Hasil untuk "Physiology"

Thiennu H. Vu, Zena Werb

The matrix metalloproteinase (MMP) family of extracellular proteinases regulates development and physiologic events. Genetic analyses using transgenic mice that have gain and loss of function of MMPs or of their endogenous inhibitors, the TIMPs, and pharmacogenetic studies with chemical inhibitors have begun to elucidate the roles that they play. It is now clear that these enzymes are important for cell migration, invasion, proliferation, and apoptosis. They regulate many developmental processes, including branching morphogenesis, angiogenesis, wound healing, and extracellular matrix degradation. The matrix metalloproteinases (MMPs) are a family of extracellular matrix (ECM)-degrading enzymes that shares common functional domains and activation mechanisms (Sternlicht et al. 2000). These are Caand Zn-dependent endopeptidases that are active at neutral pH. They are synthesized as secreted or transmembrane proenzymes and processed to an active form by the removal of an amino-terminal propeptide. The propeptide is thought to keep the enzyme in latent form by the interaction of a cysteine residue in this peptide with the zinc moiety in the enzyme active site. Disruption of this interaction triggers the cysteine switch mechanism and results in activation of the enzyme. MMPs can be activated by chaotropic agents or by cleavage of the propeptide by members of the MMP family or by other proteases. They are inhibited by a family of tissue inhibitors of metalloproteinases, the TIMPs. As a family, MMPs degrade most components of the ECM. There are now >20 members of the MMP family. There are several distinct subgroups based on preferential substrates or similar structural domains: Collagenases that are active against fibrillar collagen, gelatinases that have high activity against denatured collagens, stromelysins that degrade noncollagen components of the ECM, membranetype MMPs (MT-MMPs) that are transmembrane molecules, and other less characterized members (Fig. 1; Table 1). Because MMPs can degrade ECM molecules, their main function has been presumed to be remodeling of the ECM. They are thought to play important roles during embryonic development, as ECM remodeling is a critical component of tissue growth and morphogenesis. In fact, the discovery of MMPs was based on the observation that during amphibian metamorphosis, a collagenolytic activity has to be present to digest the collagens in tadpole tails (Gross and Lapiere 1962). The activity of MMPs during embryonic development may extend to more than the removal of unwanted ECM molecules, however. It is now clear that MMPs not only remodel the ECM, but also influence many cellular functions. MMP activity may be required during development and normal physiology in several ways: (1) to degrade ECM molecules and allow cell migration; (2) to alter the ECM micro-environment and result in alteration in cellular behavior; (3) to modulate the activity of biologically active molecules by direct cleavage, release from bound stores, or the modulating of the activity of their inhibitors (Fig 2). During tissue morphogenesis any number of these activities may contribute to the role that each MMP plays in a developmental process. Although insights into the activities of MMPs have emerged from in vitro studies, genetic and pharmacogenetic studies now indicate that MMPs do have important influence on many cellular functions. Two general approaches have been employed to identify the roles of MMPs during mammalian development: (1) general or tissue-specific expression of a transgene encoding an MMP or an MMP inhibitor (TIMP), and (2) generating null mutations in an MMP gene or TIMP gene using targeted mutagenesis. These approaches have given insights into the roles of several MMPs in development and normal physiology. The range of developmental effects seen in these function perturbation studies suggests that these enzymes do indeed participate as essential effectors of developmental processes in vivo.

P. J. Davies

A. Dornhorst

W. Larcher

William G. Hopkins

K. Schmidt‐Nielsen

M. Mcdonald

Ritchie E. Brown, D. Stevens, H. Haas

T. Klein, R. Bischoff

Matrix metalloproteases (MMPs) comprise a family of enzymes that cleave protein substrates based on a conserved mechanism involving activation of an active site-bound water molecule by a Zn2+ ion. Although the catalytic domain of MMPs is structurally highly similar, there are many differences with respect to substrate specificity, cellular and tissue localization, membrane binding and regulation that make this a very versatile family of enzymes with a multitude of physiological functions, many of which are still not fully understood. Essentially, all members of the MMP family have been linked to disease development, notably to cancer metastasis, chronic inflammation and the ensuing tissue damage as well as to neurological disorders. This has stimulated a flurry of studies into MMP inhibitors as therapeutic agents, as well as into measuring MMP levels as diagnostic or prognostic markers. As with most protein families, deciphering the function(s) of MMPs is difficult, as they can modify many proteins. Which of these reactions are physiologically or pathophysiologically relevant is often not clear, although studies on knockout animals, human genetic and epigenetic, as well as biochemical studies using natural or synthetic inhibitors have provided insight to a great extent. In this review, we will give an overview of 23 members of the human MMP family and describe functions, linkages to disease and structural and mechanistic features. MMPs can be grouped into soluble (including matrilysins) and membrane-anchored species. We adhere to the ‘MMP nomenclature’ and provide the reader with reference to the many, often diverse, names for this enzyme family in the introduction.

G. Sharma, J. Goodwin

With the looming expansion of the elderly population of the US, a thorough understanding of “normal” aging-related changes on the respiratory system is paramount. The respiratory system undergoes various anatomical, physiological and immunological changes with age. The structural changes include chest wall and thoracic spine deformities which impairs the total respiratory system compliance leading to increase work of breathing. The lung parenchyma loses its supporting structure causing dilation of air spaces: “senile emphysema”. Respiratory muscle strength decreases with age and can impair effective cough, which is important for airway clearance. The lung matures by age 20–25 years, and thereafter aging is associated with progressive decline in lung function. The alveolar dead space increases with age, affecting arterial oxygen without impairing the carbon dioxide elimination. The airways receptors undergo functional changes with age and are less likely to respond to drugs used in younger counterparts to treat the same disorders. Older adults have decreased sensation of dyspnea and diminished ventilatory response to hypoxia and hypercapnia, making them more vulnerable to ventilatory failure during high demand states (ie, heart failure, pneumonia, etc) and possible poor outcomes.

G. Madhavan

L. McCorry

This manuscript discusses the physiology of the autonomic nervous system (ANS). The following topics are presented: regulation of activity; efferent pathways; sympathetic and parasympathetic divisions; neurotransmitters, their receptors and the termination of their activity; functions of the ANS; and the adrenal medullae. In addition, the application of this material to the practice of pharmacy is of special interest. Two case studies regarding insecticide poisoning and pheochromocytoma are included. The ANS and the accompanying case studies are discussed over 5 lectures and 2 recitation sections during a 2-semester course in Human Physiology. The students are in the first-professional year of the doctor of pharmacy program.

G. Lavigne, S. Khoury, S. Abe et al.

L. Sakka, G. Coll, J. Chazal

The cerebrospinal fluid (CSF) is contained in the brain ventricles and the cranial and spinal subarachnoid spaces. The mean CSF volume is 150 ml, with 25 ml in the ventricles and 125 ml in subarachnoid spaces. CSF is predominantly, but not exclusively, secreted by the choroid plexuses. Brain interstitial fluid, ependyma and capillaries may also play a poorly defined role in CSF secretion. CSF circulation from sites of secretion to sites of absorption largely depends on the arterial pulse wave. Additional factors such as respiratory waves, the subject's posture, jugular venous pressure and physical effort also modulate CSF flow dynamics and pressure. Cranial and spinal arachnoid villi have been considered for a long time to be the predominant sites of CSF absorption into the venous outflow system. Experimental data suggest that cranial and spinal nerve sheaths, the cribriform plate and the adventitia of cerebral arteries constitute substantial pathways of CSF drainage into the lymphatic outflow system. CSF is renewed about four times every 24 hours. Reduction of the CSF turnover rate during ageing leads to accumulation of catabolites in the brain and CSF that are also observed in certain neurodegenerative diseases. The CSF space is a dynamic pressure system. CSF pressure determines intracranial pressure with physiological values ranging between 3 and 4 mmHg before the age of one year, and between 10 and 15 mmHg in adults. Apart from its function of hydromechanical protection of the central nervous system, CSF also plays a prominent role in brain development and regulation of brain interstitial fluid homeostasis, which influences neuronal functioning.

A. Bashan, R. Bartsch, J. Kantelhardt et al.

The human organism is an integrated network where complex physiological systems, each with its own regulatory mechanisms, continuously interact, and where failure of one system can trigger a breakdown of the entire network. Identifying and quantifying dynamical networks of diverse systems with different types of interactions is a challenge. Here we develop a framework to probe interactions among diverse systems, and we identify a physiological network. We find that each physiological state is characterized by a specific network structure, demonstrating a robust interplay between network topology and function. Across physiological states, the network undergoes topological transitions associated with fast reorganization of physiological interactions on time scales of a few minutes, indicating high network flexibility in response to perturbations. The proposed system-wide integrative approach may facilitate the development of a new field, Network Physiology. Humans are a network of complex physiological systems, but quantifying these diverse systems is a challenge. This study presents a method to show that each physiological state is characterized by a specific network structure, demonstrating a connection between network topology and function.

J. Bligh, K. G. Johnson, J. Bligh et al.

W. Zou, P. Gambetti

L. Asarian, N. Geary

Qian Feng, Pengfei Li, Rongshan Gao et al.

Remote photoplethysmography (rPPG) based on traditional frame-based cameras often struggles with motion artifacts and limited temporal resolution. To address these limitations, we introduce EMPD (Event-based Multimodal Physiological Dataset), the first benchmark dataset specifically designed for non-contact physiological sensing via event cameras. The dataset leverages a laser-assisted acquisition system where a high-coherence laser modulates subtle skin vibrations from the radial artery into significant signals detectable by a neuromorphic sensor. The hardware platform integrates a high-resolution event camera to capture micro-motions and intensity transients, an industrial RGB camera to provide traditional rPPG benchmarks, and a clinical-grade pulse oximeter to record ground truth PPG waveforms. EMPD contains 193 valid records collected from 83 subjects, covering a wide heart rate range (40-110 BPM) under both resting and post-exercise conditions. By providing precisely synchronized multimodal data with microsecond-level temporal precision, EMPD serves as a crucial resource for developing robust algorithms in the field of neuromorphic physiological monitoring. The dataset is publicly available at: https://doi.org/10.5281/zenodo.18765701

Emmett B. Kendall, Jonathan P. Williams, Curtis B. Storlie et al.

Detection of occult hemorrhage (i.e., internal bleeding) in patients in intensive care units (ICUs) can pose significant challenges for critical care workers. Because blood loss may not always be clinically apparent, clinicians rely on monitoring vital signs for specific trends indicative of a hemorrhage event. The inherent difficulties of diagnosing such an event can lead to late intervention by clinicians which has catastrophic consequences. Therefore, a methodology for early detection of hemorrhage has wide utility. We develop a Bayesian regime switching model (RSM) that analyzes trends in patients' vitals and labs to provide a probabilistic assessment of the underlying physiological state that a patient is in at any given time. This article is motivated by a comprehensive dataset we curated from Mayo Clinic of 33,924 real ICU patient encounters. Longitudinal response measurements are modeled as a vector autoregressive process conditional on all latent states up to the current time point, and the latent states follow a Markov process. We present a novel Bayesian sampling routine to learn the posterior probability distribution of the latent physiological states, as well as develop an approach to account for pre-ICU-admission physiological changes. A simulation and real case study illustrate the effectiveness of our approach.