Erratum: "Inference of the Local Interstellar Spectra of Cosmic-Ray Nuclei Z ⩽ 28 with the GALPROP-HELMOD Framework" (2020, ApJS, 250, 27).

[This corrects the article PMC8549769.].

The Discovery of a Low-energy Excess in Cosmic-Ray Iron: Evidence of the Past Supernova Activity in the Local Bubble.

Since its launch, the Alpha Magnetic Spectrometer-02 (AMS-02) has delivered outstanding quality measurements of the spectra of cosmic-ray (CR) species ( p ¯ , e ±, and nuclei, 1H-8O, 10Ne, 12Mg, 14Si) which resulted in a number of breakthroughs. One of the latest long-awaited surprises is the spectrum of 26Fe just published by AMS-02. Because of the large fragmentation cross section and large ionization energy losses, most of CR iron at low energies is local and may harbor some features associated with relatively recent supernova (SN) activity in the solar neighborhood. Our analysis of the new AMS-02 results, together with Voyager 1 and ACE-CRIS data, reveals an unexpected bump in the iron spectrum and in the Fe/He, Fe/O, and Fe/Si ratios at 1-2 GV, while a similar feature in the spectra of He, O, and Si and in their ratios is absent, hinting at a local source of low-energy CRs. The found excess extends the recent discoveries of radioactive 60Fe deposits in terrestrial and lunar samples and in CRs. We provide an updated local interstellar spectrum (LIS) of iron in the energy range from 1 MeV nucleon-1 to ~10 TeV nucleon-1. Our calculations employ the GALPROP-HELMOD framework, which has proved to be a reliable tool in deriving the LIS of CR p ¯ , e -, and nuclei Z ⩽ 28.

The effects of human sera conditioned by high-intensity exercise sessions and training on the tumorigenic potential of cancer cells

Purpose There is growing evidence of an association between physical activity and a reduced risk of cancer and cancer recurrence. The aim of this study was to assess the effects of exercise-conditioned human serum (HS) effects on the proliferative and tumorigenic potential of triple-negative breast cancer (TNBC) and prostate cancer (PC) cells. Moreover, modulated mechanisms and several physiological factors that can predict exercise effects were investigated. Methods Thirty healthy sedentary subjects were recruited for the study. The subjects performed two high-intensity endurance cycling (HIEC) sessions before and after a nine-week period of high-intensity interval training (HIIT). Cell tumorigenic capacity affected by HS collected before (t0), immediately after (t1), 4 h (t2), and 24 h (t3) after the HIEC sessions was evaluated by in vitro three-dimensional colony formation. The modulation of molecular pathways was analyzed by western blotting and qPCR in TNBC and PC cells, and in TNBC xenografts in exercised mice. Results All of the HIEC-conditioned HS (t1, t2, and t3) markedly impacted the proliferative and the microtumor-forming capacity of both TNBC and PC cell lines, while the HS collected from the subjects at rest did not. Modulation of the Hippo and Wnt/β-catenin pathways by HIEC-conditioned HS before and after the period of HIIT was shown. Multiple linear regression analysis showed relationships between the effects of HIEC-conditioned HS in PC cells, lactate threshold and VO2max. Conclusions These results highlight the potential of HIEC bouts in tumor progression control and the importance of optimizing an approach to identify physiological predictors of the effects of acute exercise in tertiary cancer prevention (AU)

The effects of human sera conditioned by high-intensity exercise sessions and training on the tumorigenic potential of cancer cells.

PURPOSE: There is growing evidence of an association between physical activity and a reduced risk of cancer and cancer recurrence. The aim of this study was to assess the effects of exercise-conditioned human serum (HS) effects on the proliferative and tumorigenic potential of triple-negative breast cancer (TNBC) and prostate cancer (PC) cells. Moreover, modulated mechanisms and several physiological factors that can predict exercise effects were investigated. METHODS: Thirty healthy sedentary subjects were recruited for the study. The subjects performed two high-intensity endurance cycling (HIEC) sessions before and after a nine-week period of high-intensity interval training (HIIT). Cell tumorigenic capacity affected by HS collected before (t0), immediately after (t1), 4 h (t2), and 24 h (t3) after the HIEC sessions was evaluated by in vitro three-dimensional colony formation. The modulation of molecular pathways was analyzed by western blotting and qPCR in TNBC and PC cells, and in TNBC xenografts in exercised mice. RESULTS: All of the HIEC-conditioned HS (t1, t2, and t3) markedly impacted the proliferative and the microtumor-forming capacity of both TNBC and PC cell lines, while the HS collected from the subjects at rest did not. Modulation of the Hippo and Wnt/ß-catenin pathways by HIEC-conditioned HS before and after the period of HIIT was shown. Multiple linear regression analysis showed relationships between the effects of HIEC-conditioned HS in PC cells, lactate threshold and VO2max. CONCLUSIONS: These results highlight the potential of HIEC bouts in tumor progression control and the importance of optimizing an approach to identify physiological predictors of the effects of acute exercise in tertiary cancer prevention.

Fibronectin induces capacitation-associated events through the endocannabinoid system in bull sperm.

Mammalian ejaculated spermatozoa must undergo a series of changes in the female reproductive tract, collectively called capacitation, in order to fertilize the oocyte. We reported that fibronectin (Fn), a glycoprotein from the extracellular matrix, and anandamide (AEA), one of the major members of the endocannabinoid family, are present in the bovine oviductal fluid and regulate bull sperm function. Also, AEA induces bovine sperm capacitation, through CB1 and TRPV1 receptors. In this work, we investigated if Fn induces bovine sperm capacitation thought the activation of the endocannabinoid system in this process. We incubated sperm with Fn (100 µg/ml) and/or capsazepine, a TRPV1 antagonist (0.1 µM) and some events related to sperm capacitation such as LPC-induced acrosome reaction, sperm-release from the oviduct, induction of PKA phosphorylated substrates (pPKAs) and protein tyrosine phosphorylation (pY) and nitric oxide (NO) production were assessed. Also, we studied the activity of fatty acid amide hydrolase (FAAH), the enzyme that degrades AEA. We found that Fn, via α5ß1 integrin, induced capacitation-associated events. Also, Fn stimulated signaling pathways associated to capacitation as cAMP/PKA and NO/NO synthase. Moreover, Fn decreased the FAAH activity and this correlated with sperm capacitation. Capsazepine reversed fibronectin-induced capacitation, and pPKAs and NO levels. The incubation of spermatozoa with R-methanandamide (1.4 nM), a stable analogue of AEA, increased cAMP and pPKAs levels. The presence of H89 (50 µM) or KT5720 (100 nM) (PKA inhibitors) prevented AEA-induced capacitation. In addition, R-methanandamide and capsaicin (0.01 µM), a TRPV1 agonist, increased NO production via the PKA pathway. These results indicate that Fn, through α5ß1, supports capacitation in bovine spermatozoa. This effect is dependent on the activation of TRPV1 through cAMP/PKA and NO signaling pathways. We propose that Fn could be considered as a new agent that promotes sperm capacitation in bull sperm. Our findings contribute to better understand the significance of Fn signaling in the capacitating events that lead to successful fertilization and embryo development in mammals including humans.

Vaginal delivery in SARS-CoV-2-infected pregnant women in Northern Italy: a retrospective analysis.

OBJECTIVE: To report mode of delivery and immediate neonatal outcome in women infected with COVID-19. DESIGN: Retrospective study. SETTING: Twelve hospitals in northern Italy. PARTICIPANTS: Pregnant women with COVID-19-confirmed infection who delivered. EXPOSURE: COVID 19 infection in pregnancy. METHODS: SARS-CoV-2-infected women who were admitted and delivered from 1 to 20 March 2020 were eligible. Data were collected from the clinical records using a standardised questionnaire on maternal general characteristics, any medical or obstetric co-morbidity, course of pregnancy, clinical signs and symptoms, treatment of COVID 19 infection, mode of delivery, neonatal data and breastfeeding. MAIN OUTCOME AND MEASURES: Data on mode of delivery and neonatal outcome. RESULTS: In all, 42 women with COVID-19 delivered at the participating centres; 24 (57.1%, 95% CI 41.0-72.3) delivered vaginally. An elective caesarean section was performed in 18/42 (42.9%, 95% CI 27.7-59.0) cases: in eight cases the indication was unrelated to COVID-19 infection. Pneumonia was diagnosed in 19/42 (45.2%, 95% CI 29.8-61.3) cases: of these, 7/19 (36.8%, 95% CI 16.3-61.6) required oxygen support and 4/19 (21.1%, 95% CI 6.1-45.6) were admitted to a critical care unit. Two women with COVID-19 breastfed without a mask because infection was diagnosed in the postpartum period: their newborns tested positive for SARS-Cov-2 infection. In one case, a newborn had a positive test after a vaginal operative delivery. CONCLUSIONS: Although postpartum infection cannot be excluded with 100% certainty, these findings suggest that vaginal delivery is associated with a low risk of intrapartum SARS-Cov-2 transmission to the newborn. TWEETABLE ABSTRACT: This study suggests that vaginal delivery may be associated with a low risk of intrapartum SARS-Cov-2 transmission to the newborn.

Deciphering the Local Interstellar Spectra of Secondary Nuclei with the Galprop/Helmod Framework and a Hint for Primary Lithium in Cosmic Rays.

Local interstellar spectra (LIS) of secondary cosmic-ray (CR) nuclei, lithium, beryllium, boron, and partially secondary nitrogen, are derived in the rigidity range from 10 MV to ~200 TV using the most recent experimental results combined with state-of-the-art models for CR propagation in the Galaxy and in the heliosphere. The lithium spectrum appears somewhat flatter at high energies compared to other secondary species, which may imply a primary lithium component. Two propagation packages, GALPROP and HelMod, are combined to provide a single framework that is run to reproduce direct measurements of CR species at different modulation levels, and at both polarities of the solar magnetic field. An iterative maximum-likelihood method is developed that uses GALPROP-predicted LIS as input to HelMod, which provides the modulated spectra for specific time periods of the selected experiments for the model-data comparison. The proposed LIS accommodates the low-energy interstellar spectra measured by Voyager 1, the High Energy Astrophysics Observatory-3 (HEAO-3), and the Cosmic Ray Isotope Spectrometer on board of the Advanced Composition Explorer (ACE/CRIS), as well as the high-energy observations by the Payload for Antimatter Matter Exploration and Light-nuclei Astrophysics (PAMELA), Alpha Magnetic Spectrometer-02 (AMS-02), and earlier experiments that are made deep in the heliosphere. The interstellar and heliospheric propagation parameters derived in this study are consistent with our earlier results for propagation of CR protons, helium, carbon, oxygen, antiprotons, and electrons.

Inference of the Local Interstellar Spectra of Cosmic-Ray Nuclei Z ⩽ 28 with the GalProp-HelMod Framework.

Composition and spectra of Galactic cosmic rays (CRs) are vital for studies of high-energy processes in a variety of environments and on different scales, for interpretation of γ-ray and microwave observations, for disentangling possible signatures of new phenomena, and for understanding of our local Galactic neighborhood. Since its launch, AMS-02 has delivered outstanding-quality measurements of the spectra of p ¯ , e ±, and nuclei: 1H-8O, 10Ne, 12Mg, 14Si. These measurements resulted in a number of breakthroughs; however, spectra of heavier nuclei and especially low-abundance nuclei are not expected until later in the mission. Meanwhile, a comparison of published AMS-02 results with earlier data from HEAO-3-C2 indicates that HEAO-3-C2 data may be affected by undocumented systematic errors. Utilizing such data to compensate for the lack of AMS-02 measurements could result in significant errors. In this paper we show that a fraction of HEAO-3-C2 data match available AMS-02 measurements quite well and can be used together with Voyager 1 and ACE-CRIS data to make predictions for the local interstellar spectra (LIS) of nuclei that are not yet released by AMS-02. We are also updating our already-published LIS to provide a complete set from 1H-28Ni in the energy range from 1 MeV nucleon-1 to ~100-500 TeV nucleon-1, thus covering 8-9 orders of magnitude in energy. Our calculations employ the GalProp-HelMod framework, which has proved to be a reliable tool in deriving the LIS of CR p ¯ , e -, and nuclei 1H-8O.

MRP4-mediated cAMP efflux is essential for mouse spermatozoa capacitation.

Mammalian spermatozoa must undergo biochemical and structural changes to acquire the capacity for fertilization, in a process known as capacitation. Activation of PKA enzymes is essential for capacitation, and thus cAMP levels are tightly regulated during this process. Previously, we demonstrated that during capacitation, bovine spermatozoa extrude cAMP through multidrug resistance-associated protein 4 (MRP4, also known as ABCC4), which regulates intracellular levels of the nucleotide and provides cAMP to the extracellular space. Here, we report the presence of functional MRP4 in murine spermatozoa, since its pharmacological inhibition with MK571 decreased levels of extracellular cAMP. This also produced a sudden increase in PKA activity, with decreased tyrosine phosphorylation at the end of capacitation. Blockade of MRP4 inhibited induction of acrosome reaction, hyperactivation and in vitro fertilization. Moreover, MRP4 inhibition generated an increase in Ca2+ levels mediated by PKA, and depletion of Ca2+ salts from the medium prevented the loss of motility and phosphotyrosine inhibition produced by MK571. These results were supported using spermatozoa from CatSper Ca2+ channel knockout mice. Taken together, these results suggest that cAMP efflux via MRP4 plays an essential role in mouse sperm capacitation.This article has an associated First Person interview with the first author of the paper.

HelMod in the Works: From Direct Observations to the Local Interstellar Spectrum of Cosmic-Ray Electrons.

The local interstellar spectrum (LIS) of cosmic-ray (CR) electrons for the energy range 1 MeV to 1 TeV is derived using the most recent experimental results combined with the state-of-the-art models for CR propagation in the Galaxy and in the heliosphere. Two propagation packages, GALPROP and HelMod, are combined to provide a single framework that is run to reproduce direct measurements of CR species at different modulation levels, and at both polarities of the solar magnetic field. An iterative maximum-likelihood method is developed that uses GALPROP-predicted LIS as input to HelMod, which provides the modulated spectra for specific time periods of the selected experiments for model-data comparison. The optimized HelMod parameters are then used to adjust GALPROP parameters to predict a refined LIS with the procedure repeated subject to a convergence criterion. The parameter optimization uses an extensive data set of proton spectra from 1997 to 2015. The proposed CR electron LIS accommodates both the low-energy interstellar spectra measured by Voyager 1 as well as the high-energy observations by PAMELA and AMS-02 that are made deep in the heliosphere; it also accounts for Ulysses counting rate features measured out of the ecliptic plane. The interstellar and heliospheric propagation parameters derived in this study agree well with our earlier results for CR protons, helium nuclei, and anti-protons propagation and LIS obtained in the same framework.

Deciphering the Local Interstellar Spectra of Primary Cosmic-Ray Species with helmod.

Local interstellar spectra (LIS) of primary cosmic ray (CR) nuclei, such as helium, oxygen, and mostly primary carbon are derived for the rigidity range from 10 MV to ~200 TV using the most recent experimental results combined with the state-of-the-art models for CR propagation in the Galaxy and in the heliosphere. Two propagation packages, GALPROP and helmod, are combined into a single framework that is used to reproduce direct measurements of CR species at different modulation levels, and at both polarities of the solar magnetic field. The developed iterative maximum-likelihood method uses GALPROP-predicted LIS as input to helmod, which provides the modulated spectra for specific time periods of the selected experiments for model-data comparison. The interstellar and heliospheric propagation parameters derived in this study are consistent with our prior analyses using the same methodology for propagation of CR protons, helium, antiprotons, and electrons. The resulting LIS accommodate a variety of measurements made in the local interstellar space (Voyager 1) and deep inside the heliosphere at low (ACE/CRIS, HEAO-3) and high energies (PAMELA, AMS-02).

Molecular changes and signaling events occurring in spermatozoa during epididymal maturation.

After leaving the testis, spermatozoa have not yet acquired the ability to move progressively and are unable to fertilize oocytes. To become fertilization competent, they must go through an epididymal maturation process in the male, and capacitation in the female tract. Epididymal maturation can be defined as those changes occurring to spermatozoa in the epididymis that render the spermatozoa the ability to capacitate in the female tract. As part of this process, sperm cells undergo a series of biochemical and physiological changes that require incorporation of new molecules derived from the epididymal epithelium, as well as post-translational modifications of endogenous proteins synthesized during spermiogenesis in the testis. This review will focus on epididymal maturation events, with emphasis in recent advances in the understanding of the molecular basis of this process.

A CMOS application-specified-integrated-circuit for 40 GHz high-electron-mobility-transistors automatic biasing.

This paper presents the design and the experimental results of a CMOS Automatic Control System (ACS) for the biasing of High-Electron-Mobility-Transistors (HEMT). The ACS is the first low-power mixed-signal Application-Specified-Integrated-Circuit (ASIC) able to automatically set and regulate the operating point of an off-chip 6 HEMT Low-Noise-Amplifiers (LNAs), hence it composes a two-chip system (the ACS+LNAs) to be used in the Large Scale Polarization Explorer (LSPE) stratospheric balloon for Cosmic Microwave Background (CMB) signal observation. The hereby presented ACS ASIC provides a reliable instrumentation for gradual and very stable LNAs characterization, switching-on, and operating point (<4 mV accuracy). Moreover, it simplifies the electronic instrumentation needed for biasing the LNAs, since it replaces several off-the-shelf and digital programmable device components. The ASIC prototype has been implemented in a CMOS 0.35 µm technology (12 mm2 area occupancy). It operates at 4 kHz clock frequency. The power consumption of one-channel ASIC (biasing one LNA) is 3.6 mW, whereas 30 mW are consumed by a single LNA device.

Solution of Heliospheric Propagation: Unveiling the Local Interstellar Spectra of Cosmic-ray Species.

Local interstellar spectra (LIS) for protons, helium, and antiprotons are built using the most recent experimental results combined with state-of-the-art models for propagation in the Galaxy and heliosphere. Two propagation packages, GALPROP and HelMod, are combined to provide a single framework that is run to reproduce direct measurements of cosmic-ray (CR) species at different modulation levels and at both polarities of the solar magnetic field. To do so in a self-consistent way, an iterative procedure was developed, where the GALPROP LIS output is fed into HelMod, providing modulated spectra for specific time periods of selected experiments to compare with the data; the HelMod parameter optimization is performed at this stage and looped back to adjust the LIS using the new GALPROP run. The parameters were tuned with the maximum likelihood procedure using an extensive data set of proton spectra from 1997 to 2015. The proposed LIS accommodate both the low-energy interstellar CR spectra measured by Voyager 1 and the high-energy observations by BESS, Pamela, AMS-01, and AMS-02 made from the balloons and near-Earth payloads; it also accounts for Ulysses counting rate features measured out of the ecliptic plane. The found solution is in a good agreement with proton, helium, and antiproton data by AMS-02, BESS, and PAMELA in the whole energy range.

Sperm Release From the Oviductal Epithelium Depends on Ca(2+) Influx Upon Activation of CB1 and TRPV1 by Anandamide.

The oviduct acts as a functional sperm reservoir in many mammalian species. Both binding and release of spermatozoa from the oviductal epithelium are mainly modulated by sperm capacitation. Several molecules from oviductal fluid are involved in the regulation of sperm function. Anandamide is a lipid mediator involved in reproductive physiology. Previously, we demonstrated that anandamide, through activation of the cannabinoid receptor type 1 (CB1), promotes sperm release from bovine oviductal epithelial cells, and through CB1 and the transient receptor potential vanilloid 1 (TRPV1), induces sperm capacitation. Herein we investigate co-activation between CB1 and TRPV1, and Ca(2+) influx as part of the mechanism of action of anandamide during sperm release from oviductal cells. Our results indicate that in the absence of Ca(2+) anandamide failed to release spermatozoa from oviductal epithelial cells. Additionally, sperm release promoted by cannabinoid and vanilloid agonists was abolished when the spermatozoa were preloaded with BAPTA-AM, a Ca(2+) chelator. We also determined Ca(2+) levels in spermatozoa preloaded with FURA2-AM co-cultured with oviductal cells and incubated with different cannabinoid and vanilloid agonists. The incubation with different agonists induced Ca(2+) influx, which was abolished by CB1 or TRPV1 antagonists. Our results also suggest that a phospholypase C (PLC) might mediate the activation of CB1 and TRPV1 in sperm release from the bovine oviduct. Therefore, our findings indicate that anandamide, through CB1 and TRPV1 activation, is involved in sperm release from the oviductal reservoir. An increase of sperm Ca(2+) levels and the PLC activation might be involved in anandamide signaling pathway.

Bedside diagnosis of two major clinical phenotypes of hypertensive disorders of pregnancy.

OBJECTIVE: To investigate the hypothesis that fetal abdominal circumference (AC) and uterine artery (UtA) Doppler pulsatility index (PI) could be used to select two homogeneous subgroups of women affected by hypertensive disorders of pregnancy (HDP), characterized by the coexistence of maternal hypertension with and without intrauterine growth restriction (IUGR). METHODS: This was a multicenter retrospective study of cases affected by HDP in whom fetal AC and UtA-PI had been measured at admission to fetomaternal medicine units. Maternal characteristics, pregnancy complications and outcome were recorded. These data allowed us to model the characteristics of fetal growth in cases affected by HDP, and to design composite indicators of risk factors for maternal metabolic syndrome and of severity for maternal functional organ damage. RESULTS: Measurements of fetal AC and UtA-PI allowed us to define a group of HDP cases with appropriate-for-gestational-age (AGA) fetuses (HDP-AGA), diagnosed by normal fetal AC and UtA-PI (n = 205), and a group of HDP cases with IUGR fetuses (HDP-IUGR), diagnosed by fetal AC < 5(th) centile and UtA-PI > 95(th) centile (n = 124). Curves fitted to the birth weights of these two groups were significantly different, but gestational age at admission for HDP (< 34 or ≥ 34 weeks) did not show an independent association with birth weight. When birth weight was expressed as a Z-score with respect to local reference charts, the average corresponded to the 6(th) and 48(th) centiles, respectively. The occurrence of HDP-AGA (as compared with HDP-IUGR) was significantly associated with risk factors for maternal metabolic syndrome (odds ratio, 2.79 (95% CI, 1.57-4.97)), independent of gestational age. The same risk factors yielded non-significant odds ratios for the development of late-onset (vs early-onset) HDP. Women with HDP-IUGR had worse clinical outcomes. CONCLUSIONS: This study provides new information based on simple prenatal bedside examinations that might help to differentiate HDP-IUGR from HDP-AGA fetuses. These groups are associated with different fetal growth patterns and risk factors, independent of gestational age at onset of the disease. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Expression of cyclooxygenase-1 (COX-1) and COX-2 in human male gametes from normal patients, and those with varicocele and diabetes: a potential molecular marker for diagnosing male infertility disorders.

Rising rates of varicocele and diabetes mellitus (DM) pose a significant problem to human fertility. Recent studies have pointed out the impact of cyclooxygenase (COX) in the regulation of testicular function and male fertility. Prominent COX-2 expression has been described recently in the testes of infertile patients, but little is known about the role and identity of COX isoforms in human sperm under certain disease states such as varicocele and DM. We therefore examined the expression profile and ultrastructural localization of COX-1 and COX-2 concomitantly in semen samples from healthy donors, and patients with varicocele and DM. Using Western blotting assay, 'varicocele' and 'diabetic' sperm showed enhanced COX isoforms expression with respect to the 'healthy' sperm. Immunogold labeling revealed human sperm anatomical regions containing COX-1 and COX-2, confirming their increased expression in pathological samples. Our data demonstrate that both COX isoforms are upregulated in the spermatozoa of varicocele and diabetic patients, suggesting the harmful effect of the diseases also at the sperm molecular level, going beyond the abnormal morphology described to date. In conclusion, COX enzymes may possess a biological relevance in the pathogenesis and/or maintenance of male factor infertility associated with varicocele and DM, and may be considered additional molecular markers for the diagnosis of male infertility disorders.