A key step in the analysis of circadian data is to make an accurate estimate of the underlying period. There are many different techniques and algorithms for determining period, all with different ...assumptions and with differing levels of complexity. Choosing which algorithm, which implementation and which measures of accuracy to use can offer many pitfalls, especially for the non-expert. We have developed the BioDare system, an online service allowing data-sharing (including public dissemination), data-processing and analysis. Circadian experiments are the main focus of BioDare hence performing period analysis is a major feature of the system. Six methods have been incorporated into BioDare: Enright and Lomb-Scargle periodograms, FFT-NLLS, mFourfit, MESA and Spectrum Resampling. Here we review those six techniques, explain the principles behind each algorithm and evaluate their performance. In order to quantify the methods' accuracy, we examine the algorithms against artificial mathematical test signals and model-generated mRNA data. Our re-implementation of each method in Java allows meaningful comparisons of the computational complexity and computing time associated with each algorithm. Finally, we provide guidelines on which algorithms are most appropriate for which data types, and recommendations on experimental design to extract optimal data for analysis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Auditory distance perception plays a major role in spatial awareness, enabling location of objects and avoidance of obstacles in the environment. However, it remains under-researched relative to ...studies of the directional aspect of sound localization. This review focuses on the following four aspects of auditory distance perception: cue processing, development, consequences of visual and auditory loss, and neurological bases. The several auditory distance cues vary in their effective ranges in peripersonal and extrapersonal space. The primary cues are sound level, reverberation, and frequency. Nonperceptual factors, including the importance of the auditory event to the listener, also can affect perceived distance. Basic internal representations of auditory distance emerge at approximately 6 months of age in humans. Although visual information plays an important role in calibrating auditory space, sensorimotor contingencies can be used for calibration when vision is unavailable. Blind individuals often manifest supranormal abilities to judge relative distance but show a deficit in absolute distance judgments. Following hearing loss, the use of auditory level as a distance cue remains robust, while the reverberation cue becomes less effective. Previous studies have not found evidence that hearing-aid processing affects perceived auditory distance. Studies investigating the brain areas involved in processing different acoustic distance cues are described. Finally, suggestions are given for further research on auditory distance perception, including broader investigation of how background noise and multiple sound sources affect perceived auditory distance for those with sensory loss.
The Blueprint Programmed Death Ligand 1 (PD-L1) Immunohistochemistry (IHC) Assay Comparison Project is an industrial-academic collaborative partnership to provide information on the analytical and ...clinical comparability of four PD-L1 IHC assays used in clinical trials.
A total of 39 NSCLC tumors were stained with four PD-L1 IHC assays (22C3, 28-8, SP142, and SP263), as used in the clinical trials. Three experts in interpreting their respective assays independently evaluated the percentages of tumor and immune cells staining positive at any intensity. Clinical diagnostic performance was assessed through comparisons of patient classification above and below a selected expression cutoff and by agreement using various combinations of assays and cutoffs.
Analytical comparison demonstrated that the percentage of PD-L1–stained tumor cells was comparable when the 22C3, 28-8, and SP263 assays were used, whereas the SP142 assay exhibited fewer stained tumor cells overall. The variability of immune cell staining across the four assays appears to be higher than for tumor cell staining. Of the 38 cases, 19 (50.0%) were classified above and five (13%) were classified below the selected cutoffs of all assays. For 14 of the 38 cases (37%), a different PD-L1 classification would be made depending on which assay/scoring system was used.
The Blueprint PD-L1 IHC Assay Comparison Project revealed that three of the four assays were closely aligned on tumor cell staining whereas the fourth showed consistently fewer tumor cells stained. All of the assays demonstrated immune cell staining, but with greater variability than with tumor cell staining. By comparing assays and cutoffs, the study indicated that despite similar analytical performance of PD-L1 expression for three assays, interchanging assays and cutoffs would lead to “misclassification” of PD-L1 status for some patients. More data are required to inform on the use of alternative staining assays upon which to read different specific therapy-related PD-L1 cutoffs.
There is currently considerable interest in the consequences of loss in one sensory modality on the remaining senses. Much of this work has focused on the development of enhanced auditory abilities ...among blind individuals, who are often able to use sound to navigate through space. It has now been established that many blind individuals produce sound emissions and use the returning echoes to provide them with information about objects in their surroundings, in a similar manner to bats navigating in the dark. In this review, we summarize current knowledge regarding human echolocation. Some blind individuals develop remarkable echolocation abilities, and are able to assess the position, size, distance, shape, and material of objects using reflected sound waves. After training, normally sighted people are also able to use echolocation to perceive objects, and can develop abilities comparable to, but typically somewhat poorer than, those of blind people. The underlying cues and mechanisms, operable range, spatial acuity and neurological underpinnings of echolocation are described. Echolocation can result in functional real life benefits. It is possible that these benefits can be optimized via suitable training, especially among those with recently acquired blindness, but this requires further study. Areas for further research are identified.
•Blind and sighted individuals can perceive objects using echolocation.•Cues include level, spectral envelope, emission-echo delay, and binaural differences.•On average, the blind are better echolocators than the sighted.•Visual brain areas of the blind are recruited for processing echolocation information.
Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct ...from those in the initial tumor. To explore this hypothesis, we sequenced the exornes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.
ABSTRACT
Birds and their ornithodiran ancestors are unique among vertebrates in exhibiting air‐filled sinuses in their postcranial bones, a phenomenon called postcranial skeletal pneumaticity. The ...factors that account for serial and interspecific variation in postcranial skeletal pneumaticity are poorly understood, although body size, ecology, and bone biomechanics have all been implicated as influencing the extent to which pneumatizing epithelia invade the skeleton and induce bone resorption. Here, I use high‐resolution computed‐tomography to holistically quantify vertebral pneumaticity in members of the neognath family Ciconiidae (storks), with pneumaticity measured as the relative volume of internal air space. These data are used to describe serial variation in extent of pneumaticity and to assess whether and how pneumaticity varies with the size and shape of a vertebra. Pneumaticity increases dramatically from the middle of the neck onwards, contrary to previous predictions that cervical pneumaticity should decrease toward the thorax to maintain structural integrity as the mass and bending moments of the neck increase. Although the largest vertebrae sampled are also the most pneumatic, vertebral size cannot on its own account for serial or interspecific variation in extent of pneumaticity. Vertebral shape, as quantified by three‐dimensional geometric morphometrics, is found to be significantly correlated with extent of pneumaticity, with elongate vertebrae being less pneumatic than craniocaudally short and dorsoventrally tall vertebrae. Considered together, the results of this study are consistent with the hypothesis that shape‐ and position‐specific biomechanics influence the amount of bone loss that can be safely tolerated. These results have potentially important implications for the evolution of vertebral morphology in birds and their extinct relatives.
Birds are unique among living vertebrates in having air‐filled sinuses in their postcranial skeletons, a phenomenon called postcranial skeletal pneumaticity (PSP). The factors that account for serial and interspecific variation in PSP are poorly understood. Using micro‐CT scans of stork vertebrae and geometric morphometric methods, I show that vertebral shape is strongly correlated with PSP, supporting the hypothesis that locus‐ and shape‐specific biomechanics influence skeletal pneumatization.
Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution, underpinning important ...emergent features such as drug resistance and metastasis. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours. However, the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours have not been systematically examined at single-cell resolution. Here we show, using deep-genome and single-cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single-cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies using patient-derived breast cancer xenoengraftment.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
For many people with advanced osteoarthritis, total knee replacement is an effective treatment to relieve pain and improve function. However, 10-34% of people experience chronic postsurgical pain in ...the months and years after total knee replacement. The Support and Treatment After Replacement (STAR) randomised controlled trial (ISCRTN92545361) evaluated the clinical- and cost-effectiveness of a new multifaceted and personalised care pathway, compared with usual care, for people with pain at three months after total knee replacement. Our objective was to identify factors promoting or inhibiting its implementation, and to inform future training and wider implementation of the pathway. We conducted a prospective process evaluation using qualitative interviews with eight Extended Scope Practitioners and six Principal Investigators from seven trial sites who were involved in delivering the STAR care pathway during the trial. We used Normalization Process Theory as a theoretical framework for qualitative data collection and content analysis. We identified that factors promoting the implementation of the pathway were quick familiarisation with the pathway, valuing patient-centredness, formalising referral processes, and increasing confidence to address neuropathic pain. Challenges to implementation were availability of time and resources, sensitivity in referral process, and ensuring collective understanding of the pathway. These findings have enabled us to make recommendations about the future implementation of the STAR care pathway and will inform the development of a training package, and updated manual for successful delivery in usual care. Furthermore, this model of care has potential value in diverse elective surgeries and pain conditions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent research on ocean health has found large predator abundance to be a key element of ocean condition. Fisheries can impact large predator abundance directly through targeted capture and ...indirectly through incidental capture of nontarget species or bycatch. However, measures of the global nature of bycatch are lacking for air-breathing megafauna. We fill this knowledge gap and present a synoptic global assessment of the distribution and intensity of bycatch of seabirds, marine mammals, and sea turtles based on empirical data from the three most commonly used types of fishing gears worldwide. We identify taxa-specific hotspots of bycatch intensity and find evidence of cumulative impacts across fishing fleets and gears. This global map of bycatch illustrates where data are particularly scarce—in coastal and small-scale fisheries and ocean regions that support developed industrial fisheries and millions of small-scale fishers—and identifies fishing areas where, given the evidence of cumulative hotspots across gear and taxa, traditional species or gear-specific bycatch management and mitigation efforts may be necessary but not sufficient. Given the global distribution of bycatch and the mitigation success achieved by some fleets, the reduction of air-breathing megafauna bycatch is both an urgent and achievable conservation priority.
Increasing specific conductance (SC) and chloride concentrations Cl negatively affect many stream ecosystems. We characterized spatial variability in SC, Cl, and exceedances of Environmental ...Protection Agency Cl criteria using nearly 30 million high-frequency observations (2–15 min intervals) for SC and modeled Cl from 93 sites across three regions in the eastern United States: Southeast, Mid-Atlantic, and New England. SC and Cl increase substantially from south to north and within regions with impervious surface cover (ISC). In the Southeast, Cl weakly correlates with ISC, no Cl exceedances occur, and Cl concentrations are constant with time. In the Mid-Atlantic and New England, Cl and Cl exceedances strongly correlate with ISC. Cl criteria are frequently exceeded at sites with greater than 9–10% ISC and median Cl higher than 30–80 mg/L. Tens to hundreds of Cl exceedances observed annually at most of these sites help explain previous research where stream ecosystems showed changes at (primarily nonwinter) Cl as low as 30–40 mg/L. Mid-Atlantic chronic Cl exceedances occur primarily in December–March. In New England, exceedances are common in nonwinter months. Cl is increasing at nearly all Mid-Atlantic and New England sites with the largest increases at sites with higher Cl.
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