Structural Insight into Nucleoprotein Conformation Change Chaperoned by VP35 Peptide in Marburg Virus.
Marburg virus (MARV) encodes a nucleoprotein (NP) to encapsidate its genome by oligomerization and form a ribonucleoprotein complex (RNP). According to previous investigation on nonsegmented negative-sense RNA viruses (nsNSV), the newly synthesized NPs must be prevented from indiscriminately binding to noncognate RNAs. During the viral RNA synthesis process, the RNPs undergo a transition from an RNA-bound form to a template-free form, to open access for the interaction between the viral polymerase and the RNA template. In filoviruses, this transition is regulated by VP35 peptide and other viral components. To further understand the dynamic process of filovirus RNP formation, we report here the structure of MARV NPcore, both in the apo form and in the VP35 peptide-chaperoned form. These structures reveal a typical bilobed structure, with a positive-charged RNA binding groove between two lobes. In the apo form, the MARV NP exists in an interesting hexameric state formed by the hydrophobic interaction within the long helix of the NPcore C-terminal region, which shows high structural flexibility among filoviruses and may imply critical function during RNP formation. Moreover, the VP35 peptide-chaperoned NPcore remains in a monomeric state and completely loses its affinity for single-stranded RNA (ssRNA). The structural comparison reveals that the RNA binding groove undergoes a transition from closed state to open state, chaperoned by VP35 peptide, thus preventing the interaction for viral RNA. Our investigation provides considerable structural insight into the filovirus RNP working mechanism and may support the development of antiviral therapies targeting the RNP formation of filovirus.IMPORTANCE Marburg virus is one of the most dangerous viruses, with high morbidity and mortality. A recent outbreak in Angola in 2005 caused the deaths of 272 persons. NP is one of the most essential proteins, as it encapsidates and protects the whole virus genome simultaneously with self-assembly oligomerization. Here we report the structures of MARV NPcore in two different forms. In the MARV NP apo form, we identify an interesting hexamer formed by hydrophobic interaction within a long helix, which is highly conserved and flexible among filoviruses and may indicate its critical function during the virus RNP formation. Moreover, the structural comparison with the NP-VP35 peptide complex reveals a structural transition chaperoned by VP35, in which the RNA binding groove undergoes a transition from closed state to open state. Finally, we discussed the high conservation and critical role of the VP35 binding pocket and its potential use for therapeutic development.


Influences of adult attachment in exploration.
Research into the relationship between attachment quality in both children and adults suggests links with patterns of exploration; however, exploration has been operationalized differently in studies of adults and children. This study examined adults' patterns of exploration operationalized in terms of novelty seeking, curiosity, and impulsivity, as in studies of children. Analysis indicated avoidant adults reported significantly lower curiosity than did securely attached adults, while preoccupied subjects showed no differences from either secure or avoidant groups. As in studies of children, groups did not differ on measures of novelty seeking or impulsivity.


Processing of the capsid proteins of the Betachrysovirus Fusarium graminearum virus-China 9 (FgV-ch9).
While the capsid of viruses in the Alphachrysovirus genus is built of subunits of a single coat protein, the capsid of viruses grouped in the Betachrysovirus genus may consist of subunits of two different proteins. For four of these betachrysoviruses, the detected molecular weights of the putative coat proteins differ from the sizes deduced from the nucleic acid sequence. The origin of these modifications remained unclear and it was hypothesized that the coat proteins undergo unspecific degradation. In our study, we show that these modifications are based on processing steps performed by unknown factors present in extracts of several eukaryotic organisms. Furthermore, we show that the C-terminal domain of P3 is fully degraded after capsid processing and particle assembly.


Involvement of eyestalk factors in the neuroendocrine control of osmoregulation in adult American lobster Homarus americanus.
Osmoregulatory capacity (OC) decreased by approximately 50% after eyestalk ablation in adult Homarus americanus when in dilute media. OC was used to assay sinus gland extracts. Injection of total extracts and of some HPLC-separated fractions of sinus glands into destalked lobsters increased OC. One of the described crustacean hyperglycemic hormone isoforms influences osmoregulation. Another fraction of the sinus gland extracts modifies osmoregulation but its nature remains unknown. Variations in OC were examined in response to ecdysterone, Phe-Met-Arg-Phe-NH2, and atrial natriuretic factor but effects were minimal.


Development of the ability to distinguish communicative intention and literal message meaning.
Children's ability to distinguish the literal meaning of a message and the speaker's communicative intent was investigated in 2 experiments. First- and second-grade children evaluated brief referential communication messages for ambiguity under 2 conditions. In an informed condition, the children knew which referent the speaker had intended. In an uninformed condition, they did not know the intended referent. 2 communication systems were used. In Experiment 1, the messages were written on cards and read to the child; in Experiment 2, a novel communication system was used. The developmental pattern of results was similar for both studies. The results showed that the first graders in the informed condition often claimed that an ambiguous message could not refer to a referent the speaker had not meant, whereas children in the uninformed condition were able to detect the referential ambiguity of the message. There were no condition differences for the second graders. The results suggest that young children's ability to analyze the literal meaning of a message is affected by the accessibility of the speaker's communicative intent and that children may develop a general ability to analyze representations of communicative intention.


Understanding Perceived Stress in Adolescent Inflammatory Bowel Disease.
Inflammatory bowel disease (IBD) is a chronic and debilitating illness associated with psychosocial comorbidities. Adolescents are vulnerable to the additive stress of managing IBD and navigating developmental milestones. Psychosocial factors, such as catastrophizing, illness stigma, illness uncertainty, and illness-related shame, often contribute to perceived stress in chronic illnesses. However, the combination of these variables on perceived stress in adolescents with IBD has not been examined. Participants completed a cross-sectional online self-report survey. Model 4 of PROCESS Macro in SPSS was used to test the parallel mediation model of the relationship between disease severity and perceived stress using catastrophizing, stigma, uncertainty, and shame as mediators using 10,000 bootstrap samples. T-tests were run to assess systematic differences in the dependent variable between subjects. One hundred and thirty-one adolescents (Mage = 18.95 years; 100 females) completed the survey. Females had higher stress scores than males (P =0.002), and there were no difference in stress between younger and older participants (P = 0.085), location (P = 0.484), or IBD type (P = 0.515). The total effect of disease stress on perceived stress operating through the mediators was significant, b = 0.168, SE = 0.028, 95% CI [0.112, 0.224]. Helplessness catastrophizing, illness uncertainty, and illness-related shame, but not illness stigma, were equally strong, positive mediators. The present results suggest that helplessness catastrophizing, illness uncertainty, and illness-related shame are central elements to target in stress interventions for adolescents with IBD.


Universal immunoprobe for (per)chlorate-reducing bacteria.
Recent studies in our lab have demonstrated the ubiquity and diversity of microorganisms which couple growth to the reduction of chlorate or perchlorate [(per)chlorate] under anaerobic conditions. We identified two taxonomic groups, the Dechloromonas and the Dechlorosoma groups, which represent the dominant (per)chlorate-reducing bacteria (ClRB) in the environment. As part of these studies we demonstrated that chlorite dismutation is a central step in the reductive pathway of (per)chlorate that is common to all ClRB and which is mediated by the enzyme chlorite dismutase (CD). Initial studies on CD suggested that this enzyme is highly conserved among the ClRB, regardless of their phylogenetic affiliation. As such, this enzyme makes an ideal target for a probe specific for these organisms. Polyclonal antibodies were commercially raised against the purified CD from the ClRB Dechloromonas agitata strain CKB. The obtained antiserum was deproteinated by ammonium sulfate precipitation, and the antigen binding activity was assessed using dot blot analysis of a serial dilution of the antiserum. The titers obtained with purified CD indicated that the antiserum had a high affinity for the CD enzyme, and activity was observed in dilutions as low as 10(-6) of the original antiserum. The antiserum was active against both cell lysates and whole cells of D. agitata, but only if the cells were grown anaerobically with (per)chlorate. No response was obtained with aerobically grown cultures. In addition to D. agitata, dot blot analysis employed with both whole-cell suspensions and cell lysates of several diverse ClRB representing the alpha, beta, and gamma subclasses of Proteobacteria tested positive regardless of phylogenetic affiliation. Interestingly, the dot blot response obtained for each of the ClRB cell lysates was different, suggesting that there may be some differences in the antigenic sites of the CD protein produced in these organisms. In general, no reactions were observed with cells or cell lysates of the organisms closely related to the ClRB which could not grow by (per)chlorate reduction. These studies have resulted in the development of a highly specific and sensitive immunoprobe based on the commonality of the CD enzyme in ClRB which can be used to assess dissimilatory (per)chlorate-reducing populations in environmental samples regardless of their phylogenetic affiliations.


A spatio-temporal analysis for exploring the effect of temperature on COVID-19 early evolution in Spain.
The new SARS-CoV-2 coronavirus, which causes the COVID-19 disease, was reported in Wuhan, China, in December 2019. This new pathogen has spread rapidly around more than 200 countries, in which Spain has one of the world's highest mortality rates so far. Previous studies have supported an epidemiological hypothesis that weather conditions may affect the survival and spread of droplet-mediated viral diseases. However, some contradictory studies have also been reported in the same research line. In addition, many of these studies have been performed considering only meteorological factors, which can limit the reliability of the results. Herein, we report a spatio-temporal analysis for exploring the effect of daily temperature (mean, minimum and maximum) on the accumulated number of COVID-19 cases in the provinces of Spain. Non-meteorological factors such as population density, population by age, number of travellers and number of companies have also been considered for the analysis. No evidence suggesting a reduction in COVID-19 cases at warmer mean, minimum and maximum temperatures has been found. Nevertheless, these results need to be interpreted cautiously given the existing uncertainty about COVID-19 data, and should not be extrapolated to temperature ranges other than those analysed here for the early evolution period.


Human resources issues and Australian Disaster Medical Assistance Teams: results of a national survey of team members.
Calls for disaster medical assistance teams (DMATs) are likely to continue in response to international disasters. As part of a national survey, this study was designed to evaluate Australian DMAT experience in relation to the human resources issues associated with deployment. Data was collected via an anonymous mailed survey distributed via State and Territory representatives on the Australian Health Protection Committee, who identified team members associated with Australian DMAT deployments from the 2004 South East Asian Tsunami disaster. The response rate for this survey was 50% (59/118). Most personnel had deployed to the Asian Tsunami affected areas with DMAT members having significant clinical and international experience. While all except one respondent stated they received a full orientation prior to deployment, only 34% of respondents (20/59) felt their role was clearly defined pre deployment. Approximately 56% (33/59) felt their actual role matched their intended role and that their clinical background was well suited to their tasks. Most respondents were prepared to be available for deployment for 1 month (34%, 20/59). The most common period of notice needed to deploy was 6-12 hours for 29% (17/59) followed by 12-24 hours for 24% (14/59). The preferred period of overseas deployment was 14-21 days (46%, 27/59) followed by 1 month (25%, 15/59) and the optimum shift period was felt to be 12 hours by 66% (39/59). The majority felt that there was both adequate pay (71%, 42/59) and adequate indemnity (66%, 39/59). Almost half (49%, 29/59) stated it was better to work with people from the same hospital and, while most felt their deployment could be easily covered by staff from their workplace (56%, 33/59) and caused an inconvenience to their colleagues (51%, 30/59), it was less likely to interrupt service delivery in their workplace (10%, 6/59) or cause an inconvenience to patients (9%, 5/59). Deployment was felt to benefit the affected community by nearly all (95%, 56/59) while less (42%, 25/59) felt that there was a benefit for their own local community. Nearly all felt their role was recognised on return (93%, 55/59) and an identical number (93%, 55/59) enjoyed the experience. All stated they would volunteer again, with 88% strongly agreeing with this statement. This study of Australian DMAT members provides significant insights into a number of human resources issues and should help guide future deployments. The preferred 'on call' arrangements, notice to deploy, period of overseas deployment and shift length are all identified. This extended period of operations needs to be supported by planning and provision of rest cycles, food, temporary accommodation and rest areas for staff. The study also suggests that more emphasis should be placed on team selection and clarification of roles. While the majority felt that there was both adequate pay and adequate indemnity, further work clarifying this, based on national conditions of service should be, and are, being explored currently by the state based teams in Australia. Importantly, the deployment was viewed positively by team members who all stated they would volunteer again, which allows the development of an experienced cohort of team members.


Delusions and the Right Hemisphere: A Review of the Case for the Right Hemisphere as a Mediator of Reality-Based Belief.
Delusions are beliefs that remain fixed despite evidence that they are incorrect. Although the precise neural mechanism of delusional belief remains to be elucidated, there is a predominance of right-hemisphere lesions among patients with delusional syndromes accompanied by structural pathology, suggesting that right-hemisphere lesions, or networks with key nodes in the right hemisphere, may be playing a role. The authors discuss the potential theoretical basis and empiric support for a specific right-hemisphere role in delusion production, drawing on its roles in pragmatic communication; perceptual integration; attentional surveillance and anomaly/novelty detection; and belief updating.


Targeting ERK enhances the cytotoxic effect of the novel PI3K and mTOR dual inhibitor VS-5584 in preclinical models of pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease in urgent need of newer therapeutic modalities. Majority of patients with PDAC have mutations in KRAS, which unfortunately remains an ineffectual target. Our strategy here is to target KRAS downstream effectors PI3K and mTOR. In this study, we investigated the antitumor efficacy of the novel PI3K and mTOR dual inhibitor VS-5584 in PDAC. Our data shows that PI3K/mTOR dual inhibition causes ERK activation in all tested PDAC cell lines. Although the MEK inhibitor GSK1120212 could abrogate VS-5584-induced ERK activation, it did not substantially enhance cell death in all the cell lines tested. However, combination with ERK inhibitor SCH772984 not only mitigated VS-5584-induced ERK activation but also enhanced VS-5584-induced cell death. In a xenograft model of PDAC, we observed 28% and 44% tumor inhibition for individual treatment with VS-5584 and SCH772984, respectively, while the combined treatment showed superior tumor inhibition (80%) compared to vehicle control treatment. Our findings support the clinical development of VS-5584 and ERK inhibitor combination for PDAC treatment.


'We do not talk about it': Engaging youth in Malawi to inform adaptation of a mental health literacy intervention.
There is limited knowledge on how to tackle mental health problems among youth in Africa. Literature describing community engagement (CE) approaches in low/middle-income countries (LMICs) health research is sparse. CE with youth from LMICS can help steer and shape culturally relevant interventions for stigmatised topics like mental health, resulting in better healthcare experiences. We share our experience of engaging youth in Malawi through advocacy organisations to inform cultural adaptation of a mental health literacy intervention. Young people were recruited using social media from universities and community youth organisations in Malawi to participate in focus group discussions to help culturally adapt content of an existing mental health literacy intervention. Nine online focus groups with 44 individuals were conducted. Discussions involved views and experiences of mental health, including impact of the coronavirus pandemic. Discussions were recorded, transcribed verbatim and analysed using content analysis. Transcript analyses revealed a vicious cycle of poverty and mental health problems for youth in Malawi. Four key themes were identified, 1) poverty-related socioeconomic and health challenges, 2) no one talks about mental health, 3) lacking mental health support and 4) relationship issues. These themes fed into one another within this vicious cycle which perpetually and negatively impacted their lives. The coronavirus pandemic worsened socioeconomic issues, health challenges, mental health and substance use issues, and burden on Malawi's already weak mental health system. Findings suggest increasing untreated mental health burden among Malawi's youth. It highlights great need to address mental health literacy using existing community structures like educational settings to minimise burden on a weak health system. Online focus groups are an effective way of acquiring views from various young people in Malawi on mental health. This CE approach has grown our stakeholder network, strengthening potential for future CE activities and broader research dissemination.


Factors influencing property selection for conservation revolving funds.
Finding sustainable ways to increase the amount of private land protected for biodiversity is challenging for many conservation organizations. In some countries, organizations use revolving-fund programs, whereby land is purchased and then sold to conservation-minded owners under condition they enter into a conservation covenant or easement. The sale proceeds are used to purchase, protect, and sell additional properties, incrementally increasing the amount of protected private land. Because the effectiveness of this approach relies on selecting appropriate properties, we explored factors currently considered by practitioners and how these are integrated into decision making. We conducted exploratory, semistructured interviews with managers from each of the 5 major revolving funds in Australia. Responses indicated although conservation factors are important, financial and social factors are also highly influential. A major determinant was whether the property could be resold within a reasonable period at a price that replenishes the fund. To facilitate resale, often selected properties include the potential for the construction of a dwelling. Practitioners face with clear trade-offs between conservation, financial, amenity, and other factors in selecting properties and 3 main challenges: recovering the costs of acquisition, protection, and resale; reselling the property; and meeting conservation goals. Our findings suggest the complexity of these decisions may constrain revolving-fund effectiveness. Drawing from participant responses, we identified potential strategies to mitigate these risks, such as providing adequate recreational space without jeopardizing ecological assets. We suggest managers could benefit from a shared-learning and adaptive approach to property selection given the commonalities between programs. Understanding how practitioners deal with complex decisions in the implementation of revolving funds helps identify future research to improve the performance of this conservation tool.


Circulating Levels of Cathelicidin Antimicrobial Peptide (CAMP) Are Affected by Oral Lipid Ingestion.
Obesity and related diseases are among the main public health issues in the western world. They are thought to be caused by a state of chronic, low-grade inflammation. Cathelicidin antimicrobial peptide (CAMP) was recently discovered to be expressed and secreted by adipocytes. Representing a novel immunomodulatory adipokine, CAMP might play an important role in the complex interaction between metabolism and inflammation. In a cohort of 80 volunteers, serum samples were collected prior to, and 2 h, 4 h, and 6 h after, oral lipid ingestion. CAMP, fatty acid binding proteins 2 and 4 (FABP-2/-4), and dipeptidylpeptidase-4 (DPP-4) serum concentrations were measured via ELISA. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were treated with free fatty acids, and gene expression levels of CAMP, FABP-4, and DPP-4 were quantified by RT-PCR. The mean base-line CAMP serum concentration was 55.78 ± 29.26 ng/mL, with a range of 10.77-146.24 ng/mL. Interestingly, CAMP serum levels were positively correlated with LDL cholesterol, but negatively correlated with HDL cholesterol and adiponectin. Men exhibited higher CAMP serum concentrations than women, an effect apparently linked to oral contraception in the majority of female participants. In both genders, CAMP serum concentrations significantly decreased in a stepwise manner 4 h and 6 h after oral lipid ingestion. This decline was paralleled by a rise of serum bile acid and triglyceride levels upon lipid ingestion. In human SGBS adipocytes, treatment with free fatty acids did not affect CAMP gene expression, but increased FABP-4 gene expression. In conclusion, systemic levels of the antimicrobial peptide and novel adipokine CAMP are significantly decreased upon oral lipid ingestion. While this decline might be linked to the simultaneous increase in bile acids, the underlying mechanisms remain to be elucidated. Furthermore, CAMP might indicate a putative novel cardiovascular biomarker of both inflammatory and metabolic relevance in metaflammation and adipose inflammation.


Opioid peptides modulate immune functions. A review.
In the past few years it has become evident that neuropeptides may be direct mediators in the modulation of the immune response and the unspecific defense by the brain. Lymphocytes have been thought to have opioid receptors and to respond to opioids with an increase in blastogenesis, cytotoxicity and factor release. Lymphocytes are said to release various neuropeptides. Furthermore, there are some unexplained effects of morphine on the immune system and of the immune system on morphine withdrawal. The purpose of this paper is to review what has been previously published in this field. The well established modulation of phagocyte functions by opioids will only be scanned.


Insulin sensitivity and the effects of antihypertensive agents: implications for the treatment of hypertension in the patient with diabetes mellitus.
It is now well established that non-insulin dependent diabetes mellitus is characterized by insulin resistance. Independent data have suggested that essential hypertension also is associated with abnormal glucose tolerance and an impairment of insulin action. These observations have led to the hypothesis that insulin resistance and/or hyperinsulinaemia may provide a common pathophysiological basis for the high concordance of these two diseases in many individuals. The relationship between insulin resistance, diabetes and hypertension assumes additional importance when one considers that many antihypertensive medications may impair insulin sensitivity or insulin secretion, thus leading to a further impairment of glucose tolerance or deterioration of glycaemic control. In the present review, the epidemiological and pathophysiological evidence supporting this hypothesis will be examined and the implications for treating hypertension in the patient with diabetes will be discussed.


[Treatment of arterial hypertension in children].
Hypertension in children is divided in 2 groups: primary hypertension and the secondary forms which are more severe and mostly due to kidney diseases. The medical management of hypertension includes non pharmacological intervention (diet, exercise, life-style) and pharmacological agents. The children with primary and mild hypertension may need only non pharmacological strategies. The main pharmacological agents used are: diuretics, vasodilators, sympathetic blockers, centrally acting agents, converting enzyme inhibitors. Except for hypertensive emergencies, the management of children with hypertension is facilitated by a stepped-care titration approach. Step 1: beta adrenergic blockers or vaso-dilators; step 2: combine beta adrenergic blockers with vaso-dilators or with diuretics or converting enzyme inhibitors alone; step 3: combine converting enzyme inhibitors with vaso-dilators and/or diuretics and/or beta adrenergic blockers; step 4: drugs include minoxidil, prazosin, labetalol.


Epidemiology and burden of sepsis acquired in hospitals and intensive care units: a systematic review and meta-analysis.
Sepsis is recognized as a global public health problem, but the proportion due to hospital-acquired infections remains unclear. We aimed to summarize the epidemiological evidence related to the burden of hospital-acquired (HA) and ICU-acquired (ICU-A) sepsis. We searched MEDLINE, Embase and the Global Index Medicus from 01/2000 to 03/2018. We included studies conducted hospital-wide or in intensive care units (ICUs), including neonatal units (NICUs), with data on the incidence/prevalence of HA and ICU-A sepsis and the proportion of community and hospital/ICU origin. We did random-effects meta-analyses to obtain pooled estimates; inter-study heterogeneity and risk of bias were assessed. Of the 13,239 studies identified, 51 met the inclusion criteria; 22 were from low- and middle-income countries. Twenty-eight studies were conducted in ICUs, 13 in NICUs, and ten hospital-wide. The proportion of HA sepsis among all hospital-treated sepsis cases was 23.6% (95% CI 17-31.8%, range 16-36.4%). In the ICU, 24.4% (95% CI 16.7-34.2%, range 10.3-42.5%) of cases of sepsis with organ dysfunction were acquired during ICU stay and 48.7% (95% CI 38.3-59.3%, range 18.7-69.4%) had a hospital origin. The pooled hospital incidence of HA sepsis with organ dysfunction per 1000 patients was 9.3 (95% CI 7.3-11.9, range 2-20.6)). In the ICU, the pooled incidence of HA sepsis with organ dysfunction per 1000 patients was 56.5 (95% CI 35-90.2, range 9.2-254.4) and it was particularly high in NICUs. Mortality of ICU patients with HA sepsis with organ dysfunction was 52.3% (95% CI 43.4-61.1%, range 30.1-64.6%). There was a significant inter-study heterogeneity. Risk of bias was low to moderate in ICU-based studies and moderate to high in hospital-wide and NICU studies. HA sepsis is of major public health importance, and the burden is particularly high in ICUs. There is an urgent need to improve the implementation of global and local infection prevention and management strategies to reduce its high burden among hospitalized patients.


Facile Synthesis of Unsolvated Alkali Metal Octahydrotriborate Salts MB3 H8 (M=K, Rb, and Cs), Mechanisms of Formation, and the Crystal Structure of KB3 H8.
A facile synthesis of heavy alkali metal octahydrotriborates (MB3 H8 ; M=K, Rb, and Cs) has been developed. It is simply based on reactions of the pure alkali metals with THF⋅BH3 , does not require the use of electron carriers or the addition of other reaction media such as mercury, silica gel, or inert salts as for previous procedures, and delivers the desired products at room temperature in very high yields. However, no reactions were observed when pure Li or Na was used. The reaction mechanisms for the heavy alkali metals were investigated both experimentally and computationally. The low sublimation energies of K, Rb, and Cs were found to be key for initiation of the reactions. The syntheses can be carried out at room temperature because all of the elementary reaction steps have low energy barriers, whereas reactions of LiBH4 /NaBH4 with THF⋅BH3 have to be carried out under reflux. The high stability and solubility of KB3 H8 were examined, and a crystal structure thereof was obtained for the first time.


[Endothelium-derived relaxing factor(s): endogenous nitrates in the circulation?].
Endothelial cells release a potent vasodilator which activates guanylate cyclase and thereby induces relaxation of vascular smooth muscle cells. The so-called endothelium-derived relaxing factor (EDRF) is released by acetylcholine, local and circulating hormones, and substances released from aggregating platelets or formed during activation of the coagulation cascade. Nitric oxide (NO) probably accounts for the factor's activity. Thus, endothelial cells produce endogenous nitrates causing vasodilatation and inhibition of platelet adhesion and aggregation. Under physiological conditions, EDRF may play a role in the prevention of vasospasm and thrombosis. On the other hand, the impairment of endothelial regulatory mechanisms in atherosclerosis and hypertension may be involved in the pathogenesis of vascular occlusion and thereby of myocardial infarction, stroke and peripheral vascular disease.


[Depression in pregnancy: focus on the safety of antidepressant drugs.]
Antepartum depression, frequently in comorbidity with anxiety disorders, is a severe psychopathological condition frequently reported in pregnancy and in many cases associated with obstetric and neonatal complications and potential negative consequences on child neurodevelopment. However, the pharmacological treatment of depression, during pregnancy generates a lot of concerns about the risks of such treatment for the fetus development and the neonatal health. The aim of this review is to present a selection of the latest international literature including recent original studies, systematic reviews, meta-analyses and recommendations from the guidelines, both on the risks of an untreated depressive disorders and on the risk of antidepressant therapy during gestation with drugs belonging to the SSRI and SNRI (SRI) class. An updated information of the recent risk-benefit data of these drug treatments in women with affective disorders in pregnancy may actually enable better and more conscious management of these disorders, not only for those working in the mental health field but also for general practitioners and those of other medical specialties.


Long COVID as a functional somatic symptom disorder caused by abnormally precise prior expectations during Bayesian perceptual processing: A new hypothesis and implications for pandemic response.
This review proposes a model of Long-COVID where the constellation of symptoms are in fact genuinely experienced persistent physical symptoms that are usually functional in nature and therefore potentially reversible, that is, Long-COVID is a somatic symptom disorder. First, we describe what is currently known about Long-COVID in children and adults. Second, we examine reported "Long-Pandemic" effects that create a risk for similar somatic symptoms to develop in non-COVID-19 patients. Third, we describe what was known about somatization and somatic symptom disorder before the COVID-19 pandemic, and suggest that by analogy, Long-COVID may best be conceptualized as one of these disorders, with similar symptoms and predisposing, precipitating, and perpetuating factors. Fourth, we review the phenomenon of mass sociogenic (functional) illness, and the concept of nocebo effects, and suggest that by analogy, Long-COVID is compatible with these descriptions. Fifth, we describe the current theoretical model of the mechanism underlying functional disorders, the Bayesian predictive coding model for perception. This model accounts for moderators that can make symptom inferences functionally inaccurate and therefore can explain how to understand common predisposing, precipitating, and perpetuating factors. Finally, we discuss the implications of this framework for improved public health messaging during a pandemic, with recommendations for the management of Long-COVID symptoms in healthcare systems. We argue that the current public health approach has induced fear of Long-COVID in the population, including from constant messaging about disabling symptoms of Long-COVID and theorizing irreversible tissue damage as the cause of Long-COVID. This has created a self-fulfilling prophecy by inducing the very predisposing, precipitating, and perpetuating factors for the syndrome. Finally, we introduce the term "Pandemic-Response Syndrome" to describe what previously was labeled Long-COVID. This alternative perspective aims to stimulate research and serve as a lesson learned to avoid a repeat performance in the future.


Supportive Noninvasive Tool for the Diagnosis of Breast Cancer Using a Thermographic Camera as Sensor.
Breast cancer is the leading disease in incidence and mortality among women in developing countries. The opportune diagnosis of this disease strengthens the survival index. Mammography application is limited by age and periodicity. Temperature is a physical magnitude that can be measured by using multiple sensing techniques. IR (infrared) thermography using commercial cameras is gaining relevance in industrial and medical applications because it is a non-invasive and non-intrusive technology. Asymmetrical temperature in certain human body zones is associated with cancer. In this paper, an IR thermographic sensor is applied for breast cancer detection. This work includes an automatic breast segmentation methodology, to spot the hottest regions in thermograms using the morphological watershed operator to help the experts locate the tumor. A protocol for thermogram acquisition considering the required time to achieve a thermal stabilization is also proposed. Breast thermograms are evaluated as thermal matrices, instead of gray scale or false color images, increasing the certainty of the provided diagnosis. The proposed tool was validated using the Database for Mastology Research and tested in a voluntary group of 454 women of different ages and cancer stages with good results, leading to the possibility of being used as a supportive tool to detect breast cancer and angiogenesis cases.


An effective method for studying intermolecular interactions in binary liquids with hydrogen bonds; FTIR spectra and ab initio calculations in the N-methylformamide-methanol system.
Molecular complexes in methanol (MeOH)-N-methylformamide (NMF) mixtures were studied based on their FTIR-ATR spectra, to which two methods of analysis were applied: factor analysis and a quantitative version of the difference-spectra method. The mean composition of a complex between NMF and MeOH molecules over the whole range of mixture compositions was determined. Absorbing species differentiated with regard to the interaction energies of the carbonyl oxygen with methanol molecules were recognized in both compositional regions with a marked excess of one component. Possible structures for complexes of various stoichiometries were optimized by ab initio calculations in the gas phase and both liquid NMF and MeOH using the polarizable continuum model (PCM). Thermodynamic functions calculated for the optimized structures were used to find the most stable structure for each stoichiometry. Individuals distinguished by the spectral analysis were assigned to the complexes of definite composition, and a linear correlation between the positions of the carbonyl group absorption and the total interaction energies of the complexes was found. The results of the spectral analysis of the NMF-MeOH mixtures were compared to those we obtained previously for similar binary systems, i.e., mixtures of methanol and formamide (FA) or N,N-dimethylformamide (DMF). It was shown that the factor analysis applied to the infrared spectra is an effective method for distinguishing molecular complexes with different polarizations of component molecules and allows for the detection of even weak intermolecular interactions and low-concentration species. Combined with the difference-spectra method, factor analysis provides a comprehensive picture of intermolecular interactions in binary mixtures.


Identification of a phosphorylated form of phosphoenolpyruvate carboxykinase from the yeast Saccharomyces cerevisiae.
A phosphoprotein of 65 kDa, as determined by SDS-gel electrophoresis, has been isolated from yeast crude extracts. This phospho form copurifies with phosphoenolpyruvate carboxykinase in the enzyme purification procedure worked out in our laboratory (Tortora, P., Hanozet, G.M. and Guerritore, A. (1985) Anal. Biochem. 144, 179-185). Moreover, both proteins bind strongly to 5'AMP-Sepharose 4B in the presence of Mn2+, whereas a substantially lower binding occurs if Mn2+ is replaced by Mg2+. This binding pattern is consistent with the well-known Mn2+-dependence of yeast phosphoenolpyruvate carboxykinase. These data suggest that the 65-kDa protein might be a phosphorylation product of the native enzyme. Furthermore, although the phospho form is not immunoprecipitated by anti-phosphoenolpyruvate carboxykinase antibodies, addition of Protein A-Sepharose CL-4B to crude extracts preincubated with the antibodies results in the binding to the resin of the phospho form, thus providing immunological evidence for its identification as a modified form of native enzyme. The same 65-kDa phosphoprotein is detectable in extracts from cells grown in the presence of [32P]Pi, as well as in cell extracts incubated with [gamma-32P]ATP. Moreover, digestion of the phosphoprotein with BrCN or with Staphylococcus aureus V8 proteinase, yields two and three fragments, respectively, which appear parallel to digestion products of phosphoenolpyruvate carboxykinase, again supporting the proposed identification. Finally, analysis of the phosphorylated amino acids in the 65-kDa protein shows that phosphoserine is the only labelled phosphoamino acid.


Improved reporting of DNA methylation data derived from studies of the human placenta.
Epigenetic variation is increasingly hypothesized as a mechanism underlying the effect of the in utero environment on long-term postnatal health; however, there is currently little clear data to support this in humans. A number of biological and technical factors provide challenges for the design of clinical epigenetic studies: from the type of cells or tissues that are available to the large range of predicted confounders that may impact findings. The human placenta, in addition to other neonatal tissues and whole blood, is commonly sampled for the study of epigenetic modifications. However there is little conformity for the most appropriate methods for study design, data analysis, and importantly, data interpretation. Here we present general recommendations for the reporting of DNA methylation in biological samples, with specific focus on the placenta. We outline key guidelines for: (1) placental sampling, (2) data analysis and presentation, and (3) interpretation of DNA methylation data. We emphasize the need to consider methodological noise, increase statistical power and to ensure appropriate adjustment for biological covariates. Finally, we highlight that epigenetic changes may be non-pathological and not necessarily translate into disease-associated changes. Improved reporting of DNA methylation data will be critical to identify epigenetic-based effects and to better understand the full phenotypic impact of these widely-reported epigenomic changes.


Be aware of wood in the knee.
The authors report a case of a 7-year-old boy who sustained a penetrating injury of a splinter of wood to the knee. Arthroscopic examination, removal of visualised foreign material and washout did not alleviate the symptoms of pain and swelling in its entirety. Microbiology cultures also failed to determine the cause of the on-going symptoms. Five days later, the patient underwent a mini arthrotomy through a lateral incision, which demonstrated synovitis, and removal of the remaining embedded foreign body from the lateral condyle. Although the authors advocate arthroscopy as the surgeon's first choice for removal of a foreign body from the knee, a mini-arthrotomy should also be considered to facilitate superior visualisation and easier instrumentation to remove embedded foreign bodies.


Photoresponsive Dithienylethene-Containing Tris(8-hydroxyquinolinato)aluminum(III) Complexes with Photocontrollable Electron-Transporting Properties for Solution-Processable Optical and Organic Resistive Memory Devices.
The rational design of a new class of photoresponsive tris(8-hydroxyquinolinato)aluminum(III) (Alq3) complexes has been developed. By incorporating the photochromic dithienylethene units with different peripheral heterocycles into the Alq3 framework, the photochromic properties as well as photoswitching efficiency can be readily modulated, through effective photocyclization of the Al(III) complex. Such intrinsic photochromic behavior leads to the unprecedented enhancement in the electron-transporting properties as demonstrated by the as-fabricated electron-only device, rendering the realization of photoswitchable electron mobility. In addition, one of these complexes is capable of serving as an active layer for solution-processable resistive memory devices. Photocontrollable memory performance has been achieved with a binary memory behavior, with high ON/OFF ratio and long retention time. This work represents not only the first example of photoresponsive Alq3-based electron-transporting materials but also the solution-processable Alq3-based optical and resistive memory devices with photocontrollable performance.


Measurement of ADAMTS13.
ADAMTS13, encoded on chromosome 9q34, is a member of the ADAMTS (a disintegrin and metalloprotease with thrombospondin type 1 motif) metalloprotease family, containing the common domain structure of (from the amino terminus) signal peptide, propeptide, reprolysin type metalloprotease, thrombospondin type 1 motif, cysteine-rich region, and spacer domain. ADAMTS13 cleaves von Willebrand factor (VWF) in a shear stress dependent manner. Deficiency of the enzyme causes the platelet aggregation of thrombotic thrombocytopenic purpura (TTP). Inhibitory antibodies of ADAMTS13 are detected in patients with acquired TTP, while homozygous or double heterozygous mutations of the ADAMTS13 gene cause the hereditary form of the disease 1. Targeting of the ADAMTS13 gene by recombinant technology has reproduced the phenotype of human TTP in ADAMTS13-null mice 2. Despite these advances, intense controversy and confusion persist regarding the role of ADAMTS13 assays in the diagnosis of TTP. This brief review highlights some of the contentious issues and proposes steps to improve the diagnostic value of ADAMTS13 assays.


Tumorigenicity of partial transformation mutants of Rous sarcoma virus.
Chicken embryo cells infected with partial transformation mutants of Rous sarcoma virus were tested for tumor-forming ability in chickens and in nude mice. Cells transformed by each of these partial transformation mutants display different combinations of transformation parameters. They therefore present a potentially favorable system for analyzing which properties of transformed cells are necessary for tumor formation. We found that the relative tumorigenicity of the virus mutants was generally similar in chickens and in nude mice, except that certain temperature-conditional mutants appeared to be sensitive to the differences in body temperature of the two experimental animals. (The body temperature of nude mice is 4 to 5 degrees C lower than that of chickens). Thus, the nude mouse appears to be a suitable system for testing the tumorigenicity of transformed chicken cells. Because mice are nonpermissive for Rous sarcoma virus infection and replication, it was possible to recover the transformed chicken cells from the tumors in this host and to determine what phenotypic changes they had undergone during tumor development. We also examined the relationship between various cellular properties of the virus-infected chicken cells in vitro and their tumorigenicity in nude mice. The combined results of these two studies indicated that anchorage independence and plasminogen activator production were highly correlated with the tumor-forming ability of these cells, whereas loss of fibronectin did not correlate with tumorigenicity. Furthermore, the inability of the least tumorigenic virus mutant to stimulate the phosphorylation of a 36,000-Mr target of pp60src raises the possibility that the 36,000-Mr protein plays a role in tumor formation.


Distortion of maximal elevator activity by unilateral premature tooth contact.
In four subjects the electrical activity in the anterior and posterior temporal and masseter muscles during maximal bite was recorded bilaterally with and without premature unilateral contact. Muscle activity was measured as the average level and the peak of the mean voltage with layers of strips of 0.05, 0.10, 0.15 and 2.0 mm, placed between first molars either on the left or the right side, and compared with the level of activity with undistrubed occlusion. Unilateral premature contact caused a significant asymmetry of action in all muscles under study with stronger activity ipsilaterally. With increasing thickness of the overlay the mean voltage decreased in parallel on both sides. We suggest that the asymmetry was caused by larger spindle afferent activity on the ipsilateral as compared to the contralateral side, and that the all-over decrease of muscle activity was due to a gradual reduction of activity from periodontal pressoreceptors.


Use of Crystallography and Molecular Modeling for the Inhibition of the Botulinum Neurotoxin A Protease.
Botulinum neurotoxins (BoNTs) are extremely toxic and have been deemed a Tier 1 potential bioterrorism agent. The most potent and persistent of the BoNTs is the "A" serotype, with strategies to counter its etiology focused on designing small-molecule inhibitors of its light chain (LC), a zinc-dependent metalloprotease. The successful structure-based drug design of inhibitors has been confounded as the LC is highly flexible with significant morphological changes occurring upon inhibitor binding. To achieve greater success, previous and new cocrystal structures were evaluated from the standpoint of inhibitor enantioselectivity and their effect on active-site morphology. Based upon these structural insights, we designed inhibitors that were predicted to take advantage of π-π stacking interactions present in a cryptic hydrophobic subpocket. Structure-activity relationships were defined, and X-ray crystal structures and docking models were examined to rationalize the observed potency differences between inhibitors.


Regulation of cargo transfer between ESCRT-0 and ESCRT-I complexes by flotillin-1 during endosomal sorting of ubiquitinated cargo.
Ubiquitin-dependent sorting of membrane proteins in endosomes directs them to lysosomal degradation. In the case of receptors such as the epidermal growth factor receptor (EGFR), lysosomal degradation is important for the regulation of downstream signalling. Ubiquitinated proteins are recognised in endosomes by the endosomal sorting complexes required for transport (ESCRT) complexes, which sequentially interact with the ubiquitinated cargo. Although the role of each ESCRT complex in sorting is well established, it is not clear how the cargo is passed on from one ESCRT to the next. We here show that flotillin-1 is required for EGFR degradation, and that it interacts with the subunits of ESCRT-0 and -I complexes (hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and Tsg101). Flotillin-1 is required for cargo recognition and sorting by ESCRT-0/Hrs and for its interaction with Tsg101. In addition, flotillin-1 is also required for the sorting of human immunodeficiency virus 1 Gag polyprotein, which mimics ESCRT-0 complex during viral assembly. We propose that flotillin-1 functions in cargo transfer between ESCRT-0 and -I complexes.


Thermostaphylospora grisealba gen. nov., sp. nov., isolated from mushroom compost and transfer of Thermomonospora chromogena Zhang et al. 1998 to Thermostaphylospora chromogena comb. nov.
A novel thermophilic actinomycete, designated strain 3-12XT, was isolated from mushroom compost in Guangxi University, Nanning, China. The novel isolate contained meso-diaminopimelic acid as the diagnostic diamino acid and the whole-cell sugars were glucose and ribose. The predominant menaquinones were MK-9(H4) and MK-9(H6). The polar phospholipids were diphosphatidylglycerol, hydroxy-phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannoside, ninhydrin-positive phosphoglycolipids and glycolipids. Major fatty acids were so-C16 : 0 and C17 : 0. The G+C content of the genomic DNA was 74.6 %. The 16S rRNA gene sequence analysis showed that the closest phylogenetic neighbour of strain 3-12XT was Thermomonospora chromogena ATCC 43196T (97.0 %), other closely related strains all belonged to the family Streptosporangiaceae and showed more than 6 % divergence. The chemotaxonomic characteristics of strain 3-12XT were significantly different from Thermomonospora chromogena ATCC 43196T and DNA-DNA hybridization showed low relatedness (48.6-55.6 %) between them, so they should be different species. Thermomonospora chromogena was removed from the genus Thermomonospora by Zhang et al. 1998 on the basis of phylogenetic, chemotaxonomic and phenotypic evidence, but its taxonomic position remains uncertain. Based on the phenotypic and phylogenetic data, strain 3-12XT represents a novel species in a new genus in the family Streptosporangiaceae. The name Thermostaphylospora griseoalba gen. nov., sp. nov. is proposed. The type strain of Thermostaphylospora grisealba is 3-12XT (=DSM 46781T=CGMCC 4.7160T). We also propose transferring Thermomonospora chromogenaZhang et al. 1998 to Thermostaphylospora chromogena comb. nov. (type strain ATCC 43196T=JCM 6244T).


The economic burden of low back pain: a review of studies published between 1996 and 2001.
Low back pain (LBP) poses an economic burden to society, mainly in terms of the large number of work days lost by a small percentage of patients who develop chronic LBP. The object of this review is to gain a better understanding of the societal costs of LBP and to see whether current clinical management follows evidence-based guidelines and is economically attractive, by reviewing studies on LBP with economic implications. To this end, the Medline database was searched between 1996 and 2001 using appropriate keywords, broadly defined. A total of 372 abstracts were screened and paper copies of 73 potentially relevant articles were obtained. It was found that the cost of LBP illness was high and was comparable to other disorders such as headache, heart disease, depression or diabetes, but actual cost estimates varied depending on the costing methodology employed. A small percentage of patients with chronic LBP accounts for a large fraction of the costs. Excessive and inappropriate use of diagnostic or therapeutic services can be documented but varied by region and provider type. Management according to evidence-based guidelines was not necessarily economically attractive. Interventions for acute or chronic LBP failed to show economic benefits, but demonstrated modest clinical benefits, which suggested a weak relationship between clinical and economic outcomes. The conclusion was that common definitions and costing methodologies need to be found to gain a better understanding of the true costs to society and to make studies comparable. A better definition is needed for the type for patient with LBP for whom therapeutic management is most likely to have a long-lasting economic benefit.


Furfural-cysteine model reaction in food grade nonionic oil/water microemulsions for selective flavor formation.
The thermal reaction between cysteine and furfural was investigated at 65 degrees C in five-component food grade oil/water (O/W) microemulsions of R-(+)-limonene/ethanol, EtOH/water/propylene glycol, PG/Tween 60 as apart of a systematic study on the generation of aroma compounds by utilizing structured W/O and O/W fluids. The furfural-cysteine reaction led to the formation of unique aroma compounds such as 2-furfurylthiol (FFT), 2-(2-furanyl)thiazolidine (main reaction product), 2-(2-furanyl)thiazoline, and N-(2-mercaptovinyl)-2-(2-furanyl)thiazolidine. These products were determined and characterized by GC-MS. Enhancement in flavor formation is termed "microemulsion catalysis". The chemical reaction occurs preferably at the interfacial film, and therefore a pseudophase model was assumed to explain the enhanced flavor formation. The product internal composition is dictated by process conditions such as temperature, time, pH, and mainly the nature of the interface. Increasing water/PG ratio leads to a dramatic increase in the initial reaction rate (V(0)). V(0) increased linearly as a function of the aqueous phase content, which could be due to the increase in the interfacial concentration of furfural. Microemulsions offer a new reaction medium to produce selective aroma compounds and to optimize their formation.


Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau.
Microtubule-associated protein 2c (MAP2c) is involved in neuronal development and is less characterized than its homolog Tau, which has various roles in neurodegeneration. Using NMR methods providing single-residue resolution and quantitative comparison, we investigated molecular interactions important for the regulatory roles of MAP2c in microtubule dynamics. We found that MAP2c and Tau significantly differ in the position and kinetics of sites that are phosphorylated by cAMP-dependent protein kinase (PKA), even in highly homologous regions. We determined the binding sites of unphosphorylated and phosphorylated MAP2c responsible for interactions with the regulatory protein 14-3-3ζ. Differences in phosphorylation and in charge distribution between MAP2c and Tau suggested that both MAP2c and Tau respond to the same signal (phosphorylation by PKA) but have different downstream effects, indicating a signaling branch point for controlling microtubule stability. Although the interactions of phosphorylated Tau with 14-3-3ζ are supposed to be a major factor in microtubule destabilization, the binding of 14-3-3ζ to MAP2c enhanced by PKA-mediated phosphorylation is likely to influence microtubule-MAP2c binding much less, in agreement with the results of our tubulin co-sedimentation measurements. The specific location of the major MAP2c phosphorylation site in a region homologous to the muscarinic receptor-binding site of Tau suggests that MAP2c also may regulate processes other than microtubule dynamics.


Is the MDS-UPDRS a Good Screening Tool for Detecting Sleep Problems and Daytime Sleepiness in Parkinson's Disease?
Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has separate items for measuring sleep problems (item 1.7) and daytime sleepiness (1.8). The aim of our study was to evaluate the screening sensitivity and specificity of these items to the PD Sleep Scale 2nd version (PDSS-2) and Epworth Sleepiness Scale (ESS). In this nationwide, cross-sectional study 460 PD patients were enrolled. Spearman's rank correlation coefficients were calculated between the individual items, domains, and the total score of PDSS-2 and item 1.7 of MDS-UPDRS. Similarly, the items and the total score of ESS were contrasted to item 1.8 of MDS-UPDRS. After developing generalized ordinal logistic regression models, the transformed and observed scores were compared by Lin's Concordance Correlation Coefficient. Only item 3 difficulties staying asleep and the "disturbed sleep" domain of PDSS-2 showed high correlation with "sleep problems" item 1.7 of the MDS-UPDRS. Total score of PDSS-2 had moderate correlation with this MDS-UPRDS item. The total score of ESS showed the strongest, but still moderate, correlation with "daytime sleepiness" item 1.8 of MDS-UPDRS. As intended, the MDS-UPDRS serves as an effective screening tool for both sleep problems and daytime sleepiness and identifies subjects whose disabilities need further investigation.


[Gynecologic examination, a role-playing for two].
Although pelvic examination (PE) is a common procedure in gynaecological practice, there is little discussion among gynaecologists about the decision-making process and the possible indications and contraindications. Moreover, examiners need to be aware that their approach and body language during PE will inevitably reflect their attitude toward women. At PE, there is tacit agreement between the examiner and the patient involving a cognitive restructuring of the situation. However, if memories of earlier experiences bearing some resemblance to the PE situation are aroused in the patient, and the emotions connected with them reactivated, she may become overwhelmed by the intensive reactions triggered. In such cases, the examiner needs to be able to recognise what is happening and provide the support the patient needs. Other responsibilities of the examiner at PE include recognising symptoms of post-traumatic stress reactions and vaginismus. In performing a young woman's first PE, the examiner's primary aim should be provide the experience; that PE is a benign procedure, unconnected with pain or distress; as the patient's experience at her first PE will inevitably influence all future examinations. Learning to perform a PE in such a way that it is beneficial to the patient in all these respects is an intricate and challenging task. However, experience with students and gynaecological teaching associates suggests that such skills can be taught and learned. The PE situation is charged with latent salubrious potential, which is usually insufficiently exploited.


Beta-sheet pore-forming peptides selected from a rational combinatorial library: mechanism of pore formation in lipid vesicles and activity in biological membranes.
In a previous report we described the selection of potent, beta-sheet pore-forming peptides from a combinatorial library designed to mimic membrane-spanning beta-hairpins (Rausch, J. M., Marks, J. R., and Wimley, W. C. (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 10511-10515). Here, we characterize their mechanism of action and compare the structure-function relationships in lipid vesicles to their activity in biological membranes. The pore-forming peptides bind to membrane interfaces and self-assemble into beta-sheets that cause a transient burst of graded leakage across the bilayers. Despite the continued presence of the structured peptides in the bilayer, at most peptide concentrations leakage is incomplete and ceases quickly after peptide addition with a deactivation half-time of several minutes. Molecules up to 3,000 Da escape from the transient pores, but much larger molecules do not. Fluorescence spectroscopy and quenching showed that the peptides reside mainly on the bilayer surface and are partially exposed to water, rather than in a membrane-spanning state. The "carpet" or "sinking raft" model of peptide pore formation offers a viable explanation for our observations and suggests that the selected pore-formers function with a mechanism that is similar to the natural pore-forming antimicrobial peptides. We therefore also characterized the antimicrobial and cytotoxic activity of these peptides. All peptides studied, including non-pore-formers, had sterilizing antimicrobial activity against at least some microbes, and most have low activity against mammalian cell membranes. Thus, the structure-function relationships that were apparent in the vesicle systems are similar to, but do not correlate completely with, the activity of the same peptides in biological membranes. However, of the peptides tested, only the pore-formers selected in the high-throughput screen have potent, broad-spectrum sterilizing activity against Gram-positive and Gram-negative bacteria as well as against fungi, while having only small lytic effects on human cells.


Comparative study with etidocaine and bupivacaine in epidural block.
Etidocaine 1% and bupivacaine 0.5% (both with adrenaline 5 mug/ml) have been compared in a double blind study in epidural analgesia. Time of onset, duration, recession of analgesia and intensity as well as frequency of motor blockade were recorded in a selected group of patients undergoing varicose vein stripping. The onset of action of etidocaine was more rapid. Duration, recession and intensity of analgesia were similar for the two drugs. The main difference between them was that etidocaine produced a higher frequency and greater intensity of motor blockade.


[Relation between Body Height and Combined Length of Manubrium and Mesosternum of Sternum Measured by CT-VRT in Southwest Han Population].
To establish the linear regression equation between body height and combined length of manubrium and mesostenum of sternum measured by CT volume rendering technique (CT-VRT) in southwest Han population. One hundred and sixty subjects, including 80 males and 80 females were selected from southwest Han population for routine CT-VRT (reconstruction thickness 1 mm) examination. The lengths of both manubrium and mesosternum were recorded, and the combined length of manubrium and mesosternum was equal to the algebraic sum of them. The sex-specific linear regression equations between the combined length of manubrium and mesosternum and the real body height of each subject were deduced. The sex-specific simple linear regression equations between the combined length of manubrium and mesostenum (x3) and body height (y) were established (male: y = 135.000+2.118 x3 and female: y = 120.790+2.808 x3). Both equations showed statistical significance (P < 0.05) with a 100% predictive accuracy. CT-VRT is an effective method for measurement of the index of sternum. The combined length of manubrium and mesosternum from CT-VRT can be used for body height estimation in southwest Han population.


Gold nanoparticles and cleavage-based dual signal amplification for ultrasensitive detection of silver ions.
Silver ion (Ag(+)) is a highly toxic heavy metal ion to fungi, viruses, bacteria, and animals. Therefore, Ag(+) monitoring in water or food resources has become extraordinarily important within the scope of human health. Here, we report a gold nanoparticles and enzyme cleavage-based dual signal amplification strategy for ultrasensitive detection of Ag(+) using electrochemical techniques. This sensing platform for Ag(+) has an extremely low detection limit of 470 fM, which also has satisfactory selectivity. Thus, it can be directly used in drinking water and lake water samples. Moreover, the strategy proposed in this work may have potential to be further developed as a generalized platform for the detection of other analytes by designing new DNA sequences for specific recognition.


Computational functions in biochemical reaction networks.
In prior work we demonstrated the implementation of logic gates, sequential computers (universal Turing machines), and parallel computers by means of the kinetics of chemical reaction mechanisms. In the present article we develop this subject further by first investigating the computational properties of several enzymatic (single and multiple) reaction mechanisms: we show their steady states are analogous to either Boolean or fuzzy logic gates. Nearly perfect digital function is obtained only in the regime in which the enzymes are saturated with their substrates. With these enzymatic gates, we construct combinational chemical networks that execute a given truth-table. The dynamic range of a network's output is strongly affected by "input/output matching" conditions among the internal gate elements. We find a simple mechanism, similar to the interconversion of fructose-6-phosphate between its two bisphosphate forms (fructose-1,6-bisphosphate and fructose-2,6-bisphosphate), that functions analogously to an AND gate. When the simple model is supplanted with one in which the enzyme rate laws are derived from experimental data, the steady state of the mechanism functions as an asymmetric fuzzy aggregation operator with properties akin to a fuzzy AND gate. The qualitative behavior of the mechanism does not change when situated within a large model of glycolysis/gluconeogenesis and the TCA cycle. The mechanism, in this case, switches the pathway's mode from glycolysis to gluconeogenesis in response to chemical signals of low blood glucose (cAMP) and abundant fuel for the TCA cycle (acetyl coenzyme A).


Optimal positive lymph node ratio showing the benefit of postoperative radiotherapy in pathologic N2 non-small cell lung cancer: an exploratory study using the Surveillance, Epidemiology, and End Results data.
This study aimed to identify the clinical parameters having the beneficial effect of postoperative radiotherapy (PORT) in pathologic N2 (pN2) non-small cell lung cancer (NSCLC) using the Surveillance, Epidemiology, and End Results (SEER) data. Among non-metastatic NSCLC patients in the SEER data, we included patients who diagnosed after 2002, who confirmed as pN2 after lobectomy or pneumonectomy, and who coded as underwent PORT or observation. Patients who survived less than 4 months of diagnosis were excluded in consideration of the perioperative mortality. After performing propensity score matching (PSM) on the selected patients, we compared PORT group with surgery alone group. We also performed exploratory subgroup analysis to find patients who could benefit from PORT. Among the selected 4,456 patients, 1,729 patients received PORT, and 2,727 patients did not. There was no survival benefit of PORT in all patients with pN2 disease (hazard ratio [HR] = 1.03, p = 0.5). In subgroup analyses, the patients with a positive lymph node (LN) ratio of 60%-80% showed the significant benefit of PORT (HR = 0.71, p = 0.002). PORT did not show the significant survival benefit in patients with pN2 disease after correcting the confoundedness in the SEER data. However, a specific range of LN ratios can be a potential indicator maximizing the survival benefit of PORT.


Experiences of advanced dementia care in seven European countries: implications for educating the workforce.
There is a paucity of robust research concerning the care experiences of peoplewith advanced dementia within Europe. It is essential to understand these experiences if weare to address care inequalities and create impactful dementia policies to improve servicesthat support individuals and enable family caring. To identify the strengths and weaknesses in daily life perceived by people with dementia and family caring across Europe by exemplifying experiences and the range of typical care settings for advanced dementia care in seven partner countries. Twenty two in-depth qualitative case studies were completed in seven European countries across a range of care settings considered typical within that country. Narrative accounts of care illuminated a unique set of experiences and highlighted what was working well (strengths or positive aspects) and not so well (weaknesses or negative aspects) for people with advanced dementia and family caring. A constant comparative method of analysis through thematic synthesis was used to identify the common themes. Eight key themes were identified; Early diagnosis, good coordination between service providers, future planning, support and education for carers, enabling the person with dementia to live thebest life possible and education on advanced dementia for professional and family caregiverswere all significant and recurring issues considered important for care experiences to bepositive. People with advanced dementia may have limited opportunities for self-realization and become increasingly reliant on the support of others to maximize their health and well-being. Careful attention must be given to their psychosocial well-being, living environment and family caring to enable them to live the best life possible. Building on what the case studies tell us about what works well, we discuss the potential for integrating the findings into interprofesional learning solutions for the professional workforce across Europe to champion practice-based change.


Diagnosis analysis of rectal function through using ensemble empirical mode decomposition-deep belief networks algorithm.
The rectal motility function can reflect a person's rectal health status. To diagnose the rectal motility function after artificial anal sphincter implantation, this paper proposes a rectal function diagnosis model based on ensemble empirical mode decomposition-deep belief networks (EEMD-DBNs). Because of the rectal pressure signals that are unstable and subjected to noise interferences, an EEMD framework based on EMD, which can reduce the effect of signal modal mixing, is proposed. EMD and EEMD were used to decompose the analog signal, respectively, and it was found that EEMD can significantly reduce the effect of mode aliasing. During the rectal pressure signal decomposition experiment, by analyzing the intrinsic mode functions generated by the signals from normal people and diseased patients, the rectal signals at these two different conditions can be well distinguished. Additionally, the DBN was introduced to perform deep learning to extract the multi-dimensional features of rectal signals and then output the classification results via using the top-level classifier, which can overcome the difficulties in extracting the rectal signal features. The results showed that, following the principle of balancing the diagnosis accuracy and model running speed, the best diagnosis performance was achieved when three restricted Boltzmann machines and five layers of DBN model were set, with the diagnosis rate of 85%. The diagnostic model used in this study can distinguish the signals between normal and abnormal rectal functions with accurate performance, thus providing the technical support for the recovery of the rectal motility function of artificial anal sphincter implanters.


Targeting Cash Transfers on the "Poorest of the Poor" in the Slums: How Well Did the Kenya's Older Persons Cash Transfer Programme Perform?
In resource poor environments, identifying those most in need of limited available resources is challenging. Kenya's older persons cash transfer programme (OPCT) targeted at the most poor used a 2-stage targeting process to identify beneficiaries, combining community-based selection with a proxy means-test. This paper investigates whether the process "correctly" identified targeted vulnerable older people in Nairobi's informal settlements and whether receipt of the OPCT resulted in an improvement in perceived financial wellbeing. Regression results show that individuals with greater need were covered under the OPCT. Using propensity score matching, the paper evidences that the OPCT improved subjective financial wellbeing among beneficiaries.


Abnormal levels of serum anti-elastin antibodies in patients with symptomatic carotid stenosis.
A correlation between the levels of antibodies to alpha-elastin (alpha-AEAb) and tropoelastin (tropo-AEAb) and the corresponding peptide concentration is found in human serum in health and disease. Serum elastin peptide and anti-elastin antibodies (AEAb) levels are age-related and vary with the stages of atherosclerotic vascular damage. This study aims to determine if elastin metabolism (assessed by the ratio of tropo-AEAb to alpha-AEAb) differs in patients with symptomatic carotid stenosis versus subjects with asymptomatic stenosis. Alpha-AEAb and tropo-AEAb were measured by ELISA in blood sera of 65 patients with ultrasound verified high-grade symptomatic carotid stenosis (resulting in stroke 1-7 days before measurement) compared to 51 patients with asymptomatic stenosis. Serum anti-alpha-elastin IgG levels are extremely increased in symptomatic versus asymptomatic carotid stenosis. The ratio of tropo-AEAb (reflecting elastin synthesis) to alpha-AEAb (a function of elastin degradation) was 3.7 in symptomatic stenosis versus 14.2 in asymptomatic stenosis (p<0.001). There is a significant difference in elastin metabolism in patients with symptomatic carotid stenosis versus asymptomatic stenosis. The ratio of tropo-AEAb to alpha-AEAb as an index of elastin synthesis/degradation proves useful in investigation of atherosclerotic lesions and may represent a new immunologic marker for carotid plaque destabilization.


[Time perception in depressed and manic patients].
To investigate the time perception in affective disorders by using neuropsychological tests and to try to elucidate its neurobiochemical mechanism. Using a time reproduction task, a comparative study was conducted for 28 depressive patients, 22 manic patients, and 26 age and education level matched healthy persons as healthy controls. Both depressive patients and manic patients are abnormal (P < 0.001), depressive patients over-reproduced the time interval than healthy controls (600 ms/delay 1 s: 1.6 +/- 0.6, P < 0.001; 600 ms/delay 5 s: 1.7 +/- 0.6, P < 0.001; 3 s/delay 1 s: 3.9 +/- 0.9, P < 0.001; 3 s/delay 5 s: 3.9 +/- 0.7, P < 0.001; 5 s/delay 1 s: 5.9 +/- 1.3, P < 0.001; 5 s/delay 5 s: 6.1 +/- 1.3, P < 0.001), yet manic patients under-reproduced the time interval (600 ms/delay 1 s: 0.7 +/- 0.2, P < 0.01; 600 ms/delay 5 s: 0.6 +/- 0.3, P < 0.001; 3 s/delay 1 s: 1.7 +/- 0.5, P < 0.001; 3 s/delay 5 s: 1.8 +/- 0.6, P < 0.001; 5 s/delay 1 s: 2.9 +/- 0.7, P < 0.001; 5 s/delay 5 s: 3.0 +/- 0.8, P < 0.001). The results of time reproduction task in patients were not related to age, education, duration of illness, number of admission (P > 0.05), but had some relation to severity of illness.And the results were positively correlated with the score of HAMD in depressive patients (six times: r = 0.44, 0.46, 0.73, 0.61, 0.55, 0.50, P < 0.05), but negatively with the score of BRMS in manic patients (six times: r = -0.57, -0.54, -0.71, -0.69, -0.80, -0.71, P < 0.05). Emotion will affect one's time perception. And the neurotransmitter in brain may participate in the processes of time perception.


Increase in the Culturable Cell Number of Escherichia coli during Recovery from Saline Stress: Possible Implication for Resuscitation from the VBNC State.
The change in colony-forming units (CFUs) in saline-stressed Escherichia coli cultures was examined. Exposure of E. coli cells to high saline stress decreased the number of CFUs significantly. When the culture was relieved from the stressful condition, the number of CFUs returned within 2 hr to the same level as before the stress. This recovery in the number of CFUs seemed to be independent of DNA synthesis and cell division, because the same phenomenon was also observed in the presence of nalidixic acid. However, the total cell number enumerated by microscopy was the same before and after relief from saline stress. This phenomenon was considered to be the result of the resuscitation of cells that had been in the VBNC state during saline stress. Our method, in which we examined CFU recovery in the presence of a DNA synthesis inhibitor, might be useful for further VBNC study.


[The dehydrogenation of butandiol by "vibrio parahaemolyticus" and other vibrios (author's transl)].
The butandiol dehydrogenase was examined in 64 vibrios isolated in Togo 1970/71. This enzyme was found in all of the not halophilic strains and in the species Vibrio alginolyticus, whereas the species V. parahaemolyticus exhibited as well dehydrating as not dehydrating strains. The butandiol dehydrogenase could be a good marker for epidemiologic analysis in characterizing V. parahaemolyticus strains isolated from different sources, especially if no antisera are available.


Effective dose and radiation risk under 640-slice abdominal computed tomography examination without contrast medium injection.
Medical imaging plays a crucial role in modern medicine. In order to provide fast and accurate medical diagnosis, computed tomography (CT) is a commonly used tool in radiological examinations, and 640-slice CT is the most advanced CT imaging modality. To evaluate the radiation dose and the risk under 640-slice abdominal CT examination. Examinations were performed using a 640-slice CT scanner on an Alderson-Rando anthropomorphic phantom. The used scanning acquisition parameters were the same as those used on abdominal examination without contrast medium injection in clinical practice. To measure the absorbed doses, optically stimulated luminescence dosimeters (OSLDs) were put into liver, stomach, bladder, gonads, colon, small intestine, bone marrow, and skin. According to the 1990 Recommendations of the International Commission on Radiological Protection (ICRP Publication 60), the calculated effective doses received from this examination were 0.90 mSv in males and 0.89 mSv in females. According to the 2007 Recommendations of the International Commission on Radiological Protection (ICRP Publication 103), the calculated effective dose received from this examination was 0.83 mSv in both sexes. Radiation doses obtained from the abdominal 640-slice CT examination are lower than the yearly cumulative doses received from natural radiation, revealing there is no deterministic effect and radiation risk is relatively low; therefore, this CT examination is considered safe.


Stromal cell-derived factor-1α and transforming growth factor-β1 synergistically facilitate migration and chondrogenesis of synovium-derived stem cells through MAPK pathways.
The clinical translation of tissue engineering methods is confined by the limited external cell sources, which is hopefully to be addressed by the cell guidance approach as cytokine-induced homing and differentiation of the patients' autologous cells. Synovium-derived stem cells (SDSCs) are a potent cell source for cartilage restoration due to its intrinsic proximity and tissue-specific chondrogenic capacity. In this study, stromal cell-derived factor-1α (SDF-1α) in combination with transforming growth factor β1 (TGF-β1) were used to induce SDSCs migration and chondrogenesis in vitro. The migration capacity was evaluated by transwell assay and for chondrogenic evaluation, the expression of Sox9, ACAN and COL2A1 were assessed by quantitative RT-PCR while the expression of sulfated GAG and collagen II were evaluated by Alcian Blue stain and immunohistochemistry respectively. Our data showed that SDF-1α/CXC chemokine receptor 4 (CXCR4) was involved in SDSCs migration through phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. Exogenous TGF-β1 enhanced SDF-1α-induced SDSCs migration in a concentration and time-dependent manner through CXCR4, evidenced as complete blockage by AMD3100, the CXCR4 antagonist and this effect was mediated by extracellular regulated protein kinases (ERK) activation. Moreover, the addition of SDF-1α augmented the TGF-β1-induced SDSCs chondrogenesis, evidenced by the increased pellet sizes and the expressions of COL 2A1, ACAN and Sox9. This effect was related to c-Jun N-terminal kinase (JNK) activation. Collectively, these results suggest that SDF-1α and TGF-β1 interacts with each other and synergistically enhance the SDSCs migration and chondrogenesis through MAPK pathways.


Endometrial vessel maturation in women exposed to levonorgestrel-releasing intrauterine system for a short or prolonged period of time.
Levonorgestrel-releasing intrauterine system (LNG-IUS), although inserted to reduce heavy menstruation, causes irregular early transient bleeding. The objective of the study was to document quantitative changes in endometrial vessels of short- (< or =3 months) and long-term (> or =12 months) LNG users. The area, density and maturation of endometrial vessels were quantified in 19 endometrial biopsies of women with LNG-IUS and in 10 normally ovulating patients during mid-luteal phase. Vessel maturation was evaluated by double immunostaining using anti-von Willebrand factor (endothelial cell marker) and anti-alpha Smooth Muscle Actin (vascular smooth muscle cells) antibodies. Vessel area, number and density were quantified with a novel computer-assisted image analysis system. Endometrium exposed to LNG-IUS for 1-3 months displayed a 11.5-fold increase in small naked vessel number. The partially mature vessel (alphaSMA partially positive) number increased six times. After long-term LNG-IUS treatment, the immature and partially mature vessel number remained four times higher than in the control group. Vessel area and density also increased dramatically in a time-dependent pattern with LNG-IUS use. Levonorgestrel affects blood vessel number, area, density and maturation in a time-dependent pattern that may explain the early transient increase in breakthrough bleeding with the LNG-IUS.


Prediction of occult neck disease in laryngeal cancer by means of a logistic regression statistical model.
The ability to accurately predict the presence of subclinical metastatic neck disease in clinically N0 patients with primary epidermoid cancer of the larynx would be of great value in determining whether to perform an elective neck dissection. We describe a statistical approach to estimating the probability of occult neck disease given pretreatment clinical parameters. A retrospective study was performed involving 736 clinically N0 patients with primary laryngeal cancer who were treated surgically with primary resection and ipsilateral neck dissection. Nodal involvement was determined histologically after surgical lymphadenectomy. A logistic regression model was used to derive an equation that calculated the probability of occult neck metastasis based on pretreatment T stage, tumor location, and histologic grade. The model has a sensitivity of 74%, a specificity of 87%, and can be entered into a programmable calculator.


Deprivation in London wards: mortality and unemployment trends in the 1980's.
"This paper describes the use of current estimates of population and economic activity for London's wards in developing small area social indicators. The particular focus is on changes in the spatial pattern of mortality and unemployment differences in the 1980s in relation to the wider incidence of deprivation in wards. A conditional model of change is developed for mortality and unemployment indices to assess whether spatial differences are widening over time and how far changes in these indices are linked to social class and deprivation. The evidence is of widening unemployment differences, and a slight widening in premature mortality."


The HIV care continuum among resident and non-resident populations found in venues in East Africa cross-border areas.
HIV care and treatment in cross-border areas in East Africa face challenges perhaps not seen to the same extent in other geographic areas, particularly for mobile and migrant populations. Here, we estimate the proportion of people with HIV found in these cross-border areas in each stage of the HIV care and treatment cascade, including the proportion who knows their status, the proportion on treatment and the proportion virally suppressed. Participants (n = 11,410) working or socializing in public places in selected East Africa cross border areas were recruited between June 2016 and February 2017 using the Priorities for Local AIDS Control Efforts method and administered a behavioural survey and rapid HIV test. This approach was designed to recruit a stratified random sample of people found in public spaces or venues in each cross border area. For participants testing positive for HIV, viral load was measured from dried blood spots. The proportion in each step of the cascade was estimated using inverse probability weights to account for the sampling design and informative HIV test refusals. Estimates are reported separately for residents of the cross border areas and non-residents found in those areas. Overall, 43% of participants with HIV found in cross-border areas knew their status, 87% of those participants were on antiretroviral therapy (ART), and 80% of participants on ART were virally suppressed. About 20% of people with HIV found in cross border areas were sampled outside their subdistrict or subcounty of residence. While both resident and non-resident individuals who knew their status were likely to be on ART (85% and 96% respectively), people on ART recruited outside their area of residence were less likely to be suppressed (64% suppressed; 95% CI: 43, 81) compared to residents (84% suppressed; 95% CI: 75, 93). People living in or travelling through cross-border areas may face barriers in learning their HIV status. Moreover, while non-residents were more likely to be on treatment than residents, they were less likely to be suppressed, suggesting gaps in continuity of care for people in East Africa travelling outside their area of residence despite timely initiation of treatment.


Childhood tuberculosis: out of control?
Because of the difficulty of confirming the diagnosis of childhood tuberculosis and because children do not make a significant contribution to the spread of tuberculosis, the burden of childhood tuberculosis in the world is uncertain. Several estimates make use of an arbitrary calculation assigning 10% of the tuberculosis burden to children. Available data linking the incidence of tuberculosis to the proportion of the tuberculosis caseload represented by children suggest an exponential rise in the proportion of the tuberculosis caseload caused by children as the tuberculosis incidence rises so that children may constitute nearly 40% of the caseload in certain high incidence communities. This review discusses the global burden of childhood tuberculosis and attempts to quantify this, the role of HIV/AIDS and tuberculosis in children, the problems this creates for diagnosis, and the occurrence of drug resistant tuberculosis in children. In the developing world, childhood tuberculosis is not under control, and, despite its importance as a child health problem, remains a neglected orphan disease.


Functional Implications of MicroRNAs in Crohn's Disease Revealed by Integrating MicroRNA and Messenger RNA Expression Profiling.
Crohn's disease (CD) is a debilitating inflammatory bowel disease (IBD) that emerges due to the influence of genetic and environmental factors. microRNAs (miRNAs) have been identified in the tissue and sera of IBD patients and may play an important role in the induction of IBD. Our study aimed to identify differentially expressed miRNAs and miRNAs with the ability to alter transcriptome activity by comparing inflamed tissue samples with their non-inflamed counterparts. We studied changes in miRNA-mRNA interactions associated with CD by examining their differential co-expression relative to normal mucosa from the same patients. Correlation changes between the two conditions were incorporated into scores of predefined gene sets to identify biological processes with altered miRNA-mediated control. Our study identified 28 miRNAs differentially expressed (p-values < 0.01), of which 14 are up-regulated. Notably, our differential co-expression analysis highlights microRNAs (i.e., miR-4284, miR-3194 and miR-21) that have known functional interactions with key mechanisms implicated in IBD. Most of these miRNAs cannot be detected by differential expression analysis that do not take into account miRNA-mRNA interactions. The identification of differential miRNA-mRNA co-expression patterns will facilitate the investigation of the miRNA-mediated molecular mechanisms underlying CD pathogenesis and could suggest novel drug targets for validation.


Functional connectivity and cognitive impairment in migraine with and without aura.
Several fMRI studies in migraine assessed resting state functional connectivity in different networks suggesting that this neurological condition was associated with brain functional alteration. The aim of present study was to explore the association between cognitive functions and cerebral functional connectivity, in default mode network, in migraine patients without and with aura, during interictal episodic attack. Twenty-eight migraine patients (14 without and 14 with aura) and 14 matched normal controls, were consecutively recruited. A battery of standardized neuropsychological test was administered to evaluate cognitive functions and all subjects underwent a resting state with high field fMRI examination. Migraine patients did not show abnormalities in neuropsychological evaluation, while, we found a specific alteration in cortical network, if we compared migraine with and without aura. We observed, in migraine with aura, an increased connectivity in left angular gyrus, left supramarginal gyrus, right precentral gyrus, right postcentral gyrus, right insular cortex. Our findings showed in migraine patients an alteration in functional connectivity architecture. We think that our results could be useful to better understand migraine pathogenesis.


Regulatory T cells induced by parasites and the modulation of allergic responses.
The inverse relationship between helminth infection and overt allergic reactivity has intrigued medical scientists for three decades. In the past 5 years, detailed epidemiological studies coupled with new experimental model approaches, have substantiated the negative effects of infection on allergic disease manifestation, and begun to provide mechanistic explanations for this fascinating interaction. Several key conclusions can now be drawn. First, the modulation of allergies, such as Th2-dependent pathologies, is not primarily through immune deviation (e.g. switching responsiveness to Th1), as helminth infections themselves drive strong Th2 responses. Second, helminth-infected hosts show similar levels of immune sensitisation to allergens as do uninfected counterparts, but the expression of overt allergic reactivity is suppressed. Third, the down-modulation of allergy in both human and experimental infections is consistent with the activity of T regulatory (Treg) cell populations, which suppress effector mechanisms of both Th1 and Th2 type.


Regulation of follistatin-like 3 expression by miR-486-5p modulates gastric cancer cell proliferation, migration and tumor progression.
Cancer development and progression can be regulated by the levels of endogenous factors. Gastric cancer is an aggressive disease state with poor patient prognosis, needing the development of new diagnostics and therapeutic strategies. We investigated the close association between follistatin-like 3 (FSTL3) and different cancers, and focused on its role in gastric cancer cell function. Using cancer bioinformatics, we found that FSTL3 expression is elevated in a large majority of the 33 cancers we analyzed in publicly available cancer databases. Elevated levels of FSTL3 is associated with poor patient prognosis in gastric cancer. In a comparison of normal gastric epithelial cells and gastric cancer cell lines, FSTL3 expression was consistently elevated in gastric cancer cells. Overexpression of FSTL3 promoted gastric cancer cell viability, proliferation and migration. Conversely, FSTL3 knockdown inhibits these cellular processes. Using bioinformatics, we found that the FSTL3 mRNA has a potential binding site in the 3'-UTR for a small microRNA, miR-486-5p. Further bioinformatics revealed significant negative correlation between FSTL3 and miR-486-5p levels. Using luciferase reporter constructs, we provide evidence that the 3'UTR from the FSTL3 mRNA can confer downregulation in the presence of miR-486-5p. These studies lead us to conclude that FSTL3 has oncogenic properties and increased expression of this gene product promotes gastric cancer development and progression.


Topological properties of bulk and bilayer 2M WS2: a first-principles study.
Recently discovered 2M phase of bulk WS2was observed to exhibit superconductivity with a critical temperature of 8.8 K, the highest reported among superconducting transition metal dichalcogenides. Also predicted to support protected surface states, it could be a potential topological superconductor. In the present study, we perform a detailed first-principles analysis of bulk and bilayer 2M WS2. We report a comprehensive investigation of the bulk phase, comparing structural and electronic properties obtained from different exchange correlation functionals to the experimentally reported values. By calculation of theZ2invariant and surface states, we give support for its non-trivial band nature. Based on the insights gained from the analysis of the bulk phase, we predict bilayer 2M WS2as a new two-dimensional topological material. We demonstrate its dynamical stability from first-principles phonon computations and present its electronic properties, highlighting the band inversions between the Wdand Spstates. By means ofZ2invariant computations and a calculation of the edge states, we show that bilayer 2M WS2exhibits protected, robust edge states. The broken inversion symmetry in this newly proposed bilayer also leads to the presence of Berry curvature dipole and resulting non-linear responses. We compute the Berry curvature distribution and the dipole as a function of Fermi energy. We propose that Berry curvature dipole signals, which are absent in the centrosymmetric bulk 2M WS2, can be signatures of the bilayer. We hope our predictions lead to the experimental realization of this as-yet-undiscovered two-dimensional topological material.


The filament lattice of striated muscle.
The filament lattice of striated muscle is an overlapping hexagonal array of thick and thin filaments within which muscle contraction takes place. Its structure can be studied by electron microscopy or X-ray diffraction. With the latter technique, structural changes can be monitored during contraction and other physiological conditions. The lattice of intact muscle fibers can change size through osmotic swelling or shrinking or by changing the sarcomere length of the muscle. Similarly, muscle fibers that have been chemically or mechanically skinned can be compressed with bathing solutions containing very large inert polymeric molecules. The effects of lattice change on muscle contraction in vertebrate skeletal and cardiac muscle and in invertebrate striated muscle are reviewed. The force developed, the speed of shortening, and stiffness are compared with structural changes occurring within the lattice. Radial forces between the filaments in the lattice, which can include electrostatic, Van der Waals, entropic, structural, and cross bridge, are assessed for their contributions to lattice stability and to the contraction process.


The peripheral antinociceptive effect of nalbuphine is associated with activation of ATP-sensitive K+ channels.
There is evidence that local peripheral administration of codeine and morphine produces antinociception through the activation of the ATP-sensitive K(+)-channel. Therefore we evaluated the participation of this channel in the antinociceptive action produced by nalbuphine in the formalin test. Female Wistar rats (160-200 g) were injected in the dorsal surface of the right hind paw with 50 microl of formalin (5%). Nociception was quantified as the number of flinches of the injected paw during 1 hr, whereas a reduction of the number of flinches was considered antinociception. Rats received a s.c. injection (50 microl) into the dorsal surface of the right hind paw of vehicle or increasing doses of nalbuphine (100-400 microg/paw) 20 min before formalin injection into the ipsilateral paw. To determine whether nalbuphine-induced peripheral antinociception was mediated by K(+)-channels, the effect of pretreatment (10 min before formalin injection) with the appropriate vehicle or the ATP-sensitive K(+)-channel inhibitor glibenclamide (25-100 microg/paw) on the antinociceptive effect induced by local peripheral nalbuphine (400 microg/paw) was assessed. Morphine was used as positive antinociceptive control. Local peripheral injection of nalbuphine produced a dose-dependent antinociception during both phases of the test. Local pretreatment with glibenclamide prevented nalbuphine-induced antinociception in a dose-dependent fashion in both phases of the test. Our data suggest that nalbuphine activates ATP-sensitive K(+)-channels in order to produce its peripheral antinociceptive effect.