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Abstract Human manganese superoxide dismutase (MnSOD) is a crucial oxidoreductase that maintains the vitality of mitochondria by converting superoxide (O2 ●−) to molecular oxygen (O2) and hydrogen peroxide (H2O2) with proton-coupled electron transfers (PCETs). Human MnSOD has evolved to be highly product inhibited to limit the formation of H2O2, a freely diffusible oxidant and signaling molecule. The product-inhibited complex is thought to be composed of a peroxide (O2 2−) or hydroperoxide (HO2 −) species bound to Mn ion and formed from an unknown PCET mechanism. PCET mechanisms of proteins are typically not known due to difficulties in detecting the protonation states of specific residues that coincide with the electronic state of the redox center. To shed light on the mechanism, we combine neutron diffraction and X-ray absorption spectroscopy of the product-bound, trivalent, and divalent states of the enzyme to reveal the positions of all the atoms, including hydrogen, and the electronic configuration of the metal ion. The data identifies the product-inhibited complex, and a PCET mechanism of inhibition is constructed.

ABSTRACT Purpose: This video aims to present an in-depth, step-by-step tutorial on microsurgical reconstruction for obstructive azoospermia, featuring a distinctive case involving anastomosis from vas deferens to rete testis. The primary aim of this endeavor is to offer thorough and practical insights for healthcare professionals and researchers within the realm of reproductive medicine. The video endeavors to disseminate expertise, methodologies, and perspectives that can be advantageous to individuals grappling with obstructive azoospermia, providing a significant contribution to the progress of reproductive medicine and the augmentation of existing treatment alternatives. Materials and Methods: Surgical footage was recorded using the ORBEYE 4K 3D Orbital Camera System by Olympus America, with patient consent acquired for research purposes. Additionally, a retrospective examination of patient records was undertaken to compile relevant medical histories. Results: This video furnishes an exhaustive guide to microsurgical reconstruction for obstructive azoospermia, encompassing a distinctive instance of anastomosis from vas deferens to rete testis. State-of-the-art technology, such as the ORBEYE 4K 3D Orbital Camera, heightens procedural transparency, accentuating the significance of advanced instrumentation. The ethical underpinning is emphasized by obtaining patient consent for footage utilization, and a retrospective chart review augments the repository of valuable patient data. This comprehensive approach serves as an invaluable reservoir of knowledge for medical professionals and underscores excellence in clinical and ethical healthcare research. Conclusions: Anastomosis from vas deferens to rete testis emerges as a viable surgical reconstruction alternative for obstructive azoospermia, particularly when confronted with non-dilated tubules within the epididymis.

Abstract Causing one-third of all volcanic fatalities, pyroclastic density currents create destruction far beyond our current scientific explanation. Opportunities to interrogate the mechanisms behind this hazard have long been desired, but pyroclastic density currents persistently defy internal observation. Here we show, through direct measurements of destruction-causing dynamic pressure in large-scale experiments, that pressure maxima exceed theoretical values used in hazard assessments by more than one order of magnitude. These distinct pressure excursions occur through the clustering of high-momentum particles at the peripheries of coherent turbulence structures. Particle loading modifies these eddies and generates repeated high-pressure loading impacts at the frequency of the turbulence structures. Collisions of particle clusters against stationary objects generate even higher dynamic pressures that account for up to 75% of the local flow energy. To prevent severe underestimation of damage intensities, these multiphase feedback processes must be considered in hazard models that aim to mitigate volcanic risk globally.

Abstract We formulate a Majorana mean-field theory for the extended J KΓ Kitaev model in a magnetic Zeeman field of arbitrary direction, and apply it for studying spatially inhomogeneous states harboring vortices. This mean-field theory is exact in the pure Kitaev limit and captures the essential physics throughout the Kitaev spin liquid phase. We determine the charge profile around vortices and the corresponding quadrupole tensor. The quadrupole-quadrupole interaction between distant vortices is shown to be either repulsive or attractive, depending on parameters. We predict that electrically biased scanning probe tips enable the creation of vortices at preselected positions. Our results paves the way for the electric manipulation of Ising anyons in Kitaev spin liquids.

The root maggot fly, Delia sanctijacobi (Bigot, 1885) (Diptera: Anthomyiidae), is an emerging pest of many vegetables. In this note, we report for the first time the occurrence of D. sanctijacobi damaging the tomato (Solanum lycopersicum L.) culture in Brazil. The occurrence was recorded in a tomato field located in the municipality of Coronel Freitas, Santa Catarina. The damage was characterized by roots consumption, opening of galleries in the stem and plant stand reduction. The first detection of D. sanctijacobi on tomato in Brazil brings an alert to growers and the need of future research about population dynamics and development of management strategies for this species.

Abstract Over the last decades, air pollution emissions have decreased substantially; however, inequities in air pollution persist. We evaluate county-level racial/ethnic and socioeconomic disparities in emissions changes from six air pollution source sectors (industry [SO2], energy [SO2, NOx], agriculture [NH3], commercial [NOx], residential [particulate organic carbon], and on-road transportation [NOx]) in the contiguous United States during the 40 years following the Clean Air Act (CAA) enactment (1970-2010). We calculate relative emission changes and examine the differential changes given county demographics using hierarchical nested models. The results show racial/ethnic disparities, particularly in the industry and energy generation source sectors. We also find that median family income is a driver of variation in relative emissions changes in all sectors—counties with median family income >$75 K vs. less generally experience larger relative declines in industry, energy, transportation, residential, and commercial-related emissions. Emissions from most air pollution source sectors have, on a national level, decreased following the United States CAA. In this work, we show that the relative reductions in emissions varied across racial/ethnic and socioeconomic groups.

Scientific evidence exists about the association between neurological diseases (i.e., Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, depression, and memory loss) and oxidative damage. The increasing worldwide incidence of such diseases is attracting the attention of researchers to find palliative medications to reduce the symptoms and promote quality of life, in particular, in developing countries, e.g., South America and Africa. Among potential alternatives, extracts of Cannabis Sativa L. are suitable for people who have neurological disorders, spasticity, and pain, nausea, resulting from diseases such as cancer and arthritis. In this review, we discuss the latest developments in the use of Cannabis, its subtypes and constituents, extraction methods, and relevant pharmacological effects. Biomedical applications, marketed products, and prospects for the worldwide use of Cannabis Sativa L. extracts are also discussed, providing the bibliometric maps of scientific literature published in representative countries from South America (i.e., Brazil) and Africa (i.e., South Africa). A lack of evidence on the effectiveness and safety of Cannabis, besides the concerns about addiction and other adverse events, has led many countries to act with caution before changing Cannabis-related regulations. Recent findings are expected to increase the social acceptance of Cannabis, while new technologies seem to boost the global cannabis market because the benefits of (−)-trans-delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) use have been proven in several studies in addition to the potential to general new employment.

ABSTRACT Considering the spectral differences between broadleaf weeds and narrow-leaf crops and the influence of terrain and soil variables on weed infestations, integrating such information into a machine-learning algorithm can lead to accurate weed maps. Therefore, we aim to evaluate the effectiveness of these variables in classifying the occurrence of broadleaf weeds in narrow-leaf crops. Weed data was collected at georeferenced points across two areas covering 200 ha (pasture) and 106 ha (sorghum), creating classes 0 (absence) and 1 (presence). For each sample point, we obtained 11 variables: soil clay content, cation exchange capacity, soil organic matter, terrain elevation, slope, NDVI, EVI, CIgreen, BGND (derived from PlanetScope images), and spatial information (X and Y coordinates). These variables were used as predictors of broadleaf weed presence and absence in the Random Forest classification algorithm. The presence and absence of broadleaf weeds were correctly classified in 84% and 74% of all predictions in the test sample sets for pasture and sorghum areas, respectively. This strategy represents an efficient way to map and manage the occurrence of broadleaf weeds in narrow-leaf crops.

ABSTRACTPseudomonas aeruginosa, a bacterium causing infections in immunocompromised individuals, regulates several of its virulence functions using three interlinked quorum sensing (QS) systems (las, rhl, and pqs). Despite its presumed importance in regulating virulence, dysfunction of the las system regulator LasR occurs frequently in strains isolated from various environments, including clinical infections. This newfound abundance of LasR-defective strains calls into question existing hypotheses regarding their selection. Indeed, current assumptions concerning factors driving the emergence of LasR-deficient isolates and the role of LasR in the QS hierarchy must be reconsidered. Here, we propose that LasR is not the primary master regulator of QS in all P. aeruginosa genetic backgrounds, even though it remains ecologically significant. We also revisit and complement current knowledge on the ecology of LasR-dependent QS in P. aeruginosa, discuss the hypotheses explaining the putative adaptive benefits of selecting against LasR function, and consider the implications of this renewed understanding.

Abstract A hallmark of cancer is a tumor cell’s ability to evade immune destruction. Somatic mutations in tumor cells that prevent immune destruction have been extensively studied. However, somatic mutations in tumor infiltrating immune (TII) cells, to our knowledge, have not been previously studied. Understandably so since normal hematopoiesis prevents the accumulation of somatic mutations in immune cells. However, clonal hematopoiesis does result in the accumulation of somatic mutations in immune cells. These mutations cannot “drive” tumor growth, however, they may “facilitate” it by inhibiting an effective anti-tumor immune response. To identify potential immunosuppressive clonal hematopoietic (CH) mutations in TII cells, we analyzed exome and RNA sequencing data from matched tumor and normal blood samples, and single-cell RNA sequencing data, from breast cancer patients. We selected mutations that were somatic, present in TII cells, clonally expanded, potentially pathogenic, expressed in TII cells, unlikely to be a passenger mutation, and in immune response associated genes. We identified eight potential immunosuppressive CH mutations in TII cells. This work is a first step towards determining if immunosuppressive CH mutations in TII cells can affect the progression of solid tumors. Subsequent experimental confirmation could represent a new paradigm in the etiology of cancer.

This paper presents a method for designing low carbon bio-based building materials, also named bio-concretes, produced with wood wastes in shavings form (WS) and cementitious pastes. As the aggregates phase of bio-concretes is composed of plant-based particles, known as porous and high water-absorbing materials, the bio-concretes cannot be designed by using the traditional design rules used for conventional mortar or concrete. Then, the method used in the current paper is an adaptation of a previous one that has been developed in a recent paper where bio-concretes were produced with a cement matrix, three types of bio-aggregates, and a proposal of a design abacus. However, when that abacus is used for designing WBC with low cement content in the matrix, the target compressive strength is not reached. In the present paper, the method is extended to low cement content matrix (up to 70% of cement substitution) and also considering the greenhouse gas (GHG) emission of the WBC. To obtain data for proposing a new design abacus, an experimental program was carried out by producing nine workable WBCs, varying wood volumetric fractions (40–45–50%), and water-to-binder ratios. The bio-concretes produced presented adequate consistency, lightness (density between 715 and 1207 kg/m3), and compressive strength ranging from 0.64 to 12.27 MPa. In addition, the GHG emissions of the WBC were analysed through the Life Cycle Assessment methodology. From the relationships obtained between density, compressive strength, water-to-binder ratio, cement consumption, and GHG emissions of the WBC, calibration constants were proposed for developing the updated and more complete abacus regarding an integrated mix design methodology.

Digital breast tomosynthesis (DBT) reconstructions introduce out-of-plane artifacts and false-tissue boundaries impacting the dense/adipose and breast outline (convex hull) segmentations. A virtual clinical trial method was proposed to segment both the breast tissues and the breast outline in DBT reconstructions. The DBT images of a representative population were simulated using three acquisition geometries: a left–right scan (conventional, I), a two-directional scan in the shape of a “T” (II), and an extra-wide range (XWR, III) left–right scan at a six-times higher dose than I. The nnU-Net was modified including two losses for segmentation: (1) tissues and (2) breast outline. The impact of loss (1) and the combination of loss (1) and (2) was evaluated using models trained with data simulating geometry I. The impact of the geometry was evaluated using the combined loss (1&2). The loss (1&2) improved the convex hull estimates, resolving 22.2% of the false classification of air voxels. Geometry II was superior to I and III, resolving 99.1% and 96.8% of the false classification of air voxels. Geometry III (Dice = (0.98, 0.94)) was superior to I (0.92, 0.78) and II (0.93, 0.74) for the tissue segmentation (adipose, dense, respectively). Thus, the loss (1&2) provided better segmentation, and geometries T and XWR improved the dense/adipose and breast outline segmentations relative to the conventional scan.

Globally, there has been an increase in stringent regulations governing the use of chemical soil fumigants for controlling diseases, pests, and weeds. Grafting has been identified as an effective alternative to soil fumigation for managing soilborne diseases and pests in intensive vegetable cropping systems. The majority of watermelon (Citrullus lanatus) grafting research confirms that selected rootstocks play a role in improving plant resistance or tolerance to common soilborne diseases. Currently, there is a lack of evidence-based literature on the effects of grafting on watermelon fruit quality attributes and yield components. Previous reviews report wide variation in the impact of grafting on watermelon production, depending on rootstock–scion combinations and environmental conditions. This review employed evidence-based synthesis methods to comprehensively and methodically summarize research results of the impact of grafting on watermelon, with a focus on fruit quality and yield. In this systematic review, 548 citations (studies published during 2011–21) were screened against strict inclusion criteria, and data were extracted from 47 studies. Meta-analysis of percent differences between the grafted watermelon treatment and the nongrafted or self-grafted watermelon control was performed using extracted data of yield components and a wide range of fruit quality attributes. Meta-analysis of research data with variance measures was also conducted based on a rather limited number of studies. Our findings showed higher levels of total yield, average fruit weight, fruit length and width, fruit lycopene and soluble solids content, rind thickness, flesh firmness, lightness, chroma, and flesh nitrogen (N) content in grafted watermelon treatments compared with the nongrafted or self-grafted control. In particular, total yield, average fruit weight, and flesh firmness exhibited significant increases of a more than 10% difference. In contrast, grafted plants demonstrated decreases in fruit pH, hue angle, and flesh calcium content, although the reduction was not greater than 10% relative to the control. Meta-analysis of research data with variance measures further confirmed significantly greater total yield and flesh N content in grafted watermelon treatments compared with the nongrafted or self-grafted control. In addition, the meta-analysis results confirmed greater benefits of watermelon grafting in the presence of known soilborne disease pressure in contrast to the production scenarios without soilborne disease problems.

Abstract Background During the course of history, various important lifestyle changes have caused profound transitions of the gut microbiome. These include the introduction of agriculture and animal husbandry, a shift from a nomadic to a more sedentary lifestyle, and recently increased levels of urbanization and a transition towards a more Western lifestyle. The latter is linked with shifts in the gut microbiome that have a reduced fermentative capability and which are commonly associated with diseases of affluence. In this study, in which 5193 subjects are included, we investigated the direction of microbiome shifts that occur in various ethnicities living in Amsterdam by comparing 1st and 2nd generation participants. We furthermore validated part of these findings with a cohort of subjects that moved from rural Thailand to the USA. Results The abundance of the Prevotella cluster, which includes P. copri and the P. stercorea trophic network, diminished in the 2nd generation Moroccans and Turks but also in younger Dutch, whilst the Western-associated Bacteroides/Blautia/Bifidobacterium (BBB) cluster, which has an inverse correlation with α-diversity, increased. At the same time, the Christensenellaceae/Methanobrevibacter/Oscillibacter trophic network, which is positively associated with α-diversity and a healthy BMI, decreased in younger Turks and Dutch. Large compositional shifts were not observed in South-Asian and African Surinamese, in whom the BBB cluster is already dominant in the 1st generation, but ASV-level shifts towards certain species, associated amongst others with obesity, were observed. Conclusion The Moroccan and Turkish populations, but also the Dutch population are transitioning towards a less complex and fermentative less capable configuration of the gut microbiota, which includes a higher abundance of the Western-associated BBB cluster. The Surinamese, whom have the highest prevalence of diabetes and other diseases of affluence, are already dominated by the BBB cluster. Given the continuous increase in diseases of affluence, this devolution towards low-diversity and fermentatively less capable gut microbiome compositions in urban environments is a worrying development. Video Abstract Graphical Abstract

Cognitive decline is a common feature of aging, particularly in memory domains supported by the medial temporal lobe (MTL). The ability to identify intervention strategies to treat or prevent this decline is challenging due to substantial variability between adults in terms of age of onset, rate and severity of decline, and many factors that could influence cognitive reserve. These factors can be somewhat mitigated by use of within-subject designs. Aged outbred Long-Evans rats have proven useful for identifying translationally relevant substrates contributing to age-related decline in MTL-dependent memory. In this population, some animals show reliable impairment on MTL-dependent tasks while others perform within the range of young adult rats. However, currently there are relatively few within-subject behavior protocols for assessing MTL function over time, and most require extensive training and appetitive motivation for associative learning. In the current study, we aimed to test whether water maze learning impairments in aged Long-Evans rats would be predictive of delayed recognition memory impairments and whether these odor memory impairments would be stable within subjects over multiple rounds of testing.

BackgroundImmunotherapy of cancer is an emerging field with the potential to improve long-term survival. Thus far, adoptive transfer of tumor-specific T cells represents an effective treatment option for tumors of the hematological system such as lymphoma, leukemia or myeloma. However, in solid tumors, treatment efficacy is low owing to the immunosuppressive microenvironment, on-target/off-tumor toxicity, limited extravasation out of the blood vessel, or ineffective trafficking of T cells into the tumor region. Superparamagnetic iron oxide nanoparticles (SPIONs) can make cells magnetically controllable for the site-specific enrichment. MethodsIn this study, we investigated the influence of SPION-loading on primary human T cells for the magnetically targeted adoptive T cell therapy. For this, we analyzed cellular mechanics and the T cell response after stimulation via an exogenous T cell receptor (TCR) specific for the melanoma antigen MelanA or the endogenous TCR specific for the cytomegalovirus antigen pp65 and compared them to T cells that had not received SPIONs.ResultsSPION-loading of human T cells showed no influence on cellular mechanics, therefore retaining their ability to deform to external pressure. Additionally, SPION-loading did not impair the T cell proliferation, expression of activation markers, cytokine secretion, and tumor cell killing after antigen-specific activation mediated by the TCR. ConclusionIn summary, we demonstrated that SPION-loading of T cells did not affect cellular mechanics or the functionality of the endogenous or an exogenous TCR, which allows future approaches using SPIONs for the magnetically enrichment of T cells in solid tumors.

Abstract We previously demonstrated that P. aeruginosa isolates that persisted in children with cystic fibrosis (CF) despite inhaled tobramycin treatment had increased anti-Psl antibody binding in vitro compared to those successfully eradicated. We aimed to validate these findings by directly visualizing P. aeruginosa in CF sputum. This was a prospective observational study of children with CF with new-onset P. aeruginosa infection who underwent inhaled tobramycin eradication treatment. Using microbial identification passive clarity technique (MiPACT), P. aeruginosa was visualized in sputum samples obtained before treatment and classified as persistent or eradicated based on outcomes. Pre-treatment isolates were also grown as biofilms in vitro. Of 11 patients enrolled, 4 developed persistent infection and 7 eradicated infection. P. aeruginosa biovolume and the number as well as size of P. aeruginosa aggregates were greater in the sputum of those with persistent compared with eradicated infections (p

Embolization of de novo pulmonary arteriovenous malformations (PAVMs) using high-volume detachable non-fibered (HVDNF) coils was compared to traditional non-HVDNF coils. Persistent-occlusion rates were evaluated. A total of 272 de novo (previously untreated) PAVM treatments were retrospectively stratified into those treated with non-HVDNF coils only (n = 192) and those treated with HVDNF coils with or without other coils (n = 80). Propensity score matching, followed by survival analysis and cost analysis, was performed. The overall persistent-occlusion rate was 86.0% (234/272). Persistent occlusion was achieved in 81.8% of PAVMs using non-HVDNF coils, compared with 96.3% using HVDNF coils (p = 0.0017). The mean follow-up was 30.7 ± 31.9 months versus 14.7 ± 13.4 months, respectively (p < 0.0001). Propensity-matched survival analysis demonstrated PAVMs treated with HVDNF coils recurred significantly less frequently than PAVMs treated with non-HVNDF coils (p = 0.023). The use of HVDNF coils was more expensive than standard coils, however not significantly different for the treatment of complex PAVMs. The use of high-volume detachable non-fibered coils was associated with higher persistent-occlusion rates when compared with non-HVDNF coils. HVDNF coils were more expensive on average; however, cost was similar between groups for the treatment of complex PAVMs.

ABSTRACT Advances in both laboratory and computational components of high-throughput 16S amplicon sequencing (16S HTS) have markedly increased its sensitivity and specificity. Additionally, these refinements have better delineated the limits of sensitivity, and contributions of contamination to these limits, for 16S HTS that are particularly relevant for samples with low bacterial loads, such as human cerebrospinal fluid (CSF). The objectives of this work were to (i) optimize the performance of 16S HTS in CSF samples with low bacterial loads by defining and addressing potential sources of error, and (ii) perform refined 16S HTS on CSF samples from children diagnosed with bacterial meningitis and compare results with those from microbiological cultures. Several bench and computational approaches were taken to address potential sources of error for low bacterial load samples. We compared DNA yields and sequencing results after applying three different DNA extraction approaches to an artificially constructed mock-bacterial community. We also compared two postsequencing computational contaminant removal strategies, decontam R and full contaminant sequence removal. All three extraction techniques followed by decontam R yielded similar results for the mock community. We then applied these methods to 22 CSF samples from children diagnosed with meningitis, which has low bacterial loads relative to other clinical infection samples. The refined 16S HTS pipelines identified the cultured bacterial genus as the dominant organism for only 3 of these samples. We found that all three DNA extraction techniques followed by decontam R generated similar DNA yields for mock communities at the low bacterial loads representative of CSF samples. However, the limits of detection imposed by reagent contaminants and methodologic bias precluded the accurate detection of bacteria in CSF from children with culture-confirmed meningitis using these approaches, despite rigorous controls and sophisticated computational approaches. Although we did not find current DNA-based diagnostics to be useful for pediatric meningitis samples, the utility of these methods for CSF shunt infection remains undefined. Future advances in sample processing methods to minimize or eliminate contamination will be required to improve the sensitivity and specificity of these methods for pediatric meningitis. IMPORTANCE Advances in both laboratory and computational components of high-throughput 16S amplicon sequencing (16S HTS) have markedly increased its sensitivity and specificity. These refinements have better delineated the limits of sensitivity, and contributions of contamination to these limits, for 16S HTS that are particularly relevant for samples with low bacterial loads such as human cerebrospinal fluid (CSF). The objectives of this work were to (i) optimize the performance of 16S HTS in CSF samples by defining and addressing potential sources of error, and (ii) perform refined 16S HTS on CSF samples from children diagnosed with bacterial meningitis and compare results with those from microbiological cultures. We found that the limits of detection imposed by reagent contaminants and methodologic bias precluded the accurate detection of bacteria in CSF from children with culture-confirmed meningitis using these approaches, despite rigorous controls and sophisticated computational approaches.

The healthy skeletal muscle extracellular matrix (ECM) has several functions including providing structural integrity to myofibers, enabling lateral force transmission, and contributing to overall passive mechanical properties. In diseases such as Duchenne Muscular dystrophy, there is accumulation of ECM materials, primarily collagen, which results in fibrosis. Previous studies have shown that fibrotic muscle is often stiffer than healthy muscle, in part due to the increased number and altered architecture of collagen fibers within the ECM. This would imply that the fibrotic matrix is stiffer than the healthy matrix. However, while previous studies have attempted to quantify the extracellular contribution to passive stiffness in muscle, the outcomes are dependent on the type of method used. Thus, the goals of this study were to compare the stiffness of healthy and fibrotic muscle ECM and to demonstrate the efficacy of two methods for quantifying extracellular-based stiffness in muscle, namely decellularization and collagenase digestion. These methods have been demonstrated to remove the muscle fibers or ablate collagen fiber integrity, respectively, while maintaining the contents of the extracellular matrix. Using these methods in conjunction with mechanical testing on wildtype and D2.mdx mice, we found that a majority of passive stiffness in the diaphragm is dependent on the ECM, and the D2.mdx diaphragm ECM is resistant to digestion by bacterial collagenase. We propose that this resistance is due to the increased collagen cross-links and collagen packing density in the ECM of the D2.mdx diaphragm. Taken altogether, while we did not find increased stiffness of the fibrotic ECM, we did observe that the D2.mdx diaphragm conveyed resistance against collagenase digestion. These findings demonstrate how different methods for measuring ECM-based stiffness each have their own limitations and can produce different results.

Background Lung infections are among the most consequential manifestations of cystic fibrosis (CF) and are associated with reduced lung function and shortened survival. Drugs called CF transmembrane conductance regulator (CFTR) modulators improve activity of dysfunctional CFTR channels, which is the physiological defect causing CF. However, it is unclear how improved CFTR activity affects CF lung infections.Methods We performed a prospective, multicenter, observational study to measure the effect of the newest and most effective CFTR modulator, elexacaftor/tezacaftor/ivacaftor (ETI), on CF lung infections. We studied sputum from 236 people with CF during their first 6 months of ETI using bacterial cultures, PCR, and sequencing.Results Mean sputum densities of Staphylococcus aureus, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Achromobacter spp., and Burkholderia spp. decreased by 2–3 log10 CFU/mL after 1 month of ETI. However, most participants remained culture positive for the pathogens cultured from their sputum before starting ETI. In those becoming culture negative after ETI, the pathogens present before treatment were often still detectable by PCR months after sputum converted to culture negative. Sequence-based analyses confirmed large reductions in CF pathogen genera, but other bacteria detected in sputum were largely unchanged. ETI treatment increased average sputum bacterial diversity and produced consistent shifts in sputum bacterial composition. However, these changes were caused by ETI-mediated decreases in CF pathogen abundance rather than changes in other bacteria.Conclusions Treatment with the most effective CFTR modulator currently available produced large and rapid reductions in traditional CF pathogens in sputum, but most participants remain infected with the pathogens present before modulator treatment.Trial Registration ClinicalTrials.gov NCT04038047.Funding The Cystic Fibrosis Foundation and the NIH.

Insufficient invasion of conceptus-derived trophoblast cells in the maternal decidua is a key event in the development of early-onset preeclampsia (PE), a subtype of PE associated with high maternal and fetal morbidity and mortality. Kisspeptins, a family of peptides previously shown to inhibit trophoblast cell invasion, have been implicated in the pathogenesis of early-onset PE. However, a role of kisspeptin signaling during the genesis of this syndrome has not been elucidated. Herein, we used the preeclamptic-like BPH/5 mouse model to investigate kisspeptin expression and potential upstream regulatory mechanisms in a PE-like syndrome. Expression of the kisspeptin encoding gene, Kiss1, and the 10-amino-acid kisspeptide (Kp-10), are upregulated in the non-pregnant uterus of BPH/5 females during diestrus and in the maternal-fetal interface during embryonic implantation and decidualization. Correspondingly, the dysregulation of molecular pathways downstream to kisspeptins also occurs in this mouse model. BPH/5 females have abnormal sex steroid hormone profiles during early gestation. In this study, the normalization of circulating concentrations of 17β-estradiol (E2) and progesterone (P4) in pregnant BPH/5 females not only mitigated Kiss1 upregulation, but also rescued the expression of multiple molecules downstream to kisspeptin and ameliorated adverse fetoplacental outcomes. Those findings suggest that uterine Kiss1 upregulation occurs pre-pregnancy and persists during early gestation in a PE-like mouse model. Moreover, this study highlights the role of sex steroid hormones in uteroplacental Kiss1 dysregulation and the improvement of placentation by normalization of E2, P4 and Kiss1.

Abstract Background Quantifying disease costs is critical for policymakers to set priorities, allocate resources, select control and prevention strategies, and evaluate the cost-effectiveness of interventions. Although malaria carries a very large disease burden, the availability of comprehensive and comparable estimates of malaria costs across endemic countries is scarce. Methods A literature review to summarize methodologies utilized to estimate malaria treatment costs was conducted to identify gaps in knowledge. Results Only 45 publications met the inclusion criteria. They utilize different methods, include distinct cost components, have varied geographical coverage (a country vs a city), include different periods in the analysis, and focus on specific parasite types or population groups (e.g., pregnant women). Conclusions Cost estimates currently available are not comparable, hindering broad statements on the costs of malaria, and constraining advocacy efforts towards investment in malaria control and elimination, particularly with the finance and development sectors of the government.

Abstract Recently, ocular biometrics in unconstrained environments using images obtained at visible wavelength have gained the researchers’ attention, especially with images captured by mobile devices. Periocular recognition has been demonstrated to be an alternative when the iris trait is not available due to occlusions or low image resolution. However, the periocular trait does not have the high uniqueness presented in the iris trait. Thus, the use of datasets containing many subjects is essential to assess biometric systems’ capacity to extract discriminating information from the periocular region. Also, to address the within-class variability caused by lighting and attributes in the periocular region, it is of paramount importance to use datasets with images of the same subject captured in distinct sessions. As the datasets available in the literature do not present all these factors, in this work, we present a new periocular dataset containing samples from 1122 subjects, acquired in 3 sessions by 196 different mobile devices. The images were captured under unconstrained environments with just a single instruction to the participants: to place their eyes on a region of interest. We also performed an extensive benchmark with several Convolutional Neural Network (CNN) architectures and models that have been employed in state-of-the-art approaches based on Multi-class Classification, Multi-task Learning, Pairwise Filters Network, and Siamese Network. The results achieved in the closed- and open-world protocol, considering the identification and verification tasks, show that this area still needs research and development.

Abstract The main effectors in the innate immune system of Bombyx mori L. are antimicrobial peptides (AMPs). Here, we infected B. mori with varied inoculum sizes of Pseudomonas aeruginosa ATCC 25668 cells to investigate changes in morpho-anatomical responses, physiological processes and AMP production. Ultraviolet–visible spectra revealed a sharp change in λmax from 278 to 285 nm (bathochromic shift) in the hemolymph of infected B. mori incubated for 24 h. Further, Fourier Transform InfraRed studies on the hemolymph extracted from the infected B. mori showed a peak at 1550 cm−1, indicating the presence of α-helical peptides. The peptide fraction was obtained through methanol, acetic acid and water mixture (90:1:9) extraction, followed by peptide purification using Reverse Phase High Performance Liquid Chromatography. The fraction exhibiting antibacterial properties was collected and characterized by Matrix-Assisted Laser Desorption/Ionization-Time of Flight. A linear α-helical peptide with flexible termini (LLKELWTKMKGAGKAVLGKIKGLL) was found, corresponding to a previously described peptide from ant venom and here denominated as Bm-ponericin-L1. The antibacterial activity of Bm-ponericin-L1 was determined against ESKAPE pathogens. Scanning electron microscopy confirmed the membrane disruption potential of Bm-ponericin-L1. Moreover, this peptide also showed promising antibiofilm activity. Finally, cell viability and hemolytic assays revealed that Bm-ponericin-L1 is non-toxic toward primary fibroblasts cell lines and red blood cells, respectively. This study opens up new perspectives toward an alternative approach to overcoming multiple-antibiotic-resistance by means of AMPs through invertebrates’ infection with human pathogenic bacteria.

Abstract Fibro-adipogenic progenitors (FAPs) are essential in supporting regeneration in skeletal muscle, but in muscle pathologies FAPs the are main source of excess extracellular matrix (ECM) resulting in fibrosis. Fibrotic ECM has altered mechanical and architectural properties, but the feedback onto FAPs of stiffness or ECM properties is largely unknown. In this study, FAPs’ sensitivity to their ECM substrate was assessed using collagen coated polyacrylamide to control substrate stiffness and collagen hydrogels to engineer concentration, crosslinking, fibril size, and alignment. FAPs on substrates of fibrotic stiffnesses had increased myofibroblast activation, depicted by αSMA expression, compared to substrates mimicking healthy muscle, which correlated strongly YAP nuclear localization. Surprisingly, fibrosis associated collagen crosslinking and larger fibril size inhibited myofibroblast activation, which was independent of YAP localization. Additionally, collagen crosslinking and larger fibril diameters were associated with decreased remodeling of the collagenous substrate as measured by second harmonic generation imaging. Inhibition of YAP activity through verteporfin reduced myofibroblast activation on stiff substrates but not substrates with altered architecture. This study is the first to demonstrate that fibrotic muscle stiffness can elicit FAP activation to myofibroblasts through YAP signaling. However, fibrotic collagen architecture actually inhibits myofibroblast activation through a YAP independent mechanism. These data expand knowledge of FAPs sensitivity to ECM and illuminate targets to block FAP’s from driving progression of muscle fibrosis.

Exposure to dangerous heat index levels will likely increase by 50-100% in the tropics and by a factor of 3-10 in the mid-latitudes by 2100, even if the Paris Agreement goal of limiting warming to 2°C is met, according to probabilistic projections of global warming.