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Abstract The seismic‐electromagnetic phenomenon entails the generation of transient electromagnetic signals, which can be observed both simultaneously (co‐seismic) and preceding (pre‐seismic) a seismic wave arrival. Following the most accredited hypothesis, these signals are mainly due to electrokinetic effects, generated on microscopic scale in porous media containing electrolytic fluids. Thus, the seismic‐electromagnetic signals are expected to be suitable for the detection and tracking of crustal fluids. Despite the growing interest in this phenomenon, there is a lack of freely available observational database of earthquake‐related electromagnetic signals recorded at co‐located seismic and magnetotelluric stations. To fill this gap, we set up two multicomponent monitoring stations in two seismically active areas of Southern Italy: the Gargano Promontory and the High Agri Valley. This work is both aimed to systematically analyse earthquake‐generated seismic‐electromagnetic recordings and to make the collected database accessible to the scientific community.

Targeted protein degradation with molecular glue degraders has arisen as a powerful therapeutic modality for eliminating classically undruggable disease-causing proteins through proteasome-mediated degradation. However, we currently lack rational chemical design principles for converting protein-targeting ligands into molecular glue degraders. To overcome this challenge, we sought to identify a transposable chemical handle that would convert protein-targeting ligands into molecular degraders of their corresponding targets. Using the CDK4/6 inhibitor ribociclib as a prototype, we identified a covalent handle that, when appended to the exit vector of ribociclib, induced the proteasome-mediated degradation of CDK4 in cancer cells. Further modification of our initial covalent scaffold led to an improved CDK4 degrader with the development of a but-2-ene-1,4-dione (fumarate) handle that showed improved interactions with RNF126. Subsequent chemoproteomic profiling revealed interactions of the CDK4 degrader and the optimized fumarate handle with RNF126 as well as additional RING-family E3 ligases. We then transplanted this covalent handle onto a diverse set of protein-targeting ligands to induce the degradation of BRD4, BCR-ABL and c-ABL, PDE5, AR and AR-V7, BTK, LRRK2, HDAC1/3, and SMARCA2/4. Our study undercovers a design strategy for converting protein-targeting ligands into covalent molecular glue degraders.

Targeted protein degradation has arisen as a powerful therapeutic modality for degrading disease targets. While proteolysis-targeting chimera (PROTAC) design is more modular, the discovery of molecular glue degraders has been more challenging. Here, we have coupled the phenotypic screening of a covalent ligand library with chemoproteomic approaches to rapidly discover a covalent molecular glue degrader and associated mechanisms. We have identified a cysteine-reactive covalent ligand EN450 that impairs leukemia cell viability in a NEDDylation and proteasome-dependent manner. Chemoproteomic profiling revealed covalent interaction of EN450 with an allosteric C111 in the E2 ubiquitin-conjugating enzyme UBE2D. Quantitative proteomic profiling revealed the degradation of the oncogenic transcription factor NFKB1 as a putative degradation target. Our study thus puts forth the discovery of a covalent molecular glue degrader that uniquely induced the proximity of an E2 with a transcription factor to induce its degradation in cancer cells.

A 65-year-old Caucasian male was referred to an endodontic specialist practice in a private clinic in December 2019 for the management of an asymptomatic, radiolucent lesion located at the cervical level of the distal root of his right lower first molar, noticed during a routine periapical radiograph. After an accurate evaluation with cone-beam computed tomography (CBCT), the subgingival lesion was diagnosed as a supracrestal external cervical resorption (ECR), with a circumferential spread ⩽90°, confined to dentine without pulp involvement. The lesion was treated with the following sequence: (1) a full flap accessed the ECR, (2) the granulomatous tissue was removed from the root area, (3) the cavity was refreshed and filled with a well-refined and polished resin composite, (4) the flap was sutured at the cemento-enamel junction. A mandibular CBCT scan was performed before treatment, right after treatment, and 3 years postoperatively. Compared to the 3-year posttreatment CBCT scan, the immediate posttreatment one, revealed the absence of bone loss and an unexpected coronal bone remodeling with new bone formation over the treated lesion.

Activity-based protein profiling (ABPP) is a versatile strategy for identifying and characterizing functional protein sites and compounds for therapeutic development. However, the vast majority of ABPP methods for covalent drug discovery target highly nucleophilic amino acids such as cysteine or lysine. Here, we report a methionine-directed ABPP platform using Redox-Activated Chemical Tagging (ReACT), which leverages a biomimetic oxidative ligation strategy for selective methionine modification. Application of ReACT to oncoprotein cyclin-dependent kinase 4 (CDK4) as a representative high-value drug target identified three new ligandable methionine sites. We then synthesized a methionine-targeting covalent ligand library bearing a diverse array of heterocyclic, heteroatom, and stereochemically rich substituents. ABPP screening of this focused library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric M169 site. This compound inhibited kinase activity in a dose-dependent manner on purified protein and in breast cancer cells. Further investigation of 1oxF11 found prominent cation-π and H-bonding interactions stabilizing the binding of this fragment at the M169 site. Quantitative mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast cancer cell lysates. Further biochemical analyses revealed cross-talk between M169 oxidation and T172 phosphorylation, where M169 oxidation prevented phosphorylation of the activating T172 site on CDK4 and blocked cell cycle progression. By identifying a new mechanism for allosteric methionine redox regulation on CDK4 and developing a unique modality for its therapeutic intervention, this work showcases a generalizable platform that provides a starting point for engaging in broader chemoproteomics and protein ligand discovery efforts to find and target previously undruggable methionine sites.

PURPOSE OF REVIEW: There is an important need for improved diagnostic strategies and treatment among patients with acute kidney injury (AKI). Classical randomized clinical trials have generated relevant results in AKI but are associated with shortcomings, such as high costs and sometimes lack of generalizability. In this minireview, we discuss the value and limits of pragmatic trials and platform trials for AKI research. RECENT FINDINGS: The implementation of pragmatic and platform trials in critical care settings has generated relevant clinical evidence impacting clinical practice. Pragmatic and platform designs have recently been applied to patients at risk of AKI and represent a crucial opportunity to advance our understanding of optimized treatment and strategies in patients at risk of AKI or presenting with AKI. Trials embedded in electronic health records can facilitate patient enrollment and data collection. Platform trials have allowed for a more efficient study design. Although both pragmatic and platform trials have several advantages, they also come with the challenges and shortcomings discussed in this review. SUMMARY: Pragmatic and platform trials can provide clinical answers in real-life settings, facilitate a significant sample size enrollment at a limited cost, and provide results that can have a faster implementation in clinical practice.

Abstract In this article, we consider the numerical prediction of the noise emission from a wheelset in laboratory conditions. We focus on the fluid–structure interaction leading to sound emission in the fluid domain by analyzing three different methods to account for acoustic sources. These are a discretized baffled piston using the discrete calculation method (DCM), a closed cylindrical volume using the boundary element method (BEM) and radiating elastic disks in a cubic enclosure solved with the finite element method (FEM). We provide the validation of the baffled piston and the BEM using measurements of the noise emission of a railway wheel by considering ground reflections in the numerical models. Selected space-resolved waveforms are compared with experimental results as well as with a fluid–structure interaction finite element model. The computational advantage of a discretized disk mounted on a baffle and BEM compared to FEM is highlighted, and the baffled pistons limitations caused by a lack of edge radiation effects are investigated.

Abstract Aspergillus fumigatus is a saprophytic fungus that can cause a variety of human diseases known as aspergillosis. Mycotoxin gliotoxin (GT) production is important for its virulence and must be tightly regulated to avoid excess production and toxicity to the fungus. GT self-protection by GliT oxidoreductase and GtmA methyltransferase activities is related to the subcellular localization of these enzymes and how GT can be sequestered from the cytoplasm to avoid increased cell damage. Here, we show that GliT:GFP and GtmA:GFP are localized in the cytoplasm and in vacuoles during GT production. The Mitogen-Activated Protein kinase MpkA is essential for GT production and self-protection, interacts physically with GliT and GtmA and it is necessary for their regulation and subsequent presence in the vacuoles. The sensor histidine kinase SlnASln1 is important for modulation of MpkA phosphorylation. Our work emphasizes the importance of MpkA and compartmentalization of cellular events for GT production and self-defense.

In this study, an upflow anaerobic packed-bed reactor (UAPB) produced biobutanol from the main byproduct of biodiesel plants, commonly known as glycerol. Currently, butanol production is mostly limited to pure cultures and sterilized feedstocks. Using glycerol wastes from biodiesel production demands a new paradigm because sterilization is not economically feasible for the elevated amount of glycerol generated by the biodiesel industry. Different microbial consortia were evaluated as inoculum sources to convert glycerol to butanol. In the first stage, operations were carried out with an average organic loading rate (OLR) of 13 g COD L−1 d−1. Kefir grains, sucrose auto-fermentation consortium, and heat-treated anaerobic sludge produced 16.7, 48.5, and 12.8 mg of butanol per gram of chemical oxygen demand (COD), respectively. Besides butanol production, a significant amount of ethanol (241.5 mg g−1 COD), acetate (30.3 mg g−1 COD), and butyrate (183.4 mg g−1 COD) were generated with glycerol processed by sucrose auto-fermentation consortium. In the second stage, the organic loading rates of 6.5, 13.0, and 26.0 g COD L−1 d−1 were applied to the UAPB reactor inoculated with sucrose auto-fermentation consortium. The OLR of 13.0 g COD L−1 d−1 yielded the highest production of butanol (41.5 mg g−1 COD) and generated other valuable co-products such as butyrate (246.1 mg g−1 COD), acetate (37.3 mg g−1 COD), and propionate (19.6 mg g−1 COD).

Many diseases are driven by proteins that are aberrantly ubiquitinated and degraded. These diseases would be therapeutically benefited by targeted protein stabilization (TPS). Here we present deubiquitinase-targeting chimeras (DUBTACs), heterobifunctional small molecules consisting of a deubiquitinase recruiter linked to a protein-targeting ligand, to stabilize the levels of specific proteins degraded in a ubiquitin-dependent manner. Using chemoproteomic approaches, we discovered the covalent ligand EN523 that targets a non-catalytic allosteric cysteine C23 in the K48-ubiquitin-specific deubiquitinase OTUB1. We showed that a DUBTAC consisting of our EN523 OTUB1 recruiter linked to lumacaftor, a drug used to treat cystic fibrosis that binds ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR), robustly stabilized ΔF508-CFTR protein levels, leading to improved chloride channel conductance in human cystic fibrosis bronchial epithelial cells. We also demonstrated stabilization of the tumor suppressor kinase WEE1 in hepatoma cells. Our study showcases covalent chemoproteomic approaches to develop new induced proximity-based therapeutic modalities and introduces the DUBTAC platform for TPS.

Photoaffinity labeling (PAL) is a powerful tool for the identification of non-covalent small molecule-protein interactions that are critical to drug discovery and medicinal chemistry, but this approach is limited to only a small subset of robust photocrosslinkers. The identification of new photoreactive motifs capable of covalent target capture is therefore highly desirable. Herein, we report the design, synthesis, and evaluation of a new class of PAL warheads based on the UV-triggered 1,2-photo-Brook rearrangement of acyl silanes, which hitherto have not been explored for PAL workflows. Irradiation of a series of probes in cell lysate revealed an iPr-substituted acyl silane with superior photolabeling and minimal thermal background labeling compared to other substituted acyl silanes. Further, small molecule (+)-JQ1- and rapamycin-derived iPr acyl silanes were shown to selectively label recombinant BRD4-BD1 and FKBP12, respectively, with minimal background. Together, these data highlight the untapped potential of acyl silanes as a novel, tunable scaffold for photoaffinity labeling.

The aim of the present in vitro comparative study is to validate a novel composite polymer, named “ONLY”, developed to overcome the mechanical drawbacks of conventional, metal-reinforced poly(methyl methacrylate) (PMMA) interim restoration. Ten interim restorations were designed and fabricated (five in the composite “ONLY” group, and five in the metal-reinforced PMMA group). All the samples were screwed into the prototype models, simulating a complete edentulous mandible rehabilitated with six straight implants. Outcome measures were break point (load, N) and displacement (mm) through a static compression test, and material behavior through a dynamic cyclic test method (fatigue test). A total of 20 samples were tested (10 for static and 10 for dynamic). In each group, five samples (test and control) were used. All the specimens completed the mechanical tests, as planned. There was no statistically significant difference between groups for any test. In the test group, the break point was 1953.19 ± 543.73 N, while it was 2031.10 ± 716.68 N in the control group (p = 0.775). The displacement was 1.89 ± 0.34 mm in the test group and 1.98 ± 0.75 mm in the control group (p = 0.763). Using the dynamic cyclic test method, in the control group the mean load was 2504.60 ± 972.15 N, while in the test group the mean load was 3382.00 ± 578.50 N. The difference between groups was 877.40 ± 579.30 N (p value = 0.121). Within the limitations of this in vitro study, the novel composite polymer can be used to immediately load dental implants. Further clinical research is needed to confirm these preliminary results.

This report aims to clinically evaluate the feasibility of a novel biological-oriented digital impression method for teeth prepared with a vertical preparation technique. Something that makes this case unique is that the definitive impression is taken without cord displacement, reducing the invasiveness for the patient. In addition, dental technicians can reproduce the exact emergence profile of the temporary restoration used to reshape the soft tissue contours and define the accurate finish line at the established prosthetic junction, potentially avoiding the aesthetic and biological issues of the double-cord technique. The finish line and emergence profile are transferred using the temporary restoration through a simple CAD procedure performed using the same software used to take the impression. This makes the proposed biological-oriented digital impression technique (BODIT) easy to perform, avoiding adjunctive time and costs for clinicians and patients. Conclusions: Finally, patients' satisfaction could be significantly improved.

Mud volcanoes are fluid escape structures allowing for surface venting of hydrocarbons (mostly gas but also liquid condensates and oils) and water–sediment slurries. For a better understanding of mud volcano dynamics, the characterization of the fluid dynamics within mud volcano conduits; the presence, extent, and depth of the fluid reservoirs; and the connection among aquifers, conduits, and mud reservoirs play a key role. To this aim, we performed a geoelectrical survey in the Nirano Salse Regional Nature Reserve, located at the edge of the northern Apennines (Fiorano Modenese, Italy), an area characterized by several active mud fluid vents. This study, for the first time, images the resistivity structure of the subsoil along two perpendicular cross sections down to a depth of 250 m. The electrical models show a clear difference between the northern and southern sectors of the area, where the latter hosts the main discontinuities. Shallow reservoirs, where fluid muds accumulate, are spatially associated with the main fault/fracture controlling the migration routes associated with surface venting and converge at depth towards a common clayey horizon. There is no evidence of a shallow mud caldera below the Nirano area. These findings represent a step forward in the comprehension of the Nirano Salse plumbing system and in pinpointing local site hazards, which promotes safer tourist access to the area along restricted routes.

The translation of functionally active natural products into fully synthetic small-molecule mimetics has remained an important process in medicinal chemistry. We recently discovered that the terpene natural product nimbolide can be utilized as a covalent recruiter of the E3 ubiquitin ligase RNF114 for use in targeted protein degradation-a powerful therapeutic modality within modern-day drug discovery. Using activity-based protein profiling-enabled covalent ligand-screening approaches, here we report the discovery of fully synthetic RNF114-based recruiter molecules that can also be exploited for PROTAC applications, and demonstrate their utility in degrading therapeutically relevant targets, such as BRD4 and BCR-ABL, in cells. The identification of simple and easily manipulated drug-like scaffolds that can mimic the function of a complex natural product is beneficial in further expanding the toolbox of E3 ligase recruiters, an area of great importance in drug discovery and chemical biology.

MYC is a major oncogenic transcriptional driver of most human cancers that has remained intractable to direct targeting because much of MYC is intrinsically disordered. Here, we have performed a cysteine-reactive covalent ligand screen to identify compounds that could disrupt the binding of MYC to its DNA consensus sequence in vitro and also impair MYC transcriptional activity in situ in cells. We have identified a covalent ligand, EN4, that targets cysteine 171 of MYC within a predicted intrinsically disordered region of the protein. We show that EN4 directly targets MYC in cells, reduces MYC and MAX thermal stability, inhibits MYC transcriptional activity, downregulates multiple MYC transcriptional targets, and impairs tumorigenesis. We also show initial structure-activity relationships of EN4 and identify compounds that show improved potency. Overall, we identify a unique ligandable site within an intrinsically disordered region of MYC that leads to inhibition of MYC transcriptional activity.

This paper investigates the threshold voltage shift (ΔVTH) induced by positive bias temperature instability (PBTI) in silicon carbide (SiC) power MOSFETs. By analyzing ΔVTH under various gate stress voltages (VGstress) at 150 °C, distinct mechanisms are revealed: (i) trapping in the interface and/or border pre-existing defects and (ii) the creation of oxide defects and/or trapping in spatially deeper oxide states with an activation energy of ~80 meV. Notably, the adoption of different characterization methods highlights the distinct roles of these mechanisms. Moreover, the study demonstrates consistent behavior in permanent ΔVTH degradation across VGstress levels using a power law model. Overall, these findings deepen the understanding of PBTI in SiC MOSFETs, providing insights for reliability optimization.

Obstructive sleep apneas (OSAs) and central sleep apneas (CSAs) are the most common comorbidities in Heart Failure (HF) that are strongly associated with all-cause mortality. Several therapeutic approaches have been used to treat CSA and OSA, but none have been shown to significantly improve HF prognosis. Our study evaluated the effects of a 3-months treatment with sodium-glucose cotransporter type 2 inhibitor (SGLT2i) on polygraphic parameters in patients with sleep apnea (SA) and HF, across the spectrum of ejection fraction, not treated with continuous positive air pressure (CPAP). A group of 514 consecutive elderly outpatients with HF, type 2 diabetes mellitus (T2DM) and SA, eligible for treatment with SGLT2i, were included in the investigation before starting any CPAP therapy. The two groups were compared with the t-test and Mann–Whitney test for unpaired data when appropriate. Then, a simple logistic regression model was built using 50% reduction in AHI as the dependent variable and other variables as covariates. A multivariate stepwise logistic regression model was constructed using the variables that linked with the dependent variable to calculate the odds ratio (OR) for the independent predictors associated with the reduction of 50% in AHI. The treated group experienced significant improvements in polygraphic parameters between baseline values and follow-up with reduction in AHI (28.4 ± 12.9 e/h vs. 15.2 ± 6.5 e/h; p < 0.0001), ODI (15.4 ± 3.3 e/h vs. 11.1 ± 2.6 e/h; p < 0.0001), and TC90 (14.1 ± 4.2% vs. 8.2 ± 2.0%; p < 0.0001), while mean SpO2 improved (91. 3 ± 2.3 vs. 93.8 ± 2.5); p < 0.0001. These benefits were not seen in the untreated population. The use of SGLT2i in patients suffering from HF and mixed-type SA not on CPAP therapy significantly contributes to improving polygraphic parameters.

AbstractRates of adolescent pregnancy within sub-Saharan Africa are increasing. Adolescent mothers ages 10–19 years face a distinct set of risks to their own and their children’s health, compounded by many economic, social, and epidemiological challenges, such as living with HIV. In navigating this complex developmental period, many adolescent mothers face structural barriers impeding safe transitions to adulthood and motherhood. Drawing on existing literature and emerging data, we outline three normative, legal, and policy issues – violence and gender inequity, access to sexual and reproductive health services, and access to social and structural supports – which affect the health, wellbeing and development of adolescent mothers and their children. We also highlight emergent evidence about programming and policy changes that can better support adolescent mothers and their children. These key proposed responses include removing barriers to SRH and HIV service integration; ensuring implementation of return-to-school policies; and extending social protection systems to cater for adolescent mothers. Despite ongoing global crises and shifts in funding priorities, these normative, legal, and policy considerations remain critical to safeguard the health and wellbeing of adolescent mothers and their children.

Targeted protein degradation (TPD) has emerged as a powerful tool in drug discovery for the perturbation of protein levels using heterobifunctional small molecules. E3 ligase recruiters remain central to this process yet relatively few have been identified relative to the ~ 600 predicted human E3 ligases. While, initial recruiters have utilized non-covalent chemistry for protein binding, very recently covalent engagement to novel E3's has proven fruitful in TPD application. Herein we demonstrate efficient proteasome-mediated degradation of BRD4 by a bifunctional small molecule linking the KEAP1-Nrf2 activator bardoxolone to a BRD4 inhibitor JQ1.

Molecular glues are an intriguing therapeutic modality that harness small molecules to induce interactions between proteins that typically do not interact. However, such molecules are rare and have been discovered fortuitously, thus limiting their potential as a general strategy for therapeutic intervention. We postulated that natural products bearing one or more electrophilic sites may be an unexplored source of new molecular glues, potentially acting through multicovalent attachment. Using chemoproteomic platforms, we show that members of the manumycin family of polyketides, which bear multiple potentially reactive sites, target C374 of the putative E3 ligase UBR7 in breast cancer cells, and engage in molecular glue interactions with the neosubstrate tumor-suppressor TP53, leading to p53 transcriptional activation and cell death. Our results reveal an anticancer mechanism of this natural product family, and highlight the potential for combining chemoproteomics and multicovalent natural products for the discovery of new molecular glues.