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Alzheimer’s disease (AD) is characterized by synaptic loss, which can result from dysfunctional microglial phagocytosis and complement activation. However, what signals drive aberrant microglia-mediated engulfment of synapses in AD is unclear. Here we report that secreted phosphoprotein 1 (SPP1/osteopontin) is upregulated predominantly by perivascular macrophages and, to a lesser extent, by perivascular fibroblasts. Perivascular SPP1 is required for microglia to engulf synapses and upregulate phagocytic markers including C1qa and Ctsb in presence of amyloid-β oligomers. Absence of Spp1 expression in AD mouse models results in prevention of synaptic loss. Furthermore, single-cell RNA sequencing and putative cell–cell interaction analyses reveal that perivascular SPP1 induces microglial phagocytic states in the hippocampus of a mouse model of AD. Altogether, we suggest a functional role for SPP1 in perivascular cells-to-microglia crosstalk, whereby SPP1 modulates microglia-mediated synaptic engulfment in mouse models of AD. Microglia mediate aberrant synapse engulfment in Alzheimer’s disease (AD), but the underlying mechanisms are poorly understood. Here the authors show a perivascular cells-to-microglia crosstalk that induces microglia phagocytic state resulting in synapse engulfment in two mouse models of AD.

The COSINUS (Cryogenic Observatory for SIgnatures seen in Next-generation Underground Searches) experiment aims at the detection of dark matter-induced recoils in sodium iodide (NaI) crystals operated as scintillating cryogenic calorimeters. The detection of both scintillation light and phonons allows performing an event-by-event signal to background discrimination, thus enhancing the sensitivity of the experiment. The choice of using NaI crystals is motivated by the goal of probing the long-standing DAMA/LIBRA results using the same target material. The construction of the experimental facility is foreseen to start by 2021 at the INFN Gran Sasso National Laboratory (LNGS) in Italy. It consists of a cryostat housing the target crystals shielded from the external radioactivity by a water tank acting, at the same time, as an active veto against cosmic ray-induced events. Taking into account both environmental radioactivity and intrinsic contamination of materials used for cryostat, shielding and infrastructure, we performed a careful background budget estimation. The goal is to evaluate the number of events that could mimic or interfere with signal detection while optimising the geometry of the experimental setup. In this paper we present the results of the detailed Monte Carlo simulations we performed, together with the final design of the setup that minimises the residual amount of background particles reaching the detector volume.

High-dimensional space-fractional PDEs are topics of special focus in applied disciplines, but solving them on irregular domains is challenging and deserves particular attention in scientific computing. In response to this issue, we establish a family of differential quadrature (DQ) methods for the space-fractional diffusion equations on 3D irregular domains. The fractional derivatives in space are represented by weighted linear combinations based on the functional values at scattered nodes with their weights determined by using radial basis functions (RBFs) as trial functions. The resulting system of ordinary differential equations (ODEs) are discretized by the weighted average scheme. The presented DQ methods have the virtues which are shared by the classical DQ methods. Several benchmark problems on typical irregular domains are solved to illustrate their advantages in flexibility and accuracy.

COSINUS is a dark matter (DM) direct search experiment that uses sodium iodide (NaI) crystals as cryogenic calorimeters. Thanks to the low nuclear recoil energy threshold and event-by-event discrimination capability, COSINUS will address the long-standing DM claim made by the DAMA/LIBRA collaboration. The experiment is currently under construction at the Laboratori Nazionali del Gran Sasso, Italy, and employs a large cylindrical water tank as a passive shield to meet the required background rate. However, muon-induced neutrons can mimic a DM signal therefore requiring an active veto system, which is achieved by instrumenting the water tank with an array of photomultiplier tubes (PMTs). This study optimizes the number, arrangement, and trigger conditions of the PMTs as well as the size of an optically invisible region. The objective was to maximize the muon veto efficiency while minimizing the accidental trigger rate due to the ambient and instrumental background. The final configuration predicts a veto efficiency of 99.63 ± 0.16% and 44.4 ± 5.6% in the tagging of muon events and showers of secondary particles, respectively. The active veto will reduce the cosmogenic neutron background rate to 0.11 ± 0.02 cts · kg - 1 · year - 1 , corresponding to less than one background event in the region of interest for the whole COSINUS-1 π exposure of 1000 kg · days.

Pioneering work in the 1990s first linked a novel microaerobic bacterium, Helicobacter hepaticus, with chronic active hepatitis and inflammatory bowel disease in several murine models. Targeted H. hepaticus infection experiments subsequently demonstrated its ability to induce colitis, colorectal cancer, and extraintestinal diseases in a number of mouse strains with defects in immune function and/or regulation. H. hepaticus is now widely utilized as a model system to dissect how intestinal microbiota interact with the host to produce both inflammatory and tolerogenic responses. This model has been used to make important advances in understanding factors that regulate both acquired and innate immune response within the intestine. Further, it has been an effective tool to help define the function of regulatory T cells, including their ability to directly inhibit the innate inflammatory response to gut microbiota. The complete genomic sequence of H. hepaticus has advanced the identification of several virulence factors and aided in the elucidation of H. hepaticus pathogenesis. Delineating targets of H. hepaticus virulence factors could facilitate novel approaches to treating microbially induced lower bowel inflammatory diseases.

We report on the precise mass measurements of the 91 Sr and 95 Y isotopes performed using the JYFLTRAP double Penning trap mass spectrometer. The mass-excess values from this work, ME ( 91 Sr ) = - 83645.5 ( 13 )  keV and ME ( 95 Y ) = - 81226.4 ( 10 )  keV, deviate by 6.5(52) keV and - 18 ( 7 )  keV from the Atomic Mass Evaluation 2020 (AME20). In the case of 91 Sr the new result disagrees with the ISOLTRAP value, while for 95 Y, it agrees with the older JYFLTRAP value.

To investigate a possible association between miR-101 and apoptosis of human trophoblast cells mediated by endoplasmic reticulum protein 44 (ERp44) in preeclampsia (PE), we explored the expression of miR-101 in PE placentas ( n =30) compared with normotensive pregnant placentas ( n =30) and the correlation between miR-101 and ERp44 was also analyzed. Furthermore, both the apoptotic rate of trophoblast cells and the ER stress-induced apoptotic proteins were assayed when the HTR-8/SVneo cells were treated with miR-101 mimics or inhibitors in vitro . We found a lower expression of miR-101 and an inverse correlation between miR-101 and ERp44 protein in PE placentas. Upregulation of miR-101 expression could inhibit trophoblast HTR-8/SVneo cell apoptosis and repress ER stress-induced apoptotic proteins by targeting ERp44 in vitro , whereas inhibition of miR-101 could induce HTR-8/SVneo cell apoptosis. Our findings indicated that overexpression of miR-101 could downregulate ERp44 and suppress apoptosis in trophoblast cells during PE. Therefore, loss of miR-101 expression could contribute to ER stress-induced trophoblast cell apoptosis by targeting ERp44.

This study assessed the prognostic value of LCR in patients with cancer-associated malnutrition (CAM). Systemic inflammatory markers, particularly the lymphocyte-to-C-reactive protein ratio (LCR), are related to the survival of patients with CAM. The present retrospective analysis based on a prospective multicenter cohort study, which involved 1,437 hospitalized patients with CAM. The area under the receiver operating characteristic curve (AUC) of ten inflammatory indicators — LCR, advanced lung cancer inflammation index, neutrophil-to-lymphocyte ratio, prognostic nutritional index, modified Glasgow prognostic score, systemic immune-inflammation index, albumin-to-globulin ratio, LCR score, glucose-to-lymphocyte ratio, and platelet-to-lymphocyte ratio—were constructed. Nutritional status, blood markers, and quality of life (QoL) were evaluated within 48 h of admission. The overall survival (OS) was evaluated from September 1 to December 29, 2021. A total of 1,431 cancer patients diagnosed with malnutrition based on the Global Leadership Initiative on Malnutrition (GLIM) criteria. Male patients were 62.8% of all, and the mean age was 60.66 years old. The AUC of LCR was higher than that of other inflammatory markers. The restricted cubic spline (RCS) of the Hazard ratios (HRs) showed an inverse L-shaped relationship with LCR. In addition, patients with low LCR had significantly poorer OS than those with high LCR. The addition of LCR to the model increased the predictive ability of 1-year mortality (AUC increase of 0.036), 3-year mortality (AUC increase of 0.038), and 5-year mortality (AUC increase of 0.031). Assessing the LCR can help the medical staff identify cancer patients with nutritional deficiency at high risk of oncological outcomes and develop individualized therapeutic strategies.

BackgroundEarly identification of HIV and sexually transmitted infections (STIs) leads to early intervention and treatment. We assessed whether ensemble machine-learning methods may provide an accurate assessment of the risk of acquiring HIV and STIs in both heterosexual and homosexual populations.MethodsTo develop the machine learning models, we used data from the Melbourne Sexual Health Centre’s electronic health records between January 2015 and September 2019 (210,271 consultations). We developed 31 machine learning models, using ensemble learning to predict the risk of HIV, syphilis, gonorrhoea, and chlamydia. The models included five base models (Logistic Regression (LR), Naive Bayes (NB), Deep Learning (Neural Networks) (DL), and Random Forest (RF), and Gradient Boosting Machine (GBM); and twenty-six stacked ensemble models based on the different combinations of the above five base models.ResultsThe models with the highest area under the receiver operating characteristic curve (AUC) were: for HIV (LR+GBM+RF+NB+DL, AUC=0.8048 [0.7641–0.8455]), for syphilis (GBM+RF+NB, AUC=0.8483 [0.8339–0.8627]), for gonorrhoea (LR+GBM+NB+DL, AUC=0.8136 [95%CI 0.8058–0.8214]), and for chlamydia (LR+GBM+RF+NB, AUC=0.7373 [0.7279–0.7468]). The commonly identified predictors for four infections were being men who have sex with men, male gender, self-reported STIs symptoms, having sex with an opposite-sex partner in the past 12 months, and younger age.ConclusionsOur results suggest that ensemble learning algorithms could better assess HIV/STIs risk than the individual classifiers models. Our developed machine learning-based tool using self-reported questions could reasonably accurately predict the risk of HIV, syphilis, gonorrhoea, and chlamydia in a population attending an STI service.

Recombinase-activating gene-2-deficient (Rag2⁻/⁻) mice lacking functional lymphocytes provide a useful model of chronic inflammatory bowel disease-emulating events in human colon cancer. Infection of Rag2⁻/⁻ mice with Helicobacter hepaticus led to accumulation of macrophages and neutrophils in the colon, a process temporally related to up-regulation of tissue inducible nitric oxide synthase (iNOS) expression at the site of infection and increased nitric oxide (NO) production, as evidenced by urinary excretion of nitrate. Progressive development of increasingly severe inflammation, hyperplasia, dysplasia, and cancer accompanied these changes. Concurrent administration of an iNOS inhibitor prevented NO production and abrogated epithelial pathology and inhibited the onset of cancer. The presence of Gr-1⁺ neutrophils and elevated tumor necrosis factor-α (TNF-α) expression in colon were required for increased iNOS expression and cancer, whereas interleukin-10 (IL-10) down-regulated TNF-α and iNOS expression and suppressed cancer. Anti-inflammatory CD4⁺ regulatory lymphocytes also down-regulated iNOS and reduced cancer formation. Collectively, these results confirm essential roles for inflammation, increased TNF-α expression, and elevated NO production in colon carcinogenesis.