Factors associated with pilot error in aviation crashes.
The importance of pilot error in aviation crashes has long been recognized. However, understanding and preventing pilot error remains the foremost challenge in aviation safety. This study aims to identify pilot characteristics and crash circumstances that are associated with the presence of pilot error in a large sample of aviation crashes. Different data files compiled by the National Transportation Safety Board for 329 major airline crashes, 1,627 commuter/air taxi crashes, and 27,935 general aviation crashes for the years 1983-96 were merged; and the presence of pilot error was analyzed in relation to variables indicating the characteristics of the pilot-in-command, crash circumstance, and aircraft. Multivariate logistic regression modeling was performed to assess the associations of individual variables with the likelihood of pilot error given a crash. Pilot error was a probable cause in 38% of the major airline crashes, 74% of the commuter/air taxi crashes, and 85% of the general aviation crashes. Among the factors examined, instrument meteorological condition and on-airport location were each associated with a significantly increased odds of pilot error. The likelihood of pilot error decreased as pilot certificate rating increased in commuter/air taxi and general aviation crashes. Neither pilot age nor gender was independently associated with the odds of pilot error. With adjustment for pilot characteristics and crash circumstances, flight experience as measured in total flight time showed a significant protective effect on pilot error in general aviation crashes. The prevalence and correlates of pilot error in aviation crashes vary with the type of flight operations. Adverse weather is consistently associated with a significantly elevated likelihood of pilot error, possibly due to increased performance demand.


Subtyping of ST22-MRSA-IV (Barnim epidemic MRSA strain) at a university clinic in Germany from 2002 to 2005.
Emergence of the meticillin-resistant Staphylococcus aureus (MRSA) Barnim epidemic strain (ST22-MRSA-IV) was demonstrated recently at University Hospital in Magdeburg, Germany. To aid the study of transmission events, it is important to have an epidemiological typing method with the ability to distinguish among MRSA isolates. The aim of this study was to determine the ability of phenotypic and genotypic methods to type ST22-MRSA-IV strains within a hospital for microevolution events. Forty-two ST22-MRSA-IV strains collected from 2002 to 2005 were analysed using antimicrobial testing, toxin gene analysis, PFGE, spa typing, fluorescent amplified fragment length polymorphism (fAFLP) and determination of staphylococcal interspersed repeat units (SIRUs). Four different antimicrobial patterns were observed. The majority of the isolates (n=31) were resistant towards erythromycin, ciprofloxacin and clindamycin, in addition to penicillin and oxacillin. All strains harboured the sec gene and showed a homogeneous profile of toxin genes. One isolate was typed as spa t022, two as spa t474 and the remainder belonged to spa type t032. PFGE yielded eight profiles and SIRU typing resulted in six different patterns. The fAFLP technique subdivided the individual PFGE profiles, but the grouping of isolates differed from that obtained by PFGE or SIRU typing. These results showed a diversity of ST22-MRSA-IV strains within a narrow clinical setting, indicating microevolution of the Barnim MRSA clone. The ability to distinguish among MRSA strains within an endemic setting will lead to a greater understanding of the transmission of MRSA and is necessary to be able to control the spread of various clones.


Polyubiquitinated tristetraprolin protects from TNF-induced, caspase-mediated apoptosis.
Binding of TNF to its receptor (TNFR1) elicits the spatiotemporal assembly of two signaling complexes that coordinate the balance between cell survival and cell death. We have shown previously that, following TNF treatment, the mRNA decay protein tristetraprolin (TTP) is Lys-63-polyubiquitinated by TNF receptor-associated factor 2 (TRAF2), suggesting a regulatory role in TNFR signaling. Here we demonstrate that TTP interacts with TNFR1 in a TRAF2-dependent manner, thereby initiating the MEKK1/MKK4-dependent activation of JNK activities. This regulatory function toward JNK activation but not NF-κB activation depends on lysine 105 of TTP, which we identified as the corresponding TRAF2 ubiquitination site. Disabling TTP polyubiquitination results in enhanced TNF-induced apoptosis in cervical cancer cells. Together, we uncover a novel aspect of TNFR1 signaling where TTP, in alliance with TRAF2, acts as a balancer of JNK-mediated cell survival versus death.


Accuracy and coverage of reproductive health information on the Internet accessed in English and Persian from Iran.
The Internet is a useful resource for obtaining information. We evaluated the accuracy and coverage of reproductive health information on the Internet in English- and Persian-language sites accessed from Iran. An expert committee decided on five reproductive health topics to be evaluated and specified a checklist of content for these (36 items in total). We employed selected keywords in search engines between February and March 2006. About one of every four screened websites (n = 200) addressed at least one target topic and were subjected to in-depth assessment. Three medical doctors independently rated each of the selected websites. Accuracy and coverage percentages were calculated for each website. A total of 168 English- and 32 Persian-language websites were found that addressed the specified topics. The mean accuracy and coverage percentages of the 200 websites assessed were 98.8% (95%CI 98.1-99.6) and 45.2% (95%CI 41.0-49.3), respectively. Thirty-four (17%) websites, all in English, achieved a coverage percentage of 80% or more. Academic referencing was not present in 152 (76%) websites. 'Sexually transmitted diseases' and 'family planning' were the topics with highest coverage in both the English- and Persian-language websites studied. 'Reproductive system and puberty' had the least coverage in the Persian websites. The top 20 websites found for the general population on reproductive health are reported. Websites providing comprehensive reproductive health information are not easy to locate from Iran; in particular, Persian-language websites and those targeting young people are scarce. However, for the websites identified the accuracy of information provided was acceptable. There is a need to identify high-quality, easily accessible websites for use by both professionals and the general public and to develop new ones.


Estimation of inbreeding depression on female fertility in the Finnish Ayrshire population.
Single nucleotide polymorphism (SNP) data enable the estimation of inbreeding at the genome level. In this study, we estimated inbreeding levels for 19,075 Finnish Ayrshire cows genotyped with a low-density SNP panel (8K). The genotypes were imputed to 50K density, and after quality control, 39,144 SNPs remained for the analysis. Inbreeding coefficients were estimated for each animal based on the percentage of homozygous SNPs (FPH ), runs of homozygosity (FROH ) and pedigree (FPED ). Phenotypic records were available for 13,712 animals including non-return rate (NRR), number of inseminations (AIS) and interval from first to last insemination (IFL) for heifers and up to three parities for cows, as well as interval from calving to first insemination (ICF) for cows. Average FPED was 0.02, FROH 0.06 and FPH 0.63. A correlation of 0.71 was found between FPED and FROH , 0.66 between FPED and FPH and 0.94 between FROH and FPH . Pedigree-based inbreeding coefficients did not show inbreeding depression in any of the traits. However, when FROH or FPH was used as a covariate, significant inbreeding depression was observed; a 10% increase in FROH was associated with 5 days longer IFL0 and IFL1, 2 weeks longer IFL3 and 3 days longer ICF2 compared to non-inbred cows.


Fetal androgen exposure inhibits fetal rat lung fibroblast lipid uptake and release.
Fetal lung fibroblasts provide lipid substrate for type II cell surfactant phospholipid synthesis. This process is developmental and glucocorticoid dependent. Previous studies in our laboratory demonstrating sex differences in several aspects of lung maturation suggest that these differences may be due to effects of fetal androgens. Based on these studies, we hypothesized that fetal lung fibroblast triglyceride metabolism is determined by opposing effects of fetal androgens and glucocorticoids. To model the effects of androgens on fetal lung fibroblast triglyceride metabolism, pregnant rats were treated with dihydrotestosterone (DHT) 1 mg/kg/day from the days 15 to 20 of gestation, and changes in triglyceride content of freshly isolated fetal rat lung fibroblasts (FRLF) and rates of uptake and prostaglandin E2 (PGE2)-mediated release by cultured FRLF in response to glucocorticoids in the presence or absence of DHT in vitro were measured. During lung development, the triglyceride content and rate of uptake of female-derived FRLF increased 3.5- and 4.8-fold, respectively, between days 18 and 20 of gestation. From days 19 to 22, male FRLF trigyclyceride content and rate of uptake were lower than the content and uptake by female FRLF. Maternal DHT treatment inhibited the normal developmental increase in fibroblast triglyceride content and rate of uptake between days 19 and 22 by both male and female FRLF. In the absence of maternal DHT, in vitro dexamethasone stimulated triglyceride uptake 3-fold by day 21 in FRLF. This effect was blocked by maternal pretreatment with DHT. Maternal DHT exposure prevented stimulation of triglyceride release by PGE2. Although in vitro dexamethasone stimulated triglyceride release by maternal DHT-exposed fibroblasts, it did not enhance the response to PGE2. These data suggest that in utero exposure to androgens (1) delay the developmental increase in triglyceride content and (2) oppose the effects of glucocorticoid on cultured FRLF triglyceride uptake and PGE2-mediated release.


How is the Observation of High-Order Overtones and Combinations Elucidated by the Charge-Transfer Mechanism in SERS?
The charge-transfer chemical mechanism is responsible for altering the molecular spectral pattern and providing valuable insights into the properties of adsorbates. The impact of charge transfer becomes more pronounced in SERS spectra when CT states can gain intensity through vibronic coupling with high-intensity excitations. Experimental SERS spectra of diamino molecules, such as 4,4'-diaminostilbene (DAS) and 4,4'-diaminotolane (DAT), featuring bright CT transitions, have been compared to dipyridyl compounds, such as 1,2-bis(4-pyridyl) ethylene (BPE) and 1,2-di(4-pyridyl) acetylene (DPA), characterized by nearly dark CT excitations. This comparison aims to elucidate the effect of CT transitions on the presence of overtones and combination bands. We explain this distinction using Albrecht's formalism for resonance Raman spectroscopy within the framework of path integral time-dependent density functional theory considering the Herzberg-Teller corrections. It is worth noting that the energy gap between the highest occupied metallic orbital and the lowest unoccupied molecular orbital in diamino derivatives is noticeably smaller than in compounds featuring two pyridyl rings. The high-intensity SERS-CT spectra for diamino derivatives, primarily driven by the Albrecht A term, were acquired and used to elucidate the experimental observation of high-order modes with a significant Huang-Rhys factor. Conversely, the absolute intensity of SERS-CT for dipyridyl compounds is at least 106 times smaller than that for diamines, and the C term makes a significant contribution, explaining the silent overtones.


Distinct ClC-6 and ClC-7 Cl- sensitivities provide insight into ClC-7's role in lysosomal Cl- homeostasis.
ClC-6 and ClC-7 are closely related, intracellular Cl- /H+ antiporters belonging to the CLC family of channels and transporters. They localize to acidic late endosomes and lysosomes and probably function in ionic homeostasis of these contiguous compartments. ClC-7 transport function requires association with the accessory protein Ostm1, whereas ClC-6 transport does not. To elucidate their roles in endo-lysosomes, we measured Cl- - and pH-dependences of over-expressed wild-type ClC-6 and ClC-7, as well as disease-associated mutants, using high-resolution recording protocols. Lowering extracellular Cl- (corresponding to luminal Cl- in endo-lysosomes) reduced ClC-6 currents, whereas it increased transport activity of ClC-7/Ostm1. Low extracellular Cl- activated ClC-7/Ostm 1 under acidic extracellular conditions, as well as under conditions of low intracellular chloride. Activation is conserved in ClC-7Y713C , a variant displaying disrupted PI(3,5)P2 inhibition. Detailed biophysical analysis of disease-associated ClC-6 and ClC-7 gain-of-function (GoF) variants, ClC-6Y553C and ClC-7Y713C , and the ClC-7Y577C and ClC-6Y781C correlates, identified additional functional nuances distinguishing ClC-6 and ClC-7. ClC-7Y577C recapitulated GoF produced by ClC-6Y553C . ClC-6Y781C displayed transport activation qualitatively similar to ClC-7Y713C , although current density did not differ from that of wild-type ClC-6. Finally, rClC-7R760Q , homologous to hClC-7R762Q , an osteopetrosis variant with fast gating kinetics, appeared indifferent to extracellular Cl- , identifying altered Cl- sensitivity as a plausible mechanism underlying disease. Collectively, the present studies underscore the distinct roles of ClC-6 and ClC-7 within the context of their respective localization to late endosomes and lysosomes. In particular, we suggest the atypical inhibition of ClC-7 by luminal Cl- serves to limit excessive intraluminal Cl- accumulation. KEY POINTS: ClC-6 and ClC-7 are late endosomal and lysosomal 2 Cl- /1 H+ exchangers, respectively. When targeted to the plasma membrane, both activate slowly at positive voltages. ClC-6 activity is decreased in low extracellular (i.e. luminal) chloride, whereas ClC-7 is activated by low luminal chloride, even at acidic pH. The functional gain-of-function phenotypes of the ClC-6 and ClC-7 disease mutations ClC-6Y553C and ClC-7Y715C are maintained when introduced in their respective homologues, ClC-7Y577C and ClC-6Y781C , with all mutations retaining chloride dependence of the respective wild type (WT). An osteopetrosis mutation of ClC-7 displaying fast gating kinetics (R762Q) was less sensitive to extracellular chloride compared to WT. The opposing substrate dependences of ClC-6 and ClC-7 Cl- / H+ exchangers point to non-overlapping physiological functions, leading us to propose that inhibition of ClC-7 by luminal chloride and protons serves to prevent osmotic stress imposed by hyper-accumulation of chloride.


DNA synthesis and multinucleation of mouse cells infected with SV40 in the presence of cytochalasin B.
DNA synthesis and nuclear division of mouse cells, BALB/3T3, infected with SV40 were studied and were compared with those of SV40-transformed mouse cells, mKS-A TU-7. Both SV40-infected and SV40-transformed cells behaved similarly in the presence of cytochalasin B and differently from normal noninfected cells, BALB/3T3. The chemical inhibited cytokinesis of all the cell groups but the nuclear division was inhibited only in the case of non-infected BALB/3T3. With SV40-infected BALB/3T3, multinucleation occurred with the increase of input m.o.i. by SV40. SV40-infected BALB/3T3 could enter the second S phase after release from double thymidine block in the presence of cytochalasin B, while BALB/3T3 could not enter the second S phase. In bi- or multinucleated cells of SV40-infected BALB/3T3, asynchrony of DNA synthesis among nuclei in a cell was evident, as was the case with mKS-A TU-7.


The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma.
The survival of patients with diffuse large-B-cell lymphoma after chemotherapy is influenced by molecular features of the tumors. We used the gene-expression profiles of these lymphomas to develop a molecular predictor of survival. Biopsy samples of diffuse large-B-cell lymphoma from 240 patients were examined for gene expression with the use of DNA microarrays and analyzed for genomic abnormalities. Subgroups with distinctive gene-expression profiles were defined on the basis of hierarchical clustering. A molecular predictor of risk was constructed with the use of genes with expression patterns that were associated with survival in a preliminary group of 160 patients and was then tested in a validation group of 80 patients. The accuracy of this predictor was compared with that of the international prognostic index. Three gene-expression subgroups--germinal-center B-cell-like, activated B-cell-like, and type 3 diffuse large-B-cell lymphoma--were identified. Two common oncogenic events in diffuse large-B-cell lymphoma, bcl-2 translocation and c-rel amplification, were detected only in the germinal-center B-cell-like subgroup. Patients in this subgroup had the highest five-year survival rate. To identify other molecular determinants of outcome, we searched for individual genes with expression patterns that correlated with survival in the preliminary group of patients. Most of these genes fell within four gene-expression signatures characteristic of germinal-center B cells, proliferating cells, reactive stromal and immune cells in the lymph node, or major-histocompatibility-complex class II complex. We used 17 genes to construct a predictor of overall survival after chemotherapy. This gene-based predictor and the international prognostic index were independent prognostic indicators. DNA microarrays can be used to formulate a molecular predictor of survival after chemotherapy for diffuse large-B-cell lymphoma.


Outcome and prognostic factors for osteosarcoma of the maxilla, mandible, or calvarium in dogs: 183 cases (1986-2012).
To describe the biological behavior, clinical outcome, and prognostic factors of osteosarcoma of the maxilla, mandible, or calvarium in dogs. Retrospective case series. 183 client-owned dogs with osteosarcoma of the maxilla, mandible, or calvarium. Medical records for dogs treated for osteosarcoma of the maxilla, mandible, or calvarium from 1986 through 2012 were reviewed. Dogs with a histopathologic diagnosis of osteosarcoma and treated for a primary tumor arising from these bones of the head were included. Mean age was 9.3 years, and body weight was 31.8 kg (70.0 lb). Most dogs (124/183 [67.8%]) were purebred, and the most common primary tumor site was the maxilla (80 [43.7%]). Treatments included palliative medical treatment only (11/183 [6.0%]), coarsely fractionated radiation therapy (RT; 12 [6.6%]), fractionated or stereotactic RT (18 [9.8%]), surgery (135 [73.8%]), and both surgery and fractionated RT (7 [3.8%]). Eighty-three (45.4%) dogs received adjuvant chemotherapy. Local recurrence or progression occurred in 80 of 156 (51.3%) dogs, and 60 of 156 (38.5%) dogs developed distant metastases. Median survival time for all dogs was 239 days. Dogs that underwent surgery had a median survival time of 329 days. Histologically tumor-free surgical margins were associated with significantly decreased hazards of progression or recurrence (hazard ratio [HR], 0.4) and death (HR, 0.5). Dogs with osteosarcoma of the calvarium had a significantly greater hazard of local recurrence or progression (HR, 2.0). In this study, tumor excision in dogs with histologically tumor-free margins resulted in better local control and longer survival time than did other treatment types.


Remembering, Reflecting, Reframing: Examining Students' Long-Term Perceptions of an Innovative Model for University Teaching.
This article presents a follow-up examination of 10 iterations of a blended course on educational psychology and e-learning carried out at the University of Bari. All iterations of the course considered in this study were designed using the constructive and collaborative participation (CCP) model. Our main research questions are: What are the students' long lasting memories of this course? How do the students use the skills and the competences acquired through the course across an extended period of time? In line with these research questions, the aims of this investigation can be summarized as follows: (i) to understand the students' perceptions and long lasting memories of the course and (ii) to investigate the transfer of skills and knowledge across an extended period of time, based on a self-reported survey. The analysis was carried out by administering the survey to all 196 students who took part in the course in the 2005-2015 decade. 96 participants responded to the survey. The survey is designed to collect data in two areas. First, the memories related to the course and second, the way skills and content knowledge acquired during the course have been transferred to and used in other contexts after the course ended. The data were analyzed using a mixed methods approach, which revealed trends in the responses across the decade. In general, participants remembered the teaching methodology and often recalled specific activities such as Role Taking and the creation of products through group-work. These activities and approaches seemed to provide significant learning opportunities for the students. Several students also recalled key concepts and content knowledge acquired during the course. In relation to transfer of skills, participants tended to reuse mostly transversal skills, such as communicative and organizational skills, especially in work contexts. Further, about half of the respondents reused the content knowledge of the course. This analysis is valuable because it allows us to understand the aspects of the model that are significant for the students in the long term, and to discover and interrogate the acquisition and transfer of skills useful for the students' personal and professional lives beyond the academy.


Evaluating the Big Five as an organizing framework for commonly used psychological trait scales.
The Big Five is often represented as an effective taxonomy of psychological traits, yet little research has empirically examined whether stand-alone assessments of psychological traits can be located within the Big Five framework. Meanwhile, construct proliferation has created difficulty navigating the resulting landscape. In the present research, we developed criteria for assessing whether the Big Five provides a comprehensive organizing framework for psychological trait scales and evaluated this question across three samples (Total N = 1,039). Study 1 revealed that 83% of an author-identified collection of scales (e.g., Self-Esteem, Grit, etc.) were as related to the Big Five as at least four of 30 Big Five facets, and Study 2 found that 71% of scales selected based on citation counts passed the same criterion. Several scales had strikingly large links at the Big Five facet level, registering correlations with individual Big Five facets exceeding .9. We conclude that the Big Five can indeed serve as an organizing framework for a sizable majority of stand-alone psychological trait scales and that many of these scales could reasonably be labeled as facets of the Big Five. We suggest an integrative pluralism approach, where reliable, valid scales are located within the Big Five and pertinent Big Five research is considered in all research using trait scales readily located within the Big Five. By adopting such an approach, construct proliferation may be abated and it would become easier to integrate findings from disparate fields. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Cerebrospinal fluid drainage to prevent paraplegia during thoracic and thoracoabdominal aortic aneurysm surgery: a systematic review and meta-analysis.
We undertook a quantitative systematic review of randomized controlled trials (RCTs) and observational studies to determine the effectiveness of cerebrospinal fluid (CSF) drainage to prevent paraplegia in thoracic aneurysm (TA) and thoracoabdominal aortic aneurysm (TAAA) surgery. We included RCTs and cohort studies that met the following criteria: elective or emergent aneurysm surgery involving the thoracic or thoracoabdominal aorta, documentation of postoperative neurologic deficits, and patient age older than 18 years. We excluded studies that reported results in 10 or fewer patients and duplicate publications. We identified eligible studies by searching computerized databases, our own files, and the reference lists of relevant articles and review articles. Database searching, eligibility decisions, relevance and method quality assessments, and data extraction were performed in duplicate with prespecified criteria. Of 372 publications identified in our search, 14 met our eligibility criteria. Three RCTs reported 289 patients with type I or type II TAAA. Lower limb neurologic deficits occurred in 12% of patients who underwent CSF drainage and 33% of control subjects (number needed to treat, 9; 95% confidence interval [CI], 5-50). The pooled odds ratio (OR) for development of paraplegia in patients in the CSF drainage group was 0.35 (P =.05; 95% CI, 0.12-0.99). Similar results were found in five cohort studies with a control group (pooled OR, 0.26; P =.0002; 95% CI, 0.13-0.53). When all studies were considered together the pooled OR of TA and TAAA was 0.3 (95% CI, 0.17-0.54). There was no statistical heterogeneity among studies included in the meta-analysis. In six cohort studies without a control group, the incidence of paraplegia in high-risk TA and TAAA was 7.6%. Evidence from randomized and nonrandomized trials and from cohort studies support the use of CSF drainage as an adjunct to prevent paraplegia when this adjunct is used in centers with large experience in the management of TAAA.


The presence of a temporal discrimination in the conditioned emotional response with humans.
Six college students participated in matching-to-sample tasks. Conditioned emotional response (CER) training consisted of pairing a tone with a "painful" level of shock. Three of the subjects demonstrated response suppression, one subject showed facilitation, and two showed no change. Analysis of response rate during the tone interval indicated that, for those subjects who showed response suppression, the decrease in response rate was greatest immediately before onset of the unconditioned stimulus. This temporal discrimination was similar to that obtained with infrahumans.


Melatonin alleviates brain and peripheral tissue edema in a neonatal rat model of hypoxic-ischemic brain damage: the involvement of edema related proteins.
Previous studies have indicated edema may be involved in the pathophysiology following hypoxic-ischemic encephalopathy (HIE), and melatonin may exhibit neuro-protection against brain insults. However, little is known regarding the mechanisms that involve the protective effects of melatonin in the brain and peripheral tissues after HIE. The present study aimed to examine the effects of melatonin on multiple organs, and the expression of edema related proteins in a neonatal rat model of hypoxic-ischemic brain damage (HIBD). One hundred ninety-two neonatal rats were randomly divided into three subgroups that underwent a sham surgery or HIBD. After the HIBD or sham-injury, the rats received an intraperitoneal injection of melatonin or an equal volume vehicle, respectively. We investigated the effects of melatonin on brain, kidney, and colon edema via histological examination and the expression of edema related proteins, including AQP-4, ZO-1 and occludin, via qPCR and western blot. Our data indicated (1) Melatonin reduced the histological injury in the brain and peripheral organs induced by HIBD as assessed via H-E staining and transmission electron microscopy. (2) Melatonin alleviated the HIBD-induced cerebral edema characterized by increased brain water content. (3) HIBD induced significant changes of edema related proteins, such as AQP-4, ZO-1 and occludin, and these changes were partially reversed by melatonin treatment. These findings provide substantial evidence that melatonin treatment has protective effects on the brain and peripheral organs after HIBD, and the edema related proteins, AQP4, ZO-1, and occludin, may indirectly contribute tothe mechanism of the edema protection by melatonin.


A general approach for chemical labeling and rapid, spatially controlled protein inactivation.
Chemical labeling of proteins inside of living cells can enable studies of the location, movement, and function of proteins in vivo. Here we demonstrate an approach for chemical labeling of proteins that uses the high-affinity interaction between an FKBP12 mutant (F36V) and a synthetic, engineered ligand (SLF'). A fluorescein conjugate to the engineered ligand (FL-SLF') retained binding to FKBP12(F36V) and possessed similar fluorescence properties as parental fluorescein. FL-SLF' labeled FKBP12(F36V) fusion proteins in live mammalian cells, and was used to monitor the subcellular localization of a membrane targeted FKBP12(F36V) construct. Chemical labeling of FKBP12(F36V) fusion proteins with FL-SLF' was readily detectable at low expression levels of the FKBP12(F36V) fusion, and the level of fluorescent staining with FL-SLF' was proportional to the FKBP12(F36V) expression level. This FL-SLF'-FKBP12(F36V) labeling technique was tested in fluorophore assisted laser inactivation (FALI), a light-mediated technique to rapidly inactivate fluorophore-labeled target proteins. FL-SLF' mediated FALI of a beta-galactosidase-FKBP12(F36V) fusion protein, causing rapid inactivation of >90% of enzyme activity upon irradiation in vitro. FL-SLF' also mediated FALI of a beta-galactosidase fusion expressed in living NIH 3T3 cells, where beta-galactosidase activity was reduced in 15 s. Thus, FL-SLF' can be used to monitor proteins in vivo and to target rapid, spatially and temporally defined inactivation of target proteins in living cells in a process that we call FK-FALI.


Apelin protects against angiotensin II-induced cardiovascular fibrosis and decreases plasminogen activator inhibitor type-1 production.
To test the hypothesis that apelin protects against angiotensin II (Ang II)-induced cardiovascular fibrosis and vascular remodeling. Wild-type mice administered apelin or apelin along with Ang II exhibited less cardiovascular fibrosis and decreased plasminogen activator inhibitor type-1 (PAI-1) gene expression than mice receiving Ang II, N-nitro-L-arginine methyl ester (L-NAME), apelin plus L-NAME or apelin plus Ang II plus L-NAME. In-vitro analysis using a luciferase construct driven by 3.1 kb of the human PAI-1 promoter revealed that apelin blocked Ang II-mediated PAI-1 gene expression. Immunoblotting for phosphorylated myosin phosphatase subunit and myosin light chain revealed that apelin blocked Ang II activation of the Rho kinase pathway, which is associated with induction of PAI-1 gene expression by Ang II. In addition, treatment of human aortic smooth muscle cells with apelin reduced PAI-1 mRNA and protein production in the presence and absence of Ang II. Conversely, L-NAME treatment attenuated the downregulation of PAI-1 by apelin in cells. Apelin protects against cardiac fibrosis and vascular remodeling through direct regulation of PAI-1 gene expression. This protective effect is mediated through the synergistic inhibition of Ang II signaling and increased production of nitric oxide by apelin. Our data extend previous findings and provide new insight into the molecular mechanisms by which apelin elicits a cardioprotective effect.


T Cell-Replete Haploidentical Peripheral Blood Hematopoietic Cell Transplantation for Treatment of T-Lymphoblastic Lymphoma.
BACKGROUND There is currently little information on haploidentical hematopoietic cell transplantation (haplo-HCT) for T-lymphoblastic lymphoma (T-LBL). Data about peripheral blood stem cells (PBSC) as a reliable graft source for T-LBL treatment are lacking. MATERIAL AND METHODS T-LBL patients who underwent T cell-replete haploidentical peripheral blood hematopoietic cell transplantation (haplo-PBHCT) from July 2007 to January 2017 were retrospectively evaluated. RESULTS A total of 25 patients (age ≥15 years) with median age of 24 (range 15-51) years were enrolled. The median number of CD34+ cells infused was 5.0 (1.6-14.4) 106/kg. Sustained myeloid engraftment with full donor chimerism was achieved in all patients. The cumulative incidence of grades 2 to 4 acute graft-versus-host disease (GVHD) at day 100 was 24%. Two-year extensive chronic GVHD cumulative incidence was 20%. The 3-year overall survival rate for all patients was 70%. The median survival time of the complete remission (CR) group was better than that of the non-CR group (not reached vs. 9 m) (P<0.01). The relapse rate was 17% for patients who obtained CR and were given haplo-HCT as consolidation treatment. CONCLUSIONS This study indicates that haplo-PBHCT is a safe and effective method for the treatment of T-LBL.


Wnt7a is a novel inducer of β-catenin-independent tumor-suppressive cellular senescence in lung cancer.
Cellular senescence is an initial barrier for carcinogenesis. However, the signaling mechanisms that trigger cellular senescence are incompletely understood, particularly in vivo. Here we identify Wnt7a as a novel upstream inducer of cellular senescence. In two different mouse strains (C57Bl/6J and FVB/NJ), we show that the loss of Wnt7a is a major contributing factor for increased lung tumorigenesis owing to reduced cellular senescence, and not reduced apoptosis, or autophagy. Wnt7a-null mice under de novo conditions and in both the strains display E-cadherin-to-N-cadherin switch, reduced expression of cellular senescence markers and reduced expression of senescence-associated secretory phenotype, indicating a genetic predisposition of these mice to increased carcinogen-induced lung tumorigenesis. Interestingly, Wnt7a induced an alternate senescence pathway, which was independent of β-catenin, and distinct from that of classical oncogene-induced senescence mediated by the well-known p16(INK4a) and p19(ARF) pathways. Mechanistically, Wnt7a induced cellular senescence via inactivation of S-phase kinase-associated protein 2, an important alternate regulator of cellular senescence. Additionally, we identified Iloprost, a prostacyclin analog, which initiates downstream signaling cascades similar to that of Wnt7a, as a novel inducer of cellular senescence, presenting potential future clinical translational strategies. Thus pro-senescence therapies using either Wnt7a or its mimic, Iloprost, might represent a new class of therapeutic treatments for lung cancer.


Concepts of rate responsive pacing.
Various concepts for measuring (by means of biosensors incorporated into pacemakers) biologic parameters to determine the appropriate pacing rate are reviewed. They are pH, stimulus-to-T-wave interval, blood temperature, intercardiac blood pressure change, venous oxygen saturation, intercardiac impedance (stroke volume, ejection rate, preejection interval), thoracic impedance (respiratory rate, minute volume), R-wave area, and body vibration. Those which have been incorporated in an implantable pacemaker and studied in a significant number of patients include intracardiac blood temperature, respiratory rate, respiratory minute volume, stimulus-to-T-wave interval, and body vibration. Studies of intracardiac impedance, QRS complex area, venous oxygen saturation, and right ventricular pressure are in early stages. Because no single parameter has yet proved to be an ideal indicator of metabolic need, dual-chamber pacemakers, which use atrial rate and body vibration to control pacing rate, and multisensor pacemakers are under development.


Oral immunization of rabbits with VP60 particles confers protection against rabbit hemorrhagic disease.
Rabbit hemorrhagic disease virus (RHDV) causes more than 90% mortality in adult rabbits. In this study, the cDNA of the VP60 coding sequence of RHDV was cloned under the control of the polyhedrin and p10 promoters of baculovirus to be expressed in insect cells. The expression of RHDV VP60 under the control of the p10 promoter was 5-10 times higher than using the polyhedrin promoter. The p10-derived VP60 was able to assemble into virus-like particles (VLPs). RHDV VLPs were successfully used to protect rabbits against the disease even at doses as low as 0.5 micrograms when injected intramuscularly or subcutaneously. The ability to elicit an immune response was independent of the adjuvant or the route of immunization. Remarkably, oral administration of RHDV VLPs efficiently induced protecting antibodies to RHD at doses as low as 3 micrograms. The use of binary ethylenimine for the stabilization of the VLPs was decisive for eliciting a good oral immunity. This report demonstrates the potential use of these procapsids in obtaining RHD oral vaccines and opens the door to the use of these capsids for the prevention of the disease in wild animals. Therefore, a new, and potentially important application of recombinant VLPs in the induction of protective immunity by the oral route is foreseen.


Prevalence, attitudes and knowledge of misoprostol for self-induction of abortion in women presenting for abortion at Midwestern reproductive health clinics.
In the setting of increasing restrictions to legal abortion in the United States, reports have emerged of self-induced termination of pregnancies with misoprostol, obtained without a prescription or provider. This study seeks to describe the prevalence of women seeking or employing misoprostol for self-induced abortion, and how they access information. In a cross-sectional study of women immediately following their abortion at three reproductive health clinics in the Midwestern United States, an anonymous survey queried gestational age, barriers, online investigation about self-induction and opinions concerning the availability of medical abortion. From June to September 2016, 276 women participated out of 437 presenting to the clinics during the study period. One hundred and ninety-one (74.6%) women had investigated abortion options online, and of those, 58 (30.9%) investigated misoprostol online, for home use. Women who investigated online options were less likely to have had a prior abortion than those who did not investigate online (29.3% vs. 63.1%, p < .01). They were also more likely to report prior home attempts to end this pregnancy (8.6% vs. 0%, p = .05). Overall, four (1.6%) of the respondents purchased misoprostol and three (1.2%) used it. A majority of women seeking an abortion sought online information prior to their clinic appointment, and almost a third of those had investigated misoprostol for home use. Women are accessing information regarding misoprostol for self-induction of abortion on the Internet. As barriers to legal abortion increase, women may be more likely to self-induce abortion.


A Europium Metal-Organic Framework and Its Polymer Composite Membrane as Switch-Off Fluorescence Sensors for Antibiotic Detection in Lake Water.
The detection of antibiotic residues is of great significance in monitoring their overuse in healthcare, livestock and poultry farming, and agricultural production. Herein, EuCl3 and 4,4'-dicarboxyl-diphenoxyethene (H2DPOE) ionothermally reacted in 1-methyl-3-butylimidazolium chloride to give a europium metal-organic framework (Eu-DPOE). Eu-DPOE shows different fluorescence quenching rates for sensing eight antibiotics under different excitation wavelengths. Eu-DPOE displays a fast response, high selectivity, and sensitivity in antibiotic detection by fluorescence quenching. Eu-DPOE can sensitively detect TCs (tetracyclines), NOR (norfloxacin), NFT (furazolidone), ODZ (ornidazole), SDZ (sulfadiazine), and CHL (chloramphenicol) with limits of detection below 0.5 μmol/L. It provides a convenient and rapid tool for sensing antibiotics in aqueous solution. The detection mechanism is a competition absorption between DPOE2- and antibiotics with the supports from powder X-ray diffraction (PXRD), UV-vis spectra, and fluorescence lifetime. With a composite membrane of poly(vinylidene fluoride) (PVDF) matrix loading Eu-DPOE (Eu-DPOE@PVDF), Eu-DPOE@PVDF exhibits a visual fluorescence response to NOR under a 254 nm UV lamp and NFT and CTC under 365 nm. Eu-DPOE@PVDF is applied in the quantitative detection of CTC, NOR, and NFT in lake water with recovery rates ranging from 88.37 to 113.8%. Totally, fluorescence-quenched Eu-DPOE@PVDF exhibits a fast response, high selectivity, and sensitivity in sensing CTC, NOR, and NFT.


[The perception of targeted signals in the auditory and somatosensory systems with a lesion of the brain stem].
Auditory and somatosensory evoked potentials (AEPs and SEPs) were recorded in 8 patients with malignant processes in the brainstem region and 14 healthy persons under conditions of relevant and deviant stimulation. The spatial-temporal EP characteristics were evaluated and mapped. The low-voltage AEPs to simple rhythmical stimulation were recorded in patients over the whole cortical surface. During attention activation (solving selective attention tasks) there was an increase in the amplitude of the AEPs, mainly, of their mid-latency components. Under such conditions the N200 SEP components were well expressed in both hemispheres with the maximal amplitude in the medial and anterior derivations. The spatial distribution of N350 resembled that of the N200. There was an increase in N30 amplitude in both occipital derivations and its expressed reduction in the frontal areas as compared to the situation with the simple rhythmical stimulation. In patients with the brainstem pathology the increased amplitude of these components was observed mainly in the parietal and occipital cortical areas.


Recombination and speciation.
Speciation can be viewed as the evolution of restrictions on the freedom of genetic recombination: new combinations of alleles can be generated within species, but alleles from different species cannot be brought together. Recently, there has been increasing realization that the role of chromosomal rearrangements in speciation might be primarily a result of their influence on recombination. I argue that ideas about the role of recombination in speciation should be considered in the context of the variability of recombination rates and patterns more generally and that genic as well as chromosomal causes of restricted recombination should be considered. I review patterns of variation in recombination rates and theoretical progress in understanding the conditions that favour increased or decreased rates. Although progress has been made in understanding conditions that alter overall rates of recombination, widespread variation in patterns of recombination remains largely unexplained. I consider three models for the role of locally restricted recombination in speciation and the evidence currently supporting them.


[Significance of family anamnesis in colorectal carcinoma].
To assess the familial risk of colorectal cancer among first-degree relatives of colorectal cancer patients, a tumour-related family history study was conducted in 1982-1988 on 184 patients (median age 60 [28-92] years). These family data were compared with the data recorded in the cancer register of the population of Basel. An enhanced risk among first-degree relatives was noted (relative risk: 1.8%; 95% confidence interval: 1.4-2.3). The enhanced risk was attributed exclusively to seven families involving 2-3 relatives each (the relative risk in these families being 34). In four of these seven families an autosomal dominant site-specific cancer of the colon (Lynch's syndrome I) was diagnosed. Hence, family case history of colorectal cancer patients enables the identification of relatives with a high risk for colorectal carcinoma.


Gi Protein Modulation of the Potassium Channel TASK-2 Mediates Vesicle Osmotic Swelling to Facilitate the Fusion of Aquaporin-2 Water Channel Containing Vesicles.
Vesicle fusion is a fundamental cell biological process similar from yeasts to humans. For secretory vesicles, swelling is considered a step required for the expulsion of intravesicular content. Here this concept is revisited providing evidence that it may instead represent a general mechanism. We report the first example that non-secretory vesicles, committed to insert the Aquaporin-2 water channel into the plasma membrane, swell and this phenomenon is required for fusion to plasma membrane. Through an interdisciplinary approach, using atomic force microscope (AFM), a fluorescence-based assay of vesicle volume changes and NMR spectroscopy to measure water self-diffusion coefficient, we provide evidence that Gi protein modulation of potassium channel TASK-2 localized in AQP2 vesicles, is required for vesicle swelling. Estimated intravesicular K⁺ concentration in AQP2 vesicles, as measured by inductively coupled plasma mass spectrometry, was 5.3 mM, demonstrating the existence of an inwardly K⁺ chemical gradient likely generating an osmotic gradient causing vesicle swelling upon TASK-2 gating. Of note, abrogation of K⁺ gradient significantly impaired fusion between vesicles and plasma membrane. We conclude that vesicle swelling is a potentially important prerequisite for vesicle fusion to the plasma membrane and may be required also for other non-secretory vesicles, depicting a general mechanism for vesicle fusion.


Identification of a novel serum amyloid A protein in BALB/c mice.
Four serum amyloid A protein (SAA) genes and two SAA gene products, SAA1 and SAA2, were identified in BALB/c mice. Using analytical isoelectric focusing we have identified a quantitatively significant new member of the SAA family and designated it 'SAA5'. This protein has characteristics never before described for any SAA molecule. In the highly conserved region between amino acids 33 and 44, identical in all SAAs from all species examined, SAA5 had four amino acid substitutions. In addition, the induction of SAA5 by lipopolysaccharide had different kinetics from that of the other mouse SAAs. Our data suggest that the mouse SAA gene family is more complex in composition and regulation than previously surmised.


Evidence for a single class of thrombin-binding sites of human platelets.
We previously demonstrated that human platelets bind a small number of thrombin molecules with high affinity and a larger number with relatively lower affinity (Tollefsen, D. M., Feagler, J. R., and Majerus, P. W. (1974), J. Biol. Chem. 249, 2646). In the present report, equilibrium binding studies using [125I]DIP-thrombin (diisopropylphosphoryl-thrombin) over the range of 0.0002-10 U/ml yield a Hill coefficient of 0.775. Measurements of the rate of dissociation of [125I]DIP-thrombin bound to platelets at relatively high affinity (0.04 U/ml added) indicate a much faster dissociation in the presence of 14 U/ml unlabeled DIP-thrombin (T 1/2 = 1.0 min) than in its absence (T 1/2 - 140 min). [125I]DIP-thrombin bound at low affinity (1.0U/ml added) dissociates from platelets with a T 1/2 = 1.7 min in the absence of unlabeled DIP-thrombin. These results suggest a negative cooperative interaction among receptor sites for thrombin; i.e., as thrombin binds to unoccupied sites, high-affinity receptors are apparently converted to low-affinity receptors. In an attempt to detect whether there is heterogeneity of thrombin receptors, [125I]DIP-thrombin was covalently cross-linked to intact platelets using 1 mM glutaraldehyde. A single complex (apparent molecular weight, 200 000) containing [125I]DIP-thrombin was formed throughout a range of thrombin concentrations in which both high- and low-affinity binding was observed. Since incorporation of [125I]DIP-thrombin into this complex did not occur in the absence of platelets and was inhibited by unlabeled thrombin, the complex may represent thrombin cross-linked to its receptor. We conclude that a single class of receptor sites can account for both high- and low-affinity binding of thrombin to platelets, although interaction between nonidentical sites cannot be excluded.


Serum polyamine-oxidase activity in spontaneous abortion.
Serum polyamine oxidase activity was determined in 38 women admitted to the Maternity Department of Szombathely, Hungary with clinical signs of threatened abortion between 11 and 22 weeks gestation and who aborted spontaneously with 48 h of admission. Serum polyamine oxidase activity was found to be significantly lower in these women compared with that in women having normal pregnancies of the same gestational age. The higher polyamine oxidase levels which were found in five women who aborted during oxytocin infusion probably resulted from increased contractions expelling enzyme-rich blood from the intervillous space into the maternal circulation. Present evidence is insufficient to explain the full clinical significance of these findings.


Weighted Gene Coexpression Network Analysis Identifies TBC1D10C as a New Prognostic Biomarker for Breast Cancer.
Immune checkpoint inhibitors are a promising therapeutic strategy for breast cancer (BRCA) patients. The tumor microenvironment (TME) can downregulate the immune response to cancer therapy. Our study is aimed at finding a TME-related biomarker to identify patients who might respond to immunotherapy. We downloaded raw data from several databases including TCGA and MDACC to identify TME hub genes associated with overall survival (OS) and the progression-free interval (PFI) by WGCNA. Correlations between hub genes and either tumor-infiltrating immune cells or immune checkpoints were conducted by ssGSEA. TME-related green and black modules were selected by WGCNA to further screen hub genes. Random forest and univariate and multivariate Cox regressions were applied to screen hub genes (MYO1G, TBC1D10C, SELPLG, and LRRC15) and construct a nomogram to predict the survival of BRCA patients. The C-index for the nomogram was 0.713. A DCA of the predictive model revealed that the net benefit of the nomogram was significantly higher than others and the calibration curve demonstrated a good performance by the nomogram. Only TBC1D10C was correlated with both OS and the PFI (both p values < 0.05). TBC1D10C also had a high positive association with tumor-infiltrating immune cells and common immune checkpoints (PD-1, CTLA-4, and TIGIT). We constructed a TME-related gene signature model to predict the survival probability of BRCA patients. We also identified a hub gene, TBC1D10C, which was correlated with both OS and the PFI and had a high positive association with tumor-infiltrating immune cells and common immune checkpoints. TBC1D10C may be a new biomarker to select patients who may benefit from immunotherapy.


Point of view: Should COVID-19 patients be supplemented with vitamin D?
Using Hill's methodology for exploring causality, we aimed to determine in early May 2020 whether evidence supports vitamin D as a biological determinant of COVID-19 outcomes. Vitamin D is a secosteroid hormone theoretically able to reduce COVID-19 risk through regulation of (i) the renin-angiotensin system, (ii) cellular innate and adaptive immunity, and (iii) physical barriers. Inverse associations were found between 25-hydroxyvitamin D concentrations and COVID-19 incidence and mortality. Randomized controlled trials testing vitamin D supplementation in the treatment of COVID-19 are in progress. Positive results in such studies would encourage the use of vitamin D supplements as an adjuvant treatment in COVID-19.


Clinical applications of the immunohistochemistry of filamentous proteins.
The past few years have seen great progress in our knowledge of the biology and the chemistry of intermediate filaments and other filamentous proteins. This has translated into the development of antibodies that, together with new, highly sensitive immunohistochemical methods, have resulted in much improved diagnostic accuracy. New, more specific antibodies to these and other useful markers will no doubt be developed in the future. More efficient techniques for screening of these antibodies will contribute to their rapid evaluation. Libraries of antibodies that identify subclasses of filamentous proteins will very likely become routine tools in the histopathology laboratory in the near future. Moreover, as the chemical structure of the proteins that form the complex family of intermediate filaments becomes better understood, and the DNA sequences coding them are determined, it may become feasible to use molecular genetic approaches such as in situ hybridization to gain further insight into neoplastic processes of unclear histogenesis and to develop more precise diagnostic and taxonomic instruments. Nevertheless, it is worth repeating that application of these molecular tools cannot be successful unless it is backed by a thorough understanding of the principles of histopathologic diagnosis that have been painstakingly established by generations of anatomic pathologists.


A Review of the Complex Role of Family Caregivers as Health Team Members and Second-Order Patients.
In Palliative Care, the unit of care is the patient and their family. Although members of the health care team often address the family caregiver's opinions and concerns, the focus of care remains on the needs of the patient. The readiness and willingness of the family caregiver is often overlooked as they are expected to assume a complex caregiving role. When family caregivers are not intellectually or emotionally prepared or physically capable, the caregiver is at high risk for serious health issues and cognitive, emotional, and physical decline particularly as caregiving extends over time. Family caregivers are often a neglected and at-risk population. Illustrated through the use of a case study, this article addresses the complex role of family caregivers, as both health team members and second-order patients. It emphasizes the importance of family assessment and interventions to balance the burdens and benefits of family caregiving and protect caregivers' health and well-being.


Cyclin D1 expression in Bowen's disease and cutaneous squamous cell carcinoma.
Cyclin D1 is a member of the G1 cyclin family that regulates the transition through the G1 phase of the cell cycle and is involved in the neoplastic transformation of certain tumors. This study was designed to investigate the expression of cyclin D1 in Bowen's disease (BD) and cutaneous squamous cell carcinoma (SCC). Biopsies of 30 cases with BD and 24 cases with SCC confirmed by histopathology were obtained from the Department of Dermatology of Huashan Hospital, Shanghai, China. EnVision immunohistochemical technology with a semiquantitative immunohistochemical score was applied to detect the expression of cyclin D1. Of the 24 specimens with SCC, cyclin D1 was found to be positive in 17 (70.8%), whereas of the 30 specimens with BD, cyclin D1 was found to be positive in 13 (43.3%). The expression of cyclin D1 was significantly higher in the SCC compared to that in the BD group. We did not observe a significant association of cyclin D1 expression with different pathological grades of SCC. In conclusion, cyclin D1 plays a significant role as a diagnostic marker in skin tumors and its overexpression was not found to be correlated with the degree of differentiation of SCC.


What does it cost to feed aged care residents in Australia?
Funding cuts to the aged care industry impact catering budgets and aged care staffing levels, which may in turn affect the nutritional status of aged care residents. This paper reports average food expenditure and trends in Australian residential aged care facilities (RACFs). This is a retrospective study collecting RACFs' economic outlay data through a quarterly online survey conducted over the 2015 and 2016 financial years. Data were compiled from 817 RACFs, representing 64 256 residential beds and 23 million bed-days Australia-wide. The average total spend in Australian Dollars (AUD) on catering consumables (including cutlery/crockery, supplements, paper goods) was $8.00 per resident per day (prpd) and $6.08 prpd when looking at the raw food and ingredients budget alone. Additional data from over half the RACFs (n = 456, 56%) indicate a 5% decrease in food cost ($0.31 prpd) in the last year, particularly in fresh produce, with a simultaneous 128% ($0.50 prpd) increase in cost for supplements and food replacements. Current figures are comparatively less than aged care food budgets internationally (US, UK and Canada), less than community-dwelling older adults ($17.25 prpd) and 136% less than Australian corrective services ($8.25 prpd). The current spend on food in RACFs has decreased compared with previous years, reflecting an increasing reliance on supplements, and is significantly less than current community food spend.


Initial hydraulic failure followed by late-stage carbon starvation leads to drought-induced death in the tree Trema orientalis.
Drought-induced tree death has become a serious problem in global forest ecosystems. Two nonexclusive hypotheses, hydraulic failure and carbon starvation, have been proposed to explain tree die-offs. To clarify the mechanisms, we investigated the physiological processes of drought-induced tree death in saplings with contrasting Huber values (sapwood area/total leaf area). First, hydraulic failure and reduced respiration were found in the initial process of tree decline, and in the last stage carbon starvation led to tree death. The carbohydrate reserves at the stem bases, low in healthy trees, accumulated at the beginning of the declining process due to phloem transport failure, and then decreased just before dying. The concentrations of non-structural carbohydrates at the stem bases are a good indicator of tree damage. The physiological processes and carbon sink-source dynamics that occur during lethal drought provide important insights into the adaptive measures underlying forest die-offs under global warming conditions.


TIP60 represses telomerase expression by inhibiting Sp1 binding to the TERT promoter.
HIV1-TAT interactive protein (TIP60) is a haploinsufficient tumor suppressor. However, the potential mechanisms endowing its tumor suppressor ability remain incompletely understood. It plays a vital role in virus-induced cancers where TIP60 down-regulates the expression of human papillomavirus (HPV) oncoprotein E6 which in turn destabilizes TIP60. This intrigued us to identify the role of TIP60, in the context of a viral infection, where it is targeted by oncoproteins. Through an array of molecular biology techniques such as Chromatin immunoprecipitation, expression analysis and mass spectrometry, we establish the hitherto unknown role of TIP60 in repressing the expression of the catalytic subunit of the human telomerase complex, TERT, a key driver for immortalization. TIP60 acetylates Sp1 at K639, thus inhibiting Sp1 binding to the TERT promoter. We identified that TIP60-mediated growth suppression of HPV-induced cervical cancer is mediated in part due to TERT repression through Sp1 acetylation. In summary, our study has identified a novel substrate for TIP60 catalytic activity and a unique repressive mechanism acting at the TERT promoter in virus-induced malignancies.


Women have more potential to induce browning of perirenal adipose tissue than men.
Brown adipose tissue (BAT) can generate heat by burning fatty acids, a process mediated by uncoupling protein 1 (UCP1). White adipose tissue (WAT) depots can gain BAT-like properties, and various studies have suggested that females have more active BAT or BAT-like WAT. We studied sex differences in BAT-like properties of human perirenal adipose tissue. Perirenal and subcutaneous adipose tissue was obtained from 20 male and 24 female healthy live kidney donors. Mesenchymal stem cells (MSCs), adipocyte precursor cells, were isolated from these depots to study whether intrinsic factors control BAT-like properties of the adipose tissue depots. When average outside temperature a week before harvesting was below 11°C, brown-like adipocytes expressing UCP1 were present in perirenal adipose tissue of women, but not of men. MSCs derived from perirenal adipose tissue expressed significantly more UCP1 when from female origin compared to male origin (P = 0.009). However, UCP1 protein content and oxygen consumption rate did not differ between adipocytes derived from male and female perirenal MSCs. Female perirenal adipose tissue has a higher potency to gain BAT-like properties than male perirenal adipose tissue. The degree of gaining BAT-like properties depends on sex-specific intrinsic factors and environmental triggers such as temperature.


A new writhing model of factor XII activator-induced pain for assessment of non-steroidal anti-inflammatory agents. I. Kaolin-induced writhing in mice.
The writhing reaction in mice induced by kaolin, a factor XII activator, was studied. An intraperitoneal injection of kaolin clearly induced a writhing reaction in a dose-dependent fashion, and the reaction disappeared about 10-15 min later. The writhing reaction reached a peak at 5-10 min after the injection of kaolin (0.5 ml/mouse, i.p.; 5 mg/ml saline). A simultaneous intraperitoneal injection of soybean trypsin inhibitor (SBTI, 2.5 mg/mouse) almost completely suppressed the writhing reaction caused by kaolin (2.5 mg/mouse) for the first 10 min. The kaolin-induced writhing reaction was markedly potentiated by a simultaneous intraperitoneal injection of captopril (50 micrograms/mouse). At 60 min after kaolin injection during the disappearance of the writhing reaction, the reaction reappeared when captopril was injected, but reactions observed at this later stage were completely blocked by SBTI. Indomethacin, ibuprofen and alminoprofen inhibited the writhing reaction dose-dependently. Kaolin thus induces a clear and reproducible writing reaction, which might be mainly dependent on the action of bradykinin via activation of factor XII, and should prove to be a simple and convenient model of bradykinin-induced pain for the assessment of analgesic actions.


Phenotype conversion in Pseudomonas solanacearum due to spontaneous inactivation of PhcA, a putative LysR transcriptional regulator.
Phenotype conversion (PC) in Pseudomonas solanacearum is the coordinated change in production of extracellular polysaccharide and a variety of extracellular proteins, some of which contribute to virulence. Although PC is normally spontaneous, it is mimicked by transposon inactivation of the phcA locus (S. M. Brumbley and T. P. Denny, J. Bacteriol. 172:5677-5685, 1990). The DNA sequence of a 1.8-kb region from strain AW1 that contains phcA revealed one open reading frame that should encode a polypeptide of 38.6 kDa. The PhcA protein produced in Escherichia coli by using a T7 RNA polymerase expression system was of the predicted size. The deduced amino acid sequence of PhcA is similar to that of some members of the LysR transcriptional activator gene family, especially in the amino terminus, where a putative helix-turn-helix DNA-binding motif was identified. An analogous allele (phcA1) was cloned from the spontaneous PC mutant strain AW1-PC and found to be nonfunctional in complementation studies. When phcA1 was expressed in E. coli, the PhcA1 protein was 35.5 kDa, 3 kDa smaller than PhcA. Sequence analysis of phcA1 and chimeric constructs of phcA and phcA1 confirmed that PhcA1 is truncated by a 2-bp insertion 147 nucleotides upstream of the carboxyl terminus of PhcA. Southern blot analysis of 10 additional independently isolated PC mutants of strain AW1 revealed that two strains have larger insertions (0.2 and 1.0 kb) within phcA. These results suggest that phcA encodes a DNA-binding protein that regulates the transcription of one or more of the genes involved in P. solanacearum virulence and that spontaneous PC can be attributed to one of several different insertions within this locus.


Tissue Engineering and Regenerative Medicine: New Trends and Directions-A Year in Review.
Tissue engineering (TE) is continuously evolving assimilating inputs from adjacent scientific areas and their technological advances, including nanotechnology developments that have been spawning the range of available options for the precise manipulation and control of cells and cellular environments. Simultaneously, with the maturation of the field, TE has a growing and marked impact in other fields, such as cancer and other diseases research, enabling tri-dimensional (3D) tumor/tissue models of increased complexity that more closely resemble living tissue dynamics, playing a decisive role in the development of new and improved therapies. Nevertheless, TE is still struggling with translational issues. On this matter, the advent of personalized and precision medicine has opened new perspectives, particularly with the striking evolutions enabled by 3D bioprinting technologies. Based on a modified methodology grounded in the past years' approach, we have identified and reviewed some of the most high-impact publications on the topics that are revolutionizing TE and helping to define the future directions of the field, namely: (1) New trends in TE: Personalized/precision regenerative medicine and 3D bioprinting, (2) Contributions of TE to other fields: microfabricated tissue-engineered 3D models for cancer and other diseases research, and (3) Diagnostic and theranostic tools: monitoring and real-time control of TE systems.


Risk factors associated with trajectories of mothers' depressive symptoms across the early parenting period: an Australian population-based longitudinal study.
Approximately 14 % of women experience depressive symptoms in the first postnatal year. Few studies have examined the persistence of symptoms beyond this time. This study aims to (a) assess the course of women's depressive symptoms from the first postnatal year to when their children were aged 6-7 years, (b) identify distinct groups of women defined by their symptom trajectories over time, and (c) identify antenatal and early postnatal risk factors associated with persistent symptoms. Data from 4,879 women participating in the Longitudinal Study of Australian Children were analysed using latent growth modelling and logistic regression to identify risk factors associated with class membership. For the overall sample, depressive symptoms were highest during the first postnatal year and then gradually decreased over 6-7 years. Two distinct classes were identified with the majority of women (84 %) reporting minimal symptoms over time, and 16 % experiencing persistently high symptoms. Risk factors were younger maternal age, being from a non-English speaking background, not completing high school, having a past history of depression, antidepressant use during pregnancy, child development problems, lower parenting self-efficacy, poor relationship quality, and stressful life events. This research identifies risk factors that may predispose mothers to enduring depressive symptoms, offering opportunities for early identification and targeted early intervention.


The sensitivity and specificity of cognitive screening instruments to detect cognitive impairment in older adults with severe psychiatric illness.
Older adults with severe psychiatric illness are often treated at community mental health centers (CMHCs) and these individuals commonly have numerous risk factors for cognitive impairment (CI). Brief cognitive screening instruments are frequently used to evaluate cognitive functioning in CMHCs, but the validity of these measures for detecting CI has not been adequately evaluated in this patient population. To determine the sensitivity and specificity of 2 cognitive screening measures (the Mini-Mental Status Examination [MMSE] and the Stroop Color and Word Test [SCWT]) for detecting CI in a sample of older adults with severe psychiatric illness. Data were collected from 52 older adults receiving services at a CMHC. Diagnosis of CI was made by a neuropsychologist. Sensitivity and specificity coefficients for 2 cutoff scores for the MMSE and the SCWT were calculated. A cutoff score of 25 on the MMSE yielded a sensitivity of 43.3% and a specificity of 90.4% for detecting CI, whereas a cutoff score of 21 yielded sensitivity of 13.1% and 100% specificity. Using an age- and education-corrected scaled score (SS) on the SCWT falling at or below 7 as the criterion the SCWT had 88.8% sensitivity and 36.8% specificity, whereas a cutoff score of 5 or below yielded sensitivity of 59.2% and specificity of 57.8%. Overall, the MMSE was found to be the more clinically useful cognitive screening tool for use in CMHC. Yet, because of the poor sensitivity of the MMSE for detecting CI in this patient population, alternative screening methods should be explored.


Endothelial heterogeneity and their relevance in cardiac development and coronary artery disease.
Micro- and macrovascular endothelial cells (ECs) are characterized by structural and functional heterogeneity, which is also reflected in their secretory activity. The root of this heterogeneity and related regulatory mechanisms are still poorly understood. During embryogenesis, microvascular ECs participate in organogenesis prior to the development of the fetal circulation, suggesting that ECs are capable of releasing paracrine trophogens, termed angiocrine factors (AFs). These are angiocrine growth factors, adhesion molecules, and chemokines, which are intended to promote morphogenesis and repair of the adjacent parenchyma/stroma where the vessels are located. There is a tissue and organ-specificity of AFs that traces the heterogeneity of ECs. This AF heterogeneity also traces how ECs respond to pathological conditions or exposure to cardiovascular risk factors. The study of the mechanisms that regulate endothelial and paracrine heterogeneity and that contribute to endotheliopathy represents a broad and as yet understudied area of research. A better understanding of the cellular and molecular mechanisms that regulate this heterogeneity, leading to endotheliopathy is an exciting challenge. In this brief review we will discuss experimental advances in the heterogeneity of ECs and their AF, with a focus on their involvement in the pathogenesis of coronary artery disease.


NSAID-gastroenteropathy: new aspects of pathogenesis and prevention.
Nonsteroidal anti-inflammatory drugs (NSAIDs) remain among the most commonly used medications because of their effectiveness in reducing pain and inflammation. Inhibitors of gastric acid secretion can substantially reduce the damaging effects of NSAIDs in the stomach and duodenum. However, there are no proven effective preventative or curative treatments for NSAID-induced enteropathy. In recent years, substantial progress has been made in better understanding the pathogenesis of NSAID-enteropathy, and in particular the interplay of enteric bacteria, bile and the enterohepatic recirculation of the NSAIDs. Moreover, it is becoming clear that suppression of gastric acid secretion significantly worsens NSAID-enteropathy.


'Preferential looking' for monocular and binocular acuity testing of infants.
A method is described for obtaining rapid and reliable estimates of acuity in infants, for both monocular and binocular viewing. The method depends on 'preferential looking', where the infant prefers to look at a striped pattern rather than a blank screen of matched mean luminance. A staircase procedure for testing is followed, with observations being recorded by a 'blind' observer (who does not know on which of the 2 screens the striped pattern is displayed). Monocular acuity estimates have been obtained for a group of infants 3 to 4 months old with normal refractions. Many of these infants show similar acuity values in the 2 eyes, with a few showing reliable differences between the eyes. To check reliability of the method a comparison of 2 independent interleaved staircase estimates of the same eye have been made. In general this check shows highly consistent estimates for a given eye of a given infant. Nearly all infants show slightly higher acuity estimates for binocular viewing than for monocular. The possible reasons for this difference are discussed. The clinical use of such a method is reported for a number of cases. The method has been found to be useful in a variety of clinical conditions where other available tests are not possible on young infants.


Molecular insights into the progression of crystalline silica-induced pulmonary toxicity in rats.
Identification of molecular target(s) and mechanism(s) of silica-induced pulmonary toxicity is important for the intervention and/or prevention of diseases associated with exposure to silica. Rats were exposed to crystalline silica by inhalation (15 mg m(-3), 6 h per day, 5 days) and global gene expression profile was determined in the lungs by microarray analysis at 1, 2, 4, 8 and 16 weeks following termination of silica exposure. The number of significantly differentially expressed genes (>1.5-fold change and <0.01 false discovery rate P-value) detected in the lungs during the post-exposure time intervals analyzed exhibited a steady increase in parallel with the progression of silica-induced pulmonary toxicity noticed in the rats. Quantitative real-time PCR analysis of a representative set of 10 genes confirmed the microarray findings. The number of biological functions, canonical pathways and molecular networks significantly affected by silica exposure, as identified by the bioinformatics analysis of the significantly differentially expressed genes detected during the post-exposure time intervals, also exhibited a steady increase similar to the silica-induced pulmonary toxicity. Genes involved in oxidative stress, inflammation, respiratory diseases, cancer, and tissue remodeling and fibrosis were significantly differentially expressed in the rat lungs; however, unresolved inflammation was the single most significant biological response to pulmonary exposure to silica. Excessive mucus production, as implicated by significant overexpression of the pendrin coding gene, SLC26A4, was identified as a potential novel mechanism for silica-induced pulmonary toxicity. Collectively, the findings of our study provided insights into the molecular mechanisms underlying the progression of crystalline silica-induced pulmonary toxicity in the rat. Published 2012. This article is a US Government work and is in the public domain in the USA.


Human tumor antigens for cancer vaccine development.
The adoptive transfer of tumor-infiltrating lymphocytes (TIL) along with interleukin (IL)-2 into autologous patients with cancer resulted in the objective regression of tumor, indicating that T cells play an important role in tumor regression. In the last few years, efforts have been made towards understanding the molecular basis of T-cell-mediated antitumor immunity and elucidating the molecular nature of tumor antigens recognized by T cells. Tumor antigens identified thus far could be classified into several categories: tissue-specific differentiation antigens, tumor-specific shared antigens and tumor-specific unique antigens. CD4+ T cells play a central role in orchestrating the host immune response against cancer, infectious diseases and autoimmune diseases, and we thus have attempted to identify major histocompatibility complex (MHC) class II-restricted tumor antigens as well. The identification of tumor rejection antigens provides new opportunities for the development of therapeutic strategies against cancer. This review will summarize the current status of MHC class I- and class II-restricted human tumor antigens, and their potential application to cancer treatment.


Current thoughts on the viral etiology of certain human cancers: The Richard and Hinda Rosenthal Foundation Award lecture.
The study of retroviruses now has direct relevance to the understanding of tumorigenesis in humans. This came about through direct demonstration of retroviruses as etiological agents in certain human tumors and through the discovery of a set of cellular genes (onc genes) that may play important roles in normal and abnormal cell growth by their association with certain animal retroviruses. Cellular onc genes are a group of evolutionarily conserved sequences which are homologous to the transforming genes (v-onc) of oncogenic retroviruses. Although their functions in normal cells are largely not known, the sequence homology between cellular onc genes and the transforming v-onc genes is consistent with the idea that neoplastic transformation may, in some cases, be due to abnormal expression of these genes. We have approached this problem by molecular cloning of the human c-onc genes, using these as probes to examine the levels of expression and possible modification of these genes in different neoplastic and normal cells, and by determining their precise locations on the human chromosomes to correlate with known chromosomal alterations in human tumors. Through these studies, we provided evidence for gene amplification and chromosomal translocation as two mechanisms for c-onc activation in tumor cells and implicated the c-myc gene in Burkitt's lymphomas. Human T-cell leukemia virus is a family of related T-lymphotropic viruses isolated from humans. This is the first and thus far the only exogenous human retrovirus identified. A subgroup of this family, human T-cell leukemia virus I, is etiologically associated with a distinct subtype of mature T-cell cancer called adult T-cell leukemia-lymphoma. This association is borne out by extensive seroepidemiology which revealed several regions of the world, including Southwestern Japan, the Caribbean Islands, and Africa, to be endemic; by demonstration of viral sequences clonally integrated in the adult T-cell leukemia cells; and, more remarkably, by the capacity of the virus to transform normal human T-cells in culture and in effect reproduce in vitro some of the in vivo leukemogenic events. Other subgroups that are distantly related to human T-cell leukemia virus I have been obtained from a patient with T-cell hairy cell leukemia and patients with acquired immunodeficiency syndrome. The full disease spectrum of these viruses remains to be determined.


The Treatment Efficiency and Microbiota Analysis of Sapindus mukorossi Seed Oil on the Ligature-Induced Periodontitis Rat Model.
Periodontitis is a common oral disease mainly caused by bacterial infection and inflammation of the gingiva. In the prevention or treatment of periodontitis, anti-bacterial agents are used to inhibit pathogen growth, despite increasing levels of bacterial resistance. Sapindus mukorossi Gaertn (SM) seed oil has proven anti-bacterial and anti-inflammation properties. However, the possibility of using this plant to prevent or treat periodontitis has not been reported previously. The aim of this study was to evaluate the effects of SM oil on experimental periodontitis in rats by using micro-CT and microbiota analysis. The distance between cementoenamel junction (CEJ) and alveolar bone crest (ABC) on the sagittal micro-CT slide showed that total bone loss (TBL) was significantly lower in CEJ-ABC distances between SM oil and SM oil-free groups on Day 14. Histology data also showed less alveolar bone resorption, a result consistent result with micro-CT imaging. The microbiota analyzed at phylum and class levels were compared between the SM oil and SM oil-free groups on Day 7 and Day 14. At the phylum level, Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria were the dominant bacterium. Firmicutes in box plot analysis was significantly less in the SM oil group than in the SM oil-free group on Day 7. At the class level, Bacteroidia, Gammaproteobacteria, Bacilli, Clostridia, and Erysipelotrichia were the dominant bacteria. The bacteria composition proportion of Bacilli, Clostridiay, and Erysipelotrichia could be seen in the SM oil group significantly less than in t SM oil-free group on Day 7. Overall, the present results show that topical application of SM oil can reduce bone resorption and change bacteria composition in the ligature-induced periodontitis model. According to these results, it is reasonable to suggest SM oil as a potential material for preventing oral disease.


Evidence of changing sexual behaviours and clinical attendance patterns, alongside increasing diagnoses of STIs in MSM and TPSM.
Due to rising numbers of STI diagnosis and increasing prevalence of antimicrobial resistance, we explored trends in STI testing frequency and diagnoses, alongside sexual decision making and attitudes concerning condom use and HIV pre-exposure prophylaxis (PrEP) at a large urban UK sexual health clinic. We examined 66 528 electronic patient records covering 40 321 attendees between 2016 and 2019, 3977 of whom were men who have sex with men or trans persons who have sex with men (MSM/TPSM). We also explored responses from MSM/TPSM attendees sent an electronic questionnaire between November 2018 and 2019 (n=1975) examining behaviours/attitudes towards PrEP. We measured trends in STI diagnoses and sexual behaviours including condomless anal intercourse (CAI), using linear and logistic regression analyses. Tests resulting in gonorrhoea, chlamydia or syphilis diagnoses increased among MSM/TPSM from 13.5% to 18.5% between 2016 and 2019 (p<0.001). The average MSM/TPSM STI testing frequency increased from 1.5/person/year to 2.1/person/year (p=0.017). Gay MSM/TPSM had the highest proportions of attendances resulting in diagnoses, increasing from 15.1% to 19.6% between 2016 and 2019 (p<0.001) compared with bisexual/other MSM/TPSM increasing from 6.9% to 14.5% (p<0.001), alongside smaller but significant increases in non-MSM/TPSM from 5.9% to 7.7% (p<0.001).The proportion of MSM/TPSM clinic attendees reporting CAI in the previous 3 months prior to at least one appointment in a given year increased significantly from 40.6% to 45.5% between 2016 and 2019 (p<0.0001) and average number of partners from 3.8 to 4.5 (p=0.002). Of 617 eligible questionnaire responses, 339/578 (58.7%) HIV-negative and 29/39 (74.4%) HIV-positive MSM/TPSM indicated they would be more likely to have CAI with someone on PrEP versus not on PrEP. 358/578 (61.9%) HIV-negative respondents said that PrEP use would make them more likely to have CAI with HIV-negative partners. Rising numbers of STI diagnoses among MSM/TPSM are not attributable to increased testing alone. Increased CAI and number of partners may be attributable to evolving sexual decision making among PrEP users and their partners. Proportionally, bisexual/other MSM/TPSM have the steepest increase in STI diagnoses.


Factors predicting response to dopaminergic treatment for resting tremor of Parkinson's disease.
We aimed to evaluate the clinical factors predicting response to dopaminergic treatment for resting tremor in patients with Parkinson's disease (PD). Eighty-five PD patients with prominent resting tremor, defined as tremors of score greater than 3 in at least one limb on the Unified Parkinson's Disease Rating Scale (UPDRS), were divided into those responsive or nonresponsive to dopaminergic treatment. Responsiveness was defined as a reduction of at least two points for more than 3 months in the UPDRS tremor score. Of the 85 patients, 36 (42.4%) were responsive and 49 (57.6%) were nonresponsive to dopaminergic treatment. Initial UPDRS III score (P = 0.015) and Hoehn and Yahr stage (P = 0.010) were each significantly higher in the RG than in the NRG. UPDRS subscores for rigidity (P = 0.012), bradykinesia (P = 0.021) and postural impairment (P = 0.018) also correlated with responsiveness to dopaminergic treatment. Resting tremor in PD patients was more responsive to dopaminergic treatment when accompanied by moderate degrees of bradykinesia and rigidity than in patients without other prominent parkinsonian features.


Incentive salience: novel treatment strategies for major depression.
This article proposes that a recent shift in our understanding of dopamine function may support translational research to target deficits in positive emotions and reward processing in individuals with major depressive disorder (MDD). We review how dopamine functions to modulate approach behaviors in response to positive incentives, and we describe the incentive salience hypothesis, which posits that dopamine primarily modulates "wanting," or anticipatory reward, rather than "liking," or subjective pleasure. Although the incentive salience hypothesis was first proposed to help explain how drugs of abuse may reinforce harmful behaviors in the absence of continued pleasure or "liking," it may also provide a basis for understanding and developing new treatment approaches for MDD. Specifically, it provides a rationale for combining behaviorally activating psychotherapies and pro-dopaminergic agents to target impaired reward processing in MDD.


Dealing with grief related to loss by death and chronic pain: an integrated theoretical framework. Part 1.
Based on the present authors' research and several approaches to grief related to loss by death and nonmalignant chronic pain, the paper suggests a new integrated theoretical framework for intervention in clinical settings. An open qualitative review of the literature on grief theories was performed searching for a new integrated approach in the phenomenological tradition. We then investigated the relationship between grief, loss and chronic nonmalignant pain, looking for main themes and connections and how these could be best understood in a more holistic manner. Two main themes were formulated, "relearning the world" and "adaptation". Between these themes a continuous movement emerged involving experience such as: "despair and hope", "lack of understanding and insight", "meaning disruption and increased meaning", and "bodily discomfort and reintegrated body". These were identified as paired subthemes. Grief as a distinctive experience means that health care must be aimed at each individual experience and situation. Grief experience and working with grief are considered in terms of relearning the world while walking backwards and living forwards, as described in our integrated model. We consider that this theoretical framework regarding grief should offer an integrated foundation for health care workers who are working with people experiencing grief caused by death or chronic pain.


Differentially detected coherent population trapping resonances excited by orthogonally polarized laser fields.
We demonstrate the excitation and low-noise differential detection of a coherent population trapping (CPT) resonance with two modulated optical fields with orthogonal circular polarizations. When a microwave phase delay of lambda/4 is introduced in the optical path of one of the fields, the difference in the power transmitted through the cell in each polarization shows a narrow, dispersive resonance. The differential detection allows a high degree of suppression of laser-induced noise and will enable nearly shot-noise-limited operation of atomic frequency references and magnetometers based on CPT.


[Morphological changes in the liver of patients with pulmonary tuberculosis--carriers of hepatitis B virus].
Findings of morphologic studies of the liver bioptic material taken from 42 patients with different forms of pulmonary tuberculosis, hosts of Hbs-antigen, are described. It appears that marked dystrophic, inflammatory and necrotic changes occur in patients of this category, which should be taken into account when etiotropic and pathogenetic therapy is chosen.


Innate immunity during SARS-CoV-2: evasion strategies and activation trigger hypoxia and vascular damage.
Innate immune sensing of viral molecular patterns is essential for development of antiviral responses. Like many viruses, SARS-CoV-2 has evolved strategies to circumvent innate immune detection, including low cytosine-phosphate-guanosine (CpG) levels in the genome, glycosylation to shield essential elements including the receptor-binding domain, RNA shielding and generation of viral proteins that actively impede anti-viral interferon responses. Together these strategies allow widespread infection and increased viral load. Despite the efforts of immune subversion, SARS-CoV-2 infection activates innate immune pathways inducing a robust type I/III interferon response, production of proinflammatory cytokines and recruitment of neutrophils and myeloid cells. This may induce hyperinflammation or, alternatively, effectively recruit adaptive immune responses that help clear the infection and prevent reinfection. The dysregulation of the renin-angiotensin system due to down-regulation of angiotensin-converting enzyme 2, the receptor for SARS-CoV-2, together with the activation of type I/III interferon response, and inflammasome response converge to promote free radical production and oxidative stress. This exacerbates tissue damage in the respiratory system, but also leads to widespread activation of coagulation pathways leading to thrombosis. Here, we review the current knowledge of the role of the innate immune response following SARS-CoV-2 infection, much of which is based on the knowledge from SARS-CoV and other coronaviruses. Understanding how the virus subverts the initial immune response and how an aberrant innate immune response contributes to the respiratory and vascular damage in COVID-19 may help to explain factors that contribute to the variety of clinical manifestations and outcome of SARS-CoV-2 infection.


B-cell superantigens: molecular and cellular implications.
B cell superantigens are proteins that are capable of immunoglobulin variable region mediated binding interactions with the naive B cell repertoire at frequencies that are orders of magnitude greater than occur for conventional antigens. Within this review we discuss recent observations regarding the molecular basis of these interactions and the distribution of superantigen binding capacities in different human B cell populations. These findings and current predictions regarding the relevance of these proteins to the physiologic development of immune repertoires are also discussed.


Before the cradle and beyond the grave: a lifespan/settings-based framework for health promotion.
To develop a unique framework which combines the concepts of settings and lifespan where they are applied to health promotion. The influential World Health Organisation's 1986 Ottawa Charter for Health Promotion supported certain settings being nominated as unique social systems for enabling specific health promotion activity. These initially included a whole raft of proposed settings ranging from the micro to macro; these at the time mainly being hospitals, communities, schools, workplaces, cities, villages, islands and the home and family. Several other settings have since also been added to the list - which now include health-promoting universities and health-promoting prisons. Most of the mentioned settings have in more recent times being acknowledged in the nursing literature. Discursive. A critical examination and exploration of the existing health promotion literature related to both settings and lifespan. It is possible to combine the related, but hitherto unexplored, concepts of health promotion settings and lifespan. This has resulted in a useable framework to further assist practitioners with their health promotion work. What has not yet surfaced in both the nursing and the general health promotion literature is that most settings can be linked as a whole, not just by their geographical location and proximity to each other, but also to the fact that they tend to follow a linear direction that ranges across the total lifespan. Viewing health promotion in the way that this framework proposes further assists in locating and clarifying the often confused and contested position of health promotion in nursing.


[Experimental study of combined effects of benzo(a)pyrene and ortho-cresol on the body].
Ortho-cresol (o-cresol) produces a modifying influence on the effect produced by benz/a/pyrene (BP) under mice CC57B exposure to the combined peroral administration of the two chemicals. A low-toxic dose of o-cresol (Img) abruptly activates the effect of the same dose of BP (1 mg) according to all parameters (increase of the frequency, coefficient of multiplicity and degree of malignancy of tumours, shortening of the latency period) and somewhat inhibits its activity when administered before or after BP. Simultaneous administration of o-cresol in a ++super-toxic dose (10 mg) and BP in an optimal dose (5 mg) does not change the frequency of tumours, as compared to the control, however, inhibits the progression of induces neoplasms, which is manifest in the decrease of the frequency of malignancy, multiplicity of appearance and lengthening of the time of the onset of their malignization. Simultaneous administration of o-cresol in the dose relevant to the MAC for water does not change the carcinogenic activity of BP, which testifies to the necessity of sanitary control of observing hygienic regulations for both chemicals, as the most effective measure of prophylaxis of the malignant tumours morbidity of the population.


Conformations of intrinsically disordered proteins are influenced by linear sequence distributions of oppositely charged residues.
The functions of intrinsically disordered proteins (IDPs) are governed by relationships between information encoded in their amino acid sequences and the ensembles of conformations that they sample as autonomous units. Most IDPs are polyampholytes, with sequences that include both positively and negatively charged residues. Accordingly, we focus here on the sequence-ensemble relationships of polyampholytic IDPs. The fraction of charged residues discriminates between weak and strong polyampholytes. Using atomistic simulations, we show that weak polyampholytes form globules, whereas the conformational preferences of strong polyampholytes are determined by a combination of fraction of charged residues values and the linear sequence distributions of oppositely charged residues. We quantify the latter using a patterning parameter κ that lies between zero and one. The value of κ is low for well-mixed sequences, and in these sequences, intrachain electrostatic repulsions and attractions are counterbalanced, leading to the unmasking of preferences for conformations that resemble either self-avoiding random walks or generic Flory random coils. Segregation of oppositely charged residues within linear sequences leads to high κ-values and preferences for hairpin-like conformations caused by long-range electrostatic attractions induced by conformational fluctuations. We propose a scaling theory to explain the sequence-encoded conformational properties of strong polyampholytes. We show that naturally occurring strong polyampholytes have low κ-values, and this feature implies a selection for random coil ensembles. The design of sequences with different κ-values demonstrably alters the conformational preferences of polyampholytic IDPs, and this ability could become a useful tool for enabling direct inquiries into connections between sequence-ensemble relationships and functions of IDPs.


Non-invasive method of measuring bilirubin levels in newborn infants.
We present the results of an initial trial of a transcutaneous bilirubinometer under Australian conditions. The method is non-invasive and we obtained an acceptable degree of precision. The meter readings were influences by the site where reading was taken, and by phototherapy. Shading the recording site from phototherapy lights did not improve precision. We constructed regression lines for translation of meter recordings from forehead and abdomen to serum bilirubin levels.


Self-Perception of Transgender Adolescents After Gender-Affirming Treatment: A Follow-Up Study into Young Adulthood.
Purpose: Early medical treatment for transgender adolescents should contribute to healthy psychological development, including the development of positive self-perception. However, at present, there are no longitudinal studies that have examined whether current treatment approaches meet this expectation. Therefore, the aim of this single-arm retrospective study was to examine transgender adolescents' self-perception changes over the course of irreversible medical gender-affirming treatment. Methods: The total study sample consisted of 70 adolescents (49 trans men and 21 trans women). Self-perception was assessed before the start of gender-affirming hormone treatment (mean age = 14.65, standard deviation (SD) = 2.08) and at least 6 months after gender-affirming surgeries (mean age = 20.70, SD = 1.49) by Self-Perception Profile for Adolescents (SPPA). The SPPA is a self-report measure that examines self-perception on seven different domains: Scholastic competence, social acceptance, athletic competence, physical appearance, behavioral conduct, close friendship, and global self-worth. Multilevel modeling (random intercepts model) was conducted to determine the effect of time for all domains of self-perception. Results: It was found that the domains of physical appearance and global self-worth improved significantly over the course of treatment. No domain worsened significantly over the course of treatment. The domains of scholastic competence, social acceptance, athletic competence, and close friendship remained stable over time. Conclusion: This study provides the first suggestive evidence that irreversible gender-affirming treatment for adolescents could contribute to the development of a more positive self-perception.