Identifying the ErbB/MAPK Signaling Cascade as a Therapeutic Target in Canine Bladder Cancer.
Transitional cell carcinoma (TCC) of the bladder comprises 2% of diagnosed canine cancers. TCC tumors are generally inoperable and unresponsive to traditional chemotherapy, indicating a need for more effective therapies. BRAF, a kinase in the mitogen-activated protein kinase (MAPK) pathway, is mutated in 70% of canine TCCs. In this study, we use BRAF mutant and wild-type TCC cell lines to characterize the role of BRAF mutations in TCC pathogenesis and assess the efficacy of inhibition of the MAPK pathway alone and in combination with other gene targets as a treatment for canine TCC. Analysis of MAPK target gene expression and assessment of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation following serum starvation indicated constitutive MAPK activity in all TCC cell lines. BRAF mutant TCC cell lines were insensitive to the BRAF inhibitor vemurafenib, with IC50 values greater than 5 μM, but exhibited greater sensitivity to a paradox-breaking BRAF inhibitor (IC50: 0.2-1 μM). All TCC cell lines had IC50 values less than 7 nM to the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor trametinib independent of their BRAF mutation status. ERK1/2 phosphorylation decreased after 6-hour treatments with MAPK inhibitors, but rebounded by 24 hours, suggesting the presence of resistance mechanisms. Microarray analysis identified elevated expression of the ErbB family of receptors and ligands in TCC cell lines. The pan-ErbB inhibitor sapitinib synergized with BRAF inhibition in BRAF mutant Bliley TCC cells and synergized with MEK1/2 inhibition in Bliley and BRAF wild-type Kinsey cells. These findings suggest the potential for combined MAPK and ErbB receptor inhibition as a therapy for canine TCC. SIGNIFICANCE STATEMENT: The results of this study (1) identify a novel combination strategy for canine bladder cancer treatment: targeting the ErbB/MAPK signaling cascade and (2) establish the utility of canine bladder cancer as a naturally-occurring model for human MAPK-driven cancers.


Age-dependent epidemiological patterns and strain diversity in helminth parasites.
Field studies of schistosomes and the major intestinal nematodes Trichuris trichiura and Ascaris lumbricoides repeatedly demonstrate that the intensity and prevalence of infection exhibit marked dependency on host age. Peak levels of infection typically occur in hosts aged between 10 and 14 yr in endemically infected communities. It has widely been assumed that the slow acquisition of resistance in adults is caused by repeated exposure to the same antigenic repertoire of a single parasite strain. Consequently, these empirical patterns have previously been taken to suggest that human immunity to helminth parasites confers poor protection against reinfection. Here, an alternative explanation is suggested on the basis of results from a simplified model of helminth transmission. It is proposed that the empirical observations can be attributed to the circulation of multiple helminth strains that each elicit highly protective immunity. If this hypothesis is correct, estimates of epidemiological parameters from field data and the potential for control of helminth diseases might require reevaluation.


Changing trends in the incidence of ovarian neoplasia and its relationship with the risk factors: a report of 311 cases from north-eastern anatolia region.
Ovarian cancer is one of the most common and lethal gynecologic malignancy. In Turkey, the 8(th) most commonly seen neoplasm is ovarian cancer. The risk factors of ovarian cancer are menstrual reproductive events including gravida, menarche and menopause status, and life style habits such as cigarette smoking and habitat. In this study we aimed to determine the risk factors leading to ovarian cancer in Turkish women population and show the tumor markers in this population. This study included 311 ovarian neoplasia cases diagnosed at the Pathology Department of Ataturk University in Erzurum over last seven years extending from 2005 to 2013. This study is a retrospective analysis basing on the pathology reports and accesible patient files. Serum tumor markers of the patients were retrospectively reported from their records. Conventional stained preparations existing in our archive examined by two pathologists as well independent of each other, and histopathologic diagnosis and the distribution of the sub-group was revised. A total of 311 patients were included in this study in which patients were diagnosed at the Pathology Department of Ataturk University in Erzurum. Serous cystadenoma is the most common ovarian tumor followed by mucinous cystadenoma, germ cell tumors, and dysgerminoma. All of the tumor markers were significantly normal. Upto our knowledge this was the first epidemiological study in Turkey. Analysis of each country's statistical information reflecting its own profile is also important. The relationship between the profiles of patients and types of ovarian neoplasia may give an idea about the risk factors of the disease in its region. Additionally, distribution of tumor markers might be considered for the discriminating of the benign or malign characters of the ovarian neoplasia.


Calcite and aragonite seas and the de novo acquisition of carbonate skeletons.
A longstanding question in paleontology has been the influence of calcite and aragonite seas on the evolution of carbonate skeletons. An earlier study based on 21 taxa that evolved skeletons during the Ediacaran through Ordovician suggested that carbonate skeletal mineralogy is determined by seawater chemistry at the time skeletons first evolve in a clade. Here I test this hypothesis using an expanded dataset comprising 40 well-defined animal taxa that evolved skeletons de novo in the last 600 Myr. Of the 37 taxa whose mineralogy is known with some confidence, 25 acquired mineralogies that matched seawater chemistry of the time, whereas only two taxa acquired non-matching mineralogies. (Ten appeared during times when seawater chemistry is not well constrained.) The results suggest that calcite and aragonite seas do have a strong influence on carbonate skeletal mineralogy, however, this appears to be true only at the time mineralized skeletons first evolve. Few taxa switch mineralogies (from calcite to aragonite or vice versa) despite subsequent changes in seawater chemistry, and those that do switch do not appear to do so in response to changing aragonite-calcite seas. This suggests that there may be evolutionary constraints on skeletal mineralogy, and that although there may be increased costs associated with producing a mineralogy not favored by seawater, the costs of switching mineralogies are even greater.


Effects of Insulin on Porcine Neonatal Sertoli Cell Responsiveness to FSH In Vitro.
There is ongoing debate as to whether the decline of sperm production in recent times may be related to a parallel increase in the rate of obesity and diabetes. Lower anti-Müllerian hormone (AMH) and inhibin B secretion have been observed in young hyperinsulinemic patients compared to healthy controls, suggesting a Sertoli cell (SC) dysfunction. The pathophysiological mechanisms underlying SC dysfunction in these patients are poorly understood. To the best of our knowledge, no evidence is available on the effects of insulin on SC function. Therefore, this study was undertaken to assess the effects of insulin on basal and follicle-stimulating hormone (FSH)-stimulated SC function in vitro. To accomplish this, we evaluated the expression of AMH, inhibin B and FSHR genes, the secretion of AMH and inhibin B and the phosphorylation of AKT473 and SC proliferation on neonatal porcine SC after incubation with FSH and/or insulin. We found that similar to FSH, the expression and secretion of AMH is suppressed by insulin. Co-incubation with FSH and insulin decreased AMH secretion significantly more than with FSH alone. Insulin had no effect on the expression and secretion of the inhibin B gene, but co-incubation with FSH and insulin had a lower effect on inhibin B secretion than that found with FSH alone. FSH and/or insulin increased AKT473 phosphorylation and SC proliferation. In conclusion, the results of this study showed that insulin modulates SC function. We hypothesize that hyperinsulinemia may therefore influence testicular function even before puberty begins. Therefore, particular care should be taken to avoid the onset of hyperinsulinemia in children to prevent a future deleterious effect on fertility.


[Roentgenological demonstration of pathological changes of the mucosa of the small intestine].
Use of a special high molecular guar preparation in small bowel contrast studies results in a roentgenological detection of the villous architecture of the small intestine. A diffuse villous atrophy results in a loss of the normal granular pattern. Segmental loss of granular mucosal texture is found in chronic radiogenic enteritis. In active Crohn's disease a coarser diffusely distributed granular appearance of the mucous surface occurs in addition to the segmental inflammatory changes. A coarse granular mucosal pattern with only segmental involvement is seen in mild malabsorption syndrome in the upper jejunum. Radiological signs for an intestinal protein loss syndrome is a coarse and weakly contrasted granular mucosal pattern in the lower ileum with moderate thickening of the jejunal folds and increased liquid content of the bowel.


Treatments of Epistaxis in Hereditary Hemorrhagic Telangiectasia: Systematic Review and Network Meta-Analysis.
To analyze and compare the effects of epistaxis treatments for Hereditary Hemorrhagic Telangiectasia (HHT) patients. Of total of 21 randomized controlled trials (RCT), the data from 15 RCTs (697 patients, 7 treatments: timolol, propranolol, bevacizumab, doxycycline, tacrolimus, estriol/estradiol, and tranexamic acid) were pooled for the meta-analyses while the other 6 studies (treatments: electrosurgical plasma coagulation, KTP laser, postoperative packing, tamoxifen, sclerosing agent, and estriol) were reviewed qualitatively. When compared to placebo, propranolol offered the most improved epistaxis severity score, mean difference (MD), -1.68, 95% confidence interval (95%CI) [-2.80, -0.56] followed by timolol, MD -0.40, 95%CI [-0.79, -0.02]. Tranexamic acid significantly reduced the epistaxis frequency, MD -1.93, 95%CI [-3.58, -0.28]. Other treatments had indifferent effects to placebo. Qualitative analysis highlighted the benefits of tamoxifen and estriol. The adverse events of tranexamic acid, tacrolimus, propranolol, and estradiol were significantly reported. Propranolol, timolol, tranexamic acid, tamoxifen, and estriol were effective treatments which offered benefits to HHT patients in epistaxis management. Adverse events of tranexamic acid, tacrolimus, propranolol, and estradiol should be concerned.


High dimensional profiling identifies specific immune types along the recovery trajectories of critically ill COVID19 patients.
The COVID-19 pandemic poses a major burden on healthcare and economic systems across the globe. Even though a majority of the population develops only minor symptoms upon SARS-CoV-2 infection, a significant number are hospitalized at intensive care units (ICU) requiring critical care. While insights into the early stages of the disease are rapidly expanding, the dynamic immunological processes occurring in critically ill patients throughout their recovery at ICU are far less understood. Here, we have analysed whole blood samples serially collected from 40 surviving COVID-19 patients throughout their recovery in ICU using high-dimensional cytometry by time-of-flight (CyTOF) and cytokine multiplexing. Based on the neutrophil-to-lymphocyte ratio (NLR), we defined four sequential immunotypes during recovery that correlated to various clinical parameters, including the level of respiratory support at concomitant sampling times. We identified classical monocytes as the first immune cell type to recover by restoration of HLA-DR-positivity and the reduction of immunosuppressive CD163 + monocytes, followed by the recovery of CD8 + and CD4 + T cell and non-classical monocyte populations. The identified immunotypes also correlated to aberrant cytokine and acute-phase reactant levels. Finally, integrative analysis of cytokines and immune cell profiles showed a shift from an initially dysregulated immune response to a more coordinated immunogenic interplay, highlighting the importance of longitudinal sampling to understand the pathophysiology underlying recovery from severe COVID-19.


Pesticide poisoning initially suspected as a natural death.
A pesticide poisoning victim suspected initially as having died a natural death was autopsied. The victim was a 47-year-old male. Macroscopically, signs of acute death and, in particular, general erosion in the mucosa of the airways and esophagus were observed. In the gastric contents, which had a pungent smell and a greenish-brown color, 5.00 g/L of propanil, 1.27 g/L of carbaryl, 0.38 g/L of ethylbenzene, and 0.32 g/L of xylene were detected. In the blood (serum), 21.6 mg/L of propanil, 8.1 mg/L of carbaryl, 1.7 mg/L of ethylbenzene, and 4.0 mg/L of xylene were identified. Postmortem methemoglobinemia (45%) was recognized. The cause of death was considered to have been pesticide poisoning; propanil was probably most responsible for his death. The police considered the case to be "death with illness as the suspected cause." By performing an autopsy, however, we were able to clarify that the cause of death was pesticide poisoning.


Adaptive landscape and functional diversity of Neotropical cichlids: implications for the ecology and evolution of Cichlinae (Cichlidae; Cichliformes).
Morphological, lineage and ecological diversity can vary substantially even among closely related lineages. Factors that influence morphological diversification, especially in functionally relevant traits, can help to explain the modern distribution of disparity across phylogenies and communities. Multivariate axes of feeding functional morphology from 75 species of Neotropical cichlid and a stepwise-AIC algorithm were used to estimate the adaptive landscape of functional morphospace in Cichlinae. Adaptive landscape complexity and convergence, as well as the functional diversity of Cichlinae, were compared with expectations under null evolutionary models. Neotropical cichlid feeding function varied primarily between traits associated with ram feeding vs. suction feeding/biting and secondarily with oral jaw muscle size and pharyngeal crushing capacity. The number of changes in selective regimes and the amount of convergence between lineages was higher than expected under a null model of evolution, but convergence was not higher than expected under a similarly complex adaptive landscape. Functional disparity was compatible with an adaptive landscape model, whereas the distribution of evolutionary change through morphospace corresponded with a process of evolution towards a single adaptive peak. The continentally distributed Neotropical cichlids have evolved relatively rapidly towards a number of adaptive peaks in functional trait space. Selection in Cichlinae functional morphospace is more complex than expected under null evolutionary models. The complexity of selective constraints in feeding morphology has likely been a significant contributor to the diversity of feeding ecology in this clade.


Chymotryptic inhibitor I from potatoes. The amino acid sequence of subunit A.
The amino acid sequence of subunit A of the potato chymotryptic inhibitor I was determined. The sequence was deduced from analysis of fragments and peptides derived from the protein by cleavage with cyanogen bromide, N-bromosuccinimide and dilute acid, and by digestion with trypsin, thermolysin, pepsin and papain. The molecule consists of a single polypeptide chain of 84 residues, which contains two homologous regions each of 13 amino acids. The protein does not appear to be homologous with any other known proteinase inhibitors.


Plasma and erythrocyte fatty acid patterns in patients with recurrent depression: a matched case-control study.
The polyunsaturated fatty acid (PUFA) composition of (nerve) cell membranes may be involved in the pathophysiology of depression. Studies so far, focussed mainly on omega-3 and omega-6 PUFAs. In the present study, saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) and PUFAs of the omega-3, -6 and -9 series in plasma and erythrocytes of patients with recurrent major depressive disorder (MDD-R) were compared with controls. We carried out a case-control study. The sample consisted of 137 patients with MDD-R and 65 matched non-depressed controls. In plasma and erythrocytes of patients with MDD-R the concentrations of most of the SFAs and MUFAs, and additionally erythrocyte PUFAs, all with a chain length > 20 carbon (C) atoms, were significantly lower than in the controls. In contrast, the concentrations of most of the shorter chain members (< or = 18C) of the SFAs and MUFAs were significantly higher in the patients. Estimated activities of several elongases in plasma of patients were significantly altered, whereas delta-9 desaturase activity for C14:0 and C18:0 was significantly higher. The fatty acid status of patients with MDD-R not only differs with regard to omega-3 and omega-6 PUFAs, but also concerns other fatty acids. These alterations may be due to: differences in diet, changes in synthesizing enzyme activities, higher levels of chronic (oxidative) stress but may also result from adaptive strategies by providing protection against enhanced oxidative stress and production of free radicals.


Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy.
We performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations and discovered putative tumor suppressor genes by determining homozygous deletions and loss of heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53, and DIS3 (particularly in nonhyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g., KRAS, NRAS, and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of nonmutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions.


A deletion in the PHYD gene of the Arabidopsis Wassilewskija ecotype defines a role for phytochrome D in red/far-red light sensing.
The PHYD gene of the Wassilewskija (Ws) ecotype of Arabidopsis contains a 14-bp deletion (the phyD-1 mutation) beginning at amino acid 29 of the reading frame, resulting in translation termination at a nonsense codon 138 nucleotides downstream of the deletion end point. Immunoblot analyses showed that Ws lacks phyD but contains normal levels of phyA, phyB, and phyC. By backcrossing into the Ws and Landsberg erecta genetic backgrounds, we constructed sibling pairs of PHYD+ and phyD-1 lines and of phyB- PHYD+ and phyB- phyD- lines. Hypocotyl lengths after growth under white or red light increased sequentially in strains that were B+D+, B+D-, B-D+, and B-D-. In the Ws genetic background, an increase in petiole length, a reduction in cotyledon area and in anthocyanin accumulation in seedling stems, a diminished effect of an end-of-day pulse of far-red light on hypocotyl elongation, and a decrease in the number of rosette leaves at the onset of flowering were also seen sequentially in these lines. Thus, phyD, which is approximately 80% identical in amino acid sequence to phyB, acts in conjunction with phyB in regulating many shade avoidance responses. The existence of the apparently naturally occurring phyD-1 mutation indicates that phyD is not essential in some natural environments.


Characteristics, management, and outcomes of patients with hepatocellular carcinoma in Africa: a multicountry observational study from the Africa Liver Cancer Consortium.
Hepatocellular carcinoma is a leading cause of cancer-related death in Africa, but there is still no comprehensive description of the current status of its epidemiology in Africa. We therefore initiated an African hepatocellular carcinoma consortium aiming to describe the clinical presentation, management, and outcomes of patients with hepatocellular carcinoma in Africa. We did a multicentre, multicountry, retrospective observational cohort study, inviting investigators from the African Network for Gastrointestinal and Liver Diseases to participate in the consortium to develop hepatocellular carcinoma research databases and biospecimen repositories. Participating institutions were from Cameroon, Egypt, Ethiopia, Ghana, Ivory Coast, Nigeria, Sudan, Tanzania, and Uganda. Clinical information-demographic characteristics, cause of disease, liver-related blood tests, tumour characteristics, treatments, last follow-up date, and survival status-for patients diagnosed with hepatocellular carcinoma between Aug 1, 2006, and April 1, 2016, were extracted from medical records by participating investigators. Because patients from Egypt showed differences in characteristics compared with patients from the other countries, we divided patients into two groups for analysis; Egypt versus other African countries. We undertook a multifactorial analysis using the Cox proportional hazards model to identify factors affecting survival (assessed from the time of diagnosis to last known follow-up or death). We obtained information for 2566 patients at 21 tertiary referral centres (two in Egypt, nine in Nigeria, four in Ghana, and one each in the Ivory Coast, Cameroon, Sudan, Ethiopia, Tanzania, and Uganda). 1251 patients were from Egypt and 1315 were from the other African countries (491 from Ghana, 363 from Nigeria, 277 from Ivory Coast, 59 from Cameroon, 51 from Sudan, 33 from Ethiopia, 21 from Tanzania, and 20 from Uganda). The median age at which hepatocellular carcinoma was diagnosed significantly later in Egypt than the other African countries (58 years [IQR 53-63] vs 46 years [36-58]; p<0·0001). Hepatitis C virus was the leading cause of hepatocellular carcinoma in Egypt (1054 [84%] of 1251 patients), and hepatitis B virus was the leading cause in the other African countries (597 [55%] of 1082 patients). Substantially fewer patients received treatment specifically for hepatocellular carcinoma in the other African countries than in Egypt (43 [3%] of 1315 vs 956 [76%] of 1251; p<0·0001). Among patients with survival information (605 [48%] of 1251 in Egypt and 583 [44%] of 1315 in other African countries), median survival was shorter in the other African countries than in Egypt (2·5 months [95% CI 2·0-3·1] vs 10·9 months [9·6-12·0]; p<0·0001). Factors independently associated with poor survival were: being from an African countries other than Egypt (hazard ratio [HR] 1·59 [95% CI 1·13-2·20]; p=0·01), hepatic encephalopathy (2·81 [1·72-4·42]; p=0·0004), diameter of the largest tumour (1·07 per cm increase [1·04-1·11]; p<0·0001), log α-fetoprotein (1·10 per unit increase [1·02-1·20]; p=0·0188), Eastern Cooperative Oncology Group performance status 3-4 (2·92 [2·13-3·93]; p<0·0001) and no treatment (1·79 [1·44-2·22]; p<0·0001). Characteristics of hepatocellular carcinoma differ between Egypt and other African countries. The proportion of patients receiving specific treatment in other African countries was low and their outcomes were extremely poor. Urgent efforts are needed to develop health policy strategies to decrease the burden of hepatocellular carcinoma in Africa. None.


Indirect fluorescent-antibody and quantitative agar-gel immunodiffusion tests for the serological diagnosis of paracoccidioidomycosis.
The value of various serological tests in the diagnosis of paracoccidioidomycosis was studied. Quantitative agar-gel immunodiffusion and indirect immunofluorescent tests were performed, and the results were compared with those of complement fixation and qualitative agar-gel procedures. The quantitative immunodiffusion procedure was found to serve as the simplest and safest quantitative test that could be performed for evaluation purposes, whereas the indirect fluorescent-antibody test gave nonspecific reactions and, as such, proved unsuitable.


Immunocytochemical localization of glucocorticoid receptor in human gingival fibroblasts and evidence for a colocalization of glucocorticoid receptor with cytoplasmic microtubules.
The cellular distribution of the glucocorticoid receptor (GR) in relation to various intracellular and plasma membrane structures in human fibroblasts was studied using indirect immunofluorescence techniques with monoclonal and polyclonal antibodies. During interphase, GR was located predominantly in the cytoplasm, showing a similar pattern as tubulin. In mitotic cells, GR and tubulin were localized in mitotic spindles and in telophase midbodies. Colchicine and vinblastine induced a similar redistribution of GR and tubulin to the cell periphery. This redistribution was reversible for colchicine but not for vinblastine. Vinblastine also induced paracrystals containing GR and tubulin. These results support the hypothesis that GR interacts in vivo with cytoplasmic microtubules.


Polymeric photosensitizer prodrugs for photodynamic therapy.
A targeting strategy based on the selective enzyme-mediated activation of polymeric photosensitizer prodrugs (PPP) within pathological tissue has led to the development of agents with the dual ability to detect and treat cancer. Herein, a detailed study of a simple model system for these prodrugs is described. We prepared "first-generation" PPP by directly tethering the photosensitizer (PS) pheophorbide a to poly-(L)-lysine via epsilon amide links and observed that by increasing the number of PS on a polymer chain, energy transfer between PS units improved leading to better quenching efficiency. Fragmentation of the PPP backbone by trypsin digestion gave rise to a pronounced fluorescence increase and to more efficient generation of reactive oxygen species upon light irradiation. In vitro tests using the T-24 bladder carcinoma cell line and ex vivo experiments using mouse intestines illustrated the remarkable and selective ability of these PPP to fluoresce and induce phototoxicity upon enzymatic activation. This work elucidated the basic physicochemical parameters, such as water solubility and quenching/activation behavior, required for the future elaboration of more adaptable "second-generation" PPP, in which the PS is tethered to a proteolytically stable polymer backbone via enzyme-specific peptide linkers. This polymer architecture offers great flexibility to tailor make the PPP to target any pathological tissue known to over-express a specific enzyme.


De novo intrarenal formation of angiotensin II during control and enhanced renin secretion.
In previous studies it has not been possible to determine net intrarenal formation of angiotensin II (ANG II) from arteriovenous ANG II concentrations because of the high intrarenal ANG II degradation rates (DR). This study was designed to determine ANG II-DR and to estimate net intrarenal ANG II formation during normal and enhanced renin secretion rate (RSR). In anesthetized dogs, plasma renin activity and ANG II were measured in arterial and renal venous blood by radioimmunoassay during four periods: control, renal arterial constriction (RAC), angiotensin converting enzyme (ACE) inhibition (MK 422), and MK 422 plus systemic arterial ANG II infusion. ANG II-DR was determined in each dog from the arterial-renal venous ANG II concentration difference during the period of ANG II infusion in the presence of ACE inhibition; this value was used to estimate net ANG II formation by predicting the amount of arterially delivered ANG II that escaped degradation. The average percent ANG II-DR calculated during ANG II infusion (range of 0.05 to 0.20 microgram/min) was 89 +/- 2%. In response to RAC, RSR increased from 11 +/- 3 to 24 +/- 5 ng ANG I X h-1 X min-1 X g-1. Arterial ANG II (67 +/- 11 pg/ml) and renal venous ANG II (29 +/- 6 pg/ml) increased to 133 +/- 18 and 61 +/- 10 pg/ml, respectively. Net intrarenal ANG II formation increased from 44 +/- 11 to 83 +/- 13 pg X min-1 X g-1 after renal arterial constriction. There was a significant relationship between the change in RSR and the change in ANG II formation rate.(ABSTRACT TRUNCATED AT 250 WORDS)


Arthritis Rounds: Ascites as the major manifestation of systemic lupus erythematosus.
It is uncommon for ascites secondary to severe peritoneal inflammation to be the major manifestation of systemic lupus erythematosus. Chronic nonspecific inflammation with a granular type immunofluorescent staining along the mesothelial layer of the peritoneum and peritoneal blood vessels was demonstrated in peritoneal tissue obtained at laparotomy. Paramyxovirus-like structures were seen within vascular endothelium. The ascites diminished with high-dose prednisone and cyclophosphamide therapy.


Trends in radiation exposure from clinical nuclear medicine procedures in Shanghai, China.
This study was designed to assess the trends in the frequencies of nuclear medicine procedures in Shanghai, China, and to determine their contributions to the per capita effective dose to the Shanghai population. The mean activities of radionuclides administered by nuclear medicine departments were compared with the Chinese national guidelines on diagnostic reference levels. On the basis of the three surveys carried out by Shanghai Municipal Center for Disease Control and Prevention in 1996, 1998, and 2008, the typically administered radiopharmaceuticals, levels of activity, the number of procedures, and population were systematically analyzed to assess the frequencies of nuclear medicine procedures and the per capita effective dose. The frequencies were approximately 2.77, 3.46, and 6.63 per 1000 people in 1996, 1998, and 2008, respectively. The annual per capita doses from diagnostic nuclear medicine were estimated to be 0.016, 0.022, and 0.032 mSv in 1996, 1998, and 2008, respectively. The annual frequency of therapeutic nuclear medicine procedures increased from 0.131 to 0.430 per 1000 people in the intervening 12 years. In the 12 years before 2008, diagnostic and therapeutic procedures in nuclear medicine in Shanghai increased continuously, and the annual per capita dose doubled. Increases in PET imaging and bone scans were the major contributors to the increasing frequency and magnitude of radiation exposure to the population. The activities administered for most diagnostic procedures were generally consistent with the designated reference levels.


Association Between Biliary Pathogens, Surgical Site Infection, and Pancreatic Fistula: Results of a Randomized Trial of Perioperative Antibiotic Prophylaxis in Patients Undergoing Pancreatoduodenectomy.
To establish the association between bactibilia and postoperative complications when stratified by perioperative antibiotic prophylaxis. Patients undergoing pancreatoduodenectomy experience high rates of surgical site infection (SSI) and clinically relevant postoperative pancreatic fistula (CR-POPF). Contaminated bile is known to be associated with SSI, but the role of antibiotic prophylaxis in mitigation of infectious risks is ill-defined. Intraoperative bile cultures (IOBCs) were collected as an adjunct to a randomized phase 3 clinical trial comparing piperacillin-tazobactam with cefoxitin as perioperative prophylaxis in patients undergoing pancreatoduodenectomy. After compilation of IOBC data, associations between culture results, SSI, and CR-POPF were assessed using logistic regression stratified by the presence of a preoperative biliary stent. Of 778 participants in the clinical trial, IOBC were available for 247 participants. Overall, 68 (27.5%) grew no organisms, 37 (15.0%) grew 1 organism, and 142 (57.5%) were polymicrobial. Organisms resistant to cefoxitin but not piperacillin-tazobactam were present in 95 patients (45.2%). The presence of cefoxitin-resistant organisms, 92.6% of which contained either Enterobacter spp. or Enterococcus spp., was associated with the development of SSI in participants treated with cefoxitin [53.5% vs 25.0%; odds ratio (OR)=3.44, 95% CI: 1.50-7.91; P =0.004] but not those treated with piperacillin-tazobactam (13.5% vs 27.0%; OR=0.42, 95% CI: 0.14-1.29; P =0.128). Similarly, cefoxitin-resistant organisms were associated with CR-POPF in participants treated with cefoxitin (24.1% vs 5.8%; OR=3.45, 95% CI: 1.22-9.74; P =0.017) but not those treated with piperacillin-tazobactam (5.4% vs 4.8%; OR=0.92, 95% CI: 0.30-2.80; P =0.888). Previously observed reductions in SSI and CR-POPF in patients that received piperacillin-tazobactam antibiotic prophylaxis are potentially mediated by biliary pathogens that are cefoxitin resistant, specifically Enterobacter spp. and Enterococcus spp.


Arterial oxygen saturation by non-invasive oximetry technique: an office test for determining jeopardy of status asthmaticus.
A newly developed technique in ear oximetry which can be performed in a doctor's office may obviate the need of sending an asthmatic patient to the hospital for arterial gas blood studies and may be a means of ear marking impending status asthmaticus and respiratory failure.


Factors that limit access to dental care for adults with spinal cord injury.
This study investigated dental care service utilization among adults with spinal cord injury (SCI) and identified barriers and other factors affecting utilization among this population. There were 192 subjects with SCI who participated in the oral health survey assessing dental care service utilization and they were compared with subjects from the 2004 Behavioral Risk Factors Surveillance System (BRFSS). There was no significant difference in the proportion of subjects with SCI who visited the dentist for any reason in the past year compared to the general population (65.5% vs. 68.8%, p= .350). However, subjects with SCI were less likely to go to the dentist for a dental cleaning in the past year compared to the general population (54.6% vs. 69.4%, p < .001). The three most commonly reported barriers to accessing dental care were cost (40.1%), physical barriers (22.9%), and dental fear (15.1%). Multivariate modeling showed that physical barriers and fear of dental visits were the two significant factors deterring subjects from dental visits in the past year. Physical barriers preventing access to dental facilities and dental fear are prevalent and significantly impede the delivery of dental health care to adults with SCI. Dentists should undertake necessary physical remodeling of their facilities to accommodate wheelchair users and implement appropriate strategies for the management of dental fear among patients with SCI.


Time-dependent migratory behaviors in the long-term studies of fibroblast durotaxis on a hydrogel substrate fabricated with a soft band.
Durotaxis, biased cell movement up a stiffness gradient on culture substrates, is one of the useful taxis behaviors for manipulating cell migration on engineered biomaterial surfaces. In this study, long-term durotaxis was investigated on gelatinous substrates containing a soft band of 20, 50, and 150 μm in width fabricated using photolithographic elasticity patterning; sharp elasticity boundaries with a gradient strength of 300 kPa/50 μm were achieved. Time-dependent migratory behaviors of 3T3 fibroblast cells were observed during a time period of 3 days. During the first day, most of the cells were strongly repelled by the soft band independent of bandwidth, exhibiting the typical durotaxis behavior. However, the repellency by the soft band diminished, and more cells crossed the soft band or exhibited other mixed migratory behaviors during the course of the observation. It was found that durotaxis strength is weakened on the substrate with the narrowest soft band and that adherent affinity-induced entrapment becomes apparent on the widest soft band with time. Factors, such as changes in surface topography, elasticity, and/or chemistry, likely contributing to the apparent diminishing durotaxis during the extended culture were examined. Immunofluorescence analysis indicated preferential collagen deposition onto the soft band, which is derived from secretion by fibroblast cells, resulting in the increasing contribution of haptotaxis toward the soft band over time. The deposited collagen did not affect surface topography or surface elasticity but did change surface chemistry, especially on the soft band. The observed time-dependent durotaxis behaviors are the result of the mixed mechanical and chemical cues. In the studies and applications of cell migratory behavior under a controlled stimulus, it is important to thoroughly examine other (hidden) compounding stimuli in order to be able to accurately interpret data and to design suitable biomaterials to manipulate cell migration.


Cardiac Biomarker Levels and Their Prognostic Values in COVID-19 Patients With or Without Concomitant Cardiac Disease.
The coronavirus disease 2019 (COVID-19) pandemic has become a global threat. Increases in cardiac biomarkers are common and are associated with adverse outcomes in patients with COVID-19. Although these increases are more likely to occur in cases with concomitant cardiac disease, the differences in cardiac biomarker levels between patients with and without cardiac disease and their associations with in-hospital mortality are largely unknown. A consecutive serial of laboratory-confirmed COVID-19 cases was retrospectively enrolled. Clinical characteristics, laboratory results, and outcome data were collected. The levels of cardiac biomarkers were evaluated and compared by stratifying patients according to concomitant cardiac conditions and clinical classifications. The prognostic efficacy of cardiac biomarker levels on admission was also assessed. Among the overall study population and survived patients, the cardiac biomarker levels at both the early and late stages in cardiac patients were significantly higher than those in non-cardiac patients. However, their concentrations in cardiac patients were comparable to non-cardiac ones among non-survivors. The cardiac biomarker levels at the late stage of the disease were significantly decreased compared to those at the early stage among patients who were alive. Whereas, the late-stage biomarker levels were significantly increased in patients who ultimately died. Subgroup analysis illustrated that increases in cardiac biomarkers were closely related to the severity of the disease, and were prognostic for high risks of in-hospital mortality in non-cardiac, rather than in cardiac patients. Myo and NT-proBNP, rather than Hs-TnI and CK-MB, were independently associated with in-hospital mortality in the overall population and non-cardiac patients. However, these associations were not significant among cardiac patients. In conclusion, our results helped better understand the release pattern and prognostic performance of cardiac biomarkers in patients with COVID-19. Increased levels of Myo and NT-proBNP on admission could be useful markers for early identifying high-risk patients. However, special attention must be paid when implementing the prognostic function for cardiac patients.


On the construction of diabatic and adiabatic potential energy surfaces based on ab initio valence bond theory.
A theoretical model is presented for deriving effective diabatic states based on ab initio valence bond self-consistent field (VBSCF) theory by reducing the multiconfigurational VB Hamiltonian into an effective two-state model. We describe two computational approaches for the optimization of the effective diabatic configurations, resulting in two ways of interpreting such effective diabatic states. In the variational diabatic configuration (VDC) method, the energies of the diabatic states are variationally minimized. In the consistent diabatic configuration (CDC) method, both the configuration coefficients and orbital coefficients are simultaneously optimized to minimize the adiabatic ground-state energy in VBSCF calculations. In addition, we describe a mixed molecular orbital and valence bond (MOVB) approach to construct the CDC diabatic and adiabatic states for a chemical reaction. Note that the VDC-MOVB method has been described previously. Employing the symmetric S(N)2 reaction between NH(3) and CH(3)NH(3)(+) as a test system, we found that the results from ab initio VBSCF and from ab initio MOVB calculations using the same basis set are in good agreement, suggesting that the computationally efficient MOVB method is a reasonable model for VB simulations of condensed phase reactions. The results indicate that CDC and VDC diabatic states converge, respectively, to covalent and ionic states as the molecular geometries are distorted from the minimum of the respective diabatic state along the reaction coordinate. Furthermore, the resonance energy that stabilizes the energy of crossing between the two diabatic states, resulting in the transition state of the adiabatic ground-state reaction, has a strong dependence on the overlap integral between the two diabatic states and is a function of both the exchange integral and the total diabatic ground-state energy.


Eradication of hepatitis C virus reduces the risk of hepatocellular carcinoma in patients with compensated cirrhosis.
The effect of a sustained virological response (SVR) to interferon (IFN) on clinical outcomes of hepatitis C virus (HCV)-related cirrhosis is controversial. Evaluate the effect of SVR to IFN on the incidence of hepatocellular carcinoma (HCC) and mortality in patients with compensated HCV-induced cirrhosis. A cohort of 130 consecutive patients (92 men, mean age 51.7 years) with histologically proven cirrhosis who received one or more courses of IFN monotherapy or combination therapy with ribavirin were analyzed. SVR was defined as undetectable serum HCV RNA by real-time polymerase chain reaction (PCR) 24 weeks after IFN discontinuation. HCC was assessed by alfa-fetoprotein and ultrasound every 6 months. Predictors of clinical outcomes, defined as HCC, orthotopic liver transplantation (OLT) and mortality, were assessed by Cox regression analysis. The mean follow-up was 6.4 ± 4.0 years (range 1-18). HCC developed in 21 patients: one with SVR versus 20 with non-SVR (P = 0.017). Logistic regression analysis showed that non-SVR (odds ratio [OR] = 27.0; confidence interval [CI], 1.6-452.1), male (OR = 11.6; CI, 1.8-75.4), and greater number of treatments (OR = 4.7; CI, 1.4-16.0) increased the probability of HCC development. Multivariate analysis found that SVR was associated with lower risk of HCC (HR 0.09; CI, 0.01-0.77), OLT (HR 0.04; CI, 0.003-0.63) and any event (HR 0.11; CI, 0.02-0.46) as compared to non-SVR. In compensated HCV-related cirrhosis, SVR markedly reduces the risk of HCC and improves survival. Clearance of the virus should be intensively attempted in these patients.


Novel discovery of LYVE-1 expression in the hyaloid vascular system.
The hyaloid vascular system (HVS) is a transient network nourishing developing eyes and has been widely used as a natural model to study blood vessel regression. Failure of its regression in humans leads to several blinding diseases. Lymphatic vessel endothelial hyaluronic acid receptor (LYVE-1) is a recently defined lymphatic marker that is also expressed by a subpopulation of macrophages. To date, there is no report on its expression in the HVS. This study was conducted to investigate whether LYVE-1 is expressed in the HVS and how it is associated with the vascular structure and macrophage phenotype. Normal C57BL/6 mouse eyeballs were sampled from embryonic day (E) 10.5 to postnatal (P) and adult stages for immunofluorescent microscopic studies with antibodies against LYVE-1, CD31 (panendothelial cell marker), and F4/80 (macrophage marker). Additionally, Angiopoietin-2 (Ang-2) knockout mice with abnormally persistent HVS were examined. The LYVE-1 expression was detected on normal HVS between E12.5 and P14. The LYVE-1(+) cells were F4/80(+) but CD31(-), indicating a macrophage lineage. Additionally, LYVE-1(+) cells bud on CD31(+) vessels and constitute an integral part of the network in both normal developing and Ang-2 knockout mice. This study provides the first evidence that the HVS contains a LYVE-1(+) cellular component in both physiological and pathologic conditions. This novel finding not only provides a new concept in defining the embryogenesis and pathogenesis of the HVS, it also leads to a completely natural model in which to study the functions of the LYVE-1 pathway, an important topic for lymphatic research as well.


Induction of cytochrome P450 1a1 by the food flavoring agent, maltol.
Maltol is used extensively as a flavor-enhancing agent, food preservative, antioxidant, and also in cosmetic and pharmaceutical formulations. However, a number of studies have shown that maltol may induce carcinogenicity and toxicity but the mechanisms involved remain unknown. Therefore, we examined the ability of maltol to induce the cytochrome P450 1a1 (Cyp1a1), an enzyme known to play an important role in the chemical activation of xenobiotics to carcinogenic derivatives. Our results showed that treatment of Hepa 1c1c7 cells with maltol significantly induced Cyp1a1 at mRNA, protein, and activity levels in a concentration-dependent manner. The RNA synthesis inhibitor, actinomycin D, completely blocked the Cyp1a1 mRNA induction by maltol, indicating a requirement of de novo RNA synthesis through transcriptional activation. In addition, maltol induced aryl hydrocarbon receptor (AhR)-dependent luciferase reporter gene expression in stably transfected H1L1.1c2 cells, suggesting an AhR-dependent mechanism. This is the first demonstration that the food flavoring agent, maltol, can directly induce Cyp1a1 gene expression in an AhR-dependent manner and represents a novel mechanism by which maltol promotes carcinogenicity and toxicity.


Prenatal alcohol exposure and interhemispheric transfer of tactile information: Detroit and Cape Town findings.
Previous research has demonstrated that heavy prenatal alcohol exposure affects the size and shape of the corpus callosum (CC) and compromises interhemispheric transfer of information. The aim of this study was to confirm the previous reports of poorer performance on a finger localization test (FLT) of interhemispheric transfer in a cohort of heavily exposed children and to extend these findings to a cohort of moderately exposed young adults. In Study 1, the FLT was administered to 40 heavily exposed and 23 nonexposed children from the Cape Coloured community of Cape Town, South Africa, who were evaluated for fetal alcohol syndrome (FAS) dysmorphology and growth. Anatomical images of the CC were obtained using structural MRI on a subset of these children. In Study 2, the FLT was administered to a cohort of 85 moderate-to-heavily exposed young adults participating in a 19-year follow-up assessment of the Detroit Prenatal Alcohol Exposure cohort, whose alcohol exposure had been ascertained prospectively during gestation. In Study 1, children with FAS showed more transfer-related errors than controls after adjustment for confounding, and increased transfer-related errors were associated with volume reductions in the isthmus and splenium of the CC. In Study 2, transfer-related errors were associated with quantity of alcohol consumed per occasion during pregnancy. More errors were made if the mother reported binge drinking (> or =5 standard drinks) during pregnancy than if she drank regularly (M > or = 1 drink/day) without binge drinking. These findings confirm a previous report of impaired interhemispheric transfer of tactile information in children heavily exposed to alcohol in utero and extend these findings to show that these deficits are also seen in more moderately exposed individuals, particularly those exposed to binge-like pregnancy drinking.


Parallel Genomics Uncover Novel Enterococcal-Bacteriophage Interactions.
Bacteriophages (phages) have been proposed as alternative therapeutics for the treatment of multidrug-resistant bacterial infections. However, there are major gaps in our understanding of the molecular events in bacterial cells that control how bacteria respond to phage predation. Using the model organism Enterococcus faecalis, we used two distinct genomic approaches, namely, transposon library screening and RNA sequencing, to investigate the interaction of E. faecalis with a virulent phage. We discovered that a transcription factor encoding a LytR family response regulator controls the expression of enterococcal polysaccharide antigen (epa) genes that are involved in phage infection and bacterial fitness. In addition, we discovered that DNA mismatch repair mutants rapidly evolve phage adsorption deficiencies, underpinning a molecular basis for epa mutation during phage infection. Transcriptomic profiling of phage-infected E. faecalis revealed broad transcriptional changes influencing viral replication and progeny burst size. We also demonstrate that phage infection alters the expression of bacterial genes associated with intra- and interbacterial interactions, including genes involved in quorum sensing and polymicrobial competition. Together, our results suggest that phage predation has the potential to influence complex microbial behavior and may dictate how bacteria respond to external environmental stimuli. These responses could have collateral effects (positive or negative) on microbial communities, such as the host microbiota, during phage therapy.IMPORTANCE We lack fundamental understanding of how phage infection influences bacterial gene expression and, consequently, how bacterial responses to phage infection affect the assembly of polymicrobial communities. Using parallel genomic approaches, we have discovered novel transcriptional regulators and metabolic genes that influence phage infection. The integration of whole-genome transcriptomic profiling during phage infection has revealed the differential regulation of genes important for group behaviors and polymicrobial interactions. Our work suggests that therapeutic phages could more broadly influence bacterial community composition outside their intended host targets.


A SNAI2/CTCF Interaction is Required for NOTCH1 Expression in Rhabdomyosarcoma.
Rhabdomyosarcoma (RMS) is a pediatric malignancy of the muscle with characteristics of cells blocked in differentiation. NOTCH1 is an oncogene that promotes self-renewal and blocks differentiation in the fusion negative-RMS sub-type. However, how NOTCH1 expression is transcriptionally maintained in tumors is unknown. Analyses of SNAI2 and CTCF chromatin binding and HiC analyses revealed a conserved SNAI2/CTCF overlapping peak downstream of the NOTCH1 locus marking a sub-topologically associating domain (TAD) boundary. Deletion of the SNAI2-CTCF peak showed that it is essential for NOTCH1 expression and viability of FN-RMS cells. Reintroducing constitutively activated NOTCH1-ΔE in cells with the SNAI2-CTCF peak deleted restored cell-viability. Ablation of SNAI2 using CRISPR/Cas9 reagents resulted in the loss of majority of RD and SMS-CTR FN-RMS cells. However, the few surviving clones that repopulate cultures have recovered NOTCH1. Cells that re-establish NOTCH1 expression after SNAI2 ablation are unable to differentiate robustly as SNAI2 shRNA knockdown cells; yet, SNAI2-ablated cells continued to be exquisitely sensitive to ionizing radiation. Thus, we have uncovered a novel mechanism by which SNAI2 and CTCF maintenance of a sub-TAD boundary promotes rather than represses NOTCH1 expression. Further, we demonstrate that SNAI2 suppression of apoptosis post-radiation is independent of SNAI2/NOTCH1 effects on self-renewal and differentiation.


MCL-1 Inhibition by Selective BH3 Mimetics Disrupts Mitochondrial Dynamics Causing Loss of Viability and Functionality of Human Cardiomyocytes.
MCL-1 is a well-characterized inhibitor of cell death that has also been shown to be a regulator of mitochondrial dynamics in human pluripotent stem cells. We used cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) to uncover whether MCL-1 is crucial for cardiac function and survival. Inhibition of MCL-1 by BH3 mimetics resulted in the disruption of mitochondrial morphology and dynamics as well as disorganization of the actin cytoskeleton. Interfering with MCL-1 function affects the homeostatic proximity of DRP-1 and MCL-1 at the outer mitochondrial membrane, resulting in decreased functionality of hiPSC-CMs. Cardiomyocytes display abnormal cardiac performance even after caspase inhibition, supporting a nonapoptotic activity of MCL-1 in hiPSC-CMs. BH3 mimetics targeting MCL-1 are promising anti-tumor therapeutics. Progression toward using BCL-2 family inhibitors, especially targeting MCL-1, depends on understanding its canonical function not only in preventing apoptosis but also in the maintenance of mitochondrial dynamics and function.


An investigation of computer literacy and attitudes amongst Greek post-graduate dental students.
An accurate assessment of the computer skills of students is a pre-requisite for the success of any e-learning interventions. The aim of the present study was to assess objectively the computer literacy and attitudes in a group of Greek post-graduate students, using a task-oriented questionnaire developed and validated in the University of Malmö, Sweden. 50 post-graduate students in the Athens University School of Dentistry in April 2005 took part in the study. A total competence score of 0-49 was calculated. Socio-demographic characteristics were recorded. Attitudes towards computer use were assessed. Descriptive statistics and linear regression modeling were employed for data analysis. Total competence score was normally distributed (Shapiro-Wilk test: W = 0.99, V = 0.40, P = 0.97) and ranged from 5 to 42.5, with a mean of 22.6 (+/-8.4). Multivariate analysis revealed 'gender', 'e-mail ownership' and 'enrollment in non-clinical programs' as significant predictors of computer literacy. Conclusively, computer literacy of Greek post-graduate dental students was increased amongst males, students in non-clinical programs and those with more positive attitudes towards the implementation of computer assisted learning.


Dichoptic viewing methods for binocular rivalry research: prospects for large-scale clinical and genetic studies.
Binocular rivalry (BR) is an intriguing phenomenon that occurs when two different images are presented, one to each eye, resulting in alternation or rivalry between the percepts. The phenomenon has been studied for nearly 200 years, with renewed and intensive investigation over recent decades. The rate of perceptual switching has long been known to vary widely between individuals but to be relatively stable within individuals. A recent twin study demonstrated that individual variation in BR rate is under substantial genetic control, a finding that also represented the first report, using a large study, of genetic contribution for any post-retinal visual processing phenomenon. The twin study had been prompted by earlier work showing BR rate was slow in the heritable psychiatric condition, bipolar disorder (BD). Together, these studies suggested that slow BR may represent an endophenotype for BD, and heralded the advent of modern clinical and genetic studies of rivalry. This new focus has coincided with rapid advances in 3D display technology, but despite such progress, specific development of technology for rivalry research has been lacking. This review therefore compares different display methods for BR research across several factors, including viewing parameters, image quality, equipment cost, compatibility with other investigative methods, subject group, and sample size, with a focus on requirements specific to large-scale clinical and genetic studies. It is intended to be a resource for investigators new to BR research, such as clinicians and geneticists, and to stimulate the development of 3D display technology for advancing interdisciplinary studies of rivalry.


Sexual desire discrepancy as a feature, not a bug, of long-term relationships: women's self-reported strategies for modulating sexual desire.
Sexual desire discrepancy is commonly reported by couples in long-term romantic relationships. Given the idiosyncratic nature of desire, and the lack of a "one size fits all" model approach to address desire concerns, it is useful to understand more about the range of ways that women and their partners modulate sexual desire. This study aims to assess women's strategies to influence their sexual desire and the self-reported effectiveness of these strategies. One hundred seventy-nine women who had been in a relationship with a male partner for 5+ years completed an anonymous Internet-based survey. Participants responded to three open-ended items about the strategies they use to address desire issues and how helpful those strategies are. The most common responses regarding what participants did to get desire back on track included: communication, trying to meet partner's needs, having sex without desire, and having patience/letting time work out the problem. Women also mentioned several specific strategies they had employed: communication, scheduling sex, lingerie, and a date night. However, a large number of women discussed that the issue was not resolved, and they were dissatisfied with attempted strategies. This research provides valuable insight into the construction of women's sexual desire and the strategies used to navigate sexual desire in long-term relationships.


Stimulus-selective induction of the orphan nuclear receptor NGFIB underlies different influences of angiotensin II and potassium on the human adrenal gland zona glomerulosa-specific 3β-HSD isoform gene expression in adrenocortical H295R cells.
In the adrenal, the type I 3β-hydroxysteroid dehydrogenase (HSD3B1) is expressed exclusively in the zona glomerulosa (ZG), where aldosterone is produced. Angiotensin II (AngII) and potassium (K(+)) are the major physiological regulators of aldosterone synthesis. However, their respective roles in regulation of aldosterone synthesis are not fully defined, particularly in terms of transcriptional regulation of steroidogenic enzyme genes. We previously showed that AngII can stimulate expression of HSD3B1. But, K(+) responsiveness of this gene has remained unexplored. Here, we report that K(+) stimulation lacks the ability to induce HSD3B1 expression in human adrenocortical H295R cells. Both AngII and K(+) were able to enhance transcription of the aldosterone synthase gene (CYP11B2). Promoter analysis revealed that although both AngII and K(+) activate transcription from the Ca(2+)/cAMP-responsive element (CRE) located in the CYP11B2 promoter, the orphan nuclear receptor NGFIB-responsive element (NBRE) located in the HSD3B1 promoter fails to respond to K(+), being only able to enhance transcription after AngII treatment. We found that induction of de novo protein synthesis of NGFIB occurs only after AngII treatment. This sharply contrasts with the phosphorylation that occurs in response to both AngII and K(+) on the CREB/ATF family transcription factor ATF2. Chromatin immunoprecipitation assay confirmed that the NGFIB protein occupies the HSD3B1 promoter only after AngII, while ATF2 binds to the CYP11B2 promoter in response to both AngII and K(+). These data provide evidence that downstream signals from AngII and K(+) can be uncoupled in the regulation of HSD3B1 in the human adrenocortical H295R cells.


Effect of ethanol on liver triglycerides and fatty acid composition in the golden Syrian hamster.
In choice situations, the golden Syrian hamster shows a strong preference to drink an ethanol solution to water alone. Because of the known effects of ethanol on lipid metabolism, its effects on liver fatty acids were therefore studied in the hamster. After a period of 8 weeks during which hamsters had consumed water containing 10% ethanol (4 weeks) and then 15% ethanol (4 weeks), the liver was significantly increased in weight, an effect which was shown to be due to fat accumulation as triglyceride. The fatty acid composition of the liver triglycerides and phospholipids was altered such that monounsaturated fatty acids were very significantly increased and both n-6 and n-3 essential fatty acids were proportionally decreased.


Lactic acid bacteria as a surface display platform for Campylobacter jejuni antigens.
Food poisoning and diarrheal diseases continue to pose serious health care and socioeconomic problems worldwide. Campylobacter spp. is a very widespread cause of gastroenteritis. Over the past decade there has been increasing interest in the use of lactic acid bacteria (LAB) as mucosal delivery vehicles. They represent an attractive opportunity for vaccination in addition to vaccination with attenuated bacterial pathogens. We examined the binding ability of hybrid proteins to nontreated or trichloroacetic acid (TCA)-pretreated LAB cells by immunofluorescence and Western blot analysis. In this study we evaluated the possibility of using GEM (Gram-positive enhancer matrix) particles of Lactobacillus salivarius as a binding platform for 2 conserved, immunodominant, extracytoplasmic Campylobacter jejuni proteins: CjaA and CjaD. We analyzed the binding ability of recombinant proteins that contain C. jejuni antigens (CjaA or CjaD) fused with the protein anchor (PA) of the L. lactis peptidoglycan hydrolase AcmA, which comprises 3 LysM motifs and determines noncovalent binding to the cell wall peptidoglycan. Both fused proteins, i.e. 6HisxCjaAx3LysM and 6HisxCjaDx3LysM, were able to bind to nontreated or TCA-pretreated L. salivarius cells. Our results documented that the LysM-mediated binding system allows us to construct GEM particles that present 2 C. jejuni antigens.


Voltage-independent KCNQ4 currents induced by (+/-)BMS-204352.
The compound BMS-204352 has been targeted for use against acute ischemic stroke, due to its activation of the large-conductance Ca2+-activated K-channel (BK). We have previously described that the racemate (+/-)BMS-204352 reversibly modulates KCNQ4 voltage dependency. Here we show that (+/-)BMS-204352 also induces a voltage-independent KCNQ4 current. The channels were stably expressed in human embryonic kidney cells (HEK293), and investigated by use of the whole-cell mode of the patch-clamp technique. (+/-)BMS-204352 was applied extracellularly (10 microM) in order to precipitate the robust appearance of the voltage-independent current. The voltage-independent KCNQ4 currents were recorded as instantaneous increases in currents upon hyperpolarizing or depolarizing voltage steps elicited from holding potentials of -90 or -110 mV. The voltage-independent current reversed at the equilibrium potential for potassium ( E(K)), hence was carried by a K+ conductance, and was blocked by the selective KCNQ channel blockers XE991 and linopirdine. Similar results were obtained with KCNQ4 channels transiently transfected into Chinese hamster ovary cells (CHO). When (+/-)BMS-204352 was applied to stably expressed BK channels, only the voltage dependency was modulated. Retigabine, the classic activator of KCNQ channels, did not induce voltage-independent currents. Our data indicate that KCNQ4 channels may conduct voltage-dependent and voltage-independent currents in the presence of (+/-)BMS-204352.


Laparoscopy and oncology: where do we stand today?
The clinical application of laparoscopic surgery has grown rapidly over the last few years. Since the first documentations of laparoscopic lymphadenectomy, many reports highlight the use of modern laparoscopy in the field of gynecologic oncology. Laparoscopic treatment of early-stage cervical and endometrial cancer, and laparoscopic evaluation and staging of cervical, ovarian, and endometrial carcinomas, are feasible procedures. The place of minimal-access surgery in the arsenal of gynecologic oncological surgery has been established, especially after the recent developments and practical application of video laparoscopy, novel instrumentation, and advanced surgical techniques. Although operative laparoscopy in gynecologic oncology is still in its infancy the potentiality of the procedure is underscored. Many patients may benefit from the treatment or staging of gynecologic malignancies with laparoscopic means. Literature reports highlight that laparoscopy may be an effective procedure with lower morbidity and complication rates than traditional abdominal surgery. The short hospital stay and recovery time have a positive impact in a cancer patient's quality of life, as they return to normal activities rapidly. Many risks, though, may arise from the application of minimal-access surgery in cancer patients, and many questions regarding safety and efficacy need answers, based on prospective clinical trials. We must emphasize that such studies with large patient numbers and long-term follow-up are lacking. Until results from these trials are available, laparoscopic oncologic procedures should be performed only in an investigational setting by expert teams.


Addressing Vaccination Hesitancy in Psychotherapy.
Vaccine hesitancy refers to delay in acceptance or refusal of vaccination despite availability of vaccination series. The majority of psychologists reported that they do not anticipate resuming in-person service delivery until after a vaccine was available. There are currently no best practice guidelines for making the transition back to in-office practice after the COVID-19 pandemic. This article provides some initial thoughts on relevant dimensions to consider. These include utilization of the core CDC behavioral practices of mask use and social distancing and cleaning surfaces. Psychologists are also encouraged to set positive expectations about vaccination, state clear expectations of vaccination for in-office care, actively listen to patient doubts about vaccinations, and actively exploring patient understanding of the COVID-19 disease processes and prevention efforts.


Do clinical clerks provide candidates with adequate formative assessment during Objective Structured Clinical Examinations?
Various research studies have examined the question of whether expert or non-expert raters, faculty or students, evaluators or standardized patients, give more reliable and valid summative assessments of performance on Objective Structured Clinical Examinations (OSCEs). Less studied has been the question of whether or not non-faculty raters can provide formative feedback that allows students to take advantage of the educational opportunity that OSCEs provide. This question is becoming increasingly important, however, as the strain on faculty resources increases. A questionnaire was developed to assess the quality of feedback that medical examiners provide during OSCEs. It was pilot tested for reliability using video recordings of OSCE performances. The questionnaires were then used to evaluate the feedback given during an actual OSCE in which clinical clerks, residents, and faculty were used as examiners on two randomly selected test stations. The inter-rater reliability of the 19-item feedback questionnaire was 0.69 during the pilot test. The internal consistency was found to be 0.90 during pilot testing and 0.95 in the real OSCE. Using this form, the feedback ratings assigned to clinical clerks were significantly greater than those assigned to faculty evaluators. Furthermore, performance on the same OSCE stations eight months later was not impaired by having been evaluated by student examiners. While evidence of mark inflation within the clinical clerk examiners should be addressed with examiner training, the current results suggest that clerks are capable of giving adequate formative feedback to more junior colleagues.


Human milk is a source of lactic acid bacteria for the infant gut.
To investigate whether human breast milk contains potentially probiotic lactic acid bacteria, and therefore, whether it can be considered a synbiotic food. Study design Lactic acid bacteria were isolated from milk, mammary areola, and breast skin of eight healthy mothers and oral swabs and feces of their respective breast-fed infants. Some isolates (178 from each mother and newborn pair) were randomly selected and submitted to randomly amplified polymorphic DNA (RAPD) polymerase chain reaction analysis, and those that displayed identical RAPD patterns were identified by 16S rDNA sequencing. Within each mother and newborn pair, some rod-shaped lactic acid bacteria isolated from mammary areola, breast milk, and infant oral swabs and feces displayed identical RAPD profiles. All of them, independently from the mother and child pair, were identified as Lactobacillus gasseri. Similarly, among coccoid lactic acid bacteria from these different sources, some shared an identical RAPD pattern and were identified as Enterococcus faecium. In contrast, none of the lactic acid bacteria isolated from breast skin shared RAPD profiles with lactic acid bacteria of the other sources. Breast-feeding can be a significant source of lactic acid bacteria to the infant gut. Lactic acid bacteria present in milk may have an endogenous origin and may not be the result of contamination from the surrounding breast skin.


Learning to SMILES: BAN-based strategies to improve latent representation learning from molecules.
Computational methods have become indispensable tools to accelerate the drug discovery process and alleviate the excessive dependence on time-consuming and labor-intensive experiments. Traditional feature-engineering approaches heavily rely on expert knowledge to devise useful features, which could be costly and sometimes biased. The emerging deep learning (DL) methods deliver a data-driven method to automatically learn expressive representations from complex raw data. Inspired by this, researchers have attempted to apply various deep neural network models to simplified molecular input line entry specification (SMILES) strings, which contain all the composition and structure information of molecules. However, current models usually suffer from the scarcity of labeled data. This results in a low generalization ability of SMILES-based DL models, which prevents them from competing with the state-of-the-art computational methods. In this study, we utilized the BiLSTM (bidirectional long short term merory) attention network (BAN) in which we employed a novel multi-step attention mechanism to facilitate the extracting of key features from the SMILES strings. Meanwhile, SMILES enumeration was utilized as a data augmentation method in the training phase to substantially increase the number of labeled data and enlarge the probability of mining more patterns from complex SMILES. We again took advantage of SMILES enumeration in the prediction phase to rectify model prediction bias and provide a more accurate prediction. Combined with the BAN model, our strategies can greatly improve the performance of latent features learned from SMILES strings. In 11 canonical absorption, distribution, metabolism, excretion and toxicity-related tasks, our method outperformed the state-of-the-art approaches.


One Health Lens for Antimicrobial Resistance Research and Funding: A Systematic Review.
One Health (OH) offers conceptual and applied prospects to advance planetary health and integrative biology in the 21st century. For example, The World Health Organization (WHO) has declared antimicrobial resistance (AMR) one of humanity's top 10 health threats worldwide (AMR). The AMR research, as seen through the OH lens, recognizes the interdependence and the coproduction of the health of humans, nonhuman animals, and the environment (the OH triad). Moreover, research and development (R&D) is required to generate potential solutions to prevent, diagnose, and treat infections and control the spread and emergence of AMR. However, it is still unclear how well the OH approach is integrated into current AMR R&D. In this study, we present a systematic review on the OH funding landscape for cross-sectoral AMR R&D, and its alignment/gaps with the current global strategic agenda on AMR. A systematic literature review was conducted using public databases covering the period between January 2015 and May 2022. We included the studies and reviews on AMR encompassing more than one sector of the OH triad. Out of the 777 included studies, 475 (61%) encompassed the three OH sectors. A key finding of the present systematic review is that the environment was the most neglected sector in the OH triad. AMR surveillance, transmission, and interventions are the most commonly studied priority topics. In addition, both cross-sectoral AMR literature and investments have been increasing since 2017. The operational aspect of AMR is the most researched and funded area. However, certain priority topics in the strategic research and innovation agenda of the Joint Programming Initiative on AMR are underrepresented in OH AMR research, such as diagnosis and therapeutics. To the best of authors' knowledge, this is the first study that systematically reviews the cross-sectoral literature on AMR, classifies it, and aligns and contextualizes it in regard to the funding landscape of AMR. This systematic review identifies neglected areas in AMR R&D and could serve as critical information for policymaking so as to realize the objectives of the Global Action Plan on AMR. Going forward, more cross-sectoral AMR research and funding are needed. As integrative biology and omics systems science are poised to benefit from a rapprochement with the OH lens, the present article highlights the AMR research and funding landscapes.


Stability of simian rotavirus in fresh and estuarine water.
The rates of inactivation of poliovirus 1, echovirus 7, coxsackievirus B3, and simian rotavirus SA11 were compared in polluted and nonpolluted fresh and estaurine water samples. The study was done in two parts, comparing virus survival in samples taken 1 year apart from the same sites. The survival studies were performed at 20 degrees C and at the natural pH of the water samples. In the first part of the study, the time required for a 3-log10 reduction in the initial virus titers was 2 to 3 days in the estaurine water samples and varied from 3 to greater than 14 days in the freshwater samples. In the second part of the study, no clear distinction was found between survival of viruses in freshwater samples and survival in estaurine water samples. The time required for a 3-log10 reduction in the initial virus titers in the second part of the study varied from 12 to greater than 14 days. This indicates that there is a nonseasonal change in factors in the water which affect virus survival. In this study SA11 survival time (used as a model for human virus) was well within the range exhibited by the enteroviruses, indicating that it also is environmentally stable in natural waters.


3' processing of human pre-U2 small nuclear RNA: a base-pairing interaction between the 3' extension of the precursor and an internal region.
The spliceosomal small nuclear RNAs U1, U2, U4, and U5 are transcribed by RNA polymerase II as precursors with extensions at their 3' ends. The 3' processing of these pre-snRNAs is not understood in detail. Two pathways of pre-U2 RNA 3' processing in vitro were revealed in the present investigation by using a series of human wild-type and mutant pre-U2 RNAs. Substrates with wild-type 3' ends were initially shortened by three or four nucleotides (which is the first step in vivo), and the correct mature 3' end was then rapidly generated. In contrast, certain mutant pre-U2 RNAs displayed an aberrant 3' processing pathway typified by the persistence of intermediates representing cleavage at each internucleoside bond in the precursor 3' extension. Comparison of the wild-type and mutant pre-U2 RNAs revealed a potential base-pairing interaction between nucleotides in the precursor 3' extension and a sequence located between the Sm domain and stem-loop III of U2 RNA. Substrate processing competition experiments using a highly purified pre-U2 RNA 3' processing activity suggested that only RNAs capable of this base-pairing interaction had high affinity for the pre-U2 RNA 3' processing enzyme. The importance of this postulated base-pairing interaction between the precursor 3' extension and the internal region between the Sm domain and stem-loop III was confirmed by the results obtained with a compensatory substitution that restores the base pairing, which displayed the normal 3' processing reaction. These results implicate a precursor-specific base-paired structure involving sequences on both sides of the mature cleavage site in the 3' processing of human U2 RNA.


Molecular Filters for Noise Reduction.
Living systems are inherently stochastic and operate in a noisy environment, yet despite all these uncertainties, they perform their functions in a surprisingly reliable way. The biochemical mechanisms used by natural systems to tolerate and control noise are still not fully understood, and this issue also limits our capacity to engineer reliable, quantitative synthetic biological circuits. We study how representative models of biochemical systems propagate and attenuate noise, accounting for intrinsic as well as extrinsic noise. We investigate three molecular noise-filtering mechanisms, study their noise-reduction capabilities and limitations, and show that nonlinear dynamics such as complex formation are necessary for efficient noise reduction. We further suggest that the derived molecular filters are widespread in gene expression and regulation and, particularly, that microRNAs can serve as such noise filters. To our knowledge, our results provide new insight into how biochemical networks control noise and could be useful to build robust synthetic circuits.


The Intestinal Wnt/TCF Signature.
In colorectal cancer, activating mutations in the Wnt pathway transform epithelial cells through the inappropriate expression of a TCF4 target gene program, which is physiologically expressed in intestinal crypts. We have now performed an exhaustive array-based analysis of this target gene program in colorectal cancer cell lines carrying an inducible block of the Wnt cascade. Independently, differential gene-expression profiles of human adenomas and adenocarcinomas vs normal colonic epithelium were obtained. Expression analyses of approximately 80 genes common between these data sets were performed in a murine adenoma model. The combined data sets describe a core target gene program, the intestinal Wnt/TCF signature gene set, which is responsible for the transformation of human intestinal epithelial cells. The genes were invariably expressed in adenomas, yet could be subdivided into 3 modules, based on expression in distinct crypt compartments. A module of 17 genes was specifically expressed at the position of the crypt stem cell.


BubR1 is required for the mitotic block induced by combretastatin-A4 and a novel cis-restricted ß-lactam analogue in human cancer cells.
BubR1 is a well-defined guardian of the mitotic spindle, initiating mitotic arrest in response to the lack of tension and/or chromosome alignment across the mitotic plate. However, the role of BubR1 in combretastatin-induced cell death remains unknown. In this study, we describe the effects of combretastatin A-4 (CA-4) and a synthetic cis-restricted 3,4-diaryl-2-azetidinone (ß-lactam) analogue (CA-432) on the modulation and phosphorylation of BubR1 in human cervical cancer-derived cells. We demonstrate that CA-4 and CA-432 depolymerise the microtubular network of human cervical carcinoma-derived cells. Both compounds induced the disassembly of the microtubules and the loss of microtubule tension led to the early phosphorylation of BubR1 and the late cleavage of BubR1. The phosphorylation of BubR1 correlated with the onset of G2M cell cycle arrest whilst the cleavage of BubR1 coincided with apoptosis induced by the combretastatins. The combretastatin-induced apoptosis and the BubR1 cleavage were caspase-dependent. In vitro enzyme digests demonstrated that combretastatin-activated BubR1 is a substrate for caspase-3. Gene silencing of BubR1 with small interfering RNA severely compromised combretastatin-induced G2M cell cycle arrest with a corresponding increase in the formation of polyploid cells in both cervical and breast cancer-derived cells. In summary, BubR1 is required to maintain the G2M arrest and limit the formation of polyploid cells in response to continued combretastatin exposure. Moreover, substitution of the ethylene bridge with 3,4-diaryl-2-azetidinone did not alter the tubulin depolymerising properties or the subsequent mitotic spindle checkpoint response to CA-4 in human cancer cells.


Regarding the article "Cost analysis of drug treatment in hypertensive patients at social security health care family medicine units".
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Serum cystatin C in pregnancies with normal and restricted fetal growth.
The objective of this study was to investigate circulating levels of cystatin C (an important endogenous marker of renal function) in mothers, fetuses, and neonates from intrauterine growth-restricted (IUGR; characterized by impaired nephrogenesis) and appropriate-for-gestational-age (AGA) pregnancies. Serum cystatin C levels were measured by enzyme immunoassay in 40 parturients and their 20 IUGR (<or=3rd customized centile, due to gestational pathology) and 20 AGA fetuses and neonates on postnatal day 1 (N1) and 4 (N4). Comparatively, creatinine and urea concentrations were determined in the same samples. Fetal cystatin C levels were higher in the AGA than the IUGR group (P = .001). In both groups, maternal cystatin C levels were lower than fetal (P < .001), N1 (P < .001), and N4 (P < .001) levels. Fetal levels were higher than N1 (P < .001) and N4 (P < .001), and N1 levels were higher than N4 (P = .007) ones. In both groups, no correlation existed between maternal and fetal levels, but positive correlations were found between cystatin C, creatinine, and urea levels in maternal and neonatal samples (in all cases, r >or= 0.376 and P <or= .045). Cystatin C levels did not correlate with gestational age and did not differ between males and females. Fetal cystatin C serum levels are lower in the IUGR group, significantly decrease after birth, and do not correlate with maternal levels in both groups. In addition, serum cystatin C levels positively correlate with respective creatinine and urea levels in the perinatal period.


Hybrid low-permittivity slot-rib plasmonic waveguide based on monolayer two dimensional transition metal dichalcogenide with ultra-high energy confinement.
A hybrid plasmonic waveguide design is proposed that incorporates a two-dimensional transition metal dichalcogenide monolayer covered slot-rib in between a cylindrical waveguide and a metal surface. A deep optical energy confinement (mode area ranging from λ2/1000000-λ2/100000) along with a reasonable propagation length (5μm-25μm) can be realized at the working wavelength of 1550 nm. In comparison with a traditional hybrid plasmonic waveguide, the proposed waveguide structure exhibits a smaller mode area as well as a higher figure of merit. Investigation on the influence of various two-dimensional materials on modal properties reveals that a larger permittivity provides a stronger field confinement. Owing to its excellent energy field confinement with low transmission loss, the proposed waveguide can be utilized in a variety of plasmonic devices such as compact plasmonic chips, high-integration plasmonic nano-lasers and high-sensitivity plasmonic detectors.


Oral care in the adult intensive care unit.
Nurses have not been formally trained in assessing the oral status of patients in intensive care units, and no oral care protocols for these patients are available. To assess the oral status of patients in an intensive care unit, evaluate the effects of a defined oral care protocol on the oral health status of patients in an intensive care unit, and compare oral assessments of a dental hygienist with those of intensive care nurses. A nonequivalent comparison group, longitudinal design with repeated measures was used. In phase 1, oral assessment data on the comparison group were collected by a dental hygienist. In phase 2, nurses were instructed in oral assessment and an oral care protocol. In phase 3, the oral care protocol was implemented in the treatment group, and oral assessment data were collected separately by the dental hygienist and by nurses. The mean inflammation score was significantly lower (t test P = .03) in the treatment group (mean, 3.9; SEM, 3.0) than in the comparison group (mean, 12.4; SEM, 2.2). Although not significant, the mean scores of the treatment group were also lower than those of the comparison group on scales of candidiasis, purulence, bleeding, and plaque. Correlations between scores for individual items on the oral assessment tool obtained by the dental hygienist and those obtained by nurses were all greater than 0.6386. Implementation of a well-developed oral care protocol by bedside nurses can improve oral health of patients in the intensive care unit.


Social determinants of health and tobacco use in thirteen low and middle income countries: evidence from Global Adult Tobacco Survey.
Tobacco use has been identified as the single biggest cause of inequality in morbidity. The objective of this study is to examine the role of social determinants on current tobacco use in thirteen low-and-middle income countries. We used nationally representative data from the Global Adult Tobacco Survey (GATS) conducted during 2008-2010 in 13 low-and-middle income countries: Bangladesh, China, Egypt, India, Mexico, Philippines, Poland, Russian Federation, Thailand, Turkey, Ukraine, Uruguay, and Viet Nam. These surveys provided information on 209,027 respondent's aged 15 years and above and the country datasets were analyzed individually for estimating current tobacco use across various socio-demographic factors (gender, age, place of residence, education, wealth index, and knowledge on harmful effects of smoking). Multiple logistic regression analysis was used to predict the impact of these determinants on current tobacco use status. Current tobacco use was defined as current smoking or use of smokeless tobacco, either daily or occasionally. Former smokers were excluded from the analysis. Adjusted odds ratios for current tobacco use after controlling other cofactors, was significantly higher for males across all countries and for urban areas in eight of the 13 countries. For educational level, the trend was significant in Bangladesh, Egypt, India, Philippines and Thailand demonstrating decreasing prevalence of tobacco use with increasing levels of education. For wealth index, the trend of decreasing prevalence of tobacco use with increasing wealth was significant for Bangladesh, India, Philippines, Thailand, Turkey, Ukraine, Uruguay and Viet Nam. The trend of decreasing prevalence with increasing levels of knowledge on harmful effects of smoking was significant in China, India, Philippines, Poland, Russian Federation, Thailand, Ukraine and Viet Nam. These findings demonstrate a significant but varied role of social determinants on current tobacco use within and across countries.


W-Band pulse EPR distance measurements in peptides using Gd(3+)-dipicolinic acid derivatives as spin labels.
We present high field DEER (double electron-electron resonance) distance measurements using Gd(3+) (S = 7/2) spin labels for probing peptides' conformations in solution. The motivation for using Gd(3+) spin labels as an alternative for the standard nitroxide spin labels is the sensitivity improvement they offer because of their very intense EPR signal at high magnetic fields. Gd(3+) was coordinated by dipicolinic acid derivative (4MMDPA) tags that were covalently attached to two cysteine thiol groups. Cysteines were introduced in positions 15 and 27 of the peptide melittin and then two types of spin labeled melittins were prepared, one labeled with two nitroxide spin labels and the other with two 4MMDPA-Gd(3+) labels. Both types were subjected to W-band (95 GHz, 3.5 T) DEER measurements. For the Gd(3+) labeled peptide we explored the effect of the solution molar ratio of Gd(3+) and the labeled peptide, the temperature, and the maximum dipolar evolution time T on the DEER modulation depth. We found that the optimization of the [Gd(3+)]/[Tag] ratio is crucial because excess Gd(3+) masked the DEER effect and too little Gd(3+) resulted in the formation of Gd(3+)-tag(2) complexes, generating peptide dimers. In addition, we observed that the DEER modulation depth is sensitive to spectral diffusion processes even at Gd(3+) concentrations as low as 0.2 mM and therefore experimental conditions should be chosen to minimize it as it decreases the DEER effect. Finally, the distance between the two Gd(3+) ions, 3.4 nm, was found to be longer by 1.2 nm than the distance between the two nitroxides. The origin and implications of this difference are discussed.


Dynamics of a gain-switched distributed feedback ridge waveguide laser in nanoseconds time scale under very high current injection conditions.
We present detailed experimental investigations of the temporal, spectral and spatial behavior of a gain-switched distributed feedback (DFB) laser emitting at a wavelength of 1064 nm. Gain-switching is achieved by injecting nearly rectangular shaped current pulses having a length of 50 ns and a very high amplitude up to 2.5 A. The repetition frequency is 200 kHz. The laser has a ridge waveguide (RW) for lateral waveguiding with a ridge width of 3 µm and a cavity length of 1.5 mm. Time resolved investigations show, depending on the amplitude of the current pulses, that the optical power exhibits different types of oscillatory behavior during the pulses, accompanied by changes in the lateral near field intensity profiles and optical spectra. Three different types of instabilities can be distinguished: mode beating with frequencies between 25 GHz and 30 GHz, switching between different lateral intensity profiles with a frequency of 0.4 GHz and self-sustained oscillations with a frequency of 4 GHz. The investigations are of great relevance for the utilization of gain-switched DFB-RW lasers as seed lasers for fiber laser systems and in other applications, which require a high optical power.


Integrated pseudogene annotation for human chromosome 22: evidence for transcription.
Pseudogenes are inheritable genetic elements formally defined by two properties: their similarity to functioning genes and their presumed lack of activity. However, their precise characterization, particularly with respect to the latter quality, has proven elusive. An opportunity to explore this issue arises from the recent emergence of tiling-microarray data showing that intergenic regions (containing pseudogenes) are transcribed to a great degree. Here we focus on the transcriptional activity of pseudogenes on human chromosome 22. First, we integrated several sets of annotation to define a unified list of 525 pseudogenes on the chromosome. To characterize these further, we developed a comprehensive list of genomic features based on conservation in related organisms, expression evidence, and the presence of upstream regulatory sites. Of the 525 unified pseudogenes we could confidently classify 154 as processed and 49 as duplicated. Using data from tiling microarrays, especially from recent high-resolution oligonucleotide arrays, we found some evidence that up to a fifth of the 525 pseudogenes are potentially transcribed. Expressed sequence tags (EST) comparison further validated a number of these, and overall we found 17 pseudogenes with strong support for transcription. In particular, one of the pseudogenes with both EST and microarray evidence for transcription turned out to be a duplicated pseudogene in the cat eye syndrome critical region. Although we could not identify a meaningful number of transcription factor-binding sites (based on chromatin immunoprecipitation-chip data) near pseudogenes, we did find that approximately 12% of the pseudogenes had upstream CpG islands. Finally, analysis of corresponding syntenic regions in the mouse, rat and chimp genomes indicates, as previously suggested, that pseudogenes are less conserved than genes, but more preserved than the intergenic background (all notation is available from http://www.pseudogene.org).


A parental tool to screen for posttraumatic stress in children: first psychometric results.
The Children's Revised Impact of Event Scale (CRIES-13) is a brief self-report measure designed to screen children for posttraumatic stress disorder (PTSD). This study investigates the psychometric properties of a Dutch version of the CRIES-13-parent version and evaluates its correlation with the child version. A sample of 59 trauma-exposed children (8 years-18 years) and their parents completed an assessment including the CRIES-13 (child/parent version) along with the Anxiety Disorders Interview Schedule for DSM-IV: Parent version. Results demonstrated good internal consistency (α = .87) with acceptable values for the 3 subscales. A strong correlation (r = .73) with another measure of PTSD and lower correlations with a behavioral measure (r = .15 to .38) were found, confirming the convergent/divergent validity. A cutoff score ≥ 31 emerged as the best balance between sensitivity and specificity, and correctly classified 83.6% of all children as having a diagnosis of PTSD. This study provides support for the reliability and validity of the CRIES-13-parent version as a screening measure for posttraumatic stress in children.


Content-Noise Feature Fusion Neural Network for Image Denoising in Magnetic Particle Imaging∗.
Magnetic particle imaging (MPI) is a tomographic imaging method that quantitatively determines the distribution of magnetic nanoparticles (MNPs). However, the performance of MPI is primarily limited by the noise in the receive coil and electronic devices, which causes quantification errors for MPI images. Existing methods cannot efficiently eliminate noise while preserve structural details in MPI images. To address this problem, we propose a Content-Noise Feature Fusion Neural Network equipped with tailored modules of noise learning and content learning. It can simultaneously learn content and noise features of raw MPI images. Experimental results show that the proposed method outperforms the state-of-the-art methods on structural details preservation and image noise reduction of different levels.


Design, implementation and evaluation of a community health training program in an integrated problem-based medical curriculum: a fifteen-year experience at the University of Geneva Faculty of Medicine.
In the literature the need for relevance in medical education and training has been stressed. In the last 40 years medical schools have been challenged to train doctors competent to respond to community health needs. In the mid-90s the University of Geneva Faculty of Medicine introduced an integrated medical curriculum. In this initiative a particular emphasis was put in introducing a 6-year longitudinal and multidisciplinary Community Health Program (CHP). The aims of the present article are to describe the conception, elaboration and implementation of the CHP as well as its evolution over 15 years and the evaluation of its outcomes. The CHP was at its origin elaborated by a small group of highly motivated teachers and later on developed by a multi-disciplinary group of primary care physicians, epidemiologists, public health and bio-ethics specialists, occupational health professionals, lawyers and historians. Evaluation of the program outcomes included educational innovations, new developments of the curriculum and interactions between students and the community. The CHP learning objectives and teaching modalities were defined by the multi-disciplinary group in consensus meetings which triggered a collaborative spirit among teachers and facilitated further developments. The evaluation procedures allowed the monitoring of students' satisfaction which remained high over the years, students' active participation which decreased over time and success at certifying exams which was globally as good as in basic life sciences. The evaluation also assessed outcomes such as educational innovations, new developments of the curriculum and interactions between students and the community. As suggested in the literature, our experience shows that the students' direct exposure and practice in the community health environment is an effective training approach to broaden students' education by offering them a community perspective of health and disease.


Enhanced photocarrier generation in large-scale photonic nanostructures fabricated from vertically aligned quantum dots.
We demonstrate enhanced photocarrier generation using photonic nanostructures fabricated by a wet etching technique with vertically aligned quantum dots (QDs). Using photoluminescence excitation spectroscopy, we found that the photocarrier generation in Ge/Si QDs placed close to the surface is enhanced below the band gap energy of crystalline silicon. The enhancement is explained by light trapping owing to the photonic nanostructures. Electromagnetic wave simulations indicate that the photonic nanostructure with a subwavelength size will be available to light trapping for efficient photocarrier generation by increasing their dip depth.