Duration Of Contraction Research Articles

Public pension contract minimalism

AbstractThe national pension debt and COVID crises have collided. Post‐pandemic economic decline has escalated existing financial strains on state and local pension plans, impacting workers and the public welfare. With unfunded obligations exceeding one trillion dollars, many of these plans are in jeopardy. But the movement to reform government pension contracts has yet to adopt an anchoring idea, leaving judicial decisions in disarray and policymakers without guidance about how to shore up troubled retirement systems. The crux of the problem is the many meanings of contract under state and US Contract Clauses that prevent pension reform. This Essay endorses a promising path forward—contract minimalism. “Contract minimalism” concentrates on the duration of government pension contracts. It posits that public and private employment law should be treated the same. Like its private law counterpart, public sector employment at‐will ought to consist of a daily contract interval. A contract‐a‐day concept entitles employers to change the plan prospectively, with employees receiving a proportionate share of benefits for work performed. Just as several agreements safeguard salaries for labor, they should also mirror the protection afforded to deferred benefits like pensions. Contract minimalism additionally puts public and private sector employers on the same legal footing as to the authority to change pension plan terms. Thus, it aligns public pension benefits with overlapping fields of law, placing them on a firm conceptual foundation. The minimalist approach also has the advantage over approaches that are insufficiently attentive to scarce government resources or employee old‐age security. By protecting pension benefits early and incrementally, it advances a middle path with fairer, more coherent results. In the present post‐pandemic era of hard choices, minimalism provides an equilibrium between the over‐ and under‐protection of pension benefits.

Static and dynamic pupillary features in graves disease without orbitopathy.

Pupillary contraction and dilatation are organized by the autonomic nervous system, which can also be affected by Graves' disease (GD). In this study, it was aimed to investigate the static and dynamic pupillary responses of Graves' patients in the hyperthyroid and euthyroid periods and to compare these results with the values obtained from healthy controls. 48 eyes of 24 newly diagnosed Graves' patients with clinical activity score ≤ 2 and 46 eyes of 23 age- and sex-matched healthy controls were included in the study. Patients with GD were evaluated separately in the hyperthyroid phase and after euthyroidism was achieved. After a detailed ophthalmological examination, patients undergone automatic quantitative testing to obtain static (scotopic, mesopic, low photopic, and high photopeak pupil diameters) and dynamic (pupillary contraction amplitude, latency, velocity and duration, and pupil dilation latency, velocity and duration) pupil measurements. A statistically significant difference was found between the control [4.7mm (3.7-6.9)] and hyperthyroid [5.1mm (3.6-7.8)] groups for mesopic pupil diameter (p = 0.003). Dynamic pupillometry measurements showed that hyperthyroid and euthyroid groups had greater pupil dilation delay and lower pupil dilation rate compared to the control group (p < 0.05 for all). Even in the absence of orbitopathy, patients with GD have autonomic dysregulation of pupillary functions. These changes, which prevail in the hyperthyroid phase, do not reverse when the TSH receptor antibody titer drops and the patient becomes euthyroid. Future studies are needed to elucidate the mechanism of these pupillary changes in GD.

Long-term observations of a sponge in situ reveal a rich repertoire of contractile behaviors, including winter dormancy

Sponges are remarkably active animals with a range of behaviors that are broadly termed sneezes. Little is known about what triggers sneezes or how sneezes propagate in an animal that lacks either muscular or nervous systems. We explored the triggers of sponge behavior in situ in the demosponge Suberites concinnus. The placement of this tennis ball-sized sponge at the focal point of a camera array on an instrument platform in Barkley Sound, BC, Canada, provided a unique opportunity for our investigation. The observatory has a suite of environmental sensors measuring parameters such as photosynthetically active radiation (PAR), oxygen, turbidity, salinity, pressure, current speed, and temperature. An array of 8 cameras designed for 3D imaging was used to capture hourly images. Our findings revealed both long-term (annual) and short-term (daily) behaviors in S. concinnus. The sponge contracted for 2 mo each winter. In February, it gradually expanded and became very active with short-term full-body contractions each lasting 11 h through the summer. A meta-analysis of contraction behaviors in other species of sponge showed that contraction duration is a factor of sponge size and that all sponges contract faster than they expand. Invertebrates and fish were frequently in contact with the sponge, but no single interaction was found to correlate with patterns of sponge behavior. However, significant correlations between sponge behaviors and chlorophyll and turbidity were found using generalized additive mixed models. Our study underscores the dynamic nature of these sessile filter feeders and their responses to their environment.

Novel mitochondria-targeted therapy AP39 limits mitochondrial dysregulation and diastolic dysfunction in 2D &amp; 3D human models of diabetic cardiomyopathy

Abstract Introduction Mitochondrial dysregulation has been implicated in many complications of diabetes. Mitochondrial-targeted therapies AP39 and SS31 are renoprotective, but their cardioprotective potential in diabetes has not been fully resolved. Purpose We investigated AP39 and SS31 in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-hCM) and endothelial cells (iPSC-hEC) independently in 2D culture, as well as collectively in a 3D cardiac organoid (iPSC-hCO) model also comprising fibroblasts (iPSC-hFB), under type 2 diabetes (T2D)-like conditions. Methods Cells (iPSC-hCM, iPSC-hEC, iPSC-hFB; foreskin-2 cell line) were exposed to either 5.55mM glucose (control) or T2D conditions (20mM glucose plus fatty acids, endothelin-1 and cortisol) ± AP39 (50nM) or SS31 (1µM) for 48h. Cardiac organoids were subjected to 5.55mM glucose (control) or T2D for 4 days, with AP39 (50nM) or SS31 (1µM) added on day 2. Data are expressed as mean±SEM (fold) with n=4-6 from 2-3 independent experiments. One-way ANOVA with Dunnett`s post hoc analysis was performed with P&amp;lt;0.05 considered significant. Results 2D human cells: After 48h, T2D increased mitochondrial superoxide in iPSC-hCM (2.4±0.1 fold vs control) and iPSC-hEC (3.2±0.29 fold vs control), both P&amp;lt;0.05 (measured by MitoSOX). This was blunted by both AP39 (to 1.1±0.17) and SS31 (to 1.5±0.17) in T2D iPSC-hCM (P&amp;lt;0.05), with similar impact in iPSC-hEC, to 2.9±0.26 and 1.3±0.16 fold, both P&amp;lt;0.05. T2D increased cell death in both iPSC-hCM (1.6±0.09 fold vs control) and iPSC-hEC (1.6±0.12 fold, both P&amp;lt;0.05 measured by propidium iodide staining. Interestingly, AP39 selectively blunted cell death in T2D iPSC-hCM (to 1.1±0.06, P&amp;lt;0.05), mimicked by SS31 in T2D iPSC-hEC only (to 1.0±0.10, P&amp;lt;0.05). Further, T2D-induced mitochondrial hyperpolarisation in iPSC-hCM (1.5±0.09 fold vs control, assessed using TMRM), was only protected by AP39 (1.2±0.06 fold, P&amp;lt;0.05), but not SS31. 3D human cardiac organoids: After 4 days, T2D increased total contraction duration (1.6±0.10 fold control), time to peak (1.7±0.11) and relaxation duration (1.5±0.13, indicative of diastolic dysfunction), assessed by Olympus IX71 with a DP72 camera. All 3 contractile parameters were attenuated with AP39 (to 1.5±0.06, 1.3±0.09 and 1.0±0.04 fold, respectively) or SS31 (to 1.1±0.05, 1.2±0.15 and 1.2±0.12 fold, respectively), all P&amp;lt;0.05. T2D increased mitochondrial superoxide (2.7±0.16 fold control), blunted by AP39 (to 1.8±0.16) and SS31 (to 1.9±0.17), both P&amp;lt;0.05. Cellular injury measured by LDH was evident in T2D iPSC-hCO (2.1±0.23 fold control) was limited by AP39 (to 1.2±0.09) and SS31 (to 1.1±0.07), both P&amp;lt;0.05. Conclusion Our results highlight the cardioprotective potential of AP39 and SS31 to limit mitochondrial dysregulation, cell death and contractile dysfunction in human in vitro models of T2D. These findings may facilitate their clinical progression as therapeutic options for diabetic cardiomyopathy.

Phosphoproteomics of PLN R14del heart tissue reveals major myocyte degenerate phenotype, and is attenuated by PLN antisense treatment in vitro

Abstract Background/Purpose: Phospholamban (PLN) p.Arg14del (R14del, R14Δ/+) is a pathogenic variant that can cause cardiomyopathy, characterized by PLN protein aggregation, ultimately leading to heart failure (HF). The exact pathophysiology is unknown, we aim to uncover R14Δ/+ disease mechanisms and study potential treatment using PLN antisense oligonucleotides (PLN-ASOs). Methods Phosphoproteomics was performed on human heart tissue from end-stage R14Δ/+ patients (N=6) versus other etiologies of HF (N=10) as a control. CRISPR-Cas9 engineered R14Δ/+ and isogenic control (WT) induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were extensively characterized, including the phosphoproteome, calcium transients (FLUO 4-AM), mitochondrial respiration (Seahorse Mito Stress Test) and contractility in dynamic engineered heart tissues (dyn-EHTs) before and after PLN-ASO treatment, and the results were validated in R14Δ/+ iPSC-CMs derived from R14Δ/+ patients. Results Phosphoproteomics of heart tissue from R14Δ/+ vs. other etiologies of HF identified 138 differentially expressed proteins (DEPs) and 317 differentially expressed phosphoproteins (DEPPs), therewith establishing a disease-specific signature. Phosphoproteomics of WT vs. R14Δ/+ iPSC-CMs identified 451 DEPs and 1046 DEPPs. Gene ontology analysis of end-stage R14Δ/+ heart tissue and iPSC-CMs revealed a large overlap. Here, R14Δ/+ showed to have great impact on contraction (e.g. SYNPO2L, MYH10, TTN) and calcium (e.g. AHNAK, HRC, RYR2). In line with this, functional characterization revealed that R14Δ/+ iPSC-CMs have an increased Ca2+ systolic velocity and accelerated calcium transient (decreased T50 and T90), that associated with altered calcium-related DEPPs (e.g. RYR2). In dyn-EHTs, R14Δ/+ dyn-EHTs have a decreased contraction duration, time-to-peak and ability to pace, associated with altered contractility-related DEPPs (e.g. SYNPO2L, MYH7, TTN). PLN-ASOs dose-dependently altered PLN mRNA expression and protein levels in iPSC-CMs, and 62 DEPs and 372 DEPPs were identified. PLN-ASOs increased Ca2+ diastolic velocity, which associated with altered calcium-related DEPPs (e.g. PLN, AHNAK, HRC). PLN-ASOs increased the ability of dyn-EHTs to pace and therewith improved contractility, which associated with altered contractility-related DEPPs (e.g. SYNPO2L, MYH7, TTN). PLN-ASOs dose-dependently increased basal respiration and ATP production, which associated with altered mitophagy-related DEPs (GABARAPL2 and MAP1LC3). These functional characteristics were validated in R14Δ/+ patient iPSC-CMs. Discussion: R14Δ/+ cardiomyocytes have a degenerative phenotype characterized by altered calcium transients and reduced contractility and PLN-ASOs attenuate these characteristics and improve metabolism.

Gastrocnemius Neuromuscular Activation During Standing Explosive Acceleration

The gastrocnemius muscle plays a crucial role in transmitting and generating energy during standing explosive accelerations, and as a consequence, is a muscle with high injury prevalence, especially the medial gastrocnemius (MG). This study aimed to compare the neuromuscular activation of the lateral gastrocnemius (LG) and MG during one of the most common standing explosive accelerations performed in team sports—the false start that occurs in jumps where the leg steps back before moving forward. Forty-two physically active participants (34 males: age = 24 ± 5 years, body mass = 73 ± 10.4 kg; and 8 females: age = 26 ± 5 years, body mass = 57.1 ± 6.8 kg) underwent electromyography analysis of the MG and LG in the four first foot contacts of standing explosive acceleration. The results showed that the third contact differed significantly from others (LG vs. MG: 76.48 ± 3.10 vs. 66.91 ± 2.25, p = 0.01, ES = 0.5), with the LG exhibiting earlier activation and higher peak sEMG activity compared to the MG (LG vs. MG: 0.12 ± 0.01 vs. 0.13 ± 0.01, p = 0.02, ES = 0.4). Additionally, the MG displayed longer duration contractions in all the foot contacts except the third foot contact. In conclusion, the MG showed an earlier activation timing and a longer duration of contraction than the LG in the first foot contact. Additionally, the third foot contact showed a different pattern of neuromuscular activation between the MG and LG compared to the rest of the foot contacts.

Changes in hamstrings’ active stiffness during fatigue tasks are modulated by contraction duration rather than intensity

Despite the increase in research of hamstring stiffness through the use of ultrasound-based shear wave elastography, the active stiffness of biceps femoris long head (BFlh) and semitendinosus (ST) muscles under fatigue conditions at various contraction intensities has not been sufficiently explored. This study aimed to compare the effects of knee flexor’s isometric contraction until exhaustion performed at 20% vs. 40% of maximal voluntary isometric contraction (MVIC), on the active stiffness responses of BFlh and ST. Eighteen recreationally active males performed two experimental sessions. The knee flexors’ MVIC was assessed before the fatiguing task, which involved a submaximal isometric contraction until failure at 20% or 40% of MVIC. Active muscle stiffness of the BFlh and ST was assessed using shear wave elastography. BFlh active stiffness remained relatively unaltered at 20% of MVIC, while ST active stiffness decreased from ≅ 91% contraction time (55.79 to 44.52 kPa; p < 0.001). No intramuscular stiffness changes were noted in BFlh (36.02 to 41.36 kPa; p > 0.05) or ST (63.62 to 53.54 kPa; p > 0.05) at 40% of MVIC session. Intermuscular active stiffness at 20% of MVIC differed until 64% contraction time (p < 0.05) whereas, at 40% of MVIC, differences were observed until 33% contraction time (p < 0.05). BFlh/ST ratios were not different between intensities (20%=0.75 ± 0.24 ratio vs. 40%=0.72 ± 0.32 ratio; p > 0.05), but a steeper increase in BFlh/ST ratio was found for 20% (0.004 ± 0.003 ratio/%) compared to 40% (0.001 ± 0.003 ratio/%) of MVIC (p = 0.003). These results suggest that contraction duration could play a major role in inducing changes in hamstrings’ mechanical properties during fatigue tasks compared to contraction intensity.

Abnormal Uterine Action

The uterus has three distinct layers the endometrium, myometrium, and perimetrium each playing a crucial role in the labour process. The transition from the latent to the active phase of labour is marked by an increase in the intensity and duration of contractions, with shorter intervals between them. Abnormal uterine actions can significantly contribute to dystocia, or difficult labor.T here is two main types of abnormal uterine activity that can lead to complications:  Hypotonic Uterine Activity: This occurs when the resting tone of the uterine muscle is low, resulting in weak or infrequent contractions. This can delay labour progress and may necessitate interventions.  Hypertonic Uterine Activity: In this case, the uterine muscle tone is elevated, leading to frequent but ineffective contractions. This can result in prolonged labour and increased maternal discomfort. Both conditions can confuse the progression of labour and may require careful management to ensure a safe delivery. Effective monitoring and interventions can help address these issues and improve labour outcomes.

Analyzing Business Cycles in Azerbaijan: Application of Various Filters and Spectral Analysis

This study investigates the cyclical behavior of Azerbaijan's economy and its non-oil-gas sector through the application of various filtering techniques, including the Hodrick-Prescott, Baxter-King, and Christiano-Fitzgerald filters. Utilizing quarterly GDP data from Q1 2001 to Q4 2023, we analyze the volatility, cycle duration, and significant periods of economic growth and contractions. Our analysis reveals that the Hodrick-Prescott filter shows more pronounced and volatile cyclical components, while the Baxter-King and Christiano-Fitzgerald filters provide smoother and more moderated views. Spectral analysis, employing periodograms smoothed with Bartlett, Hamming, Hann, and Parzen kernel windows, identifies cycle durations ranging from 4.1 to 19.4 quarters for total GDP and 4.3 to 19.4 quarters for non-oil-gas GDP. We find that Azerbaijan's economy exhibits higher volatility compared to advanced economies, likely due to its dependence on oil exports and susceptibility to external shocks. Key periods such as the 2008 financial crisis and the COVID-19 pandemic significantly impacted economic performance, with notable declines identified across all filtering methods. The HP filter indicates a sharp and more prolonged downturn during these crises, whereas the BK and CF filters capture less prolonged and less severe impacts. This research provides a comprehensive understanding of Azerbaijan's business cycles, highlighting the importance of robust methodologies in economic analysis. Our findings contribute to the limited literature on Azerbaijan’s economy and offer valuable insights for policymakers aiming to enhance economic stability and growth.

Association Between Temporary Employment and Current Smoking and Change in Smoking Behaviors: A Prospective Cohort Study From South Korea (2009-2018).

Previous studies have suggested that employment insecurity is associated with adverse health outcomes. We explored the association between temporary employment and smoking behaviors. We analyzed 11,795 workers (51,867 observations) from the Korea Health Panel Study (2009-2018). Employment types were categorized as regular, fixed-term, or daily, based on the duration of labor contract. The outcomes were current smoking status and changes in smoking behavior (initiation or cessation) in the following year. Generalized estimating equations were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). The proportions of fixed-term and daily workers were 41.2% and 16.4% for women and 23.6% and 12.4% for men, respectively. Temporary employment was associated with increased odds of current smoking, while also demonstrating prospective associations with changes in smoking behaviors. For instance, in prospective analyses, male workers with fixed-term and daily employments were associated with a decreased likelihood of smoking cessation (OR 0.77; 95% CI, 0.65-0.91 for fixed-term employment and OR 0.66; 95% CI, 0.52-0.83 for daily employment) in the following year compared to those with regular employment. Moreover, those experiencing consecutive temporary employment was most inversely associated with smoking cessation in both men (OR 0.56; 95% CI, 0.44-0.71) and women (OR 0.37; 95% CI, 0.16-0.85) compared to those experiencing consecutive regular employment. However, no clear association between temporary employment and smoking initiation was observed in both men and women. Temporary employment is directly associated with current smoking and inversely associated with smoking cessation. Policies are needed to improve job insecurity among temporary employees.

Investigation of the effects of tadalafil on the myocardium via electrical and isometric contractions and cardiac markers in Wistar rats

Purpose: Tadalafil, a long-acting phosphodiesterase-5 (PDE-5) inhibitor, is commonly used in the treatment of erectile dysfunction. This study investigates the contribution of tadalafil in cardiac function by measuring isometric and electrical contractions of myocardium in rats. Materials and Methods: Thirty rats were divided into five groups. Basal electrical contractions were recorded via electrocardiogram (ECG) for intervals PR (ms), QRS (ms), QT (ms), Tp (ms), Te (ms), pathological Q and heart beats/min. Then group 1 received saline for 7 days (control); group 2 received tadalafil 1 mg/kg; group 3 received tadalafil 10 mg/kg; group 4 received tadalafil 1 mg/kg for 7 days; group 5 received tadalafil 10 mg/kg for 7 days. After treatments, electrical contractions were re-performed to analyze the differences in ECG. For isometric contractions, hearts were connected to isometric power transducer to determine myocardial contractile forces (g), durations (ms) and frequencies (Hz). Serum samples were collected for cardiac creatine kinase (CK-MB) and cardiac troponin I via ELISA. Results: We found a significant decrease in CK-MB in Group 2 (395.56±124.38 pg/ml) and 3 (377.81±79.61 pg/ml), compared to Group 1 (575.32±83.54 pg/ml). The differences in cardiac contractile forces, contraction durations or frequencies were not statistically significant. Conclusion: Tadalafil did not exert obvious distruption on myocardial electrical or isometrical contractions. It is noteworthy that tadalafil 1 and 10 mg/kg reduced serum CK-MB. Shortening in QT and decrease in heart rate may have important implications on myocardial functions.

Is cardiac function associated with the clinical course of disease in patients with gout? A prospective study.

To analyze the function of the left heart in patients with different courses of gout, the independent influencing factors for left heart functional changes, and interactions between left atrial and left ventricular functions. Patients with gout (n=171) were selected; 87 patients with a disease course <10 years were included in Group I, and 84 patients with a disease course ≥10 years were included in Group II. Ninety-four healthy volunteers comprised the control group. The intergroup differences in cardiac strain parameters were statistically significant (p<.05). Moreover, the differences gradually declined with disease progression. Multivariate logistic regression analysis showed that uric acid was an independent predictor of decreased left ventricular global longitudinal strain (LVGLS). Moreover, LVGLS had a positive effect on the left atrial systolic rate (LASr) and the left atrial systolic contraction time (LASct) but no interaction with the left atrial systolic contraction duration (LAScd). The course of the disease significantly affected the function of the left heart in gout patients, and uric acid was observed to be an independent predictor of decreased LVGLS in gout patients.

An Empirical Estimation of NCAA Head Football Coaches Contract Duration

Abstract While previous research on head coach dismissals finds that team performance and managerial characteristics impact employment survival, these studies ignore the impact of contract modifications. Using an accelerated failure time survival model with hand-collected college head football coach contract data, I find that race/ethnicity affects the hazard rate of contract modifications but not the hazard rate of a head coach’s dismissal. Additionally, analysis of employment duration ignoring contract modifications may result in erroneous conclusions with respect to the effect that race/ethnicity has on a head coach’s dismissal.

Factors Influencing the Perceived Economic Benefits of Innovative Agri-Environmental Contracts

Continued innovation in contract design may enhance the delivery of agri-environmental climate public goods (AECPG), but barriers to adoption arise in terms of how farmers perceive the economic benefits. Therefore, this paper examines survey data from Ireland and the Netherlands to analyse whether land managers agree that results-based, collective action, value chain and land tenure contracts for the delivery of AECPG are understandable, applicable to their farm and economically beneficial. Using Probit models, we also identify groups of land managers who perceive the different contract types as being economically beneficial, and these findings can inform policymakers of farmer groups who need adequate consideration during the design of agri-environmental contracts. For example, greater incentives could encourage older farmers to enrol in results-based contracts in Ireland and value chain contracts in the Netherlands. We also find a link between contract duration and the perceived economic benefits of collective action contracts in both countries, with land managers in Ireland desiring a longer duration. We highlight that policymakers and land managers in Ireland could apply lessons from the design of agri-environmental contracts in the Netherlands, where they are more common and varied. Greater knowledge exchange between users and non-users of such contracts would also help bridge the gap between theory and practice in both countries.

Bus fleet decarbonization under macroeconomic and technological uncertainties: A real options approach to support decision-making

Fleet owners deal with various and critical uncertainties while planning bus fleet replacement, encompassing macroeconomic and technological factors, such as fuel and electricity prices, energy consumption, purchasing costs of electric batteries and powertrains, and bus salvage value upon resale. This paper proposes a Real Option-based framework to evaluate investment choices in different bus technologies over time (diesel, hybrid electric, compressed natural gas, and full-electric), where the proposed options usually involve replacing existing diesel fleets with alternatively powered buses. In particular, we provide a multi-option least squares Monte Carlo simulation to help fleet owners in making cost-effective investment decisions, resulting in potential cost savings of up to 10% of the annual total cost of ownership. By applying the proposed approach to different bus route types (inner-city, urban, suburban, commuter), the results show how the optimal investment choices for fleet replacement change over time. Initially, diesel buses or, at most, compressed natural gas buses are more cost-effective compared to electric technology. However, as electric technology becomes increasingly competitive, internal combustion buses are phased out. Inner-city and urban routes are better suited for the electric transition, whereas the transition may progress more slowly on other route types.Finally, we show that, under technological and macroeconomic uncertainties, the duration of contracts can strongly affect the investment decisions, in absence of specific guarantees on the new fleet.

Seasonality patterns in LNG shipping spot and time charter freight rates

The aim of this paper is to investigate the existence and the nature of seasonality in LNG freight rates of different duration contract, over different market conditions (peak and troughs) for the period from December 2010 to June 2023. We employ the HEGY method and seasonal dummy variables to test for stochastic and deterministic seasonality, respectively. Then we use Markov Switching models to test for asymmetries in seasonal fluctuations across different market conditions. We reject the existence of stochastic seasonality for all freight series while results on deterministic seasonality indicate increases in rates in June, October, and November. We also found that seasonal patterns vary across market conditions, revealing that seasonal rate movements are more pronounced when the market is in downturn. Moreover, we found that the seasonal movements present similar patterns across different trading routes. The results have implications for stakeholders across the LNG value chain.

Abstract We095: Using Human Cardiac Organoids to Elucidate the Cardioprotective Potential of Mitochondrial-Targeted Therapies in a Preclinical Model of Diabetic Cardiomyopathy

Introduction: Mitochondrial dysregulation is implicated in many complications of type 2 diabetes (T2D). Mitochondrial-targeted therapies SkQ1, AP39 and SS31 limit renal T2D complications. We sought to obtain the first evidence of the cardioprotective potential of SkQ1, AP39 and SS31 in T2D, using a human induced pluripotent stem cell (iPSC)-derived 3D multicellular cardiac organoid model of diabetic cardiomyopathy. Methods: Human cardiac organoids (foreskin-2 cell-line) generated from human iPSC-derived cardiomyocytes, cardiac fibroblasts and endothelial cells were subjected to 5.55mM glucose (control) or T2D-like conditions (20mM glucose, fatty acids, endothelin-1 and cortisol) for 4 days with supplementation of either SkQ1 (50nM), AP39 (50nM) or SS31 (1µM) on day 2. On day 4, endpoint parameters were evaluated in cardiac organoids, including contractile function (captured via Olympus IX71), mitochondrial superoxide levels (MitoSOX assay), mitochondrial membrane potential (TMRM assay), and cellular injury (lactate dehydrogenase; LDH). Data are expressed as mean±SEM (fold control) with n =4-6 from 2-3 independent experiments. One-way ANOVA with Dunnett`s post hoc analysis was performed with P&lt;0.05 considered significant. Results: After 4 days, T2D-conditions increased total contraction duration (1.55±0.10-fold control), time-to-peak (1.71±0.11-fold control, indicative of systolic dysfunction) and relaxation duration (1.46±0.13-fold control, indicative of diastolic dysfunction) in cardiac organoids. All 3 functional parameters were attenuated by AP39 (to 1.15±0.06, 1.32±0.09 and 1.04±0.04-fold control, respectively), or by SS31 (to 1.10±0.05, 1.12±0.15 and 1.09±0.12-fold control, respectively; all P&lt;0.05), but not SkQ1. T2D-conditions increased mitochondrial superoxide (2.68±0.16-fold control), which was blunted by all 3 interventions, SkQ1 to 2.00±0.29, AP39 to 1.82±0.16 and SS31 to 1.89±0.17 (all P&lt;0.05). Cellular injury was evident in T2D cardiac organoids (2.07±0.23-fold control), which was again limited by SkQ1 (to 1.06±0.11), AP39 (to 1.18±0.09) or SS31 (to 1.08±0.07), all P&lt;0.05. Conclusion: These findings in human cardiac organoids highlight the cardioprotective potential of mitochondrial-targeted therapies to limit T2D-induced cardiac dysfunction, mitochondrial dysregulation and cellular injury, potentially facilitating clinical progression of candidates such as AP39 and SS31 as new therapies for patients with diabetic cardiomyopathy.

Impact of hypothyroidism on bitch fertility and neonatal mortality and morbidity - a review of the literature

There are a few studies and case reports that postulate a connection between hypothyroidism and reproductive disorders in bitches and an increased neonatal mortality and morbidity in puppies. Other studies, however, cannot demonstrate a connection between hypothyroidism and reproductive disorders in bitches. In this work, the relevant literature is to be checked for its evidence. The connection between hypothyroidism and reproductive disorders in the bitch, puppy mortality and neonatal morbidity to hypothyroidism will be analyzed based on a literature review. For this purpose, the available German and international "English-language" literature from 1986 to January 2023 was analyzed. It turns out that only a small amount of literature contains high levels of scientific evidence, as it mostly consists of case reports and expert opinions. In some case reports a connection between estrous abnormalities, galactorrhoea and infertility and the presence of hypothyroidism could be seen, but in experimental studies and according to the opinion of other authors the connection between hypothyroidism and reproductive disorders does not exist. A negative influence of hypothyroidism on the birth process could not be clearly proven. In an experimental study, although the duration and intensity of uterine contractions were longer and weaker in animals with hypothyroidism, the interval between pup births was not affected. Only in the area of neonatal mortality and morbidity a connection with the hypothyroidism of the dam could be demonstrated. The puppies of affected bitches showed a lower birth weight and were weaker than puppies of euthyroid bitches. The importance of hypothyroidism for fertility in the bitch has not yet been documented in the literature, but this endocrinopathy seems to have an influence on neonatal vitality.

Precarious work on the rise

Precarious employment (PE) is non-standard employment with uncertain and unstable contract duration, low wages, and limited labour protections and rights. Research has associated PE with workers’ poor mental health and well-being; however, this association has been studied primarily using quantitative methods. This qualitative study seeks to examine the mechanisms between PE and mental health in the context of the COVID-19 pandemic in Ontario, Canada. Specifically, it aims to address: (Benach J, Muntaner C. Precarious employment and health: developing a research agenda. J Epidemiol Community Health. 2007;61(4):276.) How do PE and working conditions impact the mental well-being of workers and members of their close families or households?; and (Kreshpaj B, Orellana C, Burström B, Davis L, Hemmingsson T, Johansson G, et al. What is precarious employment? A systematic review of definitions and operationalizations from quantitative and qualitative studies. Scand J Work Environ Health. 2020;46(3):235–47.) How has the COVID-19 pandemic shaped these relationships? Semi-structured interviews were conducted with a sample of 40 individuals aged 25–55 engaged in PE during the first wave of the COVID-19 pandemic or whose employment was terminated due to the pandemic. Results showed that PE amplified mental health symptoms and illnesses for workers and their families. These experiences were described as chronic, where impacts were exerted on precariously employed workers through systemic discrimination and racism, colonialism, workplace hierarchies, and gendered ideologies. PE negatively impacted mental health through emotional stress about employment and income instability, insecurity, and loss; added pressure for households where both partners are engaged in PE; impacted ability to maintain or improve overall health and well-being; and barriers to social connectedness. Overall, this study characterizes multiple dimensions of PE and the consequences they have on the mental health of workers and their families.

Maternal Body Mass Index, Myometrium Contractility and Uterotonic Receptor Expression in Pregnancy

Pregnant individuals with obesity (body mass index, BMI ≥ 30 kg/m2) are more likely to experience prolonged labor and have double the risk of cesarean compared with individuals with normal weight (BMI < 25 kg/m2). The aim of this study was to evaluate whether obesity in pregnancy is associated with reduced spontaneous and oxytocin-stimulated myometrial contractile activity using ex vivo preparations. We also assessed the relationship between maternal BMI and the expression of oxytocin (OXTR) and prostaglandin (FP) receptors in the myometrial tissue. We enrolled 73 individuals with a singleton gestation undergoing scheduled cesarean delivery at term in a prospective cohort study. This included 49 individuals with a pre-pregnancy BMI ≥ 30 kg/m2 and 24 with BMI < 25.0 kg/m2. After delivery, a small strip of myometrium was excised from the upper edge of the hysterotomy. Baseline spontaneous and oxytocin stimulated myometrial contractile activity was measured using ex vivo preparations. Additionally, expression of oxytocin and prostaglandin receptors from myometrial samples were compared using qRT-PCR and western blot techniques. Spontaneous and oxytocin-stimulated contraction frequency, duration, and force were not significantly different in myometrial samples from the obese and normal-weight individuals. Myometrial OXTR gene and protein expression was also similar in the two groups. While FP gene expression was lower in the myometrial samples from the obese group, protein expression did not differ. These data help to address an important knowledge gap related to the biological mechanisms underlying the association between maternal obesity and dysfunctional labor.