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Virologica Sinica Feb 2021Tyro3, Axl, and Mertk (TAM) receptors play multiple roles in a myriad of physiological and pathological processes, varying from promoting the phagocytic clearance of...
Tyro3, Axl, and Mertk (TAM) receptors play multiple roles in a myriad of physiological and pathological processes, varying from promoting the phagocytic clearance of apoptotic cells, sustaining the immune and inflammatory homeostasis, maintaining the blood-brain barrier (BBB) integrity and central nervous system (CNS) homeostasis, to mediating cancer malignancy and chemoresistance. Growth arrest-specific protein 6 (Gas6) and protein S (Pros1) are the two ligands that activate TAM receptors. Recently, TAM receptors have been reported to mediate cell entry and infection of multitudinous enveloped viruses in a manner called apoptotic mimicry. Moreover, TAM receptors are revitalized during viral entry and infection, which sequesters innate immune and inflammatory responses, facilitating viral replication and immune evasion. However, accumulating evidence have now proposed that TAM receptors are not required for the infection of these viruses in vivo. In addition, TAM receptors protect mice against the CNS infection of neuroinvasive viruses and relieve the brain lesions during encephalitis. These protective effects are achieved through maintaining BBB integrity, attenuating proinflammatory cytokine production, and promoting neural cell survival. TAM receptors also regulate the programmed cell death modes of virus-infected cells, which have profound impacts on the pathogenesis and outcome of infection. Here, we systematically review the functionalities and underlying mechanisms of TAM receptors and propose the potential application of TAM agonists to prevent severe viral encephalitis.
Topics: Animals; Mice; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Signal Transduction; Virus Diseases; c-Mer Tyrosine Kinase
PubMed: 32720213
DOI: 10.1007/s12250-020-00264-9 -
Frontiers in Immunology 2021The immune system is unique among all biological sub-systems in its usage of DNA-editing enzymes to introduce targeted gene mutations and double-strand DNA breaks to...
Evolutionary Comparative Analyses of DNA-Editing Enzymes of the Immune System: From 5-Dimensional Description of Protein Structures to Immunological Insights and Applications to Protein Engineering.
The immune system is unique among all biological sub-systems in its usage of DNA-editing enzymes to introduce targeted gene mutations and double-strand DNA breaks to diversify antigen receptor genes and combat viral infections. These processes, initiated by specific DNA-editing enzymes, often result in mistargeted induction of genome lesions that initiate and drive cancers. Like other molecules involved in human health and disease, the DNA-editing enzymes of the immune system have been intensively studied in humans and mice, with little attention paid (< 1% of published studies) to the same enzymes in evolutionarily distant species. Here, we present a systematic review of the literature on the characterization of one such DNA-editing enzyme, activation-induced cytidine deaminase (AID), from an evolutionary comparative perspective. The central thesis of this review is that although the evolutionary comparative approach represents a minuscule fraction of published works on this and other DNA-editing enzymes, this approach has made significant impacts across the fields of structural biology, immunology, and cancer research. Using AID as an example, we highlight the value of the evolutionary comparative approach in discoveries already made, and in the context of emerging directions in immunology and protein engineering. We introduce the concept of 5-dimensional (5D) description of protein structures, a more nuanced view of a structure that is made possible by evolutionary comparative studies. In this higher dimensional view of a protein's structure, the classical 3-dimensional (3D) structure is integrated in the context of real-time conformations and evolutionary time shifts (4 dimension) and the relevance of these dynamics to its biological function (5 dimension).
Topics: Animals; Biological Evolution; Cytidine Deaminase; DNA; Humans; Protein Conformation; Protein Engineering
PubMed: 34135887
DOI: 10.3389/fimmu.2021.642343 -
Frontiers in Immunology 2020To ultimately combat the emerging COVID-19 pandemic, it is desired to develop an effective and safe vaccine against this highly contagious disease caused by the...
To ultimately combat the emerging COVID-19 pandemic, it is desired to develop an effective and safe vaccine against this highly contagious disease caused by the SARS-CoV-2 coronavirus. Our literature and clinical trial survey showed that the whole virus, as well as the spike (S) protein, nucleocapsid (N) protein, and membrane (M) protein, have been tested for vaccine development against SARS and MERS. However, these vaccine candidates might lack the induction of complete protection and have safety concerns. We then applied the Vaxign and the newly developed machine learning-based Vaxign-ML reverse vaccinology tools to predict COVID-19 vaccine candidates. Our Vaxign analysis found that the SARS-CoV-2 N protein sequence is conserved with SARS-CoV and MERS-CoV but not from the other four human coronaviruses causing mild symptoms. By investigating the entire proteome of SARS-CoV-2, six proteins, including the S protein and five non-structural proteins (nsp3, 3CL-pro, and nsp8-10), were predicted to be adhesins, which are crucial to the viral adhering and host invasion. The S, nsp3, and nsp8 proteins were also predicted by Vaxign-ML to induce high protective antigenicity. Besides the commonly used S protein, the nsp3 protein has not been tested in any coronavirus vaccine studies and was selected for further investigation. The nsp3 was found to be more conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV than among 15 coronaviruses infecting human and other animals. The protein was also predicted to contain promiscuous MHC-I and MHC-II T-cell epitopes, and the predicted linear B-cell epitopes were found to be localized on the surface of the protein. Our predicted vaccine targets have the potential for effective and safe COVID-19 vaccine development. We also propose that an "Sp/Nsp cocktail vaccine" containing a structural protein(s) (Sp) and a non-structural protein(s) (Nsp) would stimulate effective complementary immune responses.
Topics: Animals; Betacoronavirus; COVID-19; COVID-19 Vaccines; Coronavirus Infections; Epitopes, B-Lymphocyte; Humans; Immunogenicity, Vaccine; Machine Learning; Middle East Respiratory Syndrome Coronavirus; Pandemics; Pneumonia, Viral; SARS-CoV-2; Viral Proteins; Viral Vaccines
PubMed: 32719684
DOI: 10.3389/fimmu.2020.01581 -
Cureus Apr 2020Cerebral venous sinus thrombosis (CVST) is a rare condition characterized by elevated intracranial pressure due to impaired cerebral venous drainage, potentially... (Review)
Review
Cerebral venous sinus thrombosis (CVST) is a rare condition characterized by elevated intracranial pressure due to impaired cerebral venous drainage, potentially leading to life-threatening consequences. We searched the PubMed electronic database for 'cerebral venous sinus thrombosis' and 'prothrombotic' cases reported in adults (19+ years) and conducted a systematic review for the published literature in the English language pooled with a case from our institution. Data were analyzed regarding patient demographics, risk factors, clinical features, treatment modalities, and outcomes when available. Thirty cases of CVST were identified (29 case reports, of whom two were described in a case series, and the one case from our institution). The patients' mean age was 39 years (range: 19 - 65). The male: female ratio was 1.14:1. The majority (73.3%) had at least one preexisting risk factor, with prescription drug use being the most common risk factor (33.3%) shared among all patients. Most patients (83.3%) presented with at least two symptoms. The most common presenting symptoms were headache (70%), gastrointestinal disturbance (50%), and seizures (40%). Focal deficits (36.7%), vision disturbances (30%), and altered consciousness (20%) were the remaining presenting complaints. Twelve cases (40%) commented on papilledema, with 10 (83.3%) having papilledema present. Anticoagulation abnormalities were examined in 26 cases (86.7%), out of which four cases (15.4%) had isolated protein S (PS) deficiency, three cases (11.5%) had isolated antithrombin III (ATIII) deficiency, and one case (3.8%) had isolated protein C (PC) deficiency. The most common initial imaging modality (22 cases, 73.3%), and most commonly used overall (23 cases, 76.7%), was computed tomography (CT). Magnetic resonance imaging (MRI) was the second most common imaging modality for initial use (five cases, 16.7%), diagnosis or confirmation of CVST (eight cases, 26.7%), and overall (21 cases, 70%). Heparin treatment was involved in the treatment of 18 cases (60%), and warfarin treatment was used in 10 cases (33.3%). Heparin-warfarin combination treatment was utilized in eight cases (26.7%). Most patients survived (28 cases, 93.3%), while the two remaining patients died secondary to brain death from the CVST (6.7%). The findings from this study highlight the clinical characteristics of CVST. Therefore, this study aims to increase awareness of this rare entity. Physicians should maintain a high index of suspicion in order to diagnose patients presenting in the proper clinical context, given this case shares various forms of presentations with other common clinical conditions but requires long-term anticoagulation.
PubMed: 32411555
DOI: 10.7759/cureus.7654 -
Nutrients Sep 2023Active-duty military personnel are subjected to sustained periods of energy deficit during combat and training, leaving them susceptible to detrimental reductions in... (Review)
Review
Active-duty military personnel are subjected to sustained periods of energy deficit during combat and training, leaving them susceptible to detrimental reductions in body weight. The importance of adequate dietary protein intake during periods of intense physical training is well established, where previous research has primarily focused on muscle protein synthesis, muscle recovery, and physical performance. Research on how protein intake may influence body weight regulation in this population is lacking; therefore, the objective of this review was to evaluate the role of dietary protein in body weight regulation among active-duty military during an energy deficit. A literature search based on fixed inclusion and exclusion criteria was performed. English language peer-reviewed journal articles from inception to 3 June 2023 were selected for extraction and quality assessment. Eight studies were identified with outcomes described narratively. The study duration ranged from eight days to six months. Protein was directly provided to participants in all studies except for one. Three studies supplied additional protein via supplementation. The Downs and Black Checklist was used to assess study quality. Five studies were classified as good, two as fair, and one as excellent. All studies reported mean weight loss following energy deficit: the most severe was 4.0 kg. Protein dose during energy deficit varied from 0.5 g/kg/day to 2.4 g/kg/day. Six studies reported mean reductions in fat mass, with the largest being 4.5 kg. Four studies reported mean reductions in fat-free mass, while two studies reported an increase. Results support the recommendation that greater than 0.8 g/kg/day is necessary to mitigate the impact of energy deficit on a decline in lean body mass, while intakes up to 1.6 g/kg/day may be preferred. However, exact recommendations cannot be inferred as the severity and duration of energy deficit varied across studies. Longer and larger investigations are needed to elucidate protein's role during energy deficit in active-duty military.
Topics: Humans; Energy Intake; Military Personnel; Dietary Proteins; Exercise; Body Weight
PubMed: 37764730
DOI: 10.3390/nu15183948 -
Blood Advances Jan 2022Idiopathic purpura fulminans (IPF) is a rare but severe prothrombotic coagulation disorder that can occur after chickenpox or human herpesvirus 6 (HHV-6) infection. IPF...
Idiopathic purpura fulminans (IPF) is a rare but severe prothrombotic coagulation disorder that can occur after chickenpox or human herpesvirus 6 (HHV-6) infection. IPF leads to an autoantibody-mediated decrease in the plasma concentration of protein S. We conducted a retrospective multicenter study involving patients with IPF from 13 French pediatric centers and a systematic review of cases in published literature. Eighteen patients were included in our case series, and 34 patients were included as literature review cases. The median age was 4.9 years, and the diagnostic delay after the first signs of viral infection was 7 days. The lower limbs were involved in 49 patients (94%) with typical lesions. In all, 41 patients (78%) had a recent history of varicella-zoster virus infection, and 7 patients (14%) had been infected by HHV-6. Most of the patients received heparin (n = 51; 98%) and fresh frozen plasma transfusions (n = 41; 79%); other treatment options were immunoglobulin infusion, platelet transfusion, corticosteroid therapy, plasmapheresis, and coagulation regulator concentrate infusion. The antithrombin level and platelet count at diagnosis seemed to be associated with severe complications. Given the rarity of this disease, the creation of a prospective international registry is required to consolidate these findings.
Topics: Child; Child, Preschool; Humans; Chickenpox; Delayed Diagnosis; Prospective Studies; Protein S; Purpura Fulminans; Retrospective Studies
PubMed: 34788405
DOI: 10.1182/bloodadvances.2021005126 -
Turkish Neurosurgery 2022To evaluate all serum biomarkers in sports-related concussion injury (SRC) to determine diagnostic validity, changes with symptom severity, and return to play, as well...
AIM
To evaluate all serum biomarkers in sports-related concussion injury (SRC) to determine diagnostic validity, changes with symptom severity, and return to play, as well as detect early changes in serum concentration.
MATERIAL AND METHODS
Studies were searched in various electronic databases (MEDLINE/PubMed, EMBASE, CINAHL, Scopus and Cochrane databases) from their commencement to May 2021. Studies were included if athletes aged 12 years and older were diagnosed with a concussion injury and evaluated using serum biomarkers. Studies including athletes with injuries other than concussion injuries were excluded. Articles with fewer than 20 concussed athletes were excluded. There were 1782 articles identified.
RESULTS
After exclusion a total of 17 articles qualified for systematic review. S100 calcium binding protein ? (S-100?) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) showed promising results in distinguishing concussed athletes from contact sports and non-athlete controls. Most of the serum biomarkers increased within 6 hours of SRC. Serum neurofilament light protein (NFL) positively correlated with the severity of post-concussion symptoms. NFL, tau and Interleukins (IL-1 Ra and IL-6) have the potential to determine return to play.
CONCLUSION
Serum biomarker measurement is an objective tool that aids in early diagnosis and predicts the severity and prognosis of injury.
Topics: Athletic Injuries; Biomarkers; Brain Concussion; Calcium-Binding Proteins; Humans; Hydrolases; Interleukin-1; Interleukin-6; Tumor Necrosis Factor Ligand Superfamily Member 14; Ubiquitins
PubMed: 35929029
DOI: 10.5137/1019-5149.JTN.35745-21.3 -
Frontiers in Cellular Neuroscience 2021Women are more affected by stroke than men. This might, in part, be explained by sex differences in stroke pathophysiology. The hemostasis system is influenced by sex... (Review)
Review
Women are more affected by stroke than men. This might, in part, be explained by sex differences in stroke pathophysiology. The hemostasis system is influenced by sex hormones and associated with female risk factors for stroke, such as migraine. To systematically review possible sex differences in hemostatic related factors in patients with ischemic stroke in general, and the influence of migraine on these factors in women with ischemic stroke. We included 24 studies with data on sex differences of hemostatic factors in 7247 patients with ischemic stroke (mean age 57-72 years, 27-57% women) and 25 hemostatic related factors. Levels of several factors were higher in women compared with men; FVII:C (116% ± 30% vs. 104% ± 30%), FXI (0.14 UI/mL higher in women), PAI-1 (125.35 ± 49.37 vs. 96.67 ± 38.90 ng/mL), D-dimer (1.25 ± 0.31 vs. 0.95 ± 0.24 μg/mL), and aPS (18.7% vs. 12.0% positive). In contrast, protein-S (86.2% ± 23.0% vs. 104.7% ± 19.8% antigen) and P-selectin (48.9 ± 14.4 vs. 79.1 ± 66.7 pg/mL) were higher in men. Most factors were investigated in single studies, at different time points after stroke, and in different stroke subtypes. Only one small study reported data on migraine and hemostatic factors in women with ischemic stroke. No differences in fibrinogen, D-dimer, t-PA, and PAI-1 levels were found between women with and without migraine. Our systematic review suggests that sex differences exist in the activation of the hemostatic system in ischemic stroke. Women seem to lean more toward increased levels of procoagulant factors whereas men exhibit increased levels of coagulation inhibitors. To obtain better insight in sex-related differences in hemostatic factors, additional studies are needed to confirm these findings with special attention for different stroke phases, stroke subtypes, and not in the least women specific risk factors, such as migraine.
PubMed: 34858141
DOI: 10.3389/fncel.2021.711604 -
BioMed Research International 2021The SARS-CoV-2 virus is the cause of the latest pandemic of the 21st century; it is responsible for the development of COVID-19. Within the multiple study models for...
BACKGROUND
The SARS-CoV-2 virus is the cause of the latest pandemic of the 21st century; it is responsible for the development of COVID-19. Within the multiple study models for both the biology and the treatment of SARS-CoV-2, the use of stem cells has been proposed because of their ability to increase the immune response and to repair tissue. Therefore, the objective of this review is to evaluate the role of stem cells against SARS-CoV-2 and COVID-19 in order to identify their potential as a study model and as a possible therapeutic source against tissue damage caused by this virus. Therefore, the following research question was established: What is the role of stem cells in the study of SARS-CoV-2 and the treatment of COVID-19?
MATERIALS AND METHODS
A search was carried out in the electronic databases of PUBMED, Scopus, and ScienceDirect. The following keywords were used: "SARS-CoV-2," "COVID-19," and "STEM CELL," plus independent search strategies with the Boolean operators "OR" and "AND." The identified reports were those whose main objective was the study of stem cells in relation to SARS-CoV-2 or COVID-19. For the development of this study, the following inclusion criteria were taken into account: studies whose main objective was the study of stem cells in relation to SARS-CoV-2 or COVID-19 and clinical case studies, case reports, clinical trials, pilot studies, in vitro, or in vivo studies. For assessment of the risk of bias for in vitro studies, the SciRAP tool was used. The data collected for each type of study, clinical or in vitro, were analyzed with descriptive statistics using the SPSS V.22 program.
RESULTS
Of the total of studies included ( = 39), 22 corresponded to in vitro investigations and 17 to human studies (clinical cases ( = 9), case series ( = 2), pilot clinical trials ( = 5), clinical trials ( = 1)). In vitro studies that induced pluripotent stem cells were the most used ( = 12), and in clinical studies, the umbilical stem cells derived were the most reported ( = 11). The mean age of the study subjects was 58.3 years. After the application of stem cell therapy, the follow-up period was 8 days minimum and 90 days maximum. . The mechanism by which the virus enters the cell is through protein "S," located on the surface of the membrane, by recognizing the ACE2 receptor located on the target cell. The evidence that the expression of ACE2 and TMPRSS2 in stem cells indicates that stem cells from bone marrow and amniotic fluid have very little expression. This shows that stem cell has a low risk of infection with SARS-CoV-2.
CONCLUSION
The use of stem cells is a highly relevant therapeutic option. It has been shown in both in vitro studies and clinical trials that it counteracts the excessive secretion of cytokines. There are even more studies that focus on long-term follow-up; thus, the potential for major side effects can be analyzed more clearly. Finally, the ethical use of stem cells from fetal or infant origin needs to be regulated. The study was registered in PROSPERO (no. CRD42021229038). The limitations of the study were because of the methodology employed, the sample was not very large, and the follow-up period of the clinical studies was relatively short.
Topics: COVID-19; Clinical Trials as Topic; Humans; SARS-CoV-2; Stem Cell Transplantation; Stem Cells
PubMed: 34458372
DOI: 10.1155/2021/9915927