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Aedes aegypti is the primary vector of dengue fever, a viral disease which has an estimated incidence of 390 million infections annually. Conventional vector control methods have been unable to curb the transmission of the disease. We have previously reported a novel method of vector control using a tetracycline repressible self-limiting strain of Ae. aegypti OX513A which has achieved >90% suppression of wild populations. We investigated the impact of tetracycline and its analogues on the phenotype of OX513A from the perspective of possible routes and levels of environmental exposure. We determined the minimum concentration of tetracycline and its analogues that will allow an increased survivorship and found these to be greater than the maximum concentration of tetracyclines found in known Ae. aegypti breeding sites and their surrounding areas. Furthermore, we determined that OX513A parents fed tetracycline are unable to pre-load their progeny with sufficient antidote to increase their survivorship. Finally, we studied the changes in concentration of tetracycline in the mass production rearing water of OX513A and the developing insect. Together, these studies demonstrate that potential routes of exposure of OX513A individuals to tetracycline and its analogues in the environment are not expected to increase the survivorship of OX513A.

A liquid chromatography–electrospray tandem mass spectrometry (LC–MS/MS) method for the determination of antibiotics in water was developed and applied to Brazilian surface waters. Amoxicillin, ampicillin, cefalexin (CEF), ciprofloxacin (CIP), norfloxacin (NOR), sulfamethoxazole, tetracycline (TET), and trimethoprim were selected as target compounds due to their high consumption pattern in Brazil. LC and MS conditions were optimized to produce the maximum analytic response for each compound. Anion exchange and polymeric solid-phase extraction cartridges, in series, were employed during the extraction procedures. Recovery, linear range, limit of detection (LOD), and limit of quantification were calculated. LOD varied from 0.13 ng L −1 for CIP and NOR to 0.76 ng L −1 for TET. Surface water samples from the Atibaia watershed (São Paulo State, Brazil) were analyzed. Results showed that seasonal and anthropogenic aspects dictated the levels of antibiotics in the samples. An overall frequency of detection of 55% was observed during the rainy period, whereas a higher percentage (88%) was noticed for samples collected during the dry season. In the Atibaia River, sample concentrations ranged from 29 ng L −1 for CEF to 0.5 ng L −1 for NOR. In a sewage-affected stream, however, concentrations up to 2422 ng L −1 CEF were found.

The severity of coronavirus disease 2019 (COVID‐19) is a crucial problem in patient treatment and outcome. The aim of this study is to evaluate circulating level of sphingosine‐1‐phosphate (S1P) along with severity markers, in COVID‐19 patients. One hundred eleven COVID‐19 patients and forty‐seven healthy subjects were included. The severity of COVID‐19 was found significantly associated with anemia, lymphocytopenia, and significant increase of neutrophil‐to‐lymphocyte ratio, ferritin, fibrinogen, aminotransferases, lactate dehydrogenase (LDH), C‐reactive protein (CRP), and D‐dimer. Serum S1P level was inversely associated with COVID‐19 severity, being significantly correlated with CRP, LDH, ferritin, and D‐dimer. The decrease in S1P was strongly associated with the number of erythrocytes, the major source of plasma S1P, and both apolipoprotein M and albumin, the major transporters of blood S1P. Not last, S1P was found to be a relevant predictor of admission to an intensive care unit, and patient’s outcome. Circulating S1P emerged as negative biomarker of severity/mortality of COVID‐19 patients. Restoring abnormal S1P levels to a normal range may have the potential to be a therapeutic target in patients with COVID‐19. Synopsis The study demonstrates that patients with COVID‐19 experience a significant reduction of serum sphingosine‐1‐phosphate (S1P). The decrease of S1P associates with the number of erythrocytes, a major source of circulating S1P, as well as with the levels of high‐density lipoprotein (HDL)/apolipoprotein M (apoM) and albumin, the most important transporters of circulating S1P. The serum levels of S1P, erythrocytes, apoM and albumin are lower in COVID‐19 patients admitted to intensive care unit (ICU) than in no‐ICU patients. Serum S1P negatively correlates with clinical parameters including Pneumonia Severity Index and days of hospitalization. S1P levels exhibit a strong power in predicting both ICU admission and mortality. Graphical Abstract The study demonstrates that patients with COVID‐19 experience a significant reduction of serum sphingosine‐1‐phosphate (S1P). The decrease of S1P associates with the number of erythrocytes, a major source of circulating S1P, as well as with the levels of high‐density lipoprotein (HDL)/apolipoprotein M (apoM) and albumin, the most important transporters of circulating S1P.

The goal of this work was to investigate the occurrence of emerging contaminants in drinking water of the city of Campinas, Brazil. Tap water samples were analyzed using SPE-GC-MS for 11 contaminants of recent environmental concern. Six emerging contaminants (stigmasterol, cholesterol, bisphenol A, caffeine, estrone, and 17β-estradiol) were found in the samples. The latter two were detected only during the dry season, with concentrations below quantification limits. Stigmasterol showed the highest average concentration (0.34 ± 0.13 µg L −1 ), followed by cholesterol (0.27 ± 0.07 µg L −1 ), caffeine (0.22 ± 0.06 µg L −1 ), and bisphenol A (0.16 ± 0.03 µg L −1 ). In Campinas, where surface drinking water supplies receive large amounts of raw sewage inputs, the emerging contaminants levels in drinking waters were higher than median values compiled for drinking and finished water samples around the world.

In this paper we deal with the critical node problem, where a given number of nodes has to be removed from an undirected graph in order to maximize the disconnections between the node pairs of the graph. We propose an integer linear programming model with a non-polynomial number of constraints but whose linear relaxation can be solved in polynomial time. We derive different valid inequalities and some theoretical results about them. We also propose an alternative model based on a quadratic reformulation of the problem. Finally, we perform many computational experiments and analyze the corresponding results.

Background Glioblastoma is the most aggressive primary brain tumor, and, despite intensive studies, remains one of the most fatal malignancy in adult humans. Among multiple onco-promoters produced by glioblastoma cells, erythropoietin was found. However, the presence/function of Epo alternatively spliced variants in cancer remains unexplored. Here, we investigated the expression and role of Epo-variants in glioblastoma, and the therapeutic potential of their targeting through a novel monoclonal antibody (mAb). Methods Transcripts and protein levels of Epo-variants in a cohort of human brain tumors were evaluated by RT-PCR, ELISA, and immunohistochemistry. Monoclonal antibodies targeting Epo-Vs were prepared and functionally selected by assaying proliferation, migration, stemness, and angiogenesis in glioblastoma patient-derived cells. Antibody affinity for Epo/Epo-variant was determined by SPR. In vivo toxicity and therapeutic efficacy of the lead antibody were evaluated in GBM mouse models. Results We found a significant overexpression of Epo-variant transcripts in tissues and cells from GBM patients. After functional selection of newly-produced antibodies, we identified AND-C4 as the lead one for its potent anti-tumoral properties, absence of anti-erythropoietic effects and of toxicity on human brain cells. AND-C4 exhibited high affinity for the Epo-variant EV-3. We demonstrated that EV-3 was efficiently produced and secreted by glioblastoma cells, particularly by stem cells. EV-3 exerted tumorigenic, angiogenic and immunomodulatory properties, and AND-C4 was effective in antagonizing all these actions. In vivo studies in rodent glioblastoma models revealed that AND-C4 selectively bound to tumor tissue and exhibited significant efficacy on tumor growth and animal survival. Conclusion This study represents the first evidence on the presence, origin and pro-tumoral activity of EV-3 in human glioblastoma. Moreover, in vitro and in vivo results revealed AND-C4 as novel and promising anti-glioblastoma immunotherapeutic. Graphical Abstract

Background Traumatic brain injury (TBI) is a leading cause of death and long-term disability worldwide. In addition to primary brain damage, systemic immune alterations occur, with evidence for dysregulated immune responses in aggravating TBI outcome and complications. However, immune dysfunction following TBI has been only partially understood, especially in the elderly who represent a substantial proportion of TBI patients and worst outcome. Therefore, we aimed to conduct an in-depth immunological characterization of TBI patients, by evaluating both adaptive (T and B lymphocytes) and innate (NK and monocytes) immune cells of peripheral blood mononuclear cells (PBMC) collected acutely (< 48 h) after TBI in young (18–45 yo) and elderly (> 65 yo) patients, compared to age-matched controls, and also the levels of inflammatory biomarkers. Results Our data show that young respond differently than elderly to TBI, highlighting the immune unfavourable status of elderly compared to young patients. While in young only CD4 T lymphocytes are activated by TBI, in elderly both CD4 and CD8 T cells are affected, and are induced to differentiate into subtypes with low cytotoxic activity, such as central memory CD4 T cells and memory precursor effector CD8 T cells. Moreover, TBI enhances the frequency of subsets that have not been previously investigated in TBI, namely the double negative CD27- IgD- and CD38-CD24- B lymphocytes, and CD56dim CD16- NK cells, both in young and elderly patients. TBI reduces the production of pro-inflammatory cytokines TNF-α and IL-6, and the expression of HLA-DM, HLA-DR, CD86/B7-2 in monocytes, suggesting a compromised ability to drive a pro-inflammatory response and to efficiently act as antigen presenting cells. Conclusions We described the acute immunological response induced by TBI and its relation with injury severity, which could contribute to pathologic evolution and possibly outcome. The focus on age-related immunological differences could help design specific therapeutic interventions based on patients’ characteristics.

Changes in metabolism are a hallmark of cancer, but molecular signatures of altered bioenergetics to aid in clinical decision-making do not currently exist. We recently identified a group of human tumors with constitutively reduced expression of the mitochondrial structural protein, Mic60, also called mitofilin or inner membrane mitochondrial protein (IMMT). These Mic60-low tumors exhibit severe loss of mitochondrial fitness, paradoxically accompanied by increased metastatic propensity and upregulation of a unique transcriptome of Interferon (IFN) signaling and Senescence-Associated Secretory Phenotype (SASP). Here, we show that an optimized, 11-gene signature of Mic60-low tumors is differentially expressed in multiple malignancies, compared to normal tissues, and correlates with poor patient outcome. When analyzed in three independent patient cohorts of pancreatic ductal adenocarcinoma (PDAC), the Mic60-low gene signature was associated with aggressive disease variants, local inflammation, FOLFIRINOX failure and shortened survival, independently of age, gender, or stage. Therefore, the 11-gene Mic60-low signature may provide an easily accessible molecular tool to stratify patient risk in PDAC and potentially other malignancies.

Intracranial aneurysms (IAs) are very rare in children, and the characteristics of the T-cells in the IA wall are largely unknown. A comatose 7-years-old child was admitted to our center because of a subarachnoid hemorrhage due to a ruptured giant aneurysm of the right middle cerebral artery. Two days after the aneurysm clipping the patient was fully awake with left hemiparesis. T-cells from the IA wall and from peripheral blood of this patient were analyzed by multi-dimensional flow cytometry. Unbiased analysis, based on the use of FlowSOM clustering and dimensionality reduction technique UMAP, indicated that there was virtually no overlap between circulating and tissue-infiltrating T-cells. Thus, naïve T-cells and canonical memory T-cells were largely restricted to peripheral blood, while CD4 - CD8 - T-cells were strongly enriched in the IA wall. The unique CD4 + , CD8 + and CD4 - CD8 - T-cell clusters from the IA wall expressed high levels of CCR5, Granzyme B and CD69, displaying thus characteristics of cytotoxic and tissue-resident effector cells. Low Ki67 expression indicated that they were nevertheless in a resting state. Among regulatory T-cell subsets, Eomes + Tr1-like cells were strongly enriched in the IA wall. Finally, analysis of cytokine producing capacities unveiled that the IA wall contained poly-functional T-cells, which expressed predominantly IFN-γ, TNF and IL-2. CD4 + T-cells co-expressed also CD40L, and produced some IL-17, GM-CSF and IL-10. This report provides to our knowledge the first detailed characterization of the human T-cell compartment in the IA wall.

Background Adaptive deep brain stimulation (aDBS) is a closed-loop system that adjusts stimulation based on patient biomarkers. This study evaluated the cognitive safety of aDBS in Parkinson’s disease (PD). Methods Sixteen PD patients with bilateral subthalamic DBS underwent cognitive assessments (attention, language, memory) 6 days post-surgery during an 8 h protocol. Testing occurred at five time points: T1 (aDBS, medication “off”), T2/T4 (aDBS, medication “on”), and T3/T5 (aDBS “on”, medication “off”). Four patients followed the same protocol with continuousDBS (cDBS). Results Results showed no cognitive fluctuations in aDBS patients ( p ≥ 0.110). However, cDBS patients exhibited significant reaction time (RT) variations ( p = 0.019), with RTs lower at T1 than T3 ( p = 0.011) and T5 ( p = 0.021), and at T4 compared to T2 ( p = 0.002). Conclusion These findings suggest that 8 h aDBS may not adversely affect cognitive performance, providing preliminary evidence of its cognitive safety and stability in PD.