Forecasting the detection capabilities of third-generation gravitational-wave detectors using GWFAST\texttt{GWFAST}

We introduce $\texttt{GWFAST}$, a novel Fisher-matrix code for gravitational-wave studies, tuned toward third-generation gravitational-wave detectors such as Einstein Telescope (ET) and Cosmic Explorer (CE). We use it to perform a comprehensive study of the capabilities of ET alone, and of a network made by ET and two CE detectors, as well as to provide forecasts for the forthcoming O4 run of the LVK collaboration. We consider binary neutron stars, binary black holes and neutron star-black hole binaries, and compute basic metrics such as the distribution of signal-to-noise ratio (SNR), the accuracy in the reconstruction of various parameters (including distance, sky localization, masses, spins and, for neutron stars, tidal deformabilities), and the redshift distribution of the detections for different thresholds in SNR and different levels of accuracy in localization and distance measurement. We examine the expected distribution and properties of `golden events', with especially large values of the SNR. We also pay special attention to the dependence of the results on astrophysical uncertainties and on various technical details (such as choice of waveforms, or the threshold in SNR), and we compare with other Fisher codes in the literature. In a companion paper we discuss the technical aspects of the code. Together with this paper, we publicly release the code $\texttt{GWFAST}$ at https://github.com/CosmoStatGW/gwfast, and the library $\texttt{WF4Py}$ implementing state-of-the-art gravitational-wave waveforms in pure $\texttt{Python}$ at https://github.com/CosmoStatGW/WF4Py.Comment: 43 + 9 pages, 24 + 3 Figures, $\texttt{GWFAST}$ available at https://github.com/CosmoStatGW/gwfast, $\texttt{WF4Py}$ available at https://github.com/CosmoStatGW/WF4P

Lymphoid EVA1 Expression Is Required for DN1-DN3 Thymocytes Transition

Background: Thymus organogenesis and T lymphocyte development are accomplished together during fetal life. Proper development and maintenance of thymus architecture depend on signals generated by a sustained crosstalk between developing thymocytes and stromal elements. Any maturation impairment occurring in either cellular component leads to an aberrant thymic development. Gene expression occurring during T lymphocyte differentiation must be coordinated in a spatio-temporal fashion; one way in which this is achieved is through the regulation by cell-cell adhesion and interactions. Principal Findings: We examined the role played by Epithelial V-like Antigen 1 (EVA1), an Ig adhesion molecule expressed on thymus epithelial cells (TEC) and immature thymocytes, in T cell development by employing RNA interference in vitro and in vivo models. Fetal liver derived haematopoietic progenitors depleted of Eva1, displayed a delayed DN1-DN3 transition and failed to generate CD4CD8 double positive T cells in OP9-DL1 coculture system. In addition, we could observe a coordinated Eva1 up-regulation in stromal and haematopoietic cells in coculture control experiments, suggesting a possible EVA1 involvement in TEC-haematopoietic cells crosstalk mechanisms. Similarly, Rag2-cc double knock out mice, transplanted with Eva1 depleted haematopoietic progenitors displayed a 10-fold reduction in thymus reconstitution and a time delayed thymocytes maturation compared to controls. Conclusions: Our findings show that modulation of Eva1 expression in thymocytes is crucial for lymphocyte physiological developmental progression and stromal differentiation

ACCELERATED STENOTIC FLOW BY ENHANCED TRANSTHORACIC DOPPLER ECHOCARDIOGRAPHY IS SUPERIOR TO THE ASCVD RISK SCORE IN PREDICTING OBSTRUCTIVE CORONARY ATHEROSCLEROSIS IN PATIENTS WITH ATYPICAL ANGINA

Background: Atypical angina (AA) has only an intermediate probability of coronary obstructive atherosclerosis (COA). Accelerated stenotic flow (ASF) by enhanced Doppler echo (E-Doppler TTE) in the whole left main (LMCA) and left anterior descending coronary artery (LAD) is a highly feasible and reliable approach to detect both mild and critical coronary stenosis. The ASCVD risk score is a practical, non-invasive way to risk-stratify patients for COA. The relative diagnostic potential of the 2 methods in predicting COA is unknown in pts with AA. Methods: Eighty-six pts (age 30 -75 years) with AA scheduled for Angiography (CA)/IVUS (intracoronary Doppler) underwent E-Doppler TTE and ASCVD risk score assessment. ASF was expressed as % increment of velocity. COA was defined as either coronary plaque in the LAD/LMCA detected by IVUS (76 pts) or diffuse lumen irregularities in LAD along with stenosis in the other coronaries at CA (8 pts). Results: COA was present in 59 pts (69%) and absent in 27 (31%). The ASCVD score was 14±11: 36 pts were at low risk (ASCVD<10) and the other 50 at moderate/high risk. E-Doppler TTE showed a better performance than ASCVD, with 85% sensitivity and 100% specificity (cutoff ASF 23 %) versus 66% and 59% (cutoff ASCVD score 10%), confirmed by AUC comparison (graph). Conclusion: ASF had a better predictive power than the ASCVD score for COA in pts with AA. Moreover, E-Doppler TTE can reliably assess plaque severity and location in the LAD, making it a superior clinical tool compared to the ASCVD score

Targeting mGlu5 metabotropic glutamate receptors in the treatment of cognitive dysfunction in a mouse model of phenylketonuria

We studied group-I metabotropic glutamate (mGlu) receptors in Pah(enu2) (ENU2) mice, which mimic the genetics and neurobiology of human phenylketonuria (PKU), a metabolic disorder characterized, if untreated, by autism, and intellectual disability (ID). Male ENU2 mice showed increased mGlu5 receptor protein levels in the hippocampus and corpus striatum (but not in the prefrontal cortex) whereas the transcript of the mGlu5 receptor was unchanged. No changes in mGlu1 receptor mRNA and protein levels were found in any of the three brain regions of ENU2 mice. We extended the analysis to Homer proteins, which act as scaffolds by linking mGlu1 and mGlu5 receptors to effector proteins. Expression of the long isoforms of Homer was significantly reduced in the hippocampus of ENU2 mice, whereas levels of the short Homer isoform (Homer 1a) were unchanged. mGlu5 receptors were less associated to immunoprecipitated Homer in the hippocampus of ENU2 mice. The lack of mGlu5 receptor-mediated long-term depression (LTD) in wild-type mice (of BTBR strain) precluded the analysis of hippocampal synaptic plasticity in ENU2 mice. We therefore performed a behavioral analysis to examine whether pharmacological blockade of mGlu5 receptors could correct behavioral abnormalities in ENU2 mice. Using the same apparatus we sequentially assessed locomotor activity, object exploration, and spatial object recognition (spatial novelty test) after displacing some of the objects from their original position in the arena. Systemic treatment with the mGlu5 receptor antagonist, MPEP (20 mg/kg, i.p.), had a striking effect in the spatial novelty test by substantially increasing the time spent in exploring the displaced objects in ENU2 mice (but not in wild-type mice). These suggest a role for mGlu5 receptors in the pathophysiology of ID in PKU and suggest that, also in adult untreated animals, cognitive dysfunction may be improved by targeting these receptors with an appropriate therapy

Coronary Flow and Reserve by Enhanced Transthoracic Doppler Trumps Coronary Anatomy by Computed Tomography in Assessing Coronary Artery Stenosis

We report the case of a 71-year-old patient with many risk factors for coronary atherosclerosis, who underwent computed coronary angiography (CTA), in accordance with the guidelines, for recent onset atypical chest pain. CTA revealed critical (>50% lumen diameter narrowing) stenosis of the proximal anterior descending coronary, and the patient was scheduled for invasive coronary angiography (ICA). Before ICA he underwent enhanced transthoracic echo-Doppler (E-Doppler TTE) for coronary flow detection by color-guided pulsed-wave Doppler recording of the left main (LMCA) and whole left anterior descending coronary artery (LAD,) along with coronary flow reserve (CFR) in the distal LAD calculated as the ratio, of peak flow velocity during i.v. adenosine (140 mcg/Kg/m) to resting flow velocity. E-Doppler TTE mapping revealed only mild stenosis (28% area narrowing) of the mid LAD and a CFR of 3.20, in perfect agreement with the color mapping showing no flow limiting stenosis in the LMCA and LAD. ICA revealed only a very mild stenosis in the mid LAD and mild atherosclerosis in the other coronaries (intimal irregularities). Thus, coronary stenosis was better predicted by E-Doppler TTE than by CTA. Coronary flow and reserve as assessed by E-Doppler TTE trumps coronary anatomy as assessed by CTA, without exposing the patient to harmful radiation and iodinated contrast medium

Gravitational-wave cosmology with dark sirens: state of the art and perspectives for 3G detectors

A joint fit of the mass and redshift distributions of the population of Binary Black Holes detected with Gravitational-Wave observations can be used to obtain constraints on the Hubble parameter and on deviations from General Relativity in the propagation of Gravitational Waves. We first present applications of this technique to the latest catalog of Gravitational-Wave events, focusing on the comparison of different parametrizations for the source-frame mass distribution of Black Hole Binaries. We find that models with more than one feature are favourite by the data, as suggested by population studies, even when varying the cosmology. Then, we discuss perspectives for the use of this technique with third generation Gravitational-Wave detectors, exploiting the recently developed Fisher information matrix Python code GWFAST.Comment: 5 pages, 2 figures, Contribution to the ICHEP 2022 conference proceeding

Purification and Characterization of Adipose-Derived Stem Cells From Patients With Lipoaspirate Transplant

Techniques for medical tissue regeneration require an abundant source of human adult stem cells. There is increasing evidence that adipose stem cells contribute to restoration of tissue vascularization and organ function. The object of our study was to isolate and characterize adult adipose-derived stem cells from patients undergoing on lipoaspirate transplant with the aim to improve tissue regeneration. Adipose-derived stem cells were isolated and purified from the lipoaspirate of 15 patients and characterized for CD markers and the ability to differentiate toward the adipogenic lineage. We found that purified adipose stem cells express high level of CD49d, CD44, CD90, CD105, CD13, and CD71 and these markers of staminality were maintained at high level for at least 3 months and seven passages of in vitro culture. As expected, these cells resulted negative for the endothelial and hematopoietic-specific markers CD31, CD106, CD34, and CD45. Differentiation towards adipogenic lineage demonstrated that purified adipose-derived stem cells are still able to become adipocytes at least 3 months after in vitro culture. The analysis of Akt and MAPK phosphorylation confirmed a modulation of their activity during differentiation. Interestingly, we established for the first time that, among the p53 family members, a strong upregulation of p63 expression occurs in adipocytic differentiation, indicating a role for this transcription factor in adipocytic differentiation. Taken together, these data indicate that purified lipoaspirate-derived stem cells maintain their characteristic of staminality for a long period of in vitro culture, suggesting that they could be applied for cell-based therapy to improve autologous lipoaspirate transplant

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

: Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL