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The purpose of this study was to investigate the effects of partial-body cryostimulation on middle-distance runners before two 3000-m tests at the speed of the first and second ventilatory threshold, and before a time to exhaustion test at 110% of the maximal aerobic speed. Twelve amateur runners (age: 46 ± 9 years; VO2max: 51.7 ± 4.9 ml·kg-1·min-1) completed six running testing sessions in a randomized counterbalanced cross-over fashion: three of them were preceded by a partial-body cryostimulation and the other three by a control condition. The testing sessions consisted of: 1) a 3000-m continuous running test at the speed of the first ventilatory threshold; 2) a 3000-m continuous running test at the speed of the second ventilatory threshold; 3) a time to exhaustion test at 110% of the maximal aerobic speed. Heart rate, ratings of perceived exertion and visual analogue scale relative to muscle pain were recorded throughout the tests. Total quality recovery was evaluated 24-48 h after the end of each test. Distance to exhaustion was higher after partial-body cryostimulation than control condition (p = 0.018; partial-body cryostimulation: 988 ± 332 m, control: 893 ± 311 m). There were differences in the ratings of perceived exertion during each split of the 3000-m continuous running test at the speed of the second ventilatory threshold (p = 0.001). Partial-body cryostimulation can be positively considered to enhance middle-distance running performance and reduce perception of effort in amateur runners.

Background and objectivesIn 2020, the world was profoundly affected by the spread of SARS-CoV-2, a novel coronavirus first identified in December 2019, that was the causative agent of coronavirus disease 2019 (Covid-19), a severe respiratory disease classified as a pandemic by the World Health Organization (WHO) in March 2020. Covid-19 had a significant negative impact on the healthcare facilities and the economies of many countries. A need for pharmacological treatments for Covid-19 patients rapidly emerged to limit the damage caused by the disease and allow for more efficient management of hospital resources. A possible alternative treatment that has achieved encouraging results on Covid-19 is the use of monoclonal antibodies. This research aims to evaluate the cost-effectiveness of a type of monoclonal antibody, specifically the combination of casirivimab and imdevimab, and assess its impact on the Italian healthcare system.MethodsThe casirivimab and imdevimab treatment efficacy on outpatients with Covid-19 was tested using a predictive Markov model. Research endpoints include hospitalizations, Intensive Care Unit (ICU) admissions, and deaths. This was translated into terms of benefits (savings) and costs for the Italian National Health Service (NHS). The model operates on a predictive time frame of 20 weeks starting from September 2021 until January 2022. The data used to populate the model comes from international academic studies and open-access resources on online databases.ResultsThe model estimates the effects that can be achieved by administering casirivimab and imdevimab treatment on outpatients with Covid-19. According to the estimates, the treatment can prevent approximately 4,000 hospitalizations, 3,589 ICU admissions, and 1,500 deaths in the considered 20-week period. The potential cost savings amount to EUR 78 million, mainly attributable to the reduction in the number of hospitalizations and access to ICU. More specifically, a difference of EUR 15,4 million can be observed due to the reduction in the number of hospitalizations, a difference of EUR 59,3 million due to the reduction in the number in intensive care, and a difference of EUR 20,3 million due to the reduction in deaths as a consequence of the reduction of hospitalizations. These results are already very significant, considering that in Italy, only 4.76% of the population is eligible for monoclonal antibody treatment.ConclusionThe administration of casirivimab and imdevimab in outpatients with Covid-19 can accelerate recovery from the disease for patients, make hospital resource management more efficient and significantly reduce costs for healthcare facilities.

This study analyses the bycatch composition of an artisanal shrimp trawl fleet operating between Cabo Blanco and Máncora in Northern Peru between April 2019 and March 2020. A total of 300 hauls were analysed with respect to target catch and bycatch (consisting of other commercial species, discards, and macroalgae). A total of 277 species were recorded including 111 species of fish, 65 species of molluscs, 51 species of crustaceans, 22 species of algae, 12 species of cnidarian, 9 species of echinoderms, 4 species of Bryozoa and 3 species of polychaeta. Capture per unit effort (CPUE, kg.h-1) was highest for fish, followed by crustaceans, algae and molluscs. The target species Penaeus californiensis coffee shrimp constituted 17.8% of the overall catch,82.2% represented bycatch, and 50.6% represented discards. Coffee shrimps were more abundant in June and November 2019 and in January and February 2020. Highest bycatch CPUE occurred in May, June and December 2019. The most abundant species in the bycatch throughout the study period were sand perch (Diplectrum conceptione, 16% weight of the total catch), the macroalgae caulerpa (Caulerpa filiformis, 13%), sole flounder (Etropus ectenes, 6.4%), Pacific drum (Larimus pacificus, 5.7%), and lumptail searobin (Prionotus stephanophrys, 5.1%). Overall, the contribution of sand perch and flounder, exceeded the weight of coffee shrimp, therefore the interpretation that shrimp is the sole target species needs to be revised. The number of discarded species per month increased towards the spring months with the highest value in November. This study represents the first characterisation of bycatch in the artisanal trawling fishery in the Piura region in northern Peru and reveals a high proportion of bycatch in the fishery but also hints at potential temporal management measures that could be imposed to reduce the levels of bycatch. For example, the months of May and December had the greatest bycatch to shrimp ratios and the fishery could potentially be closed to avoid high bycatch risk, however, longer term information is needed to assess if the trends observed in bycatch are similar over longer periods of time. The species characterisation of bycatch also provides information for the design of modified nets which would target the reduction of small fish present in the catch.

Computation methods that predict the binding of peptides to MHC-I are important tools for screening and identifying immunogenic antigens and have the potential to accelerate vaccine and drug development. However, most available tools are sequence-based and optimized only for peptides containing the twenty canonical amino acids. This omits a large number of peptides containing non-canonical amino acids (NCAA), or residues that undergo varied post-translational modifications such as glycosylation or phosphorylation. These modifications fundamentally alter peptide immunogenicity. Similarly, existing structure-based methods are biased towards canonical peptide backbone structures, which may or may not be preserved when NCAAs are present. Rosetta FlexPepDock ab-initio is a structure-based computational protocol able to evaluate peptide-receptor interaction where no prior information of the peptide backbone is known. We benchmarked FlexPepDock ab-initio for docking canonical peptides to MHC-I, and illustrate for the first time the method's ability to accurately model MHC-I bound epitopes containing NCAAs. FlexPepDock ab-initio protocol was able to recapitulate near-native structures (≤1.5Å) in the top lowest-energy models for 20 out of 25 cases in our initial benchmark. Using known experimental binding affinities of twenty peptides derived from an influenza-derived peptide, we showed that FlexPepDock protocol is able to predict relative binding affinity as Rosetta energies correlate well with experimental values (r = 0.59, p = 0.006). ROC analysis revealed 80% true positive and a 40% false positive rate, with a prediction power of 93%. Finally, we demonstrate the protocol's ability to accurately recapitulate HLA-A*02:01 bound phosphopeptide backbone structures and relative binding affinity changes, the theoretical structure of the lymphocytic choriomeningitis derived glycosylated peptide GP392 bound to MHC-I H-2Db, and isolevuglandin-adducted peptides. The ability to use non-canonical amino acids in the Rosetta FlexPepDock protocol may provide useful insight into critical amino acid positions where the post-translational modification modulates immunologic responses.

Language production has often been described as impaired in psychiatric diseases such as in psychosis. Nevertheless, little is known about the characteristics of linguistic difficulties and their relation with other cognitive domains in patients with a first episode of psychosis (FEP), either affective or non-affective. To deepen our comprehension of linguistic profile in FEP, 133 patients with FEP (95 non-affective, FEP-NA; 38 affective, FEP-A) and 133 healthy controls (HC) were assessed with a narrative discourse task. Speech samples were systematically analyzed with a well-established multilevel procedure investigating both micro- (lexicon, morphology, syntax) and macro-linguistic (discourse coherence, pragmatics) levels of linguistic processing. Executive functioning and IQ were also evaluated. Both linguistic and neuropsychological measures were secondarily implemented with a machine learning approach in order to explore their predictive accuracy in classifying participants as FEP or HC. Compared to HC, FEP patients showed language production difficulty at both micro- and macro-linguistic levels. As for the former, FEP produced shorter and simpler sentences and fewer words per minute, along with a reduced number of lexical fillers, compared to HC. At the macro-linguistic level, FEP performance was impaired in local coherence, which was paired with a higher percentage of utterances with semantic errors. Linguistic measures were not correlated with any neuropsychological variables. No significant differences emerged between FEP-NA and FEP-A (p≥0.02, after Bonferroni correction). Machine learning analysis showed an accuracy of group prediction of 76.36% using language features only, with semantic variables being the most impactful. Such a percentage was enhanced when paired with clinical and neuropsychological variables. Results confirm the presence of language production deficits already at the first episode of the illness, being such impairment not related to other cognitive domains. The high accuracy obtained by the linguistic set of features in classifying groups support the use of machine learning methods in neuroscience investigations.

Background The relationship between COVID-19 and out-of-hospital cardiac arrests (OHCAs) has been shown during different phases of the first pandemic wave, but little is known about how to predict where cardiac arrests will increase in case of a third peak. Aim To seek for a correlation between the OHCAs and COVID-19 daily incidence both during the two pandemic waves at a provincial level. Methods We considered all the OHCAs occurred in the provinces of Pavia, Lodi, Cremona, Mantua and Varese, in Lombardy Region (Italy), from 21/02/2020 to 31/12/2020. We divided the study period into period 1, the first 157 days after the outbreak and including the first pandemic wave and period 2, the second 158 days including the second pandemic wave. We calculated the cumulative and daily incidence of OHCA and COVID-19 for the whole territory and for each province for both periods. Results A significant correlation between the daily incidence of COVID-19 and the daily incidence of OHCAs was observed both during the first and the second pandemic period in the whole territory (R = 0.4, pConclusions Our results suggest that strictly monitoring the pandemic trend may help in predict which territories will be more likely to experience an OHCAs’ increase. That may also serve as a guide to re-allocate properly health resources in case of further pandemic waves.

Porcine Reproductive and Respiratory Syndrome (PRRS) is a complex model of host/virus relationship. Disease control measures often includes "acclimatization", i.e. the exposure of PRRS-naïve gilts and sows to PRRSV-infected pigs and premises before the breeding period. In this respect, we had repeatedly observed an association between PRRSV-specific IgA responses in oral fluids (OF) of gilts and block of PRRSV spread. Therefore, we set out to investigate in vitro the inhibition of PRRSV replication by OF samples with different titers of PRRSV-specific IgA and IgG antibody, using Real-time RT PCR. PRRSV yield reduction in monocyte-derived macrophages was associated with the IgA content in OF samples, whereas the IgG-rich samples were sometimes associated with antibody-dependent enhancement (ADE) of replication. Accordingly, we could discriminate between ADE-positive and ADE-negative PRRSV strains. Next, we separated Ig isotypes in OF samples of PRRSV-infected pigs by means of protein A and size exclusion chromatography. The above results were confirmed by using separated Ig isotypes. Both dimeric and monomeric IgA were associated with the strongest reduction of PRRSV replication. The treatment of pig macrophages with separated OF antibodies before PRRSV infection was also associated with PRRSV yield reduction, along with clear changes of both CD163 and CD169 surface expression. Our results point at a role of mucosal IgA in the control of PRRSV replication by extra- and/or intracellular interaction with PRRSV, as well as by induction of signals leading to a reduced susceptibility of macrophages to PRRSV infection.

Alterations in fibroblast growth factor receptor (FGFR) genes have been identified as potential driver oncogenes. Pharmacological targeting of FGFRs may therefore provide therapeutic benefit to selected cancer patients, and proof-of-concept has been established in early clinical trials of FGFR inhibitors. Here, we present the molecular structure and preclinical characterization of INCB054828 (pemigatinib), a novel, selective inhibitor of FGFR 1, 2, and 3, currently in phase 2 clinical trials. INCB054828 pharmacokinetics and pharmacodynamics were investigated using cell lines and tumor models, and the antitumor effect of oral INCB054828 was investigated using xenograft tumor models with genetic alterations in FGFR1, 2, or 3. Enzymatic assays with recombinant human FGFR kinases showed potent inhibition of FGFR1, 2, and 3 by INCB054828 (half maximal inhibitory concentration [IC50] 0.4, 0.5, and 1.0 nM, respectively) with weaker activity against FGFR4 (IC50 30 nM). INCB054828 selectively inhibited growth of tumor cell lines with activation of FGFR signaling compared with cell lines lacking FGFR aberrations. The preclinical pharmacokinetic profile suggests target inhibition is achievable by INCB054828 in vivo with low oral doses. INCB054828 suppressed the growth of xenografted tumor models with FGFR1, 2, or 3 alterations as monotherapy, and the combination of INCB054828 with cisplatin provided significant benefit over either single agent, with an acceptable tolerability. The preclinical data presented for INCB054828, together with preliminary clinical observations, support continued investigation in patients with FGFR alterations, such as fusions and activating mutations.

IntroductionAn increase in the incidence of OHCA during the COVID-19 pandemic has been recently demonstrated. However, there are no data about how the COVID-19 epidemic influenced the treatment of OHCA victims.MethodsWe performed an analysis of the Lombardia Cardiac Arrest Registry comparing all the OHCAs occurred in the Provinces of Lodi, Cremona, Pavia and Mantua (northern Italy) in the first 100 days of the epidemic with those occurred in the same period in 2019.ResultsThe OHCAs occurred were 694 in 2020 and 520 in 2019. Bystander cardiopulmonary resuscitation (CPR) rate was lower in 2020 (20% vs 31%, pConclusionCompared to 2019, during the 2020 COVID-19 outbreak we observed a lower attitude of laypeople to start CPR, while resuscitation attempts by BLS and ALS staff were not influenced by suspected/confirmed infection, even at univariable analysis.

BACKGROUND:For many years, long-acting intramuscular (LAI) antipsychotics have been prescribed predominantly to chronic and severe patients, as a last resort when other treatments failed. Recently, a broader and earlier use of LAIs, particularly second-generation LAIs, has been emphasized. To date, few studies attempted to frame how this change in prescribing took place in real-world practice. Therefore, this study aimed to describe the clinical features of patients prescribed with LAIs, and to explore possible prescribing differences between first- and second-generations LAIs under ordinary clinical practice in Italy. METHODS:The STAR Network "Depot" Study is an observational, longitudinal, multicenter study involving 35 centers in Italy. In the cross-sectional phase, patients prescribed with LAIs were consecutively recruited and assessed over a period of 12 months. Descriptive statistics and multivariable logistic regression analyses were employed. RESULTS:Of the 451 recruited patients, 61% were males. The level of social and working functioning was heterogeneous, as was the severity of disease. Seventy-two per cent of the patients had a diagnosis of the schizophrenia spectrum. Seventy per cent were prescribed with second-generation antipsychotic (SGA) LAIs (mostly paliperidone, aripiprazole and risperidone). Compared to first-generation antipsychotic (FGA) LAIs, patients prescribed with SGA LAIs were more often younger; employed; with a diagnosis of the schizophrenia spectrum or bipolar disorder; with higher levels of affective symptoms; with fewer LAI prescriptions in the past. DISCUSSION:LAIs' prescribing practices appear to be more flexible as compared to the past, although this change is mostly restricted to SGA LAIs.

Mitogens are diverse compounds of plant and microbial origin, widely employed to test immunocompetence in animals. The blastogenic response of bovine Peripheral Blood Mononuclear Cells (PBMC) to lypopolysaccharides (LPS) has been investigated in our laboratories for a long time. In particular, a possible correlation between blastogenic response to LPS and disease resistance of periparturient dairy cows had been observed in previous studies. Most important, low responder cows presented a higher frequency of disease cases after calving, compared with high responder animals. Owing to the above, different aspects of the blastogenic response to LPS were investigated on PBMC of healthy Friesian cows, using a 72-hour Bromodeoxyuridin (BrDU) cell proliferation assay. Stimulation with LPS induced little if any replication of bovine PBMC over 72 hours despite consistent BrDU detection in all the PBMC samples under study. Poor replication of LPS-stimulated PBMC was confirmed by cell cycle and cell growth flow cytometry analyses. In particular, LPS stimulation gave rise to very low percentages of S phase cells, sometimes lower than in control, unstimulated cells, as opposed to Concanavalin A-stimulated PBMC. Magnetic separation and analysis of BrDU-treated bovine PBMC after exposure to LPS showed that both B and CD4 T cells are involved in the blastogenic response to LPS, in contrast with current data based on human and murine models. Finally, LPS caused an early, specific up-regulation of TNF-α and TLR4 genes in bovine PBMC, and significant correlations were shown between the expression of inflammatory cytokine and Indoleamine-pyrrole 2,3-dioxygenase (IDO1) genes. On the whole, our data indicate that differences in the blastogenic response to LPS could be partly accounted for by heterogenicity of responding cells (B and T lymphocytes), which might also have an impact on induction and regulation of inflammatory responses and endotoxin tolerance.

BACKGROUND:Results from phase III clinical trial CheckMate 025 have established nivolumab as the standard of care for treatment of metastatic renal-cell carcinoma (mRCC) after VEGF inhibitor failure; however, elderly patients are under-represented in the registration trial and little is known about the activity of nivolumab in this subgroup. The purpose of the Expanded Access Program was to provide nivolumab to patients with mRCC who had progressed despite treatment with other agents that were considered standard of care. METHODS:Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24 months or until progression or unacceptable toxicity. The current analysis included all patients from the EAP Italian cohort who had received ≥1 dose of nivolumab. Adverse events (AEs) were monitored using Common Terminology Criteria for Adverse Events v4.0. RESULTS:A total of 389 patients with advanced RCC were enrolled in the Italian cohort of the EAP and treated with nivolumab. Of these patients, 125 (32%) were at least 70 years of age and 70 (18%) were at least 75 years of age. Efficacy with nivolumab in the elderly patients was similar to that observed in the overall EAP population and in the CheckMate 025 trial. Safety was comparable between the elderly patients and the overall EAP population, and was consistent with what previously reported. CONCLUSION:The final results suggest that elderly patients with pretreated metastatic RCC may benefit from therapy with nivolumab.

Although schizophrenia (SCZ) and bipolar disorder (BD) share elements of pathology, their neural underpinnings are still under investigation. Here, structural Magnetic Resonance Imaging (MRI) data collected from a large sample of BD and SCZ patients and healthy controls (HC) were analyzed in terms of gray matter volume (GMV) using both voxel based morphometry (VBM) and a region of interest (ROI) approach.The analysis was conducted on two datasets, Dataset1 (802 subjects: 243 SCZ, 176 BD, 383 HC) and Dataset2, a homogeneous subset of Dataset1 (301 subjects: 107 HC, 85 BD and 109 SCZ). General Linear Model analyses were performed 1) at the voxel-level in the whole brain (VBM study), 2) at the regional level in the anatomical regions emerged from the VBM study (ROI study). The GMV comparison across groups was integrated with the analysis of GMV correlates of different clinical dimensions.The VBM results of Dataset1 showed 1) in BD compared to HC, GMV deficits in right cingulate, superior temporal and calcarine cortices, 2) in SCZ compared to HC, GMV deficits in widespread cortical and subcortical areas, 3) in SCZ compared to BD, GMV deficits in insula and thalamus (p

Several strands of evidence reported a significant overlapping, in terms of clinical symptoms, epidemiology and treatment response, between the two major psychotic disorders-Schizophrenia (SCZ) and Bipolar Disorder (BD). Nevertheless, the shared neurobiological correlates of these two disorders are far from conclusive. This study aims toward a better understanding of possible common microstructural brain alterations in SCZ and BD. Magnetic Resonance Diffusion data of 33 patients with BD, 19 with SCZ and 35 healthy controls were acquired. Diffusion indexes were calculated, then analyzed using Tract-Based Spatial Statistics (TBSS). We tested correlations with clinical and psychological variables. In both patient groups mean diffusion (MD), volume ratio (VR) and radial diffusivity (RD) showed a significant increase, while fractional anisotropy (FA) and mode (MO) decreased compared to the healthy group. Changes in diffusion were located, for both diseases, in the fronto-temporal and callosal networks. Finally, no significant differences were identified between patient groups, and a significant correlations between length of disease and FA and VR within the corpus callosum, corona radiata and thalamic radiation were observed in bipolar disorder. To our knowledge, this is the first study applying TBSS on all the DTI indexes at the same time in both patient groups showing that they share similar impairments in microstructural connectivity, with particular regards to fronto-temporal and callosal communication, which are likely to worsen over time. Such features may represent neural common underpinnings characterizing major psychoses and confirm the central role of white matter pathology in schizophrenia and bipolar disorder.

For the assessment of glucose tolerance from IVGTT data in Zucker rat, minimal model methodology is reliable but time- and money-consuming. This study aimed to validate for the first time in Zucker rat, simple surrogate indexes of insulin sensitivity and secretion against the glucose-minimal-model insulin sensitivity index (SI) and against first- (Φ1) and second-phase (Φ2) β-cell responsiveness indexes provided by C-peptide minimal model. Validation of the surrogate insulin sensitivity index (ISI) and of two sets of coupled insulin-based indexes for insulin secretion, differing from the cut-off point between phases (FPIR3-SPIR3, t = 3 min and FPIR5-SPIR5, t = 5 min), was carried out in a population of ten Zucker fatty rats (ZFR) and ten Zucker lean rats (ZLR). Considering the whole rat population (ZLR+ZFR), ISI showed a significant strong correlation with SI (Spearman's correlation coefficient, r = 0.88; P

It is well known that temporal fluctuations in small populations deeply influence evolutionary potential. Less well known is whether fluctuations can influence the evolutionary potentials of species with large census sizes. Here, we estimated genetic population parameters from as survey of polymorphic microsatellite DNA loci in archived otoliths from Adriatic European anchovy (Engraulis encrasicolus), a fish with large census sizes that supports numerous local fisheries. Stocks have fluctuated greatly over the past few decades, and the Adriatic fishery collapsed in 1987. Our results show a significant reduction of mean genetic parameters as a consequence of the population collapse. In addition, estimates of effective population size (Ne) are much smaller than those expected in a fishes with large population census sizes (Nc). Estimates of Ne indicate low effective population sizes, even before the population collapse. The ratio Ne/Ne ranged between 10-6 and 10-8, indicating a large discrepancy between the anchovy gene pool and population census size. Therefore, anchovy populations may be more vulnerable to fishery effort and environmental change than previously thought.

Colorectal cancer patients have a median age of incidence >65years although they are largely under-represented in phase-III trials. This large population contains patients unfit for treatment, those suitable for monotherapy or for doublets and the impact of chemotherapy outside clinical trial is unclear. The aim of the study was to retrospectively analyse Overall Survival(OS) of elderly metastatic colorectal cancer(mCRC) patients treated with chemotherapy in daily practice.Kaplan-Meir method was used for OS, the log-rank or Tarone-Ware test for differences between subgroups, Cox's proportional hazard model to assess the impact of known prognostic factors and treatment.751 patients with mCRC observed between January 2000 and January 2013 were collected. Median age was 79 year(75-93); Male/Female 61/39%, ECOG-PS 0-1/2 85/15%; colon/rectum 74/26%; multiple metastatic sites 34%, only liver metastasis in 41% of patients. KRAS status was studied in 35% of patients: 44% of them showed gene mutation. 20.5% of patients did not received any kind of treatment including surgery. Comorbidities observed: cardiovascular 34%, diabetes 14%, hypertension 50%. Primary tumor was resected in 80.6%; surgery of liver metastasis was done in 19% of patients (2.3% of patients >80years). 78% of patients underwent chemotherapy. Median follow up was 12 months(range 1-124). Median OS was 17 months (CI 95%15-19);median OS in no-treated patients was 5 months (4-6); mOS of patients with at least one treatment was 20 months (18-22). In KRAS mutated group median OS was 19months (15-23) while in KRAS wild type patients median OS was 25 months (20-30). At multivariate analysis sex(Female), age(80 years old or with a poor performance status (respectively p

In this pilot study for the first time, ancient DNA has been extracted from bone remains of Salmo trutta. These samples were from a stratigraphic succession located in a coastal cave of Calabria (southern Italy) inhabited by humans from upper Palaeolithic to historical times. Seven pairs of primers were used to PCR-amplify and sequence from 128 to 410 bp of the mtDNA control region of eleven samples. Three haplotypes were observed: two (ADcs-1 and MEcs-1) already described in rivers from the Italian peninsula; one (ATcs-33) belonging to the southern Atlantic clade of the AT Salmo trutta mtDNA lineage (sensu Bernatchez). The prehistoric occurrence of this latter haplotype in the water courses of the Italian peninsula has been detected for the first time in this study. Finally, we observed a correspondence between frequency of trout remains and variation in haplotype diversity that we related with ecological and demographic changes resulting from a period of rapid cooling known as the Younger Dryas.

The sustained exploitation of marine populations requires an understanding of a species' adaptive seascape so that populations can track environmental changes from short- and long-term climate cycles and from human development. The analysis of the distributions of genetic markers among populations, together with correlates of life-history and environmental variability, can provide insights into the extent of adaptive variation. Here, we examined genetic variability among populations of mature European anchovies (n = 531) in the Adriatic (13 samples) and Tyrrhenian seas (2 samples) with neutral and putative non-neutral microsatellite loci. These genetic markers failed to confirm the occurrence of two anchovy species in the Adriatic Sea, as previously postulated. However, we found fine-scale population structure in the Adriatic, especially in northern areas, that was associated with four of the 13 environmental variables tested. Geographic gradients in sea temperature, salinity and dissolved oxygen appear to drive adaptive differences in spawning time and early larval development among populations. Resolving adaptive seascapes in Adriatic anchovies provides a means to understand mechanisms underpinning local adaptation and a basis for optimizing exploitation strategies for sustainable harvests.

Enigmatic amphibian declines were first reported in southern and southeastern Brazil in the late 1980s and included several species of stream-dwelling anurans (families Hylodidae and Cycloramphidae). At that time, we were unaware of the amphibian-killing fungus Batrachochytrium dendrobatidis (Bd); therefore, pollution, habitat loss, fragmentation and unusual climatic events were hypothesized as primary causes of these declines. We now know that multiple lineages of Bd have infected amphibians of the Brazilian Atlantic forest for over a century, yet declines have not been associated specifically with Bd outbreaks. Because stream-dwelling anurans occupy an environmental hotspot ideal for disease transmission, we investigated temporal variation in population and infection dynamics of three stream-adapted species (Hylodes asper, H. phyllodes, and Cycloramphus boraceiensis) on the northern coast of São Paulo state, Brazil. We surveyed standardized transects along streams for four years, and show that fluctuations in the number of frogs correlate with specific climatic variables that also increase the likelihood of Bd infections. In addition, we found that Bd infection probability in C. boraceiensis, a nocturnal species, was significantly higher than in Hylodes spp., which are diurnal, suggesting that the nocturnal activity may either facilitate Bd zoospore transmission or increase susceptibility of hosts. Our findings indicate that, despite long-term persistence of Bd in Brazil, some hosts persist with seasonally variable infections, and thus future persistence in the face of climate change will depend on the relative effect of those changes on frog recruitment and pathogen proliferation.

A C-peptide-based assessment of β-cell function was performed here in the Zucker fatty rat, a suitable animal model of human metabolic syndrome. To this aim, a 90-min intravenous glucose tolerance test (IVGTT) was performed in seven Zucker fatty rats (ZFR), 7-to-9 week-old, and seven age-matched Zucker lean rats (ZLR). The minimal model of C-peptide (CPMM), originally introduced for humans, was adapted to Zucker rats and then applied to interpret IVGTT data. For a comprehensive evaluation of glucose tolerance in ZFR, CPMM was applied in combination with the minimal model of glucose kinetics (GKMM). Our results showed that the present CPMM-based interpretation of data is able to: 1) provide a suitable fit of C-Peptide data; 2) achieve a satisfactory estimation of parameters of interest 3) quantify both insulin secretion by estimating the time course of pre-hepatic secretion rate, SR(t), and total insulin secretion, TIS, and pancreatic sensitivity by means of three specific indexes of β-cell responsiveness to glucose stimulus (first-phase, Ф(1), second-phase, Ф(2), and steady-state, Ф(ss), never assessed in Zucker rats before; 4) detect the significant enhancement of insulin secretion in the ZFR, in face of a severe insulin-resistant state, previously observed only using a purely experimental approach. Thus, the methodology presented here represents a reliable tool to assess β-cell function in the Zucker rat, and opens new possibilities for the quantification of further processes involved in glucose homeostasis such as the hepatic insulin degradation.

The Plasmodium falciparum PfA-M1 and PfA-M17 metalloaminopeptidases are validated drug targets for the discovery of antimalarial agents. In order to identify dual inhibitors of both proteins, we developed a hierarchical virtual screening approach, followed by in vitro evaluation of the highest scoring hits. Starting from the ZINC database of purchasable compounds, sequential 3D-pharmacophore and molecular docking steps were applied to filter the virtual 'hits'. At the end of virtual screening, 12 compounds were chosen and tested against the in vitro aminopeptidase activity of both PfA-M1 and PfA-M17. Two molecules showed significant inhibitory activity (low micromolar/nanomolar range) against both proteins. Finally, the crystal structure of the most potent compound in complex with both PfA-M1 and PfA-M17 was solved, revealing the binding mode and validating our computational approach.

The developmental and stress-regulated alternative TrkAIII splice variant of the NGF receptor TrkA is expressed by advanced stage human neuroblastomas (NBs), correlates with worse outcome in high TrkA expressing unfavourable tumours and exhibits oncogenic activity in NB models. In the present study, we report that constitutive TrkAIII expression in human SH-SY5Y NB cells inhibits Rotenone, Paraquat and LY83583-induced mitochondrial free radical reactive oxygen species (ROS)-mediated death by stimulating SOD2 expression, increasing mitochondrial SOD2 activity and attenuating mitochondrial free radical ROS production, in association with increased mitochondrial capacity to produce H2O2, within the context of a more tumour stem cell-like phenotype. This effect can be reversed by the specific TrkA tyrosine kinase inhibitor GW441756, by the multi-kinase TrkA inhibitors K252a, CEP-701 and Gö6976, which inhibit SOD2 expression, and by siRNA knockdown of SOD2 expression, which restores the sensitivity of TrkAIII expressing SH-SY5Y cells to Rotenone, Paraquat and LY83583-induced mitochondrial free radical ROS production and ROS-mediated death. The data implicate the novel TrkAIII/SOD2 axis in promoting NB resistance to mitochondrial free radical-mediated death and staminality, and suggest that the combined use of TrkAIII and/or SOD2 inhibitors together with agents that induce mitochondrial free radical ROS-mediated death could provide a therapeutic advantage that may also target the stem cell niche in high TrkA expressing unfavourable NB.

Understanding cancer cell signal transduction is a promising lead for uncovering therapeutic targets and building treatment-specific markers for epithelial ovarian cancer. To brodaly assay the many known transmembrane receptor systems, previous studies have employed gene expression data measured on high-throughput microarrays. Starting with the knowledge of validated ligand-receptor pairs (LRPs), these studies postulate that correlation of the two genes implies functional autocrine signaling. It is our goal to consider the additional weight of evidence that prognosis (progression-free survival) can bring to prioritize ovarian cancer specific signaling mechanism. We survey three large studies of epithelial ovarian cancers, with gene expression measurements and clinical information, by modeling survival times both categorically (long/short survival) and continuously. We use differential correlation and proportional hazards regression to identify sets of LRPs that are both prognostic and correlated. Of 475 candidate LRPs, 77 show reproducible evidence of correlation; 55 show differential correlation. Survival models identify 16 LRPs with reproduced, significant interactions. Only two pairs show both interactions and correlation (PDGFA[Formula: see text]PDGFRA and COL1A1[Formula: see text]CD44) suggesting that the majority of prognostically useful LRPs act without positive feedback. We further assess the connectivity of receptors using a Gaussian graphical model finding one large graph and a number of smaller disconnected networks. These LRPs can be organized into mutually exclusive signaling clusters suggesting different mechanisms apply to different patients. We conclude that a mix of autocrine and endocrine LRPs influence prognosis in ovarian cancer, there exists a heterogenous mix of signaling themes across patients, and we point to a number of novel applications of existing targeted therapies which may benefit ovarian cancer.

OBJECTIVE:What role should minors play in making medical decisions? The authors examined children's and adolescents' desire to be involved in serious medical decisions and the emotional consequences associated with them. METHODS:Sixty-three children and 76 adolescents were presented with a cover story about a difficult medical choice. Participants were tested in one of four conditions: (1) own informed choice; (2) informed parents' choice to amputate; (3) informed parents' choice to continue a treatment; and (4) uninformed parents' choice to amputate. In a questionnaire, participants were asked about their choices, preference for autonomy, confidence, and emotional reactions when faced with a difficult hypothetical medical choice. RESULTS:Children and adolescents made different choices and participants, especially adolescents, preferred to make the difficult choice themselves, rather than having a parent make it. Children expressed fewer negative emotions than adolescents. Providing information about the alternatives did not affect participants' responses. CONCLUSIONS:Minors, especially adolescents, want to be responsible for their own medical decisions, even when the choice is a difficult one. For the adolescents, results suggest that the decision to be made, instead of the agent making the decision, is the main element influencing their emotional responses and decision confidence. For children, results suggest that they might be less able than adolescents to project how they would feel. The results, overall, draw attention to the need to further investigate how we can better involve minors in the medical decision-making process.

Rotavirus (RV) infection causes watery diarrhea via multiple mechanisms, primarily chloride secretion in intestinal epithelial cell. The chloride secretion largely depends on non-structural protein 4 (NSP4) enterotoxic activity in human enterocytes through mechanisms that have not been defined. Redox imbalance is a common event in cells infected by viruses, but the role of oxidative stress in RV infection is unknown. RV SA11 induced chloride secretion in association with an increase in reactive oxygen species (ROS) in Caco-2 cells. The ratio between reduced (GSH) and oxidized (GSSG) glutathione was decreased by RV. The same effects were observed when purified NSP4 was added to Caco-2 cells. N-acetylcysteine (NAC), a potent antioxidant, strongly inhibited the increase in ROS and GSH imbalance. These results suggest a link between oxidative stress and RV-induced diarrhea. Because Saccharomyces boulardii (Sb) has been effectively used to treat RV diarrhea, we tested its effects on RV-infected cells. Sb supernatant prevented RV-induced oxidative stress and strongly inhibited chloride secretion in Caco-2 cells. These results were confirmed in an organ culture model using human intestinal biopsies, demonstrating that chloride secretion induced by RV-NSP4 is oxidative stress-dependent and is inhibited by Sb, which produces soluble metabolites that prevent oxidative stress. The results of this study provide novel insights into RV-induced diarrhea and the efficacy of probiotics.

People show higher sensitivity to dread risks, rare events that kill many people at once, compared with continuous risks, relatively frequent events that kill many people over a longer period of time. The different reaction to dread risks is often considered a bias: If the continuous risk causes the same number of fatalities, it should not be perceived as less dreadful. We test the hypothesis that a dread risk may have a stronger negative impact on the cumulative population size over time in comparison with a continuous risk causing the same number of fatalities. This difference should be particularly strong when the risky event affects children and young adults who would have produced future offspring if they had survived longer. We conducted a series of simulations, with varying assumptions about population size, population growth, age group affected by risky event, and the underlying demographic model. Results show that dread risks affect the population more severely over time than continuous risks that cause the same number of fatalities, suggesting that fearing a dread risk more than a continuous risk is an ecologically rational strategy.

We have engineered a transgenic mouse on a C57BL/6 background that bears a floxed Itga2 gene. The crossing of this mouse strain to transgenic mice expressing Cre recombinase driven by the megakaryocyte (MK)-specific Pf4 promoter permits the conditional knockout of Itga2 in the MK/platelet lineage. Mice lacking MK α2β1 develop normally, are fertile, and like their systemic α2β1 knockout counterparts, exhibit defective adhesion to and aggregation induced by soluble type I collagen and a delayed onset to low dose fibrillar collagen-induced aggregation, results consistent with blockade or loss of platelet α2β1. At the same time, we observed a significant reduction in mean platelet volume, which is consistent with the reported role of α2β1 in MK maturation and proplatelet formation in vivo. This transgenic mouse strain bearing a floxed Itga2 gene will prove valuable to distinguish in vivo the temporal and spatial contributions of α2 integrin in selected cell types.

BACKGROUND: Adjuvant chemotherapy (AC) in Stage II Colon Cancer (CC) is still under debate. Choice should be based on patients and disease characteristics. According to guidelines AC should be considered in high-risk T3N0 patients. No data are available for better option in low-risk patients. The aim of the study is to retrospectively evaluate relapse-free survival (RFS) and disease-free survival (DFS) according to treatment received in T3N0 CC. METHODS: RFS and DFS are evaluated with Kaplan-Meier method. Multivariate Cox proportional hazard model was developed using stepwise regression, enter limit and remove limit were p = 0.10 and p = 0.15, respectively. RESULTS: 834 patients with T3N0 CC were recruited. Median age was 69 (29-93), M/F 463/371, 335 low-risk patients (40.2%), 387 high-risk (46.4%), 112 unknown (13.4%); 127 (15.2%) patients showed symptoms at diagnosis. Median sampled lymph nodes were 15 (1-76); 353 (42.3%) patients were treated with AC. Median follow up was 5 years (range 3-24). The 5-years RFS was 78.4% and the 5-years DFS was 76.7%. At multivariate analysis symptoms, lymph nodes, and adjuvant chemotherapy were prognostic factors for RFS. AC is prognostic factor for all endpoints. In low-risk group 5-years RFS was 87.3% in treated patients and 74.7% in non-treated patients (p 0.03); in high-risk group was respectively 82.7% and 71.4% (p 0.005). CONCLUSIONS: Data confirmed the role of known prognostic factors and suggest the relevance of adjuvant chemotherapy also in low-risk stage II T3N0 CC patients. However, the highest risk in low-risk subgroup should be identified to be submitted to AC.

Language production has often been described as impaired in psychiatric diseases such as in psychosis. Nevertheless, little is known about the characteristics of linguistic difficulties and their relation with other cognitive domains in patients with a first episode of psychosis (FEP), either affective or non-affective. To deepen our comprehension of linguistic profile in FEP, 133 patients with FEP (95 non-affective, FEP-NA; 38 affective, FEP-A) and 133 healthy controls (HC) were assessed with a narrative discourse task. Speech samples were systematically analyzed with a well-established multilevel procedure investigating both micro- (lexicon, morphology, syntax) and macro-linguistic (discourse coherence, pragmatics) levels of linguistic processing. Executive functioning and IQ were also evaluated. Both linguistic and neuropsychological measures were secondarily implemented with a machine learning approach in order to explore their predictive accuracy in classifying participants as FEP or HC. Compared to HC, FEP patients showed language production difficulty at both micro- and macro-linguistic levels. As for the former, FEP produced shorter and simpler sentences and fewer words per minute, along with a reduced number of lexical fillers, compared to HC. At the macro-linguistic level, FEP performance was impaired in local coherence, which was paired with a higher percentage of utterances with semantic errors. Linguistic measures were not correlated with any neuropsychological variables. No significant differences emerged between FEP-NA and FEP-A (p≥0.02, after Bonferroni correction). Machine learning analysis showed an accuracy of group prediction of 76.36% using language features only, with semantic variables being the most impactful. Such a percentage was enhanced when paired with clinical and neuropsychological variables. Results confirm the presence of language production deficits already at the first episode of the illness, being such impairment not related to other cognitive domains. The high accuracy obtained by the linguistic set of features in classifying groups support the use of machine learning methods in neuroscience investigations. [ABSTRACT FROM AUTHOR]

Background: The relationship between COVID-19 and out-of-hospital cardiac arrests (OHCAs) has been shown during different phases of the first pandemic wave, but little is known about how to predict where cardiac arrests will increase in case of a third peak. Aim: To seek for a correlation between the OHCAs and COVID-19 daily incidence both during the two pandemic waves at a provincial level. Methods: We considered all the OHCAs occurred in the provinces of Pavia, Lodi, Cremona, Mantua and Varese, in Lombardy Region (Italy), from 21/02/2020 to 31/12/2020. We divided the study period into period 1, the first 157 days after the outbreak and including the first pandemic wave and period 2, the second 158 days including the second pandemic wave. We calculated the cumulative and daily incidence of OHCA and COVID-19 for the whole territory and for each province for both periods. Results: A significant correlation between the daily incidence of COVID-19 and the daily incidence of OHCAs was observed both during the first and the second pandemic period in the whole territory (R = 0.4, p<0.001 for period 1 and 2) and only in those provinces with higher COVID-19 cumulative incidence (period 1: Cremona R = 0.3, p = 0.001; Lodi R = 0.4, p<0.001; Pavia R = 0.3; p = 0.01; period 2: Varese R = 0.4, p<0.001). Conclusions: Our results suggest that strictly monitoring the pandemic trend may help in predict which territories will be more likely to experience an OHCAs' increase. That may also serve as a guide to re-allocate properly health resources in case of further pandemic waves. [ABSTRACT FROM AUTHOR]