Why Pecking Order Theory Should be Included in Introductory Finance Courses

The majority of students majoring in various business administration emphases take only one finance course (Introductory Financial Management) while completing the requirements of their degrees. A primary topic commonly covered in most introductory finance courses is capital structure, with a discussion that often culminates with a discussion of optimal capital structure. Invariably the leading textbooks present optimal capital structure within the framework of the agency cost/tax shield trade-off model that evolved from Modigliani and Miller’s capital structure irrelevance hypothesis. While this approach has solid grounding in value maximization arguments and capital market equilibrium theory, it nonetheless fails to explain several commonly observed - and reported - practices in modern corporate finance. Pecking order theory offers an intriguing addition to the explanation of optimal capital structure, even in an introductory course. However, few introductory textbooks give the theory much more than a cursory mention, if it is indeed mentioned at all. The purpose of this paper is to make a case for including pecking order theory in any discussion of optimal capital structure

Stroke research at the crossroads - where are we heading?

Stroke causes 5.7 million deaths annually. This ranks stroke as the second most common cause of death and, additionally, it is a major cause of disability. Because of an ageing population, stroke incidence and costs will greatly increase in the future. This makes stroke an ongoing social and economic burden, in contrast to the only very limited therapeutic options. In the last decade vast sums were spent on translational research focused on neuroprotective strategies in the acute phase of ischaemic stroke. A plethora of candidate agents were tested in experimental models and preclinical studies, but none was proven effective in clinical trials. This gave rise to discussions about the possible reasons for this failure, ending up mainly with criticism of methodological aspects of the preclinical and clinical studies, or of the relevance of animal studies in drug development. Indeed, the question could rather be whether neuroprotection is the right target for successful stroke treatment. In this context, a paradigm change can currently be observed: the focus of experimental and translational stroke research is shifting from early neuroprotection to delayed mechanisms such as stroke-associated comorbidities, regeneration and plasticity. In this review we highlight a few recently emerging fields in translational stroke research. One such topic is the crosstalk between immunity and the injured brain as key pathomechanism in stroke. On one hand, innate and adaptive immune cells play an important role in the fate of injured brain tissue after stroke;on the other, peripheral immune alterations are critically involved in post-stroke comorbidities. Another emerging research area is the analysis of mechanisms involved in regeneration and neuronal plasticity after stroke. Here, we discuss the current understanding of basic mechanisms involved after brain injury, clinical imaging approaches and therapeutic strategies to promote regeneration in stroke patients

The gut-brain axis in ischemic stroke: its relevance in pathology and as a therapeutic target

The gut contains the largest reservoir of microorganisms of the human body, termed as the gut microbiota which emerges as a key pathophysiological factor in health and disease. The gut microbiota has been demonstrated to influence various brain functions along the gut-brain axis. Stroke leads to intestinal dysmotility and leakiness of the intestinal barrier which are associated with change of the gut microbiota composition and its interaction with the human host. Growing evidence over the past decade has demonstrated an important role of these post-stroke changes along the gut-brain axis to contribute to stroke pathology and be potentially druggable targets for future therapies. The impact of the gut microbiota on brain health and repair after stroke might be attributed to the diverse functions of gut bacteria in producing neuroactive compounds, modulating the host's metabolism and immune status. Therefore, a better understanding on the gut-brain axis after stroke and its integration in a broader concept of stroke pathology could open up new avenues for stroke therapy. Here, we discuss current concepts from preclinical models and human studies on the bi-directional communication along the microbiota- gut-brain axis in stroke

A macrophage-T cell coculture model for severe tissue injury-induced T cell death

A key observation of tissue injury, such as stroke and burn, is a state of systemic immunosuppression characterized by loss of T cells and rise of infections. Here, we present an in vitro model for cell-cell interactions between innate (macro-phages) and adaptive (T cells) immune cells. This protocol facilitates bone marrow-derived macrophages (BMDMs) and splenic T cells in a coculture model. The procedure mimics injury-induced T cell death, which is driven by inflamma-some activation in macrophages.For complete details on the use and execution of this protocol, please refer to Roth et al. (2021)

In vivo widefield calcium imaging of the mouse cortex for analysis of network connectivity in health and brain disease

The organization of brain areas in functionally connected networks, their dynamic changes, and perturbations in disease states are subject of extensive investigations. Research on functional networks in humans predominantly uses functional magnetic resonance imaging (fMRI). However, adopting fMRI and other functional imaging methods to mice, the most widely used model to study brain physiology and disease, poses major technical challenges and faces important limitations. Hence, there is great demand for alternative imaging modalities for network characterization. Here, we present a refined protocol for in vivo widefield calcium imaging of both cerebral hemispheres in mice expressing a calcium sensor in excitatory neurons. We implemented a stringent protocol for minimizing anesthesia and excluding movement artifacts which both imposed problems in previous approaches. We further adopted a method for unbiased identification of functional cortical areas using independent component analysis (ICA) on resting-state imaging data. Biological relevance of identified components was confirmed using stimulus-dependent cortical activation. To explore this novel approach in a model of focal brain injury, we induced photothrombotic lesions of the motor cortex, determined changes in inter- and intrahemispheric connectivity at multiple time points up to 56 days post-stroke and correlated them with behavioral deficits. We observed a severe loss in interhemispheric connectivity after stroke, which was partially restored in the chronic phase and associated with corresponding behavioral motor deficits. Taken together, we present an improved widefield calcium imaging tool accounting for anesthesia and movement artifacts, adopting an advanced analysis pipeline based on human fMRI algorithms and with superior sensitivity to recovery mechanisms in mouse models compared to behavioral tests. This tool will enable new studies on interhemispheric connectivity in murine models with comparability to human imaging studies for a wide spectrum of neuroscience applications in health and disease

The meningeal and choroidal infiltration routes for leukocytes in stroke

Stroke is a major health burden as it is a leading cause of morbidity and mortality worldwide. Blood flow restoration, through thrombolysis or endovascular thrombectomy, is the only effective treatment but is restricted to a limited proportion of patients due to time window constraint and accessibility to technology. Over the past two decades, research has investigated the basic mechanisms that lead to neuronal death following cerebral ischemia. However, the use of neuroprotective paradigms in stroke has been marked by failure in translation from experimental research to clinical practice. In the past few years, much attention has focused on the immune response to acute cerebral ischemia as a major factor to the development of brain lesions and neurological deficits. Key inflammatory processes after stroke include the activation of resident glial cells as well as the invasion of circulating leukocytes. Recent research on anti-inflammatory strategies for stroke has focused on limiting the transendothelial migration of peripheral immune cells from the compromised vasculature into the brain parenchyma. However, recent trials testing the blockage of cerebral leukocyte infiltration in patients reported inconsistent results. This emphasizes the need to better scrutinize how immune cells are regulated at the blood-brain interface and enter the brain parenchyma, and particularly to also consider alternative cerebral infiltration routes for leukocytes, including the meninges and the choroid plexus. Understanding how immune cells migrate to the brain via these alternative pathways has the potential to develop more effective approaches for anti-inflammatory stroke therapies

The microbiome-gut-brain axis in acute and chronic brain diseases

The gut microbiome — the largest reservoir of microorganisms of the human body — is emerging as an important player in neurodevelopment and ageing as well as in brain diseases including stroke, Alzheimer’s disease and Parkinson’s disease. The growing knowledge on mediators and triggered pathways has advanced our understanding of the interactions along the gut-brain axis. Gut bacteria produce neuroactive compounds and can modulate neuronal function, plasticity and behavior. Furthermore, intestinal microorganisms impact the host’s metabolism and immune status which in turn affect neuronal pathways in the enteric and central nervous systems. Here, we discuss the recent insights from human studies and animal models on the bi-directional communication along the microbiome-gut-brain axis in both acute and chronic brain diseases

L-Lactate Treatment at 24 h and 48 h after Acute Experimental Stroke Is Neuroprotective via Activation of the L-Lactate Receptor HCA1

Stroke is the main cause for acquired disabilities. Pharmaceutical or mechanical removal of the thrombus is the cornerstone of stroke treatment but can only be administered to a subset of patients and within a narrow time window. Novel treatment options are therefore required. Here we induced stroke by permanent occlusion of the distal medial cerebral artery of wild-type mice and knockout mice for the lactate receptor hydroxycarboxylic acid receptor 1 (HCA(1)). At 24 h and 48 h after stroke induction, we injected L-lactate intraperitoneal. The resulting atrophy was measured in Nissl-stained brain sections, and capillary density and neurogenesis were measured after immunolabeling and confocal imaging. In wild-type mice, L-lactate treatment resulted in an HCA(1)-dependent reduction in the lesion volume accompanied by enhanced angiogenesis. In HCA(1) knockout mice, on the other hand, there was no increase in angiogenesis and no reduction in lesion volume in response to L-lactate treatment. Nevertheless, the lesion volumes in HCA(1) knockout mice-regardless of L-lactate treatment-were smaller than in control mice, indicating a multifactorial role of HCA(1) in stroke. Our findings suggest that L-lactate administered 24 h and 48 h after stroke is protective in stroke. This represents a time window where no effective treatment options are currently available

Chronic T cell proliferation in brains after stroke could interfere with the efficacy of immunotherapies

Neuroinflammation is an emerging focus of translational stroke research. Preclinical studies have demonstrated a critical role for brain-invading lymphocytes in post-stroke pathophysiology. Reducing cerebral lymphocyte invasion by anti-CD49d antibodies consistently improves outcome in the acute phase after experimental stroke models. However, clinical trials testing this approach failed to show efficacy in stroke patients for the chronic outcome 3 mo after stroke. Here, we identify a potential mechanistic reason for this phenomenon by detecting chronic T cell accumulation—evading the systemic therapy—in the post-ischemic brain. We observed a persistent accumulation of T cells in mice and human autopsy samples for more than 1 mo after stroke. Cerebral T cell accumulation in the post-ischemic brain was driven by increased local T cell proliferation rather than by T cell invasion. This observation urges re-evaluation of current immunotherapeutic approaches, which target circulating lymphocytes for promoting recovery after stroke