IL-21 promotes CD8+ CTL activity via the transcription factor T-bet.
CD8(+) T cells are fundamental for immune-mediated clearance of viral infections and contribute to immune pathology in autoimmune diseases such as type 1 diabetes. To execute these functions, CD8(+) T cells must differentiate into CTLs, a process that is precisely regulated by a variety of cytokines, costimulatory molecules, and transcription factors. IL-21 is an IL-2 family cytokine and a growth factor for multiple lymphocyte effector lineages, including cytotoxic CD8(+) T cells. Recent studies demonstrate that loss of IL-21 signaling results in reduced viral clearance in models of lymphocytic choriomeningitis virus infection, and also protection from type 1 diabetes in the NOD model. This is most likely the result of impaired CD8(+) CTL function in the absence of IL-21 signaling. Currently, the mechanisms by which IL-21 promotes CTL differentiation in CD8(+) T cells remain unclear, particularly the identity of the relevant transcription factor(s). We show that IL-21 promotes CTL function in vitro and killing of pancreatic islets in vivo via the use of transgenic mice expressing IL-21 in pancreatic β cells. We demonstrate that IL-21 induces the expression of the transcription factor T-bet in CD8(+) T cells, predominantly via STAT1, and that T-bet is required for the induction of cytolytic molecules, including perforin and granzyme B in response to IL-21. Finally, we show that IL-21-induced CTL function is T-bet dependent, as T-bet deficiency results in defective IL-21-dependent cytotoxicity in CD8(+) T cells in vitro and in vivo. Thus, IL-21 drives CD8(+) CTL differentiation via the actions of the transcription factor T-bet.


Effect of an invasive plant and moonlight on rodent foraging behavior in a coastal dune ecosystem.
Understanding how invasive plants may alter predator avoidance behaviors is important for granivorous rodents because their foraging can trigger ripple effects in trophic webs. Previous research has shown that European beach grass Ammophila arenaria, an invasive species in coastal California, affects the predation of other seeds by the rodents Microtus californicus, Peromyscus maniculatus, and Reithrodontomys megalotis. This may be due to lower perceived predation risk by rodents foraging in close proximity to the cover provided by Ammophila, but this mechanism has not yet been tested. We examined the perceived predation risk of rodents by measuring the 'giving up density' of food left behind in experimental patches of food in areas with and without abundant cover from Ammophila and under varying amount of moonlight. We found strong evidence that giving up density was lower in the thick uniform vegetation on Ammophila-dominated habitat than it was in the more sparsely and diversely vegetated restored habitat. There was also evidence that moonlight affected giving up density and that it mediated the effects of habitat, although with our design we were unable to distinguish the effects of lunar illumination and moon phase. Our findings illustrate that foraging rodents, well known to be risk-averse during moonlit nights, are also affected by the presence of an invasive plant. This result has implications for granivory and perhaps plant demography in invaded and restored coastal habitats. Future research in this system should work to unravel the complex trophic links formed by a non-native invasive plant (i.e., Ammophila) providing cover favored by native rodents, which likely forage on and potentially limit the recruitment of native and non-native plants, some of which have ecosystem consequences of their own.


Diverticulitis with rupture and fatal peritonitis in a Sumatran orangutan (Pongo pygmaeus).
A 30-year-old male Sumatran orangutan (Pongo pygmaeus) presented with signs of depression, lethargy, anorexia, and diarrhea that progressed to acute colic. Exploratory laparotomy revealed fibrinopurulent peritonitis and 50 cm of devitalized small intestine. The surgically resected small intestine contained several mucosal diverticula along the mesenteric attachment; one had ruptured, resulting in peritonitis. Fifteen days after surgery, the orangutan's abdominal incision dehisced. Repeated laparotomy revealed dehiscence of the distal intestinal anastomosis site, as well as extensive adhesions and purulent exudate. The defect was repaired, and the abdomen was extensively irrigated and closed, but the animal died within 24 hours. To our knowledge, this is the first report of diverticulitis in a great ape. Diverticulosis should be considered in the differential diagnosis for great apes that present with signs of depression, lethargy, anorexia, and/or diarrhea.


The prevention of asthma--some basic needs.
The present attitude in Australia towards the treatment of asthma is reviewed and attention is drawn to the need for employment of more basic methods of prevention. The disease is not just a chest condition but a manifestation, in many if not in most cases, of a generalized weakness of sensitivity- the bronchi are simply shock organs where much of the action takes place. A plea is also made for a reappraisal of teaching about asthma and related diseases at both undergraduate and postgraduate levels.


Impact of Kenya's Frontline Epidemiology Training Program on Outbreak Detection and Surveillance Reporting: A Geographical Assessment, 2014-2017.
Rapid detection and response to infectious disease outbreaks requires a robust surveillance system with a sufficient number of trained public health workforce personnel. The Frontline Field Epidemiology Training Program (Frontline) is a focused 3-month program targeting local ministries of health to strengthen local disease surveillance and reporting capacities. Limited literature exists on the impact of Frontline graduates on disease surveillance completeness and timeliness reporting. Using routinely collected Ministry of Health data, we mapped the distribution of graduates between 2014 and 2017 across 47 Kenyan counties. Completeness was defined as the proportion of complete reports received from health facilities in a county compared with the total number of health facilities in that county. Timeliness was defined as the proportion of health facilities submitting surveillance reports on time to the county. Using a panel analysis and controlling for county-fixed effects, we evaluated the relationship between the number of Frontline graduates and priority disease reporting of measles. We found that Frontline training was correlated with improved completeness and timeliness of weekly reporting for priority diseases. The number of Frontline graduates increased by 700%, from 57 graduates in 2014 to 456 graduates in 2017. The annual average rates of reporting completeness increased from 0.8% in 2014 to 55.1% in 2017. The annual average timeliness reporting rates increased from 0.1% in 2014 to 40.5% in 2017. These findings demonstrate how global health security implementation progress in workforce development may influence surveillance and disease reporting.


Altered excitatory and inhibitory amino acid receptor binding in hippocampus of patients with temporal lobe epilepsy.
We examined binding to excitatory amino acid and inhibitory amino acid receptors in frozen hippocampal sections prepared from surgical specimens resected from 8 individuals with medically refractory temporal lobe epilepsy. The excitatory receptors studied included N-methyl-D-aspartate (NMDA), strychnine-insensitive glycine, phencyclidine, and quisqualate. The inhibitory receptors studied were gamma-aminobutyric acid type A (GABAA) and benzodiazepine. Excitatory and inhibitory amino acid receptor binding were differentially altered in the patients with temporal lobe epilepsy in comparison to 8 age-comparable autopsy control subjects, and changes in receptor binding were regionally selective in four areas. Binding to phencyclidine receptors associated with the NMDA channel was reduced by 35 to 70% in all regions in the hippocampi of the patients. In contrast, binding to the NMDA recognition site and its associated glycine modulatory site was elevated by 20 to 110% in the cornu ammonis (CA) 1 area and dentate gyrus of the hippocampus of the patients. Binding to these sites was unaffected in area CA4. Binding to the quisqualate-type excitatory amino acid receptor was unchanged in all regions except the stratum lacunosum moleculare CA1, where it was increased by 63%. GABAA and benzodiazepine receptor binding was reduced by 20 to 60% in CA1 and CA4, but unchanged in dentate gyrus. The data indicate that excitatory and inhibitory amino acid receptors are altered in the hippocampus of patients with temporal lobe epilepsy.


Impacts of mixtures of herbicides on molecular and physiological responses of the European flounder Platichthys flesus.
The widespread use of pesticides results in a growing contamination of the aquatic environment. The effects of (1) a simple mixture of a glyphosate-based formulation and AMPA (Aminomethylphosphonic acid--a primary metabolite of glyphosate) and of (2) a more complex mixture of herbicides (glyphosate/AMPA/mecoprop/acetochlor/2,4D) were explored on the molecular and physiological responses of the European flounder Platichthys flesus, considering a long-term and environmentally realistic contamination. Molecular responses were identified using suppression subtractive hybridization on liver samples: the level of gene transcription was significantly different between contaminated fishes vs control ones for 532 sequences, after a 62-day contamination. Among them, 222 sequences were identified by homology with data-based sequences; they encoded several metabolic pathways including: methionine and lipid metabolism, immunity, protein regulation, coagulation and energetic metabolism. Expression pattern of nine transcripts in the liver was confirmed by real-time PCR. The molecular study underlined that potential markers of liver injury were expressed for both mixtures, in particular betaine homocysteine methyl transferase and chemotaxin. Physiological responses were analysed considering blood parameters and condition factor; after the two months contamination period; no significant physiological difference was detected between contaminated and control fish.


Neural repetitive firing: a comparative study of membrane properties of crustacean walking leg axons.
1. Repetitive activity and membrane conductance parameters of crab walking leg axons have been studied in the double sucrose gap. 2. The responses to constant current stimulus could be classified into three catagories; highly repetitive with wide firing frequency range, type I; highly repetitive with narrow frequency range, type II; and nonrepetitive or repetitive to only a limited degree, type III. The minimum firing frequency for type I axons was much greater than for other recording techniques. 3. Voltage-clamp currents in type III axons were qualitatively similar to those of squid or lobster axon. 4. The outward membrane currents of type I and II axons showed a transient phase in addition to the usual delayed current. The magnitude of this transient was a function of both the holding and test voltages. 5. The direction of the transient current reversed in potassium-rich saline. 6. The type I repetitive response in the walking leg axons appears to be generated by the same types of conductance changes that have been demonstrated in molluscan central neurons.


Echinocandins Localized to the Target-Harboring Cell Surface Are Not Degraded but Those Entering the Vacuole Are.
Echinocandin antifungal drugs have a broad spectrum of activities and excellent safety profiles. These agents noncompetitively inhibit the formation of the major polysaccharide component of the fungal cell wall, a reaction catalyzed by the membrane-bound β-glucan synthase (GS) protein complex. We have developed fluorescent probes of three echinocandin drugs: caspofungin (CSF), anidulafungin (ANF), and rezafungin (RZF). Fluorescent echinocandins had the same spectrum of activities as the parent echinocandins, supporting the fact that conjugation of the dye did not alter their mode of action. Of the three echinocandins, ANF has the most potent in vitro activity. Investigation of the subcellular distribution of the fluorescent echinocandins in live Candida yeast cells revealed that despite their high structural similarity, each of the drug probes had a unique subcellular distribution pattern. Fluorescent CSF, which is the least potent of the three echinocandins, accumulated in Candida vacuoles; fluorescent ANF localized in the extracellular environment and on the yeast cell surface where the target GS resides; and fluorescent RZF was partitioned between the surface and the vacuole over time. Recovery of fluorescent CSF from Candida cells revealed substantial degradation over time; functional vacuoles were necessary for this degradation. Under the same conditions, fluorescent ANF was not degraded. This study supports the "target-oriented drug subcellular localization" principle. In the case of echinocandins, localization to the cell surface can contribute to improved potency and accumulation in vacuoles induces degradation leading to drug deactivation.


Observing the stages of bystander intervention in virtual reality simulation.
Understanding bystander reactions to an emergency is an important component of effective training. Four stages of bystander intervention (BI) have been previously described: noticing the situation as a problem, interpreting when it is appropriate to intervene, recognizing personal responsibility to intervene, and knowing how to intervene. Using virtual reality (VR) to simulate emergencies such as sudden cardiac arrest (SCA) can be used to study these stages. In a secondary analysis of an observational cohort study, we analyzed bystander self-efficacy for stages of BI before and after simulated SCA. Each subject participated in a single-player, immersive, VR SCA scenario. Subjects interacted with simulated bystanders through voice commands ("call 911", "get an AED"). Actions taken in scenario, like performing CPR, were documented. Scenario BI actions were compared based on dichotomized comfort/discomfort. From June 2016 to June 2017, 119 subjects participated. Average age was 37±14 years, 44% were female and 46% reported CPR training within 2 years. During the scenario, 98% "noticed the event" and "interpreted it as a problem", 78% "took responsibility", and 54% "possessed the necessary skills". Self-efficacy increased from pre- to post-scenario: noticing the event increased from 80% to 96%; interpreting as a problem increased from 86% to 97%; taking responsibility increased from 56% to 93%; possessing necessary skills increased from 47% to 63% (P<0.001). Self-efficacy to respond to an SCA event increased pre- to post-scenario. Bystanders who reported feeling comfortable "taking responsibility to intervene" during an emergency were more likely to take action during a simulated emergency.


The polycomb group protein Suz12 is required for embryonic stem cell differentiation.
Polycomb group (PcG) proteins form multiprotein complexes, called Polycomb repressive complexes (PRCs). PRC2 contains the PcG proteins EZH2, SUZ12, and EED and represses transcription through methylation of lysine (K) 27 of histone H3 (H3). Suz12 is essential for PRC2 activity and its inactivation results in early lethality of mouse embryos. Here, we demonstrate that Suz12(-/-) mouse embryonic stem (ES) cells can be established and expanded in tissue culture. The Suz12(-/-) ES cells are characterized by global loss of H3K27 trimethylation (H3K27me3) and higher expression levels of differentiation-specific genes. Moreover, Suz12(-/-) ES cells are impaired in proper differentiation, resulting in a lack of repression of ES cell markers as well as activation of differentiation-specific genes. Finally, we demonstrate that the PcGs are actively recruited to several genes during ES cell differentiation, which despite an increase in H3K27me3 levels is not always sufficient to prevent transcriptional activation. In summary, we demonstrate that Suz12 is required for the establishment of specific expression programs required for ES cell differentiation. Furthermore, we provide evidence that PcGs have different mechanisms to regulate transcription during cellular differentiation.


Carotid arterial supply of the feline brain. Applications to the study of regional cerebral ischemia.
A study of the supply to the feline brain by the carotid-middle cerebral arteries was conducted using in vivo transcardiac injection with a mixture of micropaque and carbon black. Modifications in the filling pattern of the arterial vessels were visualized following short-term occlusion of a middle cerebral artery. A modified surgical method to induce occlusion of the M-l segment of the middle cerebral artery is also described.


[Identification of risk factors (the method of logistic regression)].
Logistic regression is a model used for prediction of an event (e.g. heart attack: yes/no) using several predictor variables whereas the output is confined to values between 0 and 1. The regression coefficients describe the size of the contribution of the risk factor. In this short introduction an example is used to explain the basic principle and the advantages of the logistic regression.


The Relationship between Pain Beliefs and Physical and Mental Health Outcome Measures in Chronic Low Back Pain: Direct and Indirect Effects.
Low back pain remains a major health problem with huge societal cost. Biomedical models fail to explain the disability seen in response to reported back pain and therefore patients' beliefs, cognitions and related behaviours have become a focus for both research and practice. This study used the Pain Beliefs Questionnaire and had two aims: To examine the extent to which pain beliefs are related to disability, anxiety and depression; and to assess whether those relationships are mediated by pain self-efficacy and locus of control. In a sample of 341 chronic low back pain patients, organic and psychological pain beliefs were related to disability, anxiety and depression. However, organic pain beliefs were more strongly related to disability and depression than psychological pain beliefs. Regression analyses revealed that these relationships were in part independent of pain self-efficacy and locus of control. Further, mediation analyses revealed indirect pathways involving self-efficacy and, to a lesser extent chance locus of control, between organic pain beliefs, on the one hand, and disability, anxiety and depression, on the other. In contrast, psychological pain beliefs were only directly related to disability, anxiety and depression. Although longitudinal data are needed to corroborate our findings, this study illustrates the importance of beliefs about the nature of pain and beliefs in one's ability to cope with pain in determining both physical and mental health outcomes in chronic low back pain patients.


Protocol for LAsting Symptoms after Oesophageal Resectional Surgery (LASORS): multicentre validation cohort study.
Surgery is the primary curative treatment for oesophageal cancer, with considerable recent improvements in long-term survival. However, surgery has a long-lasting impact on patient's health-related quality of life (HRQOL). Through a multicentre European study, our research group was able to identify key symptoms that affect patient's HRQOL. These symptoms were combined to produce a tool to identify poor HRQOL following oesophagectomy (LAsting Symptoms after Oesophageal Resection (LASOR) tool). The objective of this multicentre study is to validate a six-symptom clinical tool to identify patients with poor HRQOL for use in everyday clinical practice. Included patients will: (1) be aged 18 years or older, (2) have undergone an oesophagectomy for cancer between 2015 and 2019, and (3) be at least 12 months after the completion of adjuvant oncological treatments. Patients will be given the previously created LASOR questionnaire. Each symptom from the LASOR questionnaire will be graded according to impact on quality of life and frequency of the symptom, with a composite score from 0 to 5. The previously developed LASOR symptom tool will be validated against HRQOL as measured by the European Organisation for Research and Treatment of Cancer QLQC30 and OG25. With a predicted prevalence of poor HRQOL of 45%, based on the previously generated LASOR clinical symptom tool, to validate this tool with a sensitivity and specificity of 80%, respectively, a minimum of 640 patients will need to be recruited to the study. NHS Health Research Authority (North East-York Research Ethics Committee) approval was gained 8 November 2019 (REC reference 19/NE/0352). Multiple platforms will be used for the dissemination of the research data, including international clinical and patient group presentations and publication of research outputs in a high impact clinical journal.


Influence of foot ulceration on cause-specific mortality in patients with diabetes mellitus.
The purpose of this study was to assess the odds of all-cause mortality in individuals with diabetic foot ulceration (DFU) compared with those with diabetes and no history of DFU. In addition, we sought to determine the strength of association of DFU with cardiovascular and nonvascular mortality. We obtained data for a cohort of patients who attended a secondary care diabetic foot clinic or a general diabetes clinic between 2009 and 2010. A clinic cohort of patients with diabetes and no history of DFU provided a control group. Cause-specific mortality was recorded during a median follow-up duration of 3.6 years (interquartile range, 3.3-4.2 years). The association between DFU and all-cause mortality was evaluated by Cox regression. The association between DFU and cardiovascular mortality was determined by competing risk modeling. We recorded 145 events of all-cause mortality and 27 events of cardiovascular mortality among 869 patients with diabetes. After adjustment for potential confounders, DFU was associated with both cardiovascular disease (hazard ratio, 2.53; 95% confidence interval, 0.98-6.49; P = .05) and all-cause mortality (hazard ratio, 3.98; 95% confidence interval, 2.55-6.21; P < .001). The proportion of deaths attributable to cardiovascular disease was similar between the groups (18% with diabetes only and 19% with DFU; P = .91). DFU is associated with premature death from vascular and nonvascular causes.


Avatrombopag-induced lactic acidosis in a patient with severe thrombocytopenia.
A woman in her 60s was admitted for refractory thrombocytopenia, initially presumed to be from immune thrombocytopenia (ITP). She was treated with the thrombopoietin receptor agonist (TPO-RA) avatrombopag, as well as prophylactic ciprofloxacin and fluconazole for neutropenia. She developed an anion gap metabolic acidosis with a significantly elevated lactate level peaking at 7.5 mmol/L. Other causes of lactic acidosis including hypovolaemia, sepsis, ischaemia and diabetic ketoacidosis were ruled out. Avatrombopag was discontinued, with quick resolution of the lactic acidosis. Fluconazole and ciprofloxacin were found to inhibit the metabolism of avatrombopag and were also discontinued. Worsening thrombocytopenia prompted a rechallenge with increased dose avatrombopag and severe lactic acidosis again developed, with subsequent quick resolution after drug discontinuation. We conclude that a dose-dependent lactic acidosis occurred with avatrombopag in this case. While other TPO-RAs including eltrombopag have been associated with lactic acidosis, to our knowledge, this is the first report of avatrombopag-induced lactic acidosis.


A potential role for mechanical forces in the detachment of podocytes and the progression of CKD.
Loss of podocytes underlies progression of CKD. Detachment of podocytes from the glomerular basement membrane (GBM) rather than apoptosis or necrosis seems to be the major mechanism of podocyte loss. Such detachment of viable podocytes may be caused by increased mechanical distending and shear forces and/or impaired adhesion to the GBM. This review considers the mechanical challenges that may lead to podocyte loss by detachment from the GBM under physiologic and pathophysiologic conditions, including glomerular hypertension, hyperfiltration, hypertrophy, and outflow of filtrate from subpodocyte spaces. Furthermore, we detail the cellular mechanisms by which podocytes respond to these challenges, discuss the protective effects of angiotensin blockade, and note the questions that must be addressed to better understand the relationship between podocyte detachment and progression of CKD.


Structure-cytoprotective activity relationship of simple molecules containing an alpha,beta-unsaturated carbonyl system.
In previous reports we attributed the cytoprotective activity of several sesquiterpene lactones to the presence of a nonhindered electrophilic acceptor in their structure. We suggested that the mechanism of protection would be, at least in part, mediated through a reaction between the electrophilic acceptor and the sulfhydryl-containing groups of the mucosa. We report here the gastric cytoprotective effect of simple molecules containing an alpha, beta-unsaturated carbonyl group. In the present paper, we undertake the study of molecular accessibility and molecular shape, in addition to conformational, electronic, and steric factors. Our results helped to establish two important facts connecting chemical structure with cytoprotective effect. Firstly, an adequate molecular accessibility appears to be necessary to produce the biological response, and secondly, the alpha,beta-unsaturated carbonyl system has to be included in a cyclic structure or, at least, in the proximity of a cyclic system.


Conditions suitable for the recovery of biocide-treated spores of Bacillus subtilis.
Various factors were studied in order to determine the optimum conditions for the recovery of Bacillus subtilis spores treated with two iodine preparations, two chlorine-releasing agents or glutaraldehyde. The composition of the recovery medium was not usually important except that counts on brain heart infusion agar were significantly lower than on other media for iodine-treated spores. The addition to recovery media of soluble starch, charcoal, D-glucose or yeast extract usually had no discernible beneficial effect on colony counts. Maximum counts of survivors were obtained after an incubation period of 3 days and an optimum incubation temperature of 30 or 37 degrees C. Germination and outgrowth of biocide-exposed spores were more sensitive to changes in incubation temperature than were control spores.


[Expert systems and antibiotic sensitivity test].
Artificial intelligence is a part of computer science that deals with programs mimicking intelligence of man. Artificial intelligence is now used to check the quality of the determination of antibiotics susceptibility of bacteria. This application is useful because antibiotic susceptibility is subject to biological and technical variation that have to be detected. Three types of reasoning are used either by the biologist or by expert systems: low level quality checking dealing with individual results, microbiological interpretation of the whole set of results and medical interpretation of the results. The use of artificial intelligence in these fields is sustained by the structured nature of the knowledge. Two type of expert systems are already of routine use, either based on production rules (ATB plus EXPERT, bioMerieux, La Balme-les-Grottes, France and SIR, 12A, Montpellier, France), or on object-oriented representation of the knowledge (EXPRIM from our laboratory). The main problem is, as usually in artificial intelligence applications, to transfer human expertise into an adapted knowledge base. The advantage of experts systems over man are their reproducibility of answer and their availability.


Activation of Peracetic Acid by CoFe2O4 for Efficient Degradation of Ofloxacin: Reactive Species and Mechanism.
Peroxyacetic acid (PAA)-based advanced oxidation processes (AOPs) have attracted much attention in wastewater treatment by reason of high selectivity, long half-life reactive oxygen species (ROS), and wider applicability. In this study, cobalt ferrite (CoFe2O4) was applied to activate PAA for the removal of ofloxacin (OFX). The degradation of OFX could reach 83.0% via the CoFe2O4/PAA system under neutral conditions. The low concentration of co-existing anions and organic matter displayed negligible influence on OFX removal. The contributions of hydroxyl radicals (·OH), organic radicals (R-O·), and other reactive species to OFX degradation in CoFe2O4/PAA were systematically evaluated. Organic radicals (especially CH3C(O)OO·) and singlet oxygen (1O2) were verified to be the main reactive species leading to OFX destruction. The Co(II)/Co(III) redox cycle occurring on the surface of CoFe2O4 played a significant role in PAA activation. The catalytic performance of CoFe2O4 remained above 80% after five cycles. Furthermore, the ecotoxicity of OFX was reduced after treatment with the CoFe2O4/PAA system. This study will facilitate further research and development of the CoFe2O4/PAA system as a new strategy for wastewater treatment.


Concept Analysis: Health-Promoting Behaviors Related to Human Papilloma Virus (HPV) Infection.
The concept of health-promoting behaviors incorporates ideas presented in the Ottawa Charter of Public Health and the nursing-based Health Promotion Model. Despite the fact that the concept of health-promoting behaviors has a nursing influence, literature suggests nursing has inadequately developed and used this concept within nursing practice. A further review of literature regarding health promotion behaviors and the human papilloma virus suggest a distinct gap in nursing literature. This article presents a concept analysis of health-promoting behaviors related to the human papilloma virus in order to encourage the application of the concept into nursing practice, promote continued nursing research regarding this concept, and further expand the application of health-promoting behaviors to other situations and populations within the nursing discipline. Attributes of health-promoting behaviors are presented and include empowerment, participation, community, and a positive concept of health. Antecedents, consequences, and empirical referents are also presented, as are model, borderline, and contrary cases to help clarify the concept. Recommendations for human papilloma virus health-promoting behaviors within the nursing practice are also provided.


Using Weighted Hospital Service Area Networks to Explore Variation in Preventable Hospitalization.
To demonstrate the use of multiple-membership multilevel models, which analytically structure patients in a weighted network of hospitals, for exploring between-hospital variation in preventable hospitalizations. Cohort of 267,014 people aged over 45 in NSW, Australia. Patterns of patient flow were used to create weighted hospital service area networks (weighted-HSANs) to 79 large public hospitals of admission. Multiple-membership multilevel models on rates of preventable hospitalization, modeling participants structured within weighted-HSANs, were contrasted with models clustering on 72 hospital service areas (HSAs) that assigned participants to a discrete geographic region. Linked survey and hospital admission data. Between-hospital variation in rates of preventable hospitalization was more than two times greater when modeled using weighted-HSANs rather than HSAs. Use of weighted-HSANs permitted identification of small hospitals with particularly high rates of admission and influenced performance ranking of hospitals, particularly those with a broadly distributed patient base. There was no significant association with hospital bed occupancy. Multiple-membership multilevel models can analytically capture information lost on patient attribution when creating discrete health care catchments. Weighted-HSANs have broad potential application in health services research and can be used across methods for creating patient catchments.


Key roles of Phe1112 and Ser1115 in the pore-forming IIIS5-S6 linker of L-type Ca2+ channel alpha1C subunit (CaV 1.2) in binding of dihydropyridines and action of Ca2+ channel agonists.
Voltage-dependent L-type Ca2+ channels are modulated by the binding of Ca2+ channel antagonists and agonists to the pore-forming alpha1c subunit (CaV 1.2). We recently identified Ser1115 in IIIS5-S6 linker of alpha1C subunit as a critical determinant of the action of 1,4-dihydropyridine agonists. In this study, we applied alanine-scanning mutational analysis in IIIS5-S6 linker of rat brain alpha1C subunit (rbCII) to illustrate the role of pore-forming IIIS5-S6 linker in the action of Ca2+ channel modulators. Ca2+ channel currents through wild-type (rbCII) or mutated alpha1C subunits, transiently expressed in BHK6 cells with beta1a and alpha2/delta subunits, were analyzed. The replacement of Phe1112 by Ala (F1112A) significantly impaired the sensitivity to Ca2+ channel agonists (S)-(-)-Bay k 8644 and FPL-64176, and modestly to 1,4-dihydropyridine (DHP) antagonists. The low sensitivity of F1112A and S1115A to DHP antagonists was consistent with the reduced binding affinity for [3H](+)PN200-110. The replacement of Phe1112 by Tyr, but not by Ala, restored the long openings produced by FPL-64176, thus indicating the critical role of aromatic ring of Phe1112 in the Ca2+ channel agonist action. Interestingly, double-mutant Ca2+ channel (F1112A/S1115A) failed to discriminate between Ca2+ channel agonist (S)-(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-[trifluoromethyl] phenyl)-3-pyridine carboxylic acid methyl ester (Bay k 8644) and antagonist (R)-(+)-Bay k 8644 and was blocked by the two enantiomers in an identical manner. These results indicate that both Phe1112 and Ser1115 in linker IIIS5-S6 are required for the action of Ca2+ channel agonists. A model of the DHP receptor is proposed to visualize possible interactions of Phe1112, Ser1115, and other DHP-sensing residues with a typical DHP ligand nifedipine.


Marshall-Smith syndrome: Novel pathogenic variant and previously unreported associations with precocious puberty and aortic root dilatation.
Marshall-Smith Syndrome (MRSHSS) is a very rare genetic disorder characterized by failure to thrive and characteristic dysmorphic features associated with accelerated osseous maturation. We present a nine-year-old girl who was diagnosed with MRSHSS based on characteristic clinical features supported by the identification of a novel de novo pathogenic variant in the NFIX gene. The patient also presented with precocious puberty diagnosed at five years of age and had an abnormal GnRH stimulation test indicative of central precocious puberty. Central precocious puberty has not been described in association with MRSHSS previously in the medical literature and broadens our knowledge of the natural history of MRSHSS. The causes of advanced bone age in this syndrome are also reviewed. Additionally, the patient showed progressive dilatation of the aortic root. Although connective tissue abnormalities have been described in association with MRSHSS, aortic root dilatation has not. Understanding the mechanism of comorbidities such as advanced bone age and aortic root dilatation in MRSHSS patients enables future development of anticipatory guidance, preventative care measures, and treatment guidelines.


Association of sleep time with diabetes mellitus and impaired glucose tolerance.
Experimental sleep restriction causes impaired glucose tolerance (IGT); however, little is known about the metabolic effects of habitual sleep restriction. We assessed the cross-sectional relation of usual sleep time to diabetes mellitus (DM) and IGT among participants in the Sleep Heart Health Study, a community-based prospective study of the cardiovascular consequences of sleep-disordered breathing. Participants were 722 men and 764 women, aged 53 to 93 years. Usual sleep time was obtained by standardized questionnaire. Diabetes mellitus was defined as a serum glucose level of 126 mg/dL or more (> or =7.0 mmol/L) fasting or 200 mg/dL or more (> or =11.1 mmol/L) 2 hours following standard oral glucose challenge or medication use for DM. Impaired glucose tolerance was defined as a 2-hour postchallenge glucose level of 140 mg/dL or more (> or =7.8 mmol/L) and less than 200 mg/dL. The relation of sleep time to DM and IGT was examined using categorical logistic regression with adjustment for age, sex, race, body habitus, and apnea-hypopnea index. The median sleep time was 7 hours per night, with 27.1% of subjects sleeping 6 hours or less per night. Compared with those sleeping 7 to 8 hours per night, subjects sleeping 5 hours or less and 6 hours per night had adjusted odds ratios for DM of 2.51 (95% confidence interval, 1.57-4.02) and 1.66 (95% confidence interval, 1.15-2.39), respectively. Adjusted odds ratios for IGT were 1.33 (95% confidence interval, 0.83-2.15) and 1.58 (95% confidence interval, 1.15-2.18), respectively. Subjects sleeping 9 hours or more per night also had increased odds ratios for DM and IGT. These associations persisted when subjects with insomnia symptoms were excluded. A sleep duration of 6 hours or less or 9 hours or more is associated with increased prevalence of DM and IGT. Because this effect was present in subjects without insomnia, voluntary sleep restriction may contribute to the large public health burden of DM.


Peculiar archaea found in Japanese paddy soils.
Archaeal 16S rDNA clones retrieved from paddy soil DNA were sequenced. Among 100 clones, 88 clones were assigned to methanogens and nine clones were assigned to crenarchaeota. However, three of the nine clones were phylogenetically far from the cultured crenarchaeota and closely related to marine planktonic archaea. The other three clones showed extremely novel 16S rDNA sequences and were phylogenetically far from both Crenarchaeola and Euryarchaeota. This paper reports the ubiquitous presence of crenarchaeotal and extremely novel clones in paddy soils.


[Magnesium quantification in mouse brain and cerebellum grey matter].
The magnesium content in the brain and cerebellum grey matter was determined in 20 male mice of the wistar species with a diet poor in magnesium. Significantly smaller values were found in the cerebellum in comparison to the brain of the magnesium deprived mice.


Molecular mechanisms of dopaminergic subset specification: fundamental aspects and clinical perspectives.
Dopaminergic (DA) neurons in the ventral mesodiencephalon control locomotion and emotion and are affected in psychiatric and neurodegenerative diseases, such as Parkinson's disease (PD). A clinical hallmark of PD is the specific degeneration of DA neurons located within the substantia nigra (SNc), whereas neurons in the ventral tegmental area remain unaffected. Recent advances have highlighted that the selective vulnerability of the SNc may originate in subset-specific molecular programming during DA neuron development, and significantly increased our understanding of the molecular code that drives specific SNc development. We here present an up-to-date overview of molecular mechanisms that direct DA subset specification, integrating our current knowledge about subset-specific roles of transcription factors, signaling pathways and morphogenes. We discuss strategies to further unravel subset-specific gene-regulatory networks, and the clinical promise of fundamental knowledge about subset specification of DA neurons, with regards to cell replacement therapy and cell-type-specific vulnerability in PD.


Prevalence of Chlamydophila pneumoniae antibodies in women with pre-eclampsia in Lagos, Nigeria.
The precise aetiology of pre-eclampsia has remained unknown. It is still a major contributor to maternal and perinatal morbidity and mortality. To determine the relationship between pre-eclampsia and immunoglobulin G (IgG) antibodies to Chlamydophila pneumoniae. One hundred and eleven parturients in a tertiary hospital in Lagos, Nigeria comprising 49 women with pre-eclampsia and 62 women without pre-eclampsia were studied.Peripheral blood was obtained for Chlamydophila pneumoniae antibodies which were measured using a solid-phase enzyme-linked immunosorbent assay and maternal diastolic blood pressure, perinatal morbidity and mortality were also assessed. The cases (N = 49) and controls (N = 62) were evenly matched with respect to age and parity. The women with pre-eclampsia delivered at significantly lower gestational ages than those with normotensive gestations. 66.7% of all the subjects were seropositive for Chlamydophila pneumoniae antibodies. 38 out of the 49 cases (77.6%) were positive for the Chlamydophila pneumoniae antibodies compared with 36 out of the 62 controls (58.1%) [p<0.05].Higher antibody titres were found in parous women with a previous history of pre-eclampsia compared with those without a previous history (p = 0.0308).However, there was no significant association between antibody titres and pregnancy outcome (p >0.05). Results from this study suggest a link between Chlamydophila pneumoniae IgG antibodies and pre-eclampsia. Further prospective studies with larger sizes are needed to verify this association and identify therapeutic options that will effectively prevent the onset or progression of pre-eclampsia.


Copper-Induced Stimulation of Nitrification in Biological Rapid Sand Filters for Drinking Water Production by Proliferation of Nitrosomonas spp.
Copper is a cofactor of the ammonia monooxygenase, an essential enzyme for the activity of ammonia oxidizing prokaryotes (AOP). Copper dosing at less than 1 μg/L stimulated ammonium removal in the poorly nitrifying biological filters of three full-scale drinking water treatment plants. Upon copper dosing, the ammonium concentration in the effluent decreased from up to 0.18 to less than 0.01 mg NH4+-N/L. To investigate how copper dosing affected the filter microbial community, we applied amplicon sequencing and qPCR targeting key nitrifying groups, including complete ammonia oxidizing (comammox) Nitrospira. Copper dosing increased the abundance of different nitrifiers. Multiple Nitrosomonas variants (betaproteobacterial ammonia oxidizers), which initially collectively represented 1% or less of the total community, increased almost 10-fold. Comammox Nitrospira were abundant and increased too, but their relative abundance within the AOP decreased because of Nitrosomonas proliferation. No other consistent change in the filter communities was detected, as well as no adverse effect of copper on the filters functionality. Our results show that copper dosing in three independent treatment plants was associated with consistent growth of AOP and that efficient nitrification was achieved through the joint contribution of comammox Nitrospira and an increasing fraction of betaproteobacterial ammonia oxidizers.


Synthesis of monodisperse PbSe nanorods: a case for oriented attachment.
Monodisperse, high-quality, single-crystal PbSe nanorods were synthesized in a catalyst-free, one-pot reaction using a new phosphine selenide precursor. PbSe nanorods were assembled to provide liquid-crystalline alignment or vertical alignment under controlled evaporation conditions. The growth of nanorods was monitored by TEM and absorption spectroscopy, indicating that oriented attachment could be involved to provide anisotropic PbSe nanostructures. In-plane XRD showed an enhanced (200) peak for PbSe nanorods, indicating the preferred alignment of nanorods on the substrates and their growth along the <100> direction. Absorption and emission spectra, along with lifetime measurements, show the differences between nanoscale PbSe spheres and rods.


Simultaneous Localization of Two High Affinity Divalent Metal Ion Binding Sites in the Tetracycline RNA Aptamer with Mn2+-Based Pulsed Dipolar EPR Spectroscopy.
Mg2+ ions play an essential part in stabilizing the tertiary structure of nucleic acids. While the importance of these ions is well documented, their localization and elucidation of their role in the structure and dynamics of nucleic acids are often challenging. In this work, pulsed electron-electron double resonance spectroscopy (PELDOR, also known as DEER) was used to localize two high affinity divalent metal ion binding sites in the tetracycline RNA aptamer with high accuracy. For this purpose, the aptamer was labeled at different positions with a semirigid nitroxide spin label and diamagnetic Mg2+ was replaced with paramagnetic Mn2+, which did not alter the folding process or ligand binding. Out of the several divalent metal ion binding sites that are known from the crystal structure, two binding sites with high affinity were detected: one that is located at the ligand binding center and another at the J1/2 junction of the RNA.


Landmark risk prediction of residual life for breast cancer survival.
The importance of developing personalized risk prediction estimates has become increasingly evident in recent years. In general, patient populations may be heterogenous and represent a mixture of different unknown subtypes of disease. When the source of this heterogeneity and resulting subtypes of disease are unknown, accurate prediction of survival may be difficult. However, in certain disease settings, the onset time of an observable short-term event may be highly associated with these unknown subtypes of disease and thus may be useful in predicting long-term survival. One approach to incorporate short-term event information along with baseline markers for the prediction of long-term survival is through a landmark Cox model, which assumes a proportional hazards model for the residual life at a given landmark point. In this paper, we use this modeling framework to develop procedures to assess how a patient's long-term survival trajectory may change over time given good short-term outcome indications along with prognosis on the basis of baseline markers. We first propose time-varying accuracy measures to quantify the predictive performance of landmark prediction rules for residual life and provide resampling-based procedures to make inference about such accuracy measures. Simulation studies show that the proposed procedures perform well in finite samples. Throughout, we illustrate our proposed procedures by using a breast cancer dataset with information on time to metastasis and time to death. In addition to baseline clinical markers available for each patient, a chromosome instability genetic score, denoted by CIN25, is also available for each patient and has been shown to be predictive of survival for various types of cancer. We provide procedures to evaluate the incremental value of CIN25 for the prediction of residual life and examine how the residual life profile changes over time. This allows us to identify an informative landmark point, t(0) , such that accurate risk predictions of the residual life could be made for patients who survive past t(0) without metastasis.


[Analgesic and antipyretic effects of cyproheptadine].
Cyproheptadine-HCl raised the pain thresholds during hot plat test and writhing test in mice and tail flick test in rats, strengthened the hypnotic action by subthreshold dosage of sodium pentobarbital and chloral hydrate. The ED50 were 4.4 (3.2-5.7) and 12.4 (8.4-18.2) mg/kg 30 min after ip cyproheptadine in mice and rats, respectively. The ED50 was 0.14 (0.12-0.18) mg/kg 90 min after icv cyproheptadine in mice. Cyproheptadine po 20, 40 mg/kg and ip 10, 20 mg/kg showed significant antipyretic effects on yeast-induced pyrexia in rats.


Mycobacterium kansasii arthritis of the elbow in an immunocompetent patient with a suspected soft-tissue tumor.
Mycobacterium kansasii is one of the major non-tuberculous mycobacteria species that typically cause pulmonary diseases. M. kansasii is known to cause septic arthritis as an extrapulmonary disease in immunosuppressed patients or chronic skin disease. Herein, we present a case of M. kansasii arthritis involving the elbow of an immunocompetent patient, which was initially suspected to be a soft-tissue tumor. A 70-year-old man presented with a swollen left elbow that had progressed for 18 months with deteriorating arthralgia and limited range of motion. Magnetic resonance imaging revealed filling of the intra-articular space of the elbow and surrounding of the radial head with a soft tissue mass with mixed signal intensity. Initial incisional biopsy was performed via the lateral approach to the elbow joint, and pathological examination of the mass did not reveal any evidence of malignancy. One year after the first operation, arthroscopic surgery was performed to excise the mass following the recurrence of swelling and limited function of the elbow. Pathological examination of the resected synovium revealed epithelioid granulomas containing a multinucleated giant cell and inflammatory cell infiltration, characteristic of mycobacterial infection. M. kansasii was cultured after 2 weeks of incubation of the synovial sample. He experienced full resolution of the swelling and limited function following a combination of synovectomy and multidrug antimycobacterial treatment (rifampin 600 mg/day, clarithromycin 800 mg/day, and ethambutol 750 mg/day). This case highlights the need to consider this rare infection in the differential diagnosis of intra-articular soft tissue tumor-like lesions even in immunocompetent patients.


Strengthiening systems to support mothers in infant and young child feeding at scale.
Systems strengthening is essential for implementation of large-scale nutrition interventions, including infant and young child feeding (IYCF), since rapid geographic expansion places additional burdens on service delivery systems. To document approaches for building capacity and supporting programs to scale up IYCF counseling in three different country contexts. Situational assessments, stakeholder consultations, formative research, household and frontline health worker surveys, other related studies, and program monitoring in three countries identified gaps and opportunities for strengthening IYCF service delivery. Variations in program platforms, level and roles of service providers, places of service delivery, community factors, and the needs of managers and frontline workers influenced the intervention mix used for strengthening IYCF services. The programs ranged from a highly structured and standardized package of IYCF counseling services in Vietnam delivered through government health facilities to counseling delivered at the doorstep by incentivized nongovernmental organization volunteers in Bangladesh. In Ethiopia, government health extension workers based at health posts conducted outreach visits with support from volunteers. Guidelines and standards of care, training, job aids, supportive supervision, incentives, and monitoring data can enhance performance and strengthen systems for delivering IYCF counseling services in the community or at health facilities. Leadership, financing, partnerships, and logistics support are essential to support large-scale implementation of the IYCF counseling package in diverse service delivery environments.


Tethered cord syndrome in adults.
The treatment of tethered cord syndromes in adults is discussed regarding the natural history and surgical indications. The author analyzes data obtained in patients who were diagnosed with a tethered cord in adulthood and either underwent surgical or conservative therapy between 1991 and 2009. Since 1991, data obtained in 2515 patients with spinal cord pathologies were entered into the spinal cord database, and prospective follow-up was performed through outpatient visits and questionnaires. Of the 2515 patients, 85 adults with a tethered cord syndrome formed the basis of this study. The tethering effect was caused either by a split cord malformation, a thick filum terminale, a conus medullaris lipoma with extradural extension, or various combinations of these mechanisms. The mean age of the patients was 46 ± 13 years (range 23-74 years) and the mean follow-up duration was 61 ± 62 months. Two groups were distinguished based on the absence (Group A, 43 patients) or presence (Group B, 42 patients) of an associated lipoma or dysraphic cyst (that is, dermoid, epidermoid, or neurenteric cyst). Surgery was recommended for patients with symptoms only. Short-term results were determined within 3 months of surgery, whereas long-term outcomes (clinical recurrences) were evaluated using Kaplan-Meier statistics. For all patients, pain was the most common major complaint. Severe neurological deficits were rare. In Group A, 20 of 43 patients underwent surgery, whereas in Group B 23 of 42 patients underwent surgery. Among individuals who did not undergo surgery, 17 patients refused surgery and 25 patients underwent recommended conservative treatment. Short-term postoperative results indicated a significant improvement of pain and a stabilization of neurological symptoms. Long-term results showed a good prognosis in patients in whom first-time (that is, nonrevision) surgery achieved successful untethering, with a 10-year rate of neurological stabilization in 89% of Group A and a 10-year rate of neurological stabilization in 81% of Group B patients. The benefit of secondary operations in Group B was limited, with eventual clinical deterioration occurring in all patients within 10 years. For patients treated conservatively, follow-up information could be obtained in 33 of 42 patients. Twenty-eight patients remained in stable clinical condition. Only 5 of the conservatively treated patients experienced clinical deterioration over time; in 4 of these individuals with deterioration, surgery had been recommended but was refused by the patient. The clinical recurrence rate in all conservatively treated patients was 21% after 10 years. With a recommendation for surgery this figure rose to 47% within 5 years. Surgery in adult patients with a tethered cord syndrome should be reserved for those with symptoms. In surgically treated patients, pain relief can often be achieved, and long-term neurological stabilization tends to persist more often than it does in conservatively treated patients. A conservative approach is warranted, however, in adult patients without neurological deficits. Revision surgery in patients with complex dysraphic lesions should be performed in exceptional cases only.


A review of mineral imbalances of grazing animals in southern Africa.
A historical review of mineral imbalances recognised in Southern Africa is given. The survey procedures which were followed are described in terms of sample sources, as well as the analytical procedures with emphasis on the problems encountered at each stage of the developments. A concise summary is given of the mineral patterns known to date according to the ten regions currently recognised where specific patterns of mineral imbalances are known to occur.


Pars interarticularis fenestration in the treatment of foraminal lumbar disc herniation: a further surgical approach.
A new surgical approach to foraminal disc herniation is proposed. The procedure was performed in 28 patients during a span of 3 years. The herniation was purely foraminal in 18 patients and mainly foraminal with a definite extraforaminal component in the other 10 patients. Surgical treatment was offered only after 6 weeks of therapy with anti-inflammatory drugs and strict bed rest had proved to be ineffective. To unroof the foraminal compartment, an ovoid fenestration (10 x 5 mm) is cut, with its major longitudinal axis at the level of the pars interarticularis, just medially and slightly off-center under the lateral isthmic notch, i.e., below the pedicle projection. This fenestration exposes the foraminal root compressed by the herniated disc, which can be easily removed. Treatment was successful in all patients, with swift remission of pain and only mild postoperative discomfort. All patients resumed their occupations as usual within 10 to 30 days after the operation, according to type of work. Mean follow-up is 24 months (range, 12-36 mo), without any return of pain. We propose pars interarticularis fenestration because it spares, with minimal bone removal, the facet joints and the anatomic continuity of the pars interarticularis, yet properly exposes the foraminal compartment both medially and laterally and thereby permits optimal removal of the disc herniation.


Comparative transcriptome analysis of genes involved in the drought stress response of two peanut (Arachis hypogaea L.) varieties.
The peanut is one of the most important oil crops worldwide. Qualities and yields of peanut can be dramatically diminished by abiotic stresses particularly by drought. Therefore, it would be beneficial to gain a comprehensive understanding on peanut drought-responsive transcriptional regulatory activities, and hopefully to extract critical drought-tolerance-related molecular mechanism from it. In this study, two peanut Arachis hypogaea L. varieties, NH5 (tolerant) and FH18 (sensitive), which show significantly differential drought tolerance, were screened from 23 main commercial peanut cultivars and used for physiological characterization and transcriptomic analysis. NH5 leaves showed higher water and GSH contents, faster stomatal closure, and lower relative conductivity (REC) than FH18. Under the time-course of drought-treatments 0 h (CK), 4 h (DT1), 8 h (DT2) and 24 h (DT3), the number of down-regulated differential expressed genes (DEGs) increased with the progression of treatments indicating repressive impacts on transcriptomes by drought in both peanut varieties. Nevertheless, NH5 maintained more stable transcriptomic dynamics than FH18. Furthermore, annotations of identified DEGs implicate signal transduction, the elimination of reactive oxygen species, and the maintenance of cell osmotic potential which are key drought-tolerance-related pathways. Finally, evidences from the examination of ABA and SA components suggested that the fast stomatal closure in NH5 was likely mediated through SA rather than ABA signaling. In all, these results have provided us a comprehensive overview of peanut drought-responsive transcriptomic changes, which could serve as solid foundation for further identification of the molecular drought-tolerance mechanism in peanut and other oil crops.


A histological study of the effects of enzootic abortion of ewes virus in the lactating bovine mammary gland.
Inoculation of the udders of cows with the virus of enzootic abortion of ewes resulted in a severe acute mastitis. The mastitis was characterized clinically by pyrexia, anorexia, decreased milk production, swelling and marked alteration in the physical quality of the milk. The basic lesion was necrosis of alveolar and duct epithelial cells. Virus particles were demonstrated in all levels of the mammary gland three days after inoculation illustrating the rapid spread of the agent. Cells resembling Reed-Sternberg cells and similar to those seen in experimental mastitis produced by the virus of infectious bovine rhinotracheitis were seen in tissues collected six and nine days after inoculation.


Chickadees discriminate contingency reversals presented consistently, but not frequently.
Chickadees are high-metabolism, non-migratory birds, and thus an especially interesting model for studying how animals follow patterns of food availability over time. Here, we studied whether black-capped chickadees (Poecile atricapillus) could learn to reverse their behavior and/or to anticipate changes in reinforcement when the reinforcer contingencies for each stimulus were not stably fixed in time. In Experiment 1, we examined the responses of chickadees on an auditory go/no-go task, with constant reversals in reinforcement contingencies every 120 trials across daily testing intervals. Chickadees did not produce above-chance discrimination; however, when trained with a procedure that only reversed after successful discrimination, chickadees were able to discriminate and reverse their behavior successfully. In Experiment 2, we examined the responses of chickadees when reversals were structured to occur at the same time once per day, and chickadees were again able to discriminate and reverse their behavior over time, though they showed no reliable evidence of reversal anticipation. The frequency of reversals throughout the day thus appears to be an important determinant for these animals' performance in reversal procedures.


Pursuit tracking impairments in schizophrenia and mood disorders: step-ramp studies with unmedicated patients.
Eye tracking abnormalities are highly prevalent in schizophrenia, and are among the most promising phenotypic familial markers for the disorder. The neurophysiologic mechanisms underlying these disturbances and their diagnostic specificity for schizophrenia are not yet well characterized. This study assessed eye tracking deficits using foveopetal and foveofugal step-ramp tasks (ramps moving toward and away from central fixation after an initial step respectively) across a range of target velocities in anti-psychotic-naive schizophrenia patients, previously treated but currently unmedicated chronic schizophrenia patients, unmedicated patients with either bipolar or unipolar mood disorders, and healthy volunteers. All patient groups demonstrated reduced pursuit gain in open loop and closed loop visual tracking conditions. There were no significant group differences in the latency or accuracy of catch-up saccades on foveofugal ramp tasks. These findings indicate that open and closed loop pursuit eye movements are impaired during acute episodes of schizophrenia and mood disorders. The intact accuracy of saccades to moving targets in all patient groups indicates that an adequate representation of motion information is available to the saccade system. Therefore, pursuit disturbances in mood disorders and schizophrenia seem to result, at least in part, from a disturbance in sensorimotor integration in the pursuit system after the initial extraction of sensory motion information. No eye movement abnormalities observed during performance of step ramp tasks were specific to schizophrenia.


Lung transcriptomics of K18-hACE2 mice highlights mechanisms and genes involved in the MVA-S vaccine-mediated immune response and protection against SARS-CoV-2 infection.
Unravelling the molecular mechanism of COVID-19 vaccines through transcriptomic pathways involved in the host response to SARS-CoV-2 infection is key to understand how vaccines work, and for the development of optimized COVID-19 vaccines that can prevent the emergence of SARS-CoV-2 variants of concern (VoCs) and future outbreaks. In this study, we investigated the effects of vaccination with a modified vaccinia virus Ankara (MVA)-based vector expressing the full-length SARS-CoV-2 spike protein (MVA-S) on the lung transcriptome from susceptible K18-hACE2 mice after SARS-CoV-2 infection. One dose of MVA-S regulated genes related to viral infection control, inflammation processes, T-cell response, cytokine production and IFN-γ signalling. Down-regulation of Rhcg and Tnfsf18 genes post-vaccination with one and two doses of MVA-S may represent a mechanism for controlling infection immunity and vaccine-induced protection. One dose of MVA-S provided partial protection with a distinct lung transcriptomic profile to healthy animals, while two doses of MVA-S fully protected against infection with a transcriptomic profile comparable to that of non-vaccinated healthy animals. This suggests that the MVA-S booster generates a robust and rapid antigen-specific immune response preventing virus infection. Notably, down-regulation of Atf3 and Zbtb16 genes in mice vaccinated with two doses of MVA-S may contribute to vaccine control of innate immune system and inflammation processes in the lungs during SARS-CoV-2 infection. This study shows host transcriptomic mechanisms likely involved in the MVA-S vaccine-mediated immune response against SARS-CoV-2 infection, which could help in improving vaccine dose assessment and developing novel, well-optimized SARS-CoV-2 vaccine candidates against prevalent or emerging VoCs.


Similarity measures between strings extended to sets of strings.
Similarity measures between strings (finite-length sequences of symbols) are extended to apply to sets of strings in an intuitive way which also preserves some of the desired properties of the initial similarity measure. Two quite different measures are used in the examples: the first for applications where numerical computation of pointwise similarity is needed; the second for applications which depend more heavily on substring similarity. It is presumed throughout that alphabets may be nondenumerable; in particular, the unit interval [0, 1] is used as the alphabet in the examples.


[Fracture healing after plate osteosynthesis in acute post-traumatic osteitis].
The inoculated rabbit tibia served as experimental model to evaluate the influence of stabilization for the healing of infected fractures. We also examined the importance of stabilization for the course of posttraumatic osteitis. The most important results are: 1. The course of posttraumatic osteitis is influenced positively by stabilization. In spite of the implanted foreign material the osteitis will often be reduced to a bland stage. 2. Even in the state of manifest osteitis fracture healing primarily depends on stability. After stabilization of the infected fractures we even saw primary fracture healing in a high percentage (36,4%). 3. Any instability is a much greater danger for the infected fracture as for the non-infected one. The combination of instability, inflammatory destruction and impaired circulation resulted in a pseudarthrosis in most cases examined. Furthermore our experiments showed that the stabilization of infected fractures should be done as soon as possible, i.e. at a moment, when the inflammatory destructions have not yet proceeded too far. These results confirm the findings of other authors and especially demonstrate that for the infected fracture stabilization is the decisive therapeutic principle. To obtain this stabilization one should not hesitate to implant foreign material (e.g. metal plates) even into an infected area. In selected cases therefore the "septic plate osteosynthesis" is an enlargement of the therapeutic possibilities in the difficult situation of posttraumatic osteitis.


Pediatric Onset Multiple Sclerosis and Obesity: Defining the Silhouette of Disease Features in Overweight Patients.
Obesity has been suggested as an environmental risk factor for multiple sclerosis (MS) and may negatively effect the progression of the disease. The aim of this study is to determine any correlation between overweight/obesity and the clinical and neuroradiological features at the onset of pediatric onset multiple sclerosis (POMS). Were included patients referred to the POMS Unit of the Bambino Gesù Children's Hospital between June 2012 and June 2021. The diagnosis of MS with an onset of less than 18 years was required. For all included subjects, we considered for the analysis the following data at the onset of symptoms: general data (age, sex, functional system compromised by neurological signs, weight and height), brain and spinal magnetic resonance imaging (MRI), cerebrospinal fluid exams. We identified 55 pediatric cases of POMS and divided them into two groups according to the body mass index (BMI): 60% were healthy weight (HW) and 40% were overweight/obese (OW/O). OW/O patients experienced a two-year age difference in disease onset compared to the HW patients (12.7 ± 3.8 years vs. 14.6 ± 4.1 years; p < 0.05). Onset of polyfocal symptoms was seen more frequently in OW/O patients than in HW (72.7% vs. 21.2%; p < 0.05). The pyramidal functions were involved more frequently in the OW/O group than in the HW group (50% vs. 25%; p < 0.005). Black holes were detected more frequently in OW/O patients in onset MRI scans compared to the HW group (50% vs. 15.5%; p < 0.05). Our findings suggest that being overweight/obese affects the risk of developing MS at an earlier age and is associated with an unfavorable clinical-radiological features at onset. Weight control can be considered as a preventive/therapeutic treatment.


Socioeconomic position in early life, birth weight, childhood cognitive function, and adult mortality. A longitudinal study of Danish men born in 1953.
To examine the relation between socioeconomic position in early life and mortality in young adulthood, taking birth weight and childhood cognitive function into account. A longitudinal study with record linkage to the Civil Registration System and Cause of Death Registry. The data were analysed using Cox regression. The metropolitan area of Copenhagen, Denmark. 7493 male singletons born in 1953, who completed a questionnaire with various cognitive measures, in school at age 12 years, and for whom birth certificates with data on birth and parental characteristics had been traced manually in 1965. This population was followed up from April 1968 to January 2002 for information on mortality. Mortality from all causes, cardiovascular diseases, and violent deaths. Men whose fathers were working class or of unknown social class at time of birth had higher mortality rates compared with those whose fathers were high/middle class: hazard ratio 1.39 (95% CI 1.15 to 1.67) and 2.04 (95% CI 1.48 to 2.83) respectively. Birth weight and childhood cognitive function were both related to father's social class and inversely associated with all cause mortality. The association between father's social class and mortality attenuated (HR(working class)1.30 (1.08 to 1.56); HR(unknown class)1.81 (1.30 to 2.52)) after control for birth weight and cognitive function. Mortality from cardiovascular diseases and violent deaths was also significantly higher among men with fathers from the lower social classes. The inverse association between father's social class at time of birth and early adult mortality remains, however somewhat attenuated, after adjustment for birth weight and cognitive function.


Neurodynamics: is tension contentious?
Tensioning techniqueswere the first neurodynamic techniques used therapeutically in the management of people with neuropathies. This article aims to provide a balanced evidence-informed view on the effects of optimal tensile loading on peripheral nerves and the use of tensioning techniques. Whilst the early use of neurodynamics was centered within a mechanical paradigm, research into the working mechanisms of tensioning techniques revealed neuroimmune, neurophysiological, and neurochemical effects. In-vitro and ex-vivo research confirms that tensile loading is required for mechanical adaptation of healthy and healing neurons and nerves. Moreover, elimination of tensile load can have detrimental effects on the nervous system. Beneficial effects of tensile loading and tensioning techniques, contributing to restored homeostasis at the entrapment site, dorsal root ganglia and spinal cord, include neuronal cell differentiation, neurite outgrowth and orientation, increased endogenous opioid receptors, reduced fibrosis and intraneural scar formation, improved nerve regeneration and remyelination, increased muscle power and locomotion, less mechanical and thermal hyperalgesia and allodynia, and improved conditioned pain modulation. However, animal and cellular models also show that 'excessive' tensile forces have negative effects on the nervous system. Although robust and designed to withstand mechanical load, the nervous system is equally a delicate system. Mechanical loads that can be easily handled by a healthy nervous system, may be sufficient to aggravate clinical symptoms in patients. This paper aims to contribute to a more balanced view regarding the use of neurodynamics and more specifically tensioning techniques.


Alternative to High Pressure Mercury Vapor Lamp for Photo Induced Fluorescence Analytical Methods; Application to the Determination of Pesticides in Water.
The photo-induced fluorescence method is often applied to determine non-native fluorescent compounds. It typically uses UV irradiation from a high pressure mercury vapor discharge lamp to create photo-induced fluorescent compounds, which are then quantified by fluorescence spectroscopy. However, these mercury lamps require a high-voltage power supply and may accidentally induce electric shocks and the release of mercury vapors. As an alternative, we have evaluated in this technical note new UV-C germicidal lamps. These lamps exhibit a higher power at 254 nm and allowed us to obtain a far greater amount of photo-induced compounds in a shorter time. For the first time, this new irradiation system has been applied for the determination of pesticides in water and has shown a significant increase in the method sensitivity. These good results allowed us to conclude that the new UV-C lamps are a relevant alternative to high pressure mercury vapor discharge lamps for use with photo induced fluorescent methods.


Sorafenib enhances the antitumor effects of anti-CTLA-4 antibody in a murine cancer model by inhibiting myeloid-derived suppressor cells.
This antitumor effect of sorafenib is considered to be dependent not only on its direct cytotoxicity to cancer cells but also due to the inhibition of myeloid-derived suppressor cells (MDSCs). Recently, a novel antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4), which activates lymphocytes, is currently in clinical applications. The aim of the present study was to investigate the synergistic antitumor effects of anti-CTLA-4 antibody (Ab) and sorafenib in a murine cancer model. RENCA cells were subcutaneously inoculated into mice, which were randomly divided into 4 treatment groups: sorafenib plus anti-CTLA-4 Ab, sorafenib plus control Ab, vehicle plus anti-CTLA-4 Ab, and vehicle plus control Ab. Single therapy using anti-CTLA-4 Ab suppressed tumor growth, but no difference was noted when compared with the single therapy group using sorafenib. Notably, the greatest decrease in tumor size was noted with sorafenib plus anti-CTLA-4 Ab (combination therapy), and the highest rate of tumor rejection was observed in the combination therapy group. The number of infiltrating CD4- or CD8-positive lymphocytes was strongly increased in the combination therapy group. These in vivo data indicate that sorafenib increased the immunostimulatory effect of anti-CTLA-4 Ab even when sorafenib was used at a low dose. An in vitro study using MDSCs and CD8(+) T cells showed that the inhibitory effect of MDSCs on CD8(+) T cells was significantly abrogated by the combined use of sorafenib and anti-CTLA-4 Ab. Sorafenib suppressed the expression of immunosuppressive factors in MDSCs. These data indicate that combination therapy of sorafenib and anti-CTLA-4 Ab may be effective in advanced kidney cancer patients.


Migraine and cardiovascular disease.
Migraine, especially migraine with aura is an established risk factor for ischemic lesions of the brain. Recent evidence has also linked migraine with and without aura to a broader range of ischemic vascular disorders including angina, myocardial infarction, coronary revascularization, claudication and cardiovascular mortality. The topic is therefore of considerable interest. Accordingly, herein we review the association between migraine and cardiovascular disease. We start by briefly presenting diagnostic criteria for migraine and revising its pathophysiology. We follow by summarizing the evidence on the topic. We then briefly present the results of a recent meta-analysis. We close by highlighting results of a large epidemiological study conducted after the publication of the meta-analysis.


Molecular mapping of two novel cold resistance genes in common wheat by 660K SNP array.
Low temperature and cold damage are natural factors that seriously reduce wheat yield. Thus, how to improve the cold resistance of wheat has been the focus of wheat breeders and geneticists. However, the genetic improvement for this trait has been slow, mainly because cold resistance is a complex quantitative trait and field phenotypic identification is relatively difficult. Therefore, the discovery, mapping, and cloning of the cold resistance genes of wheat provide a theoretical basis for the genetic improvement of wheat against cold resistance and facilitate the analysis of the molecular mechanisms of cold resistance in wheat. This study used the wheat line H261 and its EMS mutants LF2099 and XiNong 239 as materials. Cold trait segregation occurred in the F2 generation of mutants LF2099 and XiNong 239 at a 15:1 separation ratio. Genetic analysis showed that two dominant overlapping genes, temporarily named Wcr-3 and Wcr-4, control cold resistance in wheat. Furthermore, a combined BSA and SNP array established that Wcr-3 is between BU100519 (SSR marker) and AX-94843669 (SNP marker). The markers are 1.32 cM apart, corresponding to the 5.41 Mb physical interval on the Chinese Spring 2B chromosome with 67 functionally annotated genes. Wcr-4 is located between AX-94657955 (SNP marker) and LC-23 (SSR marker), which are 1.79 cM apart, corresponding to a 2.35 Mb physical interval on the Chinese Spring 2D chromosome, which contains 66 functionally annotated genes. Wcr-3 and Wcr-4 are two new cold resistance genes, laying the foundation for their fine mapping and cloning. The online version contains supplementary material available at 10.1007/s11032-023-01425-w.


Analysis of nuclear and mitochondrial genes in patients with pseudoexfoliation glaucoma.
Pseudoexfoliation glaucoma (PEG) is the most prevalent secondary open angle glaucoma occurring worldwide. The search for a genetic cause in PEG has been largely unsuccessful despite evidence of hereditary transmission. The nuclear genes MYOC, OPTN, WDR36, CYP1B1, OPA1, and OPA3 were sequenced in patients with PEG. The entire mitochondrial DNA (mtDNA) coding region was also sequenced, relative mtDNA content was investigated, and mitochondrial respiration was assessed. No novel or previously reported mutations were present in the nuclear genes MYOC, OPTN, CYP1B1, WDR36, OPA1, or OPA3 in 29 PEG patients. Twenty-six patients (89.7%) had no pathological or potentially pathological mtDNA mutation(s); however, three patients (10.3%) had potentially pathologic mtDNA nucleotide changes not found in controls. PEG patients did not differ significantly from controls in relative mitochondrial content (p=0.98) or in mitochondrial respiratory activity (p=0.18). These PEG patients had no mutations in nuclear genes associated with other types of glaucoma or other inherited optic neuropathies, and there was little evidence of mitochondrial abnormalities. These results imply that the nuclear genes and mitochondrial parameters evaluated here are less important determinants of PEG than other factors related to the presence of pseudoexfoliation material.


Nanomechanical model of microtubule translocation in the presence of electric fields.
Research efforts in recent years have been directed toward actively controlling the direction of translocation of microtubules on a kinesin-coated glass surface with E-fields (electric fields), opening up the possibility of engineering controllable nanodevices that integrate microtubules and motor proteins into their function. Here, we present a detailed, biophysical model that quantitatively describes our observations on the steering of microtubules by electric fields. A sudden application of an electric field parallel to the surface and normal to the translocation direction of a microtubule bends the leading end toward the anode, because Coulombic (electrophoretic) forces are dominant on negatively charged microtubules. Modeling this bending as a cantilever deflection with uniform loading requires accurate mechanical and electrical properties of microtubules, including their charge density, viscous drag, and flexural rigidity. We determined the charge density of microtubules from measurements of the electrophoretic mobility in a "zero flow" capillary electrophoresis column and estimate it to be 256 e(-) per micron of length. Viscous drag forces on deflecting microtubules in electroosmotic flows were studied theoretically and experimentally by directly characterizing flows using a caged dye imaging method. The flexural rigidity of microtubules was measured by applying E-fields to microtubules with biotinylated segments that were bound to streptavidin-coated surfaces. From the calculated loading, and the Bernoulli-Euler curvature and moment equation, we find that the flexural rigidity of microtubules depends on their length, suggesting microtubules are anisotropic. Finally, our model accurately predicts the biophysical properties and behavior of microtubules directed by E-fields, which opens new avenues for the design of biomolecular nanotransport systems.


The protein phosphatase EYA4 promotes homologous recombination (HR) through dephosphorylation of tyrosine 315 on RAD51.
Efficient DNA repair and limitation of genome rearrangements rely on crosstalk between different DNA double-strand break (DSB) repair pathways, and their synchronization with the cell cycle. The selection, timing and efficacy of DSB repair pathways are influenced by post-translational modifications of histones and DNA damage repair (DDR) proteins, such as phosphorylation. While the importance of kinases and serine/threonine phosphatases in DDR have been extensively studied, the role of tyrosine phosphatases in DNA repair remains poorly understood. In this study, we have identified EYA4 as the protein phosphatase that dephosphorylates RAD51 on residue Tyr315. Through its Tyr phosphatase activity, EYA4 regulates RAD51 localization, presynaptic filament formation, foci formation, and activity. Thus, it is essential for homologous recombination (HR) at DSBs. DNA binding stimulates EYA4 phosphatase activity. Depletion of EYA4 decreases single-stranded DNA accumulation following DNA damage and impairs HR, while overexpression of EYA4 in cells promotes dephosphorylation and stabilization of RAD51, and thereby nucleoprotein filament formation. Our data have implications for a pathological version of RAD51 in EYA4-overexpressing cancers.


Functional DNA-based hydrogel intelligent materials for biomedical applications.
Deoxyribonucleic acid (DNA) nanotechnology is a relevant research field of nano-biotechnology, which has developed rapidly in recent years. Researchers have studied DNA far more than they have studied its genetic characteristics, and now it has evolved into the field of nanomedical materials. A variety of articles based on DNA nanostructures can be obtained by rational design and controllable preparation. In particular, intelligent DNA-based hydrogel materials have attracted significant attention as an essential representative of macro DNA materials. They have shown a wide range of applications, especially in the field of biomedical applications. DNA-based hydrogels have many unique and fascinating properties, such as, excellent biocompatibility, biodegradability, basic programmability, catalytic activities, therapeutic potential, and molecular recognition and bonds. The intelligent DNA hydrogel will undergo abrupt changes in the stimulation of temperature, pH value, ionic strength, and solvent composition. These factors can also be used for applications in intelligent materials that play an essential role in biomedical sciences. To date, intelligent DNA hydrogels have been reported for many applications, including controlled drug delivery, targeted gene therapy, cancer therapy, biosensors, protein production, and 3D cell cultures. However, the large-scale production of intelligent DNA hydrogels has not yet been realized, and the synergistic multifunctional integration has not been explored. This review summarizes the current state of DNA nanostructures, especially the intelligent DNA-based hydrogel materials, and focuses on design and engineering for bio-responsive use and proposes some reasonable prospects for the future development of intelligent DNA-based hydrogel materials.


Induced pluripotent stem cells from human placental chorion for perinatal tissue engineering applications.
The reliable derivation of induced pluripotent stem cells (iPSCs) from a noninvasive autologous source at birth would facilitate the study of patient-specific in vitro modeling of congenital diseases and would enhance ongoing efforts aimed at developing novel cell-based treatments for a wide array of fetal and pediatric disorders. Accordingly, we have successfully generated iPSCs from human fetal chorionic somatic cells extracted from term pregnancies by ectopic expression of OCT4, SOX2, KLF4, and cMYC. The isolated parental somatic cells exhibited an immunophenotypic profile consistent with that of chorionic mesenchymal stromal cells (CMSCs). CMSC-iPSCs maintained pluripotency in feeder-free systems for more than 15 passages based on morphology, immunocytochemistry, and gene expression studies and were capable of embryoid body formation with spontaneous trilineage differentiation. CMSC-iPSCs could be selectively differentiated in vitro into various germ layer derivatives, including neural stem cells, beating cardiomyocytes, and definitive endoderm. This study demonstrates the feasibility of term placental chorion as a novel noninvasive alternative to dermal fibroblasts and cord blood for human perinatal iPSC derivation and may provide additional insights regarding the reprogramming capabilities of extra-embryonic tissues as they relate to developmental ontogeny and perinatal tissue engineering applications.


Quantitative phase amplitude microscopy IV: imaging thick specimens.
The ability to image phase distributions with high spatial resolution is a key capability of microscopy systems. Consequently, the development and use of phase microscopy has been an important aspect of microscopy research and development. Most phase microscopy is based on a form of interference. Some phase imaging techniques, such as differential interference microscopy or phase microscopy, have a low coherence requirement, which enables high-resolution imaging but in effect prevents the acquisition of quantitative phase information. These techniques are therefore used mainly for phase visualization. On the other hand, interference microscopy and holography are able to yield quantitative phase measurements but cannot offer the highest resolution. A new approach to phase microscopy, quantitative phase-amplitude microscopy (QPAM) has recently been proposed that relies on observing the manner in which intensity images change with small defocuses and using these intensity changes to recover the phase. The method is easily understood when an object is thin, meaning its thickness is much less than the depth of field of the imaging system. However, in practice, objects will not often be thin, leading to the question of what precisely is being measured when QPAM is applied to a thick object. The optical transfer function formalism previously developed uses three-dimensional (3D) optical transfer functions under the Born approximation. In this paper we use the 3D optical transfer function approach of Streibl not for the analysis of 3D imaging methods, such as tomography, but rather for the problem of analysing 2D phase images of thick objects. We go on to test the theoretical predictions experimentally. The two are found to be in excellent agreement and we show that the 3D imaging properties of QPAM can be reliably predicted using the optical transfer function formalism.


Solution structure and backbone dynamics of an antigen-free heavy chain variable domain (VHH) from Llama.
Camelids, (dromedaries, camels, and llamas) produce heavy-chains antibodies, with their antigen recognition sites composed of a single VH-like domain, referred to as VHH. The solution structure of one of these VHHs domains (VHH-H14), raised against the alpha subunit of the human chorionic gonadotropin hormone (hCG), has been determined by (15)N heteronuclear three-dimensional NMR spectroscopy. The framework is well resolved within the set of 20 best-calculated NMR structures and is close to that of classical VH domains from vertebrate antibodies, consisting of two antiparallel beta-sheets organized in a beta-barrel. Loops display a lower precision, especially the Complementarity Determining Regions (CDRs), involved in antigen recognition. Comparison of the three-dimensional VHH-H14 solution structure with its previously solved crystal structure (Spinelli et al., Nature Struct. Biol. 1996;3:752-757) reveals a high similarity to the framework, whereas significant conformational differences occur on CDRs, leading to the assumption that the antigen recognition site is a more mobile part. In order to deepen our insights into the dynamics of VHH-H14 in solution, (15)N relaxation was measured with longitudinal R1 and transverse R2 self-relaxation rates, and (15)N steady-state heteronuclear nuclear Overhauser enhancements (NOE), making it possible to probe picosecond-to-millisecond internal motions. Determination of dynamic parameters (S(2), tau(e), and Rex) through the Lipari-Szabo Model-free approach enables the identification of several regions with enhanced dynamics. Especially, the mobility measurements from NMR confirm that the antigen recognition site is the most mobile part of the VHH-H14 domain on picosecond-to-nanosecond fast time scales. Several residues belonging to the three CDRs are submitted to chemical exchange processes occurring on slow microsecond-to-millisecond time scales, suggesting that the formation of the VHH/antigen complex should be accompanied by structural changes.


Biosynthesis of trans-AT PKS-Derived Shuangdaolides Featuring a trans-acting Enzyme for Online Epoxidation.
Bacterial trans-acyltransferase polyketide synthases (trans-AT PKSs) synthesize natural products with intricate structures and potent biological activities. They generally contain various unusual modules or trans-acting enzymes. Herein, we report the trans-AT PKS-derived biosynthetic pathway of the shuangdaolide with a rare internal 2-hydroxycyclopentenone moiety. The multidomain protein SdlR catalyzes the synthesis of 16,17-epoxide during polyketide chain elongation. The SdlR contains a ketoreductase, an acyl carrier protein, a flavoprotein monooxygenase, and a serine hydrolase domain. This online epoxidation occurs at unusual positions away from the thioester. Then, two tailoring enzymes, SdlB and SdlQ, convert a methylene to a carbonyl group and oxidize a hydroxyl group to a carbonyl group, respectively. The following spontaneous opening of 16,17-epoxide induces the formation of a new C-C bond to generate the 2-hydroxycyclopentenone moiety. The characterization of the shuangdaolide pathway extends the understanding of the trans-AT PKSs, facilitating the mining and identification of this class of natural products.


Neuronal spike initiation modulated by extracellular electric fields.
Based on a reduced two-compartment model, the dynamical and biophysical mechanism underlying the spike initiation of the neuron to extracellular electric fields is investigated in this paper. With stability and phase plane analysis, we first investigate in detail the dynamical properties of neuronal spike initiation induced by geometric parameter and internal coupling conductance. The geometric parameter is the ratio between soma area and total membrane area, which describes the proportion of area occupied by somatic chamber. It is found that varying it could qualitatively alter the bifurcation structures of equilibrium as well as neuronal phase portraits, which remain unchanged when varying internal coupling conductance. By analyzing the activating properties of somatic membrane currents at subthreshold potentials, we explore the relevant biophysical basis of spike initiation dynamics induced by these two parameters. It is observed that increasing geometric parameter could greatly decrease the intensity of the internal current flowing from soma to dendrite, which switches spike initiation dynamics from Hopf bifurcation to SNIC bifurcation; increasing internal coupling conductance could lead to the increase of this outward internal current, whereas the increasing range is so small that it could not qualitatively alter the spike initiation dynamics. These results highlight that neuronal geometric parameter is a crucial factor in determining the spike initiation dynamics to electric fields. The finding is useful to interpret the functional significance of neuronal biophysical properties in their encoding dynamics, which could contribute to uncovering how neuron encodes electric field signals.


Neuroanatomic projections related to biting attack elicited from ventral midbrain in cats.
A single electrode was implanted in each of ten cats at a point in the ventral midbrain from which nonaffective biting attack on a rat could be elicited by electrical stimulation. A lesion was then made which was just large enough to eliminate the elicitation of attack at suprathreshold intensities from that electrode. After post-lesion survival times of 3-14 days the cats were sacrificed, and the degeneration resulting from the lesions was followed with the use of modified Nauta silver stains. Four additional cats were used as anatomic controls. Degenerating fibers were observed to descend bilaterally through the midbrain, pontine, and medullary tegmentum to the vicinity of the principal sensory and motor nuclei of the trigeminal nerve. There was, in addition, evidence of degenerating terminals within the nucleus of the facial nerve and the spinal nucleus of the trigeminal nerve. Of particular note was the observation that the degenerating fibers in the region of the nucleus of the spinal tract of the trigeminal nerve terminated in glomeruli in the rostral portion of the nucleus. Degenerating fibers ascending from the lesion were found to course along the medial forebrain bundle into the hypothalamus and the midline thalamus in a pattern very similar to that previously demonstrated after lesions of biting attack sites in the hypothalamus. The role that the neural pathways associated with ventral midbrain attack sites might play in the mediation of behavior patterns which are elicited during attack stimulation was discussed and it was concluded that the demonstrated neural pathway could provide a cogent explanation for some of the properties of centrally elicited attack behavior.


T-Type voltage gated calcium channels: a target in breast cancer?
The purpose of this review article is to discuss the potential of T-type voltage gated calcium channels (VGCCs) as drug targets in breast cancer. Breast cancer, attributable to the different molecular subtypes, has a crucial need for therapeutic strategies to counter the mortality rate. VGCCs play an important role in regulating cytosolic free calcium levels which regulate cellular processes like tumorigenesis and cancer progression. In the last decade, T-type VGCCs have been investigated in breast cancer proliferation. Calcium channel blockers, in general, have shown an anti-proliferative and cytotoxic effects. T-type VGCC antagonists have shown growth inhibition owing to the inhibition of CaV3.2 isoform. CaV3.1 isoform has been indicated as a tumour-suppressor gene candidate and is reported to support anti-proliferative and apoptotic activity in breast cancer. The distribution of T-type VGCC isoforms in different breast cancer molecular subtypes is diverse and needs to be further investigated. The role of T-type VGCCs in breast cancer migration, metastasis and more importantly in epithelial to mesenchymal transition (EMT) is yet to be elucidated. In addition, interlaced therapy, using a combination of chemotherapy drugs and T-type VGCC blockers, presents a promising therapeutic approach for breast cancer but more validation and clinical trials are needed. Also, for investigating the potential of T-type VGCC blocker therapy, there is a need for isoform-specific agonists/antagonists to define and discover roles of T-type VGCC specific isoforms. Our article provides a review of the role of T-type VGCCs in breast cancer and also discusses future of the research in this area so that it can be ascertained whether there is any potential of T-type VGCCs as drug targets in breast cancer.


Vanadium Complexes with Hydrazone or Thiosemicarbazone Ligands as Potential Anti-Mycobacterium tuberculosis Agents.
Tuberculosis (TB) is an infectious disease caused mainly by Mycobacterium tuberculosis (MTB) and still an important public health problem worldwide. Some factors like the emergence of multidrug resistant (MDR) and extensively drug-resistant (XDR) strains make urgent the research of new active compounds. Searching for new inorganic compounds against TB, three new dioxovanadium(V) complexes were obtained upon reaction of [VO(acac)2] with hydrazone and thiosemicarbazone ligands derived from di-2-pyridyl ketone. Spectroscopic studies and X-ray crystallography revealed asymmetrically oxo bridged binuclear complexes of the type [{VO(L(1,2))}2(μ-O)2], involving the hydrazone ligands, while a mononuclear square pyramidal complex of the type [VO2(L(3))] was formed with the thiosemicarbazone ligand. The compounds were tested against M. tuberculosis and three of them, with MICs values between 2.00 and 3.76 μM were considered promising for TB treatment. Such MIC values are comparable or better than those found for some drugs currently used in TB treatment.