CGeNArate: a sequence-dependent coarse-grained model of DNA for accurate atomistic MD simulations of kb-long duplexes.

We present CGeNArate, a new model for molecular dynamics simulations of very long segments of B-DNA in the context of biotechnological or chromatin studies. The developed method uses a coarse-grained Hamiltonian with trajectories that are back-mapped to the atomistic resolution level with extreme accuracy by means of Machine Learning Approaches. The method is sequence-dependent and reproduces very well not only local, but also global physical properties of DNA. The efficiency of the method allows us to recover with a reduced computational effort high-quality atomic-resolution ensembles of segments containing many kilobases of DNA, entering into the gene range or even the entire DNA of certain cellular organelles.

Time-course Changes of Field- and Laboratory-based Performance Indicators in Junior Cyclists Through a Season.

This study aimed to assess the seasonal evolution of field-based and laboratory-based performance indicators in cyclists. Thirteen Junior male road cyclists (age 17.4±0.5 years) were followed up during a season, which was divided in three phases: early season (involving mainly training sessions), mid-season (including the first competitions), and late season (including the major competitions of the season). During each phase, field-based power output data were registered for the assessment of maximum mean power values, and laboratory-based endurance (ramp test and simulated 8-minute time trial), muscle strength/power (squat, lunge, hip thrust) and body composition indicators (dual-energy X-ray absorptiometry) were also assessed. A progressive (p<0.01) increase in maximum mean power values (e.g., 3.8±0.3 and 4.5±0.4 watts/kg in early and late season, respectively, for 60-minute efforts) and on 8-minute time trial performance (i.e., 5.3±0.3 and 5.6±0.4 watts/kg, respectively) was observed through the season. Yet, more "traditional" endurance indicators (i.e., ventilatory threshold, respiratory compensation point, or maximum oxygen uptake) seemed to show a ceiling effect beyond the mid-season. In addition, neither peak power output, body composition, nor muscle strength indicators followed a similar pattern to the aforementioned field-based indicators. In summary, in Junior cyclists field-based indicators seem more sensitive to monitor endurance cyclists' changes in actual fitness and performance capacity than more "traditional" laboratory-based markers in Junior cyclists.

Torque-Cadence Profile and Maximal Dynamic Force in Cyclists: A Novel Approach.

We aimed to determine the feasibility, test-retest reliability and long-term stability of a novel method for assessing the force (torque)-velocity (cadence) profile and maximal dynamic force (MDF) during leg-pedaling using a friction-loaded isoinertial cycle ergometer and a high-precision power-meter device. Fifty-two trained male cyclists completed a progressive loading test up to the one-repetition maximum (1RM) on a cycle ergometer. The MDF was defined as the force attained at the cycle performed with the 1RM-load. To examine the test-retest reliability and long-term stability of torque-cadence values, the progressive test was repeated after 72 h and also after 10 weeks of aerobic and strength training. The participants' MDF averaged 13.4 ± 1.3 N·kg-1, which was attained with an average pedal cadence of 21 ± 3 rpm. Participants' highest power output value was attained with a cadence of 110 ± 16 rpm (52 ± 5% MDF). The relationship between the MDF and cadence proved to be very strong (R2 = 0.978) and independent of the cyclists' MDF (p = 0.66). Cadence values derived from this relationship revealed a very high test-retest repeatability (mean SEM = 4 rpm, 3.3%) and long-term stability (SEM = 3 rpm, 2.3%); despite increases in the MDF following the 10-week period. Our findings support the validity, reliability and long-term stability of this method for the assessment of the torque-cadence profile and MDF in cyclists.

Is the Record Power Profile Repeatable? A Practical Analysis and Interpretation in Professional Cyclists.

ABSTRACT: Muriel, X, Hernández-Belmonte, A, Mateo-March, M, Valenzuela, PL, Zabala, M, Barranco-Gil, D, Lucia, A, and Pallares, JG. Is the record power profile repeatable? A practical analysis and interpretation in professional cyclists. J Strength Cond Res 37(5): 1131-1134, 2023-This study assessed the repeatability of the Record Power Profile (RPP, i.e., the highest power output that a cyclist can attain for different effort durations under field-based conditions). We registered the RPP of 12 professional cyclists (age 32 ± 5 years) for efforts lasting between 30 seconds and 60 minutes during 3 periods of a season, each of 23-day duration: preparation (including training data only), specific (training and competition data), and competition (competition data only) periods. Repeatability was assessed using the highest 2 (RPP 2 ), 3 (RPP 3 ), and 5 (RPP 5 ) values of mean maximum power obtained by the cyclists for each effort duration in each of the 3 periods. Smaller standard errors of measurement ( SEM ) were found as the competitive period approached, especially for short-duration efforts (i.e., 30 seconds, 1 minute, and 5 minutes, where SEM ranged from 4.3 to 12.5%, 4.1-8.5%, and 2.6-7.0% in the preparation, specific, and competition periods, respectively). However, similar SEM values were found in the 3 periods for RPP 2 , RPP 3 , or RPP 5. In conclusion, the RPP appears as a repeatable parameter for monitoring field-based performance within the different phases of the season in professional cyclists.

Laboratory-based determinants of simulated time trial performance in cyclists.

Different laboratory-based variables are individually associated with cycling performance, but scarce evidence exists on which of them, when all assessed in combination, could best explain cycling performance. The present study aimed to examine the combined association between laboratory-based endurance, strength/power and body composition indicators with time trial performance in high-level cyclists. Ninety-four male cyclists were recruited (age: 20 ± 3.5 years, maximum oxygen uptake [V̇O2max]: 77.7 ± 5.4 ml · kg-1 · min-1). Participants performed a maximal incremental cycling test for the assessment of endurance indicators (peak power output [PPO], V̇O2max, ventilatory threshold [VT] and respiratory compensation point [RCP]), and an incremental loading test to assess muscle strength and power-related outcomes (1-repetition maximum, mean maximal power) in the squat, lunge and hip-thrust exercises. Body composition was assessed by dual energy X-ray absorptiometry. On a separate visit, participants performed a simulated 8-minute time trial to assess cycling performance (determined as the mean power output attained). Strong-to-very-strong correlations were found between all endurance indicators and time trial performance (most r-values ranging between 0.68-0.92), whereas weaker correlations were found for strength/power (r-values < 0.5) or body composition (r-values < 0.7) indicators. Multivariate regression analyses revealed that VT, RCP and PPO explained together 92% of the variance in time trial performance (p < 0.001), with no significant contribution of the remaining variables. Although different endurance, strength/power and body composition individually correlate with simulated time trial performance in high-level cyclists, the former (and particularly VT, RCP and PPO) show the strongest association when all studied in combination. These findings underscore the importance of endurance capabilities (above strength/power or body composition) for maximizing time trial performance.

Upgrading the Power Grid Functionalities with Broadband Power Line Communications: Basis, Applications, Current Trends and Challenges.

This article reviews the basis and the main aspects of the recent evolution of Broadband Power Line Communications (BB-PLC or, more commonly, BPL) technologies. The article starts describing the organizations and alliances involved in the development and evolution of BPL systems, as well as the standardization institutions working on PLC technologies. Then, a short description of the technical foundation of the recent proposed technologies and a comparison of the main specifications are presented; the regulatory activities related to the limits of emissions and immunity are also addressed. Finally, some representative applications of BPL and some selected use cases enabled by these technologies are summarized, together with the main challenges to be faced.

Clinical and Serological Features in Latin American IgG4-Related Disease Patients Differ According to Sex, Ethnicity, and Clinical Phenotype.

BACKGROUND/OBJECTIVE: Data on IgG4-related disease (IgG4-RD) come almost exclusively from cohorts from Asia, Europe, and North America. We conducted this study to describe the clinical presentation, phenotype distribution, and association with sex, ethnicity, and serological markers in a large cohort of Latin American patients with IgG4-RD. METHODS: We performed a multicenter medical records review study including 184 Latin American IgG4-RD patients. We assigned patients to clinical phenotypes: group 1 (pancreato-hepato-biliary), group 2 (retroperitoneal/aortic), group 3 (head and neck-limited), group 4 (Mikulicz/systemic), and group 5 (undefined). We focused the analysis on how sex, ethnicity, and clinical phenotype may influence the clinical and serological presentation. RESULTS: The mean age was 50.8 ± 15 years. Men and women were equally affected (52.2% vs 48.8%). Fifty-four patients (29.3%) were assigned to group 1, 21 (11.4%) to group 2, 57 (30.9%) to group 3, 32 (17.4%) to group 4, and 20 (10.8%) to group 5. Male sex was associated with biliary tract (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.36-8.26), kidney (OR, 3.4; 95% CI, 1.28-9.25), and retroperitoneal involvement (OR, 5.3; 95% CI, 1.45-20). Amerindian patients presented more frequently with atopy history and gallbladder involvement. Group 3 had a female predominance. CONCLUSIONS: Latin American patients with IgG4-RD were younger, and men and women were equally affected compared with White and Asian cohorts. They belonged more commonly to group 1 and group 3. Retroperitoneal and aortic involvement was infrequent. Clinical and serological features differed according to sex, ethnicity, and clinical phenotype.

Identification of tomato accessions as source of new genes for improving heat tolerance: from controlled experiments to field.

BACKGROUND: Due to global warming, the search for new sources for heat tolerance and the identification of genes involved in this process has become an important challenge as of today. The main objective of the current research was to verify whether the heat tolerance determined in controlled greenhouse experiments could be a good predictor of the agronomic performance in field cultivation under climatic high temperature stress. RESULTS: Tomato accessions were grown in greenhouse under three temperature regimes: control (T1), moderate (T2) and extreme heat stress (T3). Reproductive traits (flower and fruit number and fruit set) were used to define heat tolerance. In a first screening, heat tolerance was evaluated in 219 tomato accessions. A total of 51 accessions were identified as being potentially heat tolerant. Among those, 28 accessions, together with 10 accessions from Italy (7) and Bulgaria (3), selected for their heat tolerance in the field in parallel experiments, were re-evaluated at three temperature treatments. Sixteen tomato accessions showed a significant heat tolerance at T3, including five wild species, two traditional cultivars and four commercial varieties, one accession from Bulgaria and four from Italy. The 15 most promising accessions for heat tolerance were assayed in field trials in Italy and Bulgaria, confirming the good performance of most of them at high temperatures. Finally, a differential gene expression analysis in pre-anthesis (ovary) and post-anthesis (developing fruit) under heat stress among pairs of contrasting genotypes (tolerant and sensitive from traditional and modern groups) showed that the major differential responses were produced in post-anthesis fruit. The response of the sensitive genotypes included the induction of HSP genes, whereas the tolerant genotype response included the induction of genes involved in the regulation of hormones or enzymes such as abscisic acid and transferases. CONCLUSIONS: The high temperature tolerance of fifteen tomato accessions observed in controlled greenhouse experiments were confirmed in agronomic field experiments providing new sources of heat tolerance that could be incorporated into breeding programs. A DEG analysis showed the complex response of tomato to heat and deciphered the different mechanisms activated in sensitive and tolerant tomato accessions under heat stress.

Effects of an Injury Prevention Program in CrossFit Athletes: A Pilot Randomized Controlled Trial.

The present study aimed to assess the effects of an injury prevention program in CrossFit athletes. Thirty-two CrossFit athletes were randomized to either an intervention group (n=16), that performed mobility and stability exercises during the warm-up of all CrossFit sessions for a 10-week period or to a control group (n=16) that kept performing their usual warm-up. Incidence of injuries (primary outcome) as well as average training loads, fatigue and pain perception were registered during the study. The overall injury incidence rate was 0.04 per 1000 training hours, with no differences between groups (p>0.05). Similarly, no between-group differences were found for injury severity, nor for average training volume, intensity, training load, pain, or fatigue perception during the study (all p>0.05 with trivial-to-small effect sizes). In summary, a 10-week injury prevention program consisting of stability and mobility exercises provided no benefits on injury rates, fatigue and pain perception in recreational CrossFit athletes. Further research might corroborate the preliminary evidence reported here.

Validity of the Favero Assioma Duo Power Pedal System for Measuring Power Output and Cadence.

Cycling power meters enable monitoring external loads and performance changes. We aimed to determine the concurrent validity of the novel Favero Assioma Duo (FAD) pedal power meter compared with the crank-based SRM system (considered as gold standard). Thirty-three well-trained male cyclists were assessed at different power output (PO) levels (100-500 W and all-out 15-s sprints), pedaling cadences (75-100 rpm) and cycling positions (seating and standing) to compare the FAD device vs. SRM. No significant differences were found between devices for cadence nor for PO during all-out efforts (p > 0.05), although significant but small differences were found for efforts at lower PO values (p < 0.05 for 100-500 W, mean bias 3-8 W). A strong agreement was observed between both devices for mean cadence (ICC > 0.87) and PO values (ICC > 0.81) recorded in essentially all conditions and for peak cadence (ICC > 0.98) and peak PO (ICC > 0.99) during all-out efforts. The coefficient of variation for PO values was consistently lower than 3%. In conclusion, the FAD pedal-based power meter can be considered an overall valid system to record PO and cadence during cycling, although it might present a small bias compared with power meters placed on other locations such as SRM.

A predictive model for serious adverse events in adults with acute poisoning in prehospital and hospital care.

OBJECTIVE: The objective of this study was to design a risk model with variables determined before hospital arrival to predict the risk of serious adverse events in patients with acute poisoning. METHODS: A preliminary prospective, multicentre cohort study of adults with prehospital diagnosis of acute intoxication was conducted. The study was carried out in the Public Health System of the Community of Castilla-Leon (Spain), including seven advanced life support units and five hospitals, between April 1, 2018, and June 30, 2019. People aged >18 years with a main prehospital diagnosis of acute poisoning admitted to a referral hospital on advanced life support were included. The main outcome measure was prehospital and hospital serious adverse events in patients with acute poisoning. RESULTS: We included 221 patients, with a median age of 47 years (interquartile range: 33-61). The most frequent cause of poisoning was psychopharmaceuticals (111 cases, 49.8%): 38 (17.2%) patients had a serious adverse event, with a hospital mortality of 4.1% (nine cases) in the 30 days after the index event. The final model included age ≥65 years (odds ratio [OR]: 9.59, 95% confidence interval [CI]: 3.48-26.45; p < 0.001), oxygen saturation/fraction of inspired oxygen index ≤300 (OR: 15.03, 95% CI: 5.74-39.33; p < 0.001), and point-of-care lactate ≥4 mmol/L (OR: 7.68, 95% CI: 2.88-20.45; p < 0.001). The poisoning Early Warning Score was constructed from these three variables, and 1 point was assigned to each variable. The area under the curve of the score was 0.896 (95% CI: 0.82-0.96; p < 0.001). CONCLUSIONS: The poisoning Early Warning Score may help in decision-making and promote early identification of high-risk patients with acute poisoning in the prehospital context.

Pathogenic variants of DNAJC12 and evaluation of the encoded cochaperone as a genetic modifier of hyperphenylalaninemia.

Biallelic variants of the gene DNAJC12, which encodes a cochaperone, were recently described in patients with hyperphenylalaninemia (HPA). This paper reports the retrospective genetic analysis of a cohort of unsolved cases of HPA. Biallelic variants of DNAJC12 were identified in 20 patients (generally neurologically asymptomatic) previously diagnosed with phenylalanine hydroxylase (PAH) deficiency (phenylketonuria [PKU]). Further, mutations of DNAJC12 were identified in four carriers of a pathogenic variant of PAH. The genetic spectrum of DNAJC12 in the present patients included four new variants, two intronic changes c.298-2A>C and c.502+1G>C, presumably affecting the splicing process, and two exonic changes c.309G>T (p.Trp103Cys) and c.524G>A (p.Trp175Ter), classified as variants of unknown clinical significance (VUS). The variant p.Trp175Ter was detected in 83% of the mutant alleles, with 14 cases homozygous, and was present in 0.3% of a Spanish control population. Functional analysis indicated a significant reduction in PAH and its activity, reduced tyrosine hydroxylase stability, but no effect on tryptophan hydroxylase 2 stability, classifying the two VUS as pathogenic variants. Additionally, the effect of the overexpression of DNAJC12 on some destabilizing PAH mutations was examined and a mutation-specific effect on stabilization was detected suggesting that the proteostasis network could be a genetic modifier of PAH deficiency and a potential target for developing mutation-specific treatments for PKU.

Hereditary tyrosinemia type I-associated mutations in fumarylacetoacetate hydrolase reduce the enzyme stability and increase its aggregation rate.

More than 100 mutations in the gene encoding fumarylacetoacetate hydrolase (FAH) cause hereditary tyrosinemia type I (HT1), a metabolic disorder characterized by elevated blood levels of tyrosine. Some of these mutations are known to decrease FAH catalytic activity, but the mechanisms of FAH mutation-induced pathogenicity remain poorly understood. Here, using diffusion ordered NMR spectroscopy, cryo-EM, and CD analyses, along with site-directed mutagenesis, enzymatic assays, and molecular dynamics simulations, we investigated the putative role of thermodynamic and kinetic stability in WT FAH and a representative set of 19 missense mutations identified in individuals with HT1. We found that at physiological temperatures and concentrations, WT FAH is in equilibrium between a catalytically active dimer and a monomeric species, with the latter being inactive and prone to oligomerization and aggregation. We also found that the majority of the deleterious mutations reduce the kinetic stability of the enzyme and always accelerate the FAH aggregation pathway. Depending mainly on the position of the amino acid in the structure, pathogenic mutations either reduced the dimer population or decreased the energy barrier that separates the monomer from the aggregate. The mechanistic insights reported here pave the way for the development of pharmacological chaperones that target FAH to tackle the severe disease HT1.

The structural unit of melanin in the cell wall of the fungal pathogen Cryptococcus neoformans.

Melanins are synthesized macromolecules that are found in all biological kingdoms. These pigments have a myriad of roles that range from microbial virulence to key components of the innate immune response in invertebrates. Melanins also exhibit unique properties with potential applications in physics and material sciences, ranging from electrical batteries to novel therapeutics. In the fungi, melanins, such as eumelanins, are components of the cell wall that provide protection against biotic and abiotic elements. Elucidation of the smallest fungal cell wall-associated melanin unit that serves as a building block is critical to understand the architecture of these polymers, its interaction with surrounding components, and their functional versatility. In this study, we used isopycnic gradient sedimentation, NMR, EPR, high-resolution microscopy, and proteomics to analyze the melanin in the cell wall of the human pathogenic fungus Cryptococcus neoformans We observed that melanin is assembled into the cryptococcal cell wall in spherical structures ∼200 nm in diameter, termed melanin granules, which are in turn composed of nanospheres ∼30 nm in diameter, termed fungal melanosomes. We noted that melanin granules are closely associated with proteins that may play critical roles in the fungal melanogenesis and the supramolecular structure of this polymer. Using this structural information, we propose a model for C. neoformans' melanization that is similar to the process used in animal melanization and is consistent with the phylogenetic relatedness of the fungal and animal kingdoms.

Recombinant PrPSc shares structural features with brain-derived PrPSc: Insights from limited proteolysis.

Very solid evidence suggests that the core of full length PrPSc is a 4-rung ß-solenoid, and that individual PrPSc subunits stack to form amyloid fibers. We recently used limited proteolysis to map the ß-strands and connecting loops that make up the PrPSc solenoid. Using high resolution SDS-PAGE followed by epitope analysis, and mass spectrometry, we identified positions ~116/118, 133-134, 141, 152-153, 162, 169 and 179 (murine numbering) as Proteinase K (PK) cleavage sites in PrPSc. Such sites likely define loops and/or borders of ß-strands, helping us to predict the threading of the ß-solenoid. We have now extended this approach to recombinant PrPSc (recPrPSc). The term recPrPSc refers to bona fide recombinant prions prepared by PMCA, exhibiting infectivity with attack rates of ~100%. Limited proteolysis of mouse and bank vole recPrPSc species yielded N-terminally truncated PK-resistant fragments similar to those seen in brain-derived PrPSc, albeit with varying relative yields. Along with these fragments, doubly N- and C-terminally truncated fragments, in particular ~89/97-152, were detected in some recPrPSc preparations; similar fragments are characteristic of atypical strains of brain-derived PrPSc. Our results suggest a shared architecture of recPrPSc and brain PrPSc prions. The observed differences, in particular the distinct yields of specific PK-resistant fragments, are likely due to differences in threading which result in the specific biochemical characteristics of recPrPSc. Furthermore, recombinant PrPSc offers exciting opportunities for structural studies unachievable with brain-derived PrPSc.

Intradermal Phleum pratense allergoid immunotherapy. Double-blind, randomized, placebo-controlled trial.

BACKGROUND: In allergology, the intradermal approach is generally used to establish an aetiological diagnosis, with limited experience in specific allergen immunotherapy. OBJECTIVE: To evaluate the efficacy and safety of immunotherapy with an allergen extract of glutaraldehyde-polymerized Phleum pratense, administered intradermally, in patients with rhinoconjunctivitis sensitized to grass pollen. METHODS: Multicentre, randomized, double-blind, placebo-controlled clinical trial in patients from 12 to 65 years of age with rhinitis or rhinoconjunctivitis, with or without asthma, due to grass pollen allergy. Patients were divided into three groups and received a total of six doses in a weekly interval, of either placebo; 0.03 or 0.06 µg of protein per dose of P pratense allergoid. The primary objective was to evaluate the combined symptoms and medication consumption score (CSMS). The secondary objectives were symptoms and medication, tolerance to the conjunctival provocation test, specific IgE and IgG4 antibodies and the safety profile according to the WAO scale. RESULTS: The dose of 0.06 µg of protein proved to be effective versus the placebo by significantly reducing CSMS and increasing tolerance to the allergenic extract in the conjunctival provocation test, after the first pollen season. This group showed a significant reduction in specific IgE after the second pollen season relative to the baseline. There were no variations in IgG4 levels. Only one grade 2 systemic reaction was recorded. CONCLUSION & CLINICAL RELEVANCE: Intradermal immunotherapy with P pratense allergoid has been shown to be effective and safe, reducing CSMS, increasing tolerance to the conjunctival provocation test and reducing IgE levels.

Mycobacterium tuberculosis extracellular vesicle-associated lipoprotein LpqH as a potential biomarker to distinguish paratuberculosis infection or vaccination from tuberculosis infection.

BACKGROUND: Both bovine tuberculosis (TB) and paratuberculosis (PTB) are serious and widespread bacterial infections affecting many domestic and wild animal species. However, current vaccines do not confer complete protection and cause interference with other diagnostics tests, including bovine TB. Therefore, the development of "Differentiating Infected from Vaccinated Animals" (DIVA) tests are a pressing need. In this study, we have tested the feasibility of mycobacterial extracellular vesicles (EVs) as potential source of biomarkers to discriminate between Mycobacterium bovis infected, Mycobacterium avium subsp. paratuberculosis (MAP) infected and MAP-vaccinated cows. We have, initially, characterized vesicle production in the two most medically relevant species of mycobacteria for livestock, MAP and M. bovis, for being responsible for tuberculosis (TB) and paratuberculosis (PTB). RESULTS: Our results indicate that these two species produce EVs with different kinetics, morphology and size distribution. Analysis of the immunogenicity of both type of EVs showed some cross reactivity with sera from PTB+ and TB+ cows, suggesting a limited diagnostic capacity for both EVs. Conversely, we noticed that Mycobacterium tuberculosis (Mtb) EVs showed some differential reactivity between sera from MAP-vaccinated or PTB+ cows from TB+ ones. Mass spectrometry analysis (MS) identified a 19-kDa EV-associated lipoprotein as the main source of the differential reactivity. CONCLUSIONS: LpqH could be a good plasma biomarker with capacity to distinguish PTB+ or MAP-vaccinated cows from cows infected with TB.

Prospective Observational Cohort Study of the Efficacy of Bacterial Immune Prophylaxis in the Prevention of Uncomplicated, Recurrent Urinary Tract Infections.

OBJECTIVE: To investigate the long-term prophylactic effect of a vaccine on lower urinary tract infections (UTI) of bacterial and the impact of the intensity of the symptoms on the quality of life (QoL). METHODS: Adult female could be enrolled in this study if they had acute UTI at the enrolment visit and bacterial microbiological count of ≥103 CFU/mL of Escherichia coli. RESULTS: A total of 21 patients were included. Fifteen days after the administration of a vaccine for 3 months, the number of infections dropped almost to zero. Significant differences were observed in the QoL score (p < 0.05). The safety profile was good. CONCLUSIONS: In patients diagnosed with recurrent UTI and treated for 3 months with the vaccine the number of UTI episodes fell very quickly (15 days), and patients remained free of episodes and improved their QoL significantly for 1 year. These results suggest that bacterial vaccines are a possible effective alternative in the prevention of recurrent UTI.

Full-Squat as a Determinant of Performance in CrossFit.

This study analyzed the relationship between CrossFit performance and power and strength variables measured in the full-squat exercise. Twenty male trained subjects (33±7 years) performed an incremental load full-squat test for assessment of the 1-repetition maximum (1RM) and the mean (Pmean) and peak (Ppeak) power. Performance in 5 different Workouts of the Day (WODs) was measured on different days, and overall CrossFit performance was determined as the sum of the scores obtained in these WODs. Athletes were then assigned to a high (HP) or low (LP) performance group based on the median score for overall performance. Correlation analysis between squat variables and performance was performed and between-group differences were assessed. Moderate to strong (r=0.47-0.69, p<0.05) positive correlations were found between squat variables and performance in the different WODs. Overall CrossFit performance was strongly and positively associated with absolute (r=0.62, p=0.01) and relative 1RM (r=0.65, p=0.07), and relative Pmean (r=0.56, p=0.02) and Ppeak (r=0.53, p=0.03). Large differences (effect sizes ranging 1.1-1.7, all p<0.05) were observed between HP and LP for absolute and relative 1RM, relative Pmean, and absolute and relative Ppeak. In summary, strength and power indexes measured in a squat test are positively associated with CrossFit performance.

Cofactors influence the biological properties of infectious recombinant prions.

Prion diseases are caused by a misfolding of the cellular prion protein (PrP) to a pathogenic isoform named PrPSc. Prions exist as strains, which are characterized by specific pathological and biochemical properties likely encoded in the three-dimensional structure of PrPSc. However, whether cofactors determine these different PrPSc conformations and how this relates to their specific biological properties is largely unknown. To understand how different cofactors modulate prion strain generation and selection, Protein Misfolding Cyclic Amplification was used to create a diversity of infectious recombinant prion strains by propagation in the presence of brain homogenate. Brain homogenate is known to contain these mentioned cofactors, whose identity is only partially known, and which facilitate conversion of PrPC to PrPSc. We thus obtained a mix of distinguishable infectious prion strains. Subsequently, we replaced brain homogenate, by different polyanionic cofactors that were able to drive the evolution of mixed prion populations toward specific strains. Thus, our results show that a variety of infectious recombinant prions can be generated in vitro and that their specific type of conformation, i.e., the strain, is dependent on the cofactors available during the propagation process. These observations have significant implications for understanding the pathogenesis of prion diseases and their ability to replicate in different tissues and hosts. Importantly, these considerations might apply to other neurodegenerative diseases for which different conformations of misfolded proteins have been described.