The essential role of Saccharomyces cerevisiae CDC6 nucleotide-binding site in cell growth, DNA synthesis, and Orc1 association.
Saccharomyces cerevisiae Cdc6 is a protein required for the initiation of DNA replication. The biochemical function of the protein is unknown, but the primary sequence contains motifs characteristic of nucleotide-binding sites. To study the requirement of the nucleotide-binding site for the essential function of Cdc6, we have changed the conserved Lys114 at the nucleotide-binding site to five other amino acid residues. We have used these mutants to investigate in vivo roles of the conserved lysine in the growth rate of transformant cells and the complementation of cdc6 temperature-sensitive mutant cells. Our results suggest that replacement of Lys with Glu (K114E) and Pro (K114P) leads to loss-of-function in supporting cell growth, replacement of the Lys with Gln (K114Q) or Leu (K114L) yields partially functional proteins, and replacement with Arg yields a phenotype equivalent to wild-type, a silent mutation. To investigate what leads to the growth defects derived from the mutations at the nucleotide-binding site, we evaluated its gene functions in DNA replication by the assays of the plasmid stability and chromosomal DNA synthesis. Indeed, the K114P and K114E mutants showed the complete retraction of DNA synthesis. In order to test its effect on the G1/S transition of the cell cycle, we have carried out the temporal and spatial studies of yeast replication complex. To do this, yeast chromatin fractions from synchronized culture were prepared to detect the Mcm5 loading onto the chromatin in the presence of the wild-type Cdc6 or mutant cdc6(K114E) proteins. We found that cdc6(K114E) is defective in the association with chromatin and in the loading of Mcm5 onto chromatin origins. To further investigate the molecular mechanism of nucleotide-binding function, we have demonstrated that the Cdc6 protein associates with Orc1 in vitro and in vivo. Intriguingly, the interaction between Orc1 and Cdc6 is disrupted when the cdc6(K114E) protein is used. Our results suggest that a proper molecular interaction between Orc1 and Cdc6 depends on the functional ATP-binding of Cdc6, which may be a prerequisite step to assemble the operational replicative complex at the G1/S transition.


Genome-wide scan for bovine twinning rate QTL using linkage disequilibrium.
Twinning is a complex trait with negative impacts on health and reproduction, which cause economic loss in dairy production. Several twinning rate quantitative trait loci (QTL) have been detected in previous studies, but confidence intervals for QTL location are broad and many QTL are unreplicated. To identify genomic regions or genes associated with twinning rate, QTL analysis based on linkage combined with linkage disequilibrium (LLD) and individual marker associations was conducted across the genome using high-throughput single nucleotide polymorphism (SNP) genotypes. A total of 9919 SNP markers were genotyped with 200 sires and sons in 19 half-sib North American Holstein dairy cattle families. After SNPs were genotyped, informative markers were selected for genome-wide association tests and QTL searches. Evidence for twinning rate QTL was found throughout the genome. Thirteen markers significantly associated with twinning rate were detected on chromosomes 2, 5 and 14 (P < 2.3 x 10(-5)). Twenty-six regions on fourteen chromosomes were identified by LLD analysis at P < 0.0007. Seven previously reported ovulation or twinning rate QTL were supported by results of single marker association or LLD analyses. Single marker association analysis and LLD mapping were complementary tools for the identification of putative QTL in this genome scan.


Predicting Agents That Can Overcome 5-FU Resistance in Colorectal Cancers via Pharmacogenomic Analysis.
5-Fluorouracil (5-FU) is one of several chemotherapeutic agents in clinical use as a standard of care to treat colorectal cancers (CRCs). As an antimetabolite, 5-FU inhibits thymidylate synthase to disrupt the synthesis and repair of DNA and RNA. However, only a small proportion of patients benefit from 5-FU treatment due to the development of drug resistance. This study applied pharmacogenomic analysis using two public resources, the Genomics of Drug Sensitivity in Cancer (GDSC) and the Connectivity Map, to predict agents overcoming 5-FU resistance in CRC cells based on their genetic background or gene expression profile. Based on the genetic status of adenomatous polyposis coli (APC), the most frequent mutated gene found in CRC, we found that combining a MEK inhibitor with 5-FU exhibited synergism effects on CRC cells with APC truncations. While considering the gene expression in 5-FU resistant cells, we demonstrated that targeting ROCK is a potential avenue to restore 5-FU response to resistant cells with wild-type APC background. Our results reveal MEK signaling plays a pivotal role in loss-of-function, APC-mediated 5-FU resistance, and ROCK activation serves as a signature in APC-independent 5-FU resistance. Through the use of these available database resources, we highlight possible approaches to predict potential drugs for combinatorial therapy for patients developing resistance to 5-FU treatment.


Role of mineralocorticoids and glucocorticoids in blood pressure regulation in normotensive rats.
The separate role of mineralocorticoid and glucocorticoid hormone action in maintaining arterial pressure was studied in normotensive rats. Four groups were prepared: adrenalectomized (ADX) rats given 6 micrograms aldosterone/24 h (ALDO; n = 9) or 10 micrograms dexamethasone/24 h (DEX; n = 9) by intraperitoneal Alzet pumps, shamoperated controls (control; n = 10) and ADX rats with no hormone replacement (ADX; n = 9). All groups were given 1% NaCl + 2.5% glucose drinking solution. Measurements of plasma corticosterone and aldosterone and urinary aldosterone excretion confirmed the adequacy of the experimental groups. Forty-eight hours after ADX or sham, base-line intra-arterial mean arterial pressure (MAP) in conscious undisturbed rats was similar in the four groups. Captopril (1 mg/kg iv) produced a similar reduction in MAP in ALDO (-11 +/- 2 mmHg) and DEX (-12 +/- 1 mmHg) groups, despite a lower plasma renin activity (PRA) in ALDO (2.0 +/- 0.7 and 6.0 +/- 1.5 ng X ml-1 X h-1, respectively; P less than 0.05). dP (Me)TyrAVP (50 micrograms/kg iv) caused a greater decrease in MAP in ALDO (-15 +/- 3 mmHg) than in DEX (-8 +/- 1 mmHg; P less than 0.05). Combined blockade with both antagonists resulted in a greater MAP reduction in ALDO (-29 +/- 4 mmHg) than in DEX (-15 +/- 4 mmHg; P less than 0.05). These results indicate that glucocorticoid hormone action maintains arterial pressure in ADX rats by mechanisms similar to normal rats and largely independent of the renin-angiotensin system and vasopressin. In contrast, mineralocorticoid replacement alone in ADX rats requires increased participation of both peptide systems for maintenance of arterial pressure.


Factors associated with delays in treatment initiation after tuberculosis diagnosis in two districts of India.
Excessive time between diagnosis and initiation of tuberculosis (TB) treatment contributes to ongoing TB transmission and should be minimized. In India, Revised National TB Control Programme (RNTCP) focuses on indicator start of treatment within 7 days of diagnosis for patients with sputum smear-positive PTB for monitoring DOTS implementation. To determine length of time between diagnosis and initiation of treatment and factors associated with delays of more than 7 days in smear-positive pulmonary TB. Using existing programme records such as the TB Register, treatment cards, and the laboratory register, we conducted a retrospective cohort study of all patients with smear-positive pulmonary TB registered from July-September 2010 in two districts in India. A random sample of patients with pulmonary TB who experienced treatment delay of more than 7 days was interviewed using structured questionnaire. 2027 of 3411 patients registered with pulmonary TB were smear-positive. 711(35%) patients had >7 days between diagnosis and treatment and 262(13%) had delays >15 days. Mean duration between TB diagnosis and treatment initiation was 8 days (range = 0-128 days). Odds of treatment delay >7 days was 1.8 times more likely among those who had been previously treated (95% confidence interval [CI] 1.5-2.3) and 1.6 (95% CI 1.3-1.8) times more likely among those diagnosed in health facilities without microscopy centers. The main factors associated with a delay >7 days were: patient reluctance to start a re-treatment regimen, patients seeking second opinions, delay in transportation of drugs to the DOT centers and delay in initial home visits. To conclude, treatment delay >7 days was associated with a number of factors that included history of previous treatment and absence of TB diagnostic services in the local health facility. Decentralized diagnostic facilities and improved referral procedures may reduce such treatment delays.


The phosphate regulating hormone fibroblast growth factor-23.
Over the last decade, the regulation of phosphate (Pi) homeostasis has been under intense investigation. By utilizing modern biochemical and genetic tools, the pathophysiological mechanisms behind several known hereditary and acquired hypo- and hyperphosphatemic diseases have been clarified. The results of these efforts have opened new insights into the causes of Pi dysregulation and hereby also the physiological mechanisms determining Pi homeostasis. Although several potential Pi-regulating proteins have been discovered and investigated, current data strongly argues for fibroblast growth factor-23 (FGF23), a hormonal factor produced in bone, as a particularly important regulator of Pi homeostasis. In this article, we review the discovery of the FGF23 protein, as well as its biochemistry, localization of production, receptor specificity and mechanisms of action.


COVID-19 - A Covert Catalyst for Pedagogical Stocktake and Transformation: Perspectives of a Global Hub.
This article was migrated. The article was marked as recommended. Education in Hong Kong was shifted online on an abrupt and massive scale as the city faced unprecedented disruptions, first from social unrest in 2019 and then again with the COVID-19 pandemic. Concurrent modernization initiatives since early 2019 in The University of Hong Kong's Medical Faculty (HKUMed), conferred a fortuitous head start for this rapid change. Pre-clinical and clinical teaching were restructured for online delivery through e-learning solutions for didactic teaching, and new innovative approaches were developed to convert bedside to"webside" teaching. E-learning in the current circumstances provided necessary social distancing while being pedagogically sound. Students were also able to develop key communication and collaboration skills via online platforms, developing digital skills critical to their future profession. However, unforeseen issues including socioeconomic inequality, privacy concerns, and social isolation became apparent and should be addressed as medical education progresses further down the digital path. The goal must entail a sustainable and scholarly approach towards optimizing medical education in an increasingly online environment. This will help safeguard the medical curriculum against disruption and empower future medical professionals for tomorrow's practice. Here, we share experiences and perspectives from educators in a global city characterised by land scarcity and income inequality.


[Role of black bean Phaseolus vulgaris on the nutritional status of Guatemalan population].
Guatemala provides an example of epidemiological superposition, in which health problems typical of developed countries and developing countries are both observed. Nutritional deficiencies in some micronutrients like vitamin A and iron coexist alongside chronic diseases such as diabetes type II and cardiovascular diseases. The importance of black beans in the normal Guatemala diet is well known:70g per capita of black beans are consumed daily. Black beans are an important sources of protein and energy in the diet. They contain "lente" digestion carbohydrates and a high proportion of non-digested carbohydrates that may be fermented in the large intestine. Theses types of carbohydrates are associated with a low glycemic response, low serum cholesterol levels, and a decrease of colon cancer risk factors. These physiological effects may be related to colonic fermentation end products (propionic and butyric acids). Black beans also contain several antinutritional compounds (enzymatic inhibitors, haemaglutenins, saponins and phytic acid, etc.), some of them thermolabiles that are partially eliminated during culinary processes and may modify the nutritional quality of beans. Black beans play a crucial role in the etiology of several diseases in Guatemala.


PotentialNet for Molecular Property Prediction.
The arc of drug discovery entails a multiparameter optimization problem spanning vast length scales. The key parameters range from solubility (angstroms) to protein-ligand binding (nanometers) to in vivo toxicity (meters). Through feature learning-instead of feature engineering-deep neural networks promise to outperform both traditional physics-based and knowledge-based machine learning models for predicting molecular properties pertinent to drug discovery. To this end, we present the PotentialNet family of graph convolutions. These models are specifically designed for and achieve state-of-the-art performance for protein-ligand binding affinity. We further validate these deep neural networks by setting new standards of performance in several ligand-based tasks. In parallel, we introduce a new metric, the Regression Enrichment Factor EFχ (R), to measure the early enrichment of computational models for chemical data. Finally, we introduce a cross-validation strategy based on structural homology clustering that can more accurately measure model generalizability, which crucially distinguishes the aims of machine learning for drug discovery from standard machine learning tasks.


Symptom association probability and symptom sensitivity index: preferable but still suboptimal predictors of response to high dose omeprazole.
Twenty four hour oesophageal pH monitoring is frequently used to quantify the association between a patient's symptom and gastro-oesophageal reflux. Three indices (symptom association probability (SAP), symptom index (SI), and symptom sensitivity index (SSI)) are used to quantify and establish this relation. The aim of the present study was to compare these indices against the omeprazole test (OT) as an objective indicator of reflux induced symptoms. Fifty two patients with a predominant symptom of heartburn were enrolled from gastroenterology and primary care clinics. Baseline symptom score was calculated at the fist visit. All patients underwent 24 hour oesophageal pH monitoring, and symptom-reflux association indices were calculated. All patients were placed on high dose omeprazole (40 mg in the morning, 20 mg at night) after completion of pH monitoring and symptom score was recorded again after one week. Thirty eight patients completed the study. All three indices were significantly related to each other (p<0.001). SAP and SSI (with a new cut off of 1.3, but not with the commonly used 5%) had statistically significant relations with OT (p<0.05 for both). SSI had the highest positive and negative predictive values and sensitivity. The specificity of SSI and SAP was equal and lower than SI. Areas under the receiver operating characteristic (ROC) curve for the three indices were not significantly different from each other or from a hypothetical non-discriminating test. Per cent time pH <4, sex, and age had no relation to OT and no effect on its correlation with association indices. No cut off point could be found at which the results of SI could be related significantly to the OT results. SAP and SSI are significantly related to symptomatic response to high dose omeprazole; however, they are far from perfect, with a significant number of discordant cases as well as relatively small areas under the ROC curves. We suggest that the new cut off of 1.3 be used for SSI in the future. Further research is needed to identify possible methods to improve the discrimination power of these indices or to identify possible patient characteristics that may affect this relation.


A Swedish translation and validation of the Mother-to-Infant Bonding Scale.
Aim: This study aimed to test initial validity, reliability, and feasibility of the Mother-to-Infant Bonding Scale in a sample of Swedish mothers. Methods: A translation was performed through 11 steps using a forward-backward bilingual technique. For criterion validity, the Swedish translation of the Mother-to-Infant Bonding Scale (S-MIBS) was compared with the Postpartum Bonding Questionnaire, sub-scale 1 (PBQ1) and 2 (PBQ2) and Edinburgh Postnatal Depression Scale (EPDS) in a sample of 63 Swedish mothers. Internal consistency was calculated with Cronbach's alpha. For feasibility testing, the mothers were asked to grade their experience of S-MIBS and PBQ on a four-point scale. Results: The results show a correlation between S-MIBS and PBQ1 (r=0.80, p<0.001), PBQ2 (r=0.69, p<0.001) and EPDS (r=0.44, p<0.001). Internal consistency was α=0.68. Most mothers (93.1%) found S-MIBS to be easy or very easy to complete compared with PBQ (88.7%). Conclusions: The initial testing of the Swedish translation of the Mother-to-Infant Bonding Scale shows usability to measure the mother's emotions towards her healthy full-term infant.


The Aqueous Extract of Portulaca Oleracea Ameliorates Neurobehavioral Dysfunction and Hyperglycemia Related to Streptozotocin-Diabetes Induced in Ovariectomized Rats.
Diabetes mellitus is one of the most common causes of neuropathy. Although antioxidant and antidiabetic effects of the aqueous extract of purslane (Portulaca oleracea) (AEOP) have been demonstrated before by other researchers, we did not find any study that assessed the psychobiological effects of AEOP in diabetes induced animals. Thirty ovariectomized (OVX) female Wistar rats were randomly divided into 3 groups of control, Dia and Dia+AEOP. The latter group was orally treated by 300 mg/kg of AEOP for 35 days. Dia and Dia+AEOP groups were made diabetic by IP injection of 60 mg/kg of streptozotocin (STZ). The psychobiological effects of AEOP were assessed by Morris water maze (MWM), elevated plus maze (EPM), forced swimming test (FST) and tail pinch stressor (TPS). AEOP significantly decreased hyperglycemia (p<0.001). Diabetes significantly decreased their spatial cognitive performance at the training trial as well as the total distance traveled at the probe trial in MWM (p<0.05). All the diabetes related deficits at training trials were improved by AEOP treatment (p<0.05). AEOP treatment not only improved the motor deficit of Dia group in EPM, but also showed anxiolytic effects compared to both control and Dia groups (p<0.05). In the FST, no differences were observed between any groups (p>0.05). Diabetes significantly increased their non-functional masticatory activity in TPS (p≤0.001) while it was improved in Dia+AEOP group. We showed that AEOP has significant anxiolytic effects and it can improve spatial cognitive performance, locomotor deficit and stress in diabetic OVX rats.


Bovine pericardium retail preserved in glutaraldehyde and used as a vascular patch.
In this study we evaluated the performance of bovine pericardium preserved in glutaraldehyde used as a vascular patch. Fourteen young pigs, six females and eight males, weighting 10.3 - 18.4 kg were used in our study. We implanted three remnants in each pig, two in the abdominal aorta and one was juxtaposed to the peritoneum. The smooth face (SF) and rough face (RF) of each remnant were implanted turned to the vessel inner portion and one remnant was juxtaposed to the peritoneum. The animals were sacrificed in 4.5 - 8 months after surgery (75 - 109 kg). The remnants were assessed for aorta wall, fibroses formation in inner apposition and calcification related to the face turned to the vessel inner portion. The rough face showed a lower dilatation level compared to the face implanted in adjacent aorta. There was no difference between intensity and/or incidence of graft calcification when the superficies were compared. The bovine pericardium preserved in glutaraldehyde did not show alterations in its structure when implanted with different faces turned to the inner portion of vessel. When turned to the inner portion of the vessel, the rough face of the remnant presented a lower dilatation in relation to the adjacent aorta and a better quality of endothelium layer and did not show a difference between intensity and/or incidence of graft calcification.


Effects of time of L-ornithine administration on the diurnal rhythms of plasma growth hormone, melatonin, and corticosterone levels in mice.
The synthesis and secretion of many hormones such as growth hormone (GH), melatonin, and corticosterone, exhibit temporal variations over each day and night. Oral administration of several nutritional factors, including L-ornithine, modulates these hormonal secretions and induces an acute increase in plasma GH levels. However, the impact of L-ornithine on the diurnal rhythms of hormone secretion remains unclear. In this study, we evaluated whether the diurnal rhythms of plasma GH, melatonin, and corticosterone secretion were altered by the daily administration of L-ornithine as well as the timing of the administration, in CBA/N mice. Our results showed that the plasma GH levels that peaked at light phase were amplified by L-ornithine (500 mg/kg) administered at Zeitgeber time (ZT) 22, but not at ZT10. Additionally, L-ornithine (1000 mg/kg) administered at ZT22 advanced the onset of the nocturnal rise of melatonin, which resulted in the elongation of the melatonin peak. On the other hand, L-ornithine (500 and 1000 mg/kg) administered at ZT10, but not at ZT22, suppressed the diurnal rhythm peaks of plasma corticosterone. The effects of L-ornithine on plasma GH rhythms lasted for at least 2 days after cessation of the daily administration. Running wheel activity during the active phase was slightly elevated by L-ornithine administration at ZT22, but the overall patterns were only slightly affected. L-Ornithine levels in the plasma and hypophysis after a single administration of L-ornithine at ZT22 were lower than those after administration at ZT10, suggesting that the metabolic rate of L-ornithine differs between day and night. In conclusion, our data suggest that a daily administration of L-ornithine regulates the diurnal rhythms of GH, melatonin, and corticosterone in a manner dependent on administration time, which might be related to the diurnal rhythms of L-ornithine metabolism.


Steroid-induced Deficiency of Mucosal-associated Invariant T Cells in the Chronic Obstructive Pulmonary Disease Lung. Implications for Nontypeable Haemophilus influenzae Infection.
Mucosal-associated invariant T (MAIT) cells are a recently described abundant, proinflammatory T-cell subset with unknown roles in pulmonary immunity. Nontypeable Haemophilus influenzae (NTHi) is the leading bacterial pathogen during chronic obstructive pulmonary disease (COPD) exacerbations and is a plausible target for MAIT cells. To investigate whether MAIT cells respond to NTHi and the effects of inhaled corticosteroids (ICS) on their frequency and function in COPD. Eleven subjects with COPD receiving ICS, 8 steroid-naive subjects with COPD, and 21 healthy control subjects underwent phlebotomy, sputum induction, bronchoalveolar lavage, and endobronchial biopsy. Pulmonary and monocyte-derived macrophages were cultured in vitro with NTHi. Frequencies of Vα7.2+CD161+ MAIT cells, surface expression of the major histocompatibility complex-related protein 1 (MR1), and intracellular IFN-γ expression were measured by flow cytometry. MAIT-cell frequencies were reduced in peripheral blood of ICS-treated subjects with COPD (median 0.38%; interquartile range [IQR], 0.25-0.96) compared with healthy control subjects (1.8%; IQR, 1.4-2.5; P = 0.001) or steroid-naive patients with COPD (1.8%; IQR, 1.2-2.3; P = 0.04). MAIT cells were reduced in bronchial biopsies from subjects with COPD treated with steroids (0.73%; IQR, 0.46-1.3) compared with healthy control subjects (4.0%; IQR, 1.6-5.0; P = 0.02). Coculture of live NTHi increased macrophage surface expression of MR1 and induced IFN-γ from CD4 cells and CD8 cells, but most potently from MAIT cells (median IFN-γ-positive frequencies, 2.9, 8.6, and 27.6%, respectively). In vitro fluticasone and budesonide reduced MR1 surface expression twofold and decreased NTHi-induced IFN-γ secretion eightfold. MAIT cells are deficient in blood and bronchial tissue in steroid-treated, but not steroid-naive, COPD. NTHi constitutes a target for pulmonary MAIT-cell immune responses, which are significantly impaired by corticosteroids.


Molecular electrocatalysts for oxidation of hydrogen using earth-abundant metals: shoving protons around with proton relays.
Sustainable, carbon-neutral energy is needed to supplant the worldwide reliance on fossil fuels in order to address the persistent problem of increasing emissions of CO2. Solar and wind energy are intermittent, highlighting the need to develop energy storage on a huge scale. Electrocatalysts provide a way to convert between electrical energy generated by renewable energy sources and chemical energy in the form of chemical bonds. Oxidation of hydrogen to give two electrons and two protons is carried out in fuel cells, but the typical catalyst is platinum, a precious metal of low earth abundance and high cost. In nature, hydrogenases based on iron or iron/nickel reversibly oxidize hydrogen with remarkable efficiencies and rates. Functional models of these enzymes have been synthesized with the goal of achieving electrocatalytic H2 oxidation using inexpensive, earth-abundant metals along with a key feature identified in the [FeFe]-hydrogenase: an amine base positioned near the metal. The diphosphine ligands P(R)2N(R')2 (1,5-diaza-3,7-diphosphacyclooctane with alkyl or aryl groups on the P and N atoms) are used as ligands in Ni, Fe, and Mn complexes. The pendant amines facilitate binding and heterolytic cleavage of H2, placing the hydride on the metal and the proton on the amine. The pendant amines also serve as proton relays, accelerating intramolecular and intermolecular proton transfers. Electrochemical oxidations and deprotonations by an exogeneous amine base lead to catalytic cycles for oxidation of H2 (1 atm) at room temperature for catalysts derived from [Ni(P(Cy)2N(R')2)2](2+), Cp(C6F5)Fe(P(tBu)2N(Bn)2)H, and MnH(P(Ph)2N(Bn)2)(bppm)(CO) [bppm = (PAr(F)2)2CH2]. In the oxidation of H2 catalyzed by [Ni(P(Cy)2N(R')2)2](2+), the initial product observed experimentally is a Ni(0) complex in which two of the pendant amines are protonated. Two different pathways can occur from this intermediate; deprotonation followed by oxidation occurs with a lower overpotential than the alternate pathway involving oxidation followed by deprotonation. The Mn cation [Mn(P(Ph)2N(Bn)2)(bppm)(CO)](+) mediates the rapid (>10(4) s(-1) at -95 °C), reversible heterolytic cleavage of H2. Obtaining the optimal benefit of pendant amines incorporated into the ligand requires that the pendant amine be properly positioned to interact with a M-H or M(H2) bond. In addition, ligands are ideally selected such that the hydride-acceptor ability of the metal and the basicity of a pendant are tuned to give low barriers for heterolytic cleavage of the H-H bond and subsequent proton transfer reactions. Using these principles allows the rational design of electrocatalysts for H2 oxidation using earth-abundant metals.


[Effect of adaptation to cold on the alpha1- and beta-adrenergic reactions of arterial vessels of the small intestine in rabbits].
Changes in major paraments of alpha 1- and beta-adrenergic responses (EC50 and Pm) were studied in the intestine arterial blood vessels of rabbits adapted to cold for 1-30 days (daily cold exposures for 6 hours at -10 degrees C). It was shown that responses to phenylephrine, noradrenaline, adrenaline (alpha 1-agonists), isopropylnoradrenaline (beta-agonist) corresponded to the equation p = (Pm.An)/(EC50n + An) with n = 1 and n = 2, respectively. Adaptation to cold induced radically different changes in the major parameters of alpha- and beta-adrenergic responses. In the alpha-adrenergic responses, the parameters EC50 and Pm changed reciprocally. In the beta-adrenergic response, only Pm value changed while EC50 did not differ from the control over the entire period of adaptation to cold. The pronounced differences from the control gradually decreased within 1-30 days of adaptation.


Virtual simulation debriefing in health professions education: a scoping review protocol.
The objective of this scoping review is to identify and map the existing literature on virtual simulation debriefing methods utilized in health professions education. Virtual simulation has emerged as a feasible alternative to in-person learning, allowing learners to continue their education despite constraints of space, finances, and clinical placement opportunities. Virtual simulation has proven to be a vital resource for health care students during the COVID-19 pandemic. While virtual simulation provides students with continued opportunities to develop knowledge and critical thinking in a safe environment, debriefing is a crucial step for successful knowledge uptake and deeper learning. Several studies have examined this topic in various health care settings; however, there are currently no scoping reviews that have explored virtual simulation debriefing in health professions education. This review will consider primary and secondary source articles that explore debriefing of virtual simulation within any undergraduate or graduate health education programs. Any setting that provides virtual simulation and debriefing, in any country, will be included. The review will be conducted in accordance with JBI methodology for scoping reviews and will search the following databases: Cochrane Library, JBI Evidence-based Practice Database, MEDLINE, CINAHL, Epistemonikos, Embase, ERIC, PsycINFO, Nursing and Allied Health Database, and Web of Science. Studies published from 2016 onward will be considered. The data extracted will include specific details about the concept, context, studymethod, and critical findings relevant to the review objective. Data will be presented in diagrammatic or tabular format in a manner that aligns with the objective of this scoping review. Open Science Framework https://osf.io/36s5x.


Perifosine enhances mTORC1-targeted cancer therapy by activation of GSK3β in NSCLC cells.
mTORC1 inhibitors, including rapamycin and its analogs, have been actively studied both pre-clinically and clinically. However, the single treatment of mTORC1 inhibitors has been modest in most cancer types. We have previously demonstrated that the activation of PI3K/Akt and MEK/ERK signaling pathways attenuates the anticancer efficacy of mTORC1 inhibitors. In this study, we report that mTORC1 inhibition also phosphorylates and inactivates GSK3β, which is a tumor suppressor in lung cancer. Moreover, we show that perifosine, as an Akt inhibitor, decreases rapamycin-induced phosphorylation of GSK3β and elevated p-GSK3β levels in rapamycin-resistant cell lines. Combination of perifosine with mTORC1 inhibitors showed enhanced anticancer efficacy both in cell cultures and in a xenograft mouse model. In addition, perifosine inhibits the growth of both rapamycin sensitive and resistant A549 cells. However, inhibition of GSK3β by a selective inhibitor- LiCl, or downregulation of GSK3β expression by siRNA, reverses the growth inhibitory effects of perifosine on rapamycin resistant cells, suggesting the important role of GSK3β activation in enhancing mTORC1 inhibitors efficacy by perifosine. Thus, our results provide a potential therapeutic strategy to enhance mTORC1-targeted cancer therapy by using perifosine or targeting GSK3β.


In vivo genetic cell lineage tracing reveals that oviductal secretory cells self-renew and give rise to ciliated cells.
The epithelial lining of the fallopian tube is vital for fertility, providing nutrition to gametes and facilitating their transport. It is composed of two major cell types: secretory cells and ciliated cells. Interestingly, human ovarian cancer precursor lesions primarily consist of secretory cells. It is unclear why secretory cells are the dominant cell type in these lesions. Additionally, the underlying mechanisms governing fallopian tube epithelial homoeostasis are unknown. In the present study, we showed that across the different developmental stages of mouse oviduct, secretory cells are the most frequently dividing cells of the oviductal epithelium. In vivo genetic cell lineage tracing showed that secretory cells not only self-renew, but also give rise to ciliated cells. Analysis of a Wnt reporter mouse model and various Wnt target genes showed that the Wnt signaling pathway is involved in oviductal epithelial homoeostasis. By developing two triple-transgenic mouse models, we showed that Wnt/β-catenin signaling is essential for self-renewal as well as the differentiation of secretory cells. In summary, our results provide mechanistic insight into oviductal epithelial homoeostasis.


Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains.
The endocannabinoid system is still poorly understood. Recently, the basic elements that constitute it, i.e., membrane receptors, endogenous ligands, and mechanisms for termination of the signaling process, have been partially characterized. There is a considerable lack of information, however, concerning the distribution, concentration, and function of those components in the human body, particularly during pathological events. We have studied the status of some of the components of the endocannabinoid system, fatty acid amide hydrolase and cannabinoid CB1 and CB2 receptors, in postmortem brains from patients with Alzheimer's disease. Using specific polyclonal antibodies, we have performed immunohistochemical analysis in hippocampus and entorhinal cortex sections from brains of Alzheimer's disease patients. Our results show that both fatty acid amide hydrolase and cannabinoid CB2 receptors are abundantly and selectively expressed in neuritic plaque-associated astrocytes and microglia, respectively, whereas the expression of CB1 receptors remains unchanged. In addition, the hydrolase activity seems to be elevated in the plaques and surrounding areas. Thus, some elements of the endocannabinoid system may be postulated as possible modulators of the inflammatory response associated with this neurodegenerative process and as possible targets for new therapeutic approaches.


Fast Threshold Image Segmentation Based on 2D Fuzzy Fisher and Random Local Optimized QPSO.
In the paper, a real-time segmentation method that separates the target signal from the navigation image is proposed. In the approaching docking stage, the navigation image is composed of target and non-target signal, which are separately bright spot and space vehicle itself. Since the non-target signals is the main part of the navigation image, the traditional entropy-related criterions and Ostu-related criterions will bring inadequate segmentation, while the mere 2D Fisher criterion will causes over-segmentation, all the methods show their shortages in dealing with this kind of case. To guarantee a precise image segmentation, a revised 2D fuzzy Fisher is proposed in the paper to make a trade-off between positioning target regions and retaining target fuzzy boundaries. First, to reduce redundant computations in finding the threshold pair, a 2D fuzzy Fisher criterion-based integral image is established by way of simplifying the corresponding fuzzy domains. Then, to quicken the convergence, a random orthogonal component is added in its quasi-optimum particle to enhance its local searching capacity in each iteration. Experimental results show its competence of quick segmentation.


Graphite pneumoconiosis and its declining prevalence in Sri Lanka.
A study of underground miners in a graphite mine in Sri Lanka was conducted in 1987. Twelve (3.4%) of the 340 workers examined had radiographic lesions suggestive of graphite pneumoconiosis. In comparison, a survey carried out in another mine in Sri Lanka in 1972 showed that 63 (18.3%) of the 344 workers examined had similar lesions. Though the two surveys were comparable, they were conducted in two different mines. Therefore, the conclusion that the reduction in the prevalence of graphic pneumoconiosis was due to the introduction of improved dust control measures could only be tentative.


Palmar and digital flexor tendon pulleys.
Retinacular structures, called pulleys, maintain the flexor tendons of the hand in constant relationship to the joint axes and promote economy and efficiency in finger flexion. This system is composed of the transverse carpal ligament, the palmar aponeurosis pulley, and the digital flexor pulley system. Of these three components, the digital pulleys are the most critical to finger flexion. In their normal state, these pulley components are ideal in all aspects including configuration and location, which accomodates a 260 degrees arc of motion without impingement and with minimum friction while at the same time using muscle tendon excursion that is well within the natural range of the muscle. An absent pulley results in an increased moment arm and requires increased tendon excursion to produce the same arc of motion. Because muscle excursion is not a limitless factor and is directly proportional to muscle fiber length, the effectiveness of tendon excursion is dependent on maintenance of the critical relationship between pulleys and the adjacent joints. Preservation and reconstruction of this system is based on knowledge of the anatomy and an understanding of the relative functional significance of each component of the system.


Production of Mannosylerythritol Lipids Using Oils from Oleaginous Microalgae: Two Sequential Microorganism Culture Approach.
Mannosylerythritol lipids (MELs) are biosurfactants with excellent biochemical properties and a wide range of potential applications. However, most of the studies focusing on MELs high titre production have been relying in the use of vegetable oils with impact on the sustainability and process economy. Herein, we report for the first time MELs production using oils produced from microalgae. The bio-oil was extracted from Neochloris oleoabundans and evaluated for their use as sole carbon source or in a co-substrate strategy, using as an additional carbon source D-glucose, on Moesziomyces spp. cultures to support cell growth and induce the production of MELs. Both Moesziomyces antarcticus and M. aphidis were able to grow and produce MELs using algae-derived bio-oils as a carbon source. Using a medium containing as carbon sources 40 g/L of D-glucose and 20 g/L of bio-oils, Moesziomyces antarcticus and M. aphidis produced 12.47 ± 0.28 and 5.72 ± 2.32 g/L of MELs, respectively. Interestingly, there are no significant differences in productivity when using oils from microalgae or vegetable oils as carbon sources. The MELs productivities achieved were 1.78 ± 0.04 and 1.99 ± 0.12 g/L/h, respectively, for M. antarcticus fed with algae-derived or vegetable oils. These results open new perspectives for the production of MELs in systems combining different microorganisms.


Incidence, histopathologic analysis and distribution of tumours of the hand.
The aim of this large collective and meticulous study of primary bone tumours and tumourous lesions of the hand was to enhance the knowledge about findings of traumatological radiographs and improve differential diagnosis. This retrospective study reviewed data collected from 1976 until 2006 in our Bone Tumour Registry. The following data was documented: age, sex, radiological investigations, tumour location, histopathological features including type and dignity of the tumour, and diagnosis. The retrospective analysis yielded 631 patients with a mean age of 35.9 ± 19.2 years. The majority of primary hand tumours were found in the phalanges (69.7%) followed by 24.7% in metacarpals and 5.6% in the carpals. Only 10.6% of all cases were malignant. The major lesion type was cartilage derived at 69.1%, followed by bone cysts 11.3% and osteogenic tumours 8.7%. The dominant tissue type found in phalanges and metacarpals was of cartilage origin. Osteogenic tumours were predominant in carpal bones. Enchondroma was the most commonly detected tumour in the hand (47.1%). All primary skeletal tumours can be found in the hand and are most often of cartilage origin followed by bone cysts and osteogenic tumours. This study furthermore raises awareness about uncommon or rare tumours and helps clinicians to establish proper differential diagnosis, as the majority of detected tumours of the hand are asymptomatic and accidental findings on radiographs.


Violating the Energy-Momentum Proportionality of Photonic Crystals in the Low-Frequency Limit.
We theoretically show that the frequency and momentum of a photon are not necessarily proportional to one another at low frequencies in photonic crystals comprising materials with positive- and negative-valued material properties. We rigorously determine closed-form conditions for the light cone to emanate from points other than the origin of k space, ultimately decoupling the first band from the origin and demonstrating light propagation at zero energy with nonzero crystal momentum. We also numerically show that first bands can originate from an arbitrary Bloch coordinate as well as from multiple coordinates simultaneously.


Progression of left ventricular diastolic dysfunction and risk of heart failure.
Heart failure incidence increases with advancing age, and approximately half of patients with heart failure have preserved left ventricular ejection fraction. Although diastolic dysfunction plays a role in heart failure with preserved ejection fraction, little is known about age-dependent longitudinal changes in diastolic function in community populations. To measure changes in diastolic function over time and to determine the relationship between diastolic dysfunction and the risk of subsequent heart failure. Population-based cohort of participants enrolled in the Olmsted County Heart Function Study. Randomly selected participants 45 years or older (N = 2042) underwent clinical evaluation, medical record abstraction, and echocardiography (examination 1 [1997-2000]). Diastolic left ventricular function was graded as normal, mild, moderate, or severe by validated Doppler techniques. After 4 years, participants were invited to return for examination 2 (2001-2004). The cohort of participants returning for examination 2 (n = 1402 of 1960 surviving [72%]) then underwent follow-up for ascertainment of new-onset heart failure (2004-2010). Change in diastolic function grade and incident heart failure. During the 4 (SD, 0.3) years between examinations 1 and 2, diastolic dysfunction prevalence increased from 23.8% (95% confidence interval [CI], 21.2%-26.4%) to 39.2% (95% CI, 36.3%-42.2%) (P < .001). Diastolic function grade worsened in 23.4% (95% CI, 20.9%-26.0%) of participants, was unchanged in 67.8% (95% CI, 64.8%-70.6%), and improved in 8.8% (95% CI, 7.1%-10.5%). Worsened diastolic dysfunction was associated with age 65 years or older (odds ratio, 2.85 [95% CI, 1.77-4.72]). During 6.3 (SD, 2.3) years of additional follow-up, heart failure occurred in 2.6% (95% CI, 1.4%-3.8%), 7.8% (95% CI, 5.8%-13.0%), and 12.2% (95% CI, 8.5%-18.4%) of persons whose diastolic function normalized or remained normal, remained or progressed to mild dysfunction, or remained or progressed to moderate or severe dysfunction, respectively (P < .001). Diastolic dysfunction was associated with incident heart failure after adjustment for age, hypertension, diabetes, and coronary artery disease (hazard ratio, 1.81 [95% CI, 1.01-3.48]). In a population-based cohort undergoing 4 years of follow-up, prevalence of diastolic dysfunction increased. Diastolic dysfunction was associated with development of heart failure during 6 years of subsequent follow-up.


Common fragile sites (CFS) and extremely large CFS genes are targets for human papillomavirus integrations and chromosome rearrangements in oropharyngeal squamous cell carcinoma.
Common fragile sites (CFS) are chromosome regions that are prone to form gaps or breaks in response to DNA replication stress. They are often found as hotspots for sister chromatid exchanges, deletions, and amplifications in different cancers. Many of the CFS regions are found to span genes whose genomic sequence is greater than 1 Mb, some of which have been demonstrated to function as important tumor suppressors. CFS regions are also hotspots for human papillomavirus (HPV) integrations in cervical cancer. We used mate-pair sequencing to examine HPV integration events and chromosomal structural variations in 34 oropharyngeal squamous cell carcinoma (OPSCC). We used endpoint PCR and Sanger sequencing to validate each HPV integration event and found HPV integrations preferentially occurred within CFS regions similar to what is observed in cervical cancer. We also found that many of the chromosomal alterations detected also occurred at or near the cytogenetic location of CFSs. Several large genes were also found to be recurrent targets of rearrangements, independent of HPV integrations, including CSMD1 (2.1Mb), LRP1B (1.9Mb), and LARGE1 (0.7Mb). Sanger sequencing revealed that the nucleotide sequences near to identified junction sites contained repetitive and AT-rich sequences that were shown to have the potential to form stem-loop DNA secondary structures that might stall DNA replication fork progression during replication stress. This could then cause increased instability in these regions which could lead to cancer development in human cells. Our findings suggest that CFSs and some specific large genes appear to play important roles in OPSCC. © 2016 Wiley Periodicals, Inc.


Nutrient and nonnutrient components of legumes, and its chemopreventive activity: a review.
Legumes in combination with other products are the staple food for a large part of the world population, especially the low-income fragment, because their seeds provide valuable amounts of carbohydrates, fiber, and proteins, and have an important composition of essential amino acids, the sulphured amino acids being the limiting ones. Furthermore, legumes also have nonnutritional compounds that may decrease the absorption of nutrients or produce toxic effects; however, it has been reported that depending on the dose, these nonnutritional compounds also have different bioactivities as antioxidant, hypolipidemic, hypoglycemic, and anticarcinogenic agents, which have been proven in scientific studies. It has been observed that in countries with a high consumption of legumes, the incidence of colorectal cancer is lower. Some studies have shown that legume seeds are an alternative chemopreventive therapy against various cancers especially colon; this was verified in various animal models of induced by azoxymethane, a colon specific carcinogenic compound, in which a diet was supplemented with different concentrations of beans, lentils, chickpeas, or soybeans, mostly. These studies have proven the anticancer activity of legumes in early stages of carcinogenesis. Therefore, it is important to review the information available to elucidate the chemopreventive mechanisms of action of legume compounds.


Terrorism--what can the psychiatrist do?
The 1970s have yielded many situations in which psychiatrists have been summoned by agents of the state for help in resolving terrorist-related crises. This paper tries to examine the evolving role of forensic psychiatrists as they participate in such situations and reviews some of the functions involved in open community/terrorist confrontations, closed community/terrorist confrontations, and psychiatrist/terrorist relations. Positive contributions have been made by psychiatrists, but there is a lack of available information to assist them in fulfilling their tasks. Specific recommendations are made that may be of benefit to the psychiatrist.


The interaction of Leishmania donovani promastigotes and human fibroblasts in vitro.
Leishmania donovani promastigotes derived from infected hamster spleens, in either log phase or stationary phase growth, associated with human foreskin fibroblasts in vitro and assumed the morphological characteristics of amastigotes. This apparent conversion was noted within hours at 26 degrees C, 32 degrees C or 37 degrees C; in the continued presence of promastigotes, increasing numbers of amastigote-like forms were seen for 2 weeks at 26 degrees C or 32 degrees C. At 37 degrees C amastigote-like forms declined sharply after 6 days. Multiplication of amastigote-like forms was not observed at any temperature, this was also true of freshly isolated amastigotes from hamster spleens which associated with fibroblasts but did not multiply. Approximately 0.1% of promastigotes appeared to convert per day. Amastigote-like forms were seen within fibroblasts by transmission electron microscopy, surrounded by a closely applied host membrane. Scanning electron microscopy showed promastigotes with their flagellae under or within fibroblasts, but phagocytosis was not observed. These experiments suggest that the conditions required for promastigote-to-amastigote conversion may be different than those required for amastigote multiplication, and the mammalian core body temperature may not be required for promastigote conversion.


Blood-Brain Delivery Methods Using Nanotechnology.
Pathologies of the brain, of which brain cancer, Alzheimer's disease, Parkinson's disease, stroke, and multiple sclerosis, are some of the most prevalent, and that presently are poorly treated due to the difficulties associated with drug development, administration, and targeting to the brain. The existence of the blood-brain barrier, a selective permeability system which acts as a local gateway against circulating foreign substances, represents the key challenge for the delivery of therapeutic agents to the brain. However, the development of nanotechnology-based approaches for brain delivery, such as nanoparticles, liposomes, dendrimers, micelles, and carbon nanotubes, might be the solution for improved brain therapies.


Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma.
Chronic persistent asthma is characterized by poorly reversible airflow obstruction and airways inflammation and remodelling. Histopathological studies of airways removed at post mortem from patients with severe asthma reveal marked inflammatory and architectural changes associated with airway wall thickening. Increased airway smooth muscle content, occurring as a result of hyperplastic and/or hypertrophic growth, is believed to be one of the principal contributors to airway wall thickening. In recent years, significant advances have been made in elucidating the mediators and the intracellular pathways that regulate proliferation of airway smooth muscle. The contribution that smooth muscle makes to persistent airflow obstruction may not, however, be limited simply to its increased bulk within the airway wall. Interest is growing in the possibility that reversible phenotypic modulation and increased heterogeneity of airway smooth muscle function may also be a feature of the asthmatic airway. This review focuses on possible mechanisms controlling smooth muscle phenotype heterogeneity as well as on the mediators and intracellular pathways implicated in its cellular proliferation. Particular attention is paid to mechanisms involving activation of the extracellular signal regulated kinase-, protein kinase C- and phosphoinositide 3-kinase-dependent pathways, since these appear to be the major candidate second messenger pathways for G protein- and tyrosine kinase-coupled receptor-stimulated proliferation.


Pharmacogenetics of oral antidiabetic drugs.
Oral antidiabetic drugs (OADs) are used for more than a half-century in the treatment of type 2 diabetes. Only in the last five years, intensive research has been conducted in the pharmacogenetics of these drugs based mainly on the retrospective register studies, but only a handful of associations detected in these studies were replicated. The gene variants in CYP2C9, ABCC8/KCNJ11, and TCF7L2 were associated with the effect of sulfonylureas. CYP2C9 encodes sulfonylurea metabolizing cytochrome P450 isoenzyme 2C9, ABCC8 and KCNJ11 genes encode proteins constituting ATP-sensitive K(+) channel which is a therapeutic target for sulfonylureas, and TCF7L2 is a gene with the strongest association with type 2 diabetes. SLC22A1, SLC47A1, and ATM gene variants were repeatedly associated with the response to metformin. SLC22A1 and SLC47A1 encode metformin transporters OCT1 and MATE1, respectively. The function of a gene variant near ATM gene identified by a genome-wide association study is not elucidated so far. The first variant associated with the response to gliptins is a polymorphism in the proximity of CTRB1/2 gene which encodes chymotrypsinogen. Establishment of diabetes pharmacogenetics consortia and reduction in costs of genomics might lead to some significant clinical breakthroughs in this field in a near future.


Effects of replacement therapies with clotting factors in patients with hemophilia: A systematic review and meta-analysis.
Different prophylactic and episodic clotting factor treatments are used in the management of hemophilia. A summarize of the evidence is needed inform decision-making. To compare the effects of factor replacement therapies in patients with hemophilia. We performed a systematic search in PubMed, Central Cochrane Library, and Scopus. We included randomized controlled trials (RCTs) published up to December 2020, which compared different factor replacement therapies in patients with hemophilia. Random-effects meta-analyses were performed whenever possible. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The study protocol was registered in PROSPERO (CRD42021225857). Nine RCTs were included in this review, of which six compared episodic with prophylactic treatment, all of them performed in patients with hemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means [RM]: 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups (p = 0.003, I2 = 82.9%). In addition, compared to the episodic treatment group, the annualized joint bleeding rate was lower in the low-dose prophylactic group (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic group (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic group (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates (CFCs), assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration. Our results suggest that prophylactic treatment (at either low, intermediate, or high doses) is superior to episodic treatment for bleeding prevention. In patients with hemophilia A, the bleeding rate seems to have a dose-response effect. However, no study compared different doses of prophylactic treatment, and all results had a very low certainty of the evidence. Thus, future studies are needed to confirm these results and inform decision making.


[Electrocardiographic diagnosis in atrioventricular discordance].
The ECG of 37 patients with atrioventricular discordance were studied and divided in two main groups: I) Situs solitus and II) situs inversus, either a) without associated defects or b) with associated defects. It was concluded: 1) The first vector of ventricular activation, oriented in the same sense of that of atrial activation is a fundamental diagnostic sign; 2) The preponderance of anatomical right ventricle, leads to the diagnosis of unassociated defects; 3) The recognition of biventricular hypertrophy obliges to the diagnosis of associated defects; 4) The AQRS deviation and the shortening in duration of the local electrical systole help to recognized the hypertrofied ventricle and its overload; 5) The presence of right bundle branch block is not in relation to the degree of overloading; 6) The primary alterations of ventricular repolarization are univocal signs of myocardial damage.


Acute and chronic toxicity in Sprague-Dawley rats of orally-administered total lignans from Arctii Fructus, a potential therapeutic drug for diabetes.
Arctii Fructus is the dried ripe fruit of Arctium lappa L. (family Asteraceae) and is in the Chinese pharmacopoeia. Previous research showed that the total lignans from Arctii Fructus (TLAF) have pharmacological activities related to diabetes. This study evaluated the acute and chronic (26 weeks) toxicities associated with oral daily administration of TLAF in Sprague-Dawley (SD) rats. An acute-toxicity test showed that TLAF caused 10% mortality at 3,000 mg/kg × 2 (6-h interval), with toxic symptoms, such as dyspnea and tonic convulsions, indicating potential neurotoxicity. A chronic-toxicity study showed no mortality after administration. The no observed adverse-effect level was 1,800 mg/kg (approximately 54 times higher than the human clinical dose) for 26 weeks of TLAF oral administration in SD rats, with toxicity signs of excessive oral and nasal secretions and moist circumferential hair that recovered after TLAF discontinuation. In the toxicokinetic study, the two main components of TLAF, arctigenin plasma level was positively correlated with dose and tended to accumulate after multiple doses. At 1,800 mg/kg, arctiin plasma level increased and tended to accumulate after multiple doses. These results indicated that TLFA has relatively low toxicity and the potential for clinical treatment of diabetes.


Herbal ethosomal gel containing luliconazole for productive relevance in the field of biomedicine.
This study includes development, characterization, and optimization of herbal ethosomal formulation. The aim of the present study is to develop drug loaded ethosomes capped with Azadirachta indica (neem) which, was further incorporated in Carbopol 934 K thereby, resulting in the formation of ethosomal gel. The formulation is aimed to express effective treatment against fungal infection. The build was formulated using drug (Luliconazole), soyalecithin, ethanolic neem extract and propylene glycol. In total nine ethosomal, formulations of distinct concentrations of ingredients were processed, to determine out the optimized formulation among the all. Further the prepared drug loaded ethosomes were subjected to various evaluation parameters like particle size, zeta potential, polydispersity index (PDI) and % entrapment efficiency. For the evaluation of its surface morphology, transmission electron microscopy was executed whereas, atomic force microscopy was carried out which contributes in detail and depth information of surface morphology. For the analysis of thermal behavior Thermal gravimetric analysis graph was obtained for luliconazole, soyalecithin, neem extract, physical mixture and optimized formulation (LF5). Attenuated total internal reflection Fourier transforms infra-red spectroscopy was performed for luliconazole, soyalecithin, neem extract, physical mixture, and optimized formulation (LF5) to examine the interaction between the drug and the excipients. Viscosity, pH, spreadability and extrudability of the ethosomal gel were calculated to determine the suitability of the formulation for topical application. In vitro drug permeation study and antifungal activity was executed out with the aid of Wistar albino rat skin model and tube dilution assay respectively. The complete study wrap up, that this herbal ethosomal approach provides advanced sustained and targeted delivery of luliconazole. On analyzing the results, ethosomal formulation LF5 was found to be optimized one, due to its optimum concentration of soyalecithin (300 mg) and ethanol (35%). Hence it has maximum entrapment efficiency of 86.56 ± 0.74%. Optimum vesicle size, zeta potential, and PDI were found to be 155.30 ± 1.2 nm, - 42.20 ± 0.3 mV, and 0.186 ± 0.07 respectively. In vitro drug permeation study expresses release of 83.45 ± 2.51 in 24 h whereas; the in vivo activity proved that LF5 is more active and effective against Candida parapsilosis in comparison to Aspergillus niger. In the end, it was estimated that ethosomal suspension and lyophilized ethosomal suspension was utmost stable at 4 °C/60 ± 5 RH. The complete study clearly indicates that the buildup of ethosomal formulation with luliconazole and neem extract show synergistic effect thereby, expressing excellent result against the treatment of fungal infection.


A simplified method for preparing IVF granulosa cells for culture.
To validate an expedited method for the removal of erythrocytes when preparing IVF granulosa-luteal cells for culture. Granulosa cells were enriched for culturing from follicular aspirates by density gradient centrifugation and by hypo-osmotic lysis treatments. Cells prepared by either method showed the same cell viability and produced progesterone in similar quantities. Using hypo-osmotic lysis to remove erythrocytes does not impair granulosa cell viability or steroidogenesis. It avoids multiple density gradient centrifugations and washings, and yields IVF granulosa cells ready for culture efficiently.


Characteristics and reference values for cardiopulmonary exercise testing in the adult Chinese population - The Xiangya hospital exercise testing project (the X-ET project).
Reference values of cardiopulmonary exercise testing (CPX) vary with race/ethnicity. Chinese Americans are the fastest-growing racial/ethnic group in the United States. However, there is limited information about the reference values of cardiopulmonary exercise testing (CPX) variables in the Chinese population. As part of the Xiangya Hospital Exercise Testing project (the X-ET project), this cross-sectional study screened 20,696 consecutive CPXs performed by 17,802 unique individuals at Xiangya Hospital of Central South University, China, from January 1, 2002, to December 31, 2019. A total of 964 unique healthy adults/tests (42% female) aged 49 ± 12 who completed a maximal ramp incremental CPX with cycle ergometry were included in this study. The reference values of primary CPX variables were expressed as the lower limit or upper limit of normal. Stepwise linear regression was used to fit the equations of key CPX variables. Predictive accuracy analysis for the equations with a comparison between present and previous studies were performed. Peak oxygen consumption (V̇O2), carbon dioxide production, ventilation/min, work rate, and V̇O2 at the anaerobic threshold were regressed on age, height, weight, and sex. These predictive equations showed good in- and out-sample predictive accuracy. Comparison with prior research revealed that prediction equations of peak V̇O2 resultant from studies in which populations were entirely or primarily Caucasian had overestimated our subjects' actual values. The reference values and predicted equations of CPX variables in this study may provide a more appropriate framework to interpret the response to maximal ramp incremental cycle ergometry in the Chinese adult population.


PDCD2 functions as an evolutionarily conserved chaperone dedicated for the 40S ribosomal protein uS5 (RPS2).
PDCD2 is an evolutionarily conserved protein with previously characterized homologs in Drosophila (zfrp8) and budding yeast (Tsr4). Although mammalian PDCD2 is essential for cell proliferation and embryonic development, the function of PDCD2 that underlies its fundamental cellular role has remained unclear. Here, we used quantitative proteomics approaches to define the protein-protein interaction network of human PDCD2. Our data revealed that PDCD2 specifically interacts with the 40S ribosomal protein uS5 (RPS2) and that the PDCD2-uS5 complex is assembled co-translationally. Loss of PDCD2 expression leads to defects in the synthesis of the small ribosomal subunit that phenocopy a uS5 deficiency. Notably, we show that PDCD2 is important for the accumulation of soluble uS5 protein as well as its incorporation into 40S ribosomal subunit. Our findings support that the essential molecular function of PDCD2 is to act as a dedicated ribosomal protein chaperone that recognizes uS5 co-translationally in the cytoplasm and accompanies uS5 to ribosome assembly sites in the nucleus. As most dedicated ribosomal protein chaperones have been identified in yeast, our study reveals that similar mechanisms exist in human cells to assist ribosomal proteins coordinate their folding, nuclear import and assembly in pre-ribosomal particles.


[Immunochemical characterization of molecules identified in human thymic epithelium by anti-thymulin monoclonal antibodies].
Four high molecular weight molecules (ranging from 59 to 48 kd) were evidenced in the human thymic epithelium, after one and two dimensional immunoblot analyses, using monoclonal antibodies directed against synthetic thymulin. One of these immunoreactive proteins might correspond to the intra-thymic precursor of the hormone.


Colorectal Cancer Stem Cells in the Progression to Liver Metastasis.
Colorectal carcinoma (CRC) is a leading cause of cancer mortality. Tumorigenesis is a dynamic process wherein cancer stem cells (CSCs) and their microenvironment promote initiation, progression, and metastasis. Metastatic colonization is an inefficient process that is very complex and is poorly understood; however, in most cases, metastatic disease is not curable, and resistance mechanisms tend to develop against conventional treatments. An understanding of the underlying mechanisms and factors that contribute to the development of metastasis in CRC can aid in the search for specific therapeutic targets for improving standard treatments. In this review, we summarize current knowledge regarding tumor biology and the use of stroma cells as prognostic factors and inflammatory inducers associated with the use of tumor microenvironments as a promoter of cancer metastasis. Moreover, we look into the importance of CSC, pericytes, and circulating tumor cells as mechanisms that lead to liver metastasis, and we also focus on the cellular and molecular pathways that modulate and regulate epithelial-mesenchymal transition. Finally, we discuss a novel therapeutic target that can potentially eliminate CSCs as a CRC treatment.


Hemispheric control of territorial aggression in Anolis carolinensis: effects of mild stress.
Previous work has demonstrated that the brain of Anolis carolinensis is functionally split, in that the left and right eyes project predominantly to the contralateral hemisphere, and as there are minimal connections between the left and right hemispheres. Using this model, the current experiment examined the effect of mild acute stress on hemispheric regulation of territorial aggression. Thirteen adult male Anolis were paired with an antagonistic males, and eye use and behavioral responses were repeatedly measured during 3 minute behavioral trials. Trials were conducted either after exposure to mild stress, produced by handling the subject, or without stress, and they were run either in the subject's home cage or in a cage foreign to the subject. Left eye preference for aggressive movements was found during the trials run in the non-stressed conditions (p < 0.05). Conversely, stressed subjects showed a reduction in left eye/right hemisphere mediated aggressive movements relative to the non-stressed subjects but no changes in right eye/left hemisphere aggression. This effect was independent of whether or not the subject was in its home or a foreign cage. No laterality in aggressive responding was found when the subjects were placed in separate cages with visual contact. These findings suggest that territorial aggression in Anolis is preferentially initiated and processed by the left eye/right hemisphere but is subject to right-hemispheric inhibition following exposure to acute mild stress.


[Ovarian hyperstimulation syndrome].
The author discusses the etiology and pathophysiology of the Ovarian Hyperstimulation Syndrome (OHS) and its relationship with Polycystic Ovarian Disease, in which it occurs more frequently. He presents the clinical histories of five patients who, in a period of two years, developed this syndrome in three different degrees of severity, while undergoing therapy for ovulatory infertility. The clinical history of one patient, who developed the most severe manifestations of OHS, is discussed in detail. The author emphasizes the difficulties that can be faced in trying to prevent the OHS, particularly because of probably inherited characteristics which may explain why not all patients with the same risk factors develop the OHS.


Mental health services for people with intellectual disability in residential care in Israel. Trends for 1998-2006.
Persons with intellectual disability (ID) have been observed to have more mental health problems than the general population. This study was conducted to study mental health services for persons with ID (all ages) in residential care in Israel. An annual questionnaire sent to the medical clinics in all residential care centers for the period 1998-2006 was analyzed to study the trends over time in the number of recruited psychiatrists, psychiatric medication, and hospitalization for persons with ID in residential care in Israel. The results showed an increased number of psychiatrists working with this population-from 6.14 psychiatrists per 1,000 study population in 1998 to 7.75 in 2006. Psychotropic medication also increased from 46% to 51% over the same period, and psychiatric in-patient hospitalization increased from 5.48 to 7.75 per 1,000 study population. We conclude that the psychiatric services to this residential care population have increased over the study period. We see a need for a formal subspecialty in psychiatry, training, and research.


Development of a Cre-loxP-based genetic system in Aspergillus niger ATCC1015 and its application to construction of efficient organic acid-producing cell factories.
The filamentous fungus Aspergillus niger is widely used in the biotechnology industry for the production of chemicals and enzymes. Engineering of this valuable organism to improve its productivity is currently hampered by the lack of efficient genetic tools. Here, a Cre-loxP-based system for gene editing in A. niger was developed and its application in construction of A. niger cell factories to produce various organic acids was explored. Two established inducible systems, the xylanase A gene promoter Pxln and Tet-on system, were examined for driving cre expression and thus selection marker hyh deletion. Under inducing conditions, the efficiency of loxP site-specific recombination in the strain with cre driven by Pxln is about 2%, while cre driven by Tet-on system is about 34% which was used as the platform strain for further genetic engineering. As a proof of application of this system, strains containing different copies of oxaloacetate acetylhydrolase-encoding gene (oahA) were constructed, and the resultant strain S428 showed as high as 3.1-fold increase in oxalic acid production. Furthermore, an efficient malate-producing strain was generated through four-step genetic manipulation (oahA deletion, pyc, mdh3 and C4-dicarboxylate transporter gene c4t318 insertion). The resultant strain S575 achieved a titer 120.38 g/L malic acid with the flask culture, and a titer 201.24 g/L malic acid in fed-batch fermentation. These results demonstrated that this modified Cre-loxP system is a powerful tool for genetic engineering in A. niger, which has the potential to be genetically modified as a viable aciduric platform strain to produce high levels of various organic acids.


Extragonadal Germ Cell Tumors: A Single Institution Experience with Clinicopathological Correlation.
Background. Extragonadal germ cell tumors (EGCTs) are a rare heterogeneous group of tumors without evidence of primary gonadal germ cell tumors. They account for 2%-5% of overall malignancies. EGCTs are often not clinically suspected, making them challenging for pathologists. In this retrospective observational study, we describe our institutional experience among EGCTs with clinicopathological correlation. Materials and methods. All patients diagnosed as EGCTs from January 2014 to April 2023 were collected. All relevant clinical data and serum markers were retrieved from hospital medical records. Histopathology and immunohistochemistry slides were reviewed. Results. The present study included a total of 56 patients; 34 (60%) men and 22 (40%) women with a men-to-women ratio of 1.5:1. Of them, 1 patient had congenital/neonatal EGCTs, 21 patients had prepubertal EGCTs, and 34 had post-pubertal EGCTs. The common sites included are mediastinum (45%), sacrococcyx (18%), retroperitoneum (14%), and central nervous system (12%). The other rare sites were the vagina, liver, colon, and duodenum. The common germ cell tumor included mature teratoma (34%), mixed germ cell tumor (27%), seminoma/germinoma (12%), pure yolk sac tumor (11%), immature teratoma (9%), mature teratoma with somatic tumor (5%), and embryonal carcinoma (2%). All histological diagnoses of germ cell tumors were confirmed with IHC markers like PLAP, CD117 (KIT), AFP, LIN28, CD30, and β-hCG. Pre and posttreatment serum tumor marker levels were available in 37 patients. All our treated patients had a decrease or normal tumor marker levels post-therapy. Conclusion. In our study, a heterogeneous group of germ cell tumors was seen. Most of them were seen in post-pubertal adolescents and young adults. Early intervention by platinum-based combination chemotherapy in seminoma and nonseminomatous germ cell tumors has significantly improved the prognosis of malignant EGCTs similar to their germ cell counterparts.


Are Mendel's Data Reliable? The Perspective of a Pea Geneticist.
Mendel's data exhibit remarkable agreement to the ratios he predicted. In this article, alternative explanations for this close agreement (that inheritance in pea does not conform to the standard statistical model, that data were omitted, that ambiguous data were categorized to better match predicted ratios, and that some data were deliberately falsified) are tested using approaches that are designed to distinguish between these alternatives. The possibility that garden pea (Pisum sativum L.) naturally produces segregation ratios more closely matching Mendelian expectations than predicted by statistical models is rejected. Instead the opposite is found to be the case, making Mendel's results even more remarkable. Considerable evidence is introduced that Mendel omitted some of his experimental results, but this alternative cannot adequately explain the low average deviation from expectations that is characteristic of the segregation data he presented. An underlying bias in Mendel's data favoring the predicted ratio is present, but my analysis could not clearly determine whether the bias was caused by misclassifying ambiguous phenotypes or deliberate falsification of the results. A number of Mendel's statements are argued to be unrealistic in terms of practical pea genetics, suggesting that his text does not represent a strictly accurate description of his experimental methods. Mendel's article is probably best regarded as his attempt to present his model in a simple and convincing format with a minimum of additional details that might obscure his message.


Foot orthotics for low back pain: The state of our understanding and recommendations for future research.
The purpose of the article is to evaluate the literature on the use of foot orthotics for low back pain and to make specific recommendations for future research. Database searches were conducted using PubMed, EBSCO, GALE, Google Scholar, and clinicaltrials.gov. The biomedical literature was reviewed to determine the current state of knowledge on the benefits of foot orthotics for low back pain related to biomechanical mechanisms and clinical outcomes. It may be argued that foot orthotics are experimental, investigational, or unproven for low back pain due to lack of sufficient evidence for their clinical effectiveness. This conclusion is based upon lack of high quality randomized controlled trials (RCTs). However, there is extensive research on biomechanical mechanisms underlying the benefits of orthotics that may be used to address this gap. Additionally, promising pilot studies are beginning to emerge in the literature and ongoing large-scale RCTs are addressing effects of foot orthotics on chronic low back pain. Based upon the critical evaluation of the current research on foot orthotics related to biomechanical mechanisms and clinical outcomes, recommendations for future research to address the evidence-practice gaps on the use of foot orthotics for low back pain are presented.


Identifying gene regulatory modules of heat shock response in yeast.
A gene regulatory module (GRM) is a set of genes that is regulated by the same set of transcription factors (TFs). By organizing the genome into GRMs, a living cell can coordinate the activities of many genes in response to various internal and external stimuli. Therefore, identifying GRMs is helpful for understanding gene regulation. Integrating transcription factor binding site (TFBS), mutant, ChIP-chip, and heat shock time series gene expression data, we develop a method, called Heat-Inducible Module Identification Algorithm (HIMIA), for reconstructing GRMs of yeast heat shock response. Unlike previous module inference tools which are static statistics-based methods, HIMIA is a dynamic system model-based method that utilizes the dynamic nature of time series gene expression data. HIMIA identifies 29 GRMs, which in total contain 182 heat-inducible genes regulated by 12 heat-responsive TFs. Using various types of published data, we validate the biological relevance of the identified GRMs. Our analysis suggests that different combinations of a fairly small number of heat-responsive TFs regulate a large number of genes involved in heat shock response and that there may exist crosstalk between heat shock response and other cellular processes. Using HIMIA, we identify 68 uncharacterized genes that may be involved in heat shock response and we also identify their plausible heat-responsive regulators. Furthermore, HIMIA is capable of assigning the regulatory roles of the TFs that regulate GRMs and Cst6, Hsf1, Msn2, Msn4, and Yap1 are found to be activators of several GRMs. In addition, HIMIA refines two clusters of genes involved in heat shock response and provides a better understanding of how the complex expression program of heat shock response is regulated. Finally, we show that HIMIA outperforms four current module inference tools (GRAM, MOFA, ReMoDisvovery, and SAMBA), and we conduct two randomization tests to show that the output of HIMIA is statistically meaningful. HIMIA is effective for reconstructing GRMs of yeast heat shock response. Indeed, many of the reconstructed GRMs are in agreement with previous studies. Further, HIMIA predicts several interesting new modules and novel TF combinations. Our study shows that integrating multiple types of data is a powerful approach to studying complex biological systems.


[Non-linguistic cognitive symptoms of cerebral stroke].
Cognitive symptoms are common after stroke, but doctors' knowledge about such symptoms seems sparse. We review the literature and present our own clinical experience on selected cognitive losses after stroke. The most common non-linguistic cognitive symptoms are neglect (hemi-inattention), visuospatial problems (difficulties in putting elements together or to perform spatial tasks), and apraxia (difficulties in performing voluntary, purposeful tasks due to mistakes in the choice and order of motor elements). More than half of patients suffer from such symptoms in the acute phase of stroke and approximately one in four has long-lasting problems. Knowledge about these symptoms is essential for effective rehabilitation, good information to the patient and his caregivers, and for prognostic purposes. Full evaluation of cognitive losses requires a neuropsychological examination, but thorough observation of the patient combined with simple pen-and-paper tests can be very helpful.


Community composition, toxigenicity, and environmental conditions during a cyanobacterial bloom occurring along 1,100 kilometers of the Murray River.
A cyanobacterial bloom impacted over 1,100 km of the Murray River, Australia, and its tributaries in 2009. Physicochemical conditions in the river were optimal to support a bloom at the time. The data suggest that at least three blooms occurred concurrently in different sections of the river, with each having a different community composition and associated cyanotoxin profile. Microscopic and genetic analyses suggested the presence of potentially toxic Anabaena circinalis, Microcystis flos-aquae, and Cylindrospermopsis raciborskii at many locations. Low concentrations of saxitoxins and cylindrospermopsin were detected in Anabaena and Cylindrospermopsis populations. A multiplex quantitative PCR was used, employing novel oligonucleotide primers and fluorescent TaqMan probes, to examine bloom toxigenicity. This single reaction method identified the presence of the major cyanotoxin-producing species present in these environmental samples and also quantified the various toxin biosynthesis genes. A large number of cells present throughout the bloom were not potential toxin producers or were present in numbers below the limit of detection of the assay and therefore not an immediate health risk. Potential toxin-producing cells, possessing the cylindrospermopsin biosynthesis gene (cyrA), predominated early in the bloom, while those possessing the saxitoxin biosynthesis gene (sxtA) were more common toward its decline. In this study, the concentrations of cyanotoxins measured via enzyme-linked immunosorbent assay (ELISA) correlated positively with the respective toxin gene copy numbers, indicating that the molecular method may be used as a proxy for bloom risk assessment.


Self-reported Pleasantness Ratings and Examiner-Coded Defensiveness in Response to Touch in Children with ASD: Effects of Stimulus Material and Bodily Location.
Tactile defensiveness, characterized by behavioral hyperresponsiveness and negative emotional responses to touch, is a common manifestation of aberrant sensory processing in autism spectrum disorders (ASD) and other developmental disabilities (DD). Variations in tactile defensiveness with the properties of the stimulus and the bodily site of stimulation have been addressed in adults with self-report of perceived tactile pleasantness, but not in children. We presented three materials (pleasant, unpleasant, social) at three bodily sites and measured both examiner-coded defensiveness and self-reported pleasantness from a group of children with ASD and two comparison groups (one with DD, one with typical development (TD)). The main findings were: (1) children with ASD and DD showed significantly more defensiveness reactions and lower pleasantness ratings than the TD group, with higher variability, (2) there was a double dissociation for the effects of material and bodily site of stimulation: while bodily site predicted behavioral defensiveness, material predicted pleasantness rating. Additionally, it was noted that (3) the most pleasant material and the social touch conditions best distinguished ASD and DD from TD on defensiveness, and (4) within the ASD group, social impairment and defensiveness in bodily sites associated with social touch were positively correlated, suggesting a clinically relevant distinction between social and discriminative touch in ASD.


Observations of Energetic Ions and Electrons in Saturn's Magnetosphere.
The passage of Pioneer 11 by Saturn provided a detailed view of a planetary magnetosphere that is intermediate between those of Jupiter and Earth in both scale and the complexity of its dynamic processes. It appears to have at least three distinct regions: (i) an outer magnetosphere, extending from 17 to 7.5 Saturn radii, that resembles that of Earth in many important aspects; (ii) a slot region, between 7.5 and 4 Saturn radii, where a marked decrease in all protons and low-energy electrons is observed; and (iii) an inner region, extending from 4 Saturn radii to the ring edge, that features a sharp increase in the proton flux extending to energies greater than 20 million electron volts. A cutoff of both proton and electron fluxes occurred just beyond the nominal edge of the A ring.


The rapid emergence of stimulus specific perceptual learning.
Is stimulus specific perceptual learning the result of extended practice or does it emerge early in the time course of learning? We examined this issue by manipulating the amount of practice given on a face identification task on Day 1, and altering the familiarity of stimuli on Day 2. We found that a small number of trials was sufficient to produce stimulus specific perceptual learning of faces: on Day 2, response accuracy decreased by the same amount for novel stimuli regardless of whether observers practiced 105 or 840 trials on Day 1. Current models of learning assume early procedural improvements followed by late stimulus specific gains. Our results show that stimulus specific and procedural improvements are distributed throughout the time course of learning.


Nitrous oxide-based vs. nitrous oxide-free general anaesthesia and accidental awareness in surgical patients: an abridged Cochrane systematic review.
Accidental awareness during general anaesthesia can arise from a failure to deliver sufficient anaesthetic agent, or from a patient's resistance to an expected sufficient dose of such an agent. Awareness is 'explicit' if the patient is subsequently able to recall the event. We conducted a systematic review into the effect of nitrous oxide used as part of a general anaesthetic on the risk of accidental awareness in people over the age of five years undergoing general anaesthesia for surgery. We included 15 randomised controlled trials, 14 of which, representing a total of 3439 participants, were included in our primary analysis of the frequency of accidental awareness events. The awareness incidence rate was rare within these studies, and all were considered underpowered with respect to this outcome. The risk of bias across all studies was judged to be high, and 76% of studies failed adequately to conceal participant allocation. We considered the available evidence to be of very poor quality. There were a total of three accidental awareness events reported in two studies, one of which reported that the awareness was the result of a kink in a propofol intravenous line. There were insufficient data to conduct a meta- or sub-group analysis and there was insufficient evidence to draw outcome-related conclusions. We can, however, recommend that future studies focus on potentially high-risk groups such as obstetric or cardiac surgery patients, or those receiving neuromuscular blocking drugs or total intravenous anaesthesia.


[HIV vulnerability in women at social risk].
To evaluate HIV/AIDS vulnerability by risk factors in women at social risk. Study conducted in a sample of 178 female homemakers (n=101) and female health providers (n=77) from Antofagasta, Chile, in 20062007. Homemakers were considered at social risk. HIV vulnerability was estimated through a 21-item instrument comprising three domains: gender roles; relationship with the partner; and attitude toward condom use. For determining the relative weight of each dimension to total vulnerability a multiple regression analysis was carried out using the instrument's total score as dependent variable and each domain as independent variable. Overall, the domain showing the highest relative weight was attitude toward condom use (0.542), followed by relationship with the partner (0.453) and gender roles (0.379). There were weight differences between homemakers: relationship with the partner (0.597), attitude toward condom use (0.508) and gender roles (0,403); and health providers: attitude toward condom use (0.638), relationship with the partner (0.397), and gender roles (0.307). The study results allows to inferring that there are differences in factors that determine HIV vulnerability among women and gender role is the best predictor of risk among those at social risk.


Central role of defective apoptosis in autoimmunity.
Lymphocyte development, selection and education represent tightly controlled immune processes that normally prevent autoimmunity. Lymphocyte development likely induces cellular selection through apoptosis to remove potentially autoreactive cells. Dysregulated apoptosis, both interrupted as well as accelerated apoptosis, are now demonstrated as central defects in diverse murine autoimmune disease. In murine models of autoimmune lupus, mutations in cell death receptor Fas (CD95) and its ligand, FasL (CD95 L), have been identified. These errors create a lymphoid system resistant to apoptosis. In contrast, select lymphoid subpopulations of maturing autoimmune prone non-obese diabetic mice have identifiable and pathogenic T cells with both in vivo and in vitro heightened apoptosis after drug interventions. In part, these defects are due to faulty activation of transcription factors such as nuclear factor-kappaB (NF-kappaB) that normally protect against apoptotic death. The genetic basis of interrupted NF-kappaB in pathogenic memory T cells in diabetes is attributable to a developmentally controlled gene defect in an essential subunit of the proteasome. No specific gene in most common forms of human autoimmune disease has yet been identified. Functional assays from diverse laboratories repeatedly demonstrate heightened apoptosis in multiple cellular signaling pathways for cell death, suggesting a common theme in disease causality.


Coupled Plasma Filtration Adsorption for Treatment of Capillary Leak Syndrome Superimposed to Acute Generalized Exanthematous Pustolosis: A Case Report.
Coupled plasma filtration adsorption (CPFA) is an extracorporeal supportive therapy based on nonspecific adsorption of pro- and anti-inflammatory mediators combined with continuous renal replacement therapy. The main field of CPFA application is septic shock, and there are limited data about its efficacy in the treatment of other acute conditions characterized by a dysregulation in immune homeostasis. Capillary leak syndrome (CLS) defines a life-threatening condition sustained by hypercytokinemia and characterized by abrupt onset of increased capillary permeability leading to severe generalized edema and hypovolemic shock refractory to fluid administration. Therapy for CLS is not specific and, at present time, it consists in the use of steroids or intravenous immunoglobulins. We present the case of a 34-year-old woman who developed CLS superimposed to acute generalized exanthematous pustulosis after initiating therapy with hydroxychloroquine for undifferentiated connective tissue disease. CLS did not respond to steroids and intravenous immunoglobulins, while it was successfully treated with CPFA. This observation supports the possible role of CPFA in restoring a proper immunologic homeostasis not only in sepsis but also in other devastating conditions sustained by hypercytokinemia.


Critical care nurses' perceptions of the outcomes of working overtime in Canada.
Nursing overtime is being integrated into the normal landscape of practice to ensure optimal staffing levels and addresses variations in patient volume and acuity. This is particularly true in critical care where fluctuations in either are difficult to predict. The goal of this study was to explore critical care nurses' perceptions of the outcomes of working overtime. Sally Thorne's interpretive description guided the collection and analysis of data. Participants were recruited from 11 different critical care units within three large teaching hospitals in Southern Ontario, Canada. A total of 28 full- and part-time registered nurses who had worked in an intensive care unit for at least one year took part in this study. Data were collected through semistructured, audio-recorded, individual interviews that took place in rooms adjacent to participants' critical care units. Template analysis facilitated the determination and abstraction of themes using NVivo for Mac 10.1.1. Major themes highlighting the perceived outcomes of overtime included (a) physical effects, (b) impact on patient-centered care, (c) balancing family and work, (d) financial gain, and € safety is jeopardized. Nursing managers and institutions need to be accountable for staffing practices they institute, and nurses themselves may require further education regarding healthy work-life balance. There are both negative and positive consequences of nursing overtime for nurses and patients, but nurses at large valued the option to work it.


Interaction of supramolecular aggregates and the enhanced optical torque on the director in a dye doped nematic liquid crystal.
There has been strong experimental evidence that molecules of some dyes in an anisotropic solvent, nematic liquid crystal, form aggregates. We present a detailed experimental analysis of the light-induced director reorientation (DR) in a dye-doped nematic liquid crystal (known as the Jánossy effect) and a theoretical model of its strong enhancement based on the aggregates' interaction. The DR transition is found to be very different from the Frederiks effect. If the light polarization is normal to the director, the transition is jump-like first order. Moreover, light polarization along the director also induces a DR which is a smooth second order transition with a very low threshold intensity. The theoretical model which explains these effects is based on the idea that dye molecules form rodlike supramolecular aggregates. The aggregates interact via the director distortions and their effective diameter gets certain field-dependence. As a result, the related entropy depletion depends on the light intensity and polarization and can be decreased by a certain DR along with the aggregate subsystem. This entropy gain is proportional to the square of light intensity which is a two-photon effect: the first resonance photon excites the dye molecule and the second photon polarizes the aggregate. This is in line with the experimental dependence of the critical intensity on the sample thickness. A special experiment shows that the effect is not connected with a possible heat-induced isotropic phase and hydrodynamic motion.


FunSPU: A versatile and adaptive multiple functional annotation-based association test of whole-genome sequencing data.
Despite ongoing large-scale population-based whole-genome sequencing (WGS) projects such as the NIH NHLBI TOPMed program and the NHGRI Genome Sequencing Program, WGS-based association analysis of complex traits remains a tremendous challenge due to the large number of rare variants, many of which are non-trait-associated neutral variants. External biological knowledge, such as functional annotations based on the ENCODE, Epigenomics Roadmap and GTEx projects, may be helpful in distinguishing causal rare variants from neutral ones; however, each functional annotation can only provide certain aspects of the biological functions. Our knowledge for selecting informative annotations a priori is limited, and incorporating non-informative annotations will introduce noise and lose power. We propose FunSPU, a versatile and adaptive test that incorporates multiple biological annotations and is adaptive at both the annotation and variant levels and thus maintains high power even in the presence of noninformative annotations. In addition to extensive simulations, we illustrate our proposed test using the TWINSUK cohort (n = 1,752) of UK10K WGS data based on six functional annotations: CADD, RegulomeDB, FunSeq, Funseq2, GERP++, and GenoSkyline. We identified genome-wide significant genetic loci on chromosome 19 near gene TOMM40 and APOC4-APOC2 associated with low-density lipoprotein (LDL), which are replicated in the UK10K ALSPAC cohort (n = 1,497). These replicated LDL-associated loci were missed by existing rare variant association tests that either ignore external biological information or rely on a single source of biological knowledge. We have implemented the proposed test in an R package "FunSPU".


Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large.
Classical genetic methods, driven by phenotype rather than hypotheses, generally permit the identification of all proteins that serve nonredundant functions in a defined biological process. Long before this goal is achieved, and sometimes at the very outset, genetics may cut to the heart of a biological puzzle. So it was in the field of mammalian innate immunity. The positional cloning of a spontaneous mutation that caused lipopolysaccharide resistance and susceptibility to Gram-negative infection led directly to the understanding that Toll-like receptors (TLRs) are essential sensors of microbial infection. Other mutations, induced by the random germ line mutagen ENU (N-ethyl-N-nitrosourea), have disclosed key molecules in the TLR signaling pathways and helped us to construct a reasonably sophisticated portrait of the afferent innate immune response. A still broader genetic screen--one that detects all mutations that compromise survival during infection--is permitting fresh insight into the number and types of proteins that mammals use to defend themselves against microbes.