Genetics, adaptation to environmental changes and archaic admixture in the pathogenesis of diabetes mellitus in Indigenous Australians.

Indigenous Australians are particularly affected by type 2 diabetes mellitus (T2D) due to both their genetic susceptibility and a range of environmental and lifestyle risk factors. Recent genetic studies link predisposition to some diseases, including T2D, to alleles acquired from archaic hominins, such as Neanderthals and Denisovans, which persist in the genomes of modern humans today. Indo-Pacific human populations, including Indigenous Australians, remain extremely underrepresented in genomic research with a paucity of data examining the impact of Denisovan or Neanderthal lineages on human phenotypes in Oceania. The few genetic studies undertaken emphasize the uniqueness and antiquity of Indigenous Australian genomes, with possibly the largest proportion of Denisovan ancestry of any population in the world. In this review, we focus on the potential contributions of ancient genes/pathways to modern human phenotypes, while also highlighting the evolutionary roles of genetic adaptation to dietary and environmental changes associated with an adopted Western lifestyle. We discuss the role of genetic and epigenetic factors in the pathogenesis of T2D in understudied Indigenous Australians, including the potential impact of archaic gene lineages on this disease. Finally, we propose that greater understanding of the underlying genetic predisposition may contribute to the clinical efficacy of diabetes management in Indigenous Australians. We suggest that improved identification of T2D risk variants in Oceania is needed. Such studies promise to clarify how genetic and phenotypic differences vary between populations and, crucially, provide novel targets for personalised medical therapies in currently marginalized groups.

Optimizing the bioenergy water footprint by selecting SRC willow canopy phenotypes: regional scenario simulations.

BACKGROUND AND AIMS: Bioenergy is central for the future energy mix to mitigate climate change impacts; however, its intricate link with the water cycle calls for an evaluation of the carbon-water nexus in biomass production. The great challenge is to optimize trade-offs between carbon harvest and water use by choosing cultivars that combine low water use with high productivity. METHODS: Regional scenarios were simulated over a range of willow genotype × environment interactions for the major UK soil × climate variations with the process-based model LUCASS. Soil available water capacity (SAWC) ranged from 51 to 251 mm and weather represented the north-west (wet, cool), north-east (dry, cool), south-west (wet, warm) and south-east (dry, warm) of the UK. Scenario simulations were evaluated for small/open narrow-leaf (NL) versus large/closed broad-leaf (BL) willow canopy phenotypes using baseline (1965-89) and warmer recent (1990-2014) weather data. KEY RESULTS: The low productivity under baseline climate in the north could be compensated by choosing BL cultivars (e.g. 'Endurance'). Recent warmer climate increased average productivity by 0.5-2.5 t ha-1, especially in the north. The modern NL cultivar 'Resolution' had the smallest and most efficient water use. On marginal soils (SAWC <100 mm), yields remained below an economic threshold of 9 t ha-1 more frequently under baseline than recent climate. In the drought-prone south-east, 'Endurance' yielded less than 'Resolution', which consumed on average 17 mm year-1 less water. Assuming a planting area of 10 000 ha, in droughty years between 1.3 and 4.5 × 106 m3 of water could be saved, with a small yield penalty, for 'Resolution'. CONCLUSIONS: With an increase in air temperature and occasional water scarcities expected with climate change, high-yielding NL cultivars should be the preferred choice for sustainable use of marginal lands and reduced competition with agricultural food crops.

Cooperative Interactions of Three Hotspot Heparin Binding Residues Are Critical for Allosteric Activation of Antithrombin by Heparin.

Heparin allosterically activates the anticoagulant serpin, antithrombin, by binding through a sequence-specific pentasaccharide and inducing activating conformational changes in the protein. Three basic residues of antithrombin, Lys114, Lys125, and Arg129, have been shown to be hotspots for binding the pentasaccharide, but the molecular basis for such hotspot binding has been unclear. To determine whether this results from cooperative interactions, we analyzed the effects of single, double, and triple mutations of the hotspot residues on pentasaccharide binding and activation of antithrombin. Double-mutant cycles revealed that the contribution of each residue to pentasaccharide binding energy was progressively reduced when one or both of the other residues were mutated, indicating strong coupling between each pair of residues that was dependent on the third residue and reflective of the three residues acting as a cooperative unit. Rapid kinetic studies showed that the hotspot residue mutations progressively abrogated the ability of the pentasaccharide to bind productively to native antithrombin and to conformationally activate the serpin by engaging the hotspot residues in an induced-fit interaction. Examination of the antithrombin-pentasaccharide complex structure revealed that the hotspot residues form two adjoining binding pockets for critical sulfates of the pentasaccharide that structurally link these residues. Together, these findings demonstrate that cooperative interactions of Lys114, Lys125, and Arg129 are critical for the productive induced-fit binding of the heparin pentasaccharide to antithrombin that allosterically activates the anticoagulant function of the serpin.

Emerging role of serpinE2/protease nexin-1 in hemostasis and vascular biology.

Serine protease inhibitors, termed serpins, are key regulators in many biologic events. Protease nexin-1 (PN-1) is a serpin that is barely detectable in plasma but found in many organs and produced by most cell types, including monocytes, platelets, and vascular cells. It has a large inhibition spectrum because it is the most efficient tissue inhibitor of thrombin but also a powerful inhibitor of plasminogen activators and plasmin. It has a high affinity for glycosaminoglycans, such as heparan sulfates, which potentiate its activity toward thrombin and target it to the pericellular space. PN-1 has been previously largely described as a crucial regulator of the proteolytic activity in nerves and of central and peripheral nervous system function. In contrast, little was known about its involvement in hemostasis and vascular biology. This article reviews recent data underlining its emerging role as a key factor in the responses of vessels to injury. Indeed, studies of PN-1-deficient mice have established important antithrombotic and antifibrinolytic properties of this serpin that have heretofore gone unrecognized. The roles of PN-1 in the areas of hemostasis and thrombosis summarized here provide insights that may allow the development of drugs and treatment strategies to prevent or limit thrombotic disorders.

Smad2-dependent protease nexin-1 overexpression differentiates chronic aneurysms from acute dissections of human ascending aorta.

OBJECTIVE: Tissue activation of proteolysis is involved in acute intramural rupture (dissections, acute ascending aortic dissection) and in progressive dilation (aneurysms, thoracic aneurysm of the ascending aorta) of human ascending aorta. The translational aim of this study was to characterize the regulation of antiproteolytic serpin expression in normal, aneurysmal, and dissecting aorta. APPROACH AND RESULTS: We explored expression of protease nexin-1 (PN-1) and plasminogen activator inhibitor-1 and their regulation by the Smad2 signaling pathway in human tissue and cultured vascular smooth muscle cells (VSMCs) of aneurysms (thoracic aneurysm of the ascending aorta; n=46) and acute dissections (acute ascending aortic dissection; n=10) of the ascending aorta compared with healthy aortas (n=10). Both PN-1 and plasminogen activator inhibitor-1 mRNA and proteins were overexpressed in medial tissue extracts and primary VSMC cultures from thoracic aneurysm of the ascending aorta compared with acute ascending aortic dissection and controls. Transforming growth factor-ß induced increased PN-1 expression in control but not in aneurysmal VSMCs. PN-1 and plasminogen activator inhibitor-1 overexpression by aneurysmal VSMCs was associated with increased Smad2 binding on their promoters and, functionally, resulted in VSMC self-protection from plasmin-induced detachment and death. This phenomenon was restricted to aneurysms and not observed in acute dissections. CONCLUSIONS: These results demonstrate that epigenetically regulated PN-1 overexpression promotes development of an antiproteolytic VSMC phenotype and might favor progressive aneurysmal dilation, whereas absence of this counter-regulation in dissections would lead to acute wall rupture.

New prospects in the roles of the C-terminal domains of VEGF-A and their cooperation for ligand binding, cellular signaling and vessels formation.

VEGF-A is a crucial growth factor for blood vessel homeostasis and pathological angiogenesis. Due to alternative splicing of its pre-mRNA, VEGF-A is produced under several isoforms characterized by the combination of their C-terminal domains, which determines their respective structure, availability and affinity for co-receptors. As controversies still exist about the specific roles of these exon-encoded domains, we systematically compared the properties of eight natural and artificial variants containing the domains encoded by exons 1-4 and various combinations of the domains encoded by exons 5, 7 and 8a or 8b. All the variants (VEGF111a, VEGF111b, VEGF121a, VEGF121b, VEGF155a, VEGF155b, VEGF165a, VEGF165b) have a similar affinity for VEGF-R2, as determined by Surface plasmon resonance analyses. They strongly differ however in terms of binding to neuropilin-1 and heparin/heparan sulfate proteoglycans. Data indicate that the 6 amino acids encoded by exon 8a must be present and cooperate with those of exons 5 or 7 for efficient binding, which was confirmed in cell culture models. We further showed that VEGF165b has inhibitory effects in vitro, as previously reported, but that the shortest VEGF variant possessing also the 6 amino acids encoded by exon 8b (VEGF111b) is remarkably proangiogenic, demonstrating the critical importance of domain interactions for defining the VEGF properties. The number, size and localization of newly formed blood vessels in a model of tumour angiogenesis strongly depend also on the C-terminal domain composition, suggesting that association of several VEGF isoforms may be more efficient for treating ischemic diseases than the use of any single variant.

Intravenous immunoglobulin is safe and effective in controlling pre-existing paraneoplastic neuromuscular diseases in cancer patients treated with immune checkpoint inhibitors: two case reports and literature review.

Immune checkpoint inhibitors cause rare but potentially fatal neuromuscular complications, leading to a concern to use these agents in cancer patients with pre-existing autoimmune or inflammatory neuromuscular diseases. We report two such patients with paraneoplastic dermatomyositis and "seronegative" paraneoplastic demyelinating neuropathy, respectively, who have been successfully treated with immune checkpoint inhibitor monotherapy as well as maintenance intravenous immunoglobulin. While controlling the paraneoplastic or autoimmune neuromuscular diseases, the use of intravenous immunoglobulin did not compromise the anti-cancer effect of immune checkpoint inhibitor.

The impact of transoesophageal echocardiography in elderly patients with infective endocarditis.

BACKGROUND: Infective endocarditis (IE) increasingly involves older patients. Geriatric status may influence diagnostic and therapeutic decisions. AIM: To describe transoesophageal echocardiography (TEE) use in elderly IE patients, and its impact on therapeutic management and mortality. METHODS: A multicentre prospective observational study (ELDERL-IE) included 120 patients aged ≥75 years with definite or possible IE: mean age 83.1±5.0; range 75-101 years; 56 females (46.7%). Patients had an initial comprehensive geriatric assessment, and 3-month and 1-year follow-up. Comparisons were made between patients who did or did not undergo TEE. RESULTS: Transthoracic echocardiography revealed IE-related abnormalities in 85 patients (70.8%). Only 77 patients (64.2%) had TEE. Patients without TEE were older (85.4±6.0 vs. 81.9±3.9 years; P=0.0011), had more comorbidities (Cumulative Illness Rating Scale-Geriatric score 17.9±7.8 vs. 12.8±6.7; P=0.0005), more often had no history of valvular disease (60.5% vs. 37.7%; P=0.0363), had a trend toward a higher Staphylococcus aureus infection rate (34.9% vs. 22.1%; P=0.13) and less often an abscess (4.7% vs. 22.1%; P=0.0122). Regarding the comprehensive geriatric assessment, patients without TEE had poorer functional, nutritional and cognitive statuses. Surgery was performed in 19 (15.8%) patients, all with TEE, was theoretically indicated but not performed in 15 (19.5%) patients with and 6 (14.0%) without TEE, and was not indicated in 43 (55.8%) patients with and 37 (86.0%) without TEE (P=0.0006). Mortality was significantly higher in patients without TEE. CONCLUSIONS: Despite similar IE features, surgical indication was less frequently recognized in patients without TEE, who less often had surgery and had a poorer prognosis. Cardiac lesions might have been underdiagnosed in the absence of TEE, hampering optimal therapeutic management. Advice of geriatricians should help cardiologists to better use TEE in elderly patients with suspected IE.

Platelet protease nexin-1, a serpin that strongly influences fibrinolysis and thrombolysis.

BACKGROUND: Protease nexin-1 (PN-1) is a serpin that inhibits plasminogen activators, plasmin, and thrombin. PN-1 is barely detectable in plasma, but we have shown recently that PN-1 is present within the α-granules of platelets. METHODS AND RESULTS: In this study, the role of platelet PN-1 in fibrinolysis was investigated with the use of human platelets incubated with a blocking antibody and platelets from PN-1-deficient mice. We showed by using fibrin-agar zymography and fibrin matrix that platelet PN-1 inhibited both the generation of plasmin by fibrin-bound tissue plasminogen activator and the activity of fibrin-bound plasmin itself. Rotational thromboelastometry and laser scanning confocal microscopy were used to demonstrate that PN-1 blockade or deficiency resulted in increased clot lysis and in an acceleration of the lysis front. Protease nexin-1 is thus a major determinant of the lysis resistance of platelet-rich clots. Moreover, in an original murine model in which thrombolysis induced by tissue plasminogen activator can be measured directly in situ, we observed that vascular recanalization was significantly increased in PN-1-deficient mice. Surprisingly, general physical health, after tissue plasminogen activator-induced thrombolysis, was much better in PN-1-deficient than in wild-type mice. CONCLUSIONS: Our results reveal that platelet PN-1 can be considered as a new important regulator of thrombolysis in vivo. Inhibition of PN-1 is thus predicted to promote endogenous and exogenous tissue plasminogen activator-mediated fibrinolysis and may enhance the therapeutic efficacy of thrombolytic agents.

Anticoagulant and antithrombotic properties of platelet protease nexin-1.

Protease nexin-1 (PN-1) is a serpin that inhibits plasminogen activators, plasmin, and thrombin. PN-1 is barely detectable in plasma but is expressed by platelets. Here, we studied platelet PN-1 in resting and activated conditions and its function in thrombosis. Studies on human platelets from healthy donors and from patients with a Gray platelet syndrome demonstrate that PN-1 is present both at the platelet surface and in alpha-granules. The role of PN-1 was investigated in vitro using human platelets incubated with a blocking antibody and using platelets from PN-1-deficient mice. Both approaches indicate that platelet PN-1 is active on thrombin and urokinase-type plasminogen activator. Blockade and deficiency of platelet PN-1 result in accelerated and increased tissue factor-induced thrombin generation as indicated by calibrated automated thrombography. Moreover, platelets from PN-1-deficient mice respond to subthreshold doses of thrombin, as assessed by P-selectin expression and platelet aggregation. Thrombus formation, induced ex vivo by collagen in blood flow conditions and in vivo by FeCl(3)-induced injury, is significantly increased in PN-1-deficient mice, demonstrating the antithrombotic properties of platelet PN-1. Platelet PN-1 is thus a key player in the thrombotic process, whose negative regulatory role has been, up to now, markedly underestimated.

The use of a camera-enabled mobile phone to triage patients with nasal bone injuries.

OBJECTIVE: To identify the accuracy of a camera-enabled mobile phone in assessing patients with nasal bone injuries and to determine if treatment in the form of manipulation of the nasal bones and therefore outpatient attendance was necessary. METHODS: Prospective study of patients with nasal injuries attending the weekly ear-nose-throat emergency clinic. The patient is assessed and examined, and a preset questionnaire is filled out. An anteroposterior photograph and an overhead photograph of the nose are taken. The pictures are then e-mailed to a senior member of the team who reviews the pictures and determines based on the images whether intervention in the form of manipulation of nasal bones was required. The results were then compared with the actual assessment and management in the clinic. RESULTS: Of the 50 patients assessed, 94% showed a direct correlation between the perceived need for treatment based on the clinical images and the actual management in the outpatient clinic. The results also showed the test to be 88% specific and 100% sensitive. CONCLUSIONS: We conclude that the use of a mobile phone camera to assess nasal bone injuries could be a useful triage tool in correctly identifying patients who may require intervention in the form of nasal bone manipulation.

Distribution and Biodiversity of Seed-Borne Pathogenic and Toxigenic Fungi of Maize in Egypt and Their Correlations with Weather Variables.

Studies of the biodiversity of plant pathogenic and toxigenic fungi are attracting great attention to improve the predictability of their epidemics and the development of their control programs. Two hundred maize grain samples were gathered from 25 maize-growing governorates in Egypt and 189 samples were processed for the isolation and identification of seed-borne fungal microbiome. Twenty-six fungal genera comprising 42 species were identified according to their morphological characteristics and ITS DNA sequence analysis. Occurrence and biodiversity indicators of these fungal species were calculated. Ustilago maydis, Alternaria alternata, Aspergillus flavus, A. niger, Penicillium spp., Cladosporium spp. and Fusarium verticillioides were the highly frequent (>90% for each), recording the highest relative abundance (˃50%). Al-Menia governorate showed the highest species diversity and richness, followed by Sohag, Al-Nobaria and New Valley governorates. Correlations of 18 fungal species with temperature, relative humidity, precipitation, wind speed, and solar radiation were analyzed using canonical correspondence analysis. Results showed that relative humidity, temperature, and wind speed, respectively, were the most impactful weather variables. However, the occurrence and distribution of these fungi were not clearly grouped into the distinctive climatic regions in which maize crops are grown. Monitoring the occurrence and distribution of the fungal pathogens of maize grains in Egypt will play an important role in predicting their outbreaks and developing appropriate future management strategies. The findings in this study may be useful to other maize-growing countries that have similar climatic conditions.

Hospitalized cancer patients with comorbidities and low lymphocyte counts had poor clinical outcomes to immune checkpoint inhibitors.

Background: Immune checkpoint inhibitor (ICI) therapy has improved survivals with a favorable toxicity profile in a variety of cancer patients. We hypothesized that hospitalized cancer patients who have acute or chronic comorbidities may have suppressed immune systems and poor clinical outcomes to ICIs. The objective of this study was to explore clinical outcomes and predictive factors of hospitalized cancer patients who received ICI therapy at an NCI-designated Comprehensive Cancer Center. Methods: A retrospective review of electronic medical records was conducted for adult cancer patients who received an FDA-approved ICI during admission from 08/2016 to 01/2022. For each patient we extracted demographics, cancer histology, comorbidities, reasons for hospitalization, ICI administered, time from treatment to discharge, time from treatment to progression or death, and complete blood counts. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. The 95% confidence interval for survival was calculated using the exact binomial distribution. Statistical significance was defined as 2-sided p<0.05. Results: Of 37 patients identified, 2 were excluded due to lack of complete blood counts on admission. Average hospital stay was 24.2 (95% CI 16.5, 31.9) days. Ten (27.0%) patients died during the same hospitalization as treatment. Of those who followed up, 22 (59.5%) died within 90 days of inpatient therapy. The median PFS was 0.86 (95% CI 0.43, 1.74) months and median OS was 1.55 (95% CI 0.76, 3.72) months. Patients with ≥3 comorbidities had poorer PFS (2.4 vs. 0.4 months; p=0.0029) and OS (5.5 vs. 0.6 months; p=0.0006). Pre-treatment absolute lymphocyte counts (ALC) <600 cells/µL were associated with poor PFS (0.33 vs. 1.35 months; p=0.0053) and poor OS (0.33 vs. 2.34 months; p=0.0236). Pre-treatment derived neutrophil to lymphocyte ratio (dNLR) <4 was associated with good median PFS (1.6 vs. 0.4 months; p=0.0157) and OS (2.8 vs. 0.9 months; p=0.0375). Conclusions: Administration of ICI therapy was associated with poor clinical outcomes and high rates of both inpatient mortality and 90-day mortality after inpatient ICI therapy. The presence of ≥3 comorbidities, ALC <600/µL, or dNLR >4 in hospitalized patients was associated with poor survival outcomes.

Syndecan-1 Is Overexpressed in Human Thoracic Aneurysm but Is Dispensable for the Disease Progression in a Mouse Model.

Glycosaminoglycans (GAGs) pooling has long been considered as one of the histopathological characteristics defining thoracic aortic aneurysm (TAA) together with smooth muscle cells (SMCs) apoptosis and elastin fibers degradation. However, little information is known about GAGs composition or their potential implication in TAA pathology. Syndecan-1 (SDC-1) is a heparan sulfate proteoglycan that is implicated in extracellular matrix (ECM) interaction and assembly, regulation of SMCs phenotype, and various aspects of inflammation in the vascular wall. Therefore, the aim of this study was to determine whether SDC-1 expression was regulated in human TAA and to analyze its role in a mouse model of this disease. In the current work, the regulation of SDC-1 was examined in human biopsies by RT-qPCR, ELISA, and immunohistochemistry. In addition, the role of SDC-1 was evaluated in descending TAA in vivo using a mouse model combining both aortic wall weakening and hypertension. Our results showed that both SDC-1 mRNA and protein are overexpressed in the media layer of human TAA specimens. RT-qPCR experiments revealed a 3.6-fold overexpression of SDC-1 mRNA (p = 0.0024) and ELISA assays showed that SDC-1 protein was increased 2.3 times in TAA samples compared with healthy counterparts (221 ± 24 vs. 96 ± 33 pg/mg of tissue, respectively, p = 0.0012). Immunofluorescence imaging provided evidence that SMCs are the major cell type expressing SDC-1 in TAA media. Similarly, in the mouse model used, SDC-1 expression was increased in TAA specimens compared to healthy samples. Although its protective role against abdominal aneurysm has been reported, we observed that SDC-1 was dispensable for TAA prevalence or rupture. In addition, SDC-1 deficiency did not alter the extent of aortic wall dilatation, elastin degradation, collagen deposition, or leukocyte recruitment in our TAA model. These findings suggest that SDC-1 could be a biomarker revealing TAA pathology. Future investigations could uncover the underlying mechanisms leading to regulation of SDC-1 expression in TAA.

The effects of child encounters during military deployments on the well-being of military personnel: a systematic review.

Background: Military members report higher instances of trauma exposure and subsequent posttraumatic stress disorder (PTSD) relative to civilians. Encounters with children in war and conflict settings may have particularly unsettling consequences. However, the nature of these consequences has yet to be systematically examined. Objective: This systematic review sought to identify and document deployment-related encounters with children and associated outcomes reported by military personnel, as well as identify any current training programs, policies, or procedures in place regarding encountering children during deployment. Method: A total of 17 studies with 86 independent samples were included. Analyses were based primarily on qualitative data. Results: Based on the review, 77 military personnel samples documented their experiences encountering children during deployment. Most commonly, child encounters included armed children, porters/human shields, suicide bombers, and ambiguous interactions. Outcomes from encountering children during deployment were diverse, occurring both during the encounter, and described by many as persisting years following the exposure. Consequences of encounters as described by military personnel included: hesitation to complete mission objectives, mental health concerns, moral struggles, social isolation, and sleep disturbances. Of the 86 included reports, only nine provided information regarding training at any stage (pre-, during, or post-deployment) in relation to encountering children. Much of the available information underscored the lack of training, with six reports highlighting the lack of pre-deployment training and five reports describing the lack of policies, including rules of engagement, as they relate to encountering children during deployment. Only two reports described post-deployment procedures made available to military personnel following exposure to children while on deployment. Conclusions: Results from this review will be used to identify available research, develop and support training initiatives, and increase awareness regarding implications of encountering children during deployment. We further provide recommendations regarding research needs, policy implementation, and current training gaps.

Antecedentes: Los miembros de las fuerzas militares reportan mayor exposición al trauma y posterior trastorno de estrés postraumático (TEPT), comparados con civiles. Los encuentros con niños en escenarios de guerra y conflictos pueden tener consecuencias particularmente inquietantes, sin embargo, la naturaleza de estas consecuencias aún no se ha examinado sistemáticamente.Objetivo: Esta revisión sistemática buscó identificar y documentar los encuentros con niños relacionados con el despliegue militar, y los resultados asociados reportados por el personal militar, así como identificar cualquier programa de capacitación, política o procedimiento vigente en relación con el encuentro con niños durante el despliegue militar.Método: Se incluyeron un total de 17 estudios con 86 muestras independientes. Los análisis se basaron principalmente en datos cualitativos.Resultados: Según la revisión, 77 muestras de personal militar documentaron experiencias al encontrarse con niños durante el despliegue. Más comúnmente, los encuentros con niños incluyeron niños armados, porteadores/escudos humanos, terroristas suicidas e interacciones ambiguas. Los resultados del encuentro con niños durante el despliegue fueron diversos, ocurriendo durante el encuentro, y siendo descritos por muchos como persistentes años después de la exposición. Las consecuencias de los encuentros descritas por el personal militar incluyeron: vacilación para completar los objetivos de la misión, problemas de salud mental, luchas morales, aislamiento social y trastornos del sueño. De los 86 informes incluidos, solo nueve proporcionaron información sobre la capacitación en cualquier etapa (antes, durante o después del despliegue militar) en relación con el encuentro con los niños. Gran parte de la información disponible subrayó la falta de capacitación, con seis informes que destacaron la falta de capacitación previa al despliegue y cinco informes que describieron la falta de políticas, incluidas las reglas de participación, en relación con el encuentro con niños durante el despliegue. Solo dos informes describieron los procedimientos posteriores al despliegue puestos a disposición del personal militar después de la exposición a los niños durante el despliegue.Conclusiones: Los resultados de esta revisión se utilizarán para identificar la investigación disponible, desarrollar y apoyar iniciativas de capacitación y aumentar la conciencia sobre las implicaciones de encontrarse con niños durante el despliegue militar. Además, brindamos recomendaciones sobre las necesidades de investigación, la implementación de políticas y las brechas de capacitación actuales.

Angiogenic properties of the chemokine RANTES/CCL5.

Atherosclerosis is an inflammatory disease that is one of the leading causes of death in developed countries. This disease is defined by the formation of an atherosclerotic plaque, which is responsible for artery obstruction and affects the heart by causing myocardial infarction. The vascular wall is composed of three cell types and includes a monolayer of endothelial cells and is irrigated by a vasa vasorum. The formation of the vascular network from the vasa vasorum is a process involved in the destabilization of this plaque. Cellular and molecular approaches are studied by in vitro assay of activated endothelial cells and in in vivo models of neovascularization. Chemokines are a large family of small secreted proteins that have been shown to play a critical role in the regulation of angiogenesis during several pathophysiological processes such as ischaemia. Chemokines may exert their regulatory activity on angiogenesis directly by activating the vasa vasorum, or as a consequence of leucocyte infiltration through the endothelium, and/or by the induction of growth factor expression such as that of VEGF (vascular endothelial growth factor). The present review focuses on the angiogenic activity of the chemokines RANTES (regulated upon activation, normal T-cell expressed and secreted)/CCL5 (CC chemokine ligand 5). RANTES/CCL5 is released by many cell types such as platelets or smooth muscle cells. This chemokine interacts with GPCRs (G-protein-coupled receptors) and GAG (glycosaminoglycan) chains bound to HSPGs (heparan sulfate proteoglycans). Many studies have demonstrated, using RANTES/CCL5 mutated on their GAG or GPCR-binding sites, the involvement of these chemokines in angiogenic process. In the present review, we discuss two controversial roles of RANTES/CCL5 in the angiogenic process.

Protease Nexin-1 in the Cardiovascular System: Wherefore Art Thou?

The balance between proteases and protease inhibitors plays a critical role in tissue remodeling during cardiovascular diseases. Different serine protease inhibitors termed serpins, which are expressed in the cardiovascular system, can exert a fine-tuned regulation of protease activities. Among them, protease nexin-1 (PN-1, encoded by SERPINE2) is a very powerful thrombin inhibitor and can also inactivate plasminogen activators and plasmin. Studies have shown that this serpin is expressed by all cell subpopulations in the vascular wall and by circulating cells but is barely detectable in plasma in the free form. PN-1 present in platelet granules and released upon activation has been shown to present strong antithrombotic and antifibrinolytic properties. PN-1 has a broad spectrum of action related to both hemostatic and blood vessel wall protease activities. Different studies showed that PN-1 is not only an important protector of vascular cells against protease activities but also a significant actor in the clearance of the complexes it forms with its targets. In this context, PN-1 overexpression has been observed in the pathophysiology of thoracic aortic aneurysms (TAA) and during the development of atherosclerosis in humans. Similarly, in the heart, PN-1 has been shown to be overexpressed in a mouse model of heart failure and to be involved in cardiac fibrosis. Overall, PN-1 appears to serve as a "hand brake" for protease activities during cardiovascular remodeling. This review will thus highlight the role of PN-1 in the cardiovascular system and deliver a comprehensive assessment of its position among serpins.

Is the Cyanobacterial Bloom Composition Shifting Due to Climate Forcing or Nutrient Changes? Example of a Shallow Eutrophic Reservoir.

Cyanobacterial blooms in eutrophic freshwater is a global threat to the functioning of ecosystems, human health and the economy. Parties responsible for the ecosystems and human health increasingly demand reliable predictions of cyanobacterial development to support necessary decisions. Long-term data series help with identifying environmental drivers of cyanobacterial developments in the context of climatic and anthropogenic pressure. Here, we analyzed 13 years of eutrophication and climatic data of a shallow temperate reservoir showing a high interannual variability of cyanobacterial development and composition, which is a less occurring and/or less described phenomenon compared to recurrant monospecific blooms. While between 2007-2012 Planktothrix agardhii dominated the cyanobacterial community, it shifted towards Microcystis sp. and then Dolichospermum sp. afterwards (2013-2019). The shift to Microcystis sp. dominance was mainly influenced by generally calmer and warmer conditions. The later shift to Dolichospermum sp. was driven by droughts influencing, amongst others, the N-load, as P remained unchanged over the time period. Both, climatic pressure and N-limitation contributed to the high variability of cyanobacterial blooms and may lead to a new equilibrium. The further reduction of P-load in parallel to the decreasing N-load is important to suppress cyanobacterial blooms and ameliorate ecosystem health.

Biodiversity of Pathogenic and Toxigenic Seed-Borne Mycoflora of Wheat in Egypt and Their Correlations with Weather Variables.

Surveillance investigations for pathogenic and toxigenic fungi are important to refine our understanding of their epidemiology and help in predicting their outbreaks. During 2019, 198 samples of wheat grains were collected from 25 wheat-growing governorates in Egypt to detect and identify seed-borne mycoflora in vitro. Forty-four fungal species belonging to 20 genera were identified. Molecular data for these fungi were analyzed to construct a phylogenetic tree. Occurrence and biodiversity indicators were calculated. Two prevalent pathogens (average incidence > 40%) were Alternaria alternata and Cladosporium spp. Ustilago tritici was present in only seven of the 25 governorates, and less abundant than Tilletia tritici, the causal agent of stinking smut. Sinai governorate recorded the greatest species diversity, while the greatest species richness was in Qena and Sohag governorates. Canonical correspondence analysis of data for 20 fungal genera with temperature, relative humidity, precipitation, wind speed or solar radiation revealed that relative humidity was the most influential weather variable. It showed that occurrence and distribution of the 20 genera corresponded well with three out of four Egyptian climatic regions: Mediterranean, semi-arid, and arid. Knowing pathogen occurrence and distribution in Egypt is the first step to developing future disease management strategies to limit yield losses and improve food security. Despite this study being conducted on the wheat-growing areas in Egypt, our findings are useful for other wheat-growing countries that share the same climatic conditions. The correlation between a given fungus and the climatic variables can be useful in other ecosystems.

The signature 3-O-sulfo group of the anticoagulant heparin sequence is critical for heparin binding to antithrombin but is not required for allosteric activation.

Heparin and heparan sulfate glycosaminoglycans allosterically activate the serpin, antithrombin, by binding through a specific pentasaccharide sequence containing a critical 3-O-sulfo group. To elucidate the role of the 3-O-sulfo group in the activation mechanism, we compared the effects of deleting the 3-O-sulfo group or mutating the Lys(114) binding partner of this group on antithrombin-pentasaccharide interactions by equilibrium binding and rapid kinetic analyses. Binding studies over a wide range of ionic strength and pH showed that loss of the 3-O-sulfo group caused a massive approximately 60% loss in binding energy for the antithrombin-pentasaccharide interaction due to the disruption of a cooperative network of ionic and nonionic interactions. Despite this affinity loss, the 3-O-desulfonated pentasaccharide retained the ability to induce tryptophan fluorescence changes and to enhance factor Xa reactivity in antithrombin, indicative of normal conformational activation. Rapid kinetic studies showed that loss of the 3-O-sulfo group affected both the ability of the pentasaccharide to recognize native antithrombin and its ability to preferentially bind and stabilize activated antithrombin. By contrast, mutation of Lys(114) solely affected the preferential interaction of the pentasaccharide with activated antithrombin. These findings demonstrate that the 3-O-sulfo group functions as a key determinant of heparin pentasaccharide activation of antithrombin both by contributing to the Lys(114)-independent recognition of native antithrombin and by triggering a Lys(114)-dependent induced fit interaction with activated antithrombin that locks the serpin in the activated state.