Toward a modeling, optimization, and predictive control framework for fed-batch metabolic cybergenetics.

Biotechnology offers many opportunities for the sustainable manufacturing of valuable products. The toolbox to optimize bioprocesses includes extracellular process elements such as the bioreactor design and mode of operation, medium formulation, culture conditions, feeding rates, and so on. However, these elements are frequently insufficient for achieving optimal process performance or precise product composition. One can use metabolic and genetic engineering methods for optimization at the intracellular level. Nevertheless, those are often of static nature, failing when applied to dynamic processes or if disturbances occur. Furthermore, many bioprocesses are optimized empirically and implemented with little-to-no feedback control to counteract disturbances. The concept of cybergenetics has opened new possibilities to optimize bioprocesses by enabling online modulation of the gene expression of metabolism-relevant proteins via external inputs (e.g., light intensity in optogenetics). Here, we fuse cybergenetics with model-based optimization and predictive control for optimizing dynamic bioprocesses. To do so, we propose to use dynamic constraint-based models that integrate the dynamics of metabolic reactions, resource allocation, and inducible gene expression. We formulate a model-based optimal control problem to find the optimal process inputs. Furthermore, we propose using model predictive control to address uncertainties via online feedback. We focus on fed-batch processes, where the substrate feeding rate is an additional optimization variable. As a simulation example, we show the optogenetic control of the ATPase enzyme complex for dynamic modulation of enforced ATP wasting to adjust product yield and productivity.

Reflections on the Development of Fascial Tissue: Starting from Embryology.

A great many articles discuss the histological aspects of fascial tissue in detail, but at the same time, there are many contradictions within the literature. In addition, there is a paucity of scientific data that allow straightforward classification of what tissue the fascia truly is. More precise classification of fascial tissue is essential in improving clinical care and effectively framing patient needs. Embryology is an indispensable starting point for understanding the many functions of the fascial tissue. This scientific discipline allows us to observe the relationships and adaptability of fascia both at local and systemic levels. This article reflects on modern scientific knowledge concerning the classification of fascia from an embryological standpoint with the aim of improving our understanding of connective tissue.

Ageing of the Diaphragm Muscle.

The diaphragm muscle is the most important contractile district used for breathing. Like other muscles in the human body, it is subject to ageing and sarcopenia. Sarcopenia can be classified as primary (or age-related) when there are no local or systemic pathologies that cause a functional and morphological detriment of skeletal musculature. Secondary sarcopenia occurs when there is a cause or more pathological causes (illness, malnutrition, immobility) related or unrelated to ageing. In the elderly population, transdiaphragmatic pressure (Pdi) decreases by 20-41%, with a decline in the overall strength of 30% (the strength of the expiratory muscles also decreases). The article discusses the adaptation of the diaphragm muscle to ageing and some other ailments and co-morbidities, such as back pain, emotional alterations, motor incoordination, and cognitive disorders, which are related to breathing.

Fascial Nomenclature: An Update.

Throughout the development of anatomy as a scientific study, authors have been challenged to give a singular comprehensive definition of what should be considered as a fascial tissue. Instead, the multiplicity of synthesis and analysis is the true richness of scientific research: individual points of view and background look at the fascia from their own perspective, sometimes influenced by their own cultural assumptions. No person or organization in science ever have the absolute truth, because scientific truth is always evolving, driven by new observations and analysis of data. Only by observing the fascia from multiple perspectives (doctor, surgeon, osteopath, physiotherapist, bioengineer and more) can we define more fully what fascial tissue is. It becomes the synergistic result of several scientific disciplines (anatomy, cardiology, angiology, orthopaedics, osteopathy, cytology, and more). The fascia is not the exclusive domain of a few people or individual private associations, but of all researchers who journey through the study of knowledge and arrive at an understanding, improving the clinical aspects for the good of the patient, without profit. This article reviews the embryological evolution of muscle and connective tissue to affirm how the fascial system should be ideally conceptualized: an absolute anatomic functional continuum.

Osteopathic approach with a patient undergoing cardiac transplantation: the five diaphragms.

The case report presents a patient with a possible neuropathic sternal pain associated with a recent heart transplant procedure. The patient could not breathe deeply and move the upper limbs, with a trunk torsion, feeling a sharp pain under and around the left breastbone. A fascial osteopathic approach in the treatment of the pelvic floor, the respiratory diaphragm, the thoracic outlet, the tongue and the tentorium cerebelli allowed the patient to access to a cardiovascular rehabilitation program. In osteopathic medicine, these anatomical parts of the body are called the five diaphragms. To our best knowledge, this is the first case report that uses osteopathic treatment in a patient with sternal pain associated with an undergoing cardiac transplantation. The clinical importance of the case report is added to other osteopathic research with patients undergoing cardiac surgery (coronary artery bypass graft) and with multiple benefits, without side effects. One of the main goals of osteopathic treatment is to provide the patient with well-being, from many clinical points of view, allowing the person to be discharged from the hospital more quickly and/or with less pain.

The Fascial Breath.

The word diaphragm comes from the Greek (διάϕραγµα), which meant something that divides, but also expressed a concept related to emotions and intellect. Breath is part of a concept of symmorphosis, that is the maximum ability to adapt to multiple functional questions in a defined biological context. The act of breathing determines and defines our holobiont: how we react and who we are. The article reviews the fascial structure that involves and forms the diaphragm muscle with the aim of changing the vision of this complex muscle: from an anatomical and mechanistic form to a fractal and asynchronous form. Another step forward for understanding the diaphragm muscle is that it is not only covered, penetrated and made up of connective tissue, but the contractile tissue itself is a fascial tissue with the same embryological derivation. All the diaphragm muscle is fascia.

Biotensegrity or Fascintegrity?

The biotensegrity view of the living is a theoretical model and there is no mathematical study in vitro or in vivo that demonstrates its validity, taking into account the presence of liquids (blood, lymph, water), the tension produced by nerves and blood vessels, just as the displacement of the viscera and their resistances and contractions are not taken into consideration. The concept of cellular transduction is reviewed as it is the key to understanding if the passage of different mechanical information occurs only through solid structures, such as the cytoskeleton, or even liquid and viscous. The article focuses on reviewing the weaknesses of the biotensegrity model in the light of new scientific information, trying to coin another term that better reflects the dynamics of living: fascintegrity.

Cranial Osteopathy: Obscurantism and Enlightenment.

The application of cranial osteopathic manipulative medicine (OMM) is always controversial in the literature. Primary respiration related to the movement of spheno-basilar synchondrosis in the adult goes against the knowledge of complete ossification that occurs at this articulation after the pubertal phase. The idea that the operator's hands can communicate with the meninges is difficult to accept. The anatomy shows us that the fascial system involves the meninges and that from the microcellular point of view there are no layers that divide one tissue from another. The backing of new sciences, such as quantum physics, suggest that cranial palpation allows the osteopath to come into contact with the meninges. Recent scientific evidence shows that meningeal afferents can affect extracranial areas and that the pericranial musculature itself is able to influence these afferents. The article highlights some reflections in support of cranial osteopathy, based on scientific information that could help the osteopath to improve clinical work.

The Other Side of the Fascia: Visceral Fascia, Part 2.

In osteopathic clinical practice and in the teaching of osteopathic medicine, the visceral manipulation approach is included. The knowledge that some viscera satisfy the definition of fascial tissue will allow the osteopath to improve its practice. In the second part of the article, we will give a conclusive definition of fascia, and we will explain the embryological development of the heart and how the fascial tissue can be subject to manual treatment. This text is the first in the international scientific field that discusses the inclusion of some viscera in the context of what is considered fascia, through our committee for the definition and nomenclature of the fascial tissue of the Foundation of Osteopathic Research and Clinical Endorsement (FORCE).

The Other Side of the Fascia: The Smooth Muscle Part 1.

According to current scientific standards, the fascia is a connective tissue derived from two separate germ layers, the mesoderm (trunk and limbs, part of the neck) and the ectoderm (cervical tract and skull). The fascia has the property of maintaining the shape and function of its anatomical district, but it also can adapt to mechanical-metabolic stimuli. Smooth muscle and non-voluntary striated musculature originated from the mesoderm have never been properly considered as a type of fascia. They are some of the viscera present in the mediastinum, in the abdomen and in the pelvic floor. This text represents the first article in the international scientific field that discusses the inclusion of some viscera in the context of what is considered fascia, thanks to the efforts of our committee for the definition and nomenclature of the fascial tissue of the Foundation of Osteopathic Research and Clinical Endorsement (FORCE).

The Diaphragm Muscle Manual Evaluation Scale.

This is a technical report describing how to use the Manual Evaluation Diaphragm (MED) scale, the only evaluation scale in the world to generate a value for the mobility of the main respiratory muscle. In a previously published paper, we described how the areas of the diaphragm should be palpated correctly because a valid manual diaphragmatic evaluation was lacking in the literature. The MED scale emerged as a logical consequence of manual palpation, to provide reference values and allow comparisons between the assessments of different health professionals in multidisciplinary teams. The scale is the first non-instrumental approach to obtaining data on diaphragm function and provides parameters by which the effects that a therapeutic approach has on the diaphragm can be measured.

Meaning of the Solid and Liquid Fascia to Reconsider the Model of Biotensegrity.

The definition of fascia includes tissues of mesodermal derivation considered as specialized connective tissues: the blood and lymph. As water shapes rocks, bodily fluids modify the shape and functioning of bodily structures. Bodily fluids are silent witnesses to mechanotransductive information, allowing adaptation and life, transporting biochemical and hormonal signals. While the solid fascial tissue divides, supports, and connects the different parts of the body system, the liquid fascial tissue feeds and transports messages for the solid fascia. This article reconsiders the model of biotensegrity, by revising the definition of solid and liquid fascia, and tries to integrate the fascial continuum with the lymph and blood in a new model, because in the previous model, these two liquid elements were not taken into consideration. The name given to this new model is Rapid Adaptability of Internal Network (RAIN).

Symptomatology Correlations Between the Diaphragm and Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is one of the most debilitating and common gastrointestinal disorders; nevertheless, its pathophysiology is still unclear. It affects 11% of the world's population, and is characterized by alternating periods of pain and/or motility disorders with periods of remission and without any evidence of any structural and functional organic variation. It has been recently proposed that an altered contractile ability of the diaphragm muscle might adversely influence intestinal motility. The text reviews the diaphragm's functions, anatomy, and neurological links in correlation with the presence of chronic symptoms associated to IBS, like chronic low back pain, chronic pelvic pain, chronic headache, and temporomandibular joint dysfunction, vagus nerve inflammation, and depression and anxiety. The interplay between an individual's breath dynamic and intestinal behaviour is still an unaddressed point in the physiopathology of IBS, and the paucity of scientific studies should recommend further research to better understand the importance of breathing in this syndrome.

A New Concept of Biotensegrity Incorporating Liquid Tissues: Blood and Lymph.

The definition of fascia includes tissues of mesodermal derivation, considered as specialized connective tissue: blood and lymph. As water shapes rocks, bodily fluids modify shapes and functions of bodily structures. Bodily fluids are silent witnesses of the mechanotransductive information, allowing adaptation and life, transporting biochemical and hormonal signals. While the solid fascial tissue divides, supports, and connects the different parts of the body system, the liquid fascial tissue feeds and transports messages for the solid fascia. The focus of this article is to reconsider the model of biotensegrity because it does not take into account the liquid fascia, and to try to integrate the fascial continuum with the lymph and the blood in a new model. The name given to this new model is RAIN-Rapid Adaptability of Internal Network.

The Influence of Breathing on the Central Nervous System.

The functions of the diaphragm do not stop locally in its anatomy but affect the whole body system. The respiratory rhythm, directly and indirectly, affects the central nervous system (CNS). This article describes and reviews these influences, containing, for the first time, information on this subject in a single text. The ability of breath to move the brain mass and determine patterns of neural oscillation will be discussed. The role of the diaphragm in influencing motor expression and its effect on intracranial blood shifts in respiratory activity will also be discussed. It is known that the diaphragm can have multiple uses in improving the symptomatological picture of chronic diseases, but there is no current, concrete data on the effects that the rehabilitative training or manual approaches could have on the patient; in particular, on his/her cognitive and cerebral aspects in general.

Fascial preadipocytes: another missing piece of the puzzle to understand fibromyalgia?

Fibromyalgia (FM) syndrome is a chronic condition causing pain, affecting approximately 0.5%-6% of the developed countries' population, and on average, 2% of the worldwide population. Despite the large amount of scientific literature available, the FM etiology is still uncertain. The diagnosis is based on the clinical presentation and the severity of the symptomatology. Several studies pointed out pathological alterations within the central nervous system, suggesting that FM could originate from a central sensitization of the pain processing centers. Research supports the thesis of a peripheral neuropathic component, with the finding of axonal damages. The fibromyalgia patient has many myofascial system abnormalities, such as pain and fatigue, impairing the symptomatic profile. This paper revises the myopathic compensations, highlighting the possible role of the fascia in generating symptoms, being aware of the new information about the fascia's activity in stimulating inflammation and fat cell production.

Chest pain in patients with COPD: the fascia's subtle silence.

COPD is a progressive condition that leads to a pathological degeneration of the respiratory system. It represents one of the most important causes of mortality and morbidity in the world, and it is characterized by the presence of many associated comorbidities. Recent studies emphasize the thoracic area as one of the areas of the body concerned by the presence of pain with percentages between 22% and 54% in patients with COPD. This article analyzes the possible causes of mediastinal pain, including those less frequently taken into consideration, which concern the role of the fascial system of the mediastinum. The latter can be a source of pain especially when a chronic pathology is altering the structure of the connective tissue. We conclude that to consider the fascia in daily clinical activity may improve the therapeutic approach toward the patient.

New Proposal to Define the Fascial System.

At the beginning of the third millennium, we still do not have a definition of 'fascia' recognized as valid by every researcher. This article attempts to give a new definition of the fascial system, including the epidermis, by comparing the mechanical-metabolic characteristics of the connective tissue and the skin. In fact, according to the latest classification deriving from the Fascia Nomenclature Committee, the outer skin layer is not considered as part of the fascial continuum. This article highlights the reasons for taking the functional characteristics of the tissue into consideration, rather than its mere structure. A brief discussion will address the questions as to what is considered as fascial tissue and from which embryonic germ layer the epidermis is formed. The notion that all the layers intersect will be highlighted, demonstrating that quoting precise definitions of tissue stratification in the living organism probably does not correspond to what happens in vivo. What we propose as a definition is not to be regarded as a point of arrival but as another departure.

Low back pain and gastroesophageal reflux in patients with COPD: the disease in the breath.

COPD is a worsening condition that leads to a pathologic degeneration of the respiratory system. It represents one of the most important causes of mortality and morbidity in the world, and it is characterized by the presence of associated comorbidity. This article analyzes gastroesophageal reflux disease (GERD) and low back pain (LBP) in patients with COPD and tries to produce anatomo-clinical considerations on the reasons of the presence of these comorbidities. The considerations of the authors are based on the anatomic functions and characteristics of the respiratory diaphragm that are not always considered, from which elements useful to comprehend the symptomatic status of the patient can be deduced, finally improving the therapeutic approach. The information contained in the article can be of help to the clinician and for physiotherapy, and to all health professionals who gravitate around the patient's care, improving the approach to the diaphragm muscle.

Emission of Biophotons and Adjustable Sounds by the Fascial System: Review and Reflections for Manual Therapy.

Every body structure is wrapped in connective tissue or fascia, creating a structural continuity that gives form and function to every tissue and organ. The fascial tissue is uniformly distributed throughout the body, enveloping, interacting with and permeating blood vessels, nerves, viscera, meninges, bones and muscles, creating various layers at different depths and forming a tridimensional metabolic and mechanical matrix. This article reviews the literature on the emission of biophotons and adjustable sounds by the fascial system, because these biological changes could be a means of local and systemic cellular communication and become another assessment tool for manual (therapy) practitioners. This is the first article that discusses these topics in a single text, attempting to bring such information into an area of application that is beneficial to osteopaths, chiropractors, and manual therapists.