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Cerebral malaria claims the lives of over 600,000 African children every year. To better understand the pathogenesis of this devastating disease, we compared the cellular dynamics in the cortical microvasculature between two infection models, Plasmodium berghei ANKA (PbA) infected CBA/CaJ mice, which develop experimental cerebral malaria (ECM), and P. yoelii 17XL (PyXL) infected mice, which succumb to malarial hyperparasitemia without neurological impairment. Using a combination of intravital imaging and flow cytometry, we show that significantly more CD8(+) T cells, neutrophils, and macrophages are recruited to postcapillary venules during ECM compared to hyperparasitemia. ECM correlated with ICAM-1 upregulation on macrophages, while vascular endothelia upregulated ICAM-1 during ECM and hyperparasitemia. The arrest of large numbers of leukocytes in postcapillary and larger venules caused microrheological alterations that significantly restricted the venous blood flow. Treatment with FTY720, which inhibits vascular leakage, neurological signs, and death from ECM, prevented the recruitment of a subpopulation of CD45(hi) CD8(+) T cells, ICAM-1(+) macrophages, and neutrophils to postcapillary venules. FTY720 had no effect on the ECM-associated expression of the pattern recognition receptor CD14 in postcapillary venules suggesting that endothelial activation is insufficient to cause vascular pathology. Expression of the endothelial tight junction proteins claudin-5, occludin, and ZO-1 in the cerebral cortex and cerebellum of PbA-infected mice with ECM was unaltered compared to FTY720-treated PbA-infected mice or PyXL-infected mice with hyperparasitemia. Thus, blood brain barrier opening does not involve endothelial injury and is likely reversible, consistent with the rapid recovery of many patients with CM. We conclude that the ECM-associated recruitment of large numbers of activated leukocytes, in particular CD8(+) T cells and ICAM(+) macrophages, causes a severe restriction in the venous blood efflux from the brain, which exacerbates the vasogenic edema and increases the intracranial pressure. Thus, death from ECM could potentially occur as a consequence of intracranial hypertension.

Among different types of sphingolipids produced by human cells, the possible engagement of ceramide species in the pathogenesis of Alzheimer's disease (AD) has attracted recent attention. While ceramides are primarily generated by synthesis in mammalian cells, only a limited number of bacterial species, produce ceramides, including phosphoglycerol dihydroceramide (PGDHC) that is produced by the key periodontal pathogen . Emerging evidence indicates that virulence factors produced by , such as lipopolysaccharide and gingipain, may be engaged in the initiation and/or progression of AD. However, the potential role of PGDHC in the pathogenesis of AD remains unknown. Therefore, the aim of this study was to evaluate the influence of PGDHC on hallmark findings in AD. CHO-7WD10 and SH-SY-5Y cells were exposed to PGDHC and lipopolysaccharide (LPS) isolated from . Soluble Aβ42 peptide, amyloid precursor protein (APP), phosphorylated tau and senescence-associated secretory phenotype (SASP) factors were quantified using ELISA and Western blot assays. Our results indicate that -derived PGDHC, but not -LPS, upregulated secretion of soluble Aβ42 peptide and expression of APP in CHO-7WD10 cells. Furthermore, hyperphosphorylation of tau protein was observed in SH-SY-5Y cells in response to PGDHC lipid. In contrast, -LPS had little, or no significant effect on the tau phosphorylation induced in SH-SY-5Y cells. However, both PGDHC and -LPS contributed to the senescence of SH-SY5Y cells as indicated by the production of senescence-associated secretory phenotype (SASP) markers, including beta-galactosidase, cathepsin B (CtsB), and pro-inflammatory cytokines TNF-α, and IL-6. Additionally, PGDHC diminished expression of the senescence-protection marker sirtuin-1 in SH-SY-5Y cells. Altogether, our results indicate that -derived PGDHC ceramide promotes amyloidogenesis and hyperphosphorylation, as well as the production of SASP factors. Thus, PGDHC may represent a novel class of bacterial-derived virulence factors for AD associated with periodontitis.

Plasmodium falciparum malaria is responsible for nearly one million annual deaths worldwide. Because of the difficulty in monitoring the pathogenesis of cerebral malaria in humans, we conducted a study in various mouse models to better understand disease progression in experimental cerebral malaria (ECM). We compared the effect on the integrity of the blood brain barrier (BBB) and the histopathology of the brain of P. berghei ANKA, a known ECM model, P. berghei NK65, generally thought not to induce ECM, P. yoelii 17XL, originally reported to induce human cerebral malaria-like histopathology, and P. yoelii YM. As expected, P. berghei ANKA infection caused neurological signs, cerebral hemorrhages, and BBB dysfunction in CBA/CaJ and Swiss Webster mice, while Balb/c and A/J mice were resistant. Surprisingly, PbNK induced ECM in CBA/CaJ mice, while all other mice were resistant. P. yoelii 17XL and P. yoelii YM caused lethal hyperparasitemia in all mouse strains; histopathological alterations, BBB dysfunction, or neurological signs were not observed. Intravital imaging revealed that infected erythrocytes containing mature parasites passed slowly through capillaries making intimate contact with the endothelium, but did not arrest. Except for relatively rare microhemorrhages, mice with ECM presented no obvious histopathological alterations that would explain the widespread disruption of the BBB. Intravital imaging did reveal, however, that postcapillary venules, but not capillaries or arterioles, from mice with ECM, but not hyperparasitemia, exhibit platelet marginalization, extravascular fibrin deposition, CD14 expression, and extensive vascular leakage. Blockage of LFA-1 mediated cellular interactions prevented leukocyte adhesion, vascular leakage, neurological signs, and death from ECM. The endothelial barrier-stabilizing mediators imatinib and FTY720 inhibited vascular leakage and neurological signs and prolonged survival to ECM. Thus, it appears that neurological signs and coma in ECM are due to regulated opening of paracellular-junctional and transcellular-vesicular fluid transport pathways at the neuroimmunological BBB.

Maternal antibiotics administration (MAA) is among the widely used therapeutic approaches in pregnancy. Although published evidence demonstrates that infants exposed to antibiotics immediately after birth have altered recognition memory responses at one month of age, very little is known about in utero effects of antibiotics on the neuronal function and behavior of children after birth. Therefore, this study aimed to evaluate the impact of MAA at different periods of pregnancy on memory decline and brain structural alterations in young mouse offspring after their first month of life. To study the effects of MAA on 4-week-old offspring, pregnant C57BL/6J mouse dams (2–3-month-old; n = 4/group) were exposed to a cocktail of amoxicillin (205 mg/kg/day) and azithromycin (51 mg/kg/day) in sterile drinking water (daily/1 week) during either the 2nd or 3rd week of pregnancy and stopped after delivery. A control group of pregnant dams was exposed to sterile drinking water alone during all three weeks of pregnancy. Then, the 4-week-old offspring mice were first evaluated for behavioral changes. Using the Morris water maze assay, we revealed that exposure of pregnant mice to antibiotics at the 2nd and 3rd weeks of pregnancy significantly altered spatial reference memory and learning skills in their offspring compared to those delivered from the control group of dams. In contrast, no significant difference in long-term associative memory was detected between offspring groups using the novel object recognition test. Then, we histologically evaluated brain samples from the same offspring individuals using conventional immunofluorescence and electron microscopy assays. To our knowledge, we observed a reduction in the density of the hippocampal CA1 pyramidal neurons and hypomyelination in the corpus callosum in groups of mice in utero exposed to antibiotics at the 2nd and 3rd weeks of gestation. In addition, offspring exposed to antibiotics at the 2nd or 3rd week of gestation demonstrated a decreased astrocyte cell surface area and astrocyte territories or depletion of neurogenesis in the dentate gyrus and hippocampal synaptic loss, respectively. Altogether, this study shows that MAA at different times of pregnancy can pathologically alter cognitive behavior and brain development in offspring at an early age after weaning.

Bone remodelling is mediated by orchestrated communication between osteoclasts and osteoblasts which, in part, is regulated by coupling and anti‐coupling factors. Amongst formally known anti‐coupling factors, Semaphorin 4D (Sema4D), produced by osteoclasts, plays a key role in downmodulating osteoblastogenesis. Sema4D is produced in both membrane‐bound and soluble forms; however, the mechanism responsible for producing sSema4D from osteoclasts is unknown. Sema4D, TACE and MT1‐MMP are all expressed on the surface of RANKL‐primed osteoclast precursors. However, only Sema4D and TACE were colocalized, not Sema4D and MT1‐MMP. When TACE and MT1‐MMP were either chemically inhibited or suppressed by siRNA, TACE was found to be more engaged in shedding Sema4D. Anti‐TACE‐mAb inhibited sSema4D release from osteoclast precursors by ~90%. Supernatant collected from osteoclast precursors (OC‐sup) suppressed osteoblastogenesis from MC3T3‐E1 cells, as measured by alkaline phosphatase activity, but OC‐sup harvested from the osteoclast precursors treated with anti‐TACE‐mAb restored osteoblastogenesis activity in a manner that compensates for diminished sSema4D. Finally, systemic administration of anti‐TACE‐mAb downregulated the generation of sSema4D in the mouse model of critical‐sized bone defect, whereas local injection of recombinant sSema4D to anti‐TACE‐mAb‐treated defect upregulated local osteoblastogenesis. Therefore, a novel pathway is proposed whereby TACE‐mediated shedding of Sema4D expressed on the osteoclast precursors generates functionally active sSema4D to suppress osteoblastogenesis.

Since the onset of the COVID-19 pandemic, no viral genome sequences of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been documented from the Republic of Moldova, a developing country geographically located in Eastern Europe between Romania and Ukraine. Here, we report the analysis of 96 SARS-CoV-2 sequences from Delta and Omicron variants of the SARS-CoV-2 cases in the Republic of Moldova obtained between August and November 2021 and between January and May 2022. Comparison to global viral sequences showed that among the Delta variant of the SARS-CoV-2, AY.122 (n = 25), followed by AY.4.2.3 (n = 6), AY.4 (n = 5), AY.43 (n = 3), AY.98.1 (n = 3), B.1.617.2 (n = 1), AY.125 (n = 1), AY.54 (n = 1), AY.9 (n = 1), AY.126 (n = 1), and AY.33 (n = 1) were the most frequently found lineages. Furthermore, 10 lineages of the Omicron variant, namely, BA.2 (n = 14), followed by BA.2.9 (n = 10), BA.1 (n = 5), BA.1.1 (n = 5), BA.1.18 (n = 4), BA.1.15.1 (n = 3), BA.1.17.2 (n = 2), BA.1.17 (n = 2), BA.1.15 (n = 1), and BA.2.1 (n = 1) were detected. In addition, we also identified the impact of the military crisis between Russia and Ukraine, when the COVID-19 epidemiological rules collapsed, on the distribution of Delta and Omicron variants in the Republic of Moldova. Additional studies are warranted to characterize further the impact of the war between Russia and Ukraine on the genomic epidemiology of the SARS-CoV-2 in the Republic of Moldova and Eastern Europe.

Progressive generation of total joint implant‐derived wear particles is one of the major risk factors in development of peri‐prosthetic osteolysis especially in the aging society. It is commonly accepted that macrophages predominantly drive the inflammatory response to wear debris particles. Among various surface receptors that activate the macrophages to phagocytize particles, it is believed that the Toll‐like receptor 4 (TLR4) and the scavenger macrophage receptor with collagenous structure (MARCO) play key roles in recognition of wear debris particles. However, a strong body of evidence indicates an age‐dependent diminished function of human TLRs. Thus, we hypothesized that the MARCO receptor may be more engaged than TLRs in the phagocytosis of wear debris particles which in turn up‐regulate production of pro‐inflammatory cytokines from aged macrophages. We demonstrated that peritoneal macrophages isolated from aged mice show elevated expression of MARCO receptor compared to that from young mice. In contrast the expression of TLR4 was significantly decreased on the surface of aged macrophages. Furthermore, using anti‐MARCO and anti‐TLR4 neutralizing mAbs, we demonstrated the age‐dependent pathogenic role of MARCO, but not TLR4, receptor in promoting poly‐methyl methacrylate (PMMA) bone cement particles phagocytosis by macrophages leading to the release of pro‐inflammatory cytokines migration inhibitory factor and tumour necrosis factor in vitro. These data also suggest that the approach to neutralize MARCO may lead to the development of therapeutic regimen for the prevention of particle‐induced osteolysis in aged patients.

Ceramide and sphingosine are important interconvertible sphingolipid metabolites which govern various signaling pathways related to different aspects of cell survival and senescence. The conversion of ceramide into sphingosine is mediated by ceramidases. Altogether, five human ceramidases—named acid ceramidase, neutral ceramidase, alkaline ceramidase 1, alkaline ceramidase 2, and alkaline ceramidase 3—have been identified as having maximal activities in acidic, neutral, and alkaline environments, respectively. All five ceramidases have received increased attention for their implications in various diseases, including cancer, Alzheimer’s disease, and Farber disease. Furthermore, the potential anti-inflammatory and anti-apoptotic effects of ceramidases in host cells exposed to pathogenic bacteria and viruses have also been demonstrated. While ceramidases have been a subject of study in recent decades, our knowledge of their pathophysiology remains limited. Thus, this review provides a critical evaluation and interpretive analysis of existing literature on the role of acid, neutral, and alkaline ceramidases in relation to human health and various diseases, including cancer, neurodegenerative diseases, and infectious diseases. In addition, the essential impact of ceramidases on tissue regeneration, as well as their usefulness in enzyme replacement therapy, is also discussed.

Human African trypanosomiasis or sleeping sickness is a vector-borne parasitic disease that has a major impact on human health and welfare in sub-Saharan countries. Based mostly on data from animal models, it is currently thought that trypanosome entry into the brain occurs by initial infection of the choroid plexus and the circumventricular organs followed days to weeks later by entry into the brain parenchyma. However, Trypanosoma brucei bloodstream forms rapidly cross human brain microvascular endothelial cells in vitro and appear to be able to enter the murine brain without inflicting cerebral injury. Using a murine model and intravital brain imaging, we show that bloodstream forms of T. b. brucei and T. b. rhodesiense enter the brain parenchyma within hours, before a significant level of microvascular inflammation is detectable. Extravascular bloodstream forms were viable as indicated by motility and cell division, and remained detectable for at least 3 days post infection suggesting the potential for parasite survival in the brain parenchyma. Vascular inflammation, as reflected by leukocyte recruitment and emigration from cortical microvessels, became apparent only with increasing parasitemia at later stages of the infection, but was not associated with neurological signs. Extravascular trypanosomes were predominantly associated with postcapillary venules suggesting that early brain infection occurs by parasite passage across the neuroimmunological blood brain barrier. Thus, trypanosomes can invade the murine brain parenchyma during the early stages of the disease before meningoencephalitis is fully established. Whether individual trypanosomes can act alone or require the interaction from a quorum of parasites remains to be shown. The significance of these findings for disease development is now testable.

Epidemiological knowledge on pathogens in ticks feeding on birds in Moldova is scarce. To reduce this gap of information, a total of 640 migrating and native birds of 40 species were caught from 2012 to 2015 and examined for the presence of ticks in the Republic of Moldova. Altogether, 262 ticks belonging to five tick species (Ixodes ricunus n = 245, Ixodes frontalis n = 12, Haemaphysalis punctata n = 2, Hyalomma marginatum n = 2 (only males), Dermacentor marginatus n = 1) were collected from 93 birds. Of these ticks, 250 (96%) were at the stage of a nymph and 9 at the stage of a larva (3%). One imago of I. frontalis and two imagoes of Hy. marginatum were found. Generally, ticks infested 14.1% of the assessed birds belonging to 12 species. DNA was extracted from individual ticks with subsequent PCR targeting Rickettsia spp., Borrelia spp. in general, as well as relapsing fever-associated Borrelia spp., in particular, Anaplasma phagocytophilum, Neoehrlichia mikurensis, Babesia spp. and Coxiella burnetii. The bird species Turdus merula showed the heaviest infestation with ticks and the highest incidence of infected ticks. Altogether, 32.8% of the assessed ticks (n = 86) were positive for one of the pathogens. DNA of Borrelia spp. was found in 15.2% (40/262) of the investigated ticks; in 7.6% of ticks (20/262), DNA of rickettsiae was detected; 6.9% (18/262) of the ticks were positive for A. phagocytophilum DNA; in 1.5% of the ticks (4/262), DNA of Neoehrlichia mikurensis was detected, followed by 1.5% (4/262) Babesia microti and 1.5% (4/262) Borrelia miyamotoi. Within the B. burgdorferi complex, B. garinii (n = 36) was largely predominant, followed by B. valaisiana (n = 2) and B. lusitaniae (n = 2). Among the detected Rickettsia spp., R. monacensis (n = 16), R. helvetica (n = 2) and R. slovaca (n = 1) were identified. In conclusion, the study provided some new information on the prevalence of ticks on birds in Moldova, as well as the presence of DNA of pathogens in the ticks. By doing so, it provided an additional piece in the puzzle of the global epidemiology of tick-transmitted infectious diseases from a geographic side from where respective surveillance data are scarce.