Cross-architecture tuning of silicon and SiGe-based quantum devices using machine learning.

The potential of Si and SiGe-based devices for the scaling of quantum circuits is tainted by device variability. Each device needs to be tuned to operation conditions and each device realisation requires a different tuning protocol. We demonstrate that it is possible to automate the tuning of a 4-gate Si FinFET, a 5-gate GeSi nanowire and a 7-gate Ge/SiGe heterostructure double quantum dot device from scratch with the same algorithm. We achieve tuning times of 30, 10, and 92 min, respectively. The algorithm also provides insight into the parameter space landscape for each of these devices, allowing for the characterization of the regions where double quantum dot regimes are found. These results show that overarching solutions for the tuning of quantum devices are enabled by machine learning.

Genetic determinants of micronucleus formation in vivo.

Genomic instability arising from defective responses to DNA damage1 or mitotic chromosomal imbalances2 can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology1.

Data scarce modelling the impact of present and future groundwater development on Jordan multiaquifer groundwater resources.

Rapidly growing demands and climate change stresses water resources worldwide and leads to highly competitive situations between the environment and socio-economic development of a region, calling for a smart and modelling driven water resources management. However, data scarcity often prevents the realisation of a comprehensive, nation-wide resources model, which provides reliable and spatially discretized results of water resources development. We present a workflow approach to set up a large-scale multi-aquifer model, overcoming data shortage by stepwise calibration and integrating hydrological and numerical groundwater flow modelling into a coupled system. The study aims to develop such a system to assess how groundwater resources react on anthropogenic impacts on the example of the Kingdom of Jordan, one of the water poorest countries on globe. Simulated heads reliably resembled the monitored ones in >70 % of the observation wells. That makes us confident, the model represents all the states well from 1970, prior to the intense development of the country until 2015. The water balance shows an annual deficit of 1.16 million cubic meter (MCM) due to an overdraft. The discharge to the Dead Sea increased from 564 MCM/yr to 696 MCM/yr over the time period. Regional drawdowns of >250 m and groundwater depression with an extension of approx.100 km are observable in both large aquifer complexes. Most severe areas in the upper calcareous aquifer are located in the north of Amman and practically in all urban and agricultural agglomerations across the country. Groundwater tables in the deeper sandstone aquifer are particularly affected in the south as well as in the wider vicinity of the Dead Sea as consequence of its continuous dropping. Simulations of the future development of the groundwater tables indicate a severe deterioration of the situation with further declines in groundwater levels of up to 70 m.

Estimating trends in working life expectancy based on health insurance data from Germany - Challenges and advantages.

Against the backdrop of population aging and growing strain on pension systems, monitoring the development of Working Life Expectancy (WLE) is vital to assess whether the policies taken are effective. This is the first study investigating time trends and educational inequalities in WLE based on German health insurance data. The analyses are based on the data of the AOK Lower Saxony (N = 3,347,912) covering three time periods (2006-08, 2011-13, and 2016-18). WLE is defined as years spent in the labor force (i.e. in employment and unemployment) and was calculated for each age between 18 and 69 years for the three periods to depict changes over time using multistate life table analysis. Educational inequalities in 2011-13 are reported for two educational levels (8-11 years and 12-13 years of schooling). WLE increased in both sexes with increases being stronger among women. This holds irrespective of whether WLE at age 18 (35.8-38.3 years in men, 27.5-34.0 years in women) or the older working-age (e.g. at age 50 10.2-11.7 years in men, 7.8-10.5 years in men) is considered. Among women at all ages and men from their mid-20s onwards, WLE was higher among higher-educated individuals. Inequalities were most pronounced among women (e.g. Δ3.1 years in women, Δ1.3 years in men at age 50). The study supports previous research indicating that measures to extend working life are effective, but that noticeable inequalities in WLE exist. Health insurance data represent a valuable source for such research that has so far remained untapped. The data provide a suitable basis to investigate trends and inequalities in WLE. Future research should build on the strengths of the data by broadening the research towards a more comprehensive analysis of the development of WLE from a health perspective.

Hypothalamus enlargement in mood disorders.

OBJECTIVE: The purpose of this study was to determine, in vivo, whether the hypothalamus volume is reduced in patients with mood disorders. METHODS: The cross-sectional study included 20 unmedicated (MDDu) and 20 medicated patients with major depressive disorder, 21 patients with bipolar disorder, and 23 controls. Twenty of the controls were matched to the MDDu. Seven Tesla, T1-weighted magnetic resonance images were acquired and processed using methods specifically developed for high-precision volumetry of the hypothalamus. RESULTS: An overall group difference was observed for the left hypothalamus volume corrected for intracranial volume. Planned contrasts identified that the left hypothalamus was approximately 5% larger in each patient group compared with the control group. A paired t-test with the 20 matched pairs of MDDu and controls and without correction for covariates confirmed the larger left hypothalamus volume in MDDu. CONCLUSIONS: Contrary to our expectations, the hypothalamus volume was increased in patients with uni- and bipolar affective disorders. The effect was left-sided and independent of medication status or statistical correction for covariates. Supported by emerging evidence that the stress response may be related to structural and functional asymmetry in the brain, our finding suggests a crucial role of the hypothalamus in mood disorders.

Maintenance therapy with decitabine in younger adults with acute myeloid leukemia in first remission: a phase 2 Cancer and Leukemia Group B Study (CALGB 10503).

In this prospective phase 2 clinical trial conducted by Cancer and Leukemia Group B (CALGB, now the Alliance), we studied decitabine as maintenance therapy for younger adults with acute myeloid leukemia (AML) who remained in first complete remission (CR1) following intensive induction and consolidation. Given that decitabine is clinically active in AML and with hypomethylating activity distinct from cytotoxic chemotherapy, we hypothesized that 1 year of maintenance therapy would improve disease-free survival (DFS) for AML patients <60 years, who did not receive allogeneic stem cell transplantation in CR1. After blood count recovery from final consolidation, patients received decitabine at 20 mg/m2 intravenously daily for 4-5 days, every 6 weeks for eight cycles. One hundred and thirty-four patients received decitabine and 85 (63%) had favorable risk AML. The median number of cycles received was 7 (range: 1-8) and the primary reason for discontinuation was relapse. DFS at 1 year and 3 years was 79% and 54%, respectively. These results are similar to the outcomes in the historical control comprising similar patients treated on recent CALGB trials. Thus, maintenance with decitabine provided no benefit overall. Standard use of decitabine maintenance in younger AML patients in CR1 is not warranted. This trial was registered at www.clinicaltrials.gov as NCT00416598.

Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes.

Although next-generation sequencing has allowed for the detection of somatic mutations in myelodysplastic syndromes (MDS), the clinical relevance of variant allele frequency (VAF) for the majority of mutations is unknown. We profiled TP53 and 20 additional genes in our training set of 219 patients with MDS or secondary acute myeloid leukemia with findings confirmed in a validation cohort. When parsed by VAF, TP53 VAF predicted for complex cytogenetics in both the training (P=0.001) and validation set (P<0.0001). MDS patients with a TP53 VAF > 40% had a median overall survival (OS) of 124 days versus an OS that was not reached in patients with VAF <20% (hazard ratio (HR), 3.52; P=0.01) with validation in an independent cohort (HR, 4.94, P=0.01). TP53 VAF further stratified distinct prognostic groups independent of clinical prognostic scoring systems (P=0.0005). In multivariate analysis, only a TP53 VAF >40% was an independent covariate (HR, 1.61; P<0.0001). In addition, SRSF2 VAF predicted for monocytosis (P=0.003), RUNX1 VAF with thrombocytopenia (P=0.01) and SF3B1 with ringed sideroblasts (P=0.001). Together, our study indicates that VAF should be incorporated in patient management and risk stratification in MDS.

[Open double-row rotator cuff repair using the LASA-DR screw]. / Offene Double-row-Rotatorenmanschettenrekonstruktion mit der LASA-DR-Screw.

OBJECTIVE: Safe and cost-effective rotator-cuff repair. INDICATION: All types of rotator cuff lesions. CONTRAINDICATIONS: Frozen shoulder, rotator cuff mass defect, defect arthropathy. SURGICAL TECHNIQUE: Extensive four-point fixation on the bony footprint is performed using the double-row lateral augmentation screw anchor (LASA-DR) with high biomechanical stability. Following mobilization of the tendons, these are refixed in the desired configuration first medially and then laterally. To this end, two drilling channels (footprint and lateral tubercle) are created for each screw. Using the shuttle technique, a suture anchor screw is reinforced with up to four pairs of threads. The medial row is then pierced and tied, and the sutures that have been left long are tied laterally around the screw heads (double row). POSTOPERATIVE MANAGEMENT: 4 Weeks abduction pillow, resulting in passive physiotherapy, followed by initiation of active assisted physiotherapy. Full weight-bearing after 4-6 months. RESULTS: Prospective analysis of 35 consecutive Bateman-III lesions with excellent results and low rerupture rate (6%).

[Mid-Term Clinical Results after Open Rotator Cuff Reconstruction in Double-Row Technique with Titanium Anchor Screws]. / Mittelfristige Ergebnisse nach offener Rotatorenmanschettenrekonstruktion in Double-Row-Technik mit Titanankerschraube.

BACKGROUND: The double-row rotator cuff repair is discussed controversially. Despite improved biomechanical properties, reduced re-tear rates and higher costs, no significant difference compared to single-row fixation in the clinical results is found. Mid-term results of an open double-row fixation with titanium anchor screws are presented. MATERIAL AND METHODS: 237 patients (m = 142, f = 95, median age: 56.3 years) were operated in 2007 with this technique by the senior author (M. G.). Preoperatively, 2 years and 4,5 years postoperatively a subjective shoulder score (SSG) with follow-up rates of 86, 87 and 83 %, was evaluated. 5.1 years postoperatively an objective evaluation of 131 patients using the Constant-Murley scores (CS), the simple shoulder tests (SST), Gerber's shoulder value and the evaluation with school grades followed. The integrity of the cuff was checked with ultrasound. The absolute (re-tears and partial re-tears) and the relative (re-tears, partial re-tears, thinning and thickening of the cuff) re-tear rates were evaluated. RESULTS: In SSG a highly significant improvement from 51 to 83 points was found (p < 0.001). In CS 80 points (min.: 18; max.: 100), and in SST 11 points (min.: 2; max.: 12) were achieved. The shoulder value of Gerber increased significantly from preoperative 28.1 to 84.5 % 5.1 years postoperative (p < 0.001).The absolute re-tear rate, evaluated in ultrasound was 7.6 %, the relative re-tear rate 17.6 %. For primary rotator cuff reconstructions a higher CS with 82 points and a lower relative re-tear rate with 10.5 % were found. The patient's age had no significant influence on the clinical outcome. The rupture size showed a significant impact on the re-tear rate and the scores (p < 0.05). Between the operated and healthy shoulder neither strength nor mobility were found to be significantly different. Men reached a highly significant better strength than women (p < 0.001) which also resulted in a significantly better outcome in the CS (p < 0.01). The costs for open titanium transfixation technique with 330 € per case are markedly less than for arthroscopic suture bridge technique with 600 to 1000 € per case. CONCLUSION: Open double-row cuff repair with titanium screws is a safe and cost effective technique with a low re-tear rate with comparable clinical results regarding open and arthroscopic procedures.

A cytoarchitecture-driven myelin model reveals area-specific signatures in human primary and secondary areas using ultra-high resolution in-vivo brain MRI.

This work presents a novel approach for modelling laminar myelin patterns in the human cortex in brain MR images on the basis of known cytoarchitecture. For the first time, it is possible to estimate intracortical contrast visible in quantitative ultra-high resolution MR images in specific primary and secondary cytoarchitectonic areas. The presented technique reveals different area-specific signatures which may help to study the spatial distribution of cortical T1 values and the distribution of cortical myelin in general. It may lead to a new discussion on the concordance of cyto- and myeloarchitectonic boundaries, given the absence of such concordance atlases. The modelled myelin patterns are quantitatively compared with data from human ultra-high resolution in-vivo 7T brain MR images (9 subjects). In the validation, the results are compared to one post-mortem brain sample and its ex-vivo MRI and histological data. Details of the analysis pipeline are provided. In the context of the increasing interest in advanced methods in brain segmentation and cortical architectural studies, the presented model helps to bridge the gap between the microanatomy revealed by classical histology and the macroanatomy visible in MRI.

[Career perspectives of hospital health workers after maternity and paternity leave: survey and observational study in Germany]. / Weggegangen - Platz vergangen?

OBJECTIVE: A term of maternity and paternity (parental) leave becomes frequent on the career paths of medical personnel. Hospitals are highly competitive environments. The question employees universally face is how such a leave will alter their personal work situation and prospects upon return. DESIGN AND PARTICIPANTS: We questioned 709 leave-takers and 88 department heads of a German university hospital (2009-12; full data sets: n = 406 and n = 63) about their experiences. This data was validated by epidemiology data extraction and expert interviews, also in a Swiss and in a Norwegian institution. RESULTS: Parental leave elicited high emotionality (score: 4.0 +/- 2 out of 5). Superiors' appraisal of employees' parental leave was more positive than negative (p < 0.001, mean + 0.8 +/- 0.9 on a bipolar Likert scale (BLS) from - 2 to + 2). However, the annual labor turnover in leave takers doubled to 39 %; 51 % of leave-takers experienced significant task profile changes. 58 % of doctors thought about changing their employer and 17 % of leave-taking executives lost status after return. Employees' "power" and "influence" dropped significantly (p < 0.05; determined on BLS) whereas the "professional workload" increased (p < 0.001). Consequently, after return career perspectives (measured on a bipolar visual analogue scale from - 5 to + 5) were perceived significantly more negative than positive (p < 0.0001, mean: - 1.3 +/-  2), especially by high-commitment staff (i. e. female executives, mean: - 2.1 +/- 2, pΔ < 0.05 vs. others). These perceptions significantly influenced future choices concerning further terms of leave. The Swiss and Norwegian comparators appeared to have more liberal substitution and part-time schemes than the German institution. DISCUSSION: A competitive hospital environment can effectively demote leave-taking medical employees in their jobs. Despite sufficient financial arrangements high-commitment staff will only take parental leave of adequate length when an institutional framework protects their status. Data support four requirements: 1. Formal recognition of the leave taker's status pre-leave. 2. Establishment of a written ("claimable") return policy. 3. Substitution scheme for each individual, preferably by a locum. 4. Redirection of funds to facilitate part-time work schemes temporarily after return.

[Good Practice of Secondary Data Analysis (GPS): guidelines and recommendations]. / Gute Praxis Sekundärdatenanalyse (GPS): Leitlinien und Empfehlungen.

In 2005, the Working Group for the Survey and Utilisation of Secondary Data (AGENS) of the German Society for Social Medicine and Prevention (DGSMP) and the German Society for Epidemiology (DGEpi) first published "Good Practice in Secondary Data Analysis (GPS)" formulating a standard for conducting secondary data analyses. GPS is intended as a guide for planning and conducting analyses and can provide a basis for contracts between data owners. The domain of these guidelines does not only include data routinely gathered by statutory health insurance funds and further statutory social insurance funds, but all forms of secondary data. The 11 guidelines range from ethical principles and study planning through quality assurance measures and data preparation to data privacy, contractual conditions and responsible communication of analytical results. They are complemented by explanations and practical assistance in the form of recommendations. GPS targets all persons directing their attention to secondary data, their analysis and interpretation from a scientific point of view and by employing scientific methods. This includes data owners. Furthermore, GPS is suitable to assess scientific publications regarding their quality by authors, referees and readers. In 2008, the first version of GPS was evaluated and revised by members of AGENS and the Epidemiological Methods Working Group of DGEpi, DGSMP and GMDS including other epidemiological experts and had then been accredited as implementation regulations of Good Epidemiological Practice (GEP). Since 2012, this third version of GPS is on hand and available for downloading from the DGEpi website at no charge. Especially linguistic specifications have been integrated into the current revision; its internal consistency was increased. With regards to contents, further recommendations concerning the guideline on data privacy have been added. On the basis of future developments in science and data privacy, further revisions will follow.

The embryogenesis of the equine femorotibial joint: The equine interzone.

REASONS FOR PERFORMING STUDY: Articular cartilage regeneration is the focus and goal of considerable research effort. Since articular chondrocytes descend from a distinct cohort of progenitor cells located in embryonic nascent joints (interzones), establishing the timing of equine interzone formation is an essential first step towards understanding equine joint and articular cartilage development. OBJECTIVES: To establish the time frame during which the equine femorotibial interzone forms. STUDY DESIGN: Descriptive anatomical study. METHODS: Equine embryos were harvested at 37 (E37), 40, 42, 45, 50 and 65 days' gestation. The femorotibial interzone was examined using high-resolution episcopic microscopy of E37, E42, E45, E50 and E65. Additional histology and collagen-II-immunohistochemistry were performed on E42. RESULTS: At E37, the femorotibial interzone is first visible as a uniform layer, while at E42 the interzone is fully formed and consists of 3 morphologically distinct layers. The first evidence of cavitation was seen at E45. At E50, the cruciate ligaments were well formed and by E65, joint formation appeared complete. CONCLUSIONS: The embryogenesis of the equine femorotibial joint is similar to the developmental timeline of stage-matched human and murine embryos. Further studies looking at interzone formation on a cellular and molecular level may further our understanding of the intricate developmental patterns and pathways of articular cartilage development.

[The Morbidity Compression Hypothesis and its Alternatives]. / Die Morbiditätskompressionsthese und ihre Alternativen.

AIM: Fries' hypothesis of morbidity compression asserts that the length of lifetime spent in states of chronic disease and disability is decreasing. This can be explained by improved living and working conditions and by successful primary prevention. METHOD: Using the available studies on morbidity compression it is examined whether the lengths of periods spent in states of morbidity have changed in the last decades. RESULTS: For multimorbidity, chronic diseases, cognitive impairment, and for subjective health the developments are in favour of the morbidity compression hypothesis. The conclusions are nevertheless dependent on the type of health impairment considered. CONCLUSION: There is evidence that morbidity compression has taken place in the last decades. Depending on the disease, morbidity expansion and dynamic equilibrium may also have occurred. A comprehensive assessment of the development of morbidities is only possible if more diseases are considered. In addition, there is evidence that outside of Europe and the USA morbidity patterns may also develop in other directions.

[Compression or expansion of morbidity? Development of health among the older population]. / Kompression oder Expansion der Morbidität? Entwicklung der Gesundheit in der älteren Bevölkerung.

BACKGROUND: Within the context of demographic change, the development of morbidity among the older population has increasingly gained importance. In this respect, three different scenarios of the development of morbidity are discussed: the compression of morbidity, the dynamic equilibrium, and the expansion of morbidity. OBJECTIVES: This paper investigates in which way subjective and functional health have developed among the older population between 1997 and 2010. MATERIALS AND METHODS: Using German Socio-Economic Panel (GSOEP) data, the developments of subjective and functional health are examined in cross-sectional comparisons. The age groups between 65 and 89 are considered. Analyses are stratified according to gender and age. RESULTS: In comparing different cohorts, men and women from younger cohorts report better subjective and functional health compared to people born before them. Concerning subjective health, this trend mostly affects younger people (65-74 years). Elderly subjects (aged 75-89 years) in the cohort comparison between 1997 and 2010 report no improvements in subjective health. In contrast, functional health between the cohorts affected all age groups in a similar manner. CONCLUSION: Results for subjective and functional health are consistent with the compression of morbidity and the dynamic equilibrium and they do not point towards an expansion of morbidity.

Anatomically motivated modeling of cortical laminae.

Improvements in the spatial resolution of structural and functional MRI are beginning to enable analysis of intracortical structures such as heavily myelinated layers in 3D, a prerequisite for in-vivo parcellation of individual human brains. This parcellation can only be performed precisely if the profiles used in cortical analysis are anatomically meaningful. Profiles are often constructed as traverses that are perpendicular to computed laminae. In this case they are fully determined by these laminae. The aim of this study is to evaluate models for cortical laminae used so far and to establish a new model. Methods to model the laminae used so far include constructing laminae that keep a constant distance to the cortical boundaries, so-called equidistant laminae. Another way is to compute equipotentials between the cortical boundary surfaces with the Laplace equation. The Laplace profiles resulting from the gradients to the equipotentials were often-used because of their nice mathematical properties. However, the equipotentials these Laplacian profiles are constructed from and the equidistant laminae do not follow the anatomical layers observed using high resolution MRI of cadaver brain. To remedy this problem, we introduce a novel equi-volume model that derives from work by Bok (1929). He argued that cortical segments preserve their volume, while layer thickness changes to compensate cortical folding. We incorporate this preservation of volume in our new equi-volume model to generate a three-dimensional well-adapted undistorted coordinate system of the cortex. When defined by this well-adapted coordinate system, cortical depth is anatomically meaningful. We compare isocontours from these cortical depth values to locations of myelinated bands on high-resolution ex-vivo and in-vivo three-dimensional MR images. A similar comparison was performed with equipotentials computed with the Laplace equation and with equidistant isocontours. A quantitative evaluation of the equi-volume model using measured image intensities confirms that it provides a much better fit to observed cortical layering.

The dermal arteries of the human thumb pad.

The arteries of the skin have been postulated to form a profound plexus at the dermal/hypodermal junction and a superficial plexus in the papillary dermis. Our article aims to rebut this concept and to provide an alternative description of the arrangement of the dermal arteries. Employing a novel technique, we produced digital volume data (volume size: 2739 × 2054 × 3000 µm(3) ; voxel size: 1.07 × 1.07 × 2 µm(3) ) from biopsies of the skin of the thumb pads of 15 body donors. Utilizing these data, we analysed the arrangement of the dermal arteries with the aid of virtual re-sectioning tools, and, in three specimens, with high-quality three-dimensional (3D) surface models. In all specimens we observed a tree-like ramification of discrete dermal arteries. The terminal branches of the arterial trees gave rise to the ascending segments of the capillary loops of the dermal papillae. None of the specimens showed a superficial arterial plexus. This suggests that the skin of the human thumb pad can be split in discrete 'arterial units'. Each unit represents the zone of the papillary dermis and epidermal/dermal junction, to which blood is supplied exclusively by the branches of a single dermal artery. The concept of dermal arterial units is in contrast to all existing descriptions of the architecture of the dermal arteries. However, whether it can be transferred to the skin of other body parts, remains to be tested. Likewise, the consequences of arterial units for understanding the mechanisms of wound healing and the appearance and genesis of skin diseases remain to be examined.

Electron- and proton-impact excitation of hydrogenlike uranium in relativistic collisions.

The K shell excitation of H-like uranium (U(91+)) in relativistic collisions with different gaseous targets has been studied at the experimental storage ring at GSI Darmstadt. By performing measurements with different targets as well as with different collision energies, we were able to observe for the first time the effect of electron-impact excitation (EIE) process in the heaviest hydrogenlike ion. The large fine-structure splitting in H-like uranium allowed us to unambiguously resolve excitation into different L shell levels. State-of-the-art calculations performed within the relativistic framework which include excitation mechanisms due to both protons (nucleus) and electrons are in good agreement with the experimental findings. Moreover, our experimental data clearly demonstrate the importance of including the generalized Breit interaction in the treatment of the EIE process.

Portable atomic layer deposition reactor for in situ synchrotron photoemission studies.

We report the design of a portable atomic layer deposition (ALD) reactor that can be integrated into synchrotron facilities for in situ synchrotron photoemission studies. The design allows for universal installation of the system onto different beam line end stations. The ALD reactor operates as a fully functional, low vacuum deposition system under the conditions of a typical ALD reactor while allowing the samples to be analyzed in an ultrahigh vacuum (UHV) chamber through a quick transfer without vacuum break. This system not only minimizes the exposure of the UHV chamber to the ALD reactants, but it also eliminates the necessity of a beam alignment step after installation. The system has been successfully installed at the synchrotron and tested in the mechanistic studies of platinum ALD following individual half reaction cycles.