Search

Fournier’s gangrene is a potentially fatal emergency condition characterized by necrotizing fasciitis and supported by an infection of the external genital, perineal and perianal region, with a rapid and progressive spread from subcutaneous fat tissue to fascial planes.

Renal artery embolization is performed before radical nephrectomy (RN) for renal mass in order to induce preoperative infarction and to facilitate surgical intervention through decrease of intraoperative bleeding. Moreover, in metastatic renal cancer it seems to stimulate tumour-specific antibodies, even if no established benefits in clinical response or survival have been reported. The role of preoperative renal artery embolization (PRAE) in management of renal masses has been often debated and its real benefits are still unclear. Nevertheless, in huge and complex renal masses, which are often characterized by a high and anarchic blood supply and rapid local invasion, radical nephrectomy can be challenging even for skilled surgeons. The aim of this prospective randomized study was to evaluate the effectiveness and safety of PRAE in complex masses by comparing perioperative outcomes of RN with and without PRAE.

INTRODUCTION: Cognition often remains unassessed in primary care. To improve early diagnosis of neurocognitive disorder (NCD) in Switzerland, the tablet-based UCSF brain health assessment (BHA) and brain health survey (BHS) were validated. METHODS: The German BHA, BHS, and Montreal Cognitive Assessment (MoCA) were administered to 67 patients with mild/major NCD and 50 controls. BHA includes subtests of memory, executive, visuospatial, and language functioning, and informant-based BHS asks about behavior and motor functioning. RESULTS: The complete instrument (BHA + BHS) was most accurate at detecting mild NCD (AUC = 0.95) and NCD without amyloid pathology (AUC = 0.96), followed by the BHA. All measures were accurate (all AUCs > 0.95) at distinguishing major NCD and NCD with amyloid pathology (Alzheimers disease [AD]) from controls. DISCUSSION: The German BHA and BHS are more sensitive to mild NCD and non-AD presentations than the MoCA and thus have a high potential to identify patients with NCD in primary care earlier than currently used screens.

Aim: The phase III randomized controlled trial (RCT) CARTITUDE-4 (NCT04181827) demonstrated superiority of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) over daratumumab, pomalidomide and dexamethasone (DPd) and pomalidomide, bortezomib and dexamethasone (PVd) for relapsed/refractory multiple myeloma (RRMM) patients who have received one to three prior line(s) of therapy (LOT[s]) including an immunomodulatory agent and a proteasome inhibitor, and are refractory to lenalidomide. These analyses estimate the relative efficacy between cilta-cel and other common treatment regimens, for which no direct comparative evidence is available. Materials & methods: Patient data were available from the CARTITUDE-4, CASTOR, CANDOR and APOLLO RCTs. Imbalances between cohorts on key patient characteristics were adjusted for using inverse probability of treatment weighting (IPTW). Relative efficacies were estimated with response rate ratios (RRs) and 95% confidence intervals (CIs) for overall response rate (ORR), very good partial response or better rate (≥VGPR) and complete response or better rate (≥CR), and with hazard ratios (HRs) and 95% CIs for progression-free survival (PFS). Sensitivity analyses using different analytical methods and additional covariates were explored. Results: Key characteristics were well balanced across cohorts after IPTW. Cilta-cel showed statistically significant benefit in PFS (HRs: 0.11–0.51), ≥VGPR (RRs: 1.51–5.13) and ≥CR (RRs: 2.90–35.24) versus all comparators, and statistically significant improvements in ORR over most comparator regimens (RRs: 1.22–1.90). Results were consistent across sensitivity analyses. Conclusion: Cilta-cel demonstrated benefit over other common treatment regimens, highlighting its potential to become a new standard of care option for lenalidomide-refractory RRMM patients with one to three prior LOT(s). These comparisons help to demonstrate the improved efficacy of cilta-cel in countries where the standard of care may differ from DPd/PVd.

ABSTRACT: Organic agriculture comprises farming practices that discard synthetic pesticides and fertilizers. Tomato production demands huge amounts of fertilizers and pesticides. Improving efficiency of the inputs allowed for organic tomato production is a challenge to upgrade yields. Thereby, we studied the effects of the inoculation of the arbuscular mycorrhizal fungus (AMF) Rhizophagus clarus, supplying rock thermophosphate and bioactivator, alone or associated, on tomato development and yield. The experiment was achieved in a greenhouse using undetermined tomato cv. BRS-Nagai sown in polystyrene trays and afterwards transplanted to pots. Treatments included R. clarus; thermophosphate (TH) (130 g/pot); bioactivator (PenergeticK® + Penergetic®) (BI); R. clarus + TH; R. clarus + BI; R. clarus + TH+ BI and TH + BI and control (CO). From the flowering onset, plant height, height of insertion of first truss, trusses space, length, and also the diameter and fresh weight of ripe fruits of the three first trusses were assessed. AMF colonization in the roots and macronutrients in leaves and petioles were also measured. Trusses spacing variable was affected by mycorrhiza and thermophosphate. R. clarus inoculation incremented 10 and 31.85% of fresh mass of ripe fruits and mass of ripe fruits per plant, respectively. Soluble solids contents in fruits and N, P and K in the leaves and petioles were similar among treatments. AMF colonization decreased on thermophosphate fertilized plants and increased in bioactivator treatment. Results showed that root inoculation with R. clarus promoted better plant development and yield and may be used as biological inoculant mostly on organic tomato production.

Abstract Beyond motor neuron degeneration, homozygous mutations in the survival motor neuron 1 (SMN1) gene cause multiorgan and metabolic defects in patients with spinal muscular atrophy (SMA). However, the precise biochemical features of these alterations and the age of onset in the brain and peripheral organs remain unclear. Using untargeted NMR-based metabolomics in SMA mice, we identify cerebral and hepatic abnormalities related to energy homeostasis pathways and amino acid metabolism, emerging already at postnatal day 3 (P3) in the liver. Through HPLC, we find that SMN deficiency induces a drop in cerebral norepinephrine levels in overt symptomatic SMA mice at P11, affecting the mRNA and protein expression of key genes regulating monoamine metabolism, including aromatic L-amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DβH) and monoamine oxidase A (MAO-A). In support of the translational value of our preclinical observations, we also discovered that SMN upregulation increases cerebrospinal fluid norepinephrine concentration in Nusinersen-treated SMA1 patients. Our findings highlight a previously unrecognized harmful influence of low SMN levels on the expression of critical enzymes involved in monoamine metabolism, suggesting that SMN-inducing therapies may modulate catecholamine neurotransmission. These results may also be relevant for setting therapeutic approaches to counteract peripheral metabolic defects in SMA.

The electrospinning process is an effective technique for creating micro- and nanofibers from synthetic and natural polymers, with significant potential for biomedical applications and drug delivery systems due to their high drug-loading capacity, large surface area, and tunable release times. Poly(L-lactic acid) (PLLA) stands out for its excellent thermo-mechanical properties, biodegradability, and bioabsorbability. Electrospun PLLA nanofibrous structures have been extensively investigated as wound dressings, sutures, drug delivery carriers, and tissue engineering scaffolds. This study aims to create and characterize electrospun PLLA membranes loaded with spironolactone (SP), mimicking active compounds of Ganoderma lucidum (GL), to develop a biodegradable patch for topical wound-healing applications. GL, a medicinal mushroom, enhances dermal wound healing with its bioactive compounds, such as polysaccharides and ganoderic acids. Focusing on GL extracts—obtained through green extraction methods—and innovative drug delivery, we created new fibers for wound-healing potential applications. To integrate complex mixtures of bioactive compounds into the fibers, we developed a prototype using a single pure substance representing the extract mixture. This painstaking work presents the results of the fabricating, wetting, moisture properties, material resilience, and full characterization of the product, providing a robust rationale for the fabrication of fibers imbued with more complex extracts.

The human immunodeficiency virus (HIV-1) matrix protein p17 (p17) is released from infected cells as a protein capable of deregulating the biological activity of different cells. P17 variants (vp17s), more frequently detected in the plasma of HIV-1+ patients with rather than without lymphoma and characterized by amino acids insertions in their C-terminal region, were found to trigger B cell growth and clonogenicity. Vp17s endowed with B-cell-growth-promoting activity are drastically destabilized, whereas, in a properly folded state, reference p17 (refp17) does not exert any biological activity on B cell growth and clonogenicity. However, misfolding of refp17 is necessary to expose a masked functional epitope, interacting with the protease-activated receptor 1 (PAR-1), endowed with B cell clonogenicity. Indeed, it is worth noting that changes in the secondary structure can strongly impact the function of a protein. Here, we performed computational studies to show that the gain of function of vp17s is linked to dramatic conformational changes due to structural modification in the secondary-structure elements and in the rearrangement of the hydrogen bond (H-bond) network. In particular, all clonogenic vp17s showed the disengagement of two critical residues, namely Trp16 and Tyr29, from their hydrophobic core. Biological data showed that the mutation of Trp16 and Tyr29 to Ala in the refp17 backbone, alone or in combination, resulted in a protein endowed with B cell clonogenic activity. These data show the pivotal role of the hydrophobic component in maintaining refp17 stability and identify a novel potential therapeutic target to counteract vp17-driven lymphomagenesis in HIV-1+ patients.

Image-guided radiotherapy supported by surface guidance can help to track lower lung lesions’ respiratory motion while reducing a patient’s exposure to ionizing radiation. However, it is not always clear how the skin’s respiratory motion magnitude and its correlation with the lung lesion’s respiratory motion vary between different skin regions of interest (ROI). Four-dimensional computed tomography (4DCT) images provide information on both the skin and lung respiratory motion and are routinely acquired for the purpose of treatment planning in our institution. An analysis of 4DCT images for 57 patients treated in our institution has been conducted to provide information on the respiratory motion magnitudes of nine skin ROIs of the torso, a tracking structure (TS) representing a lower lung lobe lesion, as well as the respiratory motion correlations between the nine ROIs and the TS. The effects of gender and the adipose tissue volume and distribution on these correlations and magnitudes have been analyzed. Significant differences between the ROIs in both the respiratory motion magnitudes and their correlations with the TS have been detected. An overall negative correlation between the ROI respiratory magnitudes and the adipose tissue has been detected for ROIs with rib cage support. A weak to moderate negative correlation between the adipose tissue volume and ROI-to-TS respiratory correlations has been detected for upper thorax ROIs. The respiratory magnitudes in regions without rib support tend to be larger for men than for women, but no differences in the ROI-to-TS correlation between sexes have been detected. The described findings should be considered when choosing skin surrogates for lower lung lesion motion management.

Fibromyalgia (FM), a chronic disease with a high incidence in women, poses a significant challenge for diagnosis and treatment, especially due to the absence of specific biomarkers and the multifaceted nature of its symptoms, which range from neuromuscular pain to mood disorders and intestinal dysbiosis. While diagnosis currently relies on rheumatological clinical evaluations and treatment options mainly focus on symptom management, FM seems to have possible links with systemic metabolic dysfunctions with a common inflammatory root. In this context, a new therapeutic avenue emerges: could a therapeutic nutritional approach be the missing piece of the puzzle? Indeed, diet therapies employed particularly for metabolic syndromes proved recently to be efficacious for correcting systemic dysmetabolism and a high number of chronic inflammation conditions. In particular, the very-low-calorie ketogenic diet (VLCKD) demonstrated therapeutic benefits in many disorders. In the present study, we aimed to investigate the specific effects of two dietary interventions, namely the oloproteic VLCKD and the low-glycemic insulinemic (LOGI) diet, on two groups of female FM patients (FM1 and FM2) over a 45-day period. Utilizing clinical and laboratory tests, as well as non-invasive NMR metabolomic analysis of serum, urine, and saliva samples, we sought to uncover how these dietary regimens impact the metabolic dysfunctions associated with FM.

Coronaviruses are highly transmissible and pathogenic viruses for humans and animals. The vast quantity of information collected about SARS-CoV-2 during the pandemic helped to unveil details of the mechanisms behind the infection, which are still largely elusive. Recent research demonstrated that different class I/II human leukocyte antigen (HLA) alleles might define an individual susceptibility to SARS-CoV-2 spreading, contributing to the differences in the distribution of the infection through different populations; additional studies suggested that the homolog of the HLA in cats, the feline leukocyte antigen (FLA), plays a pivotal role in the transmission of viruses. With these premises, this study aimed to exploit a bioinformatic approach for the prediction of the transmissibility potential of two distinct feline coronaviruses (FCoVs) in domestic cats (feline enteric coronavirus (FeCV) and feline infectious peritonitis virus (FIPV)) using SARS-CoV-2 as the reference model. We performed an epitope mapping of nonapeptides deriving from SARS-CoV-2, FeCV, and FIPV glycoproteins and predicted their affinities for different alleles included in the three main loci in class I FLAs (E, H, and K). The predicted complexes with the most promising affinities were then subjected to molecular docking and molecular dynamics simulations to provide insights into the stability and binding energies in the cleft. Results showed the FLA proteins encoded by alleles in the FLA-I H (H*00501 and H*00401) and E (E*01001 and E*00701) loci are largely responsive to several epitopes deriving from replicase and spike proteins of the analyzed coronaviruses. The analysis of the most affine epitope sequences resulting from the prediction can stimulate the development of anti-FCoV immunomodulatory strategies based on peptide drugs.

Productive traits, total polyphenols (TPC), and antioxidant activity (DPPH) of arugula submitted to the combination (or not) of cow urine and doses of bokashi were evaluated in two experimental areas. Arugula was planted in cultivation bags with 55 dm3 of capacity in protected cultivation. The treatments were bokashi doses (0, 10, 20, and 30 g) and use (or not) of cow urine diluted 1% in water. The variables evaluated were fresh leaf biomass (FLB), dry leaf biomass (DLM), plant height (PH), chlorophyll index, TPC, and DPPH. In area 1, all agronomic variables were increased at 30 g and 20 g bokashi doses. FLB was increased by 87 and 76% with 30 g of bokashi. Cow urine only increased PH. In area 2, the use of bokashi + cow urine increased FLB, DLB, and PH with a positive quadratic response. At the maximum point, the FLB was increased by 159% with 28.92 g of bokashi. Bokashi increased FLB and DLB in the two areas in all evaluated doses. For TPC, with the use of cow urine, 10 g of bokashi increased TPC by 14%. Without the use of cow urine, increases of 17 and 33% with 10 and 30 g of bokashi were observed. The 30 g of bokashi is recommended because of increased productive traits and TPC.

The AGILE space mission was launched in 2007 to study X-ray and gamma-ray astrophysics. AGILE operated in spinning mode from 2009 until 2024 February 14, when it re-entered the Earth’s atmosphere. This work uses data acquired from the AGILE anticoincidence system (ACS) from 2019 January 1 to 2022 December 31. The ACS is designed to reject charged background particles. It also detects X-ray photons in the 50–200 KeV energy range and saves each panel count rate in the telemetry as ratemeter data, a time series with a resolution of 1.024 s. We developed a method that uses a deep learning model to predict the background count rates of the AGILE ACS top panel (perpendicular to the pointing direction of the payload detectors) using the satellite’s orbital parameters as input. Then, we use the difference between predicted and acquired count rates to detect gamma-ray bursts (GRB). We trained the model with a background-only data set. After the training, the model can predict the ACS count rates with a mean reconstruction error of 3.8%. We used the GRBs listed in the GRBweb catalog to search for significant anomalies in the ACS data. We extracted light curves of 140 bins of 1.024 s for each GRB from the AGILE ACS to cover the trigger time of the GRBs. The model detected 39 GRBs with a significance of σ ≥ 3. The results contain four GRBs detected for the first time in the AGILE data.

The first aim of research is to propose a research instrument based on Wiseman and Bogner's Model of Ecological Values, the "Coastal Environment Questionnaire" (CEQ), specifically developed to evaluate the Environmental Perception about marine and coastal ecosystems. The second aim is to explore, using CEQ, the position on the categories from Model of Ecological Values of some basic education students and some pre-service biology teachers from cities located near coastal areas from Brazil. CEQ was modified from "The Environment Questionnaire" (TEQ), which consists of a questionnaire composed of 16 items with Likert-type responses. The first process to have elaborated the new instrument changed the general situations described in the items of TEQ (most related with land environments) to situations related to marine and coastal environments. CEQ has been used with: 63 pre-service biology teachers from a non-coastal city; 79 basic education students from a non-coastal city; and 74 basic education students from a coastal city. All pre-service teachers were placed at Preservation+Utilization- category (100%). However, most students were placed at the Preservation+Utilization- category (around 70%), followed by Preservation+Utilization+ (around 25%), regardless their city location. It is expected that CEQ can be useful on research aim to better understand the perception about marine and coastal environments, contributing to development and evaluation of future Environmental Educational program focus on these important ecosystems.

The characterization of modifications of microbial proteins is of primary importance to dissect pathogen lifecycle mechanisms and could be useful in identifying therapeutic targets. Attempts to solve this issue yielded only partial and non-exhaustive results. We developed a multidisciplinary approach by coupling in vitro infection assay, mass spectrometry (MS), protein 3D modelling, and surface plasma resonance (SPR). As a proof of concept, the effect of low UV-C (273 nm) irradiation on SARS-CoV-2 spike (S) protein was investigated. Following UV-C exposure, MS analysis identified, among other modifications, the disruption of a disulphide bond within the conserved S2 subunit of S protein. Computational analyses revealed that this bond breakage associates with an allosteric effect resulting in the generation of a closed conformation with a reduced ability to bind the ACE2 receptor. The UV-C-induced reduced affinity of S protein for ACE2 was further confirmed by SPR analyses and in vitro infection assays. This comprehensive approach pinpoints the S2 domain of S protein as a potential therapeutic target to prevent SARS-CoV-2 infection. Notably, this workflow could be used to screen a wide variety of microbial protein domains, resulting in a precise molecular fingerprint and providing new insights to adequately address future epidemics.

The aim of the study is to investigate low-cost sources of organic-allowed inputs for iceberg lettuce and chicory radicchio vegetative growth. Experiments were conducted under protected cultivation. The following treatments were used: boiled chicken manure for fertigation (2.5; 5; 7.5; and 10%); Bokashi as a mineral fertilizer N-P-K (4-14-8) in the substrate; and the control (water). The total leaf biomass (TLB) (g), commercial leaf biomass (CLB) (g), plant diameter (DIA) (cm), plant height (HEI) (cm), number of leaves (NL) (for lettuce only), and chlorophyll index (CLO) (Falker index) were evaluated. The mineral fertilizer provided the highest means of production variables for both lettuce and chicory. For iceberg lettuce, the means of an organic treatment were similar to the mineral fertilizer only for the CLO variable and for the NL in BCM 10%. For radicchio chicory, the organic treatments had similar means to the mineral fertilizer for the DIA and CLO. Only Bokashi had a similar mean to mineral for the HEI variable.

Long-term kinetics of antibody (Ab) and cell-mediated immune (CMI) response to full anti-SARS-CoV-2 vaccine schedule and booster doses in Multiple Myeloma (MM) patients remain unclear. We prospectively evaluated Ab and CMI response to mRNA vaccines in 103 SARS-CoV-2-naïve MM patients (median age 66, 1 median prior line of therapy) and 63 health-workers. Anti-S-RBD IgG (Elecsys®assay) were measured before vaccination and after 1 (T1), 3 (T3), 6 (T6), 9 (T9) and 12 (T12) months from second dose (D2) and 1 month after the introduction of the booster dose (T1D3). CMI response (IGRA test) was evaluated at T3 and T12. Fully vaccinated MM patients displayed high seropositivity rate (88.2%), but low CMI response (36.2%). At T6 the median serological titer was halved (p=0.0391) in MM patients and 35% reduced (p=0.0026) in controls. D3 (94 patients) increased the seroconversion rate to 99% in MM patients and the median IgG titer in both groups (up to 2500 U/mL), maintained at T12. 47% of MM patients displayed a positive CMI at T12 and double-negativity for humoral and CMI (9.6% at T3) decreased to 1%. Anti-S-RBD IgG level ≥346 U/mL showed 20-times higher probability of positive CMI response (OR 20.6, p

The Experiment to Study Thunderstorm High-Energy Radiation (ESTHER) is a small project of the Italian National Institute for Astrophysics (INAF), devoted to the study of high-energy emissions from thunderstorms, such as Terrestrial Gamma-ray Flashes and gamma-ray glows, which will start in 2024. In order to reduce the absorption typically undergone by gamma-ray radiation in the lower layers of the atmosphere and make these events detectable on the ground, the ESTHER set-up will be installed at high altitudes on Mt. Etna (Italy). We carried out a detailed analysis of lightning occurrence in this geographic region in order to test how suitable such a location is for the installation of a detection system to investigate thunderstorms and related emissions. The analysis pointed out a strong clustering of lightning in the proximity of the mountain peak and over the main volcano craters, where the frequent presence of volcanic ashes could increase, under the conditions of humid air typical of thunderstorms, electrical conductivity. An estimate of the gamma-ray absorption in the air undergone by typical TGF radiation allowed us to evaluate the suitability of two possible installation sites suggested for the project. This study represents a preliminary work for ESTHER and serves as a launching pad for future analyses.

The common bean (Phaseolus vulgaris L.) is an important leguminous crop providing low-cost protein in developing countries worldwide. Insect pests are the main threats to common bean production, and this article focuses on the soybean looper (SL) Chrysodeixis includens (Walker, 1858) (Lepidoptera: Noctuidae), which feeds on leaves and pods. The recurrent use of synthetic chemicals may lead to pest resistance. Genetically resistant plants may diminish their use. Thus, the objective was to study common bean genotypes’ resistance toward SL. The plants were grown in greenhouse conditions. The biology, fertility life table, oviposition preference and free-choice feeding preference were analyzed. Phenol and flavonoid content were assessed in leaves using a biology assay. Uirapuru genotype negatively affected C. includens biology and reproduction. Tangará genotype favored these parameters. Genotypes Quero-Quero, Nhambu, Corujinha, Andorinha, ANFC 9, Siriri, BRS Radiante and Verdão were more attractive for third-instar larvae. Negative correlations between phenolic and flavonoid compounds with survival rate (from egg to adult) rate were found. Common bean genotypes with dark leaves are less preferred for oviposition.

Antibodies are the macromolecules of choice to ensure specific recognition of biomarkers in biological assays. However, they present a range of shortfalls including a relatively high production cost and limited tissue penetration. Peptides are relatively small molecules able to reproduce sequences of highly specific paratopes and, although they have less biospecificity than antibodies, they offer advantages like ease of synthesis, modifications of their amino acid sequences and tagging with fluorophores and other molecules required for detection. This work presents a strategy to design peptide sequences able to recognize the CD44 hyaluronic acid receptor present in the plasmalemma of a range of cells including human bone marrow stromal mesenchymal cells. The protocol of identification of the optimal amino acid sequence was based on the combination of rational design and in silico methodologies. This protocol led to the identification of two peptide sequences which were synthesized and tested on human bone marrow mesenchymal stromal cells (hBM-MSCs) for their ability to ensure specific binding to the CD44 receptor. Of the two peptides, one binds CD44 with sensitivity and selectivity, thus proving its potential to be used as a suitable alternative to this antibody in conventional immunostaining. In the context of regenerative medicine, the availability of this peptide could be harnessed to functionalize tissue engineering scaffolds to anchor stem cells as well as to be integrated into systems such as cell sorters to efficiently isolate MSCs from biological samples including various cell subpopulations. The data here reported can represent a model for developing peptide sequences able to recognize hBM-MSCs and other types of cells and for their integration in a range of biomedical applications.

Calcium (Ca) represents about 40% of the total mineral mass, mainly in the bone, providing mechanical strength to the skeleton and teeth. An adequate Ca intake is necessary for bone growth and development in children and adolescents and for maintaining bone mineral loss in elderly age. Ca deficiency predisposes to osteopenia and osteoporosis. Healthy nutrition, including an adequate intake of Ca-rich food, is paramount to prevent and cure osteoporosis. Recently, several clinical studies have demonstrated that, in conditions of Ca dysmetabolism, Ca-rich mineral water is beneficial as a valuable source of Ca to be used as an alternative to caloric Ca-rich dairy products. Although promising, these data have been collected from small groups of participants. Moreover, they mainly regard the effect of Ca-rich mineral water on bone metabolism. In contrast, an investigation of the effect of Ca supplementation on systemic metabolism is needed to address the spreading of systemic metabolic dysfunction often associated with Ca dysmetabolism. In the present study, we analyzed urine and blood sera of 120 women in perimenopausal condition who were subjected for six months to 2l daily consumption of bicarbonate–calcium mineral water marketed under ®Lete. Remarkably, this water, in addition to being rich in calcium and bicarbonate, is also low in sodium. A complete set of laboratory tests was carried out to investigate whether the specific water composition was such to confirm the known therapeutic effects on bone metabolism. Second, but not least, urine and blood sera were analyzed using NMR-based metabolomic procedures to investigate, other than the action on Ca metabolism, potential system-wide metabolic effects. Our data show that Lete water is a valid supplement for compensating for Ca dysmetabolism and preserving bone health and integrity.

Gamma-ray emission in the MeV–GeV range from explosive cosmic events is of invaluable relevance to understanding physical processes related to the formation of neutron stars and black holes. Here we report on the detection by the AGILE satellite in the MeV–GeV energy range of the remarkable long-duration gamma-ray burst GRB 221009A. The AGILE onboard detectors have good exposure to GRB 221009A during its initial crucial phases. Hard X-ray/MeV emission in the prompt phase lasted hundreds of seconds, with the brightest radiation being emitted between 200 and 300 s after the initial trigger. Very intense GeV gamma-ray emission is detected by AGILE in the prompt and early afterglow phase up to 10,000 s. Time-resolved spectral analysis shows time-variable MeV-peaked emission simultaneous with intense power-law GeV radiation that persists in the afterglow phase. The coexistence during the prompt phase of very intense MeV emission together with highly nonthermal and hardening GeV radiation is a remarkable feature of GRB 221009A. During the prompt phase, the event shows spectrally different MeV and GeV emissions that are most likely generated by physical mechanisms occurring in different locations. AGILE observations provide crucial flux and spectral gamma-ray information regarding the early phases of GRB 221009A during which emission in the TeV range was reported.

Graft versus host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Rabbit anti-T lymphocyte globulin (ATLG) in addition to calcineurin inhibitors and antimetabolites is a suitable strategy to prevent GVHD in several transplant settings. Randomized studies already demonstrated its efficacy in terms of GVHD prevention, although the effect on relapse remains the major concern for a wider use. Tailoring of ATLG dose on host characteristics is expected to minimize its side effects (immunological reconstitution, relapse, and infections). Here, day -6 to day +15 pharmacokinetics of active ATLG serum level was first assayed in an explorative cohort of 23 patients by testing the ability of the polyclonal serum to bind antigens on human leukocytes. Significantly lower levels of serum active ATLG were found in the patients who developed GVHD (ATLG_AUCCD45: 241.52 ± 152.16 vs. 766.63 +/- 283.52 (μg*day)/ml, p = 1.46e-5). Consistent results were obtained when the ATLG binding capacity was assessed on CD3+ and CD3+/CD4+ T lymphocytes (ATLG_AUCCD3: 335.83 ± 208.15 vs. 903.54 ± 378.78 (μg*day)/ml, p = 1.92e-4; ATLG_AUCCD4: 317.75 ± 170.70 vs. 910.54 ± 353.35 (μg*day)/ml, p = 3.78e-5. Concomitantly, at pre-infusion time points, increased concentrations of CD69+ extracellular vesicles (EVs) were found in patients who developed GVHD (mean fold 9.01 ± 1.33; p = 2.12e-5). Consistent results were obtained in a validation cohort of 12 additional ATLG-treated HSCT patients. Serum CD69+ EVs were mainly represented in the nano (i.e. 100 nm in diameter) EV compartment and expressed the leukocyte marker CD45, the EV markers CD9 and CD63, and CD103, a marker of tissue-resident memory T cells. The latter are expected to set up a host pro-inflammatory cell compartment that can survive in the recipient for years after conditioning regimen and contribute to GVHD pathogenesis. In summary, high levels of CD69+ EVs are significantly correlated with an increased risk of GVHD, and they may be proposed as a tool to tailor ATLG dose for personalized GVHD prevention.