MS-based glycomics and glycoproteomics methods enabling isomeric characterization.

Glycosylation is one of the most significant and abundant posttranslational modifications in mammalian cells. It mediates a wide range of biofunctions, including cell adhesion, cell communication, immune cell trafficking, and protein stability. Also, aberrant glycosylation has been associated with various diseases such as diabetes, Alzheimer's disease, inflammation, immune deficiencies, congenital disorders, and cancers. The alterations in the distributions of glycan and glycopeptide isomers are involved in the development and progression of several human diseases. However, the microheterogeneity of glycosylation brings a great challenge to glycomic and glycoproteomic analysis, including the characterization of isomers. Over several decades, different methods and approaches have been developed to facilitate the characterization of glycan and glycopeptide isomers. Mass spectrometry (MS) has been a powerful tool utilized for glycomic and glycoproteomic isomeric analysis due to its high sensitivity and rich structural information using different fragmentation techniques. However, a comprehensive characterization of glycan and glycopeptide isomers remains a challenge when utilizing MS alone. Therefore, various separation methods, including liquid chromatography, capillary electrophoresis, and ion mobility, were developed to resolve glycan and glycopeptide isomers before MS. These separation techniques were coupled to MS for a better identification and quantitation of glycan and glycopeptide isomers. Additionally, bioinformatic tools are essential for the automated processing of glycan and glycopeptide isomeric data to facilitate isomeric studies in biological cohorts. Here in this review, we discuss commonly employed MS-based techniques, separation hyphenated MS methods, and software, facilitating the separation, identification, and quantitation of glycan and glycopeptide isomers.

Neurotrauma investigation through spatial omics guided by mass spectrometry imaging: Target identification and clinical applications.

Traumatic brain injury (TBI) represents one of the major public health concerns worldwide due to the increase in TBI incidence as a result of injuries from daily life accidents such as sports and motor vehicle transportation as well as military-related practices. This type of central nervous system trauma is known to predispose patients to several neurological disorders such as Parkinson's disease, Alzheimer's disease, chronic trauamatic encephalopathy, and age-related Dementia. Recently, several proteomic and lipidomic platforms have been applied on different TBI studies to investigate TBI-related mechanisms that have broadened our understanding of its distinct neuropathological complications. In this study, we provide an updated comprehensive overview of the current knowledge and novel perspectives of the spatially resolved microproteomics and microlipidomics approaches guided by mass spectrometry imaging used in TBI studies and its applications in the neurotrauma field. In this regard, we will discuss the use of the spatially resolved microproteomics and assess the different microproteomic sampling methods such as laser capture microdissection, parafilm assisted microdissection, and liquid microjunction extraction as accurate and precise techniques in the field of neuroproteomics. Additionally, we will highlight lipid profiling applications and their prospective potentials in characterizing molecular processes involved in the field of TBI. Specifically, we will discuss the phospholipid metabolism acting as a precursor for proinflammatory molecules such as eicosanoids. Finally, we will survey the current state of spatial neuroproteomics and microproteomics applications and present the various studies highlighting their findings in these fields.

The pharmaco-epigenetics of hypertension: a focus on microRNA.

Hypertension is a major harbinger of cardiovascular morbidity and mortality. It predisposes to higher rates of myocardial infarction, chronic kidney failure, stroke, and heart failure than most other risk factors. By 2025, the prevalence of hypertension is projected to reach 1.5 billion people. The pathophysiology of this disease is multifaceted, as it involves nitric oxide and endothelin dysregulation, reactive oxygen species, vascular smooth muscle proliferation, and vessel wall calcification, among others. With the advent of new biomolecular techniques, various studies have elucidated a gaping hole in the etiology and mechanisms of hypertension. Indeed, epigenetics, DNA methylation, histone modification, and microRNA-mediated translational silencing appear to play crucial roles in altering the molecular phenotype into a hypertensive profile. Here, we critically review the experimentally determined associations between microRNA (miRNA) molecules and hypertension pharmacotherapy. Particular attention is given to the epigenetic mechanisms underlying the physiological responses to antihypertensive drugs like candesartan, and other relevant drugs like clopidogrel, aspirin, and statins among others. Furthermore, how miRNA affects the pharmaco-epigenetics of hypertension is especially highlighted.

Transcriptomic Signatures of Neuronally Derived Extracellular Vesicles Reveal the Presence of Olfactory Receptors in Clinical Samples from Traumatic Brain Injury Patients.

Traumatic brain injury (TBI) is defined as an injury to the brain by external forces which can lead to cellular damage and the disruption of normal central nervous system functions. The recently approved blood-based biomarkers GFAP and UCH-L1 can only detect injuries which are detectable on CT, and are not sensitive enough to diagnose milder injuries or concussion. Exosomes are small microvesicles which are released from the cell as a part of extracellular communication in normal as well as diseased states. The objective of this study was to identify the messenger RNA content of the exosomes released by injured neurons to identify new potential blood-based biomarkers for TBI. Human severe traumatic brain injury samples were used for this study. RNA was isolated from neuronal exosomes and total transcriptomic sequencing was performed. RNA sequencing data from neuronal exosomes isolated from serum showed mRNA transcripts of several neuronal genes. In particular, mRNAs of several olfactory receptor genes were present at elevated concentrations in the neuronal exosomes. Some of these genes were OR10A6, OR14A2, OR6F1, OR1B1, and OR1L1. RNA sequencing data from exosomes isolated from CSF showed a similar elevation of these olfactory receptors. We further validated the expression of these samples in serum samples of mild TBI patients, and a similar up-regulation of these olfactory receptors was observed. The data from these experiments suggest that damage to the neurons in the olfactory neuroepithelium as well as in the brain following a TBI may cause the release of mRNA from these receptors in the exosomes. Hence, olfactory receptors can be further explored as biomarkers for the diagnosis of TBI.

Aptamer Technologies in Neuroscience, Neuro-Diagnostics and Neuro-Medicine Development.

Aptamers developed using in vitro Systematic Evolution of Ligands by Exponential Enrichment (SELEX) technology are single-stranded nucleic acids 10-100 nucleotides in length. Their targets, often with specificity and high affinity, range from ions and small molecules to proteins and other biological molecules as well as larger systems, including cells, tissues, and animals. Aptamers often rival conventional antibodies with improved performance, due to aptamers' unique biophysical and biochemical properties, including small size, synthetic accessibility, facile modification, low production cost, and low immunogenicity. Therefore, there is sustained interest in engineering and adapting aptamers for many applications, including diagnostics and therapeutics. Recently, aptamers have shown promise as early diagnostic biomarkers and in precision medicine for neurodegenerative and neurological diseases. Here, we critically review neuro-targeting aptamers and their potential applications in neuroscience research, neuro-diagnostics, and neuro-medicine. We also discuss challenges that must be overcome, including delivery across the blood-brain barrier, increased affinity, and improved in vivo stability and in vivo pharmacokinetic properties.

Functional Selection of Tau Oligomerization-Inhibiting Aptamers.

Pathological hyperphosphorylation and aggregation of microtubule-associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently, no cure exists for Alzheimer's Disease. Aptamers offer significant potential as next-generation therapeutics in biotechnology and the treatment of neurological disorders. Traditional aptamer selection methods for Tau protein focus on binding affinity rather than interference with pathological Tau. In this study, we developed a new selection strategy to enrich DNA aptamers that bind to surviving monomeric Tau protein under conditions that would typically promote Tau aggregation. Employing this approach, we identified a set of aptamer candidates. Notably, BW1c demonstrates a high binding affinity (Kd=6.6 nM) to Tau protein and effectively inhibits arachidonic acid (AA)-induced Tau protein oligomerization and aggregation. Additionally, it inhibits GSK3ß-mediated Tau hyperphosphorylation in cell-free systems and okadaic acid-mediated Tau hyperphosphorylation in cellular milieu. Lastly, retro-orbital injection of BW1c tau aptamer shows the ability to cross the blood brain barrier and gain access to neuronal cell body. Through further refinement and development, these Tau aptamers may pave the way for a first-in-class neurotherapeutic to mitigate tauopathy-associated neurodegenerative disorders.

Nanoparticles: Attractive tools to treat colorectal cancer.

Colorectal Cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Despite the notable advances achieved over the last few decades, CRC remains a hard-to-treat deadly disease in many patients. This is attributed mainly to chemo- and immuno-resistance, which frequently emerge soon after treatment with conventional therapeutics. Systemic treatments are also constrained by their many undesired and serious side effects. More recently, nanomedicine has emerged as an attractive modality that can overcome issues of therapeutic resistance, improper delivery, or suboptimal targeting of tumor cells. Many nanomaterials, having already been examined in pre-clinical and clinical studies, are now considered biocompatible and relatively safe. Indeed, around 50 nano-formulations have so far been approved as diagnostic and therapeutic agents in humans. Here, in this review, we describe a set of imperative nanoparticles (NPs) involved in diagnosing and treating CRC. In particular, we discuss the theragnostic roles of quantum dots, iron oxide NPs, Polylactide-co-glycolic acid (PLGA) NPs, dendrimer NPs, carbon nanotubes, liposomes, and gold NPs. We dissect the molecular and clinical evidence supporting the use of these NPs in CRC. We also highlight their implications in targeted drug delivery as well as their anti-tumorigenic properties and effects on the cardinal hallmarks of CRC. We conclude by highlighting the notion that nanomedicine is emerging as an attractive approach to address the unmet needs in managing several diseases, including CRC.

Inflammation and hypertension: Underlying mechanisms and emerging understandings.

Hypertension remains a major contributor to cardiovascular disease (CVD), a leading cause of global death. One of the major insults that drive increased blood pressure is inflammation. While it is the body's defensive response against some homeostatic imbalances, inflammation, when dysregulated, can be very deleterious. In this review, we highlight and discuss the causative relationship between inflammation and hypertension. We critically discuss how the interplay between inflammation and reactive oxygen species evokes endothelial damage and dysfunction, ultimately leading to narrowing and stiffness of blood vessels. This, along with phenotypic switching of the vascular smooth muscle cells and the abnormal increase in extracellular matrix deposition further exacerbates arterial stiffness and noncompliance. We also discuss how hyperhomocysteinemia and microRNA act as links between inflammation and hypertension. The premises we discuss suggest that the blue-sky scenarios for targeting the underlying mechanisms of hypertension necessitate further research.

The Antitumor Effect of the DNA Polymerase Alpha Inhibitor ST1926 in Glioblastoma: A Proteomics Approach.

Glioblastoma Multiforme (GBM) is the most aggressive form of malignant brain tumor. The median survival rate does not exceed two years, indicating an imminent need to develop novel therapies. The atypical adamantyl retinoid ST1926 induces apoptosis and growth inhibition in different cancer types. We have shown that ST1926 is an inhibitor of the catalytic subunit of DNA polymerase alpha (POLA1), which is involved in initiating DNA synthesis in eukaryotic cells. POLA1 levels are elevated in GBM versus normal brain tissues. Therefore, we studied the antitumor effects of ST1926 in several human GBM cell lines. We further explored the global protein expression profiles in GBM cell lines using liquid chromatography coupled with tandem mass spectrometry to identify new targets of ST1926. Low sub-micromolar concentrations of ST1926 potently decreased cell viability, induced cell damage and apoptosis, and reduced POLA1 protein levels in GBM cells. The proteomics profiles revealed 197 proteins significantly differentially altered upon ST1926 treatment of GBM cells involved in various cellular processes. We explored the differential gene and protein expression of significantly altered proteins in GBM compared to normal brain tissues.

Traumatic Brain Injury in Cameroon: A Prospective Observational Study in a Level I Trauma Centre.

Background and Objective: About 14 million people will likely suffer a traumatic brain injury (TBI) per year by 2050 in sub-Saharan Africa. Studying TBI characteristics and their relation to outcomes can identify initiatives to improve TBI prevention and care. The objective of this study was to define the features and outcomes of TBI patients seen over a 1-year period in a level-I trauma centre in Cameroon. Materials and Methods: Data on demographics, causes, clinical aspects, and discharge status were collected over a period of 12 months. The Glasgow Outcome Scale-Extended (GOSE) and the Quality-of-Life Questionnaire after Brain Injury (QoLIBRI) were used to evaluate outcomes six months after TBI. Comparisons between two categorical variables were done using Pearson's chi-square test. Results: A total of 160 TBI patients participated in the study. The age group 15-45 years was most represented (78%). Males were more affected (90%). A low educational level was seen in 122 (76%) cases. Road traffic incidents (RTI) (85%), assaults (7.5%), and falls (2.5%) were the main causes of TBI, with professional bike riders being frequently involved (27%). Only 15 patients were transported to the hospital by ambulance, and 14 of these were from a referring hospital. CT-imaging was performed in 78% of cases, and intracranial traumatic abnormalities were identified in 64% of cases. Financial constraints (93%) was the main reason for not performing a CT scan. Forty-six (33%) patients were discharged against medical advice (DAMA) due to financial constraints. Mortality was 14% (22/160) and high in patients with severe TBI (46%). DAMA had poor outcomes with QoLIBRI. Only four patients received post-injury physical therapy services. Conclusions: TBI in Cameroon mainly results from RTIs and commonly affects young adult males. Lack of pre-hospital care, financial constraints limiting both CT scanning and medical care, and a lack of acute physiotherapy services likely influenced care and outcomes adversely.

Gasoline fume inhalation induces apoptosis, inflammation, and favors Th2 polarization in C57BL/6 mice.

Gasoline exposure has been widely reported in the literature as being toxic to human health. However, the exact underlying molecular mechanisms triggered by its inhalation have not been thoroughly investigated. We herein present a model of sub-chronic, static gasoline vapor inhalation in adult female C57BL/6 mice. Animals were exposed daily to either gasoline vapors (0.86 g/animal/90 min) or ambient air for 5 days/week over 7 consecutive weeks. At the end of the study period, toxic and molecular mechanisms underlying the inflammatory, oxidative, and apoptotic effects triggered by gasoline vapors, were examined in the lungs and liver of gasoline-exposed (GE) mice. Static gasoline exposure induced a significant increase (+21%) in lungs/body weight (BW) ratio in GE versus control (CON) mice along with a pulmonary inflammation attested by histological staining. The latter was consistent with increases in the transcript levels of proinflammatory cytokines [Interleukins (ILs) 4 and 6], respectively by ~ 6- and 4-fold in the lungs of GE mice compared to CON. Interestingly, IL-10 expression was also increased by ~ 10-fold in the lungs of GE mice suggesting an attempt to counterbalance the established inflammation. Moreover, the pulmonary expression of IL-12 and TNF-α was downregulated by 2- and 4-fold, respectively, suggesting the skewing toward Th2 phenotype. Additionally, GE mice showed a significant upregulation in Bax/Bcl-2 ratio, caspases 3, 8, and 9 with no change in JNK expression in the lungs, suggesting the activation of both intrinsic and extrinsic apoptotic pathways. Static gasoline exposure over seven consecutive weeks had a minor hepatic portal inflammation attested by H&E staining along with an increase in the hepatic expression of the mitochondrial complexes in GE mice. Therefore, tissue damage biomarkers highlight the health risks associated with vapor exposure and may present potential therapeutic targets for recovery from gasoline intoxication.

Characterization of Calpain and Caspase-6-Generated Glial Fibrillary Acidic Protein Breakdown Products Following Traumatic Brain Injury and Astroglial Cell Injury.

Glial fibrillary acidic protein (GFAP) is the major intermediate filament III protein of astroglia cells which is upregulated in traumatic brain injury (TBI). Here we reported that GFAP is truncated at both the C- and N-terminals by cytosolic protease calpain to GFAP breakdown products (GBDP) of 46-40K then 38K following pro-necrotic (A23187) and pro-apoptotic (staurosporine) challenges to primary cultured astroglia or neuron-glia mixed cells. In addition, with another pro-apoptotic challenge (EDTA) where caspases are activated but not calpain, GFAP was fragmented internally, generating a C-terminal GBDP of 20 kDa. Following controlled cortical impact in mice, GBDP of 46-40K and 38K were formed from day 3 to 28 post-injury. Purified GFAP protein treated with calpain-1 and -2 generates (i) major N-terminal cleavage sites at A-56*A-61 and (ii) major C-terminal cleavage sites at T-383*Q-388, producing a limit fragment of 38K. Caspase-6 treated GFAP was cleaved at D-78/R-79 and D-225/A-226, where GFAP was relatively resistant to caspase-3. We also derived a GBDP-38K N-terminal-specific antibody which only labels injured astroglia cell body in both cultured astroglia and mouse cortex and hippocampus after TBI. As a clinical translation, we observed that CSF samples collected from severe human TBI have elevated levels of GBDP-38K as well as two C-terminally released GFAP peptides (DGEVIKES and DGEVIKE). Thus, in addition to intact GFAP, both the GBDP-38K as well as unique GFAP released C-terminal proteolytic peptides species might have the potential in tracking brain injury progression.

Concomitant Guillain-Barré Syndrome and COVID-19: A Meta-Analysis of Cases.

Background and Objectives: Recent findings demonstrate that the transmigration of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) to the nervous system implicates severe neurotropic pathologies, including the onset of the rare disease called Guillain-Barré syndrome (GBS) which is characterized by immune-mediated polyneuropathy. This study aimed to identify the predisposing factors and the clinical features of coronavirus disease 2019 (COVID-19)-induced GBS. Materials and Methods: We have performed an analysis of 147 cases. A systematic review of the published research work was performed per the PRISMA statement to obtain individual participant data (IPD) for the meta-analysis. The search was conducted through PubMed, using the combined search terms "Guillain-Barré syndrome" and "COVID-19". All case reports and series in the English language with accessed full text were included in the search. Results: A systematic database search led to the retrieval of 112 peer-reviewed articles published between 1 April 2020, and 8 February 2022. The articles comprised 16 case series and 96 case reports containing IPD for 147 patients. Our findings showed that 77.6% of all cases were 40 years or older. Males comprised most of the cases (65.3%; n = 96). The intensive care unit (ICU) admission was 44.9%, and the need for mechanical ventilation (MV) was 38.1%. The patients presented with hyporeflexia or areflexia (84.4%; n = 124), lower limb strength and sensation impairment (93.2%; n = 138), upper limb strength and sensation impairment (85.7; n = 126), and somatic sensation impairment (72.8%; n = 107). The patients presented with increased cerebral spinal fluid (CSF) protein levels (92%; n = 92) and the presence of CSF albuminocytological dissociation (83.5%; n = 71). The most common variant of GBS observed was acute inflammatory demyelinating polyneuropathy (AIDP). We found that predisposing factors concomitant with COVID-19 and GBS were male gender and older age. Among the cases, patient mortality was 10.9%. Conclusions: A gap of knowledge exists regarding the complete spectrum of clinical characteristics of COVID-19-related GBS. Recent findings suggest that SARS-CoV-2 triggers GBS, as it follows a similar para-infectious pattern as the other viral agents contributing to the onset of GBS.

Spinal sarcomas and immunity: An undervalued relationship.

Sarcomas, especially spine sarcomas, are rare yet debilitating and are underestimated types of cancer. Treatment options for spine sarcomas are limited to chemotherapy, radiotherapy and surgical intervention. Accumulating evidence suggests a complex course associated with the treatment of spine sarcomas as compared to other soft tissue sarcomas in the extremities since adjuvant therapy adds limited success to the oncological outcome. Likewise, the limitations of surgical interventions imposed by the proximity and high sensitivity of the spinal cord, leads to an increased recurrence and mortality rates associated with spine sarcomas. Finding novel treatment options to spine sarcomas as such is inevitable, necessitating a more thorough understanding of the different mechanisms of the underlying etiologies of these tumors. In this review, we discuss the most recent studies tackling the involvement of the immune system; a key player in the emergence of the different types of spine sarcomas and the promising immune-mediated targeted therapy that can be applied in these kind of rare cancers.

Novel therapeutic strategies for spinal osteosarcomas.

At the dawn of the third millennium, cancer has become the bane of twenty-first century man, and remains a predominant public health burden, affecting welfare and life expectancy globally. Spinal osteogenic sarcoma, a primary spinal malignant tumor, is a rare and challenging neoplastic disease to treat. After the conventional therapeutic modalities of chemotherapy, radiation and surgery have been exhausted, there is currently no available alternative therapy in managing cases of spinal osteosarcoma. The defining signatures of tumor survival are characterised by cancer cell ability to stonewall immunogenic attrition and apoptosis by various means. Some of these biomarkers, namely immune-checkpoints, have recently been exploited as druggable targets in osteosarcoma and many other different cancers. These promising strides made by the use of reinvigorated immunotherapeutic approaches may lead to significant reduction in spinal osteosarcoma disease burden and corresponding reciprocity in increase of survival rates. In this review, we provide the background to spinal osteosarcoma, and proceed to elaborate on contribution of the complex ecology within tumor microenvironment giving arise to cancerous immune escape, which is currently receiving considerable attention. We follow this section on the tumor microenvironment by a brief history of cancer immunity. Also, we draw on the current knowledge of treatment gained from incidences of osteosarcoma at other locations of the skeleton (long bones of the extremities in close proximity to the metaphyseal growth plates) to make a case for application of immunity-based tools, such as immune-checkpoint inhibitors and vaccines, and draw attention to adverse upshots of immune-checkpoint blockers as well. Finally, we describe the novel biotechnique of CRISPR/Cas9 that will assist in treatment approaches for personalized medication.

Dysregulation of Angiotensin Converting Enzyme 2 Expression and Function in Comorbid Disease Conditions Possibly Contributes to Coronavirus Infectious Disease 2019 Complication Severity.

ACE2 has emerged as a double agent in the COVID-19 ordeal, as it is both physiologically protective and virally conducive. The identification of ACE2 in as many as 72 tissues suggests that extrapulmonary invasion and damage is likely, which indeed has already been demonstrated by cardiovascular and gastrointestinal symptoms. On the other hand, identifying ACE2 dysregulation in patients with comorbidities may offer insight as to why COVID-19 symptoms are often more severe in these individuals. This may be attributed to a pre-existing proinflammatory state that is further propelled with the cytokine storm induced by SARS-CoV-2 infection or the loss of functional ACE2 expression as a result of viral internalization. Here, we aim to characterize the distribution and role of ACE2 in various organs to highlight the scope of damage that may arise upon SARS-CoV-2 invasion. Furthermore, by examining the disruption of ACE2 in several comorbid diseases, we offer insight into potential causes of increased severity of COVID-19 symptoms in certain individuals. SIGNIFICANCE STATEMENT: Cell surface expression of ACE2 determines the tissue susceptibility for coronavirus infectious disease 2019 infection. Comorbid disease conditions altering ACE2 expression could increase the patient's vulnerability for the disease and its complications, either directly, through modulation of viral infection, or indirectly, through alteration of inflammatory status.

Visfatin: An emerging adipocytokine bridging the gap in the evolution of cardiovascular diseases.

Visfatin/nicotinamide phosphoribosyltransferase (NAMPT) is an adipokine expressed predominately in visceral fat tissues. High circulating levels of visfatin/NAMPT have been implicated in vascular remodeling, vascular inflammation, and atherosclerosis, all of which pose increased risks of cardiovascular events. In this context, increased levels of visfatin have been correlated with several upregulated pro-inflammatory mediators, such as IL-1, IL-1Ra, IL-6, IL-8, and TNF-α. Furthermore, visfatin is associated with leukocyte recruitment by endothelial cells and the production of adhesion molecules such as vascular cell adhesion molecule 1, intercellular cell adhesion molecule 1, and E-selectin, which are well known to mediate the progression of atherosclerosis. Moreover, diverse angiogenic factors have been found to mediate visfatin-induced angiogenesis. These include matrix metalloproteinases, vascular endothelial growth factor, monocyte chemoattractant protein 1, and fibroblast growth factor 2. This review aims to provide a comprehensive overview of the pro-inflammatory and angiogenic actions of visfatin, with a focus on the pertinent signaling pathways whose dysregulation contributes to the pathogenesis of atherosclerosis. Most importantly, some hypotheses regarding the integration of the aforementioned factors with the plausible atherogenic effect of visfatin are put forth for consideration in future studies. The pharmacotherapeutic potential of modulating visfatin's roles could be important in the management of cardiovascular disease, which continues to be the leading cause of death worldwide.

Long-term cognitive deficits after traumatic brain injury associated with microglia activation.

Traumatic Brain Injury (TBI) is the most prevalent of all head injuries. Microglia play an essential role in homeostasis and diseases of the central nervous system. We hypothesize that microglia may play a beneficial or detrimental role in TBI depending on their state of activation and duration. In this study, we evaluated whether TBI results in a spatiotemporal change in microglia phenotype and whether it affects sensory-motor or learning and memory functions in male C57BL/6 mice. We used a panel of neurological and behavioral tests and a multi-color flow cytometry-based data analysis followed by unsupervised clustering to evaluate isolated microglia from injured brain tissue. We characterized several microglial phenotypes and their association with cognitive deficits. TBI results in a spatiotemporal increase in activated microglia that correlated negatively with spatial learning and memory at 35 days post-injury. These observations could define therapeutic windows and accelerate translational research to improve patient outcomes.

Characterization of Traumatic Brain Injury Research in the Middle East and North Africa Region: A Systematic Review.

OBJECTIVES: Traumatic brain injury (TBI) represents a major health concern worldwide with a large impact in the Middle East and North Africa (MENA) region as a consequence of protracted wars and conflicts that adversely affect the general population. Currently, systematic TBI studies in the MENA region are lacking, nonetheless they are immensely needed to enhance trauma management and increase survival rates among TBI patients. This systematic review aims to characterize TBI in the MENA region to guide future policy choices and research efforts and inform tailored guidelines capable of improving TBI management and patient treatment and outcome. Furthermore, it will serve as a road map to evaluate and assess knowledge of trauma impact on regional health systems that can be adopted by health-care providers to raise awareness and improve trauma care. METHODS: We conducted a comprehensive search strategy of several databases including MEDLINE/Ovid, PubMed, Embase, Scopus, CINAHL, Google Scholar, and the grey literature in accordance with the PROSPERO systematic review protocol CRD42017058952. Abstracts were screened, and selected eligible studies were reviewed independently by 2 reviewers. We collected demographics information along with TBI characteristics, mortality rates, and regional distribution. Data were extracted using REDCap and checked for accuracy. RESULTS: The search strategy yielded 23,385 citations; 147 studies met the eligibility criteria and were included in this review. Motor vehicle accident (MVA) was the leading cause of TBI (41%) in the MENA region, followed by the military- (15.6%) and fall- (8.8%) related TBI. Males predominantly suffer from TBI-related injuries (85%), with a high prevalence of MVA- and military-related TBI injuries. The TBI mortality rate was 12.9%. The leading causes of mortality were MVA (68%), military (20.5%), and assault (2.9%). The vast majority of reported TBI severity was mild (63.1%) compared to moderate (10.7%) and severe TBI (20.2%). Patients mainly underwent a Glasgow Coma Scale assessment (22.1%), followed by computed tomography scan (8.9%) and surgery (4.1%). CONCLUSIONS: Despite its clinical, social, and economic burden, the evidence of TBI research in the MENA region is scarce. Further research and high-quality epidemiological studies are urgently needed to gain a deep understanding of the TBI burden in the region, facilitate the allocation of adequate resources, implement effective preventive and intervention strategies and advise on the TBI patient management as reflective on the TBI patterns and modes.

Mapping Spatiotemporal Microproteomics Landscape in Experimental Model of Traumatic Brain Injury Unveils a link to Parkinson's Disease.

Traumatic brain injury (TBI) represents a major health concerns with no clinically-approved FDA drug available for therapeutic intervention. Several genomics and neuroproteomics studies have been employed to decipher the underlying pathological mechanisms involved that can serve as potential neurotherapeutic targets and unveil a possible underlying relation of TBI to other secondary neurological disorders. In this work, we present a novel high throughput systems biology approach using a spatially resolved microproteomics platform conducted on different brain regions in an experimental rat model of moderate of controlled cortical injury (CCI) at a temporal pattern postinjury (1 day, 3 days, 7 days, and 10 days). Mapping the spatiotemporal landscape of signature markers in TBI revealed an overexpression of major protein families known to be implicated in Parkinson's disease (PD) such as GPR158, HGMB1, synaptotagmin and glutamate decarboxylase in the ipsilateral substantia nigra. In silico bioinformatics docking experiments indicated the potential correlation between TBI and PD through alpha-synuclein. In an in vitro model, stimulation with palmitoylcarnitine triggered an inflammatory response in macrophages and a regeneration processes in astrocytes which also further confirmed the in vivo TBI proteomics data. Taken together, this is the first study to assess the microproteomics landscape in TBI, mainly in the substantia nigra, thus revealing a potential predisposition for PD or Parkinsonism post-TBI.