University of North Dakota

To develop criteria for the classification of fibromyalgia, we studied 558 consecutive patients: 293 patients with fibromyalgia and 265 control patients. Interviews and examinations were performed by trained, blinded assessors. Control patients for the group with primary fibromyalgia were matched for age and sex, and limited to patients with disorders that could be confused with primary fibromyalgia. Control patients for the group with secondary-concomitant fibromyalgia were matched for age, sex, and concomitant rheumatic disorders. Widespread pain (axial plus upper and lower segment plus left- and right-sided pain) was found in 97.6% of all patients with fibromyalgia and in 69.1% of all control patients. The combination of widespread pain and mild or greater tenderness in greater than or equal to 11 of 18 tender point sites yielded a sensitivity of 88.4% and a specificity of 81.1%. Primary fibromyalgia patients and secondary-concomitant fibromyalgia patients did not differ statistically in any major study variable, and the criteria performed equally well in patients with and those without concomitant rheumatic conditions. The newly proposed criteria for the classification of fibromyalgia are 1) widespread pain in combination with 2) tenderness at 11 or more of the 18 specific tender point sites. No exclusions are made for the presence of concomitant radiographic or laboratory abnormalities. At the diagnostic or classification level, the distinction between primary fibromyalgia and secondary-concomitant fibromyalgia (as defined in the text) is abandoned.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is thatthere is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the completeprocess including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increasedautophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in manycases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as forreviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multipleassays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagyrelated protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

Glucocorticoids are among the most common therapeutic agents used in medical practice, yet their mechanisms of action are only partly understood. This review summarizes our understanding of how glucocorticoids inhibit inflammation and give rise to side effects.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

In 1981, de Bold and his colleagues made the seminal observation that infusion of extracts of atrial tissue into rats caused a copious natriuresis.1 This then led to the isolation and cloning of atrial natriuretic peptide, the first member of a family of peptides with potent natriuretic, diuretic, and vasorelaxant activity.2 Subsequent contributions from many investigators have expanded our understanding of the family of natriuretic peptides, their receptors, and their cellular actions that regulate physiologic functions. Studies using drugs to inhibit the function of some natriuretic peptide receptors or to prevent the degradation of natriuretic peptides have confirmed the importance . . .

Based on engineered or bacterial nucleases, the development of genome editing technologies has opened up the possibility of directly targeting and modifying genomic sequences in almost all eukaryotic cells. Genome editing has extended our ability to elucidate the contribution of genetics to disease by promoting the creation of more accurate cellular and animal models of pathological processes and has begun to show extraordinary potential in a variety of fields, ranging from basic research to applied biotechnology and biomedical research. Recent progress in developing programmable nucleases, such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas-associated nucleases, has greatly expedited the progress of gene editing from concept to clinical practice. Here, we review recent advances of the three major genome editing technologies (ZFNs, TALENs, and CRISPR/Cas9) and discuss the applications of their derivative reagents as gene editing tools in various human diseases and potential future therapies, focusing on eukaryotic cells and animal models. Finally, we provide an overview of the clinical trials applying genome editing platforms for disease treatment and some of the challenges in the implementation of this technology.

Tumor immune escape is an important strategy of tumor survival. There are many mechanisms of tumor immune escape, including immunosuppression, which has become a research hotspot in recent years. The programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is an important component of tumor immunosuppression, which can inhibit the activation of T lymphocytes and enhance the immune tolerance of tumor cells, thereby achieving tumor immune escape. Therefore, targeting the PD-L1/PD-1 pathway is an attractive strategy for cancer treatment; however, the therapeutic effectiveness of PD-L1/PD-1 remains poor. This situation requires gaining a deeper understanding of the complex and varied molecular mechanisms and factors driving the expression and activation of the PD-L1/PD-1 signaling pathway. In this review, we summarize the regulation mechanisms of the PD-L1/PD-1 signaling pathway in the tumor microenvironment and their roles in mediating tumor escape. Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking.

Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative opportunistic pathogen that infects patients with cystic fibrosis, burn wounds, immunodeficiency, chronic obstructive pulmonary disorder (COPD), cancer, and severe infection requiring ventilation, such as COVID-19. P. aeruginosa is also a widely-used model bacterium for all biological areas. In addition to continued, intense efforts in understanding bacterial pathogenesis of P. aeruginosa including virulence factors (LPS, quorum sensing, two-component systems, 6 type secretion systems, outer membrane vesicles (OMVs), CRISPR-Cas and their regulation), rapid progress has been made in further studying host-pathogen interaction, particularly host immune networks involving autophagy, inflammasome, non-coding RNAs, cGAS, etc. Furthermore, numerous technologic advances, such as bioinformatics, metabolomics, scRNA-seq, nanoparticles, drug screening, and phage therapy, have been used to improve our understanding of P. aeruginosa pathogenesis and host defense. Nevertheless, much remains to be uncovered about interactions between P. aeruginosa and host immune responses, including mechanisms of drug resistance by known or unannotated bacterial virulence factors as well as mammalian cell signaling pathways. The widespread use of antibiotics and the slow development of effective antimicrobials present daunting challenges and necessitate new theoretical and practical platforms to screen and develop mechanism-tested novel drugs to treat intractable infections, especially those caused by multi-drug resistance strains. Benefited from has advancing in research tools and technology, dissecting this pathogen's feature has entered into molecular and mechanistic details as well as dynamic and holistic views. Herein, we comprehensively review the progress and discuss the current status of P. aeruginosa biophysical traits, behaviors, virulence factors, invasive regulators, and host defense patterns against its infection, which point out new directions for future investigation and add to the design of novel and/or alternative therapeutics to combat this clinically significant pathogen.

We present cosmological results from a combined analysis of galaxy clustering and weak gravitational lensing, using 1321 deg 2 of griz imaging data from the first year of the Dark Energy Survey (DES Y1). We combine three two-point functions: (i) the cosmic shear correlation function of 26 million source galaxies in four redshift bins, (ii) the galaxy angular autocorrelation function of 650,000 luminous red galaxies in five redshift bins, and (iii) the galaxy-shear cross-correlation of luminous red galaxy positions and source galaxy shears. To demonstrate the robustness of these results, we use independent pairs of galaxy shape, photometric-redshift estimation and validation, and likelihood analysis pipelines. To prevent confirmation bias, the bulk of the analysis was carried out while "blind" to the true results; we describe an extensive suite of systematics checks performed and passed during this blinded phase. The data are modeled in flat CDM and wCDM cosmologies, marginalizing over 20 nuisance parameters, varying 6 (for CDM) or 7 (for wCDM) cosmological parameters including the neutrino mass density and including the 457 457 element analytic covariance matrix. We find consistent cosmological results from these three two-point functions and from their combination obtain S 8 8 m =0.3 0.5 0.773 0.026 -0.020 and m 0.267 0.030 -0.017 for CDM; for wCDM, we find S 8 0.782 0.036 -0.024 , m 0.284 0.033 -0.030 , and w -0.82 0.21 -0.20 at 68% C.L. The precision of these DES Y1 constraints rivals that from the Planck cosmic microwave background measurements, allowing a comparison of structure in the very

and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

After years of research and proselytizing, the proponents of digital game-based learning (DGBL) have been caught unaware. Like the person who is still yelling after the sudden cessation of loud music at a party, DGBL proponents have been shouting to be heard above the prejudice against games. But now, unexpectedly, we have everyone's attention. The combined weight of three factors has resulted in widespread public interest in games as learning tools.

OBJECTIVES: We provide an update of the issues surrounding health risk assessment of exposure to cadmium in food. DATA SOURCES: We reviewed epidemiologic studies published between 2004 and 2009 concerning the bioavailability of cadmium in food, assessment of exposure, and body burden estimate, along with exposure-related effects in nonoccupationally exposed populations. DATA EXTRACTION AND SYNTHESIS: Bioavailability of ingested cadmium has been confirmed in studies of persons with elevated dietary exposure, and the findings have been strengthened by the substantial amounts of cadmium accumulated in kidneys, eyes, and other tissues and organs of environmentally exposed individuals. We hypothesized that such accumulation results from the efficient absorption and systemic transport of cadmium, employing multiple transporters that are used for the body's acquisition of calcium, iron, zinc, and manganese. Adverse effects of cadmium on kidney and bone have been observed in environmentally exposed populations at frequencies higher than those predicted from models of exposure. Increasing evidence implicates cadmium in the risk of diseases that involve other tissues and organ systems at cadmium concentrations that do not produce effects on bone or renal function. CONCLUSIONS: Population data raise concerns about the validity of the current safe intake level that uses the kidney as the sole target in assessing the health risk from ingested cadmium. The data also question the validity of incorporating the default 5% absorption rate in the threshold-type risk assessment model, known as the provisional tolerable weekly intake (PTWI), to derive a safe intake level for cadmium.

A shoulder pain and disability index (SPADI) was developed to measure the pain and disability associated with shoulder pathology. The SPADI is a self-administered index consisting of 13 items divided into two subscales: pain and disability. Thirty-seven male patients with shoulder pain were used in a study to examine the measurement characteristics of the SPADI. Test-retest reliability of the SPADI total and subscale scores ranged from 0.6377 to 0.6552. Internal consistency ranged from 0.8604 to 0.9507. SPADI total and subscale scores were highly negatively correlated with shoulder range of motion (ROM) supporting the criterion validity of the index. Principal components factor analysis with and without varimax rotation supported the construct validity of the total SPADI and its subscales. High negative correlations between changes in SPADI scores and changes in shoulder ROM indicated the SPADI detected changes in clinical status over short time intervals. The SPADI should prove useful for both clinical and research purposes.

Abstract A growing interest in and concern about the adequacy and fairness of modern peer-review practices in publication and funding are apparent across a wide range of scientific disciplines. Although questions about reliability, accountability, reviewer bias, and competence have been raised, there has been very little direct research on these variables. The present investigation was an attempt to study the peer-review process directly, in the natural setting of actual journal referee evaluations of submitted manuscripts. As test materials we selected 12 already published research articles by investigators from prestigious and highly productive American psychology departments, one article from each of 12 highly regarded and widely read American psychology journals with high rejection rates (80%) and nonblind refereeing practices. With fictitious names and institutions substituted for the original ones (e.g., Tri-Valley Center for Human Potential), the altered manuscripts were formally resubmitted to the journals that had originally refereed and published them 18 to 32 months earlier. Of the sample of 38 editors and reviewers, only three (8%) detected the resubmissions. This result allowed nine of the 12 articles to continue through the review process to receive an actual evaluation: eight of the nine were rejected. Sixteen of the 18 referees (89%) recommended against publication and the editors concurred. The grounds for rejection were in many cases described as “serious methodological flaws.” A number of possible interpretations of these data are reviewed and evaluated.

Why do bacteria have shape? Is morphology valuable or just a trivial secondary characteristic? Why should bacteria have one shape instead of another? Three broad considerations suggest that bacterial shapes are not accidental but are biologically important: cells adopt uniform morphologies from among a wide variety of possibilities, some cells modify their shape as conditions demand, and morphology can be tracked through evolutionary lineages. All of these imply that shape is a selectable feature that aids survival. The aim of this review is to spell out the physical, environmental, and biological forces that favor different bacterial morphologies and which, therefore, contribute to natural selection. Specifically, cell shape is driven by eight general considerations: nutrient access, cell division and segregation, attachment to surfaces, passive dispersal, active motility, polar differentiation, the need to escape predators, and the advantages of cellular differentiation. Bacteria respond to these forces by performing a type of calculus, integrating over a number of environmental and behavioral factors to produce a size and shape that are optimal for the circumstances in which they live. Just as we are beginning to answer how bacteria create their shapes, it seems reasonable and essential that we expand our efforts to understand why they do so.

The human visual system appears to be capable of temporally integrating information in a video sequence in such a way that the perceived spatial resolution of a sequence appears much higher than the spatial resolution of an individual frame. While the mechanisms in the human visual system that do this are unknown, the effect is not too surprising given that temporally adjacent frames in a video sequence contain slightly different, but unique, information. This paper addresses the use of both the spatial and temporal information present in a short image sequence to create a single high-resolution video frame. A novel observation model based on motion compensated subsampling is proposed for a video sequence. Since the reconstruction problem is ill-posed, Bayesian restoration with a discontinuity-preserving prior image model is used to extract a high-resolution video still given a short low-resolution sequence. Estimates computed from a low-resolution image sequence containing a subpixel camera pan show dramatic visual and quantitative improvements over bilinear, cubic B-spline, and Bayesian single frame interpolations. Visual and quantitative improvements are also shown for an image sequence containing objects moving with independent trajectories. Finally, the video frame extraction algorithm is used for the motion-compensated scan conversion of interlaced video data, with a visual comparison to the resolution enhancement obtained from progressively scanned frames.

Measurements of the ice nucleating ability of aerosol particles in air masses over Florida having sources from North Africa support the potential importance of dust aerosols for indirectly affecting cloud properties and climate. The concentrations of ice nuclei within dust layers at particle sizes below 1 μm exceeded 1 cm −3 ; the highest ever reported with our device at temperatures warmer than homogeneous freezing conditions. These measurements add to previous direct and indirect evidence of the ice nucleation efficiency of desert dust aerosols, but also confirm their contribution to ice nuclei populations at great distances from source regions.

We have established a multisite, international database of 3,500 individuals diagnosed with Tourette syndrome (TS). The male:female ratio is 4.3:1 for the total sample, with wide variation among sites; the male excess occurs at every site. Anger control problems, sleep difficulties, coprolalia, and self-injurious behavior only reach impressive levels in individuals with comorbidity. Anger control problems are strongly correlated with comorbidity, regardless of site, region, or whether assessed by neurologists or psychiatrists. The mean age at onset of tics is 6.4 years. At all ages, about 12% of individuals with TS have no reported comorbidity. The most common reported comorbidity is attention-deficit-hyperactivity disorder. Males are more likely to have comorbid disorders than females. The earlier the age at onset, the greater the likelihood of a positive family history of tics. An understanding of the factors producing these and other variations might assist in better subtyping of TS. Because behavioral problems are associated with comorbidity, their presence should dictate a high index of suspicion of the latter, whose treatment may be at least as important as tic reduction. The established database can be used as the entry point for further research when large samples are studied and generalizability of results is important.

AIMS: To examine the consistency and/or variability of gender differences in drinking behavior cross-culturally. DESIGN, SETTING, PARTICIPANTS: Women's and men's responses in 16 general population surveys from 10 countries, analyzed by members of the International Research Group on Gender and Alcohol. MEASUREMENTS: Comparable measures of drinking, versus abstention, typical drinking frequencies and quantities, heavy episodic drinking, intoxication, morning drinking, and alcohol-related family and occupational problems. FINDINGS: Women and men differed little in the probability of currently drinking versus abstaining, but men consistently exceeded women in typical drinking frequencies and quantities and in rates of heavy drinking episodes and adverse drinking consequences, while women were consistently more likely than men to be life-time abstainers. In older age groups, both men and women drank smaller quantities of alcohol and were more likely to stop drinking altogether, but drinking frequencies did not change consistently with age. CONCLUSIONS: A theoretical synthesis proposes that gender roles may amplify biological differences in reactions to alcohol, and that gender differences in drinking behavior may be modified by macrosocial factors that modify gender role contrasts.