A transcriptional rheostat couples past activity to future sensory responses.

Animals traversing different environments encounter both stable background stimuli and novel cues, which are thought to be detected by primary sensory neurons and then distinguished by downstream brain circuits. Here, we show that each of the ∼1,000 olfactory sensory neuron (OSN) subtypes in the mouse harbors a distinct transcriptome whose content is precisely determined by interactions between its odorant receptor and the environment. This transcriptional variation is systematically organized to support sensory adaptation: expression levels of more than 70 genes relevant to transforming odors into spikes continuously vary across OSN subtypes, dynamically adjust to new environments over hours, and accurately predict acute OSN-specific odor responses. The sensory periphery therefore separates salient signals from predictable background via a transcriptional rheostat whose moment-to-moment state reflects the past and constrains the future; these findings suggest a general model in which structured transcriptional variation within a cell type reflects individual experience.

The role of NSP6 in the biogenesis of the SARS-CoV-2 replication organelle.

SARS-CoV-2, like other coronaviruses, builds a membrane-bound replication organelle to enable RNA replication1. The SARS-CoV-2 replication organelle is composed of double-membrane vesicles (DMVs) that are tethered to the endoplasmic reticulum (ER) by thin membrane connectors2, but the viral proteins and the host factors involved remain unknown. Here we identify the viral non-structural proteins (NSPs) that generate the SARS-CoV-2 replication organelle. NSP3 and NSP4 generate the DMVs, whereas NSP6, through oligomerization and an amphipathic helix, zippers ER membranes and establishes the connectors. The NSP6(ΔSGF) mutant, which arose independently in the Alpha, Beta, Gamma, Eta, Iota and Lambda variants of SARS-CoV-2, behaves as a gain-of-function mutant with a higher ER-zippering activity. We identified three main roles for NSP6: first, to act as a filter in communication between the replication organelle and the ER, by allowing lipid flow but restricting the access of ER luminal proteins to the DMVs; second, to position and organize DMV clusters; and third, to mediate contact with lipid droplets (LDs) through the LD-tethering complex DFCP1-RAB18. NSP6 thus acts as an organizer of DMV clusters and can provide a selective means of refurbishing them with LD-derived lipids. Notably, both properly formed NSP6 connectors and LDs are required for the replication of SARS-CoV-2. Our findings provide insight into the biological activity of NSP6 of SARS-CoV-2 and of other coronaviruses, and have the potential to fuel the search for broad antiviral agents.

Endogenous PGD2 acting on DP2 receptor counter regulates Schistosoma mansoni infection-driven hepatic granulomatous fibrosis.

Identifying new molecular therapies targeted at the severe hepatic fibrosis associated with the granulomatous immune response to Schistosoma mansoni infection is essential to reduce fibrosis-related morbidity/mortality in schistosomiasis. In vitro cell activation studies suggested the lipid molecule prostaglandin D2 (PGD2) as a potential pro-fibrotic candidate in schistosomal context, although corroboratory in vivo evidence is still lacking. Here, to investigate the role of PGD2 and its cognate receptor DP2 in vivo, impairment of PGD2 synthesis by HQL-79 (an inhibitor of the H-PGD synthase) or DP2 receptor inhibition by CAY10471 (a selective DP2 antagonist) were used against the fibrotic response of hepatic eosinophilic granulomas of S. mansoni infection in mice. Although studies have postulated PGD2 as a fibrogenic molecule, HQL-79 and CAY10471 amplified, rather than attenuated, the fibrotic response within schistosome hepatic granulomas. Both pharmacological strategies increased hepatic deposition of collagen fibers - an unexpected outcome accompanied by further elevation of hepatic levels of the pro-fibrotic cytokines TGF-ß and IL-13 in infected animals. In contrast, infection-induced enhanced LTC4 synthesis in the schistosomal liver was reduced after HQL-79 and CAY10471 treatments, and therefore, inversely correlated with collagen production in granulomatous livers. Like PGD2-directed maneuvers, antagonism of cysteinyl leukotriene receptors CysLT1 by MK571 also promoted enhancement of TGF-ß and IL-13, indicating a key down-regulatory role for endogenous LTC4 in schistosomiasis-induced liver fibrosis. An ample body of data supports the role of S. mansoni-driven DP2-mediated activation of eosinophils as the source of LTC4 during infection, including: (i) HQL-79 and CAY10471 impaired systemic eosinophilia, drastically decreasing eosinophils within peritoneum and hepatic granulomas of infected animals in parallel to a reduction in cysteinyl leukotrienes levels; (ii) peritoneal eosinophils were identified as the only cells producing LTC4 in PGD2-mediated S. mansoni-induced infection; (iii) the magnitude of hepatic granulomatous eosinophilia positively correlates with S. mansoni-elicited hepatic content of cysteinyl leukotrienes, and (iv) isolated eosinophils from S. mansoni-induced hepatic granuloma synthesize LTC4 in vitro in a PGD2/DP2 dependent manner. So, our findings uncover that granulomatous stellate cells-derived PGD2 by activating DP2 receptors on eosinophils does stimulate production of anti-fibrogenic cysLTs, which endogenously down-regulates the hepatic fibrogenic process of S. mansoni granulomatous reaction - an in vivo protective function which demands caution in the future therapeutic attempts in targeting PGD2/DP2 in schistosomiasis.

Insights into the molecular basis and mechanism of heme-triggered TLR4 signalling: The role of heme-binding motifs in TLR4 and MD2.

Haemolytic disorders, such as sickle cell disease, are accompanied by the release of high amounts of labile heme into the intravascular compartment resulting in the induction of proinflammatory and prothrombotic complications in affected patients. In addition to the relevance of heme-regulated proteins from the complement and blood coagulation systems, activation of the TLR4 signalling pathway by heme was ascribed a crucial role in the progression of these pathological processes. Heme binding to the TLR4-MD2 complex has been proposed recently, however, essential mechanistic information of the processes at the molecular level, such as heme-binding kinetics, the heme-binding capacity and the respective heme-binding sites (HBMs) is still missing. We report the interaction of TLR4, MD2 and the TLR4-MD2 complex with heme and the consequences thereof by employing biochemical, spectroscopic, bioinformatic and physiologically relevant approaches. Heme binding occurs transiently through interaction with up to four HBMs in TLR4, two HBMs in MD2 and at least four HBMs in their complex. Functional studies highlight that mutations of individual HBMs in TLR4 preserve full receptor activation by heme, suggesting that heme interacts with TLR4 through different binding sites independently of MD2. Furthermore, we confirm and extend the major role of TLR4 for heme-mediated cytokine responses in human immune cells.

Mycobacterium tuberculosis induces delayed lipid droplet accumulation in dendritic cells depending on bacterial viability and virulence.

Tuberculosis remains a global health threat with high morbidity. Dendritic cells (DCs) participate in the acute and chronic inflammatory responses to Mycobacterium tuberculosis (Mtb) by directing the adaptive immune response and are present in lung granulomas. In macrophages, the interaction of lipid droplets (LDs) with mycobacteria-containing phagosomes is central to host-pathogen interactions. However, the data available for DCs are still a matter of debate. Here, we reported that bone marrow-derived DCs (BMDCs) were susceptible to Mtb infection and replication at similar rate to macrophages. Unlike macrophages, the analysis of gene expression showed that Mtb infection induced a delayed increase in lipid droplet-related genes and proinflammatory response. Hence, LD accumulation has been observed by high-content imaging in late periods. Infection of BMDCs with killed H37Rv demonstrated that LD accumulation depends on Mtb viability. Moreover, infection with the attenuated strains H37Ra and Mycobacterium bovis-BCG induced only an early transient increase in LDs, whereas virulent Mtb also induced delayed LD accumulation. In addition, infection with the BCG strain with the reintroduced virulence RD1 locus induced higher LD accumulation and bacterial replication when compared to parental BCG. Collectively, our data suggest that delayed LD accumulation in DCs is dependent on mycobacterial viability and virulence.

MIF is essential to the establishment of house dust mite-induced airway inflammation and tissue remodeling in mice.

Macrophage migration inhibitory factor (MIF) is present in high amounts in the BALF and serum of asthmatic patients, contributing to the pathogenesis of experimental asthma induced by OVA in mice. Whether MIF contributes to the physiopathology on a more complex and relevant asthma model has not been characterized. Mif-deficient (Mif-/- ) or WT mice treated with anti-MIF antibody were challenged multiple times using house dust mite (HDM) extract by the intranasal route. HDM-challenged Mif-/- mice presented decreased airway hyperresponsiveness, lung infiltration of eosinophils, mucus hypersecretion, and subepithelial fibrosis compared to HDM-challenged WT mice. Amounts of IL-4, IL-5, and IL-13 were decreased in the lungs of Mif-/- mice upon HDM challenges, but the increase of CCL11 was preserved, compared to HDM-challenged WT mice. We also observed increased numbers of group 2 innate lymphoid cells and Th2 cells in the BALF and mediastinal LNs (mLN)-induced challenged by HDM of WT mice, but not in HDM-challenged Mif-/- mice. Anti-MIF treatment abrogated the airway infiltration of eosinophils, mucus hypersecretion, and subepithelial fibrosis in the lungs of HDM-challenged mice. In conclusion, MIF ablation prevents the pathologic hallmarks of asthma in HDM-challenged mice, reinforcing the promising target of MIF for asthma therapy.

Impact of the immune profiles of hypertensive patients with and without obesity on COVID-19 severity.

BACKGROUND: Comorbidities such as obesity, hypertension, and diabetes are associated with COVID-19 development and severity, probably due to immune dysregulation; however, the mechanisms underlying these associations are not clear. The immune signatures of hypertensive patients with obesity with COVID-19 may provide new insight into the mechanisms of immune dysregulation and progression to severe disease in these patients. METHODS: Hypertensive patients were selected prospectively from a multicenter registry of adults hospitalized with COVID-19 and stratified according to obesity (BMI ≥ 30 kg/m²). Clinical data including baseline characteristics, complications, treatment, and 46 immune markers were compared between groups. Logistic regression was performed to identify variables associated with the risk of COVID-19 progression in each group. RESULTS: The sample comprised 213 patients (89 with and 124 without obesity). The clinical profiles of patients with and without obesity differed, suggesting potential interactions with COVID-19 severity. Relative to patients without obesity, patients with obesity were younger and fewer had cardiac disease and myocardial injury. Patients with obesity had higher EGF, GCSF, GMCSF, interleukin (IL)-1ra, IL-5, IL-7, IL-8, IL-15, IL-1ß, MCP 1, and VEGF levels, total lymphocyte counts, and CD8+ CD38+ mean fluorescence intensity (MFI), and lower NK-NKG2A MFI and percentage of CD8+ CD38+ T cells. Significant correlations between cytokine and immune cell expression were observed in both groups. Five variables best predicted progression to severe COVID-19 in patients with obesity: diabetes, the EGF, IL-10, and IL-13 levels, and the percentage of CD8+ HLA-DR+ CD38+ cells. Three variables were predictive for patients without obesity: myocardial injury and the percentages of B lymphocytes and HLA-DR+ CD38+ cells. CONCLUSION: Our findings suggest that clinical and immune variables and obesity interact synergistically to increase the COVID-19 progression risk. The immune signatures of hypertensive patients with and without obesity severe COVID-19 highlight differences in immune dysregulation mechanisms, with potential therapeutic applications.

Exosomal-miRNas expression and growth factors released by mononuclear cells of CLAD patients in response to extracorporeal photopheresis.

BACKGROUND: CLAD (Chronic Lung Allograft Dysfunction) remains a serious complication following lung transplantation. Some evidence shows that portions of Extracorporeal Photopheresis (ECP)-treated patients improve/stabilize their graft function. In spite of that, data concerning molecular mechanisms are still lacking. Aims of our study were to assess whether ECP effects are mediated by Mononuclear Cells (MNCs) modulation in term of microRNAs (miRNAs) expression and growth factors release. METHODS: Cells from leukapheresis of 16 CLAD patients, at time 0 and 6-months (10 cycles), were cultured for 48h ± PHA (10 ug/ml) or LPS (2 ug/ml). Expression levels of miR-146a-5p, miR-155-5p, miR-31-5p, miR181a-5p, miR-142-3p, miR-16-5p and miR-23b-5p in MNCs-exosomes were evaluated by qRT-PCR, while ELISA assessed different growth factors levels on culture supernatants. RESULTS: Our result showed miR-142-3p down-regulation (p = 0.02) in MNCs of ECP-patients after the 10 cycles and after LPS stimulation (p = 0.005). We also find miR-146a-5p up-regulation in cells after the 10 cycles stimulated with LPS (p = 0.03). Connective tissue growth factor (CTGF) levels significantly decreased in MNCs supernatant (p = 0.04). The effect of ECP is translated into frequency changes of Dendritic Cell (DC) subpopulations and a slight increase in T regulatory cells (Treg) number and a significant decrease in CTGF release. CONCLUSIONS: ECP might affect regulatory T cell functions, since both miR-142 and miR-146a have been shown to be involved in the regulation of suppressor regulatory T cell functions and DCs. On the other side ECP, possibly by regulating macrophage activation, is able to significantly down modulate CTGF release.

SSRIs in the course of COVID-19 pneumonia: Evidence of effectiveness of antidepressants on acute inflammation. A retrospective study.

INTRODUCTION: Relationships between inflammation and mood have been observed in terms of pro-inflammatory effects induced by depressive conditions and, in parallel, by an antidepressant-induced favorable effect on the recovery of inflammatory states. Selective serotonin reuptake inhibitor (SSRI) drugs were hypothesized to improve the prognosis of COVID-19 pneumonia, a typical acute inflammation, in terms of decreased mortality rate and pro-inflammatory cytokine serum levels. METHODS: The medical records of COVID-19 pneumonia inpatients at Careggi University Hospital (Florence) were analyzed for prognosis and Interleukin 6 (IL-6) after admission for over a period of 22 months. Medical records of patients treated at admission and not discontinued until discharge with an SSRI or with vortioxetine were identified. Two groups, one treated with antidepressants, the other not treated, were evaluated according to the mentioned parameters. Multiple linear regression and logistic regression were performed. RESULTS: The entire sample composed of 1236 records (recovered patients 77.1%, deceased patients 22.9%). The treated group (n = 107) had a better prognosis than the untreated group in spite of age and comorbidity both being greater than in the untreated group. Correspondingly, IL-6 levels in the treated group were significantly lower (p < 0.01) than the levels in the untreated group, in every comparison. CONCLUSIONS: Outcomes of this study support the hypothesis of the favorable influence of some antidepressants on the prognosis of COVID-19, possibly mediated by IL-6 modulation. Reduction in acute inflammation induced by the action of antidepressants was confirmed.

Climate-related risk assessment in water safety plans: the case study of Acque Bresciane (Italy).

Acque Bresciane is a public company that manages the integrated water cycle for more than 580,000 inhabitants in the Province of Brescia, in the north of Italy, providing drinking water, waste water treatment, and sewer systems. Drinking water systems are supplied with different types of groundwater, springs, and surface water sources (from lakes and rivers) whose availability and quality can be affected by climate change events. A multidisciplinary team, in collaboration with the University of Milano Bicocca, developed a specific Water Safety Plan (WSP) risk matrix focusing on the evaluation of climate-related hazardous events and calculation of their likelihood of occurrence, also using thematic maps. Moreover, to reduce the residual risks, in the risk matrix, possible control measures are suggested, such as the activation of an emergency plan, the use of other water sources, storage tanks, and interconnection with other water distribution networks. This work shows a simple and effective tool that can be applied by drinking water utilities to evaluate climate-related catchment risks, using a WSP risk matrix, thematic maps, and possible control measures to reduce risks in terms of water quality and availability and to respond with resilience to changes.

Assessment of Imatinib Anti-Remodeling Activity on a Human Precision Cut Lung Slices Model.

Recent studies have emphasized the critical role of alteration in cellular plasticity in the development of fibrotic disorders, particularly pulmonary fibrosis, prompting further investigation into molecular mechanisms and therapeutic approaches. In this context, Precision Cut Lung Slices (PCLSs) emerge as a valuable ex vivo research tool. The process of PCLSs generation preserves most features of the naïve lung tissue, such as its architecture and complex cellular composition. We previously stimulated normal lung PCLSs with two different stimuli (fibrotic cocktail, composed by platelet lysate and TGFß, or neutrophil extracellular traps) and we observed a significant elevation of Epithelial-Mesenchymal Transition (EMT) markers from 24 h to 72 h of culture. The aim of our work was to exploit this PCLSs based ex vivo model of EMT, to evaluate the effect of imatinib, an old tyrosine kinase inhibitor with reported anti-remodeling activities in vitro and in animal models. Imatinib treatment significantly decreased α-SMA and collagen expression already starting from 24 h on stimulated PCLS. Imatinib showed a significant toxicity on unstimulated cells (3-fold increase in ACTA2 expression levels at 24 h, 1.5-fold increase in COL1A1 expression levels at 24 h, 2-fold increase in COL3A1 expression levels at 72 h). Further evaluations on specific cell lines pointed out that drug effects were mainly directed towards A549 and LFs. In conclusion, our model confirms the anti-remodeling activity of imatinib but suggests that its direct delivery to alveolar epithelial cells as recently attempted by inhalatory preparation of the drug might be associated with a non-negligible epithelial cell toxicity.

Lipid droplet accumulation occurs early following Salmonella infection and contributes to intracellular bacterial survival and replication.

Salmonellosis is a public health problem caused by Salmonella sp., a highly adapted facultative intracellular pathogen. After internalization, Salmonella sp. Manipulates several host processes, mainly through the activation of the type III secretion system (T3SS), including modification of host lipid metabolism and lipid droplet (LD) accumulation. LDs are dynamic and complex lipid-rich organelles involved in several cellular processes. The present study investigated the mechanism involved in LD biogenesis in Salmonella-infected macrophages and its role in bacterial pathogenicity. Here, we reported that S. Typhimurium induced a rapid time-dependent increase of LD formation in macrophages. The LD biogenesis was demonstrated to depend on Salmonella's viability and SPI1-related T3SS activity, with the participation of Toll-Like Receptor (TLR) signaling. We also observed that LD accumulation occurs through TLR2-dependent signaling and is counter-regulated by TLR4. Last, the pharmacologic modulation of LD formation by inhibiting diacylglycerol O-acyltransferase 1 (DGAT1) and cytosolic phospholipase A2 (cPLA2) significantly reduced the intracellular bacterial proliferation and impaired the prostaglandin E2 (PGE2 ) synthesis. Collectively, our data suggest the role of LDs on S. typhimurium intracellular survival and replication in macrophages. This data set provides new perspectives for future investigations about LDs in host-pathogen interaction.

Immune correlates of protection by vaccine against SARS-CoV-2 in patients with chronic lymphocytic leukaemia.

In chronic lymphocytic leukaemia (CLL) the efficacy of SARS-CoV-2 vaccination remains unclear as most studies have focused on humoral responses. Here we comprehensively examined humoral and cellular responses to vaccine in CLL patients. Seroconversion was observed in 55.2% of CLL with lower rate and antibody titres in treated patients. T-cell responses were detected in a significant fraction of patients. CD4+ and CD8+ frequencies were significantly increased independent of serology with higher levels of CD4+ cells in patients under a Bruton tyrosine kinase (BTK) or a B-cell lymphoma 2 (BCL-2) inhibitor. Vaccination skewed CD8+ cells towards a highly cytotoxic phenotype, more pronounced in seroconverted patients. A high proportion of patients showed spike-specific CD4+ and CD8+ cells producing interferon gamma (IFNγ) and tumour necrosis factor alpha (TNFα). Patients under a BTK inhibitor showed increased production of IFNγ and TNFα by CD4+ cells. Vaccination induced a Th1 polarization reverting the Th2 CLL T-cell profile in the majority of patients with lower IL-4 production in untreated and BTK-inhibitor-treated patients. Such robust T-cell responses may have contributed to remarkable protection against hospitalization and death in a cohort of 540 patients. Combining T-cell metrics with seroprevalence may yield a more accurate measure of population immunity in CLL, providing consequential insights for public health.

New Insights on the Mechanisms of Myocardial Injury in Hypertensive Patients With COVID-19.

PURPOSE: Myocardial injury is common in hypertensive patients with 2019 coronavirus disease (COVID-19). Immune dysregulation could be associated to cardiac injury in these patients, but the underlying mechanism has not been fully elucidated. METHODS: All patients were selected prospectively from a multicenter registry of adults hospitalized with confirmed COVID-19. Cases had hypertension and myocardial injury, defined by troponin levels above the 99th percentile upper reference limit, and controls were hypertensive patients with no myocardial injury. Biomarkers and immune cell subsets were quantified and compared between the two groups. A multiple logistic regression model was used to analyze the associations of clinical and immune variables with myocardial injury. RESULTS: The sample comprised 193 patients divided into two groups: 47 cases and 146 controls. Relative to controls, cases had lower total lymphocyte count, percentage of T lymphocytes, CD8+CD38+ mean fluorescence intensity (MFI), and percentage of CD8+ human leukocyte antigen DR isotope (HLA-DR)+ CD38-cells and higher percentage of natural killer lymphocytes, natural killer group 2A (NKG2A)+ MFI, percentage of CD8+CD38+cells, CD8+HLA-DR+MFI, CD8+NKG2A+MFI, and percentage of CD8+HLA-DR-CD38+cells. On multivariate regression, the CD8+HLA-DR+MFI, CD8+CD38+MFI, and total lymphocyte count were associated significantly with myocardial injury. CONCLUSION: Our findings suggest that lymphopenia, CD8+CD38+MFI, and CD8+HLA-DR+MFI are immune biomarkers of myocardial injury in hypertensive patients with COVID-19. The immune signature described here may aid in understanding the mechanisms underlying myocardial injury in these patients. The study data might open a new window for improvement in the treatment of hypertensive patients with COVID-19 and myocardial injury.

Metabolic reprogramming and lipid droplets are involved in Zika virus replication in neural cells.

Zika virus (ZIKV) infection is a global public health concern linked to adult neurological disorders and congenital diseases in newborns. Host lipid metabolism, including lipid droplet (LD) biogenesis, has been associated with viral replication and pathogenesis of different viruses. However, the mechanisms of LD formation and their roles in ZIKV infection in neural cells are still unclear. Here, we demonstrate that ZIKV regulates the expression of pathways associated with lipid metabolism, including the upregulation and activation of lipogenesis-associated transcription factors and decreased expression of lipolysis-associated proteins, leading to significant LD accumulation in human neuroblastoma SH-SY5Y cells and in neural stem cells (NSCs). Pharmacological inhibition of DGAT-1 decreased LD accumulation and ZIKV replication in vitro in human cells and in an in vivo mouse model of infection. In accordance with the role of LDs in the regulation of inflammation and innate immunity, we show that blocking LD formation has major roles in inflammatory cytokine production in the brain. Moreover, we observed that inhibition of DGAT-1 inhibited the weight loss and mortality induced by ZIKV infection in vivo. Our results reveal that LD biogenesis triggered by ZIKV infection is a crucial step for ZIKV replication and pathogenesis in neural cells. Therefore, targeting lipid metabolism and LD biogenesis may represent potential strategies for anti-ZIKV treatment development.

Antimicrobial consumption and drug utilization patterns among COVID-19 and non-COVID-19 patients.

OBJECTIVES: To understand differences in antimicrobial use between COVID-19 and non-COVID-19 patients. To compare two metrics commonly used for antimicrobial use: Defined Daily Dose (DDD) and Days of Therapy (DOT). To analyse the order in which antimicrobials were prescribed to COVID-19 patients using process mining techniques. METHODS: We analysed data regarding all ICU admissions from 1 January 2018 to 14 September 2020, in 17 Brazilian hospitals. Our main outcome was the antimicrobial use estimated by the DDD and DOT (Days of Therapy). We compared clinical characteristics and antimicrobial consumption between COVID-19 and non-COVID-19 patients. We used process mining to evaluate the order in which the antimicrobial schemes were prescribed to each COVID-19 patient. RESULTS: We analysed 68 405 patients admitted before the pandemic, 12 319 non-COVID-19 patients and 3240 COVID-19 patients. Comparing those admitted during the pandemic, the COVID-19 patients required advanced respiratory support more often (42% versus 12%). They also had longer ICU length of stay (6 versus 3 days), higher ICU mortality (18% versus 5.4%) and greater use of antimicrobials (70% versus 39%). Most of the COVID-19 treatments started with penicillins with ß-lactamase inhibitors (30%), third-generation cephalosporins (22%), or macrolides in combination with penicillins (19%). CONCLUSIONS: Antimicrobial prescription increased in Brazilian ICUs during the COVID-19 pandemic, especially during the first months of the epidemic. We identified greater use of broad-spectrum antimicrobials by COVID-19 patients. Overall, the DDD metric overestimated antimicrobial use compared with the DOT metric.

Halting the FGF/FGFR axis leads to antitumor activity in Waldenström macroglobulinemia by silencing MYD88.

The human fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenström macroglobulinemia (WM). WM is still an incurable disease, and patients succumb because of disease progression. Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We aimed to investigate the role of FGF/FGFR system blockade in WM by using a pan-FGF trap molecule (NSC12). Wide-transcriptome profiling confirmed inhibition of FGFR signaling in NSC12-treated WM cells; unveiling a significant inhibition of MYD88 was also confirmed at the protein level. Importantly, the NSC12-dependent silencing of MYD88 was functionally active, as it led to inhibition of MYD88-driven pathways, such as BTK and SYK, as well as the MYD88-downstream target HCK. Of note, both canonical and noncanonical NF-κB cascades were downregulated in WM cells upon NSC12 treatment. Functional sequelae exerted by NSC12 in WM cells were studied, demonstrating significant inhibition of WM cell growth, induction of WM cell apoptosis, halting MAPK, JAK/STAT3, and PI3K-Akt pathways. Importantly, NSC12 exerted an anti-WM effect even in the presence of bone marrow microenvironment, both in vitro and in vivo. Our studies provide the evidence for using NSC12 as a specific FGF/FGFR system inhibitor, thus representing a novel therapeutic strategy in WM.

Silencing of amygdala circuits during sepsis prevents the development of anxiety-related behaviours.

Sepsis is a life-threatening condition induced by a deregulated host response to severe infection. Post-sepsis syndrome includes long-term psychiatric disorders, such as persistent anxiety and post-traumatic stress disorder, whose neurobiological mechanisms remain unknown. Using a reference mouse model of sepsis, we showed that mice that recovered from sepsis further developed anxiety-related behaviours associated with an exaggerated fear memory. In the brain, sepsis induced an acute pathological activation of a specific neuronal population of the central nucleus of the amygdala, which projects to the ventral bed nucleus of the stria terminalis. Using viral-genetic circuit tracing and in vivo calcium imaging, we observed that sepsis induced persistent changes in the connectivity matrix and in the responsiveness of these central amygdala neurons projecting to the ventral bed nucleus of the stria terminalis. The transient and targeted silencing of this subpopulation only during the acute phase of sepsis with a viral pharmacogenetic approach, or with the anti-epileptic and neuroprotective drug levetiracetam, prevented the subsequent development of anxiety-related behaviours. Specific inhibition of brain anxiety and fear circuits during the sepsis acute phase constitutes a preventive approach to preclude the post-infection psychiatric outcomes.

A giant planet undergoing extreme-ultraviolet irradiation by its hot massive-star host.

The amount of ultraviolet irradiation and ablation experienced by a planet depends strongly on the temperature of its host star. Of the thousands of extrasolar planets now known, only six have been found that transit hot, A-type stars (with temperatures of 7,300-10,000 kelvin), and no planets are known to transit the even hotter B-type stars. For example, WASP-33 is an A-type star with a temperature of about 7,430 kelvin, which hosts the hottest known transiting planet, WASP-33b (ref. 1); the planet is itself as hot as a red dwarf star of type M (ref. 2). WASP-33b displays a large heat differential between its dayside and nightside, and is highly inflated-traits that have been linked to high insolation. However, even at the temperature of its dayside, its atmosphere probably resembles the molecule-dominated atmospheres of other planets and, given the level of ultraviolet irradiation it experiences, its atmosphere is unlikely to be substantially ablated over the lifetime of its star. Here we report observations of the bright star HD 195689 (also known as KELT-9), which reveal a close-in (orbital period of about 1.48 days) transiting giant planet, KELT-9b. At approximately 10,170 kelvin, the host star is at the dividing line between stars of type A and B, and we measure the dayside temperature of KELT-9b to be about 4,600 kelvin. This is as hot as stars of stellar type K4 (ref. 5). The molecules in K stars are entirely dissociated, and so the primary sources of opacity in the dayside atmosphere of KELT-9b are probably atomic metals. Furthermore, KELT-9b receives 700 times more extreme-ultraviolet radiation (that is, with wavelengths shorter than 91.2 nanometres) than WASP-33b, leading to a predicted range of mass-loss rates that could leave the planet largely stripped of its envelope during the main-sequence lifetime of the host star.

Development of a Risk Score for AKI onset in COVID-19 Patients: COV-AKI Score.

PURPOSE: Acute Kidney Injury (AKI) in COVID-19 patients is associated with increased morbidity and mortality. In the present study, we aimed to develop a prognostic score to predict AKI development in these patients. MATERIALS AND METHODS: This was a retrospective observational study of 2334 COVID 19 patients admitted to 23 different hospitals in Brazil, between January 10th and August 30rd, 2020. The primary outcome of AKI was defined as any increase in serum creatinine (SCr) by 0.3 mg/dL within 48 h or a change in SCr by ≥ 1.5 times of baseline within 1 week, based on Kidney Disease Improving Global Outcomes (KDIGO) guidelines. All patients aged ≥ 18 y/o admitted with confirmed SARS-COV-2 infection were included. Discrimination of variables was calculated by the Receiver Operator Characteristic Curve (ROC curve) utilizing area under curve. Some continuous variables were categorized through ROC curve. The cutoff points were calculated using the value with the best sensitivity and specificity. RESULTS: A total of 1131 patients with COVID-19 admitted to the ICU were included. Patients mean age was 52 ± 15,8 y/o., with a prevalence of males 60% (n = 678). The risk of AKI was 33% (n = 376), 78% (n = 293) of which did not require dialysis. Overall mortality was 11% (n = 127), while for AKI patients, mortality rate was 21% (n = 80). Variables selected for the logistic regression model and inclusion in the final prognostic score were the following: age, diabetes, ACEis, ARBs, chronic kidney disease and hypertension. CONCLUSION: AKI development in COVID 19 patients is accurately predicted by common clinical variables, allowing early interventions to attenuate the impact of AKI in these patients.