Measurement of the dispersion of air and of refractive index anomalies by wavelength- dependent nonlinear interferometry

We carry out wavelength-dependent second harmonic interference experiments using thin films of an organic dye as nonlinear optical sources. While the measured difference of refractive index between the fundamental and second harmonic wavelengths follows the theoretical expectation for air in a wide spectral region, anomalous dispersion is observed when the second harmonic light lies in the absorption band of the dye. The sensitivity of the technique to small refractive index variations may prove useful for sensing applications as well as for testing models of light dispersion in weakly dispersing and absorbing media.Preprin

A Beckwith–Wiedemann-associated CDKN1C mutation allows the identification of a novel nuclear localization signal in human p57Kip2

p57Kip2 protein is a member of the CIP/Kip family, mainly localized in the nucleus where it exerts its Cyclin/CDKs inhibitory function. In addition, the protein plays key roles in embryogenesis, differentiation, and carcinogenesis depending on its cellular localization and interactors. Mutations of CDKN1C, the gene encoding human p57Kip2, result in the development of different genetic diseases, including Beckwith–Wiedemann, IMAGe and Silver–Russell syndromes. We investigated a specific Beckwith–Wiedemann associated CDKN1C change (c.946 C>T) that results in the substitution of the C-terminal amino acid (arginine 316) with a tryptophan (R316W-p57Kip2). We found a clear redistribution of R316W-p57Kip2, in that while the wild-type p57Kip2 mostly occurs in the nucleus, the mutant form is also distributed in the cytoplasm. Transfection of two expression constructs encoding the p57Kip2 N-and C-terminal domain, respectively, allows the mapping of the nuclear localization signal(s) (NLSs) between residues 220–316. Moreover, by removing the basic RKRLR sequence at the protein C-terminus (from 312 to 316 residue), p57Kip2 was confined in the cytosol, implying that this sequence is absolutely required for nuclear entry. In conclusion, we identified an unreported p57Kip2 NLS and suggest that its absence or mutation might be of relevance in CDKN1C-associated human diseases determining significant changes of p57Kip2 localization/regulatory roles

Mutation in a conserved motif next to the insulin receptor key autophosphorylation sites de-regulates kinase activity and impairs insulin action.

We have recently reported two non-insulin-dependent diabetic patients exhibiting a heterozygous point mutation (R1152-Q) next to the key tyrosine autophosphorylation sites (Y1146, Y1150, Y1151) of the insulin receptor. In the present study, we demonstrate that the Q1152 mutation alters a previously unrecognized consensus sequence in the insulin receptor family of tyrosine kinases. To define the effect of this alteration on insulin receptor function, the mutant insulin receptor (Q1152) was constructed and overexpressed in NIH-3T3 cells. In spite of normal insulin binding, "in vivo" and "in vitro" autophosphorylation as well as transphosphorylation by the wild-type receptor (WT) were deficient in Q1152 as compared with the transfected WT receptors. Insulin-stimulated kinase activity toward poly(Glu, Tyr) 4:1 and the endogenous substrates p120 and p175 were also impaired in Q1152. However, insulin-independent kinase activity of Q1152 was 2-5-fold higher than that of WT. While insulin stimulated 2-deoxyglucose uptake and glycogen synthase activity in WT-transfected cells with a sensitivity proportional to receptor number, no insulin stimulation was observed in Q1152 cells. Similar to the kinase, insulin-independent glycogen synthase activity and 2-deoxyglucose uptake were 2-fold higher in Q1152 than in either WT or parental cells. We conclude that the Q1152 mutation deregulates insulin receptor kinase and generates insulin insensitivity in cells. Alterations in this highly conserved region of the insulin receptor may contribute to non-insulin dependent diabetes mellitin pathogenesis in humans

Behavioural responses of juvenile Daphnia magna to two organophosphorus insecticides

In this study, the behaviour of Daphnia magna was studied under equipotent and sub-lethal concentrations of two pesticides congeners: chlorpyrifos (CPF; 5 ng L-1 to 50 ng L-1) and chlorpyrifos-methyl (CPF-m; 30 ng L-1 to 300 ng L-1) with aims to assess and compare the behavioural swimming responses (BSRs) of the cladocerans elicited by both compounds at different concentrations and exposure times. A video tracking analysis after 24 h and 48 h of exposure allowed us to evaluate different behavioural responses (distance moved, average velocity, active time, and average acceleration). The results indicate that BSRs are sensitive indicators of sub-lethal stress. Highly concentration- and time-response changes for both compounds were observed during the experiments. In particular, in the first 24 h of exposure, both compounds elicited a similar decreasing trend in swimming behaviour, in which CPF induced the highest decline. Further, hypoactivity was associated with the narcotic effects of both compounds. Conversely, after 48 h of exposure, we observed an increasing tendency in the swimming parameters, particularly at the highest tested concentrations. However, the compounds did not exhibit the same trend. Rather, CPF-m induced high variations from the control groups. This reversal trend could be due to the activation of compensatory mechanisms, such as feeding, searching, or avoidance behaviours. These results suggest that BSRs are measurable active responses of organisms, which are controlled by time

Effects of a treated sewage effluent on behavioural traits in Diamesa cinerella and Daphnia magna

Recently, the use of Daphnia magna has been proposed in on-line and real-time biomonitoring programmes as an early warning system for evaluating the effluent quality of sewage treatment plants (STPs). These systems are based on recording behavioural changes in the test organism resulting from the stress caused by the effluents. Indeed, altered behavioural signals could be induced at sublethal concentrations that are significantly lower than the corresponding EC50. However, at present, it is unknown whether the sensitivity of D. magna can be representative of that of other aquatic organisms, particularly benthic macroinvertebrates. An experiment was designed to verify whether D. magna can be employed in biomonitoring programmes for STPs located in alpine areas as a surrogate for cold freshwater best-adapted species. The responses of survival and behaviour alteration to exposure to the effluent of the Tonale Pass plant (Trentino, Italian Alps, 46°N, 10°E; 1799 m a.s.l.) were compared in a laboratory population of D. magna and a wild population of the chironomid Diamesa cinerella. These larvae were collected from the Vermigliana stream 50 metres upstream of the effluent input. Both organisms were exposed for 24 and 48 hrs to the effluent as it is and to three dilutions (/10, /100, /1000). The mortality rate and behavioural responses (using video tracking systems) were recorded. No significant mortality or change in behaviour was observed in the two species when exposed to the undiluted effluent. Exposure to serial dilutions of the treated effluent did not affect the survival of either species but notably altered their behaviour at both exposure times (e.g., the time spent in activity in D. magna and the average speed of movement and the cumulative distance travelled in both), especially when exposed to the ten-times-diluted effluent. Overall, the findings of this study emphasize that even though D. magna and D. cinerella use different behavioural strategies to cope with adverse environmental conditions, their overall sensitivity to treated effluents is similar. Accordingly, the use of D. magna in biological early warning systems protocols seems to also be sufficiently protective for local, cold-adapted species of alpine freshwater ecosystems

Risk Management in Magnetic Resonance: Failure Mode, Effects, and Criticality Analysis

The aim of the study was to perform a risk management procedure in "Magnetic Resonance Examination" process in order to identify the critical phases and sources of radiological errors and to identify potential improvement projects including procedures, tests, and checks to reduce the error occurrence risk. In this study we used the proactive analysis "Failure Mode Effects Criticality Analysis," a qualitative and quantitative risk management procedure; has calculated Priority Risk Index (PRI) for each activity of the process; have identified, on the PRI basis, the most critical activities and, for them, have defined improvement projects; and have recalculated the PRI after implementation of improvement projects for each activity. Time stop and audits are performed in order to control the new procedures. The results showed that the most critical tasks of "Magnetic Resonance Examination" process were the reception of the patient, the patient schedule drafting, the closing examination, and the organization of activities. Four improvement projects have been defined and executed. PRI evaluation after improvement projects implementation has shown that the risk decreased significantly following the implementation of procedures and controls defined in improvement projects, resulting in a reduction of the PRI between 43% and 100%

Exploiting Nanotechnologies and TRPV1 Channels to Investigate the Putative Anandamide Membrane Transporter

Considerable efforts have been made to characterize the pathways regulating the extracellular levels of the endocannabinoid anandamide. However, none of such pathways has been so argued as the existence of a carrier-mediated transport of anandamide across the membrane. Apart from the lack of molecular evidence for such a carrier, the main reasons of this controversy lie in the methodologies currently used to study anandamide cellular uptake. Furthermore, the main evidence in favor of the existence of an "anandamide transporter" relies on synthetic inhibitors of this process, the selectivity of which has been questioned.We used the cytosolic binding site for anandamide on TRPV1 channels as a biosensor to detect anandamide entry into cells, and exploited nanotechnologies to study anandamide membrane transport into intact TRPV1-overexpressing HEK-293 cells. Both fluorescence and digital holographic (DH) quantitative phase microscopy were used to study TRPV1 activation. Poly-epsilon-caprolactone nanoparticles (PCL-NPs) were used to incorporate anandamide, which could thus enter the cell and activate TRPV1 channels bypassing any possible specific protein(s) involved in the uptake process. We reasoned that in the absence of such protein(s), pharmacological tools previously shown to inhibit the "anandamide transporter" would affect in the same way the uptake of anandamide and PCL-NP-anandamide, and hence the activation of TRPV1. However, when masked into PCL-NPs, anandamide cellular uptake became much less sensitive to these agents, although it maintained the same pharmacokinetics and pharmacodynamics as that of "free" anandamide.We found here that several agents previously reported to inhibit anandamide cellular uptake lose their efficacy when anandamide is prevented from interacting directly with plasma membrane proteins, thus arguing in favor of the specificity of such agents for the putative "anandamide transporter", and of the existence of such mechanism

A Modified Post-Transplant Cyclophosphamide Regimen, for Unmanipulated Haploidentical Marrow Transplantation, in Acute Myeloid Leukemia: A Multicenter Study

Abstract We report a modified post-transplant cyclophosphamide (PT-CY) regimen, for unmanipulated haploidentical marrow transplants, in 150 patients with acute myeloid leukemia (AML). All patients received a myeloablative regimen, cyclosporine A (CsA) on day 0, mycophenolate on day +1, and PT-CY 50 mg/kg on days +3 and +5. The median age was 51 (range, 17–74) years, 51 (34%) patients had active disease at transplant, and the median follow-up of surviving patients 903 (range, 150-1955) days. The cumulative incidence (CI) of engraftment, acute graft-versus-host disease (GVHD) grade II to IV, and moderate/severe chronic GVHD was 92%, 17%, and 15%, respectively. The 4-year CI of transplant-related mortality (TRM) and relapse was 20% and 24%, respectively. Four-year survival for remission patients was 72% (74% versus 67% fo

COVID-19 infection in adult patients with hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA)

Background: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. Methods: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. Results: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March–May 2020) and the second wave (October–December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. Conclusions: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.EPICOVIDEHA has received funds from Optics COMMITTM (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223)

Decoding the historical tale: COVID-19 impact on haematological malignancy patients-EPICOVIDEHA insights from 2020 to 2022

The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced.Peer reviewe