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Maize silage is by far the most used forage in the diets for dairy cows and beef cattle in a large part of the Po plain, Italy. However, its chemical composition and its nutritive value range widely according to the genotype and to the climatic and agronomic conditions, particularly with regards to the plant maturity at harvest.

Isodicentrics (idic) are structural anomalies of the Y chromosome associated with a 45,X cell line and a broad spectrum of phenotypes. We characterized the rearranged Y chromosomes from three azoospermic males by fluorescence in-situ hybridization (FISH) and PCR. Chromosome study was performed on lymphocytes and testicular biopsy. FISH analysis and PCR established the degree of mosaicism and analysed specific Y regions. Two patients showed a 45,X/46,X,?idic(Y) karyotype with varying degrees of mosaicism. FISH demonstrated the presence of two centromeres and two SRY regions. In the lymphocytes of the third patient, the presence of a small Y-derived marker was also observed. An additional cell line with two idic(Y) was present in the testicular biopsy of the same patient. PCR showed the breakpoint between SY182 (KALY) and SY121 in Yq11.221-q11.222 region in all the cases. For the evaluation of the mosaicism, different tissues must be investigated. The phenotypical sex depends more on the number of copies of the SRY gene rather than on the percentage of 45,X cells, at least in the gonads. The combined use of classical and molecular cytogenetics is necessary for delineating the chromosome regions involved allowing a better genotype–phenotype correlation. [ABSTRACT FROM AUTHOR]

Objectives: To assess the reliability and validity of measuring resting cerebral blood flow (CBF) and hippocampal CBF using a single-post-labeling delay (PLD) and a multi-PLD pseudo-continuous arterial spin labeling (pCASL) protocol for cerebrovascular reactivity (CVR) testing., Methods: 25 healthy, midlife adults (57 ± 4 years old) were imaged in a Siemens Prisma 3T magnetic resonance imaging (MRI) scanner. Resting CBF and hippocampal CBF were assessed using two pCASL protocols, our modified single-PLD protocol (pCASL-MOD) to accommodate the needs for CVR testing and the multi-PLD Human Connectome Project (HCP) Lifespan protocol to serve as the reference control (pCASL-HCP). During pCASL-MOD, CVR was calculated as the change in CBF from rest to hypercapnia (+9 mmHg increase in end-tidal partial pressure of carbon dioxide [P ET CO 2 ]) and then normalized for P ET CO 2 . The reliability and validity in resting gray matter (GM) CBF, white matter (WM) CBF, and hippocampal CBF between pCASL-MOD and pCASL-HCP protocols were examined using correlation analyses, paired t-tests, and Bland Altman plots., Results: The pCASL-MOD and pCASL-HCP protocols were significantly correlated for resting GM CBF [r = 0.72; F (1, 23) = 25.24, p < 0.0001], WM CBF [r = 0.57; F (1, 23) = 10.83, p = 0.003], and hippocampal CBF [r = 0.77; F (1, 23) = 32.65, p < 0.0001]. However, pCASL-MOD underestimated resting GM CBF (pCASL-MOD: 53.7 ± 11.1 v. pCASL-HCP: 69.1 ± 13.1 mL/100 g/min; p < 0.0001), WM CBF (pCASL-MOD: 32.4 ± 4.8 v. pCASL-HCP: 35.5 ± 6.9 mL/100 g/min; p = 0.01), and hippocampal CBF (pCASL-MOD: 50.5 ± 9.0 v. pCASL-HCP: 68.1 ± 12.5 mL/100 g / min; p < 0.0001). P ET CO 2 increased by 8.0 ± 0.7 mmHg to induce CVR (GM CBF: 4.8% ± 2.6%; WM CBF 2.9% ± 2.5%; and hippocampal CBF: 3.4% ± 3.8%)., Conclusion: Our single-PLD pCASL-MOD protocol reliably measured CBF and hippocampal CBF at rest given the significant correlation with the multi-PLD pCASL-HCP protocol. Despite the lower magnitude relative to pCASL-HCP, we recommend using our pCASL-MOD protocol for CVR testing in which an exact estimate of CBF is not required such as the assessment of relative change in CBF to hypercapnia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Decker, Sanjana, Rizzi, Kramer, Cerjanic, Johnson and Martens.)

Extracellular vesicles (EVs) derived from the plasma of oncological patients exhibit significant tumor-targeting properties, unlike those from healthy individuals. We have previously shown the feasibility of formulating the near-infrared (NIR) fluorescent dye indocyanine green (ICG) with patient-derived extracellular vesicles (PDEVs) for selective delivery to neoplastic tissue. This staining protocol holds promise for clinical application in intraoperative tumor margin imaging, enabling precise neoplastic tissue resection. To this end, we propose the ONCOGREEN protocol, involving PDEV isolation, ICG loading, and reinfusion into the same patients. Methods : By in vivo studies on mice, we outlined key pharmacological parameters of PDEVs-ICG for intraoperative tumor imaging, PDEV biodistribution kinetics, and potential treatment-related toxicological effects. Additionally, we established a plasmapheresis-based protocol for isolating autologous PDEVs, ensuring the necessary large-scale dosage for human treatment. A potential lyophilization-based preservation method was also explored to facilitate the storage and transport of PDEVs. Results : The study identified the effective dose of PDEVs-ICG necessary for clear intraoperative tumor margin imaging. The biodistribution kinetics of PDEVs showed favorable targeting to neoplastic tissues, without off-target distribution. Toxicological assessments revealed no significant adverse effects associated with the treatment. The plasmapheresis-based isolation protocol successfully yielded a sufficient quantity of autologous PDEVs, and the lyophilization preservation method maintained the functional integrity of PDEVs for subsequent clinical application. Conclusions : Our research lays the groundwork for the direct clinical application of autologous PDEVs, initially focusing on intraoperative imaging. Utilizing autologous PDEVs has the potential to accelerate the integration of EVs as a targeted delivery tool for anti-neoplastic agents to cancerous tissue. This approach promises to enhance the precision of neoplastic tissue resection and improve overall surgical outcomes for oncological patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

TFEB and TFE3 belong to the MiT/TFE family of transcription factors that bind identical DNA responsive elements in the regulatory regions of target genes. They are involved in regulating lysosomal biogenesis, function, exocytosis, autophagy, and lipid catabolism. Precise control of TFEB and TFE3 activity is crucial for processes such as senescence, stress response, energy metabolism, and cellular catabolism. Dysregulation of these factors is implicated in various diseases, thus researchers have explored pharmacological approaches to modulate MiT/TFE activity, considering these transcription factors as potential therapeutic targets. However, the physiological complexity of their functions and the lack of suitable in vivo tools have limited the development of selective MiT/TFE modulating agents. Here, we have created a reporter-based biosensor, named CLEARoptimized, facilitating the pharmacological profiling of TFEB- and TFE3-mediated transcription. This innovative tool enables the measurement of TFEB and TFE3 activity in living cells and mice through imaging and biochemical techniques. CLEARoptimized consists of a promoter with six coordinated lysosomal expression and regulation motifs identified through an in-depth bioinformatic analysis of the promoters of 128 TFEB-target genes. The biosensor drives the expression of luciferase and tdTomato reporter genes, allowing the quantification of TFEB and TFE3 activity in cells and in animals through optical imaging and biochemical assays. The biosensor's validity was confirmed by modulating MiT/TFE activity in both cell culture and reporter mice using physiological and pharmacological stimuli. Overall, this study introduces an innovative tool for studying autophagy and lysosomal pathway modulation at various biological levels, from individual cells to the entire organism. Abbreviations: CLEAR: coordinated lysosomal expression and regulation; MAR: matrix attachment regions; MiT: microphthalmia-associated transcription factor; ROI: region of interest; TBS: tris-buffered saline; TF: transcription factor; TFE3: transcription factor binding to IGHM enhancer 3; TFEB: transcription factor EB; TH: tyrosine hydroxylase; TK: thymidine kinase; TSS: transcription start site.

In the course of the Horizon 2020 project HighNESS, a second moderator concept has been developed for the European Spallation Source, which complements the currently built moderator and is optimized for high intensity with a large viewable surface area. In this work we introduce conceptual designs for neutron instruments for condensed matter research designed to make optimal use of the capabilities of this moderator. The focus is on two concepts for small-angle neutron scattering and one neutron imaging instrument, which are intended to complement corresponding instruments that are already under construction at the European Spallation Source. One small-angle neutron scattering instrument concept resembles a conventional pinhole collimator geometry and aims to profit from the proposed second moderator by enabling to illuminate larger samples and providing particularly high resolution, drawing on a 30 m collimation and corresponding detector distance. A second small-angle neutron scattering instrument concept adopts nested mirror optics that enable to efficiently exploit the large moderator size and provide high resolution by focusing on the detector. The neutron imaging instrument concept is a typical pinhole instrument that can be found at continuous sources and draws on the corresponding strengths of high flux and large homogeneous fields-of-view, while still providing moderate wavelength resolution for advanced imaging methods., (© 2024. The Author(s).)

Currently, there is limited evidence regarding various neurophysiological responses to strength exercise and the influence of the adopted practice schedule. This study aimed to assess the acute systemic effects of snatch training bouts, employing different motor learning models, on skill efficiency, electric brain activity (EEG), heart rate variability (HRV), and perceived exertion as well as mental demand in novices. In a within-subject design, sixteen highly active males (mean age: 23.13 ± 2.09 years) randomly performed snatch learning bouts consisting of 36 trials using repetitive learning (RL), contextual interference (blocked, CIb; and serial, CIs), and differential learning (DL) models. Spontaneous resting EEG and HRV activities were recorded at PRE and POST training bouts while measuring heart rate. Perceived exertion and mental demand were assessed immediately after, and barbell kinematics were recorded during three power snatch trials performed following the POST measurement. The results showed increases in alpha, beta, and gamma frequencies from pre- to post-training bouts in the majority of the tested brain regions (p values ranging from < 0.0001 to 0.02). The CIb model exhibited increased frequencies in more regions. Resting time domain HRV parameters were altered following the snatch bouts, with increased HR (p < 0.001) and decreased RR interval (p < 0.001), SDNN, and RMSSD (p values ranging from < 0.0001 to 0.02). DL showed more pronounced pulse-related changes (p = 0.01). Significant changes in HRV frequency domain parameters were observed, with a significant increase in LFn (p = 0.03) and a decrease in HFn (p = 0.001) registered only in the DL model. Elevated HR zones (> HR zone 3) were more dominant in the DL model during the snatch bouts (effect size = 0.5). Similarly, the DL model tended to exhibit higher perceived physical (effect size = 0.5) and mental exertions (effect size = 0.6). Despite the highest psycho-physiological response, the DL group showed one of the fewest significant EEG changes. There was no significant advantage of one learning model over the other in terms of technical efficiency. These findings offer preliminary support for the acute neurophysiological benefits of coordination-strength-based exercise in novices, particularly when employing a DL model. The advantages of combining EEG and HRV measurements for comprehensive monitoring and understanding of potential adaptations are also highlighted. However, further studies encompassing a broader range of coordination-strength-based exercises are warranted to corroborate these observations., Competing Interests: The authors declare no conflict of interest., (Copyright © Biology of Sport 2024.)

The purpose of the present study was to assess the acute and mid-term effects of the dynamic aeris ® -meeting- environment on brain activity, cognitive performance, heart rate variability (HRV), sleepiness, mental workload (EEG-MWI), as well as local experienced discomfort (LED) in healthy adults. Twenty-four healthy adults (16 females, age: 25.2 ± 3.1 years old) were randomly assigned to either the control (i.e., conventional meeting environment, CG) or experimental (Aeris ® dynamic meeting-environment, DG) group with a 1:1 allocation. Participants reported to the laboratory on two test sessions separated by a 2-week intervention period (5 meetings of 90 min each week). Spontaneous resting EEG and HRV activities, as well as attentional (D2-R test) and vigilance (PVT) cognitive performances, sleepiness perceptions, and EEG-MWI, were recorded at the beginning of each test session and immediately following the 90-min meeting. The LED was measured pre- and post-intervention. The changes (Δ) from pre- to post-90 min meeting and from pre- to post- intervention were computed to further examine the acute and mid-term effects, respectively. Compared to the CG, the DG showed higher Δ (pre-post 90 min-meeting) in fronto-central beta ( z = -2.41, p = 0.016, d = 1.10) and gamma ( z = -2.34, p = 0.019, d = 0.94) frequencies at post-intervention. From pre- to post-intervention, only the DG group showed a significant increase in fronto-central gamma response (Δ) to the meeting session ( z = -2.09, p = 0.04, d = 1.08). The acute use of the Aeris ® -meeting-environment during the 90-min meeting session seems to be supportive for (i) maintaining vigilance performance, as evidenced by the significant increase in N-lapses from pre- to post-90 min session only in the CG ( p = 0.04, d = 0.99, Δ = 2.5 ± 3 lapses), and (ii) improving alertness, as evidenced by the lower sleepiness score ( p = 0.05, d = -0.84) in DG compared to CG. The mid-term use of such an environment showed to blind the higher baseline values of EEG-MWI recorded in DG compared to CG ( p = 0.01, d = 1.05) and may prevent lower-back discomfort (i.e., a significant increase only in CG with p = 0.05 and d = 0.78), suggesting a less mentally and physically exhausting meeting in this environment. There were no acute and/or mid-term effects of the dynamic meeting environment on any of the HRV parameters. These findings are of relevance in the field of neuroergonomics, as they give preliminary support to the advantages of meeting in a dynamic office compared to a static office environment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Ammar, Boujelbane, Simak, Fraile-Fuente, Trabelsi, Bouaziz, Rizzi and Schöllhorn.)

Intraventricular hemorrhage is characterized by blood leaking into the cerebral ventricles and mixing with cerebrospinal fluid. A standard treatment method involves inserting a passive drainage catheter, known as an external ventricular drain (EVD), into the ventricle. EVDs have common adverse complications, including the occlusion of the catheter, that may lead to permanent neural damage or even mortality. In order to prevent such complications, a novel dual-lumen catheter (IRRAflow®) utilizing an active fluid exchange mechanism has been recently developed. However, the fluid dynamics of the exchange system have not been investigated. In this study, convective flow in a three-dimensional cerebral lateral ventricle with an inserted catheter is evaluated using an in-house lattice-Boltzmann-based fluid-solid interaction solver. Different treatment conditions are simulated, including injection temperature and patient position. Thermal and gravitational effects on medication distribution are studied using a dye simulator based on a recently-introduced (pseudo)spectral convection-diffusion equation solver. The effects of injection temperature and patient position on catheter performance are presented and discussed in terms of hematoma irrigation, vortical structures, mixing, and medication volume distribution. Results suggest that cold-temperature injections can increase catheter efficacy in terms of dye distribution and irrigation potential, both of which can be further guided by patient positioning., (© 2023. The Author(s).)

Aflatoxins (AFs) are fungal metabolites that are found in feed and food. When ruminants eat feed contaminated with aflatoxin B1 (AFB1), it is metabolised and aflatoxin M1 (AFM1) is excreted in the milk. Aflatoxins can result in hepatotoxic, carcinogenic, and immunosuppressive effects. The European Union thus set a low threshold limit (50 ng/L) for presence of AFM1 in milk. This was in view of its possible presence also in dairy products and that quantification of these toxins is mandatory for milk suppliers. In the present study, a total of 95,882 samples of whole raw milk, collected in northern Italy between 2013 and 2021, were evaluated for presence of AFM1 using an ELISA (enzyme-linked immunosorbent assay) method. The study also evaluated the relationship between feed materials collected from the same farms in the same area during the same period (2013-2021) and milk contamination. Only 667 milk samples out of 95,882 samples analysed (0.7%) showed AFM1 values higher than the EU threshold limit of 50 ng/L. A total of 390 samples (0.4%) showed values between 40 and 50 ng/L, thus requiring corrective action despite not surpassing the regulatory threshold. Combining feed contamination and milk contamination data, some feedingstuffs seem to be more effective in defying potential carryover of AFs from feed to milk. Combining the results, it can be concluded that a robust monitoring system that covers both feed, with a special focus on high risk/sentinel matrices, and milk is essential to guarantee high quality and safety standards of dairy products.

Microglia are heterogenous cells characterized by distinct populations each contributing to specific biological processes in the nervous system, including neuroprotection. To elucidate the impact of sex-specific microglia heterogenicity to the susceptibility of neuronal stress, we video-recorded with time-lapse microscopy the changes in shape and motility occurring in primary cells derived from mice of both sexes in response to pro-inflammatory or neurotoxic stimulations. With this morpho-functional analysis, we documented distinct microglia subpopulations eliciting sex-specific responses to stimulation: male microglia tended to have a more pro-inflammatory phenotype, while female microglia showed increased sensitivity to conduritol-B-epoxide (CBE), a small molecule inhibitor of glucocerebrosidase, the enzyme encoded by the GBA1 gene, mutations of which are the major risk factor for Parkinson's Disease (PD). Interestingly, glucocerebrosidase inhibition particularly impaired the ability of female microglia to enhance the Nrf2-dependent detoxification pathway in neurons, attenuating the sex differences observed in this neuroprotective function. This finding is consistent with the clinical impact of GBA1 mutations, in which the 1.5-2-fold reduced risk of developing idiopathic PD observed in female individuals is lost in the GBA1 carrier population, thus suggesting a sex-specific role for microglia in the etiopathogenesis of PD-GBA1.

Computed tomography (CT) is a diagnostic medical imaging modality commonly used to detect disease and injury. Contrast agents containing iodine, such as iohexol, are frequently used in CT examinations to more clearly differentiate anatomic structures and to detect and characterize abnormalities, including tumors. However, these contrast agents do not have a specific tropism for cancer cells, so the ability to detect tumors is severely limited by the degree of vascularization of the tumor itself. Identifying delivery systems allowing enrichment of contrast agents at the tumor site would increase the sensitivity of detection of tumors and metastases, potentially in organs that are normally inaccessible to contrast agents, such as the CNS. Recent work from our laboratory has identified cancer patient-derived extracellular vesicles (PDEVs) as effective delivery vehicles for targeting diagnostic drugs to patients' tumors. Based on this premise, we explored the possibility of introducing iohexol into PDEVs for targeted delivery to neoplastic tissue. Here, we provide preclinical proof-of-principle for the tumor-targeting ability of iohexol-loaded PDEVs, which resulted in an impressive accumulation of the contrast agent selectively into the neoplastic tissue, significantly improving the ability of the contrast agent to delineate tumor boundaries.

Aflatoxins (AFs) remain the main concern for the agricultural and dairy industries due to their effects on the performances and quality of livestock production. Aflatoxins are always unavoidable and should be monitored. The objective of this paper is to bring to light a significant volume of data on AF contamination in several animal feed ingredients in Northern Italy. The Regional Breeders Association of Lombardy has been conducting a survey program to monitor mycotoxin contamination in animal feeds, and in this paper, we present data relating to AFB1 contamination. In most cases (95%), the concentrations were low enough to ensure compliance with the European Union's (EU's) maximum admitted levels for animal feed ingredients. However, the data show a high variability in AF contamination between different matrices and, within the same matrix, a high variability year over year. High levels of AFs were detected in maize and cotton, especially in the central part of the second decade of this century, i.e., 2015-2018, which has shown a higher risk of AF contamination in feed materials in Northern Italy. Variability due to climate change and the international commodity market affect future prospects to predict the presence of AFs. Supplier monitoring and control and reduced buying of contaminated raw materials, as well as performing analyses of each batch, help reduce AF spread.

In search of more detailed explanations for body-mind interactions in physical activity, neural and physiological effects, especially regarding more strenuous sports activities, increasingly attract interest. Little is known about the underlying manifold (neuro-)physiological impacts induced by different motor learning approaches. The various influences on brain or cardiac function are usually studied separately and modeled linearly. Limitations of these models have recently led to a rapidly growing application of nonlinear models. This study aimed to investigate the acute effects of various sequences of rope skipping on irregularity of the electrocardiography (ECG) and electroencephalography (EEG) signals as well as their interaction and whether these depend on different levels of active movement noise, within the framework of differential learning theory. Thirty-two males were randomly and equally distributed to one of four rope skipping conditions with similar cardiovascular but varying coordinative demand. ECG and EEG were measured simultaneously at rest before and immediately after rope skipping for 25 mins. Signal irregularity of ECG and EEG was calculated via the multiscale fuzzy measure entropy (MSFME). Statistically significant ECG and EEG brain area specific changes in MSFME were found with different pace of occurrence depending on the level of active movement noise of the particular rope skipping condition. Interaction analysis of ECG and EEG MSFME specifically revealed an involvement of the frontal, central, and parietal lobe in the interplay with the heart. In addition, the number of interaction effects indicated an inverted U-shaped trend presenting the interaction level of ECG and EEG MSFME dependent on the level of active movement noise. In summary, conducting rope skipping with varying degrees of movement variation appears to affect the irregularity of cardiac and brain signals and their interaction during the recovery phase differently. These findings provide enough incentives to foster further constructive nonlinear research in exercise-recovery relationship and to reconsider the philosophy of classical endurance training., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 John, Barthel, Wind, Rizzi and Schöllhorn.)

This critical review considers the epistemological and historical background of the theoretical construct of motor learning for a more differentiated understanding. More than simply reflecting critically on the models that are used to solve problems-whether they are applied in therapy, physical education, or training practice-this review seeks to respond constructively to the recent discussion caused by the replication crisis in life sciences. To this end, an in-depth review of contemporary motor learning approaches is provided, with a pragmatism-oriented clarification of the researcher's intentions on fundamentals (what?), subjects (for whom?), time intervals (when?), and purpose (for what?). The complexity in which the processes of movement acquisition, learning, and refinement take place removes their predictable and linear character and therefore, from an applied point of view, invites a great deal of caution when trying to make generalization claims. Particularly when we attempt to understand and study these phenomena in unpredictable and dynamic contexts, it is recommended that scientists and practitioners seek to better understand the central role that the individual and their situatedness plays in the system. In this way, we will be closer to making a meaningful and authentic contribution to the advancement of knowledge, and not merely for the sake of renaming inventions.

To date, most neurophysiological dance research has been conducted exclusively with female participants in observational studies (i.e., participants observe or imagine a dance choreography). In this regard, the sex-specific acute neurophysiological effect of physically executed dance can be considered a widely unexplored field of research. This study examines the acute impact of a modern jazz dance choreography on brain activity and functional connectivity using electroencephalography (EEG). In a within-subject design, 11 female and 11 male participants were examined under four test conditions: physically dancing the choreography with and without music and imagining the choreography with and without music. Prior to the EEG measurements, the participants acquired the choreography over 3 weeks with one session per week. Subsequently, the participants conducted all four test conditions in a randomized order on a single day, with the EEG measurements taken before and after each condition. Differences between the male and female participants were established in brain activity and functional connectivity analyses under the condition of imagined dance without music . No statistical differences between sexes were found in the other three conditions ( physically executed dance with and without music as well as imagined dance with music ). Physically dancing and music seem to have sex-independent effects on the human brain. However, thinking of dance without music seems to be rather sex-specific. The results point to a promising approach to decipher sex-specific differences in the use of dance or music. This approach could further be used to achieve a more group-specific or even more individualized and situationally adapted use of dance interventions, e.g., in the context of sports, physical education, or therapy. The extent to which the identified differences are due to culturally specific attitudes in the sex-specific contact with dance and music needs to be clarified in future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wind, Horst, Rizzi, John, Kurti and Schöllhorn.)

In female mammals, the cessation of ovarian functions is associated with significant metabolic alterations, weight gain, and increased susceptibility to a number of pathologies associated with ageing. The molecular mechanisms triggering these systemic events are unknown because most tissues are responsive to lowered circulating sex steroids. As it has been demonstrated that isoform alpha of the estrogen receptor (ERα) may be activated by both estrogens and amino acids, we test the metabolic effects of a diet enriched in specific amino acids in ovariectomized (OVX) mice. This diet is able to block the OVX-induced weight gain and fat deposition in the liver. The use of liver-specific ERα KO mice demonstrates that the hepatic ERα, through the control of liver lipid metabolism, has a key role in the systemic response to OVX. The study suggests that the liver ERα might be a valuable target for dietary treatments for the post-menopause., (© 2021. The Author(s).)

Introduction: Laparoscopic liver surgery is spreading, encouraged by technical and technological improvement. Both the obligated narrow space and the difficulty to modify it lead to a more complex approach to the lesions located in the posterosuperior portion of the liver. Surgical strategies such as the Caudal approach or the Diamond technique could ameliorate surgical procedure, but these areas remain a challenge and are still classified as complex., Clinical Case: We discuss the case of a 68 year old man with metachronous liver metastasis in the dorsal part of segment 8. We used portal phase CT-scan Dicom data to create Three-dimensional reconstruction, which was able to show the more distal branches of intraparenchymal structures. The reconstructed images were subsequently used to plan laparoscopic liver resection., Discussion: The capability of three-dimensional reconstruction to create a realistic image allows us to use ultrasound as a navigation tool. Exploiting these two technologies together, we arrived to regulate the resection stages by recognizing previously marked structures and searching them at every intervention phase. The strategy performed demonstrates both a high level of precision and the capability to predict intraparenchymal structures., Conclusion: The advantages obtained from three-dimensional reconstruction are numerous in terms of either anatomical comprehension and technical precision, suggesting a potential improvement in surgical skill. Three-dimensional technology should be encouraged and spread to understand, in every single aspect, the potential of its use., (Copyright © 2021. Published by Elsevier Ltd.)

Nano- and microsized extracellular vesicles (EVs) are naturally occurring cargo-bearing packages of regulatory macromolecules, and recent studies are increasingly showing that EVs are responsible for physiological intercellular communication. Nanoparticles encapsulating anti-tumor theranostics represent an attractive "exosome-interfering" strategy for cancer therapy. Methods : Herein, by labeling plasma-derived EVs with indocyanine green (ICG) and following their biodistribution by in vivo and ex vivo imaging, we demonstrate the existence of nanoparticles with a highly selective cancer tropism in the blood of colorectal cancer (CRC) patients but not in that of healthy volunteers. Results : In CRC patient-derived xenograft (PDX) mouse models, we show that transplanted EVs recognize tumors from the cognate nanoparticle-generating individual, suggesting the theranostic potential of autologous EVs encapsulating tumor-interfering molecules. In large canine breeds bearing spontaneous malignant skin and breast tumors, the same autologous EV transplantation protocol shows comparable safety and efficacy profiles. Conclusions : Our data show the existence of an untapped resource of intercellular communication present in the blood of cancer patients, which represents an efficient and highly biocompatible way to deliver molecules directly to the tumor with great precision. The novel EV-interfering approach proposed by our study may become a new research direction in the complex interplay of modern personalized cancer therapy., Competing Interests: Competing Interests: Al.V., M.G., V.M. and P.C. are coinventors of the patent n. IT 102019000007785 filed on May 5th 2019, at the Italian patent office: UIBM., (© The author(s).)

Besides the pure pleasure of watching a dance performance, dance as a whole-body movement is becoming increasingly popular for health-related interventions. However, the science-based evidence for improvements in health or well-being through dance is still ambiguous and little is known about the underlying neurophysiological mechanisms. This may be partly related to the fact that previous studies mostly examined the neurophysiological effects of imagination and observation of dance rather than the physical execution itself. The objective of this pilot study was to investigate acute effects of a physically executed dance with its different components (recalling the choreography and physical activity to music) on the electrical brain activity and its functional connectivity using electroencephalographic (EEG) analysis. Eleven dance-inexperienced female participants first learned a Modern Jazz Dance (MJD) choreography over three weeks (1 h sessions per week). Afterwards, the acute effects on the EEG brain activity were compared between four different test conditions: physically executing the MJD choreography with music, physically executing the choreography without music, imaging the choreography with music, and imaging the choreography without music. Every participant passed each test condition in a randomized order within a single day. EEG rest-measurements were conducted before and after each test condition. Considering time effects the physically executed dance without music revealed in brain activity analysis most increases in alpha frequency and in functional connectivity analysis in all frequency bands. In comparison, physically executed dance with music as well as imagined dance with music led to fewer increases and imagined dance without music provoked noteworthy brain activity and connectivity decreases at all frequency bands. Differences between the test conditions were found in alpha and beta frequency between the physically executed dance and the imagined dance without music as well as between the physically executed dance with and without music in the alpha frequency. The study highlights different effects of a physically executed dance compared to an imagined dance on many brain areas for all measured frequency bands. These findings provide first insights into the still widely unexplored field of neurological effects of dance and encourages further research in this direction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Wind, Horst, Rizzi, John and Schöllhorn.)

The recent availability of a high-throughput milk analyzer performing a partial differential somatic cell count (DSCC) opened new opportunities in investigations on bovine udder health. This analyzer has a potential limitation on the accuracy of measurements when the somatic cell count (SCC) is below 50,000 cells/mL, values characterizing a good proportion of lactating cows in many herds. We obtained data for cows below this threshold, assessed the repeatability of these measurements and investigated the relationship between DSCC and udder health, milk composition and yield. Overall, 3022 cow milk test records performed on a Fossomatic™ 7/DC (Foss A/S, Hillerød, Denmark) were considered; 901 of them had an SCC ≤ 50,000 cells/mL. These latter samples were analyzed by qPCR to identify the presence of bacteria. Overall, 20.75% of the samples (187) were positive. However, the health status did not have any significant association with DSCC. The analysis of the association of DSCC on milk fat, protein and casein showed a significant decrease in their proportions as the DSCC increased, whereas it was not observed for milk yield and lactose. Therefore, DSCC in very low SCC cows may be suggested as a marker to identify early changes in milk composition., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as chemopreventive agents for many tumours; however, the mechanism responsible for their anti-neoplastic activity remains elusive and the side effects due to cyclooxygenase (COX) inhibition prevent this clinical application., Methods: Molecular biology, in silico, cellular and in vivo tools, including innovative in vivo imaging and classical biochemical assays, were applied to identify and characterise the COX-independent anti-cancer mechanism of NSAIDs., Results: Here, we show that tumour-protective functions of NSAIDs and exisulind (a sulindac metabolite lacking anti-inflammatory activity) occur through a COX-independent mechanism. We demonstrate these NSAIDs counteract carcinogen-induced proliferation by inhibiting the sirtuin 1 (SIRT1) deacetylase activity, augmenting acetylation and activity of the tumour suppressor p53 and increasing the expression of the antiproliferative gene p21. These properties are shared by all NSAIDs except for ketoprofen lacking anti-cancer properties. The clinical interest of the mechanism identified is underlined by our finding that p53 is activated in mastectomy patients undergoing intraoperative ketorolac, a treatment associated with decreased relapse risk and increased survival., Conclusion: Our study, for the first-time, links NSAID chemopreventive activity with direct SIRT1 inhibition and activation of the p53/p21 anti-oncogenic pathway, suggesting a novel strategy for the design of tumour-protective drugs.

Extracellular vesicles (EVs), are naturally occurring cargo delivery tools with the potential to be used as drug vehicles of single agents or combination therapies. We previously demonstrated that human lung cancer cell-derived EVs could be used for the systemic delivery of oncolytic virus (OVs) and chemotherapy drugs such as paclitaxel (PTX), leading to enhanced anti-tumor effects in nude mice. In the current work, we evaluated the biodistribution of EVs by using bioluminescence and fluorescence imaging technologies, thus proving the ability of these EVs-formulations to specifically target the neoplasia, while leaving other body tissues unaffected. Moreover, in vivo imaging of NFκB activation in an immunocompetent reporter mouse model allowed to demonstrate the selective ability of EVs to induce tumor-associated inflammatory reactions, which are characterized by immunogenic cell death and CD3+/CD4+/CD8+ T-cell infiltration. While EVs have the potential to induce a systemic immune reaction by pro-inflammatory cytokines, our study provides compelling evidences of a localized inflammatory effect in the peritumoral area. Collectively, our findings strongly support the systemic administration of EVs formulations with OVs alone or in combination with chemotherapy agents as a novel strategy aimed at treating primary and metastatic cancers., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Oncolytic viruses (OV) are engineered to infect, replicate in and kill cancer cells. Currently, the OV therapeutic approach is mainly restricted to neoplasia amenable to direct local administration of viral particles, while the possibility of a systemic delivery of cancer-tropic viruses would extend the OV application to the treatment of metastatic neoplasia. Herein, we applied in vivo/ex vivo imaging to demonstrate that cancer tropism is achieved when OV are encapsulated inside extracellular vesicles (EV) administered intravenously (i.v.), but not when injected intraperitoneally (i.p.). Moreover, we show that the therapeutic procedure adopted does not alter the immunomodulatory properties of the viruses.

Sex has a role in the incidence and outcome of neurological illnesses, also influencing the response to treatments. Neuroinflammation is involved in the onset and progression of several neurological diseases, and the fact that estrogens have anti-inflammatory activity suggests that these hormones may be a determinant in the sex-dependent manifestation of brain pathologies. We describe significant differences in the transcriptome of adult male and female microglia, possibly originating from perinatal exposure to sex steroids. Microglia isolated from adult brains maintain the sex-specific features when put in culture or transplanted in the brain of the opposite sex. Female microglia are neuroprotective because they restrict the damage caused by acute focal cerebral ischemia. This study therefore provides insight into a distinct perspective on the mechanisms underscoring a sexual bias in the susceptibility to brain diseases., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The Parkinson's disease (PD) evolves over an extended period of time with the onset occurring long before clinical signs begin to manifest. Characterization of the molecular events underlying the PD onset is instrumental for the development of diagnostic markers and preventive treatments, progress in this field is hindered by technical limitations. We applied an imaging approach to demonstrate the activation of Nrf2 transcription factor as a hallmark of neurodegeneration in neurotoxin-driven models of PD. In dopaminergic SK-N-BE neuroblastoma cells, Nrf2 activation was detected in cells committed to die as proven by time lapse microscopy; in the substantia nigra pars compacta area of the mouse brain, the Nrf2 activation preceded dopaminergic neurodegeneration as demonstrated by in vivo and ex vivo optical imaging, a finding confirmed by co-localization experiments carried out by immunohistochemistry. Collectively, our results identify the Nrf2 signaling as an early marker of neurodegeneration, anticipating dopaminergic neurodegeneration and motor deficits., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Most of the ageing-associated pathologies are coupled with a strong inflammatory component that accelerates the progress of the physiopathological functional decline related to ageing. The currently available pharmacological tools for the control of neuroinflammation present several side effects that restrict their application, particularly in chronic disorders. The discovery of the potential anti-inflammatory action exerted by endogenous oestrogens, as well as the finding that activation of oestrogen receptor α results in a significant decrease of inflammation at the cellular level and in models of inflammatory diseases, prompted us to embark in a series of studies aimed at the generation of reporter systems, allowing us to (i) understand the anti-inflammatory action of oestrogens at molecular level; (ii) evaluate the extent to which the action of this steroid hormone was relevant in models of pathologies characterised by a strong inflammatory component; and (iii) investigate the efficacy of novel, synthetic oestrogens endowed with anti-inflammatory activity. Accordingly, we conceived the NFκB-luc2 reporter mouse, a model characterised by dual reporter genes for fluorescence and bioluminescence imaging under the control of a synthetic DNA able to bind the transcription factor nuclear factor kappa B, the master regulator of the expression of most of the cytokines responsible for the initial phase of acute inflammation. Here, we summarise the philosophy that has driven our research in the past years, as well as some of the results obtained so far., (© 2017 British Society for Neuroendocrinology.)

Blazars are active galactic nuclei, which are powerful sources of radiation whose central engine is located in the core of the host galaxy. Blazar emission is dominated by non-thermal radiation from a jet that moves relativistically towards us, and therefore undergoes Doppler beaming. This beaming causes flux enhancement and contraction of the variability timescales, so that most blazars appear as luminous sources characterized by noticeable and fast changes in brightness at all frequencies. The mechanism that produces this unpredictable variability is under debate, but proposed mechanisms include injection, acceleration and cooling of particles, with possible intervention of shock waves or turbulence. Changes in the viewing angle of the observed emitting knots or jet regions have also been suggested as an explanation of flaring events and can also explain specific properties of blazar emission, such as intra-day variability, quasi-periodicity and the delay of radio flux variations relative to optical changes. Such a geometric interpretation, however, is not universally accepted because alternative explanations based on changes in physical conditions-such as the size and speed of the emitting zone, the magnetic field, the number of emitting particles and their energy distribution-can explain snapshots of the spectral behaviour of blazars in many cases. Here we report the results of optical-to-radio-wavelength monitoring of the blazar CTA 102 and show that the observed long-term trends of the flux and spectral variability are best explained by an inhomogeneous, curved jet that undergoes changes in orientation over time. We propose that magnetohydrodynamic instabilities or rotation of the twisted jet cause different jet regions to change their orientation and hence their relative Doppler factors. In particular, the extreme optical outburst of 2016-2017 (brightness increase of six magnitudes) occurred when the corresponding emitting region had a small viewing angle. The agreement between observations and theoretical predictions can be seen as further validation of the relativistic beaming theory.

Mutations in PTEN-induced kinase 1 (PINK1) result in a recessive familial form of Parkinson's disease (PD). PINK1 loss is associated with mitochondrial Ca 2+ mishandling, mitochondrial dysfunction, as well as increased neuronal vulnerability. Here we demonstrate that PINK1 directly interacts with and phosphorylates LETM1 at Thr192 in vitro. Phosphorylated LETM1 or the phospho-mimetic LETM1-T192E increase calcium release in artificial liposomes and facilitates calcium transport in intact mitochondria. Expression of LETM1-T192E but not LETM1-wild type (WT) rescues mitochondrial calcium mishandling in PINK1-deficient neurons. Expression of both LETM1-WT and LETM1-T192E protects neurons against MPP + -MPTP-induced neuronal death in PINK1 WT neurons, whereas only LETM1-T192E protects neurons under conditions of PINK1 loss. Our findings delineate a mechanism by which PINK1 regulates mitochondrial Ca 2+ level through LETM1 and suggest a model by which PINK1 loss leads to deficient phosphorylation of LETM1 and impaired mitochondrial Ca 2+ transport..

Estrogen deprivation is associated with delayed healing, while estrogen replacement therapy (ERT) accelerates acute wound healing and protects against development of chronic wounds. However, current estrogenic molecules have undesired systemic effects, thus the aim of our studies is to generate new molecules for topic administration that are devoid of systemic effects. Following a preliminary study, the new 17β-estradiol derivatives 1 were synthesized. The estrogenic activity of these novel compounds was evaluated in vitro using the cell line ERE-Luc B17 stably transfected with an ERE-Luc reporter. Among the 17β-estradiol derivatives synthesized, compounds 1e and 1f showed the highest transactivation potency and were therefore selected for the study of their systemic estrogenic activity. The study of these compounds in the ERE-Luc mouse model demonstrated that both compounds lack systemic effects when administered in the wound area. Furthermore, wound-healing experiments showed that 1e displays a significant regenerative and anti-inflammatory activity. It is therefore confirmed that this class of compounds are suitable for topical administration and have a clear beneficial effect on wound healing.

Deciphering the etiology of complex pathologies at molecular level requires longitudinal studies encompassing multiple biochemical pathways (apoptosis, proliferation, inflammation, oxidative stress). In vivo imaging of current reporter animals enabled the spatio-temporal analysis of specific molecular events, however, the lack of a multiplicity of loci for the generalized and regulated expression of the integrated transgenes hampers the creation of systems for the simultaneous analysis of more than a biochemical pathways at the time. We here developed and tested an in vivo-based methodology for the identification of multiple insertional loci suitable for the generation of reliable reporter mice. The validity of the methodology was tested with the generation of novel mice useful to report on inflammation and oxidative stress., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The AML1/ETO fusion protein found in acute myeloid leukemias functions as a transcriptional regulator by recruiting co-repressor complexes to its DNA binding site. In order to extend the understanding of its role in preleukemia, we expressed AML1/ETO in a murine immortalized pluripotent hematopoietic stem/progenitor cell line, EML C1, and found that genes involved in functions such as cell-to-cell adhesion and cell motility were among the most significantly regulated as determined by RNA sequencing. In functional assays, AML1/ETO-expressing cells showed a decrease in adhesion to stromal cells, an increase of cell migration rate in vitro, and displayed an impairment in homing and engraftment in vivo upon transplantation into recipient mice. Our results suggest that AML1/ETO expression determines a more mobile and less adherent phenotype in preleukemic cells, therefore altering the interaction with the hematopoietic niche, potentially leading to the migration across the bone marrow barrier and to disease progression.

Although 17β-estradiol (E2) anti-inflammatory activity has been well described, very little is known about the effects of this hormone on the resolution phase of the inflammatory process. Here, we identified a previously unreported ERα-mediated effect of E2 on the inflammatory machinery. The study showed that the activation of the intracellular estrogen receptor shortens the LPS-induced pro-inflammatory phase and, by influencing the intrinsic and extrinsic programs, triggers the resolution of inflammation in RAW 264.7 cells. Through the regulation of the SOCS3 and STAT3 signaling pathways, E2 facilitates the progression of the inflammatory process toward the IL10-dependent "acquired deactivation" phenotype, which is responsible for tissue remodeling and the restoration of homeostatic conditions. The present study may provide an explanation for increased susceptibility to chronic inflammatory diseases in women after menopause, and it suggests novel anti-inflammatory treatments for such disorders.