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The well-established manifestation of mitochondrial mutations in functional cardiac disease (e.g., mitochondrial cardiomyopathy) prompted the hypothesis that mitochondrial DNA (mtDNA) sequence and/or copy number (mtDNAcn) variation contribute to cardiac defects in congenital heart disease (CHD). MtDNAcns were calculated and rare, non-synonymous mtDNA mutations were identified in 1,837 CHD-affected proband-parent trios, 116 CHD-affected singletons, and 114 paired cardiovascular tissue/blood samples. The variant allele fraction (VAF) of heteroplasmic variants in mitochondrial RNA from 257 CHD cardiovascular tissue samples was also calculated. On average, mtDNA from blood had 0.14 rare variants and 52.9 mtDNA copies per nuclear genome per proband. No variation with parental age at proband birth or CHD-affected proband age was seen. mtDNAcns in valve/vessel tissue (320 ± 70) were lower than in atrial tissue (1,080 ± 320, p = 6.8E-21), which were lower than in ventricle tissue (1,340 ± 280, p = 1.4E-4). The frequency of rare variants in CHD-affected individual DNA was indistinguishable from the frequency in an unaffected cohort, and proband mtDNAcns did not vary from those of CHD cohort parents. In both the CHD and the comparison cohorts, mtDNAcns were significantly correlated between mother-child, father-child, and mother-father. mtDNAcns among people with European (mean = 52.0), African (53.0), and Asian haplogroups (53.5) were calculated and were significantly different for European and Asian haplogroups (p = 2.6E-3). Variant heteroplasmic fraction (HF) in blood correlated well with paired cardiovascular tissue HF (r = 0.975) and RNA VAF (r = 0.953), which suggests blood HF is a reasonable proxy for HF in heart tissue. We conclude that mtDNA mutations and mtDNAcns are unlikely to contribute significantly to CHD risk.

Analyses of seismic data from the InSight mission have provided the first in situ constraints on the thickness of the crust of Mars. These crustal thickness constraints are currently limited to beneath the lander that is located in the northern lowlands, and we use gravity and topography data to construct global crustal thickness models that satisfy the seismic data. These models consider a range of possible mantle and core density profiles, a range of crustal densities, a low-density surface layer, and the possibility that the crustal density of the northern lowlands is greater than that of the southern highlands. Using the preferred InSight three-layer seismic model of the crust, the average crustal thickness of the planet is found to lie between 30 and 72 km. Depending on the choice of the upper mantle density, the maximum permissible density of the northern lowlands and southern highlands crust is constrained to be between 2,850 and 3,100 kg m−3. These crustal densities are lower than typical Martian basaltic materials and are consistent with a crust that is on average more felsic than the materials found at the surface. We argue that a substantial portion of the crust of Mars is a primary crust that formed during the initial differentiation of the planet. Various hypotheses for the origin of the observed intracrustal seisimic layers are assessed, with our preferred interpretation including thick volcanic deposits, ejecta from the Utopia basin, porosity closure, and differentiation products of a Borealis impact melt sheet.

ABSTRACT: Hops are grown mainly for the brewing market due to the rich chemical composition that gives beer aroma and bitterness. Brazil is one of the largest beer producers and consumers in the world and one of the largest hop importers. There is growing demand and interest in producing hops for domestic supply; however, as this crop originates from a temperate climate and the Northern Hemisphere, it is important to carry out research that describes the development of hops in a tropical climate to provide information on its cultivation in Brazil, as well as to determine its behavior in organic cultivation. A randomized block design was adopted, the treatments consisted of two cropping systems, conventional and organic, for Hallertau Mittelfrueh variety cultivation, with four blocks and three plants per plot. Gas exchange analyzes of plants under both cultivation systems were performed to obtain measurements of A, g s , Ci, E, WUE and A/Ci, morphometric and yield analyzes were also carried out. In comparison with the plants of the organic system, the plants of the conventional cultivation had greater photosynthetic efficiency; however, the practices adopted in the organic cultivation system provided the plants with greater productive capacity.

Introduction The acute mountain sickness (AMS) prevalence increases with altitude; i.e.,10-25% at 2,500 m and 50-85% at ~5,000 m (Bärtsch & Swenson, 2013). Women are more likely affected by AMS than men (Richalet et al., 2012). AMS can affect exercise performance. However, the effects of the menstrual cycle (MC) on physiological responses to exercise and on tolerance to high-altitude (HA) remain underexplored. It has been reported that ovarian hormones stimulate ventilation in normoxic conditions (Saaresranta & Polo, 2002). Early findings suggest that running economy is lower in the mid-luteal (ML) compared to the early-follicular (EF) phase in normoxia (Goldsmith & Glaister, 2020). However, cycling efficiency at HA has not been explored yet. Thus, we investigated the effects of acute HA exposure on ventilatory responses at rest and during exercise in healthy females during two different phases of their MC. Methods Sixteen eumenorrheic women (age: 33 ± 7 yr; MC length: 27 ± 2 days; not taking any hormonal contraceptive) took part in this study. First, over a 6-month period, the participants’ MC were monitored using a calendar method. Then, they reached the Torino Hut (3,375 m) by cable car and spent one night at HA on two different MC phases; i.e., during the early-follicular (EF; MC day 4 ± 1) and the mid-luteal (ML; day 20 ± 2) phases. Each time, they underwent a submaximal (1.2 W/kg) test on a cycle ergometer ~17 h after arrival at HA. In addition to this, participants filled in two questionnaires, the Lake Louise AMS Score and the Groningen Sleep Quality Scale, ~16 h after arrival at HA. Results Resting ventilation was significantly higher during EF compared to ML (15.2 ± 1.9 vs. 13.2 ± 2.5 L/min, p = 0.039), while no differences were found for ventilation during exercise (53.9 ± 13.2 vs. 53.5 ± 13.4 L/min, p = 0.695), cycling efficiency (21.7 ± 0.0% vs. 19.8 ± 0.0%, p = 0.244), saturation at rest (92.4 ± 1.3 vs. 91.3 ± 3.2%, p = 0.142) and during exercise (87.2 ± 5.7 vs. 89.0 ± 4.0%, p = 0.528). Moreover, no differences in the Lake Louise AMS (2.2 ± 1.5 vs. 1.7 ± 1.5, p = 0.266) or Groningen (8.0 ± 3.3 vs. 7.5 ± 3.4, p = 0.668) scores were noted between the two MC phases. Discussion/Conclusion Despite a slightly higher resting ventilation during EF, when both oestrogens and progesterone are at their lowest levels, there were no differences in ventilatory responses to exercise and in AMS between the different phases of the MC. Consequently, there is currently very little evidence to aptly recommend a specific MC phase for mountaineering or any other HA activities (Burtscher et al., 2023). Further investigations are requested to assess whether other physiological responses to HA may be influenced by hormonal variations. References Bärtsch, P., & Swenson, E. R. (2013). Acute high-altitude illnesses. New England Journal of Medicine, 368, 2294–2302. https://doi.org/10.1056/NEJMcp1214870 Burtscher, J., Raberin, A., Brocherie, F., Malatesta, D., Manferdelli, G., Citherlet, T., Krumm, B., Bourdillon, N., Antero, J., Rasica, L., Burtscher, M. & Millet, G. P. (2023). Recommendations for women in mountain sports and hypoxia training/conditioning. Sports Medicine. Advance online publication. https://doi.org/10.1007/s40279-023-01970-6 Goldsmith, E., & Glaister, M. (2020). The effect of the menstrual cycle on running economy. The Journal of Sports Medicine and Physical Fitness, 60(4), 610–617. https://doi.org/10.23736/s0022-4707.20.10229-9 Richalet, J.-P., Larmignat, P., Poitrine, E., Letournel, M., & Canouï-Poitrine, F. (2012). Physiological risk factors for severe high-altitude illness: A prospective cohort study. American Journal of Respiratory and Critical Care Medecine, 185(2), 192–198. https://doi.org/10.1164/rccm.201108-1396OC Saaresranta, T., & Polo, O. (2002). Hormones and breathing. American College of Chest Physicians, 122(6), 2165–2182. https://doi.org/10.1378/chest.122.6.2165

Background. Despite the great attention that has been paid to HRQoL in children with respiratory allergy, few studies have addressed this aspect in relation to caregivers. The aim of our study was to evaluate the impact of childhood respiratory allergies on caregivers by means of a new method. Methods. 119 parents of children suffering from allergies (75 suffering from asthma and 44 suffering from rhinitis) were recruited from three Italian Allergy Units. Parents were asked to complete the Disease Impact On Caregiver (DIOC), a new non disease specific questionnaire, validated on the Italian population. The questionnaire consists of 31 items grouped in four factors (Performance, Personal gratification, Psychophysical endurance, Socio-emotional domain) and covers the life aspects that could be affected by the assistance duties towards an ill family member. Results. Child’s asthma resulted to have a worse impact on many aspects of a parents’ life than rhinitis. Differences resulted to be statistically significant in 19 aspects out of the 31 assessed. The worse impact of asthma versus rhinitis was confirmed in the following domains: Performance (24.0±18.2 vs 11.5±17.8), Personal gratification (26.3±20.5 vs 12.1±16.5) and Psychophysical endurance (35.0±24.8 vs 18.8±21.7). In the Socio-emotional domain no difference emerged. Conclusions. Compared to parents of rhinitics, parents of asthmatic children appear to be more compromised in their resistance to stress, mood, emotional stability, amount of spare time and leisure activities. Our results suggest the need of giving the due attention to these problems both in clinical practice and in research, in order to avoid possible interferences of the caregiver’s distress in the optimization of treatment outcome.

Abstract The sealing characteristics of the geological formation located above a CO2 storage reservoir, the so-called caprock, are essential to ensure efficient geological carbon storage. If CO2 were to leak through the caprock, temporal changes in fluid geochemistry can reveal fundamental information on migration mechanisms and induced fluid–rock interactions. Here, we present the results from a unique in-situ injection experiment, where CO2-enriched fluid was continuously injected in a faulted caprock analogue. Our results show that the CO2 migration follows complex pathways within the fault structure. The joint analysis of noble gases, ion concentrations and carbon isotopes allow us to quantify mixing between injected CO2-enriched fluid and resident formation water and to describe the temporal evolution of water–rock interaction processes. The results presented here are a crucial complement to the geophysical monitoring at the fracture scale highlighting a unique migration of CO2 in fault zones.

Orthopedic splints are external medical devices designed to support and protect the functions of the human musculoskeletal system from pathological conditions or traumatic events. Tailoring these medical solutions to the morphology of the patient’s limb is essential to ensure a correct and rapid rehabilitation pathway. Although traditional splinting techniques might achieve a unique fit, the procedures are highly dependent on the skill and experience of the medical operator, affecting the quality of the care treatment. In response to the drawbacks associated with traditional splinting techniques, the present article proposed an innovative and structured methodology to manufacture customized wrist immobilization splints, prioritizing simplicity and user-friendliness in fabrication activities. The customized splint manufacturing was based on the integration of reverse engineering (RE) and additive manufacturing (AM) techniques. The research designed a baseline model of a wrist splint, varying over different thickness values and manufacturing materials (ABS, nylon, PLA, PC, PA6-GF25, PA6-CF20). For every splint model, the production times and material costs were assessed. Technical tests were performed via finite element analysis (FEA). The conducted analysis and the resulting charts empower medical operators to select the most appropriate solution, ensuring a well-informed and effective decision-making approach.

One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage, improve the efficacy, and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, RI173, and RI172 were the most potent inhibitors in an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L, with IC50s of 300, 200, and 200 nM, which is about 5-, 19-, and 11-fold more potent than disulfiram, respectively. In addition, RI173 was tested against SARS-CoV-2 in a cell-based and toxicity assay and was shown to have a greater antiviral effect than disulfiram. The identified compounds demonstrated the promising potential of thiuram disulfide or dithiobis-(thioformate) as a reactive functional group in small molecules that could be further developed for treatment of the COVID-19 virus or related variants.

The Seismic Experiment for Interior Structure (SEIS) of the InSight mission to Mars, has been providing direct information on Martian interior structure and dynamics of that planet since it landed. Compared to seismic recordings on Earth, ground motion measurements acquired by SEIS on Mars are made under dramatically different ambient noise conditions, but include idiosyncratic signals that arise from coupling between different InSight sensors and spacecraft components. This work is to synthesize what is known about these signal types, illustrate how they can manifest in waveforms and noise correlations, and present pitfalls in structural interpretations based on standard seismic analysis methods. We show that glitches, a type of prominent transient signal, can produce artifacts in ambient noise correlations. Sustained signals that vary in frequency, such as lander modes which are affected by variations in temperature and wind conditions over the course of the Martian Sol, can also contaminate ambient noise results. Therefore, both types of signals have the potential to bias interpretation in terms of subsurface layering. We illustrate that signal processing in the presence of identified nonseismic signals must be informed by an understanding of the underlying physical processes in order for high fidelity waveforms of ground motion to be extracted. While the origins of most idiosyncratic signals are well understood, the 2.4 Hz resonance remains debated and the literature does not contain an explanation of its fine spectral structure. Even though the selection of idiosyncratic signal types discussed in this paper may not be exhaustive, we provide guidance on best practices for enhancing the robustness of structural interpretations.

This feasibility study investigates extracting thermal energy from the Bedretto tunnel in the Swiss Alps, which benefits from subsurface heat flux and rock overburden insulation. Using the simulation software COMSOL Multiphysics, we created a numerical model of the tunnel environment to evaluate which medium between rock, air, and water serves as the most effective heat source. Our findings indicate that flowing water is the most effective heat source. Potential applications include distributing the water to nearby villages and storing remaining heat in the subsurface. Estimates indicate that the total extractable thermal energy ranges between 0.8 MWth and 1.5 MWth after reducing the water temperature to 4 °C via a heat pump. The study identifies the most suitable energy sourcing locations based on efficiency and investment costs. Circulating water to individual heat pumps in Bedretto, with the natural elevation difference, enables water transport without a pump. Cost analyses reveal that the investment in piping and heat pumps can be amortized within the equipment’s lifespan with appropriate economic models. With the same initial investments, district heating systems are viable in villages with over 30 connections. The payback periods are 10 years for 60 connections, 4.5 years for 90 connections, and immediate for 200 connections.

Metal additive manufacturing technologies such as powder bed fusion (PBF) and direct energy deposition (DED) are experiencing fast development, due to the growing awareness of industries. However, high energy consumption, slow production processes, and high costs of both machines and feedstocks hamper their competitiveness, compared to conventional manufacturing techniques. Metal material extrusion (metal-MEX) can represent a cost- and energy-effective alternative for metal additive manufacturing. This article aims to assess the potential of such technology by addressing uncertainties related to product design and process stability through a preliminary geometric benchmarking study. The geometric tolerances and minimum achievable sizes of some simple geometries produced in 316L stainless steel were evaluated using geometric benchmark test artifacts (GBTAs). Process maps were also proposed to forecast the feasibility of achieving acceptable values of the investigated tolerances, based on the nominal dimensions of the features.

Karstic sinkholes are peculiar structures hosting specific biological communities. Birds are still little studied in this regard. This note reports, for the first time, original data relating to the density of breeding species occurring within a sinkhole in central Italy obtained with a fine-grained and time-expensive sampling technique (mapping method). The results were compared with data sampled with the point counts method carried out in the same phenological period. We recorded 22 breeding species, all typical of meso-thermophilous forests and ecotonal habitats of hilly central Italy. Among them, two species (Turdus merula and Troglodytes troglodytes), typical of shady, undergrowth habitats, were recorded in the deepest part of the sinkhole (−70 m from the top). No significant differences emerged between the relative frequencies of the species obtained with the two methods, except for Luscinia megarhynchos (overestimated with the mapping method) and Aegithalos caudatus (underestimated). At the community level, the comparison of the two methods revealed similar values in univariate diversity metrics, Whittaker plots did not show a significant difference (ANCOVA test), and ordinary least squares regression between the frequencies showed a highly significant correlation. Therefore, in these peculiar habitats, data obtained from the two methods are comparable: since the point counts method needs lower sampling effort, it appeared to be more effective when compared to the mapping method to study these peculiar habitats.

IntroductionThe effectiveness of canakinumab may change according to the different times it is used after Still’s disease onset. This study aimed to investigate whether canakinumab (CAN) shows differences in short- and long-term therapeutic outcomes, according to its use as different lines of biologic treatment.MethodsPatients included in this study were retrospectively enrolled from the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to Still’s disease. Seventy-seven (51 females and 26 males) patients with Still’s disease were included in the present study. In total, 39 (50.6%) patients underwent CAN as a first-line biologic agent, and the remaining 38 (49.4%) patients were treated with CAN as a second-line biologic agent or subsequent biologic agent.ResultsNo statistically significant differences were found between patients treated with CAN as a first-line biologic agent and those previously treated with other biologic agents in terms of the frequency of complete response (p =0.62), partial response (p =0.61), treatment failure (p >0.99), and frequency of patients discontinuing CAN due to lack or loss of efficacy (p =0.2). Of all the patients, 18 (23.4%) patients experienced disease relapse during canakinumab treatment, 9 patients were treated with canakinumab as a first-line biologic agent, and nine patients were treated with a second-line or subsequent biologic agent. No differences were found in the frequency of glucocorticoid use (p =0.34), daily glucocorticoid dosage (p =0.47), or concomitant methotrexate dosage (p =0.43) at the last assessment during CAN treatment.ConclusionCanakinumab has proved to be effective in patients with Still’s disease, regardless of its line of biologic treatment.

Abstract The observation of parent/child interaction is an effective method for identifying, evaluating, and monitoring adolescents and families who need or are undergoing intervention. This study aims to (1) describe a method of direct and systematic observation of dyadic interaction and (2) discuss its application in research with families with adolescents in northeastern Brazil. The data collection and analysis procedures are presented, indicating their possibilities and limits based on the lessons learned from this experience. The experience of applying the method is discussed through potential advances and challenges for the field of observational research in Psychology. It is concluded that the method of direct and systematic observation of dyadic interaction is, on the one hand, expensive in terms of expertise, time, and resources, and, on the other hand, it is a rich source of data for understanding interaction patterns in multiple contexts.

Industrial screwing is one of several industry branches' most common manufacturing processes. Good quality and structured data from these operations have increased demand with the popularization of data-driven techniques for manufacturing automation. The dataset presented in this paper comprises screwing experiments with aeronautical nuts performed by an industrial robot Kuka KR-16 in a lab setting. The data comprises force, torque, linear and angular displacements, and velocities in time-series format. The dataset contains three different experiment results: mounted, jammed, and not mounted, which can be used as labels for classification techniques.