Human endometrial cell coculture reduces the endocrine disruptor toxicity on mouse embryo development.
Previous studies suggested that endocrine disruptors (ED) are toxic on preimplantation embryos and inhibit development of embryos in vitro culture. However, information about the toxicity of endocrine disruptors on preimplantation development of embryo in human reproductive environment is lacking. Bisphenol A (BPA) and Aroclor 1254 (polychlorinated biphenyls) were used as endocrine disruptors in this study. Mouse 2-cell embryos were cultured in medium alone or vehicle or co-cultured with human endometrial epithelial layers in increasing ED concentrations. At 72 hours the percentage of normal blastocyst were decreased by ED in a dose-dependent manner while the co-culture system significantly enhanced the rate and reduced the toxicity of endocrine disruptors on the embryonic development in vitro. In conclusion, although EDs have the toxic effect on embryo development, the co-culture with human endometrial cell reduced the preimplantation embryo from it thereby making human reproductive environment protective to preimplantation embryo from the toxicity of endocrine disruptors.


Enolase-specific cross antibodies induce neutrophilic inflammation in the intestine.
The pathogenesis of ulcerative colitis (UC) is to be further investigated. House dust mites (HDM) are highly associated with the pathogenesis of immune inflammation in the body. This study aims to investigate the role of enolase (one of the HDM-derived proteins)-specific cross Abs in the induction of UC-like inflammation. The enolase specific IgG (EsIgG) was identified in UC patients by mass spectrometry. Mice were treated with EsIgG to induce inflammation in the colon mucosa. EsIgG was detected in the serum and the colon tissues of UC patients, which was positively correlated with the polymorphonuclear neutrophil (PMN) counts in the blood and colon tissues of UC patients. EsIgG formed immune complexes with the constitutive enolase in the UC colon epithelium that activated complement, induced epithelial cell apoptosis, compromised epithelial barrier functions, and resulted in UC-like inflammation in the mouse colon. In summary, UC patients have high serum levels of Abs against HDM-derived enolase and intestinal epithelial cell-derived enolase. These Abs attack the colonic epithelium to induce UC-like inflammation.


Preliminary X-ray fiber diffraction studies of cucumber green mottle mosaic virus, watermelon strain.
Fiber diffraction patterns have been obtained for cucumber green mottle mosaic virus, watermelon strain (a distant relative of tobacco mosaic virus), and two heavy-atom derivatives. These patterns and the similarity between the cucumber and the tobacco virus offer the potential of a full structure determination of the cucumber virus.


Regulation of the neuron-specific exon of clathrin light chain B.
Clathrin light chain B (LCB) is a major component of clathrin coated vesicles, which are structures involved in intracellular transport. A neuron-specific isoform of LCB is generated by incorporation of a single exon (EN) using an alternative splicing mechanism that reflects the special demands of neurons, such as axonal transport and synaptic neurotransmission. Here, we demonstrate that this neuron-specific exon is developmentally regulated and is excluded in non-neuronal cells because its 5' and 3' splice sites deviate from the mammalian consensus sequences. A gel retardation assay indicated the presence of a developmentally regulated factor in brain that binds to the neuronal exon. In addition, EN usage is repressed by increasing the concentration of htra2-beta1, a splice factor whose isoform expression is influenced by neuronal activity. We propose that a brain-specific factor is involved in EN recognition during development and adulthood. In addition, ubiquitously expressed splicing factors such as htra2-beta1 are involved in regulating EN expression in the adult brain.


The lipoxygenase pathway in zebrafish. Expression and characterization of zebrafish ALOX5 and comparison with its human ortholog.
The zebrafish (Danio rerio) is frequently employed as model organism to explore vertebrate embryogenesis but little is known about the lipoxygenase pathway in this lower vertebrate. When we searched the zebrafish genome for lipoxygenase genes we detected seven different genes localized on four different chromosomes. Four of these genes (ALOX2, ALOX3a, ALOX3b, ALOX3c) share a high degree of sequence conservation with the human ALOX5 gene, which encodes for the key enzyme of mammalian leukotriene biosynthesis. Expression profiles of the corresponding transcripts indicated that the ALOX2 gene is high level expressed during zebrafish embryogenesis whereas transcripts originating from the other three paralog genes could not be detected. To functionally compare human ALOX5 with the putative zebrafish ortholog (zebrafish ALOX2) we cloned and expressed the zebrafish enzyme in pro- and eukaryotic expression systems and characterized it as arachidonic acid 5S-lipoxygenating enzyme, which also exhibits leukotriene synthase activity. Mutagenesis studies of the triad determinants (Phe359Trp, Ala424Ile, Asn425Met) altered the reaction specificity from 5S- to dominant 15S-lipoxygenation. The finding that zebrafish expresses a functional ALOX5 together with the observation that most other human leukotriene relevant genes have an ortholog in the zebrafish genome suggests the biological relevance of leukotriene signaling in lower vertebrates.


Development and use of alefacept to treat psoriasis.
Activated memory T cells, expressing CD2, are key components in the pathogenesis of psoriasis. Alefacept binds to CD2, blocks co-stimulatory signaling, and selectively induces apoptosis of pathogenic T cells. Our objective is to present safety and efficacy results which lead to the new drug application (NDA) of alefacept for the treatment of psoriasis. We reviewed the key phase II and III trials in over 1300 patients and found that during treatment and follow-up of patients receiving 12 weekly intramuscular or intravenous injections of alefacept, about 1/3 will achieve a reduction in psoriasis area and severity index (PASI) of > or =75% and nearly 2/3 a reduction in PASI of > or =50%. Patients who achieved a > or =75% reduction from baseline PASI during or after a single course maintained a > or =50% reduction in PASI for a median duration of >7 months. Among patients who received 2 courses of alefacept, 40% and 71% of patients achieved a > or =75% and > or =50% reduction in PASI, respectively and duration of effect was prolonged. Adverse events in the placebo and active treatment arms did not differ. We conclude that alefacept significantly improves psoriasis and produces durable clinical improvement with a very favorable safety profile.


Vertigo. Current concepts in management.
Vertigo is not a disease, but a symptom. The management of vertigo requires more than the treatment of the symptom alone, as it concerns the whole physical and psychological condition of the patient. In addition to causal treatment, symptomatic treatment is needed in many cases. This specific treatment consists of vestibular exercises and drug therapy. The efficacy and use of the different drugs available are discussed.


Best Practices in the Implementation of a Point of Care Testing Program: Experience From a Tertiary Care Hospital in a Developing Country.
Implementation of a structured Point of Care Test (POCT) program is challenging. Traditionally POCT was unregulated and the aim was to introduce a structured POCT program at our tertiary care hospital to ensure compliance with regulatory standards. The purpose of this article is to describe how a hospital in a developing country with limited resources has approached POCT program initiative. The benefits offered by such systems, including cost-effectiveness, robustness and the ability to generate reliable accurate POCT results in a short time, are appropriate to the clinical and social needs of the developing world.


Identification of new antimalarial leads by use of virtual screening against cytochrome bc₁.
Cytochrome bc(1) is a validated drug target in malaria parasites. The spread of Plasmodium falciparum strains resistant to multiple antimalarials emphasizes the urgent need for new drugs. We screened in silico the ZINC and MOE databases, using ligand- and structure-based approaches, to identify new leads for development. The most active compound presented an IC(50) value against cultured P. falciparum of 2 μM and a docking pose consistent with its activity.


Developmental programming in skeletal muscle in response to overnourishment in the immediate postnatal life in rats.
Overnourishment during the suckling period [small litter (SL)] results in the development of adult-onset obesity. To investigate the mechanisms that underlie the development of insulin resistance in the skeletal muscle of young and adult female SL rats, the litter size was reduced to 3 female pups/dam (SL) while the control litter had 12 pups/dam from the postnatal Day 3 until Day 21. Protein content, mRNA expression and methylation status of the promoter region of key components in the insulin signaling pathway were determined in the skeletal muscle of SL rats. Overnutrition during the suckling period resulted in increased body weight gains, hyperphagia and adult-onset obesity as well as increased levels of serum insulin, glucose and leptin in SL rats. No differences in the expression of total protein as well as tyrosine phosphorylation of insulin receptor β and glucose transporter 4 (Glut4) were observed in skeletal muscle between two groups at both ages. A significant decrease of total insulin receptor substrate 1 (IRS-1) and an increase in serine phosphorylation of IRS-1 were observed in skeletal muscle from adult SL rats. Hypermethylation of specific cytidyl-3',5'phospho-guanylyl (CpG) dinucleotides in the proximal promoter region was observed for the Irs1 and Glut4 genes, which correlated with the reduction in Irs1 and Glut4 mRNA levels in skeletal muscle of adult SL rats. Our results suggest that epigenetic modifications of the key genes involved in the insulin signaling pathway in skeletal muscle could result in the development of insulin resistance in SL female rats.


Ultrastructure of the Bunina bodies in anterior horn cells of amyotrophic lateral sclerosis.
Light and electron microscopic studies were made on the anterior horn cells in a case o amyotrophic lateral sclerosis. Eosinophilic inclusions of Bunina type were observed almost selectively in the motor neurons of spinal cord, as well as of brain stem, at the light microscopic level. Fine structural study revealed the presence of two types of cytoplasmic inclusions. The first, mainly corresponding to the light microscopic inclusions, were homogeneous, electron-dense, round- or oval-shaped bodies with vesicular or tubular rims and ribosome particles, about 2-5 mu in diameter, which contained filaments or other cytoplasmic componenets in the clear areas within them. The second were lamellar structures (laminated cytoplasmic bodies, Morales) which appeared to be originating from endoplasmic reticulum. There was no distinct transition in these two types of inclusions and the relationship to each other is not clear. The significance of Bunina body is unknown, but some manifestation of a primary disorder, e.g., protein metabolism, rather than a secondary degenerative change in the motor neurons in amyotorophic lateral sclerosis.


Activation of soluble guanylate cyclase causes relaxation of corpus cavernosum tissue: synergism of nitric oxide and YC-1.
Nitric oxide (NO) activates corpus cavernosum smooth muscle soluble guanylate cyclase (sGC) and increases the synthesis of cGMP that results in smooth muscle relaxation and ultimately, penile erection. To characterize sGC and define the potential synergy between NO and the allosteric activator YC-1 in corpus cavernosum, rat sGC was activated by either sodium nitroprusside (SNP) or YC-1, and YC-1 potentiated the effects of SNP with a 200-fold activation of sGC. Both SNP and YC-1 decreased the Km and increased the Vmax. ODQ significantly inhibited sGC activated by SNP with IC50 of 0.5 nM, but did not affect the sGC activated by YC-1 as well as basal sGC activity. SNP and YC-1 synergistically increased intracellular cGMP levels in rabbit corpus cavernosum smooth muscle cell cultures. YC-1 significantly relaxed rabbit cavernosum tissue strips in organ baths with an EC50 of 8.4 microM. In the presence of L-nitroarginine methyl ester to block endogenous NO production, co-administration of SNP shifted the dose response of YC-1 to the left, showing the synergism of SNP and YC-1 in tissue strips. In view of the clinical efficacy of phosphodiesterase-5 inhibitors, activation of sGC may provide an alternative means for enhancing the activity of neurally derived NO during sexual stimulation in the corpus cavernosum, representing a novel approach for the treatment of erectile dysfunction.


Effects of graded reductions in internal mammary artery bypass flow on left ventricular function.
This study investigated the controversial relationship between reduction in internal mammary artery (IMA) graft blood flow and left ventricular function in a canine model. Ten dogs underwent IMA grafting to the left anterior descending coronary artery. The left anterior descending coronary artery proximal to the IMA graft was intermittently occluded while IMA flow was mechanically controlled for 5-minute periods to produce four IMA flow groups representing 100%, 75%, 50%, and 25% of unoccluded IMA graft blood flow. As a control, the left ventricle was reperfused with native left anterior descending coronary artery flow between each IMA graft flow period to allow return to steady state. Sonomicrometry was used to obtain stroke work end-diastolic dimension relationship data for regional and global left ventricular function for each of the four flow groups. The global pressure recruitable work area relationship showed a significant rightward shift at 25% of unoccluded IMA flow, whereas the regional pressure recruitable work area relationship shifted at 50% of unoccluded IMA flow. Thus, regional myocardial function is more sensitive to reductions in IMA blood flow than is global left ventricular performance, and there is a significant IMA flow reserve for global left ventricular function.


Rapid point-of-care NT-proBNP optimal cut-off point for heart failure diagnosis in primary care.
Measurement of natriuretic peptides may be recommended prior to echocardiography in patients with suspected heart failure. Cut-off point for heart failure diagnosis in primary care is not well established. We aimed to assess the optimal diagnostic cut-off value of N-terminal pro-B-type natriuretic peptide on a community population attended in primary care. Prospective diagnostic accuracy study of a rapid point-of-care N-terminal pro-B-type natriuretic peptide test in a primary healthcare centre. Consecutive patients referred by their general practitioners to echocardiography due to suspected heart failure were included. Clinical history and physical examination based on Framingham criteria, electrocardiogram, chest X-ray, N-terminal pro-B-type natriuretic peptide measurement and echocardiogram were performed. Heart failure diagnosis was made by a cardiologist blinded to N-terminal pro-B-type natriuretic peptide value, using the European Society of Cardiology diagnosis criteria (clinical and echocardiographic data). Of 220 patients evaluated (65.5% women; median 74 years [interquartile range 67-81]). Heart failure diagnosis was confirmed in 52 patients (23.6%), 16 (30.8%) with left ventricular ejection fraction <50% (39.6 [5.1]%). Median values of N-terminal pro-B-type natriuretic peptide were 715 pg/mL [interquartile range 510.5-1575] and 77.5 pg/mL [interquartile range 58-179.75] for patients with and without heart failure respectively. The best cut-off point was 280 pg/mL, with a receiver operating characteristic curve of 0.94 (95% confidence interval, 0.91-0.97). Six patients with heart failure diagnosis (11.5%) had N-terminal pro-B-type natriuretic peptide values <400 pg/mL. Measurement of natriuretic peptides would avoid 67% of requested echocardiograms. In a community population attended in primary care, the best cut-off point of N-terminal pro-B-type natriuretic peptide to rule out heart failure was 280 pg/mL. N-terminal pro-B-type natriuretic peptide measurement improve work-out diagnoses and could be cost-effectiveness.


The cyclical nature of depressed mood and future risk: Depression, rumination, and deficits in emotional clarity in adolescent girls.
Deficits in emotional clarity, the understanding and awareness of one's own emotions and the ability to label them appropriately, are associated with increased depressive symptoms. Surprisingly, few studies have examined factors associated with reduction in emotional clarity for adolescents, such as depressed mood and ruminative response styles. The present study examined rumination as a potential mediator of the relationship between depressive symptoms and changes in emotional clarity, focusing on sex differences. Participants included 223 adolescents (51.60% female, Mean age = 12.39). Controlling for baseline levels of emotional clarity, initial depressive symptoms predicted decreases in emotional clarity. Further, rumination prospectively mediated the relationship between baseline depressive symptoms and follow-up emotional clarity for girls, but not boys. Findings suggest that depressive symptoms may increase girls' tendencies to engage in repetitive, negative thinking, which may reduce the ability to understand and label emotions, a potentially cyclical process that confers vulnerability to future depression.


Morning vs afternoon sun patches in experimental forest gaps: consequences of temporal incongruency of resources to birch regeneration.
We investigated whether the timing of high light availability as sun patches within forest gaps, independent of total or peak photosynthetic photon flux (PPF), influences the physiology and growth of four coexisting birch species (Betula alleghaniensis, B. lenta, B. papyrifera, and B. populifolia). Birch seedlings were grown for two years along either the east or west sides of experimental gap structures and at two moisture levels. Seedlings positioned in the west received sun patches earlier in the day than those in the east, and environmental conditions for carbon gain were generally more favorable during the earlier sunpatches in the west; air and leaf temperatures were lower, and relative humidity higher, relative to conditions during sun patches in the cats, simulating patterns observed in natural forest gaps. Seedlings positioned along the west edges of gaps fixed more carbon earlier in the day than those in the east, and in many cases, peak net photosynthetic rates were greater for west positioned seedlings. In year two, leaf-level integrated daily carbon gain was greater for west- than eastpositioned plants, and for the most pioneer species, B. populifolia, differences between west and east seedlings were greatest at lower soil moisture levels. Despite some small effects on leaf gas exchange, the timing of high light availability, and its temporal congruence with other factors critical to carbon gain, had no significant effects on first or second year seedling biomass. The responses of birch seedlings to controlled variations in the timing of high light availability were generally much smaller than birch seedling responses to variations in other components of daily light regimes such as total integrated and peak PPF.


Persistent pharyngeal pouch derivatives in the neonate.
Internal branchial sinuses are rare compared to other branchial anomalies. A case is described in which such a sinus presented as an air-containing inflammatory lateral neck mass in a neonate and evidence is presented to support the theory that this originated from the fourth pharyngeal pouch. Review of six similar cases from the literature shows this to be a well-defined clinical entity.


Orthotopic liver transplantation for massive hepatic lymphangiomatosis.
Lymphangiomatosis is a rare malformation of the lymphatic system that causes severe symptoms secondary to progressive growth into or close to vital structures. A case report of liver failure related to this space-occupying intrahepatic mechanism is taken as a starting point for a discussion of the problems of liver transplantation related to large hepatomegalies.


Cognitive and motor outcomes of cocaine-exposed infants.
Maternal use of cocaine during pregnancy remains a significant public health problem, particularly in urban areas of the United States and among women of low socioeconomic status. Few longitudinal studies have examined cocaine-exposed infants, however, and findings are contradictory because of methodologic limitations. To assess the effects of prenatal cocaine exposure on child developmental outcomes. Longitudinal, prospective, masked, comparison birth cohort study with recruitment in 1994-1996. Obstetric unit of a large US urban teaching hospital. Four hundred fifteen consecutively enrolled infants (218 cocaine-exposed and 197 unexposed) identified from a high-risk, low-socioeconomic status, primarily black (80%) population screened through clinical interview and urine and meconium samples for drug use. The retention rate was 94% at 2 years of age. The Bayley Mental and Motor Scales of Infant Development, assessed at 6.5, 12, and 24 months of corrected age. Controlled for confounding variables, cocaine exposure had significant effects on cognitive development, accounting for a 6-point deficit in Bayley Mental and Motor Scales of Infant Development scores at 2 years, with cocaine-exposed children twice as likely to have significant delay (mental development index <80) (odds ratio, 1.98; 95% confidence interval, 1.21-3.24; P =.006). For motor outcomes, there were no significant cocaine effects. Cocaine-exposed children had significant cognitive deficits and a doubling of the rate of developmental delay during the first 2 years of life. Because 2-year outcomes are predictive of later cognitive outcomes, it is possible that these children will continue to have learning difficulties at school age.


Corrigendum: Antibiotic Resistance in Salmonella Typhimurium Isolates Recovered From the Food Chain Through National Antimicrobial Resistance Monitoring System Between 1996 and 2016.
[This corrects the article DOI: 10.3389/fmicb.2019.00985.].


A whole transcriptome profiling analysis for antidepressant mechanism of Xiaoyaosan mediated synapse loss via BDNF/trkB/PI3K signal axis in CUMS rats.
Depression is a neuropsychiatric disease resulting from deteriorations of molecular networks and synaptic injury induced by stress. Traditional Chinese formula Xiaoyaosan (XYS) exert antidepressant effect, which was demonstrated by a great many of clinical and basic investigation. However, the exact mechanism of XYS has not yet been fully elucidated. In this study, chronic unpredictable mild stress (CUMS) rats were used as a model of depression. Behavioral test and HE staining were used to detect the anti-depressant effects of XYS. Furthermore, whole transcriptome sequencing was employed to establish the microRNA (miRNA), long non-coding RNA (lncRNA), circular RNA (circRNA), and mRNA profiles. The biological functions and potential mechanisms of XYS for depression were gathered from the GO and KEGG pathway. Then, constructed the competing endogenous RNA (ceRNA) networks to illustrate the regulatory relationship between non-coding RNA (ncRNA) and mRNA. Additionally, longest dendrite length, total length of dendrites, number of intersections, and density of dendritic spines were detected by Golgi staining. MAP2, PSD-95, SYN were detected by immunofluorescence respectively. BDNF, TrkB, p-TrkB, PI3K, Akt, p-Akt were measured by Western Blotting. The results showed that XYS could increase the locomotor activity and sugar preference, decreased swimming immobility time as well as attenuate hippocampal pathological damage. A total of 753 differentially expressed lncRNAs (DElncRNAs), 28 circRNAs (DEcircRNAs), 101 miRNAs (DEmiRNAs), and 477 mRNAs (DEmRNAs) were identified after the treatment of XYS in whole transcriptome sequencing analysis. Enrichment results revealed that XYS could regulate multiple aspects of depression through different synapse or synaptic associated signal, such as neurotrophin signaling and PI3K/Akt signaling pathways. Then, vivo experiments indicated that XYS could promote length, density, intersections of synapses and also increase the expression of MAP2 in hippocampal CA1, CA3 regions. Meanwhile, XYS could increase the expression of PSD-95, SYN in the CA1, CA3 regions of hippocampal by regulating the BDNF/trkB/PI3K signal axis. The possible mechanism on synapse of XYS in depression was successfully predicted. BDNF/trkB/PI3K signal axis were the potential mechanism of XYS on synapse loss for its antidepressant. Collectively, our results provided novel information about the molecular basis of XYS in treating depression.


Insights into White Matter Damage in Alzheimer's Disease: From Postmortem to in vivo Diffusion Tensor MRI Studies.
Alzheimer's disease (AD) has traditionally been considered a disease of the gray matter (GM). However, several pathological and neuroimaging studies provided evidence of white matter (WM) abnormalities in this disease. The advent of diffusion tensor (DT) MRI allowed researchers to study in vivo cerebral WM abnormalities in AD, including the earliest stage of the disease and its atypical variants. To provide a concise overview of the main neuropathological and DT MRI studies that explored WM damage in AD providing new insights into the underlying pathophysiological mechanisms. Neuropathological studies revealed that GM and WM changes did not concur regionally in many areas, where well-preserved GM often lay over severely changed WM also in nondemented subjects with an underlying AD pathology. DT MRI studies confirmed in vivo a severe WM involvement in classical and atypical AD variants and in the prodromal stage of the disease. Microstructural WM damage was severer and more distributed than expected on the basis of cortical atrophy in all clinical AD phenotypes. AD is characterized by a relevant involvement of the WM as demonstrated by postmortem and in vivo evidence. WM microstructural damage in AD is not always secondary to neuronal loss, suggesting a role of other pathological mechanisms such as prion-like propagation of altered proteins or neuroinflammation. DT MRI offers new insight into AD pathophysiology and, more importantly, new possible targets for future experimental therapies.


Erythropoietin concentration among patients with and without preeclampsia.
Controversy exists in the literature regarding the association between erythropoietin levels and preeclampsia. This study was aimed to compare serum erythropoietin concentrations among patients with and without preeclampsia. A prospective study was designed and two groups were defined: 22 patients with preeclampsia (study group) and 19 normotensive patients (control group). Preeclampsia was defined as blood pressure higher than 140 mmHg systolic or 90 mmHg diastolic and proteinuria > 300/24 h or dipstick > 1. Women in the control group were matched for gestational age. Blood was collected in tubes containing EDTA, and centrifuged in 4 degrees C within 30 min of collection. Serum erythropoietin level was determined by ELISA (R&D Systems, Inc. Minneapolis, USA). Statistical analysis was performed using the SPSS package. Erythropoietin concentration was higher among patients with preeclampsia, but did not reach significance (24.8 +/- 8.9 mU/ml vs. 19.9 +/- 9.9 mU/ml; P-0.19). Also, hemoglobin and hematocrit levels were similar in both groups (12.0 +/- 4.2 g/dl vs. 11.6 +/- 3.9 g/dl; P-0.16 and 36.5 +/- 10.8% vs. 35.3 +/- 11.4%; P-0.13, respectively). A nonsignificant trend towards higher maternal serum levels of erythropoietin was demonstrated among patients with preeclampsia. Further prospective studies are needed to investigate the association between preeclampsia and erythropoietin.


Semiempirical calculations of model deoxyheme. Variation of calculated electromagnetic properties with electronic configuration and distance of iron from the plane.
The electronic structure of deoxyheme units and the electric field gradient at the iron nucleus are calculated as a function of the displacement of the iron from the heme plane. The high spin state has a calculated minimum energy with the iron out of plane at a distance similar to that observed for metMb. This could correspond to a relaxed form of deoxyHb, while the greater displacement observed in the intact protein could be strained. The calculated electric field gradient is relatively insensitive to iron displacement from the heme plane. This insensitivity could account for the very similar values of quadrupole splittings observed in low-affinity deoxyhemoglobin A and its separate high-affinity alpha and beta subunits, and still allow small differences in iron displacement consistent with the stereochemical trigger mechanism of cooperativity.


L3mbtl, the mouse orthologue of the imprinted L3MBTL, displays a complex pattern of alternative splicing and escapes genomic imprinting.
L3mbtl encodes a member of the Polycomb group of proteins, which function as transcriptional repressors in large protein complexes. The Drosophila D-l(3)mbt protein is considered a tumor suppressor since its inactivation results in brain tumors. The human L3MBTL gene lies in a region of chromosome 20 frequently deleted in patients with myeloid malignancies and has been proposed as a candidate 20q tumor suppressor gene. Recently we have shown that L3MBTL undergoes monoallelic methylation in hematopoietic tissues and is transcribed from the paternally derived allele. The mouse L3mbtl gene is located on chromosome 2, a region of syntenic homology with human chromosome 20, and in a region containing a number of genes subject to epigenetic regulation. Here we analyze the genomic structure and alternative splicing of L3mbtl and assess its imprinting status in mouse. L3mbtl displays a complex pattern of alternative splicing involving both 5' noncoding and coding exons and is transcribed from two promoters. Unlike its human counterpart, L3mbtl escapes imprinting and there is no differential methylation of its CpG island.


Drug release from ammonio-methacrylate-coated diltiazem particles: influence of the reservoir on membrane behavior.
Drug-layered sugar spheres 15, 45, and 64% potent were made such that each had the same particle size distribution. The particles were coated to the same coat thickness with an ammonio polymethacrylate formulation, and drug release was measured in two media. The products exhibited a sigmoidal release pattern, where a lag time was followed by relatively rapid drug release. Lag time depended on the applied polymer amount, the media used, and the sugar content, where an increase in sugar content caused greater expansion before drug release. Lag times were related to expansion. Expansion of coated sugar spheres was measured.


Rupture of pregnant noncommunicating uterine horn with fetal salvage.
A case is presented of pregnancy in an uncommunicating rudimentary uterine horn. The pregnancy proceeded to 31 gestational weeks, when the rudimentary horn ruptured. At laparotomy the surviving fetus was lying free in the peritoneal cavity, was delivered breech and subsequently did well. This is the fifth case reported of rupture of a pregnant rudimentary horn with neonatal and maternal survival.


COVID-19 and Parkinson's disease: a systematic review and meta-analysis.
This meta-analysis aimed to determine the prevalence, symptoms, and outcomes of COVID-19 in the elderly with Parkinson's disease (PD) by searching in the international databases of PubMed, Scopus, Web of Sciences, and EMBASE using the keywords of "COVID-19" and "Parkinson's." All articles related to Parkinson's disease and COVID-19 from January 2019 to October 20, 2021 were reviewed. The STATA software was used for analysis. A total of 20 articles were selected for data extraction in this meta-analysis, of which ten were cross-sectional studies (to determine the prevalence), five case-control studies, and five cohort studies (to examine the association). The results of the meta-analysis showed the prevalence of COVID-19 in patients with PD was 1.06% (95% CI 1.03-1.1%; P = 0.02), and the prevalence of their hospitalization due to COVID-19 was 0.98% (95% CI: 0.95-1.02%; P = 0.00). Also, the prevalence of depression and anxiety during the pandemic in this group was 46% (95% CI 29-64%; P = 0.00) and 43% (95% CI: 24-63%; P = 0.00), respectively. The prevalence of tremor and sleep problems were higher than those of other symptoms in the studied population. According to the results, there was no significant difference in the risk of COVID-19 infection between Parkinson's patients and healthy people. In other words, the risk of COVID-19 infection was equal in both groups (RR = 1.00 (CI 95% 0.77-1.30%; P = 0.15)). The results showed mortality and hospitalization rates of the elderly with Parkinson's disease were not significantly different from those of the general population during the COVID-19 pandemic. Also, the symptoms of Parkinson's disease and mental disorders increased during the COVID-19 pandemic. So, designing and developing more specific studies, like cohort studies, with large sample size is required for assessing these associations.


[A pilot study of measuring inferior vena cava internal diameter on transverse section plane in different sites by ultrasonography].
To investigate the shape change index (SCI) of inferior vena cava (IVC) measured from subcostal area and right mid-axillary line through ultrasonography laying the foundation for future research about SCI and volume status. A total of 107 patients were enrolled in the Critical Care Medicine Department of Peking Union Medical College Hospital from December, 2014-January, 2015. The maximal diameter (MXD) and the minimal diameter (MID) were measured transversely from subcostal area and right mid-axillary line. The SCI was calculated. Totally 47 patients (42 with spontaneous breathing and 5 on mechanical ventilation) achieved measurements on transversal plane from subcostal area and right mid-axillary line. (1) The internal diameter of IVC on longitudinal plane measured from subcostal area was statistically different from that measured from right mid-axillary line both at end inspiration (P=0.001) and at end expiration (P=0.027). (2) No difference were found in the SCI measured from subcostal and right mid-axillary line both at end inspiration and at expiration. (3) The internal diameter of IVC and the SCI measured on transversal plane from subcostal area correlated well with that measured from mid-axillary line both at end inspiration (SCI:r=0.866, P=0.000) and at end expiration (SCI: r=0.887, P=0.000). Inferior vena cava internal diameters and the shape change index measured through ultrasonography on transversal planefrom subcostal area are correlated well with those from mid-axillary line. Measurements from the two sites can be replacedby each other.


The obligatory role of calcium in the development of antigen-induced airway hyperreactivity to cold provocation in the rat isolated trachea.
The effect of antigen challenge on cold provocation (30-10 degrees C) in isolated tracheal segments from control (normal) and ovalbumin-sensitized rats was studied. Sensitization alone or acute cold provocation (10 degrees C) alone was not sufficient to cause contraction of tracheal smooth muscle preparation. Following recovery from antigen-induced responses (Schultz-Dale phenomenon) in sensitized rat segments, cold provocation induced strong contractile responses. Both the antigen-induced contractions and the subsequent development of airway hyperreactivity to cold were dependent on extracellular Ca2+ and inhibited by verapamil. The data in this study indicate that extracellular Ca2+ plays an obligatory role in the mediation of antigen-induced contractile responses as well as the subsequent development of hyperreactivity to cold provocation in rat tracheal smooth muscle.


Developmental changes in neutral glycosphingolipids of mouse placenta.
The mammalian placenta is a unique organ for the study of developmental changes. Placentas of laboratory animals such as the mouse allow for the determination of the exact stage of pregnancy, which cannot be achieved with human placenta. In this study, neutral glycosphingolipids were isolated from mouse (inbred strain C57BL/6) placentas, from day 10 to day 18 of gestation, and were separated by high performance thin layer chromatography. Densitometric measurements after orcinol staining showed, at day 10 of gestation, the presence of mono-, tetra-, tri- and dihexosylceramide in decreasing quantities, as well as four unidentified spots. On day 12, the glycosphingolipid composition changed with the disappearance of the unidentified spots and the appearance of an orcinol positive migrating similarly to the Forssman antigen; no further changes occurred between days 12 and 18 of gestation. The identity of the Forssman-like glycosphingolipid with the Forssman antigen was established by binding of 125I labelled Helix pomatia agglutinin (alpha-GalNAc specific) to glycosphingolipids separated on high performance thin layer chromatography plates, and by the reaction of the isolated glycosphingolipid with a monoclonal anti-Forssman antibody. The appearance of the Forssman antigen at day 12 of gestation coincided with the day of final maturation of the mouse placenta and subsequent cessation of growth, suggesting a possible role of the glycosphingolipid during embryonic development.


Root radial apoplastic transport contributes to shoot cadmium accumulation in a high cadmium-accumulating rice line.
Radial transport of cadmium (Cd) in roots governs the amount of Cd loaded into xylem vessels, where Cd ions are translocated upward into shoots, while the mechanism of differential Cd radial transport between the high Cd-accumulating rice line Lu527-8 and the normal rice line Lu527-4 remains ambiguous. A higher Cd distribution in cross sections and root apoplast and higher bypass flow of Cd were found in Lu527-8, explaining a greater Cd translocation through the apoplastic pathway. The lower relative area of the epidermis and the constant relative area of the cortex in Lu527-8 opened-up root radial transport for Cd. Deposition of apoplastic barriers (Casparian strips and suberin lamellae) was stimulated by Cd, which effectively prevented Cd from entering the stele through the apoplastic pathway. In Lu527-8, apoplastic barriers were further from the root apex with lower expression of genes responsible for biosynthesis of Casparian strips and suberin lamellae, enhancing radial transport of Cd. Our data revealed that the higher radial apoplastic transport of Cd played an integral role in Cd translocation, contributed to a better understanding of the mechanism involved in high Cd accumulation in Lu527-8 and helped achieve the practical application of phytoextraction.


Studies of the protective effect of different fractions of sera from pigs immune to Streptococcus suis type 2 infection.
Inoculation of mice with high doses of Streptococcus suis type 2 caused depression, anorexia, lethargy and sometimes death. This was prevented by prior inoculation of whole immune pig serum, the IgM and IgG fractions of immune pig serum and serum enriched with antibody to surface antigens. Clinical signs were not prevented by prior inoculation of pre-immune serum or serum depleted of antibody to surface antigens. Serum fractions that were protective in vivo were also opsonic in vitro. Western blot analysis identified two antigens of 44 and 78 kd that were recognized strongly by protective sera and a further four of 86, 94, 130 and 136 kd that were recognized less intensely.


Peptaibiotics: Harnessing the potential of microbial secondary metabolites for mitigation of plant pathogens.
Agricultural systems are in need of low-cost, safe antibiotics to protect crops from pests and diseases. Peptaibiotics, a family of linear, membrane-active, amphipathic polypeptides, have been shown to exhibit antibacterial, antifungal, and antiviral activity, and to be inducers of plant resistance against a wide range of phytopathogens. Peptaibiotics belong to the new generation of alternatives to agrochemicals, aligned with the United Nations Sustainable Development Goals and the One Health approach toward ensuring global food security and safety. Despite that, these fungi-derived, non-ribosomal peptides remain surprisingly understudied, especially in agriculture, where only a small number has been tested against a reduced number of phytopathogens. This lack of adoption stems from peptaibiotics' poor water solubility and the difficulty to synthesize and purify them in vitro, which compromises their delivery and inclusion in formulations. In this review, we offer a comprehensive analysis of peptaibiotics' classification, biosynthesis, relevance to plant protection, and mode of action against phytopathogens, along with the techniques enabling researchers to extract, purify, and elucidate their structure, and the databases holding such valuable data. It is also discussed how chemical synthesis and ionic liquids could increase their solubility, how genetic engineering and epigenetics could boost in vitro production, and how omics can reduce screenings' workload through in silico selection of the best candidates. These strategies could turn peptaibiotics into effective, ultra-specific, biodegradable tools for phytopathogen control.


Oral insulin delivery in rats by nanoparticles prepared with non-toxic solvents.
Nanoparticles (NPs) have shown a certain potential to overcome the drawbacks of oral peptide delivery in the gastrointestinal tract such as low peptide stability and permeability. The preparation of insulin loaded NPs was carried out with Eudragit RL or RS dissolved in different non-toxic polyethylene glycol (PEG) derivatives. The use of these non-toxic solvents allowed the design of an one step NP preparation method where insulin retained its full biological activity as it was proven in vitro and in vivo. The insulin trapping NPs were in a size range of around 150-250 nm and exhibited a pH-dependent release. The type of solvent did not distinctly influence the particle properties or insulin stability but modified significantly the performance in vivo in rats, NPs prepared with glycofurol led to a bioavailability of F=1.4 ± 1.0% after oral administration while NPs prepared with PEG 300 were hardly efficient (F=0.3 ± 0.5%). In all cases t(max) was shifted to 2h compared to 1h after subcutaneous insulin solution. In general, we believe that the method presented here is a promising way to encapsulate sensitive drugs, especially for the production of peptide loaded NPs.


[Geomagnetic effects on hepatic function in different phases of the annual cycle].
Investigations on 496 Wistar rats have revealed that in winter geomagnetic deviations (GMD) have no effect on hepatic function of the intact animals. GMD in spring and summer provoked functional impairment of the liver while in autumn intact and CCl4 hepatitis rats exhibited GMD-related normalization of liver function. Thus, efficacy of physiotherapeutic correction of the liver depends on the phase of the annual cycle and geomagnetic situation.


Cu-Ce oxide Co-loaded silicon nanocapsules for hydrogen peroxide self-supplied Fenton-like catalysis and synergistically antibacterial therapy.
Antibacterial strategies based on reactive oxygen species (ROS) have opened up a new avenue for overcoming the great challenges of antibiotics topic including lack of broad-spectrum antibiotics and the emergence of super-resistant bacteria. Herein, we leveraged a strategy of constructing synergistic catalytic active sites to develop a simple yet efficient Fenton-like active nanocomposite, and investigated its catalysis mechanism and antibacterial performance thoroughly. This strategy provides a new direction for boosting the catalytic activity of nanocomposite catalysts for wide application. Specifically, by uniformly loading copper oxide and ceria onto the surface of silica nanocapsules (SiO2 NCs), we fabricated a bimetallic oxide nanocomposite Cu0.75Ce0.62O2@SiO2 NC, which performed superior Fenton-like capability in a wide pH range without additional exogenetic hydrogen peroxide (H2O2). Such excellent catalytic activity was originated from the charge interaction between the two metal oxide components, where formation of Cu+ and oxygen vacancies (OVs) was mutually reinforcing, resulting in a synergistic effect to produce H2O2 and catalyze the generation of •OH under the slight acid condition (pH = 6.0). In view of the outstanding Fenton-like activity, the Cu0.75Ce0.62O2@SiO2 NC was employed in antimicrobial testing, which demonstrated exceptional high in vitro antimicrobial efficacy against both the S. aureus and E. coli in a neutral environment (pH = 7.4). The excellent performance of the bimetallic nanocomposite Cu0.75Ce0.62O2@SiO2 NC, including its facile and mild preparation, high water-solubility and stability, superior catalytic and antimicrobial performances, manifests a promising broad-spectrum antibiotic that can be anticipated to deal with the contamination of the environment by bacteria.


Iron sparing and recycling in a compartmentalized cell.
This review focuses on economizing, prioritizing and recycling iron in Chlamydomonas, a reference organism for discovering mechanisms of acclimation to poor iron nutrition in the plant lineage. The metabolic flexibility of Chlamydomonas offers a unique opportunity to distinguish the impact of iron nutrition on photosynthetic versus respiratory metabolism, and the contribution of subcellular compartments to iron storage and mobilization. Mechanisms of iron sparing include down regulation of protein abundance by transcript reduction or protein degradation. Two well-studied examples of hierarchical iron allocation are the maintenance of FeSOD in the plastid and heterotrophic metabolism in acetate-grown cells at the expense of photosynthetic metabolism. The latter implicates the existence of a pathway for inter-compartment iron recycling when access to iron becomes limiting.


Role of the bicarbonate-responsive soluble adenylyl cyclase in cholangiocyte apoptosis in primary biliary cholangitis; a new hypothesis.
Primary biliary cholangitis (PBC) is a chronic fibrosing cholangiopathy characterized by an autoimmune stereotype and defective biliary bicarbonate secretion due to down-regulation of anion exchanger 2 (AE2). Despite the autoimmune features, immunosuppressants are ineffective while two bile acid-based therapies (ursodeoxycholic acid and obeticholic acid) have been shown to improve biochemical and histological features of cholestasis and long-term prognosis. However, the etiology and pathogenesis of PBC is largely unknown. Recently, it has been shown that microRNA-506 (miR-506) on chromosome X is up-regulated in PBC cholangiocytes and suppresses AE2 expression, which sensitizes cholangiocytes to bile salt-induced apoptosis by activating soluble adenylyl cyclase (sAC), an evolutionarily conserved bicarbonate sensor. In this review, we discuss the experimental evidence for the emerging role of the miR-506-AE2-sAC axis in PBC pathogenesis. We further hypothesize that the initial disease trigger induces an X-linked epigenetic change, leading to a female-biased activation of the miR-506-AE2-sAC axis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen.


Cold-sensitive mutants of p34cdc2 that suppress a mitotic catastrophe phenotype in fission yeast.
The p34cdc2 protein kinase plays a central role in the regulation of the eukaryotic cell cycle, being required both in late G1 for the commitment to S-phase and in late G2 for the initiation of mitosis. p34cdc2 also determines the precise timing of entry into mitosis in fission yeast, where a number of gene products that regulate p34cdc2 activity have been identified and characterised. To investigate further the mitotic role of p34cdc2 in this organism we have isolated new cold-sensitive p34cdc2 mutants. These are defective only in their G2 function and are extragenic suppressors of the lethal premature entry into mitosis brought about by mutating the mitotic inhibitor p107wee1 and overproducing the mitotic activator p80cdc25. One of the mutant proteins p34cdc2-E8 is only functional in the absence of p107wee1, and all the mutant strains have reduced histone H1 kinase activity in vitro. Each mutant allele has been cloned and sequenced, and the lesions responsible for the cold-sensitive phenotypes identified. All the mutations were found to map to regions that are conserved between the fission yeast p34cdc2 and functional homologues from higher eukaryotes.


Expression of autoantibodies to recombinant (U1) RNP-associated 70K antigen in systemic lupus erythematosus.
To determine the specificity of antibodies to the (U1) ribonucleoprotein antigen in systemic lupus erythematosus (SLE), patient sera were tested for binding to a recombinant human 70K antigen. By solid-phase immunoassay, we detected anti-70K reactivity in sera from 31 of 96 patients with systemic lupus erythematosus (SLE), demonstrating that anti-70K antibodies may occur in patients with SLE as well as other clinical diagnoses. In sequential sera from 2 of these patients, we found that anti-70K binding varied dramatically over the course of disease. The changes in anti-70K antibody levels did not correlate with clinical events nor evolving antibody reactivity with the Sm-specific antigens.


Buddleja officinalis Maxim.: A review of its botany, ethnopharmacology, phytochemistry, pharmacology, and therapeutic potential for ophthalmic diseases.
Buddleja officinalis Maxim. (B. officinalis), commonly known as "Menghua" "Yangerduo" is a widely recognized traditional herbal medicine in China, Korea, and Vietnam. For thousands of years, it has been used to treat dry eye disease, conjunctivitis, keratitis, eye ulcers, eye pain, cough, asthma, hemoptysis, and other medical conditions. This review article aims to provide a concise summary of the botany, ethnopharmacology, phytochemistry, pharmacology, medicinal potential, and application of B. officinalis in treating ophthalmic diseases and critically evaluates the existing literature to establish a scientific basis for its reasonable utilization and further investigation. The information reviewed in this study was collected from various electronic resources, including the Web of Science, PubMed, and Google Scholar. To date, 80 structurally diverse compounds have been isolated and characterized from B. officinalis, primarily flavonoids, phenylethanoids, triterpenoids, and monoterpenes. Extracts and compounds derived from B. officinalis have been reported to possess broad pharmacological effects including anti-dry eye disease, anti-inflammation, anti-oxidation, anti-diabetes, anti-obesity, improving osteoporosis and treatment of skin diseases. This review provides a reference for the future studies on of B. officinalis. As a natural medicinal plant, B. officinalis is worthy of further development in botany, ethnopharmacology, phytochemistry, pharmacology, and therapeutic potential for ophthalmic diseases. Although some components have demonstrated multiple pharmacological activities, their mechanisms of action remain unclear. Further studies on the underlying molecular basis and mechanism of action are warranted.


Orphan receptor IL-17RD tunes IL-17A signalling and is required for neutrophilia.
Interleukin-17A, the prototypical member of the interleukin-17 cytokine family, coordinates local tissue inflammation by recruiting neutrophils to sites of infection. Dysregulation of interleukin-17 signalling has been linked to the pathogenesis of inflammatory diseases and autoimmunity. The interleukin-17 receptor family members (A-E) have a broad range of functional effects in immune signalling yet no known role has been described for the remaining orphan receptor, interleukin-17 receptor D, in regulating interleukin-17A-induced signalling pathways. Here we demonstrate that interleukin-17 receptor D can differentially regulate the various pathways employed by interleukin-17A. Neutrophil recruitment, in response to in vivo administration of interleukin-17A, is abolished in interleukin-17 receptor D-deficient mice, correlating with reduced interleukin-17A-induced activation of p38 mitogen-activated protein kinase and expression of the neutrophil chemokine MIP-2. In contrast, interleukin-17 receptor D deficiency results in enhanced interleukin-17A-induced activation of nuclear factor-kappa B and interleukin-6 and keratinocyte chemoattractant expression. Interleukin-17 receptor D disrupts the interaction of Act1 and TRAF6 causing differential regulation of nuclear factor-kappa B and p38 mitogen-activated protein kinase signalling pathways.


Characterization of cationic amino acid transporter and its gene expression in rat hepatic stellate cells in relation to nitric oxide production.
Nitric oxide is a potent mediator of hepatic sinusoidal hemodynamics and affects hepatic stellate cells (Ito cells, fat-storing cells). Although nitric oxide production may depend on the induction of inducible nitric oxide synthase and on transport of extracellular L-arginine, the precise mechanisms controlling nitric oxide production in stellate cells have not been well characterized. Using stellate cells prepared from the male Wistar rat, kinetic analysis of L-arginine transport and reverse transcription-polymerase chain reaction for cationic amino acid transporter were carried out. The effect of tumor necrosis factor-alpha and interferon-gamma on L-arginine transport, mRNA expression of cationic amino acid transporter and inducible nitric oxide synthase, and nitric oxide production of stellate cells was assessed. The L-arginine transport system functioning in the transformed hepatic stellate cells was system y+, possibly mediated by cationic amino acid transporter-1 and cationic amino acid transporter-2B (Km approximately 50 microM). Tumor necrosis factor-alpha enhanced cationic amino acid transporter-2B mRNA expression and L-arginine transport, whereas cationic amino acid transporter-1 mRNA expression remained unchanged. Interferon-gamma induced the expression of inducible nitric oxide synthase mRNA without obvious changes in L-arginine transport. Interferon-gamma in combination with tumor necrosis factor-alpha induced nitric oxide production with an enhancement in cationic amino acid transporter-2B mRNA expression, inducible nitric oxide synthase mRNA expression, and L-arginine transport, while extracellular L-lysine competitively inhibited this nitric oxide production. In transformed hepatic stellate cells, tumor necrosis factor-alpha and interferon-gamma have a crucial role in nitric oxide production, and extracellular L-arginine transport and inducible nitric oxide synthase expression are regulated in a differential cytokine-specific manner. As the estimated Km of L-arginine transporter in transformed hepatic stellate cells is very similar to the physiological L-arginine concentration in portal vein, we assume that increased portal L-arginine concentration may easily affect sinusoidal blood flow through enhancement of autocrine nitric oxide production in transformed hepatic stellate cells of diseased liver.


Safety considerations in the evolving legal landscape of psychedelic-assisted psychotherapy.
International drug policy is rapidly evolving in tandem with promising evidence for psychedelic-assisted psychotherapy (PAP) in treating a range of mental health conditions. Canada is among the countries increasingly expanding access to psychedelic substances for therapeutic purposes. The 8-year ban on medical exemptions through the Canadian Special Access Programme was recently reversed in January 2022 and the first exemptions for legal possession and personal use of psilocybin mushrooms were granted in 2020, nearly 50 years since their criminalization. In view of the evolving evidence base and regulatory landscape for PAP illustrated by recent shifts in Canadian and international drug policy, this piece seeks to clarify the special range of factors which ought to be considered to safely expand access to psychedelics. Streamlining access to safe and evidence-based compassionate use of PAP will provide a timely treatment option to those currently in need while encouraging further research and outcome surveillance to refine best practices.


Prosthesis-patient mismatch in high-risk patients with severe aortic stenosis: A randomized trial of a self-expanding prosthesis.
We compared the incidence of prosthesis-patient mismatch (PPM) between transcatheter aortic valve replacement (TAVR) using a self-expanding bioprosthesis and surgical aortic valve replacement (SAVR) in the CoreValve US High Risk Pivotal Trial. We sought to determine the influence of PPM on clinical outcomes. Patients with severe aortic stenosis and at increased risk for surgery were randomized 1:1 to TAVR or SAVR. Postoperative PPM was defined by the effective orifice area index (EOAi) as severe PPM (EOAi ≤ 0.65 cm(2)/m(2)) and no severe PPM (EOAi > 0.65 cm(2)/m(2)); clinical outcomes were analyzed in the TAVR arm (n = 389) and SAVR arm (n = 353). Left ventricular mass index and regression were analyzed at baseline and 1 year. The incidence of severe PPM in the SAVR group at 1 year was 25.7% versus 6.2% in the TAVR group (P < .0001). Left ventricular mass index regression at 1 year was 6.8% for TAVR and 15.1% for SAVR in patients with severe PPM. At 1 year the rate of all-cause mortality and acute kidney injury were significantly greater in all patients (TAVR + SAVR) with severe PPM compared with no severe PPM (20.6% vs 12.0% [P = .0145] for death and 19.2% vs 8.5% [P = .0008] for acute kidney injury). In patients with high surgical risk and severe aortic stenosis, severe PPM is more common in patients treated with SAVR than those treated with TAVR. Patients with severe PPM are a greater risk for death and acute kidney injury than patients without severe PPM.


[Psychosis in elderly post-traumatic stress disorder patients].
Late-onset post-traumatic stress disorder (PTSD) patients with traumatic experiences from World War II often present psychotic features. Twelve psychotic elderly PTSD patients were compared with 22 nonpsychotic elderly PTSD patients for age, marital status, age of traumatization, age of onset of psychiatric symptoms, and psychiatric comorbidities. The contents of delusions and hallucinations were registered as well as trauma details. The psychotic PTSD patients were significantly older (80 years vs 74), later traumatized (20 years vs 14), more frequently demented (75% vs 27%), and more frequently widowed (83% vs 50%). The contents of their psychotic features often were related to traumatic experiences in early life. Psychoses of traumatized elderly patients should be registered regarding psychotic content to discover a possible relation between traumatic experiences and psychosis. The International Classification of Diseases 11th Edition should include the subtype "PTSD with simultaneous psychotic features."


Forced oscillatory parameters as predictors of COPD assessment test improvement in untreated COPD patients.
Few studies have examined whether baseline spirometry and the forced oscillation technique (FOT) would predict The COPD Assessment Test (CAT) score improvement after treatment of untreated COPD patients. The study subjects included 65 untreated COPD patients. They underwent the CAT, spirometry, and FOT (MostGraph) before and after treatment for more than 2 months. In addition, recursive partitioning analysis was performed using spirometry and the FOT parameters to identify the predictors of CAT improvement (CAT score ≥2). CAT scores and lung function significantly improved after treatment. Recursive partitioning analysis identified 3 improved classes, defined by Rrs at 20 Hz (R20), Xrs at 5 Hz (X5), and ΔX5, but not by spirometry. The accuracy of predicting CAT improvement was as follows: odds ratio, 25.3; 95 % confidence interval, 6.1 to 104.1; sensitivity, 91.2 %; specificity, 71.0 %; positive likelihood ratio, 3.14; and negative likelihood ratio, 0.12. FOT helps predict improved health status in untreated COPD patients.


Personalized Nutrition in the Management of Female Infertility: New Insights on Chronic Low-Grade Inflammation.
Increasing evidence on the significance of nutrition in reproduction is emerging from both animal and human studies, suggesting a mutual association between nutrition and female fertility. Different "fertile" dietary patterns have been studied; however, in humans, conflicting results or weak correlations are often reported, probably because of the individual variations in genome, proteome, metabolome, and microbiome and the extent of exposure to different environmental conditions. In this scenario, "precision nutrition", namely personalized dietary patterns based on deep phenotyping and on metabolomics, microbiome, and nutrigenetics of each case, might be more efficient for infertile patients than applying a generic nutritional approach. In this review, we report on new insights into the nutritional management of infertile patients, discussing the main nutrigenetic, nutrigenomic, and microbiomic aspects that should be investigated to achieve effective personalized nutritional interventions. Specifically, we will focus on the management of low-grade chronic inflammation, which is associated with several infertility-related diseases.


Link to slower access to care: what is the stigma?: an Indian perspective.
Stigma and discrimination have been "bed fellows" of HIV and AIDS in India. Perpetuated by lack of awareness, deep-rooted traditional beliefs, adherence to harmful practices, and a moralistic tag associated with a condition connected with sex (in India the method of HIV transmission being largely heterosexual in nature) and high-risk individuals such as sex workers, it made it difficult for the country to fight an epidemic that was hard to track, estimate, diagnose, and treat. Various interventions under India's National AIDS Control Program (NACP) have targeted stigma and discrimination among different groups. The program has been fairly successful in its outreach programs, bringing about a reduction in adult HIV prevalence and new infections. As the country transitions from NACP Phase III (2007-2012) to IV (2012-2017), making treatment and longevity its top priority, stigma is no longer such a terrifying word. This review discusses the social and cultural context of HIV/AIDS-related stigma in general and highlights various policies and intervention programs that have led India's campaign against HIV/AIDS-driven stigma into the testing, care, support, and treatment ambit.


The relationship between treatment modality, demographic characteristics, and staff perceptions concerning their jobs in 26 Philadelphia drug treatment centers.
The staffs of 26 Philadelphia drug treatment centers, representing four major treatment modalities, were interviewed concerning their attitudes and perceptions of treatment and the treatment milieu. By employing canonical correlation, two basic modality contrasts were found that significantly differentiated these attitudes and perceptions: (1) staff in small therapeutic communities tended to manifest more positive attitudes than their counterparts in large methadone maintenance settings, and (2) outpatient drug-free staff tended to be more satisfied and optimistic than detoxification staff.


[Neuro-urological diagnosis and therapy of lower urinary tract dysfunction in patients with spinal cord injury : S2k Guideline of the German-Speaking Medical Society of Paraplegia (DMGP), AWMF register no. 179/001].
Most patients with spinal cord injury (SCI) suffer from neurogenic lower urinary tract dysfunction (NLUTD), bowel dysfunction and sexual dysfunction. If these remain untreated, severe medical complications and serious limitations (restrictions) in quality of life are imminent. In the long term, there are considerable differences in the treatment results of highly specialized centers versus other treatment facilities. Against this background, a consensus-based guideline, according to the AWMF (Association of the Scientific Medical Societies in Germany) criteria (S2k), was developed by the neuro-urology working group of the DMPG (German-Speaking Medical Society of Paraplegia). The guideline defines the principles and objectives of the neuro-urological care of patients with SCI and discusses in detail the principles of diagnosis and therapy of NLUTD. The need for video-urodynamic studies as a basis for the classification of the NLUTD and as a foundation for the development of a treatment strategy is emphasized. Both conservative and surgical therapy options and their indications are explained in detail. Possible complications and their prevention in the long-term course of SCI are presented with a particular consideration of the specific features of urinary tract infections and autonomic dysreflexia. Finally, the principles of the provision of urological appliances are discussed. The presented S2k guideline provides the current standards in the neuro-urological care of patients with NLUTD due to SCI. Their consistent implementation both in the acute and chronic phase as well as in the context of lifelong surveillance of SCI patients should prevent the impending complications of NLUTD.


Natural chitosan-based carbon dots as an eco-friendly and effective corrosion inhibitor for mild steel in HCl solution.
Polysaccharide chitosan and L-histidine were applied to synthesize chitosan-based carbon dots (CA-CDs) by a simple laser ablation method. After characterization of the CA-CDs by FT-IR, UV-vis, Raman, XRD, TEM, and XPS, the CA-CDs were introduced as an eco-friendly and high-performance corrosion inhibitor for mild steel (MS) in 1.0 M HCl solution. The inhibition action and mechanism of CA-CDs were determined by weight loss and electrochemical measurements, in combination with SEM, AFM, and XPS. The results show that CA-CDs as mixed-type inhibitors could effectively weaken the corrosion of MS in 1.0 M HCl solution, and their maximum inhibition efficiency reaches 97.4 % at 40 mg L-1. The adsorption behavior of CA-CDs well obeys the Langmuir adsorption isotherm containing both chemisorption and physisorption. The chemisorption mainly results from the multiple adsorption sites in the CA-CDs, and the physical adsorption is due to the blocking and barrier effect of CA-CD nanoparticles. Both adsorption behaviors were proposed to elucidate the corrosion inhibition mechanism of CA-CDs.


Placement of endosteal implants combined with chin bone onlay graft for dental reconstruction in patients with grafted alveolar clefts.
Endosteal implants were inserted into grafted alveoli after particulate cancellous bone and marrow grafting in seven patients with cleft lip or palate in conjunction with simultaneous chin bone onlay grafting. In these patients, the alveolar bone height of the bony bridge was insufficient when evaluated by both computed tomographic and periapical radiographic images. The age at first implant surgery ranged from 14 to 28 years. Although four of the seven patients had an uneventful course, three had wound dehiscence, and in all but one of them the exposed chin bone underwent partial or total necrosis. Ultimately all seven implants integrated into the bone, and the alveolar bone height was increased in all but one patient. The results indicate that chin bone onlay grafting with simultaneous implant insertion is useful in patients with cleft lip or palate with insufficient alveolar bone height.


Dynamic prediction model and risk assessment chart for cardiovascular disease based on on-treatment blood pressure and baseline risk factors.
For patients with hypertension, an individual risk prediction tool for cardiovascular disease based on on-treatment blood pressure is needed and would be useful. The objective of this study was to establish a 3-year risk prediction model for cardiovascular disease based on data from 13 052 patients with no history of cardiovascular disease in the Olmesartan Mega study to determine the relationship between Cardiovascular Endpoints and Blood Pressure Goal Achievement study. To develop dynamic prediction models including on-treatment blood pressure, a Cox proportional hazard model using the sliding landmarking method with three landmark points (6, 12 and 18 months from baseline) was used. The prediction model included blood pressure (<130/85 mm Hg, ⩾130/85 to <140/90 mm Hg, ⩾140/90 to <160/100 mm Hg and ⩾160/100 mm Hg) as a time-dependent covariate and well-known baseline risk factors (sex, age, smoking, family history of coronary artery disease and diabetes) as covariates. The 3-year risk assessment chart was constructed using the combination of all risk factors in the prediction model, and six different colors were displayed on each chart corresponding to the predicted probability of cardiovascular disease. Judging from the chart, if an elderly man with diabetes and other risk factors had a blood pressure of <130/85 mm Hg at 6 months, the risk of cardiovascular disease would be 8.0%, whereas the risk would be 8.6% if he had a blood pressure of ⩾130/85 to <140/90 mm Hg. The risk assessment chart developed from the large-scale observational study data would help physicians to more easily assess the cardiovascular disease risk for hypertensive patients on antihypertensive treatments.


Hyperhidrosis and the sympatho-adrenal system.
Some disorders in which excessive sweating, hyperhidrosis, is a symptom are also characterized by increased sympatho-adrenal activity. Such disorders are hypotension, hypoglycemia, pheochromocytoma and hyperthyroidism. Sweat glands are controlled by a cholinergic innervation but can also be stimulated by adrenergic agents whose effects can be blocked by both alpha- and beta-receptor blocking drugs. An adrenergic innervation has also been demonstrated. There is evidence that the adrenergic component of sweating particularly secretion of the adrenal medulla, is responsible for the enhancement of sweating during exercise but not for the hyperhidrosis present in these disorders since sweating in these circumstances can be effectively blocked by cholinergic blocking compounds. Cutaneous vasoconstriction due to elevated plasma catecholamines reduces the rate of evaporation of sweat and allows sweat to accumulate on the skin. It is suggested that in the case of hypotension and insulin hypoglycemia sweating results from general sympathetic stimulation and that adrenal medullary hormones are not an essential component of the response. Hyperhidrosis in pheochromocytoma may be due to central activation of heat loss mechanisms resulting from the passage of plasma catecholamines across the blood-brain barrier combined with increased thermogenesis and cutaneous vasoconstriction. The hyperhidrosis of hyperthyroidism is probably due to increased thermogenesis.


Acute kidney injury caused by tenofovir disoproxil fumarate and diclofenac co-administration.
The renal elimination of tenofovir (TFV) may be subject to renal drug-drug interactions that may increase the risk of kidney injury. Case reports indicated that diclofenac might increase TFV-associated nephrotoxicity via a drug-drug interaction, leading to an increased intracellular TFV concentration in proximal tubular cells. A retrospective analysis of data for all patients from the Frankfurt HIV Cohort (FHC) who had diclofenac prescriptions between January 2008 and June 2012 was carried out. Among 89 patients with diclofenac use, 61 patients (68.5%) were treated with tenofovir disoproxil fumarate (TDF) and 28 patients (31.5%) were treated with TDF-sparing combination antiretroviral therapy (cART). Thirteen patients (14.6%) developed acute kidney injury (AKI) shortly after initiating diclofenac treatment. AKI occurred exclusively in TDF-treated patients, although all had previously stable renal function. All cases were accompanied by new onset of at least two parameters indicating proximal tubular damage, such as normoglycaemic-glucosuria and hypophosphataemia. TFV-associated nephrotoxicity was demonstrated by renal biopsy in four cases. Additionally, 11.5% of patients on TDF treatment developed new-onset proximal tubular damage, while having a preserved glomerular filtration rate. In contrast, diclofenac did not affect renal function in patients with TDF-sparing cART, as only one case of isolated hypophataemia was observed in these patients. In univariate analysis, risk factors for AKI were TDF-containing cART (P = 0.0076) and pre-existing hypophosphataemia (P = 0.0086). Drug-drug interaction caused by diclofenac could exacerbate TFV-associated nephrotoxicity. Diclofenac should be used with caution in patients on TDF therapy, especially in those with hypophosphataemia. Our findings need to be confirmed in larger studies.


Intermolecular domain swapping induces intein-mediated protein alternative splicing.
Protein sequences are diversified on the DNA level by recombination and mutation and can be further increased on the RNA level by alternative RNA splicing, involving introns that have important roles in many biological processes. The protein version of introns (inteins), which catalyze protein splicing, were first reported in the 1990s. The biological roles of protein splicing still remain elusive because inteins neither provide any clear benefits nor have an essential role in their host organisms. We now report protein alternative splicing, in which new protein sequences can be produced by protein recombination by intermolecular domain swapping of inteins, as elucidated by NMR spectroscopy and crystal structures. We demonstrate that intein-mediated protein alternative splicing could be a new strategy to increase protein diversity (that is, functions) without any modification in genetic backgrounds. We also exploited it as a post-translational protein conformation-driven switch of protein functions (for example, as highly specific protein interference).


Relativistic electron mirrors from nanoscale foils for coherent frequency upshift to the extreme ultraviolet.
Reflecting light from a mirror moving close to the speed of light has been envisioned as a route towards producing bright X-ray pulses since Einstein's seminal work on special relativity. For an ideal relativistic mirror, the peak power of the reflected radiation can substantially exceed that of the incident radiation due to the increase in photon energy and accompanying temporal compression. Here we demonstrate for the first time that dense relativistic electron mirrors can be created from the interaction of a high-intensity laser pulse with a freestanding, nanometre-scale thin foil. The mirror structures are shown to shift the frequency of a counter-propagating laser pulse coherently from the infrared to the extreme ultraviolet with an efficiency >10(4) times higher than in the case of incoherent scattering. Our results elucidate the reflection process of laser-generated electron mirrors and give clear guidance for future developments of a relativistic mirror structure.


Activation of peroxymonosulfate by α-MnO2 for Orange Ⅰ removal in water.
Developing high-efficiency catalysts for peroxymonosulfate (PMS)-based advanced oxidation processes is important for eliminating pollutants in water. Herein, α-MnO2 with major exposed {110} and {100} facets prepared via a hydrothermal method were used as catalysts to activate PMS for the degradation of Orange Ⅰ (OⅠ). α-MnO2-100, with more abundant surface hydroxyl groups and greater reductive ability, performed remarkably better than α-MnO2-110 for degrading OⅠ. OⅠ removal of 86.20% was obtained in the α-MnO2-100/PMS system. The apparent rate constant of OⅠ removal over α-MnO2-100 was 2.11 times higher than that of α-MnO2-110. The effects of PMS concentration, catalyst dosage, OⅠ concentration, initial pH, anions and humic acid (HA) on OⅠ degradation in the α-MnO2-100/PMS system were systematically investigated. Quenching experiments and electron paramagnetic resonance (EPR) demonstrated that SO4•-, •OH, O2•- and 1O2 were the reactive oxygen species (ROS) in the α-MnO2-100/PMS system. Moreover, the possible degradation pathway of OⅠ in the α-MnO2-100/PMS system was proposed. This work provides an ideal metal oxide catalyst for sewage remediation.


Proteomic and phosphoproteomic analysis reveal threonine deficiency increases hepatic lipid deposition in Pekin ducks via reducing STAT phosphorylation.
Dietary threonine (Thr) deficiency enhances triglyceride (TG) deposition in the liver of Pekin ducks, which injures hepatic function and impairs growth performance. However, the underlying molecular mechanisms remain unclear. In the present study, we investigated the effects of dietary Thr deficiency on the expressions of proteins and phosphoproteins in liver of Pekin ducks, to identify the underlying molecular changes. A total of 300 one-day-old ducklings were divided into 3 groups with 10 replicates of 10 birds. All ducks were fed corn-wheat-peanut meal diets containing 0.46%, 0.71%, and 0.96% Thr, respectively, from 1 to 21 days of age. Growth performance, serum parameters, hepatic TG content, and expression of genes involved in lipid metabolism of Pekin ducks were determined. A Thr deficiency group (Thr-D, 0.46% Thr) and a Thr sufficiency group (Thr-S, 0.71% Thr) were selected for subsequent proteomic and phosphoproteomic analysis. The results showed that Thr-D reduced the growth performance (P < 0.001), and increased the plasma concentrations of cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and hepatic TG (P < 0.05). Thr-D increased gene expression related to fatty acid and TG synthesis (P < 0.05). A total of 176 proteins and 259 phosphosites (containing 198 phosphoproteins) were observed to be differentially expressed as a result of Thr-D. The upregulated proteins were enriched in the pathway related to amino acid metabolism, peroxisome. The downregulated proteins were enriched in linolenic and arachidonic acid metabolism, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. The upregulated phosphoproteins were enriched in the pathways related to fatty acid biosynthesis, fructose and mannose metabolism, and glycolysis/gluconeogenesis. Thr-D reduced the phosphorylation of STAT1 at S729 and STAT3 at S728, and expression of STAT5B. In contrast, Thr-D increased non-receptor tyrosine-protein kinase (TYK2) expression and STAT1 phosphorylation at S649. Taken together, dietary Thr-D increased hepatic TG accumulation by upregulating the expression of genes and proteins, and phosphoproteins related to fatty acid and triglyceride synthesis. Furthermore, these processes might be regulated by the JAK-STAT signaling pathway, especially the phosphorylation of STAT1 and STAT3.


Biologic therapy in the idiopathic inflammatory myopathies.
The idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases resulting from inflammation of muscle and manifesting as weakness, though a range of extra-muscular manifestations are observed. These are often correlated closely with disease subtype and the presence of myositis-specific/myositis-associated antibodies. IIM are notoriously difficult to treat and often refractory to glucocorticoid therapy and synthetic immunosuppressants. Both the innate and adaptive immune systems are implicated in the pathogenesis of IIM. A growing understanding of the key cytokines as well as the cell-mediated and antibody effectors of disease has identified multiple potential targets for biologic therapy. The most widely used of these is B-cell depletion via rituximab though the tumour necrosis factor inhibitors and other biologic therapies used in diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis have also been trialled. This review summarises the literature thus far on biologic therapy in IIM, highlighting both the significant trials that influence current treatment regimens and also the continuing need for further research to inform more effective therapies.


Cytochrome bd-I in Escherichia coli is less sensitive than cytochromes bd-II or bo'' to inhibition by the carbon monoxide-releasing molecule, CORM-3: N-acetylcysteine reduces CO-RM uptake and inhibition of respiration.
CO-releasing molecules (CO-RMs) are potential therapeutic agents, able to deliver CO - a critical gasotransmitter - in biological environments. CO-RMs are also effective antimicrobial agents; although the mechanisms of action are poorly defined, haem-containing terminal oxidases are primary targets. Nevertheless, it is clear from several studies that the effects of CO-RMs on biological systems are frequently not adequately explained by the release of CO: CO-RMs are generally more potent inhibitors than is CO gas and other effects of the molecules are evident. Because sensitivity to CO-RMs cannot be predicted by sensitivity to CO gas, we assess the differential susceptibilities of strains, each expressing only one of the three terminal oxidases of E. coli - cytochrome bd-I, cytochrome bd-II and cytochrome bo', to inhibition by CORM-3. We present the first sensitive measurement of the oxygen affinity of cytochrome bd-II (Km 0.24μM) employing globin deoxygenation. Finally, we investigate the way(s) in which thiol compounds abolish the inhibitory effects of CORM-2 and CORM-3 on respiration, growth and viability, a phenomenon that is well documented, but poorly understood. We show that a strain expressing cytochrome bd-I as the sole oxidase is least susceptible to inhibition by CORM-3 in its growth and respiration of both intact cells and membranes. Growth studies show that cytochrome bd-II has similar CORM-3 sensitivity to cytochrome bo'. Cytochromes bo' and bd-II also have considerably lower affinities for oxygen than bd-I. We show that the ability of N-acetylcysteine to abrogate the toxic effects of CO-RMs is not attributable to its antioxidant effects, or prevention of CO targeting to the oxidases, but may be largely due to the inhibition of CO-RM uptake by bacterial cells. A strain expressing cytochrome bd-I as the sole terminal oxidase is least susceptible to inhibition by CORM-3. N-acetylcysteine is a potent inhibitor of CO-RM uptake by E. coli. Rational design and exploitation of CO-RMs require a fundamental understanding of their activity. CO and CO-RMs have multifaceted effects on mammalian and microbial cells; here we show that the quinol oxidases of E. coli are differentially sensitive to CORM-3. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins.


Facile synthesis of sewage sludge-derived in-situ multi-doped nanoporous carbon material for electrocatalytic oxygen reduction.
Developing efficient, low-cost, and stable carbon-based catalysts for oxygen reduction reaction (ORR) to replace the expensive platinum-based electrocatalysts remains a major challenge that hamper the practical application of fuel cells. Here, we report that N, Fe, and S co-doped nanoporous carbon material, derived via a facile one-step pyrolysis of sewage sludge, the major byproduct of wastewater treatment, can serve as an effective electrocatalyst for ORR. Except for the comparable catalytic activity with commercial 20% Pt/C via a nearly four-electron transfer pathway in both alkaline and acid medium, the as-synthesized co-doped electrocatalyst also exhibits excellent methanol crossover resistance and outstanding long-term operation stability. The organic compounds in sewage sludge act as the carbon source and the in-situ N and S dopant in the fabrication, while the inorganic compounds serve as the in-built template and the in-situ Fe dopant. Our protocol demonstrates a new approach in the economic and eco-friendly benign reuse of sewage sludge, and also provides a straightforward route for synthesizing excellent carbon-based electrocatalysts as promising candidates for ORR directly from a type of waste/pollution.


D-valine as a selective agent for normal human and rodent epithelial cells in culture.
A nutrient medium has been developed to enable the growth of normal epithelial cells while selectively inhibiting fibroblast proliferation. In this medium, D-valine is substituted for L-valine; and only those cells containing D-amino acid oxidase can convert the D-amino acid into its essential L-enantiomer. The ability to select for cells with this enzyme has enabled us to maintain epithelial cell populations free from fibroblast overgrowth. The presence of D-amino acid oxidase has been histochemically confirmed in the epithelial cells selected from renal cell suspensions and explants. The ability to proliferate in the selective medium is transmitted to the clonal progeny of these cells. Moreover, epithelial cell proliferation of this medium indicates the presence of D-amino acid oxidase, which we have detected in tissues where it had not previously been reported-fetal human kidney, lung, and cord. Fibroblasts will not grow in the selective medium, but will proliferate normally if the product of the D-amino acid oxidase reaction is supplied.


Studies on skin aging. Preparation and properties of fucose-rich oligo- and polysaccharides. Effect on fibroblast proliferation and survival.
Skin aging represents an important chapter of connective tissue aging and concerns an organ of vital importance. Here we describe the preparation as well as the biological properties of fucose-rich oligo- and polysaccharides (FROPs), composed of polymers of a trisaccharide containing galactose, acetyl galacturonic acid and fucose, from the original high molecular weight bacterial polysaccharide (Fucogel), Solabia, France). Using endoglycosidases, oligo- and polysaccharides were prepared and characterized by physical and chemical procedures. The non-reducing end-groups comprise equal amounts of galactose and fucose. The here-described biological properties are: stimulation of cell proliferation of cultured human skin fibroblasts, protection of cells against ascorbate-induced cytotoxicity due to the release of reactive oxygen species (ROS). Properties elsewhere described concern the inhibition of matrix metallo-proteinases 2 and 9 (MMP-2 and MMP-9), their expression and activation. Using fluorescein isothiocyanate (FITC)-labeled polysaccharides, their interaction with cell membranes and also their penetration and accumulation in cells, especially in the cell nucleus could be demonstrated, probably via cell-membrane receptor-mediated mechanisms. We describe some of the symptoms of skin aging and show, that the here-described polysaccharide preparations are susceptible to slow down some of the cellular and molecular mechanisms involved, partly by the mediation of the above-mentioned receptors, partly by acting directly on the regulation of gene expression.


An air-machine for infants and children.
Modifications to the Jobson Air-machine are described which permit its use in infants and children under three years of age.


The End-to-End Provenance Project.
Data provenance is a machine-readable summary of the collection and computational history of a dataset. Data provenance confers or adds value to a dataset, helps reproduce computational analyses, or validates scientific conclusions. The people of the End-to-End Provenance Project are a community of professionals who have developed software tools to collect and use data provenance.


Flanders virus replication and protein synthesis.
The prototype strain of Flanders virus (61-7484) has been adapted to grow in Vero cell cultures and a plaque assay has been developed. Electron micrographs of infected cells revealed rod-shaped virions budding in clusters from the plasma membrane, consistent with the tentative classification of Flanders virus as a member of the Rhabdoviridae. Viral proteins were identified by SDS-PAGE and immunological techniques using Flanders virus-specific antibodies. Eight virus-associated proteins were detected. The relative molecular weights obtained by SDS-PAGE were 180,000, 81,000, 54,000, 43,000, 33,000, 27,000, 23,000, and 19,000. Evidence is presented that two of these proteins (43,000 and 23,000 mol wt) are in vivo cleavage products. The 81,000 mol wt protein was glycosylated and phosphorylated and did not label well with [35S]methionine or 14C-amino acids. The 54,000 and 33,000 mol wt proteins were phosphorylated. When 35S-radiolabeled virus was purified by pelleting at 90,000 g followed by isopycnic sucrose gradient centrifugation, all eight virus proteins were present in the peak fractions which contained the radiolabel and infectivity.


Novel base triples in RNA structures revealed by graph theoretical searching methods.
Highly hydrogen bonded base interactions play a major part in stabilizing the tertiary structures of complex RNA molecules, such as transfer-RNAs, ribozymes and ribosomal RNAs. We describe the graph theoretical identification and searching of highly hydrogen bonded base triples, where each base is involved in at least two hydrogen bonds with the other bases. Our approach correlates theoretically predicted base triples with literature-based compilations and other actual occurrences in crystal structures. The use of 'fuzzy' search tolerances has enabled us to discover a number of triple interaction types that have not been previously recorded nor predicted theoretically. Comparative analyses of different ribosomal RNA structures reveal several conserved base triple motifs in 50S rRNA structures, indicating an important role in structural stabilization and ultimately RNA function.


Large cohort dose-volume response analysis of parotid gland function after radiotherapy: intensity-modulated versus conventional radiotherapy.
To compare parotid gland dose-volume response relationships in a large cohort of patients treated with intensity-modulated (IMRT) and conventional radiotherapy (CRT). A total of 221 patients (64 treated with IMRT, 157 with CRT) with various head-and-neck malignancies were prospectively evaluated. The distribution of tumor subsites in both groups was unbalanced. Stimulated parotid flow rates were measured before and 6 weeks, 6 months, and 1 year after radiotherapy. Parotid gland dose-volume histograms were derived from computed tomography-based treatment planning. The normal tissue complication probability (NTCP) model proposed by Lyman was fit to the data. A complication was defined as stimulated parotid flow ratio <25% of the pretreatment flow rate. The relative risk of complications was determined for IMRT vs. CRT and adjusted for the mean parotid gland dose using Poisson regression modeling. One year after radiotherapy, NTCP curves for IMRT and CRT were comparable with a TD(50) (uniform dose leading to a 50% complication probability) of 38 and 40 Gy, respectively. Until 6 months after RT, corrected for mean dose, different complication probabilities existed for IMRT vs. CRT. The relative risk of a complication for IMRT vs. CRT after 6 weeks was 1.42 (95% CI 1.21-1.67), after 6 months 1.41 (95% CI; 1.12-1.77), and at 1 year 1.21 (95% CI 0.87-1.68), after correcting for mean dose. One year after radiotherapy, no difference existed in the mean dose-based NTCP curves for IMRT and CRT. Early after radiotherapy (up to 6 months) mean dose based (Lyman) models failed to fully describe the effects of radiotherapy on the parotid glands.


The activity of the metaepiphyseal chondrocytes in the humerus of growing mammals.
In the postnatal period of development of animals there have been established differences in the length of the distal and proximal metaphyses, as well as in the biosynthesis of sulphated proteoglycans and collagen proteins by chondrocytes. The local peculiarities of the functional and reproductive activity of chondrocytes exert influence upon the histological structure of metaphyses. The locomotive function with its certain supporting-power loads on various joints is supposed to be the main cause for these changes.


Blood pressure variability and baroreflex sensitivity are not different in spontaneously hypertensive rats and stroke-prone spontaneously hypertensive rats.
To demonstrate and compare hemodynamic phenotypes of blood pressure (BP), blood pressure variability (BPV) and baroreflex sensitivity (BRS) in genetic hypertensive rats. BP was recorded continuously in conscious, freely moving rats using a computerized technique. BPV was expressed as the standard deviation of beat-to-beat BP values during a 1-h period. BRS was determined by measuring the heart period prolongation in response to the elevation in BP produced by an intravenous injection of phenylephrine. Body weight and heart period were not different between spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHR-SP) at the age of 15 weeks. The BP level was markedly higher in SHR-SP than SHR, whereas there were no significant differences in BPV and BRS. Quantitatively, systolic, diastolic and mean BP were significantly elevated by 36.9%, 42.9% and 39.5%, respectively, in SHR-SP compared with SHR (P < 0.01). However, their variabilities were elevated only by 14.0%, 0.4% and 10.1%, respectively, without statistical significance (P > 0.05). BPV and BRS were not changed in parallel with the BP alterations in SHR and SHR-SP.


Association Between Gut Microbiota and Elevated Serum Urate in Two Independent Cohorts.
Hyperuricemia is a precursor to gout and is often present in other metabolic diseases that are promoted by microbiome dysbiosis. We undertook this study to examine the association of gut microbiota with hyperuricemia and serum urate levels in humans. Study participants were derived from a community-based observational study, the Xiangya Osteoarthritis Study (discovery cohort). Hyperuricemia was defined as the presence of a serum urate level >357 μmoles/liter in women and >416 μmoles/liter in men. Gut microbiota were analyzed using 16S ribosomal RNA sequencing of stool samples. We examined the relationship of microbiota dysbiosis (i.e., richness, diversity, composition, and relative abundance of microbiota taxa) and predicted functional pathways to prevalent hyperuricemia and serum urate levels. We verified the associations in an independent observational study, the Step Study (validation cohort). The discovery cohort consisted of 1,392 subjects from rural areas (mean age 61.3 years, 57.4% women, 17.2% with hyperuricemia). Participants with hyperuricemia had decreased richness and diversity, altered composition of microbiota, and lower relative abundances of genus Coprococcus compared to those with normouricemia. Predicted KEGG metabolism pathways including amino acid and nucleotide metabolisms were significantly altered in subjects with hyperuricemia compared to those with normouricemia. Gut microbiota richness, diversity, and low relative abundances of genus Coprococcus were also associated with high levels of serum urate. These findings were replicated in the validation cohort with 480 participants. Gut microbiota dysbiosis is associated with elevated serum urate levels. Our study examines the possibility that microbiota dysbiosis may modulate these levels.


A Transgenic Heavy Chain IgG Mouse Platform as a Source of High Affinity Fully Human Single-Domain Antibodies for Therapeutic Applications.
The antibody repertoires of transgenic mice expressing human heavy chain only antibodies (HCAbs) can be retrieved from immune cells after antigen challenge. Compared with genetically modified rodents expressing conventional human antibodies (tetramers consisting of two heavy chains paired with two light chains), there is no chain pairing problem, since each antibody consists of a heavy chain dimer which is solely responsible for antigen binding. HCAbs can be obtained by classical hybridoma fusion, or the generation of phage libraries or eukaryotic cell libraries displaying or secreting HCAbs. Combined transcriptomic/serum proteomic approaches can also be used to determine the repertoire of antibodies, as well as single cell technologies such as the Beacon system that enable capture of immune cells of interest, analysis, and sequencing of antibodies in a short period of time. Here, we describe a protocol for obtaining monoclonal HCAbs from immunized Harbour transgenic mice through the generation and screening of HEK cell libraries of secreted antibodies. The method can be used routinely and is fast and affordable for everyone. Selected VH regions (single domains) are sequenced and individual HCAbs can be produced and purified from the same expression vector that is used for library generation (hIgG1 Fc). They can also be cloned into other expression plasmids and reformatted to equip them with a particular effector function, modify lifespan in serum, or optimize valency and avidity depending on the specific aim.


Intra-crystalline protein diagenesis (IcPD) in Patella vulgata. Part II: Breakdown and temperature sensitivity.
Artificial diagenesis of the intra-crystalline proteins isolated from Patella vulgata was induced by isothermal heating at 140 °C, 110 °C and 80 °C. Protein breakdown was quantified for multiple amino acids, measuring the extent of peptide bond hydrolysis, amino acid racemisation and decomposition. The patterns of diagenesis are complex; therefore the kinetic parameters of the main reactions were estimated by two different methods: 1) a well-established approach based on fitting mathematical expressions to the experimental data, e.g. first-order rate equations for hydrolysis and power-transformed first-order rate equations for racemisation; and 2) an alternative model-free approach, which was developed by estimating a "scaling" factor for the independent variable (time) which produces the best alignment of the experimental data. This method allows the calculation of the relative reaction rates for the different temperatures of isothermal heating. High-temperature data were compared with the extent of degradation detected in sub-fossil Patella specimens of known age, and we evaluated the ability of kinetic experiments to mimic diagenesis at burial temperature. The results highlighted a difference between patterns of degradation at low and high temperature and therefore we recommend caution for the extrapolation of protein breakdown rates to low burial temperatures for geochronological purposes when relying solely on kinetic data.