Search

Traumatic brain injury (TBI) results in both morbidity and mortality in which both innate and adaptive immune responses play an important role in the pathogenesis of TBI. Nonetheless, the role of gamma-delta (γδ) T cells in acute and chronic TBI is unknown. Here, we show that γδ T cells affect the pathophysiology of TBI as early as one day and up to one year after injury. TCRδ−/− mice exhibited reduced inflammation in acute TBI and improved neurocognitive functions in chronic TBI. We found that Vγ1 and Vγ4 γδ T cell subsets played opposing roles in TBI. Vγ4 γδ T cells infiltrate the brain and secrete IFN-γ and IL-17 that activate microglia and induce neuroinflammation, whereas Vγ1 γδ T cells infiltrate the brain and secrete TGF-β that maintains microglial homeostasis and dampens TBI. These findings provide new insights on the role of different γδ T cell subsets after brain injury and provide novel avenues for the development of targeted γδ T-cell-based therapy for the treatment of TBI.

Summary Myeloid suppressor cells promote tumor growth by a variety of mechanisms which are not fully characterized. We identified myeloid cells (MCs) expressing the latency-associated peptide (LAP) of TGF-β on their surface and LAPHi MCs that stimulate Foxp3+ Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-β inhibits the tolerogenic ability of LAPHi MCs. Furthermore, adoptive transfer of LAPHi MCs promotes Treg accumulation and tumor growth in vivo. Conversely, anti-LAP antibody, which reduces LAPHi MCs, slows cancer progression. Single-cell RNA-Seq analysis on tumor-derived immune cells revealed LAPHi dominated cell subsets with distinct immunosuppressive signatures, including those with high levels of MHCII and PD-L1 genes. Analogous to mice, LAP is expressed on myeloid suppressor cells in humans, and these cells are increased in glioma patients. Thus, our results identify a previously unknown function by which LAPHi MCs promote tumor growth and offer therapeutic intervention to target these cells in cancer., Graphical abstract, Highlights • Several myeloid cell subsets express surface LAP • Myeloid cells that express surface LAP possess immunosuppressive properties • LAP expressing myeloid cells induce Tregs and inhibit effector T cell function • LAP expressing myeloid cells promote tumor growth, Immunology; Cancer

Degradomics is a proteomics sub-discipline whose goal is to identify and characterize protease-substrate repertoires. With the aim of deciphering and characterizing key signature breakdown products, degradomics emerged to define encryptic biomarker neoproteins specific to certain disease processes. Remarkable improvements in structural and analytical experimental methodologies as evident in research investigating cellular behavior in neuroscience and cancer have allowed the identification of specific degradomes, increasing our knowledge about proteases and their regulators and substrates along with their implications in health and disease. A physiologic balance between protein synthesis and degradation is sought with the activation of proteolytic enzymes such as calpains, caspases, cathepsins, and matrix metalloproteinases. Proteolysis is essential for development, growth, and regeneration; however, inappropriate and uncontrolled activation of the proteolytic system renders the diseased tissue susceptible to further neurotoxic processes. In this article, we aim to review the protease-substrate repertoires as well as emerging therapeutic interventions in spinal cord injury at the degradomic level. Several protease substrates and their breakdown products, essential for the neuronal structural integrity and functional capacity, have been characterized in neurotrauma including cytoskeletal proteins, neuronal extracellular matrix glycoproteins, cell junction proteins, and ion channels. Therefore, targeting exaggerated protease activity provides a potentially effective therapeutic approach in the management of protease-mediated neurotoxicity in reducing the extent of damage secondary to spinal cord injury.

Traumatic brain injuries (TBIs) present a chief public health threat affecting nations worldwide. As numbers of patients afflicted by TBI are expected to rise, the necessity to increase our understanding of the pathophysiological mechanism(s) as a result of TBI mounts. TBI is known to augment the risk of developing a number of neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD). Hence, it is rational to assume that a common mechanistic ground links the pathophysiology of NDs to that of TBIs. Through this review, we aim to identify the protein-protein interactions, differential proteins expression, and PTMs, mainly glycosylation, that are involved in the pathogenesis of both ND and TBI. OVID and PubMed have been rigorously searched to identify studies that utilized advanced proteomic platforms (MS based) and systems biology tools to unfold the mechanism(s) behind ND in an attempt to unveil the mysterious biological processes that occur postinjury. Various PTMs have been found to be common between TBI and AD, whereas no similarities have been found between TBI and PD. Phosphorylated tau protein, glycosylated amyloid precursor protein, and many other modifications appear to be common in both TBI and AD. PTMs, differential protein profiles, and altered biological pathways appear to have critical roles in ND processes by interfering with their pathological condition in a manner similar to TBI. Advancement in glycoproteomic studies pertaining to ND and TBI is urgently needed in order to develop better diagnostic tools, therapies, and more favorable prognoses.

Background Hospital disaster and emergency preparedness are critical for country-specific readiness level to withstand disasters. Lebanon has consistently experienced man-made and natural disasters. This study sought to perform a comprehensive assessment of the country's level of hospital disaster and emergency preparedness. Method A 3-step methodology was designed. We first developed a Hospital Disaster and Emergency Preparedness (HDEP) tool following a comprehensive literature review. Second, we conducted a modified Delphi process with local experts to tailor the HDEP tool to the Lebanese context. Third, we administered the tool to directors of hospitals with at least a 100 bed capacity across all governates in Lebanon. Results Twenty four hospitals were included. All (100%) had a disaster and emergency response plan, but only 83% of hospital plans included a recovery phase, and 62% included a formal surge capacity plan. Most hospitals were equipped with basic medical/pharmaceutical supplies, onsite laboratories, blood banks and imaging facilities. Disaster-only medical carts and disaster-only supplies were available in only 33% and 42% of the hospitals, respectively. The majority of hospitals (71%) had a medical ICU, but only 25% had a surgery-specific ICU. A backup communication system was reported in only 66.7% of hospitals. Only 79% of hospitals routinely perform disaster drills. Post-disaster mental health services were present in 15% of surveyed hospitals. Conclusion A formal HDEP plan was common to Lebanese hospitals however gaps in disaster preparedness were identified. Future initiatives should focus on building upon existing resources and capacities to strengthen readiness and improve coordination.

Several neurologic diseases exhibit different prevalence and severity in males and females, highlighting the importance of understanding the influence of biologic sex and gender. Beyond host-intrinsic differences in neurologic development and homeostasis, evidence is now emerging that the microbiota is an important environmental factor that may account for differences between men and women in neurologic disease. The gut microbiota is composed of trillions of bacteria, archaea, viruses, and fungi, that can confer benefits to the host or promote disease. There is bidirectional communication between the intestinal microbiota and the brain that is mediated via immunologic, endocrine, and neural signaling pathways. While there is substantial interindividual variation within the microbiota, differences between males and females can be detected. In animal models, sex-specific microbiota differences can affect susceptibility to chronic diseases. In this review, we discuss the ways in which neurologic diseases may be regulated by the microbiota in a sex-specific manner.

This case-control study explores the association between pregnancy/birth complications and other factors with Autism Spectrum Disorder (ASD) in Lebanese subjects aged 2–18 years. Researchers interviewed 136 ASD cases from the American University of Beirut Medical Center Special Kids Clinic, and 178 controls selected by systematic digit dialing in the Greater-Beirut area. Male gender (Adjusted Odds Ratio [95% CI]: 3.9 [2.2–7.0]); postpartum feeding difficulties (2.5 [1.2–5.4]); maternal infections/complications during pregnancy (2.9 [1.5–5.5], 2.1 [1.1–3.9]); consanguinity (2.5 [1.0–6.0]); family history of psychiatric disorders (2.2 [1.1–4.4]) were risk factors for ASD. Being born first/second (0.52 [0.28–0.95]) and maternal psychological support during pregnancy (0.49 [0.27–0.89]) were negatively associated with ASD. Identifying ASD correlates is crucial for instigating timely screening and subsequent early intervention.

Neurological disorders represent major health concerns in terms of comorbidity and mortality worldwide. Despite a tremendous increase in our understanding of the pathophysiological processes involved in disease progression and prevention, the accumulated knowledge so far resulted in relatively moderate translational benefits in terms of therapeutic interventions and enhanced clinical outcomes. Aiming at specific neural molecular pathways, different strategies have been geared to target the development and progression of such disorders. The kallikrein-kinin system (KKS) is among the most delineated candidate systems due to its ubiquitous roles mediating several of the pathophysiological features of these neurological disorders as well as being implicated in regulating various brain functions. Several experimental KKS models revealed that the inhibition or stimulation of the two receptors of the KKS system (B1R and B2R) can exhibit neuroprotective and/or adverse pathological outcomes. This updated review provides background details of the KKS components and their functions in different neurological disorders including temporal lobe epilepsy, traumatic brain injury, stroke, spinal cord injury, Alzheimer’s disease, multiple sclerosis and glioma. Finally, this work will highlight the putative roles of the KKS components as potential neurotherapeutic targets and provide future perspectives on the possibility of translating these findings into potential clinical biomarkers in neurological disease.

Protein glycosylation is a posttranslational modification that affects more than half of all known proteins. Glycans covalently bound to biomolecules modulate their functions by both direct interactions, such as the recognition of glycan structures by binding partners, and indirect mechanisms that contribute to the control of protein conformation, stability, and turnover. The focus of this Review is the discussion of aberrant glycosylation related to brain cancer. Altered sialylation and fucosylation of N- and O-glycans play a role in the development and progression of brain cancer. Additionally, aberrant O-glycan expression has been implicated in brain cancer. This Review also addresses the clinical potential and applications of aberrant glycosylation for the detection and treatment of brain cancer. The viable roles glycans may play in the development of brain cancer therapeutics are addressed as well as cancer-glycoproteomics and personalized medicine. Glycoprotein alterations are considered as a hallmark of cancer while high expression in body fluids represents an opportunity for cancer assessment.

Degradomics has recently emerged as a subdiscipline in the omics era with a focus on characterizing signature breakdown products implicated in various disease processes. Driven by promising experimental findings in cancer, neuroscience, and metabolomic disorders, degradomics has significantly promoted the notion of disease-specific "degradome." A degradome arises from the activation of several proteases that target specific substrates and generate signature protein fragments. Several proteases such as calpains, caspases, cathepsins, and matrix metalloproteinases (MMPs) are involved in the pathogenesis of numerous diseases that disturb the physiologic balance between protein synthesis and protein degradation. While regulated proteolytic activities are needed for development, growth, and regeneration, uncontrolled proteolysis initiated under pathological conditions ultimately culminates into apoptotic and necrotic processes. In this chapter, we aim to review the protease-substrate repertoires in neural injury concentrating on traumatic brain injury. A striking diversity of protease substrates, essential for neuronal and brain structural and functional integrity, namely, encryptic biomarker neoproteins, have been characterized in brain injury. These include cytoskeletal proteins, transcription factors, cell cycle regulatory proteins, synaptic proteins, and cell junction proteins. As these substrates are subject to proteolytic fragmentation, they are ceaselessly exposed to activated proteases. Characterization of these molecules allows for a surge of "possible" therapeutic approaches of intervention at various levels of the proteolytic cascade.

Traumatic brain injury is a detrimental medical condition particularly when accompanied by diabetes. There are several comorbidities going along with diabetes including, but not limited to, kidney failure, obesity, coronary artery disease, peripheral vascular disease, hypertension, stroke, neuropathies and amputations. Unlike diabetes type 1, diabetes type 2 is more common in adults who simultaneously suffer from other comorbid conditions making them susceptible to repetitive fall incidents and sustaining head trauma. The resulting brain insult exacerbates current psychiatric disorders such as depression and anxiety, which, in turn, increases the risk of sustaining further brain traumas. The relationship between diabetes, traumatic brain injury and psychiatric health constitutes a triad forming a non-reversible vicious cycle. At the proteomic and psychiatric levels, cellular, molecular and behavioral alterations have been reported with the induction of non-traumatic brain injury in diabetic models such as stroke. However, research into traumatic brain injury has not been systematically investigated. Thus, in cases of diabetic neuropathy complicated with traumatic brain injury, utilizing fine structural and analytical techniques allows the identification of key biological markers that can then be used as innovative diagnostics as well as novel therapeutic targets in an attempt to treat diabetes and its sequelae especially those arising from repetitive mild brain trauma.

The aim of this study was to determine the incidence and genetic diversity of astrovirus (AstV) detected in children hospitalized for gastroenteritis (GE).A multi-center, hospital-based surveillance study was conducted across Lebanon to investigate the incidence of AstV among diarrheal hospitalizations. Viral RNA was extracted from stool samples collected between 2011 and 2013 from children, below the age of 5years, hospitalized for GE at six medical centers across Lebanon. Demographic and clinical data were collected and analyzed. RNA of eligible samples (n=739) was screened by two AstV-specific PCR assays followed by genotype-specific PCR. Sanger sequencing and phylogenetic analysis were performed for genotypic characterization.Overall, 5.5% (41/739) of rotavirus-negative stool samples collected from hospitalized children5years old tested positive for AstV infection. AstV infections were detected all year long. Diarrhea, dehydration, vomiting and fever were the most common symptoms associated with AstV infections. Children aged 48-59months had the highest incidence of AstV. Using the Vesikari Scoring System to assess clinical severity, 85.4% of children with AstV had a score11, indicating severe GE. Genotype-specific PCR identified 22 classical and 4 MLB-like AstV specimens. Further sequencing and phylogenetic analysis of orf1b and orf2 genes revealed that AstV classical 1-3, 5, 6, and 8, MLB-1, VA-1 and -2 genotypes circulated in Lebanon. Recombination between classical AstV strains was detected in several cases as evident by the lack of congruency in the tree topologies of the orf1b and orf2. Two cases of mixed infections between classical and non-classical genotypic strains were recorded.High genetic diversity was detected among AstVs in Lebanon. AstVs are associated with 5.5% of non-rotavirus GE-associated hospitalizations in children under five years in Lebanon.

Degradomics has recently emerged as a subdiscipline in the omics era with a focus on characterizing signature breakdown products implicated in various disease processes. Driven by promising experimental findings in cancer, neuroscience, and metabolomic disorders, degradomics has significantly promoted the notion of disease-specific "degradome." A degradome arises from the activation of several proteases that target specific substrates and generate signature protein fragments. Several proteases such as calpains, caspases, cathepsins, and matrix metalloproteinases (MMPs) are involved in the pathogenesis of numerous diseases that disturb the physiologic balance between protein synthesis and protein degradation. While regulated proteolytic activities are needed for development, growth, and regeneration, uncontrolled proteolysis initiated under pathological conditions ultimately culminates into apoptotic and necrotic processes. In this chapter, we aim to review the protease-substrate repertoires in neural injury concentrating on traumatic brain injury. A striking diversity of protease substrates, essential for neuronal and brain structural and functional integrity, namely, encryptic biomarker neoproteins, have been characterized in brain injury. These include cytoskeletal proteins, transcription factors, cell cycle regulatory proteins, synaptic proteins, and cell junction proteins. As these substrates are subject to proteolytic fragmentation, they are ceaselessly exposed to activated proteases. Characterization of these molecules allows for a surge of "possible" therapeutic approaches of intervention at various levels of the proteolytic cascade.

Respiratory syncytial virus (RSV) is a common cause of respiratory tract infections in children and immunocompromised individuals. A multi-center surveillance of the epidemiologic and molecular characteristics of RSV circulating in Lebanon was performed. The attachment (G) and fusion (F) glycoproteins were analyzed and compared to those reported regionally and globally. 16% (83/519) of the nasopharyngeal swabs collected during the 2016/17 season tested positive for RSV; 50% (27/54) were RSV-A and 50% (27/54) were RSV-B. Phylogenetic analysis of the G glycoprotein revealed predominance of the RSVA ON1 genotype, in addition to two novel Lebanese genotype variants, hereby named LBA1 and LBA2, which descended from the ON1 and NA2 RSV-A genotypes, respectively. RSV-B strains belonged to BA9 genotype except for one BA10. Deduced amino acid sequences depicted several unique substitutions, alteration of glycosylation patterns and the emergence of palivizumab resistance among the Lebanese viruses. The emergence of ON1 and other novel genotypes that are resistant to palivizumab highlights the importance of monitoring RSV globally.

The complement system is one of the body’s major innate immune defense mechanisms in vertebrates. Its function is to detect foreign bodies and promote their elimination through opsonisation or lysis. Complement proteins play an important role in the immunopathogenesis of several disorders. However, excessive complement activation does not confer more protection but instead leads to several autoimmune and inflammatory diseases. With inappropriate activation of the complement system, activated complement proteins and glycoproteins may damage both healthy and diseased tissues. Development of complement inhibitors represents an effective approach in controlling dysregulated complement activity and reducing disease severity, yet few studies have investigated the nature and role of novel complement inhibitory proteins of viral origin. Viral complement inhibitors have important implications in understanding the importance of complement inhibition and their role as a promising novel therapeutic approach in diseases caused by dysregulated complement function. In this review, we discuss the role and importance of complement inhibitors derived from several viruses in the scope of human inflammatory and autoimmune diseases.

The original version of this article unfortunately contained a mistake. The family name of Hadi Abou El Hassan was incorrect. The correct name is Hadi Abou-El-Hassan.

Traumatic brain injury, often referred to as the "silent epidemic," is a nondegenerative, non-congenital insult to the brain due to a blow or penetrating object that disrupts the function of the brain leading to permanent or temporary impairment of cognition, physical and psychosocial functions. Traumatic brain injury usually has poor prognosis for long-term treatment and is a major cause of mortality and morbidity worldwide; approximately 10 million deaths and/or hospitalizations annually are directly related to traumatic brain injury. Traumatic brain injury involves primary and secondary insults. Primary injury occurs during the initial insult, and results from direct or indirect force applied to the physical structures of the brain. Secondary injury is characterized by longer-term degeneration of neurons, glial cells, and vascular tissues due to activation of several proteases, glutamate and pro-inflammatory cytokine secretion. In addition, there is growing evidence that the blood-brain barrier is involved in the course of traumatic brain injury pathophysiology and has detrimental effects on the overall pathology of brain trauma, as will be discussed in this work.