Use of mesothelin as a marker for mesothelial cells in cytologic specimens.
Immunocytochemistry is often employed for the distinction between mesothelial cells and adenocarcinoma. Mesothelin has recently been reported to be expressed in reactive mesothelial cells and epithelioid mesotheliomas. The objective of this study is to determine the utility of mesothelin as marker for mesothelial cells in cytologic preparations. Thirty cell blocks were retrieved from the archives and immunostained with monoclonal antibody directed against mesothelin and calretinin. Heat-induced epitope retrieval technique was employed, and the immunostaining was accomplished using an automated stainer. These tissue blocks were from 35 patients (17 females and 18 males) with a median age of 64 years. Nine were benign effusions, 11 mesotheliomas, and 18 metastatic adenocarcinomas. The presence of any immunoreactivity, irrespective of level of intensity or percentage of cells, was considered positive for mesothelin expression. Follow up included correlation with pathology materials obtained at surgery and review of medical records. Mesothelin staining was positive in 7/9 benign cases, 8/11 mesotheliomas, and 8/18 adenocarcinomas. The difference of mesothelin expression between mesothelial cells and adenocarcinoma was statistically significant. For calretinin, all cases, except 2 malignant mesotheliomas and 3 adenocarcinomas, showed positive staining with calretinin. As a marker for mesothelial cells, the sensitivity and specificity of mesothelin were 73% and 55%, respectively, and the sensitivity and specificity of calretinin were 95% and 86%, respectively. Therefore, mesothelin is not a sensitive or a specific marker for mesothelial cells in cytologic specimens when compared with calretinin.


Persistent hepatitis B virus and HIV coinfections in dually humanized mice engrafted with human liver and immune system.
Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), remains a major medical problem. HBV has a high propensity for progressing to chronicity and can result in severe liver disease, including fibrosis, cirrhosis, and hepatocellular carcinoma. CHB patients frequently present with viral coinfection, including human immunodeficiency virus type (HIV) and hepatitis delta virus. About 10% of chronic HIV carriers are also persistently infected with HBV, which can result in more exacerbated liver disease. Mechanistic studies of HBV-induced immune responses and pathogenesis, which could be significantly influenced by HIV infection, have been hampered by the scarcity of immunocompetent animal models. Here, we demonstrate that humanized mice dually engrafted with components of a human immune system and a human liver supported HBV infection, which was partially controlled by human immune cells, as evidenced by lower levels of serum viremia and HBV replication intermediates in the liver. HBV infection resulted in priming and expansion of human HLA-restricted CD8+ T cells, which acquired an activated phenotype. Notably, our dually humanized mice support persistent coinfections with HBV and HIV, which opens opportunities for analyzing immune dysregulation during HBV and HIV coinfection, and preclinical testing of novel immunotherapeutics.


Familial polycystic ovaries: a genetic disease?
High resolution ultrasonography was used to establish the presence of polycystic ovaries (PCO) in 50 women with symptoms of polycystic ovary syndrome and in 17 women with congenital adrenal hyperplasia. One hundred and thirty-seven post-menarcheal, premenopausal female members of the families of these patients were scanned to assess the heredity of the condition. Familial PCO was found in 56 of the 61 pedigrees (92%) in which sufficient members were available for study. The frequency of PCO in the relatives of the patients with congenital adrenal hyperplasia was no different from that found in the main group. Twenty-four out of thirty-six (67%) mothers of probands and 45 out of 52 (87%) sisters of probands were affected. The segregation ratio (fraction of females affected) for all sibships was 107 out of 133 (80.5%). The volumes of the polycystic ovaries (mean 9.97 ml, 95% confidence limits (CL) +/- 0.75) were significantly different from those of the normal ovaries (mean 5.38 ml, 95% CL +/- 0.26) (P less than 0.0001), although there was no significant difference between the volumes of the ovaries of the probands and those of their affected relatives. Even after allowing for a high frequency of PCO in the general population (22%), the observed segregation ratios were significantly different from those predicted for autosomal dominant (P less than 10(-4)) and X-linked dominant (P = 0.0002) modes of inheritance. A number of mechanisms which might account for the observed segregation ratio are considered. These include meiotic drive due to a genetic segregation distorted, vertical transmission of an infective agent, and environmental factors, such as the effect of maternal androgen on gonadal development.


Online misinformation is linked to early COVID-19 vaccination hesitancy and refusal.
Widespread uptake of vaccines is necessary to achieve herd immunity. However, uptake rates have varied across U.S. states during the first six months of the COVID-19 vaccination program. Misbeliefs may play an important role in vaccine hesitancy, and there is a need to understand relationships between misinformation, beliefs, behaviors, and health outcomes. Here we investigate the extent to which COVID-19 vaccination rates and vaccine hesitancy are associated with levels of online misinformation about vaccines. We also look for evidence of directionality from online misinformation to vaccine hesitancy. We find a negative relationship between misinformation and vaccination uptake rates. Online misinformation is also correlated with vaccine hesitancy rates taken from survey data. Associations between vaccine outcomes and misinformation remain significant when accounting for political as well as demographic and socioeconomic factors. While vaccine hesitancy is strongly associated with Republican vote share, we observe that the effect of online misinformation on hesitancy is strongest across Democratic rather than Republican counties. Granger causality analysis shows evidence for a directional relationship from online misinformation to vaccine hesitancy. Our results support a need for interventions that address misbeliefs, allowing individuals to make better-informed health decisions.


Crystal structures of the Bacillus licheniformis BS3 class A beta-lactamase and of the acyl-enzyme adduct formed with cefoxitin.
The Bacillus licheniformis BS3 beta-lactamase catalyzes the hydrolysis of the beta-lactam ring of penicillins, cephalosporins, and related compounds. The production of beta-lactamases is the most common and thoroughly studied cause of antibiotic resistance. Although they escape the hydrolytic activity of the prototypical Staphylococcus aureus beta-lactamase, many cephems are good substrates for a large number of beta-lactamases. However, the introduction of a 7alpha-methoxy substituent, as in cefoxitin, extends their antibacterial spectrum to many cephalosporin-resistant Gram-negative bacteria. The 7alpha-methoxy group selectively reduces the hydrolytic action of many beta-lactamases without having a significant effect on the affinity for the target enzymes, the membrane penicillin-binding proteins. We report here the crystallographic structures of the BS3 enzyme and its acyl-enzyme adduct with cefoxitin at 1.7 A resolution. The comparison of the two structures reveals a covalent acyl-enzyme adduct with perturbed active site geometry, involving a different conformation of the omega-loop that bears the essential catalytic Glu166 residue. This deformation is induced by the cefoxitin side chain whose position is constrained by the presence of the alpha-methoxy group. The hydrolytic water molecule is also removed from the active site by the 7beta-carbonyl of the acyl intermediate. In light of the interactions and steric hindrances in the active site of the structure of the BS3-cefoxitin acyl-enzyme adduct, the crucial role of the conserved Asn132 residue is confirmed and a better understanding of the kinetic results emerges.


Investigating interactional competencies in Parkinson's disease: the potential benefits of a conversation analytic approach.
Around 70% of people who develop Parkinson's disease (PD) experience speech and voice changes. Clinicians often find that when asked about their primary communication concerns, PD clients will talk about the difficulties they have 'getting into' conversations. This is an important area for clients and it has implications for quality of life and clinical management. To review the extant literature on PD and communication impairments in order to reveal key topic areas, the range of methodologies applied, and any gaps in knowledge relating to PD and social interaction and how these might be usefully addressed. A systematic search of a number of key databases and available grey literatures regarding PD and communication impairment was conducted (including motor speech changes, intelligibility, cognitive/language changes) to obtain a sense of key areas and methodologies applied. Research applying conversation analysis in the field of communication disability was also reviewed to illustrate the value of this methodology in uncovering common interactional difficulties, and in revealing the use of strategic collaborative competencies in naturally occurring conversation. In addition, available speech and language therapy assessment and intervention approaches to PD were examined with a view to their effectiveness in promoting individualized intervention planning and advice-giving for everyday interaction. A great deal has been written about the deficits underpinning communication changes in PD and the impact of communication disability on the self and others as measured in a clinical setting. Less is known about what happens for this client group in everyday conversations outside of the clinic. Current speech and language therapy assessments and interventions focus on the individual and are largely impairment based or focused on compensatory speaker-oriented techniques. A conversation analysis approach would complement basic research on what actually happens in everyday conversation for people with PD and their co-participants. The potential benefits of a conversation analysis approach to communication disability in PD include enabling a shift in clinical focus from individual impairment onto strategic collaborative competencies. This would have implications for client-centred intervention planning and the development of new and complementary clinical resources addressing participation. The impact would be new and improved support for those living with the condition as well as their families and carers.


The wisdom of experience: becoming an effective principal investigator.
As an American Cancer Society mentored research scholar recipient, I interviewed 11 experienced principal investigators actively engaged in cancer research with Indigenous peoples throughout the USA to learn helpful skills and advice for someone beginning a research career. Emergent themes provide helpful advice for beginning researchers as well as reminders for experienced investigators. Themes could serve as a catalyst for continued conversations among researchers and include: being a visionary, keeping up with the science, building relationships, protecting research participants and the community, publishing and disseminating, being organized, recognizing opportunity, understanding funders, being budget wise, staying focused, learning from failures, being holistic, being open to learning, having fun, and practicing self-care.


Femtosecond laser ablation inductively coupled plasma mass spectrometry: fundamentals and capabilities for depth profiling analysis.
Laser ablation coupled to inductively coupled plasma mass spectrometry has become a versatile and powerful analytical method for direct solid analysis. The applicability has been demonstrated on a wide variety of samples, where major, minor, and trace element concentrations or isotope ratio determinations have been of interest. The pros and cons of UV-nsec laser ablation have been studied in detail, and indicate that aerosol generation, aerosol transport, and aerosol excitation-ionization within the ICP contribute to fractionation effects, which prevent this method from a more universal application to all matrices and all elements. Recent progresses in IR-fs and UV-fs laser ablation coupled to ICP-MS have been reported, which increase the inter-matrix and multi-element quantification capabilities of this method. These fundamental improvements in LA-ICP-MS are of significant importance for entering new applications in material science and related research fields. In particular, because coatings (conducting and non-conducting) consist of single or multilayers of various elemental composition and of different thickness (nm-mm range), significant progress in the field of depth profiling with fs-laser ablation can be expected. Therefore, in-depth profile analysis of polymers, semiconductors, and metal sample investigations, using ultra-fast laser ablation for sampling and the currently achievable figures of merit, are discussed. In this review manuscript, the enhanced capabilities of fs-LA-ICP-MS for direct solid sampling are highlighted, and it is discussed about current methods used for quantitative analysis and depth profiling, the ablation process of UV-ns and UV-fs, the influence of the laser beam profile, aerosol structure and transport efficiency, as well as the influence of the ICP-MS (e.g., vaporization and ionization efficiency in the plasma, and type of mass analyzer).


Crowd-sourced BioGames: managing the big data problem for next-generation lab-on-a-chip platforms.
We describe a crowd-sourcing based solution for handling large quantities of data that are created by e.g., emerging digital imaging and sensing devices, including next generation lab-on-a-chip platforms. We show that in cases where the diagnosis is a binary decision (e.g., positive vs. negative, or infected vs. uninfected), it is possible to make accurate diagnosis by crowd-sourcing the raw data (e.g., microscopic images of specimens/cells) using entertaining digital games (i.e., ) that are played on PCs, tablets or mobile phones. We report the results and the analysis of a large-scale public experiment toward diagnosis of malaria infected human red blood cells (RBCs), where binary responses from approximately 1000 untrained individuals from more than 60 different countries are combined together (corresponding to more than 1 million cell diagnoses), resulting in an accuracy level that is comparable to those of expert medical professionals. This platform holds promise toward cost-effective and accurate tele-pathology, improved training of medical personnel, and can also be used to manage the "Big Data" problem that is emerging through next generation digital lab-on-a-chip devices.


Challenges to polycentric governance of an international development project tackling land degradation in Swaziland.
To effectively address the drivers and impacts of land degradation requires polycentric governance systems that facilitate international development projects (IDPs). This paper analyses an IDP aiming to reduce land degradation in Swaziland. A longitudinal-style qualitative approach draws on repeat household surveys, semi-structured interviews and focus groups. We aim to identify the changes that have taken place since the departure of the IDP funders, and the subsequent dynamics between stakeholders. We: (1) chart the evolution of the institutional structures and processes of the IDP; and (2) assess community perceptions of IDP outcomes. Lack of meaningful participation at various stages of the PMC caused the project to lose momentum following the departure of the funders. We discuss these findings in relation to a polycentric approach, and identify how multi-stakeholder IDP can be facilitated as part of wider polycentric governance approaches to inform policies to combat land degradation within Swaziland and more widely.


Laminin reduces expression of the human alpha6 integrin subunit gene by altering the level of the transcription factors Sp1 and Sp3.
Damage to the corneal epithelium results in the massive secretion of fibronectin (FN) shortly after corneal injury, which is later replaced by the secretion of laminin (LM). Laminin is recognized by receptors (alpha6beta1 and alpha6beta4) that belong to the integrin family. The authors characterized the regulatory influence exerted by laminin on the Sp1/Sp3-mediated alpha6 gene promoter function. Recombinant plasmids bearing the CAT reporter gene, fused to various segments from the alpha6 promoter, were transfected into rabbit corneal epithelial cells (RCECs) grown on untreated or on LM-coated culture plates or into Sp1-deficient Drosophila Schneider cells. Expression and DNA binding of Sp1/Sp3 was monitored with the use of Western blot and electrophoretic mobility shift assays (EMSAs), respectively. DNA target sites for Sp1/Sp3 in the alpha6 gene promoter were identified in vitro by DNAse I footprinting. Binding of Sp1 and of a few other transcription factors was also examined in vivo by chromatin immunoprecipitation (ChIP) assays. Expression of the alpha6 mRNA in RCECs grown on LM-coated culture plates was also assessed by Northern blot and RT-PCR analyses. Transfection experiments provided evidence that both Sp1 and Sp3 positively influence alpha6 promoter activity in Sp1/Sp3-deficient SL2 Schneider cells. Two GC-rich target sites for Sp1/Sp3 (a proximal and a distal site) were identified in the alpha6 promoter by DNAse I footprinting. Binding of Sp1/Sp3 was further validated in vivo by ChIP. Transfections conducted into RCECs grown on LM-coated culture plates resulted in repression of the activity directed by the alpha6 promoter. This LM-mediated negative regulatory influence also translated into a similar reduction in the expression of the endogenous alpha6 mRNA as revealed by both RT-PCR and Northern blot analyses. Most of all, results from EMSA and Western blot analyses suggested that the LM-mediated repression of the alpha6 promoter activity results in part from the proteolytic cleavage of Sp1/Sp3. Unlike FN, which functions as an activator of alpha5 gene transcription, LM repressed transcription, directed by the alpha6 gene promoter, by altering the nuclear levels of Sp1 and Sp3. Reappearance of LM in the basement membrane after repair of the corneal damage is therefore expected to substantially contribute to the final steps of this process by influencing the degree to which genes that encode protein products requested for cell adhesion and migration, such as integrin genes, are expressed during corneal wound healing.


Replication and Active Partition of Integrative and Conjugative Elements (ICEs) of the SXT/R391 Family: The Line between ICEs and Conjugative Plasmids Is Getting Thinner.
Integrative and Conjugative Elements (ICEs) of the SXT/R391 family disseminate multidrug resistance among pathogenic Gammaproteobacteria such as Vibrio cholerae. SXT/R391 ICEs are mobile genetic elements that reside in the chromosome of their host and eventually self-transfer to other bacteria by conjugation. Conjugative transfer of SXT/R391 ICEs involves a transient extrachromosomal circular plasmid-like form that is thought to be the substrate for single-stranded DNA translocation to the recipient cell through the mating pore. This plasmid-like form is thought to be non-replicative and is consequently expected to be highly unstable. We report here that the ICE R391 of Providencia rettgeri is impervious to loss upon cell division. We have investigated the genetic determinants contributing to R391 stability. First, we found that a hipAB-like toxin/antitoxin system improves R391 stability as its deletion resulted in a tenfold increase of R391 loss. Because hipAB is not a conserved feature of SXT/R391 ICEs, we sought for alternative and conserved stabilization mechanisms. We found that conjugation itself does not stabilize R391 as deletion of traG, which abolishes conjugative transfer, did not influence the frequency of loss. However, deletion of either the relaxase-encoding gene traI or the origin of transfer (oriT) led to a dramatic increase of R391 loss correlated with a copy number decrease of its plasmid-like form. This observation suggests that replication initiated at oriT by TraI is essential not only for conjugative transfer but also for stabilization of SXT/R391 ICEs. Finally, we uncovered srpMRC, a conserved locus coding for two proteins distantly related to the type II (actin-type ATPase) parMRC partitioning system of plasmid R1. R391 and plasmid stabilization assays demonstrate that srpMRC is active and contributes to reducing R391 loss. While partitioning systems usually stabilizes low-copy plasmids, srpMRC is the first to be reported that stabilizes a family of ICEs.


Anatomical-clinical investigations of variations of the human coronary arteries.
Variations of the human coronary arteries have always attracted the attention of many researchers. A review of the literature shows that variations can cause ischemic heart disease or sudden cardiac death. The aim of the investigations was to examine the existence and clinical significance of variations of the human coronary arteries. Special attention has been focused on myocardial bridging of the coronary arteries and coronary arteriovenous fistula. Our investigations were carried out on the human hearts at the Department of Anatomy and on patients at the Cardiology Department of University Clinical Centre in Sarajevo. Using the method of dissection and coronary angiography we established the existence of variations of the coronary arteries (variations of origin, distribution) on the human hearts without macroscopic visible changes as well as on patients with ischemic changes (angina pectoris, myocardial infarction, congenital cardiovascular malformation etc.). We established the higher incidence of ischemic changes on patients with variations of coronary arteries.


Urinary levels of cigarette smoke constituent metabolites are prospectively associated with lung cancer development in smokers.
Polycyclic aromatic hydrocarbons (PAH) are believed to be among the principal causative agents for lung cancer in smokers, but no epidemiologic studies have evaluated the relationship of PAH uptake and metabolism to lung cancer. In this study, we quantified prediagnostic urinary levels of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), a validated biomarker of PAH uptake and metabolism, as well as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), and cotinine and its glucuronides (total cotinine), validated biomarkers of uptake of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and nicotine, respectively, in relation to lung cancer risk among current smokers in a nested case-control study within a cohort of 18,244 Chinese men in Shanghai, China. Urinary levels of PheT, total NNAL, and total cotinine were significantly higher in cases than controls (N = 476 matched pairs). ORs (95% confidence intervals) for lung cancer in the second, third, fourth, and fifth quintiles of PheT were 1.70 (1.00-2.88), 1.07 (0.62-1.84), 1.48 (0.86-2.53), and 2.34 (1.33-4.11), respectively, relative to the lowest quartile (P(trend) = 0.023) after adjustment for self-reported smoking intensity and duration and urinary total NNAL and total cotinine. This study also confirmed that urinary total NNAL and total cotinine are independently related to lung cancer risk.


Treatment of irritable bowel syndrome. A case control experience.
As optimal therapy for irritable bowel syndrome (IBS) remains elusive, current approach to therapy is based on symptomatic treatment. With this case-control experience we wanted to determine the beneficial effect in IBS patients of a dietary integrator (IBS Active), composed of L-tryptophan, inulin, angelica, vegetal charcoal, vitamin PP, group B vitamins (B1, B2, B6) and probiotics (Lactobacillus sporogenes, Lactobacillus acidophilus, Streptococcus thermophilus). The treatment group comprised 37 patients (11 men and 27 women; mean age, 44.3+/-5.1 years) given IBS Active (440 mg bid) over a mean period of 6 months (range, 5-8). The control group comprised 28 patients (6 men and 22 women; mean age, 48.6+/-3.7 years) who were instructed to continue their customary therapy for 6 months (range, 5-7). All subjects were assessed for the presence of abdominal pain and/or distension, constipation, diarrhea and alternating constipation and diarrhea. Compared with baseline values, the reduction in abdominal pain in the treatment group was 62% (P<0.0001), 55% (P<0.0001) in abdominal distension, 58% (P=0.05) in constipation, 33% (P=0.3) in diarrhea, and 62% (P=0.01) in alternation constipation and diarrhea. Compared with baseline values, no statistically significant reduction in symptoms was found in the control group. Post-treatment comparison between the two groups showed that the study product had reduced symptoms and that the difference was statistically significant for abdominal pain (P<0.000001), abdominal distension (P=0.003) and constipation (P=0.03). The use of IBS Active led to a significant improvement in pain symptoms, abdominal distension and regulation of bowel movement in IBS patients. Further study is needed to evaluate the long-term benefit of the study product.


A cryptic fimbrial gene in Serratia marcescens.
The gene coding for the mannose-sensitive hemagglutinating fimbriae in Serratia marcescens US5 was cloned into Escherichia coli K4 with a cosmid vector system. One of the transformants, US5-1, expressed two morphologically distinct fimbriae, one that was 5-nm wide and one that was 3-nm wide. The latter fimbria was morphologically and serologically indistinguishable from that of strain US5. Genetic analysis of transformant US5-1 showed that the gene responsible for the 5-nm-wide fimbriae was located more than 10 kilobases away from the gene responsible for the 3-nm-wide fimbriae. The molecular sizes of the subunits of these two fimbriae, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, were 19 kilodaltons for the 3-nm-wide fimbriae and 20 kilodaltons for the 5-nm-wide fimbriae. Serologically, the 5-nm-wide fimbriae did not cross-react with monoclonal or polyclonal antibodies raised against the mannose-sensitive hemagglutinating fimbriae of strain US5. Strain EL101, which expressed only the 5-nm-wide fimbriae, did not agglutinate chicken or human erythrocytes. These experimental results suggest that the gene for the 5-nm-wide fimbriae is cryptic in strain US5 and is expressed in E. coli K4 only after it is moved by transformation.


Are informal caregivers less happy than noncaregivers? Happiness and the intensity of caregiving in combination with paid and voluntary work.
Informal caregivers are one of the pillars of home health care. In the Netherlands, the free help they provide to sick or disabled family members, acquaintances or friends exceeds the number of hours of home care provided by professionals. While the government welcomes their contribution, there is concern about the potential burden their work imposes on them. On the one hand, there is concern that informal caregiving could be experienced as a burden and diminish subjective well-being; on the other, helping others as a meaningful activity might increase their subjective well-being. Happiness ratings (as an indicator of subjective well-being) of persons whose involvement in informal caregiving, voluntary work and paid work ranged from none to full time were analysed using multivariate regression models, which also took into account levels of physical disability and socio-economic characteristics (age, sex, household composition, education level). The sample consisted of 336 informal caregivers and 1765 noncaregivers in the Dutch population. In line with the subjective well-being assumption, the results suggest that caregivers are happier than noncaregivers when they provide care for <6 hours a week; and in line with the burden assumption, the results show that providing care for more than 11 hours a week is associated with lower levels of happiness. Other results contradicted the burden assumption that combining caregiving with paid or voluntary work is associated with more time burden and less happiness. The result that combining caregiving with paid employment or volunteering is related to higher rates of happiness confirms the subjective well-being assumption. It is concluded that these cross-sectional results open ways to longitudinal research that can inform governments in the development of policies to support informal caregivers.


Interactions Between Strains of 2,4-Diacetylphloroglucinol-Producing Pseudomonas fluorescens in the Rhizosphere of Wheat.
ABSTRACT Strains of fluorescent Pseudomonas spp. that produce the antibiotic 2,4-diacetylphoroglucinol (2,4-DAPG) are among the most effective rhizobacteria controlling diseases caused by soilborne pathogens. The genotypic diversity that exists among 2,4-DAPG producers can be exploited to improve rhizosphere competence and biocontrol activity. Knowing that D-genotype 2,4-DAPG-producing strains are enriched in some take-all decline soils and that P. fluorescens Q8r1-96, a representative D-genotype strain, as defined by whole-cell repetitive sequence-based polymerase chain reaction (rep-PCR) with the BOXA1R primer, is a superior colonizer of wheat roots, we analyzed whether the exceptional rhizosphere competence of strain Q8r1-96 on wheat is characteristic of other D-genotype isolates. The rhizosphere population densities of four D-genotype strains and a K-genotype strain introduced individually into the soil were significantly greater than the densities of four strains belonging to other genotypes (A, B, and L) and remained above log 6.8 CFU/g of root over a 30-week cycling experiment in which wheat was grown for 10 successive cycles of 3 weeks each. We also explored the competitive interactions between strains of different genotypes inhabiting the same soil or rhizosphere when coinoculated into the soil. Strain Q8r1-96 became dominant in the rhizosphere and in nonrhizosphere soil during a 15-week cycling experiment when mixed in a 1:1 ratio with either strain Pf-5 (A genotype), Q2-87 (B genotype), or 1M1-96 (L genotype). Furthermore, the use of the de Wit replacement series demonstrated a competitive disadvantage for strain Q2-87 or strong antagonism by strain Q8r1-96 against Q2-87 in the wheat rhizosphere. Amplified rDNA restriction analysis and sequence analysis of 16S rDNA showed that species of Arthrobacter, Chryseobacterium, Flavobacterium, Massilia, Microbacterium, and Ralstonia also were enriched in culturable populations from the rhizosphere of wheat at the end of a 30-week cycling experiment in the presence of 2,4-DAPG producers. Identifying the interactions among 2,4-DAPG producers and with other indigenous bacteria in the wheat rhizosphere will help to elucidate the variability in biocontrol efficacy of introduced 2,4-DAPG producers and fluctuations in the robustness of take-all suppressive soils.


Validity and utility of patient-reported health measures on hospital admission.
Patient perceptions of their health are often inadequately captured and explored on hospital admission where physiologic and other objective measures are the focus of attention. Therefore, we conducted a prospective study to develop and validate measures of several domains of patient-reported health status at the time of admission to a general medicine inpatient service, and to determine the value of these new measures in predicting length of stay (LOS). Within 2 hours of the time that a decision to admit a patient was made, research assistants delivered a structured interview that captured patients' current symptoms, functional status, mood, and perceived health. Interviews were conducted between 8 a.m. and 11 p.m., 5 days per week from July 1996 through June 1997. During this time, there were 3621 unique patients admitted to the medicine service; 2672 (74%) of these patients were eligible for an interview. Eighty-eight percent of the 2672 eligible patients were interviewed. In addition to the patient-reported measures captured through the structured interview, the acute physiology score (APS) of the APACHE II was calculated for all subjects. The internal consistency (i.e., Cronbach's alpha) of the scales was 0.76 or greater and concurrent validity (i.e., correlation) of the patient-reported measures with the APS was 0.01 to 0.13. Overall perceived health was correlated 0.20 to 0.45 with symptoms and functional status, and was correlated 0.07 with the APS. The patient-reported measures performed comparably to the APS in predicting LOS (R-square = 0.08). When the patient-reported measures and the APS were included in the same model, the R-square was 0.14. These analyses suggest that patient-reported measures of health and function on admission hold validity, and that responses to as few as 15 questions can provide data that may help to explain differences in length of a hospital stay.


A longitudinal assessment of host-microbe-parasite interactions resolves the zebrafish gut microbiome's link to Pseudocapillaria tomentosa infection and pathology.
Helminth parasites represent a significant threat to the health of human and animal populations, and there is a growing need for tools to treat, diagnose, and prevent these infections. Recent work has turned to the gut microbiome as a utilitarian agent in this regard; components of the microbiome may interact with parasites to influence their success in the gut, meaning that the microbiome may encode new anthelmintic drugs. Moreover, parasite infections may restructure the microbiome's composition in consistent ways, implying that the microbiome may be useful for diagnosing infection. The innovation of these utilities requires foundational knowledge about how parasitic infection, as well as its ultimate success in the gut and impact on the host, relates to the gut microbiome. In particular, we currently possess limited insight into how the microbiome, host pathology, and parasite burden covary during infection. Identifying interactions between these parameters may uncover novel putative methods of disrupting parasite success. To identify interactions between parasite success and the microbiome, we quantified longitudinal associations between an intestinal helminth of zebrafish, Pseudocapillaria tomentosa, and the gut microbiome in 210 4-month-old 5D line zebrafish. Parasite burden and parasite-associated pathology varied in severity throughout the experiment in parasite-exposed fish, with intestinal pathologic changes becoming severe at late time points. Parasite exposure, burden, and intestinal lesions were correlated with gut microbial diversity. Robust generalized linear regression identified several individual taxa whose abundance predicted parasite burden, suggesting that gut microbiota may influence P. tomentosa success. Numerous associations between taxon abundance, burden, and gut pathologic changes were also observed, indicating that the magnitude of microbiome disruption during infection varies with infection severity. Finally, a random forest classifier accurately predicted a fish's exposure to the parasite based on the abundance of gut phylotypes, which underscores the potential for using the gut microbiome to diagnose intestinal parasite infection. These experiments demonstrate that P. tomentosa infection disrupts zebrafish gut microbiome composition and identifies potential interactions between the gut microbiota and parasite success. The microbiome may also provide a diagnostic that would enable non-destructive passive sampling for P. tomentosa and other intestinal pathogens in zebrafish facilities.


Improved robust watermarking through attack characterization.
In this paper, we propose an approach to improve the performance of a broad class of watermarking schemes through attack characterization. Robust and reference watermarks are both embedded into a signal. The reference watermark is used to characterize any modifications of the resulting marked signal, so that the robust watermark can be more reliably extracted. Analysis and simulations are provided to demonstrate the effectiveness of the approach.


Prostate cancer detection, characterization, and clinical outcomes in men aged 70 years and older referred for transrectal ultrasound and prostate biopsies.
To evaluate the diagnostic findings and treatment options chosen in men aged 70 years and older referred for prostate biopsy. Age, prostate-specific antigen (PSA), biopsy pathology, clinical stage, treatment pursued, and treatment outcome were analyzed in 210 men age 70 years and older referred for transrectal ultrasound and prostate biopsies. All patients were followed for a mean of 46.9 months (range 28 to 63). Cancer was found in 120 (56.8%) of the patients. The cancer detection rate was significantly higher (81.0%) in patients aged 80 years and older than those younger than 80 years. Cancer patients aged 80 years and older had a higher rate of poorly differentiated cancer (64.7%) compared with the 70 to 74-year-olds (33.3%) and 75 to 79-year-olds (32.1%). The patients aged 80 years and older also had a larger proportion of high-stage cancer. The patients younger than 80 years had a significantly higher incidence of stable/falling PSA with treatment compared with the older patients. Of the 210 patients, 41 (19.4%) died within 5 years of the diagnostic procedure; 3 died of prostate cancer. The death rate was not significantly different among the three age groups evaluated. None of the patients aged 80 years and older died of prostate cancer. Patients aged 80 years and older who are diagnosed with prostate cancer are less likely to respond well to treatment and usually die of unrelated causes. Aggressive diagnosis, staging, and treatment in octogenarians should be guided by the patients' symptoms, overall health, and personal preferences.


Psychosocial outcome of children evaluated for short stature.
To assess the psychosocial functioning of adults who were evaluated as children for short stature and were not treated with human growth hormone. Inception cohort study. Hospital-based pediatric endocrinology clinic. From 1975 to 1980, medical record review indicated that 181 of the children referred to our clinic for concerns about short stature were non-growth hormone deficient. In 1992 and 1993, we were able to recruit 35 of these patients for a follow-up study. Eligible subjects were at least 18 years of age at the time of follow-up. Standardized self-report questionnaires assessed various domains of psychosocial adjustment. Also, a brief test of intellectual functioning was administered and subjects underwent a semistructured in-person interview to evaluate pragmatic functioning and experiences associated with short stature. Few significant differences between the study sample and standardization samples were found on measures of psychosocial and intellectual functioning. Within-group childhood height during the first evaluation appointment was not significantly associated with most adult measures of psychosocial adjustment. Shorter adult stature was significantly associated with lower educational achievement, lower self-esteem, and greater emotional distress. The absence of significant psychosocial distress or impairment in these subjects brings into question one basis for hormonal treatment for non-growth hormone deficient short stature; that short stature in childhood is likely to lead to psychological dysfunction in adulthood. The results, however, also suggest that shorter stature in adulthood may constitute a psychosocial stressor, increasing vulnerability across several domains.


The Effect of Anodal Transcranial Direct Current Stimulation on Quadriceps Maximal Voluntary Contraction, Corticospinal Excitability, and Voluntary Activation Levels.
Kristiansen, M, Thomsen, MJ, Nørgaard, J, Aaes, J, Knudsen, D, and Voigt, M. The effect of anodal transcranial direct current stimulation on quadriceps maximal voluntary contraction, corticospinal excitability, and voluntary activation levels. J Strength Cond Res 36(6): 1540-1547, 2022-Anodal transcranial direct current stimulation (a-tDCS) has previously been shown to improve maximal isometric voluntary contraction (MVIC), possibly through an upregulation of corticospinal excitability. Because muscle strength is an essential part of the performance of many sports, any ergogenic effect of a-tDCS on this parameter could potentially increase performance outcomes. The purpose of this study was to investigate the effect of a-tDCS on MVIC, voluntary activation levels (VALs), and corticospinal excitability, assessed by eliciting motor-evoked potentials (MEPs), in untrained subjects. Thirteen subjects completed 2 test sessions in which they received either a-tDCS or sham stimulation for 3 consecutive intervals of 10 minutes, separated by 5-minute breaks. Before and after each stimulation session, transcranial magnetic stimulation was used to elicit MEPs, and femoral nerve stimulation was used to assess VAL by measuring twitch torque during an MVIC test and in a relaxed state. Two-way analyses of variance with statistical significance set at p ≤ 0.05 were used to test for differences. A significant main effect was identified, as the MVIC pre-test (271.2 ± 56.6 Nm) was on average 4.1% higher compared to the post-test (260.6 ± 61.4 Nm) (p = 0.05). No significant differences were found in MEP, MVIC, or VAL as a result of stimulation type or time. In healthy subjects, the potential for improvement in corticospinal excitability may be negligible, which may in turn explain the lack of improvements in MEP, MVIC, and VAL after a-tDCS. The small decrease in MVIC for both conditions and nonsignificant changes in MEP and VAL do not justify the use of a-tDCS in combination with sporting performance in which the intent is to increase maximal isometric strength performance in the quadriceps muscle of healthy subjects.


Recruitment order of motoneurons in stretch reflexes is highly correlated with their axonal conduction velocity.
Motor units of soleus and medial gastrocnemius (MG) muscles were studied in pairs during stretch reflexes in the decerebrate cat to determine the relation between their recruitment orders and axonal conduction velocities. In 97% of soleus pairs, the motor unit with the lower axonal conduction velocity was recruited first. Since the soleus is a homogeneous muscle in the cat, differences in motor-unit type are, therefore, not a sine qua non for orderly recruitment nor is recruitment random within homogeneous populations of motor units, as recently proposed (28). In the medial gastrocnemius, a heterogeneous muscle, the same high correlation (97%) between recruitment sequence and conduction velocity was observed. Thus, the factors that determine recruitment order in heterogeneous muscles are as closely correlated with axonal diameter as they are in homogeneous muscles. Comparison of axonal conduction velocities in our sample of MG units with those in three samples of type-identified MG units studied by other investigators also suggests that motor-unit type is not the critical factor controlling the sequence of activation in heterogeneous muscles. It is concluded that the combined effects of all presynaptic and postsynaptic factors that determine susceptibility to discharge in motoneurons during stretch reflexes are strictly correlated with their axonal conduction velocities, as predicted by the size principle.


Artificial intelligence opportunities in cardio-oncology: Overview with spotlight on electrocardiography.
Cardiovascular disease is a leading cause of death among cancer survivors, second only to cancer recurrence or development of new tumors. Cardio-oncology has therefore emerged as a relatively new specialty focused on prevention and management of cardiovascular consequences of cancer therapies. Yet challenges remain regarding precision and accuracy with predicting individuals at highest risk for cardiotoxicity. Barriers such as access to care also limit screening and early diagnosis to improve prognosis. Thus, developing innovative approaches for prediction and early detection of cardiovascular illness in this population is critical. In this review, we provide an overview of the present state of machine learning applications in cardio-oncology. We begin by outlining some factors that should be considered while utilizing machine learning algorithms. We then examine research in which machine learning has been applied to improve prediction of cardiac dysfunction in cancer survivors. We also highlight the use of artificial intelligence (AI) in conjunction with electrocardiogram (ECG) to predict cardiac malfunction and also atrial fibrillation (AF), and we discuss the potential role of wearables. Additionally, the article summarizes future prospects and critical takeaways for the application of machine learning in cardio-oncology. This study is the first in a series on artificial intelligence in cardio-oncology, and complements our manuscript on echocardiography and other forms of imaging relevant to cancer survivors cared for in cardiology clinical practice.


The Fourth Year of Medical School: Time for Reassessment: AOA Critical Issues.
Most U.S. medical schools follow the 4-year model, consisting of 2 preclinical years, core clinical experience, and a fourth year intended to permit students to increase clinical competency, to explore specialty areas, and to transition to residency. Although the design and delivery of Years 1 through 3 have evolved to meet new challenges and expectations, the structure of Year 4 remains largely unchanged. For most students considering a career in orthopaedics, Year 4 is a series of elective rotations in which educational objectives become secondary to interviewing for residency programs. Most accreditation bodies recognize the importance of attainment of competency over the duration of medical school as the goal of educating physicians, and thus, there is a growing interest in reexamining the traditional medical school curriculum with the goal of integrating the final phases of undergraduate education and the first phases of postgraduate education.A literature search was undertaken to identify publications on the duration of medical education. Pilot approaches to competency-based integration of undergraduate medical school and postgraduate training in orthopaedic surgery were reviewed.There have been few data suggesting that 4 years of medical education is superior to shorter-duration programs. Three approaches to competency-based integration of undergraduate medical school and postgraduate training are presented. Their goal is to use student and faculty time more effectively. Each approach offers the opportunity to lower the cost and to decrease the time required for Board Certification in Orthopaedic Surgery. Two approaches shorten the entire duration of medical school and graduate training by using various proportions of the fourth year to begin residency, and one approach expands the duration of orthopaedic training by starting in the fourth year of medical school and including training equivalent to a fellowship program into the residency experience.The effectiveness of such programs will form the basis for revisions to the current orthopaedic training paradigm, resulting in a more effective, efficient, and integrated orthopaedic training curriculum.


Crystal structures of Xanthomonas campestris OleA reveal features that promote head-to-head condensation of two long-chain fatty acids.
OleA is a thiolase superfamily enzyme that has been shown to catalyze the condensation of two long-chain fatty acyl-coenzyme A (CoA) substrates. The enzyme is part of a larger gene cluster responsible for generating long-chain olefin products, a potential biofuel precursor. In thiolase superfamily enzymes, catalysis is achieved via a ping-pong mechanism. The first substrate forms a covalent intermediate with an active site cysteine that is followed by reaction with the second substrate. For OleA, this conjugation proceeds by a nondecarboxylative Claisen condensation. The OleA from Xanthomonas campestris has been crystallized and its structure determined, along with inhibitor-bound and xenon-derivatized structures, to improve our understanding of substrate positioning in the context of enzyme turnover. OleA is the first characterized thiolase superfamily member that has two long-chain alkyl substrates that need to be bound simultaneously and therefore uniquely requires an additional alkyl binding channel. The location of the fatty acid biosynthesis inhibitor, cerulenin, that possesses an alkyl chain length in the range of known OleA substrates, in conjunction with a single xenon binding site, leads to the putative assignment of this novel alkyl binding channel. Structural overlays between the OleA homologues, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase and the fatty acid biosynthesis enzyme FabH, allow assignment of the two remaining channels: one for the thioester-containing pantetheinate arm and the second for the alkyl group of one substrate. A short β-hairpin region is ordered in only one of the crystal forms, and that may suggest open and closed states relevant for substrate binding. Cys143 is the conserved catalytic cysteine within the superfamily, and the site of alkylation by cerulenin. The alkylated structure suggests that a glutamic acid residue (Glu117β) likely promotes Claisen condensation by acting as the catalytic base. Unexpectedly, Glu117β comes from the other monomer of the physiological dimer.


GK4, a G-protein-coupled receptor with a phosphatidylinositol phosphate kinase domain in Phytophthora infestans, is involved in sporangia development and virulence.
For dispersal and host infection plant pathogens largely depend on asexual spores. Pathogenesis and sporulation are complex processes that are governed by cellular signalling networks including G-protein and phospholipid signalling. Oomycetes possess a family of novel proteins called GPCR-PIPKs (GKs) that are composed of a seven-transmembrane spanning (7-TM) domain fused to a phosphatidylinositol phosphate kinase (PIPK) domain. Based on this domain structure GKs are anticipated to link G-protein and phospholipid signal pathways; however, their functions are currently unknown. Expression analyses of the 12 GK genes in Phytophthora infestans and their orthologues in Phytophthora sojae, revealed differential expression during asexual development. PiGK1 and PiGK4 were fused to monomeric red fluorescent protein (mRFP) and ectopically expressed in P. infestans. In growing hyphae different subcellular distribution patterns were observed indicating that these two GKs act independently during development. We focused on the functional analyses of PiGK4. Its localization suggested involvement in cell differentiation and elongation and its 7-TM domain showed a canonical GPCR membrane topology. Silencing of GK4 and overexpression of full-length and truncated constructs in P. infestans revealed that PiGK4 is not only involved in spore germination and hyphal elongation but also in sporangia cleavage and infection.


Beneficial effects of hydrogen-rich saline against spinal cord ischemia-reperfusion injury in rabbits.
Hydrogen-rich saline (HS) is reported to be a new therapeutic agent in ischemia-reperfusion (I/R)-induced organ damage. The present study was designed to investigate the beneficial effects of HS against spinal cord I/R injury and its associated mechanisms. Spinal cord ischemia was induced by infrarenal aortic occlusion for 20min in male New Zealand white rabbits. Different doses of HS were intravenously (i.v.) administered at 5min before or after the beginning of reperfusion. Moreover, the roles of mitochondrial ATP-sensitive potassium channels (mitoKATP), oxidative stress, inflammatory cytokines and apoptosis was assessed. Here, we found that I/R-challenged rabbits exhibited significant spinal cord injury characterized by the decreased numbers of normal motor neurons and hind-limb motor dysfunction, which was significantly ameliorated by 5mL/kg and 10mL/kg HS treatment before reperfusion or 10mL/kg HS treatment after reperfusion. However, the protective effects of HS treatment in spinal cord I/R injury were partially abolished by the selective mitoKATP channel blocker 5-hydroxydecanoate (5-HD). Moreover, we showed that the beneficial effects of 10mL/kg HS treatment against spinal cord I/R damage were associated with the decreased levels of oxidative products [8-iso-prostaglandin F2α (8-iso-PGF2α) and malondialdehyde (MDA)] and pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and high-mobility group box 1 (HMGB1)], as well as the increased activities of antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)] in serum at 6h, 12h, 24h, 48h and 72h after reperfusion and in spinal cord at 72h after reperfusion. Furthermore, HS treatment (10mL/kg) reduced caspase-3 activity in the spinal cord of this model. Thus, HS may be an effective therapeutic agent for spinal cord I/R injury via activation of mitoKATP channels as well as reduction of oxidative stress, inflammatory cytokines and apoptosis.


[The impact of training based on the Baby-Friendly Hospital Initiative on breastfeeding practices in the Northeast of Brazil].
To evaluate the impact of training based on the Baby Friendly Hospital Initiative on breastfeeding practices in maternity wards and during the first 6 months of life. Ninety percent of nursing auxiliaries and midwives were trained at two institutions (A and B) in Palmares, Pernambuco state. Three hundred and thirty-four mothers were interviewed within the first 48 hours and 10 days after childbirth to evaluate breastfeeding practices at the maternities and fulfillment of steps 4 through 10 of the Baby Friendly Hospital Initiative. A subset of 166 mothers received seven home visits to evaluate breastfeeding practices throughout the first 6 months of life and to compare results with those of a cohort study conducted in the area in 1998. The performance of maternity B was significantly better than that of maternity A, from steps 4 to 10 and also in terms of exclusive breastfeeding and offering less water or tea to infants (p < 0.001). The comparison with a previous cohort study demonstrated an improvement in breastfeeding practices at the maternity wards and an increase of exclusive breastfeeding prevalence (from 21.2 to 70%), during the first 48 hours after delivery and throughout the first six months. The training promoted partial change to some practices related to breastfeeding, having a positive effect on total and exclusive breastfeeding at the maternity wards. However, there was no significant change to these practices over the first 6 months of life, suggesting the need for effective interventions to support exclusive breastfeeding in the health sector and in the community.


Observer effects on the rating of perceived exertion and affect during exercise in recreationally active males.
This study examined the effect of introducing either a male or female observer on the ratings of perceived exertion (RPE) and affect of male runners during a moderate intensity running task. 10 moderately active men completed three 20-min. moderate intensity running trials at 60% of their peak treadmill running speed. Each participant completed three trials in random order: control, male-observed, and female-observed, where either the male or female observer joined the trial after 10 min. of the trial had elapsed, during which RPE and affect were monitored. The introduction of a female observer caused a significant decrease in RPE, whereas the introduction of a male observer caused a significant increase in RPE compared to the control trial. Affect was higher in the presence of both a male and female observer compared to control. It was concluded that there is a social, interpersonal, psychological dimension to RPE during exercise.


Simulation of nanoparticle-mediated near-infrared thermal therapy using GATE.
Application of nanotechnology for biomedicine in cancer therapy allows for direct delivery of anticancer agents to tumors. An example of such therapies is the nanoparticle-mediated near-infrared hyperthermia treatment. In order to investigate the influence of nanoparticle properties on the spatial distribution of heat in the tumor and healthy tissues, accurate simulations are required. The Geant4 Application for Emission Tomography (GATE) open-source simulation platform, based on the Geant4 toolkit, is widely used by the research community involved in molecular imaging, radiotherapy and optical imaging. We present an extension of GATE that can model nanoparticle-mediated hyperthermal therapy as well as simple heat diffusion in biological tissues. This new feature of GATE combined with optical imaging allows for the simulation of a theranostic scenario in which the patient is injected with theranostic nanosystems that can simultaneously deliver therapeutic (i.e. hyperthermia therapy) and imaging agents (i.e. fluorescence imaging).


A tool for assessing the usefulness of prevalence studies done for surveillance purposes: the example of hypertension.
Every year dozens of cross-sectional studies are carried out that estimate the prevalence of risk factors for chronic noncommunicable diseases. Given that, there is potentially a large amount of information that could be extremely useful for risk factor surveillance. However, there are good reasons to question the methodological rigor and the reliability of the results coming from many of these studies. The potential benefits of the data are curtailed by the studies' shortcomings, in part often because there is no clear and explicit methodological information providing the details needed to assess the procedures that were actually used, as well as a failure to apply a uniform methodology that would allow comparisons over time or across studies. This paper is intended to be both a didactic and practical tool. It describes the construction of an instrument for assessing the usefulness of prevalence studies done within the context of surveillance activities, using the example of hypertension. The paper discusses and illustrates the most common pitfalls found with prevalence studies, and it also offers methodological standards that can guide future prevalence studies as well as stimulate future research efforts in this area.


ReaxFF Molecular Dynamics Simulation for the Graphitization of Amorphous Carbon: A Parametric Study.
A parametric study of ReaxFF for molecular dynamics simulation of graphitization of amorphous carbon was conducted. The responses to different initial amorphous carbon configurations, simulation time steps, simulated temperatures, and ReaxFF parameter sets were investigated. The results showed that a time step shorter than 0.2 fs is sufficient for the ReaxFF simulation of carbon using both Chenoweth 2008 and Srinivasan 2015 parameter sets. The amorphous carbon networks produced using both parameter sets at 300 K are similar to each other, with the first peak positions of pair distribution function curves located between the graphite sp2 bond peak position and the diamond sp3 bond peak position. In the graphitization process, the graphene fragment size increases and the orientation of graphene layers transforms to be parallel with each other with the increase of temperature and annealing time. This parallel graphene structure is close to the crystalline graphite. Associated with this graphitization is the presence of small voids and pores which arise because of the more efficient atomic packing relative to a disordered structure. For all initial densities, both potential parameter sets exhibit the expected behavior in which the sp2 fraction increases significantly over time. The sp2 fraction increases with increasing temperature. The differences of sp2 fraction at different temperatures are more obvious in lower density at 1.4 g/cm3. When density is increased, the gap caused by different temperatures becomes small. This study indicates that both Chenoweth 2008 and Srinivasan 2015 potential sets are appropriate for molecular dynamics simulations in which the growth of graphitic structures is investigated.


Eco-physiological adaptations that favour freshwater cyanobacteria in a changing climate.
Climate change scenarios predict that rivers, lakes, and reservoirs will experience increased temperatures, more intense and longer periods of thermal stratification, modified hydrology, and altered nutrient loading. These environmental drivers will have substantial effects on freshwater phytoplankton species composition and biomass, potentially favouring cyanobacteria over other phytoplankton. In this Review, we examine how several cyanobacterial eco-physiological traits, specifically, the ability to grow in warmer temperatures; buoyancy; high affinity for, and ability to store, phosphorus; nitrogen-fixation; akinete production; and efficient light harvesting, vary amongst cyanobacteria genera and may enable them to dominate in future climate scenarios. We predict that spatial variation in climate change will interact with physiological variation in cyanobacteria to create differences in the dominant cyanobacterial taxa among regions. Finally, we suggest that physiological traits specific to different cyanobacterial taxa may favour certain taxa over others in different regions, but overall, cyanobacteria as a group are likely to increase in most regions in the future.


Ancient mitogenomes of Phoenicians from Sardinia and Lebanon: A story of settlement, integration, and female mobility.
The Phoenicians emerged in the Northern Levant around 1800 BCE and by the 9th century BCE had spread their culture across the Mediterranean Basin, establishing trading posts, and settlements in various European Mediterranean and North African locations. Despite their widespread influence, what is known of the Phoenicians comes from what was written about them by the Greeks and Egyptians. In this study, we investigate the extent of Phoenician integration with the Sardinian communities they settled. We present 14 new ancient mitogenome sequences from pre-Phoenician (~1800 BCE) and Phoenician (~700-400 BCE) samples from Lebanon (n = 4) and Sardinia (n = 10) and compare these with 87 new complete mitogenomes from modern Lebanese and 21 recently published pre-Phoenician ancient mitogenomes from Sardinia to investigate the population dynamics of the Phoenician (Punic) site of Monte Sirai, in southern Sardinia. Our results indicate evidence of continuity of some lineages from pre-Phoenician populations suggesting integration of indigenous Sardinians in the Monte Sirai Phoenician community. We also find evidence of the arrival of new, unique mitochondrial lineages, indicating the movement of women from sites in the Near East or North Africa to Sardinia, but also possibly from non-Mediterranean populations and the likely movement of women from Europe to Phoenician sites in Lebanon. Combined, this evidence suggests female mobility and genetic diversity in Phoenician communities, reflecting the inclusive and multicultural nature of Phoenician society.


[Management of candidemia and invasive candidiasis].
Candida species is the fourth most common cause of bloodstream infection and is the leading cause of invasive fungal infection among hospitalized patients. Acute disseminated candidiasis remains a life-threatening disease that now occurs mainly in intensive care units hospitalized patients. Delay in treatment of Candida bloodstream infections could be minimized by the development of more rapid and sensitive diagnostic techniques for the identification of Candida bloodstream infections. Current guidelines for the management of invasive candidiasis recommend fluconazole or an echinocandin as the primary therapeutic option. The optimal choice of the antifungal agent should depend on local epidemiology, prior antifungal therapy and patient's characteristics.


Dietary salt intake as a potential modifier of airway responsiveness in bronchial asthma.
While pharmacologic treatment of chronic asthma is usually highly effective, medications often have significant side-effects or exhibit tachyphylaxis. Alternative and/or complementary treatments that reduce dependence on pharmacologic medications are of interest in reducing the severity of asthma. This review analyzes the literature that has evaluated dietary salt intake as a potential modifier of the severity of asthma and airway responsiveness. High dietary intakes of salt, greater than 9 g/d, are common in Western civilizations, as is asthma. The question is whether reducing dietary salt intake potentially would improve pulmonary function and airway responsiveness in individuals with asthma. This review details the existing studies in this regard and includes the studies that have evaluated dietary salt on the severity of exercise-induced asthma (exercise-induced bronchoconstriction [E1B]). From a critical analysis of the existing literature, the data that support a role for dietary salt reduction for reducing severity of asthma and airway responsiveness in individuals with asthma is considered encouraging but not clinically convincing. The existing studies have suffered from a variety of experimental and population limitations. In contrast, the data from studies that have altered dietary salt and evaluated severity of EIB in nonatopic individuals is much more convincing. In each study so far, lowering dietary salt has reduced the severity of EIB to subclinical levels. Correspondingly, the supplementing of diets to higher than normal salt intake increased EIB significantly. This review concludes that the data are sufficient to warrant a clinical trial that is properly controlled and randomized to further investigate the influence of dietary salt intake on pulmonary function, airway responsiveness, symptoms, quality of life, and medication requirements in asthma and EIB.


Characterization of the adhesive dermal secretion of Euprymna scolopes Berry, 1913 (Cephalopoda).
Bio-adhesion is a common and crucial process in nature and is used by several different species for camouflage, prey capture, hatching or to avoid drifting. Four genera of cephalopods belonging to four different families (Euprymna, Sepiolidae; Idiosepius, Idiosepiidae; Nautilus, Nautilidae; and Sepia, Sepiidae) produce glue for temporary attachment. Euprymna species live in near-shore benthic habitats of the Indo-Pacific Ocean, are nocturnal and bury into the seafloor during the day. The animals secrete adhesives through their epithelial glands to completely coat themselves with sand. In cases of danger, they instantaneously release the sandy coat as a sinking decoy to deflect predators. Earlier morphological investigations have shown that the adhesive gland cells of Euprymna scolopes are scattered on the dorsal epidermis. It has been proposed that neutral mucopolysaccharides, secreted by one gland type (goblet cells), are responsible for adhesion, whereas the release of the glue could be caused by acidic mucoproteins produced by ovate cells in the ventral epidermis. The ultrastructural re-investigation of the Euprymna epithelium in this study has indicated the presence of a new gland type (named flask cell), exclusively located in the dorsal epithelium and always neighboured to the known goblet cells. Based on our histochemical observations, the secretory material of the ovate cells does not display a strong reaction to tests for acidic groups, as had been previously assumed. Within the dermis, a large muscle network was found that was clearly distinctive from the normal mantle musculature. Based on our data, an antagonistic gland system, as previously proposed, seems to be unlikely for Euprymna scolopes. We hypothesize that the adhesive secretion is formed by two gland types (goblet and flask cells). The release of the sand coat may occur mechanically, i.e. by contraction of the dermal mantle muscle, and not chemically through the ovate cells.


T cell gelatinases mediate basement membrane transmigration in vitro.
T cell homing into extravascular sites requires penetration across the subendothelial basal lamina, a specialized nonfibrillar connective tissue structure that anchors endothelial cells to parenchymal surfaces. Herein, we show that normal human T cells express gelatinases A and B, two matrix metalloproteinases active against the major basal lamina constituents, collagen types IV and V. Expression is confirmed at both the mRNA and protein levels. Gelatinase B is expressed constitutively, whereas gelatinases A and B expression is induced by T cell activation. In vitro migration of resting T cells across a basal lamina equivalent is mediated by gelatinase B, because it is specifically blocked by GM6001, a hydroxamic acid inhibitor of matrix metalloproteinases. Inhibition of T cell homing by interference with gelatinase function may represent a useful approach to the treatment of T cell-mediated autoimmune diseases.


Child mortality estimation: accelerated progress in reducing global child mortality, 1990-2010.
Monitoring development indicators has become a central interest of international agencies and countries for tracking progress towards the Millennium Development Goals. In this review, which also provides an introduction to a collection of articles, we describe the methodology used by the United Nations Inter-agency Group for Child Mortality Estimation to track country-specific changes in the key indicator for Millennium Development Goal 4 (MDG 4), the decline of the under-five mortality rate (the probability of dying between birth and age five, also denoted in the literature as U5MR and (5)q(0)). We review how relevant data from civil registration, sample registration, population censuses, and household surveys are compiled and assessed for United Nations member states, and how time series regression models are fitted to all points of acceptable quality to establish the trends in U5MR from which infant and neonatal mortality rates are generally derived. The application of this methodology indicates that, between 1990 and 2010, the global U5MR fell from 88 to 57 deaths per 1,000 live births, and the annual number of under-five deaths fell from 12.0 to 7.6 million. Although the annual rate of reduction in the U5MR accelerated from 1.9% for the period 1990-2000 to 2.5% for the period 2000-2010, it remains well below the 4.4% annual rate of reduction required to achieve the MDG 4 goal of a two-thirds reduction in U5MR from its 1990 value by 2015. Thus, despite progress in reducing child mortality worldwide, and an encouraging increase in the pace of decline over the last two decades, MDG 4 will not be met without greatly increasing efforts to reduce child deaths.


Enhancing Intervention for Residual Rhotic Errors Via App-Delivered Biofeedback: A Case Study.
Recent research suggests that visual-acoustic biofeedback can be an effective treatment for residual speech errors, but adoption remains limited due to barriers including high cost and lack of familiarity with the technology. This case study reports results from the first participant to complete a course of visual-acoustic biofeedback using a not-for-profit iOS app, Speech Therapist's App for /r/ Treatment. App-based biofeedback treatment for rhotic misarticulation was provided in weekly 30-min sessions for 20 weeks. Within-treatment progress was documented using clinician perceptual ratings and acoustic measures. Generalization gains were assessed using acoustic measures of word probes elicited during baseline, treatment, and maintenance sessions. Both clinician ratings and acoustic measures indicated that the participant significantly improved her rhotic production accuracy in trials elicited during treatment sessions. However, these gains did not transfer to generalization probes. This study provides a proof-of-concept demonstration that app-based biofeedback is a viable alternative to costlier dedicated systems. Generalization of gains to contexts without biofeedback remains a challenge that requires further study. App-delivered biofeedback could enable clinician-research partnerships that would strengthen the evidence base while providing enhanced treatment for children with residual rhotic errors. https://doi.org/10.23641/asha.5116318.


Capillary electrophoresis of natural products: current applications and recent advances.
Capillary electrophoresis (CE) was introduced as a new analytical technique in the 1970s and rapidly proved to be a powerful tool for the separation and detection of various classes of natural and synthetic compounds. Since the availability of commercially manufactured high-performance instruments, CE represents an interesting alternative to high-pressure liquid chromatography (HPLC), mainly because of its speed and high separation efficiency. In this overview a short description of the basic and widely used CE methods will be given and the applicability of these methods for the analysis of natural products will be discussed. Due to the growing number of publications dealing with CE or CE/MS of secondary plant metabolites, an exhaustive overview of all current applications cannot be given in this contribution. Therefore, the focus of this mini-review will be on the advances and new aspects of recently published CE methods in natural products analysis.


Malaria after international travel: a GeoSentinel analysis, 2003-2016.
More than 30,000 malaria cases are reported annually among international travellers. Despite improvements in malaria control, malaria continues to threaten travellers due to inaccurate perception of risk and sub-optimal pre-travel preparation. Records with a confirmed malaria diagnosis after travel from January 2003 to July 2016 were obtained from GeoSentinel, a global surveillance network of travel and tropical medicine providers that monitors travel-related morbidity. Records were excluded if exposure country was missing or unascertainable or if there was a concomitant acute diagnosis unrelated to malaria. Records were analyzed to describe the demographic and clinical characteristics of international travellers with malaria. There were 5689 travellers included; 325 were children <18 years. More than half (53%) were visiting friends and relatives (VFRs). Most (83%) were exposed in sub-Saharan Africa. The median trip duration was 32 days (interquartile range 20-75); 53% did not have a pre-travel visit. More than half (62%) were hospitalized; children were hospitalized more frequently than adults (73 and 62%, respectively). Ninety-two per cent had a single Plasmodium species diagnosis, most frequently Plasmodium falciparum (4011; 76%). Travellers with P. falciparum were most frequently VFRs (60%). More than 40% of travellers with a trip duration ≤7 days had Plasmodium vivax. There were 444 (8%) travellers with severe malaria; 31 children had severe malaria. Twelve travellers died. Malaria remains a serious threat to international travellers. Efforts must focus on preventive strategies aimed on children and VFRs, and chemoprophylaxis access and preventive measure adherence should be emphasized.


Inhalation developmental neurotoxicity study of ethylbenzene in Crl-CD rats.
This study was conducted to evaluate the potential adverse effects of whole-body inhalation exposure of F0 and F1 parental animals from a 2-generation reproduction study of ethylbenzene on nervous system functional and/or morphologic end points in the F2 offspring from four groups of male and female Crl:CD (SD)IGS BR rats. Thirty rats/sex/group for F0 and 25/sex/group for F1 were exposed to 0, 25, 100, and 500 ppm ethylbenzene for six hours daily for at least 70 consecutive days prior to mating for the F0 and F1 generations. Inhalation exposure for the F0 and F1 females continued throughout mating and gestation through Gestation Day (GD) 20. On lactation days (LD) 1-4, the F0 and F1 females received no inhalation exposure, but instead were administered ethylbenzene in corn oil via oral gavage at dosages estimated to result in similar internal maternal exposure based upon PBPK modeling estimates (0, 26, 90, and 342 mg/kg/day, respectively, divided into three equal doses, approximately two hours apart). Inhalation exposure of the F0 and F1 females was reinitiated on LD 5 and continued through weaning on postnatal day (PND) 21. Survival, body weights, and physical landmarks were assessed in selected F2 offspring. Neurobehavioral development of one F2-generation treatment derived offspring/sex/litter was assessed in a functional observational battery (FOB; PND 4, 11, 22, 45, and 60), motor activity sessions (PND 13, 17, 21, and 61), acoustic startle testing (PND 20 and 60), a Biel water maze learning and memory task (initiated on PND 26 or 62), and in evaluations of whole-brain measurements and brain morphometric and histologic assessments (PND 21 and 72). There were no adverse effects on reproductive performance in either the F0 or F1 parental generations exposed to up to 500 ppm ethylbenzene [Faber et al. Birth Defects Res Part B 77:10-21, 2006]. In the current developmental neurotoxicity component, parental ethylbenzene exposure did not adversely affect offspring survival, clinical condition, body weight parameters, or acquisition of developmental landmarks of the F2-generation treatment derived offspring. There were no alterations in FOB parameters, motor activity counts, acoustic startle endpoints, or Biel water maze performance in offspring attributed to parental ethylbenzene exposure. A few isolated instances of statistically significant differences obtained in the treatment-derived groups occurred sporadically, and were attributed to unusual patterns of development and/or behavior in the concurrent control group. There were no exposure-related differences in any neuropathology parameters in the F2-generation treatment derived offspring. The no observed adverse effect level (NOAEL) for maternal reproductive toxicity, developmental toxicity, and developmental neurotoxicity in this study was considered to be 500 ppm/342 mg/kg/day ethylbenzene, the highest exposure level tested in the study.


Mobile phone radiation might alter protein expression in human skin.
Earlier we have shown that the mobile phone radiation (radiofrequency modulated electromagnetic fields; RF-EMF) alters protein expression in human endothelial cell line. This does not mean that similar response will take place in human body exposed to this radiation. Therefore, in this pilot human volunteer study, using proteomics approach, we have examined whether a local exposure of human skin to RF-EMF will cause changes in protein expression in living people. Small area of forearm's skin in 10 female volunteers was exposed to RF-EMF (specific absorption rate SAR = 1.3 W/kg) and punch biopsies were collected from exposed and non-exposed areas of skin. Proteins extracted from biopsies were separated using 2-DE and protein expression changes were analyzed using PDQuest software. Analysis has identified 8 proteins that were statistically significantly affected (Anova and Wilcoxon tests). Two of the proteins were present in all 10 volunteers. This suggests that protein expression in human skin might be affected by the exposure to RF-EMF. The number of affected proteins was similar to the number of affected proteins observed in our earlier in vitro studies. This is the first study showing that molecular level changes might take place in human volunteers in response to exposure to RF-EMF. Our study confirms that proteomics screening approach can identify protein targets of RF-EMF in human volunteers.


Effects of low oxygen concentrations and metabolic inhibitors on proteoglycan and protein synthesis rates in the intervertebral disc.
The intervertebral disc is the largest asvacular structure in the body; consequently, there are steep gradients in O2 concentration, with PO2 falling to as low as 1% O2 in the centre of the disc. We investigated the effect of O2 concentration on the rates of O2 consumption, lactate production, and sulphate and proline incorporation in bovine caudal discs. We also investigated the effects of metabolic inhibitors of energy production pathways on tracer incorporation. Samples from the outer annulus and nucleus pulposus were incubated for 24 hours in 1-21% O2. Rates were measured during the last 4 hours of incubation. As O2 concentration was reduced from 10 to 1% O2, O2 consumption rates fell by around 75% and lactate production rates almost doubled; the bovine discs thus showed a positive progressive Pasteur effect. Incorporation rates of [3H]proline and [35S]sulphate were lowest at 1% O2. In the nucleus, but not in the outer annulus, the rate of [35S]incorporation peaked at 5% O2, where it was 30% greater than at 21% O2 and 150% greater than at 1% O2. The competitive glycolysis inhibitor 2-deoxyglucose, the oxidative phosphorylation uncoupler 2,4-dinitrophenol, and the oxidative phosphorylation inhibitor sodium azide all markedly reduced sulphate incorporation. These results, together with previous measurements of CO2 production rates, suggest that a functionally significant fraction of the disc's energy is supplied by oxidative phosphorylation. However, low levels of PO2, 2,4-dinitrophenol, and sodium azide have been reported to reduce sulphate incorporation in articular cartilage, a tissue that derives its energy almost entirely from glycolysis.


In vivo biochemistry: quantifying ion and metabolite levels in individual cells or cultures of yeast.
Over the past decade, we have learned that cellular processes, including signalling and metabolism, are highly compartmentalized, and that relevant changes in metabolic state can occur at sub-second timescales. Moreover, we have learned that individual cells in populations, or as part of a tissue, exist in different states. If we want to understand metabolic processes and signalling better, it will be necessary to measure biochemical and biophysical responses of individual cells with high temporal and spatial resolution. Fluorescence imaging has revolutionized all aspects of biology since it has the potential to provide information on the cellular and subcellular distribution of ions and metabolites with sub-second time resolution. In the present review we summarize recent progress in quantifying ions and metabolites in populations of yeast cells as well as in individual yeast cells with the help of quantitative fluorescent indicators, namely FRET metabolite sensors. We discuss the opportunities and potential pitfalls and the controls that help preclude misinterpretation.


Untangling the roles of fire, grazing and rainfall on small mammal communities in grassland ecosystems.
In grassland systems across the globe, ecologists have been attempting to understand the complex role of fire, grazing and rainfall in creating habitat heterogeneity and the consequences of anthropogenic control of these factors on ecosystem integrity and functioning. Using a South African grassland ecosystem as a model, we investigated the impact of fire and grazing pressure on small mammal communities during three differing periods of a rainfall cycle. Over 2 years, 15,203 trap nights revealed 1598 captures of 11 species (nine rodents, one macroscelid and one insectivore). Results highlighted the importance of the interplay between factors and showed that the role of fire, grazing and rainfall in determining small mammal abundance was species-dependant. While no two species were affected by the same environmental variables, grass cover or height was important to 56% of species. Considered independently, high rainfall had a positive influence on small mammal abundance and diversity, although the lag period in population response was species-specific. High grazing negatively affected overall abundance, but specifically in Mastomys coucha; fire alone had little immediate impact on small mammal diversity. Six months after the fire, vegetation cover had recovered to similar levels as unburned areas, although small mammal diversity and richness were higher in burned areas than unburned areas. Grazing levels influenced the rate of vegetation recovery. In conclusion, low-level grazing and burning can help to maintain small mammal biodiversity, if conducted under appropriate rainfall levels. A too high grazing pressure, combined with fire, and/or fire conducted under drought conditions can have a negative impact on small mammal biodiversity. To maintain small mammal diversity in grassland ecosystems, the combined effects of the previous year's rainfall and existing population level as well as the inhibition of vegetation recovery via grazing pressure need to be taken into consideration before fire management is applied.


Comparison of aqueous concentrations of angiogenic and inflammatory cytokines in diabetic macular oedema and macular oedema due to branch retinal vein occlusion.
The involvement of cytokines in the aqueous humour is important in the development and progression of diabetic macular oedema (DMO) and macular oedema (MO) due to branch retinal vein occlusion (BRVO-MO). In this study, the concentrations of cytokines in the aqueous humour of eyes with DMO and BRVO-MO were measured and compared. Prospective, observational case series. Aqueous samples were obtained from 18 eyes with DMO (DMO group), 12 eyes with BRVO-MO (BRVO-MO group), and 16 normal eyes (control group). The aqueous levels of cytokines, including interleukin (IL)-2, IL-5, IL-6, IL-8, IL-12p70, IL-13, monocytochemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), platelet-derived growth factor-AA (PDGF)-AA, transforming growth factor-α (TGF-α), interferon-γ (IFN-γ), epidermal growth factor, fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF), were measured. The aqueous levels of IL-8, MCP-1, PDGF-AA and VEGF were higher, and IL-13 was lower in the DMO group compared with the control group. The aqueous levels of IL-8 and VEGF were higher in the BRVO-MO group than in the control group. Compared with the IL-6 and MCP-1 levels in the BRVO-MO group, those levels were significantly higher in the DMO group. Correlation analyses revealed that IL-8 was positively and IFN-γ was negatively correlated with the severity of MO in the DMO group. In the BRVO-MO group, IL-8 and was positively correlated with severity of MO and retinal ischaemia. DMO and BRVO-MO may differ in terms of pathogenesis because the cytokine concentrations in the aqueous humour differ. The results suggest that the inflammatory reaction may be more activated in DMO than in BRVO-MO, and ischaemic insult may play a central role in the development of BRVO-MO.


Review: Does size matter? Placental debris and the pathophysiology of pre-eclampsia.
A variety of 'debris' is shed from the syncytial surface of the human placenta ranging from large deported multinuclear fragments to sub-cellular components. It is increasingly clear that at least some of this material has signalling functions. Many categories of circulating debris are increased in pre-eclampsia, and exhibit proteins that are pro-inflammatory and could contribute to the systemic inflammatory response in normal pregnancy, which is exaggerated in pre-eclampsia. It is now evident that there is a large 'hidden' population of microvesicles and nanovesicles (including exosomes) which are hard to investigate because of their size. We have used a new technology, nanoparticle tracking analysis, to measure the size and concentration of syncytiotrophoblast vesicles prepared by placental perfusion. The vesicles range in size from 50 nm to 1 μm with the majority being <500 nm (which includes both exosomes and microvesicles). We speculate whether changes not only in the numbers, but also in the size (beneficial syncytiotrophoblast exosomes and harmful microvesicles) might be important in the maternal syndrome of pre-eclampsia.


[Evaluation of an immunochromatography test using enzyme immunoassay for rapid detection of influenza A and B viruses].
We evaluated the performance of an improved version of Espline Influenza A & B-N (Fujirebio Inc., Japan), an immunochromatography test using enzyme immunoassay for rapid diagnosis of influenza A and B. The test produced positive results for four strains of influenza viruses and thirty-one influenza viral antigens and negative results for all of thirty strains of other respiratory viruses that were tested. The detection limit of this test was 5.8 x 10(2) to 5.8 x 10(3) pfu/assay, which is more sensitive than the old version of Espline. Furthermore, 715 respiratory specimens collected from the patients (children, 79.4%; adults, 18.5%; unknown, 2.1%) with influenza-like illnesses during the 2002/2003 influenza season in Japan were tested as part of a clinical evaluation of this test. The relative performance of this test compared to cell culture and nested RT-PCR results were examined. In the cell cultures, influenza viruses were detected in 488 of the 715 specimens (overall, 68.3%; AH3, 41.7%; B, 26.4%; AH3 and B, 0.1%). For influenza A, the sensitivity of this test was 95.4% (125/131) for nasal aspirates, 96.8% (92/95) for nasal swabs, and 85.1% (63/74) for throat swabs. For influenza B, the sensitivity of this test was 91.2% (52/57) for nasal aspirates, 88.1% (59/67) for nasal swabs, and 71.6% (48/67) for throat swabs. The new test exhibited a remarkably higher sensitivity to influenza A in throat swabs than the old version of Espline. Only two false positive results were obtained out of a total of 223 virus negative specimens; the specificity of the test was 100% (88/88) for nasal aspirates, 97.6% (81/83) for nasal swabs, and 100% (52/52) for throat swabs. We conclude that the new Espline Influenza A&B-N rapid diagnostic test is easy to use and has a high sensitivity and specificity, especially for influenza A.


The antibody aducanumab reduces Aβ plaques in Alzheimer's disease.
Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.


Loss of synaptonemal complex protein-1, a synaptonemal complex protein, contributes to the initiation of follicular assembly in the developing rat ovary.
In the rat ovary, germ and somatic cells become organized into primordial follicles 48-72 h after birth. Although several genes have been implicated in the control of early follicular growth, less is known about the factors involved in the formation of primordial follicles. Using the method of differential display of mRNAs, we found several genes differentially expressed at the time of follicular assembly. One of them encodes synaptonemal complex protein-1 (SCP1), a core component of the protein complex that maintains recombining chromosomes together during prophase I of the first meiotic division in germ cells. This association, evident during the pachytene stage, ends when chromosomal desynapsis begins in the diplotene stage at the end of prophase I. Oocytes become arrested in the diplotene/dictate stage before becoming enclosed into primordial follicles, suggesting that oocytes must complete meiotic prophase I before becoming competent to direct follicle assembly. We now show that attainment of the diplotene stage results in follicular formation. In developing rat ovaries, SCP1 mRNA expression is confined to oocytes and decreases precipitously within 24 h after birth, preceding the organization of primordial follicles. The premature loss of SCP1, achieved via treatment with an antisense oligodeoxynucleotide targeting SCP1 mRNA, resulted in more oocytes reaching the diplotene stage, as evidenced by a decrease in the number of oocytes containing germ cell nuclear antigen-1 (a nuclear protein whose expression ceases in diplotene) and an increase in the number of oocytes expressing MSY2 (a cytoplasmic Y box protein expressed in oocytes that have become arrested in diplotene). SCP1-deficient ovaries exhibited an increased number of newly formed follicles, suggesting that completion of meiotic prophase I endows oocytes with the ability to orchestrate follicular assembly.


Light-emitting diode therapy reduces persistent inflammatory pain: Role of interleukin 10 and antioxidant enzymes.
During the last decades, the use of light-emitting diode therapy (LEDT) has increased significantly for the treatment of wound healing, analgesia and inflammatory processes. Nevertheless, scientific data on the mechanisms responsible for the therapeutic effect of LEDT are still insufficient. Thus, this study investigated the analgesic, anti-inflammatory and anti-oxidative effect of LEDT in the model of chronic inflammatory hyperalgesia. Mice injected with Complete Freund's Adjuvant (CFA) underwent behavioral, i.e. mechanical and hot hyperalgesia; determination of cytokine levels (tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), IL-10), oxidative stress markers (protein carbonyls and thiobarbituric acid reactive species (TBARS)) and antioxidant enzymes (catalase (CAT) and superoxide dismutase (SOD)). Additionally, mice were pretreated with either naloxone or fucoidin and mechanical hyperalgesia was assessed. LEDT inhibited mechanical and thermal hyperalgesia induced by CFA injection. LEDT did not reduce paw edema, neither influenced the levels of TNF-α and IL1-β; although it increased the levels of IL-10. LEDT significantly prevented TBARS increase in both acute and chronic phases post-CFA injection; whereas protein carbonyl levels were reduced only in the acute phase. LEDT induced an increase in both SOD and CAT activity, with effects observable in the acute but not in the chronic. And finally, pre-administration of naloxone or fucoidin prevented LEDT analgesic effect. These data contribute to the understanding of the neurobiological mechanisms involved in the therapeutic effect of LEDT as well as provides additional support for its use in the treatment of painful conditions of inflammatory etiology.


Web-spinning caterpillar stalks snails.
Moths and butterflies compose one of the most diverse insect orders, but they are overwhelmingly herbivorous. Less than 0.2% are specialized predators, indicating that lepidopteran feeding habits are highly constrained. We report a Hawaiian caterpillar that specializes on snails, a unique food source requiring an unusual feeding strategy. The caterpillar uses silk to restrain live prey. All caterpillars have silk glands, but none are known to use silk in this spiderlike fashion. Considering the canalization of caterpillar diets, evolution to attack and feed on snails is an anomaly. Hawaii s isolation and consequently disharmonic biota likely promote evolutionary experiments that occur nowhere else.


Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy.
Label-free chemical contrast is highly desirable in biomedical imaging. Spontaneous Raman microscopy provides specific vibrational signatures of chemical bonds, but is often hindered by low sensitivity. Here we report a three-dimensional multiphoton vibrational imaging technique based on stimulated Raman scattering (SRS). The sensitivity of SRS imaging is significantly greater than that of spontaneous Raman microscopy, which is achieved by implementing high-frequency (megahertz) phase-sensitive detection. SRS microscopy has a major advantage over previous coherent Raman techniques in that it offers background-free and readily interpretable chemical contrast. We show a variety of biomedical applications, such as differentiating distributions of omega-3 fatty acids and saturated lipids in living cells, imaging of brain and skin tissues based on intrinsic lipid contrast, and monitoring drug delivery through the epidermis.


Yersinia enterocolitica-mediated degradation of neutrophil extracellular traps (NETs).
Neutrophil extracellular trap (NET) formation is described as a tool of the innate host defence to fight against invading pathogens. Fibre-like DNA structures associated with proteins such as histones, cell-specific enzymes and antimicrobial peptides are released, thereby entrapping invading pathogens. It has been reported that several bacteria are able to degrade NETs by nucleases and thus evade the NET-mediated entrapment. Here we studied the ability of three different Yersinia serotypes to induce and degrade NETs. We found that the common Yersinia enterocolitica serotypes O:3, O:8 and O:9 were able to induce NETs in human blood-derived neutrophils during the first hour of co-incubation. At later time points, the NET amount was reduced, suggesting that degradation of NETs has occurred. This was confirmed by NET degradation assays with phorbol-myristate-acetate-pre-stimulated neutrophils. In addition, we found that the Yersinia supernatants were able to degrade purified plasmid DNA. The absence of Ca(2+) and Mg(2+) ions, but not that of a protease inhibitor cocktail, completely abolished NET degradation. We therefore postulate that Y. enterocolitica produces Ca(2+)/Mg(2+)-dependent NET-degrading nucleases as shown for some Gram-positive pathogens.


Emission polarization of random lasers in organic dye solutions.
This Letter presents a polarimetric study of the emission of random lasers from organic dyes. Coherent lasing modes from samples with ethanol solvent showed a high degree of polarization and did not influence each other in polarization. The proper choice of a laser dye with asymmetric absorption momenta, a highly viscous solvent, and a linear pump polarization can cause the random lasing emission to be completely linearly polarized for all wavelengths within the amplification range.