Orf: a family with unusual complications.
Three members of a farming family and their local postman contracted orf. One of those affected had had no direct contact with infected sheep. Two of the family developed a widespread papulo-vesicular eruption of the skin and mucosae with pyrexia, malaise and lymphadenopathy lasting 4-5 weeks. The eruption did not resemble erythema multiforme or the toxic erythemas usually associated with this infection.


[Evaluation of passive cardiomyoplasty using left- and right-ventricular volume measurements by EBCT and MRI in patients with chronic congestive heart failure].
To evaluate the efficacy of passive cardiomyoplasty with the determination of biventricular volumes, global systolic function as well as left-ventricular muscle mass. In 19 patients with congestive heart failure of idiopathic or ischemic origin, a polyester mesh-graft was implanted around both ventricles for stabilization and functional support. Before and three months after surgery, 15 patients underwent EBCT and 4 patients with impaired renal function underwent MRI, for the evaluation of the volume and ejection fraction of both ventricles. EBCT demonstrated a decrease from 385 to 310 ml in LV-EDV, from 312 to 242 ml in LV-ESV, from 209 to 160 ml in RV-EDV and from 149 to 87 ml in RV-ESV, and an increase from 20 to 26% in LV-EF and from 37 to 50% in RV-EF as well as a reduction of LV-MM from 300 to 274 g (p < 0.05 each). Similar results were obtained by MRI. Following passive cardiomyoplasty, EBCT and MRI revealed an improvement of the global systolic function as well as a reduction of biventricular volumes and left-ventricular muscle mass.


Is Moulage effective in improving clinical skills of nursing students for the assessment of pressure injury?
In wound care simulations, the practice can be performed on 3D-wounds formed by moulage. Moulage helps the student to perceive the etiology, physiology, and healing processes of the wound, and it can also be used to improve the students' wound assessment skills. The aim of this study is to investigate the effectiveness of moulage in the improvement of pressure injury assessment skills of nursing students. A quasi-experimental study. A nursing faculty at a public university. All fourth-year students (n = 73) who take the simulation elective course were invited to participate. Fall semester students (n = 38) constituted the control group and spring semester students (n = 35) formed the intervention group. The coin-flipping method was used to match the education period and student groups. The intervention group simulation was performed using moulage, and the control group simulation was performed using a pressure ulcer visuals. The same simulation scenarios were used for both groups. The data were collected using the Simulation Design Scale, Student Satisfaction and Self-Confidence Scale, and student identification form, knowledge test, performance checklist and feedback form developed by the researchers. Students' knowledge scores for pressure injury assessment have improved significantly in both the intervention group (pre-test:61.71 ± 9.77 and post-test 70.57 ± 12.53, t = -4.27, p < 0.001) and the control group (pre-test: 66.81 ± 13.47 and post-test 73.06 ± 15.50, t = -2.34, p = 0.02). Laboratory and clinical pressure injury assessment skill scores of the intervention group students were significantly higher than the control group. Besides, the correct staging percentages of the intervention group students are higher than the control group students during the clinical practice (χ2 = 5.05, p = 0.02). It can be concluded that the simulation with moulage was effective in improving the skills of nursing students who received training for pressure injury assessment and in transferring what they learned to the clinical setting.


Renal and neurological side effects of colistin in critically ill patients.
Colistin is a complex polypeptide antibiotic composed mainly of colistin A and B. It was abandoned from clinical use in the 1970s because of significant renal and, to a lesser extent, neurological toxicity. Actually, colistin is increasingly put forward as salvage or even first-line treatment for severe multidrug-resistant, Gram-negative bacterial infections, particularly in the intensive care setting. We reviewed the most recent literature on colistin treatment, focusing on efficacy and toxicity issues. The method used for literature search was based on a PubMed retrieval using very precise criteria.Despite large variations in dose and duration, colistin treatment produces relatively high clinical cure rates. Colistin is potentially nephrotoxic but currently used criteria tend to overestimate the incidence of kidney injury. Nephrotoxicity independently predicts fewer cures of infection and increased mortality. Total cumulative colistin dose is associated with kidney damage, suggesting that shortening of treatment duration could decrease the incidence of nephrotoxicity. Factors that may enhance colistin nephrotoxicity (i.e., shock, hypoalbuminemia, concomitant use of potentially nephrotoxic drugs) must be combated or controlled. Neurotoxicity does not seem to be a major issue during colistin treatment. A better knowledge of colistin pharmacokinetics in critically ill patients is imperative for obtaining colistin dosing regimens that ensure maximal antibacterial activity at minimal toxicity.


Lichenoid proliferative leukoplakia, lichenoid lesions with evolution to proliferative leukoplakia or a continuum of the same precancerous condition? A revised hypothesis.
Multiple white plaques of the oral mucosa are usually associated with potentially malignant disorders such as oral lichen planus, oral lichenoid lesions and proliferative verrucous leukoplakia. Previous studies in the current literature describe a potential clinical overlap in these entities. The aim of this study is to review clinicopathological and evolutive features of these Oral Potentially Malignant Disorders highlighting the dynamic changes of diagnoses. It was previously hypothesized that a subset of patients with oral lichen planus or oral lichenoid diagnosis, could develop multiple white plaques during the natural history of the disease, fulfilling diagnostic criteria for proliferative verrucous leukoplakia. Consequently, these entities could, under certain conditions, obey a continuum of the same precancerous condition in the context of the field cancerization theory, increasing the risk of malignant transformation. Nevertheless, there is limited scientific evidence concerning this issue. Further studies are needed to understand the biological and evolutive features of the link between these oral potentially malignant disorders. Regardless of its diagnosis, these patients with multifocal white lesions must be carefully monitored to detect early malignant transformation.


Protective effects of grape seed proanthocyanidins on cardiovascular remodeling in DOCA-salt hypertension rats.
Cardiovascular remodeling, as a hallmark of hypertension-induced pathophysiology, causes substantial cardiovascular morbidity and mortality. There is increasing evidence that has demonstrated a broad spectrum of pharmacological and therapeutic benefits of grape seed proanthocyanidins (GSP) against oxidative stress and cardiovascular diseases. In this study, 180- to 200-g SD rats treated with DOCA (120 mg/week sc with 1% NaCl and 0.2% KCl in drinking water) and GSP (150, 240, 384 mg/kg) or amlodipine (ALM) (5 mg/kg) for 4 weeks were recruited. The protective effects of GSP on blood pressure and cardiovascular remodeling in rats with DOCA-salt-induced hypertension were investigated. Our results indicated that DOCA-salt could induce hypertension, cardiovascular remodeling and dysfunction, oxidative stress and the release of endothelin-1 (ET-1) and could increase JNK1/2 and p38MAPK phosphorylation. GSP or ALM treatments significantly improved hypertension, cardiovascular remodeling and dysfunction and oxidative stress, restrained the release of ET-1 and down-regulated the JNK1/2 and p38MAPK phosphorylation. These findings demonstrate that GSP has protective effects against increase of blood pressure induced by DOCA-salt hypertension and cardiovascular remodeling by inhibiting the reactive oxygen species/mitogen-activated protein kinase pathway via restraining the release of ET-1.


[[Calciuria and phosphaturia during fasting. Effect of calcitonin alone or with a thyroid hormonotherapy combination].
The author compares 4 groups of obese individuals subjected to fasting for 7 days: Some took no medication, the others received either triiodothyronine (100 to 150 microgram per day), or calcitonin (1 unit MRC per day) or both triiodothyronine and calcitonin. An increase in calciuria and phosphaturia was observed with either triiodothyronine or calcitonin. Triiodothyronine in association with calcitonin did not increase further the calciuria caused by calcitonin but increased phosphaturia. The author offers an explanation for these various observations.


Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis.
Acute intermittent porphyria (AIP) is an autosomal dominant disease characterized by mutations of the gene coding for porphobilinogen deaminase (PBGD). Until now, sixteen different mutations have been described. In an effort to investigate further the molecular epidemiology of AIP, we have undertaken a systematic study of different exons of the PBGD gene from a large number of unrelated patients. Here, we have examined seven of the fifteen exons of the gene from 43 unrelated Dutch and French AIP patients using denaturing gradient gel electrophoresis after polymerase chain reaction amplification. Eleven new mutations were found, accounting for the enzymatic defect in about half of the patients. This study further documents the molecular heterogeneity of the mutations responsible for AIP and describes an efficient strategy to detect the mutations in patients with previously unknown abnormalities.


Pathogenesis, diagnosis and management of pneumorrhachis.
Pneumorrhachis (PR), the presence of intraspinal air, is an exceptional but eminent radiographic finding, accompanied by different aetiologies and possible pathways of air entry into the spinal canal. By reviewing the literature and analysing a personal case of traumatic cervical PR after head injury, we present current data regarding the pathoanatomy, clinical and radiological presentation, diagnosis and differential diagnosis and treatment modalities of patients with PR and associated pathologies to highlight this uncommon phenomenon and outline aetiology-based guidelines for the practical management of PR. Air within the spinal canal can be divided into primary and secondary PR, descriptively classified into extra- or intradural PR and aetiologically subsumed into iatrogenic, traumatic and nontraumatic PR. Intraspinal air is usually found isolated not only in the cervical, thoracic and, less frequently, the lumbosacral regions but can also be located in the entire spinal canal. PR is almost exceptional associated with further air distributions in the body. The pathogenesis and aetiologies of PR are multifold and can be a diagnostic challenge. The diagnostic procedure should include spinal CT, the imaging tool of choice. PR has to be differentiated from free intraspinal gas collections and the coexistence of air and gas within the spinal canal has to be considered differential diagnostically. PR usually represents an asymptomatic epiphenomenon but can also be symptomatic by itself as well as by its underlying pathology. The latter, although often severe, might be concealed and has to be examined carefully to enable adequate patient treatment. The management of PR has to be individualized and frequently requires a multidisciplinary regime.


Cannabinoids and monoamine neurotransmission with focus on monoamine oxidase.
Progress in understanding the mechanisms of action of cannabinoids was made after discovery of cannabinoid receptors and finding their endogenous ligands. New findings are obtained using both endogenous cannabinoids and plant or synthetic cannabinoids. Activation of cannabinoid receptors on synaptic terminals results in regulation of ion channels, neurotransmitter release and synaptic plasticity. Neuromodulation of synapses by cannabinoids is proving to have a wide range of functional effects, making them potential targets as medical preparations in a variety of illnesses, including some neurodegenerative and mental disorders. Brain monoamines are involved in many of the same processes affected by neuropsychiatric disorders and by different psychotropic drugs, including cannabinoids. Basic information is summarized in the paper about mechanisms of action of cannabinoids on monoaminergic systems, with a view to inhibition of monoamine oxidase.


Synthesis and anti-HIV activity of some novel chain-extended phosphoramidate derivatives of d4T (stavudine): esterase hydrolysis as a rapid predictive test for antiviral potency.
Novel chain-extended nucleoside phosphoramidates of the anti-human immunodeficiency virus (HIV) drug d4T (stavudine) have been prepared as possible membrane-permeable prodrugs of the bio-active free 5'-monophosphates. Phosphorochloridate chemistry gave the target compounds in moderate to high yields, and all materials were fully characterized by spectroscopic and analytical methods. The compounds are related to the previously reported phenyl methoxyalaninyl derivative of d4T, which was shown to be a potent and selective inhibitor of HIV. In this study the amino acid nitrogen and ester moieties were separated by methylene spacers of between two and six carbon atoms. In vitro evaluation of these compounds indicated an almost complete lack of anti-HIV activity, the compounds being several orders of magnitude less potent than the corresponding alpha-amino acid derivatives. The reasons for the virtual lack of anti-HIV activity appear to involve poor enzyme-mediated hydrolysis.


Seroprevalence and risk factors for Helicobacter pylori infection in Greenlanders.
In contrast to most populations worldwide, the incidence of gastric cancer increases among Inuit in Greenland. Contributing factors to this increase are unknown, but Helicobacter pylori may be involved. However, little is known regarding the epidemiology of H. pylori in Arctic communities. With the aim of determining age-specific prevalence, risk factors, and association with clinical conditions of H. pylori infection, we carried out a population-based study of H. pylori in Sisimiut, the second biggest town of Greenland. A population-based sample of 685 persons had serum drawn that was analyzed for H. pylori IgG antibodies using enzyme-linked immunosorbent assay (ELISA). Risk factors analyses were carried out using multivariate logistic regression models. The seroprevalence was lowest among children aged 0-4 years (6%), but increased rapidly thereafter. In persons aged 15-87 years the seroprevalence had stabilized around 58%. Total number of children in household, number of older, but not younger, siblings and narrow age gap to closest older sibling were associated with H. pylori seropositivity. In contrast, number of adults in household and socioeconomic status did not influence serostatus. The age-specific prevalence pattern in Greenland is intermediate between that of developing and developed countries. The risk factor pattern indicates crowding and older siblings in particular to be key elements in risk of infection.


The risk factors for nosocomial infection in chinese patients with active rheumatoid arthritis in shanghai.
Objective. To analyse the potential risk factors of nosocomial infections in patients with active rheumatoid arthritis (RA). Methods. A total of 2452 active RA patients at Hospitals in Shanghai between January 2009 and February 2011 were analyzed. Their demographic and clinical characteristics were compared with those without infection, and the potential risk factors were determined by logistic regression analysis. Results. Multivariate analysis indicated the gender (OR = 0.70, 95% CI 0.53-0.92), duration in hospital (OR = 1.03 , 95%CI 1.01-1.05), number of organs involved (OR = 0.82, 95%CI 0.72-0.92), number of disease-modifying antirheumatic drugs ((DMARDs) (OR = 1.22, 95%CI 1.061-1.40)), corticosteroid therapy (OR = 1.02, 95%CI 1.01-1.03), peripheral white blood cell counts ((WBC) (OR = 1.04, 95%CI 1.00-1.08)), levels of serum albumin (OR = 0.98, 95%CI 0.97-0.99), and C-reactive protein ((CRP) (OR = 1.03 , 95%CI 1.01-1.04)) that were significantly associated with the risk of infections. Conclusion. The female patients, longer hospital stay, more organs involved, more DMARDs, corticosteroid usage, high counts of WBC, lower serum albumin, and higher serum CRP were independent risk factors of infections in active RA patients.


Associations Between Delay Discounting and Connectivity of the Valuation-control System in Healthy Young Adults.
The process of valuation assists in determining if an object or course of action is rewarding. Delay discounting is the observed decay of a rewards' subjective value over time. Encoding the subjective value of rewards across a spectrum has been attributed to brain regions belonging to the valuation and executive control systems. The valuation system (VS) encodes reward value over short and long delays, influencing reinforcement learning and reward representation. The executive control system (ECS) becomes more active as choice difficulty increases, integrating contextual and mnemonic information with salience signals in the modulation of decision-making. Here, we aimed to identify resting-state functional connectivity-based patterns of the VS and ECS correlated with value-setting and delay discounting (outside-scanner paradigm) in a large (n = 992) cohort of healthy young adults from the Human Connectome Project (HCP). Results suggest the VS may be involved in value-setting of small, immediate rewards while the ECS may be involved in value-setting and delay discounting for large and small rewards over a range of delays. We observed magnitude sensitive connections involving the posterior cingulate cortex, time-sensitive connections with the ventromedial and lateral prefrontal cortex while connections involving the posterior parietal cortex appeared both magnitude- and time-sensitive. The ventromedial prefrontal cortex and posterior parietal cortex could act as "comparator" regions, weighing the value of small rewards against large rewards across various delay duration to aid in decision-making.


Association of GEMIN4 gene polymorphisms with the risk of colorectal cancer in the Polish population.

Aim: Gem-associated protein 4 (GEMIN4), a member of the GEMIN gene family, is a key compound of the regulating factors responsible for miRNA biogenesis. Genetic variability within this gene can alter the risk for development of colorectal cancer (CRC) as was shown for other genes involved in miRNA biogenesis. Therefore, presented study was intended to identify genetic variants of three single nucleotide polymorphisms (SNPs) in the GEMIN4 gene (rs1062923, rs2740348 and rs910925) and their relationship with CRC.

Methods: The study comprised 203 patients and 179 age and sex matched controls. Genotyping of GEMIN4 gene variants was done using Taqman® assay. The association of GEMIN4 variants with CRC was done by odds ratio analysis. Haplotype analysis was done to see the combined effect of studied variants on CRC.

Results: Patients carrying all variant genotypes for GEMIN4 rs1062923 (odds ratio [OR]= 0.205; 95% confidence interval [CI] = 0.1034-0.4065 for CC variant and [OR] = 0.1436; [CI] = 0.0869-0.2373 for CT variant, respectively) and GEMIN4 rs2740348 (odds ratio [OR] = 0.4498; 95% confidence interval [CI] = 0.2342-0.8637 for CC variant and [OR] = 0.3986; [CI] = 0.2043-0.7776 for CG variant, respectively) showed significant association in lower occurrence of cancer, whereas in case of GEMIN4 G/C rs910925 variant genotype, no significance correlation was found.

Conclusion: Our study gives a substantive support for the association between the GEMIN4 gene variants/miRNA biogenesis and CRC risk.</br&gt.


Bariatric Surgery and COVID-19: What We Have Learned from the Pandemic in Iran: a Retrospective Observational Cohort Study.
Little is known about the symptoms of coronavirus disease 2019 (COVID-19) on patients with morbid obesity following bariatric surgery (BS) in Iran. Thus, we sought to investigate the symptoms and effect of COVID-19 in patients with morbid obesity following, or candidates for, BS in Iran. In this retrospective observational cohort study, we enrolled 236 morbid obese patients following (surgical group) or candidates (nonsurgical group) for bariatric surgery. Demographics, probable COVID-19 incidence, acute and persistent COVID-19 symptoms, and clinical outcome parameters of bariatric patients and candidates for BS were compared. The incidence of probable COVID-19 was assessed including the clinical definition of probable case, according to World Health Organization criteria. The incidence of probable COVID-19 among surgical and nonsurgical groups was significantly different (20.6% vs 26.08%, respectively, p = 0.046). The probable case of surgical patients had a shorter length of symptoms and hospitalization duration, and a lower proportion of admission in ICUs and hospitals with respect to nonsurgical patients (p < 0.001). Surgical patients had a greater prevalence of persistent symptoms including anorexia, food intolerance, and anosmia-hyposmia than nonsurgical patients. Moreover, surgical patients with probable COVID-19 had a significantly higher proportion of diabetic patients than surgical patients without probable COVID-19 (20% vs 9.3%). These findings highlight the need to evaluate the persistent symptoms of COVID-19 and the importance of nutritional support for at least several weeks after COVID-19 symptom onset. Moreover, it seems that COVID-19 incidence in post-bariatric surgery patients could reduce the effectiveness of bariatric surgery in the resolution of diabetes.


Adaptive parameter estimation for the expanded sandwich model.
An expanded-sandwich system is a nonlinear extended block-oriented system in which memoryless elements in conventional block-oriented systems are displaced by memory submodels. Expanded-sandwich system identification has received extensive attention in recent years due to the powerful ability of these systems to describe actual industrial systems. This study proposes a novel recursive identification algorithm for an expanded-sandwich system, in which an estimator is developed on the basis of parameter identification error data rather than the traditional prediction error output information. In this scheme, a filter is introduced to extract the available system information based on miserly structure layout, and some intermediate variables are designed using filtered vectors. According to the developed intermediate variables, the parameter identification error data can be obtained. Thereafter, an adaptive estimator is established by integrating the identification error data compared with the classic adaptive estimator based on the prediction error output information. Thus, the design framework introduced in this research provides a new perspective for the design of identification algorithms. Under a general continuous excitation condition, the parameter estimation values can converge to the true values. Finally, experimental results and illustrative examples indicate the availability and usefulness of the proposed method.


A two pathway model for N2O emissions by ammonium oxidizing bacteria supported by the NO/N2O variation.
In this work, a new model for nitritation combining two N2O emission pathways was confronted with both NO and N2O measurements during nitrification. The model was calibrated with batch experiments and validated with long-term data collected in a sequencing batch reactor (SBR). A good prediction of the evolution of N2O emissions for a varying level of nitrite was demonstrated. The NO/N2O ratio was shown to vary during nitritation depending on the nitrite level. None of the models based on a single pathway could describe this variation of the NO/N2O ratio. In contrast, the 2 pathway model was capable of describing the trends observed for the NO/N2O ratio and gave better predictions of N2O emission factors. The model confirmed that the decrease of the NO/N2O ratio can be explained by an increase of the ND pathway to the detriment of the NN pathway. The ND pathway was systematically the predominant pathway during nitritation. The combined effect of nitrite (or free nitrous acid) and dissolved oxygen (DO) on the contribution of each pathway was in agreement with practical observations and the literature.


Multiple anechoic hepatic nodules in a patient with malignant lymphoma: report of a case with an emphasis on B-mode sonograms.
We present a case of hepatic malignant lymphoma (ML) in which the hepatic ML nodules were imaged as round anechoic nodules with posterior echo enhancement, mimicking hepatic cysts on B-mode ultrasonography (US). However, the boundary echo between the nodules and the surrounding hepatic tissue seemed to be less distinct than that of a hepatic cyst. Contrast-enhanced US showed the nodules to be hypervascular, which ruled out the possibility of hepatic cysts. Our observation stresses the importance of boundary echo for the diagnosis of hepatic ML on B-mode US. We also offer a possible explanation for this phenomenon.


Correction to: The 3.5-year survival rates of primary molars treated according to three treatment protocols: a controlled clinical trial.
Mw. M. Mijan will defend her PhD thesis on 15th September 2017. Whilst reviewing her work in preparation to the event, we discovered a few irregularities that prompted a recheck of the database and ditto analyses. These activities have lead to a few textual changes in the publication.


Modality-specific occult intrarenal pseudoaneurysm in a renal allograft and the legacy of catheter angiography.
A 69-year-old man with history of end-stage-renal disease (ESRD) underwent successful kidney transplantation from a cadaveric donor in November 2011. However, posttransplant recovery was complicated by delayed graft function and recurrent gross hematuria. Serial Doppler ultrasound (US) of the renal allograft demonstrated a pseudoaneurysm with interval increase in size. However, it could not be visualized with other modalities, including an initial angiogram (postoperative day 49) and a second angiogram (postoperative day 68), followed by surgical exploration (postoperative day 71), which demonstrated complete intra-aneurysmal thrombosis on intraoperative Doppler US. Unfortunately, the patient's hematuria continued and a repeat Doppler US 48 hours later demonstrated a persistent pseudoaneurysm. Therefore, on postoperative day 75, we performed targeted percutaneous intra-aneurysmal thrombin injection under dual image guidance, which showed complete intra-aneurysmal thrombosis on intraprocedural Doppler US. Hematuria recurred the next day. A third angiogram (postoperative day 77) finally illuminated the hidden pseudoaneurysm occult on the first and second angiographic studies (sensitivity [index case] 33%) and surgery. This allowed for successful coil embolization of a subsegmental feeding branch with an excellent outcome. We support a more aggressive management with serial angiography and embolization of the intrarenal symptomatic pseudoaneurysm rather than surgery in renal allograft recipients, with the benefits outweighing the risks.


Gene expression profiling to identify genes associated with high-invasiveness in human squamous cell carcinoma with epithelial-to-mesenchymal transition.
The process of epithelial-to-mesenchymal transition (EMT) involves the acquisition of high-invasiveness by tumor. Snail represses target genes and induces EMT. In this study, we defined the signatures of gene expressions by cDNA microarray analyses in both human squamous cell carcinoma (SCC) cell lines with spontaneous EMT and with Snail-induced EMT, which exhibited high-invasive behavior in vitro. Of the 17,000 cDNA probes, 61 genes were found differentially expressed with >2- or <0.5-fold ratio and shared among the EMT phenotype cell lines, indicating candidates for invasion-associated genes regulated by Snail. Category analysis showed that these genes were mainly classified as development/differentiation, metabolism, apoptosis, angiogenesis and cell adhesion. These data illustrated that Snail regulates various molecular pathways for the establishment of EMT and the acquisition of high-invasiveness in SCC cells, yielding insight into the progression of SCC.


The effect of self-organizing map architecture based on the value migration network centrality measures on stock return. Evidence from the US market.
Complex financial systems are the subject of current research interest. The notion of complex network is used for understanding the value migration process. Based on the stock data of 498 companies listed in the S&P500, the value migration network has been constructed using the MST-Pathfinder filtering network approach. The analysis covered 471 companies included in the largest component of VMN. Three methods: (i) complex networks; (ii) artificial neural networks and (iii) MARS regression, are developed to determine the effect of network centrality measures and rate of return on shares. A network-based data mining analysis has revealed that the topological position in the value migration network has a pronounced impact on the stock's returns.


The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes.
The early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic β cells. Here we show that exposure to proinflammatory cytokines reveals a marked plasticity of the β-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the β-cell transcriptome, proteome and three-dimensional chromatin structure. Our data indicate that the β-cell response to cytokines is mediated by the induction of new regulatory regions as well as the activation of primed regulatory elements prebound by islet-specific transcription factors. We find that T1D-associated loci are enriched with newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human β cells. Our study illustrates how β cells respond to a proinflammatory environment and implicate a role for stimulus response islet enhancers in T1D.


Adsorption of phenol, p-chlorophenol and p-nitrophenol onto functional chitosan.
Functional chitosan, chemically modified by salicylaldehyde (CS-SA), beta-cyclodextrin (CS-CD), and a cross-linked beta-cyclodextrin polymer (EPI-CD) were prepared as adsorbents to remove phenol, p-nitrophenol and p-chlorophenol from aqueous solution. Langmuir and Freundlich models were applied to describe the adsorption isotherm of phenols, and adsorption parameters were evaluated. Functional chitosan displayed outstanding adsorption ability for phenols. To our surprise, CS-CD exhibited specific adsorption ability for p-chlorophenol. The possible adsorption interaction was discussed. Effects of pH and KCl on the adsorption suggested that the adsorption of phenols was predominated by hydrogen bonding, hydrophobic interaction and pi-pi interaction not electrostatic interaction. Effect of temperature indicated that the low temperature was favorable for the adsorption of phenols. Separation of phenols and adsorbent regeneration were carried out by simple washing with ethanol and filtrating.


An HLA-C amino-acid variant in addition to HLA-B*27 confers risk for ankylosing spondylitis in the Korean population.
The presence of the HLA-B*27 allele is a major risk factor for the development of ankylosing spondylitis (AS), which causes chronic inflammation of the spine and other sites. We investigated residual effects outside HLA-B within the major histocompatibility complex (MHC) region in the Korean population. Using the Korean HLA reference panel, we inferred the classic HLA alleles and amino-acid residues of the six HLA genes (HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1) and MHC single-nucleotide polymorphisms in 3820 Korean subjects, including 654 Korean cases of AS and 3166 controls, who were genotyped by using Immunochip. Logistic regression and log-likelihood ratio tests were used in AS association tests for imputed markers. The most significant associations were identified at amino-acid positions in the epitope-binding site of HLA-B (P = 1.71 × 10(-481) at position 70, P = 7.20 × 10(-479) at position 97, and P = 2.54 × 10(-484) at positions 114), highlighting the risk effect of the HLA-B*27 allele and the protective effects of other classic alleles. A secondary effect was located at the leucine at amino-acid position 116 in the epitope-binding site of HLA-C (P = 1.69 × 10(-14)), completely tagging the HLA-C*15:02 allele. This residue had a large effect in HLA-B*27-negative patients (odds ratio = 6.6, 95 % confidence interval = 3.8 to 11.4). The four amino-acid positions of HLA-B and -C account for most of the associations between AS and MHC in the Korean population. This finding updates the list of AS susceptibility loci and provides new insight into AS pathogenesis mediated by MHC class I molecules.


Association between jejunal remodeling in fasting rats and hypersensitivity of intestinal afferent nerves to mechanical stimulation.
Remodeling of Intestinal properties and hypersensitivity of intestinal afferents to mechanical stimulation were previously demonstrated in a fasting rat model. Other studies investigated the association between mechanical and histological remodeling during fasting. This study aimed to further explore the relationship between the jejunal remodeling and intestinal afferent hypersensitivity by combining afferent nerve recordings with histological and mechanical data. Eight male Sprague Dawley rats had no access to food for 7 days (Fasting group). Seven male rats served as controls (Control group). Jejunal segments were studied in vitro in an organ bath for analysis of afferent signaling and for analysis of mechanical and histomorphological parameters. Correlation analyses were done to analyze association between nerve activity (spike rate increase ratio, SRIR) at distension levels of 20, 40 and 80 cmH2O and mechanical stress and histomorphological changes of the jejunal segments. Compared with the Control group, the main findings in jejunal segments in the Fasting group were (1) Most histomorphometry parameters were reduced (P < 0.05-P < 0.001), (2) SRIR values were higher (P < 0.001), (3) The relative numbers of intermuscular and submucosal neurons were increased (P < 0.05-P < 0.01), and (4) SRIR was negatively correlated with intestinal wall thickness, circumferential muscle layer thickness and positively correlated with the inner residual strain, the number of neurons, and the mechanical stress. In conclusion, the fasting-induced histomorphological remodeling (reduced wall thickness and increased relative number of neurons) and biomechanical remodeling (residual strain changes and high stress level) of the intestine in fasting rats were associated with hypersensitivity of intestinal afferents. Afferent hypersensitivity appears to be dependent on stress rather than on strain.


Characterization of biodegradable drug delivery vehicles with the adhesive properties of leukocytes.
The site-specific expression of selectins (E- and P-selectin) on endothelial cells of blood vessels during inflammation provides an opportunity for the targeted delivery of anti-inflammatory drugs to inflammatory sites. Previous work in our laboratory has shown that artificial capsules with the adhesive properties of leukocytes can be made by attaching leukocyte adhesive ligands to polystyrene microspheres. In this work, we have adapted this technology to create a targeted delivery system using biodegradable, poly lactic-co-glycolic-acid (PLGA) microspheres. Biotinylated-Sialyl Lewis(x) (sLe(x)), a carbohydrate that serves as a ligand to selectins, was attached to the surface of avidin-linked PLGA microspheres. These carbohydrate-coated microspheres mimic the adhesive behavior of leukocytes on selectins in flow chambers, displaying slow rolling under flow. The rolling velocities displayed by sLe(x)-coated microspheres were similar to those displayed by leukocytes rolling on P- or E-selectin coated surfaces, and these rolling velocities, which relate to the residence time of the capsules, can be tuned by changing the density of carbohydrate residues on microsphere surfaces. We have also demonstrated that these microspheres will release model drugs on a time scale of several days. Therefore, we have made a targeted drug delivery vehicle that mimics the adhesive properties of leukocytes and is biodegradable.


The role of mechanical impact in action-related auditory attenuation.
A number of studies have shown that sounds temporally close to one's own finger movements elicit lower-amplitude auditory event-related potentials (ERPs) than do the same tones when they are only listened to. In these studies, the actions have involved making a mechanical contact with an object. In the present study, the role of mechanical contact with an object was investigated in action-related auditory attenuation. In three experiments, participants performed a time-interval production task. In each experiment, in one condition the action involved touching an object, but no mechanical contact was made in the other. The estimated tone-related ERP contributions to the action-tone coincidence ERP waveforms (calculated by subtracting the action-related ERP from the coincidence ERP) were more attenuated when the action involved moving the finger and making a mechanical contact at the end of the movement. However, when participants kept their finger on a piezoelectric element and applied pressure impulses without moving their finger, the action did not result in stronger attenuation of the tone-related auditory ERP estimates. Although these results may suggest that auditory ERP attenuation is stronger for actions resulting in mechanical impact, they also imply that mechanical impact may confound and lead to the overestimation of auditory ERP attenuation in such paradigms, because the impact may result in faint but audible sounds.


Predicting isoproturon long-term mineralization from short-term experiment: Can this be a suitable approach?
A worldwide used pesticide - isoproturon (IPU) - was selected to test whether short-term experiments can be used to predict long-term mineralization of IPU in soil. IPU-mineralization was measured for 39 and 265 days in four different agricultural soils with a low mineralization dynamic. Additionally, in one soil IPU dissipation, formation and dissipation of metabolites, formation of non-extractable residues (NER) and (14)C-microbial biomass from (14)C-IPU were monitored for 39 and 265 days. The data from short-term and long-term experiments were used for model fitting. The long-term dynamics of IPU mineralization were considerably overestimated by the short-term experiments in two soils with neutral pH, while in two other soils with low pH and lower mineralization, the long-term mineralization of IPU could be sufficiently predicted. Additional investigations in one of the soils with neutral pH showed that dissipation of IPU and metabolites could be correctly predicted by the short-term experiment. However, the formation of NER and (14)C-microbial biomass were remarkably overestimated by the short-term experiment. Further, it could be shown that the released NER and (14)C-microbial biomass were the main contributors of (14)CO2 formation at later incubation stages. Taken together, our results indicate that in soils with neutral pH short-term experiments were inadequate to predict the long-term mineralization of IPU.


Ovarian hormone effects on 5-hydroxytryptamine(2A) and 5-hydroxytryptamine(2C) receptor mRNA expression in the ventral hippocampus and frontal cortex of female rats.
Alterations in female gonadal hormones are associated with anxiety and mood changes. The aim of the present study was to determine influences of chronic gonadal hormone supplementation on 5-HT(2A) and 5-HT(2C) receptor mRNA levels in the ventral hippocampus and the frontal cerebral cortex. Ovariectomized adult female Sprague-Dawley rats (n=37) received implantation of subcutaneous pellets containing different dosages of 17beta-estradiol alone or in combination with progesterone, or placebo pellets, for 2 weeks. Serotonin receptor mRNA levels were analyzed by in situ hybridization in the ventral hippocampus and 5-HT(2A) receptor mRNA also in the frontal cortex. Estradiol treatment in combination with low-dose progesterone increased 5-HT(2A) receptor mRNA by 43% in the CA2 region of the ventral hippocampus, while estradiol combined with high-dose progesterone increased the expression of this gene by 84% in ventral CA1. 5-HT(2A) mRNA expression in the frontal cortex was not influenced by hormone manipulation. 5-HT(2C) receptor gene expression was in the ventral hippocampus decreased in the CA2, ventral CA1 and the subiculum subregions by high-dose estradiol treatment (8-20% decreases). Effects on mood by gonadal hormones can be mediated, at least partly, through influences on 5-HT(2A) and 5-HT(2C) receptor expression.


Investigation of small molecule inhibitors of the SARS-CoV-2 papain-like protease by all-atom microsecond modelling, PELE Monte Carlo simulations, and in vitro activity inhibition.
The SARS-CoV-2 papain-like (PLpro) protease is essential for viral replication. We investigated potential antiviral effects of hypericin relative to the well-known noncovalent PLpro inhibitor GRL-0617. Molecular dynamics and PELE Monte Carlo simulations highlight favourable binding of hypericin and GRL-0617 to the naphthalene binding pocket of PLpro. Although not potent as GRL-0617 (45.8 vs 1.6 µM for protease activity, respectively), in vitro fluorogenic enzymatic assays with hypericin show concentration-dependent inhibition of both PLpro protease and deubiquitinating activities. Given its use in supplementations and the FDA conditional approval of a synthetic version, further evaluation of hypericin as a potential SARS-CoV-2 antiviral is warranted.


Synthesis and application of a green surfactant for the treatment of water containing PFAS/ hazardous metal ions.
In this work, the effectiveness of a biodegradable and natural surfactant synthesized through a novel method has been studied through the ion flotation process to treat waters containing Per/Poly Fluoroalkyl Substances (PFAS) and heavy-metal ions. This cysteine-based surfactant, which is environmentally acceptable, showed considerable solubility and foaming ability over a wide range of pH. It also could remove 97-99(%) of 5 mg/L of cadmium, chromium, copper, nickel, zinc, and manganese ions in a single batch physicochemical process. Moreover, for the first time, a foam fractionation method in association with using this cysteine-based surfactant was applied for perfluorooctanoic acid (PFOA) removal from water. This surfactant was used as a co-surfactant and could readily remove 72% of PFOA (40 mg/L) from water. The characterization of the surfactant was undertaken using 1H NMR, FT-IR, elemental analysis, melting point, and determination of its critical micelle concentration (CMC). This environmentally friendly surfactant has high potential applications in green chemistry especially in the treatment of waters contaminated with PFAS/heavy-metal ions.


Twenty-Eight Cases of Extraocular Sebaceous Carcinoma: A Correlative Clinicopathological and Immunohistochemical Analysis of Extraocular Sebaceous Carcinomas and Benign Sebaceous Gland Tumors.
Extraocular sebaceous carcinoma (ESC) is a rare appendiceal skin tumor. In contrast to ocular sebaceous carcinoma, information about the exact cellular architecture of these lesions is scarce and the histogenesis of ESC is unknown. Here, we extend our previous study and investigate 28 extraocular carcinomas in comparison to 54 benign sebaceous tumors and 8 cases of normal sebaceous glands using a broad spectrum of antibodies against p63, several keratins, adipophilin, EMA, Ki67, androgen receptor, and mismatch repair proteins. This observational study demonstrates that p63- and K5/14-positive basaloid cells are key cells in normal sebaceous gland and in all sebaceous tumors and that these basaloid cells give rise to EMA+, adipophilin+ sebocytes, and K5/14+, K7±, K10± ductal structures. Finally, about half of ESC is associated with superficial in situ neoplasia, which provides evidence that at least part of these carcinomas arises from flat superficial in situ carcinoma. In contrast to the normal sebaceous gland, about half of all sebaceous tumors lack keratin K7. MMR protein IHC-profiles role will be discussed.


Comparative Transcriptomics Reveals the Molecular Mechanism of the Parental Lines of Maize Hybrid An'nong876 in Response to Salt Stress.
Maize (Zeamays L.) is an essential food crop worldwide, but it is highly susceptible to salt stress, especially at the seedling stage. In this study, we conducted physiological and comparative transcriptome analyses of seedlings of maize inbred lines An'nong876 paternal (cmh15) and An'nong876 maternal (CM37) under salt stress. The cmh15 seedlings were more salt-tolerant and had higher relative water content, lower electrolyte leakage, and lower malondialdehyde levels in the leaves than CM37. We identified 2559 upregulated and 1770 downregulated genes between salt-treated CM37 and the controls, and 2757 upregulated and 2634 downregulated genes between salt-treated cmh15 and the controls by RNA sequencing analysis. Gene ontology functional enrichment analysis of the differentially expressed genes showed that photosynthesis-related and oxidation-reduction processes were deeply involved in the responses of cmh15 and CM37 to salt stress. We also found differences in the hormone signaling pathway transduction and regulation patterns of transcription factors encoded by the differentially expressed genes in both cmh15 and CM37 under salt stress. Together, our findings provide insights into the molecular networks that mediate salt stress tolerance of maize at the seedling stage.


Effects of variation of ion and methylation of carrier on the rate constants of macrotetralide-mediated ion transport in lipid bilayers.
The effects of methylation on the rate constants of carrier-mediated ion transport have been studied on monooleindecane bilayers with K+, Rb+, NH4+, and Tl+ ions, using the series of homologue carriers, nonactin, monactin, dinactin, trinactin, and tetranactin, each member of the series differing from the previous one by only one methyl group. Measurements of the amplitude and time constant of the current relaxation after a voltage jump over a large domain of voltage and permeant ion concentration, together with a computer curve-fitting procedure, have allowed us, without the help of steady-state current-voltage data, to deduce and compare the values of the various rate constants for ion transport: formation (kRi) and dissociation (kDi) of the ion-carrier complex at the interface, translocation across the membrane interior of the carrier (ks) and the complex (kis). With the additional information from steady-state low-voltage conductance measurements, we have obtained the value of the aqueous phase-membrane and torus-membrane partition coefficient of the carrier (gammas and gammas). From nonactin to tetranactin with the NH4+ ion, kis, and gammas are found to increase by factors of 5 and 3, respectively, kDi and gammas to decrease respectively by factors 8 and 2, while kRi and ks are practically invariant. Nearly identical results are found for K+, Rb+, and Tl+ ions. kRi, ks and kis are quite invariant from one ion to the other except for Tl+ were kRi is about five times larger. On the other hand, kDi depends strongly on the ion, indicating that dissociation is the determining step of the ionic selectivity of a given carrier. The systematic variations in the values of the rate constants with increasing methylation are interpreted in terms of modification of energy barriers induced by the carrier increasing size. Within this framework, we have been able to establish and verify a fundamental relationship between the variations of kis and kDi with methylation.


Mitochondrial DNA quantification correlates with the developmental potential of human euploid blastocysts but not with that of mosaic blastocysts.
We aimed to study the association between adjusted mtDNA levels in human trophectoderm biopsy samples and the developmental potential of euploid and mosaic blastocysts. We analyzed relative mtDNA levels in 2,814 blastocysts obtained from 576 couples undergoing preimplantation genetic testing for aneuploidy from June 2018 to June 2021. All patients underwent in vitro fertilization in a single clinic; the study was blinded-mtDNA content was unknown at the time of single embryo transfer. The fate of the euploid or mosaic embryos transferred was compared with mtDNA levels. Euploid embryos had lower mtDNA than aneuploid and mosaic embryos. Embryos biopsied on Day 5 had higher mtDNA than those biopsied on Day 6. No difference was detected in mtDNA scores between embryos derived from oocytes of different maternal ages. Linear mixed model suggested that blastulation rate was associated with mtDNA score. Moreover, the specific next-generation sequencing platform used have a significant effect on the observed mtDNA content. Euploid embryos with higher mtDNA content presented significantly higher miscarriage rates and lower live birth rates, while no significant difference was observed in the mosaic cohort. Our results will aid in improving methods for analyzing the association between mtDNA level and blastocyst viability.


Transarticular fusion for treatment of cystic lesion arising from an odontoid fracture.
Odontoid fractures are the most common upper cervical spine fracture. There are two mechanisms in which odontoid fractures occur, most commonly hyperflexion of the neck resulting in displacement of the dens anteriorly and hyperextension resulting in posterior dens displacement. Type 2 fractures are the most common and are associated with significant non-union rates after treatment. One possible consequence of an odontoid fracture is a synovial cyst, resulting in spinal cord compression, presenting as myelopathy or radiculopathy. Synovial cysts as a result of spinal fracture, usually of the facet joint, are most common in the lumbar region, followed by the thoracic and then cervical region; cervical cysts are rare. Fracture and subsequent cyst formation is thought to be related to hyper-motion or trauma of the spine. This is reinforced by the appearance of spinal synovial cysts most commonly at the level of L4/5; this being the region with the biggest weight-bearing function. The most common site of cervical cyst formation is at the level of C7/T1; this is a transitional joint subjected to unique stress and mechanical forces not present at higher levels. Treatment of a cervical synovial cyst at the level of the odontoid is challenging with little information available in the literature. The majority of cases appear to implement posterior surgical resection of the cyst, with fusion of adjacent cervical vertebrae to stabilise the fracture, resulting in restricted range of movement. We describe a case concerning a 39-year-old female who presented with uncertain cause of odontoid fracture, resulting in a cystic lesion compressing the upper cervical spinal cord. Minimal invasive surgery of C1/C2 transarticular fusion was successfully performed resulting in significant improvement of neurological symptoms in this patient. At 1-year follow-up, the cyst had resolved without surgical removal and this was confirmed by radiological measures.


The effect of in vivo hyperoxic exposure on the release of endogenous histamine from the rat isolated perfused lung.
Female rats were exposed to either 1 atm air or 100% O2 for 12, 24, or 48 hr. The rats were killed, the lungs were removed, and an isolated perfused lung (IPL) system was prepared. The isolated lung preparation was perfused with a modified Krebs-Henseleit buffer in a recirculating system, and the effect of the O2 exposures on histamine release from the IPL was determined. The effect of these O2 exposures on malondialdehyde formation in the IPL also was examined. Maximal release of histamine occurred after 20 min of perfusion. A linear relationship was found between the maximal histamine concentration released into the perfusate and the length of time the rats were exposed to normobaric hyperoxia. Malondialdehyde in lung perfusate also increased in a linear manner with increasing O2 exposure time. Addition of the H1-receptor antagonist, d-chlorpheniramine, to the perfusate completely inhibited basal histamine release from the IPL of both air- and O2-exposed rats, while addition of the H2-receptor antagonist, metamide, potentiated the release process. There was no significant effect demonstrated when an equimolar concentration of atropine was added to the perfusate. Arterial plasma histamine from rats exposed to 100% O2 for 24 hr increased 40% when compared to air-exposed controls, while histamine release from the IPL increased 75%. In conclusion, exposure of rats to normobaric hyperoxia caused both histamine release and malondialdehyde formation. Histamine release probably occurred as a result of a free radical-induced peroxidation of the lipid membrane of histamine-containing mast cells. Release of histamine from the IPL may be an early biochemical marker of damage by O2.


An Experimental Tool to Estimate the Probability of a Nucleotide Presence in the Crystal Structures of the Nucleotide-Protein Complexes.
A correlation between the ligand-protein affinity and the identification of the ligand in the experimental electron density maps obtained by X-ray crystallography has been tested for a number of RNA-binding proteins. Bacterial translation regulators ProQ, TRAP, Rop, and Hfq together with their archaeal homologues SmAP have been used. The equilibrium dissociation constants for the N-methyl-anthraniloyl-labelled adenosine and guanosine monophosphates titrated by the proteins have been determined by the fluorescent anisotropy measurements. The estimated stability of the nucleotide-protein complexes has been matched with a presence of the nucleotides in the structures of the proposed nucleotide-protein complexes. It has been shown that the ribonucleotides can be definitely identified in the experimental electron density maps at equilibrium dissociation constant <10 μM. At KD of 20-40 μM, long incubation of the protein crystals in the nucleotide solution is required to obtain the structures of the complexes. The complexes with KD value higher than 50 μM are not stable enough to survive in crystallization conditions.


Constituents from Hoya parasitica and their cell growth inhibitory activity.
An androstanoid, hoyasterone (1), a sesquiterpene, 15-bulnesolic acid (2), and a phenolic compound, 1-(4-hydroxy-3-methoxyphenyl)-1-methoxypropan-2-ol (3), together with a known triterpene, dihydrocanaric acid, were isolated from Hoya parasitica. Structures were elucidated by 1 D and 2 D NMR and mass spectroscopic analysis. Among the isolated compounds, only dihydrocanaric acid exhibited growth inhibitory activity against both HeLa and SW480 cells.


Alleged drug facilitated sexual assault (DFSA) in Northern Ireland from 1999 to 2005. A study of blood alcohol levels.
Alleged sexual assault cases, identified from the forensic science Northern Ireland (FSNI) database, which had toxicology assays carried out on either blood or urine samples, were examined for the years 1999 up to and including 2005. In 1999 there were 30 toxicology requests while in 2005 there were 51, representing a 70% increase. The percentage of cases containing alcohol, drugs or both increased from 66% in 1999 to 78% in 2005. The estimated average blood alcohol concentration remained broadly similar throughout the spread of years. It was found to be 218mg% (milligrams per 100 millilitres) in 1999 and 217mg% in 2005. The actual number of cases studied within the 12h cut-off time rose from 9 in 1999 to 22 in 2005. The relationship between negative toxicology results and time delay between the alleged assault and forensic sampling was examined. This showed that between 44% and 74% of cases were found to have a time delay of >12h. Some of these cases may therefore represent false negative results. The presence of drugs, either alone or in combination with other drugs, doubled between 1999 and 2005. Increased identification was found with antidepressants, recreational drugs, benzodiazepines and analgesics, some of which were also associated with alcohol consumption. The findings are sufficient to cause alarm for the health and safety of certain individuals and their increased vulnerability to sexual assault in some social settings. Additionally, the legal implications of what constitutes valid consent needs to be considered further in the light of these findings, if attrition rates are to improve.


B7-H3 Expression in Merkel Cell Carcinoma-Associated Endothelial Cells Correlates with Locally Aggressive Primary Tumor Features and Increased Vascular Density.
Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune-checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease.Experimental Design: Expression of immune-regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA, and OX-40) was assessed using singlet chromogenic IHC in 10 primary MCCs. Multiplex immunofluorescence quantified CD31 and B7-H3 expression in 52 primary and 25 metastatic MCCs. B7-H3 and CD31 expressions were tabulated as a series of independent (X,Y) cell centroids. A spatial G-function, calculated based on the distribution of distances of B7-H3+ (X,Y) cell centroids around the CD31+ (X,Y) cell centroids, was used to estimate a colocalization index equivalent to the percentage of CD31-positive cell centroids that overlap with a B7-H3-positive cell centroid. Primary and metastatic MCCs exhibit a dynamic range of colocalized CD31 and B7-H3 expression. Increasing colocalized expression of B7-H3 with CD31 significantly associated with increased tumor size (P = 0.0060), greater depth of invasion (P = 0.0110), presence of lymphovascular invasion (P = 0.0453), and invasion beyond skin (P = 0.0428) in primary MCC. Consistent with these findings, increasing colocalized expression of B7-H3 and CD31 correlated with increasing vascular density in primary MCC, but not metastatic MCC. Our results demonstrate that colocalized expression of B7-H3/CD31 is a poor prognostic indicator and suggest therapies targeting B7-H3 may represent an effective approach to augmenting immune-activating therapies for MCC.


Preparation of Cu-Ni alloy nanocrystallites in water-in-oil microemulsions.
The well-mixed copper-nickel nanoparticles were prepared when the molar ratio of Cu2+ to Ni2+ was 1:1 by simultaneous reduction of CuSO4 and NiCl2 with hydrazine in the microemulsion of SDS/n-butanol/n-heptane/water at 70 degrees C, and was characterized by TEM, ED, TGA, EDS, and XRD. ED analysis and XRD patterns suggest the formation of the homogeneous alloy structure in the bimetallic nanoparticles. Average size of the sample calculated from the full width at medium height of peak 111 in the XRD patterns using Scherrer formula is 5.53 nm. TEM photographs show a narrow distribution of Cu-Ni nanoparticles that essentially are monodispersed and the mean diameter is 12 nm. The results indicate that the composition and size of alloy nanoparticles depend on the mole ratio of H2O to SDS, the method of addition of Cu2+ and Ni2+, and the mole ratio of Cu2+ and Ni2+ in the initial precursor solution.


Ocular traumas in working age adults in Finland - Helsinki Ocular Trauma Study.
To describe epidemiology, causes, treatments and outcomes of ocular injuries in adults aged 17 to 60 in southern Finland. All new ocular trauma patients admitted to the Helsinki University Eye Hospital (HUEH), during 1 year in 2011-2012. The data were from hospital records and prospectively from patient questionnaires. The follow-up time was 3 months. The incidence for ocular injury was 88/100 000/year. From 831 trauma patients, 80% were men, 34% were work-related injuries, and 11% were assaults. Most of the injuries were minor traumas (54%). Contusions (22.5%) and chemical injuries and burns (13%) were common. Fractures (5%), lid wounds (3%), open globe injuries (OGI, 2%) and optic nerve injuries (0.5%) were rare. The main causes of ocular injury were superficial foreign bodies (33%), chemicals (13%), body parts (13%) and sports equipment (10%). The most dangerous objects were needles, stones, pellet guns, tools and guns. No patient with OGI used protective eyewear. All OGI and most of contusions needed a lifelong follow-up. Permanent impairment (73 patients, 9%) was caused most often by body parts, sports equipment and work tools. A typical ocular trauma patient was a man aged 31-45 with a minor trauma caused by a foreign body at work and a final visual acuity of 20/20. Most common serious injuries were contusion, OGI or fracture at home or at work and were caused by a body part, sport equipment or work tool. Factors causing common and serious eye injuries provide the targets for protective measures.


Analysis of fetal sex in TCC sample DNA: a contribution to the validation of this approach.
We compared two methods of collection of transcervical cell samples, mucus aspiration and cytobrush, with respect to the efficiency in determining fetal sex and we correlated the results with the week of gestation (7-11 weeks) to evaluate if the age of gestation influenced the success of the analysis. DNA extracted from TCC samples recovered by mucus aspiration (n = 27) and cytobrush (n = 36) were analysed by nested PCR to predict fetal sex. The statistical indices of sensitivity, specificity, positive predictive value and negative predictive value were determined, and compared with those of other studies previously performed. No statistically significant difference was found between the two methods of TCC sampling concerning the success of fetal sex prediction which was high for both methods (78 per cent and 89 per cent) and no correlation with the week of gestation was found. Transcervical cell sampling represents an encouraging prospect for first-trimester prenatal diagnosis even when the least invasive techniques are used.


Sentinel lymph node biopsy for melanoma: a critical update for dermatologists after two decades of experience.
The technique of lymphatic mapping and sentinel node biopsy represents a minimally invasive approach to accurately stage the regional lymph node basin as a component of the initial management of selected patients with stage I and II cutaneous melanomas. In addition to its significant role in accurate regional nodal staging and prognosis, important goals of this procedure include improved regional disease control and possible survival benefit. After 20 years of experience, questions and some controversy persist. This review provides the dermatology community with a critical analysis of major publications that have defined the role of sentinel node biopsy, addresses several contemporary issues, and provides recommendations for appropriate patient referral.


GRP78 induced by estrogen plays a role in the chemosensitivity of endometrial cancer.
Molecular chaperone 78 kDa glucose-regulated protein (GRP78) is a residential protein in the endoplasmic reticulum (ER) that is induced by an unfolded-protein response triggered under many kinds of stress against a cell. GRP78 is also known to act as an anti-apoptotic factor by protecting ER-stress-induced cell death. In this study, we examined the significance of GRP78 expression in endometrial cancer. Tissue samples obtained from patients with a diagnosis of enodometrial cancer were subjected to immunohistochemistry and RT-PCR to determine protein and mRNA expression levels of GRP78 and estrogen receptor α. We used Western blot and RT-PCR to examine whether estrogen induced GRP78 expression in cancer cell lines. Western blots and MTT assays of GRP78 siRNA transfected Ishikawa and HHUA cells were used to demonstrate whether GRP78 is involved in chemoresistence. GRP78 was highly expressed in well and moderately differentiated endometrial carcinoma. Estrogen induced GRP78 expression, which was correlated with cell viability and resistance to paclitaxel and cisplatin. Western blot analysis indicated that active caspase-3 and the 85-kDa protein poly (ADP-ribose) polymerase (PARP) were increased by incubation with either paclitaxel or cisplatin, suggesting that the apoptotic pathway was involved in cancer-drug-induced cell death. These results may open up a novel therapeutic strategy for endometrial cancer: namely, the targeting of GRP78 to sensitize the tumor cell to chemotherapy.


Synthesis of ordered mesoporous crystalline carbon-anatase composites with high titania contents.
A direct-triblock-copolymer templating method is demonstrated to synthesize ordered mesoporous crystalline C-TiO(2) (MCT) composites using phenolic resins and acid-base pairs [acidic TiCl(4) and basic counterpart Ti(OC(4)H(7))(4)] as carbon and titanium sources, respectively. The composites possess highly crystalline anatase pore walls that are "glued" by amorphous carbon, ordered mesostructure, high surface areas (approximately 200 m(2)/g), and large pore volumes (approximately 0.15 cm(3)/g). The titania content is as high as 87 wt%. MCT composite favors the immobilization of proteins and enhances the electrocatalytic properties in relation to the reduction of hydrogen peroxide.


Minimally invasive protocols and quantification for microglia-mediated perineuronal net disassembly in mouse brain.
Enzymatic digestion of the extracellular matrix with chondroitinase-ABC reinstates juvenile-like plasticity in the adult cortex as it also disassembles the perineuronal nets (PNNs). The disadvantage of the enzyme is that it must be applied intracerebrally and it degrades the ECM for several weeks. Here, we provide two minimally invasive and transient protocols for microglia-enabled PNN disassembly in mouse cortex: repeated treatment with ketamine-xylazine-acepromazine (KXA) anesthesia and 60-Hz light entrainment. We also discuss how to analyze PNNs within microglial endosomes-lysosomes. For complete details on the use and execution of this protocol, please refer to Venturino et al. (2021).


Preeclampsia at term can be classified into 2 clusters with different clinical characteristics and outcomes based on angiogenic biomarkers in maternal blood.
An antiangiogenic state has emerged as a mechanism of disease in preeclampsia. Angiogenic biomarkers are used in the risk assessment of this syndrome, particularly of early disease. The role of an antiangiogenic state in late preeclampsia is unclear. This study aimed to determine the prevalence, characteristics, and clinical significance of angiogenic/antiangiogenic factor abnormalities in women with preeclampsia stratified according to gestational age at delivery. Two studies were conducted: (1) a longitudinal nested case-control study comprising women with preeclampsia (n=151) and a control group (n=540); and (2) a case series of patients with preeclampsia (n=452). In patients with preeclampsia, blood was collected at the time of diagnosis. Plasma concentrations of placental growth factor and soluble fms-like tyrosine kinase-1 were determined by enzyme-linked immunosorbent assays. An abnormal angiogenic profile was defined as a plasma ratio of placental growth factor and soluble fms-like tyrosine kinase-1 expressed as a multiple of the median <10th percentile for gestational age based on values derived from the longitudinal study. The proportion of patients diagnosed with preeclampsia who had an abnormal angiogenic profile was determined in the case-series participants and stratified by gestational age at delivery into early (≤34 weeks), intermediate (34.1-36.9 weeks), and term (≥37 weeks) preeclampsia. The demographics, clinical characteristics, and pregnancy outcomes of women with preeclampsia with and without an abnormal angiogenic profile were compared. The prevalence of an abnormal angiogenic profile was higher in preterm than in term preeclampsia (for early, intermediate, and term in the case-control study: 90%, 100%, and 39%; for the case series: 98%, 80%, and 55%, respectively). Women with preeclampsia at term who had an abnormal angiogenic profile were more frequently nulliparous (57% vs 35%), less likely to smoke (14% vs 26%), at greater risk for maternal (14% vs 5%) or neonatal (7% vs 1%) complications, and more often had placental lesions consistent with maternal vascular malperfusion (42% vs 23%; all, P<.05) than those without an abnormal profile. Women with preeclampsia at term who had a normal angiogenic profile had a higher frequency of chronic hypertension (36% vs 21%) and were more likely to have class ≥2 obesity (41% vs 23%) than those with an abnormal profile (both, P<.05). Patients with early preeclampsia had an abnormal angiogenic profile in virtually all cases, whereas only 50% of women with preeclampsia at term had such abnormalities. The profile of angiogenic biomarkers can be used to classify patients with preeclampsia at term, on the basis of mechanisms of disease, into 2 clusters, which have different demographics, clinical characteristics, and risks of adverse maternal and neonatal outcomes. These findings provide a simple approach to classify preeclampsia at term and have implications for future clinical care and research.


Elongation differences between the sub-tendons of gastrocnemius medialis and lateralis during plantarflexion in different frontal plane position of the foot.
Gastrocnemius medialis (GM) and lateralis (GL) act at the ankle complex in the sagittal and frontal planes and there is evidence that their actions can be somewhat uncoupled from each other. Some independence of GM and GL from each other could be advantageous, e.g. to stabilise the ankle complex in unstable walking conditions. Given the compartmentalised structure of the Achilles tendon, the sub-tendons of GM and GL may exhibit different elongation during plantarflexion contractions, particularly with the foot in different frontal plane positions. METHODS: Sub-tendon elongation was determined from 18 participants during ramped isometric plantarflexion contractions to 70% of their maximum voluntary contraction (MVC) level with the foot in neutral, inversion and eversion. One-dimensional statistical parametric mapping was applied to determine elongation differences. Elongation within a sub-tendon did not differ in the three foot positions. Elongation was similar between both sub-tendons at very low contraction levels, but GM sub-tendon elongation exceeded GL sub-tendon displacement significantly from 30% MVC. The elongation differences between the sub-tendons were not affected by foot position. Greater GM sub-tendon elongation is likely caused by the greater force production capability of GM but may also indicate that the sub-tendons of GM and GL have different mechanical properties, which is currently unknown. Elongation differences were contraction level dependent suggesting that contributions of GM and GL to plantarflexion torque may also be contraction level dependent.


[Questions about the ADVANCE study].
The symptoms of secondary hyperparathyroidism (SHPT) were substantially changed by the availability of cinacalcet (CC). The recent ADVANCE study, which was a prospective randomized trial comparing two treatment strategies-CC plus low doses of calcitriol analogues (CA) versus higher doses of CA without CC-reports the absence of difference in the primary endpoint, i.e. coronary artery calcification score progression after 12 months. The progression of coronary calcification was related to the initial hypercalcemia and hyperphosphataemia, and low serum PTH level. What was the rationale for defining SHPT with only serum PTH value of more than 300 pg/mL or more than 150 pg/mL associated with a high Ca×P product? Why was this coronary score chosen as the primary endpoint and why was a seemingly short observational period used? Is it correct to consider all forms of SHPT equivalent in terms of set point, response to conventional treatment, or vascular and bone consequences? Why are the biological values of patients not provided? Were the CAs, dialysate calcium, and PTH assay values really equal? Why were only calcium-based phosphate binders used? The main controversial point of the study was to consider all HPT cases as equivalent and able to be treated by one fixed strategy. Therefore, the nephrologist community should conduct relevant independent studies in order to improve the diagnosis and treatment of SHPT.


Mucosal-associated invariant T (MAIT) cells provide B-cell help in vaccinated and subsequently SIV-infected Rhesus Macaques.
Mucosal-associated invariant T (MAIT) cells help combat opportunistic infections. Thus, MAIT cells are of interest in HIV/SIV vaccination and infection. We investigated MAIT cell dynamics and function in rhesus macaque blood and bronchoalveolar lavage (BAL) following mucosal adenovirus (Ad)-SIV recombinant priming, intramuscular SIV envelope boosting and infection following repeated low-dose intravaginal SIV exposures. Increased frequencies of blood MAIT cells over the course of vaccination were observed, which were maintained even 12-weeks post-SIV infection. BAL MAIT cells only increased after the first Ad immunization. Vaccination increased MAIT cell levels in blood and BAL expressing the antiviral cytokine IFN-γ and TNF-α and the proliferation marker Ki67. Upon T cell-specific α-CD3, α-CD28 stimulation, MAIT cells showed a greater capacity to secrete cytokines/chemokines associated with help for B cell activation, migration and regulation compared to CD3+MR1- cells. Culture of MAIT cell supernatants with B cells led to greater tissue like memory B cell frequencies. MAIT cell frequencies in blood and BAL correlated with SIV-specific antibody levels in rectal secretions and with SIV-specific tissue resident memory B cells. Overall, SIV vaccination influenced MAIT cell frequency and functionality. The potential for MAIT cells to provide help to B cells was evident during both vaccination and infection.


Effect of addition of organic waste on reduction of Escherichia coli during cattle feces composting under high-moisture condition.
To ensure Escherichia coli reduction during cattle feces composting, co-composting with a variety of organic wastes was examined. A mixture of dairy cattle feces and shredded rice straw (control) was blended with organic wastes (tofu residue, rice bran, rapeseed meal, dried chicken feces, raw chicken feces, or garbage), and composted using a bench-scale composter under the high-moisture condition (78%). The addition of organic waste except chicken feces brought about maximum temperatures of more than 55 degrees C and significantly reduced the number of E. coli from 10(6) to below 10(2)CFU/g-wet after seven days composting, while in the control treatment, E. coli survived at the same level as that of raw feces. Enhancements of the thermophilic phase and E. coli reduction were related to the initial amount of easily digestible carbon in mass determined as BOD. BOD value more than 166.2 mg O2/DMg brought about significant E. coli reduction.


Purification of UDP-N-acetylglucosamine:glycoprotein N-acetylglucosamine-1-phosphotransferase from Acanthamoeba castellanii and identification of a subunit of the enzyme.
UDP-N-acetylglucosamine:glycoprotein N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) from the soil amoeba Acanthamoeba castellanii has been purified over 100,000-fold by means of wheat germ agglutinin-Sepharose affinity chromatography, DEAE-cellulose chromatography, concanavalin A-Sepharose affinity chromatography, orange A-agarose dye chromatography, and gel filtration on Superose 6. The most purified enzyme has an estimated specific activity of at least 5 mumol of GlcNAc-phosphate transferred/min/mg of protein using alpha-methylmannoside as acceptor. The molecular weight of the native enzyme is approximately 250,000, as determined by gel filtration and glycerol gradients in H2O and D2O. A protein with an apparent M(r) of 97,000 in small scale preparations and its putative proteolytic fragment of 43,000 in large scale preparations co-purifies with the enzyme activity. This protein is covalently modified with GlcNAc-[32P]phosphate when the enzyme preparation is incubated with [beta-32P]UDP-GlcNAc in the absence of an acceptor substrate. The labeling of the 97(43)-kDa protein requires active enzyme and is completely inhibited by the addition of the acceptor substrate alpha-methylmannoside. The GlcNAc-[32P]phosphate transferred to the protein is not bound to serine, threonine, tyrosine, or mannose residues. The 97(43)-kDa protein with covalently bound GlcNAc-P does not serve as a kinetically competent enzyme-substrate intermediate. However, preincubation of GlcNAc-phosphotransferase with UDP-GlcNAc does result in a decrease in the Vmax of the enzyme in subsequent assays. Taken together, these data are consistent with the 97(43)-kDa protein being a subunit of GlcNAc-phosphotransferase.


T cells: an emerging cast of roles in bipolar disorder.
Bipolar disorder (BD) is a distinctly heterogeneous and multifactorial disorder with a high individual and social burden. Immune pathway dysregulation is an important pathophysiological feature of BD. Recent studies have suggested a potential role for T lymphocytes in the pathogenesis of BD. Therefore, greater insight into T lymphocytes' functioning in patients with BD is essential. In this narrative review, we describe the presence of an imbalance in the ratio and altered function of T lymphocyte subsets in BD patients, mainly in T helper (Th) 1, Th2, Th17 cells and regulatory T cells, and alterations in hormones, intracellular signaling, and microbiomes may be potential causes. Abnormal T cell presence explains the elevated rates of comorbid inflammatory illnesses in the BD population. We also update the findings on T cell-targeting drugs as potentially immunomodulatory therapeutic agents for BD disease in addition to classical mood stabilizers (lithium, valproic acid). In conclusion, an imbalance in T lymphocyte subpopulation ratios and altered function may be involved in the development of BD, and maintaining T cell immune homeostasis may provide an overall therapeutic benefit.


d-Amphetamine and fixed-interval performance: effects of establishing the drug as a discriminative stimulus.
The effects of d-amphetamine were examined as a function of conditioning history. The compound (0.5 mg/kg) (1) increased the response rate of rats under a fixed-interval 60-sec schedule, (2) produced greater increases in responding under the fixed-interval schedule when drug administration had been explicitly paired with a fixed-ratio 20 schedule, and (3) decreased responding under the fixed-interval schedule when the drug had been paired with electric shock punishment. Randomly giving amphetamine before fixed-ratio or punishment sessions did not produce such modifications of drug effects under the fixed-interval schedule. These results, like earlier findings, indicate that drug effects can be modified by conditioning history.


Notice of Retraction: Inappropriate Image Duplication in "Recellularization of Acellular Human Small Intestine Using Bone Marrow Stem Cells".
STEM CELLS TRANSLATIONAL MEDICINE 2013;2:307-315; http://dx.doi.org/10.5966/sctm.2012-0108 The above-referenced article published on March 13, 2013 in Stem Cells Translational Medicine has been retracted by agreement between the Journal Editors and co-publishers, AlphaMed Press and Wiley Periodicals, Inc. The retraction has been agreed to with acknowledgment of problems with Figure 3, which we believe make some of the data unreliable.


Lipid and carbohydrate metabolism in IDDM during moderate and intense exercise.
Insulin-dependent diabetes mellitus (IDDM) is characterized by a metabolic and hormonal disarray that may be more evident during exercise. However, the metabolic response to exercise of different intensities has not been evaluated in IDDM. We therefore used stable isotope techniques and indirect calorimetry to quantify substrate kinetics and oxidation during 30 min of exercise at 45 and 75% of maximal oxygen uptake (Vo2max) in seven men with IDDM (D group) infused with insulin at a constant basal rate. Normal control subjects (C group) matched for age, weight, and Vo2max were also studied. During moderate exercise, glucose uptake (Rd) was lower in the D than in the C group (15.3 +/- 1.0 vs. 20.8 +/- 1.6 mumol.min-1.kg-1; P < 0.05). Carbohydrate oxidation also tended to be lower in the D group (71.0 +/- 7.2 vs. 87.5 +/- 10.6 mumol.min-1.kg-1; P = 0.08). The D group relied on fat oxidation to a greater extent than did the C group (16.9 +/- 1.1 vs. 10.4 +/- 1.6 mumol.min-1.kg-1; P < 0.05). The enhanced fat oxidation was not due to increased lipolysis because no differences occurred in glycerol release (Ra) or in plasma free fatty acid Ra or concentration, and the source of the extra lipid appeared to be intramuscular fat stores. These differences in substrate metabolism were not evident during exercise at 75% of Vo2max. The lower glucose uptake and oxidation in the diabetic subjects during moderate, but not intense, exercise suggest that glucose metabolism is regulated differently depending on exercise intensity.(ABSTRACT TRUNCATED AT 250 WORDS)


Transmission of macrolide-resistant Mycoplasma pneumoniae within a family.
Outbreaks of Mycoplasma pneumoniae have occurred in closed surroundings, including among families, university students, in military camps, and in schools, but available data on outbreaks of macrolide-resistant (MR) M. pneumoniae are limited. We encountered a family outbreak of MR M. pneumoniae pneumonia in four sisters (16, 14, 10, and 8 years of age). M. pneumoniae was isolated from all four patients, and an A-to-G transition at position 2063 in domain V of the 23S rRNA gene was identified. Although three of four patients received azithromycin, which is the first-choice antimycoplasmal agent, this agent was not effective. All isolates had an identical antibiotic susceptibility pattern. The MIC values for 14- and 15-membered macrolides, such as erythromycin, clarithromycin, and azithromycin, were >128, >128, and 64 μg/ml, respectively. On admission, all four patients were diagnosed with suspected M. pneumoniae pneumonia using the Japanese Respiratory Society (JRS) guidelines scoring system. We carried out culture and polymerase chain reaction tests for the detection of M. pneumoniae in their parents (mother, 49 years old, and father, 56 years old) four times, but no M. pneumoniae organism was detected using either test. In conclusion, MR M. pneumoniae strains can occur in outbreaks in closed surroundings, such as within families, as well as macrolide-sensitive strains. To prevent outbreaks of M. pneumoniae infection, especially MR M. pneumoniae, in closed populations, physicians should pay careful attention to the potential occurrence of infections involving MR M. pneumoniae.


Domestic science: making chemistry your cup of tea.
In the early Victorian home, there were plenty of scientific lessons to be uncovered. With the appropriate interrogation, everyday objects could transform seemingly mundane activities such as eating breakfast, washing clothes or reading by candle-light into household lectures that gave children a familiar base from which to explore the hidden properties and marvellous histories of common commodities. Responding to an unprecedented hunger for scientific knowledge, a profusion of introductory texts appeared in the mid-nineteenth century that directed lessons into homes across Britain and beyond. In particular, the science of chemistry found its way into this domestic setting, as writers promoted its practice and practitioners as a source of authoritative expertise on everyday life. One of the most compelling illustrations of this encounter between the public and chemistry took place over a simple cup of tea.


[Pancreatic juice and stress ulcers of the rat (author's transl)].
In 55 rats the role of pancreatic juice for the development of stress ulcers was stuided. After ligation of the common bile duct the stress ulcer incidence was significantly decreased. An additional pancreaticogastrostomy was followed by an even lower ulcer frequency. After pancreaticojejunostomy a higher ulcer incidence was found as after bile duct ligation alone. The role of a duodenogastric reflux for development of stress ulcers is discussed. The ulcerogenic property of bile acids and of the combination of bile and pancreatic juice, caused by lysolecithin, is demonstrated. Pancreatic juice doesn't work as an ulcerogenic substance, but possibly has a protective function by uffering the hydrochloric acid.


Quantification of nitrite and nitrate in seawater by triethyloxonium tetrafluoroborate derivatization-headspace SPME GC-MS.
Triethyloxonium tetrafluoroborate derivatization combined with direct headspace (HS) or SPME-gas chromatography-mass spectrometry (GC-MS) is proposed here for the simultaneous determination of nitrite and nitrate in seawater at micromolar level after conversion to their corresponding volatile ethyl-esters (EtO-NO and EtO-NO(2)). Isotopically enriched nitrite [(15)N] and nitrate [(15)N] are employed as internal standards and for quantification purposes. HS-GC-MS provided instrumental detection limits of 0.07 μM NO(2)(-) and 2 μM NO(3)(-). Validation of the methodology was achieved by determination of nitrite and nitrate in MOOS-1 (Seawater Certified Reference Material for Nutrients, NRC Canada), yielding results in excellent agreement with certified values. All critical aspects connected with the potential inter-conversion between nitrite and nitrate (less than 10%) were evaluated and corrected for by the use of the isotopically enriched internal standard.


Effect of novobiocin on initiation of DNA replication in Bacillus subtilis.
The initiation of DNA replication of small replicons in vitro involves conformational changes in the whole DNA molecule or in the region near to the replication origin. One striking finding has been the role of DNA gyrase (that is, the necessity for supercoiled structure) in the initial stage of ColE1 replication in vitro. However, little is known about the effect of gyrase on the initiation of replication of bacterial chromosomes in vivo. We have constructed a map of cleavage sites of restriction enzymes at the region of the origin of replication of the Bacillus subtilis chromosome (accompanying paper). This has now enabled us to examine the effect of novobiocin, a selective inhibitor of DNA gyrase, on the replication of the specific chromosomal segments near the origin and to seek a possible role for the gyrase in the initiation of chromosomal replication. We have found that only a limited segment of the chromosome at the origin region was replicated in the presence of novobiocin. This effect allowed us to locate the site of the origin of replication to within a DNA fragment of molecular weight 3.4 x 10(6).


Transiently "Undead" Enterocytes Mediate Homeostatic Tissue Turnover in the Adult Drosophila Midgut.
We reveal surprising similarities between homeostatic cell turnover in adult Drosophila midguts and "undead" apoptosis-induced compensatory proliferation (AiP) in imaginal discs. During undead AiP, immortalized cells signal for AiP, allowing its analysis. Critical for undead AiP is the Myo1D-dependent localization of the initiator caspase Dronc to the plasma membrane. Here, we show that Myo1D functions in mature enterocytes (ECs) to control mitotic activity of intestinal stem cells (ISCs). In Myo1D mutant midguts, many signaling events involved in AiP (ROS generation, hemocyte recruitment, and JNK signaling) are affected. Importantly, similar to AiP, Myo1D is required for membrane localization of Dronc in ECs. We propose that ECs destined to die transiently enter an undead-like state through Myo1D-dependent membrane localization of Dronc, which enables them to generate signals for ISC activity and their replacement. The concept of transiently "undead" cells may be relevant for other stem cell models in flies and mammals.


The inguinal hernia: not always straightforward, not always a hernia.
Swelling in the groin may represent much more than an inguinal hernia and an inguinal hernia may be much more complicated than it seems upon superficial consideration. Intraperitoneal or retroperitoneal hemorrhage as well as many other congenital, inflammatory, infectious, or neoplastic processes occurring either locally or at distance from the groin may present in the groin, simulating a hernia, or within an inguinal hernia sac itself. Delayed and spontaneous rupture of the spleen are not rare occurrences. The case discussed, an episode of delayed rupture of the spleen presenting as blood within an inguinal hernia sac, serves to emphasize that following a complete clinical evaluation many entities other than simple inguinal hernia must be considered if a thorough differential diagnosis of a groin mass is to be developed.


MMP-9-cleaved osteopontin isoform mediates tumor immune escape by inducing expansion of myeloid-derived suppressor cells.
As an extracellular matrix protein, osteopontin (OPN) has been shown to play an important role in regulation of the immune response to tumors. Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid progenitors, are major components of the immune suppressive tumor microenvironment and contribute to tumor evasion of the immune response. However, the specific regulating mechanisms underlying MDSCs expansion remain unclear. Here, we found that MDSCs accumulated in the spleen and tumors of 3LL tumor-bearing mice. Supernatant collected from 3LL cells was able to induce the expansion of MDSCs in peripheral blood mononuclear cell (PBMC) in vitro. Results of enzyme linked immunosorbent assay showed high levels of OPN and matrix metalloproteinase-9 (MMP-9) in this supernatant. Silencing OPN can effectively reduce MDSCs frequency in vivo and in vitro. Furthermore, a specific fragment of OPN, OPN-32 kDa cleaved by MMP-9 was detected in the supernatant from 3LL cells. Overexpression of OPN-32 kDa in 3LL cells induced MDSCs expansion. Inhibition of MMP-9 by monoclonal antibody and inhibitor (TIMP-1) reduced MDSCs expansion in vitro and in vivo. These findings suggest that the MMP-9-cleaved OPN fragment, OPN-32kDa, was responsible for MDSCs expansion, which may contribute to tumor's evasion of the immune response.


Computational fragment-based screening using RosettaLigand: the SAMPL3 challenge.
SAMPL3 fragment based virtual screening challenge provides a valuable opportunity for researchers to test their programs, methods and screening protocols in a blind testing environment. We participated in SAMPL3 challenge and evaluated our virtual fragment screening protocol, which involves RosettaLigand as the core component by screening a 500 fragments Maybridge library against bovine pancreatic trypsin. Our study reaffirmed that the real test for any virtual screening approach would be in a blind testing environment. The analyses presented in this paper also showed that virtual screening performance can be improved, if a set of known active compounds is available and parameters and methods that yield better enrichment are selected. Our study also highlighted that to achieve accurate orientation and conformation of ligands within a binding site, selecting an appropriate method to calculate partial charges is important. Another finding is that using multiple receptor ensembles in docking does not always yield better enrichment than individual receptors. On the basis of our results and retrospective analyses from SAMPL3 fragment screening challenge we anticipate that chances of success in a fragment screening process could be increased significantly with careful selection of receptor structures, protein flexibility, sufficient conformational sampling within binding pocket and accurate assignment of ligand and protein partial charges.


Rehmannia glutinosa polysaccharides attenuates colitis via reshaping gut microbiota and short-chain fatty acid production.
Ulcerative colitis is a gastrointestinal disease closely related to intestinal epithelial barrier damage and intestinal microbiome imbalance; however, effective treatment methods are currently limited. Rehmannia glutinosa polysaccharide (RGP) is an important active ingredient with a wide range of pharmacological activities, although its protective effect on colitis remains to be explored. In the present study, we verified the in vitro anti-inflammatory effect of RGP, and observed the ameliorating effect of RGP on dextran sulfate sodium-induced colitis in mice. The results showed that (i) RGP attenuates lipopolysaccharide-induced overexpression of inflammatory factors in RAW264.7 cells; (ii) RGP improves the pathological damage caused by DSS, including weight loss, increased disease activity index and intestinal tissue ulcers; (iii) RGP improves tight junction proteins to protects the tightness of the intestinal epithelium; (iv) RGP inhibits the expression of inflammatory factors through the nuclear factor-kappa B pathway, and improved the of intestinal tissues inflammation; and (v) RGP can maintain the species diversity of intestinal microbes, increase the content of short-chain fatty acids and then restore the imbalance of intestinal microecology. RGP can improve the intestinal microbiota to strengthen the intestinal epithelial barrier and protect against DSS-induced colitis. © 2022 Society of Chemical Industry.


Characterization of Au and Bimetallic PtAu Nanoparticles on PDDA-Graphene Sheets as Electrocatalysts for Formic Acid Oxidation.
Nanocomposite materials of the Au nanoparticles (Au/PDDA-G) and the bimetallic PtAu nanoparticles on poly-(diallyldimethylammonium chloride) (PDDA)-modified graphene sheets (PtAu/PDDA-G) were prepared with hydrothermal method at 90 °C for 24 h. The composite materials Au/PDDA-G and PtAu/PDDA-G were evaluated by transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and thermogravimetric analysis (TGA) for exploring the structural characterization for the electrochemical catalysis. According to TEM results, the diameter of Au and bimetallic PtAu nanoparticles is about 20-50 and 5-10 nm, respectively. X-ray diffraction (XRD) results indicate that both of PtAu and Au nanoparticles exhibit the crystalline plane of (111), (200), (210), and (311). Furthermore, XRD data also show the 2°-3° difference between pristine graphene sheets and the PDDA-modified graphene sheets. For the catalytic activity tests of Au/PDDA-G and PtAu/PDDA-G, the mixture of 0.5 M aqueous H2SO4 and 0.5 M aqueous formic acid was used as model to evaluate the electrochemical characterizations. The catalytic activities of the novel bimetallic PtAu/graphene electrocatalyst would be anticipated to be superior to the previous electrocatalyst of the cubic Pt/graphene.


Remote monitoring and follow-up of cardiovascular implantable electronic devices in the Netherlands : An expert consensus report of the Netherlands Society of Cardiology.
Remote monitoring of cardiac implanted electronic devices (CIED: pacemaker, cardiac resynchronisation therapy device and implantable cardioverter defibrillator) has been developed for technical control and follow-up using transtelephonic data transmission. In addition, automatic or patient-triggered alerts are sent to the cardiologist or allied professional who can respond if necessary with various interventions. The advantage of remote monitoring appears obvious in impending CIED failures and suspected symptoms but is less likely in routine follow-up of CIED. For this follow-up the indications, quality of care, cost-effectiveneness and patient satisfaction have to be determined before remote CIED monitoring can be applied in daily practice. Nevertheless remote CIED monitoring is expanding rapidly in the Netherlands without professional agreements about methodology, responsibilities of all the parties involved and that of the device patient, and reimbursement. The purpose of this consensus document on remote CIED monitoring and follow-up is to lay the base for a nationwide, uniform implementation in the Netherlands. This report describes the technical communication, current indications, benefits and limitations of remote CIED monitoring and follow-up, the role of the patient and device manufacturer, and costs and reimbursement. The view of cardiology experts and of other disciplines in conjunction with literature was incorporated in a preliminary series of recommendations. In addition, an overview of the questions related to remote CIED monitoring that need to be answered is given. This consensus document can be used for future guidelines for the Dutch profession.