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Exaggerated cold-induced vasoconstriction can precipitate a pathogenesis called Raynaud’s phenomenon (RP). Interestingly, RP is significantly more prevalent in females than age-matched men, highlighting the potential implication of 17β-estradiol (E2) in the etio-pathogenesis of this disease. Indeed, we have previously reported that E2 stimulates the expression of vascular alpha 2C-adrenoceptors (α2C-AR), the sole mediator of cold-induced constriction of cutaneous arterioles. This induced expression occurs through the cyclic adenosine monophosphate → exchange protein activated by cAMP→ Ras-related protein 1→ c-Jun N-terminal kinase→ activator protein-1 (cAMP/Epac/Rap/JNK/AP-1 pathway). On the basis that estrogen-induced rapid cAMP accumulation and JNK activation occurs so rapidly we hypothesized that a non-classic, plasma membrane estrogen receptor was the mediator. We then showed that an impermeable form of E2, namely E2:BSA, mimics E2 effects suggesting a role for the membranous G-protein coupled estrogen receptor (GPER) in E2-induced α2C-AR expression. Our current working hypothesis and unpublished observations further cement this finding, as G1, a GPER agonist, mimics while G15, a GPER antagonist, abrogates estrogen’s effect on the expression of vascular α2C-AR. These, and other observations, highlight the potential of GPER as a tractable target in the management of RP, particularly in pre-menopausal women.

Traumatic brain injury (TBI), a growing public health problem, appears to result not only from major andprimary injury but also from a complex interplay among inflammatory, biochemical, and neurohormonal changes, as well as genetic components acting on brain tissue. As a result, characterization and classification of TBI requires multidimensional approaches that are able to encompass the diverse and highly complex clinical picture of TBI across the continuum of severities and broad spectrum of pathobiological processes. Emerging evidence suggests that an increasing number of biologic substances, commonly referred to in today’s vernacular as biomarkers, can provide unprecedented opportunities for detecting and classifying injury, and identifying pathophysiologic mechanisms potentially leading to more effective targeted therapies. In this Research Topic, we include comprehensive reviews of the current literature on this topic ranging from proteomics techniques applied for the first time to central nervous system (CNS) biomarker discovery (1) to potential clinical applications of existing biomarkers of brain injury in specific settings such as ICU, pediatric TBI (2), and the military-relevant battlefield casualty (3). In particular, to address the unique circumstances and consequences of sustaining a TBI in combat and the demand for specific practices of management and care of soldiers, presentations (3, 4) have been included from outstanding researchers of the Combat Casualty Care Research Program (CCCRP) for Brain Trauma and Neuroprotection, a program specifically focused on developing neuroprotective and neurorestorative strategies for military-relevant TBI. We have also added a chapter on blast TBI to emphasize the potential problem of TBI following exposure to blast (5). Finally, we expanded discussions to explore the potential of brain damage biomarkers as tools for predicting long-term consequences of TBI (6) and to outline their roles in other CNS diseases such as neurodegeneration (Parkinson’s disease) (7), subarachnoid hemorrhage (8), and hypoxic ischemic encephalopathy (9, 10). We have strived to assemble a multidisciplinary group of internationally recognized researchers and clinicians highly relevant to this research domain (11–13). As the translation of brain damage biomarkers has already transformed from research tools to being aids in clinical decision-making, this Research Topic will be evolutionary reading for neurotrauma scientists and clinicians interested in the potential of a simple biofluid-based diagnostic test to refine the clinical characterization of TBI offering more accurate disease phenotyping. Such improved molecular characterization integrated with traditional approaches, including clinical examination and structural and functional neuroimaging, will allow the field to develop improved clinical practice guidelines and tailor therapeutic interventions to the patient’s individual pathophysiology, thereby leading to effective management and improved patient outcome. This Research Topic would not have been possible without the support and help of many people. First, we thank the chapter authors for devoting their time and effort to produce valuable contributions that provide comprehensive frameworks and critical insights. We also thank the members of the editorial board for their dedicated assistance and for providing informed perspectives on the chapters. Last, and most important, we thank all patients with TBI and their families for their invaluable contributions. To improve their outcome and quality of life represents our ultimate goal and our greatest source of inspiration to foster knowledge in this critical research area.

Although neuropsychiatric (NP) disorders are among the top causes of disability worldwide with enormous financial costs, they can still be viewed as part of the most complex disorders that are of unknown etiology and incomprehensible pathophysiology. The complexity of NP disorders arises from their etiologic heterogeneity and the concurrent influence of environmental and genetic factors. In addition, the absence of rigid boundaries between the normal and diseased state, the remarkable overlap of symptoms among conditions, the high inter-individual and inter-population variations, and the absence of discriminative molecular and/or imaging biomarkers for these diseases makes difficult an accurate diagnosis. Along with the complexity of NP disorders, the practice of psychiatry suffers from a “top-down” method that relied on symptom checklists. Although checklist diagnoses cost less in terms of time and money, they are less accurate than a comprehensive assessment. Thus, reliable and objective diagnostic tools such as biomarkers are needed that can detect and discriminate among NP disorders. The real promise in understanding the pathophysiology of NP disorders lies in bringing back psychiatry to its biological basis in a systemic approach which is needed given the NP disorders’ complexity to understand their normal functioning and response to perturbation. This approach is implemented in the systems biology discipline that enables the discovery of disease-specific NP biomarkers for diagnosis and therapeutics. Systems biology involves the use of sophisticated computer software “omics”-based discovery tools and advanced performance computational techniques in order to understand the behavior of biological systems and identify diagnostic and prognostic biomarkers specific for NP disorders together with new targets of therapeutics. In this review, we try to shed light on the need of systems biology, bioinformatics, and biomarkers in neuropsychiatry, and illustrate how the knowledge gained through these methodologies can be translated into clinical use providing clinicians with improved ability to diagnose, manage, and treat NP patients.