Studies Of Paleozoic Fungi. Iv. Wood‐Decaying Fungi In Callixylon Newberryi From The Upper Devonian

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141580/1/ajb208449.pd

The Oldest Mineralized Bryozoan? A Possible Palaeostomate in the Lower Cambrian of Nevada, USA

All skeletal marine invertebrate phyla appeared during the Cambrian explosion, except for Bryozoa with mineralized skeletons, which first appear in the Early Ordovician. However, the skeletal diversity of Early Ordovician bryozoans suggests a preceding interval of diversification. We report a possible earliest occurrence of palaeostomate bryozoans in limestones of the Cambrian Age 4 Harkless Formation, western United States. Following recent interpretations of the early Cambrian Protomelission as a soft-bodied bryozoan, our findings add to the evidence of early Cambrian roots for the Bryozoa. The Harkless fossils resemble some esthonioporate and cystoporate bryozoans, showing a radiating pattern of densely packed tubes of the same diameter and cross-sectional shape. Further, they show partitioning of new individuals from parent tubes through the formation of a separate wall, a characteristic of interzooecial budding in bryozoans. If confirmed as bryozoans, these fossils would push back the appearance of mineralized skeletons in this phylum by ~30 million years and impact interpretations of their evolution

Determinación de la diversidad genética del citomegalovirus humano en diferentes poblaciones de pacientes en Costa Rica

Seroprevalence of HCMV in Costa Rica is greater than 95% in adults; primary infections occur early in life and is the most frequent congenital infection in newborns. The objectives of this study were to determine the genetic variability and genotypes of HCMV gB gene in Costa Rica. Samples were collected from alcoholics, pregnant women, blood donors, AIDS patients, hematology-oncology (HO) children and HCMV isolates from neonates with cytomegalic inclusion disease. A semi-nested PCR system was used to obtain a product of 293-296 bp of the gB gene to be analyzed by Single Stranded Conformational Polymorphism (SSCP) and sequencing to determine the genetic polymorphic pattern and genotypes, respectively. AIDS patients showed the highest polymorphic diversity with 14 different patterns while fifty-six percent of HO children samples showed the same polymorphic pattern, suggesting in this group a possible nosocomial infection. In neonates three genotypes (gB1, gB2 and gB3), were determined while AIDS patients and blood donors only showed one (gB2). Of all samples analyzed only genotypes gB1, 2 and 3 were determined, genotype gB2 was the most frequent (73%) and mixed infections were not detected. The results of the study indicate that SSCP could be an important tool to detect HCMV intra-hospital infections and suggests a need to include additional study populations to better determine the genotype diversity and prevalence.La seroprevalencia de citomegalovirus es mayor del 95% en la población adulta de Costa Rica; la infección primaria ocurre muy temprano en la vida y es la infección congénita más frecuente en recién nacidos. El objetivo de este trabajo fue determinar la variabilidad genética y los genotipos del gene gB del citomegalovirus humano. Se recolectaron muestras de sangre de mujeres embarazadas, alcohólicos, pacientes con SIDA, niños con trastornos hemato-oncológicos, donadores de sangre y se incluyeron aislamientos de citomegalovirus de neonatos con enfermedad congénita. Se utilizó un sistema de PCR semi-anidado para obtener una banda de 293-296 pares de bases, la cual fue analizada por la técnica de Polimorfismo conformacional de banda simple (PCBS) y secuenciada para determinar los patrones genéticos polimórficos y los genotipos, respectivamente. La mayor diversidad polimórfica se encontró en los pacientes con SIDA con 14 patrones diferentes mientras que en los niños con trastornos hemato-oncológicos se demostró el mismo patrón en el 56% de los casos, sugiriendo una posible infección nosocomial en este grupo. En los neonatos se encontraron tres genotipos (gB1, gB2, gB3) mientras que en los pacientes con SIDA y en los donadores de sangre solo se demostró el gB2. En las muestras analizadas se determinaron los genotipos gB1, gB2 y gB3 y el gB2 se determinó en el 73% de los casos, no se detectaron infecciones mixtas. Los resultados de este trabajo indican que la técnica del PCBS puede ser una herramienta importante para detectar el citomegalovirus humano en infecciones intrahospitalarias y se sugiere la importancia de incluir poblaciones de estudio adicionales para determinar mejor la diversidad genética y su prevalencia

The structural basis for high affinity binding of α1-acid glycoprotein to the potent antitumor compound UCN-01

The α1-acid glycoprotein (AGP) is an abundant blood plasma protein with important immunomodulatory functions coupled to endogenous and exogenous ligand-binding properties. Its affinity for many drug-like structures, however, means AGP can have a significant effect on the pharmokinetics and pharmacodynamics of numerous small molecule therapeutics. Staurosporine, and its hydroxylated forms UCN-01 and UCN-02, are kinase inhibitors that have been investigated at length as antitumour compounds. Despite their potency, these compounds display poor pharmokinetics due to binding to both AGP variants, AGP1 and AGP2. The recent renewed interest in UCN-01 as a cytostatic protective agent prompted us to solve the structure of the AGP2–UCN-01 complex by X-ray crystallography, revealing for the first time the precise binding mode of UCN-01. The solution NMR suggests AGP2 undergoes a significant conformational change upon ligand binding, but also that it uses a common set of sidechains with which it captures key groups of UCN-01 and other small molecule ligands. We anticipate that this structure and the supporting NMR data will facilitate rational redesign of small molecules that could evade AGP and therefore improve tissue distribution

Food insecurity in Detroit: exploring the relationship between patient-reported food insecurity and proximity to healthful grocery stores

Objective: The objective of the current study was to determine if patients of a large health care system in Detroit who self-identify as food insecure live further away from healthy grocery stores compared with food secure patients. Second, we explored whether food insecurity and distance to healthy grocery stores are related to ecological measures of vehicle availability in the area of residence. Design: A secondary data analysis that uses baseline data from a pilot intervention/feasibility study. Setting: Detroit, Michigan, USA. Participants: Patients of Henry Ford Health System were screened for food insecurity to determine eligibility for a pilot intervention/feasibility study (i.e. Henry’s Groceries for Health), conducted through a collaboration with Gleaners Community Foodbank of Southeastern Michigan. Only patients residing in Detroit city limits (including Highland Park and Hamtramck) were included in the secondary analysis. Of the 1,100 patients included in the analysis, 336 (31 %) were food insecure. Results: After accounting for socio-demographic factors associated with food insecurity, we did not find evidence that food insecure patients lived further away from healthier grocery stores, nor was this modified by ecological measures of vehicle access. However, some neighbourhoods were identified as having a significantly higher risk of food insecurity. Conclusions: Food insecure patients in Detroit are perhaps limited by social and political determinants and not their immediate neighbourhood geography or physical access to healthy grocery stores. Future research should explore the complexity in linkages between household socio-economic factors, socio-cultural dynamics and the neighbourhood food environment

Novel chemical library screen identifies naturally occurring plant products that specifically disrupt glioblastoma-endothelial cell interactions

Tumor growth is not solely a consequence of autonomous tumor cell properties. Rather, tumor cells act upon and are acted upon by their microenvironment. It is tumor tissue biology that ultimately determines tumor growth. Thus, we developed a compound library screen for agents that could block essential tumor-promoting effects of the glioblastoma (GBM) perivascular stem cell niche (PVN). We modeled the PVN with three-dimensional primary cultures of human brain microvascular endothelial cells in Matrigel. We previously demonstrated stimulated growth of GBM cells in this PVN model and used this to assay PVN function. We screened the Microsource Spectrum Collection library for drugs that specifically blocked PVN function, without any direct effect on GBM cells themselves. Three candidate PVN-disrupting agents, Iridin, Tigogenin and Triacetylresveratrol (TAR), were identified and evaluated in secondary in vitro screens against a panel of primary GBM isolates as well as in two different in vivo intracranial models. Iridin and TAR significantly inhibited intracranial tumor growth and prolonged survival in these mouse models. Together these data identify Iridin and TAR as drugs with novel GBM tissue disrupting effects and validate the importance of preclinical screens designed to address tumor tissue function rather than the mechanisms of autonomous tumor cell growth

Inhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel

Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloid fibrillogenesis. It is modelled by exposure of the protein to non-physiological low pH in vitro and is inhibited by small molecule compounds, such as the drug tafamidis. We have recently identified a new mechano-enzymatic pathway of TTR fibrillogenesis in vitro, catalysed by selective proteolytic cleavage, which produces a high yield of genuine amyloid fibrils. This pathway is efficiently inhibited only by ligands that occupy both binding sites in TTR. Tolcapone, which is bound with similar high affinity in both TTR binding sites without the usual negative cooperativity, is therefore of interest. Here we show that TTR fibrillogenesis by the mechano-enzymatic pathway is indeed more potently inhibited by tolcapone than by tafamidis but neither, even in large molar excess, completely prevents amyloid fibril formation. In contrast, mds84, the prototype of our previously reported bivalent ligand TTR 'superstabiliser' family, is notably more potent than the monovalent ligands and we show here that this apparently reflects the critical additional interactions of its linker within the TTR central channel. Our findings have major implications for therapeutic approaches in TTR amyloidosis

Diatom teratologies as biomarkers of contamination: Are all deformities ecologically meaningful?

Contaminant-related stress on aquatic biota is difficult to assess when lethal impacts are not observed. Diatoms, by displaying deformities (teratologies) in their valves, have the potential to reflect sub-lethal responses to environmental stressors such as metals and organic compounds. For this reason, there is great interest in using diatom morphological aberrations in biomonitoring. However, the detection and mostly the quantification of teratologies is still a challenge; not all studies have succeeded in showing a relationship between the proportion of abnormal valves and contamination level along a gradient of exposure. This limitation in part reflects the loss of ecological information from diatom teratologies during analyses when all deformities are considered. The type of deformity, the severity of aberration, species proneness to deformity formation, and propagation of deformities throughout the population are key components and constraints in quantifying teratologies. Before a metric based on diatom deformities can be used as an indicator of contamination, it is important to better understand the “ecological signal” provided by this biomarker. Using the overall abundance of teratologies has proved to be an excellent tool for identifying contaminated and non-contaminated environments (presence/absence), but refining this biomonitoring approach may bring additional insights allowing for a better assessment of contamination level along a gradient. The dilemma: are all teratologies significant, equal and/or meaningful in assessing changing levels of contamination? This viewpoint article examines numerous interrogatives relative to the use of diatom teratologies in water quality monitoring, provides selected examples of differential responses to contamination, and proposes solutions that may refine our understanding and quantification of the stress. This paper highlights the logistical problems associated with accurately evaluating and interpreting teratologies and stimulates more discussion and research on the subject to enhance the sensitivity of this metric in bioassessments

Changes in Muscle Metabolism are Associated with Phenotypic Variability in Golden Retriever Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is an X-chromosome-linked disorder and the most common monogenic disease in people. Affected boys are diagnosed at a young age, become non-ambulatory by their early teens, and succumb to cardiorespiratory failure by their thirties. Despite being a monogenic condition resulting from mutations in the DMD gene, affected boys have noteworthy phenotypic variability. Efforts have identified genetic modifiers that could modify disease progression and be pharmacologic targets. Dogs affected with golden retriever muscular dystrophy (GRMD) have absent dystrophin and demonstrate phenotypic variability at the functional, histopathological, and molecular level. Our laboratory is particularly interested in muscle metabolism changes in dystrophin-deficient muscle. We identified several metabolic alterations, including myofiber type switching from fast (type II) to slow (type I), reduced glycolytic enzyme expression, reduced and morphologically abnormal mitochondria, and differential AMP-kinase phosphorylation (activation) between hypertrophied and wasted muscle. We hypothesize that muscle metabolism changes are, in part, responsible for phenotypic variability in GRMD. Pharmacological therapies aimed at modulating muscle metabolism can be tested in GRMD dogs for efficacy

Effects of self-transcendence on neural responses to persuasive messages and health behavior change

Self-transcendence refers to a shift in mindset from focusing on self-interests to the well-being of others. We offer an integrative neural model of self-transcendence in the context of persuasive messaging by examining the mechanisms of self-transcendence in promoting receptivity to health messages and behavior change. Specifically, we posited that focusing on values and activities that transcend the self can allow people to see that their self-worth is not tied to a specific behavior in question, and in turn become more receptive to subsequent, otherwise threatening health information. To test whether inducing self-transcendent mindsets before message delivery would help overcome defensiveness and increase receptivity, we used two priming tasks, affirmation and compassion, to elicit a transcendent mindset among 220 sedentary adults. As preregistered, those who completed a self-transcendence task before health message exposure, compared with controls, showed greater increases in objectively logged levels of physical activity throughout the following month. In the brain, self-transcendence tasks up-regulated activity in a region of the ventromedial prefrontal cortex, chosen for its role in positive valuation and reward processing. During subsequent health message exposure, self-transcendence priming was associated with increased activity in subregions of the ventromedial prefrontal cortex, implicated in self-related processing and positive valuation, which predicted later decreases in sedentary behavior. The present findings suggest that having a positive self-transcendent mindset can increase behavior change, in part by increasing neural receptivity to health messaging