Near-chromosomal de novo assembly of Bengal tiger genome reveals genetic hallmarks of apex predation.
The tiger, a poster child for conservation, remains an endangered apex predator. Continued survival and recovery will require a comprehensive understanding of genetic diversity and the use of such information for population management. A high-quality tiger genome assembly will be an important tool for conservation genetics, especially for the Indian tiger, the most abundant subspecies in the wild. Here, we present high-quality near-chromosomal genome assemblies of a female and a male wild Indian tiger (Panthera tigris tigris). Our assemblies had a scaffold N50 of >140 Mb, with 19 scaffolds corresponding to the 19 numbered chromosomes, containing 95% of the genome. Our assemblies also enabled detection of longer stretches of runs of homozygosity compared to previous assemblies, which will help improve estimates of genomic inbreeding. Comprehensive genome annotation identified 26,068 protein-coding genes, including several gene families involved in key morphological features such as the teeth, claws, vision, olfaction, taste, and body stripes. We also identified 301 microRNAs, 365 small nucleolar RNAs, 632 transfer RNAs, and other noncoding RNA elements, several of which are predicted to regulate key biological pathways that likely contribute to the tiger's apex predatory traits. We identify signatures of positive selection in the tiger genome that are consistent with the Panthera lineage. Our high-quality genome will enable use of noninvasive samples for comprehensive assessment of genetic diversity, thus supporting effective conservation and management of wild tiger populations.


Substance abuse and panic-related anxiety: a critical review.
The relationship between substance abuse and panic-related anxiety can be divided into two broad areas: the incidence of anxiety disorders in substance abuse patients and the incidence of substance abuse in patients with panic-related anxiety disorders. Studies indicate that approx. 10-40% of alcoholics have a panic-related anxiety disorder, and about 10-20% of anxiety disorder patients abuse alcohol or other drugs. The majority of patients with both an anxiety and alcohol disorder report that anxiety problems preceded alcohol problems. In some cases substance abuse (e.g. cocaine) triggers the onset of panic attacks. Most patients believe that self-medication is efficacious despite the fact that they appear to have a more serious clinical condition (e.g. higher rates of depression). Directions for future research are outlined, including the proposal for a study to examine the effects of an anxiety intervention procedure for anxious alcoholics to reduce relapse rates.


Early and late adverse effects of radioiodine for pediatric differentiated thyroid cancer.
Radioiodine-131 (I131) therapy for differentiated thyroid cancer (DTC) is generally a safe and effective treatment, but it has some potential side effects, which have been well described in adults but less analyzed in children. Our aim was to describe early and late adverse events of radioactive I131 in pediatric patients. All consecutive patients ≤18 years treated for DTC in the period 1980-2015 were retrospectively analyzed for early and late side effects of radioiodine. Early side effects include nausea/emesis, radiation thyroiditis, sialadenitis, dry mouth, and transient bone marrow (BM) suppression. Late complications include permanent salivary gland dysfunction, permanent BM suppression, pulmonary fibrosis, second cancers, and fertility problems. One hundred five pediatric patients were treated with I131 for DTC in our department for a total amount of 302 radioiodine treatments. In total, 127 early complications were recorded: 44 episodes of nausea/emesis; 30 sialoadenitis, 24 thyroiditis, 18 dry mouth, and 11 transient BM suppression. Early side effects were correlated with the amount of radioactivity administered in any treatment. Twelve children developed ≥1 late complication for a total of 20 complications: two permanent salivary gland dysfunction, four permanent BM suppression, five pulmonary fibrosis, four second malignancies, and five fertility alterations. Late events, except fertility alterations, were correlated with the number of therapies and cumulative activities of I131. In conclusion, early side effects of I131 are associated with the amount of administrated activities of each treatment, while the late effects are correlated with the number of treatments and cumulative activities of radioiodine, except for fertility problems.


Associations of Wnt5a expression with liver injury in chronic hepatitis B virus infection.
Aberrant Wnt5a expression contributes to immunity, inflammation and tissue damage. However, it remains unknown whether Wnt5a is associated with liver injury in chronic hepatitis B virus (HBV) infection. We aimed to explore the potential role of Wnt5a expression in liver injury caused by chronic HBV infection. Wnt5a mRNA levels in peripheral blood mononuclear cells (PBMCs) were analyzed in 31 acute-on-chronic hepatitis B liver failure (ACHBLF) patients, 82 chronic hepatitis B (CHB) patients, and 20 healthy controls using quantitative real-time polymerase chain reaction. Intrahepatic Wnt5a protein expression from 32 chronic HBV infection patients and 6 normal controls was evaluated by immunohistochemical staining. Wnt5a mRNA expression was increased in CHB patients and ACHBLF patients compared to healthy controls and correlated positively with liver injury markers. Additionally, there was a significant correlation between Wnt5a mRNA expression and HBV DNA load in all patients and CHB patients but not in ACHBLF patients. Furthermore, intrahepatic Wnt5a protein expression was elevated in chronic HBV infection patients compared to that in normal controls. Moreover, chronic HBV infection patients with higher hepatic inflammatory grades had increased intrahepatic Wnt5a protein expression compared with lower hepatic inflammatory grades. In addition, the cut-off value of 12.59 for Wnt5a mRNA level was a strong indicator in predicting ACHBLF in CHB patients. We found that Wnt5a expression was associated with liver injury in chronic HBV infection patients. Wnt5a might be involved in exacerbation of chronic HBV infection.


Scores of RINGS but no PHDs in ubiquitin signaling.
Recently, it has been reported that PHD fingers of MEKK1 kinase and a family of viral and cellular membrane proteins have E3 ubiquitin ligase activity. Here we describe unique sequence and structural signatures that distinguish PHD fingers from RING fingers, which function primarily as E3 ubiquitin ligases, and demonstrate that the Zn-binding modules of the above proteins are distinct versions of the RING domain rather than PHD fingers. Thus, currently available data reveal extreme versatility of RINGs and their derivatives that function as E3 ubiquitin ligases but provide no evidence of this activity among PHD fingers whose principal function appears to involve specific protein-protein and possibly protein-DNA interactions in chromatin.


Personality trait domains predict psychiatric symptom and functional outcomes.
A review of high intensity, high dose mentalization-based inpatient psychiatric treatment indicated large effect-size reductions in symptoms of depression, anxiety, somatization, and improving emotion-regulation functioning (Allen et al., 2017). This study examined the impact of pathological personality traits has on baseline symptoms and functioning, as well as their impact on the longitudinal course in a large cohort of adult inpatient psychiatric sample (N = 804). The Personality Inventory for DSM-5 (PID-5; Krueger et al., 2012) was used to assess trait domains impact on longitudinal outcomes (anxiety, depression, somatic symptoms, and functional impairment) using hierarchical repeated measures modeling. Results indicate Negative Affectivity and Detachment were related to higher admission severity in all four outcome domains. Psychoticism was related to somatic symptoms, while Antagonism and Disinhibition were related to functional impairment. Paradoxically, when symptoms were plotted over 2-week intervals during hospitalization, patients with higher admission PID-5 trait scores exhibited greater improvement over time. The PID-5 appears to contribute to prediction of treatment outcome response above and beyond demographic and burden of illness. Importantly, the findings add to a growing body of literature indicating that impairments in personality traits do not preclude positive treatment response, particularly when treatments target pathological personality features. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Organization of associating or crosslinked actin filaments in confinement.
A key factor of actin cytoskeleton organization in cells is the interplay between the dynamical properties of actin filaments and cell geometry, which restricts, confines and directs their orientation. Crosslinking interactions among actin filaments, together with geometrical cues and regulatory proteins can give rise to contractile rings in dividing cells and actin rings in neurons. Motivated by recent in vitro experiments, in this work we performed computer simulations to study basic aspects of the interplay between confinement and attractive interactions between actin filaments. We used a spring-bead model and Brownian dynamics to simulate semiflexible actin filaments that polymerize in a confining sphere with a rate proportional to the monomer concentration. We model crosslinking, or attraction through the depletion interaction, implicitly as an attractive short-range potential between filament beads. In confining geometries smaller than the persistence length of actin filaments, we show rings can form by curving of filaments of length comparable to, or longer than the confinement diameter. Rings form for optimal ranges of attractive interactions that exist in between open bundles, irregular loops, aggregated, and unbundled morphologies. The probability of ring formation is promoted by attraction to the confining sphere boundary and decreases for large radii and initial monomer concentrations, in agreement with prior experimental data. The model reproduces ring formation along the flat plane of oblate ellipsoids.


[Contrast media-enhanced 3D MR angiography before endovascular treatment of aneurysm in the abdominal aorta, iliac artery and peripheral vessels].
The value of DSA for the measurement of aortic and peripheral arterial aneurysm dimensions before endovascular treatment is limited by projection effects. It was evaluated if additional gadolinium-enhanced three-dimensional MR angiography (3D-CEMRA) could compensate for the disadvantages of DSA. 21 patients with 35 aneurysms in the abdominal aorta (14), iliac (9) and femoropopliteal vessels (12) were assessed with DSA (7 with calibrated catheter, 14 with yardstick) and 3D-CEMRA (TR/TE 7.8/2.1 ms, flip-angle 40 degrees, Matrix 512 x 224, FOV 500 mm, eff. slice 1.8 mm). We measured and compared aneurysm dimensions on both modalities. 3D-CEMRA was regarded as the reference method to evaluate the dimension of DSA-projection effects. Diameter and length of aneurysms were underestimated on DSA with the yardstick as reference. The deviation ranged from 15% (+/- 5%) in the aorta to 21% (+/- 10%) in the iliac vessels. Only with calibrated catheters as reference (7/21 DSA), were the distances on DSA correlated well with MRA. In 2/35 aneurysms 3D-CEMRA detected thrombosis with difference between length of inner lumen dilatation on DSA and whole aneurysm length. 2/5 accessory renal arteries found on DSA were not detected on 3D-CEMRA. 3D-CEMRA is a valuable adjunct to DSA for pre-interventional diagnostics of aortic and peripheral arterial aneurysms. It provides exact evaluation of aneurysm dimensions and information about partial thrombosis.


Familial clear cell renal cell carcinoma (FCRC): clinical features and mutation analysis of the VHL, MET, and CUL2 candidate genes.
Familial renal cell carcinoma (RCC) is genetically heterogeneous. Genetic predisposition to clear cell RCC (CCRCC) is a major feature of von Hippel-Lindau (VHL) disease (MIM 193300) and has rarely been associated with chromosome 3 translocations. In addition, familial papillary (non-clear cell) RCC may result from germline mutations in the MET proto-oncogene (MIM 164860). However, rare kindreds with familial CCRCC (FCRC) not linked to the VHL tumour suppressor gene have been described suggesting that further familial RCC susceptibility genes exist. To investigate the genetic epidemiology of FCRC, we undertook a clinical and molecular study of FCRC in nine kindreds with two or more cases of CCRCC in first degree relatives. FCRC was characterised by an earlier age at onset (mean 47.1 years, 52% of cases <50 years of age) than sporadic cases. These findings differ from the only previous report of two FCRC kindreds and have important implications for renal surveillance in FCRC. The molecular basis of CCRCC susceptibility was investigated in nine FCRC kindreds and seven isolated cases with features of possible genetic susceptibility to CCRCC (four bilateral CCRCC aged <50 years and three with unilateral CCRCC aged <30 years). No germline mutations were detected in the VHL or MET genes, suggesting that FCRC is not allelic with VHL disease or HPRC. As binding of the VHL gene product to the CUL2 protein is important for pVHL function, we then searched for germline CUL2 mutations. Although CUL2 polymorphisms were identified, no pathogenic mutations were detected. These findings further define the clinical features of FCRC and exclude a major role for mutations in VHL, MET, or CUL2 in this disorder.


Risk and disease.
The way that diseases such as high blood pressure (hypertension), high cholesterol, and diabetes are defined is closely tied to ideas about modifiable risk. In particular, the threshold for diagnosing each of these conditions is set at the level where future risk of disease can be reduced by lowering the relevant parameter (of blood pressure, low-density lipoprotein, or blood glucose, respectively). In this article, I make the case that these criteria, and those for diagnosing and treating other "risk-based diseases," reflect an unfortunate trend towards reclassifying risk as disease. I closely examine stage 1 hypertension and high cholesterol and argue that many patients diagnosed with these "diseases" do not actually have a pathological condition. In addition, though, I argue that the fact that they are risk factors, rather than diseases, does not diminish the importance of treating them, since there is good evidence that such treatment can reduce morbidity and mortality. For both philosophical and ethical reasons, however, the conditions should not be labeled as pathological. The tendency to reclassify risk factors as diseases is an important trend to examine and critique.


Food protein-stabilized nanoemulsions as potential delivery systems for poorly water-soluble drugs: preparation, in vitro characterization, and pharmacokinetics in rats.
Nanoemulsions stabilized by traditional emulsifiers raise toxicological concerns for long-term treatment. The present work investigates the potential of food proteins as safer stabilizers for nanoemulsions to deliver hydrophobic drugs. Nanoemulsions stabilized by food proteins (soybean protein isolate, whey protein isolate, β-lactoglobulin) were prepared by high-pressure homogenization. The toxicity of the nanoemulsions was tested in Caco-2 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide viability assay. In vivo absorption in rats was also evaluated. Food protein-stabilized nanoemulsions, with small particle size and good size distribution, exhibited better stability and biocompatibility compared with nanoemulsions stabilized by traditional emulsifiers. Moreover, β-lactoglobulin had a better emulsifying capacity and biocompatibility than the other two food proteins. The pancreatic degradation of the proteins accelerated drug release. It is concluded that an oil/water nanoemulsion system with good biocompatibility can be prepared by using food proteins as emulsifiers, allowing better and more rapid absorption of lipophilic drugs.


[Biochemical evaluation of various respiration conditions during simulation of extended flight].
During a simulated long-term mission with participation of male volunteers biochemical effects of various conditions of oxygen supply including breathing the cabin air at 2.4 km, pure oxygen, and intermittent hypoxia/hyperoxia, i.e. breathing the cabin air for 50 min and pure O2 for 10 min every hour in flight were studied. This assessment of respiration conditions by biochemical criteria allowed to recognize the combination of short hyperoxia and cabin air as the optimum to be taken into accounted in attacking the problem of oxygen supply of aviators in extended flights.


Three-dimensional endoscopic OCT using sparse sampling with a miniature magnetic-driven scanning probe.
We propose to apply sparse sampling and compressive sensing (CS) reconstruction in three-dimensional (3D) endoscopic optical coherence tomography (OCT) to reduce the amount of data required in the imaging process. We used a homemade miniature side-imaging magnetic-driven scanning probe with an outer diameter of 1.4 mm in a 1310 nm swept-source OCT system to acquire two-dimensional (2D) circumferential cross-sectional images of an ex vivo pigeon trachea sample. 3D imaging is then achieved by reconstruction from the multiple 2D images acquired while pulling the sample with a translation stage. Given a total translation distance, we achieved sparse sampling by randomizing the step sizes of the translation stage such that the total number of the acquired 2D frames was reduced compared with conventional 3D imaging with equally spaced step positions. We tested the CS reconstruction with reduced 2D frame numbers of 40%, 60%, and 80% compared with the case of equally spaced step positions. The results show that it is possible to recover reasonable OCT images using sparse sampling with CS reconstruction. Compared with the conventional equally spaced sampling method, our method provides a novel way for image acquisition and reconstruction that could significantly reduce the amount of 3D OCT imaging data, and thus the acquisition time.


Magnetic resonance analysis of suprasellar tumors of childhood.
A retrospective analysis of the magnetic resonance (MR) images in 53 pediatric patients with pathologically proven suprasellar tumors was performed, in an attempt to identify the characteristic MR features of these tumors and assess the capability of MR to predict a histologic differentiation. The tumors analyzed included 29 astrocytomas, 11 craniopharyngiomas, 4 germinomas, 3 pituitary adenomas with suprasellar extension, 2 teratomas, 1 spindle cell tumor, 1 primitive neuroectodermal tumor, 1 arachnoid cyst and 1 chordoma of the clivus with suprasellar extension. Thirty patients received intravenous Gd-DTPA as part of their MR exam. Certain MR features, while not pathognomonic, are quite helpful in the differentiation of craniopharyngiomas from chiasmatic/hypothalamic astrocytomas. Presence of a high signal intensity component on T1-weighted images, cyst formation with macrocystic predominance, irregular, heterogeneous solid portion, and smooth ring cyst wall enhancement represent the key characteristics of craniopharyngiomas. Solid predominance with microcysts, long T1 and T2 relaxation times, intense enhancement after contrast administration and extension along the posterior optic pathways are the typical MR findings of chiasmatic/hypothalamic astrocytomas. Presence of diabetes insipidus in correlation with the MR findings of a well-marginated, round or lobular tumor with prolonged T1 and T2 relaxation times, which enhances strongly after Gd-DTPA administration may be the clue in the diagnosis of suprasellar germinomas. Teratomas can be separated from other pediatric suprasellar neoplasms on the basis of internal heterogeneity with presence of fat, calcium and various soft tissue densities. Tumors invading the suprasellar cistern by extension are easily differentiated by identification of the primary site of origin. The above features, while not pathognomonic, are quite helpful in making a specific diagnosis.


Anomalous scaling at the quantum critical point in itinerant antiferromagnets.
We show that the Hertz phi(4) theory of quantum criticality is incomplete as it misses anomalous nonlocal contributions to the interaction vertices. For antiferromagnetic quantum transitions, we found that the theory is renormalizable only if the dynamical exponent z=2. The upper critical dimension is still d=4 - z=2; however, the number of marginal vertices at d=2 is infinite. As a result, the theory has a finite anomalous exponent already at the upper critical dimension. We show that for d<2 the Gaussian fixed point splits into two non-Gaussian fixed points. For both fixed points, the dynamical exponent remains z=2.


Structure and activity of uroguanylin and guanylin from the intestine and urine of rats.
Uroguanylin and guanylin are related peptides that activate common guanylate cyclase signaling molecules in the intestine and kidney. Uroguanylin was isolated from urine and duodenum but was not detected in extracts from the colon of rats. Guanylin was identified in extracts from small and large intestine but was not detected in urine. Uroguanylin and guanylin have distinct biochemical and chromatographic properties that facilitated the separation, purification, and identification of these peptides. Northern assays revealed that mRNA transcripts for uroguanylin were more abundant in small intestine compared with large intestine, whereas guanylin mRNA levels were greater in large intestine relative to small intestine. Synthetic rat uroguanylin and guanylin had similar potencies in the activation of receptors in T84 intestinal cells. Production of uroguanylin and guanylin in the mucosa of duodenum is consistent with the postulate that both peptides influence the activity of an intracellular guanosine 3',5'-cyclic monophosphate signaling pathway that regulates the transepithelial secretion of chloride and bicarbonate in the intestinal epithelium.


Sex differences in interpersonal problems: a circumplex analysis.
The structure and magnitude of sex differences in interpersonal problems across several data sets were examined, guided by the interpersonal circumplex model and the structural summary method. Data were self-reported interpersonal difficulties, assessed with the 64-item version of the Inventory of Interpersonal Problems (IIP; L. M. Horowitz, S. E. Rosenberg, B. A. Baer, G. Ureño, & V. S. Villaseñor, 1988). In Study 1, the authors focused on sex differences at the level of specific interpersonal complaints (item level). In Study 2, the authors examined sex differences in octant scores of the IIP circumplex (scale level), in a reanalysis of archival data. The structural summary method was used to identify points of maximum difference between men and women in the interpersonal continuum and to estimate effect sizes. Results from the 2 studies converged in suggesting a dimension of difference involving problems in Hostile-Dominance vs. Friendly-Submission. The magnitude of effect size was consistent with previous reports in the personality literature. These sex differences appeared to be best explained by a one-dimensional model. Findings were generally consistent across 3 different types of samples.


Submucosal tunneling endoscopic resection using methylene-blue guidance for cardial subepithelial tumors originating from the muscularis propria layer.
Submucosal tunneling endoscopic resection (STER) of subepithelial tumors (SETs) originating from the muscularis propria (MP) layer in the cardia is rarely performed due to the difficulty of creating a submucosal tunnel for resection. The aim of this study is to evaluate the feasibility of STER using methylene-blue guidance for SETs originating from the MP layer in the cardia. From January 2012 to December 2014, 56 patients with SETs originating from the MP layer in the cardia were treated with STER using methylene-blue guidance. The complete resection rate and adverse event rate were the main outcome measurements. Successful complete resection by STER was achieved in all 56 cases (100%). The median size of the tumor was 1.8 cm. Nine patients (15.3%) had adverse events including subcutaneous emphysema, pneumoperitoneum, pneumothorax, and pleural effusion. These nine patients recovered successfully after conservative treatment without endoscopic or surgical intervention. No residual or recurrent tumors were detected in any patient during the follow-up period (median, 25 months). The adverse event rate was significantly higher for tumors originating in the deeper MP layers (46.7%) than in the superficial MP layers (4.9%) (P < 0.05), differed significantly according to tumor size (5.4% for tumors < 2.0 cm vs. 36.8% for tumors ≥ 2.0 cm; P < 0.05), and also differed significantly in relation to the tumor growth pattern (4.1% for the intraluminal growth vs. 100% for the extraluminal growth; P < 0.001). STER using methylene-blue guidance appears to be a feasible method for removing SETs originating from the MP layer in the cardia.


Ketamine induces anxiolytic effects in adult zebrafish: A multivariate statistics approach.
Ketamine inappropriate use has been associated with serious consequences for human health. Anesthetic properties of ketamine are well-known, but its side effects are poorly described, including the effects on anxiety. In this context, animal models are a safe way to conduct this neurobehavioral research and zebrafish (Danio rerio) is an interesting model which has several advantages. The validation and interpretation of results of behavioral assays requires a suitable statistical approach, and the use of multivariate statistical methods has been little explored, especially in zebrafish behavioral models. Here, we investigated the anxiolytic-induced effects of ketamine in adult zebrafish, using Light-Dark Test and proposing the Multivariate Statistics methods (PCA, HCA and SIMCA) to analyze the results. In addition, we compared the processing of data to the one carried out by analysis of variance (ANOVA) ketamine produced significant concentration of exposure-dependent anxiolytic effects, increasing time in white area and number of crossings and decreasing latency to first access to white area. Average entry duration behavior resulted in a slight decrease from control to treatment groups, with an observed concentration-dependent increase among the exposed groups. PCA results indicated that two principal components represent 88.74% of all the system information. HCA and PCA results showed a higher similarity among control and treatment groups exposed to lower concentrations of ketamine and among treatment groups exposed to concentrations of 40 and 60 mg L(-1). In SIMCA results, interclasses distances were concentration of exposure-dependent increased and misclassifications and interclasses residues results also support these findings. These findings confirm the anxiolytic potential of ketamine and zebrafish sensibility to this drug. In summary, our study confirms that zebrafish and multivariate statistics data validation are an appropriate and viable behavioral model for the study of psychoactive substances, providing a detailed and reliable analysis.


Exposure to zinc oxide nanoparticles affects testicular structure, reproductive development and spermatogenesis in parental and offspring male rats.
This study aimed to comprehensively evaluate the toxicity exerted by zinc oxide nanoparticles (ZnO NPs) on rat testis and its effects on fertility and progeny development. Different concentrations of ZnO NPs were administered by gavage to Sprague Dawley (SD) rats to examine the adverse effects resulting from pre- and post-natal exposure. Systemic distribution of ZnO NPs, developmental performance, sperm parameters, reproductive performance, histopathological examination, and sex hormone levels were determined scheduled in the experimental rats and their male offspring. The comparative in vitro cytotoxicity of the ZnO NPs was determined among C18-4, TM3, and TM4 cells. The toxicity exerted by ZnO NPs on germ cells in vitro and the effects on the expression of cytoskeleton and blood-testis barrier (BTB)-related proteins were also determined. After oral gavage, ZnO NPs mainly accumulated in the liver and testes of rats; 350 mg/kg ZnO NPs adversely affected the epididymal weight, sperm motility, and hormone levels but did not affect the fertility of rats. In addition, 350 mg/kg ZnO NPs significantly reduced the reproductive and developmental performance of offspring male rats. Testicular histopathological and electron microscopic ultrastructure examinations showed more significant abnormal structural changes than those observed in parental rats. The results of in vitro cell experiments further showed that ZnO NPs exerted cytotoxic effects on germ cells, and led to DNA damage, nucleoskeleton and cytoskeleton alterations, and could regulate actin changes through changes in LC3B. It is possible that ZnO NPs act directly on TM4 cells by penetrating the BTB, causing damage to the cytoskeleton and disrupting the dynamic balance of the BTB, thereby destroying the microenvironment necessary for spermatogenesis, which may lead to poor reproduction in rats.


Gravimetric Standard Gas Mixtures for Global Monitoring of Atmospheric SF6.
In this study, standard gas mixtures of SF6 in synthetic air were gravimetrically developed as a suite consisting of 6 mixtures with mole fractions of SF6 ranging from 5 to 15 pmol/mol. For precision in weighing the gas fills, an automatic weighing system coupled with a high sensitivity mass balance was used and a gravimetry precision of 3 mg (2σ) was achieved. Impurity profiles of the raw gases were determined by various analyzers. In particular, sub pmol/mol levels of SF6 in the matrix components (N2, O2, and Ar) were carefully measured, since the mole fraction of SF6 in the final step can be significantly biased by this trace amount of SF6 in the raw gases of the matrix components. Gravimetric dilution of SF6 by purity-assessed N2 was performed in 6 steps to achieve a mole fraction of 440 pmol/mol. In the final step, O2 and Ar were added to mimic the atmospheric composition. Gravimetric fractions of SF6 and the associated standard uncertainty in each step were computed according to the ISO 6142 and JCGM 100:2008, respectively, and validated experimentally. Eventually, the SF6 fraction uncertainty of the standard gas mixtures combined by uncertainties of gravimetric preparation and verification measurements were found to be nominally 0.08% at a 95% confidence interval. A comparison with independent calibration standards from NOAA shows agreement within 0.49%, satisfying the extended WMO compatibility goal, 0.05 ppt.


Cardiac allograft rejection: examination of the expression and function of the decoy chemokine receptor D6.
Inflammatory cell recruitment during allograft rejection is driven by a group of inflammatory cytokines termed chemokines. Chemokines are presented on the surface of the vascular endothelium where they ligate specific receptors expressed on the surface of leukocytes. Recently, a group of nonsignaling chemokine receptors have been described. These bind and internalize chemokines but do not drive leukocyte migration. It is believed that these compete with classical signaling receptors to modulate inflammation. This study describes the first examination of the human decoy chemokine receptor D6 during rejection; D6 binds at least 12 potent proinflammatory chemokines. The expression of D6 by graft infiltrating leukocytes was examined in cardiac allografts by confocal microscopy on biopsy sections (n=19). Cytokine regulation of D6 was examined in vitro, and a chemokine scavenging assay was performed using the prototypical transplant-associated chemokine CCL5/RANTES. D6 expression was found to be higher in the biopsies taken from more severe cardiac allograft rejection (P<0.01) and was predominantly localized to graft infiltrating CD45(+)CD68(+) leukocytes. In vitro studies demonstrated that the transforming growth factor-beta strongly increased the expression of D6 by monocytes, which significantly enhanced D6-mediated chemokine scavenging (by 85%, P<0.05). We present the first examination of the biology of D6 during rejection and identify a transplant-associated cytokine that is able to regulate its expression. These data suggest an exciting new mechanism for the antiinflammatory actions of transforming growth factor-beta. Understanding the expression patterns of D6 may provide important insight into the regulation and control of inflammatory cell recruitment during allograft rejection.


Targeting motor cortex high-excitability states defined by functional connectivity with real-time EEG-TMS.
We tested previous post-hoc findings indicating a relationship between functional connectivity (FC) in the motor network and corticospinal excitability (CsE), in a real-time EEG-TMS experiment in healthy participants. We hypothesized that high FC between left and right motor cortex predicts high CsE. FC was quantified in real-time by single-trial phase-locking value (stPLV), and TMS single pulses were delivered based on the current FC. CsE was indexed by motor-evoked potential (MEP) amplitude in a hand muscle. Possible confounding factors (pre-stimulus μ-power and phase, interstimulus interval) were evaluated post hoc. MEPs were significantly larger during high FC compared to low FC. Post hoc analysis revealed that the FC condition showed a significant interaction with μ-power in the stimulated hemisphere. Further, inter-stimulus interval (ISI) interacted with high vs. low FC conditions. In summary, FC was confirmed to be predictive of CsE, but should not be considered in isolation from μ-power and ISI. Moreover, FC was complementary to μ-phase in predicting CsE. Motor network FC is another marker of real-time accessible CsE beyond previously established markers, in particular phase and power of the μ rhythm, and may help define a more robust composite biomarker of high/low excitability states of human motor cortex.


The role of acidocalcisomes in parasitic protists.
Acidocalcisomes are acidic organelles with a high concentration of phosphorus present as pyrophosphate (PP(i)) and polyphosphate (poly P) complexed with calcium and other cations. The acidocalcisome membrane contains a number of pumps (Ca(2+)-ATPase, V-H(+)-ATPase, H(+)-PPase), exchangers (Na(+)/H(+), Ca(2+)/H(+)), and channels (aquaporins), while its matrix contains enzymes related to PP(i) and poly P metabolism. Acidocalcisomes have been observed in pathogenic, as well as non-pathogenic prokaryotes and eukaryotes, e.g. Chlamydomonas reinhardtii, and Dictyostelium discoideum. Some of the potential functions of the acidocalcisome are the storage of cations and phosphorus, the participation of phosphorus in PP(i) and poly P metabolism, calcium homeostasis, maintenance of intracellular pH homeostasis, and osmoregulation. In addition, acidocalcisomes resemble lysosome-related organelles (LRO) from mammalian cells in many of their properties. For example, we found that platelet dense granules, which are LROs, are very similar to acidocalcisomes. They share a similar size, acidic properties, and both contain PP(i), poly P, and calcium. Recent work that indicates that they also share the system for targeting of their membrane proteins through adaptor protein 3 reinforces this concept. The fact that acidocalcisomes interact with other organelles in parasitic protists, e.g. the contractile vacuole in Trypanosoma cruzi, and other vacuoles observed in Toxoplasma gondii, suggests that these cellular compartments may be associated with the endosomal/lysosomal pathway.


Motion management in positron emission tomography/computed tomography for radiation treatment planning.
Hybrid positron emission tomography (PET)/computed tomography (CT) scanners combine, in a unique gantry, 2 of the most important diagnostic imaging systems, a CT and a PET tomograph, enabling anatomical (CT) and functional (PET) studies to be performed in a single study session. Furthermore, as the 2 scanners use the same spatial coordinate system, the reconstructed CT and PET images are spatially co-registered, allowing an accurate localization of the functional signal over the corresponding anatomical structure. This peculiarity of the hybrid PET/CT system results in improved tumor characterization for oncological applications, and more recently, it was found to be also useful for target volume definition (TVD) and treatment planning in radiotherapy (RT) applications. In fact, the use of combined PET/CT information has been shown to improve the RT treatment plan when compared with that obtained by a CT alone. A limiting factor to the accuracy of TVD by PET/CT is organ and tumor motion, which is mainly due to patient respiration. In fact, respiratory motion has a degrading effect on PET/CT image quality, and this is also critical for TVD, as it can lead to possible tumor missing or undertreatment. Thus, the management of respiratory motion is becoming an increasingly essential component in RT treatment planning; indeed, it has been recognized that the use of personalized motion information can improve TVD and, consequently, permit increased tumor dosage while sparing surrounding healthy tissues and organs at risk. This review describes the methods used for motion management in PET/CT for radiation treatment planning. The article covers the following: (1) problems caused by organ and lesion motion owing to respiration, and the artifacts generated on CT, PET, and PET/CT images; (2) data acquisition and processing techniques used to manage respiratory motion in PET/CT studies; and (3) the use of personalized motion information for TVD and radiation treatment planning.


Fecal Microbiota Transplantation in Patients With Recurrent Clostridium difficile Infection: A Four-Year Single-Center Retrospective Review.
Clostridium difficile infection (CDI) is a common cause of hospital and community-acquired diarrhea with an annual incidence of 453,000 cases in the USA. The white race, female gender, and age over 65 years are known risk factors. Recurrence of CDI is a major problem in patients taking antibiotics for prolonged periods. These patients are observed to have reduced diversity of the intestinal microbiome. Fecal microbiota transplantation (FMT) can restore the healthy flora in the gut, thus breaking the cycle of recurrent infection. Our study aimed to analyze the efficacy of FMT and the recurrence of CDI after FMT. We also aimed to investigate the effects of comorbidities on the outcome of FMT. After obtaining approval from the institutional review board, we included 64 patients who had received FMT at our institution from October 2015 to November 2019. All the patients over 16 years of age in both inpatient and outpatient settings were included. Patients under 16 years of age and patients treated without FMT were excluded. Frozen stool from a standardized stool bank (OpenBiome) was used. The thawed specimen was instilled into the terminal ileum or the cecum. Patients were followed up for the next 1 year for analysis of improvement in symptoms, recurrence, and repeat FMT. On the 2-months follow-up, 75% of patients reported symptomatic improvement, 15.6% reported no improvement while 9.4% did not follow up. Twenty-six (40.6%) patients had CDI recurrence in the following year; and 69.2% of patients with recurrence underwent a repeat FMT. There was no statistically significant correlation between CDI recurrence and the age (P value = 0.68), gender (P value = 0.61), previous use of proton pump inhibitors (PPIs, P value = 0.11) or antibiotics (P value = 0.45). There was a statistically significant correlation noted with the use of immunosuppressants and recurrence (P value = 0.04). FMT is a successful treatment modality for refractory and recurrent CDI. Repeat treatments can be beneficial if there is a lack of initial response. Being immunosuppressed with medications is associated with the risk of recurrence.


Hepatitis C in HIV-infected patients: impact of direct-acting antivirals.
Approximately 30% of HIV-infected patients are co-infected with hepatitis C virus (HCV). After the release of highly active antiretroviral therapy, liver disease has become the leading cause of morbidity and mortality in HIV patients. Prior to 2011, HCV treatment with pegylated-interferon and ribavirin in HCV/HIV co-infected patients only allowed 14-38% of patients with HCV genotype 1 to achieve a sustained virologic response (SVR). Additionally, treatment was commonly discontinued as a result of adverse events. Recently, simeprevir and sofosbuvir have been approved by the US Food and Drug Administration (FDA) for HCV mono-infection. Sofosbuvir has been given FDA approval in co-infected patients offering unprecedented SVR rates and the potential for interferon-free therapy. HCV therapies that are in the pipeline offer improved treatment times, safety profiles, and rates of SVR. Despite these improvements, several new issues including adherence, drug-drug interactions with antiretroviral therapies, adverse events, resistance, and patient selection may complicate therapy. This article reviews the current status of direct-acting antivirals (DAA)-containing regimens for HIV/HCV co-infected patients in the USA. New results investigating telaprevir and boceprevir are also discussed as they are relevant for locations where new DAAs are not available. The impact future interferon-free therapies may have on co-infected patients is also discussed.


Orienting the superficial inferior epigastric artery (SIEA) pedicle in a stacked SIEA-deep inferior epigastric perforator free flap configuration for unilateral tertiary breast reconstruction.
Superficial inferior epigastric artery (SIEA) flaps represent a useful option in autologous breast reconstruction. However, the short-fixed pedicle can limit flap inset options. We present a challenging flap inset successfully addressed by de-epithelialization, turnover, and counterintuitive rotation. A 47-year-old woman underwent left tertiary breast reconstruction with stacked free flaps using right deep inferior epigastric perforator and left SIEA vessels. Antegrade and retrograde anastomoses to the internal mammary (IM) vessels were preferred; additionally, the thoracodorsal vessels were unavailable due to previous latissimus dorsi breast reconstruction. Optimal shaping required repositioning of the lateral ends of the flaps superiorly, which would position the ipsilateral SIEA hemi-flap pedicle lateral to and out of reach of the IM vessels. This problem was overcome by turning the SIEA flap on its long axis, allowing the pedicle to sit medially with the lateral end of the flap positioned superiorly. The de-epithelialized SIEA flap dermis was in direct contact with the chest wall, enabling its fixation. This method of flap inset provides a valuable solution for medializing the SIEA pedicle while maintaining an aesthetically satisfactory orientation. This technique could be used in ipsilateral SIEA flap breast reconstructions that do not require a skin paddle, as with stacked flaps or following nipple-sparing mastectomy.


Malignant fibrous histiocytoma of the heart.
A 33-year-old woman presented signs and symptoms which suggested mitral stenosis and insufficiency. Subsequent echocardiographic and angiographic testing demonstrated a left atrial tumor which was suspected clinically to be a left atrial myxoma. At surgery, the tumor was partially resected and histological examination revealed that the mass to be a malignant fibrous histiocytoma. At autopsy, the tumor was found to be localized in the heart, and there was no metastasis.


Detection of Neospora from tissues of experimentally infected rhesus macaques by PCR and specific DNA probe hybridization.
Neospora is a newly recognized Toxoplasma-like cyst-forming coccidian parasite that causes abortion or congenital infections in naturally or experimentally infected animals. In this study, pregnant rhesus macaques were inoculated with culture-derived tachyzoites of a bovine Neospora isolate, and tissue samples from various major organs were collected from dams and fetuses for the detection of parasite DNA by using oligonucleotide primers COC-1 and COC-2 for PCR amplification of a conserved coccidial nuclear small-subunit rRNA gene sequence, and amplification products were confirmed by hybridization with a Neospora-specific DNA probe. PCR products were amplified from DNAs of different fetal monkey tissues, including brain, heart, lung, liver, spleen, skeletal muscle, skin, and placenta. In addition, Neospora DNA was amplified from the brain, heart, and lung tissues of infected rhesus macaque dams. The PCR and probe hybridization system may provide an effective method for the detection of Neospora infection in fetuses and dams from nonhuman primates and may be useful in determining the zoonotic potential of Neospora.


Hemocytic encapsulation of implants in the tick Dermacentor variabilis.
Implants of Epon, inserted in Dermacentor variabilis (Say) through incisions in the cuticle, were encapsulated by hemocytes. We followed this process at intervals of 1,3,6, 12 and 24 h, and every 24 h thereafter up to 120 h. Degranulation of Type 1 granulocytes and coagulation of hemolymph were first seen at 1 h after implantation and were the earliest evidence of encapsulation. By 3 h after implantation, the degranulation and disintegration of granulocytes had formed a matrix at the Epon surface. From 6 h until encapsulation was completed, plasmatocytes and granulocytes continued to respond to degranulation and formed multiple cell layers around the Epon implant. The capsule was complete at 72 h after implantation. Completion was marked by decreasing degranulation, migration of hemocytes from the outermost layers of the capsule, and by the appearance of loosely attached hemocytes on the outer surface of the capsule. The most common junctional complex observed was gap junctions.


[Structural and dynamic analysis of affective disorders in alcoholism].
Two criteria are suggested for estimating affective pathology in alcoholism: polarity and energetic saturation. The use of the two criteria demonstrates consistent dynamics of affective disorders associated with alcoholism: a decrease of the rate of the energetically saturated forms of the emotional manifestations (euphoria, anxiety), transformation of depressions and dysphorias to sluggish nonaggressive motively combined forms of the syndromes. The use of the psychological self-estimation test demonstrated a phenomenon of ambivalence of emotional experiences, coexistence of polar feelings which might explain specific characteristics of alcoholic patients' emotionality such as lability of the cerebral structures in alcoholism. Consistent dynamics of affective disorders and characteristic ambivalence of the emotional life may serve evidence for their specificity in alcoholism and do not prove the hypothesis that alcoholization is but a provoking factor of the preexistent emotional pathology.


How does emotional wellbeing relate to underachievement in a general population sample of young adolescents: a neurocognitive perspective.
Underachievement in school during early adolescence predicts future economic and personal difficulties. Particular neurocognitive skills on the domain of executive functions start to mature during adolescence. This fact and the physical and psychological changes typical for the transition from childhood to adulthood make adolescents vulnerable to emotional problems. The current study investigated the relationship between mild emotional problems which are highly prevalent among adolescents and underachievement in school, and the role of neurocognitive functioning in this relation. This study was conducted in a substantial sample of typical developing young adolescents who just made the transition to secondary education. Pupils were on average 12.5 years old (standard deviation 0.5), and 45% of the included sample were girls. Emotional wellbeing was associated with underachievement [Odds ratio (OR) 5.15, 95% confidence interval (CI) 3.06-8.68] after adjusting for background variables. Self-reported neurocognitive functioning partly explained the relation between emotional wellbeing and underachievement (OR 2.22, 95% CI 1.23-3.99), yet, emotional wellbeing remained statistically associated with underachievement after correcting for additional confounders (OR 1.99, 95% CI 1.08-3.66). The observed findings suggest that emotional wellbeing plays an essential role in underachievement during the first year of secondary education.


Aqueous dispersions of oligomer-grafted carbon nanomaterials with controlled surface charge and minimal framework damage.
Functionalised carbon nanomaterials (CNMs), with an undamaged carbon framework and controlled physiochemical properties, are desirable for a wide range of scientific studies and commercial applications. The use of a thermochemical grafting approach provides a versatile means to functionalise both multi-walled carbon nanotubes (MWCNTs) and carbon black (CB) nanoparticles without altering their inherent structures. The functionalisation process was investigated by employing various types of grafting monomers; to improve water solubility, reagents were chosen that introduced an ionic character either intrinsically or after further chemical reactions. The degree of grafting for both MWCNTs and CB ranged from 3-27 wt%, as established by thermal gravimetric analysis (TGA). Raman spectroscopy confirmed that the structural framework of the MWCNTs was unaffected by the thermochemical treatment. The effectiveness of the surface modification was demonstrated by significantly improved dispersibility and stability in water, and further quantified by zeta-potential analysis. The concentration of stable, individualised and grafted MWCNTs in water ranged from ∼30 to 80 μg mL(-1) after centrifugation at 10 000 g for 15 min, whereas functionalised CB in water showed improved dispersibility up to ∼460 μg mL(-1). The successful preparation of structurally identical but differently functionalised nanoparticle panels, with high water compatibility and minimal framework damage, is useful for controlled experiments. For example, they can be used to explore the relationship between toxicological effects and specific physiochemical properties, such as surface charge and geometry.


Loosened nucleosome linker folding in transcriptionally active chromatin of chicken embryo erythrocyte nuclei.
We have investigated the mechanism of the electrophoresis-driven chromatin aggregation which had been described by Weintraub (1984, Cell 38, 17-27) as a putative mean for propagation of genetic repression in eukaryotes. We show that the oligonucleosome aggregates are assembled de novo at the starting zone of DNP electrophoresis. A new system of native two-dimensional DNP electrophoresis has been worked out to separate the oligonucleosome aggregates ('A' particles) and the freely-migrating oligonucleosomes ('B' particles). The 'B' particle fraction which is derived from transcriptionally-active chromatin regions undergoes an extensive nuclease degradation of its DNA termini during the nuclease digestion. This fraction is partially depleted of histones H1 and H5 and is enriched in HMG nonhistone proteins. 'A' particles comprise the repressed chromatin DNA fragments which are about 60 b.p. longer than the corresponding DNA oligomers of 'B' particles. An oligonucleosome preparation containing the elongated DNA oligomers has been also isolated by means of sucrose gradient ultracentrifugation. Exonuclease III mapping reveals that the two chromatin fractions differ by an extent of terminal linker DNA trimming during the Micrococcal nuclease digestion rather than by the nucleosome repeat length. The complex character of nuclease digestion is not observed when the chromatin is digested in solution after the nuclear lysis. We argue that the protection of terminal oligonucleosome linkers is due to selective condensation of inactive chromatin in chicken erythrocyte nuclei and that the terminal DNA tails together with linker histones bound to them mediate the aggregation of repressed chromatin fragments.


The miR-668 binding site variant rs1046322 on WFS1 is associated with obesity in Southeast Asians.
The Wolfram syndrome 1 gene (WFS1) is the main causative locus for Wolfram syndrome, an inherited condition characterized by childhood-onset diabetes mellitus, optic atrophy, and deafness. Global genome-wide association studies have listed at least 19 WFS1 variants that are associated with type 2 diabetes (T2D) and metabolic traits. It has been suggested that miRNA binding sites on WFS1 play a critical role in the regulation of the wolframin protein, and loss of WFS1 function may lead to the pathogenesis of diabetes. In the Hungarian population, it was observed that a 3' UTR variant from WFS1, namely rs1046322, influenced the affinity of miR-668 to WFS1 mRNA, and showed a strong association with T2D. In this study, we genotyped a large cohort of 2067 individuals of different ethnicities residing in Kuwait for the WFS1 rs1046322 polymorphism. The cohort included 362 Southeast Asians (SEA), 1045 Arabs, and 660 South Asians (SA). Upon performing genetic association tests, we observed significant associations between the rs1046322 SNP and obesity traits in the SEA population, but not in the Arab or SA populations. The associated traits in SEA cohort were body mass index, BMI (β=1.562, P-value=0.0035, Pemp=0.0072), waist circumference, WC (β=3.163, P-value=0.0197, Pemp=0.0388) and triglyceride, TGL (β=0.224, P-value=0.0340). The association with BMI remained statistically significant even after multiple testing correction. Among the SEA individuals, carriers of the effect allele at the SNP had significantly higher BMI [mean of 27.63 (3.6) Kg/m2], WC [mean of 89.9 (8.1) cm], and TGL levels [mean of 1.672 (0.8) mmol/l] than non-carriers of the effect allele. Our findings suggest a role for WFS1 in obesity, which is a risk factor for diabetes. The study also emphasizes the significant role the ethnic background may play in determining the effect of genetic variants on susceptibility to metabolic diseases.


Enhanced killing of Escherichia coli using a combination of polyhexamethylene biguanide hydrochloride and 1-bromo-3-chloro-5,5- dimethylimidazolidine-2,4-dione.
The bactericidal activities of polyhexamethylene biguanide hydrochloride (PHMB), 1-bromo-3-chloro-5,5-dimethylimidazolidine-2,4-dione (BCDMH) and the combination of the two (designated as PB) were compared using Escherichia coli as the test organism. PB exhibited strong bactericidal activity: 10 mg/L PHMB combined with 8 mg/L BCDMH resulted in approximately 5.74 log10 reduction (LR), whereas 320 mg/L PHMB or 20 mg/L BCDMH was about 5.53 and 6.56 LR, respectively. Analyses using scanning electron microscopy, flow cytometry and atomic absorption spectroscopy indicated that PB, PHMB and BCDMH disrupted cell membranes and changed membrane structure and permeability, resulting in the leakage of intracellular soluble proteins and ions. PB exerted stronger effects on potassium and magnesium leakage, membrane potential and permeability than BCDMH did. PB caused less protein leakage than PHMB did. These results suggest that at a relatively low concentration, PB exhibited good bactericidal activity and physiological effect on E. coli.


The pain of low status: the relationship between subjective socio-economic status and analgesic prescriptions in a Scottish community sample.
There is a strong positive relationship between objective measures of socio-economic status (OSS) and general health. However, there is an increasing interest in the relationship between health and subjective socio-economic status (SSS), which describes one's perceived rank in relation to the rest of the society, based on factors such as income, occupation and education. While the relationship between SSS and general health is well established, the relationship between SSS and pain has received little attention. Gathering both self-report questionnaire data and General Practitioner medical data from a large representative community sample in Scotland between 2012 and 2013 (N = 1824), we investigated the relationship between SSS and prescriptions for analgesic drugs. We found that higher levels of SSS significantly predicted lower odds of participants having been prescribed at least one analgesic drug in the previous six months. We obtained this result even after controlling for OSS-related variables (education, occupational status and geographical location) and demographic variables (age and gender). This suggests that, just like the relationship between SSS and general health, SSS has important effects on pain that go beyond the influence of OSS.


A follow-up of the introduction of a maximum entitlement period for receiving sickness benefits in Sweden: A nationwide register-based study.
In 2008, Sweden introduced a policy change to limit the number of days for sickness benefits (SB). This study aimed to elucidate the characteristics of those who reached the maximum entitlement period for receiving sickness benefits (MEPSB) and their future main source of income. Methods: All 5,309,759 individuals, aged 20-63 and residents of Sweden in 2009 were followed from July 2008 to July 2010 regarding SB-days and date of MEPSB and then categorised into three groups: I) no SB-days, II) ongoing SB-days, and III) MEPSB. Mean numbers of SB-days 2.5 years before and 2 years after the policy change and main source of income in 2011 were assessed. Associations between sociodemographic factors, occupation and paid work as main source of income were estimated by odds ratio (OR). Results: A total of 0.7% reached MEPSB in 2010. The mean numbers of SB-days before and after the policy change were higher in the MEPSB group than in the other two groups. In the MEPSB group, 14% had their main source of income from paid work in 2011; this was more common among women born in Sweden (OR = 1.29), people living with a partner and children (women OR = 1.29; men OR = 1.48), and those with occupations representing high educational levels. Conclusions: One out of seven individuals with MEPSB in 2010 had their main source of income from paid work in 2011, although they had a long-term SB before and after the policy change. Further research is warranted to address the long-term effects of this policy change.


Separate banks of information channels encode size and aspect ratio.
Size and aspect ratio are ecologically important visual attributes. Relative size confers depth, and aspect ratio is a size-invariant cue to object identity. The mechanisms of their analyses by the visual system are uncertain. In a series of three psychophysical experiments we show that adaptation causes perceptual repulsion in these properties. Experiment 1 shows that adaptation to a square causes a subsequently viewed smaller (larger) test square to appear smaller (larger) still. Experiment 2 reveals that a test rectangle with an aspect ratio (height/width) of two appears more slender after adaptation to rectangles with aspect ratios less than two, while the same test stimulus appears more squat after adaptation to a rectangle with an aspect ratio greater than two. Significantly, aftereffect magnitudes peak and then decline as the sizes or aspect ratios of adaptor and test diverge. Experiment 3 uses the results of Experiments 1 and 2 to show that the changes in perceived aspect ratio are due to adaptation to aspect ratio rather than adaptation to the height and width of the stimuli. The results are consistent with the operation of distinct banks of information channels tuned for different values of each property. The necessary channels have log-Gaussian sensitivity profiles, have equal widths when expressed as ratios, are labeled with their preferred magnitudes, and are distributed at exponentially increasing intervals. If an adapting stimulus reduces each channel's sensitivity in proportion to its activation then the displacement of the centroid of activity due to a subsequently experienced test stimulus predicts the measured size or aspect ratio aftereffect.


Effect of antidepressant treatment on peripheral inflammation markers - A meta-analysis.
Major Depressive Disorder (MDD) in accordance to the inflammatory concept is associated with complex immunological disturbances in the central nervous system (CNS). This is reflected by elevated plasma levels of inflammatory cytokines in depressed subjects. Although numerous studies report significant influence of antidepressants on pro-inflammatory/anti-inflammatory cytokines balance, the available data is often inconsistent regarding specific cytokines and drugs used. We aimed to perform a comprehensive meta-analysis of the effect of antidepressant treatment on a wide array of cytokines. We performed a systematic search of 6 databases, which yielded 32 studies measuring the levels of selected cytokines before and at a second time-point during antidepressant treatment. For meta-analysis of selected studies with a continuous measure we analysed variables containing the number of cases, mean and standard deviation of the level of IL-1ß, IL-2, IL-5, IL-6, IL-8, IL-10, CRP, TNF-α, IFN-γ levels observed in the different studies, in the intervention groups before and after antidepressant treatment. Statistical analysis revealed significant decreases of IL-4, IL-6, and IL-10 in MDD subjects after antidepressant treatment. In case of IL-1ß the decrease was significant exclusively for SSRI drugs. We did not find any significant effect of antidepressant medication on IL-2, TNF-α IFN-γ and CRP. Antidepressant treatment affects the levels of cytokines in depression. The immunological imbalance in MDD is complex and seems to be mediated by other factors yet to be elucidated. The credibility of our results is limited by high heterogeneity among studies and very few studies with a placebo-controlled design. Research with MDD subtypes, response to treatment status and cytokine associations with the kynurenine pathway taken into account pose a promising target for future studies.


The dynamic proliferation of CanSINEs mirrors the complex evolution of Feliforms.
Repetitive short interspersed elements (SINEs) are retrotransposons ubiquitous in mammalian genomes and are highly informative markers to identify species and phylogenetic associations. Of these, SINEs unique to the order Carnivora (CanSINEs) yield novel insights on genome evolution in domestic dogs and cats, but less is known about their role in related carnivores. In particular, genome-wide assessment of CanSINE evolution has yet to be completed across the Feliformia (cat-like) suborder of Carnivora. Within Feliformia, the cat family Felidae is composed of 37 species and numerous subspecies organized into eight monophyletic lineages that likely arose 10 million years ago. Using the Felidae family as a reference phylogeny, along with representative taxa from other families of Feliformia, the origin, proliferation and evolution of CanSINEs within the suborder were assessed. We identified 93 novel intergenic CanSINE loci in Feliformia. Sequence analyses separated Feliform CanSINEs into two subfamilies, each characterized by distinct RNA polymerase binding motifs and phylogenetic associations. Subfamily I CanSINEs arose early within Feliformia but are no longer under active proliferation. Subfamily II loci are more recent, exclusive to Felidae and show evidence for adaptation to extant RNA polymerase activity. Further, presence/absence distributions of CanSINE loci are largely congruent with taxonomic expectations within Feliformia and the less resolved nodes in the Felidae reference phylogeny present equally ambiguous CanSINE data. SINEs are thought to be nearly impervious to excision from the genome. However, we observed a nearly complete excision of a CanSINEs locus in puma (Puma concolor). In addition, we found that CanSINE proliferation in Felidae frequently targeted existing CanSINE loci for insertion sites, resulting in tandem arrays. We demonstrate the existence of at least two SINE families within the Feliformia suborder, one of which is actively involved in insertional mutagenesis. We find SINEs are powerful markers of speciation and conclude that the few inconsistencies with expected patterns of speciation likely represent incomplete lineage sorting, species hybridization and SINE-mediated genome rearrangement.


Nonmuscle myosin II regulates migration but not contraction in rat hepatic stellate cells.
To identify and characterize the function of nonmuscle myosin II (NMM II) isoforms in primary rat hepatic stellate cells (HSCs). Primary HSCs were isolated from male Sprague-Dawley rats by pronase/collagenase digestion. Total RNA and protein were harvested from quiescent and culture-activated HSCs. NMM II isoform (II-A, II-B and II-C) gene and protein expression were measured by RealTime polymerase chain reaction and Western blot analyses respectively. NMM II protein localization was visualized in vitro using immunocytochemical analysis. For in vivo assessment, liver tissue was harvested from bile duct-ligated (BDL) rats and NMM IIisoform expression determined by immunohistochemistry. Using a selective myosin II inhibitor and siRNA-mediated knockdown of each isoform, NMM II functionality in primary rat HSCs was determined by contraction and migration assays. NMM II-A and II-B mRNA expression was increased in culture-activated HSCs (Day 14) with significant increases seen in all pair-wise comparisons (II-A: 12.67 ± 0.99 (quiescent) vs 17.36 ± 0.78 (Day 14), P < 0.05; II-B: 4.94 ± 0.62 (quiescent) vs 13.90 ±0.85 (Day 14), P < 0.001). Protein expression exhibited similar expression patterns (II-A: 1.87 ± 2.50 (quiescent) vs 58.64 ± 8.76 (Day 14), P < 0.05; II-B: 1.17 ± 1.93 (quiescent) vs 103.71 ± 21.73 (Day 14), P < 0.05). No significant differences were observed in NMM II-C mRNA and protein expression between quiescent and activated HSCs. In culture-activated HSCs, NMM II-A and II-B merged with F-actin at the cellular periphery and throughout cytoplasm respectively. In vitro studies showed increased expression of NMM II-B in HSCs activated by BDL compared to sham-operated animals. There were no apparent increases of NMM II-A and II-C protein expression in HSCs during hepatic BDL injury. To determine the contribution of NMM II-A and II-B to migration and contraction, NMM II-A and II-B expression were downregulated with siRNA. NMM II-A and/or II-B siRNA inhibited HSC migration by approximately 25% compared to scramble siRNA-treated cells. Conversely, siRNA-mediated NMM II-A and II-B inhibition had no significant effect on HSC contraction; however, contraction was inhibited with the myosin II inhibitor, blebbistatin (38.7% ± 1.9%). Increased expression of NMM II-A and II-B regulates HSC migration, while other myosin IIclasses likely modulate contraction, contributing to development and severity of liver fibrosis.


[Hashimoto's encephalopathy: an anatomicoclinical observation].
Hashimoto's encephalopathy (HE) is a rare neurological complication of chronic lymphocytic thyroiditis. As its clinical presentation is aspecific, other etiologies of acute encephalopathy have to be ruled out. We report the case of a 29-year old woman with neuropsychiatric signs preceding coma, myoclonus and epileptic seizures. Clinical and electroencephalographic features were consistent with the diagnosis of new variant of Creutzfeldt-Jakob disease. However, high titres of antithyroid antibodies in serum directed towards the diagnosis of HE. Despite oral steroids, the patient died five months later. Neuropathological findings ruled out spongiform encephalopathy and disclosed aspecific activated microglia. Our observation suggests that this process could be involved in the pathogenesis of HE. Even in the absence of clinical dysthyroidism, HE diagnosis has to be suspected in the settings of acute encephalopathy associated with seric antithyroid antibodies.


Poisoning with N-3-pyridylmethyl-N'-p-nitrophenylurea (Vacor). Immunoperoxidase demonstration of beta-cell destruction.
A 49-year-old woman ate N-3-pyridylmethyl-N'-p'nitrophenylurea (PNU; Vacor) and was admitted to the hospital 12 hours later with a blood glucose level of 940 mg/dl and an anion-gap metabolic acidosis. Her diabetes was successfully treated, but she contained to manifest severe orthostatic hypotension. A painless ileus developed, followed by cecal perforation and death. Immunoperoxidase staining of paraffin-embedded pancreatic tissue obtained during postmortem examination clearly demonstrated the pancreatic beta-cell destruction. Results of this same staining technique also suggested that fewer alpha cells were present.


High-throughput assessment of vacancy formation and surface energies of materials using classical force-fields.
In this work, we present an open access database for surface and vacancy-formation energies using classical force-fields (FFs). These quantities are essential in understanding diffusion behavior, nanoparticle formation and catalytic activities. FFs are often designed for a specific application, hence, this database allows the user to understand whether a FF is suitable for investigating particular defect and surface-related material properties. The FF results are compared to density functional theory and experimental data whenever applicable for validation. At present, we have 17 506 surface energies and 1000 vacancy formation energies calculation in our database and the database is still growing. All the data generated, and the computational tools used, are shared publicly at the following websites: www.ctcms.nist.gov/~knc6/periodic.html, https://jarvis.nist.gov and https://github.com/usnistgov/jarvis. Approximations used during the high-throughput calculations are clearly mentioned. Using some of the example cases, we show how our data can be used to directly compare different FFs for a material and to interpret experimental findings such as using Wulff construction for predicting equilibrium shape of nanoparticles. Similarly, the vacancy formation energies data can be useful in understanding diffusion related properties.


Half a diagnosis: gap in confirming infection among hepatitis C antibody-positive patients.
Recent guidelines recommend testing all individuals born during 1945-1965 for hepatitis C virus (HCV) antibody. For antibody-positive patients, subsequent RNA testing is necessary to determine current infection status. This study aimed to assess whether clinicians order HCV RNA tests as recommended for antibody-positive patients and to identify barriers to such testing. We sampled individuals newly reported to the New York City Department of Health and Mental Hygiene's HCV surveillance system and collected information from clinicians. For patients without RNA test results, we asked the reason an RNA test was not ordered and requested that the clinician order the test. Of 245 antibody-positive patients, 67% were tested for HCV RNA (for 21% of these, the test was ordered only after our request); 33% had no RNA testing despite our request. Patients without RNA testing were seen in medical facilities (47%), detox facilities (30%), and jail/prison (15%). Reasons RNA testing was not done were that the patient did not return for follow-up (35%), the facility does not do RNA testing (22%), and the patient was tested in jail (15%). In our study, one third of patients did not get complete testing for accurate diagnosis of HCV, which is essential for medical management. Additional education for clinicians about the importance of RNA testing may help. However, with improved antiviral treatments now available for HCV, it is time for reflex HCV RNA testing for positive antibody tests to become routine, just as reflex Western blot testing is standard for human immunodeficiency virus.


Improved electrodeposited iridium oxide pH sensor fabricated on etched titanium substrates.
In the present paper, the preparation and characterization of an improved solid-state pH sensor are described. The sensor is based on anodically electrodeposited iridium oxide film, as a pH-sensing layer. Merits of the present sensor include (i) excellent adhesion of the pH sensitive layer to the substrate, (ii) excellent reproducibility of sensor fabrication, (iii) faster preparation procedure, and (iv) low cost of the titanium substrate. These advantages are realized by combining acid-etched titanium as the electrode substrate with an optimized electrodeposition solution consisting of IrCl4 as an iridium source, hydrogen peroxide, potassium oxalate, and potassium carbonate. Heating the electrodeposition solution to 90 degrees C reduced the time required for solution development from approximately 3 days to 10 min. The pH-sensing layer is protected with a layer of Nafion and a microporous polyester membrane. The improved sensor showed a super-Nernstian response (-73.7 +/- 1.2 mV/pH unit) in the pH range of 1.5-11.5. The present pH sensor, fabricated in a tubular form, is used as a detector in a flow injection analysis (FIA) system for pH measurements. Optimization of the FIA experimental parameters resulted in a linear dependence of peak heights on the pH of the injected samples in the pH range of 2-11.


Parvalbumin gene transfer corrects diastolic dysfunction in diseased cardiac myocytes.
Heart failure frequently involves diastolic dysfunction that is characterized by a prolonged relaxation. This prolonged relaxation is typically the result of a decreased rate of intracellular Ca(2+) sequestration. No effective treatment for this decreased Ca(2+) sequestration rate currently exists. As an approach to possibly correct diastolic dysfunction, we hypothesized that expression of the Ca(2+) binding protein parvalbumin in cardiac myocytes would lead to increased rates of Ca(2+) sequestration and mechanical relaxation. Parvalbumin, which is normally absent in cardiac tissue, is known to act as a soluble relaxing factor in fast skeletal muscle fibers by acting as a delayed Ca(2+) sink. As a test of the hypothesis, gene transfer was used to express parvalbumin in isolated adult cardiac myocytes. We report here that expression of parvalbumin dramatically increases the rate of Ca(2+) sequestration and the relaxation rate in normal cardiac myocytes. Importantly, parvalbumin fully restored the relaxation rate in diseased cardiac myocytes isolated from an animal model of human diastolic dysfunction. These findings indicate that parvalbumin gene transfer offers unique potential as a possible direct treatment for diastolic dysfunction in failing hearts.


Discovering microproteins: making the most of ribosome profiling data.
Building a reference set of protein-coding open reading frames (ORFs) has revolutionized biological process discovery and understanding. Traditionally, gene models have been confirmed using cDNA sequencing and encoded translated regions inferred using sequence-based detection of start and stop combinations longer than 100 amino-acids to prevent false positives. This has led to small ORFs (smORFs) and their encoded proteins left un-annotated. Ribo-seq allows deciphering translated regions from untranslated irrespective of the length. In this review, we describe the power of Ribo-seq data in detection of smORFs while discussing the major challenge posed by data-quality, -depth and -sparseness in identifying the start and end of smORF translation. In particular, we outline smORF cataloguing efforts in humans and the large differences that have arisen due to variation in data, methods and assumptions. Although current versions of smORF reference sets can already be used as a powerful tool for hypothesis generation, we recommend that future editions should consider these data limitations and adopt unified processing for the community to establish a canonical catalogue of translated smORFs.


Analysis of the hormone-binding domain of steroid receptors using chimeras generated by homologous recombination.
The glucocorticoid receptor and the mineralocorticoid receptor are members of the steroid receptor family that exhibit ligand cross-reactivity. Specificity of steroid receptor action is investigated in the present work by the construction and characterization of chimeras between the glucocorticoid receptor and the mineralocorticoid receptor. We used an innovative approach to make novel steroid receptor proteins in vivo that in general, contrary to our expectations, show increased ligand specificity compared to the parental receptors. We describe a receptor that is specific for the potent synthetic glucocorticoid triamcinolone acetonide and does not bind aldosterone. A further set of chimeras has an increased ability to discriminate between ligands, responding potently to mineralocorticoids and only very weakly to synthetic glucocorticoids. A chimera with the fusion site in the hinge highlights the importance of the region between the DNA-binding and the hormone-binding domains since, unlike both the glucocorticoid and mineralocorticoid receptors, it only responds to mineralocorticoids. One chimera has reduced specificity in that it acts as a general corticoid receptor, responding to glucocorticoids and mineralocorticoids with similar potency and efficacy. Our data suggest that regions of the glucocorticoid and mineralocorticoid receptor hormone-binding domains are functionally non-reciprocal. We present transcriptional, hormone-binding, and structure-modeling evidence that suggests that receptor-specific interactions within and across domains mediate aspects of specificity in transcriptional responses to steroids.


Lycopene enrichment of cultured airway epithelial cells decreases the inflammation induced by rhinovirus infection and lipopolysaccharide.
Rhinovirus infection results in increased release of inflammatory mediators from airway epithelial cells in asthma. As an antioxidant, lycopene offers protection from adverse effects of inflammation. The aim of this study was to find an appropriate method of lycopene enrichment of airway epithelial cells and to determine the effects of lycopene enrichment on the inflammatory response of cells infected by rhinovirus or exposed to lipopolysaccharide. Lycopene enrichment of airway epithelial cells using solubilisation in tetrahydrofuran versus incorporation in liposomes was compared. After determining that solubilisation of lycopene in tetrahydrofuran was the most suitable method of lycopene supplementation, airway epithelial cells (Calu-3) were incubated with lycopene (dissolved in tetrahydrofuran) for 24 h, followed by rhinovirus infection or lipopolysaccharide exposure for 48 h. The release of interleukin-6, interleukin-8 and interferon-gamma induced protein-10 (IP-10) and their messenger RNA levels were measured using enzyme linked immunosorbent assay and reverse transcription polymerase chain reaction, respectively. Viral replication was measured by tissue culture infective dose of 50% assay. Lycopene concentration of cells and media were analysed using high-performance liquid chromatography. Preincubation of airway epithelial cells with lycopene (dissolved in tetrahydrofuran) delivered lycopene into the cells and resulted in a 24% reduction in interleukin-6 after rhinovirus-1B infection, 31% reduction in IP-10 after rhinovirus-43 infection and 85% reduction in rhinovirus-1B replication. Lycopene also decreased the release of IL-6 and IP-10 following exposure to lipopolysaccharide. We conclude that lycopene has a potential role in suppressing rhinovirus induced airway inflammation.


The temporal expression of osteopontin (SPP-1) in the rodent model of alcoholic steatohepatitis: a potential biomarker.
Previous studies from our laboratory have shown that osteopontin (OPN) mediates neutrophil infiltration into the liver in a rodent model of alcoholic steatohepatitis (ASH). The objective of this study was to investigate the temporal and spatial pattern of hepatic OPN mRNA and protein expression during the progression of alcoholic liver disease. OPN mRNA and protein expression were evaluated using real time PCR, in situ hybridization, Western blot and immunohistochemistry respectively. ASH was induced in male Sprague-Dawley rats by feeding EtOH-containing Lieber-DeCarli diet for 6 weeks, followed by a single injection of lipopolysaccharide (LPS, 10 mg/kg, ip). Rats were sacrificed 2-, 12-and 24-hour post LPS injection. A progressive induction of OPN mRNA was observed that preceded hepatic neutrophil infiltration and the increase in OPN mRNA correlated with increases in OPN protein expression. OPN mRNA was localized primarily to the biliary epithelium. The data indicates that OPN is transcribed and translated within the biliary epithelium. These findings suggest a potential role of OPN as an early biomarker in predicting inflammatory liver diseases such as ASH.


Immunological mechanisms affecting angiogenesis and their relation to porcine pregnancy success.
Prenatal mortality due to loss of lymphocyte-promoted endometrial angiogenesis is being investigated as a major cause of litter reductions during pregnancy in pigs. This review discusses immune mechanisms influencing porcine endometrial angiogenesis as well as additional signalling molecules that may play important roles in the compromise of peri-implantation and mid-gestation fetal pig survival. These include dendritic cells, signalling molecules such as toll-like receptors, chemokines and ficolins. Together these cells and molecules regulate immune responses and, ideally, protect the mother and prevent immune-based conceptus losses. Dendritic cells were recently shown to be angiogenic. Their tolerogenic role at the maternal-fetal interface coupled with the ability to secrete and respond to angiogenic factors suggests that dendritic cells are the key coordinators of angiogenesis at the porcine maternal-fetal interface. Chemokines coordinate the localization of immune effector and endothelial cells. The balance between pro-angiogenic and anti-angiogenic chemokines is addressed in relation to conceptus viability. Ficolins, components of the lectin-mediated complement activation pathway, are used for self/non-self recognition. Together, these components of the immune system could regulate lymphocyte- and non-lymphocyte-promoted endometrial angiogenesis to determine conceptus survival.


Asymmetric inclusion process.
We introduce and explore the asymmetric inclusion process (ASIP), an exactly solvable bosonic counterpart of the fermionic asymmetric exclusion process (ASEP). In both processes, random events cause particles to propagate unidirectionally along a one-dimensional lattice of n sites. In the ASEP, particles are subject to exclusion interactions, whereas in the ASIP, particles are subject to inclusion interactions that coalesce them into inseparable clusters. We study the dynamics of the ASIP, derive evolution equations for the mean and probability generating function (PGF) of the sites' occupancy vector, obtain explicit results for the above mean at steady state, and describe an iterative scheme for the computation of the PGF at steady state. We further obtain explicit results for the load distribution in steady state, with the load being the total number of particles present in all lattice sites. Finally, we address the problem of load optimization, and solve it under various criteria. The ASIP model establishes bridges between statistical physics and queueing theory as it represents a tandem array of queueing systems with (unlimited) batch service, and a tandem array of growth-collapse processes.


Update on low-calorie sweeteners to benefit dental health.
Ten different types of high-intensity, low-calorie sweeteners that have potential dental applications as sugar substitutes are appraised, taking into consideration their general properties, safety and toxicological assessment, metabolic fate in the body, regulatory status and any dental research that has been carried out on them. Attention focuses on the continuing expansion in the wide diversity of types of sweeteners becoming available, the multiple sweetener concept, the growing interest in materials of natural origin, and the distinction between non-cariogenic and actively anti-cariogenic properties of the individual sweeteners.


Hybrid Metrology for Nanostructured Optical Metasurfaces.
Metasurfaces have garnered increasing research interest in recent years due to their remarkable advantages, such as efficient miniaturization and novel functionalities compared to traditional optical elements such as lenses and filters. These advantages have facilitated their rapid commercial deployment. Recent advancements in nanofabrication have enabled the reduction of optical metasurface dimensions to the nanometer scale, expanding their capabilities to cover visible wavelengths. However, the pursuit of large-scale manufacturing of metasurfaces with customizable functions presents challenges in controlling the dimensions and composition of the constituent dielectric materials. To address these challenges, the combination of block copolymer (BCP) self-assembly and sequential infiltration synthesis (SIS), offers an alternative for fabrication of high-resolution dielectric nanostructures with tailored composition and optical functionalities. However, the absence of metrological techniques capable of providing precise and reliable characterization of the refractive index of dielectric nanostructures persists. This study introduces a hybrid metrology strategy that integrates complementary synchrotron-based traceable X-ray techniques to achieve comprehensive material characterization for the determination of the refractive index on the nanoscale. To establish correlations between material functionality and their underlying chemical, compositional and dimensional properties, TiO2 nanostructures model systems were fabricated by SIS of BCPs. The results from synchrotron-based analyses were integrated into physical models, serving as a validation scheme for laboratory-scale measurements to determine effective refractive indices of the nanoscale dielectric materials.


The benefits associated with volunteering among seniors: a critical review and recommendations for future research.
There is an urgent need to identify lifestyle activities that reduce functional decline and dementia associated with population aging. The goals of this article are to review critically the evidence on the benefits associated with formal volunteering among older adults, propose a theoretical model of how volunteering may reduce functional limitations and dementia risk, and offer recommendations for future research. Database searches identified 113 papers on volunteering benefits in older adults, of which 73 were included. Data from descriptive, cross-sectional, and prospective cohort studies, along with 1 randomized controlled trial, most consistently reveal that volunteering is associated with reduced symptoms of depression, better self-reported health, fewer functional limitations, and lower mortality. The extant evidence provides the basis for a model proposing that volunteering increases social, physical, and cognitive activity (to varying degrees depending on characteristics of the volunteer placement) which, through biological and psychological mechanisms, leads to improved functioning; we further propose that these volunteering-related functional improvements should be associated with reduced dementia risk. Recommendations for future research are that studies (a) include more objective measures of psychosocial, physical, and cognitive functioning; (b) integrate qualitative and quantitative methods in prospective study designs; (c) explore further individual differences in the benefits associated with volunteering; (d) include occupational analyses of volunteers' specific jobs in order to identify their social, physical, and cognitive complexity; (e) investigate the independent versus interactive health benefits associated with volunteering relative to engagement in other forms of activity; and (f) examine the relationship between volunteering and dementia risk.


[Temperature measurement--where, when and how?].
The mercury thermometer may no longer be sold in Sweden, and is soon to be proscribed in the other Scandinavian countries. How reliable are other thermometers, and should body temperature be measured orally, rectally or in some other way?


Human adult T-cell leukemia virus: molecular cloning of the provirus DNA and the unique terminal structure.
Adult T-cell leukemia virus (ATLV) is a human retrovirus closely associated with adult T-cell leukemia. The integrated provirus DNA and cDNA from virion RNA were molecularly cloned and their structures were analyzed. Clone lambda ATM-1 of an integrated provirus DNA in the MT-1 cell line, established from adult T-cell leukemia cells by cocultivation with cord lymphocytes, contained DNA about 13,000 base pairs (bp) long and long terminal repeats (LTR) at both ends of the viral sequence that were about 8,000 bp long. These two LTR sequences were linked to cellular sequences with direct repeats of 7 bp. Each LTR consisted of 754 bp including inverted repeats of 2 bp at the ends and the T-A-T-A-A box, characteristics in common with those of LTRs of other known retroviruses. Adjacent to the 5' LTR there was a sequence identical to the tRNAPro binding site in murine leukemia virus, suggesting that tRNAPro is a primer for reverse transcription of the viral genome. From these structural features, the mechanism of ATLV replication was suggested to be the same as that of other known animal retroviruses. However, the length of the small terminal repeats at the ends of the RNA genome, 228 +/- 1 bases, is much longer than the lengths, up to 80 bases, of those in avian, mouse, or primate retroviruses so far analyzed. These findings suggest that ATLV should be classified in a distinct group of retroviruses with bovine leukemia virus which also makes unusually long strong-stop cDNA.


Endoscopic Resection with One-Port Placement: A Newly Developed Technique for the Safe Management of Advanced Endoscopic Resection for Gastric Gastrointestinal Stromal Tumors.
Endoscopic full-thickness resection (EFTR) without laparoscopic assistance (pure EFTR) is an emerging, less invasive treatment for gastrointestinal stromal tumors (GISTs). However, the technique has seldom been performed outside China because of concerns regarding pneumoperitoneum, maintenance of endoscopic view, and endoscopic suturing. This study aimed to evaluate the efficacy and safety of endoscopic resection with one-port placement (EROPP) for gastric GISTs. This retrospective study included 17 patients with gastric GISTs originating from the muscularis propria who underwent EROPP between 2019 and 2022. One camera port was inserted in the umbilicus before initiating the endoscopic procedure to maintain intra-abdominal pressure, which was monitored and adjusted via this port. While allowing for conversion to laparoscopic surgery if needed, EFTR was performed as follows: (1) circumferential incision of the mucosal and submucosal layers around the lesion was performed by typical endoscopic submucosal dissection; (2) an intentional perforation and subsequent seromuscular resection was made using dental floss and an endo-clip for traction; and (3) closure of the gastric full-thickness defect was performed with an over-the-scope clip (OTSC) after peroral retrieval of the specimen. We retrospectively assessed the short-term outcomes and safety. All procedures were completed successfully without conversion to laparoscopic surgery. The median size of the resected tumors was 23 mm (range, 8-35 mm), the median resection time was 36 min (range, 22-95 min), and closure time was 18 min (range, 10-45 min). The rates of en bloc and complete resection were 100% and 88%, respectively. In 2 cases, another port was added to aspirate the leaking fluid or check the condition of the endoscopic closure. All gastric defects were endoscopically closed, mainly using OTSCs. The recovery course for all patients was uneventful, and no adverse events were reported. EROPP is a safe and minimally invasive treatment for gastric GISTs and appears to be suitable for introducing EFTR procedures.


Zip6 Transporter Is an Essential Component of the Lymphocyte Activation Machinery.
Zinc deficiency causes immune dysfunction. In T lymphocytes, hypozincemia promotes thymus atrophy, polarization imbalance, and altered cytokine production. Zinc supplementation is commonly used to boost immune function to prevent infectious diseases in at-risk populations. However, the molecular players involved in zinc homeostasis in lymphocytes are poorly understood. In this paper, we wanted to determine the identity of the transporter responsible for zinc entry into lymphocytes. First, in human Jurkat cells, we characterized the effect of zinc on proliferation and activation and found that zinc supplementation enhances activation when T lymphocytes are stimulated using anti-CD3/anti-CD28 Abs. We show that zinc entry depends on specific pathways to correctly tune the NFAT, NF-κB, and AP-1 activation cascades. Second, we used various human and murine models to characterize the zinc transporter family, Zip, during T cell activation and found that Zip6 was strongly upregulated early during activation. Therefore, we generated a Jurkat Zip6 knockout (KO) line to study how the absence of this transporter affects lymphocyte physiology. We found that although Zip6KO cells showed no altered zinc transport or proliferation under basal conditions, under activation, these KO cells showed deficient zinc transport and a drastically impaired activation program. Our work shows that zinc entry into activated lymphocytes depends on Zip6 and that this transporter is essential for the correct function of the cellular activation machinery.


Adapting Management of Sarcomas in COVID-19: An Evidence-Based Review.
With the novel coronavirus disease (COVID-19) being declared a global pandemic by the World Health Organization, the Indian healthcare sector is at the forefront to deliver optimal care. Patients with cancer especially are at serious risk for increased chances of morbidity and mortality due to their immunocompromised state. Currently there is a paucity of definitive guidelines for the management of sarcomas during the pandemic in a resource-constrained and diverse population setting like India. Health care professionals from various specialties involved in the management of sarcomas have collaborated to discuss various aspects of evidence-based sarcoma management during the COVID-19 pandemic. This article provides structured recommendations for HCP to adapt to the situation, optimize treatment protocols with judicious use of all resources while providing evidence-based treatment for sarcoma patients.


GABAA receptor-mediated input change on orexin neurons following sleep deprivation in mice.
Orexins are bioactive peptides, which have been shown to play a pivotal role in vigilance state transitions: the loss of orexin-producing neurons (orexin neurons) leads to narcolepsy with cataplexy in the human. However, the effect of the need for sleep (i.e., sleep pressure) on orexin neurons remains largely unknown. Here, we found that immunostaining intensities of the α1 subunit of the GABAA receptor and neuroligin 2, which is involved in inhibitory synapse specialization, on orexin neurons of mouse brain were significantly increased by 6-h sleep deprivation. In contrast, we noted that immunostaining intensities of the α2, γ2, and β2/3 subunits of the GABAA receptor and Huntingtin-associated protein 1, which is involved in GABAAR trafficking, were not changed by 6-h sleep deprivation. Using a slice patch recording, orexin neurons demonstrated increased sensitivity to a GABAA receptor agonist together with synaptic plasticity changes after sleep deprivation when compared with an ad lib sleep condition. In summary, the GABAergic input property of orexin neurons responds rapidly to sleep deprivation. This molecular response of orexin neurons may thus play a role in the changes that accompany the need for sleep following prolonged wakefulness, in particular the decreased probability of a transition to wakefulness once recovery sleep has begun.


Inactivation by acivicin of rat brain CTP and GMP synthetases and depression of CTP and GTP concentrations.
Evidence was provided that injection of acivicin (25 mg/kg, i.p.) into the rat inactivated brain CTP and GMP synthetases. Under the same circumstances, CTP and GTP concentrations in the rat brain decreased following the decline in the activities of CTP and GMP synthetases. The decrease in enzymic activities and nucleotide concentrations progressed with time. The decline in CTP and GMP synthetase activities and CTP and GTP concentrations caused by acivicin occurred more slowly and to a lesser extent than in liver and hepatoma 3924A. The delay in the expression of acivicin action in the rat brain was attributed to a possible slower entrance of acivicin and the lower concentration than might have been attained in the rat brain. These considerations are based on the rapid disappearance of acivicin from rat plasma noted earlier. The decline in CTP concentration in rat brain might interfere with neuronal function. The decline in GTP concentration might be expressed through the depletion of biopterins which are generated from GTP in the brain. The possible relevance to the biochemical basis of paranoid schizophrenia which occurs reversibly after high-dose acivicin or tiazofurin treatment was discussed.