A Cross-Sectional and Longitudinal Study of Novel Metaphor and Metonymy Comprehension in Children, Adolescents, and Adults With Autism Spectrum Disorder.
Previous studies have shown that comprehension of figurative language is impaired in individuals with autism spectrum disorder (ASD). However, most studies have focused on lexicalized expressions and have only examined performance at one particular point in time, without examining how performance changes over development. The current study examined the comprehension of novel metaphor and metonymy in individuals with ASDs from a large age range, using both a cross-sectional (Experiment 1) and longitudinal design (Experiment 2). Performance in the ASD group was lower compared to typically developing (TD) controls, across all ages. Importantly, the results from Experiments 1 and 2 showed that, although chronological age was not a good predictor for performance of either novel metaphor or metonymy in the cross-sectional design, performance improved when longitudinal data was considered. Correlations between vocabulary knowledge, visuo-spatial abilities and figurative language comprehension abilities were also explored.


Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy.
Structural variations disrupting the gene encoding the neuron-specific splicing regulator RBFOX1 have been reported in three patients exhibiting epilepsy in comorbidity with other neuropsychiatric disorders. Consistently, the Rbfox1 knockout mouse model showed an increased susceptibility of seizures. The present candidate gene study tested whether exon-disrupting deletions of RBFOX1 increase the risk of idiopathic generalized epilepsies (IGEs), representing the largest group of genetically determined epilepsies. Screening of microdeletions (size: >40 kb, coverage >20 markers) affecting the genomic sequence of the RBFOX1 gene was carried out by high-resolution single-nucleotide polymorphism (SNP) arrays in 1,408 European patients with idiopathic generalized epilepsy (IGE) and 2,256 population controls. Validation of RBFOX1 deletions and familial segregation analysis were performed by quantitative polymerase chain reaction (qPCR). We detected five exon-disrupting RBFOX1 deletions in the IGE patients, whereas none was observed in the controls (p = 0.008, Fisher's exact test). The size of the exonic deletions ranged from 68 to 896 kb and affected the untranslated 5'-terminal RBFOX1 exons. Segregation analysis in four families indicated that the deletions were inherited, display incomplete penetrance, and heterogeneous cosegregation patterns with IGE. Rare deletions affecting the untranslated 5'-terminal RBFOX1 exons increase risk of common IGE syndromes. Variable expressivity, incomplete penetrance, and heterogeneous cosegregation patterns suggest that RBFOX1 deletions act as susceptibility factor in a genetically complex etiology, where heterogeneous combinations of genetic factors determine the disease phenotype.


Network medicine, multimorbidity and the lung in the elderly.
Noncommunicable diseases, including cardiovascular, metabolic and respiratory diseases, among others, are the major medical challenge of the 21st century. Most noncommunicable diseases are related to the ageing process and often co-occur in the same individual. However, it is unclear whether the index disease is somehow influencing the development of the other ones (comorbidity) or whether all of them (including the index disease) simply represent the clinical expression of pathological ageing (multimorbidity). The pathobiology of ageing, chronic obstructive pulmonary disease (COPD) and concomitant disorders is complex. A new field of research, known as systems biology if applied to model systems or network medicine if applied to human beings, has emerged over the past decade or so, to address biological complexity in a holistic, integrated way. It offers, therefore, great potential to decipher the relationship between ageing, COPD and comorbidities/multimorbidities. In this State of the Art review we present the basic concepts of systems biology, use some examples to illustrate the potential of network medicine to address complex medical problems, and review some recent publications that show how a systems-based research strategy can contribute to improve our understanding of multimorbidity and age-related respiratory diseases.


Agreement between student dietitians' identification of refeeding syndrome risk with refeeding guidelines, electrolytes and other dietitians: a pilot study.
Limited research exists concerning how consistently and accurately student and newly-graduated dietitians are identifying refeeding syndrome risk in hospitalised patients. The present study aimed to determine the consistency of students' and newly-graduated dietitians' classification of refeeding syndrome risk, as well as agreement with the application of comparison tools such as the National Institute for Health and Care Excellence guidelines, patients' electrolytes and supplementation, and clinical dietitians previously surveyed. Recently-graduated and final-year Griffith University dietetics students were invited to complete an online survey. The survey questioned demographics and asked respondents to classify the level of refeeding syndrome risk (i.e. none, some, high, unsure) in 13 case studies. Electrolytes and supplementation data were sourced from electronic patient records. Chi-squared tests, t-tests and linear regression analyses were conducted. Fifty-three eligible people responded [n = 53 of 112, mean (SD) age 26 (4) years, 89% female, 34% graduates]. Respondents' answers were generally more consistent and more likely to agree with comparison tools when two tools showed the same level of refeeding syndrome risk (49-98%, β = 0.626-1.0994, P < 0.001) than when they differed (11-49%). Respondents' level of agreement with refeeding identification guidelines, electrolyte levels, supplementation and dietitians previously surveyed did not differ by graduate status, degree level, clinical placement status or having read refeeding syndrome guidelines recently (P > 0.05). Students' and new graduates' identification of refeeding syndrome risk improved when there was consistency between guidelines, electrolytes and dietitians' responses. More research is needed to improve the evidence behind refeeding guidelines, with the aim of enhancing the accuracy and consistency of assessment.


Releif of severe fecal impactions with water-soluble contrast enemas.
High fecal impaction resulted in complete bowel obstruction in 2 children following renal transplantation and in one adult on chemotherapy and narcotics. The usual methods of relief failed, and water-soluble contrast enemas with a high osmolality were employed. Fluoroscopic control assured placement of the enema fluid at the site of obstruction, where it was very effective in relieving the impaction. It is suggested that such high-osmolality enemas be considered in patients with severe high fecal impactions before surgery is contemplated.


What does diffusion tensor imaging (DTI) tell us about cognitive networks in temporal lobe epilepsy?
Diffusion tensor imaging (DTI) has provided considerable insight into our understanding of epilepsy as a network disorder, revealing subtle alterations in white matter microstructure both proximal and distal to the epileptic focus. These white matter changes have been shown to assist with lateralizing the seizure focus, as well as delineating the location/anatomy of key white matter tracts (i.e., optic radiations) for surgical planning. However, only recently have studies emerged describing the utility of DTI for probing cognitive networks in patients with epilepsy and for examining the structural plasticity within these networks both before and after epilepsy surgery. Here, we review the current literature describing the use of DTI for understanding language and memory networks in patients with temporal lobe epilepsy (TLE), as well as the extant literature on networks associated with executive functioning and global intelligence. Studies of memory and language reveal a complex network of frontotemporal fibers that contribute to naming and fluency performance in TLE, and demonstrate that these networks appear to undergo adaptive changes in response to surgical intervention. Although studies of executive functioning and global intelligence have been less conclusive, there is accumulating evidence that aberrant communication between frontoparietal and medial temporal networks may underlie working memory impairment in TLE. More recently, multimodal imaging studies have provided evidence that disruptions within these white matter networks co-localize with functional changes observed on functional MRI. However, structure-function associations are not entirely coherent and may breakdown in patients with TLE, especially those with a left-sided seizure focus. Although the reasons for discordant findings are unclear, small sample sizes, heterogeneity within patient populations and limitations of the current tensor model may account for contradictory and null findings. Improvements in imaging hardware and higher field strengths have now paved the way for the implementation of advanced diffusion techniques, and these advanced models show great promise for improving our understanding of how network dysfunction contributes to cognitive morbidity in TLE.


Application of laser ablation ICP-MS and traditional techniques to the study of black crusts on building stones: a new methodological approach.
In this work, we propose an innovative application of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) as a methodological approach for the chemical characterisation of black crusts on stone monuments, associated with traditional micro-morphological (optical and scanning electron microscopy) and infrared spectroscopic techniques (FTIR). This new approach was tested on black crusts developing on two marble substrates, one, the columns of the San Cosimato cloister in Rome, and the other, a sculpture representing an angel, located in Pessano con Bornago, a small industrial town near Milan. The main aim of this study was to develop and test the reliability of the LA-ICP-MS analytical method on black crusts and to explore the idea that trace element concentrations in black crusts can be applied to investigate their origin and the relations between concentrations of polluting elements in black crusts and environmental conditions. The results obtained by applying traditional techniques find considerable support in the innovative method used here, which could determine the concentrations of a large number of trace elements (including heavy metals) in the black crusts examined, and thus could also be used as a reliable indicator of environmental pollution.


Purification and characterization of the cytochrome c oxidase from Rhodopseudomonas sphaeroides.
When grown aerobically in the dark, Rhodopseudomonas sphaeroides develops a respiratory chain similar to that in mitochondria and the photosynthetic apparatus is suppressed. The aa3-type cytochrome c oxidase from Rps. sphaeroides has been purified in Triton X-100 by affinity chromatography with Sepharose 4B coupled to yeast cytochrome c. The oxidase contains 14 nmol heme a/mg protein and is composed of three polypeptide subunits with relative molecular masses of 45000, 37000 and 35000. The enzyme is highly active in the presence of detergents, with a maximal velocity of 300 s-1/mol oxidase using either yeast or horse-heart cytochrome c. The Rps. sphaeroides oxidase is cross-reactive with antibodies directed against the oxidases from Paracoccus denitrificans and Saccharomyces cerevisiae. A particularly close relationship is indicated in the case of P. denitrificans. The Rps. sphaeroides oxidase has been incorporated into phospholipid vesicles. The resulting oxidase in these vesicles demonstrates high enzymatic activity and a respiratory control ratio of 5. Using these vesicles, no evidence for proton extrusion accompanying cytochrome c oxidation was observed. The data suggest that the Rps. sphaeroides oxidase does not function as a proton pump.


Membrane protein CAR promotes hematopoietic regeneration upon stress.
Adult hematopoietic stem cells (HSCs) are quiescent most of the time, and how HSCs switch from quiescence to proliferation following hematopoietic stress is unclear. Here we demonstrate that upon stress the coxsackievirus and adenovirus receptor CAR (also known as CXADR) is upregulated in HSCs and critical for HSC entry into the cell cycle. WT HSCs were detected more rapid repopulation ability than the CAR cKO counterparts. After 5-FU treatment, CAR cKO HSCs had lower levels of Notch1 expression and elevated protein level of Numb, a Notch antagonist. The Notch signaling inhibitor DAPT, dominant negative form of MAML (a transcriptional coactivator of Notch), or dominant negative mutant of LNX2 (an E3 ligase that acts on Numb and binds to CAR), all were capable of abrogating the function of CAR in HSCs. We conclude that CAR activates Notch1 signaling by downregulating Numb protein expression to facilitate entry of quiescent HSCs into the cell cycle during regeneration.


Interaction between birth complications and early maternal rejection in predisposing individuals to adult violence: specificity to serious, early-onset violence.
The authors previously reported that birth complications interact with early maternal rejection in predisposing individuals to violence at age 18 years. This study extended the follow-up period for violent offending from 18 years to 34 years, thus increasing the sample of violent offenders threefold and allowing more detailed analyses on onset and type of violence, the form of maternal rejection, and the effect of maternal mental illness. Complications in the births of 4,269 males in Denmark, maternal rejection of these individuals before the age of 1 year, and their histories of criminal offenses at age 34 years were assessed. The biosocial interaction previously observed held for violent but not nonviolent crime, was specific to more serious forms of violence and not threats of violence, held for early-onset but not late-onset violence, and was not accounted for by psychiatric illness in the mothers. Being reared in a public care institution in the first year of life and the mother's attempt to abort the fetus were the key aspects of maternal rejection that interacted with birth complications in predisposing a subject to violence. These findings 1) indicate that the mechanisms underlying early-onset, serious violence differ from those for less serious, late-onset violence, 2) implicate very early factors in the development of violence, 3) highlight the potential importance of integrating psychosocial with biological factors in understanding and preventing violence, and 4) suggest that interventions to reduce birth complications and maternal rejection may help reduce violence.


Hyperemesis Gravidarum: Strategies to Improve Outcomes.
Hyperemesis gravidarum (HG) is a debilitating and potentially life-threatening pregnancy disease marked by weight loss, malnutrition, and dehydration attributed to unrelenting nausea and/or vomiting; HG increases the risk of adverse outcomes for the mother and child(ren). The complexity of HG affects every aspect of a woman's life during and after pregnancy. Without methodical intervention by knowledgeable and proactive clinicians, life-threatening complications may develop. Effectively managing HG requires an understanding of both physical and psychosocial stressors, recognition of potential risks and complications, and proactive assessment and treatment strategies using innovative clinical tools.


Crash and injury reduction following installation of roundabouts in the United States.
This study estimated potential reductions in motor vehicle crashes and injuries associated with the use of roundabouts as an alternative to signal and stop sign control at intersections in the United States. An empiric Bayes procedure was used to estimate changes in motor vehicle crashes following conversion of 24 intersections from stop sign and traffic signal control to modern roundabouts. There were highly significant reductions of 38% for all crash severities combined and of 76% for all injury crashes. Reductions in the numbers of fatal and incapacitating injury crashes were estimated at about 90%. Results are consistent with numerous international studies and suggest that roundabout installation should be strongly promoted as an effective safety treatment.


Towards sustainable public health surveillance for enteric fever.
Enteric fever that results from infection by the typhoidal Salmonellas (Salmonella Typhi and Salmonella Paratyphi A, B and C) is a life-threatening preventable illness. Surveillance of enteric fever is important to understand current burden of disease, to track changes in human health burden from increasing antimicrobial resistance and to assess the impact of efforts to reduce disease burden. Since enteric fever occurs predominantly in low income communities, expensive surveillance is not sustainable. Traditional hospital-based surveillance does not estimate population burden and intensive community-based cohort studies do not capture the severe disease that is crucial to policy decisions. While cohort studies have been considered the gold standard for incidence estimates, the resources required to conduct them are great; as a consequence, estimates of enteric fever burden have been highly geographically and temporally restricted. A hybrid approach combining laboratory diagnosis that is already being conducted in healthcare centers with community-based surveillance of health care facility use offers a low-cost, sustainable approach to generate policy relevant data.


Risks for All-Cause Mortality: Stratified by Age, Estimated Glomerular Filtration Rate and Albuminuria.
The relative reduction of risk for all-cause mortality among the elderly has been described as attenuated compared to younger subjects, but the risk for all-cause mortality increases with age when absolute risk is considered. The objectives of the present inquiry were to calculate the relative and absolute risks of all-cause mortality based on incidence rate ratios, and summarize these risks for age, gender, and race strata. We conclude that strata-specific risk summaries are more informative than a single all-encompassing risk summary, and that gender- and race-specific strata need to be considered as well as age-specific strata. © 2017 S. Karger AG, Basel.


Assessment of the impact of good pharmacy practices training among drug dispensers in Bangladesh.
Background: Training improves dispensing behavior of drug dispensers in low- and middle-income countries. Between 2018 and 2020, a total of 5,059 Grade C pharmacists, who completed a 3-month training course for availing a "Grade C pharmacist certificate" were trained on Good Pharmacy Practice (GPP) in 11 districts in Bangladesh by Management Sciences for Health (MSH) under Better Health in Bangladesh (BHB) project. We assessed the impact of GPP among trained Grade C pharmacists under the BHB project compared to those who did not receive GPP training under the BHB project (non-trained), and explored the major challenges towards achieving GPP. Methods: We created a database of trained Grade C pharmacists provided by MSH and randomly selected the trained Grade C pharmacists for recruitment following consent. We created another database of the non-trained Grade C pharmacist who were deployed within a 1-km radius of a trained Grade C pharmacist, and randomly recruited one non-trained against one trained Grade C pharmacist. A semi structured questionnaire was administered to obtain information about knowledge of GPP, including guidelines of dispensing medicines, temperature maintenance, medicine storage, counseling customers and labeling medicines. Dispensing behavior was directly observed following a structured tool. Chi-square test (for categorical variables) and independent sample t-tests (for continuous variables) were applied for comparison between the trained and the non-trained Grade C pharmacists. A logistic regression model was applied to explore an association between knowledge and practice between the two groups. Results: Between February and March 2021, 220 trained and 220 non-trained Grade C pharmacists were recruited. Mean age (SD) of the participants was 41 years (10.5) and 98.4% were male. Compared to the non-trained, the trained Grade C pharmacists had better knowledge about the guidelines of dispensing medicines (97.7% vs 89.5%, p < 0.001), temperature maintenance (91.8% vs 45.5%, p = 0.001), medicine storage (92.3% vs 40.5%, p = 0.001) counseling customers (99.5% vs 92.3%, p < .001) and labeling medicines (91.0% vs 80%, p < 0.001). General dispensing behavior was observed to be better among the trained than the non-trained with labeling of medicines (63.2% vs 53.4%, p = 0.038), counseling customers (39.1% vs 28.6%, p = 0.021) and using a room thermometer for maintaining ambient temperature in the medicine shops (56.8% vs26.8%, p < 0.001). Bad behavior of the customers (39.5%) and lack of GPP knowledge among Grade C pharmacists (28.6%) were recognized to be challenges towards achieving GPP in Bangladesh. Conclusion: Training led to better knowledge and practices about dispensing medicines among Grade C pharmacists in Bangladesh. Periodic training may promote achieving GPP in Bangladesh.


Clinical findings in Pelizaeus-Merzbacher disease.
Pelizaeus-Merzbacher disease is a rare X-linked disease characterized by defective central nervous system myelination owing to a mutation in the proteolipid protein 1 gene. Few studies report detailed clinical findings in children with genetic confirmation of mutations in the proteolipid protein 1 gene. We reviewed the records of 10 boys with Pelizaeus-Merzbacher disease and one symptomatic carrier girl. Their median age was 2 1/2 years (range 10 months to 20 years). Nine had proteolipid protein 1 gene duplications, one had a point mutation, and one had a single codon deletion. The families of eight patients reported perinatal complications, including maternal hypertension (three patients) and meconium aspiration (three patients). All of the patients were social and interactive, but all had difficulty with expressive speech. All patients presented with nystagmus and had hypotonia that progressed to spasticity, affecting the legs more than the arms; ataxia also contributed to motor impairment. Additional problems reported regarded feeding (eight patients) and sleep (three patients). Further work is needed to clarify the variations in disease course and the relationship of genotype to phenotype.


Investigation of the potential involvement of eicosanoid metabolites in anti-diuretic hormone signaling in Rhodnius prolixus.
The use of naturally occurring plant-derived compounds for controlling insect pests remains an attractive alternative to potentially dangerous synthetic chemical compounds. One prospective plant-based compound, isoforms of the so-called jack bean urease (JBU) from the jack bean, Canavalia ensiformis, as well a derived peptide, Jaburetox-2Ec, have insecticidal effects on an array of insect species. In the Chagas' disease vector, Rhodnius prolixus, some of the physiological effects attributed to these urease isoforms include inhibition of serotonin (5-HT)-stimulated fluid secretion by the Malpighian tubules (MTs). Here, we investigated whether the effects of these exogenous urease isoforms were targeting the neuroendocrine network involved in the anti-diuretic hormone (RhoprCAPA-2) signaling cascade. We show that pharmacological agents known to interfere with eicosanoid metabolite biosynthesis do not affect RhoprCAPA-2 inhibition of 5-HT-stimulated fluid secretion by MTs. In addition, we demonstrate that RhoprCAPA-2 inhibition of MTs is independent of extracellular or intracellular calcium. Using a heterologous system for analysis of receptor activation, we show that neither JBU nor Jaburetox-2Ec are agonists of the anti-diuretic hormone receptor, RhoprCAPAr1. Finally, activation of the receptor using sub-maximal doses of the natural ligand, RhoprCAPA-2, was not influenced by the presence of either JBU or Jaburetox-2Ec indicating that the urease isoforms do not compete with RhoprCAPA-2 for binding and activation of RhoprCAPAr1. Taken together, these results suggest that at least two distinct mechanisms leading to inhibition of fluid secretion by MTs exist in R. prolixus and, unlike the urease-related effects, the eicosanoid metabolite pathway is not involved in RhoprCAPA-2 mediated anti-diuresis.


Endogenous carbon monoxide suppression stimulates bile acid-dependent biliary transport in perfused rat liver.
This study aimed to investigate whether carbon monoxide (CO), a product of heme oxygenase that degrades protoheme IX, serves as an endogenous modulator for biliary transport. To that end, effects of zinc protoporphyrin IX (ZnPP), a heme oxygenase inhibitor, on the biliary transport were tested in perfused rat liver. Perfusion of 1 microM ZnPP abolished detectable levels of CO in the venous perfusate and increased bile acid-dependent bile output accompanying an increased secretion of bile salts. The ZnPP-induced choleresis coincided with a reduction of tissue guanosine 3',5'-cyclic monophosphate (cGMP) levels and a decrease in vascular conductance. On administration of 2.5 microM CO, ZnPP-elicited choleresis, decreases in vascular conductance, and cGMP levels were all attenuated. Treatment with 1 microM 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP) partly attenuated the ZnPP-induced choleresis in concert with repression of vascular conductance. Furthermore, treatment of the liver with methylene blue, a guanylate cyclase inhibitor, evoked a choleresis similar to that induced by ZnPP. Thus endogenous CO suppression stimulates the biliary transport in part through a cGMP-dependent mechanism.


Perspective: medical students' perceptions of the poor: what impact can medical education have?
There is currently little knowledge or understanding of medical students' knowledge and attitudes toward the poor. Teaching hospitals bring students face-to-face with poor and uninsured patients on a regular basis. However, an overview of the research available suggests that this contact does not result in students' greater understanding and empathy for the plight of the poor and may, in fact, lead to an erosion of positive attitudes toward the poor. A basic understanding of justice suggests that as the poor are disproportionately the subjects of medical training, this population should enjoy a proportionate benefit for this service. Furthermore, medicine's social contract with the public is often thought to include an ideal of service to the underserved and a duty to help educate the general public regarding the health needs of our nation. In their discussion, the authors situate medical students' attitudes toward the poor within larger cultural perspectives, including attitudes toward the poor and attributions for poverty. They provide three suggestions for improving trainees' knowledge of and attitudes toward the poor-namely, increasing the socioeconomic diversity of students, promoting empathy through curricular efforts, and focusing more directly on role modeling. The authors argue that service learning, especially efforts that include gaining detailed knowledge of a particular person or persons, coupled with critical reflection, presents a very promising direction toward achieving these goals. Finally, they posit an agenda for future educational research that might contribute to the increased efficacy of medical education in this important formative domain.


Insight into catalyst speciation and hydrogen co-evolution during enantioselective formic acid-driven transfer hydrogenation with bifunctional ruthenium complexes from multi-technique operando reaction monitoring.
Transfer hydrogenation of acetophenone from formic acid/triethylamine mixtures catalysed by the Ikariya-Noyori complex [(mesitylene)RuCl(R,R)-(TsDPEN)] has been investigated using simultaneous high-resolution FlowNMR and FlowUV-Vis spectroscopies coupled with on-line sampling head-space mass spectrometry and chiral high-performance liquid chromatography using an integrated, fully automated recirculating flow setup. In line with previous observations, the combined results show a gradual switch from formic acid dehydrogenation to hydrogen transfer mediated by the same Ru-hydride complex, and point to a Ru-formate species as the major catalyst intermediate. Hydrogen bonding in the formic acid/triethylamine mixture emerges as a sensitive 1H NMR probe for the transfer hydrogenation activity of the system and can be used to locate optimum reaction conditions.


The quiet renaissance of protein nuclear magnetic resonance.
From roughly 1985 through the start of the new millennium, the cutting edge of solution protein nuclear magnetic resonance (NMR) spectroscopy was to a significant extent driven by the aspiration to determine structures. Here we survey recent advances in protein NMR that herald a renaissance in which a number of its most important applications reflect the broad problem-solving capability displayed by this method during its classical era during the 1970s and early 1980s.


[How do point amino acid substitutions affect the protein structure?].
In order to estimate the influence of point mutations on the protein structure, 552 pairs of structurally aligned proteins with pairwise sequence identities greater than 60% were analyzed. We selected all isolated point mismatches from these alignments. The statistics of local conformational changes corresponding to these mismatches was studied. This study revealed two surprising aspects: (a) only an extremely minor fraction (< 3%) of all observed mutations leads to significant changes in local conformations; (b) observed substitutions, which affect local conformation are more frequently those of similar (high scoring) amino acid pairs rather than the substitutions thought of as "hazardous" (low scoring), although the overall average score of the changing substitutions is still lower than the corresponding average score for the substitutions that leave the structure unchanged.


The NsrR regulon in nitrosative stress resistance of Salmonella enterica serovar Typhimurium.
Nitric oxide (NO·) is an important mediator of innate immunity. The facultative intracellular pathogen Salmonella has evolved mechanisms to detoxify and evade the antimicrobial actions of host-derived NO· produced during infection. Expression of the NO·-detoxifying flavohaemoglobin Hmp is controlled by the NO·-sensing transcriptional repressor NsrR and is required for Salmonella virulence. In this study we show that NsrR responds to very low NO· concentrations, suggesting that it plays a primary role in the nitrosative stress response. Additionally, we have defined the NsrR regulon in Salmonella enterica sv. Typhimurium 14028s using transcriptional microarray, qRT-PCR and in silico methods. A novel NsrR-regulated gene designated STM1808 has been identified, along with hmp, hcp-hcr, yeaR-yoaG, ygbA and ytfE. STM1808 and ygbA are important for S. Typhimurium growth during nitrosative stress, and the hcp-hcr locus plays a supportive role in NO· detoxification. ICP-MS analysis of purified STM1808 suggests that it is a zinc metalloprotein, with histidine residues H32 and H82 required for NO· resistance and zinc binding. Moreover, STM1808 and ytfE promote Salmonella growth during systemic infection of mice. Collectively, these findings demonstrate that NsrR-regulated genes in addition to hmp are important for NO· detoxification, nitrosative stress resistance and Salmonella virulence.


Subacute Sclerosing Panencephalitis of the Brainstem as a Clinical Entity.
Subacute sclerosing panencephalitis (SSPE) is a rare progressive neurological disorder of early adolescence caused by persistent infection of the measles virus, which remains prevalent worldwide despite an effective vaccine. SSPE is a devastating disease with a characteristic clinical course in subcortical white matter; however, atypical presentations of brainstem involvement may be seen in rare cases. This review summarizes reports to date on brainstem involvement in SSPE, including the clinical course of disease, neuroimaging presentations, and guidelines for treatment. A comprehensive literature search was performed for English-language publications with keywords "subacute sclerosing panencephalitis" and "brainstem" using the National Library of Medicine PubMed database (March 1981-September 2017). Eleven articles focusing on SSPE of the brainstem were included. Predominant brainstem involvement remains uncharacteristic of SSPE, which may lead to misdiagnosis and poor outcome. A number of case reports have demonstrated brainstem involvement associated with other intracranial lesions commonly presenting in later SSPE stages (III and IV). However, brainstem lesions can appear in all stages, independent of higher cortical structures. The varied clinical presentations complicate diagnosis from a neuroimaging perspective. SSPE of the brainstem is a rare but important clinical entity. It may present like canonical SSPE or with unique clinical features such as absence seizures and pronounced ataxia. While SSPE generally progresses to the brainstem, it can also begin with a primary focus of infection in the brainstem. Awareness of varied SSPE presentations can aid in early diagnosis as well as guide management and treatment.


A seroprevalence study to determine the frequency of hantavirus infection in people exposed to wild and pet fancy rats in England.
Recent cases of acute kidney injury due to Seoul hantavirus infection from exposure to wild or pet fancy rats suggest this infection is increasing in prevalence in the UK. We conducted a seroprevalence study in England to estimate cumulative exposure in at-risk groups with contact with domesticated and wild rats to assess risk and inform public health advice. From October 2013 to June 2014, 844 individual blood samples were collected. Hantavirus seroprevalence amongst the pet fancy rat owner group was 34.1% (95% CI 23·9-45·7%) compared with 3·3% (95% CI 1·6-6·0) in a baseline control group, 2·4% in those with occupational exposure to pet fancy rats (95% CI 0·6-5·9) and 1·7% with occupational exposure to wild rats (95% CI 0·2-5·9). Variation in seroprevalence across groups with different exposure suggests that occupational exposure to pet and wild rats carries a very low risk, if any. However incidence of hantavirus infection among pet fancy rat owners/breeders, whether asymptomatic, undiagnosed mild viral illness or more severe disease may be very common and public health advice needs to be targeted to this at-risk group.


[Activity of the dehydrogenases of the myocardium and lymphocytes in experimental hypoxia].
The activity of succinatedehydrogenase, mitochondrial alpha-glycerophosphatedehydrogenase and NADH2-diaphorase was studied cytochemically and histochemically in the myocardium and lymphocytes of rats and mice after the effect of hypoxia in a hyperbaric chamber. A short-duration effect of hypoxia and step-wise adaptation during a month was shown to result in a growing activity of the enzymes both in the lymphocytes and in the myocardium. Hypoxia during a month and readaptation during the same period caused a monotonous decrease of the activity of dehydrogenases. The conducted analysis permitted to reveal a distinct correlation between the activity of dehydrogenases in the lymphocytes and in the myocardium. The authors emphasize the similarity of the changes in the activity of the enzymes in the lymphocytes and in the myocardium.


[Onecut transcription factors: role in the development of the pancreas and the liver].
The development of the organism involves the formation of tissues that differ by the morphology and functions of the cells they contain. This results from the synthesis, coordinated in time and space, of a tissue-specific set of proteins. Transcription factors, which control gene expression, play a crucial role in this process. We have discovered a family of tissue-restricted transcription factors, called Onecut, whose prototype is HNF-6 (OC-1) and the two other mammalian members are OC-2 and OC-3. During embryogenesis, HNF-6 controls in the endoderm the transcription of genes which code for other transcription factors. In this way, HNF-6 regulates several developmental programs. To identify these programs, we have inactivated the Hnf6 gene in the mouse. This has shown that HNF-6 is a key factor in pancreas development and its endocrine differentiation, as well as in formation of the biliary tract. The Hnf6-/- mice develop diabetes mellitus and cholestasis. The patterns of expression of OC-2 and OC-3 superimpose partially, and coincide in part with that of HNF-6. This suggests functional interactions between the OC factors during tissue differentiation. We are tackling this question by studying the phenotype of mice in which one or several Onecut genes have been inactivated.


The TRAPP complex: insights into its architecture and function.
Vesicle-mediated transport is a process carried out by virtually every cell and is required for the proper targeting and secretion of proteins. As such, there are numerous players involved to ensure that the proteins are properly localized. Overall, transport requires vesicle budding, recognition of the vesicle by the target membrane and fusion of the vesicle with the target membrane resulting in delivery of its contents. The initial interaction between the vesicle and the target membrane has been referred to as tethering. Because this is the first contact between the two membranes, tethering is critical to ensuring that specificity is achieved. It is therefore not surprising that there are numerous 'tethering factors' involved ranging from multisubunit complexes, coiled-coil proteins and Rab guanosine triphosphatases. Of the multisubunit tethering complexes, one of the best studied at the molecular level is the evolutionarily conserved TRAPP complex. There are two forms of this complex: TRAPP I and TRAPP II. In yeast, these complexes function in a number of processes including endoplasmic reticulum-to-Golgi transport (TRAPP I) and an ill-defined step at the trans Golgi (TRAPP II). Because the complex was first reported in 1998 (1), there has been a decade of studies that have clarified some aspects of its function but have also raised further questions. In this review, we will discuss recent advances in our understanding of yeast and mammalian TRAPP at the structural and functional levels and its role in disease while trying to resolve some apparent discrepancies and highlighting areas for future study.


Box-Behnken study design for optimization of bicalutamide-loaded nanostructured lipid carrier: stability assessment.
Bicalutamide (BCM) is an anti-androgen drug used to treat prostate cancer. In this study, nanostructured lipid carriers (NLCs) were chosen as a carrier for delivery of BCM using Box-Behnken (BB) design for optimizing various quality attributes such as particle size and entrapment efficiency which is very critical for efficient drug delivery and high therapeutic efficacy. Stability of formulated NLCs was assessed with respect to storage stability, pH stability, hemolysis, protein stability, serum protein stability and accelerated stability. Hot high-pressure homogenizer was utilized for formulation of BCM-loaded NLCs. In BB response surface methodology, total lipid, % liquid lipid and % soya lecithin was selected as independent variable and particle size and %EE as dependent variables. Scanning electron microscopy (SEM) was done for morphological study of NLCs. Differential scanning calorimeter and X-ray diffraction study were used to study crystalline and amorphous behavior. Analysis of design space showed that process was robust with the particle size less than 200 nm and EE up to 78%. Results of stability studies showed stability of carrier in various storage conditions and in different pH condition. From all the above study, it can be concluded that NLCs may be suitable carrier for the delivery of BCM with respect to stability and quality attributes.


Red Blood Cell Distribution Width: A Novel Predictive Indicator for Cardiovascular and Cerebrovascular Diseases.
The red blood cell distribution width (RDW) obtained from a standard complete blood count (CBC) is a convenient and inexpensive biochemical parameter representing the variability in size of circulating erythrocytes. Over the past few decades, RDW with mean corpuscular volume (MCV) has been used to identify quite a few hematological system diseases including iron-deficiency anemia and bone marrow dysfunction. In recent years, many clinical studies have proved that the alterations of RDW levels may be associated with the incidence and prognosis in many cardiovascular and cerebrovascular diseases (CVDs). Therefore, early detection and intervention in time of these vascular diseases is critical for delaying their progression. RDW as a new predictive marker and an independent risk factor plays a significant role in assessing the severity and progression of CVDs. However, the mechanisms of the association between RDW and the prognosis of CVDs remain unclear. In this review, we will provide an overview of the representative literatures concerning hypothetical and potential epidemiological associations between RDW and CVDs and discuss the underlying mechanisms.


Circulating and intraprostatic sex steroid hormonal profiles in relation to male pattern baldness and chest hair density among men diagnosed with localized prostate cancers.
Prospective cohort studies of circulating sex steroid hormones and prostate cancer risk have not provided a consistent association, despite evidence from animal and clinical studies. However, studies using male pattern baldness as a proxy of early-life or cumulative androgen exposure have reported significant associations with aggressive and fatal prostate cancer risk. Given that androgens underlie the development of patterned hair loss and chest hair, we assessed whether these two dermatological characteristics were associated with circulating and intraprostatic concentrations of sex steroid hormones among men diagnosed with localized prostate cancer. We included 248 prostate cancer patients from the NCI Prostate Tissue Study, who answered surveys and provided a pre-treatment blood sample as well as fresh frozen adjacent normal prostate tissue. Male pattern baldness and chest hair density were assessed by trained nurses before surgery. General linear models estimated geometric means and 95% confidence intervals (95%CIs) of each hormone variable by dermatological phenotype with adjustment for potential confounding variables. Subgroup analyses were performed by Gleason score (<7 vs ≥7) and race (European American vs. African American). We found strong positive associations of balding status with serum testosterone, dihydrotestosterone (DHT), estradiol, and sex hormone-binding globulin (SHBG), and a weak association with elevated intraprostatic testosterone. Conversely, neither circulating nor intraprostatic sex hormones were statistically significantly associated with chest hair density. Age-adjusted correlation between binary balding status and three-level chest hair density was weak (r = 0.05). There was little evidence to suggest that Gleason score or race modified these associations. This study provides evidence that balding status assessed at a mean age of 60 years may serve as a clinical marker for circulating sex hormone concentrations. The weak-to-null associations between balding status and intraprostatic sex hormones reaffirm differences in organ-specific sex hormone metabolism, implying that other sex steroid hormone-related factors (eg, androgen receptor) play important roles in organ-specific androgenic actions, and that other overlapping pathways may be involved in associations between the two complex conditions.


Mice lacking NMDA receptors in parvalbumin neurons display normal depression-related behavior and response to antidepressant action of NMDAR antagonists.
The underlying circuit imbalance in major depression remains unknown and current therapies remain inadequate for a large group of patients. Discovery of the rapid antidepressant effects of ketamine--an NMDA receptor (NMDAR) antagonist--has linked the glutamatergic system to depression. Interestingly, dysfunction in the inhibitory GABAergic system has also been proposed to underlie depression and deficits linked to GABAergic neurons have been found with human imaging and in post-mortem material from depressed patients. Parvalbumin-expressing (PV) GABAergic interneurons regulate local circuit function through perisomatic inhibition and their activity is NMDAR-dependent, providing a possible link between NMDAR and the inhibitory system in the antidepressant effect of ketamine. We have therefore investigated the role of the NMDAR-dependent activity of PV interneurons for the development of depression-like behavior as well as for the response to rapid antidepressant effects of NMDAR antagonists. We used mutant mice lacking NMDA neurotransmission specifically in PV neurons (PV-Cre+/NR1f/f) and analyzed depression-like behavior and anhedonia. To study the acute and sustained effects of a single NMDAR antagonist administration, we established a behavioral paradigm of repeated exposure to forced swimming test (FST). We did not observe altered behavioral responses in the repeated FST or in a sucrose preference test in mutant mice. In addition, the behavioral response to administration of NMDAR antagonists was not significantly altered in mutant PV-Cre+/NR1f/f mice. Our results show that NMDA-dependent neurotransmission in PV neurons is not necessary to regulate depression-like behaviors, and in addition that NMDARs on PV neurons are not a direct target for the NMDAR-induced antidepressant effects of ketamine and MK801.


The vulnerable phase after hospitalization for heart failure.
Despite available therapy, mortality and readmission rates within 60-90 days of discharge for patients hospitalized with heart failure (HF) approach 15% and 30%, respectively. This early postdischarge period has been termed the 'vulnerable phase' and accounts for a disproportionate amount of the >US$30 billion spent annually on HF care in the USA. The pathophysiology underlying these early adverse events is likely associated with persistently elevated filling pressures at time of discharge and subsequent acute or subacute worsening of postdischarge haemodynamics. Despite limited proven strategies to reduce early adverse events, hospitals in the USA face penalties for 30-day readmission rates that exceed current expectations, and an urgent need exists for novel approaches to improve early postdischarge outcomes. The objective of this Review is to describe the early postdischarge problem among patients hospitalized for HF, the associated patient profile and pathophysiology, and the limitations of current postdischarge treatment strategies. We also identify therapeutic targets and outline a progressive management approach that should be considered by clinicians for reducing early postdischarge morbidity and mortality. Although these strategies require prospective validation, they are practical, affordable, and have the potential to improve patient outcomes substantially after HF hospitalization.


Hydrophobicity and haemolytic potential of oxo derivatives of cholic, deoxycholic and chenodeoxycholic acids.
The objective of this work was to study the effect of structure of bile acids on their membranolytic potential and extent of overlapping of the information about the membranolytic potential of bile acids and their physico-chemical parameters, namely: retention index R(M0) (as a measure of bile acid hydrophobicity, reversed-phase thin-layer chromatography (RPTLC)), lecithin solubilisation (measure of the interaction of bile acids with phospholipids) and critical micellar concentration (CMC). It was found that bile acid concentrations at 100% lysis of erythrocyte membranes is described best by their CMC values, whereas at 50% lysis the parameter used is lecithin solubilisation. This indicates that different mixed micelles are formed in the membrane lysis at lower and higher concentrations of bile acids. Replacement of the hydroxyl (OH) group in the bile acid molecule with an oxo group yields derivatives with lowered hydrophobicity, power of lecithin solubilisation, tendency for self-aggregation as well as the membranolytic activity.


Project ESTEEM protocol: a randomized controlled trial of an LGBTQ-affirmative treatment for young adult sexual minority men's mental and sexual health.
Young gay and bisexual men disproportionately experience depression, anxiety, and substance use problems and are among the highest risk group for HIV infection in the U.S. Diverse methods locate the source of these health disparities in young gay and bisexual men's exposure to minority stress. In fact, minority stress, psychiatric morbidity, substance use, and HIV risk fuel each other, forming a synergistic threat to young gay and bisexual men's health. Yet no known intervention addresses minority stress to improve mental health, substance use problems, or their joint impact on HIV risk in this population. This paper describes the design of a study to test the efficacy of such an intervention, called ESTEEM (Effective Skills to Empower Effective Men), a 10-session skills-building intervention designed to reduce young gay and bisexual men's co-occurring health risks by addressing the underlying cognitive, affective, and behavioral pathways through which minority stress impairs health. This study, funded by the National Institute of Mental Health, is a three-arm randomized controlled trial to examine (1) the efficacy of ESTEEM compared to community mental health treatment and HIV counseling and testing and (2) whether ESTEEM works through its hypothesized cognitive, affective, and behavioral minority stress processes. Our primary outcome, measured 8 months after baseline, is condomless anal sex in the absence of PrEP or known undetectable viral load of HIV+ primary partners. Secondary outcomes include depression, anxiety, substance use, sexual compulsivity, and PrEP uptake, also measured 8 months after baseline. Delivering specific stand-alone treatments for specific mental, behavioral, and sexual health problems represents the current state of evidence-based practice. However, dissemination and implementation of this one treatment-one problem approach has not been ideal. A single intervention that reduces young gay and bisexual men's depression, anxiety, substance use, and HIV risk by reducing the common minority stress pathways across these problems would represent an efficient, cost-effective alternative to currently isolated approaches, and holds great promise for reducing sexual orientation health disparities among young men. Registered October 10, 2016 to ClinicalTrials.gov Identifier: NCT02929069 .


Mammalian hybrid prophagophore is a precursor to autophagosomes.
The precursors to mammalian autophagosomes originate from preexisting membranes contributed by a number of sources, and subsequently enlarge through intermembrane lipid transfer, then close to sequester the cargo, and merge with lysosomes to degrade the cargo. Using cellular and in vitro membrane fusion analyses coupled with proteomic and biochemical studies we show that autophagosomes are formed from a hybrid membrane compartment referred to as a prophagophore or HyPAS (hybrid preautophagosomal structure). HyPAS is initially LC3-negative and subsequently becomes an LC3-positive phagophore. The prophagophore emerges through fusion of RB1CC1/FIP200-containing vesicles, derived from the cis-Golgi, with endosomally derived ATG16L1 membranes. A specialized Ca2+-responsive apparatus controls prophagophore biogenesis and can be modulated by pharmacological agents such as SIGMAR1 agonists and antagonists including chloroquine. Autophagic prophagophore formation is inhibited during SARS-CoV-2 infection and is recapitulated by expression of SARS-CoV-2 nsp6. These findings show that mammalian autophagosomal prophagophores emerge via the convergence of secretory and endosomal pathways in a process that is targeted by microbial factors including coronaviral membrane proteins.Abbreviations: CLEM, correlative light and electron microscopy; CQ, chloroquine; HyPAS, hybrid preautophagosomal; strcuture/prophagophore; LC3, microtubule associated protein 1 light chain 3; RUPEX, a combination of RUSH and APEX2 systems; SARS-CoV-2, SARS-CoV-2 virus, causative agent of COVID19.


Enzyme immunosorbent assay of prolactin with penicillinase as label.
This competitive, rapid, and sensitive enzyme immunosorbent assay for measuring human prolactin in plasma involves penicillinase (EC 184.108.40.206) as label. Microtiter plate wells coated with goat anti-rabbit gamma globulin are filled with antibody to prolactin and plasma sample or reference prolactin and incubated with penicillinase-labeled prolactin for 1 h at 37 degrees C. The enzyme activity of the bound complex is then measured. The assay is as sensitive as radioimmunoassay, the detection limit being 2.5 ng of prolactin per milliliter of plasma. The plasma prolactin values obtained by enzyme immunoassay correlated well with those determined by radioimmunoassay: r = 0.98, slope = 1.00, intercept = 1.11 ng/mL (n = 53).


The dependence of terahertz radiation on the built-in electric field in semiconductor microstructures.
The amplitudes of terahertz radiation are measured for a series of GaAs surface intrinsic-N(+) structures with various built-in surface electric fields as the bias. As the surface field is lower than the so-called "critical electric field" related with the energy difference between the Gamma to L valley of the semiconductor, the amplitude is proportional to the product of the surface field and the number of photo-excited carriers. As the surface field exceeds the critical field, the amplitude is independent of the surface field but proportional to the product of the critical field and the number of the photo-excited carriers.


Supporting Guided Exploratory Visual Analysis on Time Series Data with Reinforcement Learning.
The exploratory visual analysis (EVA) of time series data uses visualization as the main output medium and input interface for exploring new data. However, for users who lack visual analysis expertise, interpreting and manipulating EVA can be challenging. Thus, providing guidance on EVA is necessary and two relevant questions need to be answered. First, how to recommend interesting insights to provide a first glance at data and help develop an exploration goal. Second, how to provide step-by-step EVA suggestions to help identify which parts of the data to explore. In this work, we present a reinforcement learning (RL)-based system, Visail, which generates EVA sequences to guide the exploration of time series data. As a user uploads a time series dataset, Visail can generate step-by-step EVA suggestions, while each step is visualized as an annotated chart combined with textual descriptions. The RL-based algorithm uses exploratory data analysis knowledge to construct the state and action spaces for the agent to imitate human analysis behaviors in data exploration tasks. In this way, the agent learns the strategy of generating coherent EVA sequences through a well-designed network. To evaluate the effectiveness of our system, we conducted an ablation study, a user study, and two case studies. The results of our evaluation suggested that Visail can provide effective guidance on supporting EVA on time series data.


Priorities in the benefit-risk assessment of new drugs.
With the present emphasis on animal safety data, human benefit and risk may be inadequately quantified at the clinical trial stage and the assessment of risk from adverse reaction reporting is also based on methods that lack epidemiological precision. Under these conditions there must be serious doubts about the accuracy of assessment of some of the new drugs that come under suspicion. Suggestions have been made for improving the situation. A closer scrutiny of human data at the clinical trial stage, while involving some increase in the requirements for clinical trial data, would be advantageous for the pharmaceutical industry as well as for other interested parties if it were part of a deliberate change of emphasis from animal to human evidence of safety and from absolute to relative efficacy data in the assessment of product licenses.


The effects of an essential oil and an amine fluoride/stannous fluoride mouthrinse on supragingival plaque regrowth.
The side effects of chlorhexidine (CHX) have stimulated the search for alternative antiplaque agents such as amine fluoride/stannous fluoride (ASF) and essential oils (EO). The aim of the study was to investigate the plaque-inhibiting effects of two commercially available mouthrinses containing ASF and EO, respectively. The study was an observer-masked, randomized, 5 x 5 Latin square cross-over design, balanced for carryover effects, involving 15 volunteers in a 4-day plaque regrowth model. A 0.12% CHX rinse and a saline solution served as positive and negative controls, respectively. On day 1, subjects received professional prophylaxis, suspended oral hygiene measures, and commenced rinsing with their allocated rinses. On day 5, subjects were scored for disclosed plaque. The ASF rinse was tested at two dosages: 10 and 20 ml (ASF-10 and ASF-20, respectively). The ASF and EO rinses showed a significant inhibition of plaque regrowth compared to saline (P <0.0001), but the lowest plaque indices were obtained with the CHX product (P <0.01). There were no significant differences among products containing ASF-10, ASF-20, and EO (P >0.05). There was no correlation between the occurrence of side effects and the use of a particular rinse product (P >0.2). ASF and EO mouthrinses exerted effective and similar plaque inhibition. The two dosages tested for ASF did not differ in plaque reduction. These findings, together with those from long-term trials, suggest that ASF and EO rinses may represent effective alternatives to CHX rinse as adjuncts to oral hygiene.


Changes in activity levels in the first month after stroke.
[Purpose] To quantify the activity levels of individuals in an acute stroke ward, and to determine if their activity levels change within the first month after stroke. [Methods] In this pilot study, participant activity was monitored prospectively over a single day from 8 a.m. to 5 p.m. on two separate occasions. Individuals with confirmed stroke > 18 years of age and less than 15 days post-stroke at the time of recruitment were eligible for inclusion in this study. Activity was recorded using an electronic device. The first day was scheduled within 15 days and the second at four weeks post-stroke. We looked at the following activity categories: number of transitions, and the times spent lying, sitting and in dynamic activity. [Results] Sixteen individuals were included in this study with a median age of 79.5 years (interquartile range 62.5 to 85). Fifty-six % of the participants had mild, 31% had moderate and 13% had severe stroke, according to the NIHSS score. There were no significant changes in number of transitions, or times spent in dynamic activity and lying and sitting. [Conclusion] Activity levels were low at an acute stroke ward and did not significantly change within the first month.


Vitellogenin RNAi halts ovarian growth and diverts reproductive proteins and lipids in young grasshoppers.
Reduced reproduction extends lifespan of females in many animals. To test the effects of reproduction on storage of macronutrients, we block reproductive output in the lubber grasshopper by injecting RNAi against the precursor to egg-yolk protein, vitellogenin, in early adulthood. Controls were injected with either buffer or RNAi against the major storage protein in the hemolymph, hexamerin-90. Vitellogenin RNAi greatly reduced both levels of mRNA for vitellogenin and ovarian growth, in comparison to both controls. Fat body mass was increased upon vitellogenin RNAi, but concentrations of the three hexameric storage proteins from the hemolymph were not. Surprisingly, hemolymph vitellogenin levels were increased upon vitellogenin RNAi. Total reproductive protein (hemolymph vitellogenin plus ovarian vitellin) was unchanged by vitellogenin RNAi, as reproductive protein was diverted to the hemolymph. Similarly, the increased lipid storage upon vitellogenin RNAi was largely attributable to the reduction in lipid in the ovary, due to decreased ovarian growth. A BLAST search revealed that the 515 bp sequence of vitellogenin used for RNAi had three 11 bp regions identical to the vitellogenin receptor of the cockroach Leucophaea maderae. This suggests that our treatment, in addition to reducing levels of vitellogenin transcript, may have also blocked transport of vitellogenin from the hemolymph to the ovary. This would be consistent with halted ovarian growth simultaneous with high levels of vitellogenin in the hemolymph. Nonetheless, the accumulation of vitellogenin, instead of hexameric storage proteins, is inconsistent with a simple model of the trade-off between reproduction and storage. This was observed in young females; future studies will address whether investment of proteins may shift to the soma as individuals age. Overall, our results suggest that blockage of reproduction in young grasshoppers redirects lipids to storage and reproductive proteins to the hemolymph.


Tuberculosis treatment in a refugee and migrant population: 20 years of experience on the Thai-Burmese border.
Although tuberculosis (TB) is a curable disease, it remains a major global health problem and an important cause of morbidity and mortality among vulnerable populations, including refugees and migrants. To describe results and experiences over 20 years at a TB programme in refugee camps on the Thai-Burmese border in Tak Province, Thailand, and to identify risk factors associated with adverse outcomes (e.g., default, failure, death). Retrospective review of routine records of 2425 patients admitted for TB treatment in the Mae La TB programme between May 1987 and December 2005. TB cases notified among refugees decreased over 20 years. Among patients treated with a first-, second- or third-line regimen, 77.5% had a successful outcome, 13.5% defaulted, 7.6% died and 1.3% failed treatment. Multivariate analysis for new cases showed higher likelihood of adverse outcomes for patients who were Burmese migrants or Thai villagers, male, aged >15 years or with smear-negative pulmonary TB. These findings suggest that treatment outcomes depend on the programme's capacity to respond to specific patients' constraints. High-risk groups, such as migrant populations, need a patient-centred approach, and specific, innovative strategies have to be developed based on the needs of the most vulnerable and marginalised populations.


Gram stain-specific-probe-based real-time PCR for diagnosis and discrimination of bacterial neonatal sepsis.
Sepsis is a serious disease with high mortality in newborns. It is very important to have a convenient and accurate method for pathogenic diagnosis of neonatal sepsis. We developed a method of simultaneous detection and Gram classification of clinically relevant bacterial pathogens causing sepsis directly from blood samples with Gram stain-specific-probe-based real-time PCR (GSPBRT-PCR). With GSPBRT-PCR, 53 clinically important strains representing 25 gram-positive and 28 gram-negative bacterial species were identified correctly with the corresponding Gram probe. The limits of the GSPBRT-PCR assay in serial dilutions of the bacteria revealed that Staphylococcus aureus could be detected at concentrations of 3 CFU per PCR and Escherichia coli at concentrations as low as 1 CFU per PCR. The GSPBRT-PCR assay was further evaluated on 600 blood specimens from patients with suspicion of neonatal sepsis and compared to the results obtained from blood cultures. The positive rate of the GSPBRT-PCR array was 50/600 (8.33%), significantly higher than that of blood culture (34/600; 5.67%) (P = 0.00003). When blood culture was used as a control, the sensitivity of GSPBRT-PCR was 100%, the specificity was 97.17%, and the index of accurate diagnosis was 0.972. This study suggests that GSPBRT-PCR is very useful for the rapid and accurate diagnosis of bacterial infection and that it can have an important impact on the current inappropriate and unnecessary use of antibiotics in the treatment of newborns.


Surface ozone climatology of South Eastern Brazil and the impact of biomass burning events.
In the austral spring, biomass fires affect a vast area of South America each year. We combined in situ ozone (O3) data, measured in the states of São Paulo and Paraná, Brazil, in the period 2014-2017, with aerosol optical depth, co-pollutants (NOx, PM2.5 and PM10) and air backtrajectories to identify sources, transport and geographical patterns in the air pollution data. We applied cluster analysis to hourly O3 data and split the investigation area of approximately 290,000 km2 into five groups with similar features in terms of diurnal, weekly, monthly and seasonal O3 concentrations. All groups presented a peak in September and October, associated with the fire activities and enhanced photochemistry. The highest mean O3 concentrations were measured inland whilst, besides having lower concentrations, the coastal group was also associated with the smallest diurnal and seasonal variations. The latter was attributed to lower photochemical activity due to frequently occurring overcast weather situation. The mean annual regional contribution of O3 over the area was 61 μg/m3, with large seasonal and intersite variabilities (from 35 to 84 μg/m3). The long-range transport of smoke contributed with between 23 and 41% of the total O3 during the pollution events. A pollution outbreak in September 2015 caused many-fold increases in O3, PM2.5 and PM10 across the investigation area, which exceeded the World Health Organisation recommendations. We show that the regional transport of particulates and gas due to biomass burning overlays the local emissions in already highly polluted cities. Such an effect can outweigh local measures to curb anthropogenic air pollution in cities.


Therapeutic strategies to reduce asthma exacerbations.
Asthma exacerbations can occur in patients with all degrees of asthma severity. They generally develop over 5 to 7 days and are most often initiated by an upper respiratory tract infection (usually with human rhinovirus) or by environmental allergen exposure in atopic subjects. Inhaled corticosteroids (ICSs) taken on a regular basis are very effective in reducing the risk of asthma exacerbations, and the combination of ICSs and long-acting inhaled β₂-agonists further reduces this risk. In addition, use of the combination of the ICS budesonide and the long-acting inhaled β₂-agonist formoterol, both as maintenance asthma treatment and also as rescue treatment (instead of a short-acting inhaled β₂-agonist), has a significant further beneficial effect on asthma exacerbation risk. Other therapies that have been demonstrated to reduce severe asthma exacerbations are leukotriene receptor antagonists, which have been demonstrated to be effective most consistently in this regard in children, and anti-IgE mAbs, which are effective in subjects with difficult-to-treat allergic asthma. Approximately 50% of severe asthma exacerbations are eosinophilic in nature, whereas many of the remaining are neutrophilic. Several studies have demonstrated that making asthma treatment decisions based on minimizing airway eosinophil numbers (measured in induced sputum) can reduce the risks of severe exacerbations. In addition, treatment of patients with severe asthma with an anti-IL-5 mAb also reduces the number of severe asthma exacerbations, demonstrating a central role of eosinophils in many exacerbations.


COX-2 has a critical role during incorporation of structural bone allografts.
Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX) activity, reduced pain and are commonly used in patients with skeletal injury. In this article we will also present data to show that selective COX-2 inhibitor delays allograft healing and incorporation. In contrast, local delivery of prostaglandin E2 (PGE2) enhanced bone formation at cortical bone graft junction. A 4-mm mid-diaphyseal segmental femoral defect was created and then repaired by frozen bone allograft of the same size. A 22-gauge metal pin was placed in the intramedullary cavity to stabilize the bone graft. Healing was evaluated weekly by X ray and by a semiquantitative histomorphometric analysis at 5 weeks postsurgery. Celecoxib (25 mg/kg/day) and Ketorolac (4 mg/kg/day) were administered daily for 2 weeks or 5 weeks. PGE2 was infused locally at a dose of 800 nmol/kg per day via osmotic minipump for 4 weeks. Inhibition of cyclooxygenase by daily administration of the Celecoxib or Ketorolac for 5 weeks reduced new bone ingrowth by about 60% (P < 0.05). The percentage of bony bridging in both drug-treated groups was significantly decreased at 5 weeks. Temporal administration of Celecoxib for 2 weeks also significantly reduced bone formation by 45% and withdrawal of the Celecoxib only led to slight recovery of bone formation at the graft side. In contrast to the inhibitory effects of NSAIDS, PGE2 infusion at the cortical bone junction increased bone formation by about twofold. These results demonstrated that COX-2 is essential for bone allograft incorporation. Furthermore, our data support the notion that COX-2-dependent PGE2 produced at the early stage of bone healing is prerequisite for efficient skeletal repair.


The legal ramifications of the NCCN practice guidelines.
Physicians concerned about being sued for medical malpractice for following (or deviating from) a clinical practice guideline written by the National Comprehensive Cancer Network (NCCN) or otherreputable group should keep in mind one general principle: "Good medicine is good law." In other words, if a physician follows a course of action in line with the professional standard of care, regardless of whether or not he or she adheres to a particular guideline, that individual has little to worry about with regard to malpractice liability. The standard of care against which malpractice liability is measured is defined informally as "what a similar doctor would do under similar circumstances." Thus, if most oncologists observe the NCCN guidelines (or if their practice already comports with them), the guidelines will serve as the professional standard against which all oncologists' conduct will be measured. If oncologists ignore the NCCN guidelines, the malpractice standard will continue to reflect the way oncologists actually treat cancer patients.


Contact and impact on the frontline: Effects of relational job architecture and perceived safety climate on strain and motivational outcomes during COVID-19.
The COVID-19 pandemic has dramatically impacted the relational nature of work, particularly for frontline workers who provide their labor in person. However, little is known about how relational job characteristics during the pandemic may affect workers or how frontline and nonfrontline workers may respond differently. We integrate theory on relational job architecture with the job demands-resources model to understand the effects of contact and impact during the pandemic. We propose contact as a job demand that increases strain outcomes among frontline workers and impact as a job resource that increases motivational outcomes among all workers. In addition, we propose perceived safety climate as a critical resource for mitigating the negative effects of contact among frontline workers and amplifying the positive effects of impact among all workers. We test hypotheses among 452 full-time workers (209 frontline, 243 nonfrontline) using a two-wave survey design. We find no support for the idea that contact operates as a job demand among frontline workers. In contrast, among nonfrontline workers, contact was associated with higher levels of burnout at lower levels of job impact and perceived safety climate. Impact and perceived safety climate acted as important resources among all workers, predicting both motivational and strain outcomes 4 months later. In addition, the positive effects of impact on prosocial motivation were amplified at higher levels of perceived safety climate among all workers. Our results suggest that impactful work, when conducted in a safe climate, is a key resource for enhancing prosocial motivation during crisis situations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Nonsurgical periodontal treatment.
The primary goal of nonsurgical periodontal therapy is to control microbial periodontal infection by removing bacterial biofilm, calculus, and toxins from periodontally involved root surfaces. A review of the scientific literature indicates that mechanical nonsurgical periodontal treatment predictably reduces the levels of inflammation and probing pocket depths, increases the clinical attachment level and results in an apical shift of the gingival margin. Another parameter to be considered, in spite of the lack of scientific evidence, is the reduction in the degree of tooth mobility, as clinically experienced. It is important to point out that nonsurgical periodontal treatment presents limitations such as the long-term maintainability of deep periodontal pockets, the risk of disease recurrence, and the skill of the operator. A high number of posttreatment residual pockets exhibiting bleeding on probing and > 5 mm deep are related to lower clinical stability. The successful treatment of plaque-induced periodontitis will restore periodontal health, but with reduced periodontium. In such cases, anatomical damage from previous periodontal disease will persist and inverse architecture of soft tissue may impair home plaque removal. The clinician can select one of the following therapeutic options according to the individual patient's needs: - Quadrant/sextant wise instrumentation (conventional staged debridement, CSD). - Instrumentation of all pockets within a 24-hour period with (full mouth disinfection [FMD]) or without (full mouth scaling and root planing [FMSRP]) local antiseptics. Both procedures can be associated with systemic antimicrobials. -CSD or FMD in combination with laser or photodynamic therapy. Patients with aggressive periodontitis constitute a challenge to the clinician. To date there are no established protocols for controlling the disease. However, data from the literature on the application of the FMD protocol combined with amoxicillin-metronidazole systemic administration are promising. A new classification in supra- and subcrestal nonsurgical periodontal therapy will be proposed. The supracrestal therapy includes the treatment of gingivitis, nonsurgical coverage of recession-type defects, treatment of suprabony defects and papilla reconstruction techniques. Within subcrestal periodontal therapy, it is of paramount importance to preserve both marginal tissues and connective fibers inserted in the root cementum at the apical part of the bony defects.


Thyroid dysfunction in an adult female population: A population-based study of Latin American Vertebral Osteoporosis Study (LAVOS) - Puerto Rico site.
To determine the prevalence of hypothyroidism in an adult female population in Puerto Rico and to determine the relationship between hypothyroidism, bone mineral density and vertebral and non-vertebral fractures in this population. Data from the 400 subjects' database of the Latin American Vertebral Osteoporosis Study (LAVOS), Puerto Rico site was reviewed. Patient's medical history, anthropometric data, current medications, laboratories, and DXA results was extracted. Subjects with thyroid dysfunction were identified based on their previous medical history and levels of TSH. Bone Mineral Density was classified using the World Health Organization criteria. Crude prevalence of thyroid dysfunction were estimated with a confidence of 95% and weighted by the population distribution by age, according to the distribution by age group in the 2000 census. Bone mineral densities and prevalence of vertebral and non-vertebral fractures were compared among the groups. The weighted prevalence of hyperthyroidism in this population was 0.0043% (95% CI: -0.0021%, 0.0107%). The weighted prevalence of hypothyroidism was 24.2% (95% CI: 19.9%, 28.4%). Increased prevalence of hypothyroidism was found in participants 70 years or older. The mean BMD at spine, hip and femoral neck was similar among the groups. No difference in the proportion of participants with vertebral and non-vertebral fractures was found among the groups. Our study found a high prevalence of hypothyroidism among adult postmenopausal females in Puerto Rico. No association between hypothyroidism and decreased bone mineral densities, vertebral or non-vertebral fractures was found in this population.


Effect of protic ionic liquid and surfactant structure on partitioning of polyoxyethylene non-ionic surfactants.
The partitioning constants and Gibbs free energies of transfer of poly(oxyethylene) n-alkyl ethers between dodecane and the protic ionic liquids (ILs) ethylammonium nitrate (EAN) and propylammonium nitrate (PAN) are determined. EAN and PAN have a sponge-like nanostructure that consists of interpenetrating charged and apolar domains. This study reveals that the ILs solvate the hydrophobic and hydrophilic parts of the amphiphiles differently. The ethoxy groups are dissolved in the polar region of both ILs by means of hydrogen bonds. The environment is remarkably water-like and, as in water, the solubility of the ethoxy groups in EAN decreases on warming, which underscores the critical role of the IL hydrogen-bond network for solubility. In contrast, amphiphile alkyl chains are not preferentially solvated by the charged or uncharged regions of the ILs. Rather, they experience an average IL composition and, as a result, partitioning from dodecane into the IL increases as the cation alkyl chain is lengthened from ethyl to propyl, because the IL apolar volume fraction increases. Together, these results show that surfactant dissolution in ILs is related to structural compatibility between the head or tail group and the IL nanostructure. Thus, these partitioning studies reveal parameters for the effective molecular design of surfactants in ILs.


Spatial structure and anti-fatigue of polysaccharide from Inonotus obliquus.
The aim of this study was to evaluate the spatial structure and potential antifatigue activity of polysaccharide fractions which was extracted from Inonotus obliquus. The first polysaccharide fractions of Inonotus obliquus (PIO-1) were obtained after hot-water extraction and purification by DEAE cellulose-52 chromatography. Results of the forced swimming test showed that the doses (50 mg/kg) of PIO-1 could increase the climbing duration and swimming time as well as reduced the immobility time in the PIO treated mice. The fatigue related metabolic parameters showed that PIO-1 decreased the level of blood lactic acid (BLA), urea nitrogen (BUN) and lactic dehydrogenase (LDH). Additionally, PIO-1 significantly decreased the 5-HT concentrations in the mice brain. The results of monosaccharide analysis showed that the molar ratio of mannose, glucose, galactose, xylose and arabinose with the molar ratio of 1.0:1.9:3.5:18.5:5.7. The molecular morphology of the PIO-1 observed under atomic force microscopy (AFM). There were many spherical and heterogeneous clumps existed in the images. Therefore, current study indicated polysaccharide PIO-1 not only has great potential to postpone physical fatigue but also shown potential to improve mental fatigue.


Evaluation of a pictograph enhancement system for patient instruction: a recall study.
We developed a novel computer application called Glyph that automatically converts text to sets of illustrations using natural language processing and computer graphics techniques to provide high quality pictographs for health communication. In this study, we evaluated the ability of the Glyph system to illustrate a set of actual patient instructions, and tested patient recall of the original and Glyph illustrated instructions. We used Glyph to illustrate 49 patient instructions representing 10 different discharge templates from the University of Utah Cardiology Service. 84 participants were recruited through convenience sampling. To test the recall of illustrated versus non-illustrated instructions, participants were asked to review and then recall a set questionnaires that contained five pictograph-enhanced and five non-pictograph-enhanced items. The mean score without pictographs was 0.47 (SD 0.23), or 47% recall. With pictographs, this mean score increased to 0.52 (SD 0.22), or 52% recall. In a multivariable mixed effects linear regression model, this 0.05 mean increase was statistically significant (95% CI 0.03 to 0.06, p<0.001). In our study, the presence of Glyph pictographs improved discharge instruction recall (p<0.001). Education, age, and English as first language were associated with better instruction recall and transcription. Automated illustration is a novel approach to improve the comprehension and recall of discharge instructions. Our results showed a statistically significant in recall with automated illustrations. Subjects with no-colleague education and younger subjects appeared to benefit more from the illustrations than others.


Stress versus coarticulation: toward an integrated approach to explicit speech segmentation.
Although word stress has been hailed as a powerful speech-segmentation cue, the results of 5 cross-modal fragment priming experiments revealed limitations to stress-based segmentation. Specifically, the stress pattern of auditory primes failed to have any effect on the lexical decision latencies to related visual targets. A determining factor was whether the onset of the prime was coarticulated with the preceding speech fragment. Uncoarticulated (i.e., concatenated) primes facilitated priming. Coarticulated ones did not. However, when the primes were presented in a background of noise, the pattern of results reversed, and a strong stress effect emerged: Stress-initial primes caused more pruning than non-initial-stress primes, regardless of the coarticulatory cues. The results underscore the role of coarticulation in the segmentation of clear speech and that of stress in impoverished listening conditions. More generally, they call for an integrated and signal-contingent approach to speech segmentation.


Circulating 25-hydroxyvitamin D and risk of endometrial cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers.
A nested case-control study, including 830 cases and 992 controls from 7 cohorts, was conducted to evaluate the association of circulating 25-hydroxyvitamin D (25(OH)D), the best indicator of vitamin D status, with risk of endometrial cancer. Matching factors included age at blood donation, date of blood donation, and race. Conditional logistic regression was used in the main analysis. The median concentration of 25(OH)D was slightly lower in cases (49.4 nmol/L) than in controls (50.8 nmol/L) (P = 0.08). However, there was no association between 25(OH)D concentration and disease risk, after adjustment for body mass index. Compared with the 50-<75 nmol/L 25(OH)D category, the body mass index-adjusted odds ratios and 95% confidence intervals were 1.08 (95% confidence interval: 0.73, 1.57) for the <25 nmol/L category and 0.90 (95% confidence interval: 0.51, 1.58) for the > or =100 nmol/L category (P(trend) = 0.99). Similarly null results were observed after further adjustment for other known risk factors and in stratified analyses. Although an effect of circulating 25(OH)D at high concentrations cannot be ruled out (the highest category of 25(OH)D was > or =100 nmol/L, and for stratified analyses, > or =75 nmol/L), these results do not support a protective role of vitamin D against endometrial cancer.


CpG oligonucleotides enhance proliferative and effector responses of B Cells in HIV-infected individuals.
Stimulation through TLR represents a new therapeutic approach for enhancing Ab responses to vaccination. Considering that Ab responses are decreased in HIV disease and that B cells express TLR9 and respond to TLR9 agonists, we investigated the responsiveness of B cell subpopulations from HIV-infected and uninfected individuals to the TLR9 agonist CpG oligonucleotide type B (CpG-B) in the presence and absence of BCR ligation and T cell help (CD40L). CpG-B was equally effective in stimulating the proliferation of naive B cells of HIV-infected individuals and HIV-negative individuals, and, when combined with BCR and CD40 ligation, cytokine secretion by naive B cells was also comparable in HIV-infected and uninfected individuals. In contrast, CD27(+) memory/activated B cells of HIV-infected individuals with active disease were less responsive to CpG-B in terms of proliferation and cytokine secretion when compared with CD27(+) B cells of HIV-negative and HIV-infected individuals whose viremia was controlled by antiretroviral therapy. These findings suggest that despite abnormalities in memory B cells of HIV-infected individuals with active disease, naive B cells of HIV-infected individuals, irrespective of disease status, can respond to TLR9 agonists and that the incorporation of such agents in vaccine formulations may enhance their Ab responses to vaccination.


Hybrid solar cells from MDMO-PPV and silicon nanocrystals.
Solution-processed bulk heterojunction solar cells from silicon nanocrystals (Si NCs) and poly(3-hexylthiophene) (P3HT) have shown promising power conversion efficiencies. Here we report on an attempt to enhance the performance of Si NC-polymer hybrid solar cells by using poly[2-methoxy-5-(3',7'-dimethyloctyloxy)-1,4-phenylenevinylene] (MDMO-PPV) as a hole conductor, which is expected to yield a higher open circuit voltage than P3HT due to its lower highest occupied molecular orbital (HOMO). Bulk heterojunction solar cells consisting of 3-5 nm silicon nanocrystals (Si NCs) and poly[2-methoxy-5-(3',7'-dimethyloctyloxy)-1,4-phenylenevinylene] (MDMO-PPV) have been fabricated. The properties of the hybrid Si NC/MDMO-PPV devices were studied as a function of the Si NC/MDMO-PPV weight ratio. Cells of 58 wt% 3-5 nm Si NCs showed the best overall performance under simulated one-sun AM 1.5 global illumination (100 mW cm(-2)). Compared to composite films of Si NCs and poly(3-hexylthiophene), we indeed observed an improved open circuit voltage but a lower power conversion efficiency from the Si NC/MDMO-PPV devices. The lower efficiency of Si NC/MDMO-PPV is correlated to the lower hole mobility and narrower absorption spectrum of MDMO-PPV compared to P3HT.


The protocol for a multisite, double blind, randomized, placebo-controlled trial of axillary nerve stimulation for chronic shoulder pain.
Shoulder impingement syndrome is one of the most common causes of shoulder pain, accounting for approximately 30% of all shoulder pain. Approximately 35% of patients with shoulder impingement syndrome are refractory to conservative treatment. For patients who fail conservative treatment, there is no established treatment to successfully treat their chronic pain. Prior randomized control trials have demonstrated efficacy for the use of a single lead intramuscular peripheral nerve stimulation of the axillary nerve at the motor points of the deltoid muscle for treatment of hemiplegic shoulder pain. This is the first controlled trial to utilize the same novel technology to treat shoulder impingement syndrome outside of the stroke population. This is a dual-site, placebo-controlled, double-blinded, randomized control trial. Participants will be randomized to two treatment groups. The intervention group will be treated with active peripheral nerve stimulation of the axillary nerve of the affected shoulder and the control group will be treated with sham peripheral nerve stimulation of the axillary nerve of the affected shoulder. Both groups will receive a standardized exercise therapy program directed by a licensed therapist. This study protocol will allow the investigators to determine if this novel, non-pharmacologic treatment of shoulder pain can demonstrate the same benefit in musculoskeletal patients which has been previously demonstrated in the stroke population. Clinicaltrials.gov, NCT03752619. Registered on 26 November 2018.


Preliminary results on the plasma environment of saturn from the pioneer 11 plasma analyzer experiment.
The Ames Research Center Pioneer 11 plasma analyzer experiment provided measurements of the solar wind interaction with Saturn and the character of the plasma environment within Saturn's magnetosphere. It is shown that Saturn has a detached bow shock wave and magnetopause quite similar to those at Earth and Jupiter. The scale size of the interaction region for Saturn is roughly one-third that at Jupiter, but Saturn's magnetosphere is equally responsive to changes in the solar wind dynamic pressure. Saturn's outer magnetosphere is inflated, as evidenced by the observation of large fluxes of corotating plasma. It is postulated that Saturn's magnetosphere may undergo a large expansion when the solar wind pressure is greatly diminished by the presence of Jupiter's extended magnetospheric tail when the two planets are approximately aligned along the same solar radial vector.


Role of connexin 43 in different forms of intercellular communication - gap junctions, extracellular vesicles and tunnelling nanotubes.
Communication is important to ensure the correct and efficient flow of information, which is required to sustain active social networks. A fine-tuned communication between cells is vital to maintain the homeostasis and function of multicellular or unicellular organisms in a community environment. Although there are different levels of complexity, intercellular communication, in prokaryotes to mammalians, can occur through secreted molecules (either soluble or encapsulated in vesicles), tubular structures connecting close cells or intercellular channels that link the cytoplasm of adjacent cells. In mammals, these different types of communication serve different purposes, may involve distinct factors and are mediated by extracellular vesicles, tunnelling nanotubes or gap junctions. Recent studies have shown that connexin 43 (Cx43, also known as GJA1), a transmembrane protein initially described as a gap junction protein, participates in all these forms of communication; this emphasizes the concept of adopting strategies to maximize the potential of available resources by reutilizing the same factor in different scenarios. In this Review, we provide an overview of the most recent advances regarding the role of Cx43 in intercellular communication mediated by extracellular vesicles, tunnelling nanotubes and gap junctions.


[Yacon root extract improves lipid metabolism in hyperlipidemic rats by inhibiting HMGCR expression and activating the PPARα/CYP7A1/CPT-1 pathway].
To investigate the effect of yacon root extract on lipid metabolism in rats with hyperlipidemia (HLP) and its underlying mechanisms. SD rat models of HLP induced by high- fat diet feeding for 8 weeks were randomized into the model group, fenofibrate treatment group (27 mg/kg), and yacon extract treatment groups at doses of 5, 2.5 and 1.25 g/kg (n=10). The rats were given corresponding drug treatments via gavage for 8 weeks. After the treatments, the rats were observed for body weight changes, liver coefficient, liver pathology, and serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). The mRNA and protein expressions of HMGCR, PPARα, CYP7A1, and CPT-1 in the liver were detected using RT-qPCR and Western blotting. Compared with those in the model group, the rats treated with fenofibrate and 5 g/kg yacon root extract showed significantly slower body weight gain and lower liver coefficient (P < 0.05) with lower serum levels of TG, TC, and LDL- C (P < 0.05) but higher HDL- C level (P < 0.05). The HLP rat models showed obvious fatty degeneration and vacuolar changes in the liver, which were significantly alleviated by fenofibrate treatment and by treatment with yacon root extract in a dose-dependent manner. Both fenofibrate and 5 g/kg yacon root extract significantly lowered the mRNA and protein expression levels of HMGCR (P < 0.001) and increased the expressions of PPARα, CYP7A1, and CPT-1 in the liver of HLP rats (P < 0.001). Yacon root extract can reduce serum TG and TC levels in HLP rats possibly by inhibiting HMGCR expression and activating the PPARα/CYP7A1/CPT-1 signaling pathway, thereby promoting fatty acid β oxidation and bile acid metabolism.


Documenting the untold histories of late-diagnosed autistic adults: a qualitative study protocol using oral history methodology.
Receiving a diagnosis of autism in adulthood is increasingly common for a subset of individuals who were either misdiagnosed in childhood or missed out on a diagnosis altogether. This qualitative study, coproduced with autistic people, invites late-diagnosed autistic adults to share their life histories to (1) understand better the consequences of living without a diagnosis, (2) elucidate what precipitates an autism diagnosis in mid-to-late adulthood and (3) identify the perceived impact of receiving that diagnosis. Oral histories have been a successful way to uncover overlooked and marginalised voices. We therefore adopt qualitative, oral history methodology in this study to understand these adults' experiences, especially of living in an era when autism was not well known. We will recruit 24 participants who will (1) have been born before 1975, (2) have received a clinical, autism diagnosis after the age of 35, (3) be English-speaking and (4) have spent most of their childhood and adulthood living in Australia. Participants will take part in four sessions, including the main, qualitative, oral history interview, through a range of possible formats to facilitate inclusion. The interview data will be analysed using reflexive thematic analysis. The protocol has received institutional research ethics approval from Macquarie University's Human Research Ethics Committee (Ref.: 52019556310562). This study will yield understanding of the life experiences of autistic adults, especially middle-aged and older Australians, should inform more effective diagnostic practices and provide insight into the key factors that might promote resilience and enhance quality of life in autistic people. The findings will be disseminated to academic and clinical audiences through journal articles and conference presentations and to the autistic and autism communities through accessible reports. The interviews will also be prepared for digital archiving, which will enable ongoing access for future generations and communities.


Complex interplay between autophagy and oxidative stress in the development of pulmonary disease.
The autophagic pathway involves the encapsulation of substrates in double-membraned vesicles, which are subsequently delivered to the lysosome for enzymatic degradation and recycling of metabolic precursors. Autophagy is a major cellular defense against oxidative stress, or related conditions that cause accumulation of damaged proteins or organelles. Selective forms of autophagy can maintain organelle populations or remove aggregated proteins. Dysregulation of redox homeostasis under pathological conditions results in excessive generation of reactive oxygen species (ROS), leading to oxidative stress and the associated oxidative damage of cellular components. Accumulating evidence indicates that autophagy is necessary to maintain redox homeostasis. ROS activates autophagy, which facilitates cellular adaptation and diminishes oxidative damage by degrading and recycling intracellular damaged macromolecules and dysfunctional organelles. The cellular responses triggered by oxidative stress include the altered regulation of signaling pathways that culminate in the regulation of autophagy. Current research suggests a central role for autophagy as a mammalian oxidative stress response and its interrelationship to other stress defense systems. Altered autophagy phenotypes have been observed in lung diseases such as chronic obstructive lung disease, acute lung injury, cystic fibrosis, idiopathic pulmonary fibrosis, and pulmonary arterial hypertension, and asthma. Understanding the mechanisms by which ROS regulate autophagy will provide novel therapeutic targets for lung diseases. This review highlights our current understanding on the interplay between ROS and autophagy in the development of pulmonary disease.


[Preclinical in vitro and in vivo models for the assessment of biological activity in biosimilarity studies].
A drug that contains a recombinant protein as an active principle is called a biotechnological drug or biopharmaceutical.There are currently over 300 biopharmaceuticals worldwide. Many of these contains a similar active principle (biosimilar drug) as other previously registered (innovator drug). It has suggested that due to the complex implications in a formulation containing a protein, the manufacturing process is a key factor for efficacy and safety requirements. In fact, certain variability has been detected of the protein properties in different lots (or batches) of the same manufacturer, which produce changes at a clinical level. For this reason, the evaluation of biosimilar drugs has acquired great relevance, being the preclinical level of one of the more important stages of the development due to its lower cost (with respect to the clinical level) and its high capacity to detect formulation-manufacture problems. However, the demonstration of comparability at physicochemical, preclinical, and clinical levels is required in order to achieve market registration. In this review the in vitro and in vivo models used for the assessment of proposed biosimilars will be discussed.