CLOCK gene circannual expression in cluster headache.

BACKGROUND: Cluster headache is a primary headache disorder characterized by bouts with circadian and circannual patterns. The CLOCK gene has a central role in regulating circadian rhythms. Here, we investigate the circannual CLOCK expression in a population of cluster headache patients in comparison to matched controls. METHODS: Patients with cluster headache were sampled two to four times over at least one year, both in or outside bouts, one week after each solstice and equinox. The expression of CLOCK was measured by quantitative real-time polymerase chain reaction (RT-PCR) in the peripheral blood. RESULTS: This study included 50 patients and 58 matched controls. Among the patient population, composed of 42/50 males (84%) with an average age of 44.6 years, 45/50 (90%) suffered from episodic cluster headache. Two to four samples were collected from each patient adding up to 161 samples, 36 (22.3%) of which were collected within a bout. CLOCK expression for cluster headache patients was considerably different from that of the control population in winter (p-value mean = 0.006283), spring (p-value mean = 0.000006) and summer (p-value mean = 0.000064), but not in autumn (p-value mean = 0.262272). For each season transition, the variations in CLOCK expression were more pronounced in the control group than in the cluster headache population. No statistically significant differences were found between bout and non-bout samples. No individual factors (age, sex, circadian chronotype, smoking and coffee habits or history of migraine) were related to CLOCK expression. CONCLUSIONS: We observed that CLOCK expression in cluster headache patients fluctuates less throughout the year than in the control population. Bout activity and lifestyle factors do not seem to influence CLOCK expression.

Artificial intelligence-based computer-aided system for knee osteoarthritis assessment increases experienced orthopaedic surgeons' agreement rate and accuracy.

PURPOSE: The aims of this study were to (1) analyze the impact of an artificial intelligence (AI)-based computer system on the accuracy and agreement rate of board-certified orthopaedic surgeons (= senior readers) to detect X-ray features indicative of knee OA in comparison to unaided assessment and (2) compare the results to those of senior residents (= junior readers). METHODS: One hundred and twenty-four unilateral knee X-rays from the OAI study were analyzed regarding Kellgren-Lawrence grade, joint space narrowing (JSN), sclerosis and osteophyte OARSI grade by computerized methods. Images were rated for these parameters by three senior readers using two modalities: plain X-ray (unaided) and X-ray presented alongside reports from a computer-assisted detection system (aided). After exclusion of nine images with incomplete annotation, intraclass correlations between readers were calculated for both modalities among 115 images, and reader performance was compared to ground truth (OAI consensus). Accuracy, sensitivity and specificity were also calculated and the results were compared to those from a previous study on junior readers. RESULTS: With the aided modality, senior reader agreement rates for KL grade (2.0-fold), sclerosis (1.42-fold), JSN (1.37-fold) and osteophyte OARSI grades (3.33-fold) improved significantly. Reader specificity and accuracy increased significantly for all features when using the aided modality compared to the gold standard. On the other hand, sensitivity only increased for OA diagnosis, whereas it decreased (without statistical significance) for all other features. With aided analysis, senior readers reached similar agreement and accuracy rates as junior readers, with both surpassing AI performance. CONCLUSION: The introduction of AI-based computer-aided assessment systems can increase the agreement rate and overall accuracy for knee OA diagnosis among board-certified orthopaedic surgeons. Thus, use of this software may improve the standard of care for knee OA detection and diagnosis in the future. LEVEL OF EVIDENCE: Level II.

Fiber Optic Load Cells with Enhanced Sensitivity by Optical Vernier Effect.

Developing technologies capable of constantly assessing and optimizing day-to-day activities has been a research priority for several years. A key factor in such technologies is the use of highly sensitive sensors to monitor in real-time numerous parameters, such as temperature and load. Due to their unique features, optical fiber sensors became one of the most interesting and viable solutions for applications dependent on those parameters. In this work, we present an optical fiber load sensor, called load cell, based on Fabry-Pérot hollow cavities embedded in a polymeric material. By using the load cells in a parallel configuration with a non-embedded hollow cavity, the optical Vernier effect was generated, allowing maximum sensitivity values of 0.433 nm N-1 and 0.66 nm °C-1 to be attained for vertical load and temperature, respectively. The proposed sensor's performance, allied with the proposed configuration, makes it a viable and suitable device for a wide range of applications, namely those requiring high thermal and load sensitivities.

Performance Analysis of Scattering-Level Multiplexing (SLMux) in Distributed Fiber-Optic Backscatter Reflectometry Physical Sensors.

Optical backscatter reflectometry (OBR) is a method for the interrogation of Rayleigh scattering occurring in each section of an optical fiber, resulting in a single-fiber-distributed sensor with sub-millimeter spatial resolution. The use of high-scattering fibers, doped with MgO-based nanoparticles in the core section, provides a scattering increase which can overcome 40 dB. Using a configuration-labeled Scattering-Level Multiplexing (SLMux), we can arrange a network of high-scattering fibers to perform a simultaneous scan of multiple fiber sections, therefore extending the OBR method from a single fiber to multiple fibers. In this work, we analyze the performance and boundary limits of SLMux, drawing the limits of detection of N-channel SLMux, and evaluating the performance of scattering-enhancement methods in optical fibers.

Embedded Fiber Sensors to Monitor Temperature and Strain of Polymeric Parts Fabricated by Additive Manufacturing and Reinforced with NiTi Wires.

This paper focuses on three main issues regarding Material Extrusion (MEX) Additive Manufacturing (AM) of thermoplastic composites reinforced by pre-functionalized continuous Nickel-Titanium (NiTi) wires: (i) Evaluation of the effect of the MEX process on the properties of the pre-functionalized NiTi, (ii) evaluation of the mechanical and thermal behavior of the composite material during usage, (iii) the inspection of the parts by Non-Destructive Testing (NDT). For this purpose, an optical fiber sensing network, based on fiber Bragg grating and a cascaded optical fiber sensor, was successfully embedded during the 3D printing of a polylactic acid (PLA) matrix reinforced by NiTi wires. Thermal and mechanical perturbations were successfully registered as a consequence of thermal and mechanical stimuli. During a heating/cooling cycle, a maximum contraction of ≈100 µm was detected by the cascaded sensor in the PLA material at the end of the heating step (induced by Joule effect) of NiTi wires and a thermal perturbation associated with the structural transformation of austenite to R-phase was observed during the natural cooling step, near 33.0 °C. Regarding tensile cycling tests, higher increases in temperature arose when the applied force ranged between 0.7 and 1.1 kN, reaching a maximum temperature variation of 9.5 ± 0.1 °C. During the unload step, a slope change in the temperature behavior was detected, which is associated with the material transformation of the NiTi wire (martensite to austenite). The embedded optical sensing methodology presented here proved to be an effective and precise tool to identify structural transformations regarding the specific application as a Non-Destructive Testing for AM.

Inscription of Bragg gratings in undoped PMMA mPOF with Nd:YAG laser at 266†nm wavelength.

We present the first Bragg gratings fabricated in two, three and five rings undoped PMMA microstructured polymer optical fibres (mPOFs) with relative low cost 266 nm Nd:YAG laser in the 850 nm region. The fibers were connectorised with commercial ferrules for easy coupling with silica patch cables. Temperature, humidity and strain sensitivities are measured and also the impact of ring structure and the diameter of POF on the characterization measurements are studied for potential applications. We also analyzed the effect of the number of hexagonal rings structure in gratings fabrication, noticing that larger number of rings lead to more difficulties to obtain strong gratings, where we consider this performance due to the scattering effects. We demonstrate Bragg gratings fabrication in 5-rings structure mPOF after 6 min by using 266 nm Nd:YAG laser whereas no Bragg gratings have been fabricated so far using 325 nm He-Cd laser system. Up to 30 dB relative reflected power gratings are obtained in two rings mPOF, showing good time stability and promising results for undoped mPOF applications.

Highly sensitive fiber optic temperature and strain sensor based on an intrinsic Fabry-Perot interferometer fabricated by a femtosecond laser.

In this Letter, we report on a simple, but highly sensitive sensor based on two intrinsic Fabry-Perot interferometers (FPIs) inscribed in a standard single-mode optical fiber. A brief theoretical study on the Vernier effect is presented, in which a simulation of the sensitivity magnification factor dependence on the FPI's length is performed. Based on the simulation results, the FPIs were fabricated using a custom micromachining setup that integrates a near-infrared femtosecond laser and a motorized XYZ platform. Using the Vernier effect, sensitivities of 145 pm/µÎµ and 927 pm/°C were obtained for strain and temperature, respectively. The sensor's performance combined with its versatile and customizable configuration allows real-time and in situ strain and temperature monitoring under harsh environments.

The effect of gene interactions on the long-term response to selection.

The role of gene interactions in the evolutionary process has long been controversial. Although some argue that they are not of importance, because most variation is additive, others claim that their effect in the long term can be substantial. Here, we focus on the long-term effects of genetic interactions under directional selection assuming no mutation or dominance, and that epistasis is symmetrical overall. We ask by how much the mean of a complex trait can be increased by selection and analyze two extreme regimes, in which either drift or selection dominate the dynamics of allele frequencies. In both scenarios, epistatic interactions affect the long-term response to selection by modulating the additive genetic variance. When drift dominates, we extend Robertson's [Robertson A (1960)Proc R Soc Lond B Biol Sci153(951):234-249] argument to show that, for any form of epistasis, the total response of a haploid population is proportional to the initial total genotypic variance. In contrast, the total response of a diploid population is increased by epistasis, for a given initial genotypic variance. When selection dominates, we show that the total selection response can only be increased by epistasis when some initially deleterious alleles become favored as the genetic background changes. We find a simple approximation for this effect and show that, in this regime, it is the structure of the genotype-phenotype map that matters and not the variance components of the population.

Wheelchair Pressure Ulcer Prevention Using FBG Based Sensing Devices.

In this work, a fiber Bragg grating (FBG) based sensing system for wheelchair pressure ulcer prevention was developed. Six FBGs were strategically positioned in a wheelchair to monitor the more prominent bone areas, namely scapulas (right (SR) and left (SL)), ischiatic zone (right (IR) and left (IL)), and heels (right (HR) and left (HL)). The sensing architecture was tested by a female user during pressure relief exercises, to verify its effectiveness on pressure monitoring. The proposed system proves to be a compact and reliable solution for wheelchair pressure ulcer prevention, making it a suitable alternative to existing conventional electronic sensors, with the advantage of being immune to electromagnetic interferences and usable in humid environments. In addition to the pressure, the breathing rate was also monitored. By combining the proposed sensing architecture with a wheelchair user detection software, it is possible to create alerts for the user to know when a new position should be adopted, in order to relieve the pressure in a specific area, thus avoiding one of the biggest problems for such patients, pressure ulcers.

Strain, temperature, moisture, and transverse force sensing using fused polymer optical fibers.

This paper presents the characterization of polymer optical fibers (POFs) submitted to the catastrophic fuse effect towards intensity-variation-based sensing of strain, transverse force, temperature, and moisture. In the experiments, POFs with and without the fuse effect are tested and the results are compared with respect to the sensitivity, linearity, and root mean squared error (RMSE). The fused POFs have higher linearity and lower RMSE than non-fused POFs in strain and transverse force sensing. Also, the sensitivity of the fused POFs is higher in transverse force and temperature sensing, which can be related to the higher sensitivity to the curvature that the transverse force creates on the POF and to the more significant variations of the refractive index with temperature increase. Additionally, the fused POFs present lower moisture absorption than the non-fused POFs. The presented results indicate a great potential of the fused POFs intensity-variation-based sensing applications of various physical parameters.

Stress-induced mutagenesis: Stress diversity facilitates the persistence of mutator genes.

Mutator strains are expected to evolve when the availability and effect of beneficial mutations are high enough to counteract the disadvantage from deleterious mutations that will inevitably accumulate. As the population becomes more adapted to its environment, both availability and effect of beneficial mutations necessarily decrease and mutation rates are predicted to decrease. It has been shown that certain molecular mechanisms can lead to increased mutation rates when the organism finds itself in a stressful environment. While this may be a correlated response to other functions, it could also be an adaptive mechanism, raising mutation rates only when it is most advantageous. Here, we use a mathematical model to investigate the plausibility of the adaptive hypothesis. We show that such a mechanism can be mantained if the population is subjected to diverse stresses. By simulating various antibiotic treatment schemes, we find that combination treatments can reduce the effectiveness of second-order selection on stress-induced mutagenesis. We discuss the implications of our results to strategies of antibiotic therapy.

Dynamics of Transcription Factor Binding Site Evolution.

Evolution of gene regulation is crucial for our understanding of the phenotypic differences between species, populations and individuals. Sequence-specific binding of transcription factors to the regulatory regions on the DNA is a key regulatory mechanism that determines gene expression and hence heritable phenotypic variation. We use a biophysical model for directional selection on gene expression to estimate the rates of gain and loss of transcription factor binding sites (TFBS) in finite populations under both point and insertion/deletion mutations. Our results show that these rates are typically slow for a single TFBS in an isolated DNA region, unless the selection is extremely strong. These rates decrease drastically with increasing TFBS length or increasingly specific protein-DNA interactions, making the evolution of sites longer than ∼ 10 bp unlikely on typical eukaryotic speciation timescales. Similarly, evolution converges to the stationary distribution of binding sequences very slowly, making the equilibrium assumption questionable. The availability of longer regulatory sequences in which multiple binding sites can evolve simultaneously, the presence of "pre-sites" or partially decayed old sites in the initial sequence, and biophysical cooperativity between transcription factors, can all facilitate gain of TFBS and reconcile theoretical calculations with timescales inferred from comparative genomics.

Toward a unifying framework for evolutionary processes.

The theory of population genetics and evolutionary computation have been evolving separately for nearly 30 years. Many results have been independently obtained in both fields and many others are unique to its respective field. We aim to bridge this gap by developing a unifying framework for evolutionary processes that allows both evolutionary algorithms and population genetics models to be cast in the same formal framework. The framework we present here decomposes the evolutionary process into its several components in order to facilitate the identification of similarities between different models. In particular, we propose a classification of evolutionary operators based on the defining properties of the different components. We cast several commonly used operators from both fields into this common framework. Using this, we map different evolutionary and genetic algorithms to different evolutionary regimes and identify candidates with the most potential for the translation of results between the fields. This provides a unified description of evolutionary processes and represents a stepping stone towards new tools and results to both fields.

Genetic background alters dominance relationships between mat alleles in the ciliate Tetrahymena thermophila.

The pattern of inheritance and mechanism of sex determination can have important evolutionary consequences. We studied probabilistic sex determination in the ciliate Tetrahymena thermophila, which was previously shown to cause evolution of skewed sex ratios. We find that the genetic background alters the sex determination patterns of mat alleles in heterozygotes and that allelic interaction can differentially influence the expression probability of the 7 sexes. We quantify the dominance relationships between several mat alleles and find that A-type alleles, which specify sex I, are indeed recessive to B-type alleles, which are unable to specify that sex. Our results provide additional support for the presence of modifier loci and raise implications for the dynamics of sex ratios in populations of T. thermophila.

Targeting circulating labile heme as a defense strategy against malaria.

Severe presentations of malaria emerge as Plasmodium (P.) spp. parasites invade and lyse red blood cells (RBC), producing extracellular hemoglobin (HB), from which labile heme is released. Here, we tested whether scavenging of extracellular HB and/or labile heme, by haptoglobin (HP) and/or hemopexin (HPX), respectively, counter the pathogenesis of severe presentations of malaria. We found that circulating labile heme is an independent risk factor for cerebral and non-cerebral presentations of severe P. falciparum malaria in children. Labile heme was negatively correlated with circulating HP and HPX, which were, however, not risk factors for severe P. falciparum malaria. Genetic Hp and/or Hpx deletion in mice led to labile heme accumulation in plasma and kidneys, upon Plasmodium infection This was associated with higher incidence of mortality and acute kidney injury (AKI) in ageing but not adult Plasmodium-infected mice, and was corroborated by an inverse correlation between heme and HPX with serological markers of AKI in P. falciparum malaria. In conclusion, HP and HPX act in an age-dependent manner to prevent the pathogenesis of severe presentation of malaria in mice and presumably in humans.

The rare DRB1*04:08-DQ8 haplotype is the main HLA class II genetic driver and discriminative factor of Early-onset Type 1 diabetes in the Portuguese population.

Introduction: Early-onset Type 1 diabetes (EOT1D) is considered a disease subtype with distinctive immunological and clinical features. While both Human Leukocyte Antigen (HLA) and non-HLA variants contribute to age at T1D diagnosis, detailed analyses of EOT1D-specific genetic determinants are still lacking. This study scrutinized the involvement of the HLA class II locus in EOT1D genetic control. Methods: We conducted genetic association and regularized logistic regression analyses to evaluate genotypic, haplotypic and allelic variants in DRB1, DQA1 and DQB1 genes in children with EOT1D (diagnosed at ≤5 years of age; n=97), individuals with later-onset disease (LaOT1D; diagnosed 8-30 years of age; n=96) and nondiabetic control subjects (n=169), in the Portuguese population. Results: Allelic association analysis of EOT1D and LaOT1D unrelated patients in comparison with controls, revealed that the rare DRB1*04:08 allele is a distinctive EOT1D susceptibility factor (corrected p-value=7.0x10-7). Conversely, the classical T1D risk allele DRB1*04:05 was absent in EOT1D children while was associated with LaOT1D (corrected p-value=1.4x10-2). In corroboration, HLA class II haplotype analysis showed that the rare DRB1*04:08-DQ8 haplotype is specifically associated with EOT1D (corrected p-value=1.4x10-5) and represents the major HLA class II genetic driver and discriminative factor in the development of early onset disease. Discussion: This study uncovered that EOT1D holds a distinctive spectrum of HLA class II susceptibility loci, which includes risk factors overlapping with LaOT1D and discriminative genetic configurations. These findings warrant replication studies in larger multicentric settings encompassing other ethnicities and may impact target screening strategies and follow-up of young children with high T1D genetic risk as well as personalized therapeutic approaches.

Renal control of life-threatening malarial anemia.

Iron recycling prevents the development of anemia under homeostatic conditions. Whether iron recycling was co-opted as a defense strategy to prevent the development of anemia in response to infection is unclear. We find that in severe Plasmodium falciparum malaria, the onset of life-threatening anemia is associated with acute kidney injury (AKI), irrespective of parasite load. Using a well-established experimental rodent model of malaria anemia, we identify a transcriptional response that endows renal proximal tubule epithelial cells (RPTECs) with the capacity to store and recycle iron during P. chabaudi chabaudi (Pcc) infection. This response encompasses the induction of ferroportin 1/SLC40A1, which exports iron from RPTECs and counteracts AKI while supporting compensatory erythropoiesis and preventing the onset of life-threatening malarial anemia. Iron recycling by myeloid cells is dispensable to this protective response, suggesting that RPTECs provide an iron-recycling salvage pathway that prevents the pathogenesis of life-threatening malarial anemia.

Sequential Organ Failure Assessment Score in the ICU As a Predictor of Long-Term Survival After Cardiac Surgery.

OBJECTIVES: The Sequential Organ Failure Assessment (SOFA) score is a predictor of mortality in ICU patients. Although it is widely used and has been validated as a reliable and independent predictor of mortality and morbidity in cardiac ICU, few studies correlate early postoperative SOFA with long-term survival. DESIGN: Retrospective observational cohort study. SETTING: Tertiary academic cardiac surgery ICU. PATIENTS: One-thousand three-hundred seventy-nine patients submitted to cardiac surgery. INTERVENTIONS: SOFA 24 hours, SOFA 48 hours, mean, and highest SOFA scores were correlated with survival at 12 and 24 months. Wilcoxon tests were used to analyze differences in variables. Multivariate logistic regressions and likelihood ratio test were used to access the predictive modeling. Receiver operating characteristic curves were used to assess accuracy of the variables in separating survivor from nonsurvivors. MEASUREMENTS AND MAIN RESULTS: Lower SOFA scores have better survival rates at 12 and 24 months. Highest SOFA and SOFA at 48 hours showed to be better predictors of outcome and to have higher accuracy in distinguishing survivors from nonsurvivors than initial SOFA and mean SOFA. A decreasing score during the first 48 hours had mortality rates of 4.9%, while an unchanged or increased score was associated with a mortality rate of 5.7%. CONCLUSIONS: SOFA score in the ICU after cardiac surgery correlated with survival at 12 and 24 months. Patients with lower SOFA scores had higher survival rates. Differences in survival at 12 months were better correlated with the absolute value at 48 hours than with its variation. SOFA score may be useful to predict long-term outcomes and to stratify patients with higher probability of mortality.

Phenotypic architecture of sociality and its associated genetic polymorphisms in zebrafish.

Sociality relies on motivational and cognitive components that may have evolved independently, or may have been linked by phenotypic correlations driven by a shared selective pressure for increased social competence. Furthermore, these components may be domain-specific or of general-domain across social and non-social contexts. Here, we used zebrafish to test if the motivational and cognitive components of social behavior are phenotypically linked and if they are domain specific or of general domain. The behavioral phenotyping of zebrafish in social and equivalent non-social tests shows that the motivational (preference) and cognitive (memory) components of sociality: (1) are independent from each other, hence not supporting the occurrence of a sociality syndrome; and (2) are phenotypically linked to non-social traits, forming two general behavioral modules, suggesting that sociality traits have been co-opted from general-domain motivational and cognitive traits. Moreover, the study of the association between single nucleotide polymorphisms (SNPs) and each behavioral module further supports this view, since several SNPs from a list of candidate "social" genes, are statistically associated with the motivational, but not with the cognitive, behavioral module. Together, these results support the occurrence of general-domain motivational and cognitive behavioral modules in zebrafish, which have been co-opted for the social domain.