Hepatitis C Virus Indirectly Disrupts DNA Damage-Induced p53 Responses by Activating Protein Kinase R.
Many DNA tumor viruses promote cellular transformation by inactivating the critically important tumor suppressor protein p53. In contrast, it is not known whether p53 function is disrupted by hepatitis C virus (HCV), a unique, oncogenic RNA virus that is the leading infectious cause of liver cancer in many regions of the world. Here we show that HCV-permissive, liver-derived HepG2 cells engineered to constitutively express microRNA-122 (HepG2/miR-122 cells) have normal p53-mediated responses to DNA damage and that HCV replication in these cells potently suppresses p53 responses to etoposide, an inducer of DNA damage, or nutlin-3, an inhibitor of p53 degradation pathways. Upregulation of p53-dependent targets is consequently repressed within HCV-infected cells, with potential consequences for cell survival. Despite this, p53 function is not disrupted by overexpression of the complete HCV polyprotein, suggesting that altered p53 function may result from the host response to viral RNA replication intermediates. Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated ablation of double-stranded RNA (dsRNA)-activated protein kinase R (PKR) restored p53 responses while boosting HCV replication, showing that p53 inhibition results directly from viral activation of PKR. The hepatocellular abundance of phosphorylated PKR is elevated in HCV-infected chimpanzees, suggesting that PKR activation and consequent p53 inhibition accompany HCV infection in vivo These findings reveal a feature of the host response to HCV infection that may contribute to hepatocellular carcinogenesis.IMPORTANCE Chronic infection with hepatitis C virus (HCV) is the leading cause of liver cancer in most developed nations. However, the mechanisms whereby HCV infection promotes carcinogenesis remain unclear. Here, we demonstrate that HCV infection inhibits the activation of p53 following DNA damage. Contrary to previous reports, HCV protein expression is insufficient to inhibit p53. Rather, p53 inhibition is mediated by cellular protein kinase R (PKR), which is activated by HCV RNA replication and subsequently suppresses global protein synthesis. These results redefine our understanding of how HCV infection influences p53 function. We speculate that persistent disruption of p53-mediated DNA damage responses may contribute to hepatocellular carcinogenesis in chronically infected individuals.


Population genomics: whole-genome analysis of polymorphism and divergence in Drosophila simulans.
The population genetic perspective is that the processes shaping genomic variation can be revealed only through simultaneous investigation of sequence polymorphism and divergence within and between closely related species. Here we present a population genetic analysis of Drosophila simulans based on whole-genome shotgun sequencing of multiple inbred lines and comparison of the resulting data to genome assemblies of the closely related species, D. melanogaster and D. yakuba. We discovered previously unknown, large-scale fluctuations of polymorphism and divergence along chromosome arms, and significantly less polymorphism and faster divergence on the X chromosome. We generated a comprehensive list of functional elements in the D. simulans genome influenced by adaptive evolution. Finally, we characterized genomic patterns of base composition for coding and noncoding sequence. These results suggest several new hypotheses regarding the genetic and biological mechanisms controlling polymorphism and divergence across the Drosophila genome, and provide a rich resource for the investigation of adaptive evolution and functional variation in D. simulans.


The postulations á la D'Alembert and á la Cauchy for higher gradient continuum theories are equivalent: a review of existing results.
In order to found continuum mechanics, two different postulations have been used. The first, introduced by Lagrange and Piola, starts by postulating how the work expended by internal interactions in a body depends on the virtual velocity field and its gradients. Then, by using the divergence theorem, a representation theorem is found for the volume and contact interactions which can be exerted at the boundary of the considered body. This method assumes an a priori notion of internal work, regards stress tensors as dual of virtual displacements and their gradients, deduces the concept of contact interactions and produces their representation in terms of stresses using integration by parts. The second method, conceived by Cauchy and based on the celebrated tetrahedron argument, starts by postulating the type of contact interactions which can be exerted on the boundary of every (suitably) regular part of a body. Then it proceeds by proving the existence of stress tensors from a balance-type postulate. In this paper, we review some relevant literature on the subject, discussing how the two postulations can be reconciled in the case of higher gradient theories. Finally, we underline the importance of the concept of contact surface, edge and wedge s-order forces.


Streptokinase clot lysis in acute occlusions of the cranial circulation: study in rabbits.
An animal model of acute cerebrovascular thromboembolism was developed to evaluate the feasibility of selective fibrinolysis. In 20 Flemish Giant rabbits, autologous clot was deposited via selected catheterization of the distal end of the common carotid artery. The rates of clot lysis with streptokinase were compared in eight control rabbits and after three different dosage regimens in four rabbits each. Group A received selective infusion of 5000 U/hr; group B received 4000 U/min for 1 hr, 3000 U/min for 2 hr, and 5000 U/hr for 2 hr; and group C was treated similar to group B plus receiving an initial 20,000 U bolus of streptokinase. Lysis was evaluated by serial angiograms obtained hourly for up to 6 hr after the clot was deposited. Five proximal vessels arising from the common carotid artery were chosen for the angiographic grading system. The control group showed beginning lysis after 5-6 hr. Group A appeared to show a slight improvement about 4 hr after clotting. Group B demonstrated an early and greater improvement at 2 hr that appeared to be sustained throughout the experiment. Group C showed no difference compared with the control group. The Dunnet t procedure and the Kruskel-Wallis nonparametric analysis of variance were used for comparing the angiograms of the treatment groups with those of the control group at corresponding study times. The results of these animal experiments do not indicate a definite benefit of streptokinase treatment alone over no treatment. Further controlled studies are needed before the value of streptokinase in routine clinical practice can be determined.


Gaze-based and attention-based rehearsal in spatial working memory.
How do we maintain information about spatial configurations in mind? Many working memory (WM) models assume that rehearsal processes are used to counteract forgetting in WM. Here, we investigated the contributions of gaze-based and attention-based rehearsal for protecting spatial representations from time-based forgetting. Participants memorized 6 locations selected from a grid of 30 scattered dots. Memory was tested after 1.5 or 4.5 s, and this interval was either blank or the grid remained onscreen (which is assumed to provide rehearsal support). In 2 experiments, we monitored eye movements during the retention phase, or asked participants to fixate the screen center. In 3 subsequent experiments, we tested spatial WM under dual-task conditions inhibiting shifts of visuospatial attention or central attention to the memoranda. Memory was better and more resistant to time-based forgetting in the grid than blank condition. Recording of fixations showed more frequent and efficient gaze-based rehearsal in the presence of the grid. Fixations toward distractor locations occurred at a similar frequency in the blank and grid conditions, and it did not predict incorrect recalls. Inhibition of eye-movements or shifts of visuospatial attention impaired memory overall, but it did not change the grid benefit nor the rate of time-based forgetting. In contrast, distracting central attention increased time-based forgetting regardless of grid presence. These results indicate that (a) the grid benefit is only partially explained by rehearsal; (b) gaze-errors (i.e., distractor fixations) do not lead to more forgetting; and (c) the maintenance of spatial representations over time depends on central processing. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Reliability and Efficacy of the Epworth Sleepiness Scale: Is There Still a Place for It?
The Epworth sleepiness scale (ESS) is a commonly used questionnaire to evaluate patients for excessive daytime sleepiness (EDS). The ESS has been validated as a measure of EDS, but a number of studies have shown more test-retest variability in clinical settings compared to the original validation study. This observation of higher-than-expected test-retest variability has called into question the utility of the ESS as a clinical tool to assess EDS. The purpose of this review article is to summarize how studies of test-retest variability in clinical populations compare to the original validation study of Johns and to highlight where they differ. Furthermore, use of the ESS as a continuous variable (with no specified cutoff value) versus a categorical variable (normal versus high) is described. These observations are put into a clinical context by comparing the test-retest variability observed on the ESS with that of the multiple sleep latency test (MSLT). Finally, how contributors to ESS scores differ within certain subpopulations is described. The ESS remains an important tool to measure EDS in patient populations, but an awareness of its limitations needs to be considered.


The influence of family context on life, educational and occupational ideal among middle school students in China.
This study examined the relationship between family context of middle school students on their educational and occupational ideals. Middle school students (N = 2000) responded to questions assessing family location, family structure, parental educational level and family economic status, as well as to the Middle School Students' Ideals Questionnaire. Multivariate analysis of variance indicated that life, educational and occupational ideals of female students and students in lower grades were higher than that of male students and students in higher grades. Regression analysis indicated that paternal education level have a positive association with educational and occupational ideals, but not life ideals, and family economic status have a positive relation to life ideals, but not educational and occupational ideals. Moreover, the interaction between family economic status and family location has a negative association with students' life, educational and occupational ideals. These results suggest that different factors predicted different ideals of adolescents, and that family economic status had a negative moderating effect on the relationship between family location and ideals of students.


Network analysis of psychopathy in forensic patients.
The question of which features represent the most central components of psychopathy remains unresolved and is the subject of considerable debate. Network analysis, which is a relatively new way to conceptualize mental disorders that emphasizes complex causal systems, provides a means to graphically and quantitatively describe the centrality of the various symptoms of a disorder. We applied association and adaptive LASSO networks on two samples of forensic patients. The first sample included forensic inpatients (N = 277) who were administered the Psychopathy Checklist-Revised (Hare, 2003), and the second sample included patients who previously had been civilly committed (N = 1136), who were administered the Psychopathy Checklist: Screening Version (Hart, Cox, & Hare, 1995). The models indicated the items on the affective facet are highly central across both samples and methods, and the item "lack of remorse" was especially central to the networks. Conversely, interpersonal, lifestyle, and antisocial facets generally resulted in low centrality in the models of both samples. Thus, the models lend support to the importance of affective deficits as the primary feature of psychopathy when psychopathy is assessed using the Hare Psychopathy Checklist measures. (PsycINFO Database Record


Updates in perioperative coagulation: physiology and management of thromboembolism and haemorrhage.
Understanding of blood coagulation has evolved significantly in recent years. Both new coagulation proteins and inhibitors have been found and new interactions among previously known components of the coagulation system have been discovered. This increased knowledge has led to the development of various new diagnostic coagulation tests and promising antithrombotic and haemostatic drugs. Several such agents are currently being introduced into clinical medicine for both the treatment or prophylaxis of thromboembolic disease and for the treatment of bleeding. This review aims to elucidate these new concepts and to outline some consequences for clinical anaesthesia and perioperative medicine.


Cancer risk and diet in India.
India is a developing country with one of the most diverse populations and diets in the world. Cancer rates in India are lower than those seen in Western countries, but are rising with increasing migration of rural population to the cities, increase in life expectancy and changes in lifestyles. In India, rates for oral and oesophageal cancers are some of the highest in the world. In contrast, the rates for colorectal, prostate, and lung cancers are one of the lowest. Studies of Indian immigrants in Western societies indicate that rates of cancer and other chronic diseases, such as coronary heart disease and diabetes, increase dramatically after a generation in the adopted country. Change of diet is among the factors that may be responsible for the changing disease rates. Diet in India encompasses diversity unknown to most other countries, with many dietary patterns emanating from cultural and religious teachings that have existed for thousands of years. Very little is known, however, about the role of the Indian diet in causation of cancer or its role, if any, in prevention of cancer, although more attention is being focused on certain aspects of the Indian diet, such as vegetarianism, spices, and food additives. Of particular interest for cancer prevention is the role of turmeric (curcumin), an ingredient in common Indian curry spice. Researchers also have investigated cumin, chilies, kalakhar, Amrita Bindu, and various plant seeds for their apparent cancer preventive properties. Few prospective studies, however, have been conducted to investigate the role of Indian diet and its various components in prevention of cancer. From a public health perspective, there is an increasing need to develop cancer prevention programs responsive to the unique diets and cultural practices of the people of India.


A factor X-activating cysteine protease from malignant tissue.
A proteolytic procoagulant has been identified in extracts of human and animal tumors and in cultured malignant cells. It directly activated Factor X but its similarity to other Factor S-activating serine proteases was not clear. This study describes work done to determine whether this enzyme, cancer procoagulant, is a serine or cysteine protease. Purified cancer procoagulant from rabbit V2 carcinoma was bound to a p-chloromercurialbenzoate-agarose affinity column and was eluted with dithiothreitol. The initiation of recalcified, citrated plasma coagulation activity by cancer procoagulant was inhibited by 5 mM diisopropylfluorophosphate, 1 mM phenylmethylsulfonylfluoride, 0.1 mM HgCl2, and 1 mM iodoacetamide. Activity was restored in the diisopropylfluorophosphate-, phenylmethylsulfonylfluoride-, and HgCl2-inhibited samples by 5 mM dithiothreitol; iodoacetamide inhibition was irreversible. Russell's viper venom, a control Factor X-activating serine protease, was not inhibited by either 0.1 mM HgCl2 or 1 mM iodoacetamide. The direct activation of Factor X by cancer procoagulant in a two-stage assay was inhibited by diisopropylfluorophosphate and iodoacetamide. Diisopropylfluorophosphate inhibits serine proteases, and an undefined impurity in most commercial preparations inhibits cysteine proteases. Hydrolysis of diisopropylfluorophosphate with CuSO4 and imidazole virtually eliminated inhibition of thrombin, but cancer procoagulant inhibition remained complete, suggesting that cancer procoagulant was inhibited by the undefined impurity. These results suggest that cancer procoagulant is a cysteine endopeptidase, which distinguishes it from other coagulation factors including tissue factor. This and other data suggest that neoplastic cells produce this unique cysteine protease which may initiate blood coagulation.


Unilateral nonhaemorrhagic adrenal infarction as a cause of abdominal pain during pregnancy.
Adrenal infarction is usually associated with bilateral adrenal hemorrhage in the setting of antiphospholipid syndrome or hemodynamic variation. Few cases of unilateral nonhemorrhagic adrenal infarction (NHAI) have been described in the literature. Here, we report a case occurring during pregnancy. A 30-year-old woman presented at 32 weeks of gestation with sudden-onset right abdominal pain and contractions. Unilateral adrenal infarction was diagnosed following computed tomography (CT). It showed an enlarged right adrenal, without hyperenhancement. Because of persisting contractions, despite medical care, she delivered a healthy, albeit premature, girl. Abdominal pain decreased right after delivery. Three month later, CT imaging showed atrophy of the right adrenal and a normal left adrenal. The patient's adrenal hormonal function was normal. Accurate diagnosis of NHAI remains difficult as its clinical presentation is not specific. It can only be performed with adrenal imaging. Magnetic resonance imaging shows diffuse enlargement of one or both adrenals and an edema on T2-weighted images. Anticoagulation therapy may be discussed. Patients should be evaluated between 3 and 6 months after the event to assess adrenal size and function. In summary, NHAI during pregnancy is probably underdiagnosed and obstetricians should be aware of this or diagnostic difficulty.


Screen of Drug Use: Diagnostic Accuracy of a New Brief Tool for Primary Care.
Illicit drug use is prevalent, and primary care provides an ideal setting in which to screen for drug use disorders (DUDs) and negative consequences of drug use (NCDU). Comprehensive reviews have concluded that existing drug use screening instruments are not appropriate for routine use in primary care. To develop and validate a screening instrument for drug use. We revised items drawn from existing screening instruments and conducted signal detection analyses to develop the new instrument. We approached 3173 patients at 2 primary care clinics in a US Department of Veterans Affairs health care system from February 1, 2012, through April 30, 2014. A total of 1300 (41.0%) patients consented to the study, of whom 1283 adults were eligible (mean [SD] age, 62.2 [12.6] years). In the last 12 months, 241 (18.8%) participants reported using illicit drugs or prescription medication for a nonmedical purpose, and 189 (14.7%) reported 1 or more NCDU. A total of 133 (10.4%) patients met DSM-IV criteria for a DUD. The sample was randomly divided first to develop the measure and then to validate it. The Mini-International Diagnostic Interview was used as the criterion for DUDs, and the Inventory of Drug Use Consequences was used as the criterion for NCDU. The screening instrument has 2 questions. The first is, "How many days in the past 12 months have you used drugs other than alcohol?" Patients meet that criterion with a response of 7 or more days. The second question asks, "How many days in the past 12 months have you used drugs more than you meant to?" A response of 2 or more days meets that criterion. The screening instrument was 100% sensitive and 93.73% specific for DUDs (643 patients); when replicated in the second half of the sample (640 patients), it was 92.31% sensitive and 92.87% specific. The screening instrument was 93.18% sensitive and 96.03% specific for NCDU (643 patients); when replicated in the second half of the sample (640 patients), it was 83.17% sensitive and 96.85% specific. The 2-item screen of drug use has excellent statistical properties and is a brief screening instrument for DUDs and problems suitable for busy US Department of Veterans Affairs primary care clinics.


Composition, structure and mechanical properties define performance of pulmonary surfactant membranes and films.
The respiratory surface in the mammalian lung is stabilized by pulmonary surfactant, a membrane-based system composed of multiple lipids and specific proteins, the primary function of which is to minimize the surface tension at the alveolar air-liquid interface, optimizing the mechanics of breathing and avoiding alveolar collapse, especially at the end of expiration. The goal of the present review is to summarize current knowledge regarding the structure, lipid-protein interactions and mechanical features of surfactant membranes and films and how these properties correlate with surfactant biological function inside the lungs. Surfactant mechanical properties can be severely compromised by different agents, which lead to surfactant inhibition and ultimately contributes to the development of pulmonary disorders and pathologies in newborns, children and adults. A detailed comprehension of the unique mechanical and rheological properties of surfactant layers is crucial for the diagnostics and treatment of lung diseases, either by analyzing the contribution of surfactant impairment to the pathophysiology or by improving the formulations in surfactant replacement therapies. Finally, a short review is also included on the most relevant experimental techniques currently employed to evaluate lung surfactant mechanics, rheology, and inhibition and reactivation processes.


Community-based care for youths with early and very-early onset bipolar I disorder.
Phenomenological and treatment differences between children and adolescents with bipolar I disorder in a public mental health system were examined. A systematic medical record review was performed on a sample of 83 patients, focusing on documented DSM IV symptoms of mania or depression, attention deficit hyperactivity disorder, conduct disorder, schizophrenia, and post-traumatic stress disorder. Cross-tabulation and logistic regression analyses were performed comparing the presence/absence of symptoms for each disorder and treatments provided for children and adolescents. Prepubertal patients were significantly more likely to be male, easily distracted, inattentive, detached from others, hyper-vigilant, prescribed stimulant medication, and to meet the diagnostic criteria for attention-deficit/hyperactivity disorder or Conduct Disorder than adolescents. Consistent with the published literature, phenomenological differences between children and adolescents are present and being recognized for differential diagnosis and treatment by community practitioners. More attention to documenting some cardinal symptoms of mania, the persistence of bipolar symptoms, and the nature of cycling for those with mixed states is needed.


Evaluation of a new selective medium for the isolation of Corynebacterium urealyticum.
A new selective medium (CBU agar) was compared with blood agar (BA) medium for primary isolation of Corynebacterium urealyticum from urine and skin samples of hospitalised patients. Overall, the CBU agar detected C. urealyticum in 14 (4.6%) of 302 urine samples and the BA medium detected the organism in four (1.3%), but most cultures which were positive only on CBU agar had < 10(4) cfu/ml. Six strains of C. urealyticum were isolated from 60 skin samples with CBU agar, whereas none was detected with BA. Although most skin samples had heavy inocula, the selective agar facilitated the recognition of low colony counts (< or = 10 cfu/plate) of C. urealyticum by reducing the growth of competing flora. Challenge of the selective medium with reference and clinical strains showed that CBU agar was inhibitory for gram-negative bacteria and reduced the gram-positive flora, allowing the growth of C. urealyticum strains. The new selective medium appears to be a useful epidemiological tool to study urinary and skin colonisation by C. urealyticum.


IFN-gamma, tumor necrosis factor-alpha, and urokinase regulate the expression of urokinase receptors on human monocytes.
The ability of macrophages to reach inflammatory loci is crucial in the function of cellular immunity. Invasive properties of macrophages may be due to the proteinase urokinase which binds to cell surface receptors, and thereby confers on macrophages the capacity for localized proteolysis of the interstitium. Here, we investigated the role of the macrophage-activating factors IFN-gamma, TNF-alpha, and granulocyte-macrophage-CSF and of urokinase on the expression of urokinase receptors by human cultured monocytes. IFN-gamma and TNF-alpha induced increased urokinase binding to human cultured monocytes in a time- and dose-dependent fashion. At optimal concentrations, IFN-gamma (200 U/ml) increased the number of receptors/cell from 14,000 to 64,000, TNF-alpha (50 U/ml) to 30,000, and combinations of IFN-gamma and TNF-alpha to 90,000. Granulocyte-macrophage-CSF had no effect. The enhanced urokinase binding is due to increased numbers of urokinase receptors and not an increased affinity of the receptor for urokinase. In the presence of urokinase during monocyte activation, IFN-gamma induced only 25,000 receptors/cell. However, urokinase does not inhibit increased receptor expression when the cells are activated with TNF-alpha. The effect of urokinase on induction of urokinase receptors by combinations of IFN-gamma and TNF-alpha varied with the dosage of TNF-alpha: A combination of IFN-gamma (200 U/ml) and TNF-alpha (15 U/ml) induced 38,000 receptors/cell in the presence and 90,000 receptors/cells in the absence of urokinase, whereas IFN-gamma (200 U/ml) and TNF-alpha (20 U/ml) induced 90,000 receptors/cell in the absence and presence of urokinase. These studies demonstrate that IFN-gamma, TNF-alpha, and urokinase collectively regulate the number of urokinase receptors on human monocytes. The induction of urokinase receptors may be responsible for increased invasiveness of the activated macrophage.


Cardiac overexpression of melusin protects from dilated cardiomyopathy due to long-standing pressure overload.
We have previously shown that genetic ablation of melusin, a muscle specific beta 1 integrin interacting protein, accelerates left ventricle (LV) dilation and heart failure in response to pressure overload. Here we show that melusin expression was increased during compensated cardiac hypertrophy in mice subjected to 1 week pressure overload, but returned to basal levels in LV that have undergone dilation after 12 weeks of pressure overload. To better understand the role of melusin in cardiac remodeling, we overexpressed melusin in heart of transgenic mice. Echocardiography analysis indicated that melusin over-expression induced a mild cardiac hypertrophy in basal conditions (30% increase in interventricular septum thickness) with no obvious structural and functional alterations. After prolonged pressure overload (12 weeks), melusin overexpressing hearts underwent further hypertrophy retaining concentric LV remodeling and full contractile function, whereas wild-type LV showed pronounced chamber dilation with an impaired contractility. Analysis of signaling pathways indicated that melusin overexpression induced increased basal phosphorylation of GSK3beta and ERK1/2. Moreover, AKT, GSK3beta and ERK1/2 were hyper-phosphorylated on pressure overload in melusin overexpressing compared with wild-type mice. In addition, after 12 weeks of pressure overload LV of melusin overexpressing mice showed a very low level of cardiomyocyte apoptosis and stromal tissue deposition, as well as increased capillary density compared with wild-type. These results demonstrate that melusin overexpression allows prolonged concentric compensatory hypertrophy and protects against the transition toward cardiac dilation and failure in response to long-standing pressure overload.


Legionella and Legionnaires' disease: 25 years of investigation.
There is still a low level of clinical awareness regarding Legionnaires' disease 25 years after it was first detected. The causative agents, legionellae, are freshwater bacteria with a fascinating ecology. These bacteria are intracellular pathogens of freshwater protozoa and utilize a similar mechanism to infect human phagocytic cells. There have been major advances in delineating the pathogenesis of legionellae through the identification of genes which allow the organism to bypass the endocytic pathways of both protozoan and human cells. Other bacteria that may share this novel infectious process are Coxiella burnetti and Brucella spp. More than 40 species and numerous serogroups of legionellae have been identified. Most diagnostic tests are directed at the species that causes most of the reported human cases of legionellosis, L. pneumophila serogroup 1. For this reason, information on the incidence of human respiratory disease attributable to other species and serogroups of legionellae is lacking. Improvements in diagnostic tests such as the urine antigen assay have inadvertently caused a decrease in the use of culture to detect infection, resulting in incomplete surveillance for legionellosis. Large, focal outbreaks of Legionnaires' disease continue to occur worldwide, and there is a critical need for surveillance for travel-related legionellosis in the United States. There is optimism that newly developed guidelines and water treatment practices can greatly reduce the incidence of this preventable illness.


Single-neuron analysis of human thalamus in patients with intention tremor and other clinical signs of cerebellar disease.
Tremor that occurs as a result of a cerebellar lesion, cerebellar tremor, is characteristically an intention tremor. Thalamic activity may be related to cerebellar tremor because transmission of some cerebellar efferent signals occurs via the thalamus and cortex to the periphery. We have now studied thalamic neuronal activity in a cerebellar relay nucleus (ventral intermediate-Vim) and a pallidal relay nucleus (ventralis oral posterior-Vop) during thalamotomy in patients with intention tremor and other clinical signs of cerebellar disease (tremor patients). The activity of single neurons and the simultaneous electromyographic (EMG) activity of the contralateral upper extremity in tremor patients performing a pointing task were analyzed by spectral cross-correlation analysis. EMG spectra during intention tremor often showed peaks of activity in the tremor-frequency range (1.9-5.8 Hz). There were significant differences in thalamic neuronal activity between tremor patients and controls. Neurons in Vim and Vop had significantly lower firing rates in tremor patients than in patients undergoing thalamic surgery for pain (pain controls). Other studies have shown that inputs to Vim from the cerebellum are transmitted through excitatory connections. Therefore the present results suggest that tremor in these tremor patients is associated with deafferentation of the thalamus from cerebellar efferent pathways. The thalamic X EMG cross-correlation functions were studied for cells located in Vim and Vop. Neuronal and EMG activity were as likely to be significantly correlated for cells in Vim as for those in Vop. Cells in Vim were more likely to have a phase lag relative to EMG than were cells in Vop. In monkeys, cells in the cerebellar relay nucleus of the thalamus, corresponding to Vim, are reported to lead movement during active oscillations at the wrist. In view of these monkey studies, the present results suggest that cells in Vim are deafferented and have a phase lag relative to tremor that is not found in normal active oscillations. The difference in phase of thalamic spike X EMG activity between Vim and Vop may contribute to tremor because lesions of pallidum or Vop are reported to relieve cerebellar tremor.


[Cytokine secretion in whole blood of healthy subjects following oral administration of Urtica dioica L. plant extract].
Twenty healthy volunteers ingested for 21 days 2 capsules b.i.d. of an IDS 23/1 containing nettle leaf extract (Rheuma-Hek). Before and after 7 and 21 days the basal and the lipopolysaccharide (LPS) stimulated tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) concentrations were measured ex vivo. In vitro the effects of IDS 23/1 on the release of these cytokines were determined. Additionally basal interleukin-4 (IL-4) and interleukin-10 (IL-10) levels were recorded. Orally taken the test drug has ex vivo no effect on basal levels of TNF-alpha, IL-1 beta, IL-4, IL-6 or IL-10 which were always below detection limits. After 7 and 21 days ingestion ex vivo a decrease of LPS stimulated TNF-alpha release of 14.6 and 24.0%, respectively, was observed. IL-1 beta was reduced for 19.2 and 39.3%. In vitro IDS 23/1 added to whole blood resulted in an exceeded inhibition of LPS stimulated TNF-alpha and IL-1 beta secretion which correlated with the duration of the drug ingestion. Using the highest tested IDS 23/1 concentration the inhibition reached 50.5 (day 0) to 79.5% (day 21) for TNF-alpha and 90.0 (day 0) to 99.2% (day 21) for IL-1 beta, respectively. IDS 23/1 induced a pronounced release of IL-6 in absence of LPS only in vitro. The detected IL-6 concentrations were comparable to those after LPS stimulation, additive effects could not be observed. The absence of detectable IL-6 concentrations in whole blood ex vivo after oral ingestion of the tested drug as well as the differences in the inhibition patterns for TNF-alpha and IL-1 beta ex vivo and ex vivo in vitro suggest that the extract contains different pharmacological effective compounds with varying bioavailabilities.


Relation between electromyography and anal manometry of the external anal sphincter.
Thirteen patients with faecal incontinence and 26 control subjects were studied to investigate whether a quantitative electromyographic (EMG) signal could be correlated to anal manometry. Three different electrodes were used--a concentric needle electrode, a disposable sponge electrode, and a hard anal plug electrode. The maximum amplitude of the EMG recording was used as a quantitative parameter. Linear regression showed significant correlation between EMG and anal manometry with the sponge electrode, both at rest and during squeeze. Significant correlation was also found with the concentric needle electrode during squeeze but not at rest. No correlation was found with the hard anal plug electrode either during squeeze or at rest. Reproducibility studies using the sponge electrode showed acceptable day to day variation. In conclusion, quantitative EMG recordings from a disposable sponge electrode placed in the anal canal correlate well to anal manometry and may be used for assessment of sphincter function, but the hard anal plug electrode cannot be recommended.


Adipose tissue transcriptional response of lipid metabolism genes in growing Iberian pigs fed oleic acid v. carbohydrate enriched diets.
Diet influences animal body and tissue composition due to direct deposition and to the nutrients effects on metabolism. The influence of specific nutrients on the molecular regulation of lipogenesis is not well characterized and is known to be influenced by many factors including timing and physiological status. A trial was performed to study the effects of different dietary energy sources on lipogenic genes transcription in ham adipose tissue of Iberian pigs, at different growth periods and on feeding/fasting situations. A total of 27 Iberian male pigs of 28 kg BW were allocated to two separate groups and fed with different isocaloric feeding regimens: standard diet with carbohydrates as energy source (CH) or diet enriched with high oleic sunflower oil (HO). Ham subcutaneous adipose tissue was sampled by biopsy at growing (44 kg mean BW) and finishing (100 kg mean BW) periods. The first sampling was performed on fasted animals, while the last sampling was performed twice, with animals fasted overnight and 3 h after refeeding. Effects of diet, growth period and feeding/fasting status on gene expression were explored quantifying the expression of a panel of key genes implicated in lipogenesis and lipid metabolism processes. Quantitative PCR revealed several differentially expressed genes according to diet, with similar results at both timings: RXRG, LEP and FABP5 genes were upregulated in HO group while ME1, FASN, ACACA and ELOVL6 were upregulated in CH. The diet effect on ME1 gene expression was conditional on feeding/fasting status, with the higher ME1 gene expression in CH than HO groups, observed only in fasting samples. Results are compatible with a higher de novo endogenous synthesis of fatty acids (FA) in the carbohydrate-supplemented group and a higher FA transport in the oleic acid-supplemented group. Growth period significantly affected the expression of most of the studied genes, with all but PPARG showing higher expression in finishing pigs according to a pattern dissimilar from the usual in cosmopolitan pig breeds. Feeding/fasting status only influenced PPARG gene transcription. The lack of effects of feeding/fasting status on lipogenic gene expression and the higher ME1 response to diet in fasting samples than in postprandial sampling, suggest the persistence of de novo lipogenesis during fasting. Overall results improve the understanding of the influence of different factors on lipid metabolism regulation in Iberian pigs.


Ochratoxin A in several grains in Iran.
Ochratoxin A content in 100 grain and derived products were determined by high-performance liquid chromatography with immunoaffinity column clean-up and fluorometric detection. Ochratoxin A was detected in 32% of green gram, 13.3% of chickpea, 10% of lentil and 17.5% of wheat flour. Ochratoxin contamination was below the regulatory limits of the European Union and of Iran. Recovery was 97% and the limit of detection was 0.12 ng g⁻¹.


Methotrexate in the treatment of rheumatoid arthritis. II. In vivo effects on bone mineral density.
To determine the effect of methotrexate (MTX) on bone mineral density (BMD) in rheumatoid arthritis (RA). One hundred and sixteen non-steroid-treated RA subjects (90 women) were studied in a prospective, longitudinal, non-randomized study. Subjects started MTX (n=36) or sulphasalazine (n=23) or continued long-term (>5 yr) treatment with MTX (n=28) or other disease-modifying anti-rheumatic drugs (n=29). BMD was estimated at entry and after 1 yr. Markers of bone turnover were measured at entry and at 1 yr, and additionally at 3 and 6 months in those starting treatment. Bone biopsies were taken before and after MTX treatment in four subjects. The primary outcome was change in BMD Z score and secondary outcomes were changes in bone turnover markers and bone formation by histomorphometry. Univariate analysis of covariance found that MTX at baseline was associated with reduced BMD at the femoral neck. However, femoral neck BMD was also associated with radiological damage score for the hand. Multivariate analysis and discriminant analysis of the subset of post-menopausal women showed that reduced bone density associated with MTX was due to confounders such as disease activity. There was no adverse effect of MTX on bone turnover markers or on measures of bone formation in biopsies. No adverse effect of low-dose MTX (mean 10 mg/week) on bone formation in RA was found.


An update on drug induced liver injury.
Drug induced liver injury (DILI) is an uncommon cause of acute and chronic liver injury of increasing importance to patients, clinicians, and regulators. The incidence of DILI due to an individual agent is not well defined but population-based studies suggest that the overall incidence of DILI may be as high as 10 to 15 cases per 100000 patient years. Bona fide risk factors for DILI are also not well established, but ongoing multicenter registry studies such as the Drug Induced Liver Injury Network are attempting to identify the role of genetic, environmental, and immunological factors in DILI pathogenesis and outcomes. Acute hepatocellular injury (~50%) is more common than mixed or cholestatic liver injury but jaundiced DILI subjects with either type of liver injury have a ~10% risk of short-term mortality. Antibiotics are the most commonly implicated agents associated with DILI, but there are emerging reports of liver injury associated with the use of a multitude of herbal and dietary supplements. Despite their widespread use, the HMG-CoA reductase inhibitors or statins are an uncommon cause of idiosyncratic DILI. Furthermore, recent studies have shown that statins are actually safe and efficacious to use in hyperlipidemic patients with chronic liver disease. Acetaminophen hepatotoxicity remains a leading cause of severe acute liver injury. Limiting the amount of acetaminophen in prescription narcotic products may help reduce the incidence of future non-intentional overdoses but educating patients and providers of the multitude of over the counter products that contain acetaminophen is also recommended.


A university system's approach to enhancing the educational mission of health science schools and institutions: the University of Texas Academy of Health Science Education.
The academy movement developed in the United States as an important approach to enhance the educational mission and facilitate the recognition and work of educators at medical schools and health science institutions. Academies initially formed at individual medical schools. Educators and leaders in The University of Texas System (the UT System, UTS) recognized the academy movement as a means both to address special challenges and pursue opportunities for advancing the educational mission of academic health sciences institutions. The UTS academy process was started by the appointment of a Chancellor's Health Fellow for Education in 2004. Subsequently, the University of Texas Academy of Health Science Education (UTAHSE) was formed by bringing together esteemed faculty educators from the six UTS health science institutions. Currently, the UTAHSE has 132 voting members who were selected through a rigorous, system-wide peer review and who represent multiple professional backgrounds and all six campuses. With support from the UTS, the UTAHSE has developed and sustained an annual Innovations in Health Science Education conference, a small grants program and an Innovations in Health Science Education Award, among other UTS health science educational activities. The UTAHSE represents one university system's innovative approach to enhancing its educational mission through multi- and interdisciplinary as well as inter-institutional collaboration. The UTAHSE is presented as a model for the development of other consortia-type academies that could involve several components of a university system or coalitions of several institutions.


Criticality in dynamic arrest: correspondence between glasses and traffic.
Dynamic arrest is a general phenomenon across a wide range of dynamic systems including glasses, traffic flow, and dynamics in cells, but the universality of dynamic arrest phenomena remains unclear. We connect the emergence of traffic jams in a simple traffic flow model directly to the dynamic slowing down in kinetically constrained models for glasses. In kinetically constrained models, the formation of glass becomes a true (singular) phase transition in the limit T→0. Similarly, using the Nagel-Schreckenberg model to simulate traffic flow, we show that the emergence of jammed traffic acquires the signature of a sharp transition in the deterministic limit p→1, corresponding to overcautious driving. We identify a true dynamic critical point marking the onset of coexistence between free flowing and jammed traffic, and demonstrate its analogy to the kinetically constrained glass models. We find diverging correlations analogous to those at a critical point of thermodynamic phase transitions.


Effect of ageing on neurocognitive function by stage of HIV infection: evidence from the Multicenter AIDS Cohort Study.
The demographics of the HIV epidemic in the USA have shifted towards older age. We aimed to establish the relationship between the processes of ageing and HIV infection in neurocognitive impairment. With longitudinal data from the Multicenter AIDS Cohort Study, a long-term prospective cohort study of the natural and treated history of HIV infection among men who have sex with men in the USA, we examined the effect of ageing, HIV infection (by disease stage), and their interaction on five neurocognitive domains: information processing speed, executive function, episodic memory, working memory, and motor function. We controlled for duration of serostatus in a subanalysis, as well as comorbidities and other factors that affect cognition. Analyses were by linear mixed models for longitudinal data. 5086 participants (47 886 visits) were included in the analytic sample (2278 HIV-seropositive participants contributed 20 477 visits and 2808 HIV-seronegative control participants contributed 27 409 visits). In an a-priori multivariate analysis with control variables including comorbidities and time since seroconversion, significant, direct negative effects of ageing were noted on all neurocognitive domains (p<0·0001 for all). Similar effects were noted for late-stage HIV disease progression on information processing speed (p=0·002), executive function (p<0·0001), motor function (p<0·0001), and working memory (p=0·001). Deleterious interaction effects were also noted in the domains of episodic memory (p=0·03) and motor function (p=0·02). A greater than expected effect of ageing on episodic memory and motor function with advanced stages of HIV infection suggests that these two domains are most susceptible to the progression of neurocognitive impairment caused by ageing in individuals with HIV. This deficit pattern suggests differential damage to the hippocampus and basal ganglia (specifically nigrostriatal pathways). Older individuals with HIV infection should be targeted for regular screening for HIV-associate neurocognitive disorder, particularly with tests referable to the episodic memory and motor domains. National Institute of Mental Health.


Central obesity and health-related factors among middle-aged men: a comparison among native Japanese and Japanese-Brazilians residing in Brazil and Japan.
The objective of this study was to investigate the influence of different cultural environments on the development of obesity by examining the association of central obesity, lifestyle, and selected coronary risk factors among people with identical Japanese genetic backgrounds living in Japan and Brazil. One hundred and four native Japanese and 286 Japanese-Brazilians residing in Brazil and Japan aged 35 years or over were studied. Obesity, metabolic risk factors for coronary disease, and history of regular sports activity, daily physical activity, and eating habits were assessed. The results showed Japanese-Brazilians residing in Brazil with significantly higher waist circumference values, and greater prevalence of central obesity compared to native Japanese and Japanese-Brazilians residing in Japan. The risk of developing central obesity was found to be 2.8 times higher among Japanese-Brazilians residing in Brazil. However, this association was no longer found to be significant after adjusting for lifestyle factors in the logistic model. Additionally, waist circumference was found to be significantly associated with metabolic risk factors for coronary disease. These findings suggest substantial variation in measures of central obesity among the three groups of Japanese ancestry, and underscore the heterogeneity of risk factors among communities of Japanese ancestry living in different cultural environments. The results also suggest that immigrant men exposed to the Brazilian cultural environment are more susceptible to the development of central obesity, and it seems to be associated with various lifestyle items and metabolic risk factors for coronary disease.


Effects of Genetic Variants in the Nicotine Metabolism Pathway on Smoking Cessation.
We aimed to investigate the associations of various genetic variants in the nicotine metabolism pathway with smoking cessation (SC) in the Chinese Han population. A case-control study was conducted where 363 successful smoking quitters were referred to as cases, and 345 failed smoking quitters were referred to as controls. A total of 42 genetic variants in 10 genes were selectedand genotyped. The weighted gene score was applied to analyze the whole gene effect. Logistic regression was used to explore associations of each genetic variant and gene score with smoking cessation. Our study found that the variants CYP2A6∗4, rs11726322, rs12233719, and rs3100 were associated with a higher probability of quitting smoking, while rs3760657 was associated with a lower probability of quitting smoking. Moreover, the gene scores of CYP2D6, FMO3, UGT2B10, UGT1A9, UGT2B7, and UGT2B15 were shown to exert a positive effect, while the gene score of CYP2B6 was detected to exert a negative effect on successful smoking cessation. This study revealed that genetic variants in the nicotine metabolic pathway were associated with smoking cessation in the Chinese Han population.


Coral-associated bacteria, quorum sensing disrupters, and the regulation of biofouling.
Marine biofouling, the settlement of microorganisms and macroorganisms on structures submerged in seawater, although economically detrimental, is a successful strategy for survival in hostile environments, where coordinated bacterial communities establish biofilms via the regulation of quorum sensing (QS) communication systems. The inhibition of QS activity among bacteria isolated from different coral species was investigated to gain further insight into its potency in the attenuation, or even the prevention, of undesirable biofouling on marine organisms. It is hypothesized that coral mucus/microorganism interactions are competitive, suggesting that the dominant communities secrete QS disruptive compounds. One hundred and twenty bacterial isolates were collected from healthy coral species and screened for their ability to inhibit QS using three bioreporter strains. Approximately 12, 11, and 24% of the isolates exhibited anti-QS activity against Escherichia coli pSB1075, Chromobacterium violaceum CV026, and Agrobacterium tumefaciens KYC55 indicator strains, respectively. Isolates with positive activity against the bioluminescent monitor strains were scanned via a cytotoxic/genotoxic, E. coli TV1061 and DPD2794 antimicrobial panel. Isolates detected by C. violaceum CV026 and A. tumefaciens KYC55 reporter strains were tested for their ability to inhibit the growth of these reporter strains, which were found to be unaffected. Tests of the Favia sp. coral isolate Fav 2-50-7 (>98% similarity to Vibrio harveyi) for its ability to attenuate the formation of biofilm showed extensive inhibitory activity against biofilms of Pseudomonas aeruginosa and Acinetobacter baumannii. To ascertain the stability and general structure of the active compound, cell-free culture supernatants exposed to an increasing temperature gradient or to digestion by proteinase K, were shown to maintain potent QS attenuation and the ability to inhibit the growth of biofilms. Mass spectrometry confirmed the presence of a low molecular mass compound. The anti-QS strategy exemplified in the coral mucus is a model with potentially wide applications, including countering the ecological threat posed by biofilms. Manipulating synchronized bacterial behavior by detecting new QS inhibitors will facilitate the discovery of new antifouling compounds.


Bilateral, single-session, laparoscopic adrenalectomy was associated with favorable outcomes in a cohort of dogs.
To report perioperative characteristics and outcome following bilateral, single-session, laparoscopic adrenalectomy (BSSLA) in dogs. Client-owned dogs (n = 6). Medical records were reviewed and perioperative data collected, including preoperative diagnostic imaging, operative details, complications, and need for conversion to open laparotomy. Bilateral, single-session, laparoscopic adrenalectomy was performed on the right or left side with a standard 3- or 4-portal transperitoneal technique. The dog was repositioned to contralateral recumbency, and laparoscopic adrenalectomy was repeated. Follow-up information was collected by telephone interviews with the owners and/or referring veterinarian. Median age and weight of dogs were 126 months and 14.75 kg, respectively. Contrast-enhanced CT (CECT) was performed in all dogs. Median maximal tumor diameter was 2.6 and 2.3 cm for the right and left-sided tumors, respectively. Median surgical and anesthesia times were 158 and 240 minutes, respectively. Conversion to open laparotomy was performed in 1 dog following renal vein laceration during initial adrenalectomy. Left adrenalectomy and ureteronephrectomy were performed, and the right adrenal tumor was left in situ. Cardiac arrest occurred in 1 dog following initial adrenalectomy (left); however, the dog was resuscitated successfully, and contralateral laparoscopic adrenalectomy was performed without complication. All dogs survived to hospital discharge. Follow-up ranged from 60 to 730 days (median, 264 days) for dogs that successfully underwent BSSLA. BSSLA was associated with favorable outcomes in this cohort of dogs. Laparoscopy may be considered in dogs with bilateral, modestly sized, noninvasive adrenal tumors.


MicroRNA-1 regulates the proliferation of vascular smooth muscle cells by targeting insulin-like growth factor 1.
The aim of this study was to investigate the role of microRNAs (miRNAs or miRs) in vascular smooth muscle cell (VSMC) proliferation and to elucidate the underlying molecular mechanisms. In a previous study, using microarray analysis, differentially expressed miRNAs were identified in primary VSMCs isolated from the medial layer of the thoracic aorta obtained from spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats. Among others, miR-1 was identified to be downregulated in VSMCs from SHRs. Thus, in the present study, we focused on miR-1, the downregulation of which was confirmed by RT-qPCR and western blot analysis in VSMCs isolated from SHRs. We identified insulin-like growth factor 1 (IGF1) as a potential target gene of miR-1, and we subsequently validated IGF1 as a target gene of miR-1 by luciferase assay. The results revealed that the exogenous overexpression of miR-1 significantly suppressed the expression of IGF1. Additionally, we demonstrated that the downregulation of IGF1 by the introduction of miR-1 attenuated the proliferation of the VSMCs, suggesting that IGF1 is a target gene of miR-1 and that the effects of miR-1 are mediated through IGF1. In conclusion, the findings of our study demonstrate that miR-1 is significantly downregulated in VSMCs and that it is an important regulator of cell proliferation. Therefore, IGF1 may be involved in the regulation of VSMC proliferation by targeting miR-1.


Highly efficient hydrogen production and selective CO2 reduction by the C3N5 photocatalyst using only visible light.
The production of energy sources by metal-free photocatalysts based on graphitic carbon nitride (g-C3N4) has garnered substantial attention. In this study, nitrogen-rich carbon nitride (C3N5) was successfully synthesized through the thermal polycondensation of 3-amino-1,2,4-triazole. The structural and physical characterization has suggested that a portion of the triazine rings, which constitute the structural framework of g-C3N4, may be substituted with five-membered rings in C3N5. Furthermore, the polymerization of C3N5 proceeded more extensively than that of g-C3N4 from melamine precursors. The increased nitrogen content in C3N5 resulted in a heightened number of π-electrons and a narrowed energy bandgap, with the potential of the valence band maximum being negatively shifted. Additionally, photocatalytic assessments encompassing nitro blue tetrazolium reduction, H2 production from triethanolamine aqueous solution, and CO2 reduction in the liquid phase were performed. All findings demonstrated that C3N5 exhibits significantly superior photocatalytic properties compared to g-C3N4. It is particularly noteworthy that C3N5 selectively generates methanol and H2 from oversaturated CO2 solutions under visible light irradiation, while g-C3N4 selectively generates formaldehyde. These outcomes strongly indicate that C3N5 serves as a metal-free, visible-light-responsive photocatalyst, capable of contributing to both the production of renewable energy sources and the reduction of greenhouse effect gases.


Efficient clearance of Aspergillus fumigatus in murine lungs by an ultrashort antimicrobial lipopeptide, palmitoyl-lys-ala-DAla-lys.
Aspergillus fumigatus is an opportunistic fungal pathogen responsible for invasive aspergillosis in immunocompromised individuals. The inefficiency of antifungal agents and high mortality rate resulting from invasive aspergillosis remain major clinical concerns. Recently, we reported on a new family of ultrashort cationic lipopeptides active in vitro against fungi. Mode of action studies supported a membranolytic or a detergent-like effect. Here, we screened several lipopeptides in vitro for their anti-A. fumigatus activity. To investigate the therapeutic properties of the selected peptides in vivo, we challenged immunosuppressed C57BL/6 wild-type mice intranasally with DsRed-labeled A. fumigatus conidia and subsequently treated the animals locally with the lipopeptides. Confocal microscopic analysis revealed the degradation of DsRed-labeled hyphal forms and residual conidia in the lungs of the mice. The most efficient peptide was tested further using a survival assay and was found to significantly prolong the life of the treated animals, whereas no mice survived with the current standard antifungal treatment with amphotericin B. Moreover, as opposed to the drug-treated lungs, the peptide-treated lungs did not display any toxicity of the peptide. Our results highlight the potential of this family of lipopeptides for the treatment of pulmonary invasive aspergillosis.


[Working adaptation in brain workers: sociohygienic aspects].
The parameters of subjective well-being in teachers and their significance in a possible reduction in work capacity and precocious retirement were studied. The teachers with low need satisfaction levels were found to have increased subjective stress or fatigability on doing their work and decreased rest recovery of work capacity. Lower need satisfaction levels with negative reasons for refusal to continue work activities appear to be one of the factors of professional aging and its related reduction in their active work period.


An introgression on wheat chromosome 4DL in RL6077 (Thatcher*6/PI 250413) confers adult plant resistance to stripe rust and leaf rust (Lr67).
Adult plant resistance (APR) to leaf rust and stripe rust derived from the wheat (Triticum aestivum L.) line PI250413 was previously identified in RL6077 (=Thatcher*6/PI250413). The leaf rust resistance gene in RL6077 is phenotypically similar to Lr34 which is located on chromosome 7D. It was previously hypothesized that the gene in RL6077 could be Lr34 translocated to another chromosome. Hybrids between RL6077 and Thatcher and between RL6077 and 7DS and 7DL ditelocentric stocks were examined for first meiotic metaphase pairing. RL6077 formed chain quadrivalents and trivalents relative to Thatcher and Chinese Spring; however both 7D telocentrics paired only as heteromorphic bivalents and never with the multivalents. Thus, chromosome 7D is not involved in any translocation carried by RL6077. A genome-wide scan of SSR markers detected an introgression from chromosome 4D of PI250413 transferred to RL6077 through five cycles of backcrossing to Thatcher. Haplotype analysis of lines from crosses of Thatcher × RL6077 and RL6058 (Thatcher*6/PI58548) × RL6077 showed highly significant associations between introgressed markers (including SSR marker cfd71) and leaf rust resistance. In a separate RL6077-derived population, APR to stripe rust was also tightly linked with cfd71 on chromosome 4DL. An allele survey of linked SSR markers cfd71 and cfd23 on a set of 247 wheat lines from diverse origins indicated that these markers can be used to select for the donor segment in most wheat backgrounds. Comparison of RL6077 with Thatcher in field trials showed no effect of the APR gene on important agronomic or quality traits. Since no other known Lr genes exist on chromosome 4DL, the APR gene in RL6077 has been assigned the name Lr67.


Understanding the Interplay between COX-2 and hTERT in Colorectal Cancer Using a Multi-Omics Analysis.
Cyclooxygenase 2 (COX-2) is involved in the initial steps of colorectal cancer (CRC) formation, playing a key role in the catalysis of arachidonic acid to prostaglandin E2 (PGE2). The human telomerase reverse transcriptase (hTERT or TERT) also plays an important role in colorectal cancer growth, conferring sustained cell proliferation and survival. Although hTERT induces COX-2 expression in gastric and cervical cancer, their interaction has not been investigated in the context of CRC. COX-2, PGE2 levels, and telomerase activity were evaluated by immunohistochemistry, ELISA, and TRAP assay in 49 colorectal cancer samples. PTGS1, PTGS2, PTGES3, TERT mRNA, and protein levels were investigated using RNA-seq and antibody-based protein profiling data from the TCGA and HPA projects. A multi-omics comparison was performed between PTGS2 and TERT, using RNAseq, DNA methylation, copy number variations (CNVs), single nucleotide polymorphisms (SNPs), and insertions/deletions (Indels) data. COX-2 expression was positive in 40/49 CRCs, bearing cytoplasmic and heterogeneous staining, from moderate to high intensity. COX-2 staining was mainly detected in the stroma of the tumor cells and the adjacent normal tissues. PGE2 expression was lower in CRC compared to the adjacent normal tissue, and inversely correlated to telomerase activity in right colon cancers. COX-1 and COX-2 were anticorrelated with TERT. Isoform structural analysis revealed the most prevalent transcripts driving the differential expression of PTGS1, PTGS2, PTGES3, and TERT in CRC. COX-2 expression was significantly higher among B-Raf proto-oncogene, serine/threonine kinase, mutant (BRAFmut) tumors. Kirsten ras oncogene (KRAS) mutations did not affect COX-2 or TERT expression. The promoter regions of COX-2 and TERT were reversely methylated. Our data support that COX-2 is involved in the early stages of colorectal cancer development, initially affecting the tumor's stromal microenvironment, and, subsequently, the epithelial cells. They also highlight an inverse correlation between COX-2 expression and telomerase activity in CRC, as well as differentially methylated patterns within the promoter regions of COX-2 and TERT.


Characterization of the extracellular bactericidal factors of rat alveolar lining material.
The surfactant fraction (55,000-g pellet) of leukocyte-free rat bronchoalveolar lavage fluid contains factors that rapidly kill and lyse pneumococci. These factors were purified and identified biochemically by using a quantitative bactericidal test to monitor fractionation procedures. 91% of the antipneumococcal activity of rat surfactant was recovered in chloroform after extraction of rat surfactant with chloroform-methanol (Bligh-Dyer procedure). After chromatography on silicic acid with chloroform, acetone, and methanol, all detectable antibacterial activity (approximately 80% of the initial activity) eluted with the neutral lipids in chloroform. When rechromatographed on silicic acid with hexane, hexane-chloroform, and chloroform, the antibacterial activity eluted with FFA. Thin-layer chromatography (TLC) established that the antibacterial activity was confined to the FFA fraction. Gas-liquid chromatography showed that the fatty acid fraction contained a mixture of long-chain FFA (C12 to C22) of which 66.7% were saturated and 32.4% were unsaturated. The quantity of TLC-purified FFA needed to kill 50% of 10(8) pneumococci under standardized conditions (one bactericidal unit) was 10.6 +/- 0.5 micrograms. Purified FFA acted as detergents, causing release of [3H]choline from pneumococcal cell walls and increased bacterial cell membrane permeability, evidenced by rapid unloading of 3-O-[3H]methyl-D-glucose. FFA acting as detergents appear to account for the bactericidal and bacteriolytic activity of rat pulmonary surfactant for pneumococci.


Bone growth retardation in mouse embryos expressing human collagenase 1.
Cellular growth and differentiation are readouts of multiple signaling pathways from the intercellular and/or extracellular milieu. The extracellular matrix through the activation of cellular receptors transmits these signals. Therefore, extracellular matrix proteolysis could affect cell fate in a variety of biological events. However, the biological consequence of inadequate extracellular matrix degradation in vivo is not clear. We developed a mouse model expressing human collagenase (matrix metalloproteinase-1, MMP-1) under the control of Col2a1 promoter. The mice showed significant growth retardation during embryogenesis and a loss of the demarcation of zonal structure and columnar array of the cartilage. Immunological examination revealed increased degradation of type II collagen and upregulation of fibronectin and alpha(5)-integrin subunit in the transgenic cartilage. The resting zone and proliferating zone of the growth plate cartilage exhibited a simultaneous increase in bromodeoxyuridine (BrdU)-incorporated proliferating cells and terminal deoxynucleotidyl transferase-mediated X-dUTP nick-end labeling-positive apoptotic cells, respectively. Chondrocyte differentiation was not disturbed in the transgenic mice as evidenced by normal expression of the Ihh and type X collagen expression. These data demonstrate that type II collagen proteolysis is an important determinant for the skeletal outgrowth through modulation of chondrocyte survival and cartilagenous growth.


Utility of chest radiographs after guidewire exchanges of central venous catheters.
To determine whether chest radiographs are warranted after uncomplicated guidewire exchanges of central venous catheters in patients admitted to a Level I trauma intensive care unit. Prospective study performed in two phases. Intensive care unit in a Level I trauma center. Patients admitted to a Level I trauma center intensive care unit who required central venous catheter guidewire exchanges. Criteria for uncomplicated guidewire exchanges were established and followed. A catheter exchange checklist was completed at each procedure, and a chest radiograph was performed after each guidewire exchange. The complications followed were catheter malposition, pneumothorax, hemothorax, and cardiac tamponade. Results were reviewed after 3 mos, and a second phase of the study was initiated in which chest radiographs were obtained selectively and were not performed for uncomplicated exchanges. If obtained, subsequent radiographs were reviewed, and patients were followed to discharge for complications. One hundred central venous catheter exchanges with postprocedure radiographs were evaluated in phase I. The only complication identified was one malpositioned catheter. In phase II, 110 patients were followed. Eighty-four patients did not have chest radiographs performed after guidewire exchange; 69 patients had subsequent radiographs documenting good placement of the catheter, and 15 patients did not have a radiograph before death (n = 2) or discharge from the hospital (n = 13). Sixteen patients had postprocedure radiographs performed. There were no malpositioned catheters or complications related to guidewire exchanges. Chest radiographs are unwarranted after uncomplicated guidewire exchanges of central venous catheters in hemodynamically stable, monitored patients. Eliminating these radiographs will result in significant cost and time savings without adversely affecting patient outcome.


Mechanism linking T-wave alternans to the genesis of cardiac fibrillation.
Although T-wave alternans has been closely associated with vulnerability to ventricular arrhythmias, the cellular processes underlying T-wave alternans and their role, if any, in the mechanism of reentry remain unclear. -T-wave alternans on the surface ECG was elicited in 8 Langendorff-perfused guinea pig hearts during fixed-rate pacing while action potentials were recorded simultaneously from 128 epicardial sites with voltage-sensitive dyes. Alternans of the repolarization phase of the action potential was observed above a critical threshold heart rate (HR) (209+/-46 bpm) that was significantly lower (by 57+/-36 bpm) than the HR threshold for alternation of action potential depolarization. The magnitude (range, 2.7 to 47.0 mV) and HR threshold (range, 171 to 272 bpm) of repolarization alternans varied substantially between cells across the epicardial surface. T-wave alternans on the surface ECG was explained primarily by beat-to-beat alternation in the time course of cellular repolarization. Above a critical HR, membrane repolarization alternated with the opposite phase between neighboring cells (ie, discordant alternans), creating large spatial gradients of repolarization. In the presence of discordant alternans, a small acceleration of pacing cycle length produced a characteristic sequence of events: (1) unidirectional block of an impulse propagating against steep gradients of repolarization, (2) reentrant propagation, and (3) the initiation of ventricular fibrillation. Repolarization alternans at the level of the single cell accounts for T-wave alternans on the surface ECG. Discordant alternans produces spatial gradients of repolarization of sufficient magnitude to cause unidirectional block and reentrant ventricular fibrillation. These data establish a mechanism linking T-wave alternans of the ECG to the pathogenesis of sudden cardiac death.


P3HT-graphene bilayer electrode for Schottky junction photodetectors.
We have investigated the effect of a poly (3-hexylthiophene-2.5-diyl)(P3HT)-graphene bilayer electrode on the photoresponsivity characteristics of Si-based Schottky photodetectors. P3HT, which is known to be an electron donor and absorb light in the visible spectrum, was placed on CVD grown graphene by dip-coating method. The results of the UV-vis and Raman spectroscopy measurements have been evaluated to confirm the optical and electronic modification of graphene by the P3HT thin film. Current-voltage measurements of graphene/Si and P3HT-graphene/Si revealed rectification behavior confirming a Schottky junction formation at the graphene/Si interface. Time-resolved photocurrent spectroscopy measurements showed the devices had excellent durability and a fast response speed. We found that the maximum spectral photoresponsivity of the P3HT-graphene/Si photodetector increased more than three orders of magnitude compared to that of the bare graphene/Si photodetector. The observed increment in the photoresponsivity of the P3HT-graphene/Si samples was attributed to the charge transfer doping from P3HT to graphene within the spectral range between near-ultraviolet and near-infrared. Furthermore, the P3HT-graphene electrode was found to improve the specific detectivity and noise equivalent power of graphene/Si photodetectors. The obtained results showed that the P3HT-graphene bilayer electrodes significantly improved the photoresponsivity characteristics of our samples and thus can be used as a functional component in Si-based optoelectronic device applications.


Effect of sibling perception of differential parental treatment in sibling dyads with one disabled child.
To examine sibling perception of parental differential treatment in families of children with pervasive developmental disorder (PDD), Down syndrome (DS), and nondisabled controls. Sibling self-concept and social support were studied in the context of sibling perceptions of parental differential treatment and caretaker plus teacher evaluations of sibling behavioral adjustment. Measures were completed at time 1 and time 2. The effect of parental stress and the difficulty of the disabled child, as well as the sibling relationship, were considered. For siblings of PDD children, internalizing and externalizing behavior problems identified by caretakers were evident at time 1 and more accentuated at time 2, at which time teachers also identified these difficulties. DS siblings were reported by caretakers and teachers to have only internalizing problems and only at time 2. These difficulties related to the perception for PDD siblings that they were preferred over their disabled sibling and for the DS sibling that their disabled sibling was preferred. Feelings of low competence predicted internalizing difficulties. Social support, especially over time, had a positive effect for all siblings, including the controls. The elucidation of specific mechanisms contributing to adjustment problems in the siblings of disabled children will allow for the development of specific preventive interventions.


Human Monkeypox-A Global Public Health Emergency.
Monkeypox, a viral zoonosis caused by an Orthopoxvirus, is clinically characterized by fever, headache, lymphadenopathy, myalgia, rash and burdened by some complications that can be severe and life threatening. Monkeypox, endemic in some central and west African countries, in tropical areas near equator, rose to the headlines following its recent outbreak in non-endemic countries of Europe and the USA. Thus, the World Health Organization, worried about the growing dimension of the problem, declared monkeypox a global public health emergency. Now, after months of careful observation, the western scientific research is drawing conclusion that African endemic countries represent a reserve pool able to feed, through travelers and sexual networks, the outbreak in non-endemic countries in which high-risk communities such as gay and bisexual men are the most affected. Prevention through vaccination and early diagnosis are the core to breaking the chain of diffusion of this epidemic. Particular attention should be paid to avoid the spread from endemic countries, also implementing the economic investments in their public health system. Information campaigns and assistance to high-risk classes in non-endemic countries are important priorities, however, assuming that specific treatments for this disease are still tentative.


Dried plum prevents bone loss in a male osteoporosis model via IGF-I and the RANK pathway.
Previously, dietary supplementation with dried plums, a rich source of polyphenolic compounds with antioxidant and anti-inflammatory properties, has been shown to improve bone density, microstructure and biomechanics in female animal models of osteopenia. We designed this study to determine the extent to which dried plum prevents skeletal deterioration in gonadal hormone deficient male animals and to begin to understand its mechanism of action. Sixty 6-month-old male Sprague-Dawley rats were either sham-operated (Sham = 1 group) or orchidectomized (ORX = 4 groups) and randomly assigned to dietary treatments: standard semi-purified diet (Control) with either LD = 5%, MD = 15%, or HD = 25% (w/w) dried plum for 90 days. At the end of the treatment period, both the MD and HD dried plum completely prevented the ORX-induced decrease in whole body, femur, and lumbar vertebra bone mineral density (BMD). Biomechanical testing indicated that the MD and HD of dried plum prevented the ORX-induced decrease in ultimate load of the cortical bone as well as the compressive force and stiffness of trabecular bone within the vertebrae. Analyses of trabecular microarchitecture of the distal femur metaphysis and vertebral body revealed that HD dried plum protected against the decrease in trabecular bone volume (BV/TV) induced by ORX. In the distal femur, all doses of dried plum improved trabecular number (TbN) and separation (TbSp) compared to the ORX-control group, while MD and HD dried plum prevented the ORX-induced changes in vertebral TbN and TbSp. At the end of the 90-day treatment, no remarkable changes in serum osteocalcin or alkaline phosphatase in any of the treatment groups were observed, while serum insulin-like growth factor (IGF)-I was increased by dried plum. The ORX-induced increase in urinary deoxypyridinoline (DPD) excretion was completely prevented by all doses of dried plum coinciding with down-regulation of gene expression for receptor activator of NFkappa-B ligand (RANKL) and osteoprotegerin (OPG) in the bone. We conclude that dried plum prevents osteopenia in androgen deficient male rats, and these beneficial effects may be attributed in part to a decrease in osteoclastogenesis via down-regulation of RANKL and stimulation of bone formation mediated by IGF-I.


Head impulse test in unilateral vestibular loss: vestibulo-ocular reflex and catch-up saccades.
Quantitative head impulse test (HIT) measures the gain of the angular vestibulo-ocular reflex (VOR) during head rotation as the ratio of eye to head acceleration. Bedside HIT identifies subsequent catch-up saccades after the head rotation as indirect signs of VOR deficit. To determine the VOR deficit and catch-up saccade characteristics in unilateral vestibular disease in response to HIT of varying accelerations. Eye and head rotations were measured with search coils during manually applied horizontal HITs of varying accelerations in patients after vestibular neuritis (VN, n = 13) and unilateral vestibular deafferentation (UVD, n = 15) compared to normal subjects (n = 12). Normal VOR gain was close to unity and symmetric over the entire head-acceleration range. Patients with VN and UVD showed VOR gain asymmetry, with larger ipsilesional than contralesional deficits. As accelerations increased from 750 to 6,000 degrees /sec(2), ipsilesional gains decreased from 0.59 to 0.29 in VN and from 0.47 to 0.13 in UVD producing increasing asymmetry. Initial catch-up saccades can occur during or after head rotation. Covert saccades during head rotation are most likely imperceptible, while overt saccades after head rotation are detectable by clinicians. With increasing acceleration, the amplitude of overt saccades in patients became larger; however, initial covert saccades also became increasingly common, occurring in up to about 70% of trials. Head impulse test (HIT) with high acceleration reveals vestibulo-ocular reflex deficits better and elicits larger overt catch-up saccades in unilateral vestibular patients. Covert saccades during head rotation, however, occur more frequently with higher acceleration and may be missed by clinicians. To avoid false-negative results, bedside HIT should be repeated to improve chances of detection.


Pharmacological evaluation of continentalic acid for antidiabetic potential.
Diabetes is a complex endocrine and metabolic disorder. Continentalic acid is a natural drug product found in roots of Aralia continentalis (family Araliaceae), which used in traditional medicine for treatment of rheumatic arthritis, lumbag, lameness, inflammation, gastritis, nephritis and diabetes mellitus. This study is aim to investigate the continentalic acid anti-diabetic potential. In-silico, in-vitro, in-vivo and molecular techniques were used to investigate various effects of continentalic acid by Auto Doc Vina, α-amylase and α-glucosidase inhibitory assay and alloxan-induced diabetes rats model. In-silico results revealed that continentalic acid exhibits binding energy values of - 5 to - 9.3Kcal/mol against selected targets. In-vitro assay showed that continentalic acid caused α-amylase and α-glucosidase enzymes inhibition. In-vivo finding exhibits that continentalic acid (50 mg/kg) decreased blood glucose level, body weight, oral glucose tolerance overload, glycosylated hemoglobin, triglycerides, total cholesterol, low density lipoprotein, aspartate transaminase, aspartate aminotransferase, alkaline phosphate, total bilirubin and increased high density lipoprotein (P < 0.05, P < 0.01, P < 0.001 vs. diabetic control group). In animals pancreas and liver tissues, continentalic acid enhanced glutathione-s-transferase, reduced glutathione, catalase and decreased lipid hydroperoxide level, improved cellular architecture in histopathological examination and decrease expression of inflammatory markers: cyclooxygenase 2, tumor necrosis factor alpha, phosphorylated-nuclear factor kappa B, prostaglandins E2, interleukin-18 and increased heme oxygenase-1, as evidenced in immunohistochemistry and enzyme-linked immunosorbent assay molecular investigations. This study shows that continentalic acid exhibited binding affinities against the different targets and anti-diabetic action, mediated possibly through α-amylase and α-glucosidase inhibition, anti-hyperlipidemic, hepatoprotection, antioxidant and anti-inflammatory pathways.


The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming.
Induced pluripotent stem cells (iPSCs) can be derived from somatic cells by ectopic expression of different transcription factors, classically Oct4 (also known as Pou5f1), Sox2, Klf4 and Myc (abbreviated as OSKM). This process is accompanied by genome-wide epigenetic changes, but how these chromatin modifications are biochemically determined requires further investigation. Here we show in mice and humans that the histone H3 methylated Lys 27 (H3K27) demethylase Utx (also known as Kdm6a) regulates the efficient induction, rather than maintenance, of pluripotency. Murine embryonic stem cells lacking Utx can execute lineage commitment and contribute to adult chimaeric animals; however, somatic cells lacking Utx fail to robustly reprogram back to the ground state of pluripotency. Utx directly partners with OSK reprogramming factors and uses its histone demethylase catalytic activity to facilitate iPSC formation. Genomic analysis indicates that Utx depletion results in aberrant dynamics of H3K27me3 repressive chromatin demethylation in somatic cells undergoing reprogramming. The latter directly hampers the derepression of potent pluripotency promoting gene modules (including Sall1, Sall4 and Utf1), which can cooperatively substitute for exogenous OSK supplementation in iPSC formation. Remarkably, Utx safeguards the timely execution of H3K27me3 demethylation observed in embryonic day 10.5-11 primordial germ cells (PGCs), and Utx-deficient PGCs show cell-autonomous aberrant epigenetic reprogramming dynamics during their embryonic maturation in vivo. Subsequently, this disrupts PGC development by embryonic day 12.5, and leads to diminished germline transmission in mouse chimaeras generated from Utx-knockout pluripotent cells. Thus, we identify Utx as a novel mediator with distinct functions during the re-establishment of pluripotency and germ cell development. Furthermore, our findings highlight the principle that molecular regulators mediating loss of repressive chromatin during in vivo germ cell reprogramming can be co-opted during in vitro reprogramming towards ground state pluripotency.


Expression and possible role of 20alpha-hydroxysteroid dehydrogenase in the placenta of the goat.
20Alpha-hydroxysteroid dehydrogenase (20alpha-HSD) catalyzes the conversion of progesterone to its inactive form 20alpha-dihydroprogesterone (20alpha-OHP). 20Alpha-HSD is expressed in the murine placenta, suggesting a role, yet unidentified, played by this enzyme during the course of pregnancy. To elucidate the possible roles of 20alpha-HSD during pregnancy, 20alpha-HSD gene expression in the placenta was examined by Northern blot analysis, and progestin (progesterone and 20alpha-OHP) concentrations in the maternal and fetal sera and the amniotic fluid were measured by radioimmunoassay in pregnant Shiba goats. The expression of 20alpha-HSD mRNA was observed in the placenta and the intercaruncular part of the uterus during mid to late pregnancy. Analysis by in situ hybridization revealed that 20alpha-HSD mRNA was mainly localized in the endometrial epithelium of the caruncle side of the placenta. Considerable enzyme activity of 20alpha-HSD was also detected in the cytosolic fraction of the placenta and intercaruncular part of the uterus. Although concentrations of progesterone and 20alpha-OHP in the maternal serum showed similar profiles, progesterone levels in the fetal serum stayed extremely low throughout the pregnancy. The 20alpha-OHP concentration in the fetal serum was always higher than that in the maternal serum. In the amniotic fluid, the concentrations of both progesterone and 20alpha-OHP remained at very low levels throughout the pregnancy. These results support the notion that 20alpha-HSD protects the fetus from the cytotoxic effects of progesterone, and thereby maintains the normal development of the fetus.


Exploring the Role of Habitat on the Wettability of Cicada Wings.
Evolutionary pressure has pushed many extant species to develop micro/nanostructures that can significantly affect wettability and enable functionalities such as droplet jumping, self-cleaning, antifogging, antimicrobial, and antireflectivity. In particular, significant effort is underway to understand the insect wing surface structure to establish rational design tools for the development of novel engineered materials. Most studies, however, have focused on superhydrophobic wings obtained from a single insect species, in particular, the Psaltoda claripennis cicada. Here, we investigate the relationship between the spatially dependent wing wettability, topology, and droplet jumping behavior of multiple cicada species and their habitat, lifecycle, and interspecies relatedness. We focus on cicada wings of four different species: Neotibicen pruinosus, N. tibicen, Megatibicen dorsatus, and Magicicada septendecim and take a comparative approach. Using spatially resolved microgoniometry, scanning electron microscopy, atomic force microscopy, and high speed optical microscopy, we show that within cicada species, the wettability of wings is spatially homogeneous across wing cells. All four species were shown to have truncated conical pillars with widely varying length scales ranging from 50 to 400 nm in height. Comparison of the wettability revealed three cicada species with wings that are superhydrophobic (>150°) with low contact angle hysteresis (<5°), resulting in stable droplet jumping behavior. The fourth, more distantly related species (Ma. septendecim) showed only moderate hydrophobic behavior, eliminating some of the beneficial surface functional aspects for this cicada. Correlation between cicada habitat and wing wettability yielded little connection as wetter, swampy environments do not necessarily equate to higher measured wing hydrophobicity. The results, however, do point to species relatedness and reproductive strategy as a closer proxy for predicting wettability and surface structure and resultant enhanced wing surface functionality. This work not only elucidates the differences between inter- and intraspecies cicada wing topology, wettability, and water shedding behavior but also enables the development of rational design tools for the manufacture of artificial surfaces for energy and water applications.


A Dutchman in London: reflections of a hospital chief executive from the Netherlands in the NHS.
The NHS is a fascinating health care system and is enjoying a lot of support from all layers of British society. However, it is clear that the system has excellent features but also areas that can be improved. A number of years as a chief executive in one of London's largest hospital has brought me a wealth of impressions, experiences, and understanding about working in the NHS. Contrasting those to my previous experience as chief executive in Amsterdam (The Netherlands) provides an interesting insight. Very strong features of the NHS are the high level of health care professionals, the focus on quality and safety, and involvement of patients and the public. However, the NHS can significantly improve by addressing the lack of clinical professionals in the lead, curtailing ever increasing bureaucracy, and reducing its peculiar preference for outsourcing even the most crucial activities to private parties. The frequent inability to swiftly and successfully complete goal-directed negotiations as well as the large but from a clinical point of view irrelevant private sector are areas of sustained bewilderment. Lastly, the drive for innovation and transformation as well as the level of biomedical research in the NHS and supported by the British universities is fascinating and outstanding.


Gene Expression and Yeast Two-Hybrid Studies of 1R-MYB Transcription Factor Mediating Drought Stress Response in Chickpea (Cicer arietinum L.).
Drought stress has been one of the serious constraints affecting chickpea productivity to a great extent. Genomics-assisted breeding has a potential to accelerate breeding precisely and efficiently. In order to do so, understanding the molecular mechanisms for drought tolerance and identification of candidate genes are crucial. Transcription factors (TFs) have important roles in the regulation of plant stress related genes. In this context, quantitative real time-PCR (qRT-PCR) was used to study the differential gene expression of selected TFs, identified from large-scale expressed sequence tags (ESTs) analysis, in contrasting drought responsive genotypes. Root tissues of ICC 4958 (tolerant), ICC 1882 (sensitive), JG 11 (elite), and JG 11+ (introgression line) were used for the study. Subsequently, a candidate single repeat MYB (1R-MYB) transcript that was remarkably induced in the drought tolerant genotypes under drought stress was cloned (coding sequence region for the 1R-MYB protein) and subjected to yeast two-hybrid (Y2H) analysis. The screening of a root cDNA library with Y2H using the 1R-MYB bait protein, identified three CDS encoding peptides namely, galactinol-sucrose galactosyltransferase 2, CBL (Calcineurin B-like)-interacting serine/threonine-protein kinase 25, and ABA responsive 17-like, which were confirmed by co-transformation in yeast. These findings provide preliminary insights into the ability of this 1R-MYB transcription factor to co-regulate drought tolerance mechanism in chickpea.


Proteogenomic database construction driven from large scale RNA-seq data.
The advent of inexpensive RNA-seq technologies and other deep sequencing technologies for RNA has the promise to radically improve genomic annotation, providing information on transcribed regions and splicing events in a variety of cellular conditions. Using MS-based proteogenomics, many of these events can be confirmed directly at the protein level. However, the integration of large amounts of redundant RNA-seq data and mass spectrometry data poses a challenging problem. Our paper addresses this by construction of a compact database that contains all useful information expressed in RNA-seq reads. Applying our method to cumulative C. elegans data reduced 496.2 GB of aligned RNA-seq SAM files to 410 MB of splice graph database written in FASTA format. This corresponds to 1000× compression of data size, without loss of sensitivity. We performed a proteogenomics study using the custom data set, using a completely automated pipeline, and identified a total of 4044 novel events, including 215 novel genes, 808 novel exons, 12 alternative splicings, 618 gene-boundary corrections, 245 exon-boundary changes, 938 frame shifts, 1166 reverse strands, and 42 translated UTRs. Our results highlight the usefulness of transcript + proteomic integration for improved genome annotations.


Emotional processes in binge drinking: A systematic review and perspective.
Binge drinking is a widespread alcohol consumption pattern commonly engaged by youth. Here, we present the first systematic review of emotional processes in relation to binge drinking. Capitalizing on a theoretical model describing three emotional processing steps (emotional appraisal/identification, emotional response, emotional regulation) and following PRISMA guidelines, we considered all identified human studies exploring emotional abilities among binge drinkers. A literature search was conducted in PubMed, Scopus, and PsychINFO, and a standardized methodological quality assessment was performed for each study. The main findings offered by the 43 studies included are: 1) regarding emotional appraisal/identification, binge drinking is related to heightened negative emotional states, including greater severity of depressive and anxiety symptoms, and have difficulties in recognizing emotional cues expressed by others; 2) regarding emotional response, binge drinkers exhibit diminished emotional response compared with non-binge drinkers; 3) regarding emotional regulation, no experimental data currently support impaired emotion regulation in binge drinking. Variability in the identification and measurement of binge drinking habits across studies limits conclusions. Nevertheless, current findings establish the relevance of emotional processes in binge drinking and set the stage for new research perspectives to identify the nature and extent of emotional impairments in the onset and maintenance of excessive alcohol use.


Syndromes of thyroid hormone resistance.
Resistance to the action of thyroid hormone can involve both peripheral tissues and the pituitary (global resistance), the pituitary only or peripheral tissues alone. Global resistance is of variable severity and has been observed in more than 60 individuals, the majority occurring in 17 families. Affected subjects are commonly eumetabolic and have goiters, elevated plasma levels of total and free thyroxine and triiodothyronine, normal thyroid hormone metabolism, and normal serum TSH levels (albeit high for the corresponding levels of thyroid hormone). A variable degree of delayed bone maturation, mental retardation, learning disabilities, and hearing defects have been reported; and a variety of treatment regimens, most of which are aimed at reducing the level of plasma hormones and/or goiter, have been attempted before the correct diagnosis has been reached. The clinical disorder is equally common in males and females and appears to be due to one or more autosomal gene mutations. The causes for the hormone resistance may be heterogeneous, either influencing the receptor for thyroid hormones or some unidentified steps in hormone action. At present, the diagnosis is one of exclusion; no effective therapy is available, and all measures designed to lower serum thyroid hormone levels should be avoided.


Surface epithelial changes in endometrial adenocarcinoma: diagnostic pitfalls in curettage specimens.
A total of 161 uteri removed for endometrial cancer were studied in order to characterize the histopathologic features of the endometrial surface epithelium. Of these, 116 had endometrioid endometrial adenocarcinoma, and 45 had other endometrial cancers. A total of 57 (49%) of the endometrioid endometrial adenocarcinomas showed the following surface epithelial changes: seven had a conspicuous microglandular pattern simulating cervical microglandular hyperplasia; 17 had syncytial aggregates of relatively bland-appearing eosinophilic cells, frequently with papillary or squamoid differentiation simulating papillary syncytial change or other endometrial epithelial metaplasias; and 33 had mixed patterns. The surface epithelial changes varied in extent from rare foci to extensive surface replacement and were largely confined to FIGO grade I and II tumors. Cytologic atypicality varied from mild to moderate and was consistently less than that of the underlying carcinoma. Similar changes were present in some of the prior curettings; in some scanty curettings an unequivocal diagnosis of carcinoma was not possible. Consequently, further clinical investigation is indicated if these changes are present in scanty curettings from postmenopausal women.


Potent growth inhibitory activity of zidovudine on cultured human breast cancer cells and rat mammary tumors.
Originally designed as an antitumor agent, zidovudine (AZT) has exhibited only marginal tumor growth inhibitory activity. Recently, three abstracts have described positive clinical outcomes for a small number of patients with advanced breast cancer treated with weekly infusions of either methotrexate or cisplatin and AZT. Consequently, we conducted a preclinical study of the anti-breast cancer and anti-mammary tumor activity of AZT. Here we have demonstrated that AZT, alone, has a preferential in vitro and in vivo effect on breast and mammary cancer cells. It is 1000 times as potent as an inhibitor of the in vitro growth of the human breast cancer cell line MCF-7 (IC50 = 10 +/- 5 nM) than of the growth of the T-cell leukemia cell line CEM (IC50 = 14 +/- 2 microM). A novel mechanism for this preferential effect on growth is indicated by the 3-4-fold increase in production of phosphorylated AZT (mono-, di-, and triphosphate) in MCF-7 relative to CEM. We extended these in vitro observations to in vivo studies in rats and found that AZT is a potent in vivo inhibitor of the growth of methylnitrosourea-induced rat mammary tumors without any apparent toxic effects on internal organs. These preclinical results demonstrate, for the first time, that AZT has significant anti-breast cancer activity and strongly suggest that the clinical usefulness of this drug is worthy of investigation.