Effects of mixing in threshold models of social behavior.
We consider the dynamics of an extension of the influential Granovetter model of social behavior, where individuals are affected by their personal preferences and observation of the neighbors' behavior. Individuals are arranged in a network (usually the square lattice), and each has a state and a fixed threshold for behavior changes. We simulate the system asynchronously by picking a random individual and we either update its state or exchange it with another randomly chosen individual (mixing). We describe the dynamics analytically in the fast-mixing limit by using the mean-field approximation and investigate it mainly numerically in the case of finite mixing. We show that the dynamics converge to a manifold in state space, which determines the possible equilibria, and show how to estimate the projection of this manifold by using simulated trajectories, emitted from different initial points. We show that the effects of considering the network can be decomposed into finite-neighborhood effects, and finite-mixing-rate effects, which have qualitatively similar effects. Both of these effects increase the tendency of the system to move from a less-desired equilibrium to the "ground state." Our findings can be used to probe shifts in behavioral norms and have implications for the role of information flow in determining when social norms that have become unpopular in particular communities (such as foot binding or female genital cutting) persist or vanish.


Most invasive species largely conserve their climatic niche.
The ecological niche is a key concept for elucidating patterns of species distributions and developing strategies for conserving biodiversity. However, recent times are seeing a widespread debate whether species niches are conserved across space and time (niche conservatism hypothesis). Biological invasions represent a unique opportunity to test this hypothesis in a short time frame at the global scale. We synthesized empirical findings for 434 invasive species from 86 studies to assess whether invasive species conserve their climatic niche between native and introduced ranges. Although the niche conservatism hypothesis was rejected in most studies, highly contrasting conclusions for the same species between and within studies suggest that the dichotomous conclusions of these studies were sensitive to techniques, assessment criteria, or author preferences. We performed a consistent quantitative analysis of the dynamics between native and introduced climatic niches reported by previous studies. Our results show there is very limited niche expansion between native and introduced ranges, and introduced niches occupy a position similar to native niches in the environmental space. These findings support the niche conservatism hypothesis overall. In particular, introduced niches were narrower for terrestrial animals, species introduced more recently, or species with more native occurrences. Niche similarity was lower for aquatic species, species introduced only intentionally or more recently, or species with fewer introduced occurrences. Climatic niche conservatism for invasive species not only increases our confidence in transferring ecological niche models to new ranges but also supports the use of niche models for forecasting species responses to changing climates.


Spatial scales of bacterial community diversity at cold seeps (Eastern Mediterranean Sea).
Cold seeps are highly productive, fragmented marine ecosystems that form at the seafloor around hydrocarbon emission pathways. The products of microbial utilization of methane and other hydrocarbons fuel rich chemosynthetic communities at these sites, with much higher respiration rates compared with the surrounding deep-sea floor. Yet little is known as to the richness, composition and spatial scaling of bacterial communities of cold seeps compared with non-seep communities. Here we assessed the bacterial diversity across nine different cold seeps in the Eastern Mediterranean deep-sea and surrounding seafloor areas. Community similarity analyses were carried out based on automated ribosomal intergenic spacer analysis (ARISA) fingerprinting and high-throughput 454 tag sequencing and were combined with in situ and ex situ geochemical analyses across spatial scales of a few tens of meters to hundreds of kilometers. Seep communities were dominated by Deltaproteobacteria, Epsilonproteobacteria and Gammaproteobacteria and shared, on average, 36% of bacterial types (ARISA OTUs (operational taxonomic units)) with communities from nearby non-seep deep-sea sediments. Bacterial communities of seeps were significantly different from those of non-seep sediments. Within cold seep regions on spatial scales of only tens to hundreds of meters, the bacterial communities differed considerably, sharing <50% of types at the ARISA OTU level. Their variations reflected differences in porewater sulfide concentrations from anaerobic degradation of hydrocarbons. This study shows that cold seep ecosystems contribute substantially to the microbial diversity of the deep-sea.


The glycerol backbone of phospholipids derives from noncarbohydrate precursors in starved lung cancer cells.
Cancer cells are reprogrammed to consume large amounts of glucose to support anabolic biosynthetic pathways. However, blood perfusion and consequently the supply with glucose are frequently inadequate in solid cancers. PEPCK-M (PCK2), the mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK), has been shown by us and others to be functionally expressed and to mediate gluconeogenesis, the reverse pathway of glycolysis, in different cancer cells. Serine and ribose synthesis have been identified as downstream pathways fed by PEPCK in cancer cells. Here, we report that PEPCK-M-dependent glycerol phosphate formation from noncarbohydrate precursors (glyceroneogenesis) occurs in starved lung cancer cells and supports de novo glycerophospholipid synthesis. Using stable isotope-labeled glutamine and lactate, we show that PEPCK-M generates phosphoenolpyruvate and 3-phosphoglycerate, which are at least partially converted to glycerol phosphate and incorporated into glycerophospholipids (GPL) under glucose and serum starvation. This pathway is required to maintain levels of GPL, especially phosphatidylethanolamine (PE), as shown by stable shRNA-mediated silencing of PEPCK-M in H23 lung cancer cells. PEPCK-M shRNA led to reduced colony formation after starvation, and the effect was partially reversed by the addition of dioleyl-PE. Furthermore, PEPCK-M silencing abrogated cancer growth in a lung cancer cell xenograft model. In conclusion, glycerol phosphate formation for de novo GPL synthesis via glyceroneogenesis is a newly characterized anabolic pathway in cancer cells mediated by PEPCK-M under conditions of severe nutrient deprivation.


Long-Term Functional and Anatomical Outcome after Descemet Stripping Automated Endothelial Keratoplasty: A Prospective Single-Center Study.
To investigate the long-term anatomical and functional outcomes of Descemet stripping automated endothelial keratoplasty (DSAEK). Prospective follow-up of 114 eyes (95 subjects) after DSAEK for endothelial dysfunction. Measurements included best spectacle-corrected visual acuity (BSCVA), straylight, endothelial cell density (ECD), and graft thickness. The mean follow-up time was 5.1 ± 1.5 years. Four grafts ultimately failed (after 5 to 7 years). From baseline up to 1 year after DSAEK, mean BSCVA improved by 0.30 logMAR. This beneficial effect remained until the last follow-up (LFU). After DSAEK, straylight was reduced. ECD sharply dropped by 900 cells/mm2 (33%) immediately after surgery and, thereafter, steadily decreased at a rate of 11 cells/mm2 per month. No significant correlation was observed between graft thickness at 3 years and BSCVA. We observed a low graft failure rate and a normalization of graft thickness. Postoperative straylight remained elevated relative to the normal population. The sharp initial and the subsequent more gradual ECD decline are consistent with other studies. A significant and prolonged functional gain can be achieved by posterior lamellar grafting for endothelial dysfunction.


Mode of reproduction in Arabidopsis suecica.
The breeding system of Arabidopsis suecica was investigated through genetic analysis of microsatellite segregation patterns in five controlled crosses as well as in 16 single-mother families collected in the wild. Analysis of single and two-locus segregations in the F2 generation following a cross clearly shows that A. suecica is reproduces sexually. The single-mother families show a high level of homozygosity corroborating earlier results indicating a high level of inbreeding. The high level of individual homozygosity is due both to a high level of selfing and to the underlying population structure.


Damage to the epithelial basement membrane in the corneas of diabetic rabbits.
Epithelial healing problems and basement membrane abnormalities have been observed in the corneas of patients with diabetes mellitus. In this study the rates of corneal epithelial wound healing following transcorneal freezing (with a 6-mm-diameter probe cooled in liquid nitrogen) were compared in diabetic (alloxan-induced) and nondiabetic rabbits. Also compared was the extent of injury to the epithelial basement membrane between the two groups. The overall rate of wound healing was faster in the diabetic animals; the wounds closed at 40 hours after freezing in diabetic animals and at 45 hours after in the nondiabetic controls. The lamina densa of the basement membrane was removed by the freezing procedure in two thirds of the diabetic animals but not in any of the controls. The results of this study indicate that epithelial healing problems in diabetes may be related to damage to the basement membrane, with resulting poor adhesion of regenerating epithelial cells.


Protocol for the Arterial Revascularisation Trial (ART). A randomised trial to compare survival following bilateral versus single internal mammary grafting in coronary revascularisation [ISRCTN46552265].
Standard coronary artery bypass graft surgery uses a single internal mammary artery and supplemental vein or radial artery grafts. Several observational studies have suggested a survival benefit with two internal mammary artery grafts compared to a single internal mammary artery graft, but this has not been tested in a randomised trial. The Arterial Revascularisation Trial is a Medical Research Council and British Heart Foundation funded, multi-centre international trial comparing single internal mammary artery grafting versus bilateral internal mammary artery grafting. Twenty centres in the UK, Australia, Poland and Brazil are planning to randomise 3000 coronary artery bypass graft surgery patients to single or bilateral internal mammary artery grafting. Supplemental grafts may be either saphenous vein or radial artery. Coronary artery bypass grafting can be performed as an on-pump or off-pump procedure. The primary outcome is survival at 10 years and secondary end-points include clinical events, quality of life and cost effectiveness. The effect of age, left ventricular function, diabetes, number of grafts, vein grafts and off-pump surgery are pre-specified subgroups. The Arterial Revascularisation Trial is one of the first randomised trials to evaluate the effects on survival and other clinical outcomes of single internal mammary artery grafting versus bilateral internal mammary artery grafting, and will help to establish the best approach for patients requiring coronary artery bypass graft surgery.


Essential Oil Composition and Larvicidal Evaluation of Platycladus orientalis against Two Mosquito Vectors, Anopheles stephensi and Culex pipiens.
Natural plant products as larvicides could be considered as desirable alternatives to synthetic chemical insecticides for vector management. This study was undertaken to assess the mosquito larvicide activity of the essential oil from fresh leaves of Platycladus orientalis against two medically important species of mosquito vectors. Essential oil was extracted by hydrodistillation and analyzed with gas chromatography and mass spectrometry (GC-MS). Fresh leaves of P. orientalis tree (500g) were collected in June 2014 from Tehran, Iran and was authenticated at the Department of Medical Entomology and Vector Control, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.In addition, the larvicidal potential of oil was evaluated against late-3rd or young-4th instar larvae of Anopheles stephensi and Culex pipiens under laboratory condition. The mortality counts were made after 24h and LC50 and LC90 values were calculated. Forty-six components in leaves of P. orientalis were identified. The major components were α-Pinene (20.17%), 3-Carene (14%) and Cedrol (9.51%). The LC50 values against An. stephensi and Cx. pipiens larvae were 11.67ppm and 18.60ppm after 24h, respectively. Platycladus orientalis oil could be considered as a natural larvicide for mosquito larval control.


What is the role of harm reduction when drug users say they want abstinence?
Quantitative survey data indicate that most drug users starting treatment want abstinence rather than harm reduction (McKeganey et al., 2004). This finding has been seized upon by those seeking 'evidence' that abstinence is the bedrock of recovery and harm reduction is a negative and oppositional philosophy. However, all research involves questions of meaning, definition and value and an alternative research paradigm and different study design can provide important additional insights into treatment aspirations, including the desire for abstinence. Qualitative interviews conducted with 30 recovering heroin users (15 males and 15 females) in Southern England in 2009 confirm that those starting treatment often report a desire for abstinence. Nonetheless, drug users are frequently uncertain about their ability to achieve this and can have very different and inconsistent understandings of what being abstinent means. We suggest that the work of the critical theorist Habermas (1970, 1991) could improve our understanding of abstinence and is consistent with recent efforts to achieve a working definition of recovery. Importantly, our qualitative data also reveal that drug users have treatment aspirations that extend far beyond their drug consumption. They additionally want to improve relationships, engage in meaningful activities, acquire material possessions, and achieve better mental and physical health. Moreover, these broader life goals are often inextricably linked to their drug taking. From this, we conclude that both abstinence and harm reduction discourses should more routinely prioritise the many diverse 'wellness' goals that so clearly motivate treatment clients. The harm reduction field will then likely find that it has more in common with abstinence-oriented services and the broader recovery agenda than it might otherwise have imagined.


Dexmedetomidine attenuates the propofol-induced long-term neurotoxicity in the developing brain of rats by enhancing the PI3K/Akt signaling pathway.
Propofol induces short- and long-term neurotoxicity. Our previous study showed that dexmedetomidine (Dex) can attenuate the propofol-induced acute neurotoxicity in rodents by enhancing the PI3K/Akt signaling. However, whether treatment of young rats with Dex could protect them from long-term neurotoxicity induced by propofol is unclear. Seven-day-old male Sprague Dawley rats were randomized and injected intraperitoneally with saline (100 μL, NS), propofol (100 mg/kg), Dex (75 μg/kg), propofol (100 mg/kg) plus Dex (25, 50 or 75 μg/kg), 10% dimethyl sulfoxide (DMSO, 100 μL) or TDZD-8 (a GSK3β inhibitor, 1 mg/kg), or intracerebroventricularly with DMSO (5 μL) or LY294002 (a PI3K inhibitor, 25 μg/5 μL DMSO). Other rats in the experimental group were injected with the same doses of propofol, Dex and LY294002 or TDZD-8. All the rats were monitored until they were 9 weeks old. Their spatial learning and memory were tested by Morris water maze. The neuronal apoptosis, expression of PSD95, expression and phosphorylation of Akt and GSK3β and synaptic ultrastructures were determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, immunohistochemistry, Western blot and transmission electron microscopy assays, respectively. Compared with the NS control group, young rats injected with intralipid, Dex, TDZD-8, LY294002 or DMSO alone did not show any significant change as they aged. Propofol significantly increased the escape latency time, hippocampal neuroapoptosis and synaptic ultrastructural changes but decreased the relative levels of PSD95 expression, and Akt and GSK3β phosphorylation in the developing hippocampus of the rats. The neuronal toxic effects of propofol were significantly mitigated by the pretreatment with a higher dose of Dex. The neuroprotective effect of Dex was enhanced by the treatment with TDZD-8, but was completely abrogated by the treatment with LY294002. Our results indicated that the pretreatment of young rats with Dex attenuated the propofol-induced long-term neurotoxicity in their developing hippocampus by enhancing the PI3K/Akt signaling.


CSF 5-HIAA, serum cortisol, and age differentially predict vegetative and cognitive symptoms in depression.
Prior studies have shown that both cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5-HIAA) and serum cortisol levels are related to overall symptom severity in depression. In the present study, 30 unmedicated inpatients meeting Research Diagnostic Criteria (RDC) criteria for depression participated in serum cortisol collection and a lumbar puncture for CSF. A multiple regression evaluated the ability of CSF 5-HIAA, serum cortisol, and age to predict cognitive and vegetative symptom clusters of the Hamilton Rating Scale for Depression. The multiple regression to predict the vegetative symptom cluster was highly significant overall (p = 0.002) and found that age and cortisol but not 5-HIAA predicted vegetative symptoms. The regression to predict the cognitive cluster narrowly missed overall significance (p = 0.06). Both CSF 5-HIAA and serum cortisol predicted cognitive symptoms and 5-HIAA predicted the cognitive cluster more strongly than cortisol. Age did not predict cognitive symptoms. The results suggest a dissociation between serum cortisol levels and CSF 5-HIAA in predicting vegetative and cognitive symptom clusters in depression.


Suicide mortality and agricultural rationalization in post-war Europe.
The relationship between agricultural rationalization and suicide mortality has been little researched. On the basis of the hypothesis that agricultural rationalization leads to more suicide, this study investigated whether a general relationship could be found between structural change in agriculture and suicide mortality in post-war Europe. Due to the expected small size of the effect, the data were deliberately collected so as to maximize the variation in the independent variable. Annual national-level data on suicide mortality, the percentage of the work force in agricultural employment, and the unemployment level were collected from those countries and 10-year periods where the structural changes (reductions in employment) in agriculture between 1950 and 1995 had been most and least pronounced. In order to avoid confounders, the annual changes in the variables' values were correlated with each other, adding a control for the level of unemployment, and allowing for lagged effects. The annual changes in the levels of agricultural employment and those of suicide mortality did not covary at all. Controlling for unemployment levels did not change this, nor could any lagged effects be found. At the most general level, no causal relation between agricultural rationalization and suicide mortality was detected. This lack of a universal relation does not, however, preclude the possibility of the relationship existing given certain socio-historical circumstances.


Relation of light reflectance to histological and physical evaluations of cotton leaf maturity.
Cotton plants were grown hydroponically with controlled environment. Third, growth chamber grown true leaves of cotton plants were tagged on the day they became macroscopically visible. Beginning 3.0 days after tagging,five leaf harvests representing maturity dates were made at successive 2- or 3-day intervals. Measurements with a spectrophotometer made on the leaves showed that the largest increase in reflectance, about 5%, and decrease in transmittance, about 8%, occurred between average values for after-tagging-ages of 3.5 days and 8.0 days over the 0.75-1.35-micro wavelength interval. Between after-tagging-ages of 3.5 days and 8.0 days, leaves expanded approximately fivefold, numbers of intercellular spaces approximately doubled, and thicknesses increased 14%. The theory of diffuse reflectance and transmittance of a compact leaf of equivalent water thickness (EWT) specified by D is generalized to include also the noncompact leaf characterized by many intercellular air spaces, can be regarded as a pile of N compact layers separated by infinitesimal air spaces. The void area index (VAI) of a noncompact leaf is given by N - 1, where N is not necessarily an integer. Predictions from the generalized theory include a measure of the water, air, and plant pigments in a leaf. An effective dispersion curve associated with the leaf surfaces is also obtained. A derived parameter D/N largely determines the reflectance and transmittance of a typical leaf over the 1.40-2.50-micro spectral range. A cotton leaf is highly compact when it first unfolds. At this point D/N ~ 180 micro. This value is essentially the leaf thickness. Intercellular air spaces develop rapidly during the next few days, and D/N decreases in value to about 130 micro Subsequently, the leaf cells increase in size with no substantial further increase in the number of intercellular air spaces. This final growth phase is characterized by a slight increase in D/N to a maximum value of about 140 micro. Maximum reflectance of the leaf corresponds to a minimum value of D/N. The parameter D/N is highly correlated with the amount of intercellular air spaces in a leaf.


Landscape genetics of fishers (Martes pennanti) in the Northeast: dispersal barriers and historical influences.
Habitat fragmentation and overtrapping are thought to have resulted in severe population declines for fisher (Martes pennanti) across the northeastern United States, and by the end of the 1930s only 3 remnant populations remained. Subsequent trapping cessation, extensive reintroduction programs, and natural recolonization have helped fishers to reclaim much of their historical range. The degree to which these processes have impacted genetic structure in this species, however, remains unknown. We used 11 microsatellites from tissue samples (n = 432) of fishers to characterize contemporary population structure in light of historical population structure and thus to determine the relative influence of anthropogenic disturbances and natural landscape features in shaping genetic structure of the contemporary population. Our results indicated that 3 well-differentiated contemporary populations are present that correspond well with what would be expected based on their reported history. A course barrier to dispersal appears in the western portion of the study area associated with several lakes including Lake George and Great Sacandaga Lake. Large-scale reintroduction efforts and natural recolonizations have largely had predictable impacts on population structure. An important exception is the substantial impact of the reintroduction of fishers to Vermont.


[Intraoperative analgesic effect of epidural ketamine, clonidine or dexmedetomidine for upper abdominal surgery.].
Low dose ketamine decreases nociception by blocking NMDA receptor channels. Alpha2-adrenergic receptor activation triggers intense analgesic response. This study aimed at evaluating the effects of epidural ketamine, clonidine and dexmedetomidine, in patients undergoing upper abdominal surgery. Participated in this randomized double-blind study 70 patients of both genders, aged 18 to 50 years, physical status ASA I or II, submitted to subcostal cholecystectomy under general anesthesia associated to lumbar epidural anesthesia. Lumbar epidural anesthesia was randomly induced as follows: 20 mL of 0.75% ropivacaine and 1 mL of 0.9% saline solution (n = 10); Ketamine group: 20 mL of 0.75% ropivacaine and 0.5 mg.kg-1 ketamine (n = 20); Clonidine group: 20 mL of 0.75% ropivacaine and 1 mL clonidine (150 microg) (n = 20); Dexmedetomidine group: 20 mL of 0.75% ropivacaine and 2 microg.kg-1 dexmedetomidine (n = 20). Anesthesia was induced with etomidate, alfentanil and rocuronium and was maintained with isoflurane and alfentanil. Analgesia was evaluated by clinical signs and inhalational anesthetic inspired concentration was evaluated by anesthetic gases analysis during surgery. All patients receiving ketamine, clonidine or dexmedetomidine had heart rate and systemic blood pressure decrease and have not required perioperative analgesic complementation. For the same patients, isoflurane inspired concentration varied from 0.5vol% to 1vol% and there were no clinical signs or responses suggesting inadequate anesthetic levels. Epidural ketamine, clonidine or dexmedetomidine decreases alfentanil consumption and isoflurane inspired concentration in the intraoperative period of upper abdominal surgery.


Implementation of a Follow-Up System for Pediatric Sepsis Survivors in a Large Academic Pediatric Intensive Care Unit.
Background: Survivors of pediatric sepsis often develop new morbidities and deterioration in quality of life after sepsis, leading to a need for improved follow-up for children who survive sepsis. Objective: To implement a follow-up system for pediatric sepsis survivors in a pediatric health system. Methods: We performed a retrospective case series of patients treated for sepsis from October 2018 through October 2019 in a pediatric intensive care unit in a quaternary children's hospital, and describe implementation of a follow-up system for sepsis survivors. Program planning started in 2017 with multidisciplinary meetings including physical, occupational, and speech therapists, teachers, neuropsychologists, and coordinators from other survivorship programs (neonatology, stroke, and oncology). In 2018, a workshop was held to consult with local and national experts. The Pediatric Sepsis Survivorship Program launched in October 2018 led by a nurse coordinator who met with families to educate about sepsis and offer post-discharge follow-up. Patients with high pre-existing medical complexity or established subspecialty care were referred for follow-up through existing care coordination or subspecialty services plus guidance to monitor for post-sepsis morbidity. For patients with low-moderate medical complexity, the nurse coordinator administered a telephone-based health-assessment 2-3 months after discharge to screen for new physical or psychosocial morbidity. Patients flagged with concerns were referred to their primary physician and/or to expedited neuropsychological evaluation to utilize existing medical services. Results: Of 80 sepsis patients, 10 died, 20 were referred to care coordination by the program, and 13 had subspecialty follow-up. Five patients were followed in different health systems, four were adults not appropriate for existing follow-up programs, four remained hospitalized, and four were missed due to short stay or unavailable caregivers. The remaining 20 patients were scheduled for follow-up with the Pediatric Sepsis Program. Nine patients completed the telephone assessment. Four patients were receiving new physical or occupational therapy, and one patient was referred for neuropsychology evaluation due to new difficulties with attention, behavior, and completion of school tasks. Conclusions: Implementation of an efficient, low-cost pediatric sepsis survivorship program was successful by utilizing existing systems of care, when available, and filling a follow-up gap in screening for select patients.


MINSTED fluorescence localization and nanoscopy.
We introduce MINSTED, a fluorophore localization and super-resolution microscopy concept based on stimulated emission depletion (STED) that provides spatial precision and resolution down to the molecular scale. In MINSTED, the intensity minimum of the STED doughnut, and hence the point of minimal STED, serves as a movable reference coordinate for fluorophore localization. As the STED rate, the background and the required number of fluorescence detections are low compared with most other STED microscopy and localization methods, MINSTED entails substantially less fluorophore bleaching. In our implementation, 200-1,000 detections per fluorophore provide a localization precision of 1-3nm in standard deviation, which in conjunction with independent single fluorophore switching translates to a -100-fold improvement in far-field microscopy resolution over the diffraction limit. The performance of MINSTED nanoscopy is demonstrated by imaging the distribution of Mic60 proteins in the mitochondrial inner membrane of human cells.


EGFR mutations in US Hispanic versus non-Hispanic white patients with lung adenocarcinoma.
Lung cancer is the leading cause of cancer deaths worldwide. First-generation tyrosine kinase inhibitors improve progression-free survival in lung cancers with epidermal growth factor receptor (EGFR) mutations. EGFR mutations occur predominantly in exons 19 and 21 in lung adenocarcinomas of Asians (∼30%), whites (∼15%), and African Americans (∼19%). However, minimal information exists on the prevalence or type of genetic changes that occur in lung cancers in US Hispanic patients. We investigated the EGFR mutation frequency in primary lung adenocarcinomas in US Hispanics compared with non-Hispanic whites. To evaluate EGFR mutations in lung adenocarcinomas from US Hispanic patients compared with those from non-Hispanic white patients. DNA samples were extracted from paraffin-embedded tissue of consecutive lung adenocarcinomas from 83 patients. Samples were collected from 40 Hispanics and 43 non-Hispanic whites. Mutations in EGFR were analyzed using a custom assay. Results.-Fourteen of 83 patients (16.9%) had EGFR mutations in their tumor DNA, including 6 of 40 Hispanics (15.0%) and 8 of 43 non-Hispanic whites (18.6%). No association with age, sex, or tumor stage was identified. Smoking history could not be obtained for most of the 83 patients, although 8 of the 11 patients with EGFR mutations for whom smoking history was obtained were nonsmokers. Most of the tumors with EGFR mutations (12 of 14; 85.7%) were acinar with lepidic or papillary subtypes. EGFR mutations occurred in exon 19 (42.8%), exon 18 (28.6%), exon 20 (28.6%), and exon 21 (14.3%). Two cases had 2 mutations identified in different exons. The frequency of EGFR mutations is similar in US Hispanics compared with non-Hispanic whites.


Electronic application to improve management of infections in low-income neonatal units: pilot implementation of the NeoTree beta app in a public sector hospital in Zimbabwe.
There are 2. 4 million annual neonatal deaths worldwide. Simple, evidence-based interventions such as temperature control could prevent approximately two-thirds of these deaths. However, key problems in implementing these interventions are a lack of newborn-trained healthcare workers and a lack of data collection systems. NeoTree is a digital platform aiming to improve newborn care in low-resource settings through real-time data capture and feedback alongside education and data linkage. This project demonstrates proof of concept of the NeoTree as a real-time data capture tool replacing handwritten clinical paper notes over a 9-month period in a tertiary neonatal unit at Harare Central Hospital, Zimbabwe. We aimed to deliver robust data for monthly mortality and morbidity meetings and to improve turnaround time for blood culture results among other quality improvement indicators. There were 3222 admissions and discharges entered using the NeoTree software with 41 junior doctors and 9 laboratory staff trained over the 9-month period. The NeoTree app was fully integrated into the department for all admission and discharge documentation and the monthly presentations became routine, informing local practice. An essential factor for this success was local buy-in and ownership at each stage of the project development, as was monthly data analysis and presentations allowing us to rapidly troubleshoot emerging issues. However, the laboratory arm of the project was negatively affected by nationwide economic upheaval. Our successes and challenges piloting this digital tool have provided key insights for effective future roll-out in Zimbabwe and other low-income healthcare settings.


Inhibition of RAS-mediated transformation and tumorigenesis by targeting the downstream E3 ubiquitin ligase seven in absentia homologue.
Constitutively active RAS small GTPases promote the genesis of human cancers. An important goal in cancer biology is to identify means of countervailing activated RAS signaling to reverse malignant transformation. Oncogenic K-RAS mutations are found in virtually all pancreatic adenocarcinomas, making the RAS pathway an ideal target for therapeutic intervention. How to best contravene hyperactivated RAS signaling has remained elusive in human pancreatic cancers. Guided by the Drosophila studies, we reasoned that a downstream mediator of RAS signals might be a suitable anti-RAS target. The E3 ubiquitin ligase seven in absentia (SINA) is an essential downstream component of the Drosophila RAS signal transduction pathway. Thus, we determined the roles of the conserved human homologues of SINA, SIAHs, in mammalian RAS signaling and RAS-mediated tumorigenesis. We report that similar to its Drosophila counterpart, human SIAH is also required for oncogenic RAS signaling in pancreatic cancer. Inhibiting SIAH-dependent proteolysis blocked RAS-mediated focus formation in fibroblasts and abolished the tumor growth of human pancreatic cancer cells in soft agar as well as in athymic nude mice. Given the high level of conservation of RAS and SIAH function, our study provides useful insights into altered proteolysis in the RAS pathway in tumor initiation, progression, and oncogenesis. By targeting SIAH, we have found a novel means to contravene oncogenic RAS signaling and block RAS-mediated transformation/tumorigenesis. Thus, SIAH may offer a novel therapeutic target to halt tumor growth and ameliorate RAS-mediated pancreatic cancer.


Brain systems mediating cognitive interference by emotional distraction.
Flexible behavior depends on our ability to cope with distracting stimuli that can interfere with the attainment of goals. Emotional distracters can be particularly disruptive to goal-oriented behavior, but the neural systems through which these detrimental effects are mediated are not known. We used event-related functional magnetic resonance imaging to investigate the effect of emotional and nonemotional distracters on a delayed-response working memory (WM) task. As expected, this task evoked robust activity during the delay period in typical WM regions (dorsolateral prefrontal cortex and lateral parietal cortex). Presentation of emotional distracters during the delay interval evoked strong activity in typical emotional processing regions (amygdala and ventrolateral prefrontal cortex) while simultaneously evoking relative deactivation of the WM regions and impairing WM performance. These results provide the first direct evidence that the detrimental effect of emotional distracters on ongoing cognitive processes entails the interaction between a dorsal neural system associated with "cold" executive processing and a ventral system associated with "hot" emotional processing.


Theoretical studies on conjugated phenyl-cored thiophene dendrimers for photovoltaic applications.
Pi-conjugated dendrimers are an important class of materials for optoelectronic devices, especially for light-harvesting systems. We report here a theoretical investigation of the optical response and of the excited-state properties of three-arm and four-arm phenyl-cored dendrimers for photovoltaic applications. A variety of theoretical methods are used and evaluated against each other to calculate vertical transition energies, absorption and excitation spectra with vibronic structure, charge transport, and excitonic behavior upon photoexcitation and photoemission processes. Photophysical phenomena in these dendrimers are, in general, better explained with ab initio methods rather than with semiempirical techniques. Calculated reorganization energies were found to correlate well with the device photocurrent data where available. The excitons formed during photoexcitation are calculated to be more delocalized than the ones formed after vibrational relaxation in the excited states for fluorescence emission. The localization of excitons in emission processes is a result of geometrical changes in the excited state coupled with vibronic modes. Correlated electron-hole pair diagrams illustrate breaking of pi-conjugation in three-arm dendrimers due to meta linkage of arms with the core, whereas four-arm dendrimers are not affected by such breaking due to presence of ortho and para branching. Yet, ortho branching causes large twist angles between the core and the arms that are detrimental to pi-electron system delocalization over the structure.


Oxidised guanidinohydantoin (Ghox) and spiroiminodihydantoin (Sp) are major products of iron- and copper-mediated 8-oxo-7,8-dihydroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine oxidation.
8-Oxo-7,8-dihydroguanine (8-oxoGua), an important biomarker of DNA damage in oxidatively generated stress, is highly reactive towards further oxidation. Much work has been carried out to investigate the oxidation products of 8-oxoGua by one-electron oxidants, singlet oxygen, and peroxynitrite. This report details for the first time, the iron- and copper-mediated Fenton oxidation of 8-oxoGua and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo). Oxidised guanidinohydantoin (Gh(ox)) was detected as the major product of oxidation of 8-oxoGua with iron or copper and hydrogen peroxide, both at pH 7 and pH 11. Oxaluric acid was identified as a final product of 8-oxoGua oxidation. 8-oxodGuo was subjected to oxidation under the same conditions as 8-oxoGua. However, dGh(ox) was not generated. Instead, spiroiminodihydantoin (Sp) was detected as the major product for both iron and copper mediated oxidation at pH 7. It was proposed that the oxidation of 8-oxoGua was initiated by its one-electron oxidation by the metal species, which leads to the reactive intermediate 8-oxoGua (+), which readily undergoes further oxidation. The product of 8-oxoGua and 8-oxodGuo oxidation was determined by the 2'-deoxyribose moiety of the 8-oxodGuo, not whether copper or iron was the metal involved in the oxidation.


Correlation between "Candidatus Liberibacter solanacearum" infection levels and fecundity in its psyllid vector.
The potato/tomato psyllid, Bactericera cockerelli (Šulc) transmits the bacterium, "Candidatus (Ca.) Liberibacter solanacearum" (Lso), also known as "Ca. Liberibacter psyllaurous", which causes zebra chip disease in potato and other solanaceous crops. The authors previously showed that fecundity and nymph survival is significantly reduced in Lso-infected psyllids compared to uninfected psyllids on tomato. However, it is not known whether the level of the pathogen is correlated with concomitant reduction in fitness of the psyllid vector. Using quantitative PCR assays, Lso levels were determined in adult female founders of isofemale lines for whom several life history traits were previously recorded. Analysis of psyllid isofemale lines revealed that Lso infection levels in founders or mothers was negatively correlated with 7-day fecundity, nymph survival percentage, and number of F1 progeny including eggs, nymphs and adults. There was a significant negative density-dependent relationship between Lso level and fecundity. That is, psyllids experienced decreasing levels in fecundity with increasing bacterial titer. There was no apparent negative density-dependent relationship between Lso copies and number of nymphs, nymph survival percentage and number of adults. The negative effect of Lso on psyllid fecundity is likely due to direct effects of the bacteria on the insect host and not via the host plant. Taken together, these findings suggest that the level of Lso in its psyllid vector correlates with reduction in psyllid fitness.


Clinical Decision Support Tool and Rapid Point-of-Care Platform for Determining Disease Severity in Patients with COVID-19.
SARS-CoV-2 is the virus that causes coronavirus disease (COVID-19) which has reached pandemic levels resulting in significant morbidity and mortality affecting every inhabited continent. The large number of patients requiring intensive care threatens to overwhelm healthcare systems globally. Likewise, there is a compelling need for a COVID-19 disease severity test to prioritize care and resources for patients at elevated risk of mortality. Here, an integrated point-of-care COVID-19 Severity Score and clinical decision support system is presented using biomarker measurements of C-reactive protein (CRP), N-terminus pro B type natriuretic peptide (NT-proBNP), myoglobin (MYO), D-dimer, procalcitonin (PCT), creatine kinase-myocardial band (CK-MB), and cardiac troponin I (cTnI). The COVID-19 Severity Score combines multiplex biomarker measurements and risk factors in a statistical learning algorithm to predict mortality. The COVID-19 Severity Score was trained and evaluated using data from 160 hospitalized COVID-19 patients from Wuhan, China. Our analysis finds that COVID-19 Severity Scores were significantly higher for the group that died versus the group that was discharged with median (interquartile range) scores of 59 (40-83) and 9 (6-17), respectively, and area under the curve of 0.94 (95% CI 0.89-0.99). These promising initial models pave the way for a point-of-care COVID-19 Severity Score system to impact patient care after further validation with externally collected clinical data. Clinical decision support tools for COVID-19 have strong potential to empower healthcare providers to save lives by prioritizing critical care in patients at high risk for adverse outcomes.


Comparison of Transcutaneous Electric Nerve Stimulation (TENS) and Microcurrent Nerve Stimulation (MENS) in the Management of Masticatory Muscle Pain: A Comparative Study.
Temporomandibular disorders (TMDs) are a heterogeneous group of pathologies affecting the temporomandibular joint (TMJ), the jaw muscles, or both. Epidemiological studies of TMD reveal a prevalence of 82% in the general population with 48% of them presenting with clinical features of muscle tenderness and difficulty in mouth opening. TMD are considered to be the most common orofacial pain conditions of nondental origin. The patients with TMD were randomly divided into two groups, A and B, based on their VAS scale. Group A consists of two subgroups 1 and 2 each consisting of 15 patients. Group B consists of two subgroups 3 and 4 consisting of 15 patients. Patients in Group A were given TENS for twenty minutes, and the frequency is adjusted as follows: (i) subgroup 1: TENS frequency at a range of 0-5 (VAS measuring 1-5) and (ii) subgroup 2: TENS frequency at a range of 5 and above (VAS measuring 6-10). Patients in Group B were given MENS for twenty minutes, and the frequency adjusted as follows: (i) subgroup 3: MENS frequency at range of 0-5 (VAS measuring 1-5) and (ii) subgroup 4: MENS frequency at a range of 5 and above (VAS measuring 6-10). Each patient was recalled for five consecutive days for the treatment, and the same intensity and frequency were maintained throughout the treatment period. The improvement in VAS is seen to be highly significant statistically in MENS subgroup 4 (moderate-to-severe pain). Subgroups 1 and 3 had improvement in VAS which was comparable in both TENS and MENS groups. In the present study, it was found that TENS and MENS are equally effective in improving the functional mouth opening. MENS showed better and immediate effect in relief of pain. Microcurrent also has the advantage of being subthreshold, and hence the side effects such as tingling sensation and paresthesia seen to occur in some patients following TENS are absent. TENS and MENS can be considered as the first line of treatment in patients with acute and chronic masticatory muscle pain and also as an effective treatment option in cases of functional mouth opening.


ACE2 Expression Is Increased in the Lungs of Patients With Comorbidities Associated With Severe COVID-19.
Patients who died from COVID-19 often had comorbidities, such as hypertension, diabetes, and chronic obstructive lung disease. Although angiotensin-converting enzyme 2 (ACE2) is crucial for SARS-CoV-2 to bind and enter host cells, no study has systematically assessed the ACE2 expression in the lungs of patients with these diseases. Here, we analyzed over 700 lung transcriptome samples from patients with comorbidities associated with severe COVID-19 and found that ACE2 was highly expressed in these patients compared to control individuals. This finding suggests that patients with such comorbidities may have higher chances of developing severe COVID-19. Correlation and network analyses revealed many potential regulators of ACE2 in the human lung, including genes related to histone modifications, such as HAT1, HDAC2, and KDM5B. Our systems biology approach offers a possible explanation for increased COVID-19 severity in patients with certain comorbidities.


Expression of the Na/P(i)-cotransporter type IIb in Sf9 cells: functional characterization and purification.
In mammals the type IIb Na/P(i)-cotransporter is expressed in various tissues such as intestine, brain, lung and testis. The type IIb cotransporter shows 51% homology with the renal type IIa Na/P(i)-cotransporter, for which a detailed model of the secondary structure has emerged based on recent structure/function studies. To make the type IIb Na/P(i)-cotransporter available for future structural studies, we have expressed this cotransporter in Sf9 cells. Sf9 cells were infected with recombinant baculovirus containing 6His NaPi-IIb. Infected cells expressed a polypeptide of approximately 90 kDa, corresponding to a partially glycosylated form of the type IIb cotransporter. Transport studies demonstrated that the type IIb protein expressed in Sf9 cells mediates transport of phosphate in a Na-dependent manner with similar kinetic characteristics (apparent K(m)s for sodium and phosphate and pH dependence) as previously described. Solubilization experiments demonstrated that, in contrast to the type IIa cotransporter, the type IIb can be solubilized by nonionic detergents and that solubilized type IIb Na/P(i)-cotransporter can be purified by Ni-NTA chromatography.


Ki-67 detects a nuclear matrix-associated proliferation-related antigen. II. Localization in mitotic cells and association with chromosomes.
In interphase cells the proliferation-associated antigen recognized by monoclonal antibody Ki-67 is almost exclusively located in the nucleoli. When cells at several stages of mitosis were examined for the localization of the Ki-67 antigen, a striking redistribution could be observed. During prophase the distinct nucleolar Ki-67 fluorescence changed to a bright irregular meshwork throughout the nucleoplasm. At metaphase the antigen appeared to be distributed in a reticulate structure surrounding the condensed chromosomes, while at late telophase a punctated staining of the entire nucleoplasm was observed, which preceded the typical nucleolar localization pattern in each of the two daughter cells. Immunolabelling with Ki-67 of metaphase chromosome spreads revealed a circumferential staining of the individual chromosomes. The Ki-67 antigen is preserved in nuclear matrix preparations obtained after in situ fractionation of interphase cells. When mitotic cells were exposed to such treatments, the obtained fluorescence data suggested that the antigen may be part of the chromosome scaffold. Quantification of the Ki-67 fluorescence signal using flow cytometry revealed the highest staining intensities in mitotic cells. Furthermore, it was shown that nutritionally deprived cells became negative for Ki-67.


Biomarkers of myocardial injury with different energy sources for atrial fibrillation catheter ablation.
Our study aims to compare acute myocardial injury biomarker rise after atrial fibrillation ablation performed with different technologies. One hundred and ten patients were treated with pulmonary vein isolation with 4 different technologies: open-irrigated tip radiofrequency (RF) catheter in35 patients (Group A), cryoballoon in 35 patients (Group B), visually guided laser balloon in 20 patients (Group C), open-irrigated tip RF catheter with contact-force-sensing technology in 20 patients (Group D). Post-procedure samples of cardiac troponin I (cTnI) and creatinine kinase-MB (CK-MB) were collected at 19 ± 3 h and 43 ± 3 h after ablation. At the first postprocedural sample, cTnI and CK-MB levels were found elevated in all 110 patients with a median value of 2.11 ng/mL and 8.95 ng/mL, respectively. Group B showed cTnI levels increased (median 5.96 ng/mL) compared to other groups (median Group A: 1.72 ng/mL, Group C: 1.54 ng/mL, Group D: 2.0 ng/mL; p < 0.001). Also CK-MB levels resulted higher in cryoablation (median 26.4 ng/mL) compared to other groups (median Group A: 6.40 ng/mL, Group C: 7.15 ng/mL, Group D: 6.50 ng/mL; p < 0.001). No significant association was observed between biomarker levels and recurrences of atrial fibrillation after a mean follow-up of 369 ± 196 days. Highest markers for myocardial injury were observed in the cryoballoon group. It is possible that a longer delivery energy duration and other factors affecting lesion size resulted in higher amount of cardiac injury in cryoablation. The higher levels of cardiac biomarkers did not translate into a better outcome and its physiologic significance is unknown.


An experimental study on bioremediation and photolysis of enrofloxacin.
Recent studies have identified the occurrence of a vast number of pharmaceuticals into the municipal wastewater through excreted urine and feces. Some of these pharmaceutical compounds are degraded in the environment. However, there have been reports on the presence of pharmaceutical active compounds in drinking water. Concerns have been raised over the potential adverse effects of these pharmaceuticals on public health and the aquatic environment. In order to investigate the removal process of pharmaceutical enrofloxacin, a unit consisting of a structured packing rotating biological contactor (spRBC) was designed and constructed as a biological treatment unit. The removal rate reached a maximum of 70% in this biological unit. In the meantime, the effect of photolysis process on the effluent of the biological unit was also studied. In the direct photolysis, the removal performance reached 51% and by adding H2O2 the removal efficiency was increased to 87%. The removal efficiency for the entire system including spRBC and an ultraviolet radiation unit was 94%.


Different presentations of ophthalmic aspergillosis.
Aspergillus species is found worldwide and does not normally cause disease. However, when the immune system is compromised, it can invade many organs and be responsible for severe disease. The authors present cases with both classical and atypical features of ophthalmic aspergillosis. Case series of three patients. All patients were female and had a long history of methylprednisolone use. The first two presented with endogenous endophthalmitis. One case was unilateral with a classical presentation of endophthalmitis. The other presented with a very severe bilateral acute retinal necrosis like syndrome. General work-up revealed disseminated disease in both cases. The diagnosis was made by serum immunologic testing in one case and after direct examination and culture from vitrectomy in the other. Despite intense antimycotic therapy, both patients died. The third patient presented with a unilateral progressive painful orbital apex syndrome. An orbital lesion was demonstrated by computed tomography scan and was unresponsive to methylprednisolone. Diagnosis of sino-orbital syndrome was made on biopsy. The lesion responded poorly to different antimycotic therapies, invaded the chiasma, and the patient lost all visual acuity. This case series illustrates that ophthalmic aspergillosis can present acutely with a devastating intraocular inflammation or more indolently in the setting of sino-orbital aspergillosis. Both forms have a poor visual prognosis and the systemic form is frequently associated with a fatal outcome.


Structural analysis of CYP2C9 and CYP2C5 and an evaluation of commonly used molecular modeling techniques.
This work had two separate aims: to evaluate different modeling techniques and to make a detailed structural characterization of CYP2C9. To achieve these goals, the consensus principal component analysis (CPCA) technique and distance measurements were used to explore available crystal structures, newly built homology models, and repeated molecular dynamics simulations. The CPCA was based on molecular interaction fields focused on the active site regions of the proteins and include detailed amino acid analysis. The comparison of the CYP2C9 and CYP2C5 crystal structures revealed differences in the flexible regions such as the B-C and F-G loop and the N and C termini. Cross homology models of CYP2C9 and CYP2C5, using their respective crystal structures as templates, indicated that such models were more similar to their templates than to their target proteins. Inclusion of multiple templates slightly improved the similarity to the crystal target in some cases and could be recommended even though it requires a careful manual alignment process. The application of molecular dynamics simulations to highly flexible proteins such as cytochromes P450 is also explored and the information is extracted by the CPCA. Advantages and drawbacks are presented for the different modeling techniques. Despite the varying modeling success, the models give insight and understanding by the mutual forming and discarding of hypotheses. This is a dynamic process since the crystal structures are improving with time and, therefore, the answers to the models are also changing accordingly.


Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer.
We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.


Anchored phylogenomics illuminates the skipper butterfly tree of life.
Butterflies (Papilionoidea) are perhaps the most charismatic insect lineage, yet phylogenetic relationships among them remain incompletely studied and controversial. This is especially true for skippers (Hesperiidae), one of the most species-rich and poorly studied butterfly families. To infer a robust phylogenomic hypothesis for Hesperiidae, we sequenced nearly 400 loci using Anchored Hybrid Enrichment and sampled all tribes and more than 120 genera of skippers. Molecular datasets were analyzed using maximum-likelihood, parsimony and coalescent multi-species phylogenetic methods. All analyses converged on a novel, robust phylogenetic hypothesis for skippers. Different optimality criteria and methodologies recovered almost identical phylogenetic trees with strong nodal support at nearly all nodes and all taxonomic levels. Our results support Coeliadinae as the sister group to the remaining skippers, the monotypic Euschemoninae as the sister group to all other subfamilies but Coeliadinae, and the monophyly of Eudaminae plus Pyrginae. Within Pyrginae, Celaenorrhinini and Tagiadini are sister groups, the Neotropical firetips, Pyrrhopygini, are sister to all other tribes but Celaenorrhinini and Tagiadini. Achlyodini is recovered as the sister group to Carcharodini, and Erynnini as sister group to Pyrgini. Within the grass skippers (Hesperiinae), there is strong support for the monophyly of Aeromachini plus remaining Hesperiinae. The giant skippers (Agathymus and Megathymus) once classified as a subfamily, are recovered as monophyletic with strong support, but are deeply nested within Hesperiinae. Anchored Hybrid Enrichment sequencing resulted in a large amount of data that built the foundation for a new, robust evolutionary tree of skippers. The newly inferred phylogenetic tree resolves long-standing systematic issues and changes our understanding of the skipper tree of life. These resultsenhance understanding of the evolution of one of the most species-rich butterfly families.


The quality of reporting of orthopaedic randomized trials with use of a checklist for nonpharmacological therapies.
The Consolidated Standards of Reporting Trials statement for the reporting of randomized controlled trials has been limited by its applicability to surgical trials. In response, a Checklist to Evaluate a Report of a Nonpharmacological Trial was recently developed by the Consolidated Standards of Reporting Trials group to address reporting issues in surgical trials. We aimed (1) to apply the checklist for nonpharmacological therapies to orthopaedic randomized controlled trials across multiple journals from 2004 through 2005, and (2) to survey authors when methodological safeguards itemized in the checklist were not reported to determine whether they actually had been performed. We hypothesized that lack of reporting of a methodological safeguard did not necessarily mean it had not been conducted. We searched for relevant orthopaedic randomized controlled trials across eight journals in the period from January 2004 through December 2005. We applied the Checklist to Evaluate a Report of a Nonpharmacological Trial to all eligible studies. We contacted authors to determine what methodological safeguards were actually used, especially when details remained unclear from the publication. We included eighty-seven randomized controlled trials from eighty-five scientific reports. In assessing the randomized controlled trials with the checklist for nonpharmacological therapies, seventy-three studies (84%) had unclear reporting of treatment allocation concealment. Only seventeen studies (20%) mentioned surgeon skill or experience. The blinding of patients, ward staff, rehabilitation staff, clinical outcome assessors, and nonclinical outcome assessors was unclear in forty-eight (55%), sixty-three (72%), sixty-four (74%), forty (46%), and thirty-three studies (38%), respectively. Authors from forty-three randomized controlled trials responded to our survey. The results of the survey showed that 41% (95% confidence interval, 25% to 58%) of the trials had adequate allocation concealment when this had been unclear from the report. Although the surgical experience of the investigators was rarely reported, most authors (70%) acknowledged that they had defined "surgical expertise criteria" such as minimum case criteria, specialized training, and clinical performance. The survey also showed that 28% to 40% of the trials had blinding of relevant groups despite the fact that the reporting of such blinding had been unclear in the publications. The quality of reporting in the orthopaedic literature was highly variable. Readers should not assume that bias-reducing safeguards that were not reported in a randomized controlled trial did not occur. Our study reinforces the need for the consistent use of a tool like the Checklist to Evaluate a Report of a Nonpharmacological Trial to assess the methodology of surgical trials.


Barrier function regulates epidermal DNA synthesis.
We examined the possibility that the cutaneous permeability barrier regulates epidermal DNA synthesis in two acute and two chronic models of barrier perturbation. In animals treated topically with acetone, DNA synthesis is increased 102%, in tape-stripped animals 127%, in essential fatty acid deficient animals 50%, and in animals chronically treated with topical lovastatin 64%. This linkage between disturbances in barrier function and increased DNA synthesis is further supported by specific and correlative observations: (a) in these disparate models, artificial replacement of the barrier with a water-impermeable membrane inhibits the expected increase in DNA synthesis; (b) the extent of the burst in DNA synthesis is proportional to the degree of barrier abrogation; (c) the inhibition of DNA synthesis by membranes is directly related to the degree of permeability of these occlusive membranes, i.e., the more impermeable the greater the degree of inhibition; (d) topical treatment with lipids that restore barrier function corrects the increase in DNA synthesis; and (e) barrier abrogation with acetone produces an increase in epidermal DNA synthesis without altering bulk protein synthetic rates in contrast to events known to follow injury or cell replacement. Autoradiographic studies show that the increase in DNA synthesis after acetone treatment is limited to the epidermal basal layer. This constellation of findings strongly suggests that cutaneous barrier function is one factor that regulates epidermal DNA synthesis.


Evaluation of macular function using focal macular electroretinography in eyes with macular edema associated with branch retinal vein occlusion.
To study the usefulness of focal macular electroretinography (fmERG) for evaluation of macular function in eyes with macular edema (ME) associated with branch retinal vein occlusion (BRVO). The authors prospectively performed fmERG on 34 patients with untreated unilateral BRVO at the initial visit and 12 months later. Amplitudes and latencies of the a-wave, b-wave, and photopic negative response (PhNR) were compared with visual acuity, with retinal sensitivity measured by microperimetry, and with measurements obtained by optical coherence tomography. In eyes with ME from BRVO, amplitudes of the a-wave, b-wave, and PhNR were reduced significantly and latencies were prolonged significantly compared with those of healthy fellow eyes (P < 0.05). Relative amplitudes and latencies were not correlated with visual acuity but, rather, tended to be correlated with retinal sensitivity within the macular area. Among all parameters studied by fmERG, relative amplitude of the PhNR was most strongly correlated with central foveal thickness (r = -0.465; P = 0.007). In addition, the height of the serous retinal detachment showed a correlation with the relative amplitude of the PhNR (r = -0.376; P = 0.034). At 12 months, the amplitude of the b-wave and the PhNR improved significantly, in parallel with resolution of the ME (P = 0.015; P = 0.033). In eyes with ME from BRVO, amplitudes and latencies seen by fmERG were correlated with other biological parameters. Based on findings of the present study, fmERG appears to be useful as a functional examination within the macular area affected by BRVO.


First Report of Leaf Spot Caused by Phyllosticta yuccae on Yucca filamentosa in Brazil.
Yucca filamentosa L. (Agavaceae), commonly known as Adam's needle, is known in Brazil as "agulha-de-adão." It is an ornamental garden plant with medicinal properties (4). In 2010, 100% of Y. filamentosa seedlings and plants were observed with a severe leaf spot disease in two ornamental nurseries located in the municipality of Viçosa, Minas Gerais, Brazil. Initially, lesions were dark brown, elliptical, and scattered, and later became grayish at the center with a reddish brown margin, irregular and coalescent. Infected leaf samples were deposited in the herbarium at the Universidade Federal de Viçosa (Accession Nos. VIC32054 and VIC32055). A fungus was isolated from the leaf spots and single-spore pure cultures were obtained on potato dextrose agar (PDA). The sporulating single-spore cultures were deposited at the Coleção de Culturas de Fungos Fitopatogênicos "Prof. Maria Menezes" (CMM 1843 and CMM 1844). On the leaf, the fungus produced pycnidial conidiomata that were scattered or gregarious, usually epiphyllous, immersed, dark brown, unilocular, subglobose, and 95 to 158 × 108 to 175 μm, with a minute, subcircular ostiole. Conidiogenous cells were blastic, hyaline, conoidal, or short cylindrical. Conidia were aseptate, hyaline, smooth walled, coarsely granular, broadly ellipsoidal to subglobose or obovate, usually broadly rounded at both ends, occasionally truncate at the base or indented slightly at the apex, and 7.5 to 13.5 × 6 to 10 μm. Conidia were also surrounded by a slime layer, usually with a hyaline, flexuous, narrowly conoidal or cylindrical, mucilaginous apical appendage that was 10 to 16 μm long. Spermatia were hyaline, dumbbell shaped to cylindrical, both ends bluntly rounded, and 3 to 5 × 1 to 1.5 μm. These characteristics matched well with the description of Phyllosticta yuccae Bissett (1). To confirm this identification, DNA was extracted using a Wizard Genomic DNA Purification Kit and amplified using primers ITS1 and ITS4 (2) for the ITS region (GenBank Accession Nos. JX227945 and JX227946) and EF1-F and EF2-R (3) for the TEF-1α (JX227947 and JX227948). The sequencing was performed by Macrogen, South Korea. The ITS sequence matched sequence No. JN692541, P. yuccae, with 100% identity. To confirm Koch's postulates, four leaves of Y. filamentosa (five plants) were inoculated with 6-mm-diameter plugs from a 7-day-old culture growing on PDA. The leaves were covered with plastic sack and plants were maintained at 25°C. In a similar manner, fungus-free PDA plugs were placed on five control plants. Symptoms were consistently similar to those initially observed in the nurseries and all plants developed leaf spots by 15 days after inoculation. P. yuccae was successfully reisolated from the symptomatic tissue and control plants remained symptomless. P. yuccae has been previously reported in Canada, the Dominican Republic, Guatemala, Iran, and the United States of America. To our knowledge, this is the first report of P. yuccae causing disease in Y. filamentosa in Brazil and it may become a serious problem for the nurseries, due to the severity of the disease and the lack of chemical products to control this pathogen. References: (1) J. Bissett. Can. J. Bot. 64:1720, 1986. (2) M. A. Innis et al. PCR Protocols: A guide to methods and applications. Academic Press, 1990. (3) Jacobs et al. Mycol. Res. 108:411, 2004. (4) H. Lorenzi and H. M. Souza. Plantas Ornamentais no Brasil. Instituto Plantarum, 2001.


Effects of gluten-free, dairy-free diet on childhood nephrotic syndrome and gut microbiota.
Emerging evidence suggests an association between food sensitivity and gut microbiota in children with nephrotic syndrome. Diminished proteinuria resulted from eliminating cow's milk and the use of an oligoantigenic diet which excluded gluten, especially in patients with immune-related conditions, i.e., celiac disease and nephrotic syndrome. The mechanisms underlying the association of diet, gut microbiota, and dysregulation of the immune system are unknown. Gut microbiota is influenced by a number of factors including diet composition and other environmental epigenetic exposures. The imbalance in gut microbiota may be ameliorated by gluten-free and dairy-free diets. Gluten-free diet increased the number of unhealthy bacteria while reducing bacterial-induced cytokine production of IL-10. Thus, gluten-free diet may influence the composition and immune function of gut microbiota and should be considered a possible environmental factor associated with immune-related disease, including nephrotic syndrome. Furthermore, the imbalance of gut microbiota may be related to the development of cow's milk protein allergy. Investigations are needed to fill the gaps in our knowledge concerning the associations between the gut microbiome, environmental exposures, epigenetics, racial influences, and the propensity for immune dysregulation with its inherent risk to the developing individual.


A novel beta-glucoside-specific PTS locus from Streptococcus mutans that is not inhibited by glucose.
A regulon from Streptococcus mutans that plays a role in the utilization of beta-glucosides has been isolated, sequenced and subjected to sequence analysis. This regulon encodes a beta-glucoside-specific Enzyme II (EII) component (bglP) of the phosphoenolpyruvate-dependent phosphotransferase system (PTS) and a phospho-beta-glucosidase (bglA) which is responsible for the breakdown of the phospho-beta-glucosides within the cell. Both the bglP and bglA gene products have significant similarity with proteins that have similar functions from Clostridium longisporum, Listeria monocytogenes, Erwinia chrysanthemi, Escherichia coli, Klebsellia oxytoca and Bacillus subtilis. The potential functions of the BglP and BglA proteins are supported by phenotypic data from both S. mutans and E. coli. A chromosomal deletion in S. mutans spanning the bglP and bglA genes resulted in a strain that was unable to hydrolyse the beta-glucoside aesculin in the presence of glucose. When glucose was removed from the medium, the deletion strain regained the ability to break down aesculin. These data suggest that S. mutans possesses an alternative mechanism from the one described in this report for breaking down beta-glucosides. This second mechanism was repressed by glucose while the regulon described here was not. Complementation studies in E. coli CC118 also suggest a potential role for this regulon in the utilization of other beta-glucosides. When a plasmid containing the 8 kb beta-glucoside-specific regulon was transformed into E. coli CC118, the transformed strain was able to break down the beta-glucoside arbutin.


Ribosomal RNA kink-turn motif--a flexible molecular hinge.
Ribosomal RNA K-turn motifs are asymmetric internal loops characterized by a sharp bend in the phosphodiester backbone resulting in "V" shaped structures, recurrently observed in ribosomes and showing a high degree of sequence conservation. We have carried out extended explicit solvent molecular dynamics simulations of selected K-turns, in order to investigate their intrinsic structural and dynamical properties. The simulations reveal an unprecedented dynamical flexibility of the K-turns around their X-ray geometries. The K-turns sample, on the nanosecond timescale, different conformational substates. The overall behavior of the simulations suggests that the sampled geometries are essentially isoenergetic and separated by minimal energy barriers. The nanosecond dynamics of isolated K-turns can be qualitatively considered as motion of two rigid helix stems controlled by a very flexible internal loop which then leads to substantial hinge-like motions between the two stems. This internal dynamics of K-turns is strikingly different for example from the bacterial 5S rRNA Loop E motif or BWYV frameshifting pseudoknot which appear to be rigid in the same type of simulations. Bistability and flexibility of K-turns was also suggested by several recent biochemical studies. Although the results of MD simulations should be considered as a qualitative picture of the K-turn dynamics due to force field and sampling limitations, the main advantage of the MD technique is its ability to investigate the region close to K-turn ribosomal-like geometries. This part of the conformational space is not well characterized by the solution experiments due to large-scale conformational changes seen in the experiments. We suggest that K-turns are well suited to act as flexible structural elements of ribosomal RNA. They can for example be involved in mediation of large-scale motions or they can allow a smooth assembling of the other parts of the ribosome.


NICU Admissions After a Policy to Eliminate Elective Early Term Deliveries Before 39 Weeks' Gestation.
Early term infants (37-<39 weeks' gestation) are at higher risk of adverse outcomes than term infants (39-<41 weeks' gestation). We hypothesized that a policy to eliminate elective, early term deliveries would result in fewer NICU admissions and shorter lengths of stay among infants born ≥37 weeks. This was a retrospective cohort study of singleton infants born ≥37 weeks at a tertiary medical center from 2004 to 2015 (preperiod: 2004-2008; postperiod: 2010-2015; washout period: 2009). We compared the incidence of early term delivery, NICU admissions (short: ≥4-<24 hours, long: ≥24 hours), NICU diagnoses, and stillbirths in both periods. We used modified Poisson regression to calculate adjusted risk ratios. There were 20 708 and 24 897 singleton infants born ≥37 weeks in the pre- and postperiod, respectively. The proportion of early term infants decreased from 32.5% to 25.7% (P < .0001). NICU admissions decreased nonsignificantly (9.2% to 8.8%; P = .22), with a significant reduction in short NICU stays (5.4% to 4.6%; adjusted risk ratio: 0.85 [95% confidence interval: 0.79-0.93]). Long NICU stays increased slightly (3.8% to 4.2%), a result that was nullified by adjusting for neonatal hypoglycemia. A nonsignificant increase in the incidence of stillbirths ≥37 to <40 weeks was present in the postperiod (7.5 to 10 per 10 000 births; P = .46). Reducing early term deliveries was associated with fewer short NICU stays, suggesting that efforts to discourage early term deliveries in uncomplicated pregnancies may minimize mother-infant separation in the newborn period.


CRM1 protein-mediated regulation of nuclear clusterin (nCLU), an ionizing radiation-stimulated, Bax-dependent pro-death factor.
Expression of the clusterin (CLU) gene results in the synthesis of a conventional secretory isoform set (pre- and mature secretory clusterin proteins, psCLU/sCLU), as well as another set of intracellular isoforms, appearing in the cytoplasm (pre-nuclear CLU, pnCLU) and in the nucleus as an ∼55-kDa mature nuclear clusterin (nCLU) form. These two isoform sets have opposing cell functions: pro-survival and pro-death, respectively. Although much is known about the regulation and function of sCLU as a pro-survival factor, the regulation and function of endogenous nCLU in cell death are relatively unexplored. Here, we show that depletion of endogenous nCLU protein using siRNA specific to its truncated mRNA increased clonogenic survival of ionizing radiation (IR)-exposed cells. nCLU-mediated apoptosis was Bax-dependent, and lethality correlated with accumulation of mature nCLU protein. nCLU accumulation was regulated by CRM1 because binding between CRM1 and nCLU proteins was significantly diminished by leptomycin B (LMB), and nuclear levels of nCLU protein were significantly enhanced by LMB and IR co-treatment. Moreover, LMB treatment significantly enhanced IR-induced nCLU-mediated cell death responses. Importantly, bax(-/-) and bax(-/-)/bak(-/-) double knock-out cells were resistant to nCLU-mediated cell death, whereas bak(-/-) or wild-type bax(+/+)/bak(+/+) cells were hypersensitive. The regulation of nCLU by CRM1 nuclear export/import may explain recent clinical results showing that highly malignant tumors have lost the ability to accumulate nCLU levels, thereby avoiding growth inhibition and cell death.


Comparison of reproductive outcome in oligozoospermic men with high sperm DNA fragmentation undergoing intracytoplasmic sperm injection with ejaculated and testicular sperm.
To investigate the effectiveness of intracytoplasmic sperm injection (ICSI) using testicular sperm as a strategy to overcome infertility in men with high sperm DNA fragmentation (SDF). Prospective, observational, cohort study. Private IVF centers. A total of 147 couples undergoing IVF-ICSI and day 3 fresh ETs whose male partner has oligozoospermia and high SDF. Sperm injections were carried out with ejaculated sperm (EJA-ICSI) or testicular sperm (TESTI-ICSI) retrieved by either testicular sperm extraction (TESE) or testicular sperm aspiration (TESA). SDF levels were reassessed on the day of oocyte retrieval in both ejaculated and testicular specimens. Percentage of testicular and ejaculated spermatozoa containing fragmented DNA (%DFI) and clinical pregnancy, miscarriage, and live-birth rates. The %DFI in testicular sperm was 8.3%, compared with 40.7% in ejaculated sperm. For the TESTI-ICSI group versus the EJA-ICSI group, respectively, the clinical pregnancy rate was 51.9% and 40.2%, the miscarriage rate was 10.0% and 34.3%, and the live-birth rate was 46.7% and 26.4%. ICSI outcomes were significantly better in the group of men who had testicular sperm used for ICSI compared with those with ejaculated sperm. SDF was significantly lower in testicular specimens compared with ejaculated counterparts. Our results suggest that TESTI-ICSI is an effective option to overcome infertility when applied to selected men with oligozoospermia and high ejaculated SDF levels.


Simplifying and expanding the scope of boron imidazolate framework (BIF) synthesis using mechanochemistry.
Mechanochemistry enables rapid access to boron imidazolate frameworks (BIFs), including ultralight materials based on Li and Cu(i) nodes, as well as new, previously unexplored systems based on Ag(i) nodes. Compared to solution methods, mechanochemistry is faster, provides materials with improved porosity, and replaces harsh reactants (e.g. n-butylithium) with simpler and safer oxides, carbonates or hydroxides. Periodic density-functional theory (DFT) calculations on polymorphic pairs of BIFs based on Li+, Cu+ and Ag+ nodes reveals that heavy-atom nodes increase the stability of the open SOD-framework relative to the non-porous dia-polymorph.


Nobiletin prevents cadmium-induced neuronal apoptosis by inhibiting reactive oxygen species and modulating JNK/ERK1/2 and Akt/mTOR networks in rats.
Objectives Cadmium (Cd), an extremely noxious environmental pollutant is known to induce oxidative stress leading to neurodegenerative diseases. Nobiletin, a citrus flavonoid is reported to possess various pharmacological properties. This study investigates the effects of nobiletin over Cd-induced neuronal apoptosis in rodent experimental model. Methods To separate group of male Sprague Dawley rats, Cd (2 mL/kg/day) was subcutaneously injected for one month which results in a dose level of 1 mg/kg Cd. Couple of days prior to Cd injection, the treatment group rats regularly received nobiletin (50, 100, or 200 mg/kg b.wt) orally through the study period. Results Cd-induced ROS levels and malondialdehyde (MDA) content were inhibited by nobiletin and improved glutathione levels. Nobiletin reduced neuronal apoptosis induced by Cd and raised cleaved caspase-3 levels. Intriguingly, nobiletin blocked JNK and Erk1/2 phosphorylation and down-regulated the pathways. Raised expression of kinases - MKK and ASK1 were reduced by nobiletin. Discussion The suppressed expression of phosphatases - PP2A and PP5 were up-regulated on nobiletin treatment. Nobiletin significantly blocked the activation of Akt/mTOR signaling. Enhanced phosphorylation of S6K1, Akt, and 4E-BP1 induced by Cd was significantly inhibited by nobiletin. The raised levels of raptor and rictor proteins were remarkably down-regulated on nobiletin treatment. Collectively, the observations of this study indicate protective effects of nobiletin against Cd-induced neurotoxicity.


Natural cholinesterase inhibitors from marine organisms.
Covering: Published between 1974 up to 2018Inhibition of cholinesterases is a common approach for the management of several disease states. Most notably, cholinesterase inhibitors are used to alleviate the symptoms of neurological disorders like dementia and Alzheimer's disease and treat myasthenia gravis and glaucoma. Historically, most drugs of natural origin have been isolated from terrestrial sources and inhibitors of cholinesterases are no exception. However, the last 50 years have seen a rise in the quantity of marine natural products with close to 25 000 reported in the scientific literature. A number of marine natural products with potent cholinesterase inhibitory properties have also been reported; isolated from a variety of marine sources from algae to ascidians. Representing a diverse range of structural classes, these compounds provide inspirational leads that could aid the development of therapeutics. The current paper aims to, for the first time, comprehensively summarize the literature pertaining to cholinesterase inhibitors derived from marine sources, including the first papers published in 1974 up to 2018. The review does not report bioactive extracts, only isolated compounds, and a specific focus lies on compounds with reported dose-response data. In vivo and mechanistic data is included for compounds where this is reported. In total 185 marine cholinesterase inhibitors and selected analogs have been identified and reported and some of the compounds display inhibitory activities comparable or superior to cholinesterase inhibitors in clinical use.


Generation of cylindrical vector vortex beams by two cascaded metasurfaces.
We present a simple and efficient method to generate any cylindrical vector vortex (CVV) beams based on two cascaded metasurfaces. The metasurface works as a space-variant Panchratnam-Berry phase element and can produce any desirable vortex phase and vector polarization. The first metasurface is used to switch the sign of topological charges associated with vortex, and the second metasurface is applied to manipulate the local polarization. This method allows us to simultaneously manipulate polarization and phase of the CVV beams.


Induction of the Cpx envelope stress pathway contributes to Escherichia coli tolerance to antimicrobial peptides.
Antimicrobial peptides produced by multicellular organisms as part of their innate system of defense against microorganisms are currently considered potential alternatives to conventional antibiotics in case of infection by multiresistant bacteria. However, while the mode of action of antimicrobial peptides is relatively well described, resistance mechanisms potentially induced or selected by these peptides are still poorly understood. In this work, we studied the mechanisms of action and resistance potentially induced by ApoEdpL-W, a new antimicrobial peptide derived from human apolipoprotein E. Investigation of the genetic response of Escherichia coli upon exposure to sublethal concentrations of ApoEdpL-W revealed that this antimicrobial peptide triggers activation of RcsCDB, CpxAR, and σ(E) envelope stress pathways. This genetic response is not restricted to ApoEdpL-W, since several other antimicrobial peptides, including polymyxin B, melittin, LL-37, and modified S4 dermaseptin, also activate several E. coli envelope stress pathways. Finally, we demonstrate that induction of the CpxAR two-component system directly contributes to E. coli tolerance toward ApoEdpL-W, polymyxin B, and melittin. These results therefore show that E. coli senses and responds to different antimicrobial peptides by activation of the CpxAR pathway. While this study further extends the understanding of the array of peptide-induced stress signaling systems, it also provides insight into the contribution of Cpx envelope stress pathway to E. coli tolerance to antimicrobial peptides.


The ecology of entrainment: Foundations of coordinated rhythmic movement.
Entrainment has been studied in a variety of contexts including music perception, dance, verbal communication and motor coordination more generally. Here we seek to provide a unifying framework that incorporates the key aspects of entrainment as it has been studied in these varying domains. We propose that there are a number of types of entrainment that build upon pre-existing adaptations that allow organisms to perceive stimuli as rhythmic, to produce periodic stimuli, and to integrate the two using sensory feedback. We suggest that social entrainment is a special case of spatiotemporal coordination where the rhythmic signal originates from another individual. We use this framework to understand the function and evolutionary basis for coordinated rhythmic movement and to explore questions about the nature of entrainment in music and dance. The framework of entrainment presented here has a number of implications for the vocal learning hypothesis and other proposals for the evolution of coordinated rhythmic behavior across an array of species.


Heterosexual transmission of human immunodeficiency virus (HIV) in northern California: results from a ten-year study.
To examine rates of and risk factors for heterosexual transmission of human immunodeficiency virus (HIV), the authors conducted a prospective study of infected individuals and their heterosexual partners who have been recruited since 1985. Participants were recruited from health care providers, research studies, and health departments throughout Northern California, and they were interviewed and examined at various study clinic sites. A total of 82 infected women and their male partners and 360 infected men and their female partners were enrolled. Over 90% of the couples were monogamous for the year prior to entry into the study; < 3% had a current sexually transmitted disease (STD). The median age of participants was 34 years, and the majority were white. Over 3,000 couple-months of data were available for the follow-up study. Overall, 68 (19%) of the 360 female partners of HIV-infected men (95% confidence interval (CI) 15.0-23.3%) and two (2.4%) of the 82 male partners of HIV-infected women (95% CI 0.3-8.5%) were infected. History of sexually transmitted diseases was most strongly associated with transmission. Male-to-female transmission was approximately eight-times more efficient than female-to-male transmission and male-to-female per contact infectivity was estimated to be 0.0009 (95% CI 0.0005-0.001). Over time, the authors observed increased condom use (p < 0.001) and no new infections. Infectivity for HIV through heterosexual transmission is low, and STDs may be the most important cofactor for transmission. Significant behavior change over time in serodiscordant couples was observed.


Strong interactions between copper halides and unsaturated systems: new metallocycles? Or the importance of deformation.
The complexes formed by CuF with CC double and triple bonds have been studied at the MP2 and CCSD(T) computational levels. The interaction of CuF with acetylene, ethylene and their fluoro derivatives is very strong, with interaction energies close to those of conventional covalent bonds. Hence, these complexes could be actually viewed as a new kind of metallocycles, with significantly strong Cu-C linkages. All electronic indexes analyzed by means of the AIM, ELF and NBO formalisms, indicate that the strength of the interaction should increase with the number of fluorine substituents in both series of compounds. Surprisingly, however, although both series of compounds exhibit the same bonding arrangements, they follow opposite stability trends and the expected increase of the interaction energies with the number of fluorine substituents is only observed in the acetylene series. The reason for this unexpected behavior is once more associated with the effects triggered by the distortion of the interacting subunits. Deformation not only has a direct energetic cost but dramatically affects the intrinsic properties of the interacting systems.


Mec1, INO80, and the PAF1 complex cooperate to limit transcription replication conflicts through RNAPII removal during replication stress.
Little is known about how cells ensure DNA replication in the face of RNA polymerase II (RNAPII)-mediated transcription, especially under conditions of replicative stress. Here we present genetic and proteomic analyses from budding yeast that uncover links between the DNA replication checkpoint sensor Mec1-Ddc2 (ATR-ATRIP), the chromatin remodeling complex INO80C (INO80 complex), and the transcription complex PAF1C (PAF1 complex). We found that a subset of chromatin-bound RNAPII is degraded in a manner dependent on Mec1, INO80, and PAF1 complexes in cells exposed to hydroxyurea (HU). On HU, Mec1 triggers the efficient removal of PAF1C and RNAPII from transcribed genes near early firing origins. Failure to evict RNAPII correlates inversely with recovery from replication stress: paf1Δ cells, like ino80 and mec1 mutants, fail to restart forks efficiently after stalling. Our data reveal unexpected synergies between INO80C, Mec1, and PAF1C in the maintenance of genome integrity and suggest a mechanism of RNAPII degradation that reduces transcription-replication fork collision.


Diagnosing migraine in research and clinical settings: the validation of the Structured Migraine Interview (SMI).
Migraine is a common disorder that is highly co-morbid with psychopathological conditions such as depression and anxiety. Despite the extensive research and availability of treatment, migraine remains under-recognised and undertreated. The aim of this study was to design a short and practical screening tool to identify migraine for clinical and research purposes. The structured migraine interview (SMI) based on the International Classification of Headache Disorders (ICHD) criteria was used in a clinical setting of headache sufferers and compared to clinical diagnosis by headache specialist. In addition to the validating characteristics of the interview different methods of administration were also tested. The SMI has high sensitivity (0.87) and modest specificity (0.58) when compared to headache specialist's clinical diagnosis. Our study demonstrated that a structured interview based on the ICHD criteria is a useful and valid tool to identify migraine in research settings and to a limited extent in clinical settings, and could be used in studies on large samples where clinical interviews are less practical.


Superparamagnetic Nanoparticles as High Efficiency Magnetic Resonance Imaging T2 Contrast Agent.
Nanoparticle-based magnetic resonance imaging T2 negative agents are of great interest, and much effort is devoted to increasing cell-loading capability while maintaining low cytotoxicity. Herein, two classes of mixed-ligand protected magnetic-responsive, bimetallic gold/iron nanoparticles (Au/Fe NPs) synthesized by a two-step method are presented. Their structure, surface composition, and magnetic properties are characterized. The two classes of sulfonated Au/Fe NPs, with an average diameter of 4 nm, have an average atomic ratio of Au to Fe equal to 7 or 8, which enables the Au/Fe NPs to be superparamagnetic with a blocking temperature of 56 K and 96 K. Furthermore, preliminary cellular studies reveal that both Au/Fe NPs show very limited toxicity. MRI phantom experiments show that r2/r1 ratio of Au/Fe NPs is as high as 670, leading to a 66% reduction in T2 relaxation time. These nanoparticles provide great versatility and potential for nanoparticle-based diagnostics and therapeutic applications and as imaging contrast agents.


Low-fat dairy consumption and reduced risk of hypertension: the Seguimiento Universidad de Navarra (SUN) cohort.
Some observational studies have shown a beneficial effect of dairy consumption on blood pressure, especially in overweight and relatively young (<40 y) persons. However, no results from prospective studies conducted in a free-living population exist that show this association in middle-aged adults. The aim of the present study was to assess whether total, low-fat, and whole-fat dairy consumption was associated prospectively with the risk of hypertension. This was a prospective study conducted in 5880 university graduates in Spain, aged >20 y in 2000 (mean age: 37 y), free of hypertension and cardiovascular disease at baseline, and followed-up with mailed questionnaires for a median of 27 mo. Dairy consumption was assessed with a previously validated semiquantitative food-frequency questionnaire. One hundred eighty new cases of hypertension were identified. The hazard ratio of hypertension between extreme quintiles of low-fat dairy product consumption was 0.46 (95% CI: 0.26, 0.84; P for trend = 0.02) after adjustment for the main known risk factors for hypertension and several dietary factors. No significant association between whole-fat dairy products or total calcium intake and incident hypertension was seen. In this Mediterranean cohort, low-fat dairy consumption, but not whole-fat dairy consumption, was associated with a lower risk of incident hypertension.


Drug-mediated ototoxicity and tinnitus: alleviation with melatonin.
This review evaluates the published basic science and clinical reports related to the role of melatonin in reducing the side effects of aminoglycosides and the cancer chemotherapeutic agent cisplatin, in the cochlea and vestibule of the inner ear. A thorough search of the literature was performed using available databases for the purpose of uncovering articles applicable to the current review. Cochlear function was most frequently evaluated by measuring otoacoustic emissions and their distortion products after animals were treated with cytotoxic drugs alone or in combination with melatonin. Vestibular damage due to aminoglycosides was evaluated by estimating hair cell loss in explanted utricles of newborn rats. Tinnitus was assessed in patients who received melatonin using a visual analogue scale or the Tinnitus Handicap Inventory. Compared to a mixture of antioxidants which included tocopherol, ascorbate, glutathione and N-acetyl-cysteine, melatonin, also a documented antioxidant, was estimated to be up to 150 times more effective in limiting the cochlear side effects, evaluated using otoacoustic emission distortion products, of gentamicin, tobramycin and cisplatin. In a dose-response manner, melatonin also reduced vestibular hair cell loss due to gentamicin treatment in explanted utricles of newborn rats. Finally, melatonin (3 mg daily) limited subjective tinnitus in patients. These findings suggest the potential use of melatonin to combat the ototoxicity of aminoglycosides and cancer chemotherapeutic agents. Additional studies at both the experimental and clinical levels should be performed to further document the actions of melatonin at the cochlear and vestibular levels to further clarify the protective mechanisms of action of this ubiquitously-acting molecule. Melatonin's low cost and minimal toxicity profile supports its use to protect the inner ear from drug-mediated damage.


Spinal muscular atrophy: clinical spectrum and genetic mutations in Pakistani children.
In Pakistan the rate of consanguineous marriages is high, thus, the chance of incidence of autosomal recessive disorders is likely to be high. The aim of this study is to investigate the clinical characteristics and genetics of spinal muscular atrophy (SMA) in children who presented to Aga Khan University, Karachi. This study was a retrospective review of the medical charts of children (neonate: 15 years) with discharge diagnosis of SMA during last 10 years. Demographic features, consanguinity, and diagnostic analysis (including genetic analysis) were noted. During the study period 67 children had a discharge diagnosis of SMA. Werdnig Hoffman disease (SMA type I) was the commonest variant seen in 37 (56%) children. Overall 68% were infants. High parental consanguinity was observed in 68% of the study cohort. The history of delayed development and undiagnosed early death was observed in the families of 19 children. Genetic testing was performed in 22 (33%) children. Survival motor neuron (SMN) 1 gene deletion was found in 19 (86%) of the 22 patients in whom the gene analysis was done and 13 (68%) were also positive for neuronal apoptosis inhibitory proteins (NAIP) deletion. SMA is not an uncommon neurodegenerative disorder in Pakistan and SMA type I was the most common type. SMN1 gene deletion was the most common genetic deletion found in this study. In addition, family history of developmental delay and frequent early deaths highlights the need for implementation of prenatal diagnosis for early detection, effective control, and management of this disorder in Pakistan.