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Abstract Collider-testable type I seesaw extensions of the Standard Model are generally protected by an approximate lepton number (LN) symmetry. Consequently, they predict pseudo-Dirac heavy neutral leptons (HNLs) composed of two nearly degenerate Majorana fields. The interference between the two mass eigenstates can induce heavy neutrino-antineutrino oscillations ( N N ¯ Os $$ N\overline{N}\textrm{Os} $$ ) leading to observable lepton number violation (LNV), even though the LN symmetry is approximately conserved. These N N ¯ Os $$ N\overline{N}\textrm{Os} $$ could be resolved in long-lived HNL searches at collider experiments, such as the proposed Future Circular e + e − Collider (FCC-ee) or Circular Electron Positron Collider (CEPC). However, during their Z-pole runs, the LN carried away by the light (anti)neutrinos produced alongside the HNLs prevents LNV from being observed directly. Nevertheless, N N ¯ Os $$ N\overline{N}\textrm{Os} $$ materialise as oscillating signatures in final state distributions. We discuss and compare a selection of such oscillating observables, and perform a Monte Carlo simulation to assess the parameter space in which N N ¯ Os $$ N\overline{N}\textrm{Os} $$ could be resolved.

Abstract The WNT6 ligand is a well-known activator of the WNT signaling pathway, considered a vital player in several important physiologic processes during embryonic development and maintaining homeostasis throughout life, regulating the proliferation and differentiation of multiple stem/progenitor cell types. More recently, as it is the case for many key molecular regulators of embryonic development, dysregulation of WNT6 has been implicated in cancer development and progression in multiple studies. In this review, we overview the most significant recent findings regarding WNT6 in the context of human malignancies, exploring its influence on multiple dimensions of tumor pathophysiology and highlighting the putative underlying WNT6-associated molecular mechanisms. We also discuss the potential clinical implications of WNT6 as a prognostic and therapeutic biomarker. This critical review highlights the emerging relevance of WNT6 in multiple human cancers, and its potential as a clinically-useful biomarker, addressing key unanswered questions that could lead to new opportunities in patient diagnosis, stratification, and the development of rationally-designed precision therapies.

Abstract A given dose of hypoxia causes a greater increase in pulmonary ventilation during physical exercise than during rest, representing an exercise‐induced potentiation of the acute hypoxic ventilatory response (HVR). This phenomenon occurs independently from hypoxic blood entering the contracting skeletal muscle circulation or metabolic byproducts leaving skeletal muscles, supporting the contention that neural mechanisms per se can mediate the HVR when humoral mechanisms are not at play. However, multiple neural mechanisms might be interacting intricately. First, we discuss the neural mechanisms involved in the ventilatory response to hypoxic exercise and their potential interactions. Current evidence does not support an interaction between the carotid chemoreflex and central command. In contrast, findings from some studies support synergistic interactions between the carotid chemoreflex and the muscle mechano‐ and metaboreflexes. Second, we propose hypotheses about potential mechanisms underlying neural interactions, including spatial and temporal summation of afferent signals into the medulla, short‐term potentiation and sympathetically induced activation of the carotid chemoreceptors. Lastly, we ponder how exercise‐induced potentiation of the HVR results in hyperventilation‐induced hypocapnia, which influences cerebral blood flow regulation, with multifaceted potential consequences, including deleterious (increased central fatigue and impaired cognitive performance), inert (unchanged exercise) and beneficial effects (protection against excessive cerebral perfusion).

Abstract Background Multiheme cytochromes c (MHC) provide prokaryotes with a broad metabolic versatility that contributes to their role in the biogeochemical cycling of the elements and in energy production in bioelectrochemical systems. However, MHC have only been isolated and studied in detail from a limited number of species. Among these, Desulfuromonadia spp. are particularly MHC-rich. To obtain a broad view of the diversity of MHC, we employed bioinformatic tools to study the cytochromome encoded in the genomes of the Desulfuromonadia class. Results We found that the distribution of the MHC families follows a different pattern between the two orders of the Desulfuromonadia class and that there is great diversity in the number of heme-binding motifs in MHC. However, the vast majority of MHC have up to 12 heme-binding motifs. MHC predicted to be extracellular are the least conserved and show high diversity, whereas inner membrane MHC are well conserved and show lower diversity. Although the most prevalent MHC have homologues already characterized, nearly half of the MHC families in the Desulforomonadia class have no known characterized homologues. AlphaFold2 was employed to predict their 3D structures. This provides an atlas of novel MHC, including examples with high beta-sheet content and nanowire MHC with unprecedented high numbers of putative heme cofactors per polypeptide. Conclusions This work illuminates for the first time the universe of experimentally uncharacterized cytochromes that are likely to contribute to the metabolic versatility and to the fitness of Desulfuromonadia in diverse environmental conditions and to drive biotechnological applications of these organisms.

Abstract Endothelin type B receptor (ETBR) plays a crucial role in regulating blood pressure and humoral homeostasis, making it an important therapeutic target for related diseases. ETBR activation by the endogenous peptide hormones endothelin (ET)−1–3 stimulates several signaling pathways, including Gs, Gi/o, Gq/11, G12/13, and β-arrestin. Although the conserved NPxxY motif in transmembrane helix 7 (TM7) is important during GPCR activation, ETBR possesses the lesser known NPxxL motif. In this study, we present the cryo-EM structure of the ETBR–Gi complex, complemented by MD simulations and functional studies. These investigations reveal an unusual movement of TM7 to the intracellular side during ETBR activation and the essential roles of the diverse NPxxL motif in stabilizing the active conformation of ETBR and organizing the assembly of the binding pocket for the α5 helix of Gi protein. These findings enhance our understanding of the interactions between GPCRs and G proteins, thereby advancing the development of therapeutic strategies.

Macroalgae are a natural oceanic resource of inexhaustible abundance for the biomass energy industry with growth rates that are three to four times greater than those of terrestrial plants. The objective of this study was to evaluate the sustainability of macroalgae as biomass for biorefining through two investigations. Firstly, the deposition of macroalgae was sampled through 28 collections on seven beaches in the city of Maceió, Brazil, over a two-year period using a zigzag sampling method, covering a deposition area of 135,000 m2. From this, it was estimated that daily collection would yield 5.03 t/ha of dry biomass. Secondly, the calorific values of macroalgal biomass energy and pellet compounds were calculated. The lower calorific value (8.82 MJ/kg) found from a compound of 13 species analyzed was similar to that of the main biomass used in Brazil to obtain energy, i.e., sugarcane bagasse, which has been evaluated as 8.91 MJ/kg. Macroalgal biomass in the form of condensed energy pellets was found to have a higher calorific value of 20.18 MJ/kg, i.e., 1.2% greater than the average for terrestrial biomass pellets. Based on the results obtained, it was observed that macroalgal biomass has the possibility of becoming a new renewable feedstock with potential for bioenergy. The estimates for the deposition of biomass show possibilities for producing biofuels from marine algal raw material, which provides scope for creating another sustainable alternative for global energy issues with a reduction in environmental problems.

Abstract Chitosans are promising biopolymers for diverse applications, with material properties and bioactivities depending i.a. on their pattern of acetylation (PA). Commercial chitosans are typically produced by heterogeneous deacetylation of chitin, but whether this process yields chitosans with a random or block-wise PA has been debated for decades. Using a combination of recently developed in vitro assays and in silico modeling surprisingly revealed that both hypotheses are wrong; instead, we found a more regular PA in heterogeneously deacetylated chitosans, with acetylated units overrepresented at every third position in the polymer chain. Compared to random-PA chitosans produced by homogeneous deacetylation of chitin or chemical N-acetylation of polyglucosamine, this regular PA increases the elicitation activity in plants, and generates different product profiles and distributions after enzymatic and chemical cleavage. A regular PA may be beneficial for some applications but detrimental for others, stressing the relevance of the production process for product development.

Cybercrime is growing rapidly, and it is increasingly important to use advanced tools to combat it and support investigations. One of the battlefronts is the forensic investigation of mobile devices to analyze their misuse and recover information. Mobile devices present numerous challenges, including a rapidly changing environment, increasing diversity, and integration with the cloud/IoT. Therefore, it is essential to have a secure and reliable toolbox that allows an investigator to thwart, discover, and solve all problems related to mobile forensics while deciphering investigations, whether criminal, civil, corporate, or other. In this work, we propose an original and innovative instantiation of a structure in a forensic toolbox for mobile devices, corresponding to a set of different applications, methods, and best practice information aimed at improving and perfecting the investigative process of a digital investigator. To ensure scientific support for the construction of the toolbox, the Design Science Research (DSR) methodology was applied, which seeks to create new and unique artifacts, drawing on the strength and knowledge of science and context. The toolbox will help the forensic investigator overcome some of the challenges related to mobile devices, namely the lack of guidance, documentation, knowledge, and the ability to keep up with the fast-paced environment that characterizes the mobile industry and market. Doi: 10.28991/ESJ-2024-08-03-011 Full Text: PDF

Abstract Objective The aim of this study was to assess the relative efficacy of medications used following severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection on self‐reported alterations in taste and/or smell function. Methods Seven hundred and fourteen persons with self‐reported postcoronavirus disease 2019 (post‐COVID‐19) chemosensory disorders were personally interviewed regarding specific medications they were administered following the acute phase of the disease. The dependent measure—self‐reported total recovery of chemosensory symptoms—was subjected to stepwise logistic regression. Independent predictors included demographic and clinical variables, in addition to specific medications used to mitigate disease symptoms (i.e., systemic corticosteroids, oseltamivir, vitamin C, ibuprofen, hydroxychloroquine, azithromycin, ivermectin, nitazoxanide, anticoagulants, and zinc). Results The median time between COVID‐19 symptom onset and the interviews was 81 days (interquartile range: 60–104). Of the 714 subjects, 249 (34.9%) reported total recovery of their chemosensory function; 437 (61.2%) had at least one treatment since the beginning of the disease. Women and those with more comorbidities had undergone more treatments. The recovery rates of the treated and nontreated groups did not differ significantly. Nonetheless, respondents who had used nitazoxanide tended to have a higher rate of self‐reported taste or smell recovery. Those who took oral zinc were less likely to improve. Conclusions No medication employed during the first months after SARS‐CoV‐2 infection had a clear positive effect on returning self‐reported smell or taste function to normal, although nitrazoxide trended in a positive direction. Oral zinc had a negative effect on the reported recovery of these senses.

Abstract The black rat (Rattus rattus) is a globally invasive species that has been widely introduced across Africa. Within its invasive range in West Africa, R. rattus may compete with the native rodent Mastomys natalensis, the primary reservoir host of Lassa virus, a zoonotic pathogen that kills thousands annually. Here, we use rodent trapping data from Sierra Leone and Guinea to show that R. rattus presence reduces M. natalensis density within the human dwellings where Lassa virus exposure is most likely to occur. Further, we integrate infection data from M. natalensis to demonstrate that Lassa virus zoonotic spillover risk is lower at sites with R. rattus. While non-native species can have numerous negative effects on ecosystems, our results suggest that R. rattus invasion has the indirect benefit of decreasing zoonotic spillover of an endemic pathogen, with important implications for invasive species control across West Africa.

Purpose: This is a case report of a 31-year-old male patient presenting progressive and markedly asymmetric keratoconus treated with sequential intracorneal ring segment (ICRS) implantation followed by accelerated corneal cross-linking (CXL). Observations: The follow-up after the last procedure revealed a thin, opacified cornea with an unexpected massive flattening of up to 20.3 D. The central flattening attributed to the individual effect of CXL (post-ICRS-implant vs. post-CXL) was 19.1 D. Conclusions and Importance: This original case reports how CXL followed by ICRS implant may result in an early and extreme corneal remodeling. Moreover, such an unusual combination of extreme corneal flattening, thinning, and opacification may imitate a clinical manifestation of central toxic keratopathy and suggests that eyes with ICRS implantation must be followed closely if CXL is performed sequentially after.

Summary:. Augmentation mastopexy has attracted the attention of numerous authors seeking to improve surgical outcomes and ensure breast implant stability. The utilization of the dual plane technique with a lateral sling, pioneered by Ono and Karner, has demonstrated effectiveness in providing long-term implant support. However, challenges arise in cases of anatomical variations, such as a short pectoralis major (PM) muscle or chest, necessitating alternative approaches like the composite sling. This study presents a technique designed to elongate and broaden the lateral sling to enhance implant support. The composite sling incorporates components from the abdominal part of the PM muscle, the aponeurotic/muscular part of the external oblique muscle, and the cranial part of the rectus abdominis. Procedures were performed on 29 patients using the composite sling technique from July 2022 to October 2023. The follow-up period ranged from 6 to 18 months (average of 11.89 months). The lateral sling approach was successfully extended to cases with a short PM muscle or chest, previously managed using the dual plane technique without inferolateral support. No increase in complications or implant displacements was observed compared with the original lateral sling approach. However, four reoperations addressed issues such as dog ears, scarring, and minor asymmetries. Consistent results were observed throughout the follow-up period, particularly in maintaining upper pole fullness and preventing lower pole ptosis. The composite sling approach provides a viable solution for cases where the original sling technique is impractical. Its implementation could broaden surgical options and optimize results, particularly in cases of unfavorable anatomy.

Summary: Background: Leishmaniases are neglected diseases transmitted by sand flies. They disproportionately affect vulnerable groups globally. Understanding the relationship between climate and disease transmission allows the development of relevant decision-support tools for public health policy and surveillance. The aim of this modelling study was to develop an indicator that tracks climatic suitability for Leishmania infantum transmission in Europe at the subnational level. Methods: Historical records of sand fly vectors, human leishmaniasis, bioclimatic indicators, and environmental variables were integrated in a machine learning framework (XGBoost) to predict suitability in two past periods (2001–2010 and 2011–2020). We further assessed if predictions were associated with human and animal disease data from selected countries (France, Greece, Italy, Portugal, and Spain). Findings: An increase in the number of climatically suitable regions for leishmaniasis was detected, especially in southern and eastern countries, coupled with a northward expansion towards central Europe. The final model had excellent predictive ability (AUC = 0.970 [0.947–0.993]), and the suitability predictions were positively associated with human leishmaniasis incidence and canine seroprevalence for Leishmania. Interpretation: This study demonstrates how key epidemiological data can be combined with open-source climatic and environmental information to develop an indicator that effectively tracks spatiotemporal changes in climatic suitability and disease risk. The positive association between the model predictions and human disease incidence demonstrates that this indicator could help target leishmaniasis surveillance to transmission hotspots. Funding: European Union Horizon Europe Research and Innovation Programme (European Climate-Health Cluster), United Kingdom Research and Innovation.

Abstract The present study modeled the adsorption process of the drug diclofenac sodium on activated charcoal. For this purpose, a mass balance-based model was used considering a fixed bed column. The mass transfer rate in the solid phase was represented by a driving force model proposed in this study, and a gamma exponent with a range of 0 > γ ≤ 2 was assigned to the model. Different isotherms were adopted to represent the equilibrium at the solid/liquid interface: the Langmuir, Freundlich, Sips and Redlich-Peterson isotherms. The modeling was approached from the perspective of Bayesian statistics, and the Markov chain Monte Carlo method was used for parameter estimation. Model validation was performed with experimental data obtained under different operating conditions of initial concentration ($C_{0

Nasal fracture is the most common type of facial fracture in modern populations and is usually related to interpersonal violence. Nevertheless, this type of injury has been scarcely studied in bioanthropological field. In this study, it was characterized and discussed the oldest known Southern Patagonia individual presenting nasal fracture, among other lesions, most probably resulting from interpersonal violence. We reanalysed the individual 2 from Orejas de Burro 1 site dated from Late Holocene, the nasal fossae and other skull bones to study nasal fractures using a recent method developed by Magalhães et al. (2020). Orejas de Burro 1 -2- presented nine fractures, four of them in the nasal area and showing different timing: one postmortem, two perimortem, and one antemortem. The other facial lesions consisted of four diastatic fractures and one in the fragile septum. The individual presented a high-energy injury resulting in intense bone disruption and displacement of nasal and facial bones produced by a lateral blow, which may be related to an episode of interpersonal violence. While some likely options are regionally known, it is highly difficult to assess the cause of the injury and the blunt object associated with this episode since there is a situation of equifinality. This is the oldest known record case reported of a nasal fracture in Southern Patagonia and one of the oldest of South America. Also, it is the early evidence of traumatic injury, possibly due to an episode of interpersonal violence.

Abstract The thorough characterization of chitosan-cleaving enzymes is crucial to unveil structure–function relationships of this promising class of biomolecules for both, enzymatic fingerprinting analyses and to use the enzymes as biotechnological tools to produce tailor-made chitosans for diverse applications. Analyzing polymeric substrates as well as oligomeric products has been established as an effective way to understand the actions of enzymes, but it currently requires separate, rather laborious methods to obtain the full picture. Here, we present ultra high performance size exclusion chromatography coupled to refractive index and mass spectrometry detection (UHPSEC-RI-MS) as a straightforward method for the semi-quantitative analysis of chitosan oligomers of up to ten monomers in length. Additionally, the method allows to determine the average molecular weight of the remaining polymers and its distribution. By sampling live from an ongoing enzymatic reaction, UHPSEC-RI-MS offers the unique opportunity to analyze polymers and oligomers simultaneously—i.e., to monitor the molecular weight reduction of the polymeric substrate over the course of the digestion, while at the same time analyzing the emerging oligomeric products in a semi-quantitative manner. In this way, a single simple analysis yields detailed insights into an enzyme’s action on a given substrate.

Abstract The mesophilic purple sulfur phototrophic bacterium Allochromatium (Alc.) vinosum (bacterial family Chromatiaceae) has been a favored model for studies of bacterial photosynthesis and sulfur metabolism, and its core light-harvesting (LH1) complex has been a focus of numerous studies of photosynthetic light reactions. However, despite intense efforts, no high-resolution structure and thorough biochemical analysis of the Alc. vinosum LH1 complex have been reported. Here we present cryo-EM structures of the Alc. vinosum LH1 complex associated with reaction center (RC) at 2.24 Å resolution. The overall structure of the Alc. vinosum LH1 resembles that of its moderately thermophilic relative Alc. tepidum in that it contains multiple pigment-binding α- and β-polypeptides. Unexpectedly, however, six Ca ions were identified in the Alc. vinosum LH1 bound to certain α1/β1- or α1/β3-polypeptides through a different Ca2+-binding motif from that seen in Alc. tepidum and other Chromatiaceae that contain Ca2+-bound LH1 complexes. Two water molecules were identified as additional Ca2+-coordinating ligands. Based on these results, we reexamined biochemical and spectroscopic properties of the Alc. vinosum LH1–RC. While modest but distinct effects of Ca2+ were detected in the absorption spectrum of the Alc. vinosum LH1 complex, a marked decrease in thermostability of its LH1–RC complex was observed upon removal of Ca2+. The presence of Ca2+ in the photocomplex of Alc. vinosum suggests that Ca2+-binding to LH1 complexes may be a common adaptation in species of Chromatiaceae for conferring spectral and thermal flexibility on this key component of their photosynthetic machinery.

Abstract Huntington's disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the HTT gene. In addition to germline CAG expansions, somatic repeat expansions in neurons also contribute to HD pathogenesis. The DNA mismatch repair gene, MSH3, identified as a genetic modifier of HD onset and progression, promotes somatic CAG expansions, and thus presents a potential therapeutic target. However, what extent of MSH3 protein reduction is needed to attenuate somatic CAG expansions and elicit therapeutic benefits in HD disease models is less clear. In our study, we employed potent di-siRNAs to silence mouse Msh3 mRNA expression in a dose-dependent manner in HdhQ111/+ mice and correlated somatic Htt CAG instability with MSH3 protein levels from simultaneously isolated DNA and protein after siRNA treatment. Our results reveal a linear correlation with a proportionality constant of ~ 1 between the prevention of somatic Htt CAG expansions and MSH3 protein expression in vivo, supporting MSH3 as a rate-limiting step in somatic expansions. Intriguingly, despite a 75% reduction in MSH3 protein levels, striatal nuclear HTT aggregates remained unchanged. We also note that evidence for nuclear Msh3 mRNA that is inaccessible to RNA interference was found, and that MSH6 protein in the striatum was upregulated following MSH3 knockdown in HdhQ111/+ mice. These results provide important clues to address critical questions for the development of therapeutic molecules targeting MSH3 as a potential therapeutic target for HD.

Wireless communications with greater transmission capacities are possible in the millimeter wave (mmWave) region. However, to overcome the significant propagation losses in this frequency band, it is necessary to employ more efficient and intelligent antennas based on MIMO and beam-steering phased array technologies. This paper demonstrates the fabrication of a beam steerable array antenna using a $4\times 4$ Butler matrix at 60 GHz employing the metallic nanowire membrane (MnM) substrate. This substrate has the advantage of interconnecting two metallization layers by vias fabricated through its nanopores. Experimental characterization of the fabricated samples shows that the MnM platform represents a high-potential candidate for millimeter-wave front-ends supporting the beam-steering technique.

Sorafenib is a multikinase inhibitor indicated for first-line treatment of unresectable hepatocellular carcinoma. Despite its widespread use in the clinic, the existing knowledge of sorafenib mode-of-action remains incomplete. To build upon the current understanding, we used the Cellular Thermal Shift Assay (CETSA) coupled to Mass Spectrometry (CETSA-MS) to monitor compound binding to its target proteins in the cellular context on a proteome-wide scale. Among the potential sorafenib targets, we identified aldehyde dehydrogenase 2 (ALDH2), an enzyme that plays a major role in alcohol metabolism. We validated the interaction of sorafenib with ALDH2 by orthogonal methods using pure recombinant protein, proving that this interaction is not mediated by other cellular components. Moreover, we showed that sorafenib inhibits ALDH2 activity, supporting a functional role for this interaction. Finally, we were able to demonstrate that both ALDH2 protein expression and activity were reduced in sorafenib-resistant cells compared to the parental cell line. Overall, our study allowed the identification of ALDH2 as a novel sorafenib target and sheds light on its potential role in both hepatocellular carcinoma and sorafenib resistance condition.

The article aims to address the use of the theoretical-methodological teaching strategy, Problematized Experimental Activity (PEA), to introduce a method employed in chemometrics, called Principal Component Analysis, through digital images linked to a smartphone app (REDGIM®). The application of a didactic workshop occurred in the pandemic context of SARS-CoV2, in remote teaching, with students of the undergraduate course in Chemistry of a public University of Espírito Santo. The students were divided into two groups and developed solutions to a proposed problem, working with the themes: differentiation of false and true banknotes, and recognition of patterns in vegetable oils. The groups presented promising results in terms of learning in the development of their experimental methodologies and were able to have contact with analysis of chemical problems that are still little explored in the undergraduate course.

ABSTRACT For decades, cells of the Gram-positive bacterial pathogen Staphylococcus aureus were thought to lack a dedicated elongation machinery. However, S. aureus cells were recently shown to elongate before division, in a process that requires a shape elongation division and sporulation (SEDS)/penicillin-binding protein (PBP) pair for peptidoglycan synthesis, consisting of the glycosyltransferase RodA and the transpeptidase PBP3. In ovococci and rod-shaped bacteria, the elongation machinery, or elongasome, is composed of various proteins besides a dedicated SEDS/PBP pair. To identify proteins required for S. aureus elongation, we screened the Nebraska Transposon Mutant Library, which contains transposon mutants in virtually all non-essential staphylococcal genes, for mutants with modified cell shape. We confirmed the roles of RodA/PBP3 in S. aureus elongation and identified GpsB, SsaA, and RodZ as additional proteins involved in this process. The gpsB mutant showed the strongest phenotype, mediated by the partial delocalization from the division septum of PBP2 and PBP4, two penicillin-binding proteins that synthesize and cross-link peptidoglycan. Increased levels of these PBPs at the cell periphery versus the septum result in higher levels of peptidoglycan insertion/crosslinking throughout the entire cell, possibly overriding the RodA/PBP3-mediated peptidoglycan synthesis at the outer edge of the septum and/or increasing stiffness of the peripheral wall, impairing elongation. Consequently, in the absence of GpsB, S. aureus cells become more spherical. We propose that GpsB has a role in the spatio-temporal regulation of PBP2 and PBP4 at the septum versus cell periphery, contributing to the maintenance of the correct cell morphology in S. aureus.IMPORTANCEStaphylococcus aureus is a Gram-positive clinical pathogen, which is currently the second cause of death by antibiotic-resistant infections worldwide. For decades, S. aureus cells were thought to be spherical and lack the ability to undergo elongation. However, super-resolution microscopy techniques allowed us to observe the minor morphological changes that occur during the cell cycle of this pathogen, including cell elongation. S. aureus elongation is not required for normal growth in laboratory conditions. However, it seems to be essential in the context of some infections, such as osteomyelitis, during which S. aureus cells apparently elongate to invade small channels in the bones. In this work, we uncovered new determinants required for S. aureus cell elongation. In particular, we show that GpsB has an important role in the spatio-temporal regulation of PBP2 and PBP4, two proteins involved in peptidoglycan synthesis, contributing to the maintenance of the correct cell morphology in S. aureus.

Abstract We discuss the impact of heavy neutrino-antineutrino oscillations ( N N ¯ Os $$ \textrm{N}\overline{\textrm{N}}\textrm{Os} $$ ) on heavy neutral lepton (HNL) searches at proposed electron-positron colliders such as the future circular e + e − collider (FCC-ee). During the Z pole run, HNLs can be produced alongside a light neutrino or antineutrino that escapes detection and can decay into a charged lepton or antilepton together with an off-shell W boson. In this case, signals of lepton number violation (LNV) only show up in the final state distributions. We discuss how N N ¯ Os $$ \textrm{N}\overline{\textrm{N}}\textrm{Os} $$ , a typical feature of collider-testable low-scale seesaw models where the heavy neutrinos form pseudo-Dirac pairs, modify such final state distributions. For example, the forward-backward asymmetry (FBA) of the reconstructed heavy (anti)neutrinos develops an oscillatory dependence on the HNL lifetime. We show that these oscillations can be resolvable for long-lived HNLs. We also discuss that when the N N ¯ Os $$ \textrm{N}\overline{\textrm{N}}\textrm{Os} $$ are not resolvable, they can nevertheless significantly modify the theory predictions for FBAs and observables such as the ratio of the total number of HNL decays into ℓ − over ones into ℓ +, in an interval of the angle θ between the HNL and the beam axis. Our results show that N N ¯ Os $$ \textrm{N}\overline{\textrm{N}}\textrm{Os} $$ should be included in collider simulations of HNLs at the FCC-ee.

The by-products of the wine industry represent a global production of 10.5 to 13.1 million tons of wine pomace annually. This study examines the chemical composition and energy potential of wine pomace and distillation stillage, evaluating their suitability for pellet production within ENplus® standards. Proximate analysis, elemental analysis, and calorimetric analysis were conducted on samples of the two by-products collected in a local Distillery in Portugal. The results reveal that wine pomace has a higher volatile matter content (62.695%) than distillation stillage, which, however, has lower ash content (3.762%) and higher fixed carbon (31.813%). Calorimetric analyses show that distillation stillage has a superior low heating value compared to wine pomace, with values exceeding 19 MJ/kg. Both by-products, however, exceed ENplus® limits for ash (≤0.70), nitrogen (≤0.3), and sulfur (≤0.04) content, presenting challenges for use as high-quality fuel pellets. Combining these biomasses with other materials could reduce the pollutant content of the pellet and improve efficiency. This study highlights the need for pre-treatment strategies to lower ash content and enhance combustion. Policy support for sustainable practices is essential to optimize the use of wine pomace and distillation stillage as renewable energy sources.

This study presents the dielectric properties of a barium titanate–gadolinium ferrite composite material, obtained through a solid-state reaction method. The aim of this research was to create a composite material with enhanced dielectric properties compared to each individual component, and to investigate the electrical properties of the composites, using impedance spectroscopy. The structural and morphologic properties were analyzed using X-ray diffraction and scanning electron microscopy, respectively. Impedance spectroscopy measurements were performed over a wide frequency range (100–0.1 GHz) and temperature (45–170 °C) to evaluate the electrical behavior of the material. The dielectric relaxations were analyzed using the Havriliak–Negami function, and the key electrical parameters such as relaxation frequency, dielectric strength, and electrical conductivity were extracted. Several relaxation processes were identified, which depend on the mixture of the initial titanate and ferrite materials, and a correlation between structural, morphologic, and electrical properties was exposed. The sample with the highest dielectric constant was the 25 wt% gadolinium ferrite composite, with ε′ close to 240 and loss tangent values below 0.1, affording it the more appropriate composition for energy storage devices such as lead-free dielectric capacitors.

The study of the perceived affective qualities (PAQs) in soundscape assessments have increased in recent years, with methods varying from in-situ to laboratory. Through technological advances, virtual reality (VR) has facilitated evaluations of multiple locations in the same experiment. In this paper, VR reproductions of different urban sites were presented in an online and laboratory environment testing three locations in Greater Manchester ('Park', 'Plaza', and pedestrian 'Street') in two population densities (empty and busy) using ISO/TS 12913-2 (2018) soundscape PAQs. The studied areas had audio and video recordings prepared for 360 video and binaural audio VR reproductions. The aims were to observe population density effects within locations (Wilcoxon test) and variations between locations (Mann-Whitney U test) within methods. Population density and comparisons among locations demonstrated a significant effect on most PAQs. Results also suggested that big cities can present homogenous sounds, composing a 'blended' urban soundscape, independently of functionality. These findings can support urban design in a low-cost approach, where urban planners can test different scenarios and interventions.

Wildlife trafficking creates favorable scenarios for intra- and inter-specific interactions that can lead to parasite spread and disease emergence. Among the fauna affected by this activity, primates are relevant due to their potential to acquire and share zoonoses - infections caused by parasites that can spread between humans and other animals. Though it is known that most primate parasites can affect multiple hosts and that many are zoonotic, comparative studies across different contexts for animal-human interactions are scarce. We conducted a multi-parasite screening targeting the detection of zoonotic infections in wild-caught monkeys in nine Peruvian cities across three contexts: captivity (zoos and rescue centers, n = 187); pet (households, n = 69); and trade (trafficked or recently confiscated, n = 132). We detected 32 parasite taxa including mycobacteria, simian foamyvirus, bacteria, helminths, and protozoa. Monkeys in the trade context had the highest prevalence of hemoparasites (including Plasmodium malariae/brasilianum, Trypanosoma cruzi, and microfilaria) and enteric helminths and protozoa were less common in pet monkeys. However, parasite communities showed overall low variation between the three contexts. Parasite richness (PR) was best explained by host genus and the city where the animal was sampled. Squirrel (genus Saimiri) and wooly (genus Lagothrix) monkeys had the highest PR, which was ~2.2 times the PR found in tufted capuchins (genus Sapajus) and tamarins (genus Saguinus/Leontocebus) in a multivariable model adjusted for context, sex, and age. Our findings illustrate that the threats of wildlife trafficking to One Health encompass exposure to multiple zoonotic parasites well-known to cause disease in humans, monkeys, and other species. We demonstrate these threats continue beyond the markets where wildlife is initially sold; monkeys trafficked for the pet market remain a reservoir for and contribute to the translocation of zoonotic parasites to households and other captive facilities where contact with humans is frequent. Our results have practical applications for the healthcare of rescued monkeys and call for urgent action against wildlife trafficking and ownership of monkeys as pets.

Background:. Augmentation mastopexy remains a challenging surgery and has been frequently associated with suboptimal outcomes and remarkable reoperation rates, and one of the greatest challenges in mastopexy surgery is areolar lift, especially when implants are simultaneously used. Through the authors’ experience, this study is aimed to show a modification of the vertical approach with greater safety of the areolar pedicle. Methods:. The study included all patients who underwent augmentation mastopexy surgery performed by the authors between 2019 and 2022, whether primary or nonprimary, and performed a retrospective chart review of all patients who underwent this procedure. Results:. The length of the areolar lift ranged from 0 cm to 14 cm. Among the 17.4% of nonprimary mastopexies, the longest areolar lift was 11 cm. No cases of nipple–areola complex ischemia/necrosis were observed. With this technique, there were 6.2% complications (n = 31), none of which were considered serious. Conclusions:. This surgical sequence is a safe option for areolar lift in augmentation mastopexy. The vertical approach also has the advantage of producing considerably shorter horizontal scars. It is also reproducible, keeping the implant stable, which results in consistent long-term results.

Abstract Introduction Sexual violence is one of the most severe traumatic events. It is associated with a higher risk for post-traumatic stress disorder (PTSD) development. Sleep disturbances such as insomnia are frequently reported by PTSD patients and play a key role in the development and course of the disorder. Sleep disturbances are associated with higher levels of pro-inflammatory cytokines emphasizing the importance of sleep studies in individuals with PTSD. Objectives To investigate the association between subjective and objective sleep measurements and PTSD symptoms with inflammatory markers in women with PTSD following sexual assault. Methods In this longitudinal study fifty-seven women with PTSD were evaluated for sleep measurements and inflammatory markers. Participants completed the Clinician-Administered PTSD Scale, the Beck Depression Inventory, the Pittsburgh Sleep Quality Index (PSQI), and the Insomnia Severity Index. In addition, patients underwent full in-lab polysomnography and serum levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) measurement. All assessments were performed at baseline and after one year. Patients received pharmacological and/or psychological interventions between baseline and one-year follow-up. Results Despite improving PTSD symptoms severity and sleep quality (expressed in PSQI), we found an increase in the inflammatory markers IL-1β, TNF-α, IL-6 and CRP after one year of follow-up. These findings suggest that neurobiological processes may advance independently of PTSD symptoms. We found a significant increase in the levels of IL-1β and TNF-α associated with decreased slow-wave sleep (p = 0.019 and p = 0.018 respectively), IL-6 associated with arousal index (p = 0.024), and CRP associated with insomnia severity (p = 0.012), and sleep duration longer than 6 h per night (p

DNA data storage based on synthetic oligonucleotides is a major attraction due to the possibility of storage over long periods. Nowadays, the quantity of data generated has been growing exponentially, and the storage capacity needs to keep pace with the growth caused by new technologies and globalization. Since DNA can hold a large amount of information with a high density and remains stable for hundreds of years, this technology offers a solution for current long-term data centers by reducing energy consumption and physical storage space. Currently, research institutes, technology companies, and universities are making significant efforts to meet the growing need for data storage. DNA data storage is a promising field, especially with the advancement of sequencing techniques and equipment, which now make it possible to read genomes (i.e., to retrieve the information) and process this data easily. To overcome the challenges associated with developing new technologies for DNA data storage, a message encoding and decoding exercise was conducted at a Brazilian research center. The exercise performed consisted of synthesizing oligonucleotides by the phosphoramidite route. An encoded message, using a coding scheme that adheres to DNA sequence constraints, was synthesized. After synthesis, the oligonucleotide was sequenced and decoded, and the information was fully recovered.

Leptospira interrogans disseminates hematogenously to reach the target organs by disrupting epithelial adherens junctions (AJs), thus causing leptospirosis, which is a globally neglected zoonotic disease. L. interrogans induces E-cadherin (E-cad) endocytosis and cytoskeletal rearrangement during AJ disassembly, but the detailed mechanism remains unknown. Elucidation of AJ disassembly mechanisms will guide new approaches to developing vaccines and diagnostic methods. In this study, we combine proteomic and imaging analysis with chemical inhibition studies to demonstrate that disrupting the AJs of renal proximal tubule epithelial cells involves the degradation of two armadillo repeat-containing proteins, p0071 and p120-catenin, that stabilize E-cad at the plasma membrane. Combining proteasomal and lysosomal inhibitors substantially prevented p120-catenin degradation, and monolayer integrity destruction without preventing p0071 proteolysis. In contrast, the pan-caspase inhibitor Z-VAD-FMK inhibited p0071 proteolysis and displacement of both armadillo repeat-containing proteins from the cell-cell junctions. Our results show that L. interrogans induces p120-catenin and p0071 degradation, which mutually regulates E-cad stability by co-opting multiple cellular degradation pathways. This strategy may allow L. interrogans to disassemble AJs and disseminate through the body efficiently.

Rhodobacter capsulatus is a favored model organism for studying bacterial photosynthesis. Here the authors present a structure of its light-harvesting–reaction center complex, which reveals that it forms a crescent shape containing only 10 LH1 αβ-subunits.

It is imperative that decision-makers recognize when the intensity of human interference in regard to forest losses may result in adverse conditions for water ecosystem services. Several studies have indicated that defining thresholds is appropriate for indicating the ideal relationship between natural ecosystems and land uses in such a way as to ensure ecosystem service supply, but this knowledge is not readily available for different water services. To predict tipping points of change in the availability of seven water-related services, we assessed 11 catchments with different proportions of natural forests (Brazilian cerradão) and eucalyptus plantations. We analyzed water samples for 13 physical–chemical–biological parameters, which by specific aggregation functions define indices for each water service. We applied the piecewise model to evaluate the relationships between water service indices and natural forest cover. The results indicated that the highest potential gains occurred above 45% of forest. Landscapes with less than 20% natural forests tended to become unsustainable in maintaining services. Erosion control had a higher correlation with the decrease in natural forests.

Abstract Shale gas has become one of the important contributors to the global energy supply. The declining pattern of the gas production rate with time from an unconventional gas reservoir is due to the depletion of shale gas stored in the nanovoids of the shale formation. However, there are only limited ways to predict the variation of the gas production rate with time from an unconventional gas reservoir. This is due to the multiple transport mechanisms of gas in nano-scale pores and changes in shale gas permeability with pressures in nano-scale pores, which is impacted by the pore structure of the shale. In this study, the permeability-pressure (K-p) relationship for different shales (Eagle Ford, Haynesville, Longmaxi and Opalinus) were determined using an equivalent anisotropic pore network model (PNM). This PNM has REV-scale shale gas flow in randomly generated nanovoids and their connection in the shale matrix, and the multiphase flow of shale gas including viscous flow, slip flow and Knudsen diffusion. These predicted K-p correlations were then used in a finite element model (FEM) to predict the variation of the gas production rate with time (flux-time curves) at the macroscale. The simulation results show that the flux-time curves can be simplified to two linear segments in logarithmic coordinates, which are influenced by the fracture length and initial gas pressure. The predicted results using the PNM-FEM were validated by comparing them with the reported field test data. The method described in this study can be used to upscale the gas transport process from micro- to macroscale, which can provide a predictive tool for the gas production in shales.

Abstract In this large cohort of healthcare workers, we aimed to estimate the rate of reinfections by SARS-CoV-2 over 2 years of the COVID-19 pandemic. We investigated the proportion of reinfections among all the cases of SARS-CoV-2 infection from March 10, 2020 until March 10, 2022. Reinfection was defined as the appearance of new symptoms that on medical evaluation were suggestive of COVID-19 and confirmed by a positive RT-PCR. Symptoms had to occur more than 90 days after the previous infection. These 2 years were divided into time periods based on the different variants of concern (VOC) in the city of São Paulo. There were 37,729 medical consultations due to COVID-19 at the hospital’s Health Workers Services; and 25,750 RT-PCR assays were performed, of which 23% (n = 5865) were positive. Reinfection by SARS-CoV-2 was identified in 5% (n = 284) of symptomatic cases. Most cases of reinfection occurred during the Omicron period (n = 251; 88%), representing a significant increase on the SARS-CoV-2 reinfection rate before and during the Omicron variant period (0.8% vs. 4.3%; p

Abstract Background The relationship between indices of mechanical ventilation and pulmonary artery pressures remains ill-defined in ARDS. As our understanding of mechanical ventilation has progressed, there is now a greater appreciation of the impact of high driving pressures and mechanical power in perpetuating lung injury. However, the relationship between the newer derived indices of mechanical ventilation and pulmonary artery pressure is unclear. We performed a post hoc analysis of the Fluid and Catheters Treatment Trial (FACTT) trial to investigate the associations between mechanical ventilation indices in ARDS patients and the prevalence of pulmonary hypertension. This may help elucidate future clinical targets for more, right ventricular protective, mechanical ventilation strategies. Methods We performed a post hoc analysis of the FACTT database to identify ARDS patients who had a pulmonary artery catheter (PAC) inserted and pulmonary artery pressure readings recorded. We excluded any patient with a PAC inserted who was spontaneously breathing, as driving pressure and mechanical power are not validated in this cohort. Three independent analyses were performed: a univariate analysis, to assess for associations between mPAP and mechanical ventilation parameters using Pearson correlation coefficients, a multivariate analysis, to assess for independent associations with mPAP using a multiple regression model according to Akaike’s information criteria and finally an analysis for nonlinearity, using the best-fitting model according to the Bayesian information criterion (BIC) from linear, quadratic, fractional polynomial and restricted cubic spline models. Results All the ventilation parameters demonstrated a significant correlation with mPAP, except tidal volume (once adjusted for respiratory rate) in the univariate analysis. The multivariate analysis demonstrated that the blood pH level, P/F ratio, PaCO2 level, mean airway pressure and the mechanical power indexed to compliance were independently associated with mPAP. In the final nonlinear analysis, associations did not differ from linearity except for 4 variables for which the fractional polynomial was the best-fitting model. These were mechanical power (p = 0.01 compared to the linear model), respiratory rate (p = 0.04), peak pressure (p = 0.03) and mean airway pressure (p = 0.01). Two nonlinear variables associated with mPAP were assessed in more detail, respiratory rate and mechanical power. Inflexion points at a respiratory rate of 16.8 cycles per minute and a mechanical power of 8.8 J/min were demonstrated. Conclusions The associations identified between mPAP and mechanical ventilation variables in this analysis would suggest that classical ARDS lung protective strategies, including low tidal volume ventilation and permissive hypercapnia, may negatively impact the management of the subset of ARDS patients with associated right ventricular dysfunction or ACP. Additionally, respiratory rates above 17 cycles per minute show an incremental increase in mPAP. Therefore, increases in tidal volume (within the limitation of driving pressure

The rising energetical needs of modern society have been increasingly pushing for the improvement in energy efficiency. Thin-film solar cell technology encompasses several types of devices whose purpose is to gather energy emitted from a luminous source and convert it into usable electrical energy for a variety of applications, particularly low-powered devices. Micro concentrator solar cells are promising devices to solve the materials availability problem and address the power conversion efficiency simultaneously. Since the energy conversion efficiency for this type of solar cell is not particularly high, it stands out to benefit greatly from using an optical concentrator element to increase the light intensity reaching the active surface. The micro-concentrator element is comprised of a micro-lens array, which can be manufactured by different technologies, such as polymer injection moulding, extrusion, or hot embossing. In this work, we explore how hot embossing can be used to inexpensively produce spherical lenses with Ø 1 mm in an array according to micro concentrator solar cell requirements. A simple compression system coupled with an infrared lamp heat chamber was used to emboss PMMA disks. Different mould insert manufacturing technologies were used and different hot embossing parameters were assessed. The process replicability of the micro-lens cavities was determined by infinite focus microscopy and optical microscopy. The most promising lens array was achieved with a mould insert produced by μ-EDM (with Ra and Rz values of 0.6 μm and 4.58 μm, respectively).

Degree of polymerisation, fraction and pattern of acetylation change the material and biological properties of chitosan. Here, the authors show that enzymes can N-acetylate fully deacetylated chitosan to replicate the natural control over acetylation pattern not found in chemically produced chitosan allowing more control over properties.

The cryo-EM structure of the unusual light-harvesting 1–reaction center (LH1–RC) complex from Rpi. globiformis, the most acidophilic anaerobic purple bacteria, is presented, characterized and compared to other photosynthetic bacteria.

Chemically modified siRNAs distinguish between mutant and normal huntingtin based on a single nucleotide difference and lower mutant huntingtin specifically in patient derived cells and in a mouse model of Huntington’s disease.

The convolution of membranes called cristae is a critical structural and functional feature of mitochondria. Crista structure is highly diverse between different cell types, reflecting their role in metabolic adaptation. However, their precise three-dimensional (3D) arrangement requires volumetric analysis of serial electron microscopy and has therefore been limiting for unbiased quantitative assessment. Here, we developed a novel, publicly available, deep learning (DL)-based image analysis platform called Python-based human-in-the-loop workflow (PHILOW) implemented with a human-in-the-loop (HITL) algorithm. Analysis of dense, large, and isotropic volumes of focused ion beam-scanning electron microscopy (FIB-SEM) using PHILOW reveals the complex 3D nanostructure of both inner and outer mitochondrial membranes and provides deep, quantitative, structural features of cristae in a large number of individual mitochondria. This nanometer-scale analysis in micrometer-scale cellular contexts uncovers fundamental parameters of cristae, such as total surface area, orientation, tubular/lamellar cristae ratio, and crista junction density in individual mitochondria. Unbiased clustering analysis of our structural data unraveled a new function for the dynamin-related GTPase Optic Atrophy 1 (OPA1) in regulating the balance between lamellar versus tubular cristae subdomains.

Abstract Background Inflammatory state within the ovaries can disrupt normal follicular dynamics, leading to reduced oocyte quality and infertility. How the production of inflammatory mediators generated by macrophages with different gene expression profile (M1 and M2) might activate inflammatory pathways, such as cyclooxygenase-2 (COX-2) and 5-, 12-, and 15-lipoxygenase (LOX), in human granulosa cells (hGCs) remains unclear. Methods In this study, we evaluated how M1 and M2 macrophages found in the ovaries affect the functions of hGCs isolated from women undergoing assisted reproductive technology (ART) and human ovarian granulosa COV434 cells. For this purpose, a model of interaction between hGCs and COV434 cells and conditioned media (CMs) obtained from culture of M0, M1 and M2 macrophages was established. We used real-time PCR and western blotting to detect the expression of COX-2 and 5-, 12-, and 15-LOX as biomarkers of oocyte competence. Results Our data showed that M2 macrophages with anti-inflammatory characteristics were able to significantly increase the expression of COX-2 in hGCs. We also demonstrated that M1 macrophages with pro-inflammatory characteristics were able to significantly increase the expression of 12-LOX in hGCs. However, there was no observed expression of 5-LOX and no significant alteration in the expression of 15-LOX in hGCs. Regarding COV434 cells, we found that CM from M2 macrophage resulted in an increase in COX-2, 5-LOX and 15-LOX mRNA and protein levels. No expression of 12-LOX by COV434 cells was observed when exposed to CMs from M1 and M2 macrophages. Conclusions Our research indicated that the production of pro-resolving mediators by hGCs can, at least in part, reverse the physiological inflammation present in the ovaries.

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. The prognosis of patients is very poor, with a median overall survival of ~ 15 months after diagnosis. Cadherin‐3 (also known as P‐cadherin), a cell–cell adhesion molecule encoded by the CDH3 gene, is deregulated in several cancer types, but its relevance in GBM is unknown. In this study, we investigated the functional roles, the associated molecular signatures, and the prognostic value of CDH3/P‐cadherin in this highly malignant brain tumor. CDH3/P‐cadherin mRNA and protein levels were evaluated in human glioma samples. Knockdown and overexpression models of P‐cadherin in GBM were used to evaluate its functional role in vitro and in vivo. CDH3‐associated gene signatures were identified by enrichment analyses and correlations. The impact of CDH3 in the survival of GBM patients was assessed in independent cohorts using both univariable and multivariable models. We found that P‐cadherin protein is expressed in a subset of gliomas, with an increased percentage of positive samples in grade IV tumors. Concordantly, CDH3 mRNA levels in glioma samples from The Cancer Genome Atlas (TCGA) database are increased in high‐grade gliomas. P‐cadherin displays oncogenic functions in multiple knockdown and overexpression GBM cell models by affecting cell viability, cell cycle, cell invasion, migration, and neurosphere formation capacity. Genes that were positively correlated with CDH3 are enriched for oncogenic pathways commonly activated in GBM. In vivo, GBM cells expressing high levels of P‐cadherin generate larger subcutaneous tumors and cause shorter survival of mice in an orthotopic intracranial model. Concomitantly, high CDH3 expression is predictive of shorter overall survival of GBM patients in independent cohorts. Together, our results show that CDH3/P‐cadherin expression is associated with aggressiveness features of GBM and poor patient prognosis, suggesting that it may be a novel therapeutic target for this deadly brain tumor.

Abstract Background Breast cancer is a leading cause of death in premenopausal women. Progesterone drives expansion of luminal progenitor cells, leading to the development of poor-prognostic breast cancers. However, it is not known if antagonising progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to promote breast cancer formation. Methods In healthy premenopausal women with and without a BRCA mutation we studied (i) estrogen and progesterone levels in saliva over an entire menstrual cycle (n = 20); (ii) cancer-free normal breast-tissue from a control population who had no family or personal history of breast cancer and equivalently from BRCA1/2 mutation carriers (n = 28); triple negative breast cancer (TNBC) biopsies and healthy breast tissue taken from sites surrounding the TNBC in the same individuals (n = 14); and biopsies of ER+ve/PR+ve stage T1–T2 cancers and healthy breast tissue taken from sites surrounding the cancer in the same individuals (n = 31); and (iii) DNA methylation and DNA mutations in normal breast tissue (before and after treatment) from clinical trials that assessed the potential preventative effects of vitamins and antiprogestins (mifepristone and ulipristal acetate; n = 44). Results Daily levels of progesterone were higher throughout the menstrual cycle of BRCA1/2 mutation carriers, raising the prospect of targeting progesterone signalling as a means of cancer risk reduction in this population. Furthermore, breast field cancerization DNA methylation signatures reflective of (i) the mitotic age of normal breast epithelium and (ii) the proportion of luminal progenitor cells were increased in breast cancers, indicating that luminal progenitor cells with elevated replicative age are more prone to malignant transformation. The progesterone receptor antagonist mifepristone reduced both the mitotic age and the proportion of luminal progenitor cells in normal breast tissue of all control women and in 64% of BRCA1/2 mutation carriers. These findings were validated by an alternate progesterone receptor antagonist, ulipristal acetate, which yielded similar results. Importantly, mifepristone reduced both the TP53 mutation frequency as well as the number of TP53 mutations in mitotic-age-responders. Conclusions These data support the potential usage of antiprogestins for primary prevention of poor-prognostic breast cancers. Trial registration Clinical trial 1 Mifepristone treatment prior to insertion of a levonorgestrel releasing intrauterine system for improved bleeding control – a randomized controlled trial, clinicaltrialsregister.eu, 2009-009014-40 ; registered on 20 July 2009. Clinical trial 2 The effect of a progesterone receptor modulator on breast tissue in women with BRCA1 and 2 mutations, clinicaltrials.gov, NCT01898312 ; registered on 07 May 2013. Clinical trial 3 A pilot prevention study of the effects of the anti- progestin Ulipristal Acetate (UA) on surrogate markers of breast cancer risk, clinicaltrialsregister.eu, 2015-001587-19 ; registered on 15 July 2015.