Comparative and functional triatomine genomics reveals reductions and expansions in insecticide resistance-related gene families.
Triatomine insects are vectors of Trypanosoma cruzi, a protozoan parasite that is the causative agent of Chagas' disease. This is a neglected disease affecting approximately 8 million people in Latin America. The existence of diverse pyrethroid resistant populations of at least two species demonstrates the potential of triatomines to develop high levels of insecticide resistance. Therefore, the incorporation of strategies for resistance management is a main concern for vector control programs. Three enzymatic superfamilies are thought to mediate xenobiotic detoxification and resistance: Glutathione Transferases (GSTs), Cytochromes P450 (CYPs) and Carboxyl/Cholinesterases (CCEs). Improving our knowledge of key triatomine detoxification enzymes will strengthen our understanding of insecticide resistance processes in vectors of Chagas' disease. The discovery and description of detoxification gene superfamilies in normalized transcriptomes of three triatomine species: Triatoma dimidiata, Triatoma infestans and Triatoma pallidipennis is presented. Furthermore, a comparative analysis of these superfamilies among the triatomine transcriptomes and the genome of Rhodnius prolixus, also a triatomine vector of Chagas' disease, and other well-studied insect genomes was performed. The expression pattern of detoxification genes in R. prolixus transcriptomes from key organs was analyzed. The comparisons reveal gene expansions in Sigma class GSTs, CYP3 in CYP superfamily and clade E in CCE superfamily. Moreover, several CYP families identified in these triatomines have not yet been described in other insects. Conversely, several groups of insecticide resistance related enzymes within each enzyme superfamily are reduced or lacking in triatomines. Furthermore, our qRT-PCR results showed an increase in the expression of a CYP4 gene in a T. infestans population resistant to pyrethroids. These results could point to an involvement of metabolic detoxification mechanisms on the high levels of pyrethroid resistance detected in triatomines from the Gran Chaco ecoregion. Our results help to elucidate the potential insecticide resistance mechanisms in vectors of Chagas' disease and provide new relevant information for this field. This study shows that metabolic resistance might be a contributing cause of the high pyrethroid resistance observed in wild T. infestans populations from the Gran Chaco ecoregion, area in which although subjected to intense pyrethroid treatments, vector control has failed. This study opens new avenues for further functional studies on triatomine detoxification mechanisms.


[Nasopharyngeal carcinoma in Tunisian children: retrospective epidemiological, clinical and biological study about 48 cases].
Report epidemiological, clinical and biological aspects of nasopharyngeal carcinoma in Tunisian children. Our retrospective study from 1994 to 2001 included all children treated for nasopharyngeal carcinoma in the Salah Azaïz Cancer Institute of Tunis. Initial investigation consisted of ENT and general examination, nasopharyngeal CT-scan, abdominal echography, chest X-ray and bone scintigraphy. Biological markers included blood-count, erythrocytes sedimentation and serum lactic dehydrogenase. All children received neoadjuvant chemotherapy (adriamycin, cisplatin) and irradiation therapy. There were 48 children with a median age of 13,7 years and a sex ratio of 1,4 (28/20). Lesions are staged T2, T3 and T4 in 2,1 %, 18,7% and 79,2% of cases. All patients have cervical palpable nodes at diagnosis classified as N1 (8,3%), N2 (33.3%) and N3 (58.3%). A significant correlation was found between serum lactic dehydrogenase and the N stage (p = 0.02). After follow up, recurrence of disease was noted for three children, persistent disease for two children and metastatic disease in five cases. The overall and relapse free survival at 5 years were 79.1% and 68.9% respectively. Patients aged 13 or lower had poorer 5 overall survival rate (72.3%) than older age group (84.2%).


Growth hormone attenuates Na(+)-dependent hepatic amino acid transport in endotoxemic rats.
The effects of human growth hormone (GH) on hepatic Na(+)-dependent amino acid transport were studied in endotoxin-treated rats. Adult rats received GH (6 mg/kg BW subQ q 12 hours x 4 doses) or vehicle prior to a single dose of Escherichia coli endotoxin (LPS, 7.5 mg/kg BW IP). Four hours after LPS administration, livers were excised and hepatocyte plasma membrane vesicles (HPMVs) were prepared by differential and Percoll density gradient centrifugation. Hepatocyte plasma membrane vesicle transport of [3H]-MeAIB, a highly selective system A substrate, [3H]-glutamine, a selective system N substrate, and [35S]-cysteine, a system ASC substrate, were measured by a rapid mixing/filtration technique. Vesicle purity and functionality were assessed by marker enzyme measurements and classic overshoots and timecourses that showed similar vesicle size. Endotoxin treatment resulted in a two-fold increase in the activities of systems N and ASC, which was the result of an increase in carrier Vmax (Km was unchanged), and a four-fold stimulation of system A. Pre-treatment with GH diminished the endotoxin-induced increase in Na(+)-dependent amino acid transport by 60%-80%; this reduction in carrier-mediated transport activity was a result of a decrease in Vmax, consistent with a decrease in the number of functional transporter proteins in the plasma membrane. Growth hormone treatment attenuates the endotoxin-induced increase in the activities of the major Na(+)-dependent transporters in rat liver. This may diminish hepatic ureagenesis and spare amino acids for peripheral protein synthesis and thereby explain, at least in part, the ability of growth hormone to promote positive nitrogen balance in catabolic states.


Impact of the Coronavirus Disease Pandemic on Mental Health among Local Residents in Korea: a Cross Sectional Study.
This study aimed to evaluate traumatic stress and mental health problems associated with the prolonged coronavirus disease pandemic and to determine the differences across different age groups. A total of 1,151 individuals who visited Gwangmyeong City Mental Health Welfare Center, South Korea, or accessed the website from September 1 to December 31, 2020, were included in the study. Mental health problems such as traumatic stress (Primary Care Posttraumatic Stress Disorder Screen for the Diagnostic and Statistical Manual of Mental Disorder-5); depression (Patient Health Questionnaire-9 and Children's Depression Inventory); anxiety (Generalized Anxiety Disorder-7 and Penn State Worry Questionnaire for Children); suicide risk (P4 Screener); and demographic information were evaluated. The participants were divided into three groups based on age group: children and adolescents, adults, and the elderly. The results showed that 24.7%, 20.9%, 16.8%, and 20.5% of the participants were at high-risk for traumatic stress, depression, anxiety, and suicide, respectively. The difference in the proportion of high-risk groups by age of all participants was significant for traumatic stress, depression, anxiety, and suicide risk. In particular, the percentage of high-risk groups in all areas was the highest in the adult group. Also, in most areas, the ratio of the high-risk groups for children and adolescent group was the lowest, but the suicide risk-related ratio was not (adolescent group: 20.9%, adult group: 25%, elderly group 9.3%). These results suggest that there is a need for continued interest in the mental health of the general population even after the initial period of coronavirus disease. Additionally, this study may be helpful when considering the resilience or risk factors of mental health in a prolonged disaster situation.


Diffusion-driven looping provides a consistent framework for chromatin organization.
Chromatin folding inside the interphase nucleus of eukaryotic cells is done on multiple scales of length and time. Despite recent progress in understanding the folding motifs of chromatin, the higher-order structure still remains elusive. Various experimental studies reveal a tight connection between genome folding and function. Chromosomes fold into a confined subspace of the nucleus and form distinct territories. Chromatin looping seems to play a dominant role both in transcriptional regulation as well as in chromatin organization and has been assumed to be mediated by long-range interactions in many polymer models. However, it remains a crucial question which mechanisms are necessary to make two chromatin regions become co-located, i.e. have them in spatial proximity. We demonstrate that the formation of loops can be accomplished solely on the basis of diffusional motion. The probabilistic nature of temporary contacts mimics the effects of proteins, e.g. transcription factors, in the solvent. We establish testable quantitative predictions by deriving scale-independent measures for comparison to experimental data. In this Dynamic Loop (DL) model, the co-localization probability of distant elements is strongly increased compared to linear non-looping chains. The model correctly describes folding into a confined space as well as the experimentally observed cell-to-cell variation. Most importantly, at biological densities, model chromosomes occupy distinct territories showing less inter-chromosomal contacts than linear chains. Thus, dynamic diffusion-based looping, i.e. gene co-localization, provides a consistent framework for chromatin organization in eukaryotic interphase nuclei.


Interlimb coordination evoked by unilateral mechanical perturbation during body-weight supported gait.
During locomotion, motor strategies can rapidly compensate for any obstruction or perturbation that could interfere with forward progression. Here we studied the contribution of interlimb pathways for evoking muscle activation patterns in the case where body weight is externally supported and vestibular feedback is limited. The experiments were conducted using a novel device intended for gait therapy: the MIT-Skywalker. The subject's body weight was supported by an underneath saddle-like seat, and a chest harness was used to provide stabilization of the torso. Eight neurologically healthy individuals were asked to walk on the MIT-Skywalker, while one side of its split belt treadmill was unexpectedly dropped either before heel-strike or during mid-stance. Leg kinematics will be reported. We found that unilateral perturbations evoked responses at the contralateral limb, which were observed in both kinematic and neuromuscular level. The latency of most responses exceeded 100 msec, which suggests a supraspinal (i.e. not local) pathway.


Multifocal vascular lesions.
Multifocal vascular lesions are important to recognize and appropriately diagnose. Generally first noticed on the skin, multifocal vascular lesions may have systemic involvement. Distinguishing among the different types of multifocal vascular lesions is often based on clinical features; however, radiological imaging and/or biopsy are frequently needed to identify distinct features and guide treatment. Knowledge of the systemic associations that can occur with different vascular anomalies may reduce life-threatening complications, such as coagulopathy, bleeding, cardiac compromise, and neurologic sequelae. This review provides a synopsis of the epidemiology, pathogenesis, presentation, workup, and treatment of several well-recognized multifocal vascular tumors and malformations.


Genetic design: rising above the sequence.
Genetic engineering has developed around technologies enabling the targeted in vitro recombination of DNA molecules found in living organisms. As a result, the development of new DNA molecules has been primarily focused on cloning strategies that allow their assembly from existing DNA fragments. As chemical gene synthesis matures, the design of synthetic DNA molecules becomes the bottleneck of many biotechnology projects. It becomes urgent to develop representations of synthetic genetic systems more abstract than their DNA sequence. Abstraction makes it possible to reuse simple components to build complex systems or to break down a complex engineering problem into manageable tasks. Specialized computer languages or a general purpose XCell Description Language are promising avenues to build abstraction hierarchies for synthetic biology.


Immunoglobulin light chain kappa deletion rearrangement as a marker of clonality in mantle cell lymphoma.
Mantle cell lymphoma (MCL) express immunoglobulin light chain lambda (IgL-lambda) more frequently than other non-Hodgkin's lymphomas, and IgL-lambda producing B-cells usually delete one or both alleles of their IgL-kappa genes. This inactivation is mediated by a rearrangement between the kappa deletion element (kappa de) and the Recombinant Signal Sequence (RSS) in the region between the Joining genes and the Constant region, or the RSS at the 3'-site of a Variable (Vkappa) segment. This deletion appears as a feasible tool for detecting monoclonality and minimal residual disease by polymerase chain reaction (PCR). Among twelve MCL patients studied, ten presented IgL-lambda expression, and all but one among these revealed a monoclonal kappa de rearrangement by PCR analysis. Six of the nine cases showed a fusion between the kappa de and the intron RSS, whilst three with a Vkappa segment. Since MCL has the worst prognosis of all B-cell lymphomas and high-dose chemotherapy regimens have been proposed, PCR for the kappa de rearrangement might be a useful molecular tool to evaluate the ability of the different treatment modalities to eradicate the malignant clones.


Treatment with catalpol protects against cisplatin-induced renal injury through Nrf2 and NF-κB signaling pathways.
Cisplatin (CP) is one of the most widely used chemotherapy drugs for cancer treatment, but it often leads to nephrotoxicity. It is well known that catalpol exhibits antioxidant and anti-inflammatory functions, thus the present study aimed to investigate the potential protective effects of catalpol on CP-induced kidney injury in rats, in addition to determining the underlying mechanisms. Sprague-Dawley rats were treated with 25, 50 or 100 mg/kg catalpol for two days, injected with 20 mg/kg cisplatin and catalpol on day 3 and sacrificed on day 4. The histological analysis of isolated kidney tissues was performed using hematoxylin and eosin staining, cleaved caspase-3 expression levels were analyzed using western blotting and the expression levels of inflammatory cytokines in the tissues, including tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6, IL-8, IL-10 and inducible nitric oxide synthase (iNOS) were evaluated using ELISAs. Furthermore, the mRNA and protein expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), kelch-like ECH-associated protein 1 (Keap1), NF-κB and inhibitory κB (IκB) were determined using reverse transcription-quantitative PCR and western blotting, respectively. The results revealed that the treatment with catalpol prevented the histopathological injury and renal dysfunction caused by CP. In addition, catalpol significantly suppressed the CP-induced apoptosis of tubular cells, inhibited the CP-induced upregulation of TNF-α, IL-1β, IL-6, IL-8 and iNOS and promoted the production of the anti-inflammatory cytokine IL-10. Additionally, the mRNA and protein expression levels of Nrf2, HO-1 and IκB in the kidney tissues were increased, whereas the expression levels of Keap1 and NF-κB were significantly decreased following the treatment with catalpol. In conclusion, these results suggested that catalpol may inhibit CP-induced renal injury and suppress the associated inflammatory response through activating the Nrf2 and inhibiting the NF-κB signaling pathways, respectively.


Indications that live poultry markets are a major source of human H5N1 influenza virus infection in China.
Human infections of H5N1 highly pathogenic avian influenza virus have continued to occur in China without corresponding outbreaks in poultry, and there is little conclusive evidence of the source of these infections. Seeking to identify the source of the human infections, we sequenced 31 H5N1 viruses isolated from humans in China (2005 to 2010). We found a number of viral genotypes, not all of which have similar known avian virus counterparts. Guided by patient questionnaire data, we also obtained environmental samples from live poultry markets and dwellings frequented by six individuals prior to disease onset (2008 and 2009). H5N1 viruses were isolated from 4 of the 6 live poultry markets sampled. In each case, the genetic sequences of the environmental and corresponding human isolates were highly similar, demonstrating a link between human infection and live poultry markets. Therefore, infection control measures in live poultry markets are likely to reduce human H5N1 infection in China.


Dominances in finger arteries.
We studied the patterns of dominance in the palmar digital arteries of the fingers in 39 fresh cadaver arms which had been injected with coloured latex solution. We also performed photoplethysmographic studies in 20 hands. The ulnar digital artery in the index finger and the radial digital artery of the little finger were usually dominant, and their counterparts were slim and often hypoplastic. The findings are relevant to digit revascularization and might influence the planning of digital island-flaps or toe transfers.


Attention behaviours but not pain-related behaviours are modified by the presence of a twin in lambs undergoing castration by rubber ring.
The social context of social species such as sheep can modify their physiological and behavioural responses to stressors, through social buffering and social facilitation. Social buffering can lead to amelioration of stress, while social facilitation can lead to stress responses in an observer animal in the presence of a conspecific in distress. The current study investigated twin lambs undergoing ring castration, grouped either homogeneously with a castrated lamb (actor), or heterogeneously with a non-castrated lamb (observer) to examine the impact of social grouping on behavioural responses. Each lamb was scored for two classes of behaviour: pain-related behaviours and postures that are putatively related to the response to castration; and attentional behaviours directed at its twin. Thus, each lamb participated in the experiment as an actor exhibiting pain-related behaviours and postures, and as an observer of its twin. When behaviours of lambs were assessed as actors, there was a significant (P < 0.05) effect of castration but no significant effect of social grouping on expression of pain-related behaviours. When behaviours of lambs were assessed as observers, homogeneous grouping of castrated lambs increased attention towards the other twin in comparison to non-castrated lambs grouped homogeneously or lambs grouped heterogeneously (P < 0.01). Non-castrated lambs grouped homogeneously demonstrated significantly lower numbers of head direction changes (P < 0.001) and lower number of ear posture changes (P < 0.05) than heterogeneously grouped or castrated lambs. This study indicates that social attention between twin lambs is not clearly dependent on pain status of the actor lamb. It suggests that in order for the observer lamb to provide significant attention to the actor lamb displaying pain-related behaviour, the observer lamb also needs to be experiencing pain concurrently. Furthermore, there is some evidence that the presence of pain-related behaviours can lead to increased attention to the surrounding environment in non-castrated lambs. Understanding the effect of concurrent experience and varying social context assists us to improve our understanding of results of other experiments on pain-related behavioural responses.


Hormonal profile in early luteal phase after triggering ovulation with gonadotropin-releasing hormone agonist in high-responder patients.
The major limitations associated with gonadotropin-releasing hormone agonist (GnRHa) triggering are inferior clinical outcomes in fresh embryo transfer cycles caused by luteal phase insufficiency following the GnRHa triggering. We included 153 high-risk patients in this study. In group I, the patients received gonadotropin-releasing hormone agonist (GnRHa) trigger + 1,500 IU human chorionic gonadotropin (hCG) support on the oocyte pick-up (OPU) day; in group II, the patients had a dual trigger (GnRHa + 1,500 IU hCG); and in group III (control), 10,000 IU hCG trigger was prescribed for the final oocyte maturation. The levels of LH, estradiol, and progesterone were evaluated in serum on the stimulation starting day, day 6 of stimulation, on the day of the trigger administration, OPU day, days 3 and 5 post-OPU, and day 14 post-ET, as well as in follicular fluid. Progesterone concentration was significantly lower in group I on OPU+5 compared to the hCG group (I vs. III, р = 0.0065). Progesterone levels were significantly lower in group II in serum on OPU+5 compared to groups I and III (I vs. II, р = 0.0068; II vs. III, р = 1.76 × 108). The progesterone levels were significantly higher in follicular fluid in group III compared to the study groups (I vs. III, р = 0.002; II vs. III, p = 0.009). However, no significant differences in clinical outcomes were found between the groups. Then, we divided all women into pregnant and non-pregnant groups and found that estradiol (p = 0.00009) and progesterone (p = 0.000036) on the day of the pregnancy test were significantly higher in the pregnant women group. Also, progesterone on OPU day was significantly higher in the non-pregnant group (p = 0.033). Two cases of moderate ovarian hyperstimulation syndrome (OHSS) late-onset occurred in group I (3.5%, 2/56), no case of moderate/severe OHSS late-onset in group II, and three cases of moderate late-onset in group III (5.7%, 3/53). The low-dose hCG supplementation improves the luteal phase insufficiency after GnRHa triggering, which is confirmed by the comparable pregnancy rates in fresh transfer cycles between the groups. However, low-dose hCG carries a similar risk of OHSS as the full dose of hCG in high-responder patients.


Spatial distribution of thoron and radon concentrations in the indoor air of a traditional Japanese wooden house.
A radon-thoron discriminative passive dosimeter has been developed that can estimate both radon (222Rn) and thoron (220Rn) concentrations at the same time. Two polycarbonate films are installed as solid-state nuclear track detectors in the dosimeter housing. One film registers alpha tracks originating from predominantly thoron and its progeny together with a small contribution from radon, and the other film registers alpha tracks originating from radon and its progeny together with a negligible contribution from thoron. The lower detection limit is estimated to be 2.9 Bq m-3 for the radon concentration and 9.0 Bq m-3 for the thoron concentration for 2 mo exposure. Preliminary measurements from 1991-1992, in a traditional Japanese wooden house located in Kyoto, indicated that the indoor thoron concentration increases exponentially as the interior mud (or plaster-coated) wall is approached. A soil-based plaster commonly used in Japanese wooden houses to fill walls (or as a surface coating on the walls) is the probable source of the indoor thoron. Since thoron is not measured by the usual radon measurements, and the majority of Japanese houses are made of wood, attention should be paid to indoor thoron and its decay products, which may give a significant fraction of the total natural radiation exposure to the general public.


Si/TiO2/Ag Multistorey Structures with Interfacial Charge Transfer for a Recyclable Surface-Enhanced Raman Scattering Substrate.
In this work, highly ordered TiO2/Ag bilayer structures on p-type silicon (Si) wafers are prepared by photolithography and electrochemical self-assembly methods. The interfacial charge transfer (CT) of this Si/TiO2/Ag multistorey structure with a specially aligned work function is studied. This is important to deduce the interfacial electron migration behavior of SERS. The three-dimensional finite-difference time-domain (3D FDTD) simulation is used to explore the combined CT-EM enhancement mechanism. The result shows that the electron movement under the CT mechanism can induce the resonance effect of free electrons to further improve EM performance. In addition, the effect of agglomerated Ag nanoparticle size distribution on the SERS property and the self-cleaning property of Si/TiO2/Ag multistorey structures is investigated. Finally, this unique structure of highly ordered Si/TiO2/Ag SERS substrate shows superior sensitivity, reproducibility, and stability. Rhodamine 6G (R6G) with trace concentrations as low as 10-15 M can be detected, and the EF is estimated to be about 8.9 × 1013. The relative standard deviation (RSD) at 1511 cm-1 is about 4.7%. These results are very promising for the practical application of the SERS technique in the rapid trace determination in many fields.


Identification of genetic heterogeneity of Alzheimer's disease across age.
The risk of APOE for Alzheimer's disease (AD) is modified by age. Beyond APOE, the polygenic architecture may also be heterogeneous across age. We aim to investigate age-related genetic heterogeneity of AD and identify genomic loci with differential effects across age. Stratified gene-based genome-wide association studies and polygenic variation analyses were performed in the younger (60-79 years, N = 14,895) and older (≥80 years, N = 6559) age-at-onset groups using Alzheimer's Disease Genetics Consortium data. We showed a moderate genetic correlation (rg = 0.64) between the two age groups, supporting genetic heterogeneity. Heritability explained by variants on chromosome 19 (harboring APOE) was significantly larger in younger than in older onset group (p < 0.05). APOE region, BIN1, OR2S2, MS4A4E, and PICALM were identified at the gene-based genome-wide significance (p < 2.73 × 10-6) with larger effects at younger age (except MS4A4E). For the novel gene OR2S2, we further performed leave-one-out analyses, which showed consistent effects across subsamples. Our results suggest using genetically more homogeneous individuals may help detect additional susceptible loci.


Assessing individual differences in proneness to shame and guilt: development of the Self-Conscious Affect and Attribution Inventory.
Individual differences in proneness to shame and proneness to guilt are thought to play an important role in the development of both adaptive and maladaptive interpersonal and intrapersonal processes. But little empirical research has addressed these issues, largely because no reliable, valid measure has been available to researchers interested in differentiating proneness to shame from proneness to guilt. The Self-Conscious Affect and Attribution Inventory (SCAAI) was developed to assess characteristic affective, cognitive, and behavioral responses associated with shame and guilt among a young adult population. The SCAAI also includes indices of externalization of cause or blame, detachment/unconcern, pride in self, and pride in behavior. Data from 3 independent studies of college students and 1 study of noncollege adults provide support for the reliability of the main SCAAI subscales. Moreover, the pattern of relations among the SCAAI subscales and the relation of SCAAI subscales to 2 extant measures of shame and guilt support the validity of this new measure. The SCAAI appears to provide related but functionally distinct indices of proneness to shame and guilt in a way that these previous measures have not.


Serpinopathies and the conformational dementias.
The serpin superfamily of serine proteinase inhibitors has a central role in controlling proteinases in many biological pathways in a wide range of species. The inhibitory function of the serpins involves a marked conformational transition, but this inherent molecular flexibility also renders the serpins susceptible to point mutations that result in aberrant intermolecular linkage and polymer formation. The effects of such protein aggregation are cumulative, with a progressive loss of cellular function that results in diseases as diverse as cirrhosis and emphysema. The recent recognition that mutations in a serpin can also result in late-onset dementia provides insights into changes that underlie other conformational diseases, such as the amyloidoses, the prion encephalopathies and Huntington and Alzheimer diseases.


High-resolution melt analysis to identify and map sequence-tagged site anchor points onto linkage maps: a white lupin (Lupinus albus) map as an exemplar.
* The provision of sequence-tagged site (STS) anchor points allows meaningful comparisons between mapping studies but can be a time-consuming process for nonmodel species or orphan crops. * Here, the first use of high-resolution melt analysis (HRM) to generate STS markers for use in linkage mapping is described. This strategy is rapid and low-cost, and circumvents the need for labelled primers or amplicon fractionation. * Using white lupin (Lupinus albus, x = 25) as a case study, HRM analysis was applied to identify 91 polymorphic markers from expressed sequence tag (EST)-derived and genomic libraries. Of these, 77 generated STS anchor points in the first fully resolved linkage map of the species. The map also included 230 amplified fragment length polymorphisms (AFLP) loci, spanned 1916 cM (84.2% coverage) and divided into the expected 25 linkage groups. * Quantitative trait loci (QTL) analyses performed on the population revealed genomic regions associated with several traits, including the agronomically important time to flowering (tf), alkaloid synthesis and stem height (Ph). Use of HRM-STS markers also allowed us to make direct comparisons between our map and that of the related crop, Lupinus angustifolius, based on the conversion of RFLP, microsatellite and single nucleotide polymorphism (SNP) markers into HRM markers.


Asymmetrical Flow Field-Flow Fractionation Methods for Quantitative Determination and Size Characterization of Thiols and for Mercury Size Speciation Analysis in Organic Matter-Rich Natural Waters.
Asymmetrical flow field-flow fractionation (AF4) efficiently separates various macromolecules and nano-components of natural waters according to their hydrodynamic sizes. The online coupling of AF4 with fluorescence (Fluo) and UV absorbance (UV) detectors (FluoD and UVD, respectively) and inductively coupled plasma-mass spectrometry (ICP-MS) provides multidimensional information. This makes it a powerful tool to characterize and quantify the size distributions of organic and inorganic nano-sized components and their interaction with trace metals. In this study, we developed a method combining thiol labeling by monobromo(trimethylammonio)bimane bromide (qBBr) with AF4-FluoD to determine the size distribution and the quantities of thiols in the macromolecular dissolved organic matter (DOM) present in highly colored DOM-rich water sampled from Shuya River and Lake Onego, Russia. We found that the qBBr-labeled components of DOM (qB-DOM) were of humic type, characterized by a low hydrodynamic size (d h < 2 nm), and have concentrations <0.3 μM. After enrichment with mercury, the complexes formed between the nano-sized components and Hg were analyzed using AF4-ICP-MS. The elution profile of Hg followed the distribution of the UV-absorbing components of DOM, characterized by slightly higher sizes than qB-DOM. Only a small proportion of Hg was associated with the larger-sized components containing Fe and Mn, probably inorganic oxides that were identified in most of the samples from river to lake. The size distribution of the Hg-DOM complexes was enlarged when the concentration of added Hg increased (from 10 to 100 nM). This was explained by the presence of small iron oxides, overlapping the size distribution of Hg-DOM, on which Hg bound to a small proportion. In addition, to provide information on the dispersion of macromolecular thiols in colored DOM-rich natural water, our study also illustrated the potential of AF4-FluoD-UVD-ICP-MS to trace or quantify dynamic changes while Hg binds to the natural nano-colloidal components of surface water.


Perinatal Mental Health; The Role and the Effect of the Partner: A Systematic Review.
Pregnancy is a transitional period involving the most complex experiences in a woman's life, during which the woman's psychological status can be affected by a wide range of psychosocial variables. However, positive interpersonal relationships appear to constitute a supportive network that significantly influences perinatal mental health. Therefore, the presence of a supportive partner works psycho-protectively against the difficulties and pressures created by the transition to maternity. The aim of this study was to review systematically the influence of the partner on the woman's psychology during the perinatal period. Fourteen research articles from PubMed/Medline, Google Scholar and PsycINFO were included in the review from a total of 1846 articles. Most studies have shown a correlation between the support from the partner and prenatal depression and anxiety. Support from the spouse during childbirth is related to the extent to which women feel safe during labor as well as the stress during childbirth. The role of the partner is very important in the occurrence of perinatal mental disorders in women. Of course, more research needs to be done in the field of perinatal mental health. The risk factors that lead to mental disorders need to be clarified and the role of the partner in the perinatal period requires reinforcement and needs to be given the necessary importance.


Production of Recombinant RNA in Escherichia coli Using Eggplant Latent Viroid as a Scaffold.
Similar to viruses, viroids can also be engineered and transformed into useful biotechnological tools. We describe here a viroid-based system to produce large amounts of recombinant RNA in Escherichia coli. A precursor of eggplant latent viroid (ELVd), with the RNA of interest inserted between positions U245 and U246, is co-expressed in E. coli along the chloroplastic isoform of the eggplant tRNA ligase, the enzyme that mediates the circularization of this viroid in the infected plants. In the bacterial cells, the chimeric ELVd-RNA-of-interest precursor self-cleaves through the embedded hammerhead ribozymes, and the monomer is recognized and circularized by the co-expressed tRNA ligase. The resulting circular RNA, likely bound to the tRNA ligase, accumulates to a high concentration in the bacterial cells.


Plant material and its biochar differ in their effects on nitrogen mineralization and nitrification in a subtropical forest soil.
Natural wildfires have a great effect on soil N transformation in subtropical forest. The pyrogenic organic matter (PyOM) in forest soils is mainly derived from the plant material burnt during forest fires, which affects soil N composition, N mineralization and nitrification. This study examined the effects of typical fresh plant material (leaves and twigs of Castanopsis sclerophylla, representing litter) and its biochar (representing PyOM) on N mineralization and nitrification in a subtropical forest soil. The soils were incubated with the plant material (PM), its biochar (BC) and their combinations for 84 days. Both PM and BC considerably increased soil pH and dissolved organic C, whereas PM decreased NO3--N and dissolved organic N. The additions of PM alone, and its combinations with BC resulted in net N immobilization. The rates of net N mineralization rapidly increased in first 14 days and then became stable following the addition of PM to soil. Moreover, the additions of PM and BC increased the abundances of archaeal amoA and bacterial amoA, especially with PM. The abundance of bacterial amoA correlated positively with soil pH and dissolved organic C, while archaeal amoA showed the opposite. Biochar affected soil properties and N transformation more significantly in the presence of PM, highlighting the need for further research on the interactions of plant litter and its biochar.


A challenging case of heparin-induced skin necrosis without thrombocytopenia.
Heparin-induced skin necrosis (HISN) is a rare complication of heparin anticoagulation. The condition occurs in various situations, including in heparin-naive and exposed individuals, in areas local or distant from the heparin injection site, and with or without frank thrombocytopenia. We present a case in which a patient treated for a pulmonary embolism with therapeutic unfractionated heparin (UFH) develops this adverse event. Symptoms were reversed with cessation of UFH and transition to bivalirudin without surgical debridement. The patient initially had anti-PF4 antibodies present but subsequent testing showed borderline antibodies and a negative serotonin release assay. After starting bivalirudin, the patient was later switched to fondaparinux without further consequences. This case illustrates the pathogenesis of HISN and provides an example of inconsistently abnormal laboratory values. Additionally, it provides two novel exposures the mRNA-1273 vaccine and the immune checkpoint inhibitor pembrolizumab that, to our knowledge, have not been previously reported.


A logical approach to semantic interoperability in healthcare.
Singapore is in the process of rolling out a number of national e-health initiatives, including the National Electronic Health Record (NEHR). A critical enabler in the journey towards semantic interoperability is a Logical Information Model (LIM) that harmonises the semantics of the information structure with the terminology. The Singapore LIM uses a combination of international standards, including ISO 13606-1 (a reference model for electronic health record communication), ISO 21090 (healthcare datatypes), and SNOMED CT (healthcare terminology). The LIM is accompanied by a logical design approach, used to generate interoperability artifacts, and incorporates mechanisms for achieving unidirectional and bidirectional semantic interoperability.


Destruction and reformation of an iron-sulfur cluster during catalysis by lipoyl synthase.
Lipoyl synthase (LipA) catalyzes the last step in the biosynthesis of the lipoyl cofactor, which is the attachment of two sulfhydryl groups to C6 and C8 of a pendant octanoyl chain. The appended sulfur atoms derive from an auxiliary [4Fe-4S] cluster on the protein that is degraded during turnover, limiting LipA to one turnover in vitro. We found that the Escherichia coli iron-sulfur (Fe-S) cluster carrier protein NfuA efficiently reconstitutes the auxiliary cluster during LipA catalysis in a step that is not rate-limiting. We also found evidence for a second pathway for cluster regeneration involving the E. coli protein IscU. These results show that enzymes that degrade their Fe-S clusters as a sulfur source can nonetheless act catalytically. Our results also explain why patients with NFU1 gene deletions exhibit phenotypes that are indicative of lipoyl cofactor deficiencies.


Impact of inhalation therapy on the incidence of carious lesions in patients with asthma and COPD.
The aim of this study was to investigate the incidence of carious lesions, the amount of salivary flow rate and pH value in patients with asthma and chronic obstructive pulmonary diseases (COPD), using inhalation therapy. The obtained results were compared with the results of adult healthy subjects, forming a control group. The study included 80 participants aging between 18 and 65 years. The experimental group (EG) was comprised of 40 participants, previously diagnosed with asthma or COPD undergoing inhalation therapy for more than five years. The control group (CG), comprised of 40 participants, mirrored the same age and gender status of the EG. Dental status was determined by decayed, missing, and filled teeth (DMFT index). Quantity and pH value of saliva were determined in the laboratory. In the EG, the mean value of the salivary flow rate and pH value were statistically significantly lower than in the CG (p<0.001). Patients in the EG had a higher value of DMFT index when compared with the CG, although the difference was not statistically significant (p=0.199). Mean number of decayed teeth, as well as missing teeth, in the EG was statistically significantly higher than in the CG (p<0.001). Mean number of filled teeth in the EG was statistically significantly lower than in the CG (p<0.001). It was found that patients undergoing inhalation therapy face increasing risk of dental caries due to the lower salivary flow rate and pH value along with the inhalation therapy. They should receive intensive preventive care, including oral hygiene instruction and dietary advice.


Influence of primer & probe chemistry and amplification target on reverse transcription digital PCR quantification of viral RNA.
Compared to other PCR technologies, digital PCR is a potentially highly accurate approach for the quantification of nucleic acid fragments. This study describes the impact of four experimental factors, namely primer and probe chemistry, PCR amplification target, duplexing, and template type, on the measurement results obtained by reverse transcription digital PCR (RT-dPCR) of viral RNA using influenza A virus as a model. Along conventional dual labelled probes (DLP), alternative primer and probe chemistries, including Zip Nucleic Acids (ZNAs), Locked Nucleic Acids (LNAs), and Scorpions(®), were compared with two RNA template types: i) total genomic RNA extracted from cell cultured influenza A and ii) a synthetically prepared RNA transcript (In vitro transcribed RNA). While apparently duplexing or a different PCR target choice did not have a significant influence on the estimated RNA copy numbers, the impact of the choice of primer and probe chemistry and template type differed significantly for some methods. The combined standard uncertainty of the dPCR analysis results has been assessed, taking into account both the repeatability and the intermediate precision of the procedure. Our data highlight the importance of dPCR method optimisation and the advantage of using a more sophisticated primer and probe chemistry, which turned out to be dependent on the template type. Considerations are provided with respect to the molecular diagnostics of viral RNA pathogens, and more specifically, for precise quantification of RNA, which is of tremendous importance for the development of RNA calibration materials and the qualification of these calibrants as certified reference materials.


Trends in Gallbladder Disease in Young Adults: A Growing Concern.
Millennials (age: 25-32 years) and Generation-Z individuals (age: 10-25 years) exhibit a shift in the occurrence of gallbladder diseases, which may be related to changes in lifestyle and genetics. In light of these findings, we performed a retrospective observational study on patients who underwent gallbladder surgeries to determine the trend in gallbladder diseases in young adults. Both categorical and continuous data on 90 patients were collected between January 2020 and June 2021 and analysed retrospectively, with differences considered significant at a p-value of 0.05. The diagnosis of gallstones in young adults is presently complicated, as the signs and symptoms of biliary tract sickness differ significantly between those under and over 30 years of age. We observed that gallbladder diseases and their complications were highly common in individuals between the ages of 21 and 25 years. We discovered that gallstones were more common in teenagers than previously thought. Delays in intervention resulted in future complications which could have been avoided.


[20-year survival in women with breast cancer].
We analysed 170 women with carcinoma of the breast who survived 20 years after local or loco-regional therapy, without adjuvant chemo-hormonotherapy. Patients with axillary lymph nodes metastases constitute thirty-six percent of this group.


A Case of Trauma-Induced Arterial Thrombosis Mimicking Vasculitis.
Vasculitis mimickers are structural or pathologic entities that resemble the vasculitis clinical presentation and/or diagnostic findings. Their presence can be a conundrum, and physicians require careful assessment and adequate knowledge physicians when considering a diagnosis of vasculitis. Although they are considered mimickers, the therapeutic approach for most of them differs widely from that of vasculitis as high-dose steroids and potent immunosuppressive regimens are usually indicated in the latter. In fact, steroid therapy is contraindicated and is considered harmful in some of these mimickers (e.g. segmental arterial mediolysis). Therefore, it is important to distinguish them from vasculitis to prevent complications from immunosuppressive therapy. Hereby, we present a challenging case of a 64-year-old man who presented with acute gangrenous changes on his right fingers due to arterial thrombus after trauma resembling vasculitis.


Target-triggered cyclic assembly of DNA-protein hybrid nanowires for dual-amplified fluorescence anisotropy assay of small molecules.
Aptamer-based fluorescence anisotropy (FA) assays have attracted great interest in recent years. However, a key factor that determines FA value is molar mass, thus limiting the utility of this assay for the detection of small molecules. To solve this problem, streptavidin, as a molar mass amplifier, was used in a hybridization chain reaction (HCR) to construct a target-triggered cyclic assembly of DNA-protein hybrid nanowires for highly sensitive detection of small molecules by fluorescence anisotropy. In this assay, one blocking DNA strand is released by target-aptamer recognition. The DNA then serves as an initiator to trigger enzyme-free autonomous cross-opening of hairpin probes via HCR to form a DNA nanowire for further assembly of streptavidin. Using adenosine triphosphate (ATP) as the small molecule target, this novel dual-amplified, aptamer-based FA assay affords high sensitivity with a detection limit of 100 nM. This limit of detection (LOD) is much lower than that of the disassembly approach without HCR amplification or the assembly strategy without streptavidin. In contrast to the previous turn-off disassembly approaches based on nonspecific interactions between the aptamer probe and amplification moieties, the proposed aptamer-based FA assay method exhibits a turn-on response to ATP, which can increase sensing reliability and reduce the risk of false hits. Moreover, because of its resistance to environmental interferences, this FA assay has been successfully applied for direct detection of 0.5 μM ATP in complex biological samples, including cell media, human urine, and human serum, demonstrating its practicality in real complex biological systems.


Vancomycin Presoaking of the Graft Appears to Prevent Infection After Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-analysis.
Background: Vancomycin presoaking of the graft has been shown to decrease infection rates in some case series of anterior cruciate ligament (ACL) reconstruction. Purpose: We sought to substantiate the efficacy of vancomycin presoaked grafts for the prevention of infection after ACL reconstruction. Methods: We performed a systematic review of Medline and OVID to assess the incidence of postoperative infection in studies comparing patients undergoing ACL reconstruction with the use of vancomycin presoaked ACL grafts and a control group of patients undergoing ACL reconstruction without the use of presoaked grafts. The efficacy of vancomycin presoaking was calculated using the Agresti-Coull confidence interval. Relative risk (RR) was calculated for every study and the total sample. Results: The 11 studies that met inclusion criteria comprised 24,298 patients. In patients with vancomycin presoaking of the graft, 1 infection was reported in 8764 cases (0.01% rate). In the studies with control groups that did not have vancomycin presoaked grafts, there were 125 infections in 15,534 ACL reconstructions (0.8% rate). The efficacy of vancomycin presoaking in preventing infection after ACL reconstruction was 99.9% (0.999%-1.000% CI). The overall RR obtained was 0.07 (0.03-0.16 CI). All included studies were retrospective cohort studies (level III). Conclusions: Vancomycin presoaking of the graft has been shown to decrease infection rates after ACL reconstruction in studies of low evidence level. This suggests the need for prospective randomized controlled trials addressing this issue so that recommendations on the routine use of vancomycin presoaking of ACL grafts can be made with confidence.


Long-term survival after surgery for primary hepatic sarcoma in adults.
Patients with primary hepatic sarcomas benefit from resection, with possible long-term cure. Retrospective and prospective cohort study. University hospitals of Hamburg-Eppendorf and Düsseldorf, Germany. Between 1985 and 2006, 22 patients (8 men and 14 women; median age at initial diagnosis, 54 years [range, 19-80 years]) were surgically treated for primary hepatic sarcomas. Tumor resection with curative intent ranging from nonanatomical resection to liver transplant. Effects on overall survival were analyzed using the log-rank test. The majority of tumors were more than 5 cm (n = 19), with a median tumor size of 7 cm (range, 4-14 cm); of intermediate differentiation (G2; n = 15); and classified as leiomyosarcoma (n = 7). Ten patients received a hemihepatectomy. In 4 patients, a bisegmentectomy was performed and in 2 patients, a segmentectomy, while 4 patients received a nonanatomical resection. Liver transplant was performed in 2 patients. In 18 patients, complete tumor resection (R0) was achieved. Perioperative mortality was 0%. Median follow-up was 88 months (range, 6-246 months). Local recurrence occurred in 6 patients. Distant metastases were diagnosed in 10 patients, predominantly in the lung (n = 6). The 5-year survival after surgery was 65%, with 41% of the patients living more than 10 years without disease. Patients with angiosarcoma had a poor prognosis (P = .03). Although primary hepatic sarcoma is a rare malignant tumor, no standard treatment is established. A long-term survival is possible after complete tumor resection in a preselected population with early-stage disease.


Local modulation of plus-end transport targets herpesvirus entry and egress in sensory axons.
The core structures of many viruses move within cells by association with host cytoskeletal motor proteins; however, the mechanisms by which intracellular viral particles are transported toward sites of replication or the cell periphery at distinct stages of infection remain to be understood. The regulation of herpesvirus directional transport in sensory neurons was examined by tracking individual viral capsids within axons at multiple frames per s. After entry into axons, capsids underwent bidirectional and saltatory movement to the cell body independently of endosomes. A comparison of entry transport to a previous analysis of capsid axonal transport during egress revealed that capsid targeting in and out of cells occurs by modulation of plus-end, but not minus-end, motion. Entry transport was unperturbed by the presence of egressing virus from a prior infection, indicating that transport direction is not modulated globally by viral gene expression, but rather directly by a component of the viral particle.


Two isomeric cucurbitane derivatives.
Two isomeric cucurbitane derivatives, 3beta,7alpha,11beta-triacetoxycucurbit-5(10)-ene, (I), and 3beta,7alpha,11beta-triacetoxy-5alpha-cucurbit-1(10)-ene, (II), both C(36)H(58)O(6), have their single endocyclic C=C double bonds in different positions. This results in differences in the conformation of the four-ring system, which is close to a half-chair/half-chair/chair/half-chair arrangement in (I) and to a half-chair/twist-boat/boat/half-chair arrangement in (II). The orientation of some of the substituents is also different; the 3beta-acetoxy group is in an equatorial position in (I) but in an axial position in (II), while the 11beta-acetoxy group occupies an axial position in (I) and an equatorial position in (II). The asymmetric unit of (I) contains two symmetry-independent molecules which do not differ significantly, being related by a pseudo-twofold axis of symmetry. In both structures, the aliphatic chain fragments are disordered and the disorder persists at lower temperatures.


Depression in the physically ill.
The risk of depression is increased in many medical and surgical conditions. Specific serotonin reuptake inhibitors are generally recommended as first line treatment in the physically ill. Care must be taken in prescribing antidepressants in the physically ill, because of side-effects, hepatic and renal impairment, and potential for drug interactions.


A possible link between infection with burkholderia bacteria and systemic lupus erythematosus based on epitope mimicry.
We previously demonstrated that purified polyclonal and monoclonal anti-dsDNA antibodies bind a 15-mer peptide ASPVTARVLWKASHV in ELISA and Dot blot. This 15-mer peptide partial sequence ARVLWKASH shares similarity with burkholderia bacterial cytochrome B 561 partial sequence ARVLWRATH. In this study, we show that purified anti-dsDNA antibodies react with burkholderia fungorum bacterial cell lysates in Western blot. We used anti-dsDNA antibodies to make an anti-dsDNA antibodies affinity column and used this column to purify the burkholderia fungorum bacterial protein. Purified anti-dsDNA antibodies bind specifically to purified bacterial antigen and purified bacterial antigen blocked the anti-dsDNA antibodies binding to dsDNA antigen. Sera with anti-dsDNA antibodies bind specifically to purified bacterial antigen. We obtained protein partial sequence of RAGTDEGFG which is shared with burkholderia bacterial transcription regulator protein sequence. Sera with anti-dsDNA antibodies bind to RAGTDEGFG peptide better than control groups. These data support our hypothesis that the origin of anti-dsDNA antibodies in SLE may be associated with burkholderia bacterial infection.


[Some aspects of the skin infestation by Demodex folliculorum].
The importance of demodicids (Demodex folliculorum and D. brevis) infestation and their effect on skin lesions has been described based on literature data and our own clinical and parasitological investigations. Hair follicle mites have been detected in 45% of patients with rosacea, 27% of patients with perioral dermatitis, 28% of patients suffering from seborrhoeic dermatitis and in 3 out of 7 patients with chronic blepharitis. Clinical picture of demodecosis included erythemato-papulous and pustulous (rosacea-like) skin lesions together with erythemato-desquamative changes of the face.


Nanocellulose-Based Materials for Water Treatment: Adsorption, Photocatalytic Degradation, Disinfection, Antifouling, and Nanofiltration.
Nanocelluloses are promising bio-nano-materials for use as water treatment materials in environmental protection and remediation. Over the past decades, they have been integrated via novel nanoengineering approaches for water treatment processes. This review aims at giving an overview of nanocellulose requirements concerning emerging nanotechnologies of waster treatments and purification, i.e., adsorption, absorption, flocculation, photocatalytic degradation, disinfection, antifouling, ultrafiltration, nanofiltration, and reverse osmosis. Firstly, the nanocellulose synthesis methods (mechanical, physical, chemical, and biological), unique properties (sizes, geometries, and surface chemistry) were presented and their use for capturing and removal of wastewater pollutants was explained. Secondly, different chemical modification approaches surface functionalization (with functional groups, polymers, and nanoparticles) for enhancing the surface chemistry of the nanocellulose for enabling the effective removal of specific pollutants (suspended particles, microorganisms, hazardous metals ions, organic dyes, drugs, pesticides fertilizers, and oils) were highlighted. Thirdly, new fabrication approaches (solution casting, thermal treatment, electrospinning, 3D printing) that integrated nanocelluloses (spherical nanoparticles, nanowhiskers, nanofibers) to produce water treatment materials (individual composite nanoparticles, hydrogels, aerogels, sponges, membranes, and nanopapers) were covered. Finally, the major challenges and future perspectives concerning the applications of nanocellulose based materials in water treatment and purification were highlighted.


Peroxidase-mediated bromination of unsaturated fatty acids to form bromohydrins.
Eosinophil peroxidase and myeloperoxidase (MPO) catalyze the oxidation of bromide by hydrogen peroxide to produce hypobromous acid (HOBr). Hypochlorous acid, which is also generated by MPO, reacts with unsaturated fatty acids to form chlorohydrins. In this study the equivalent reaction of HOBr, produced from MPO, bromide, and hydrogen peroxide, with oleic (18:1), linoleic (18:2), and arachidonic (20:4) acids has been investigated. Thin-layer chromatography detected one major product of higher polarity than the unmodified fatty acids and additional more polar products with the polyunsaturated fatty acids. Similar results were observed with N-bromosuccinimide-derived HOBr. Gas chromatography-mass spectrometry (GC-MS) and electrospray MS identified the major products of 18:1 as the isomeric 9,10-bromohydrins based on retention time and mass spectrometric isotope and fragmentation patterns. The products of 18:2 and 20:4 were too unstable for analysis by GC-MS. Electrospray MS identified the mono- and bisbromohydrins formed from 18:2 and 20:4 based on mass/charge ratios of the molecular ions and the presence of bromine isotope patterns. Other oxidation products not containing bromine, such as dihydroxy derivatives, were detected as well. Fatty acid bromohydrins could contribute to the antimicrobial activity and inflammatory tissue damage by eosinophils and neutrophils, and could potentially be useful specific markers for HOBr production in vivo.


Chronic myelomonocytic leukaemia (an analysis of fourteen consecutive cases).
Fourteen consecutive cases of chronic myelomonocytic leukaemia aged 6 to 73 (mean 40.5) years were reviewed to define the natural history of the disease and the risk of acute transformation. The common presenting features included anaemia, fever, purpura, and bleeding tendencies. Abnormal karyotypes were seen in 4 of 6 patients subjected to cytogenetic analysis. Low dose cytosine arabinoside achieved complete remission in two and partial remission in one, of the four patients treated with this modality. The mean survival was 5.6 (range 2-12) months and two patients) evolved to acute myeloid leukaemia. The long term survival with the present form of therapy in chronic myelomonocytic leukaemia is poor.


Differential activation of promutagens by alloenzymes of human sulfotransferase 1A2 expressed in Salmonella typhimurium.
Various enzymatically formed sulfuric acid esters are chemically reactive and mutagenic. This metabolic activation pathway is not detected in standard in-vitro mutagenicity test systems. We describe the construction of Salmonella typhimurium TA1538-derived strains expressing alloenzymes *1, *2, *3, *5, *6 of human sulfotransferase 1A2 (SULT1A2). The reference compounds, 1-hydroxymethylpyrene (1-HMP), N-hydroxy-2-acetylaminofluorene (OH-AAF) and 2-hydroxylamino-5-phenylpyridine (OH-APP), were activated to mutagens in these strains. Their activity differed 7- to 16-fold between strains expressing various alloenzymes. It was strongest and weakest in the strains expressing the common alloenzymes, *1 and *2, respectively. The SULT1A2 protein expression levels, and the V(max) and K(m) values with the reference substrate 4-nitrophenol, varied 2.5-, 4-, and 110-fold, respectively, in cytosolic preparations from strains TA1538-SULT1A2*1 and *2. Strains with varying protein levels were constructed via insertion of silent mutations in the 5'-part of the cDNA. TA1538-SULT1A2*1Z and TA1538-SULT1A2*2Y showed equal expression levels of alloenzymes *1 and *2, respectively, which were 3 times above those of TA1538-SULT1A2*1. The mutagenicity of OH-AAF and OH-APP was unchanged in strain TA1538-SULT1A2*1Z versus *1, and moderately increased in TA1538-SULT1A2*2Y versus *2. The influence of the protein level was stronger with 1-HMP. Nevertheless, mutagenic activity of 1-HMP was still 11 times higher in TA1538-SULT1A2*1Z than in TA1538-SULT1A2*2Y. Thus, differences in the properties between alloenzymes can lead to differences in the activation of promutagens. The model compounds were also tested in strains expressing the other ten human SULTs identified. Whereas OH-AAF and OH-APP showed the highest mutagenic activities in strains expressing SULT1A2, 1-HMP was more potent in strains expressing other SULT forms. With the limitation that little is known about the tissue distribution and regulation of SULT1A2, the findings suggest that its polymorphism may affect the individual susceptibility towards procarcinogens, in particular certain aromatic amines and amides.


Insight into Potential Anticancer Activity of Algal Flavonoids: Current Status and Challenges.
Flavonoids are some of the most precious phytochemicals, believed to be found largely in terrestrial plants. With the advancement of phytochemical research and marine bioprospecting, flavonoids have also been reported by the research of microalgae and macroalgae. High growth rate with minimal nutritional and growth requirement, saving arable land and rich metabolic profile make microalgae an excellent repertoire of novel anticancer compounds, such as flavonoids. In addition, marine algae, especially seaweeds contain different types of flavonoids which are assumed to have unique chemical structures and bioactivities than their terrestrial counterparts. Flavonoids are not only good antioxidants but also have the abilities to kill cancer cells by inducing apoptosis and autophagy. However, the study of the anticancer properties of flavonoids is largely limited to terrestrial plants. This review offers an insight into the distribution of different classes of flavonoids in eukaryotic microalgae, cyanobacteria and seaweeds with their possible anticancer activities. In addition, extraction and purification methods of these flavonoids have been highlighted. Finally, prospects and challenges to use algal flavonoids as anticancer agents have been discussed.


Layer-by-layer assembly of thin films containing exfoliated pristine graphene nanosheets and polyethyleneimine.
A method for the modification of surface properties through the deposition of stabilized graphene nanosheets is described. Here, the thickness of the film is controlled through the use of the layer-by-layer technique, where the sequential adsorption of the cationic polyethyleneimine (PEI) is followed by the adsorption of anionic graphene sheets modified with layers of polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO) surfactants. The graphene particles were prepared using the surfactant-assisted liquid-phase exfoliation technique, with the low residual negative charge arising from edge defects. The buildup of the multilayer assembly through electrostatic interactions was strongly influenced by the solution conditions, including pH, ionic strength, and ionic species. Thereby, not only could the thickness of the film be tailored through the choice of the number of bilayers deposited but the viscoelastic properties of the film could also be modified by changing solution conditions at which the different species were deposited. The quartz crystal microbalance was used to measure the mass of graphene and polyelectrolyte immobilized at the interface as well as to probe the energy dissipated in the adsorbed layer.


The natural history of exercise: a 10-yr follow-up of a cohort of runners.
To determine the pattern of exercise and associated adverse events, including injuries, a mail survey was conducted on participants in the 1980 Peachtree Road Race Study for whom we were able to obtain current addresses. A total of 535 persons responded, 326 men and 209 women, representing 72% of those with identifiable addresses. Although only 56% of respondents reported that they were still running in 1990, 81% reported that they were still exercising regularly. The cumulative probability for continuing to run was 0.71 for men and 0.56 for women. Injury (31%) was the chief reason given by men for stopping permanently. For women, 28% stopped because they chose another form of exercise. Fifty-three percent of respondents had at least one injury during the 10-yr interval. The probability of experiencing an injury was associated with higher weekly mileage. The knee was the most frequently injured site. Thirty-nine percent of women and 35% of men reported being verbally assaulted. Approximately 10% of persons were hit by thrown objects or bitten by a dog. In a group of recreational runners, almost half had stopped running 10 yr later, but over 80% were still physically active. Many runners sustain injuries or suffer hazards related to their exercise.


Hormone levels and infection of Haemoproteus danilewskyi in free-ranging blue jays (Cyanocitta cristata).
Annual spring relapse of blood parasite infections in birds is believed to be the result of hormonal changes associated with breeding. As part of a larger study on the epizootiology of Haemoproteus danilewskyi in blue jays in south-central Florida, we studied the relationship between H. danilewskyi infections and levels of luteinizing hormone, prolactin, progesterone, testosterone, estradiol, and corticosterone. We found a positive association between intensity of H. danilewskyi infection and corticosterone levels in females but not in males. We also found no association between infection and levels of prolactin, luteinizing hormone, progesterone, testosterone, or estradiol in males or females. In addition, we found a positive relationship between levels of corticosterone and handling time and between corticosterone and testosterone levels. We suggest a possible influence of corticosterone on spring relapse of Haemoproteus spp. infections in birds but provide no support for the influence of breeding hormones on relapse of these parasites.


Graphene Oxide-Graft-Poly(l-lactide)/Poly(l-lactide) Nanocomposites: Mechanical and Thermal Properties.
The surface modification of graphene sheets with polymer chains may greatly hinder its aggregation and improve its phase compatibility with a polymer matrix. In this work, poly(l-lactic acid)-grafted graphene oxide (GO-g-PLLA) was prepared via a simple condensation polymerization method, realizing its dispersion well in organic solvents, which demonstrated that the surface of GO changed from hydrophilic to hydrophobic. GO-g-PLLA can disperse homogeneously in the PLLA matrix, and the tensile test showed that the mechanical properties of GO-g-PLLA/PLLA were much better than that of GO/PLLA; compared with GO, only 3% GO-g-PLLA content can realize a 37.8% increase in the tensile strength for their PLLA composites. Furthermore, the differential scanning calorimetry (DSC) and polarized optical microscopy (POM) results demonstrated that GO-g-PLLA shows a nucleating agent effect and can promote the crystallization of PLLA.


The PulmoSphere™ platform for pulmonary drug delivery.
Spray-dried PulmoSphere™ formulations comprise phospholipid-based small, porous particles. Drug(s) may be incorporated in or with PulmoSphere formulations in three formats: solution-, suspension-, and carrier-based systems. The multiple formats may be administered to the respiratory tract with multiple delivery systems, including portable inhalers (pressurized, metered-dose inhaler and dry-powder inhaler), nebulizers, and via liquid dose instillation in conjunction with partial liquid ventilation. The PulmoSphere platform (particles, formats, delivery systems) enables pulmonary delivery of a broad range of drugs independent of their physicochemical properties and lung dose. The engineered particles provide significant improvements in lung targeting and dose consistency, relative to current marketed inhalers.


pH-dependence of the ATP-driven uptake of noradrenaline by bovine chromaffin-granule ghosts.
The kinetic parameters of noradrenaline uptake by chromaffin granule ghosts have been measured at external pH values between 6.5 and 8.5. The log of the Km for noradrenaline decreased linearly with pH with a slope of -1.0, indicating that the observed affinity increase of originated in deprotonation of a single chemical group. This result is interpreted as showing that the neutral form of monoamines is the true substrate for the amine carrier. The Km of the carrier for the neutral form of noradrenaline was calculated as 0.1 microM. The maximal velocity, V, of the uptake reaction was constant from pH 6.5 to 8.0 and decreased at more alkaline pH values. Since the proton electrochemical gradient delta muH+ generated by the membrane H+-pump was independent of the pH in the range 6.5-9.5, the pH dependence of the maximal velocity of uptake reflects the pH profile of the monoamine transporter.


Inpatient capacity at children's hospitals during pandemic (H1N1) 2009 outbreak, United States.
Quantifying how close hospitals came to exhausting capacity during the outbreak of pandemic influenza A (H1N1) 2009 can help the health care system plan for more virulent pandemics. This ecologic analysis used emergency department (ED) and inpatient data from 34 US children's hospitals. For the 11-week pandemic (H1N1) 2009 period during fall 2009, inpatient occupancy reached 95%, which was lower than the 101% occupancy during the 2008-09 seasonal influenza period. Fewer than 1 additional admission per 10 inpatient beds would have caused hospitals to reach 100% occupancy. Using parameters based on historical precedent, we built 5 models projecting inpatient occupancy, varying the ED visit numbers and admission rate for influenza-related ED visits. The 5 scenarios projected median occupancy as high as 132% of capacity. The pandemic did not exhaust inpatient bed capacity, but a more virulent pandemic has the potential to push children's hospitals past their maximum inpatient capacity.


[The treatment of extensive onychomycosis in aged patients].
The aim of the study was to present the own observations concerning treatment of patients above 50 years of age suffering the toe nail dermatophyte onychomycosis with intensified subungual keratosis and considerable nail plates destruction. Three different treatment methods were administered: 40 patients were treated only with itraconazole pulse method for 3 month, 35 patients besides itraconazole were given also pentoxifylline. In case of 20 individuals besides 3-month itraconazole pulse method treatment, the amorolfine varnish application onto changed nails once a week for 6 month was administered. In the group of patients treated only with itraconazole, in 22 cases (55,0%) the cure was obtained, while in the group of individuals given the combined therapy with pentoxifylline, the cures made 71,4% (25 individuals). From among patients treated with itraconazole and external amorolfine application the cures made 75,0% (15 individuals).


The effects of photodynamic therapy using differently substituted zinc phthalocyanines on vessel constriction, vessel leakage and tumor response.
The effects of four different zinc phthalocyanines were studied during and after photodynamic therapy (PDT). Measurements of vessel constriction, vessel leakage, tumor interstitial pressure, eicosanoid release, and tumor response of chondrosarcoma were made in Sprague-Dawley rats. Animals were injected intravenously with 1 mumol/kg of mono-, di-, or tetrasulfonated zinc phthalocyanine, or 1 mumol/kg of a zinc phthalocyanine substituted with four tertiary butyl groups. Tissues were exposed to 400 J/cm2 670 nm light 24 h after photosensitizer injection. An additional group of animals was given indomethacin before treatment. The use of the monosulfonated and tertiary butyl substituted zinc phthalocyanines in PDT caused the release of specific eicosanoids, caused vessel constriction, and induced venule leakage and increases in tumor interstitial pressure. Tumor cures of 27% and 7% were observed. Photodynamic therapy using the disulfonated zinc phthalocyanine did not induce vessel constriction or the release of eicosanoids, however, tumor cure was 43%. The use of the tetrasulfonated zinc phthalocyanine caused intermediate effects between the mono- and disulfonated compounds. The administration of indomethacin to animals completely inhibited the effects of PDT using the monosulfonated compound but had minimal effects on treatment using the disulfonated compound. This suggests that the monosulfonated and disulfonated compounds act by different mechanisms of destruction.


A cross-sectional study of cardiovascular disease and associated factors.
Cardiovascular diseases (CVD) are a major cause of mortality and morbidity in Poland. Data on risk factors of CVD in this country are limited. The presented study investigated risk factors of self-reported CVD within the Polish- Norwegian Study (PONS). PONS is an ongoing prospective study in Poland. The data used was provided by 3,853 participants, aged 45-64, during baseline interviews. Prevalence of chronic diseases among participants was as follows: hypertension, 38.4%; diabetes, 5.9%; and CVD, 11.0%. There was no association between CVD and gender and place of residence. CVD was associated with ever-smoking (OR= 1.25; 95% CI: 1.00-1.55), whereas there was an inverse association with alcohol drinking in the year preceding enrolment in the study (OR= 0.50; 95% CI: 0.39-0.63). CVD was associated with body mass index (BMI), as well as with measures of abdominal adiposity, in the following order: waist to height ratio>waist circumference>waist to hip ratio; however, none of these measures showed a stronger association with CVD than BMI. Both hypertension (OR= 1.33; 95% CI: 1.05-1.68) and diabetes (OR= 1.33; 95% CI: 1.05-1.68) were associated with CVD in adjusted models. This study shows the association between several risk factors and prevalence of self-reported CVD and provides information about distribution of those factors among an adult population in Poland. The results of the ongoing PONS study in a prospective setting will provide more accurate risk estimates for the observed associations, as well as risk estimates for other risk factors of CVD, including dietary factors, and attributable risks for various factors.


Promoting youth purpose: a review of the literature.
This article reviews the research literature on teaching and supporting purpose in adolescence and young adulthood. An extensive search revealed that most studies on youth purpose examine psychological correlates and neglect instructional and social supports. School is an effective context for fostering purpose, yet reported approaches for explicitly instructing for purpose are rare after the early 1990s, reflecting a trend away from a language of purpose as a discrete endeavor in education since at least the 1960s. Furthermore, research on the outcomes of early purpose instruction curricula is not present in empirical journal articles. Nevertheless, a concern for fostering youth purpose has not disappeared from education; rather, it is subsumed under approaches that foster more comprehensive positive student outcomes, such as character, civic engagement, and positive youth development. Key curricular approaches to these outcomes are therefore also reviewed and examined for insights into how purpose can be fostered.


Antibiotic usage for initial empirical treatment of infections in hospitalized patients in West Germany.
Antibiotic usage for initial empirical treatment of infections in hospitalized patients was assessed by means of a questionnaire sent to physicians in charge of surgical and medical intensive care units, departments of neurosurgery, neurology, general surgery, thoracic surgery, internal medicine and pediatrics. Analysis of a total of 82 questionnaires filled in by the various departments revealed that the most frequently used regimens for initial empirical therapy were combinations of a broad spectrum penicillin with an amino-glycoside or of a second generation cephalosporin with an aminoglycoside in intensive care. Third generation cephalosporins ranked third among combination partners with aminoglycosides. Imipenem and fluoroquinolones were used only rarely for first line treatment. Second line treatment was most frequently with third generation cephalosporins or imipenem/cilastatin for internal wards and intensive care with an extension for staphylococcal infections with vancomycin or teicoplanin as the most frequent additional antibiotics. Patterns of antibiotic usage changed with regard to infection sites with a predominance of third generation cephalosporins or broad spectrum penicillins in combination with an aminoglycoside and metronidazole in abdominal sepsis and peritonitis. In case of pneumonia a differentiation between community acquired and hospital acquired pneumonias was made. Treatment was predominantly carried out with penicillin G, ampicillin or a second generation cephalosporin with or without the addition of an aminoglycoside in case of community acquired pneumonia. The addition of clindamycin or metronidazole was considered for suspected staphylococcal infection or aspiration pneumonia. Third generation cephalosporins were preferred for pneumonia treatment in surgical patients.


Bioinformatics platform development: from gene to lead compound.
In the past 10 yr, the field of bioinformatics has been characterized by the mapping of many genomes. These efforts have stimulated explosive development of novel bioinformatics and experimental approaches to predict the functions and metabolic role of the new proteins. The main application of the work is to search, validate, and prioritize new targets for designing a new generation of drugs. Modern computer and experimental methods for discovery of new lead compounds have also expanded and integrated into the process referred to as rational drug design. They are directed to accelerate and optimize the drug discovery process using experimental and virtual (computer-aided drug discovery) methods. Recently, these methods and approaches have merged into a "from gene to lead" platform that includes the processes from new target discovery through obtaining highly effective lead compounds. This chapter describes the strategies as employed by the "From Gene to Lead" platform, including the major computer and experimental approaches and their interrelationship. The latter part of the chapter contains some examples of the steps required for implementing this platform.


Second-Line Systemic Therapy for Highly Aggressive Neuroendocrine Prostate Cancer.
Neuroendocrine prostate cancer (NEPC) is generally an aggressive form of prostate cancer that can arise de novo or develop as a castration-resistant mechanism. While first-line platinum-based chemotherapy is effective against NEPC, its limited response duration and subsequent treatments pose significant clinical challenges. Standard second-line treatments have not been established due to the limited data available. The aim of this review was to reveal the current status of second-line therapy for NEPC. A literature search was conducted using PubMed and Web of Science and a total of 13 articles were included in this review. Prospective and retrospective studies demonstrated that treatment outcome of second-line therapy using platinum with etoposide or docetaxel was unfavorable and progression-free survival was 3 months or shorter. Amrubicin and irinotecan were also frequently used as second-line therapy, however, efficacy of these agents was modest and response duration was less than 6 months. NEPC patients with homologous recombination repair gene alterations may benefit from treatment with poly (ADP-ribose) polymerase (PARP) inhibitors. Ongoing clinical studies investigate various agents, including immune checkpoint inhibitors, molecularly targeted agents, and PARP inhibitors. With the increasing recognition and active biopsy of NEPC lesions, the number of NEPC patients is anticipated to rise. Accumulating more knowledge and experience is crucial in developing novel treatment strategies to combat this disease.


Gazella arabica dareshurii: a remarkable relict population on Farur Island, Iran.
The islands in the Persian Gulf are home to several species of gazelles, i.e., Gazella bennettii, G. subgutturosa, and a new subspecies of Mountain gazelles which was discovered on Farur Island and described for the first time in 1993 as Gazella gazella dareshurii. Later, phylogenetic analyses showed that the Mountain gazelles consist of two species: G. gazella and G. arabica. As the Farur gazelles are more closely related to the Arabian forms of the Mountain gazelles, this subspecies is regarded to be G. arabica dareshurii. Until now, the origin of this subspecies has been an enigma. Here, we used mitochondrial cyt b, two nuclear introns (CHD2 and ZNF618), and morphological data to address this question by investigating the taxonomic position of the Farur gazelles. The results show that this population is monophyletic and split from other G. arabica populations probably 10,000 BP. It is a natural relict population that was trapped on the island due to the rising sea levels of the Persian Gulf after the Last Glacial Maximum. Intermittent drought and flooding are suggested to be the main factors balancing population growth in the absence of natural predators on this monsoon-influenced island. Conservation actions should focus on preserving the natural situation of the island (cease introducing mesquite tree and other invasive species, stop building new construction and roads, and caution in providing water sources and forage), and possibly introducing individuals to other islands (not inhabited by gazelles) or to fenced areas on the Iranian mainland (strictly isolated from other gazelle populations) when the population reaches the carrying capacity of the island.


Clinical pharmacology and pharmacogenetics in a genomics era: the DMET platform.
While no genome-wide pharmacogenetics study has yet been published, the field of pharmacogenetics is moving towards exploratory, large-scale analyses of the interaction between genetic variation and drug treatment. The Drug Metabolizing Enzymes and Transporters (DMET) platform offers a standardized set of 1936 variants in 225 genes related to drug absorption, distribution, metabolism and elimination that is useful to scan the genome for previously unknown associations between variation in absorption, distribution, metabolism and elimination genes and pharmacokinetic and pharmacodynamic outcomes of drug treatment. The purpose of this review is to put the DMET platform into context within the current study designs that have been used in pharmacogenetics, and to explore the role that DMET has played - and will play - in future pharmacogenetics studies.


Mutations in the sodium channel associated with pyrethroid resistance in the greenhouse whitefly, Trialeurodes vaporariorum.
Trialeurodes vaporariorum Westwood is an important pest of protected crops in temperate regions of the world. Resistance to pyrethroid insecticides is long established in this species, but the molecular basis of the mechanism(s) responsible has not previously been disclosed. Mortality rates of three European strains of T. vaporariorum to the pyrethroid bifenthrin were calculated, and each possessed significant resistance (up to 662-fold) when compared with a susceptible reference strain. Direct sequencing revealed three amino acid substitutions in the para-type voltage-gated sodium channel (the pyrethroid and DDT target site) of bifenthrin-resistant T. vaporariorum at positions previously implicated with pyrethroid or DDT resistance (M918L, L925I and T929I) in other related species. This study indicates that resistance to bifenthrin in T. vaporariorum is associated with target-site insensitivity, and that the specific mutations in the sodium channel causing resistance may differ between localities.


Nanostructure-initiator mass spectrometry (NIMS) imaging of brain cholesterol metabolites in Smith-Lemli-Opitz syndrome.
Cholesterol is an essential component of cellular membranes that is required for normal lipid organization and cell signaling. While the mechanisms associated with maintaining cholesterol homeostasis in the plasma and peripheral tissues have been well studied, the role and regulation of cholesterol biosynthesis in normal brain function and development have proven much more challenging to investigate. Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol synthesis characterized by mutations of 7-dehydrocholesterol reductase (DHCR7) that impair the reduction of 7-dehydrocholesterol (7DHC) to cholesterol and lead to neurocognitive deficits, including cerebellar hypoplasia and austism behaviors. Here we have used a novel mass spectrometry-based imaging technique called cation-enhanced nanostructure-initiator mass spectrometry (NIMS) for the in situ detection of intact cholesterol molecules from biological tissues. We provide the first images of brain sterol localization in a mouse model for SLOS (Dhcr7(-/-)). In SLOS mice, there is a striking localization of both 7DHC and residual cholesterol in the abnormally developing cerebellum and brainstem. In contrast, the distribution of cholesterol in 1-day old healthy pups was diffuse throughout the cerebrum and comparable to that of adult mice. This study represents the first application of NIMS to localize perturbations in metabolism within pathological tissues and demonstrates that abnormal cholesterol biosynthesis may be particularly important for the development of these brain regions.


The prevalence and characterization of antibiotic-resistant and virulent Escherichia coli strains in the municipal wastewater system and their environmental fate.
Antibiotics are widely used in human and veterinary medicine and in animal production, which increases their concentrations in aquatic ecosystems and contributes to selective pressure on environmental microorganisms. The objective of this study was to identify antibiotic resistance determinants in Escherichia coli strains isolated from untreated and treated wastewater (UWW and TWW) and from river water sampled downstream and upstream (URW and DRW) from the effluent discharge point. The analyzed antibiotic groups were beta-lactams, tetracyclines and fluoroquinolones which are widely used in human and veterinary medicine. The virulence of the isolated E. coli strains was also analyzed, and their clonal relatedness was determined by ERIC (enterobacterial repetitive intergenic consensus sequence) PCR. The highest counts of bacteria resistant to beta-lactams, tetracyclines and fluoroquinolones were noted in UWW at 6.4×104, 4.2×104 and 3.1×103CFU/mL, respectively. A total of 317 E. coli isolates resistant to at least one group of antibiotics were selected among bacterial isolates from river water and wastewater samples. Nearly 38% of those isolates were resistant to all of the tested antibiotics. The highest percent (43%) of multidrug-resistant isolates was noted in UWW samples. Isolates resistant to beta-lactams most frequently harbored blaTEM and blaOXA genes. The group of genes encoding resistance to tetracyclines was most frequently represented by tetA, tetB and tetK, whereas the qnrS gene was noted in isolates resistant to fluoroquinolones. Virulence genes bfpA (65%), ST (56%) and eae (39%) were most widely distributed in all isolates, regardless of their origin. The results of this experiment reveal the dangers associated with environmental contamination by drug-resistant and virulent E. coli strains distributed with treated wastewater. Multidrug resistance was determined more frequently in strains isolated from DRW than in isolates from URW samples. Our findings provide valuable inputs for evaluating public health hazards associated with bacterial contamination.


Special considerations in mapping and ablation of focal ventricular arrhythmias originating from the left ventricular outflow tract in patients with a transcatheter aortic valve replacement.
Transcatheter aortic valve replacements (TAVRs) have been increasingly performed in high-risk patients with severe aortic stenosis. Focal ventricular arrhythmias (VAs) originating from the left ventricular outflow tract (LVOT) can occur after a TAVR, and radiofrequency catheter ablation (RFCA) should be considered as a treatment option when those VAs are drug-refractory. There are specific challenges in the RFCA of LVOT VAs after a TAVR because the tubular structure of the TAVR device sits in the LVOT. However, if the anatomical background of the TAVR and LVOT VAs are well understood and the anatomical relationship between the TAVR device and LVOT is sufficiently evaluated, RFCA of LVOT VAs in patients with a TAVR should be safe and highly successful.


[The variation of hepatic duct confluence and asymptomatic common bile duct stone with routine intraoperative cholangiogram during laparoscopic cholecystectomy].
Intraoperative cholangiogram (IOC) during laparoscopic cholecystectomy (LC) has been used to evaluate bile duct stone. But, the routine use of IOC remains controversial. With routine IOC during LC, we reviewed the variation of hepatic duct confluence and try to suggest the diagnostic criteria of asymptomatic common bile duct (CBD) stone. We reviewed the medical record of 970 consecutive patients who underwent LC with IOC from January 1999 to December 2009, retrospectively. Nine hundered seventy patients were enrolled. IOC were successful in 957 (98.7%) and unsuccessful in 13 (1.3%). Eighty two of 957 patients (8.2%) were excluded because of no or poor radiologic image. According to Couinaud's classification, 492 patients (56.2%) had type A hepatic duct confluence, 227 patients (26.1%) type B, 15 patients (17%) type C1, 43 patients (4.9%) type C2, 72 patients (8.2%) type D1, 21 patients (2.4%) type D2, 1 patient (0.1%) type E1, 1 patient (0.1%) type E2, 2 patients (0.2%) type F, and 1 patient (0.1%) no classified type. The CBD stone was found in 116 of 970 (12.2%) patients. In 281 patients, preoperative serologic and radiologic tests did not show abnormality. When preoperative findings were not remarkable, there was no difference of clinical features between patients with or without CBD stones. Although IOC during LC has some demerits, it is a safe and accurate method for the detection of CBD stone and the anatomic variation of intrahepatic duct.


The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis.
Increased stromal collagen deposition in human breast tumours correlates with metastases. We show that activation of the collagen I receptor DDR2 (discoidin domain receptor 2) regulates SNAIL1 stability by stimulating ERK2 activity, in a Src-dependent manner. Activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation and increased protein half-life. DDR2-mediated stabilization of SNAIL1 promotes breast cancer cell invasion and migration in vitro, and metastasis in vivo. DDR2 expression was observed in most human invasive ductal breast carcinomas studied, and was associated with nuclear SNAIL1 and absence of E-cadherin expression. We propose that DDR2 maintains SNAIL1 level and activity in tumour cells that have undergone epithelial-mesenchymal transition (EMT), thereby facilitating continued tumour cell invasion through collagen-I-rich extracellular matrices by sustaining the EMT phenotype. As such, DDR2 could be an RTK (receptor tyrosine kinase) target for the treatment of breast cancer metastasis.


Interplay between innate immunity and negative-strand RNA viruses: towards a rational model.
The discovery of a new class of cytosolic receptors recognizing viral RNA, called the RIG-like receptors (RLRs), has revolutionized our understanding of the interplay between viruses and host cells. A tremendous amount of work has been accumulating to decipher the RNA moieties required for an RLR agonist, the signal transduction pathway leading to activation of the innate immunity orchestrated by type I interferon (IFN), the cellular and viral regulators of this pathway, and the viral inhibitors of the innate immune response. Previous reviews have focused on the RLR signaling pathway and on the negative regulation of the interferon response by viral proteins. The focus of this review is to put this knowledge in the context of the virus replication cycle within a cell. Likewise, there has been an expansion of knowledge about the role of innate immunity in the pathophysiology of viral infection. As a consequence, some discrepancies have arisen between the current models of cell-intrinsic innate immunity and current knowledge of virus biology. This holds particularly true for the nonsegmented negative-strand viruses (Mononegavirales), which paradoxically have been largely used to build presently available models. The aim of this review is to bridge the gap between the virology and innate immunity to favor the rational building of a relevant model(s) describing the interplay between Mononegavirales and the innate immune system.


Genome-wide association study identifies novel loci for plasma levels of protein C: the ARIC study.
Protein C is an important endogenous anticoagulant in hemostasis. Deficiencies of protein C due to genetic mutations or a low level of circulating protein C increase the risk of venous thromboembolism. We performed a genome-wide association scan for plasma protein C antigen concentration with approximately 2.5 million single-nucleotide polymorphisms in 8048 individuals of European ancestry and a replication analysis in a separate sample of 1376 individuals in the Atherosclerosis Risk in Communities Study. Four independent loci from 3 regions were identified with genome-wide significance: 2p23 (GCKR, best SNP rs1260326, P = 2.04 × 10(-17)), 2q13-q14 (PROC, rs1158867, P = 3.77 × 10(-36)), 20q11 (near and within PROCR, rs8119351, P = 2.68 × 10(-203)), and 20q11.22 (EDEM2, rs6120849, P = 7.19 × 10(-37) and 5.23 × 10(-17) before and after conditional analysis, respectively). All 4 loci replicated in the independent sample. Furthermore, pooling the discovery and replication sets yielded an additional locus at chromosome 7q11.23 (BAZ1B, rs17145713, P = 2.83 × 10(-8)). The regions marked by GCKR, EDEM2, and BAZ1B are novel loci that have not been previously reported for association with protein C concentration. In summary, this first genome-wide scan for circulating protein C concentration identified both new and known loci in the general population. These findings may improve the understanding of physiologic mechanisms in protein C regulation.


Electronic dispersion pre-compensation for 10.709-Gb/s using a look-up table and a directly modulated laser.
A novel electronic dispersion pre-compensation scheme for a directly modulated laser is described and experimentally demonstrated for transmission distances beyond 200 km using a low-cost laser packaged for 2.5-Gb/s while operated at 10.709-Gb/s. A single look-up-table (LUT) for the drive current is designed to mitigate the effects of fiber dispersion, the intrinsic nonlinear modulation response of the laser, and the laser package. Experimental results show that an 11-bit LUT can compensate the dispersion of 202 km of standard single mode fiber with a required optical-signal-to-noise-ratio of 18.61 dB at a bit error ratio of 3.8 × 10(-3).


Characterization of stx2 tubular response in a rat experimental model of hemolytic uremic syndrome.
In Argentina, hemolytic uremic syndrome (HUS) constitutes the most frequent cause of acute renal failure in children. The aim of our study was to analyze the early tubular response under the effect of Shiga toxin type 2 (Stx2) in a rat experimental model of HUS. Adult male Sprague-Dawley rats were injected intraperitoneally with culture supernatant from recombinant Escherichia coli expressing Stx2. Functional, histological, immunohistochemical and Western blot studies were performed at 48 h postinoculation. Renal tubules showed the loss of the epithelial markers E-cadherin and β-catenin, and an increase in transforming growth factor-β1 expression. We detected the expression of α-smooth muscle actin in the interstitium and fibrosis in the periglomerular areas. Our results indicate that the early tubular response to the effects of Stx2 is related to an immunophenotype change of tubular cells and the presence of mild fibrosis in the interstitium.


[Effect of L-arginine on pro- and antioxidant status of the rat vessels and lungs in experimental rhabdomyolysis].
The glycerol administration was found to cause accumulation of the total heme in rat blood serum, vessels and lungs that are accompanied by increase of TBA-reactive products and protein carbonyl derivates contents. A decrease of superoxide dismutase activity and an increase of reduced glutathione in lung were observed. Heme entering the vessels and lungs is accompanied by elevation in heme oxygenase activity. Pretreatment by L-arginine (0.5 h before glycerol administration) didn't affect blood serum and vessels changes caused by glycerol injection. However, in lungs, L-arginine prevents TBA-reactive products and protein carbonyl derivates accumulation, the decrease ofsuperoxide dismutase activity and causes the ealier heme oxygenase induction. Prooxidant effects of heme in tissues studied and possible mechanisms of L-arginine protective action in lung under experimental rhabdomyolysis are discussed.


Magnetoquantum Oscillations at THz Frequencies in InSb.
The ac magnetoconductance of bulk InSb at THz frequencies in high magnetic fields, as measured by the transmission of THz radiation, shows a field-induced transmission, which at high temperatures (≈100 K) is well explained with classical magnetoplasma effects (helicon waves). However, at low temperatures (4 K), the transmitted radiation intensity shows magnetoquantum oscillations that represent the Shubnikov-de Haas effect at THz frequencies. At frequencies above 0.9 THz, when the radiation period is shorter than the Drude scattering time, an anomalously high transmission is observed in the magnetic quantum limit that can be interpreted as carrier localization at high frequencies.