Blood markers of alcoholic liver disease.
Not all heavy drinkers develop severe alcoholic liver disease. Genetic factors are probably involved, but no corresponding useful markers have been developed thus far. Of greater practical applicability is the recognition of early changes in the liver that may indicate that the process of scarring or fibrosis has been initiated. Measurement of breakdown products of collagen, the protein of the fibrotic tissue, have been found to be useful for detecting these early stages. Assessment of glutamic dehydrogenase activity in the serum also provides some indication of the degree of inflammation and necrosis present in the liver, but not of the alcohol intake. The severity of the latter can be assessed with a variety of biological markers, to which circulating antibodies against acetaldehyde adducts have recently been added.


When we like what we know--a parametric fMRI analysis of beauty and familiarity.
This paper presents a neuroscientific study of aesthetic judgments on written texts. In an fMRI experiment participants read a number of proverbs without explicitly evaluating them. In a post-scan rating they rated each item for familiarity and beauty. These individual ratings were correlated with the functional data to investigate the neural correlates of implicit aesthetic judgments. We identified clusters in which BOLD activity was correlated with individual post-scan beauty ratings. This indicates that some spontaneous aesthetic evaluation takes place during reading, even if not required by the task. Positive correlations were found in the ventral striatum and in medial prefrontal cortex, likely reflecting the rewarding nature of sentences that are aesthetically pleasing. On the contrary, negative correlations were observed in the classic left frontotemporal reading network. Midline structures and bilateral temporo-parietal regions correlated positively with familiarity, suggesting a shift from the task-network towards the default network with increasing familiarity.


Effects of loxapine on the sleep of chronic schizophrenics.
The sleep patterns of four male chronic schizophrenic patients were monitored throughout the various phases of a 1-year therapeutic trial with loxapine succinate, a newly developed neuroleptic. Compared with the initial drug-free baseline, the early drug period was characterized by an increase in REM percentage, REM density, and REM activity. During the drug maintenance period, the increase in REM phasic events was accompanied by an increase in total sleep. Severe insomnia was noted during the initial period of drug withdrawal. The absence of time lag between changes in drug administration schedule and the associated alterations in sleep patterns was in contrast with the time latency of the therapeutic response. This neuroleptic on sleep and on psychopathology are mediated by different mechanisms.


Multi stage high rate biomethanation of poultry litter with self mixed anaerobic digester.
A multi stage high rate biomethanation process with novel self mixed anaerobic digester (SMAD) was developed in the present study to reduce the hydraulic residence time (HRT), increase the volatile solids (VS) loading rate, improve the VS destruction efficiency and enhance the methane yield. Specific design features of SMAD were useful in mixing the digester contents without consuming power and de-alienated the problem of scum formation. In the first phase, poultry litter having 10% total solids (TS) was subjected to high rate biomethanation in multi stage configuration (SMAD-I and II in series with UASB reactor). It was observed that gross VS reduction of 58%, gross methane yield of 0.16 m3 kg(-1) (VS reduced) and VS loading rate of 3.5 kg VS m(-3) day(-1) at HRT of 13 days was obtained. In the second phase SMAD-II was bypassed from the process scheme keeping the other parameters same as in the first phase. The results obtained were not as encouraging as in the first phase. The study showed that multi stage configuration with SMAD design improved the anaerobic digestion process efficiency of poultry litter.


Avulsion fracture of the hamulus from clay gunshot sport: a case report.
We report a case of hamulus (hook of hamate) fracture nonunion and secondary flexor digitorum profundus tendon rupture caused by repetitive wrist hyperextension sustained during clay shotgun shooting. The hyperextension caused avulsion of the hamulus by the pisohamate ligament. The hamulus was excised and a flexor digitorum profundus tendon transfer of the ring to small finger side to side was performed with satisfactory outcome.


Optimizing agent behavior over long time scales by transporting value.
Humans prolifically engage in mental time travel. We dwell on past actions and experience satisfaction or regret. More than storytelling, these recollections change how we act in the future and endow us with a computationally important ability to link actions and consequences across spans of time, which helps address the problem of long-term credit assignment: the question of how to evaluate the utility of actions within a long-duration behavioral sequence. Existing approaches to credit assignment in AI cannot solve tasks with long delays between actions and consequences. Here, we introduce a paradigm where agents use recall of specific memories to credit past actions, allowing them to solve problems that are intractable for existing algorithms. This paradigm broadens the scope of problems that can be investigated in AI and offers a mechanistic account of behaviors that may inspire models in neuroscience, psychology, and behavioral economics.


Bullous pemphigoid. Occurrence in a patient with mycosis fungoides receiving PUVA and topical nitrogen mustard therapy.
A 57-year-old woman with mycosis fungoides developed blisters within cutaneous plaques while receiving PUVA therapy and topical nitrogen mustard. Direct and indirect immunofluorescence studies showed the findings of bullous pemphigoid. Her bullous disease was controlled after cessation of these therapies and institution of prednisone and methotrexate. During the 5 months following completion of a course of electron-beam therapy, she has been free of the cutaneous manifestations of both diseases. Previous instances of PUVA-related pemphigoid have occurred in psoriatics. The role of ultraviolet light in the induction of pemphigoid is discussed, particularly with regard to its possible interaction with the altered skin of psoriasis or mycosis fungoides. Some of the rare cases of bullous mycosis fungoides might actually have represented ultraviolet-unmasked bullous pemphigoid.


Factors contributing to the potency of CD8+ T cells.
CD8+ cytotoxic T lymphocytes (CTLs) play a crucial role in targeting virus-infected and cancer cells. Although other cytotoxic lymphocytes such as CD4+ T and natural killer (NK) cells, as well as chimeric antigen receptor (CAR)-T cells, can also identify and destroy aberrant cells, they seem to be significantly less potent based on available experimental data. Here, I contemplate the molecular mechanisms controlling the sensitivity and kinetics of granule-mediated CD8+ T cell cytolytic responses. I posit that the clustering of MHC-I molecules and T cell receptors (TCRs) on the cell surface, as well as the contribution of the CD8 co-receptor, are major factors driving exceptionally potent cytolytic responses. I also contend that CD8+ T cells with known specificity and engineered TCR-T cells might be among the most efficient cytolytic effectors for treating patients suffering from viral infections or cancer.


The landscape of prognostic and immunological role of myosin light chain 9 (MYL9) in human tumors.
Recent studies have shown that myosin light chain 9 (MYL9) plays a vital role in immune infiltration, tumor invasion, and metastasis; however, the prognostic and immunological role of MYL9 has not been reported. The purpose of this study was to explore the potential prognostic and immunological roles of MYL9 in human cancers by public datasets mainly including the cancer genome atlas (TCGA) and Gene expression omnibus. The expression pattern and prognostic value of MYL9 were analyzed across multiple public datasets in different cancer. The correlations between MYL9 expression and immune infiltration among multiple cancers were analyzed by using the TIMER2.0. The MYL9-related gene enrichment analysis was implemented by mainly using KEGG and GO datasets. MYL9 was lowly expressed in most cancers, such as breast cancer, lung adenocarcinoma and squamous cell carcinoma, and stomach adenocarcinoma; but it was highly expressed in several cancers, such as cholangiocarcinoma, head and neck squamous cell carcinoma, and liver hepatocellular carcinoma. Furthermore, MYL9 expression was distinctively associated with prognosis in adrenocortical carcinoma, colon adenocarcinoma, brain glioma, lung cancer, ovarian cancer, gastric cancer, breast cancer, blood cancer, and prostate cancer patients. The expressions of MYL9 were significantly associated with the infiltration of cancer-associated fibroblasts, B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, dendritic cell in different tumors as well as immune markers. In addition, we found that the functional mechanisms of MYL9 involved muscle contraction and focal adhesion. MYL9 can serve as a prognostic signature in pan-cancer and is associated with immune infiltration. This pan-cancer study is the first to show a relatively comprehensive understanding of the prognostic and immunological roles of MYL9 across different cancers.


Genomic data of two Bacillus and two Pseudomonas strains isolated from the acid mine drainage site at Mamut Copper Mine, Ranau, Malaysia.
The genomic data of four bacteria strains isolated from the abandoned Mamut Copper Mine, an Acid Mine Drainage (AMD) site is presented in this report. Two of these strains belong to the genus Bacillus, while the other two belong to the genus Pseudomonas. The draft genome size of Pseudomonas sp. strain MCMY3 was 6,396,595 bp (GC: 63.3%), Bacillus sp. strain MCMY6 was 6,815,573 bp (GC: 35.2%), Bacillus sp. strain MCMY13 was 5,559,059 bp (GC: 35.5%) and Pseudomonas sp. strain MCMY15 was 7,381,777 bp (GC: 64.8%). These four genomes contained 493, 495, 495 and 579 annotated subsystems, respectively. The sequence data are available at GenBank sequence read archive with accessions numbers SRX7859406, SRX7859404, SRX7859405 and SRX7293032 for strains MCMY3, MCMY6, MCMY13 and MCMY15, respectively.


Nutritional screening of older home-dwelling Norwegians: a comparison between two instruments.
It is important to obtain knowledge about the prevalence of nutritional risk and associated factors among older home-dwelling people in order to be able to meet nutritional challenges in this group in the future and to plan appropriate interventions. The aim of this survey was to investigate the prevalence of home-dwelling older people at nutritional risk and to identify associated factors using two different nutritional screening instruments as self-report instruments. This study had a cross-sectional design. A postal questionnaire, including the Norwegian versions of the Nutritional Form for the Elderly (NUFFE-NO) and Mini Nutritional Assessment - Short Form (MNA-SF), background variables, and health-related questions was sent to a randomized sample of 6033 home-dwelling older people in southern Norway. A total of 2106 (34.9%) subjects were included in the study. Data were analyzed using descriptive statistics and logistic regression analyses. When using the NUFFE-NO and MNA-SF, 426 (22.3%) and 258 (13.5%) older persons, respectively, were identified to be at nutritional risk. The risk of undernutrition increased with age. Several predictors for being at risk of undernutrition, including chronic disease/handicap and receiving family help, as well as protective factors, including sufficient food intake and having social contacts, were identified. Health professionals must be aware of older people's vulnerability to risk of undernutrition, perform screening, and have a plan for preventing under-nutrition. For that purpose, MNA-SF and NUFFE-NO can be suggested for screening older people living at home.


PTPRT regulates the interaction of Syntaxin-binding protein 1 with Syntaxin 1 through dephosphorylation of specific tyrosine residue.
PTPRT (protein tyrosine phosphatase receptor T), a brain-specific tyrosine phosphatase, has been found to regulate synaptic formation and development of hippocampal neurons, but its regulation mechanism is not yet fully understood. Here, Syntaxin-binding protein 1, a key component of synaptic vesicle fusion machinery, was identified as a possible interaction partner and an endogenous substrate of PTPRT. PTPRT interacted with Syntaxin-binding protein 1 in rat synaptosome, and co-localized with Syntaxin-binding protein 1 in cultured hippocampal neurons. PTPRT dephosphorylated tyrosine 145 located around the linker between domain 1 and 2 of Syntaxin-binding protein 1. Syntaxin-binding protein 1 directly binds to Syntaxin 1, a t-SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein, and plays a role as catalysts of SNARE complex formation. Syntaxin-binding protein 1 mutant mimicking non-phosphorylation (Y145F) enhanced the interaction with Syntaxin 1 compared to wild type, and therefore, dephosphorylation of Syntaxin-binding protein 1 appeared to be important for SNARE-complex formation. In conclusion, PTPRT could regulate the interaction of Syntaxin-binding protein 1 with Syntaxin 1, and as a result, the synaptic vesicle fusion appeared to be controlled through dephosphorylation of Syntaxin-binding protein 1.


Clinical effects of oral motor intervention combined with non-nutritive sucking on oral feeding in preterm infants with dysphagia.
To explore the effectiveness of oral motor intervention combined with non-nutritive sucking in treating premature infants with dysphagia. Sixty preterm infants admitted to the neonatal intensive care unit of the present study's hospital were selected and randomly divided into the control and intervention groups. The control group was given non-nutritive sucking intervention alone, while the intervention group was given oral motor intervention combined with non-nutritive sucking. The oral motor ability, milk sucking amount and sucking rate, feeding efficiency and outcomes, and the occurrence of adverse reactions were measured and compared. Compared to first-day interventions, preterm infant oral feeding readiness assessment scale-Chinese version (PIOFRAS-CV) scores of the two groups significantly increased after 14 days of intervention, and this score was higher in the intervention group compared to the control group. Similarly, after 14 days of intervention, the intervention group's milk sucking rate and amount were significantly higher than the control group. Also, after the intervention, the intervention group's total oral feeding weeks were considerably lower, while the feeding efficiency and body weight were significantly higher than the control group. Moreover, the overall adverse reaction rate in the intervention group was lower than that in the control group. Oral motor intervention combined with non-nutritive sucking can significantly improve the oral motor ability of premature newborns, promote the process of oral feeding, improve the outcome of oral feeding, and reduce the occurrence of adverse effects. The combined intervention seems to have a beneficial effect on oral feeding proficiency in preterm infants.


Systematic identification of endogenous strong constitutive promoters from the diazotrophic rhizosphere bacterium Pseudomonas stutzeri DSM4166 to improve its nitrogenase activity.
Biological nitrogen fixation converting atmospheric dinitrogen to ammonia is an important way to provide nitrogen for plants. Pseudomonas stutzeri DSM4166 is a diazotrophic Gram-negative bacterium isolated from the rhizosphere of cereal Sorghum nutans. Endogenous constitutive promoters are important for engineering of the nitrogen fixation pathway, however, they have not been systematically characterized in DSM4166. Twenty-six candidate promoters were identified from DSM4166 by RNA-seq analysis. These 26 promoters were cloned and characterized using the firefly luciferase gene. The strengths of nineteen promoters varied from 100 to 959% of the strength of the gentamicin resistance gene promoter. The strongest P12445 promoter was used to overexpress the biological nitrogen fixation pathway-specific positive regulator gene nifA. The transcription level of nitrogen fixation genes in DSM4166 were significantly increased and the nitrogenase activity was enhanced by 4.1 folds determined by the acetylene reduction method. The nifA overexpressed strain produced 359.1 µM of extracellular ammonium which was 25.6 times higher than that produced by the wild-type strain. The endogenous strong constitutive promoters identified in this study will facilitate development of DSM4166 as a microbial cell factory for nitrogen fixation and production of other useful compounds.


Partial recovery from visual object agnosia: a 10 year follow-up study.
We describe a young woman, J.R., who sustained a very severe head injury in 1981 at the age of 17 years. She was assessed in 1982 and found to have visual agnosia. Since then J.R. has been assessed on several occasions over a period of ten years. Her agnosia for real objects has resolved and she has improved on the identification of other classes of stimuli. However, she still has some problems with the identification of line drawings, photographs and model animals. Her drawing from memory remains particularly poor and she has difficulty with visual imagery. We consider her residual deficits in the light of Farah's (1990) theoretical framework; this proposes that associative agnosia could be due to a disconnection syndrome, a loss of stored visual representations or to the loss of knowledge of how to perceive objects. J.R.'s residual impairments appear to be mainly due to a loss of access to visual representations in the absence of visual input.


An update on optic neuritis.
Optic neuritis (ON) is the most common cause of subacute optic neuropathy in young adults. Although most cases of optic neuritis (ON) are classified as typical, meaning idiopathic or associated with multiple sclerosis, there is a growing understanding of atypical forms of optic neuritis such as antibody mediated aquaporin-4 (AQP4)-IgG neuromyelitis optica spectrum disorder (NMOSD) and the recently described entity, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). Differentiating typical ON from atypical ON is important because they have different prognoses and treatments. Findings of atypical ON, including severe vision loss with poor recovery with steroids or steroid dependence, prominent optic disc edema, bilateral vision loss, and childhood or late adult onset, should prompt serologic testing for AQP4-IgG and MOG-IgG. Although the traditional division of typical and atypical ON can be helpful, it should be noted that there can be severe presentations of otherwise typical ON and mild presentations of atypical ON that blur these traditional lines. Rare causes of autoimmune optic neuropathies, such as glial fibrillary acidic protein (GFAP) and collapsin response-mediator protein 5 (CRMP5) autoimmunity also should be considered in patients with bilateral painless optic neuropathy associated with optic disc edema, especially if there are other accompanying suggestive neurologic symptoms/signs. Typical ON usually recovers well without treatment, though recovery may be expedited by steroids. Atypical ON is usually treated with intravenous steroids, and some forms, such as NMOSD, often require plasma exchange for acute attacks and long-term immunosuppressive therapy to prevent relapses. Since treatment is tailored to the cause of the ON, elucidating the etiology of the ON is of the utmost importance.


Association of the intestinal brush-border membrane phospholipase A2 and lysophospholipase activities (phospholipase B) with a stalked membrane protein.
We have attempted to determine the size and membrane orientation of a recently described rat jejunal brush-border protein possessing phospholipase A2 and lysophospholipase activities (phospholipase B) (Pind, S. and Kuksis, A. [1988] Biochim, Biophys. Acta 938, 211-221). The phospholipase A2 and lysophospholipase activities were renatured following nonreducing sodium dodecyl sulphate polyacrylamide gel electrophoresis of the total membrane proteins and were shown to migrate as a component of a protein band having a relative molecular mass of 170 kDa. This band accounted for approximately 1% of the total Coomassie Blue staining proteins. Phospholipase B was also shown to be solubilized from the membranes, in an active form, by a proteolytic digestion with papain. Papain solubilization resulted in a loss of the hydrophobic properties observed for the intact phospholipase. These results suggest that the active site of the phospholipase projects from the luminal surface of the membrane vesicles. In support of this, phospholipase activity towards exogenous, detergent-solubilized phosphatidylcholine was demonstrated under conditions in which the membranes remained intact. We conclude that the phospholipase B has the characteristics of a stalked, brush-border membrane protein and may be considered as another digestive enzyme anchored in this membrane.


The impact of small-scale green infrastructure on the affective wellbeing associated with urban sites.
The largest public space in any city is its streets. Investments which incorporate small-scale green infrastructure into streetscapes can bring more nature into the lives of urban residents worldwide, including those living in even the most economically and spatially constraint places. However, little is known about the impact of such small-scale investments on urban residents' affective perceptions of their local environments and how to design these investments to maximise their positive impacts. In the current study, we use photo simulation techniques and an adapted form of the Positive and Negative Affective Schedule to examine the impact of small-scale green infrastructure interventions on the affective perceptions of low, middle and high-income sites in Santiago Chile. Our results, based on 62,478 reports of affective perceptions from 3,472 people, indicate that green infrastructure investments can both promote positive affect and, to a lesser, but still substantial extent reduce negative affect. The magnitudes of these relationships vary across discrete affective measures and for many of these measures, both positive and negative, a minimum of 16% increase in green coverage is required to see an impact. Finally, we find people associated lower affect with low, compared to middle and high, income sites but that these affective inequalities can be addressed, at least in part, through green infrastructure interventions.


Selective increase in monocyte p38 mitogen-activated protein kinase activity in metabolic syndrome.
Metabolic syndrome is a common disorder that predisposes to both cardiovascular disease and diabetes. There is paucity of data on cellular signal transduction pathways in metabolic syndrome. This study determined monocyte mitogen-activated protein kinase activity in patients with metabolic syndrome. The p38, extracellular signal-regulated kinase-1/2 and Jun N-terminal kinase-mitogen-activated protein kinase activities were assayed in isolated monocytes from patients with metabolic syndrome and controls (n = 36 per group) and correlated with features of metabolic syndrome, inflammation and oxidative stress biomarkers. A significant increase in p38 mitogen-activated protein kinase activity was observed in metabolic syndrome even following adjustment for adiposity. There were no significant differences in extracellular signal-regulated kinase-1/2 and Jun N-terminal kinase activities. P38 mitogen-activated protein kinase activity correlated significantly with homeostasis model assessment-estimated insulin resistance and biomarkers of inflammation and oxidative stress. We are first to observe a selective increase in monocyte p38 mitogen-activated protein kinase activity in metabolic syndrome and suggest it as a pivotal molecular target for ameliorating insulin resistance and inflammation.


Impaired cerebral autoregulation distal to carotid stenosis/occlusion is associated with increased risk of stroke at cardiac surgery with cardiopulmonary bypass.
Severe carotid stenosis and occlusion are associated with an increased risk of stroke during and after cardiac surgery with cardiopulmonary bypass. Relevance of an impaired cerebral autoregulation caused by stenosis/occlusion is unknown. We prospectively assessed the incidence of stroke in relation to severity of carotid disease and corresponding autoregulatory reserve in 2797 patients who had coronary artery bypass graft and/or valve surgery with cardiopulmonary bypass. Patients underwent preoperative carotid sonography and, in case of severe extracranial disease, transcranial Doppler sonography with carbon dioxide stimulation to assess cerebrovascular reserve capacity. Sixty-seven (2.4%) patients had an ischemic stroke, which was fatal in 5. Anterior hemispheric stroke occurred in 42 (1.9%) patients with no/low-grade stenosis, 6 (1.8%) with medium-grade stenosis, 1 (0.6%) with high-grade stenosis/occlusion and normal autoregulation, and 3 (27.3%) with high-grade stenosis/occlusion and exhausted autoregulatory reserve. Increased risk was observed in patients with high-grade stenosis/occlusion and exhausted autoregulatory reserve also after adjustment for potential confounders (adjusted odds ratio [OR] 28.3, 95% confidence interval [CI] 5.8-139.1). Stroke risk was not increased in patients with stenosis/occlusion and normal autoregulation (1.5%, adjusted OR 0.6, 95% CI 0.2-1.6). Cerebrovascular reserve capacity evaluated by preoperative transcranial Doppler carbon dioxide testing is a major determinant of stroke risk in patients with carotid artery stenosis/occlusion undergoing cardiac surgery with cardiopulmonary bypass. Its assessment facilitates identification of patients with an excess perioperative stroke risk.


The effect of increased maternal PaO2 upon the fetus during labor.
The effect of increased maternal PaO2 upon the fetus during labor was studied in 36 subhuman primates. The animals were divided into two groups, one in which the fetus was not asphyxiated and showed no evidence of fetal distress (Group I) and another in which the fetus was acidotic, hypoxic, and exhibited the pattern of late deceleration of the heart rate (Group II). One hundred per cent oxygen was administered to the mothers for a period of 30 minutes. Elevation of maternal PaO2 to 430 mm. Hg increased fetal oxygen levels in Group I. and in most instances in Group II, without significant changes in the acid-base state. In Group II, maternal hyperoxemia also abolished or reduced the frequency of late deceleration of the fetal heart in most animals but had little or no effect on fetal blood pressure. Termination of high-concentration oxygen to the mother resulted in a fall in maternal and fetal oxygen levels to their original values and the reappearance of late fetal heart decelerations. Thus, administration of high-concentration oxygen to the mother for the treatment of fetal distress may be of some benefit. The problems of fetal acidosis and hypotension are not cured, however, and may still progress if there is placental insufficiency or cord compression. Therefore, this treatment should be regarded as a temporary supportive measure only.


Molecular mimicry or structural mimicry?
"Molecular mimicry" should be changed to "structural mimicry". The immune system recognizes shapes--three-dimensional shapes--not sequences. For two sequences to act biologically similar they must possess similar three-dimensional structures.


Microdialysis probes alter presynaptic regulation of dopamine terminals in rat striatum.
The insertion of microdialysis probes into the rat striatum disrupts dopaminergic activity near the probe track. The present study suggests that a substantial fraction of DA terminals near the probe track (200 μm) survive the probe implantation itself but that the surviving terminals experience altered presynaptic inhibition. We found that probe implantation did not just alter the amplitude of evoked dopamine responses recorded by voltammetry, but also changed their temporal profile in a fashion similar to that previously observed by quinpirole, an agonist of dopamine D2 autoreceptors. Altered presynaptic inhibition is supported by a hypersensitivity of evoked dopamine responses recorded near to microdialysis probes to raclopride, a D2 antagonist. Further, we found that evoked dopamine release was also hypersensitive to a final dose of the dopamine transporter inhibitor, nomifensine.


Family psychotherapy with the homosexual family: a community psychiatry approach to homosexuality.
The author points out that homosexual families are not being treated by family psychotherapy despite an indicated need. This situation is inconsistent with good community psychiatry and behooves the mental health workers to become aware of and to work through his unrecognized negative feelings which are interfering with provision of services. Among the main resistances are the lack of familiarity and comfort with the family psychotherapy technique, inability to resist a greater gratification that comes from focusing on sex rather than on a less titillating relationship issue, and judgmental and condemning attitudes toward homosexuality that come from intrapsychic and societal sources.


Experimental psychopathology paradigms for alcohol use disorders: Applications for translational research.
In spite of high prevalence and disease burden, scientific consensus on the etiology and treatment of Alcohol Use Disorder (AUD) has yet to be reached. The development and utilization of experimental psychopathology paradigms in the human laboratory represents a cornerstone of AUD research. In this review, we describe and critically evaluate the major experimental psychopathology paradigms developed for AUD, with an emphasis on their implications, strengths, weaknesses, and methodological considerations. Specifically we review alcohol administration, self-administration, cue-reactivity, and stress-reactivity paradigms. We also provide an introduction to the application of experimental psychopathology methods to translational research including genetics, neuroimaging, pharmacological and behavioral treatment development, and translational science. Through refining and manipulating key phenotypes of interest, these experimental paradigms have the potential to elucidate AUD etiological factors, improve the efficiency of treatment developments, and refine treatment targets thus advancing precision medicine.


Current Management of Benign Epithelial Gastric Polyps.
Purpose of review Benign epithelial gastric polyps, although typically asymptomatic, are identified incidentally on upper endoscopy in up to 23% of patients. These include fundic gland, hyperplastic, and adenomatous polyps. Their appropriate characterization is critical as some have malignant potential, may be indicative of a gastric mucosal field defect, or may be related to an underlying polyposis syndrome. This review will discuss the current management of benign epithelial gastric polyps. Recent findings Association of gastric polyps with proton pump inhibitor use, Helicobacter pylori infection, risk of malignant transformation, and association with polyposis syndromes have been the focus of recent literature. Summary All symptomatic polyps, polyps larger than 1 cm in size, and polyps later found to contain dysplasia or cancer should be completely removed. Additionally, random biopsies from the intervening non-polypoid mucosa should be obtained. Finally, identification of multiple polyps of fundic gland type and/or concomitant dysplasia should raise suspicion for an underlying polyposis syndrome and prompt appropriate workup. Surveillance is generally only indicated if there is confirmed dysplasia and/or carcinoma within the polyp itself or if preneoplastic changes are identified in the non-polypoid gastric mucosa.


Analyses of genes encoding the Glycogen Synthase Kinases in rice and Arabidopsis reveal mechanisms which regulate their expression during development and responses to abiotic stresses.
Plant Glycogen Synthase Kinases (GSKs) enable a crosstalk among the brassinosteroid signaling and phytohormonal- and stress-response pathways to regulate various physiological processes. Initial information about regulation of the GSK proteins' activity was obtained, however, mechanisms that modulate expression of the GSK genes during plant development and stress responses remain largely unknown. Taking into account the importance of the GSK proteins, combined with the lack of in-depth knowledge about modulation of their expression, research in this area may provide a significant insight into mechanisms regulating these aspects of plant biology. In the current study, a detailed analysis of the GSK promoters in rice and Arabidopsis was performed, including identification of the CpG/CpNpG islands, tandem repeats, cis-acting regulatory elements, conserved motifs, and transcription factor-binding sites. Moreover, characterization of expression profiles of the GSK genes in different tissues, organs and under various abiotic stress conditions was performed. Additionally, protein-protein interactions between products of the GSK genes were predicted. Results of this study provided intriguing information about these aspects and insight into various regulatory mechanisms that influence non-redundant and diverse functions of the GSK genes during development and stress responses. Therefore, they may constitute a reference for future research in other plant species.


Activation of intracisternal a particles by 5-azacytidine in mouse Ki-BALB cell line.
5-Azacytidine activates the production of intracisternal A particles (IAPs) in mouse Ki-BALB cell line as ascertained by electron microscopy scanning and numeration. Efficiency of the activation is higher than that obtained with iododeoxyuridine. The increase in particle production is concentration and time dependent. The results obtained in our system correlate the high IAP expression after drug treatment with a demethylation of IAP-related genes sequences.


Rational Design of Ultralarge Pb1-x Snx Te Nanoplates for Exploring Crystalline Symmetry-Protected Topological Transport.
Ultralarge topological crystalline insulator Pb1-x Snx Te nanoplates are developed by controlling substrate surface chemical properties in a cost-efficient chemical vapor deposition (CVD) process. Dominant topological surface transport is demonstrated by a gate-voltage-controlled weak (anti)localization effect, indicating the potential application of these nanoplates to low-dissipation topological transistors.


Effectiveness of internet-based and mobile-based interventions for adults with overweight or obesity experiencing symptoms of depression: a systematic review protocol.
Internet-based and mobile-based interventions (IMIs) provide innovative low-threshold and cost-effective prevention and self-management options for mental health problems complementary to standard treatment. The objective of this systematic review is to summarise the effectiveness and to critically evaluate studies on IMIs addressing comorbid depressive symptoms in adults with overweight or obesity. The study authors will systematically search the databases MEDLINE, Cochrane Library, PsycINFO, Web of Science, Embase and Google Scholar (for grey literature) for randomised controlled trials (RCTs) of IMIs for individuals with overweight or obesity and comorbid depressive symptoms without restrictions on publication date (planned inception 1 June 2023 to 1 December 2023). Two reviewers will independently extract and evaluate data from studies eligible for inclusion by assessing quality of evidence and qualitatively synthesising results. Preferred Reporting Items for Systematic reviews Meta-Analyses (PRISMA) standards and the revised Cochrane Risk of Bias tool in RCTs (RoB 2) will be applied. Ethical approval is not required as no primary data will be collected. Study results will be disseminated through publication in a peer-reviewed journal and presentations on conferences. CRD42023361771.


Remuneration and Recruitment of Study Participants for AD Cohort Studies From the General Public and From Minority Communities.
Offering remuneration for participation in studies of aging and Alzheimer Disease (AD) may improve recruitment, particularly among minoritized and low-income groups. But remuneration may also raise ethical problems and reduce altruistic motivations for participation. A nationally representative sample of Americans (N=2030) with large (N=500) Black and Hispanic oversamples was asked about willingness to participate in a longitudinal AD cohort study after random assignment of remuneration ($0, $50/visit, $100/visit). Respondents were then asked about their perceived burden, risks, and societal contribution from participation. An offer of remuneration increased willingness to participate, with no difference between $50 and $100. The increase was similar across racial, ethnic, and income groups. Remuneration did not affect perceived risks or altruistic benefits. Compensation caused Whites and Hispanics, but not Blacks, to lower the perceived burden. Modest levels of remuneration are likely to improve recruitment to AD research studies without causing collateral ethical or motivation problems. Remuneration does not differentially enhance minority recruitment.


Prevalence of Antimicrobial Resistance Among the Hydrogen Sulfide Producing Bacteria Isolated on XLD Agar from the Poultry Fecal Samples.
Poultry products remain as one of the most popular and extensively consumed foods in the world and the introduction of hydrogen sulfide (H2S) producing antibiotic resistant bacterial species into it is an emerging challenge. The current study has been designed to analyze the distribution of antibiotic resistance among the H2S producing bacteria isolated from the fecal samples of chickens from different poultry farms. Here, twenty bacterial isolates were selected based on their ability to produce H2S on XLD agar, and the16S rDNA sequencing was carried out for their molecular identification. The results showed the isolates as belong to Salmonella spp. and Citrobacter spp. and in the antibiotic susceptibility test (AST), three of the Salmonella strains were found to be resistant to antibiotics such as tetracycline, doxycycline, nalidixic acid, and amikacin. Also, fourteen Citrobacter strains showed resistance towards azithromycin, and furthermore, eleven of them were also resistant to streptomycin. Resistance towards tetracycline was observed among five of the Citrobacter strains, and seven were resistant to doxycycline. Further molecular screening by the PCR has showed three of the Salmonella strains along with eight Citrobacter isolates to have tetA gene along with four of the Citrobacter strains to have co-harbored blaTEM gene. The results on biofilm formation have also demonstrated three Salmonella strains along with nine Citrobacter strains to have the ability to form moderate biofilm. The study thus describes the occurrence of H2S producing multidrug-resistant bacteria in poultry feces, which might contribute towards the dissemination of antibiotic resistance genes to other microorganisms including human pathogens with likely risk to treat disease conditions.


Lysophosphatidylserine increases membrane potentials in rat C6 glioma cells.
Previously, we reported on the distinct effects of bioactive lysophospholipids, including lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), and sphingosylphosphorylcholine (SPC), on membrane potentials in rat C6 glioma cells. In the present report we have tested lysophosphatidylserine (LPS), another bioactive lysophospholipid, on membrane potentials in the same cell line. Membrane potentials were estimated by measuring the fluorescence changes of DiBAC-loaded glioma cells. LPS largely increased membrane potentials in a concentration-dependent manner. The LPS-induced membrane potential increases were not affected by treatment with pertussis toxin, implying no involvement of Gi/o proteins. In contrast to other lysophospholipids, the LPS-induced membrane potential increase was not diminished by a Na(+)-free media but was enhanced by suramin. Furthermore, this change was blunted by EIPA, an inhibitor of Na(+)/H(+) exchanger, but not by SITS, a specific inhibitor of bicarbonate transporter. Our observations suggest that LPS acts on membrane potentials in a unique manner in the C6 glioma cells, although the precise action mechanism requires additional investigation.


Solid-state fermentation of phytase from cassava dregs.
Phytases produced by numerous microorganisms and plants degrade phytic acid that has chelated with metal ions in food and feed. It is important to study phytase for the role of metal ions in nutrition of animals and humans as well as in the reduction of organic phosphate content of aqueous environment. This article reports on solid-state fermentation of phytase from a new substrate of cassava dregs. Large quantities of cassava dregs are produced in tropical areas as a byproduct of cassava starch processing. Protein and inorganic salts were found to be low in cassava dregs. Cassava dregs could be employed for phytase synthesis after the addition of a nitrogen source and mineral salts. Ammonium nitrate was the best nitrogen source among the nitrogen sources investigated, including beef extract, yeast extract, urea, ammonium nitrate, sodium nitrate, and ammonium sulfate. Sodium dodecyl sulfate promoted phytase production from cassava dregs. A maximum phytase yield of 6.73 U/g of dry mass was obtained. The obtained phytase was stable at feed-processing temperature, since 70% of initial enzyme activity was maintained after 30 min of treatment at 75 degrees C.


Standard error of immunological dating of evolutionary time.
The empirical variance of the immunological distance as measured by microcomplement fixation with albumin is determined. The variance obtained is at least two times larger than the mean when the mean is small and the ratio of the variance to the mean increases with increasing mean. Thus, the immunological dating of evolutionary time has a large standard error. It is shown that in bird lysozymes the relationship between immunological distance (y) and the number of amino acid substitutions per 100 sites (x) is given by y = 4.2 x approximately.


Prostate-specific antigen response to deferred combined androgen blockade therapy using bicalutamide predicts survival after subsequent oestrogen and docetaxel therapies in patients with castration-resistant prostate cancer.
What's known on the subject? and What does the study add? The additional use of anti-androgen (deferred combined androgen blockade [CAB] therapy) for patients with castration-resistant prostate cancer (CRPC) initially treated with androgen deprivation monotherapy (ADMT) can provide a clinical response, although the reported response rates vary widely. Our previous study, which reported a response rate of 66% to deferred CAB therapy, suggested that deferred CAB responders would also respond better to subsequent therapies than non-responders because the difference in cancer-specific survival between the deferred CAB responders and the non-responders was much larger than the progression-free survival rates for the responders. The present study showed that PSA response to deferred CAB therapy predicts clinical outcomes after subsequent oestrogen and docetaxel therapy. We propose that PSA response to deferred CAB be used for planning individualized treatment that includes secondary hormonal therapy and chemotherapy. To evaluate whether there is any association between prostate-specific antigen (PSA) response to deferred combined androgen blockade (CAB) therapy using bicalutamide in patients with castration-resistant prostate cancer (CRPC), initially treated with castration monotherapy, and the clinical outcomes after subsequent oestrogen and docetaxel therapies. Fifty-six patients with advanced prostate cancer, who were refractory to both initial castration monotherapy and subsequent deferred CAB, received oestrogen therapy (estramustine phosphate 140 or 280 mg/day in 50 patients, diethylstilbestrol diphosphate 100 mg/day orally in six patients). Of the 56 patients, 33 underwent docetaxel therapy (median dose 55 mg/m(2), every 4-8 weeks, median 6 courses) when they became refractory to oestrogen therapy. A deferred CAB response was defined as a decrease of >50% in PSA levels after the addition of bicalutamide. The difference in cancer-specific survival (CSS) after confirmation of resistance to initial castration monotherapy between the deferred CAB responders and the non-responders was evaluated, and outcomes after oestrogen and docetaxel therapies were also compared between the two groups. A response to deferred CAB was observed in 27 (48%) of the 56 patients. There was no significant difference between the responders and the non-responders in pretreatment clinical variables, including Gleason score, metastatic sites, PSA level at diagnosis, and PSA nadir during castration monotherapy. A deferred CAB response was a significant predictor of CSS after confirmation of resistance to initial castration monotherapy. The deferred CAB responders had significantly longer progression-free survival (PFS) (median 3.2 months in the responders, 2.1 month in the non-responders, P = 0.04) and CSS (median 3.0 years in the responders, 1.5 years in the non-responders, P = 0.04) after oestrogen therapy. Likewise, PFS (median 8.2 months in the responders, 2.2 months in the non-responders, P < 0.01) and CSS (median not reached in the responders, 1.4 years in the non-responders, P < 0.01) after docetaxel therapy was significantly longer in the deferred CAB responders. PSA response to deferred CAB predicts clinical outcomes after subsequent oestrogen and docetaxel therapies in patients with CRPC, and provides useful information for planning individualized optimum treatment courses that include secondary hormonal therapy and chemotherapy.


Immuno-histochemical and -cytochemical evidence suggesting the presence of Campylobacter jejuni and Campylobacter coli in cases of porcine intestinal adenomatosis.
Antisera against a number of Campylobacter species were used in immuno-histochemical and -cytochemical studies on cases of porcine intestinal adenomatosis. Avidin-biotin-complex (ABC) and streptavidin immunoperoxidase methods were used on formalin-fixed, paraffin-embedded and frozen sections. Protein A gold method was used on formaldehyde fixed and frozen sections for immuno-cytochemistry. The antisera used were raised in rabbits by subcutaneous or intravenous injection of living or formalin treated organisms. Anti-sera against different serotypes of the thermotolerant, catalase positive campylobacters, Campylobacter jejuni and Campylobacter coli, gave positive reactions in the immuno-histochemical studies. The staining was found in intestinal epithelial cells both in the ileum and in the colon and was restricted to the apical cytoplasm of adenomatous epithelial cells. The staining had a granular pattern, the positive structures sometimes having the shape of Campylobacter. Epithelial cells in areas with normal differentiation of goblet cells did not stain. In contrast, no staining resulted with antisera against Campylobacter sputorum subsp. mucosalis and Campylobacter hyointestinalis. Immuno-cytochemistry, using antisera against Campylobacter jejuni, showed that the positive staining in altered epithelial cells were restricted to intracellular organisms having a structure resembling Campylobacter spp.


Male and Female Perceptions and Experiences of Sexual and Gender-based Violence in South Kivu, Eastern DRC.
Conflict settings are often the context of some of the highest rates of sexual and gender-based violence (SGBV). Although women are disproportionately the victims of SGBV, they are not the only victims. Indirect impacts of SGBV also impact men, families, and communities. Examining SGBV as only a woman's concern reinforces the hegemonic gender-binary view that SGBV somehow does not include men, who can be direct victims of SGBV, family members of female victims of SGBV, and/or perpetrators of SGBV. This qualitative study seeks to fill a gap by exploring the impact of SGBV on individuals, families, and communities, and potential options to ameliorate those issues. Data were collected in 2019 from community-based discussions in South Kivu, Democratic Republic of Congo. Women described being direct victims of SGBV, as well as the burden of being at constant alert to the possible threat of violence. Men talked more about SGBV being perpetrated against women, and the indirect effect on men's perception of their social husband and/or father role to protect and provide for their family. Taken together, women and men describe three types of violence: sexual violence by an unknown assailant who is often associated the rebel groups or the military; sexual violence from a known assailant within one's community; and sexual or physical violence within intimate partnerships (i.e., intimate partner violence). Women focused more on community-based solutions to reduce their exposure to violence, while men discussed the government's responsibility to end the long-standing conflict that has severely disrupted lives. Practically, these findings support the need to specify different types of SGBV, and the opportunity to tailor interventions by type.


Clinicoelectrographic concordance between monozygotic twins with severe myoclonic epilepsy in infancy.
Clinical features of a pair of monozygotic male twins, both with severe myoclonic epilepsy in infancy (SME), are described. They were almost completely concordant with respect to seizure onset, clinical seizure symptomatology, interictal, and ictal EEG expressions and seizure prognosis. The existence of such twins suggests the possibility that a genetic factor is determinant in the etiology of this particular epileptic syndrome.


Reciprocal transport between ramets increases growth of Fragaria chiloensis when light and nitrogen occur in separate patches but only if patches are rich.
Fragaria chiloensis is a stoloniferous perennial herb that grows on coastal sand dunes where scattered shrubs create small patches of lower photon flux density (PFD) but higher soil nitrogen availability. The potential effects of resource transport between ramets when PFD and soil nitrogen are negatively associated in space were tested by comparing the growth of pairs of ramets in which the vascular connection between ramets was either severed or left intact. One ramet in each pair was given high PFD but a low level of soil nitrogen and the other ramet was given low PFD but high N. The analogous effects of resource transport likely to be realized in nature were tested by substituting a more realistic medium soil nitrogen level in place of the high level. Results suggested that connected ramets exchanged carbon and nitrogen under both regimes of soil nitrogen heterogeneity. In the low versus high nitrogen regime, connected ramets had higher combined dry biomass and different patterns of dry mass partitioning from those of severed ramets; effect of connection was greater on ramets given low PFD and high N and on younger ramets. In the low versus medium nitrogen regime, connected ramets had different patterns of partitioning only. Apparent reciprocal resource transport between ramets can enhance the growth of ramets with complementary resource deficiencies, but may affect growth in dry mass only when maximum resource levels are high.


The value of cystatin C in evaluating the severity and prognosis of patients with severe fever with thrombocytopenia syndrome.
Severe fever with thrombocytopenia syndrome (SFTS) is a novel emerging viral infectious disease. We explore the value of cystatin C (CysC) level in the evaluation of disease severity and prognosis in patients with SFTS. 254 patients with SFTS were enrolled in this study. According to the classification and the outcome of the disease, the patients were divided into the general group and the severe group, the severe patients were divided into the fatal group and the non-fatal group. We compared the laboratory indexes by univariate and multivariate logistic regression analysis to explore the severity and prognostic risk factors of SFTS disease, ROC curve and Kaplan-Meier survival analysis curve were drawn to analyze the independent risk factors and the predictive value of disease severity and prognosis. Univariate analysis showed that the CysC level in severe group and fatal group was significantly higher than general group and non-fatal group (P < 0.05), respectively. Multivariate logistic regression showed that the CysC level was an independent risk factor for severe and death in SFTS patients, and it can effectively predict the risk of severe (AUC = 0.711, 95% CI: 0.645-0.777) and death (AUC = 0.814, 95% CI: 0.737-0.89). The risk of death in patients with cystatin C ≥ 1.23 mg/L was 5.487 times higher than that in patients with cystatin C < 1.23 mg/L. The CysC level have good predictive value for disease severity and prognosis in patients with SFTS. Trial registration Not applicable.


Kinetics of microbial growth with mixtures of carbon sources.
Several investigations have shown that during growth in carbon-limited chemostats the simultaneous utilisation of carbon substrates which usually provoke diauxie under batch conditions, i.e., 'mixed substrate growth,' is probably the rule under ecologically relevant growth conditions. In contrast, the models presently available for the description of the kinetics of microbial growth are all based on the use of single substrates. Systematic studies in chemostat culture have shown that steady-state residual concentrations of individual compounds were consistently lower during mixed substrate growth than during growth with the single substrates. This effect is clearly demonstrated for the case of Escherichia coli growing with mixtures of glucose plus galactose. The data presented indicate that the extent of reduction of steady-state residual substrate concentration is dependent on the proportions of the substrates in the mixture, the nature of substrates mixed and the regulation pattern of enzymes involved in their breakdown. If this behaviour can be shown to be typical for growth under environmental conditions, it may provide an explanation why microbes still grow relatively fast at the low substrate concentrations encountered in nature.


Glucocorticoid Effect in Cancer Patients.
The use of glucocorticoids is very varied in the context of cancer patients and includes the treatment of symptoms related to cancer, but also the management of the most common side effects of antitumor treatments or adverse events related to the immune system. There is a quantity of experimental evidence demonstrating that cancer cells are immunogenic. However, the effective activation of anticancer T cell responses closely depends on an efficient antigen presentation carried out by professional antigen-presenting cells such as dendritic cells (DCs). The classic strategies to improve the medical management of inflammation are aimed at exacerbating the host's immune response. Although successful in treating a number of diseases, these drugs have limited efficacy and variable responses can lead to unpredictable results. The ideal therapy should reduce inflammation without inducing immunosuppression and remains a challenge for healthcare personnel.


The enhancement of immunosuppressive effects of cyclosporine A on human T-cells using fusogenic liposomes.
The aim of this study was to prepare and characterize neutral, positively charged, negatively charged and fusogenic liposomes of different sizes that contain cyclosporine A (CyA) and to evaluate their immunosuppressive activity on human T-cells. Neutral liposomes containing CyA were prepared from dipalmitoylphosphatidylcholine (DPPC) and cholesterol using the solvent evaporation method. To prepare positively charged, negatively charged and fusogenic liposomes containing CyA; stearylamine (SA), dicetylphosphate (DCP) and dioleoylphosphatidylethanolamine (DOPE) were added to the neutral liposome formulation, respectively. To reduce the size of liposomes containing CyA, extrusion through polycarbonate filters (1000, 400 and 100 nm) was used. The liposomes were characterized by their size, zeta potential and encapsulation efficiency. The in vitro immunosuppressive effects of an aqueous solution of CyA and different liposomes containing CyA were determined on human T-cells by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. The mean diameter of the various multilamellar vesicle (MLV) liposomes containing CyA was between 1.76 and 2.49 microm. The encapsulation efficiency for the different MLV and extruded liposomes containing CyA ranged from 73% to 90%. In vitro immunosuppressive evaluation by T-cell culture showed that fusogenic liposomes have the best inhibitory effects on T-cell proliferation compared to the other liposomes. Reducing the size of the liposomes did not affect the in vitro immunosuppressive activity. The average IC(50) for the aqueous solution of CyA and the neutral, positively charged, negatively charged and fusogenic liposomes containing CyA was 4.98 x 10(-2), 7.38, 1.43, 3.84 x 10(-3) and 7.93 x 10(-5) mM, respectively. The results of this study indicate that fusogenic liposomes have the strongest immunosuppressive activity and could be considered as a suitable delivery system for CyA.


ASC/chondrocyte-laden alginate hydrogel/PCL hybrid scaffold fabricated using 3D printing for auricle regeneration.
Tissue engineering using adipose derived stem cells (ASCs) has become one of the most promising treatments for defective articular cartilage owing to the stability and dynamic differentiation of ASCs. In this study, we fabricated a 3D hybrid scaffold using poly(ε-caprolactone) (PCL) to support the mechanical properties of the regenerating auricle cartilage, and injected a cell-laden alginate hydrogel, containing a mixture of ASCs and chondrocytes, into the PCL scaffold. Using the cell-laden 3D auricle structure, the in vitro chondrogenesis of the ASCs with and without the presence of chondrocytes was examined. Additionally, the feasibility of utilizing the 3D cell-laden auricle structure for cartilage tissue engineering was evaluated in a rat model. In our in vitro and in vivo experiments, we observed that as the ASCs were co-cultured with the chondrocytes, chondrogenic differentiation was encouraged, and the regeneration of cartilage was significantly increased.


Clinical and Patient-Reported Outcomes of 19 Patients Undergoing Clitoral and Labial Reconstruction After Female Genital Mutilation/Cutting.
Female genital mutilation/cutting (FGM/C) is the intentional alteration, removal, or injury of female genitalia for non-medical reasons. Approximately 200 million females have been victims of FGM/C, and genital reconstructive procedures are increasing in demand. The objectives of this study were to assess clinical and patient-reported outcomes after FGM/C reconstruction to help guide treatment practices. Adult patients undergoing anatomic reconstruction after FGM/C were retrospectively identified. Outcomes included clitoral, labial, and donor site surgical site occurrences (SSO) and the need for revision operations. Patient-reported outcomes were assessed using an adapted version of the Female Sexual Function Index (FSFI), a validated outcomes instrument that assesses sexual function through 6 domains, with each domain having a maximum score of 6. Nineteen patients were identified in our review. Patients presented for reconstruction due to dyspareunia, inability to orgasm, chronic infections, to normalize appearance, and/or to "feel normal." There were no SSOs and two revision operations for adhesions. 74% of patients completed the FSFI postoperatively. Despite most patients seeking repair for inability to orgasm and/or dyspareunia, the median scores for these domains were 4.6 and 5.2. Patients' desire to engage in sexual activity scored lowest (3.9), and patients reported concerns over the appearance of their genitalia (50%) that affected self-confidence (85.7%). FGM/C reconstruction is safe and contributes to improvements in physical sexual health. Psychological trauma may contribute to lessened sexual desire and self-confidence even after reconstruction. Multidisciplinary treatment is important to address the long-term psychological effects of this practice. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Substance P is markedly increased in plasma of patients with hepatic coma.
Substance P (determined as immunoreactive substance P [i-SP]), noradrenaline, and adrenaline were measured in plasma of 18 patients with hepatic coma (stage I-IV), 16 healthy controls, and 10 critically ill patients without evidence of hepatocellular disease. Plasma i-SP (119 +/- 13 fmol/ml) was significantly higher in patients with hepatic coma than in healthy controls (13 +/- 2 fmol/ml) or control patients (23 +/- 4 fmol/ml). Plasma i-SP rose in parallel with plasma noradrenaline and adrenaline. There was a significant direct correlation between plasma i-SP and noradrenaline. Increase in plasma i-SP and noradrenaline was associated with a decrease in systemic vascular resistance and an increase in cardiac index and was most pronounced in those patients who finally died in coma. Deterioration in the dying patients was accompanied by a further significant increase in plasma i-SP. Immunoreactivity was identified as authentic SP by high performance liquid chromatography in 3 representative patients. Accumulation of the vasodilating peptide SP in plasma of patients with hepatic coma may be important in the pathogenesis of the cardiovascular disturbances associated with this disease.


Enhanced FcαRI-mediated neutrophil migration towards tumour colonies in the presence of endothelial cells.
Neutrophils potently kill tumour cells in the presence of anti-tumour antibodies in vitro. However, for in vivo targeting, the neutrophils need to extravasate from the circulation by passing through endothelial barriers. To study neutrophil migration in the presence of endothelial cells in vitro, we established a three-dimensional collagen culture in which SK-BR-3 tumour colonies were grown in the presence or absence of an endothelial barrier. We demonstrated that - in contrast to targeting FcγR on neutrophils with mAbs - targeting the immunoglobulin A Fc receptor (FcαRI) instead triggered neutrophil migration and degranulation leading to tumour destruction, which coincided with release of the pro-inflammatory cytokines interleukin (IL)-1β and tumour necrosis factor (TNF)-α. Interestingly, neutrophil migration was enhanced in the presence of endothelial cells, which coincided with production of significant levels of the neutrophil chemokine IL-8. This supports the idea that stimulation of neutrophil FcαRI, but not FcγR, initiates cross-talk between neutrophils and endothelial cells, leading to enhanced neutrophil migration towards tumour colonies and subsequent tumour killing.


Spatial Cognition: Goal-Vector Cells in the Bat Hippocampus.
A new study recording from the hippocampus of flying bats has revealed populations of neurons tuned to the egocentric direction of the goal, the distance to the goal or their conjunction during spatial navigation.


Positive and negative regulation of the erythropoietin gene.
In order to investigate positive and negative regulatory elements of the erythropoietin (Epo) gene, synthetic oligonucleotides were designed to control Epo transcription by means of an antigen strategy. We devised a new method for detecting regulatory elements of genes that have a weak promoter. Synthetic oligonucleotides were incubated with Hep3B cells in the presence or absence of CoCl2 or hypoxia. To exclude the effect of translational regulation, Epo mRNA concentration was determined by competitive polymerase chain reaction. The addition of antisense oligonucleotide for CACCC elements decreased the production of Epo mRNA in a dose-dependent fashion when cells were stimulated by CoCl2 or hypoxia. In contrast, the addition of antisense oligonucleotide for the GATA element caused a dose-dependent stimulation of Epo mRNA production either in the presence or absence of CoCl2 or hypoxia. Triple helix formation was revealed by electrophoresis. CACCC elements were demonstrated to be positive regulatory elements of the Epo gene, whereas the GATA element was a negative regulatory element. Furthermore, by gel mobility shift assays, we demonstrated evidence for the presence of factors in Hep3B cell nuclear extract that specifically bind to CACCC or GATA elements. Based on these observations, we presented the possibility that triple helix formation could serve as a novel means for transcriptional regulation of the gene.


Interactions between inhibition factors on microbial stability of fruit-based systems.
Measurement of metabolic CO2 by head space gas chromatography was used in the preparation of shelf-life maps of fruit-based systems. The systems analysed, all of which were peach-based, differed with respect to aw (0.995, 0.934 and 0.890), pH (3.02, 3.60 and 4.09) and benzoic acid concentration (0, 100 and 200 ppm). The test microorganism was a strain of Saccharomyces cerevisiae isolated from spoiled soft-drinks and chosen for its characteristic of multiple resistance. Three different thermal treatments were applied (54 degrees C for 15 min, 58 degrees C for 8 min, 63 degrees C for 3 min) to the systems and their effectiveness was evaluated in relation to the untreated controls. In contrast with observations for osmotolerant species, the relative preservative effectiveness on the test strain decreased with reducing aw and showed only a slight synergistic action with thermal treatment. Besides, the aw of the systems interacted synergistically with the thermal treatment effectiveness in a manner differing from that described for osmotolerant species.


Role of pentamer complex-specific and IgG subclass 3 antibodies in HCMV hyperimmunoglobulin and standard intravenous IgG preparations.
HCMV hyperimmunoglobulin-preparations (HIG) contain high concentrations of HCMV-specific IgG. The reduced maternofetal-HCMV-transmission rate of IgG may be due to HCMV-specific neutralizing antibodies against the HCMV pentameric complex (PC). In contrast to HIG, standard intravenous immunoglobulin (IVIG) may have more neutralization (NT) capacity than HIG due to higher IgG subclass 3 levels (Planitzer et al., 2011). We investigated the HCMV-specific NT-capacity of HIG Cytotect®, using a recombinant pentameric complex (gHgLUL128-131A) for specific antibody-depletion. We used a modified UL130-peptide (TANQNPSPPWSKLTYSKPH) based on original-sequence of Saccoccio et al. (Vaccine 29(15):2705-2711, 2011) (SWSTLTANQNPSPPWSKLTY) as neutralization target. Both UL130-peptides and the PC were bound via sixfold HisTag and anti-HisTag mAbs to magnetic beads to deplete HCMV-specific IgGs from HIG (Cytotect®). Modifying this depletion strategy, we analyzed the role of IgG subclass 3 in both HIG and IVIG. After CMV IgG-normalization of HIG and IVIG, we found a significant trend towards a decrease (16%) of neutralization-capacity for the UL130 TAN-peptide, but not for the original UL130 SWS-peptide. However, highly significant loss of NT-capacity could be only observed by PC depletion (42%). The IgG subclass 3 depletion revealed no significant reduction of NT-capacity in both HIG and IVIG. Via specific antibody depletion, we could demonstrate that pentameric complex-specific antibodies are present in HIG and bind to the recombinant PC resulting in a highly significant reduction of NT-capacity compared to the UL130 TAN-and SWS-peptides. We could not confirm the functional role of IgG subclass 3 neutralizing antibodies in IgG-preparations.


Inequalities in access to minimally invasive general surgery: a comprehensive nationwide analysis across 20 years.
Minimally invasive surgery (MIS) has profoundly changed standards of care and lowered perioperative morbidity, but its temporal implementation and factors favoring MIS access remain elusive. We aimed to comprehensibly investigate MIS adoption across different surgical procedures over 20 years, identify predictors for MIS amenability and compare propensity score-matched outcomes among MIS and open surgery. Nationwide retrospective analysis of all hospitalizations in Switzerland between 1998 and 2017. Appendectomies (n = 186,929), cholecystectomies (n = 57,788), oncological right (n = 9138) and left hemicolectomies (n = 21,580), rectal resections (n = 13,989) and gastrectomies for carcinoma (n = 6606) were included. Endpoints were assessment of temporal MIS implementation, identification of predictors for MIS access and comparison of propensity score-matched outcomes among MIS and open surgery. The rates of MIS increased for all procedures during the study period (p ≤ 0.001). While half of all appendectomies were performed laparoscopically by 2005, minimally invasive oncological colorectal resections reached 50% only by 2016. Multivariate analyses identified older age (p ≤ 0.02, except gastrectomy), higher comorbidities (p ≤ 0.001, except rectal resections), lack of private insurance (p ≤ 0.01) as well as rural residence (p ≤ 0.01) with impaired access to MIS. Rural residence correlated with low income regions (p ≤ 0.001), which themselves were associated with decreased MIS access. Geographical mapping confirmed strong disparities for rural and low-income areas in MIS access. Matched outcome analyses revealed benefits of MIS for length of stay, decreased surgical site infection rates for MIS appendectomies and cholecystectomies and higher mortality for open cholecystectomies. No consistent morbidity or mortality benefit for MIS compared to open colorectal resections was observed. Unequal access to MIS exists in disfavor of older and more comorbid patients and those lacking private insurance, living in rural areas, and having lower income. Efforts should be made to ensure equal MIS access regardless of socioeconomic or geographical factors.


Identification of association fibers using ex vivo diffusion tractography in Alexander disease brains.
Alexander disease (AxD) is a neurodegenerative disorder caused by heterozygous Glial Fibrillary Acidic Protein mutation. The characteristic structural findings of AxD, such as leukodystrophic features, are well known, while association fibers of AxD remain uninvestigated. The aim of this study was to explore global and subcortical fibers in four brains with AxD using ex vivo diffusion tractography METHODS: High-angular-resolution diffusion magnetic resonance imaging (HARDI) tractography and diffusion-tensor imaging (DTI) tractography were used to evaluate long and short association fibers and compared to histological findings in brain specimens obtained from four donors with AxD and two donors without neurological disorders RESULTS: AxD brains showed impairment of long association fibers, except for the arcuate fasciculus and cingulum bundle, and abnormal trajectories of the inferior longitudinal and fronto-occipital fasciculi on HARDI tractography and loss of multidirectionality in subcortical fibers on DTI tractography. In histological studies, AxD brains showed diffuse low density on Klüver-Barrera and neurofilament staining and sporadic Rosenthal fibers on hematoxylin and eosin staining CONCLUSIONS: This study describes the spatial distribution of degenerations of short and long association fibers in AxD brains using combined tractography and pathological findings.


Incorporation of copper ions into crystals of T2 copper-depleted laccase from Botrytis aclada.
Laccases belong to the class of multicopper oxidases catalyzing the oxidation of phenols accompanied by the reduction of molecular oxygen to water without the formation of hydrogen peroxide. The activity of laccases depends on the number of Cu atoms per enzyme molecule. The structure of type 2 copper-depleted laccase from Botrytis aclada has been solved previously. With the aim of obtaining the structure of the native form of the enzyme, crystals of the depleted laccase were soaked in Cu(+)- and Cu(2+)-containing solutions. Copper ions were found to be incorporated into the active site only when Cu(+) was used. A comparative analysis of the native and depleted forms of the enzymes was performed.


Afamin: an early predictor of preeclampsia.
Oxidative stress is involved in the pathogenesis of hypertensive disorders such as preeclampsia (PE) and associated with the human vitamin E-binding protein afamin. The aim of this study was, therefore, to analyse afamin in the first trimester of patients developing PE later in pregnancy and in control subjects without pregnancy complications. In this retrospective study, 137 serum samples from the first trimester of pregnancy were analysed in a case-control study design. 39 patients developed PE (10 patients with early-onset and 29 patients with late onset disease) and 98 women had an uncomplicated pregnancy. Mann-Whitney U test, t test, logistic regression and ROC analyses were performed for statistical evaluation. Pregnant women developing PE presented with higher afamin concentrations in the first trimester [median 101.81 mg/L; interquartile range (IQR) 88.94-113.26] compared to subjects with uncomplicated pregnancy (median 86.40; IQR 75.26-96.92; p < 0.001). After adjusting for confounders, the odds ratio per afamin standard deviation was 1.60 (95% CI: 1.04-2.58; p = 0.04). An afamin threshold concentration of 87.8 mg/L exhibited the best sensitivity (79.5%) and specificity (57.1%) in predicting PE. Subgroup analysis of early- and late-onset disease resulted in substantially higher afamin concentrations in women with developing late-onset PE compared to controls (p < 0.001) with an odds ratio per afamin standard deviation of 1.62 (95% CI: 0.98-2.70; p = 0.06). Serum afamin concentrations are elevated in the first trimester among patients developing PE compared to controls. Substantial differences were observed mainly among patients with late-onset PE.


A simple procedure for solid-phase synthesis of peptide nucleic acids with N-terminal cysteine.
Problems were encountered during attempts to prepare N-terminal cysteine-substituted peptide nucleic acids (PNAs) from commercially available, Fmoc-protected monomers. These problems have been surmounted by the use of an S-t-butylmercapto protecting group on the cysteine moiety. The solid-phase syntheses are carried out via a simplified procedure which should be generally useful for manual PNA synthesis.


Correction: Comprehensive bioinformatics analysis of Mycoplasma pneumoniae genomes to investigate underlying population structure and type-specific determinants.
[This corrects the article DOI: 10.1371/journal.pone.0174701.].


Assessing Therapeutic Response to Radium-223 with an Automated Bone Scan Index among Metastatic Castration-Resistant Prostate Cancer Patients: Data from Patients in the J-RAP-BSI Trial.
To evaluate the usefulness of change in the automated bone scan index (aBSI) value derived from bone scintigraphy findings as an imaging biomarker for the assessment of treatment response and survival prediction in metastatic castration-resistant prostate cancer (mCRPC) patients treated with Ra-223. This study was a retrospective investigation of a Japanese cohort of 205 mCRPC patients who received Ra-223 in 14 hospitals between July 2016 and August 2020 and for whom bone scintigraphy before and after radium-223 treatment was available. Correlations of aBSI change, with changes in the serum markers alkaline phosphatase (ALP) and prostate-specific antigen (PSA) were evaluated. Additionally, the association of those changes with overall survival (OS) was assessed using the Cox proportional-hazards model and Kaplan-Meier curve results. Of the 205 patients enrolled, 165 (80.5%) completed six cycles of Ra-223. Following treatment, ALP decline (%ALP < 0%) was noted in 72.2% (148/205), aBSI decline (%aBSI < 0%) in 52.7% (108/205), and PSA decline (%PSA < 0%) in 27.8% (57/205). Furthermore, a reduction in both aBSI and ALP was seen in 87 (42.4%), a reduction in only ALP was seen in 61 (29.8%), a reduction in only aBSI was seen in 21 (10.2%), and in both aBSI and ALP increasing/stable (≥0%) was seen in 36 (17.6%) patients. Multiparametric analysis showed changes in PSA [hazard ratio (HR) 4.30, 95% confidence interval (CI) 2.32-8.77, p < 0.0001], aBSI (HR 2.22, 95%CI 1.43-3.59, p = 0.0003), and ALP (HR 2.06, 95%CI 1.35-3.14, p = 0.0008) as significant prognostic factors for OS. For mCRPC patients treated with Ra-223, aBSI change is useful as an imaging biomarker for treatment response assessment and survival prediction.


Nuclear magnetic resonance-based modeling and refinement of protein three-dimensional structures and their complexes.
Nuclear magnetic resonance (NMR) has become a well-established method to characterize the structures of biomolecules in solution. High-quality structures are now produced, thanks to both experimental and computational developments, allowing the use of new NMR parameters and improved protocols and force fields in structure calculation and refinement. In this chapter, we give a short overview of the various types of NMR data that can provide structural information, and then focus on the structure calculation methodology itself. We discuss and illustrate with tutorial examples both "classical" structure calculation and refinement approaches as well as more recently developed protocols for modeling biomolecular complexes.


Change in bioelectrical impedance following laparoscopic and open abdominal surgery.
The effect of surgery, and in particular, the relative effects of open and laparoscopic abdominal surgery on whole body bioelectrical impedance (BI) has been investigated. Repeated measurements of BI were performed over a 60 h period in 12 patients undergoing laparoscopic surgery (group A) and in 12 patients undergoing elective open abdominal surgery for benign conditions (group B). Control measurements were performed upon 4 healthy adult subjects over the same time period. Attempts were made to relate postoperative changes in BI in group A and group B to changes in net postoperative fluid balance. The postoperative disturbance in BI was significantly greater in group B than group A (P < 0.001 Mann-Whitney-U test) and differed significantly from the minor fluctuations of BI observed in the control group (P < 0.001 Mann-Whitney-U test). The fluctuations in BI observed after laparoscopic surgery were not significantly greater than those seen in the control group (P = 0.1 Mann- Whitney U test). Changes in BI in both group A and B did not correlate with changes in net postoperative fluid balance, which suggests that the effect of surgery upon BI was related to changes of body water distribution rather than changes in total body water volume.


DC potentials of the lateral wall of the scala media.
We recorded DC potential and resistance changes of the cochlear lateral wall in guinea pigs, using (3M KCl) electrolyte glass microelectrodes. The patterns found for slow penetration showed different potential and resistance characteristics at different segments of the lateral wall. In addition, our findings demonstrate that the monitoring of microelectrode tip resistance is a useful procedure for DC cochlear recordings.


Loss of MeCP2 function is associated with distinct gene expression changes in the striatum.
Rett syndrome (RTT) is a neurodevelopmental disorder characterized by developmental regression beginning 6-18months after birth, followed by a lifetime of intellectual disability, stereotyped behaviors, and motor deficits. RTT is caused by mutations in the gene encoding MeCP2, a methyl-CpG binding protein believed to modulate gene transcription. Gene expression studies of individual brain regions have reported that Mecp2 loss-of-function leads to both activation and repression of its gene targets in mice. Conditional deletion of MeCP2 from different brain regions has revealed unique insights into the role of these structures in mediating particular RTT-like phenotypes. However, the function of MeCP2 in the striatum, a major brain region involved in motor control and executive cognitive functions, has yet to be studied. Here, we characterized the gene expression changes in the striatum of Mecp2 mutant mice. We found a number of differentially expressed genes in the striatum of both constitutive Mecp2-null mice and mice lacking MeCP2 only from forebrain GABAergic neurons. These changes only occurred when MeCP2 expression levels had reached mature levels and RTT-like symptoms were manifest, supporting a role for MeCP2 in maintaining proper brain function. Many of the gene expression changes identified in the striatum have not previously been shown to change in the hypothalamus or cerebellum. Bioinformatic analysis of differentially expressed genes in striatum as well as hypothalamus and cerebellum revealed that loss of MeCP2 does not affect the global landscape of gene expression. Additionally, we uncovered a number of differentially expressed genes in the liver of Mecp2-null mice suggesting an important role for MeCP2 in non-neuronal tissues. Collectively, our data suggest that the differential expression of genes following loss of MeCP2 occurs in a tissue- or cell-type specific manner and thus MeCP2 function should be understood in a cellular context.


Endovascular presence of Chlamydia pneumoniae DNA is a generalized phenomenon in atherosclerotic vascular disease.
The common respiratory pathogen Chlamydia pneumoniae has been implicated in the pathogenesis of coronary artery disease and acute myocardial infarction. In order to verify the endovascular presence of potentially viable chlamydia by detection of genomic DNA, we examined atherosclerotic arteries from various vascular regions using a C. pneumoniae specific nested polymerase chain reaction (PCR). The samples were obtained during surgical revascularization procedures or at autopsy. Chlamydial DNA was detected in 51/238 (21%) atherosclerotic samples. A total of 17 non-atherosclerotic control samples were PCR-negative. Chlamydial presence was detected in 36/140 (26%) vascular samples obtained at coronary revascularization procedures, in 9/61 (15%) samples from carotid artery stenosis, 3/17 (18%) samples from the aorta, and 3/20 (15%) iliac artery samples. Histomorphological discrimination of infected and non-infected arterial samples was not possible. Antichlamydial IgG and IgM response as examined by microimmunofluorescence assay did not aid identification of individual endovascular infection. C. pneumoniae is present in a significant proportion of atherosclerotic arteries. Its occurrence in atheromatous plaques is not limited to coronary arteries and may be considered indicative of an infectious component in atherosclerosis. However, it remains unclear whether chlamydia actually initiates atherosclerotic injury, facilitates its progression, or merely colonizes pre-existing atheromata.


Serotonin and substance P afferents to parafascicular and central medial nuclei.
Potent analgesia is elicited by electrical stimulation of the periaqueductal gray (PAG), dorsal raphe nucleus (DRN) and intralaminar thalamus. Horseradish peroxidase conjugated wheat germ agglutinin (HRP-WGA) was stereotaxically pressure injected into the parafascicular (PF) or central medial (CM) nucleus to identify brainstem afferents to the intralaminar thalamus. WGA-immunoreactive (-ir) neurons were identified in the DRN, PAG and lateral dorsal tegmentum (LDTg) after PF and CM injections. Many retrogradely labeled cells in the DRN and ventral PAG were also serotonin-ir, and a portion of WGA-ir cells in the LDTg were substance P-ir. These results substantiate previous studies implicating the intralaminar thalamus and periaqueductal region, as well as serotonin and substance P, in antinociception.


Identification of factors associated with residual malaria transmission using school-based serological surveys in settings pursuing elimination.
Targeted research on residual malaria transmission is important to improve strategies in settings pursuing elimination, where transmission reductions prove challenging. This study aimed to detect and characterize spatial heterogeneity and factors associated with Plasmodium falciparum infections and exposure, P. falciparum apical membrane antigen 1 (PfAMA1) antibody (Ab) response, in the Central Highlands of Madagascar (CHL). From May to July 2014, a cross-sectional school-based survey was carried out in 182 fokontany (villages) within 7 health districts of the CHL. Rapid diagnostic tests (RDTs) and a bead-based immunoassay including PfAMA1 antigen biomarker were used to estimate malaria prevalence and seroprevalence, respectively. Local Moran's I index was used to detect spatial "hotspots". Remotely sensed environmental data-temperature, vegetation indices, land covers, and elevation-were used in multivariable mixed-effects logistic regression models to characterize factors associated with malaria infection and cumulative exposure. Among 6,293 school-children ages 2-14 years surveyed, RDT prevalence was low at 0.8% (95% CI 0.6-1.1%), while PfAMA1 Ab seroprevalence was 7.0% (95% CI 6.4-7.7%). Hotspots of PfAMA1 Ab seroprevalence were observed in two districts (Ankazobe and Mandoto). Seroprevalence increased for children living > 5 km from a health centre (adjusted odds ratio (OR) = 1.6, 95% CI 1.2-2.2), and for those experiencing a fever episode in the previous 2 weeks (OR 1.7, 95% CI 1.2-2.4), but decreased at higher elevation (for each 100-m increase, OR = 0.7, 95% CI 0.6-0.8). A clear age pattern was observed whereby children 9-10 years old had an OR of 1.8 (95% CI 1.2-2.4), children 11-12 years an OR of 3.7 (95% CI 2.8-5.0), and children 13-14 years an OR of 5.7 (95% CI 4.0-8.0) for seropositivity, compared with younger children (2-8 years). The use of serology in this study provided a better understanding of malaria hotspots and associated factors, revealing a pattern of higher transmission linked to geographical barriers in health care access. The integration of antibody-assays into existing surveillance activities could improve exposure assessment, and may help to monitor the effectiveness of malaria control efforts and adapt elimination interventions.


Dipole Moment Propels π-Stacking of Heterodimers of Fluorophenylacetylenes.
Electronic and vibrational spectroscopic investigations in combination with quantum chemical calculations were carried out to probe the formation of four sets of heterodimers of phenylacetylene with 2-fluorohenylacetylene, 3-fluorophenylacetylene, 4-fluorophenylacetylene, and 2,6-difluorophenylacetylene. The interaction of phenylacetylene with fluorophenylacetylenes leads to marginal (2-9 cm-1) red-shifts in the acetylenic C-H stretching frequencies of fluorophenylacetylenes, which suggests that constituent monomers are minimally perturbed in the heterodimer. On the other hand, the density-functional-theory-based calculations indicate that π-stacked structures outweigh other structures incorporating C-H···π and C-H···F interactions by about 8 kJ mol-1 or more. The IR spectra in the acetylenic C-H stretching region were interpreted based on the perturbed dipole model, which suggests formation of predominantly antiparallel π-stacked structures, propelled by dipole moment. However, the energy decomposition analysis suggests that among stabilizing components dispersion dominates, while electrostatics plays a pivotal role in the formation of the π-stacked structures. Interestingly, the ability of 2-fluorophenylacetylene and 2,6-difluorophenylacetylene to π-stack differs significantly, even though both of them have almost identical dipole moments and the dipole moment propels the formation of π-stack structures. These results suggest π-stacking transcends the classical electrostatic description in terms of dipole moment.


3D COMBO chrRNA-DNA-ImmunoFISH.
Epigenetic mechanisms govern the quality, the stability, and the responsiveness of transcriptional programs to the environment. This regulation is ensured via the concerted action of different players (transcription factors, "reader" and "writer" enzymes, histone marks, structural proteins, noncoding regulatory RNAs) that flow in the 3D organization of the genome. Indeed, nuclear architecture participates in the punctual and cell-type-specific regulation of transcription. Hence, the fine dissection of these mechanisms will allow a deeper understanding of the gene expression machinery. In this chapter, we propose a challenging imaging-based method to study the reciprocal interactions between chromatin-associated RNAs, genomic loci, and chromatin compartment with a procedure of 3D COMBO chrRNA-DNA-ImmunoFISH, specifically developed to preserve the nuclear integrity and topology of human primary T cells. We believe that our protocol will contribute to the improvement of epigenetic studies on the 3D nuclear structure of T cell subsets, possibly shedding light on the still hidden epigenetic players responsible for the great plasticity and functional diversification exerted by T cells.


Fibroblast Growth Factor 23, Mineral Metabolism, and Adiposity in Normal Kidney Function.
Obesity is associated with poor bone mineralization and quality. Fibroblast growth factor 23 (FGF23) plays an important role in skeletal physiology. To test hypothesis that greater adiposity results in higher FGF23 levels among individuals with normal estimated glomerular filtration rate (eGFR). Cross-sectional analyses among participants with eGFR ≥60 mL/min/1.73m2. We assessed the association between crude [body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR); n = 5610] and refined (abdominal adipose tissue area by computed tomography; n = 1313) measures of adiposity and FGF23 using multivariable linear regression. Serum FGF23. FGF23 was higher across BMI categories (BMI <25: 37.7; BMI 25 to 29.99: 38.7; BMI 30 to 39.99: 39.8; BMI ≥40: 40.9 pg/mL, unadjusted P trend < 0.0001). The association between BMI and FGF23 was independent of known confounders of FGF23 (adjusted β = +7.2% higher FGF23 per 10 kg/m2; P < 0.0001). Similar results were observed using WC and WHR. Abdominal adipose tissue area was also independently associated with higher FGF23 (P < 0.01). Notably, the positive associations between FGF23 and adiposity were observed despite the fact that eGFR did not decline and serum phosphate levels did not increase with adiposity. In a large cohort with normal kidney function, adiposity was associated with higher FGF23 levels independent of known confounders, including eGFR and phosphate. Further studies are needed to evaluate the causes of higher FGF23 in settings of greater adiposity and the potential impact on skeletal health.


Sagittal height differences of disposable soft contact lenses.
We aim to improve contact lens fitting by using an innovative and simple photogrammetry imaging system to find the sagittal height (SAG) of soft contact lenses. Eleven different types of commercially available soft contact lenses were measured, and five different lenses per package of each lens type were evaluated. The lenses were inserted in a polymethyl methacrylate cell with parallel faces containing a solution of saline and fluorescein to improve the contrast against the background. For every lens, two photographs from the top view and five photographs from the side view were taken. Using homothetic transformations, we calculated the sagittal height. The SAG of all lenses ranged from 3450 to 3907 μm. Differences can be appreciated between SAG of different materials. Performing an ANOVA test, we confirm that the intra-packaging sagitta is reliable for every lens. Comparing the measured SAG with the calculated spherical one, we confirm that the majority of lenses, eight out of eleven, have a spherical geometry for the internal side. Finally, we are able to group the type of lenses that present similar SAG apart from the data reported on the blister. Optical coherence tomography measurement of the eye sagitta over a given chord helped finding the first lens to fit, because matching contact lens sagitta and ocular sagitta is the key for a good fitting. In our work, we found that the majority of brands use single sphere geometry for internal surface of disposable soft contact lenses.


Neutrophil NET formation is regulated from the inside by myeloperoxidase-processed reactive oxygen species.
Neutrophil extracellular traps (NETs) are mesh-like DNA fibers clad with intracellular proteins that are cast out from neutrophils in response to certain stimuli. The process is thought to depend on reactive oxygen species (ROS) generated by the phagocyte NADPH-oxidase and the ROS-modulating granule enzyme myeloperoxidase (MPO), but when, how, and where these factors contribute is so far uncertain. The neutrophil NADPH-oxidase can be activated at different cellular sites and ROS may be produced and processed by MPO within intracellular granules, even in situations where a phagosome is not formed, e.g., upon stimulation with phorbol myristate acetate (PMA). We investigated the subcellular location of ROS production and processing by MPO in the context of PMA-induced NET formation. Complete neutralization of extracellular ROS was not sufficient to block NET formation triggered by PMA, indicating that intragranular ROS are critical for NETosis. Employing a set of novel MPO-inhibitors, inhibition of NET formation correlated with inhibition of intragranular MPO activity. Also, extracellular addition of MPO was not sufficient to rescue NET formation in completely MPO-deficient neutrophils and specific neutralization by luminol of MPO-processed ROS within intracellular granules led to a complete block of PMA-triggered NET formation. We show for the first time that inhibition of intragranular MPO activity, or neutralization of intragranular MPO-processed ROS by luminol effectively block NET formation. Our data demonstrate that ROS must be formed and processed by MPO in order to trigger NET formation, and that these events have to occur within intracellular granules.


Determination of some rheological parameters for the characterization of activated sludge.
The rheological characterization of activated sludge originating from different aeration tanks and from a lab-scale plant was carried out using rotation tests. Two rheological parameters were used: limit viscosity (mu(infinity)) and reduced hysteresis area (rHa). Mu(infinity) was strongly influenced by the total suspended solids (TSS) content of sludge and an exponential relation was found between TSS and the rheological parameter mu(infinity). Significant differences in sludge viscosity were found for sludge of different origins, but all of 10 g/l TSS content, indicating ability of viscosity to show different sludge qualities. Marked changes in activated sludge microorganisms communities were shown to have an influence on rheological parameters. During aerobic digestion of sludge, variations in mu(infinity) were noticed, indicating change of sludge quality. An over-growth of filamentous bacteria species was shown to induce a particular rheological behavior which could be characterized by rHa. This parameter was proposed as an index of filamentous bacteria proliferation in activated sludge aeration tanks.


MicroRNA-33a-3p suppresses cell migration and invasion by directly targeting PBX3 in human hepatocellular carcinoma.
MicroRNAs (miRNAs) have been shown to function as either oncogenes or tumor suppressors by negatively regulating target genes involved in tumor initiation and progression. In this study, we demonstrated that down-regulation of miR-33a-3p in human primary hepatocellular cancer (HCC) specimens was significantly associated with metastases and poor survival. Over-expression of miR-33a-3p in HepG2 cells remarkably suppressed not only cell growth, migration and invasion, but also tumor growth and metastases in the chick embryo chorioallantoic membrane (CAM) assay, and down-regulated Pre-B-Cell Leukemia Homeobox 3 (PBX3) expression. Conversely, inhibition of miR-33a-3p in Bel-7402 cells resulted in increased of cell growth, spreading and invasion. Furthermore, rescue experiments by over-expression PBX3 completely eliminated the inhibitory effects of miR-33a-3p on tumor growth and metastasis, both in vitro and in vivo. The luciferase assay showed that 3'-untranslated regions (3'-UTRs) of PBX3 were inhibited significantly by miR-33a-3p, while mutations in the miR-33a-3p pairing residues rescued the luciferase expression. Taken together, our findings suggest that miR-33a-3p suppressed the malignant phenotype while also inhibiting PBX3 expression in hepatocellular cancer, implying that miR-33a-3p may be a promising biomarkers and therapy target for HCC intervention.


[Isolated accessory liver (hepar succenturiatum) at the neck of the gallbladder. Case report with review of the literature].
We report on a 34 year-old female patient whose gallbladder was removed because of cholecystolithiasis. On histological examination of the fatty tissue surrounding the neck of the gallbladder an accessory liver was detected. Accessory liver tissue is nearly always an incidental finding at operations and autopsies. It arises in the vicinity of the gallbladder from residual liver cells in the caudal part of the embryonic liver anlage. In the differential diagnosis ectopic liver tissue has to be distinguished from other heterotopic tissues. Accessory livers may also be found in certain other organs and structures which lie in close proximity to the liver during fetal life.