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The imputation of missing values in multivariate time-series data is a basic and popular data processing technology. Recently, some studies have exploited Recurrent Neural Networks (RNNs) and Generative Adversarial Networks (GANs) to impute/fill the missing values in multivariate time-series data. However, when faced with datasets with high missing rates, the imputation error of these methods increases dramatically. To this end, we propose a neural network model based on dynamic contribution and attention, denoted as ContrAttNet. ContrAttNet consists of three novel modules: feature attention module, iLSTM (imputation Long Short-Term Memory) module, and 1D-CNN (1-Dimensional Convolutional Neural Network) module. ContrAttNet exploits temporal information and spatial feature information to predict missing values, where iLSTM attenuates the memory of LSTM according to the characteristics of the missing values, to learn the contributions of different features. Moreover, the feature attention module introduces an attention mechanism based on contributions, to calculate supervised weights. Furthermore, under the influence of these supervised weights, 1D-CNN processes the time-series data by treating them as spatial features. Experimental results show that ContrAttNet outperforms other state-of-the-art models in the missing value imputation of multivariate time-series data, with average 6% MAPE and 9% MAE on the benchmark datasets.
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OBJECTIVE: Although oxidative stress is a recognized factor of inflammation, the correlation between oxidative balance score (OBS), a biomarker indicating the balance of oxidation and antioxidant, and rheumatoid arthritis (RA), an immune system disease that tends to occur in women, remains unexplored. Hence, the aim of this study was to investigate the potential association between OBS and RA in women. METHODS: Observational surveys were performed by employing information extracted from the National Health and Nutrition Examination Survey (NHANES) for the period 2007-2018. Various statistical techniques were employed to investigate the association between OBS and RA, encompassing multivariable logistic regression analysis, subgroup analyses, smooth curve fitting, and threshold effect analysis. RESULTS: The study included 8219 female participants, including 597 patients with RA. The results showed that higher Total OBS (TOBS) significantly correlated with lower RA prevalence in the entirely modified model [odd ratio (OR) = 0.968; 95% confidence interval (CI) = 0.952 to 0.984; P = 0.0001]. Dietary OBS (DOBS) and lifestyle OBS (LOBS) also negatively correlated with RA. This association was remarkably consistent across TOBS subgroups by age, race, education level, family poverty-to-income ratio (PIR), hypertension and diabetes. Smooth curve fitting and threshold effect analysis also revealed the linear relationship between OBS and RA. CONCLUSIONS: Overall, OBS was negatively associated with RA in female. This study suggested that an antioxidant diet and lifestyle may be promising measures to prevent RA in female.
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Antioxidantes , Artrite Reumatoide , Humanos , Feminino , Antioxidantes/metabolismo , Inquéritos Nutricionais , Estudos Transversais , Artrite Reumatoide/epidemiologia , Estresse OxidativoRESUMO
BACKGROUND: Relative handgrip strength (RHGS) was positively correlated with healthy levels of cardiovascular markers and negatively correlated with metabolic disease risk. However, its association with hyperlipidemia remains unknown. The present study investigated the link between RHGS and hyperlipidemia, utilizing data from the National Health and Nutrition Examination Survey (NHANES) and further examined the hypothesis that inflammation may serve a mediating role within this relationship. METHODS: Data were extracted from 4610 participants in the NHANES database spanning 2011-2014 to explore the correlation between RHGS and hyperlipidemia using multivariate logistic regression models. Subgroup analyses were conducted to discern the correlation between RHGS and hyperlipidemia across diverse populations. Additionally, smooth curve fitting and threshold effect analysis were conducted to validate the association between RHGS and hyperlipidemia. Furthermore, the potential mediating effect of inflammation on this association was also explored. RESULTS: According to the fully adjusted model, RHGS was negatively correlated with hyperlipidemia [odds ratio (OR) = 0.575, 95% confidence interval (CI) = 0.515 to 0.643], which was consistently significant across all populations, notably among women. Smooth curve fitting and threshold effect analysis substantiated the negative association between RHGS and hyperlipidemia. Moreover, the mediating effects analysis indicated the white blood cell (WBC) count, neutrophil (Neu) count, and lymphocyte (Lym) count played roles as the mediators, with mediation ratios of 7.0%, 4.3%, and 5.0%, respectively. CONCLUSIONS: This study identified a prominent negative correlation between RHGS and hyperlipidemia. Elevated RHGS may serve as a protective factor against hyperlipidemia, potentially through mechanisms underlying the modulation of inflammatory processes.
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Força da Mão , Hiperlipidemias , Inflamação , Inquéritos Nutricionais , Humanos , Hiperlipidemias/fisiopatologia , Hiperlipidemias/sangue , Hiperlipidemias/epidemiologia , Feminino , Masculino , Inflamação/sangue , Pessoa de Meia-Idade , Adulto , Contagem de Leucócitos , Idoso , Razão de Chances , Modelos Logísticos , NeutrófilosRESUMO
Reperfusion therapy is the primary treatment strategy for acute myocardial infarction (AMI). Paradoxically, it can lead to myocardial damage, namely myocardial ischemia/reperfusion injury (MIRI). This study explored whether oroxylin A (OA) protects the myocardium after MIRI by inhibiting ferroptosis and the underlying mechanism. In vivo, we established an MIRI model to investigate the protective effect of OA. In vitro, H9C2 cells were used to explore the regulation of ferroptosis by OA through immunofluorescence staining, western blotting, assay kits, etc. Additionally, RNA sequencing analysis (RNA-seq) and network pharmacology analyses were conducted to elucidate the molecular mechanisms. Our results showed that MIRI caused cardiac structural and functional damage in rats. MIRI promoted ferroptosis, which was consistently observed in vitro. However, pretreatment with OA reversed these effects. The mitogen-activated protein kinases (MAPK) signaling pathway participated in the MIRI process, with dual-specificity phosphatase 10 (DUSP10) found to regulate it. Further confirmation was provided by knocking down DUSP10 using small interfering RNA (siRNA), demonstrating the activation of the DUSP10/MAPK-Nrf2 pathway by OA to protect H9C2 cells from ferroptosis. Our research has demonstrated the mitigating effect of OA on MIRI and the improvement of myocardial function for the first time. The inhibition of ferroptosis has been identified as one of the mechanisms through which OA exerts its myocardial protective effects. Moreover, we have first unveiled that DUSP10 serves as an upstream target involved in mediating ferroptosis, and the regulation of the DUSP10/MAPK-Nrf2 pathway by OA is crucial in inhibiting ferroptosis to protect the myocardium.
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Due to various reasons, such as limitations in data collection and interruptions in network transmission, gathered data often contain missing values. Existing state-of-the-art generative adversarial imputation methods face three main issues: limited applicability, neglect of latent categorical information that could reflect relationships among samples, and an inability to balance local and global information. We propose a novel generative adversarial model named DTAE-CGAN that incorporates detracking autoencoding and conditional labels to address these issues. This enhances the network's ability to learn inter-sample correlations and makes full use of all data information in incomplete datasets, rather than learning random noise. We conducted experiments on six real datasets of varying sizes, comparing our method with four classic imputation baselines. The results demonstrate that our proposed model consistently exhibited superior imputation accuracy.
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We propose a 3D measurement method based on 2D grating dual-channel and Littrow equal-optical path incidence to detect the 3D displacement of a 2D grating in the X-, Y-, and Z-directions. The 2D grating is combined with the Littrow incidence method and a turning element to cause the Littrow diffracted light with frequency f1 to interfere with the reference light at frequency f2, and the displacement data in the X-, Y-, and Z-directions are obtained using the separation-dual-channel phase decoupling algorithm. A corresponding test experimental platform is constructed, and linear error evaluation and step error evaluation experiments are performed to determine the displacements in the X-, Y-, and Z-directions. The results obtained show that all linearity errors are within ±60 nm in the 10 mm measurement ranges in the X-, Y-, and Z-directions, and the test resolution is within ±5 nm. The proposed method can thus realize nanoscale synchronous measurement of X-, Y-, and Z-direction 3D displacements.
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We propose a new symmetrical heterodyne grating displacement measurement method, based on 2D grating and single diffraction quadruple subdivision method. Using a dual-frequency laser with a wavelength of 632.8â nm, output power of 2.2â mW, and a 1200â l/mm 2D grating, eight diffracted light beams interfere in pairs in the X and Y directions through a turning element. The detection system's measurement accuracy was assessed experimentally. The system measurement resolution in the X and Y directions is better than 3â nm; the grating displacement measurement errors within a 10â mm range are better than ±30â nm and ±40â nm, and the repeatability error is better than ±25â nm. The method is not only applicable to nanoscale 2D displacement measurement technology but also can be used for ultra-precision positioning and ultra-precision processing, with the potential for picometer-level improvement.
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For the research and development of sensor systems, the collection and fusion of sensing data is the core. In order to make sensor data acquisition change with the change in environment, a dynamic data acquisition and fusion method based on feedback control is proposed in this paper. According to the sensing data acquisition and fusion model, the optimal acquisition of sensor data is achieved through real-time dynamic judgment of the collected data, decision-making of the next acquisition time interval, and adjustment. This model enables the sensor system to adapt to different environments. An experimental study of the proposed model was carried out on an experimental platform, and the results show that the proposed model can not only reflect the change in sensing data but also improve the transmission efficiency.
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The loss of electronic medical records has seriously affected the practical application of biomedical data. Therefore, it is a meaningful research effort to effectively fill these lost data. Currently, state-of-the-art methods focus on using Generative Adversarial Networks (GANs) to fill the missing values of electronic medical records, achieving breakthrough progress. However, when facing datasets with high missing rates, the imputation accuracy of these methods sharply deceases. This motivates us to explore the uncertainty of GANs and improve the GAN-based imputation methods. In this paper, the GRUD (Gate Recurrent Unit Decay) network and the UGAN (Uncertainty Generative Adversarial Network) are proposed and organically combined, called UGAN-GRUD. In UGAN-GRUD, it highlights using GAN to generate imputation values and then leveraging GRUD to compensate them. We have designed the UGAN and the GRUD network. The former is employed to learn the distribution pattern and uncertainty of data through the Generator and Discriminator, iteratively. The latter is exploited to compensate the former by leveraging the GRUD based on time decay factor, which can learn the specific temporal relations in electronic medical records. Through experimental research on publicly available biomedical datasets, the results show that UGAN-GRUD outperforms the current state-of-the-art methods, with average 13% RMSE (Root Mean Squared Error) and 24.5% MAPE (Mean Absolute Percentage Error) improvements.
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Since the physical meaning of the fields of the dataset is unknown, we have to use the feature interaction method to select the correlated features and exclude uncorrelated features. The current state-of-the-art methods employ various methods based on feature interaction to predict advertisement Click-Through Rate (CTR); however, the feature interaction based on potential new feature mining is rarely considered, which can provide effective assistance for feature interaction. This motivates us to investigate methods that combine potential new features and feature interactions. Thus, we propose a potential feature excitation learning network (PeNet), which is a neural network model based on feature combination and feature interaction. In PeNet, we treat the row compression and column compression of the original feature matrix as potential new features, and proposed the excitation learning mechanism that is a weighted mechanism based on residual principle. Through this excitation learning mechanism, the original embedded features and potential new features are subjected to weighted interaction based on the residual principle. Moreover, a deep neural network is exploited to iteratively learn and iteratively combine features. The excitation learning structure of PeNet neural network is well demonstrated in this paper, that is, the control flow of embedding, compression, excitation and output, which further strengthens the correlated features and weakens the uncorrelated features by compressing and expanding the features. Experimental results on multiple benchmark datasets indicate the PeNet as a general-purpose plug-in has more superior performance and better efficiency than previous state-of-the-art methods.
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Publicidade , Redes Neurais de Computação , Aprendizado de MáquinaRESUMO
Cardiovascular diseases (CVDs) are the primary drivers of the growing public health epidemic and the leading cause of premature mortality and economic burden worldwide. With decades of research, CVDs have been proven to be associated with the dysregulation of the inflammatory response, with macrophages playing imperative roles in influencing the prognosis of CVDs. Autophagy is a conserved pathway that maintains cellular functions. Emerging evidence has revealed an intrinsic connection between autophagy and macrophage functions. This review focuses on the role and underlying mechanisms of autophagy-mediated regulation of macrophage plasticity in polarization, inflammasome activation, cytokine secretion, metabolism, phagocytosis, and the number of macrophages. In addition, autophagy has been shown to connect macrophages and heart cells. It is attributed to specific substrate degradation or signalling pathway activation by autophagy-related proteins. Referring to the latest reports, applications targeting macrophage autophagy have been discussed in CVDs, such as atherosclerosis, myocardial infarction, heart failure, and myocarditis. This review describes a novel approach for future CVD therapies.
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Doenças Cardiovasculares , Humanos , Inflamação/metabolismo , Macrófagos/metabolismo , Autofagia , FagocitoseRESUMO
OBJECTIVE: This study aimed to analyze the associations between rheumatoid arthritis (RA) and all-cause mortality and cardiovascular disease (CVD)-related mortality using data from the National Health and Nutrition Examination Survey (NHANES) and examine the potential mediating role of depression in these correlations. METHODS: 19,165 participants across five NHANES cycles from 2007 to 2016 participated in this study. Multifactorial Cox regression models between RA, depression and two mortality outcomes and multifactorial regression models between RA and depression were constructed to examine their associations. The mediating role of depression has also been investigated. RESULTS: The prevalence of RA in this study was 6.57 %, the all-cause mortality of RA patients was 20.57 %, and the CVD-related mortality was 6.12 %. In the fully adjusted model, RA was associated with all-cause mortality [hazard ratio (HR) = 1.28, 95 % confidence interval (CI) = 1.12 to 1.48] and CVD-related mortality (HR = 1.33, 95 % CI = 1.03 to 1.72), without detectable interaction among subgroups (P for interaction >0.05). RA also had a positive correlation with depression. Depression score demonstrated pronounced mediating effects in the connections between RA and two types of mortality, with mediation ratios of 18.2 % and 18.9 %. LIMITATIONS: The diagnosis of RA is self-reported and may be subject to recall bias. CONCLUSIONS: RA was positively correlated with the risk of all-cause mortality and CVD-related mortality. Depression partially mediates these associations. Close attention to and active improvement of mental health in RA patients will be critical to decrease all-cause mortality and CVD-related mortality.
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Artrite Reumatoide , Doenças Cardiovasculares , Depressão , Inquéritos Nutricionais , Humanos , Artrite Reumatoide/mortalidade , Artrite Reumatoide/psicologia , Artrite Reumatoide/complicações , Masculino , Feminino , Doenças Cardiovasculares/mortalidade , Pessoa de Meia-Idade , Estudos Prospectivos , Depressão/epidemiologia , Depressão/psicologia , Adulto , Causas de Morte , Modelos de Riscos Proporcionais , Idoso , Prevalência , Estados Unidos/epidemiologia , Fatores de RiscoRESUMO
Ischemic heart disease (IHD) is a prevalent cardiovascular condition that remains the primary cause of death due to its adverse ventricular remodelling and pathological changes in end-stage heart failure. As a complex pathologic condition, it involves intricate regulatory processes at the cellular and molecular levels. The immune system and cardiovascular system are closely interconnected, with immune cells playing a crucial role in maintaining cardiac health and influencing disease progression. Consequently, alterations in the cardiac microenvironment are influenced and controlled by various immune cells, such as macrophages, neutrophils, dendritic cells, eosinophils, and T-lymphocytes, along with the cytokines they produce. Furthermore, studies have revealed that Gata6+ pericardial cavity macrophages play a key role in regulating immune cell migration and subsequent myocardial tissue repair post IHD onset. This review outlines the role of immune cells in orchestrating inflammatory responses and facilitating myocardial repair following IHD, considering both macro and micro views. It also discusses innovative immune cell-based therapeutic strategies, offering new insights for further research on the pathophysiology of ischemic heart disease and immune cell-targeted therapy for IHD.
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Despite advances in treatment, myocardial infarction remains the leading cause of heart failure and death worldwide, and the restoration of coronary blood flow can also cause heart damage. In this study, we found that corosolic acid (CA), also known as plant insulin, significantly protects the heart from ischemia-reperfusion (I/R) injury. In addition, CA can inhibit oxidative stress and improve mitochondrial structure and function in cardiomyocytes. Subsequently, our study demonstrated that CA improved the expression of the mitophagy-related proteins Prohibitin 2 (PHB2), PTEN-induced putative kinase protein-1 (PINK1), and Parkin. Meanwhile, through molecular docking, we found an excellent binding between CA and PHB2 protein. Finally, the knockdown of PHB2 eliminated the protective effect of CA on hypoxia-reoxygenation in cardiomyocytes. Taken together, our study reveals that CA increases mitophagy in cardiomyocytes via the PHB2/PINK1/Parkin signaling pathway, inhibits oxidative stress response, and maintains mitochondrial function, thereby improving cardiac function after I/R.
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Ferroptosis is a newly defined mode of cellular demise. The increasing investigation supports that ferroptosis is a crucial factor in the complex mechanisms of myocardial ischemia-reperfusion (I/R) injury. Hence, targeting ferroptosis is a novel strategy for treating myocardial injury. Although evidence suggests that trimetazidine (TMZ) is potentially efficacious against myocardial injury, the exact mechanism of this efficacy is yet to be fully elucidated. This study aimed to determine whether TMZ can act as a ferroptosis resistor and affect I/R-mediated myocardial injury. To this end, researchers have constructed in vitro and in vivo models of I/R using H9C2 cardiomyocytes, primary cardiomyocytes, and SD rats. Here, I/R mediated the onset of ferroptosis in vitro and in vivo, as reflected by excessive iron aggregation, GSH depletion, and the increase in lipid peroxidation. TMZ largely reversed this alteration and attenuated cardiomyocyte injury. Mechanistically, we found that TMZ upregulated the expression of Sirt3. Therefore, we used si-Sirt3 and 3-TYP to interfere with Sirt3 action in vitro and in vivo, respectively. Both si-Sirt3 and 3-TYP partly mitigated the inhibitory effect of TMZ on I/R-mediated ferroptosis and upregulated the expression of Nrf2 and its downstream target, GPX4-SLC7A11. These results indicate that TMZ attenuates I/R-mediated ferroptosis by activating the Sirt3-Nrf2/GPX4/SLC7A11 signaling pathway. Our study offers insights into the mechanism underlying the cardioprotective benefits of TMZ and establishes a groundwork for expanding its potential applications.
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Exosomes, as nanoscale extracellular vesicles (EVs), are secreted by all types of cells to facilitate intercellular communication in living organisms. After being taken up by neighboring or distant cells, exosomes can alter the expression levels of target genes in recipient cells and thereby affect their pathophysiological outcomes depending on payloads encapsulated therein. The functions and mechanisms of exosomes in cardiovascular diseases have attracted much attention in recent years and are thought to have cardioprotective and regenerative potential. This review summarizes the biogenesis and molecular contents of exosomes and details the roles played by exosomes released from various cells in the progression and recovery of cardiovascular disease. The review also discusses the current status of traditional exosomes in cardiovascular tissue engineering and regenerative medicine, pointing out several limitations in their application. It emphasizes that some of the existing emerging industrial or bioengineering technologies are promising to compensate for these shortcomings, and the combined application of exosomes and biomaterials provides an opportunity for mutual enhancement of their performance. The integration of exosome-based cell-free diagnostic and therapeutic options will contribute to the further development of cardiovascular regenerative medicine.
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Doenças Cardiovasculares , Exossomos , Medicina Regenerativa , Exossomos/metabolismo , Humanos , Doenças Cardiovasculares/terapia , Doenças Cardiovasculares/metabolismo , Animais , Medicina Regenerativa/métodos , Engenharia Tecidual/métodosRESUMO
The glutathione (GSH) system is considered to be one of the most powerful endogenous antioxidant systems in the cardiovascular system due to its key contribution to detoxifying xenobiotics and scavenging overreactive oxygen species (ROS). Numerous investigations have suggested that disruption of the GSH system is a critical element in the pathogenesis of myocardial injury. Meanwhile, a newly proposed type of cell death, ferroptosis, has been demonstrated to be closely related to the GSH system, which affects the process and outcome of myocardial injury. Moreover, in facing various pathological challenges, the mammalian heart, which possesses high levels of mitochondria and weak antioxidant capacity, is susceptible to oxidant production and oxidative damage. Therefore, targeted enhancement of the GSH system along with prevention of ferroptosis in the myocardium is a promising therapeutic strategy. In this review, we first systematically describe the physiological functions and anabolism of the GSH system, as well as its effects on cardiac injury. Then, we discuss the relationship between the GSH system and ferroptosis in myocardial injury. Moreover, a comprehensive summary of the activation strategies of the GSH system is presented, where we mainly identify several promising herbal monomers, which may provide valuable guidelines for the exploration of new therapeutic approaches.
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Ferroptose , Animais , Estresse Oxidativo , Glutationa/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Coração , Espécies Reativas de Oxigênio/metabolismo , MamíferosRESUMO
Cardiovascular diseases (CVDs) and metabolic disorders are major components of noncommunicable diseases, causing an enormous health and economic burden worldwide. There are common risk factors and developmental mechanisms among them, indicating the far-reaching significance in exploring the corresponding therapeutic targets. MST1/2 kinases are well-established proapoptotic effectors that also bidirectionally regulate autophagic activity. Recent studies have demonstrated that MST1/2 influence the outcome of cardiovascular and metabolic diseases by regulating immune inflammation. In addition, drug development against them is in full swing. In this review, we mainly describe the roles and mechanisms of MST1/2 in apoptosis and autophagy in cardiovascular and metabolic events as well as emphasis on the existing evidence for their involvement in immune inflammation. Moreover, we summarize the latest progress of pharmacotherapy targeting MST1/2 and propose a new mode of drug combination therapy, which may be beneficial to seek more effective strategies to prevent and treat CVDs and metabolic disorders.
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Ischemic disease is a class of diseases in which an organ is ischemic due to vascular occlusion, a major contributor to death and disability worldwide. However, when the blood flow is restored, more severe damage occurs than ischemia alone and is known as ischemic-reperfusion injury (IRI). During reperfusion, the imbalance between the production of reactive oxygen species (ROS) and buffering capacity of the antioxidant defense system results in cell damage and death. Nuclear factor E2-related factor 2 (Nrf2) significantly affects antioxidant stress damage. The function of Nrf2 in the pathological process of IRI has been widely discussed, but the impact of epigenetic modifications associated with Nrf2 remains unclear. This article provides a comprehensive overview of the role and mechanism of Nrf2-related epigenetic modifications in the IRI of various organs, including the brain, heart, liver, and kidney. In addition, we summarize agonists that may target epigenetic regulation of Nrf2, which may be beneficial in seeking more effective strategies to improve IRI.
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Fator 2 Relacionado a NF-E2 , Traumatismo por Reperfusão , Antioxidantes/metabolismo , Epigênese Genética , Humanos , Isquemia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismoRESUMO
The photoperiod regulates the seasonal reproduction of mammals by affecting the follicle development, for which the granulosa cells provide nutrition. However, the underlying mechanism remains unclear. Here, Djungarian hamsters (Phodopus sungorus) were raised under different photoperiods to study the ovarian status and explore the potential mechanism of the follicle development mediated by the FSH-Nodal/ALK7 signaling pathway. Compared with the moderate daylight (MD) group, the short daylight (SD) group exhibited a significant decrease in the ovarian weight and increase in the atretic follicle number and granulosa cell apoptosis, whereas the long daylight (LD) group showed an increase in the ovarian weight, the growing follicle number, and the antral follicle number, but a decrease in the granulosa cell apoptosis. Based on these findings, the key genes of the Nodal/ALK7 signaling pathway controlling the granulosa cell apoptosis were studied using the quantitative real-time polymerase chain reaction and western blotting. In the SD group, the follicle-stimulating hormone (FSH) concentration significantly decreased and the Nodal/ALK7/Smad signaling pathways were activated, while the phosphatidylinositol 3-kinase (PIK3)/Akt signaling pathway was inhibited. The BAX expression was significantly increased, while the Bcl-xL expression was significantly decreased, leading to an increase in the caspase-3 activity, the granulosa cell apoptosis, and ovarian degeneration. However, in the LD group, the FSH concentration significantly increased, the Nodal/ALK7/Smad signaling pathway was inhibited, and the PIK3/Akt signaling pathway was activated. Taken together, our results indicate that the photoperiod can regulate the apoptosis of the granulosa cells by regulating the concentration of FSH, activating or inhibiting the Nodal/ALK7 signaling pathway, thereby affecting the ovarian function. Our research provides an important theoretical basis for understanding the photoperiod-regulated mechanisms of the mammalian seasonal reproduction.