV and V [Simpson's index of diversity (SID) = 57.52%; 95% CI 38.35-76.69], whereas hospital-associated MRSE carried 17 SCCmec structures (SID = 82.67%; 95% CI 77.38-87.96). Isolates of the same PFGE type had a much higher number of different SCCmec types when collected in the hospital than in the community. Our data suggest that the S. epidermidis population is composed of hospital-associated clonal types, community-associated clonal types and types that are able to survive in both environments. Moreover, adaptation to the hospital environment in S. epidermidis appears to promote an increase in the frequency and diversification of SCCmec.


Predominant copper deficiency during prolonged enteral nutrition through a jejunostomy tube compared to that through a gastrostomy tube.
Trace element deficiencies are known to occur during long-term enteral nutrition feeding. We compared the serum concentrations of trace elements between patients treated with gastrostomy and those treated with jejunostomy. Our subjects were 36 patients who underwent percutaneous endoscopic gastrostomy (PEG group) and 23 patients who underwent percutaneous endoscopic jejunostomy (PEJ group) and were maintained with enteral tube feeding for more than one year. The serum concentrations of copper, zinc, selenium, and iron were measured in the two groups. Clinical manifestations and the effectiveness of supplementation therapy against copper deficiency were also investigated. From 6 months after the onset of enteral feeding, the copper concentration of the PEJ group was significantly decreased compared with that of the PEG group (p<0.001). There were no significant differences in the concentrations of zinc, selenium, or iron between the two groups. Severe copper deficiency was observed in 6 patients of the PEJ group and was accompanied with neutropenia and anemia. The copper deficiency was successfully treated in all of these patients by supplementation with 10-40 g of cocoa powder a day which was equivalent to a total daily dose of 1.36-2.56 mg of copper. Prolonged PEJ tube nutrition tends to result in copper deficiency, and cocoa supplementation is effective for treating such copper deficiency.


Translational control of collagen prolyl 4-hydroxylase-alpha(I) gene expression under hypoxia.
Hypoxia is a pro-fibrotic stimulus, which is associated with enhanced collagen synthesis, as well as with augmented collagen prolyl 4-hydroxylase (C-P4H) activity. C-P4H activity is controlled mainly by regulated expression of the alpha C-P4H subunit. In this study we demonstrate that the increased synthesis of C-P4H-alpha(I) protein in human HT1080 fibroblasts under long term hypoxia (36 h, 1% oxygen) is controlled at the translational level. This is mediated by an interaction of RNA-binding protein nucleolin (approximately 64 kDa form) at the 5'- and 3'-untranslated regions (UTR) of the mRNA. The 5'/3'-UTR-dependent mechanism elevates the C-P4H-alpha(I) expression rate 2.3-fold, and participates in a 5.3-fold increased protein level under long term hypoxia. The interaction of nucleolin at the 5'-UTR occurs directly and depends on the existence of an AU-rich element. Statistical evaluation of the approximately 64-kDa nucleolin/RNA interaction studies revealed a core binding sequence, corresponding to UAAAUC or AAAUCU. At the 3'-UTR, nucleolin assembles indirectly via protein/protein interaction, with the help of another 3'-UTR-binding protein, presumably annexin A2. The increased protein level of the approximately 64-kDa nucleolin under hypoxia can be attributed to an autocatalytic cleavage of a high molecular weight nucleolin form, without alterations in nucleolin mRNA concentration. Thus, the alteration of translational efficiency by nucleolin, which occurs through a hypoxia inducible factor independent pathway, is an important step in C-P4H-alpha(I) regulation under hypoxia.


[Integration without equalization: on necessary modifications of therapeutic strategies in the treatment of migrants].
Given an increased knowledge for the special requirements of patients with a history of migration in mental health care, different approaches varying between an adaptation of existing systems and the implementation of specialized institutions are being discussed. The present study investigates the treatment courses of 55 first generation immigrants and a control sample of 55 native patients treated in a psychiatric day clinic of a university clinic. Besides the application of questionnaires concerning treatment outcome, a detailed content analysis of treatment records was performed investigating the preference for different therapeutic approaches, migration- and culture-related aspects as well as language problems. Treatment outcome and the reactions to different therapeutic strategies (i. e., verbal-oriented vs. body-centered approaches) suggest a good fit of a common treatment concept also for patients from different countries of origin and ethnic backgrounds. Qualitative analyses, however, imply that migration biography and cultural diversity should be included in diagnostic and therapeutic considerations to a much bigger extent. Language problems, in contrast, appeared to be less salient in the present study.


Role of Oxidative Stress in Prognosis of Ovarian Cancer.
Ovarian cancer is one of the most lethal gynecological malignancies. Mitochondria are the predominant source of reactive oxygen species (ROS) in the cell. Besides mitochondria nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) enzymes generate a significant amount of ROS in the cell. The present work establishes an interesting link between NOX4 enzyme (which is an important source of reactive oxygen species "ROS") and PHB1 (as a holdase type chaperone in mitochondrial stress). The current study was conducted on 60 patients with ovarian tumours (benign, borderline and malignant) and 20 healthy volunteers (as a control group). NOX4 expression was assessed by TaqMan® real time gene expression assay, while cellular expression of prohibitin was evaluated by immunohistochemistry. There was a significant increase in prohibitin expression from benign cystadenoma to malignant tumors. In addition, there was an increase in NOX4 expression. In conclusion, over-expression of PHB1 and NOX4 in malignant ovarian tissues suggest that PHB1 is associated with tumorigenesis via activation of NOX4 enzyme with subsequent release of ROS in the cells.


Rudimentary horn pregnancy - ten years of experience.
This study aimed to evaluate data on early diagnosis and therapeutic management of rudimentary horn pregnancy (RHP). Patients diagnosed with RHP at a tertiary center between for two periods of 2008-2012 and 2013-2018 were analysed retrospectively. We obtained information of patients from hospital electronic archive registration system. Data on demographic characteristics, clinical presentation, gestational age at presentation, presenting symptoms, diagnostic methods, and therapeutic management were noted and analysed by descriptive statistical method. Demographic datas, the complaint of patient's admission to hospital, history of cesarean section, preliminary diagnosis and intraoperative diagnosis were compared between periods of 2008-2012 and 2013-2018. A total of 14 RHP patients were included. Eight (57.1%) of these patients were diagnosed between 2008-2012 (Group 1), whereas six patients (42.9%) were diagnosed between 2013-2018 (Group 2). Rudimentary horn was non-communicating in 13 patients (92.8%). Communicated form was observed in 1 patient in group 1. RHP was diagnosed on the left side in nine patients (64.2%). Six of these patients were observed in group 1 and 3 were in group 2. The pre-rupture diagnosis was made in 10 (71.4%) patients. Six (100%) of 10 patients were in group 2. In addition, in group 1, four patients (50%) experienced intraoperative RHP rupture. RHP was diagnosed before rupture in 2 (33.3%) patients in group 2. It is an indication of advanced ultrasonographic technology as well as increased carefulness on the physician side and raised alertness on the patient side that today both RHP and preoperative rupture of RHP are less frequent. Still, further awareness is required among physicians of the necessity of excision of a rudimentary horn that is detected at the time of C-section.


Comparison of metals in eelgrass (Zostera marina L.) and the environment across the North Pacific Ocean: Environmental processes drive source delivery.
Seagrass beds play a critical role in biodiversity maintenance, serving as nursery habitats for fisheries, and aiding in carbon and sediment sequestration in the ecosystem. These habitats receive dissolved and particulate material inputs, like nutrients and heavy metals, affecting both plant health and the ecosystem. Eelgrass (Zostera marina L.), sediments, and water were randomly collected at twenty sites along the temperate North Pacific coasts of Asia and North America to assess heavy metals concentrations (Cr, Cu, Zn, Cd, and Pb). This aimed to understand heavy metal distribution and accumulation patterns in eelgrass tissues, revealing crucial factors influencing metal accumulation. The sampling included various areas, from pristine marine reserves to human-influenced zones, covering industrial, agricultural, and aquaculture regions, enabling a thorough analysis. This study's uniqueness lies in comparing heavy metal distributions in eelgrass tissues with sediments, uncovering unique accumulation patterns. Aboveground eelgrass tissues mainly accumulated Cd, Zn, and Cu, while belowground tissues stored Cr and Pb. Aboveground eelgrass tissues proved reliable in indicating Cd and Pb concentrations in sediments. However, the correlation between Cu, Zn, and Cr in eelgrass tissues and environmental concentrations seemed less direct, requiring further investigation into factors affecting metal accumulation in seagrass. Human activities are probable major contributors to heavy metal presence in Asian marine environments, whereas oceanographic processes serve as primary metal sources in North American Pacific estuaries. Critical discoveries emphasize the necessity for ongoing research on phytotoxic thresholds and in-depth studies on the complex connections between seagrass physiology and environmental metal concentrations. Understanding these dynamics is crucial for evaluating the broader impact of heavy metal pollution on coastal ecosystems and developing effective conservation measures.


Management of open abdomen.
Non-closure of abdominal fascia and the resultant open abdomen after laparotomy has become a major advance in the management of critically ill or injured patients. The benefits of open abdomen are many and include the prevention of intra-abdominal hypertension and the consequent abdominal compartment syndrome. Appropriately and exquisitely managed, it can provide all the benefits and prevent highly morbid complications of leaving the abdomen open. This review will provide some insights into such management.


Photostability and photobactericidal properties of porphyrin-layered double hydroxide-polyurethane composite films.
The photostability and photobactericidal properties of PdTPPC (Pd(ii)-5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin)-Zn2Al/PU (polyurethane) composite films have been studied in order to investigate their applicability as new photodynamic surfaces. These films comprise a PdTPPC porphyrin photosensitizer intercalated between the lamella of Zn2Al layered double hydroxide and dispersed (1 wt%) into a polyurethane matrix. The study of the photophysical behaviour shows that the Zn2Al LDH host enhances the chemical stability of the PdTPPC guest by minimizing photobleaching and quenching aggregation effects. The singlet oxygen production under irradiation of PdTPPC-Zn2Al/PU composite films is confirmed by the observation of an O2(1Δg) emission band centered at 1274 nm. Furthermore, the value of the rate constant kq for the PdTPPC phosphorescence quenching by oxygen kq = (8.2 ± 0.3) 10-2 s-1 Pa-1 indicates a slow diffusion of oxygen into and out of the PU polymer. In a second step, accelerating light ageing tests are conducted to determine the effect of singlet oxygen production on the chemical and mechanical stability of the PU matrix. Oxygen uptake experiments coupled with ATR-IR measurements indicate the probable formation of hydroxylated photoproducts but with no detrimental effects on the microstructure and the viscoelastic properties of the PU matrix as evidenced by dynamical mechanical analysis. Finally, in vitro preliminary antimicrobial tests show that PdTPPC-Zn2Al/PU composite films are able to inhibit S. aureus growth with no release of PdTPPC biocide from the PdTPPC-Zn2Al/PU composite film. We also observe a total inhibition of P. aeruginosa growth suggesting an efficacy against biofilm formation.


Antigen-specific immune decoys intercept and exhaust autoimmunity to prevent disease.
Relapsing-remitting patterns of many autoimmune diseases such as multiple sclerosis (MS) are perpetuated by a recurring circuit of adaptive immune cells that amplify in secondary lymphoid organs (SLOs) and traffic to compartments where antigen is abundant to elicit damage. Some of the most effective immunotherapies impede the migration of immune cells through this circuit, however, broadly suppressing immune cell migration can introduce life-threatening risks for patients. We developed antigen-specific immune decoys (ASIDs) to mimic tissues targeted in autoimmunity and selectively intercept autoimmune cells to preserve host tissue. Using Experimental Autoimmune Encephalomyelitis (EAE) as a model, we conjugated autoantigen PLP139-151 to a microporous collagen scaffold. By subcutaneously implanting ASIDs after induction but prior to the onset of symptoms, mice were protected from paralysis. ASID implants were rich with autoimmune cells, however, reactivity to cognate antigen was substantially diminished and apoptosis was prevalent. ASID-implanted mice consistently exhibited engorged spleens when disease normally peaked. In addition, splenocyte antigen-presenting cells were highly activated in response to PLP rechallenge, but CD3+ and CD19 + effector subsets were significantly decreased, suggesting exhaustion. ASID-implanted mice never developed EAE relapse symptoms even though the ASID material had long since degraded, suggesting exhausted autoimmune cells did not recover functionality. Together, data suggested ASIDs were able to sequester and exhaust immune cells in an antigen-specific fashion, thus offering a compelling approach to inhibit the migration circuit underlying autoimmunity.


Epigenetic vulnerabilities of leukemia harboring inactivating EZH2 mutations.
Epigenetic regulators such as the polycomb repressive complex 2 (PRC2) play a critical role in both normal development and carcinogenesis. Mutations and functional dysregulation of PRC2 complex components such as EZH2 are implicated in various forms of cancer and associated with poor prognosis. This study investigated the epigenetic vulnerabilities of acute myeloid leukemia (AML) and myelodysplastic/myeloproliferative disorders (MDS/MPN) by performing a chemical probe screen in patient cells. Paradoxically, we observed increased sensitivity to EZH2 and EED inhibitors in AML and MDS/MPN patient cells harboring EZH2 mutations. Expression analysis indicated that EZH2 inhibition elicited upregulation of pathways responsible for cell death and growth arrest, specifically in patient cells with mutant EZH2. The identified EZH2 mutations had drastically reduced catalytic activity, resulting in lower cellular H3K27me3 levels and were associated with decreased EZH2 and PRC2 component EED protein levels. Overall, this study provides an important understanding of the role of EZH2 dysregulation in blood cancers and may indicate disease etiology for these poor prognosis AML and MDS/MPN cases.


Transcriptional regulation of the gene encoding the major surfactant protein (SP-A) in rabbit fetal lung.
The expression of the major protein of rabbit pulmonary surfactant (SP-A), a glycoprotein of Mr congruent to 29,000-36,000, is regulated during development and by hormones. In the present study, utilizing a cDNA insert complementary to mRNA coding for SP-A and nuclear transcription elongation assays, we have investigated the developmental and hormonal regulation of transcription of the SP-A gene in rabbit fetal lung tissue. The relative rates of transcription of SP-A mRNA increased as a function of the gestational age of the fetus. The rate of transcription reached a maximum level in lung tissues of 28-day gestational age fetuses and declined slightly in those of neonatal rabbits. The relative rate of transcription of SP-A mRNA increased in rabbit fetal lung explants maintained in organ culture in control medium as a function of incubation time. Dibutyryl cyclic AMP (Bt2cAMP) treatment of fetal lung explants increased the rate of transcription of SP-A mRNA over that of control tissues by several-fold; after 12 h of incubation in the presence of Bt2cAMP, there was greater than 4-fold increase in the rate of transcription of SP-A mRNA as compared to control lung explants. In contrast, glucocorticoids had a rapid effect to decrease the rate of SP-A mRNA transcription. The rapid effect of glucocorticoids to inhibit the transcription of SP-A mRNA was transient; in fetal lung explants incubated in the presence of dexamethasone for greater than 24 h, there was an increase in the rate of transcription of SP-A mRNA over that of control explants. Cycloheximide caused an inhibition of both basal as well as Bt2cAMP-stimulated rates of transcription of SP-A mRNA in the rabbit fetal lung tissue in vitro. This finding is suggestive of a role of labile protein factor(s) in mediating transcription of the SP-A gene as well as its induction by Bt2cAMP. The magnitude of changes in the relative rates of transcription of SP-A mRNA during development of rabbit fetal lung in vitro as well as those effected by hormones in vitro were similar to changes in the steady-state levels of SP-A mRNA, suggestive that the regulation of the levels of SP-A mRNA in fetal rabbit lung tissue both in vivo and in vitro occurs primarily at the transcriptional level.


Determination of Echinococcus Granulosus Genotypes in Livestock Slaughtered in Shush County, Southwest Iran Using PCR-RFLP.
Echinococosis is a zoonotic disease caused by the larval stages of Echinococcus spp. that occurs in most parts of the world. Herein, we aimed to evaluate the genotypes of isolated hydatid cysts from slaughtered animals in Shush county, southwestern Iran. Totally, 96 hydatid cysts were collected, including 11 buffaloes, 13 cattle, 12 goat and 60 sheep. The PCR was done by a primer pair (BDI and 4s) to amplify ITS1 fragment. Four restriction endonucleases including AluI, HpaII, RsaI, and TaqI were used for RFLP products and enzymatic reactions were electrophoresed. Finally, twenty PCR products were sent for sequencing and phylogenetic tree was drawn with MEGA6. Molecular identification of 96 hydatid cysts demonstrated a distinctive 1000 bp fragment in all samples from four animal hosts. RFLP analysis showed similar digestion patterns in all samples. AluI digestion yielded 800 bp and 200 bp fragments, HpaII digestion made 700 bp and 300 bp fragments and RsaI digestion entailed 655 and 345segments. Moreover, TaqI rendered no digestion pattern on rDNA-ITS1 region. Additionally, E. granulosus sensu stricto (G1-3 complex) was the prevailing genotype in all livestock samples, according to PCR-RFLP and sequencing analyses.


The population growth consequences of variation in individual heterozygosity.
Heterozygosity has been associated with components of fitness in numerous studies across a wide range of taxa. Because heterozygosity is associated with individual performance it is also expected to be associated with population dynamics. However, investigations into the association between heterozygosity and population dynamics have been rare because of difficulties in linking evolutionary and ecological processes. The choice of heterozygosity measure is a further issue confounding such studies as it can be biased by individual differences in the frequencies of the alleles studied, the number of alleles at each locus as well as the total number of loci typed. In this study, we first examine the differences between the principal metrics used to calculate heterozygosity using long-term data from a marked population of Soay sheep (Ovis aries). Next, by means of statistical transformation of the homozygosity weighted by loci index, we determine how heterozygosity contributes to population growth in Soay sheep by modelling individual contributions to population growth (p(t(i))) as a function of several covariates, including sex, weight and faecal egg count--a surrogate of parasitic nematode burden in the gut. We demonstrate that although heterozygosity is associated with some components of fitness, most notably adult male reproductive success, in general it is only weakly associated with population growth.


Dynamic adhesion of eryptotic erythrocytes to endothelial cells via CXCL16/SR-PSOX.
Suicidal death of erythrocytes, or eryptosis, is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine exposure at the cell surface. Eryptosis is triggered by increase of cytosolic Ca2+ activity, which may result from treatment with the Ca2+ ionophore ionomycin or from energy depletion by removal of glucose. The present study tested the hypothesis that phosphatidylserine exposure at the erythrocyte surface fosters adherence to endothelial cells of the vascular wall under flow conditions at arterial shear rates and that binding of eryptotic cells to endothelial cells is mediated by the transmembrane CXC chemokine ligand 16 (CXCL16). To this end, human erythrocytes were exposed to energy depletion (for 48 h) or treated with the Ca2+ ionophore ionomycin (1 μM for 30 min). Phosphatidylserine exposure was quantified utilizing annexin-V binding, cell volume was estimated from forward scatter in FACS analysis, and erythrocyte adhesion to human vascular endothelial cells (HUVEC) was determined in a flow chamber model. As a result, both, ionomycin and glucose depletion, triggered eryptosis and enhanced the percentage of erythrocytes adhering to HUVEC under flow conditions at arterial shear rates. The adhesion was significantly blunted in the presence of erythrocyte phosphatidylserine-coating annexin-V (5 μl/ml), of a neutralizing antibody against endothelial CXCL16 (4 μg/ml), and following silencing of endothelial CXCL16 with small interfering RNA. The present observations demonstrate that eryptotic erythrocytes adhere to endothelial cells of the vascular wall in part by interaction of phosphatidylserine exposed at the erythrocyte surface with endothelial CXCL16.


The increased sensitivity of irregular peripheral canal and otolith vestibular afferents optimizes their encoding of natural stimuli.
Efficient processing of incoming sensory input is essential for an organism's survival. A growing body of evidence suggests that sensory systems have developed coding strategies that are constrained by the statistics of the natural environment. Consequently, it is necessary to first characterize neural responses to natural stimuli to uncover the coding strategies used by a given sensory system. Here we report for the first time the statistics of vestibular rotational and translational stimuli experienced by rhesus monkeys during natural (e.g., walking, grooming) behaviors. We find that these stimuli can reach intensities as high as 1500 deg/s and 8 G. Recordings from afferents during naturalistic rotational and linear motion further revealed strongly nonlinear responses in the form of rectification and saturation, which could not be accurately predicted by traditional linear models of vestibular processing. Accordingly, we used linear-nonlinear cascade models and found that these could accurately predict responses to naturalistic stimuli. Finally, we tested whether the statistics of natural vestibular signals constrain the neural coding strategies used by peripheral afferents. We found that both irregular otolith and semicircular canal afferents, because of their higher sensitivities, were more optimized for processing natural vestibular stimuli as compared with their regular counterparts. Our results therefore provide the first evidence supporting the hypothesis that the neural coding strategies used by the vestibular system are matched to the statistics of natural stimuli.


Simultaneous RP-HPLC Estimation of Trifluoperazine Hydrochloride and Chlordiazepoxide in Tablet Dosage Forms.
A binary mixture of trifluoperazine HCl and chlordiazepoxide was determined using reversed-phase liquid chromatography method using methanol:water (97:03, v/v) pumped at a flow rate of 1.0 ml/min. Quantification was achieved with ultraviolet detection at 262 nm over concentration ranges of 0.1-1 and 0.5-5 mug/ml; mean accuracies were 101.05+/-0.47 and 98.97+/-0.33 %, respectively. The method was successively applied to tablet dosage forms as no chromatographic interferences from the tablet excipients were observed. The method retained its accuracy and precision when the standard addition technique was applied.


[Clinical signs of visceral leishmaniasis in adults: is the manner of presentation changing?].
Although the typical clinical signs and symptoms of visceral leishmaniasis (VL) are always the same, in the recent years the disease has emerged in new settings, for example in HIV infected individuals, in organ transplant recipients, in patients with chronic liver disease, in pregnancy. At the same time, VL has emerged as a model for exploring the host-parasite interplay for intracellular infections. The common feature of VL is that it is fatal without treatment. Liposomal Amphotericin B is the first line treatment in developed countries. Unfortunately, the high cost makes this treatment unaffordable for developing countries.


Effect of fenugreek (Trigonella foenum-graecum L.) intake on glycemia: a meta-analysis of clinical trials.
Fenugreek is a herb that is widely used in cooking and as a traditional medicine for diabetes in Asia. It has been shown to acutely lower postprandial glucose levels, but the long-term effect on glycemia remains uncertain. We systematically reviewed clinical trials of the effect of fenugreek intake on markers of glucose homeostasis. PubMed, SCOPUS, the Cochrane Trials Registry, Web of Science, and BIOSIS were searched up to 29 Nov 2013 for trials of at least 1 week duration comparing intake of fenugreek seeds with a control intervention. Data on change in fasting blood glucose, 2 hour postload glucose, and HbA1c were pooled using random-effects models. A total of 10 trials were identified. Fenugreek significantly changed fasting blood glucose by -0.96 mmol/l (95% CI: -1.52, -0.40; I² = 80%; 10 trials), 2 hour postload glucose by -2.19 mmol/l (95% CI: -3.19, -1.19; I² = 71%; 7 trials) and HbA1c by -0.85% (95% CI: -1.49%, -0.22%; I² = 0%; 3 trials) as compared with control interventions. The considerable heterogeneity in study results was partly explained by diabetes status and dose: significant effects on fasting and 2 hr glucose were only found for studies that administered medium or high doses of fenugreek in persons with diabetes. Most of the trials were of low methodological quality. Results from clinical trials support beneficial effects of fenugreek seeds on glycemic control in persons with diabetes. However, trials with higher methodology quality using a well characterized fenugreek preparation of sufficient dose are needed to provide more conclusive evidence.


Functional iron deficiency anemia was associated with higher mortality in chronic kidney disease patients: the NHANES III follow-up study.
Anemia, a common complication of chronic kidney disease (CKD), is associated with poor prognosis. However, it is not completely clear whether this association is caused by anemia per se or other comorbidities. Whether different types of iron deficiency anemia can predict the outcomes of CKD remains unclear. The dataset from NHANES III was analyzed and Cox multivariate regression models and propensity score matching (PSM) method were used to evaluate the effect of anemia on mortality. Of 4103 patients with CKD, 14.6% had anemia. Among those with anemia, 38.8% had absolute iron deficiency (AID), and 19.8% had functional iron deficiency (FID). During the median follow-up time of 13.8 years, 2964 deaths and 804 cardiovascular deaths were observed. Anemia was robustly associated with a high risk of all-cause mortality in CKD patients after adjusting covariates by two multivariate regression models (Model 1: HR = 1.485, 95%CI:1.340-1.647, p < 0.001; Model 2: HR = 1.391, 95%CI:1.250-1.546, p < 0.001). In the PSM cohort, anemia was still an independent risk factor for all-cause mortality (Model 1: HR = 1.443, 95%CI: 1.256-1.656, p < 0.001; Model 2: HR = 1.357, 95%CI:1.177-1.564, p < 0.001). In the CKD population, anemia patients with FID had the highest risk of mortality than the other anemia groups (p < 0.05), while AID had a mortality rate similar to those without anemia (p > 0.05). In conclusion, anemia was associated with a worse prognosis in patients with CKD, which may be attributed to the higher mortality risk of FID rather than AID. AID wasn't associated with a higher mortality rate compared with CKD patients without anemia.


A simple unified approach for estimating natural direct and indirect effects.
An important problem within both epidemiology and many social sciences is to break down the effect of a given treatment into different causal pathways and to quantify the importance of each pathway. Formal mediation analysis based on counterfactuals is a key tool when addressing this problem. During the last decade, the theoretical framework for mediation analysis has been greatly extended to enable the use of arbitrary statistical models for outcome and mediator. However, the researcher attempting to use these techniques in practice will often find implementation a daunting task, as it tends to require special statistical programming. In this paper, the authors introduce a simple procedure based on marginal structural models that directly parameterize the natural direct and indirect effects of interest. It tends to produce more parsimonious results than current techniques, greatly simplifies testing for the presence of a direct or an indirect effect, and has the advantage that it can be conducted in standard software. However, its simplicity comes at the price of relying on correct specification of models for the distribution of mediator (and exposure) and accepting some loss of precision compared with more complex methods. Web Appendixes 1 and 2, which are posted on the Journal's Web site (http://aje.oupjournals.org/), contain implementation examples in SAS software (SAS Institute, Inc., Cary, North Carolina) and R language (R Foundation for Statistical Computing, Vienna, Austria).


Sooo Sweeet! Presence of Long Vowels in Brand Names Lead to Expectations of Sweetness.
Throughout the history of languages, poets and writers have used linguistic tools to enhance euphony in their creations. One of the widely used tools to convey melody in any written (or spoken) creative art form is the use of long vowels. This paper examines the linkages between long (vs. short) vowel sounds and taste expectations of sweetness. Across four studies, we demonstrate that people expect products with brand names containing long vowels to taste sweeter than those including short vowel sounds. In studies 1 and 2, we demonstrate this association with the use of self-reported measures, and in studies 3 and 4, we employ indirect measures (implicit taste-shape correspondence and Single Category Implicit Association Test (SC-IAT) paradigm) to show the effect holds at a subconscious level of processing. Previous research in this field has typically linked vowel position (high vs. low or front vs. back) with product or brand attribute expectations. This paper contributes to the growing body of literature in this field by demonstrating the importance of vowel length in sound symbolism, and more precisely, how it pertains to the taste continuum.


Relations between the nuclear activity and the variable 3H-amino acid incorporation pattern in Amoeba proteus.
Tracer kinetic studies have revealed the existence of a variable pattern of 3H-amino acid incorporation into amoeba proteins during the early G2 phase of the cell cycle. Two peaks of incorporation of [3H]leucine were found to occur at 19 and 22 h, whereas a single peak at 17 h was noticed in the amoebae labelled with [3H]lysine. An almost 2-fold increase of the labelled amino acid incorporation occurred during the peak periods, while the other periods showed a more or less steady state of incorporation, suggesting a basal rate of synthesis at these times. In a detailed study involving the peaks and the basal incorporation period of [3H]leucine, it was shown that the removal of the nucleus or Actinomycin D treatment eliminated the peaks but the base line protein synthesis was not affected. This suggests that for the peak synthetic periods, mRNA is probably transcribed concurrently, followed by immediate translation, whereas long-life mRNA accounts for the basal synthetic activity.


Evolutionary ecophysiology of seed desiccation sensitivity.
Desiccation sensitive (DS) seeds do not survive dry storage due to their lack of desiccation tolerance. Almost half of the plant species in tropical rainforests produce DS seeds and therefore the desiccation sensitivity of these seeds represents a problem for and long-term biodiversity conservation. This phenomenon raises questions as to how, where and why DS (desiccation sensitive)-seeded species appeared during evolution. These species evolved probably independently from desiccation tolerant (DT) seeded ancestors. They adapted to environments where the conditions are conducive to immediate germination after shedding, e.g. constant and abundant rainy seasons. These very predictable conditions offered a relaxed selection for desiccation tolerance that eventually got lost in DS seeds. These species are highly dependent on their environment to survive and they are seriously threatened by deforestation and climate change. Understanding of the ecology, evolution and molecular mechanisms associated with seed desiccation tolerance can shed light on the resilience of DS-seeded species and guide conservation efforts. In this review, we survey the available literature for ecological and physiological aspects of DS-seeded species and combine it with recent knowledge obtained from DT model species. This enables us to generate hypotheses concerning the evolution of DS-seeded species and their associated genetic alterations.


Regulated cell death in neutrophils: From apoptosis to NETosis and pyroptosis.
Neutrophils are among the most abundant immune cells, representing about 50%- 70% of all circulating leukocytes in humans. Neutrophils rapidly infiltrate inflamed tissues and play an essential role in host defense against infections. They exert microbicidal activity through a variety of specialized effector mechanisms, including phagocytosis, production of reactive oxygen species, degranulation and release of secretory vesicles containing broad-spectrum antimicrobial factors. In addition to their homeostatic turnover by apoptosis, recent studies have revealed the mechanisms by which neutrophils undergo various forms of regulated cell death. In this review, we will discuss the different modes of regulated cell death that have been described in neutrophils, with a particular emphasis on the current understanding of neutrophil pyroptosis and its role in infections and autoinflammation.


Parameter optimization toward optimal microneedle-based dermal vaccination.
Microneedle-based vaccination has several advantages over vaccination by using conventional hypodermic needles. Microneedles are used to deliver a drug into the skin in a minimally-invasive and potentially pain free manner. Besides, the skin is a potent immune organ that is highly suitable for vaccination. However, there are several factors that influence the penetration ability of the skin by microneedles and the immune responses upon microneedle-based immunization. In this study we assessed several different microneedle arrays for their ability to penetrate ex vivo human skin by using trypan blue and (fluorescently or radioactively labeled) ovalbumin. Next, these different microneedles and several factors, including the dose of ovalbumin, the effect of using an impact-insertion applicator, skin location of microneedle application, and the area of microneedle application, were tested in vivo in mice. The penetration ability and the dose of ovalbumin that is delivered into the skin were shown to be dependent on the use of an applicator and on the microneedle geometry and size of the array. Besides microneedle penetration, the above described factors influenced the immune responses upon microneedle-based vaccination in vivo. It was shown that the ovalbumin-specific antibody responses upon microneedle-based vaccination could be increased up to 12-fold when an impact-insertion applicator was used, up to 8-fold when microneedles were applied over a larger surface area, and up to 36-fold dependent on the location of microneedle application. Therefore, these influencing factors should be considered to optimize microneedle-based dermal immunization technologies.


A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss.
Cannabinoid CB(2) agonists have been shown to alleviate behavioral signs of inflammatory and neuropathic pain in animal models. AM1241, a CB(2) agonist, does not demonstrate central nervous system side effects seen with CB(1) agonists such as hypothermia and catalepsy. Metastatic bone cancer causes severe pain in patients and is treated with analgesics such as opiates. Recent reports suggest that sustained opiates can produce paradoxical hyperalgesic actions and enhance bone destruction in a murine model of bone cancer. In contrast, CB(2) selective agonists have been shown to reduce bone loss associated with a model of osteoporosis. Here we tested whether a CB(2) agonist administered over a 7day period inhibits bone cancer-induced pain as well as attenuates cancer-induced bone degradation. A murine bone cancer model was used in which osteolytic sarcoma cells were injected into the intramedullary space of the distal end of the femur. Behavioral and radiographic image analysis was performed at days 7, 10 and 14 after injection of tumor cells into the femur. Osteolytic sarcoma within the femur produced spontaneous and touch evoked behavioral signs of pain within the tumor-bearing limb. The systemic administration of AM1241 acutely or for 7days significantly attenuated spontaneous and evoked pain in the inoculated limb. Sustained AM1241 significantly reduced bone loss and decreased the incidence of cancer-induced bone fractures. These findings suggest a novel therapy for cancer-induced bone pain, bone loss and bone fracture while lacking many unwanted side effects seen with current treatments for bone cancer pain.


The interplay of electrode- and bio-materials in a redox-cycling-based clozapine sensor.
We investigate gold, TiN, and platinum in combination with a chitosan-catechol-based redox-cycling system (RCS) for electrochemical detection of the antipsychotic clozapine. We have previously demonstrated the RCS for detection of clozapine in serum, but challenges remain regarding low signal-to-noise ratios. This can be mitigated by selection of electrode materials with beneficial surface morphologies and/or compositions. We employ cyclic voltammetry to assess the redox current generated by clozapine, and differentiate solely surface-area-based effects from clozapine-specific ones using a standard redox couple. We find that nano- and microstructured platinum greatly amplifies the clozapine signal compared to gold (up to 1490-fold for platinum black). However, the material performs poorly in the presence of chloride ions, and RCS modification provides no further amplification. The RCS combined with atomic-layer-deposited (ALD) TiN, on the other hand, increases the signal by 7.54 times, versus 2.86 times for RCS on gold, with a 9.2-fold lower variability, indicating that the homogenous and chemically inert properties of ALD-TiN may make it an ideal electrode material.


Inhibitory Effect on RT-PCR and Restriction Enzyme Activity by Ommochrome and Its Mechanism.
To explore the physiological role and/or pharmacological effects of ommochrome, which is a natural organic pigment widely distributed in Protostomia, we attempted to investigate the influence of ommochrome on RT-PCR and activities of restriction enzymes. It was found that ommin, an ommochrome purified from the diapause eggs of Bombyx mori, inhibited the RT-PCR and restriction enzyme activities. The mechanism of these inhibitory reactions is assumed to be the direct binding of ommochrome to DNA rather than acting against the enzymes because, similarly to actinomycin D, there is a phenoxazine ring in the structure of ommin that is known to be intercalated to DNA. To reveal the ommin/DNA interaction, it was investigated by computational approaches such as molecular docking, molecular dynamics simulation, and free energy calculation. From the computational analyses, it was expected that ommin would bind to DNA with almost the same strength as actinomycin D and intercalate into DNA. This is the first report on the pharmacological effect of ommochrome and its inhibitory mechanism obtained from biochemical and computational analyses.


Melatonin rhythms in renal transplant recipients with sleep-wake disturbances.
We assessed salivary melatonin levels in renal transplant (RTx) recipients who participated in a randomised, multicentre wait-list controlled trial on the effect of bright light therapy on their sleep and circadian rhythms. A large proportion of RTx recipients in our cohort had unexpectedly low melatonin values, which precluded calculation of the dim-light melatonin onset (DLMO) as a circadian marker. Thus, the aim of this post hoc analysis was to describe the melatonin profile of home-dwelling RTx recipients diagnosed with sleep-wake disturbances (SWDs). The participants were characterised by means of sleep questionnaires, validated psychometric instruments [Pittsburgh sleep quality Index (PSQI), Epworth sleepiness scale (ESS), Morningness-Eveningness Questionnaire (MEQ) and Depression, Anxiety and Stress Scale (DASS)] in addition to melatonin assay in saliva. Data were analysed with descriptive statistics and group comparisons made with appropriate post hoc tests. RTx recipients [n = 29 (aged 54.83 ± 13.73, transplanted 10.62 ± 6.84 years ago)] were retrospectively grouped into two groups: RTx recipients whose dim light melatonin onset (DLMO) could be calculated (n = 11) and those whose DLMO could not be calculated (n = 18). RTx recipients having a measurable DLMO had a number of differences from those without DLMO: they were younger [46.4 ± 14.9 compared to 60.0 ± 10.3 (p = .007)], had higher haemoglobin values [135.36 ± 12.01 versus 122.82 ± 11.56 (p = .01)], less anxiety [4 (0;8) versus 12 (6.5;14) (p = .021)] and a better overall sense of coherence [SOC Score: 71.09 ± 12.78 versus 56.28 ± 15.48 (p = 0.013)]. These results suggest that RTx recipients whose DLMO could be calculated have less health impairments, underlying the relevance of a stable circadian system.


Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery.
Selective serotonin reuptake inhibitors (SSRIs) might theoretically reduce post-stroke disability by direct effects on the brain. This Cochrane Review was first published in 2012 and last updated in 2019. To determine if SSRIs are more effective than placebo or usual care at improving outcomes in people less than 12 months post-stroke, and to determine whether treatment with SSRIs is associated with adverse effects. We searched the Cochrane Stroke Group Trials Register (last searched 7 January 2021), Cochrane Controlled Trials Register (CENTRAL, Issue 7 of 12, 7 January 2021), MEDLINE (1946 to 7 January 2021), Embase (1974 to 7 January 2021), CINAHL (1982 to 7 January 2021), PsycINFO (1985 to 7 January 2021), and AMED (1985 to 7 January 2021). PsycBITE had previously been searched (16 July 2018). We searched clinical trials registers. We included randomised controlled trials (RCTs) recruiting stroke survivors within the first year. The intervention was any SSRI, at any dose, for any period, and for any indication. The comparator was usual care or placebo. Studies reporting at least one of our primary (disability score or independence) or secondary outcomes (impairments, depression, anxiety, quality of life, fatigue, cognition, healthcare cost, death, adverse events and leaving the study early) were included in the meta-analysis. The primary analysis included studies at low risk of bias. We extracted data on demographics, stroke type and, our pre-specified outcomes, and bias sources. Two review authors independently extracted data. We used mean difference (MD) or standardised mean differences (SMDs) for continuous variables, and risk ratios (RRs) for dichotomous variables, with 95% confidence intervals (CIs). We assessed bias risks and applied GRADE criteria. We identified 76 eligible studies (13,029 participants); 75 provided data at end of treatment, and of these two provided data at follow-up. Thirty-eight required participants to have depression to enter. The duration, drug, and dose varied. Six studies were at low risk of bias across all domains; all six studies did not need participants to have depression to enter, and all used fluoxetine. Of these six studies, there was little to no difference in disability between groups SMD -0.0; 95% CI -0.05 to 0.05; 5 studies, 5436 participants, high-quality evidence) or in independence (RR 0.98; 95% CI 0.93 to 1.03; 5 studies, 5926 participants; high-quality evidence) at the end of treatment. In the studies at low risk of bias across all domains, SSRIs slightly reduced the average depression score (SMD 0.14 lower, 95% CI 0.19 lower to 0.08 lower; 4 studies; 5356 participants, high-quality evidence) and there was a slight reduction in the proportion with depression (RR 0.75, 95% CI 0.65 to 0.86; 3 studies, 5907 participants, high-quality evidence). Cognition was slightly better in the control group (MD -1.22, 95% CI -2.37 to -0.07; 4 studies, 5373 participants, moderate-quality evidence). Only one study (n = 30) reported neurological deficit score (SMD -0.39, 95% CI -1.12 to 0.33; low-quality evidence). SSRIs resulted in little to no difference in motor deficit (SMD 0.03, -0.02 to 0.08; 6 studies, 5518 participants, moderate-quality evidence). SSRIs slightly increased the proportion leaving the study early (RR 1.57, 95% CI 1.03 to 2.40; 6 studies, 6090 participants, high-quality evidence). SSRIs slightly increased the outcome of a seizure (RR 1.40, 95% CI 1.00 to 1.98; 6 studies, 6080 participants, moderate-quality evidence) and a bone fracture (RR 2.35, 95% CI 1.62 to 3.41; 6 studies, 6080 participants, high-quality evidence). One study at low risk of bias across all domains reported gastrointestinal side effects (RR 1.71, 95% CI 0.33, to 8.83; 1 study, 30 participants). There was no difference in the total number of deaths between SSRI and placebo (RR 1.01, 95% CI 0.82 to 1.24; 6 studies, 6090 participants, moderate quality evidence). SSRIs probably result in little to no difference in fatigue (MD -0.06; 95% CI -1.24 to 1.11; 4 studies, 5524 participants, moderate-quality of evidence), nor in quality of life (MD 0.00; 95% CI -0.02 to 0.02, 3 studies, 5482 participants, high-quality evidence). When all studies, irrespective of risk of bias, were included, SSRIs reduced disability scores but not the proportion independent. There was insufficient data to perform a meta-analysis of outcomes at end of follow-up. Several small ongoing studies are unlikely to alter conclusions. There is high-quality evidence that SSRIs do not make a difference to disability or independence after stroke compared to placebo or usual care, reduced the risk of future depression, increased bone fractures and probably increased seizure risk.


Autologous induction of the human T-cell-dependent monocyte procoagulant activity: a possible link between immunoregulatory phenomena and blood coagulation.
Activated monocytes acquire the ability to induce clot formation in platelet-poor citrated human plasma. The generation of this procoagulant activity (PCA) is dependent upon an interactive pathway between monocytes and T lymphocytes. Here we show that an ongoing autologous mixed lymphocyte reaction (AMLR) can elicit a T-cell-instructed PCA. PCA was measured by the ability of the cells to accelerate the clotting time of pooled citrated platelet-poor human plasma. AMLR was measured by tritiated thymidine incorporation. PCA and AMLR had very similar kinetics. Correlation coefficients between both reactions ranged from 0.59 to 0.99. Addition of an anti-DR monoclonal antibody blocked both reactions. T-Lymphocyte-depleted cell populations did not increase their level of PCA after 6 days in culture. Addition of autologous T cells to the T-depleted population restored its ability to produce PCA. Cyclosporin A blocked the peripheral blood mononuclear cell ability to generate PCA. A lymphokine generated during the AMLR was able to induce PCA in normal mononuclear cells. The results indicate that self recognition activates monocytes to produce PCA and suggests that this mechanism may represent a link between immunoregulatory phenomena and blood coagulation.


[Study on the anti-sepsis mechanism of ursolic acid by targeting myeloid differentiation protein-2].
To explore the mechanism of ursolic acid in treating sepsis using myeloid differentiation protein-2 (MD-2) as the research carrier. The affinity of ursolic acid and MD-2 was determined by biofilm interferometry technique, and the bonding mode between ursolic acid and MD-2 was tested with the aid of molecular docking technique. Raw 264.7 cells were cultured in RPMI 1640 medium and subcultured was conducted when the cell density reached 80%-90%. The second-generation cells were used for in the experiment. The effects of 8, 40 and 100 mg/L ursolic acid on cell viability were assessed by methyl thiazolyl tetrazolium (MTT) method. Cells were divided into blank group, lipopolysaccharide (LPS) group (LPS 100 μg/L) and ursolic acid group (100 μg/L LPS treatment after addition of 8, 40 or 100 mg/L ursolic acid). The effect of ursolic acid on the release of cytokines nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukins (IL-6, IL-1β) were evaluated by enzyme-linked immunosorbent assay (ELISA). The influence of ursolic acid on the mRNA expressions of TNF-α, IL-6, IL-1β, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were detected by reverse transcription-polymerase chain reaction (RT-PCR). The implication of ursolic acid on the protein expressions of LPS-Toll-like receptor 4 (TLR4)/MD-2-nuclear factor-κB (NF-κB) pathway were tested by Western blotting. Ursolic acid could bind to the hydrophobic cavity of MD-2 through hydrophobic bond with the amino acid residues of the protein. Therefore, ursolic acid showed high affinity with MD-2 [dissociation constant (KD) = 1.43×10-4]. The cell viability were decreased slightly, with the concentration of ursolic acid increasing, and the cell viability of 8, 40 and 100 mg/L ursolic acid were 96.01%, 94.32% and 92.12%, respectively, and there was no significant difference compared with the blank group (100%). Compared with the blank group, the cytokine level of the LPS group was significantly increased. The level of cytokines were significantly reduced by the treatment of 8, 40 and 100 mg/L ursolic acid, and the higher the concentration, the more obvious effect [compared between 100 mg/L ursolic acid group and LPS group: IL-1β (μmol/L): 38.018±0.675 vs. 111.324±1.262, IL-6 (μmol/L): 35.052±1.664 vs. 115.255±5.392, TNF-α (μmol/L): 39.078±2.741 vs. 119.035±4.269, NO (μmol/L): 40.885±2.372 vs. 123.405±1.291, all P < 0.01]. Compared with the blank group, the mRNA expressions of TNF-α, IL-6, IL-1β, iNOS and COX-2 in the LPS group were significantly increased, and the protein expressions of MD-2, myeloid differentiation factor 88 (MyD88), phosphorylation NF-κB p65 (p-NF-κB p65) and iNOS in the LPS-TLR4/MD-2-NF-κB pathway were significantly up-regulated. Compared with the LPS group, the mRNA expressions of TNF-α, IL-6, IL-1β, iNOS and COX-2 were significantly reduced by the treatment of 100 mg/L ursolic acid bound with MD-2 protein [TNF-α (2-ΔΔCt): 4.659±0.821 vs. 8.652±0.787, IL-6 (2-ΔΔCt): 4.296±0.802 vs. 11.132±1.615, IL-1β (2-ΔΔCt): 4.482±1.224 vs. 11.758±1.324, iNOS (2-ΔΔCt): 1.785±0.529 vs. 4.249±0.811, COX-2 (2-ΔΔCt): 5.591±1.586 vs. 16.953±1.651, all P < 0.01], and the proteins expressions of MD-2, MyD88, p-NF-κB p65 and iNOS in the LPS-TLR4/MD-2-NF-κB pathway were significantly down-regulated (MD-2/β-actin: 0.191±0.038 vs. 0.704±0.049, MyD88/β-actin: 0.470±0.042 vs. 0.875±0.058, p-NF-κB p65/β-actin: 0.178±0.012 vs. 0.571±0.012, iNOS/β-actin: 0.247±0.035 vs. 0.549±0.033, all P < 0.01). However, there was no difference in protein expression of NF-κB p65 among the three groups. Ursolic acid inhibits the release and expression of cytokines and mediators and regulates LPS-TLR4/MD-2-NF-κB signaling pathway by blocking MD-2 protein, and thus plays an anti-sepsis role.


Glycerol-plasticized agarose separator suppressing dendritic growth in Li metal battery.
The growth of dendrite is the major limitation to the development of the Li-metal battery. To solve it, we disclose the preparation and performances of separator (MAGly) with a complete "green" formulation using biosourced and sustainable compounds: agarose as biopolymer along with glycerol as plasticizing agent. The natural biopolymer films are non-porous in nature and possess high elasticity with high stiffness along a wide temperature range (-35 to 180 °C), able to prevent the perpendicular dendritic Li growth. Moreover, they provide high Li+ ionic conductivity, which was evident from electrochemical symmetrical battery tests resulted in efficient plating/stripping of Li metal, without dendrite formation. Preliminary tests in Li battery, with LiFePO4 as positive electrode show very satisfying performance regarding the same test with the commercial Celgard® separator. Furthermore, the application of this new sustainable separator can be extended to post Li-metal system as demonstrated by the electrochemical tests realized with K+/K.


Neighborhood disadvantage and adolescent behavior problems: how do inferences differ across definitions of disadvantage?
Various definitions of neighborhood disadvantage (ND) exist, yet evidence is lacking on how ND operationalization may impact scientific inference. We used data from wave 6 of the Fragile Families study, excluding those without census tract or behavior problem data (n = 2363). Outcomes included five scales from the caregiver-reported Child Behavior Checklist (CBCL) and a self-reported delinquency scale. ND was defined in four ways: (1) a modified Sampson definition which included four neighborhood poverty variables; (2) a poverty-only definition which only included percent households below poverty; (3) an overextended definition which added a mediator between the ND-behavior relationship, and (4) an expanded definition which added six additional ND variables to the modified Sampson definition. Using effect estimates from generalized linear models, differences were calculated using percent change-in-estimate, with the modified Sampson as the referent. Effect estimates were similar for the modified Sampson and expanded definitions (< 5% difference). The poverty-only definition differed from the modified Sampson unsystematically. Estimates for the overextended definition were consistently larger compared to modified Sampson (10-37% greater). The expanded and modified Sampson definitions produced similar results. Poverty-only and overextended ND definitions should be interpreted with caution.


Characterizing the behavior, uptake, and toxicity of NM300K silver nanoparticles in Caenorhabditis elegans.
Using Caenorhabditis elegans as a model organism, we addressed the potential linkage among toxicity of NM300K Ag nanoparticles (AgNPs), their particle size distribution, and the presence of dissolved Ag in the test media. Of the 3 endpoints assessed (growth, fertility, and reproduction), reproduction was the most sensitive, with the 50% effect concentration (EC50) ranging from 0.26 to 0.84 mg Ag L-1 and 0.08 to 0.11 mg Ag L-1 for NM300K and AgNO3 , respectively. Silver uptake by C. elegans was similar for both forms of Ag, whereas bioaccumulation was higher in AgNO3 exposure. The observed differences in toxicity between NM300K and AgNO3 did not correlate with bioaccumulated Ag, which suggests that toxicity is a function of the type of exposing agent (AgNPs vs AgNO3 ) and its mode of action. Before addition of the food source (Escherichia coli), size fractionation revealed that dissolved Ag comprised 13 to 90% and 4 to 8% of total Ag in the AgNO3 and NM300K treatments, respectively. No dissolved Ag was detectable in the actual test media due to immediate Ag adsorption to bacteria. The results of the present study indicate that information on behavior and characterization of exposure conditions is essential for nanotoxicity studies. Environ Toxicol Chem 2018;37:1799-1810. © 2018 SETAC.


Whole and fractionated yellow pea flours reduce fasting insulin and insulin resistance in hypercholesterolaemic and overweight human subjects.
The objective of the present study was to compare whole pea flour (WPF) to fractionated pea flour (FPF; hulls only) for their ability to reduce risk factors associated with CVD and diabetes in overweight hypercholesterolaemic individuals. Using a cross-over design, twenty-three hypercholesterolaemic overweight men and women received two-treatment muffins/d containing WPF, FPF or white wheat flour (WF) for 28 d, followed by 28 d washout periods. Daily doses of WPF and FPF complied with the United States Department of Agriculture's recommended level of intake of half a cup of pulses/d (approximately 50 g/d). Dietary energy requirements were calculated for each study subject, and volunteers were only permitted to eat food supplied by the study personnel. Fasting insulin, body composition, urinary enterolactone levels, postprandial glucose response, as well as fasting lipid and glucose concentrations, were assessed at the beginning and at the end of each treatment. Insulin concentrations for WPF (37·8 (SEM 3·4) pmol/ml, P = 0·021) and FPF (40·5 (SEM 3·4) pmol/ml, P = 0·037) were lower compared with WF (50·7 (SEM 3·4) pmol/ml). Insulin homeostasis modelling assessment showed that consumption of WPF and FPF decreased (P < 0·05) estimates of insulin resistance (IR) compared with WF. Android:gynoid fat ratios in women participants were lower (P = 0·027) in the WPF (1·01 (sem 0·01) group compared with the WF group (1·06 (SEM 0·01). Urinary enterolactone levels tended to be higher (P = 0·087) in WPF compared with WF. Neither treatment altered circulating fasting lipids or glucose concentrations. In conclusion, under a controlled diet paradigm, a daily consumption of whole and fractionated yellow pea flours at doses equivalent to half a cup of yellow peas/d reduced IR, while WPF reduced android adiposity in women.


Indium variations in a petrologic suite of L-group chondrites.
Indium concentrations have been determined by neutron activation in four members of each of the L3, L4, L5, and L6 chondritic meteorite classes. The range of concentrations is found to be from 0.14 to 22 parts per billion, with the highest values in L3 chondrites and the lowest values in the L5 and L6 classes. Plots of indium concentration versus relative mean deviation of pyroxene iron content, total carbon concentration, and primordial argon-36 concentration show positive correlations to varying degrees. Indium concentration appears to be a valuable parameter relating to variable formation conditions of the chondritic meteorites during the early history of the solar system.


Isolation and characterization of cbbL and cbbS genes encoding form I ribulose-1,5-bisphosphate carboxylase/oxygenase large and small subunits in Nitrosomonas sp. strain ENI-11.
The cbbL and cbbS genes encoding form I ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO) large and small subunits in the ammonia-oxidizing bacterium Nitrosomonas sp. strain ENI-11 were cloned and sequenced. The deduced gene products, CbbL and CbbS, had 93 and 87% identity with Thiobacillus intermedius CbbL and Nitrobacter winogradskyi CbbS, respectively. Expression of cbbL and cbbS in Escherichia coli led to the detection of RubisCO activity in the presence of 0.1 mM isopropyl-beta-D-thiogalactopyranoside (IPTG). To our knowledge, this is the first paper to report the genes involved in the carbon fixation reaction in chemolithotrophic ammonia-oxidizing bacteria.


The tomato as a functional food.
Tomatoes are the fourth most commonly consumed fresh vegetable and the most frequently consumed canned vegetable in the American diet. There is emerging epidemiology data supporting the connection between increased tomato consumption and reduced risk for both cardiovascular disease and prostate cancer. Here we will summarize the nutrient and the phytochemical content of tomatoes and tomato products, and how these bioactive components might act together to modulate disease development. Recent animal studies have investigated tomatoes, lycopene, and prostate cancer using the N-methyl-N-nitrosourea and Dunning rat models. These animal studies also suggest that diets containing tomatoes may decrease the risk or the progression of prostate cancer. Due to the frequency and the extent of tomato consumption, the supporting epidemiological and animal data, which connect increased intakes with decreased cancer and cardiovascular disease risk, tomato's role in the American diet is of undeniable importance as part of a healthy diet.


In vitro and in vivo evaluation of chemically modified degradable starch microspheres for topical haemostasis.
Degradable starch microspheres (DSMs) are starch chains cross-linked with epichlorhydrin, forming glycerol-ether links. DSMs have been used for many years for temporary vascular occlusion and drug delivery in treatment of malignancies. They are also approved and used for topical haemostasis by absorbing excess fluid from the blood and concentrating endogenous coagulation factors, thereby facilitating haemostasis. This mechanism of action is not sufficient for larger bleedings in current chemical formulations of DSMs, and modification of DSMs to trigger activation of platelets or coagulation would be required for use in such applications. Chemical modifications of DSMs with N-octenyl succinic anhydride, chloroacetic acid, acetic anhydride, diethylaminoethyl chloride and ellagic acid were performed and evaluated in vitro with thrombin generation and platelet adhesion tests, and in vivo using an experimental renal bleeding model in rat. DSMs modified to activate platelets in vitro were superior in haemostatic capacity in vivo. Further studies with non-toxic substances are warranted to confirm these results and develop the DSM as a more effective topical haemostatic agent.


Preoperative prognostic value of dynamic contrast-enhanced MRI-derived contrast transfer coefficient and plasma volume in patients with cerebral gliomas.
The prognostic value of dynamic contrast-enhanced MR imaging-derived plasma volume obtained in tumor and the contrast transfer coefficient has not been well-established in patients with gliomas. We determined whether plasma volume and contrast transfer coefficient in tumor correlated with survival in patients with gliomas in addition to other factors such as age, type of surgery, preoperative Karnofsky score, contrast enhancement, and histopathologic grade. This prospective study included 46 patients with a new pathologically confirmed diagnosis of glioma. The contrast transfer coefficient and plasma volume obtained in tumor maps were calculated directly from the signal-intensity curve without T1 measurements, and values were obtained from multiple small ROIs placed within tumors. Survival curve analysis was performed by dichotomizing patients into groups of high and low contrast transfer coefficient and plasma volume. Univariate analysis was performed by using dynamic contrast-enhanced parameters and clinical factors. Factors that were significant on univariate analysis were entered into multivariate analysis. For all patients with gliomas, survival was worse for groups of patients with high contrast transfer coefficient and plasma volume obtained in tumor (P < .05). In subgroups of high- and low-grade gliomas, survival was worse for groups of patients with high contrast transfer coefficient and plasma volume obtained in tumor (P < .05). Univariate analysis showed that factors associated with lower survival were age older than 50 years, low Karnofsky score, biopsy-only versus resection, marked contrast enhancement versus no/mild enhancement, high contrast transfer coefficient, and high plasma volume obtained in tumor (P < .05). In multivariate analysis, a low Karnofsky score, biopsy versus resection in combination with marked contrast enhancement, and a high contrast transfer coefficient were associated with lower survival rates (P < .05). In patients with glioma, those with a high contrast transfer coefficient have lower survival than those with low parameters.


Survey of instructions for authors on how to report an update of a systematic review: guidance is needed.
Systematic reviews have become the cornerstone of evidence-based healthcare. Approximately half of the systematic reviews are out of date after 5.5 years, and keeping them up to date remains a huge challenge. Despite new guidance on when and how to update systematic reviews, there seems to be a lack of guidance on how to report updates of systematic reviews. Therefore, we decided to systematically analyse instruction for authors in biomedical journals regarding guidance on reporting updates of systematic reviews. We conducted a survey investigating 250 journals. The journal list was derived by a twofold strategy. First, we chose a list of journals that were included in a recently published survey of systematic reviews. This list was augmented by a PubMed search for published updates of systematic reviews. For each journal, we checked the instructions for authors for any content or links related to updating systematic reviews in September 2016. Out of 250 journals, we found only one with guidance clearly related to updates of systematic reviews, namely the BioMed Central journal, Systematic Reviews Nevertheless, concrete guidance on reporting is lacking as it is stated that authors are encouraged to be innovative in how to report and present systematic review updates. This makes clear that there remains a fundamental uncertainty of how authors willing to update a previously published systematic review should act as even the leading journal in evidence syntheses does not have clear guidance. Debate is necessary on how to report updates of systematic reviews.


Non-operative Management of Acute Knee Injuries.
Acute knee injuries are commonly encountered in both the clinical and sideline setting and may be treated operatively or non-operatively. This article describes an evidence-based approach to non-operative acute knee injury. This includes history, physical exam, imaging, and initial management. In addition, the non-operative management of three such injuries-ligament injury, meniscus injury, and patellar dislocation injury-will be discussed via a case-based practical approach. Aside from grade III ACL tears, most acute knee ligament injuries, especially in the absence of other concurrent injuries, can be treated non-operatively. There is new evidence that acute traumatic meniscus tears in those younger than 40 can be successfully treated non-operatively and can do equally, as well as those that undergo surgery, at 1 year out from injury. Based on the current literature, a short period of knee bracing in extension with progression to weightbearing to tolerance is recommended after initial patellar dislocation. Many of the most common acute knee injuries, including MCL tears, meniscus tears, and patellar dislocations, can be managed non-operatively. A detailed systemic approach to initial evaluation, including pertinent history, physical exam, and appropriate imaging, is essential and complementary to the subsequent non-operative treatment algorithm.


Third chromosome candidate genes for conspecific sperm precedence between D. simulans and D. mauritiana.
Male - female incompatibilities can be critical in keeping species as separate and discrete units. Premating incompatibilities and postzygotic hybrid sterility/inviability have been widely studied as isolating barriers between species. In recent years, a number of studies have brought attention to postmating prezygotic barriers arising from male - male competition and male - female interactions. Yet little is known about the genetic basis of postmating prezygotic isolation barriers between species. Using D. simulans lines with mapped introgressions of D. mauritiana into their third chromosome, we find at least two D. mauritiana introgressions causing male breakdown in competitive paternity success. Eighty one genes within the mapped introgressed regions were identified as broad-sense candidates on the basis of male reproductive tract expression and male-related function. The list of candidates was narrowed down to five genes based on differences in male reproductive tract expression between D. simulans and D. mauritiana. Another ten genes were confirmed as candidates using evidence of adaptive gene coding sequence diversification in the D. simulans and/or D. mauritiana lineage. Our results show a complex genetic basis for conspecific sperm precedence, with evidence of gene interactions between at least two third chromosome loci. Pleiotropy is also evident from correlation between conspecific sperm precedence and female induced fecundity and the identification of candidate genes that might exert an effect through genetic conflict and immunity. We identified at least two loci responsible for conspecific sperm precedence. A third of candidate genes within these two loci are located in the 89B cytogenetic position, highlighting a possible major role for this chromosome position during the evolution of species specific adaptations to postmating prezygotic reproductive challenges.


Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome.
The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual disabilities. Here, we show that during mouse synaptogenesis and in human FXS fibroblasts, a dual dysregulation of APP and the α-secretase ADAM10 leads to the production of an excess of soluble APPα (sAPPα). In FXS, sAPPα signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPα levels, restoring translational control, synaptic morphology, and behavioral plasticity. Thus, proper control of ADAM10-mediated APP processing during a specific developmental postnatal stage is crucial for healthy spine formation and function(s). Downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating FXS phenotypes.


Subcellular compartmentation in control of converging pathways for proline and arginine metabolism in Saccharomyces cerevisiae.
Enzymes of proline biosynthesis and proline degradation which act on the same compound, delta 1-pyrroline-5-carboxylate, are physically separated in yeast cells. The enzyme responsible for the final step in proline biosynthesis, pyrroline-5-carboxylate reductase, converts pyrroline-5-carboxylate to proline and is located in the cytoplasm. The last enzyme in the proline degradative pathway, pyrroline-5-carboxylate dehydrogenase, converts pyrroline-5-carboxylate to glutamate and is found in the particulate fraction of the cell, presumably in the mitochondrion. By subcellular compartmentation, yeast cells avoid futile cycling between proline and pyrroline-5-carboxylate.


Chloroplast Phylogenomic Analyses Resolve Multiple Origins of the Kengyilia Species (Poaceae: Triticeae) via Independent Polyploidization Events.
Kengyilia is a group of allohexaploid species that arose from two hybridization events followed by genome doubling of three ancestral diploid species with different genomes St, Y, and P in the Triticeae. Estimating the phylogenetic relationship in resolution of the maternal lineages has been difficult, owing to the extremely low rate of sequence divergence. Here, phylogenetic reconstructions based on the plastome sequences were used to explore the role of maternal progenitors in the establishment of Kengyilia polyploid species. The plastome sequences of 11 Kengyilia species were analyzed together with 12 tetraploid species (PP, StP, and StY) and 33 diploid taxa representing 20 basic genomes in the Triticeae. Phylogenomic analysis and genetic divergence patterns suggested that (1) Kengyilia is closely related to Roegneria, Pseudoroegneria, Agropyron, Lophopyrum, Thinopyrum, and Dasypyrum; (2) both the StY genome Roegneria tetraploids and the PP genome Agropyron tetraploids served as the maternal donors during the speciation of Kengyilia species; (3) the different Kengyilia species derived their StY genome from different Roegneria species. Multiple origins of species via independent polyploidization events have occurred in the genus Kengyilia, resulting in a maternal haplotype polymorphism. This helps explain the rich diversity and wide adaptation of polyploid species in the genus Kengyilia.


Manual Compared With Electric Vacuum Aspiration for Treatment of Molar Pregnancy.
To evaluate uterine evacuation of patients with molar pregnancy, comparing manual with electric vacuum aspiration. This is a retrospective cohort study of patients with molar pregnancy followed at the Rio de Janeiro Trophoblastic Disease Center from January 2007 to December 2016. The individual primary study outcomes were incomplete uterine evacuation, uterine perforation, development of uterine synechia, and development of postmolar gestational trophoblastic neoplasia. Secondary endpoints were other features of the perioperative outcomes (operative time, rate of transfusion, hemoglobin change, length of stay) and the clinical course of neoplasia (Prognostic Risk Score, presence of metastases, time to remission, and need for multiagent chemotherapy). Among 1,727 patients with molar pregnancy, 1,206 underwent electric vacuum aspiration and 521 underwent manual vacuum aspiration. After human chorionic gonadotropin normalization, patients with benign molar pregnancy were followed for 6 months and patients treated for gestational trophoblastic neoplasia were followed for 12 months. Baseline risk factors for gestational trophoblastic neoplasia and demographic features were similar between the treatment groups. Uterine synechia developed less frequently after manual vacuum aspiration than after electric vacuum aspiration, 6 of 521 vs 63 of 1,206 (adjusted odds ratio [OR] 0.21, 95% CI 0.09-0.49), despite no differences in the occurrence of incomplete uterine evacuation, 65 of 521 vs 161 of 1,206 (adjusted OR 0.93, 95% CI 0.69-1.27), development of postmolar gestational trophoblastic neoplasia, 90 of 521 vs 171 of 1,206 (adjusted OR 1.26, 95% CI 0.96-1.67), or the need for multiagent chemotherapy, 22 of 521 vs 41 of 1,206 (adjusted OR 0.81, 95% CI 0.73-1.28). Manual vacuum aspiration appears to be similar to electric vacuum aspiration for treatment of molar pregnancy and may be associated with less development of uterine synechia.


Effects of Coffee Intake on Dyslipidemia Risk According to Genetic Variants in the ADORA Gene Family among Korean Adults.
Current evidence on the effects of coffee intake on cardiovascular diseases is not consistent, in part contributed by the genetic variability of the study subjects. While adenosine receptors (ADORAs) are involved in caffeine signaling, it remains unknown how genetic variations at the ADORA loci correlate the coffee intake with cardiovascular diseases. The present study examined the associations of coffee intake with dyslipidemia risk depending on genetic variants in the ADORA gene family. The study involved a population-based cohort of 4898 Korean subjects. Consumption of more than or equal to a cup of coffee per day was associated with lower dyslipidemia risk in females carrying the ADORA2B minor allele rs2779212 (OR: 0.645, 95% CI: 0.506-0.823), but not in those with the major allele. At the ADORA2A locus, male subjects with the minor allele of rs5760423 showed instead an increased risk of dyslipidemia when consuming more than or equal to a cup of coffee per day (OR: 1.352, 95% CI: 1.014-1.802). The effect of coffee intake on dyslipidemia risk differs depending on genetic variants at the ADORA loci in a sex-specific manner. Our study suggests that a dietary guideline for coffee intake in the prevention and management of dyslipidemia ought to consider ADORA-related biomarkers carefully.


Risk for ASD in Preterm Infants: A Three-Year Follow-Up Study.
The aim of this study was to examine the long-term risk for autism spectrum disorders (ASD) in individuals who are born preterm and full-term using both observational instruments and parental reports. Neonatal risk factors and developmental characteristics associated with ASD risk were also examined. Participants included 110 preterm children (born at a gestational age of ≤ 34 weeks) and 39 full-term children assessed at ages 18, 24, and 36 months. The Autism Diagnostic Observation Schedule, the Modified Checklist for Autism in Toddlers, the Autism Diagnostic Interview-Revised, the Social Communication Questionnaire, and the Mullen Scales of Early Learning were administered. The long-term risk for ASD was higher when parental reports were employed compared to observational instruments. At 18 and 24 months, a higher long-term risk for ASD was found for preterm children compared to full-term children. At 36 months, only one preterm child and one full-term child met the cutoff for ASD based on the ADOS, yet clinical judgment and parental reports supported an ASD diagnosis for the preterm child only. Earlier gestational age and lower general developmental abilities were associated with elevated ASD risk among preterm children.


Sialidases affect the host cell adherence and epsilon toxin-induced cytotoxicity of Clostridium perfringens type D strain CN3718.
Clostridium perfringens type B or D isolates, which cause enterotoxemias or enteritis in livestock, produce epsilon toxin (ETX). ETX is exceptionally potent, earning it a listing as a CDC class B select toxin. Most C. perfringens strains also express up to three different sialidases, although the possible contributions of those enzymes to type B or D pathogenesis remain unclear. Type D isolate CN3718 was found to carry two genes (nanI and nanJ) encoding secreted sialidases and one gene (nanH) encoding a cytoplasmic sialidase. Construction in CN3718 of single nanI, nanJ and nanH null mutants, as well as a nanI/nanJ double null mutant and a triple sialidase null mutant, identified NanI as the major secreted sialidase of this strain. Pretreating MDCK cells with NanI sialidase, or with culture supernatants of BMC206 (an isogenic CN3718 etx null mutant that still produces sialidases) enhanced the subsequent binding and cytotoxic effects of purified ETX. Complementation of BMC207 (an etx/nanH/nanI/nanJ null mutant) showed this effect is mainly attributable to NanI production. Contact between BMC206 and certain mammalian cells (e.g., enterocyte-like Caco-2 cells) resulted in more rapid sialidase production and this effect involved increased transcription of BMC206 nanI gene. BMC206 was shown to adhere to some (e.g. Caco-2 cells), but not all mammalian cells, and this effect was dependent upon sialidase, particularly NanI, expression. Finally, the sialidase activity of NanI (but not NanJ or NanH) could be enhanced by trypsin. Collectively these in vitro findings suggest that, during type D disease originating in the intestines, trypsin may activate NanI, which (in turn) could contribute to intestinal colonization by C. perfringens type D isolates and also increase ETX action.


Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-kappaB inhibitor, through downregulation of NFATc1.
(-)-DHMEQ, a newly designed NF-kappaB inhibitor, inhibited RANKL-induced osteoclast differentiation in mouse BMMs through downregulation of the induction of NFATc1, an essential transcription factor of osteoclastogenesis. Bone destruction is often observed in advanced case of rheumatoid arthritis and neoplastic diseases, including multiple myeloma. Effective and nontoxic chemotherapeutic agents are expected for the suppression of these bone destructions. RANKL induces activation of NF-kappaB and osteoclastogenesis in bone marrow-derived monocyte/macrophage precursor cells (BMMs). Targeted disruption or pharmacological suppression of NF-kappaB result in impaired osteoclastogenesis, but how NF-kappaB is involved in the regulation of osteoclastogenesis is not known. The effect of (-)-dehydroxymethylepoxyquinomicin [(-)-DHMEQ] on osteoclast differentiation was studied using a culture system of mouse BMMs stimulated with RANKL and macrophage colony-stimulating factor. The mechanism of the inhibition was studied by biochemical analysis such as immunoblotting and retroviral transfer experiments. (-)-DHMEQ strongly inhibited RANKL-induced NF-kappaB activation in BMMs and inhibited RANKL-induced formation of TRACP(+) multinucleated cells. Interestingly, (-)-DHMEQ specifically inhibited the RANKL-induced expression of NFATc1 but not the expressions of TRAF6 or c-fos. Inhibition of osteoclast differentiation by (-)-DHMEQ was rescued by overexpression of NFATc1, suggesting that the inhibition is not caused by a toxic effect. Moreover, pit formation assays showed that (-)-DHMEQ also inhibited the bone-resorbing activity of mature osteoclasts. The inhibition of NF-kappaB suppresses osteoclastogenesis by downregulation of NFATc1, suggesting that NFATc1 expression is regulated by NF-kappaB in RANKL-induced osteoclastogenesis. Our results also indicate the possibility of (-)-DHMEQ becoming a new therapeutic strategy against bone erosion.


Evaluation of three industrial Escherichia coli strains in fed-batch cultivations during high-level SOD protein production.
In the biopharmaceutical industry, Escherichia coli (E. coli) strains are among the most frequently used bacterial hosts for producing recombinant proteins because they allow a simple process set-up and they are Food and Drug Administration (FDA)-approved for human applications. Widespread use of E. coli in biotechnology has led to the development of many different strains, and selecting an ideal host to produce a specific protein of interest is an important step in developing a production process. E. coli B and K-12 strains are frequently employed in large-scale production processes, and therefore are of particular interest. We previously evaluated the individual cultivation characteristics of E. coli BL21 and the K-12 hosts RV308 and HMS174. To our knowledge, there has not yet been a detailed comparison of the individual performances of these production strains in terms of recombinant protein production and system stability. The present study directly compared the T7-based expression hosts E. coli BL21(DE3), RV308(DE3), and HMS174(DE3), focusing on evaluating the specific attributes of these strains in relation to high-level protein production of the model protein recombinant human superoxide dismutase (SOD). The experimental setup was an exponential carbon-limited fed-batch cultivation with minimal media and single-pulse induction. The host strain BL21(DE3) produced the highest amounts of specific protein, followed by HMS174(DE3) and RV308(DE3). The expression system HMS174(DE3) exhibited system stability by retaining the expression vector over the entire process time; however, it entirely stopped growing shortly after induction. In contrast, BL21(DE3) and RV308(DE3) encountered plasmid loss but maintained growth. RV308(DE3) exhibited the lowest ppGpp concentration, which is correlated with the metabolic stress level and lowest degradation of soluble protein fraction compared to both other strains. Overall, this study provides novel data regarding the individual strain properties and production capabilities, which will enable targeted strain selection for producing a specific protein of interest. This information can be used to accelerate future process design and implementation.


Multiscale topological properties of functional brain networks during motor imagery after stroke.
In recent years, network analyses have been used to evaluate brain reorganization following stroke. However, many studies have often focused on single topological scales, leading to an incomplete model of how focal brain lesions affect multiple network properties simultaneously and how changes on smaller scales influence those on larger scales. In an EEG-based experiment on the performance of hand motor imagery (MI) in 20 patients with unilateral stroke, we observed that the anatomic lesion affects the functional brain network on multiple levels. In the beta (13-30 Hz) frequency band, the MI of the affected hand (Ahand) elicited a significantly lower smallworldness and local efficiency (Eloc) versus the unaffected hand (Uhand). Notably, the abnormal reduction in Eloc significantly depended on the increase in interhemispheric connectivity, which was in turn determined primarily by the rise of regional connectivity in the parieto-occipital sites of the affected hemisphere. Further, in contrast to the Uhand MI, in which significantly high connectivity was observed for the contralateral sensorimotor regions of the unaffected hemisphere, the regions with increased connectivity during the Ahand MI lay in the frontal and parietal regions of the contralaterally affected hemisphere. Finally, the overall sensorimotor function of our patients, as measured by Fugl-Meyer Assessment (FMA) index, was significantly predicted by the connectivity of their affected hemisphere. These results improve on our understanding of stroke-induced alterations in functional brain networks.


Evaluation of MLC leaf positioning accuracy for static and dynamic IMRT treatments using DAVID in vivo dosimetric system.
Accuracy and precision of leaf positioning in multileaf collimators (MLCs) are significant factors for the accuracy of IMRT treatments. This study aimed to inves-tigate the accuracy and repeatability of the MLC leaf positioning via the DAVID invivo dosimetric system for dynamic and static MLC systems. The DAVID system was designed as multiwire transmission ionization chamber which is placed in accessory holder of linear accelerators. Each wire of DAVID system corresponds to a MLC leaf-pair to verify the leaf positioning accuracy during IMRT treatment and QA. In this study, verifications of IMRT plans of five head and neck (H&N) and five prostate patients treated in a Varian DHX linear accelerator with 80-leaf MLC were performed using DAVID system. Before DAVID-based dosimetry, Electronics Portal Imaging Device (EPID) and PTW 2D ARRAY dosimetry system were used for 2D verification of each plan. The measurements taken by DAVID system in the first day of the treatments were used as reference for the following measurements taken over the next four weeks. The deviations in leaf positioning were evaluated by "Total Deviation (TD)" parameter calculated by DAVID software. The delivered IMRT plans were originally prepared using dynamic MLC method. The same plans were subsequently calculated based on static MLC method with three different intensity levels of five (IL5), 10 (IL10) and 20 (IL20) in order to compare the performances of MLC leaf positioning repeatability for dynamic and static IMRT plans. The leaf positioning accuracy is also evaluated by analyzing DynaLog files based on error histograms and root mean square (RMS) errors of leaf pairs' positions. Moreover, a correlation analysis between simultaneously taken DAVID and EPID measurements and DynaLog file recordings was subsequently performed. In the analysis of DAVID outputs, the overall deviations of dynamic MLC-based IMRT calculated from the deviations of the four weeks were found as 0.55% ± 0.57% and 1.48% ± 0.57% for prostate and H&N patients, respectively. The prostate IMRT plans based on static MLC method had the overall deviations of 1.23% ± 0.69%, 3.07% ± 1.07%, and 3.13% ± 1.29% for intensity levels of IL5, IL10, and IL20, respectively. Moreover, the overall deviations for H&N patients were found as 1.87% ± 0.86%, 3.11% ± 1.24%, and 2.78% ± 1.31% for the static MLC-based IMRT plans with intensity levels of IL5, IL10 and IL20, respectively. Similar with the DAVID results, the error rates in DynaLog files showed upward movement comparing the dynamic IMRT with static IMRT with high intensity levels. In respect to positioning errors higher than 0.005 cm, static prostate IMRT plans with intensity levels of IL10 and IL20 had 1.5 and 2.6 times higher error ratios than dynamic prostate IMRT plans, respectively, while these values stepped up to 8.4 and 12.0 for H&N cases. On the other hand, according to the leaf pair readings, reconstructed dose values from DynaLog files had significant correlation (r = 0.80) with DAVID and EPID readings while a stronger relationship (r = 0.98) was found between the two dosimetric systems. The correlation coefficients for deviations from reference plan readings were found in the interval of -0.21-0.16 for all three systems. The dynamic MLC method showed higher performance in repeatability of leaf positioning than static MLC methods with higher intensity levels even though the deviations in the MLC leaf positioning were found to be under the acceptance threshold for all MLC methods. The high intensity levels increased the position-ing deviations along with the delivery complexity of the static MLC-based IMRT plans. Moreover, DAVID and EPID readings and DynaLog recordings showed mutually strong correlation, while no significant relationship was found between deviations from reference values.


[Dual effects of glucocorticoids on the gastric mucosa].
In this review we systematise and analyze data of literature about the effect of glucocorticoids on the gastric mucosa. There are convincing results that show the adaptive gastoprotective nature of endogenous glucocorticoids, which are produced during acute stress-induced activation of the HPA axis. The role glucocorticoid hormones play in the effect of chronic stress remains little-studied. We have seen that after single administration of glucocorticoids, there can arise gastroprotective and ulcerogenic effects. Although. the question about the effect of therapy using glucocorticoid hormones on gastric ulceration is being debated, the data confirm the ulcerogenic influence that large doses of these hormones have on experimental animals. The initial gastroprotective effect that glucocorticoid hormones have, even after their single administration can be transformed into an ulcerogenic effect with a prolongation of the hormonal action, but not of the hormone dose. We are discussing the possible mechanism behind the transformation.


Cognitive ability is associated with suspected reporting errors on food frequency questionnaires.
To examine potential for bias in reported total energy intake on a Food Frequency Questionnaire (FFQ) among older adults. Longitudinal cohort study. 2,706 Community-dwelling Black and White older adults, aged 70-79 years, enrolled in the Health, Aging, and Body Composition study. Multivariate logistic regression analyses were conducted with potential errors on reported total energy intake on the Food Frequency Questionnaire (FFQ) as the outcome variable and with cognitive ability, measured by the Modified Mini Mental State Exam (3MS) as the primary independent variable. The regression model controlled for site, race, gender, age, body size, and physical activity. Separate models were fit using 3MS as a continuous variable and for multiple 3MS cutpoints. All models revealed similar findings. Cognitive ability was inversely associated with potential errors in reporting total energy intake, whereby a five-point increase in 3MS scores was associated with a 14% decreased likelihood of reporting errors (Odds Ratio=0.86, 95% Confidence Interval: 0.77, 0.95). Additionally, compared to White women, White men were 2 times more likely, and Black women and Black men were 3 times more likely, to have errors in reporting total energy intake. This study provides evidence that for older adults, lower cognition scores are associated with increased potential errors in reporting total energy intake. Dietary reporting from older adults may be inaccurate due to cognitive deficits. A brief assessment of cognitive function may assist clinicians in dietary evaluations and recommendation and may benefit studies using FFQ data where the measure of cognitive function could be utilized to stratify data analyses and conduct sensitivity analyses.


Nurses' perception of the value of clinical supervision.
Literature on clinical supervision includes few references to the experiences of those being supervised. In this qualitative study two groups of intensive care nurses were surveyed for their views on clinical supervision: 10 NICU staff who had experience of one-to-one supervision and 15 PICU staff without that experience. In addition, six NICU nurses were interviewed to elicit their understanding and perceptions of aspects of the process. A range of themes and categories emerged which identified issues for practice and management, including the value of supervision, its effect on care and requirements for its successful implementation.


Fecal multi-omics analysis reveals diverse molecular alterations of gut ecosystem in COVID-19 patients.
Gut ecosystem has profound effects on host physiology and health. Gastrointestinal (GI) symptoms were frequently observed in patients with COVID-19. Compared with other organs, gut antiviral response can result in more complicated immune responses because of the interactions between the gut microbiota and host immunity. However, there are still large knowledge gaps in the impact of COVID-19 on gut molecular profiles and commensal microbiome, hindering our comprehensive understanding of the pathogenesis of SARS-CoV-2 and the treatment of COVID-19. We performed longitudinal stool multi-omics profiling to systemically investigate the molecular phenomics alterations of gut ecosystem in COVID-19. Gut proteomes of COVID-19 were characterized by disturbed immune, proteolysis and redox homeostasis. The expression and glycosylation of proteins involved in neutrophil degranulation and migration were suppressed, while those of proteases were upregulated. The variable domains of Ig heavy chains were downregulated and the overall glycosylation of IgA heavy chain constant regions, IgGFc-binding protein, and J chain were suppressed with glycan-specific variations. There was a reduction of beneficial gut bacteria and an enrichment of bacteria derived deleterious metabolites potentially associated with multiple types of diseases (such as ethyl glucuronide). The reduction of Ig heave chain variable domains may contribute to the increase of some Bacteroidetes species. Many bacteria ceramide lipids with a C17-sphingoid based were downregulated in COVID-19. In many cases, the gut phenome did not restore two months after symptom onset. Our study indicates widely disturbed gut molecular profiles which may play a role in the development of symptoms in COVID-19. Our findings also emphasis the need for ongoing investigation of the long-term gut molecular and microbial alterations during COVID-19 recovery process. Considering the gut ecosystem as a potential target could offer a valuable approach in managing the disease.