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We study boundedness of weak solutions to elliptic systems of partial differential equations in divergence form, under the so-called p,q growth conditions. Examples are obtained by writing the Euler system of some double phase functionals.

Let us consider continuous minimizers $ u : \bar \Omega \subset \mathbb{R}^n \to \mathbb{R}^n $ of $ \mathcal{F}(v) = \int_{\Omega} [|Dv|^p \, + \, |{\rm det}\,Dv|^r] dx, $ with $ p > 1 $ and $ r > 0 $; then it is known that every component $ u^\alpha $ of $ u = (u^1, ..., u^n) $ enjoys maximum principle: the set of interior points $ x $, for which the value $ u^\alpha(x) $ is greater than the supremum on the boundary, has null measure, that is, $ \mathcal{L}^n(\{ x \in \Omega: u^\alpha (x) > \sup_{\partial \Omega} u^\alpha \}) = 0 $. If we change the structure of the functional, it might happen that the maximum principle fails, as in the case $ \mathcal{F}(v) = \int_{\Omega}[\max\{(|Dv|^p - 1); 0 \} \, + \, |{\rm det}\,Dv|^r] dx, $ with $ p > 1 $ and $ r > 0 $. Indeed, for a suitable boundary value, the set of the interior points $ x $, for which the value $ u^\alpha(x) $ is greater than the supremum on the boundary, has a positive measure, that is $ \mathcal{L}^n(\{ x \in \Omega: u^\alpha (x) > \sup_{\partial \Omega} u^\alpha \}) > 0 $. In this paper we show that the measure of the image of these bad points is zero, that is $ \mathcal{L}^n(u(\{ x \in \Omega: u^\alpha (x) > \sup_{\partial \Omega} u^\alpha \})) = 0 $, provided $ p > n $. This is a particular case of a more general theorem.

We prove the existence of a solution to a quasilinear system of degenerate equations, when the datum is in a Marcinkiewicz space. The main assumption asks the off-diagonal coefficients to have support in the union of a geometric progression of squares.

People affected by COVID-19 are exposed to, among others, abnormal clotting and endothelial dysfunction, which may result in deep vein thrombosis, cerebrovascular disorders, and ischemic and non-ischemic heart diseases, to mention a few. Treatments for COVID-19 include antiplatelet (e.g., aspirin, clopidogrel) and anticoagulant agents, but their impact on morbidity and mortality has not been proven. In addition, due to viremia-associated interconnected prothrombotic and proinflammatory events, anti-inflammatory drugs have also been investigated for their ability to mitigate against immune dysregulation due to the cytokine storm. By retrieving patent literature published in the last two years, small molecules patented for long-COVID-related blood clotting and hematological complications are herein examined, along with supporting evidence from preclinical and clinical studies. An overview of the main features and therapeutic potentials of small molecules is provided for the thromboxane receptor antagonist ramatroban, the pan-caspase inhibitor emricasan, and the sodium–hydrogen antiporter 1 (NHE-1) inhibitor rimeporide, as well as natural polyphenolic compounds.

We conducted a monocentric observational study aimed at evaluating the vaccine safety and the pharmaceutical service provided at a community pharmacy (C.PHARM) in the Puglia Region in the period from 29 December 2021 to 12 March 2022 using data from 550 patients of various ages and sexes and with concomitant diseases. We collected anamnestic data, the number of hospitalizations, and any post-vaccination adverse reactions. Interviews using the integrated EQ5 method were also performed to evaluate the quality of the service offered and any therapy preference. As expected, the vaccines were reactogenic after the first dose in the patients with mild–moderate reactions, with younger age and female gender as risk factors. Immune-allergic reactions of a moderate–severe degree were observed in adult females. In the elderly, the vaccination was well tolerated. Comirnaty® showed a favorable O.R. < 1 vs. other vaccines. No cardiovascular events or hospitalizations were observed up to May 2023. Regional data indicate that all treatments during May 2023 were correlated with the viremia. PaxlovidTM was prescribed in 3% of the patients in our center and in 1.46% in the region, and distributed/dispensed on behalf of third parties in accordance with a novel distribution/dispensation protocol of the C.PHARM that resulted in a safe vaccination center providing appropriate patient inclusion during vaccination.

Abstract A plethora of different electronic and optoelectronic devices have been developed lately, for biosensing applications (e.g., label‐free, fast, and easier to operate) based on a detecting interface accommodating the biorecognition elements, anchored by thiolate self‐assembled monolayers (SAMs) on a gold surface. Here, a surface plasmon resonance (SPR) characterization of anti‐p24 anchored on different SAMs is performed to investigate the effect of the SAM structure on the antibodies’ packing efficiency and the sensors’ analytical figures of merit. Notably, the mixed SAM deposited from a solution 10:1 of 3‐mercaptopropionic acid and 11‐mercaptoundecanoic acid (11MUA) is compared to that resulting from a solution 10:1 of ad hoc synthesized N‐(2‐hydroxyethyl)‐3‐mercaptopropanamide (NMPA)/11MUA. Despite the improvement in the anti‐p24 surface coverage registered using the 11MUA/NMPA SAM, the latter produces a significant decrease in the antibodies’ binding efficiency against human immunodeficiency virus p24 protein. To provide a molecular rationale behind the SPR data, density functional theory calculations are also undertaken. A comprehensive physical view of the main competing phenomena affecting the biorecognition events at a biofunctionalized gold detecting interface is represented here.

Abstract The ultrasensitive measurement of protein markers plays a pivotal role in the early diagnosis of infectious and progressive diseases. Recently, digital methods such as those enabled by the Simoa Planar Array technology (SP‐X System) have made significant progress in reaching ultrasensitive detection with clinically relevant protein biomarkers. The elicited Simoa technology is based on printing high‐density capturing antibodies layers on the bottom of the wells of a microtiter plate, followed by a standard sandwich‐type immunometric chemiluminescent detection. Such assay, reaching limit‐of‐detections (LODs) in the low femtomolar range, can be conveniently customized. An optimized Simoa SP‐X assay for detecting and quantifying immunoglobulin M (IgM, non‐specific indicator of inflammation) is developed herein and optimized. A full factorial experimental design is undertaken to optimize the assay, leading to a reduced experimental effort and increased quality of the information obtained concerning the traditional one‐variable‐at‐a‐time approach. The optimization process leads to an IgM LOD of 4 fm that compares well with those achieved with commercially available Simoa Planar Array kits. Remarkably, depositing both the capturing and detecting layer from a solution (0.1 µg mL−1) one order of magnitude less concentrated than in standard kits is needed, and the assay's cost is sizably reduced.

The coumarin core (i.e., 1-benzopyran-2 (2H)-one) is a structural motif highly recurrent in both natural products and bioactive molecules. Indeed, depending on the substituents and branching positions around the byciclic core, coumarin-containing compounds have shown diverse pharmacological activities, ranging from anticoagulant activities to anti-inflammatory, antimicrobial, anti-HIV and antitumor effects. In this survey, we have reported the main scientific results of the 20-years investigation on the coumarin core, exploited by the research group headed by Prof. Angelo Carotti (Bari, Italy) either as a scaffold or a pharmacophore moiety in designing novel biologically active small molecules.

Abstract Pathogens ultra‐sensitive detection is vital for early diagnosis and provision of restraining actions and/or treatments. Among plant pathogens, Xylella fastidiosa is among the most threatening as it can infect hundreds of plant species worldwide with consequences on agriculture and the environment. An electrolyte‐gated transistor is here demonstrated to detect X. fastidiosa at a limit‐of‐quantification (LOQ) of 2 ± 1 bacteria in 0.1 mL (20 colony‐forming‐unit per mL). The assay is carried out with a millimeter‐wide gate functionalized with Xylella‐capturing antibodies directly in saps recovered from naturally infected plants. The proposed platform is benchmarked against the quantitave polymerase chain reaction (qPCR) gold standard, whose LOQ turns out to be at least one order of magnitude higher. Furthermore, the assay selectivity is proven against the Paraburkholderia phytofirmans bacterium (negative‐control experiment). The proposed label‐free, fast (30 min), and precise (false‐negatives, false‐positives below 1%) electronic assay, lays the ground for an ultra‐high performing immunometric point‐of‐care platform potentially enabling large‐scale screening of asymptomatic plants.

Inflammatory cells are emerging markers in various cancers in human trials. The relationship between the inflammatory cells response, cancer grade, and progression has been investigated experimentally in a spontaneous canine model of breast cancer and in the unselected population (18–64 years.o.) under anti-HER2 treatments that represent the most prevalent population in this cancer type. The canine data (N samples = 101) were collected retrospectively for diagnosis in our regional area and evaluated by immunohistochemistry and haemato-chemistry. The inflammatory and immune-related adverse reactions (ADR) in humans were evaluated using EudraVigilance. The “Proportional Reporting Ratio” (PRR) of the mabs was calculated for each ADR with values >2 indicative of high risk. In dogs, we found elevated immunostaining of CD68-macrophages in the lymph node of the aggressive cancer G3 and infiltrating CD20+-lymphocyte. A high density of CD20 + lymphocytes was observed in G1 and a decrease in the density was observed with the histological degree of the tumors. The animals with the sample in G1 showed reduced serum platelet and neutrophil count and elevated lymphocytes and the opposite in severely affected animals. Inflammatory reactions with edema, skin reactions, extravasation, loss of effectiveness, and platelet count decrease (PRR > 13) were found with trastuzumab emtansine in humans, in the absence of immune system reactions. Trastuzumab i.v.-s.c. showed immune system reactions, loss of effectiveness, intolerances with drug withdrawal, technological issues (PRR > 7), and neutrophil count decrease reports. These reactions were less frequently reported for pertuzumab i.v. Case reports of platelet and neutrophil count decrease were not associated with disease progression with a better outcome in humans as in canine breast cancer. Therefore, infiltrating CD68-macrophages are associated with G3, while infiltrating CD20+ and elevated serum lymphocytes in parallel with reduced platelet and neutrophil count play a favorable role in human and canine breast cancer.

We evaluated the effects of a new extract (70% acetonitrile, 2E0217022196DIPFARMTDA) of Lens culinaris Medik (Terre di Altamura SRL, Altamura BA) to prevent cytotoxic damage from cisplatin, staurosporine, irinotecan, doxorubicin, and the glucocorticoid dexamethasone. The acetonitrile–water extract (range 0.1–5 mg/mL) was obtained by extracting 10 g of lentil flour with 50 milliliters of the acetonitrile–water extraction mixture in a 70:30 ratio, first for 3 h and then overnight in a shaker at room temperature. The next day, the extract was filtered and passed through a Rotavapor to obtain only the aqueous component and eliminate that with acetonitrile, and then freeze-dried to finally have the powdered extract. In vitro experiments showed that the extract prevented the cytotoxic damage induced by cisplatin, irinotecan, and doxorubicin on HEK293 and SHSY5Y cell lines after 24–96 h. In murine osteoblasts after 24–72 h of incubation time, the extract was cytoprotective against all chemicals. The extract was effective against dexamethasone, leading to synergic cell proliferation in all cell types. In bone marrow cells, the extract is cytoprotective after 72 h against doxorubicin, staurosporine, and dexamethasone. Instead, on muscle fibers, the extract has a synergic effect with chemotherapeutics, increasing cytotoxicity induced by doxorubicin and staurosporine. LC-MS attested to the existence of several phenolic structures in the extract. The most abundant families of compounds were flavonoids (25.7%) and mellitic acid (18%). Thus, the development of this extract could be implemented in the area of research related to the chemoprevention of damage to renal, neuronal, bone marrow cells, and osteoblasts by chemotherapeutics; moreover, it could be used as a reinforcer of cytotoxic action of chemotherapeutics on muscle fibers.

The cytoprotective effects of a novel hydroalcoholic extract (0.01–5 mg/mL) from Lens culinaria (Terre di Altamura Srl) were investigated within murine native skeletal muscle fibers, bone marrow cells, and osteoblasts, and in cell lines treated with the apoptotic agent staurosporine (2.14 × 10−6 M), the alkylating drug cisplatin (10−4 M), the topoisomerase I inhibitor irinotecan (10−4 M), the antimitotic pro-oxidant doxorubicin (10−6 M), and the immunosuppressant dexamethasone (2 × 10−6 M). An amount of 10g of plant material was used to obtain a 70% ethanol/water product, following two-step extraction, evaporation, lyophilization, and storage at −20 °C. For the murine osteoblasts, doxorubicin reduced survival by −65%, dexamethasone by −32% and −60% after 24 and 48 h of incubation time, respectively. The extract was effective in preventing the osteoblast count-reduction induced by dexamethasone; it was also effective at preventing the inhibition of mineralization induced by dexamethasone. Doxorubicin and cisplatin caused a significant reduction in cell growth by −77% for bone marrow cells, −43% for irinotecan, and −60% for dexamethasone, but there was no evidence for the cytoprotective effects of the extract in these cells. Staurosporine and doxorubicin caused a fiber death rate of >−40% after 18 and 24 h of incubation, yet the extract was not effective at preventing these effects. The extract was effective in preventing the staurosporine-induced reduction of HEK293 proliferation and colony formation in the crystal violet DNA staining and the clonogenic assays. It was also effective for the cisplatin-induced reduction in HEK293 cell proliferation. The extract, however, failed to protect the SHSY5Y neurons against cisplatin and irinotecan-induced cytotoxicity. A UV/VIS spectroscopy analysis showed three peaks at the wavelengths of 350, 260, and 190 nm, which correspond to flavonoids, proanthocyanins, salicylates, and AA, constituting the extract. These data suggest the possible development of this extract for use against dexamethasone-induced bone loss and renal chemotherapy-induced damage.

Summary: Triple-negative breast cancer (TNBC) is a high heterogeneous group of tumors with a distinctly aggressive nature and high rates of relapse. So far, the lack of any known targetable proteins has not allowed a specific anti-tumor treatment. Therefore, the identification of novel agents for specific TNBC targeting and treatment is desperately needed. Here, by integrating cell-SELEX (Systematic Evolution of Ligands by EXponential enrichment) for the specific recognition of TNBC cells with high-throughput sequencing technology, we identified a panel of 2′-fluoropyrimidine-RNA aptamers binding to TNBC cells and their cisplatin- and doxorubicin-resistant derivatives at low nanomolar affinity. These aptamers distinguish TNBC cells from both non-malignant and non-TNBC breast cancer cells and are able to differentiate TNBC histological specimens. Importantly, they inhibit TNBC cell capacity of growing in vitro as mammospheres, indicating they could also act as anti-tumor agents. Therefore, our newly identified aptamers are a valuable tool for selectively dealing with TNBC. : Biochemistry; Cell Biology; Cancer Subject Areas: Biochemistry, Cell Biology, Cancer

We prove a local boundedness result for local minimizers of a class of non-convex functionals, under special structure assumptions on the energy density. The proof follows the lines of that in [CupLeoMas17], where a similar result is proved under slightly stronger assumptions on the energy density.

Un ebook in formato EPUB3 può esprimere comportamenti e contenuti che sfruttino lo status digitale, senza limitarsi a replicare in digitale contenuti e comportamenti della versione cartacea. Tra le caratteristiche peculiari dello stato digitale, oltre alla multicodicaltà ed interattività, vi è la rappresentazione semantica. In EPUB3 è possibile rappresentare formalmente in una porzione di testo ciò di cui si sta parlando. Ad esempio, in un brano di un libro di storia è possibile rappresentare il fatto che si parla di un dato evento storico, del periodo in cui l'evento si è tenuto, dei personaggi coinvolti, del luogo in cui è avvenuto, e così via, in modo che sia il libro stesso anche a saperlo e non solo il lettore. La marcatura semantica può abilitare varie funzionalità, da un motore di ricerca semantico sino a comportamenti da "intelligenza artificiale". Il motore di ricerca semantico, ad esempio, consente di effettuare sull'opera editoriale interrogazioni del tipo: "fammi vedere tutti i personaggi storici citati", "fammi vedere i luoghi nei quali sono avvenuti eventi storici", "fammi vedere i personaggi coinvolti in eventi storici in dato periodo di tempo", eccetera. Ne mostriamo qui un esempio concreto, in un ebook in formato EPUB3 realizzato con ePubEditor, un tool autore che consente di redigere ebook davvero digitali, ebook cioè che oltre ad avere contenuti multimediali e comportamenti interattivi, includono marcature semantiche e un motore di ricerca che le sfrutta. Il file risultante è un ebook in formato EPUB3 conforme e validato.

The fusion oncoprotein Bcr-Abl is an aberrant tyrosine kinase responsible for chronic myeloid leukemia and acute lymphoblastic leukemia. The auto-inhibition regulatory module observed in the progenitor kinase c-Abl is lost in the aberrant Bcr-Abl, because of the lack of the N-myristoylated cap able to bind the myristoyl binding pocket also conserved in the Bcr-Abl kinase domain. A way to overcome the occurrence of resistance phenomena frequently observed for Bcr-Abl orthosteric drugs is the rational design of allosteric ligands approaching the so-called myristoyl binding pocket. The discovery of these allosteric inhibitors although very difficult and extremely challenging, represents a valuable option to minimize drug resistance, mostly due to the occurrence of mutations more frequently affecting orthosteric pockets, and to enhance target selectivity with lower off-target effects. In this perspective, we will elucidate at a molecular level the structural bases behind the Bcr-Abl allosteric control and will show how artificial intelligence can be effective to drive the automated de novo design towards off-patent regions of the chemical space.

La sostanziale differenza tra book ed e-book è data dal fatto che nel libro cartaceo (book), il contenuto e il “dispositivo di lettura” sono integrati, mentre l’e-book distingue il contenuto (file) dal dispositivo utilizzato per fruirlo. Oltre a ciò, la tecnologia digitale consente di esplorare forme espressive del tutto inedite rispetto alla carta, che non sono date solo dalla multimedialità e interattività, ma anche da aspetti funzionali dei dispositivi digitali e dello “status” digitale del contenuto per molti versi non ancora del tutto attuati ed implementati. Il formato EPUB, meglio di altri, consente di applicare queste peculiarità ad un e-book e di svilupparlo in modo semplice ed immediato tramite uno degli strumenti autore disponibili sul mercato, quale, ad esempio, EPUB Editor, un tool online particolarmente utilizzato in contesto scolastico e didattico, di cui vengono dati esempi di lavori realizzati.

We prove boundedness of distributional solutions u to linear elliptic equations − div(a(x)Du(x)) = − div f(x)+f0(x) where the right hand side f,f0 is only in L^{1,λ}.

Matrix metalloproteinases (MMP) are well-known biological targets implicated in tumour progression, homeostatic regulation, innate immunity, impaired delivery of pro-apoptotic ligands, and the release and cleavage of cell-surface receptors. Hence, the development of potent and selective inhibitors targeting these enzymes continues to be eagerly sought. In this paper, a number of alloxan-based compounds, initially conceived to bias other therapeutically relevant enzymes, were rationally modified and successfully repurposed to inhibit MMP-2 (also named gelatinase A) in the nanomolar range. Importantly, the alloxan core makes its debut as zinc binding group since it ensures a stable tetrahedral coordination of the catalytic zinc ion in concert with the three histidines of the HExxHxxGxxH metzincin signature motif, further stabilized by a hydrogen bond with the glutamate residue belonging to the same motif. The molecular decoration of the alloxan core with a biphenyl privileged structure allowed to sample the deep S(1)' specificity pocket of MMP-2 and to relate the high affinity towards this enzyme with the chance of forming a hydrogen bond network with the backbone of Leu116 and Asn147 and the side chains of Tyr144, Thr145 and Arg149 at the bottom of the pocket. The effect of even slight structural changes in determining the interaction at the S(1)' subsite of MMP-2 as well as the nature and strength of the binding is elucidated via molecular dynamics simulations and free energy calculations. Among the herein presented compounds, the highest affinity (pIC(50) = 7.06) is found for BAM, a compound exhibiting also selectivity (>20) towards MMP-2, as compared to MMP-9, the other member of the gelatinases.