First in-human radiation dosimetry of 68Ga-NODAGA-RGDyK.
Integrin-targeting radiopharmaceuticals have potential broad applications, spanning from cancer theranostics to cardiovascular diseases. We have previously reported preclinical dosimetry results of 68Ga-NODAGA-RGDyK in mice. This study presents the first human dosimetry of 68Ga-NODAGA-RGDyK in the five consecutive patients included in a clinical imaging protocol of carotid atherosclerotic plaques. Five male patients underwent whole-body time-of-flight (TOF) PET/CT scans 10, 60 and 120 min after tracer injection (200 MBq). Quantification of 68Ga activity concentration was first validated by a phantom study. To be used as input in OLINDA/EXM, time-activity curves were derived from manually drawn regions of interest over the following organs: brain, thyroid, lungs, heart, liver, spleen, stomach, kidneys, red marrow, pancreas, small intestine, colon, urinary bladder and whole body. A separate dosimetric analysis was performed for the choroid plexuses. Female dosimetry was extrapolated from male data. Effective doses (EDs) were estimated according to both ICRP60 and ICRP103 assuming 30-min and 1-h voiding cycles. The body regions receiving the highest dose were urinary bladder, kidneys and choroid plexuses. For a 30-min voiding cycle, the EDs were 15.7 and 16.5 μSv/MBq according to ICRP60 and ICRP103, respectively. The extrapolation to female dosimetry resulted in organ absorbed doses 17% higher than those of male patients, on average. The 1-h voiding cycle extrapolation resulted in EDs of 19.3 and 19.8 μSv/MBq according to ICRP60 and ICRP103, respectively. A comparison is made with previous mouse dosimetry and with other human studies employing different RGD-based radiopharmaceuticals. According to ICRP60/ICRP103 recommendations, an injection of 200 MBq 68Ga-NODAGA-RGDyK leads to an ED in man of 3.86/3.92 mSv. For future therapeutic applications, specific attention should be directed to delivered dose to kidneys and potentially also to the choroid plexuses. Clinical trial.gov, NCT01608516.


[Frequency and pathotypes of diarrheagenic Escherichia coli in Peruvian children with and without diarrhea].
INTRODUCTION; Diarrheagenic E. coli (DEC) are a major cause of diarrhea in children in developing countries. However, they are not part of routine diagnosis in clinical laboratories. To determine the DEC prevalence in Peruvian children and to describe the genetic variability of these strains. A total of 8 003 E. coli strains previously isolated from eight different studies of diarrhea in children, mainly from peri-urban areas of Lima, were analyzed. Diagnosis of DEC was done with Multiplex real-time PCR using genes for each of the 6 DEC groups. Conventional PCR was performed for the detection of additional virulence genes. Globally, the mean prevalence in diarrhea samples (n=4,243) was: enteroaggregative E. coli (EAEC) 9.9%, enteropathogenic E. coli (EPEC) 8.5%, enterotoxigenic E. coli (ETEC) 6.9%, diffusely adherent E. coli (DAEC) 4.8%, Shiga toxin-producing E. coli (STEC) 0.8% and enteroinvasive E. coli (EIEC) 0.6%. The relative frequency of each pathogen varies according to the age and the type of study. The main pathotypes in control samples (n=3,760) were EPEC (10.9%) and EAEC (10.4%). An important variability in the virulence genes frequency and molecular resistance mechanisms for each pathotype was found, without differences between diarrhea and control groups. DEC are a major cause of diarrhea in Peruvian children. These pathogens are highly heterogeneous. Additional studies are required to determine the prevalence in rural areas of Peru and in severe diarrhea cases.


Regional cerebral glucose metabolism of women with trichotillomania.
Positron emission tomography and 18-F-fluorodeoxyglucose were used to study resting cerebral glucose metabolism in 10 adult women with trichotillomania and 20 age-matched female controls. As a group, the patients with trichotillomania showed significantly increased global (mean gray matter) and normalized right and left cerebellar and right superior parietal glucose metabolic rates. Contrary to expectation, this pattern differed from that seen in our previous investigation of obsessive-compulsive disorder. Clomipramine hydrochloride-induced improvement was negatively correlated with anterior cingulate and orbital frontal metabolism, of particular interest because similar results had been obtained for obsessive-compulsive disorder.


Closure of pericardium after open heart surgery. A way to prevent postoperative cardiac tamponade.
Between July 1968 and December 1975, 821 patients underwent open heart operations. In 596 cases the pericardium was left open and in 225 the pericardium was closed. Forty-one patients in the open pericardium group required reoperation and 23 of these had tamponade. Four patients in the closed pericardium group had reoperation but there was not a single case of tamponade. In most cases that required reoperation the bleeding was from extrapericardial sources. Absence of tamponade in the closed pericardium group can be explained by the fact that blood from extrapericardial sources of bleeding cannot collect round the heart because the pericardium is closed. Thus closure of pericardium helps to prevent tamponade. Reoperations some months or years after the original operation are technically easier and less hazardous if the pericardium has been closed because the closed pericardium prevents the heart from becoming adherent to the back of sternum and also because there are fewer adhesions in the pericardial cavity.


How we developed a trainee-led book group as a supplementary education tool for psychiatric training in the 21st century.
Postgraduate medical education has, in recent years, become a dynamic field with the increasing availability of innovative and interactive teaching techniques. Anecdotal evidence suggests that the current focus of psychiatric training on the acquisition of scientific and clinical knowledge is inadequate to address the multidimensional nature of psychiatry. Supplementary teaching tools may be usefully applied to address this need. A group of trainees at the Maudsley Hospital and Institute of Psychiatry (UK) pioneered the use of a book group as an innovative teaching tool to enhance the psychiatric training experience by, amongst other aspects, facilitating dialogue between peers on fundamental epistemological issues raised by critical engagement with seminal psychiatric texts. Feedback from members suggested that participation in the book group broadened the overall learning potential and experience of psychiatry. The key ingredients were identified as: (i) collaborative peer-to-peer learning; (ii) the use of 'flipped classroom' model; and (iii) joint ownership. The book group has demonstrated real potential to facilitate direct trainee engagement with the multi-faceted nature of psychiatry as a complex humanistic discipline within an informal learning space.


Self-Powered Forward Error-Correcting Biosensor Based on Integration of Paper-Based Microfluidics and Self-Assembled Quick Response Codes.
This paper extends our previous work on silver-enhancement based self-assembling structures for designing reliable, self-powered biosensors with forward error correcting (FEC) capability. At the core of the proposed approach is the integration of paper-based microfluidics with quick response (QR) codes that can be optically scanned using a smart-phone. The scanned information is first decoded to obtain the location of a web-server which further processes the self-assembled QR image to determine the concentration of target analytes. The integration substrate for the proposed FEC biosensor is polyethylene and the patterning of the QR code on the substrate has been achieved using a combination of low-cost ink-jet printing and a regular ballpoint dispensing pen. A paper-based microfluidics channel has been integrated underneath the substrate for acquiring, mixing and flowing the sample to areas on the substrate where different parts of the code can self-assemble in presence of immobilized gold nanorods. In this paper we demonstrate the proof-of-concept detection using prototypes of QR encoded FEC biosensors.


Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.
Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.


The effect of phospholipid transfer protein on lipoprotein metabolism and atherosclerosis.
Phospholipid transfer protein (PLTP) is a member of the lipid transfer/lipopolysaccharide binding protein gene family. Recently, the crystal structure of one of the members of the gene family, bactericidal permeability increasing protein, was solved, providing potential insights into the mechanisms of action of PLTP. These molecules contain intrinsic lipid binding sites and appear to act as carrier proteins that shuttle between lipoproteins to redistribute lipids. The phenotype of PLTP transgenic and gene knock out mice indicates that PLTP plays a major role in the metabolism of high-density lipoprotein (HDL) and apoB-containing lipoproteins and thereby influences the concentration, apolipoprotein content, and size of lipoprotein particles in plasma. Recent data indicate that PLTP deficiency in mice is associated with a decrease of atherosclerosis, despite decreased HDL levels. At lease two underlined mechanisms are involved in the reduction of atherosclerosis in PLTP deficient status, 1) reduction of apoB-containing lipoprotein production and levels; and 2) increase of anti-oxidation potential. Human studies indicated that PLTP activity positively correlated with aging, obesity, diabetes and coronary artery disease. A challenge for the future will be the inhibition of PLTP for therapeutic benefit.


Haptic to visual cross-modal recognition of objects in the vervet monkey.
Five juvenile vervet monkeys (Cercopithecus aethiops) were tested using the Cowey and Weiskrantz technique. The animals had access in the dark to distasteful biscuits of one shape and tasteful biscuits of another shape. Later they were shown a pair of biscuits, one of each shape, and the animal's first selection was scored. A single pair of shapes was used with flavor assigned daily according to a Gellerman schedule. In 69 percent of trials the monkeys selected the tasteful shape (P less than 0.001). The performance in the second half of testing was higher than in the beginning which suggests that some kind of learning set develops.


A Machine Learning Approach to COVID-19 Detection via Graphene Field-Effect-Transistor (GFET).
In the wake of the COVID-19 pandemic, there has been a need for reliable diagnostic testing. However, state-of-the-art detection methods rely on laboratory tests and also vary in accuracy. We evaluate that the usage of a graphene field-effect-transistor (GFET) coupled with machine learning can be a promising alternate diagnostic testing method. We processed the current-voltage data gathered from the GFET sensors to assess information about the presence of COVID-19 in biosamples. We perform binary classification using the following machine learning algorithms: Linear Discriminant Analysis (LDA), Support Vector Machines (SVM) with the Radial Basis Function (RBF) kernel, and K-Nearest Neighbors (KNN) in conjunction with Principal Component Analysis (PCA). We find that LDA and SVM with RBF proved to be the most accurate in identifying positive and negative samples, with accuracies of 99% and 98.5%, respectively. Based on these results, there is promise to develop a bioelectronic diagnostic method for COVID-19 detection by combining GFET technology with machine learning.


[Justice concern, perceived procedural justice, and subjective validity of the results in the labor tribunal system in Japan: A comparison of parties between labors and employers].
The labor tribunal system, which is a form of alternative dispute resolution rather than a type of lawsuit, requires both parties' agreements to settle disputes and maintains a high settlement rate. As most of parties involved in the system are said to expect that labor problems should be settled fairly, it is assumed that they will readily accept the results of fair procedures. However, it seems that laborers who submit claims for compensation have a different concept of justice than employers or company employees in charge of settlements and this determines the attitudes toward the results. This study conducted a survey of participants in the labor tribunal system, and suggest that laborers attribute the validity of this system's results directly to judges, while company representatives attribute it to the procedure conducted by the judges.


The Impact of Neighborhood-Level Factors on Perceived Quality of Hospice Service Satisfaction: A Geographic Information System Study.
Racial/ethnic minorities are underrepresented in hospice care in the United States, despite this being the standard of care for terminally ill individuals. Research indicates that location of services (e.g., rural vs. urban) plays a role in the differences in quality and quantity of services observed. However, the influences of neighborhood structural characteristics on quality of hospice services have not been explored. The purpose of this study was to explore the relationship between hospice neighborhood characteristics and caregiver-rated satisfaction with services in Florida. Data were derived from the Consumer Assessment of Healthcare Providers and Systems Hospice Survey and American Community Survey; ArcGIS was used to generate heat maps to provide visual representations. Findings showed that higher neighborhood immigrant density predicted lower family satisfaction with timely care, communication, spiritual support, and likelihood to recommend the agency services. The U.S. population is projected to continue to grow in its diversity, and thus understanding neighborhood characteristics associated with racial/ethnic minorities' perception of care quality are important for shaping care improvements.


Dual specificity phosphatase 1 has a protective role in osteoarthritis fibroblast‑like synoviocytes via inhibition of the MAPK signaling pathway.
Increasing evidence indicates the important role of inflammation in the pathogenesis and progression of osteoarthritis (OA). Dual specificity phosphatase 1 (DUSP1), a negative regulator of the mitogen‑activated protein kinase (MAPK) signaling pathway, has anti‑inflammatory properties. In the present study, the expression of DUSP1 was investigated in human OA fibroblast‑like synoviocytes (FLSs), human normal FLSs and OA FLSs pretreated with dexamethasone at the mRNA and protein levels. Then, the activation of MAPK pathway proteins and the expression of matrix metalloproteinase‑13 (MMP‑13) and cyclooxygenase‑2 (COX‑2) were measured by western blot analysis in the three groups of cells. Dexamethasone induced the expression of DUSP1 and inhibited the activation of the MAPK pathway and reduced the expression of MMP‑13 and COX‑2 in OA FLSs. However, the role of DUSP1 remained unclear. To clarify this, the effects of overexpression of DUSP1 in OA FLSs were determined using a DUSP1‑overexpressing lentivirus. The results demonstrated that overexpression of DUSP1 in OA FLSs inhibited the activation of the MAPK pathway and expression of OA‑associated mediators. The findings of the present study indicate that DUSP1 has a protective role in OA FLSs and may be a potential target in the treatment of OA.


Behavioral responses of terrestrial mammals to COVID-19 lockdowns.
COVID-19 lockdowns in early 2020 reduced human mobility, providing an opportunity to disentangle its effects on animals from those of landscape modifications. Using GPS data, we compared movements and road avoidance of 2300 terrestrial mammals (43 species) during the lockdowns to the same period in 2019. Individual responses were variable with no change in average movements or road avoidance behavior, likely due to variable lockdown conditions. However, under strict lockdowns 10-day 95th percentile displacements increased by 73%, suggesting increased landscape permeability. Animals' 1-hour 95th percentile displacements declined by 12% and animals were 36% closer to roads in areas of high human footprint, indicating reduced avoidance during lockdowns. Overall, lockdowns rapidly altered some spatial behaviors, highlighting variable but substantial impacts of human mobility on wildlife worldwide.


2SNP: scalable phasing method for trios and unrelated individuals.
Emerging microarray technologies allow affordable typing of very long genome sequences. A key challenge in analyzing of such huge amount of data is scalable and accurate computational inferring of haplotypes (i.e., splitting of each genotype into a pair of corresponding haplotypes). In this paper, we first phase genotypes consisting only of two SNPs using genotypes frequencies adjusted to the random mating model and then extend phasing of two-SNP genotypes to phasing of complete genotypes using maximum spanning trees. Runtime of the proposed 2SNP algorithm is O(nm (n + log m), where n and m are the numbers of genotypes and SNPs, respectively, and it can handle genotypes spanning entire chromosomes in a matter of hours. On datasets across 23 chromosomal regions from HapMap[11], 2SNP is several orders of magnitude faster than GERBIL and PHASE while matching them in quality measured by the number of correctly phased genotypes, single-site and switching errors. For example the 2SNP software phases entire chromosome (10(5) SNPs from HapMap) for 30 individuals in 2 hours with average switching error 7.7%. We have also enhanced 2SNP algorithm to phase family trio data and compared it with four other well-known phasing methods on simulated data from [15]. 2SNP is much faster than all of them while loosing in quality only to PHASE. 2SNP software is publicly available at http://alla.cs.gsu.edu/~software/2SNP.


Histoenzymological mapping of acetylcholinesterase and butyrylcholinesterase in the diencephalon and mesencephalon of Uromastix hardwickii.
The paper deals with a detailed histochemical mapping of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the diencephalon and mesencephalon of Uromastix hardwickii. In AChE in contrast to BChE preparations, most of the nuclei reveal intense activity Interestingly, the hypothalamic nuclei demonstrate positive reactions to AChE but totally negative reactions in BChE preparations. The enzymatic activity in fiber tracts is totally negative for AChE; on the contrary, it is intensely positive for BChE. Neurosecretory substance, in the hypothalamic region, is positive for the two preparations of the enzymes. The role of these enzymes, as related to the functional activities of the various nuclei and fiber tracts, has also been discussed.


Chitosan/glyphosate formulation as a potential, environmental friendly herbicide with prolonged activity.
Although there are many reports on the dangers posed by glyphosate, this herbicide is still one of the most popular and widely used total weed killers. Therefore, great effort should be made to minimize exposure to this herbicide and limit its losses into the environment. The aim of this study was to prepare a new formulation consisted of various molecular weight chitosans with glyphosate and their evaluation toward active substance release, phytotoxicity, and preliminary herbicidal efficiency. The phytotoxicity study of the obtained chitosan/glyphosate formulations was determined based on the Organisation for Economic Co-operation and Development 208 guideline. Among all tested formulations evaluated for phytotoxicity, that containing the highest molecular weight of chitosan was found to be the least toxic, showing simultaneously the most effective herbicidal activity against selected weeds. The release rate of glyphosate from the obtained formulations was dependent on the molecular weight and viscosity of chitosan.


[Word generation in bilinguals--fMRI study with implications for language and memory processes].
For over a century the cerebral representation of language functions is a matter of debate. In Neuroscience language is regarded as one of the most lateralized cognitive functions. Thus, while the language which is acquired first in most cases is processed by the left hemisphere some studies in brain damaged but also experimental investigations propose a pivotal role of the right hemisphere in second language processing. By the advent of modern neuroimaging it is now possible to study language lateralization and bilinguality also in healthy subjects. We studied first and second language abilities in a group of bilingual, healthy individuals by means of functional magnetic resonance imaging (fMRI) with a word-fluency paradigm. While we found a predominantly left prefrontal activity during both first and also second language processing an additional right prefrontal activation was registered during the use of second language. Our findings are discussed on the basis of an interaction between language and memory processes.


Nucleus caudalis dorsal root entry zone lesioning for the treatment of anesthesia dolorosa.
Deafferentation facial pain (anesthesia dolorosa) can occur after injury of the first-order trigeminal nerve. It is often debilitating and difficult to treat. The authors report the treatment of anesthesia dolorosa in a 69-year-old man with a 7-year history of pain. The pain occurred after an open resection of a right trigeminal neuroma. After treatment with medications failed, the patient was treated with nucleus caudalis (dorsal root entry zone) lesioning. His facial pain was immediately and completely eliminated. The authors describe the technique of this central neuroablative procedure, and they review the available literature regarding this procedure as well as the current evidence base for neuromodulatory surgeries. After the 1-year follow-up, the authors conclude that the patient attained lasting relief.


[Mechanisms of transmitting excitation in the electromechanical connections system of frog phasic muscle fibers].
The effect of replacement of Na ions by isomorphic Li ions on the dynamic parameters of isometric contractions and the distribution of Na, K, and Li in the frog m. sartorius involved increase of the muscle maximum tension during first 10-15 min. A possible role of Na and Li ions in the muscle contraction is discussed with regard to the assumption of a mechanism of participation of Na ions in the transmission of excitation from the plasmic membrane to the sarcoplasmic reticulum membrane.


Weight counseling for elderly patients in primary care: how often and how much time.
Some 20 million Americans over the age of 60 will soon be obese. As a result, they will likely suffer lower life-expectancy, higher disability, and higher health care costs. How much time do physicians spend with elders, especially obese elders, in helping them plan weight loss? This study, which analyzed 352 videotaped visits with elderly patients and their provider, has found that only a third of the visibly obese patients were counseled, and that the average time spent discussing the subject--if discussed--was 103 seconds. This is probably less than a fifth of the time needed to adequately counsel patients about weight loss. In addition, the study has found that both provider and patient characteristics determine if and how long discussion lasts.


The polypeptide structure of canine coronavirus and its relationship to porcine transmissible gastroenteritis virus.
Canine coronavirus (CCV) isolate 1-71 was grown in secondary dog kidney cells and purified by rate zonal centrifugation. Polyacrylamide gel electrophoresis revealed four major structural polypeptides with apparent mol. wt. of 203800 (gp204), 49800 (p50), 31800 (gp32) and 21600 (gp22). Incorporation of 3H-glucosamine into gp204, gp32 and gp22 indicated that these were glycopolypeptides. Comparison of the structural polypeptides of CCV and porcine transmissible gastroenteritis virus (TGEV) by co-electrophoresis demonstrated that TGEV polypeptides corresponded closely, but not identically, with gp204, p50 and gp32 of CCV and confirmed that gp22 was a major structural component only in the canine virus. The close similarities in structure of the two coronaviruses augments the relationship established by serology.


The administration of drugs and tranquillisers where it can lead to dependence on the part of the patient in hospital.
Prevention of the development of dependence on drugs and tranquillizers in hospital is a task which requires constant vigilance on the part of the hospital authorities as well as the right attitude on the part of prescribing doctors, administrating nurses and receiving public.


In utero management of hydrops fetalis caused by critical aortic stenosis.
Hydrops fetalis is rarely associated with congestive heart failure caused by obstructive left-sided heart lesions. There are rare cases of live born neonates with critical congenital valvar aortic stenosis and hydrops reported in the literature, all with fatal outcomes. This report describes, to the best of our knowledge, the first two newborns who were diagnosed prenatally to have hydrops fetalis caused by critical valvar aortic stenosis, who were treated prenatally with digoxin and who postnatally had successful percutaneous balloon aortic valvuloplasty. Both patients had not only left but right ventricular dysfunction. We speculate that right ventricular dysfunction was a contributing factor in the development of hydrops in these patients and in utero medical therapy with digoxin is associated with resolution of the hydrops before delivery.


Recent Toxoplasmosis Infection With Acute Myopericarditis and Persistent Troponin Elevation in an Immunocompetent Patient.
Although often considered as "begnin", acute infections in young healthy adults can lead to heart inflammation, including acute myocarditis. We report a rare case of myopericarditis in a young immunocompetent adult, in the context of recent toxoplasmosis infection. Clinical presentation was common acute pericarditis, but with risk biomarkers: high troponin I levels and multiple inflammation-compatible images on MR-scan. Diagnosis of myopericarditis was established. In spite of spontaneous favourable clinical evolution, troponin remained elevated. MR-scan is shown; acute myocarditis in the context of an acute toxoplasmosis infection is discussed.


The different strategies for designing GPCR and kinase targeted libraries.
In recent years the trend in combinatorial library design has shifted to include target class focusing along with diversity and drug-likeness criteria. In this manuscript we review the computational tools available for target class library design and highlight the areas where they have proven useful in our work. The protein kinase family is used to illustrated structure-based target class focused library design, and the G-protein coupled receptor (GPCR) family is used to illustrate ligand-based target class focused library design. Most of the tools discussed are those designed for libraries targeted to a single protein and are simply applied "brute-force" to a large number of targets within the family. The tools that have proven to be the most useful in our work are those that can extract trends from the computational data such as docking and clustering or data mining large amounts of structure activity or high throughput screening data. Finally, areas where improvements are needed in the computational tools available for target class focusing are highlighted. These areas include tools to extract the relevant patterns from all available information for a family of targets, tools to efficiently apply models for all targets in the family rather than just a small subset, mining tools to extract the relevant information from the computational absorption, distribution, metabolism, excretion and toxicity (ADMET) and targeting data, and tools to allow interactive exploration of the virtual space around a library to facilitate the selection of the library that best suits the needs of the design team.


Misconceptions and false expectations in neutral evolution.
Neutral evolution results from random recurrent mutation and genetic drift. A small part of random evolution, that which is related to protein or DNA polymorphisms, is the subject of the Neutral Theory of Evolution. One of the foundations of this theory is the demonstration that the mutation rate (m) is equal to the substitution rate. Since both rates are independent of population size, they are independent of drift, which is dependent upon population size. Neutralists have erroneously equated the substitution rate with the fixation rate, despite the fact that they are antithetical conceptions. The neutralists then applied the random walk stochastic model to justify alleles or bases that were fixated or eliminated. In this model, once the allele or base frequencies reach the monomorphic states (values of 1.0 or 0.0), the absorbing barriers, they can no longer return to the polymorphic state. This operates in a pure mathematical model. If recurrent mutation occurs (as in biotic real systems) fixation and elimination are impossible. A population of bacteria in which m = 10(-8) base mutation (or substitution)/site/generation and the reproduction rate is 1000 cell cycle/year should replace all its genome bases in approximately 100,000 years. The expected situation for all sites is polymorphism for the four bases rather than monomorphism at 1.0 or 0.0 frequencies. If fixation and elimination of a base for more than 500,000 years are impossible, then most of the neutral theory is untenable. A new complete neutral model, which allows for recurrent substitutions, is proposed here based on recurrent mutation or substitution and drift alone. The model fits a binomial or Poisson distribution and not a geometric one, as does neutral theory.


[Problems of pregnancy and labor in drug addicts].
Obstetrical problems during pregnancy and labor of drug-dependent female patients. Drug-abuse during pregnancy constitutes an increase of risks as well to the pregnant woman and the fetus as to the mother and to the newborn. In a retrospective study the problems of antenatal care and therapy and the effect on the fetal outcome are discussed.


The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer's disease.
Recent studies show that intracellular cholesterol levels can modulate the processing of amyloid precursor protein to Abeta peptide. Moreover, cholesterol-rich apoE-containing lipoproteins may also promote Abeta clearance. Agonists of the liver X receptor (LXR) transcriptionally induce genes involved in intracellular lipid efflux and transport, including apoE. Thus, LXR agonists have the potential to both inhibit APP processing and promote Abeta clearance. Here we show that LXR agonist, TO901317, increased hippocampal ABCA1 and apoE and decreased Abeta42 levels in APP transgenic mice. TO901317 had no significant effects on levels of Abeta40, full length APP, or the APP processing products. Next, we examined the effects of TO901317 in the contextual fear conditioning paradigm; TO901317 completely reversed the contextual memory deficit in these mice. These data demonstrate that LXR agonists do not directly inhibit APP processing but rather facilitate the clearance of Abeta42 and may represent a novel therapeutic approach to Alzheimer's disease.


Soy protein/soy polysaccharide complex nanogels: folic acid loading, protection, and controlled delivery.
In this study, we developed a facile approach to produce nanogels via self-assembly of folic acid, soy protein, and soy polysaccharide. High-pressure homogenization was introduced to break down the original aggregates of soy protein, which benefits the binding of soy protein with soy polysaccharide and folic acid at pH 4.0. After a heat treatment that causes the soy protein denaturation and gelation, folic acid-loaded soy protein/soy polysaccharide complex nanogels were fabricated. The nanogels have a polysaccharide surface that makes the nanogels dispersible in acidic conditions where folic acid is insoluble and soy protein forms precipitates after heating. More importantly, the protein and polysaccharide can inhibit the reactions between dissolved oxygen and folic acid during UV irradiation. After the preparation and storage of the nanogels in the presence of heat, oxygen, and light in acidic conditions, most of the folic acid molecules in the nanogels remain in their natural structure and can be released rapidly at neutral pH, that is, in the intestine. Because most food and beverages are acidic, the nanogels are a suitable delivery system of folic acid in food and beverages.


Covert Consciousness and Covert Ethics.
Rights Come to Mind: Brain Injury, Ethics, and the Struggle for Consciousness (2015) by Joseph J. Fins offers rich narratives of families and patients who experience disorders of consciousness in flawed health-care systems that are not clinically, structurally, financially, or ethically prepared to respond to the inherent complexities of these conditions. In 2018, only a few years after the publication of this book, the medical guidelines for these disorders officially changed with key publications in Neurology. Fins has called on bioethicists to respond to these significant developments, and this paper serves as a response to that call. This article offers a critical analysis of a couple of Fins's arguments. But it also emphasizes the importance of these developments and Fins's work for thinking through bedside and organizational ethics issues that arise in advocating for patients with disorders of consciousness.


Prosodic changes in aphasic speech: timing.
Controversy remains about the impairment of prosody in aphasia, particularly with regard to speech timing. This paper addresses this topic through an analysis of timing in four sets of a common morphological paradigm. The paradigm consisted of a basic form (stem) and two longer derived forms (e.g. zip, zipper, zippering). Normally, vowel durations are shorter in longer derived forms (e.g. zippering) than in the stem (e.g. zip), due to a process called 'initial shortening'. Twelve patients with aphasia (four each Broca, Wernicke, and Anomic), and 11 age-matched healthy adults were assessed. Structural (CT) and functional brain imaging (PET) were available for all patients. While all groups showed initial shortening between the stem and the derived forms, the patients with Broca's aphasia presented an inverse pattern between the two derived forms (longer initial vowel in 'zippering' than 'zipper'), and the patients with Wernicke's aphasia produced significantly longer vowel durations overall than the healthy participants. The results are related to radiological information regarding the location of structural and functional brain damage and relative preservation and loss of prosodic features in cerebral damage.


Expression of the c-erbB-3/HER-3 and c-erbB-4/HER-4 growth factor receptors and their ligands, neuregulin-1 alpha, neuregulin-1 beta, and betacellulin, in normal endometrium and endometrial cancer.
The objective of this study was to determine the immunohistochemical expression of the c-erbB-3 and c-erbB-4 growth factor receptors and their principal ligands, the neuregulins and betacellulin, in normal endometrium and determine whether there was evidence of under- or overexpression in endometrial adenocarcinoma. Immunohistochemistry was performed using well-characterized antibodies against each of the five proteins analyzed on formalin-fixed, paraffin-embedded archival material. Forty-three normal endometrial samples (16 proliferative, 19 secretory, and 8 hyperplastic) and 41 endometrial adenocarcinoma cases were analyzed. There was variable expression of the growth factor receptors and the ligands in the two principal phases of the menstrual cycle as well as in endometrial adenocarcinoma. In normal endometrium, the c-erbB-3 receptor was weakly expressed in both phases. The c-erbB-4 receptor and all of the ligands examined, neuregulin alpha, neuregulin beta, and betacellulin, were expressed at significantly higher levels in the secretory as compared with the proliferative phase of the menstrual cycle, suggesting a role for these proteins in endometrial maturation. In endometrial adenocarcinoma, overexpression of c-erbB-3, c-erbB-4, and betacellulin with underexpression of neuregulin a as compared with normal controls was observed. Neuregulin beta expression was not found to be significantly different in the two groups. These results suggest that signaling through the c-erbB-3 and c-erbB-4 receptors and the ligands neuregulin alpha, neuregulin beta, and betacellulin are important in endometrial carcinogenesis.


Activities of natural methyl farnesoids on pupariation and metamorphosis of Drosophila melanogaster.
Methyl farnesoate (MF) and juvenile hormone (JH III), which bind with high affinity to the receptors USP and MET, respectively, and bisepoxy JH III (bisJH III) were assessed for several activities during Drosophila larval development, and during prepupal development to eclosed adults. Dietary MF and JH III were similarly active, and more active than bisJH III, in lengthening larval development prior to pupariation. However, the order of activity was changed (JH III>bisJH III>MF) with respect to preventing prepupae from eclosing as normal adults, whether administered in the larval diet or as topically applied at the white puparium stage. If endogenous production of all three larval methyl farnesoids was suppressed by a strongly driven RNAi against HMGCR in the corpora allata cells, most larvae did not attain pupariation. Farnesol (which has no demonstrated life-necessary function in larval life except in corpora allata cells as a precursor to methyl farnesoid biosynthesis) when incorporated into the diet rescued attainment of pupariation in a dose-dependent manner, presumably by rescuing endogenous production of all three hormones. A more mild suppression of endogenous methyl farnesoid production enabled larval attainment of pupariation. However, in this background dietary MF had increased activity in preventing puparia from attaining normal adult eclosion. The physiological relevance of using exogenous methyl farnesoids to block prepupal development to normally eclosed adults was tested by, instead, protecting in prepupae the endogenous titer of methyl farnesoids. JH esterase normally increases during the mid-late prepupal stage, presumably to clear endogenous methyl farnesoids. When JH esterase was inhibited with an RNAi, it prevented attainment of adult eclosion. Cultured adult corpora allata from male and female Aedes aegypti released both MF and JH III, and the A. aegypti nuclear receptor USP bound MF with nanomolar affinity. These A. aegypti data support the use of Drosophila as a model for mosquitoes of the binding of secreted MF to USP.


The association between different types of physical activity and smoking behavior.
Smoking is harmful, which has become a major public health burden. Physical activity may be related to smoking. Physical activity is one of the current methods for smoking control and smoking cessation. Different types of physical activity may have different effect on smoking behavior. The purpose of this study was to identify the direction and extent of the impact of different types of physical activity above moderate intensity (including work physical activity, recreational physical activity, commuter physical activity and sedentary behavior) on smoking behavior. In this study, a total of 2,015 individuals (1,233 males and 782 females, mean age 54.02±17.31 years) was selected from the representative population aged 20 and above in the National Health and Nutrition Survey of the United States from 2017 to 2018. Physical activity was assessed using the Global Physical Activity Questionnaire (GPAQ) ; the tobacco use questionnaire (SMQ) was used to determine whether the sample had smoking behavior at this stage. Binary Logistic regression analysis was performed with various physical activities as independent variables and smoking behavior as dependent variables. All data were analyzed through Statistical Product and Service Solutions (SPSS) 26.0. After adjusted for all confounding variables, physical activity at work was close to significantly associated with smoking behavior (P=0.053), odds ratio (OR) =1.135 (95%Cl: 0.999-1.289). Recreational physical activity was significantly associated with smoking behavior (P < 0.001), OR=0.729 (95%Cl: 0.639-0.832). Commuting physical activity was significantly associated with smoking behavior (P < 0.001), OR=1.214 (95%Cl:1.048-1.405). Sedentary behavior was significantly associated with smoking behavior (P < 0.001), OR=1.363 (95%Cl: 1.154-1.611). Given that different types of physical activity have different associations with smoking behavior. Therefore, when physical activity is used as a tobacco control measurement, it is necessary to pay attention to the type and environment of physical activity. Recreational physical activities should be appropriately increased, sedentary behavior should be reduced, and smoking prohibit environment should be expanded as far as possible to achieve better clinical intervention effects.


How do hospitalization experience and institutional characteristics influence inpatient satisfaction? A multilevel approach.
Over the last several years, interest in benchmarking health services' quality--particularly patient satisfaction (PS)--across organizations has increased. Comparing patient experiences of care across hospitals requires risk adjustment to control for important differences in patient case-mix and provider characteristics. This study investigates the individual-level and organizational-level determinants of PS with public hospitals by applying hierarchical models. The analysis focuses on the effect of hospital characteristics, such as self-discharges, on overall evaluations and on across hospital variation in scores. Sociodemographics, admission mode, place of residence, hospitalization ward and continuity of care were statistically significant predictors of inpatient satisfaction. Interestingly, it was observed that hospitals with a higher percentage of Patients Leaving Against Medical Advice (PLAMA) received lower scores. The latter result suggests that the percentage of PLAMA may provide a useful measure of a hospital's inability to meet patient needs and a proxy indicator of PS with hospital care.


The impact of smoking on prevalence of psoriasis and psoriatic arthritis.
In this systematic literature review and meta-analysis, we aimed to investigate the impact of cigarette smoking on the prevalence and incidence of psoriasis and psoriatic arthritis (PsA). We performed a systematic literature review using the MEDLINE, EMBASE and Cochrane Central Register databases. The literature included publications from January 1980 to July 2019. The studies that provided clear information on the number of patients with ever smoking data were included in the meta-analysis. The systematic literature review identified 52 and 24 articles for the prevalence of smoking in psoriasis and PsA, respectively. Of these, 16 articles on psoriasis and three and four (general population and psoriasis, respectively) articles on PsA met the criteria and were included in the meta-analysis. The prevalence of ever smoking was increased in psoriasis compared with the general population (OR: 1.84; 95% CI: 1.4, 2.3). For PsA the prevalence of ever smoking was reduced in psoriasis patients (OR: 0.70; 95% CI: 0.60, 0.81), but not changed compared with the general population (OR: 1.10; 95% CI: 0.92, 1.32). This meta-analysis showed that ever smoking increases the risk of psoriasis in the general population, but may reduce the risk of PsA in psoriasis patients. The latter may be also due to the collider effect. Whether smoking cessation neutralizes the risk of developing psoriasis requires a well-defined smoking data collection for the past history and this is currently unavailable in the literature.


Cutaneous angiosarcoma in a patient with xeroderma pigmentosum.
Xeroderma pigmentosum (XP) is a DNA repair defect syndrome associated with an increased risk to developing skin neoplasms on sun-exposed cutaneous surfaces. This report describes the case of a 15-year-old boy with XP who developed cutaneous angiosarcoma. The patient was cured with surgery alone, despite incomplete resection, and he is alive without evidence of disease 40 months after diagnosis. It is the fourth reported case--and the third in pediatric age--of the association of XP with this soft part sarcoma.


Minireview: Steroid-regulated paracrine mechanisms controlling implantation.
Implantation is an essential process during establishment of pregnancy in mammals. It is initiated with the attachment of the blastocyst to a receptive uterine epithelium followed by its invasion into the stromal tissue. These events are profoundly regulated by the steroid hormones 17β-estradiol and progesterone. During the past several years, mouse models harboring conditional gene knockout mutations have become powerful tools for determining the functional roles of cellular factors involved in various aspects of implantation biology. Studies using these genetic models as well as primary cultures of human endometrial cells have established that the estrogen receptor α, the progesterone receptor, and their downstream target genes critically regulate uterine growth and differentiation, which in turn control embryo-endometrial interactions during early pregnancy. These studies have uncovered a diverse array of molecular cues, which are produced under the influence of estrogen receptor α and progesterone receptor and exchanged between the epithelial and stromal compartments of the uterus during the progressive phases of implantation. These paracrine signals are critical for acquisition of uterine receptivity and functional interactions with the embryo. This review highlights recent work describing paracrine mechanisms that govern steroid-regulated uterine epithelial-stromal dialogue during implantation and their roles in fertility and disease.


Posterior Parietal Cortex Guides Visual Decisions in Rats.
Neurons in putative decision-making structures can reflect both sensory and decision signals, making their causal role in decisions unclear. Here, we tested whether rat posterior parietal cortex (PPC) is causal for processing visual sensory signals or instead for accumulating evidence for decision alternatives. We disrupted PPC activity optogenetically during decision making and compared effects on decisions guided by auditory versus visual evidence. Deficits were largely restricted to visual decisions. To further test for visual dominance in PPC, we evaluated electrophysiological responses after individual sensory events and observed much larger response modulation after visual stimuli than auditory stimuli. Finally, we measured trial-to-trial spike count variability during stimulus presentation and decision formation. Variability decreased sharply, suggesting that the network is stabilized by inputs, unlike what would be expected if sensory signals were locally accumulated. Our findings suggest that PPC plays a causal role in processing visual signals that are accumulated elsewhere.SIGNIFICANCE STATEMENT Defining the neural circuits that support decision making bridges a gap between our understanding of simple sensorimotor reflexes and our understanding of truly complex behavior. However, identifying brain areas that play a causal role in decision making has proved challenging. We tested the causal role of a candidate component of decision circuits, the rat posterior parietal cortex (PPC). Our interpretation of the data benefited from our use of animals trained to make decisions guided by either visual or auditory evidence. Our results suggest that PPC plays a causal role specifically in visual decision making and may support sensory aspects of the decision, such as interpreting the visual signals so that evidence for a decision can be accumulated elsewhere.


The novel FAAH inhibitor, MCH1, reduces the infarction area in the motor cortex-related region but does not affect the sensorimotor function or memory and spatial learning in rats exposed to transient middle cerebral artery occlusion.
Macamides, amides of fatty acids first isolated from maca (Lepidium meyenii) are potentially responsible for the reduction of ischemic injury in the stroke animal model followed by maca extract administration. This deduction comes from its ability to inhibit the fatty acid amide hydrolase activity, an enzyme related to the endocannabinoid anandamide hydrolysis. However, no study about the effects of isolated macamides on in-vivo models has been published yet. Our objective was to evaluate the effect of a 10-day 30 mg/kg i.p. MCH1 administration, the macamide with the higher FAAH inhibition capability, on the neurological recovery and brain infarction area of Sprague-Dawley rats exposed to the transient middle cerebral artery occlusion (MCAO) model. Our results showed that the group receiving MCH1 for 10 days did not improve Garcia's neurological score compared to receiving the vehicle only. Likewise, the MCH1 group did not improve their sensorimotor dysfunction as indicated by the latency to detect and remove the tape from the contralateral forepaw in the adhesive removal test, and a similar number of errors with the contralateral forepaw in the foot fault test compared to the vehicle group at the 10th day. Evaluation of the spatial memory and learning using the Barnes test showed longer latency to reach the escape box in the Vehicle and MCH1 groups compared to the control group (no MCAO) only in the retrieval test, while no effect of MCAO procedure or MCH1 administration was observed in the reversal learning test. Despite the lack of behavioral effect of MCH1, analysis of the infarcted areas in the brain using the 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining method in the seven consecutive coronal sections revealed that the infarcted area in the first (bregma + 4.2 mm) and fifth (bregma -3.8 mm) coronal sections of the MCAO + MCH1 group remained similar to the Control group. These results provide evidence that MCH1 can limit damage from ischemic stroke, although it is not reflected in neurological or sensorimotor behavior and spatial learning and memory.


A Full Quantum Eigensolver for Quantum Chemistry Simulations.
Quantum simulation of quantum chemistry is one of the most compelling applications of quantum computing. It is of particular importance in areas ranging from materials science, biochemistry, and condensed matter physics. Here, we propose a full quantum eigensolver (FQE) algorithm to calculate the molecular ground energies and electronic structures using quantum gradient descent. Compared to existing classical-quantum hybrid methods such as variational quantum eigensolver (VQE), our method removes the classical optimizer and performs all the calculations on a quantum computer with faster convergence. The gradient descent iteration depth has a favorable complexity that is logarithmically dependent on the system size and inverse of the precision. Moreover, the FQE can be further simplified by exploiting a perturbation theory for the calculations of intermediate matrix elements and obtaining results with a precision that satisfies the requirement of chemistry application. The full quantum eigensolver can be implemented on a near-term quantum computer. With the rapid development of quantum computing hardware, the FQE provides an efficient and powerful tool to solve quantum chemistry problems.


The universally conserved GTPase HflX is an RNA helicase that restores heat-damaged Escherichia coli ribosomes.
The ribosome-associated GTPase HflX acts as an antiassociation factor upon binding to the 50S ribosomal subunit during heat stress in Escherichia coli Although HflX is recognized as a guanosine triphosphatase, several studies have shown that the N-terminal domain 1 of HflX is capable of hydrolyzing adenosine triphosphate (ATP), but the functional role of its adenosine triphosphatase (ATPase) activity remains unknown. We demonstrate that E. coli HflX possesses ATP-dependent RNA helicase activity and is capable of unwinding large subunit ribosomal RNA. A cryo-electron microscopy structure of the 50S-HflX complex in the presence of nonhydrolyzable analogues of ATP and guanosine triphosphate hints at a mode of action for the RNA helicase and suggests the linker helical domain may have a determinant role in RNA unwinding. Heat stress results in inactivation of the ribosome, and we show that HflX can restore heat-damaged ribosomes and improve cell survival.


Histamine synthesis and gastric secretion after portacaval shunt.
In man there is an increased incidence of peptic ulcer after portacaval shunt. In the rat, 2 months after portacaval anastomosis, there is a generalized increase in the histamine content of the soft tissues, and the increase is most marked in the acid-secreting portion of the stomach. This appears to be secondary to increased activity of the histamine-synthesizing enzyme, histidine decarboxylase. A histidine decarboxylase inhibitor can prevent such hypersecretion of acid in the stomach of these animals.


A noncoding motoric equivalent measures most of what the digit symbol does, including age changes.
The Digit Symbol test and a copying test with identical graphomotor requirements but not visual search, memory, or coding demands were given to 108 normal volunteers and neurologically screened physical rehabilitation patients age 20 to 90 yr. The ratio of coding to copying scores did not change over age, and the high correlations between them were similar across age groups. Little variance was unaccounted for; gross lapses in nonmotoric functions such as memory or attention may prevent Digit Symbol's use with some patients, but subtler decrements need not be invoked to explain age effects. Tentative norms provided here allow evaluation of individual deviations in coding/copying ratios or exploratory use of the copying test to monitor the course of disease or drug titration with patients whose linguistic or perceptual deficits invalidate Digit Symbol or Trail Making tests. If discrepant ratios characterize some groups of patients, the ratios may become useful diagnostic indices. If coding and copying are as closely related for patients with cerebral dysfunction as for normals, the copying test may become a useful alternative to Digit Symbol with patients unable to comply reliably with its requirements.


Preparation of rat serum suitable for mammalian whole embryo culture.
Mammalian whole embryo culture (WEC) is a widely used technique for examining pharmacological toxicity in developing mouse and rat embryos and for investigating the mechanisms of developmental processes. Immediately centrifuged (IC) rat serum is commonly used for WEC and is essential for the growth and development of cultured mouse and rat embryos ex vivo. For the culture of midgestation embryos (i.e., E8.0-12.5 for the mouse, and E10.0-14.5 for the rat), 100% rat serum is the best media for supporting the growth of the embryo ex vivo. To prepare rat serum suitable for WEC, the collected blood should be centrifuged immediately to separate the blood cells from the plasma fraction. After centrifugation, the fibrin clot forms in the upper layer; this clot should be squeezed gently using a pair of sterile forceps and subsequently centrifuged to completely separate the blood cells from the serum. In this video article, we demonstrate our standard protocol for the preparation of optimal IC rat serum, including blood collection from the abdominal aorta of male rats and extraction of the serum by centrifugation.


Ubiquitination of Sec22b by a novel Legionella pneumophila ubiquitin E3 ligase.
Legionella pneumophila is a facultative intracellular pathogen that causes legionellosis. The key to its virulence is the delivery of hundreds of effector proteins into host cells via the defective in organelle trafficking/intracellular multiplication type IV secretion system. These effectors modulate numerous host signaling pathways to create a niche called the Legionella-containing vacuole (LCV) permissive for its intracellular replication. Previous investigation revealed that exploitation of the host ubiquitin system is among the most important strategies used by L. pneumophila to coopt host processes for its benefit. Here, we show that the effector Legionella ubiquitin ligase gene 15 (Lug15) (Lpg2327), which has no detectable homology with any enzyme involved in ubiquitin signaling, is an E3 ligase. In L. pneumophila-infected cells, Lug15 is localized on the LCV and impacts its association with polyubiquitinated proteins. We also demonstrate that Sec22b is ubiquitinated and recruited to the LCV by Lug15. Thus, our results establish Lug15 as a novel E3 ligase that functions to recruit a SNARE protein to remodel the L. pneumophila phagosome.IMPORTANCEProtein ubiquitination is one of the most important post-translational modifications that plays critical roles in the regulation of a wide range of eukaryotic signaling pathways. Many successful intracellular bacterial pathogens can hijack host ubiquitination machinery through the action of effector proteins that are injected into host cells by secretion systems. Legionella pneumophila is the etiological agent of legionellosis that is able to survive and replicate in various host cells. The defective in organelle trafficking (Dot)/intracellular multiplication (Icm) type IV secretion system of L. pneumophila injects over 330 effectors into infected cells to create an optimal environment permissive for its intracellular proliferation. To date, at least 26 Dot/Icm substrates have been shown to manipulate ubiquitin signaling via diverse mechanisms. Among these, 14 are E3 ligases that either cooperate with host E1 and E2 enzymes or adopt E1/E2-independent catalytic mechanisms. In the present study, we demonstrate that the L. pneumophila effector Legionella ubiquitin ligase gene 15 (Lug15) is a novel ubiquitin E3 ligase. Lug15 is involved in the remodeling of LCV with polyubiquitinated species. Moreover, Lug15 catalyzes the ubiquitination of host SNARE protein Sec22b and mediates its recruitment to the LCV. Ubiquitination of Sec22b by Lug15 promotes its noncanonical pairing with plasma membrane-derived syntaxins (e.g., Stx3). Our study further reveals the complexity of strategies utilized by L. pneumophila to interfere with host functions by hijacking host ubiquitin signaling.


Methanol-to-olefin conversion in ABC-6 zeolite cavities: unravelling the role of cavity shape and size from density functional theory calculations.
We report a density functional theory (DFT) study to investigate methanol-to-olefin (MTO) conversion in four types of ABC-6 zeolite cavities (cha, avl, aft and h1) by varying their shape and size. Based on a side-chain alkylation mechanism, the reaction energies and barriers of methylations, deprotonations and eliminations for hydrocarbon pool (HP) intermediates are calculated. In the cha cavity, methylations and eliminations are found to possess low barriers as attributed to the strong confinement effect of the elliptical and small cha cavity. The avl and aft cavities also exhibit low barriers of the first and second methylations, and similar barriers of eliminations for producing olefins as in cha. Due to the narrow shape and large size of the h1 cavity, most of the reaction barriers in h1 are the highest. The stabilities of HP species and transition states in the four cavities are quantified by the Gibbs energy profiles. It is found that aft with a wide dimension is favorable for the stability, especially for the charged HP species. The DFT calculation results reveal that the activity and selectivity of MTO conversion in zeolite cavities are strongly governed by the confinement effect, which depends on cavity shape and size. We also predict that zeolites with aft cavities might have good performance for MTO conversion.


Reduced specificity of autobiographical memory and depression: the role of executive control.
It has been widely established that depressed mood states and clinical depression, as well as a range of other psychiatric disorders, are associated with a relative difficulty in accessing specific autobiographical information in response to emotion-related cue words on an Autobiographical Memory Test (AMT; J. M. G. Williams & K. Broadbent, 1986). In 8 studies the authors examined the extent to which this relationship is a function of impaired executive control associated with these mood states and clinical disorders. Studies 1-4 demonstrated that performance on the AMT is associated with performance on measures of executive control, independent of depressed mood. Furthermore, Study 1 showed that executive control (as measured by verbal fluency) mediated the relationship between both depressed mood and a clinical diagnosis of eating disorder and AMT performance. Using a stratified sample in Study 5, the authors confirmed the positive association between depressed mood and impaired performance on the AMT. Studies 6-8 involved experimental manipulations of the parameters of the AMT designed to further indicate that reduced executive control is to a significant extent driving the relationship between depressed mood and AMT performance. The potential role of executive control in accounting for other aspects of the AMT literature is discussed.


Infectious epiphysitis and valvular endocarditis in a red deer (Cervus elaphus).
A 10-month-old male red deer (Cervus elaphus) was presented with severe lameness and enlargement of the fetlock areas of both front and one hind legs. Radiographs demonstrated an epiphysitis and osteomyelitis of the distal metacarpal and metatarsal bones. Post mortem revealed pus containing Corynebacterium pyogenes and Staphylococcus aureus in the lesions, and an accompanying valvular endocarditis of the right atrioventricular valve.


[Influence of an Er:YAG laser on the surface structure of titanium implants].
In addition to conventional treatment modalities (mechanical and chemical), the use of lasers has been proposed for cleaning and detoxification of implant surfaces. The aim of the present clinical investigation was (1) to evaluate the effects of an Er:YAG laser on the surface properties of titanium implants in vivo and (2) to determine the effectiveness of this treatment modality for subgingival calculus removal. This investigation was conducted on eight implants of two patients, considered for explantation due to severe peri-implantitis inflammation. Immediately before explanatation, six implants were instrumented subgingivally with an Er:YAG laser (100 mJ/pulse and 10 Hz). Two implants served as a control. All titanium implants were examined using scanning electron microscopy by one calibrated and blinded examiner. In comparison to the untreated control group, non-surgical instrumentation of titanium implants with an Er:YAG laser resulted in an effective removal of subgingival calculus without leading to any thermal damages. However, all samples of the test group revealed amounts of residual debris which should be taken into account under clinical conditions.


Inferring modulators of genetic interactions with epistatic nested effects models.
Maps of genetic interactions can dissect functional redundancies in cellular networks. Gene expression profiles as high-dimensional molecular readouts of combinatorial perturbations provide a detailed view of genetic interactions, but can be hard to interpret if different gene sets respond in different ways (called mixed epistasis). Here we test the hypothesis that mixed epistasis between a gene pair can be explained by the action of a third gene that modulates the interaction. We have extended the framework of Nested Effects Models (NEMs), a type of graphical model specifically tailored to analyze high-dimensional gene perturbation data, to incorporate logical functions that describe interactions between regulators on downstream genes and proteins. We benchmark our approach in the controlled setting of a simulation study and show high accuracy in inferring the correct model. In an application to data from deletion mutants of kinases and phosphatases in S. cerevisiae we show that epistatic NEMs can point to modulators of genetic interactions. Our approach is implemented in the R-package 'epiNEM' available from https://github.com/cbg-ethz/epiNEM and https://bioconductor.org/packages/epiNEM/.


Association of single nucleotide polymorphisms in CFH, ARMS2 and HTRA1 genes with risk of age-related macular degeneration in Egyptian patients.
Age-related macular degeneration (AMD) is one of the leading causes of blindness in the elderly worldwide. Several single nucleotide polymorphisms (SNPs) have been linked to the risk of developing AMD. We aimed to examine the association between AMD and SNPs on CFH, ARMS2 and HTRA1 in Egyptians, a previously unstudied population. Genomic DNA was extracted from 26 AMD patients and 20 controls. Genotyping was performed using PCR followed by allele-specific restriction digestion and direct sequencing. CFH rs1061170 was significantly associated with AMD with the frequency of the risk C allele being 0.53 in patients and 0.17 in controls (p < 0.017). The odds ratio (OR) for the TC genotype was 5.5 (95% CI: 1.1-26.4) and for combined TC + CC genotypes was 8 (95% CI: 1.7-37.1). ARMS2 rs10490924 was also significantly associated with the risk allele T found at a frequency of 0.5 in AMD and 0.15 in controls (p < 0.017, χ(2) test). The OR for the TG genotype was 4.667 (95% CI: 1.2-18.4) and for combined TG + TT genotypes was 7 (95% CI: 1.8-26.5). HTRA1 rs11200638 also was significantly associated, with the risk allele A found at a frequency of 0.44 in patients and 0.17 in controls (p < 0.017, χ(2) test). OR for GA genotype was 5 (95% CI: 1.2-20.9) and for the combined GA + AA genotypes was 6 (95% CI: 1.4-24.7). Our data demonstrates significant association between AMD and rs1061170 on CFH, rs10490924 on ARMS2 and rs11200638 on HTRA1 in Egyptian patients. These findings are in agreement with previous findings in Caucasians.


Investigation of H7N2 avian influenza outbreaks in two broiler breeder flocks in Pennsylvania, 2001-02.
An avian influenza (AI) outbreak occurred in meat-type chickens in central Pennsylvania from December 2001 to January 2002. Two broiler breeder flocks were initially infected almost simultaneously in early December. Avian influenza virus (AIV), H7N2 subtype, was isolated from the two premises in our laboratory. The H7N2 isolates were characterized as a low pathogenic strain at the National Veterinary Services Laboratories based on molecular sequencing of the virus hemagglutinin cleavage site and virus challenge studies in specific-pathogen-free leghorn chickens. However, clinical observations and pathologic findings indicated that this H7N2 virus appeared to be significantly pathogenic in meat-type chickens under field conditions. Follow-up investigation indicated that this H7N2 virus spread rapidly within each flock. Within 7 days of the recognized start of the outbreak, over 90% seroconversion was observed in the birds by the hemagglutination inhibition test. A diagnosis of AI was made within 24 hr of bird submission during this outbreak using a combination of virus detection by a same-day dot-enzyme-linked immunosorbent assay and virus isolation in embryonating chicken eggs. Follow-up investigation revealed that heavy virus shedding (90%-100% of birds shedding AIV) occurred between 4 and 7 days after disease onset, and a few birds (15%) continued to shed virus at 13 days post-disease onset, as detected by virus isolation on tracheal and cloacal swabs. AIV was not detected in or on eggs laid by the breeders during the testing phase of the outbreak. The two flocks were depopulated at 14 days after disease onset, and AIV was not detected on the two premises 23 days after depopulation.


Effect of anion substitution on the structural and transport properties of argyrodites Cu7PSe6-xSx.
Inspired by the good performance of argyrodites as ion conducting thermoelectrics and as solid electrolytes we investigated the effect of isovalent S2- substitution for Se2- in Cu7PSe6. At room temperature Cu7PSe6 crystallizes in the primitive cubic β-polymorph of the argyrodite structure and transforms to the face-centered high-temperature (HT) γ-modification above 320 K. The transition for the homologous Cu7PS6 occurs at 510 K. Promising thermoelectric and ion conducting properties are observed only in the HT modification, where the cations are mobile. Using Rietveld refinements against X-ray diffraction data the effect of isovalent S2- substitution for Se2- on the structural and transport properties in Cu7PSe6-xSx was analyzed. While a step-wise incorporation of S2- showed typical behavior for a homogeneous solid solution series, the analysis of the diffraction data gave clear evidence of anion ordering due to site preference of the sulfide ions, which can be rationalized using Pearson's HSAB concept. This leads to a stabilization of the HT structure even at lower temperatures. This selective control enables new strategies for the design of argyrodite materials, as isovalent substitution not only allows an engineering of properties, but also permits the stabilization of the polymorph with the most promising properties.


Normalization in the fitting of data by iterative methods. Application to tracer kinetics and enzyme kinetics.
1. The normalization of biochemical data to weight them appropriately for parameter estimation is considered, with reference particularly to data from tracer kinetics and enzyme kinetics. If the data are in replicate, it is recommended that the sum of squared deviations for each experimental variable at each time or concentration point is divided by the local variance at that point. 2. If there is only one observation for each variable at each sampling point, normalization may still be required if the observations cover more than one order of magnitude, but there is no absolute criterion for judging the effect of the weighting that is produced. The goodness of fit that is produced by minimizing the weighted sum of squares of deviations must be judged subjectively. It is suggested that the goodness of fit may be regarded as satisfactory if the data points are distributed uniformly on either side of the fitted curve. A chi-square test may be used to decide whether the distribution is abnormal. The proportion of the residual variance associated with points on one or other side of the fitted curve may also be taken into account, because this gives an indication of the sensitivity of the residual variance to movement of the curve away from particular data points. These criteria for judging the effect of weighting are only valid if the model equation may reasonably be expected to apply to all the data points. 3. On this basis, normalizing by dividing the deviation for each data point by the experimental observation or by the equivalent value calculated by the model equation may both be shown to produce a consistent bias for numerically small observations, the former biasing the curve towards the smallest observations, the latter tending to produce a curve that is above the numerically smaller data points. It was found that dividing each deviation by the mean of observed and calculated variable appropriate to it produces a weighting that is fairly free from bias as judged by the criteria mentioned above. This normalization factor was tested on published data from both tracer kinetics and enzyme kinetics.


Role of laminin in the attachment and metastasis of murine tumor cells.
We have studied the attachment of two murine metastatic cell lines and of a transformed, nonmetastatic sarcoma cell line to type IV (basement membrane) collagen. The metastatic cells attached preferentially to type IV collagen, whereas the nonmetastic cells attached best to type I collagen. Laminin increased both the rate and the number of metastatic cells attaching to type IV collagen, while fibronectin had no effect. Antibodies to laminin prevented the attachment of metastatic cells to type IV collagen, while antibodies to fibronectin prevented the attachment of the nonmetastatic cells. The number of pulmonary metastases which formed after i.v. injection of cells into C57BL mice was used to measure the metastatic propensity of these cell lines. A subpopulation of the metastatic cells selected for by their ability to attach to type IV collagen in the presence of laminin produced more metastases than did unattached cells or cells attached with fibronectin. In addition, incubation of metastatic cells with antibody to laminin prior to injection into mice markedly reduced the number of lung metastases. These data suggest that laminin promotes the attachment of metastatic tumor cells to basement membrane during the metastaatic process.


Persistent Increase in Blood Pressure After Renal Nerve Stimulation in Accessory Renal Arteries After Sympathetic Renal Denervation.
Blood pressure response to renal denervation is highly variable, and the proportion of responders is disappointing. This may be partly because of accessory renal arteries too small for denervation, causing incomplete ablation. Renal nerve stimulation before and after renal denervation is a promising approach to assess completeness of renal denervation and may predict blood pressure response to renal denervation. The objective of the current study was to assess renal nerve stimulation-induced blood pressure increase before and after renal sympathetic denervation in main and accessory renal arteries of anaesthetized patients with drug-resistant hypertension. The study included 21 patients. Nine patients had at least 1 accessory renal artery in which renal denervation was not feasible. Renal nerve stimulation was performed in the main arteries of all patients and in accessory renal arteries of 6 of 9 patients with accessory arteries, both before and after renal sympathetic denervation. Renal nerve stimulation before renal denervation elicited a substantial increase in systolic blood pressure, both in main (25.6±2.9 mm Hg; P<0.001) and accessory (24.3±7.4 mm Hg; P=0.047) renal arteries. After renal denervation, renal nerve stimulation-induced systolic blood pressure increase was blunted in the main renal arteries (Δ systolic blood pressure, 8.6±3.7 mm Hg; P=0.020), but not in the nondenervated renal accessory renal arteries (Δ systolic blood pressure, 27.1±7.6 mm Hg; P=0.917). This residual source of renal sympathetic tone may result in persistent hypertension after ablation and partly account for the large response variability.


Rabies virus ocular disease: T-cell-dependent protection is under the control of signaling by the p55 tumor necrosis factor alpha receptor, p55TNFR.
Following brain infection, the Challenge Virus Standard strain of rabies virus infects the retina. Rabies virus ocular infection induces the infiltration of neutrophils and predominantly T cells into the eye. The role of tumor necrosis factor alpha (TNF-alpha)-lymphotoxin signaling in the control of rabies virus ocular infection and inflammatory cell infiltration was assessed using mice lacking the p55 TNF-alpha receptor (p55TNFR(-/-) mice). The incidence of ocular disease and the intensity of retinal infection were greater in p55TNFR(-/-) mice than in C57BL/6 mice: the aggravation correlated with less neutrophil and T-cell infiltration. This indicates that cellular infiltration is under the control of the p55 TNF-alpha receptor and suggests that inflammatory cells may protect the eye against rabies virus ocular infection. The role of T cells following rabies virus ocular disease was assessed by comparison of rabies virus infection in nude mice with their normal counterparts. Indeed, the incidence and severity of the rabies virus ocular disease were higher in athymic nude mice than in BALB/c mice, indicating that T lymphocytes are protective during rabies virus ocular infection. Moreover, few T cells and neutrophils underwent apoptosis in rabies virus-infected retina. Altogether, these data suggest that T lymphocytes and neutrophils are able to enter the eye, escape the immune privilege status, and limit rabies virus ocular disease. In conclusion, rabies virus-mediated eye disease provides a new model for studying mechanisms regulating immune privilege during viral infection.


Role of methionine containing antioxidant combination in the management of pain in chronic pancreatitis: a systematic review and meta-analysis.
Pain in CP results from inflammation and neuroimmune alterations that are associated with oxidative stress, among other mechanisms. This is marked by depletion of antioxidant defenses including methionine, which is a donor of methyl moieties that maintains the acinar transsulfuration pathway. We performed a systematic review and meta-analysis of trials evaluating methionine-containing antioxidants in CP. Literature search was conducted in Medline/Pubmed, EMBASE, and Cochrane databases. Systematic review and meta-analysis was performed per PRISMA guidelines. Main study outcome was pain relief. GRADE system was used for quality assessment. Heterogeneity was assessed by the Q and I(2) measures; publication bias by Egger's test. Random-effect model (DerSimonian and Laird) was used if there was heterogeneity. Eight studies (n = 411) were identified that used methionine-containing antioxidants. The study duration ranged from 10 wks to 12 months. All studies used methionine, organic selenium, ascorbate, beta-carotene and alpha-tocoferol. Four studies (including two RCTs) that reported change in pain scores were metaanalyzed. Though overall effect [standardized difference in means (95% CI)] on pain score reduction was -0.95 (-1.738 to -0.160) (z = -2.36; p = 0.018), the significance was lost when the two RCTs were meta-analyzed. RCTs that reported the number of pain free patients had a statistically significant overall effect of -3.204 (p = 0.001). Though more patients on methionine containing antioxidants had adverse events, majority of them were mild. Methionine containing antioxidants appear to result in pain reduction in a significant proportion of CP patients. Further randomized controlled trials with homogeneous outcome measures are needed.


Individual differences and knockout in zebrafish reveal similar cognitive effects of BDNF between teleosts and mammals.
The remarkable similarities in cognitive performance between teleosts and mammals suggest that the underlying cognitive mechanisms might also be similar in these two groups. We tested this hypothesis by assessing the effects of the brain-derived neurotrophic factor (BDNF), which is critical for mammalian cognitive functioning, on fish's cognitive abilities. We found that individual differences in zebrafish's learning abilities were positively correlated with bdnf expression. Moreover, a CRISPR/Cas9 mutant zebrafish line that lacks the BDNF gene (bdnf-/-) showed remarkable learning deficits. Half of the mutants failed a colour discrimination task, whereas the remaining mutants learned the task slowly, taking three times longer than control bdnf+/+ zebrafish. The mutants also took twice as long to acquire a T-maze task compared to control zebrafish and showed difficulties exerting inhibitory control. An analysis of habituation learning revealed that cognitive impairment in mutants emerges early during development, but could be rescued with a synthetic BDNF agonist. Overall, our study indicates that BDNF has a similar activational effect on cognitive performance in zebrafish and in mammals, supporting the idea that its function is conserved in vertebrates.


[Dynamics of morphofunctional organization and developmental potential of mouse embryos in the state of "two-cell block in vitro"].
Vital observation in combination with electron microscopy and immunocytochemistry was used for studying structural organization and developmental potential of BALB/c mouse embryos after cleavage cessation at a two cell stage caused by the "two-cell block in vitro" phenomenon. Modification of structure and viability of embryos was followed for 2 days from the time of cleavage arrest. Several hours before cleavage arrest, changes in mitochondrian distribution were noticed in embryos, no other disturbances in structural organization of blastomeres being obvious. Embryos, whose development was arrested for 24 h, remained viable and demonstrated some morphological changes similar to those seen in normally developing embryos of the same age. Towards the end of a 48 h block period some embryos died, the surviving embryos remained morphologically intact and metabolically active. At the same time, the nuclei of the latter frequently displayed chromatin condensation near the nuclear membrane, which is similar to the pattern of chromatin reorganization in the nuclei of early apoptotic cells. Our results support a concept on the "two-cell block in vitro" phenomenon as a specific functional state of embryos, and well compare with data on a partial realization by blocked embryos of the developmental program.


A trial of vidarabine for cytomegalovirus infection in renal transplant patients.
Vidarabine was evaluated in renal transplant patients as a potential therapeutic agent in cytomegalovirus (CMV) infection. Four patients received vidarabine on an open protocol, then ten additional patients were enrolled in a double-blind protocol. Among the nine patients who received vidarabine, no notable clinical improvement occurred in either the vidarabine- or placebo-treated groups. Thus, vidarabine showed no therapeutic effect in the treatment of CMV infections at the dosages used. Four patients showed dramatic CNS deterioration within several days of the onset of vidarabine therapy. Tremors and myoclonus were common, and one patient had unusual brain pathologic changes with widespread neuronal chromatolysis. The pathologic findings in the brain in the other three patients were complex and included intracerebral hemorrhage, Fabry's disease, coccidioidomycosis meningitis, and cerebral vascular occlusion. Thus, there was no conclusive proof that vidarabine contributed to the sudden neurologic deterioration of these patients.


Use of the AutoCapture Pacing System with implantable defibrillator leads.
Previous studies using various bipolar pacemaker leads have shown that the AutoCapture (AC) Pacing System is able to verify ventricular capture and regulate pacing output, increasing patient safety with respect to unexpected threshold changes and potentially prolonging device longevity. An increasing number of patients with implantable cardioverter defibrillators (ICDs) require ventricular pacing that contributes to a shortening of longevity of these systems. This prospective study tested the compatibility of the AC system with bipolar ICD leads. The AC algorithm was evaluated prior to ICD testing in 30 ICD recipients. A single coil, active fixation, true bipolar ventricular lead was implanted in 21 patients, and a dual coil, passive fixation, integrated bipolar ventricular lead was implanted in 9 patients. A ventricular evoked response sensitivity test and an AC threshold test were performed using a pacemaker with the ventricular AC algorithm. AC was recommended in 22/30 (73.3%) of implants, including 20/21 (95.2%) with the single coil and 2/9 (22.2%) with the dual coil lead. Mean polarization was lower (1.23 +/- 0.95 mV vs 3.70 +/- 2.33 mV, P = 0.013) while the mean evoked response was higher (18.04 +/- 8.29 mV vs 10.13 +/- 4.22 mV, P = 0.002) with the single coil leads. Automatic threshold tracking using the AC is compatible with ICD leads. Leads with lower polarization and greater evoked response are more likely to result in recommendation of AC use. Use of this system offers the potential for increasing ICD generator longevity and improving patient safety in response to late unexpected threshold increases.


The influence of neuromuscular blockade on phase lag entropy and bispectral index: A randomized, controlled trial.
The aim of this study is to compare the effects of neuromuscular blockade (NMB) on phase lag entropy (PLE) and the bispectral index (BIS). We recorded the BIS, electromyograph (EMG) activity on a BIS monitor (EMG_BIS), PLE, and EMG activity on a PLE monitor (EMG_PLE) in 40 patients receiving general anesthesia. During the awake state, we analyzed the changes in parameters before and 2 min after the eyes were closed. During sedation, we compared the changes in the parameters before and at 4 min after injecting rocuronium (group R) or normal saline (group C) between the two groups. During anesthesia, we compared the changes in parameters before and at 4 min after injecting sugammadex (group B) or normal saline (group D) between the two groups. During the awake state, the BIS, EMG_BIS, and EMG_PLE, but not PLE, decreased significantly with closed eyes. An effect of EMG on the BIS was evident, but not on PLE. During sedation, the BIS decreased with the decrease in EMG_BIS regardless of NMB caused by rocuronium, but NMB decreased PLE, although the degree of the decrease in EMG_PLE after NMB was similar to that after placebo. To determine the effect of NMB on electroencephalograms (EEGs) in groups R and C, we plotted the power spectra before and at 4 min after injecting rocuronium or normal saline. Changes in slow and delta frequency bands were observed at 4 min after injecting rocuronium relative to before injecting rocuronium. There was no effect of EMG on either the BIS or PLE during anesthesia. In conclusion, the effect of electromyograph activity and/or neuromuscular blockade on BIS or PLE depends on the level of consciousness.


Implementing infection prevention and control capacity building strategies within the context of Ebola outbreak in a "Hard-to-Reach" area of Liberia.
In August 2014, WHO declared that Ebola outbreak ravaging West Africa including Liberia had become a Public Health Emergency of International Concern (PHEIC). Infection prevention and control (IPC) among healthcare workers was pivotal in reducing healthcare worker infection and containing the recent EVD outbreak. Hard to reach areas (HTRA) presents peculiar challenges in public health emergencies. We present the result of IPC capacity building strategies deployed in Gbarpolu County: an HTRA of Liberia. Between April to October 2015, we conducted IPC training and mentorship at the county, district and facility levels in a selected HTRA of Liberia using the keep Safe, Keep Serving manual and the WHO core components of infection control. Serial follow-up assessments and mentoring using the Liberian Minimum standard tool for safe care in Liberian health facilities (MST) were done. 180 (100%) facility based healthcare workers were trained: including 59 clinicians (32%) and 121 (67%) non-clinicians. 100% of the healthcare workers in four selected very HTRAs were trained and underwent facility based-mentorship. Compliance with IPC practice increased: the MST score increased from 75% to 90% and for the MST score for waste management and isolation increased 60% to 87%. Strengthening the capacity of healthcare workers for IPC was instrumental for containing the EVD epidemic but also critical for routine safe and quality services. A culture of IPC among healthcare workers in HTRA can be implemented through capacity building and training.


Chromosome evolution in dendropsophini (Amphibia, Anura, Hylinae).
Dendropsophini is the most species-rich tribe within Hylidae with 234 described species. Although cytogenetic information is sparse, chromosome numbers and morphology have been considered as an important character system for systematic inferences in this group. Using a diversity of standard and molecular techniques, we describe the previously unknown karyotypes of the genera Xenohyla, Scarthyla and Sphaenorhynchus and provide new information on Dendropsophus and Lysapsus. Our results reveal significant karyotype diversity among Dendropsophini, with diploid chromosome numbers ranging from 2n = 22 in S. goinorum, 2n = 24 in Lysapsus, Scinax, Xenohyla, and almost all species of Sphaenorhynchus and Pseudis, 2n = 26 in S. carneus, 2n = 28 in P. cardosoi, to 2n = 30 in all known Dendropsophus species. Although nucleolar organizer regions (NORs) and C-banding patterns show a high degree of variability, NOR positions in 2n = 22, 24 and 28 karyotypes and C-banding patterns in Lysapsus and Pseudis are informative cytological markers. Interstitial telomeric sequences reveal a diploid number reduction from 24 to 22 in Scarthyla by a chromosome fusion event. The diploid number of X. truncata corroborates the character state of 2n = 30 as a synapomorphy of Dendropsophus.


Proapoptotic bcl-2 family members, Bax and Bak, are essential for developmental photoreceptor apoptosis.
Apoptosis has been implicated in retinal development and degeneration, but the specific apoptotic pathways used are incompletely understood. The purpose of this study was to characterize the roles in retinal development of the proapoptotic Bcl-2 family members Bax and Bak. Eyes from mice at postnatal day (P)7, during the peak of developmental apoptosis in the retina, were processed for TdT-dUTP terminal nick-end labeling (TUNEL) to determine whether Bax knockout or double Bax/Bak knockout causes a defect in developmental apoptosis. Adult (>2-month-old) eyes from wild-type, Bak(-/-), Bax(-/-), and Bax(-/-)Bak(-/-) mice were analyzed by histology and immunocytochemistry to identify persistent retinal cells. Adult Bax(-/-)Bak(-/-) eyes showed significant increases in the number of inner retinal cells, with an almost complete absence of TUNEL-positive cell death at P7. Some of these persistent cells in the inner retina notably included rod photoreceptors that normally undergo apoptosis after failure to migrate to the outer retina. These inner nuclear layer (INL) rods contained markers of early rod differentiation: rod opsin, arrestin, and recoverin. However, they did not form ectopic outer segments or contain the associated markers ROM-1, peripherin-2, and RP1. Bax and Bak are important for retinal development and are the first apoptotic factors identified as essential for developmental photoreceptor apoptosis. Future studies will investigate the potential role of Bax and Bak in mediating pathologic photoreceptor death.


Calculating life? Duelling discourses in interdisciplinary systems biology.
A high profile context in which physics and biology meet today is in the new field of systems biology. Systems biology is a fascinating subject for sociological investigation because the demands of interdisciplinary collaboration have brought epistemological issues and debates front and centre in discussions amongst systems biologists in conference settings, in publications, and in laboratory coffee rooms. One could argue that systems biologists are conducting their own philosophy of science. This paper explores the epistemic aspirations of the field by drawing on interviews with scientists working in systems biology, attendance at systems biology conferences and workshops, and visits to systems biology laboratories. It examines the discourses of systems biologists, looking at how they position their work in relation to previous types of biological inquiry, particularly molecular biology. For example, they raise the issue of reductionism to distinguish systems biology from molecular biology. This comparison with molecular biology leads to discussions about the goals and aspirations of systems biology, including epistemic commitments to quantification, rigor and predictability. Some systems biologists aspire to make biology more similar to physics and engineering by making living systems calculable, modelable and ultimately predictable-a research programme that is perhaps taken to its most extreme form in systems biology's sister discipline: synthetic biology. Other systems biologists, however, do not think that the standards of the physical sciences are the standards by which we should measure the achievements of systems biology, and doubt whether such standards will ever be applicable to 'dirty, unruly living systems'. This paper explores these epistemic tensions and reflects on their sociological dimensions and their consequences for future work in the life sciences.


Utility of IOLMaster 700 Swept-Source Optical Coherence Tomography in Detecting Macular Disease for Preoperative Cataract Surgery Patients.
To assess the efficacy of IOLMaster 700 (IOLM) biometer swept-source optical coherence tomography (SS-OCT) in detecting macular pathology before cataract surgery and to compare IOLM SS-OCT characteristics of foveal pathology with a widely used spectral-domain OCT (SD-OCT) system. Retrospective analysis of 1156 consecutive eyes with IOLMaster 700 SS-OCT undergoing cataract surgery from January to June 2017 was performed. Approximately a third of these eyes (327 eyes) also had a SD-OCT scan performed previously. A single reviewer assessed each SS-OCT scan and identified them as "normal" or "abnormal." SS-OCT sensitivity and specificity in identifying foveal pathology was assessed using findings on Spectralis SD-OCT scans as the gold standard. Of 327 eyes with both IOLM SS-OCT and Spectralis SD-OCT scans, 121 eyes (37.0%) had abnormal SS-OCT scans. Of these 121 eyes, SD-OCT scans confirmed pathology in 104 eyes (86.0%). Of the remaining 206 eyes graded to have normal SS-OCT scans, 84 eyes (40.8%) had normal SD-OCT scans, and 122 eyes (59.2%) had pathologic findings on SD-OCT scans. For each pathologic condition, subtle but definitive differences existed in the appearance of the IOLM SS-OCT and SD-OCT images. Using a normal or abnormal Spectralis SD-OCT scan as confirmation of absence or presence of foveal pathology respectively, we found a high positive predictive value (86.0%) of an abnormal IOLM SS-OCT scan and a high specificity (83.2%) but low sensitivity (46.0%) and negative predictive value (40.8%) of a normal-appearing SS-OCT scan. These results suggest that an abnormal IOLM SS-OCT scan in an eye without known pathology is a strong indicator of an abnormal macula and should prompt further evaluation of the retina to identify pathology prior to cataract surgery. Importantly, IOLM SS-OCT scans do not detect all macular pathology and cannot be used as a screening test for identifying macular pathology.


The incidence of plastic ingestion by fishes: from the prey's perspective.
One of the primary threats to ocean ecosystems from plastic pollution is ingestion by marine organisms. Well-documented in seabirds, turtles, and marine mammals, ingestion by fish and sharks has received less attention until recently. We suggest that fishes of a variety of sizes attack drifting plastic with high frequency, as evidenced by the apparent bite marks commonly left behind. We examined 5518 plastic items from random plots on Kamilo Point, Hawai'i Island, and found 15.8% to have obvious signs of attack. Extrapolated to the entire amount of debris removed from the 15 km area, over 1.3 tons of plastic is attacked each year. Items with a bottle shape, or those blue or yellow in color, were attacked with a higher frequency. The triangular edges or punctures left by teeth ranged from 1 to 20 mm in width suggesting a variety of species attack plastic items. More research is needed to document the specific fishes and rates of plastic ingestion.


GAM-NGS: genomic assemblies merger for next generation sequencing.
In recent years more than 20 assemblers have been proposed to tackle the hard task of assembling NGS data. A common heuristic when assembling a genome is to use several assemblers and then select the best assembly according to some criteria. However, recent results clearly show that some assemblers lead to better statistics than others on specific regions but are outperformed on other regions or on different evaluation measures. To limit these problems we developed GAM-NGS (Genomic Assemblies Merger for Next Generation Sequencing), whose primary goal is to merge two or more assemblies in order to enhance contiguity and correctness of both. GAM-NGS does not rely on global alignment: regions of the two assemblies representing the same genomic locus (called blocks) are identified through reads' alignments and stored in a weighted graph. The merging phase is carried out with the help of this weighted graph that allows an optimal resolution of local problematic regions. GAM-NGS has been tested on six different datasets and compared to other assembly reconciliation tools. The availability of a reference sequence for three of them allowed us to show how GAM-NGS is a tool able to output an improved reliable set of sequences. GAM-NGS is also a very efficient tool able to merge assemblies using substantially less computational resources than comparable tools. In order to achieve such goals, GAM-NGS avoids global alignment between contigs, making its strategy unique among other assembly reconciliation tools. The difficulty to obtain correct and reliable assemblies using a single assembler is forcing the introduction of new algorithms able to enhance de novo assemblies. GAM-NGS is a tool able to merge two or more assemblies in order to improve contiguity and correctness. It can be used on all NGS-based assembly projects and it shows its full potential with multi-library Illumina-based projects. With more than 20 available assemblers it is hard to select the best tool. In this context we propose a tool that improves assemblies (and, as a by-product, perhaps even assemblers) by merging them and selecting the generating that is most likely to be correct.