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Exercise training leads to physiological cardiac hypertrophy and the protective axis of the renin-angiotensin system composed of angiotensin-converting enzyme 2, angiotensin-(1-7), and Mas receptor seems involved in this process. However, the role of the basal activity of the Mas receptor in exercise-induced physiological cardiac hypertrophy is still unclear. We evaluated the effects of the Mas receptor blockade on the left ventricular structure and function of rats submitted to running training. Rats were assigned to 4 groups: sedentary (S), sedentary + A-779 (Mas receptor antagonist, 120 µg/kg/day, i.p.; SA), trained (60-minute treadmill running sessions, five days a week, 8 weeks; T), and trained + A-779 (TA). Systolic blood pressure was higher in sedentary and trained rats treated with A-779 at the end of the experimental period. The A-779 treatment prevented the left ventricular hypertrophy evoked by physical exercise and increased collagen deposition in sedentary and trained rats. Cardiomyocytes from the SA group presented increased length and thickness of the sarcomeres, elongated mitochondria, glycogen deposits, and enlarged cisterns of the sarcoplasmic reticulum. TA group presented a reduced sarcomere thickness and cytoplasm with a degenerative aspect. These findings show that the basal activity of the Mas receptor is essential for the proper turnover of the extracellular matrix in the myocardium and the maintenance of the sarcomeric structure of cardiomyocytes., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Standard-of-care first-line treatments for paroxysmal nocturnal hemoglobinuria (PNH) include the anti-C5 therapies eculizumab and ravulizumab. However, persistent anemia, likely due to extravascular hemolysis, and reduced quality of life (QoL) due to frequent infusions remain concerns. Iptacopan is a first-in-class oral proximal complement inhibitor that targets factor B in the alternative pathway (upstream of C5), limiting intravascular and extravascular hemolysis., Areas Covered: In patients previously treated with anti-C5 therapies or naive to complement inhibitors, iptacopan 200 mg twice daily resulted in clinically meaningful results in the pivotal phase 3 APPLY-PNH (NCT04558918) and APPOINT-PNH (NCT04820530) trials. Treatment with iptacopan was safe, and no treatment-related adverse events led to discontinuation., Expert Opinion: APPLY-PNH and APPOINT-PNH reported clinically meaningful improvements in hemoglobin, bilirubin, and lactate dehydrogenase levels; transfusion avoidance; reticulocyte count; and fatigue. Iptacopan's safety profile was comparable to other complement inhibitors. Oral iptacopan therapy allows patients to avoid infusions, limit clinical visits, decrease medical costs, improve anemia that persists with other complement inhibitors, and improve QoL. Long-term follow-up will further assess infections, thrombosis, and breakthrough hemolysis. Before treatment, physicians need to discuss current therapeutic options with patients for shared decision-making. Guidelines are being created to assist healthcare professionals in this advancing field.

DNA origami nanotechnology has great potential in multiple fields including biomedical, biophysical, and nanofabrication applications. However, current production pipelines lead to single-use devices incorporating a small fraction of initial reactants, resulting in a wasteful manufacturing process. Here, we introduce two complementary approaches to overcome these limitations by recycling the strand components of DNA origami nanostructures (DONs). We demonstrate reprogramming entire DONs into new devices, reusing scaffold strands. We validate this approach by reprogramming DONs with complex geometries into each other, using their distinct geometries to verify successful scaffold recycling. We reprogram one DON into a dynamic structure and show both pristine and recycled structures display similar properties. Second, we demonstrate the recovery of excess staple strands postassembly and fold DONs with these recycled strands, showing these structures exhibit the expected geometry and dynamic properties. Finally, we demonstrate the combination of both approaches, successfully fabricating DONs solely from recycled DNA components.

The aim of this study was to evaluate the effects of chrysin on the ventral prostate of spontaneously hypertensive rats (SHR). Ten-week-old male Wistar and SHR rats received 100 mg/kg/day of chrysin (TW and TSHR) or 200 µL/day of the dilution vehicle (CW and CSHR) for 70 days. After the treatment, the animals were euthanized and the prostates were dissected out, fixed, and processed for further morphological, immunohistochemical, and biochemical analyses. Blood was collected for serological analysis. Chrysin did not interfere with the blood pressure. Morphologically, the epithelial height increased in TW and decreased in TSHR. Stereology showed an increase in the epithelial and stromal relative frequency, and a decrease in the lumen of TW, whereas the epithelium in TSHR was reduced. Normal alveoli decreased, and hyperplastic alveoli had an increment in TW, whereas in TSHR normal alveoli increased and intense hyperplasia decreased. The secretion area was reduced in TW. Immunohistochemical analysis showed a smaller number of PCNA-positive cells in TW. Finally, the biochemical analysis showed a reduction in malondialdehyde, carbonylated proteins, superoxide dismutase, and catalase in TW and TSHR. We concluded that the chrysin effect is dependent on the context in which this flavonoid is employed. In normal conditions, the anabolic potential of the chrysin was favored, disrupting the morphology of the prostate. However, when used in animals predisposed to develop hyperplasia, this flavonoid attenuates the hyperplastic status, improving the morphology of the gland., (© 2024 International Federation of Cell Biology.)

Acute myeloid leukemia (AML) is the most common and lethal leukemia in adults. AML consists of many genetic subtypes which limits broad applicability of targeted therapy. We discovered that the hematopoietic restricted tetraspanin CD37 is expressed on all primary AML blasts and thus may represent a common therapeutic target for AML regardless of subtype. We demonstrate that the internalization properties of CD37 are distinct in AML blasts when compared to normal blood cells, and that CD37 rapidly accumulates inside AML blasts via dynamin-dependent endocytosis. Our work revealed that the clinically relevant anti-CD37 antibody drug conjugate (ADC) Debio 1562 (αCD37-DM1) is highly cytotoxic to AML blasts, but not normal hematopoietic stem cells. We found that αCD37-DM1 improved clinical outcomes and overall survival in multiple in vivo models of AML. Together, these data demonstrate that targeting CD37 with an ADC such as αCD37-DM1 is a feasible and promising therapeutic option for the treatment of AML., (Copyright © 2024 American Society of Hematology.)

Background: Few investigations evaluated smoking's impact on the periodontal proteome. Therefore, this study aimed to analyse the influence of tobacco on the overall periodontal proteome and the differential expression of gingival crevicular fluid (GCF) proteins using sequential window acquisition of all theoretical mass spectra (SWATH-MS)., Methods: GCF samples were collected from 40 periodontitis subjects (stages III-IV). These were separated based on smoking status into smokers (17), ex-smokers (10), and non-smokers (13). Samples were analysed using SWATH-MS, and proteins were identified using the UniProt human-specific database. Data are available via ProteomeXchange with the identifier PXD043474. Principal component analysis (PCA) was employed to examine the spectral mass distribution of the proteome. Protein expression was different for a p-value <0.05 and a log2 fold change ≥0.3 (upregulated) or ≤-0.3 (downregulated)., Results: The distribution of overall proteome did not differ between non-smokers, smokers, and ex-smokers. Considering protein expression, 23 were differentially expressed in smokers vs. non-smokers (16 upregulated and 7 downregulated), 17 in ex-smokers vs. non-smokers (2 upregulated and 15 downregulated), and only 8 in smokers vs. ex-smokers (7 upregulated and 1 downregulated). Smoking increased the expression of proteins related to epithelial hyperkeratinization (keratins type II cytoskeletal 4, type I cytoskeletal 13 and type I cytoskeletal 19, cornulin, and fatty acid-binding protein 5). However, multiple immunoglobulins were underexpressed when comparing smokers and ex-smokers to non-smokers., Conclusion: Although smoking does not significantly modify the overall GCF proteome associated with periodontitis, it alters the expression of several proteins compared to never-smokers and ex-smokers., Plain Language Summary: Smoking is a critical risk factor for the development and progression of periodontitis. However, evidence of the effect of smoking on the subgingival proteome is scarce. Therefore, this study aimed to determine the impact of smoking on the overall proteome and differential expression of gingival crevicular fluid (GCF) proteins using the sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomic technique. For this purpose, GCF samples were collected from 40 subjects with periodontitis, of which 17 were smokers, 10 were ex-smokers, and 13 were non-smokers. These samples were analysed by SWATH-MS, and proteins were identified using the UniProt human-specific database. Analysis of the overall proteome showed that its distribution was not significantly different between smokers, ex-smokers, and non-smokers. However, several proteins were found to be differentially expressed according to the smoking status. Smoking can increase the expression of several keratins and proteins related to hyperkeratinization of the epithelium. However, in ex-smokers, these proteins return to similar levels to those of non-smokers. Moreover, smoking may induce a lower expression of proteins related to adaptive immunity, such as immunoglobulins. This immunosuppressive effect may persist in ex-smokers., (© 2024 The Author(s). Journal of Periodontology published by Wiley Periodicals LLC on behalf of American Academy of Periodontology.)

This study investigates the thermochemical decomposition and gasification performance of biochars produced from blends of waste lignocellulosic biomass and waste insulation electrical cables at varying temperatures. Characterization tests revealed changes, particularly in ash content (27.5 %-34 %) and elemental composition, with nitrogen content increasing notably in biochar samples compared to the original feedstock. Van Krevelen diagrams demonstrated a reduction in O/C and H/C ratios with increasing production temperature, resembling fossil fuels more closely. The thermogravimetric and the derived thermogravimetric profiles illustrated distinct degradation stages influenced by heating rates and production temperature. Macro-TGA tests provided insights into biomass residue behavior under gasification conditions, indicating higher reaction rates at elevated temperatures. Syngas analysis highlighted the impact of temperature and equivalence ratio on syngas composition, with higher temperatures favoring hydrogen-rich gas production. The observed trends in cold gas efficiency (42.61 %-50.40 %) and carbon conversion efficiency (45.83 %-50.40 %) underscore the significance of temperature control in maximizing gasification performance. Biochars produced at higher temperatures demonstrated superior gasification performance, suggesting potential for optimizing biochar production processes to enhance energy recovery and waste valorization., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Abstract: Severe aplastic anemia (SAA) is a rare hematologic condition for which there is no clear management algorithm. A panel of 11 experts on adult and pediatric aplastic anemia was assembled and, using the RAND/University of California, Los Angeles modified Delphi panel method, evaluated >600 varying patient care scenarios to develop clinical recommendations for the initial and subsequent management of patients of all ages with SAA. Here, we present the panel's recommendations to rule out inherited bone marrow failure syndromes, on supportive care before and during first-line therapy, and on first-line (initial management) and second-line (subsequent management) therapy of acquired SAA, focusing on when transplant vs medical therapy is most appropriate. These recommendations represent the consensus of 11 experts informed by published literature and experience. They are intended only as general guidance for experienced clinicians who treat patients with SAA and are in no way intended to supersede individual physician and patient decision making. Current and future research should validate this consensus using clinical data. Once validated, we hope these expert panel recommendations will improve outcomes for patients with SAA., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Mechanical forces play key roles in biological processes such as cell migration and sensory perception. In recent years molecular force sensors have been developed as tools for in situ force measurements. Here we use all-atom steered molecular dynamics simulations to predict and study the relationship between design parameters and mechanical properties for three types of molecular force sensors commonly used in cellular biological research: two peptide- and one DNA-based. The peptide-based sensors consist of a pair of fluorescent proteins, which can undergo Förster resonance energy transfer (FRET), linked by spider silk (GPGGA) n or synthetic (GGSGGS) n disordered regions. The DNA-based sensor consists of two fluorophore-labeled strands of DNA that can be unzipped or sheared upon force application with a FRET signal as readout of dissociation. We simulated nine sensors, three of each kind. After equilibration, flexible peptide linkers of three different lengths were stretched by applying forces to their N- and C-terminal Cα atoms in opposite directions. Similarly, we equilibrated a DNA-based sensor and pulled on the phosphate atom of the terminal guanine of one strand and a selected phosphate atom on the other strand in the opposite direction. These simulations were performed at constant velocity (0.01 nm/ns - 10 nm/ns) and constant force (10 pN - 500 pN) for all versions of the sensors. Our results show how the force response of these sensors depends on their length, sequence, configuration and loading rate. Mechanistic insights gained from simulations analyses indicate that interpretation of experimental results should consider the influence of transient formation of secondary structure in peptide-based sensors and of overstretching in DNA-based sensors. These predictions can guide optimal fluorophore choice and facilitate the rational design of new sensors for use in protein, DNA, hybrid systems, and molecular devices., Competing Interests: DECLARATION OF INTERESTS. We confirm that there are no conflicting interests associated with this publication.

Introduction: Microbiome-based clinical applications that improve diagnosis related to oral health are of great interest to precision dentistry. Predictive studies on the salivary microbiome are scarce and of low methodological quality (low sample sizes, lack of biological heterogeneity, and absence of a validation process). None of them evaluates the impact of confounding factors as batch effects (BEs). This is the first 16S multi-batch study to analyze the salivary microbiome at the amplicon sequence variant (ASV) level in terms of differential abundance and machine learning models. This is done in periodontally healthy and periodontitis patients before and after removing BEs., Methods: Saliva was collected from 124 patients (50 healthy, 74 periodontitis) in our setting. Sequencing of the V3-V4 16S rRNA gene region was performed in Illumina MiSeq. In parallel, searches were conducted on four databases to identify previous Illumina V3-V4 sequencing studies on the salivary microbiome. Investigations that met predefined criteria were included in the analysis, and the own and external sequences were processed using the same bioinformatics protocol. The statistical analysis was performed in the R-Bioconductor environment., Results: The elimination of BEs reduced the number of ASVs with differential abundance between the groups by approximately one-third (Before=265; After=190). Before removing BEs, the model constructed using all study samples (796) comprised 16 ASVs (0.16%) and had an area under the curve (AUC) of 0.944, sensitivity of 90.73%, and specificity of 87.16%. The model built using two-thirds of the specimens (training=531) comprised 35 ASVs (0.36%) and had an AUC of 0.955, sensitivity of 86.54%, and specificity of 90.06% after being validated in the remaining one-third (test=265). After removing BEs, the models required more ASVs (all samples=200-2.03%; training=100-1.01%) to obtain slightly lower AUC (all=0.935; test=0.947), lower sensitivity (all=81.79%; test=78.85%), and similar specificity (all=91.51%; test=90.68%)., Conclusions: The removal of BEs controls false positive ASVs in the differential abundance analysis. However, their elimination implies a significantly larger number of predictor taxa to achieve optimal performance, creating less robust classifiers. As all the provided models can accurately discriminate health from periodontitis, implying good/excellent sensitivities/specificities, the salivary microbiome demonstrates potential clinical applicability as a precision diagnostic tool for periodontitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Regueira-Iglesias, Suárez-Rodríguez, Blanco-Pintos, Relvas, Alonso-Sampedro, Balsa-Castro and Tomás.)

DNA origami nanostructures (DOs) are promising tools for applications including drug delivery, biosensing, detecting biomolecules, and probing chromatin substructures. Targeting these nanodevices to mammalian cell nuclei could provide impactful approaches for probing, visualizing, and controlling biomolecular processes within live cells. We present an approach to deliver DOs into live-cell nuclei. We show that these DOs do not undergo detectable structural degradation in cell culture media or cell extracts for 24 hours. To deliver DOs into the nuclei of human U2OS cells, we conjugated 30-nanometer DO nanorods with an antibody raised against a nuclear factor, specifically the largest subunit of RNA polymerase II (Pol II). We find that DOs remain structurally intact in cells for 24 hours, including inside the nucleus. We demonstrate that electroporated anti-Pol II antibody-conjugated DOs are piggybacked into nuclei and exhibit subdiffusive motion inside the nucleus. Our results establish interfacing DOs with a nuclear factor as an effective method to deliver nanodevices into live-cell nuclei.

The variability in the expression of different P-glycoprotein (P-gp) genes in parasitic nematodes of ruminants such as Haemonchus contortus (Hco-pgp) may be caused by different factors including nematode biology, geographical region and anthelmintic pressure. This study analysed the relative expression level of 10 P-gp genes in two H. contortus (Hco-pgp) field isolates from Yucatan, Mexico: 1) PARAISO (IVM-resistant) and 2) FMVZ-UADY (IVM-susceptible). These isolates were compared with a susceptible reference isolate from Puebla, Mexico, namely "CENID-SAI". In all cases H. contortus adult males were used. The Hco-pgp genes (1, 2, 3, 4, 9, 10, 11, 12, 14 and 16) were analysed for each isolate using the RT-qPCR technique. The Hco-pgp expressions were pairwise compared using the 2 -ΔΔCt method and a t-test. The PARAISO isolate showed upregulation compared to the CENID-SAI isolate for Hco-pgp 1, 3, 9, 10 and 16 (P < 0.05), and the PARAISO isolate showed upregulation vs. FMVZ-UADY isolate for Hco-pgp 2 and 9 (P < 0.05), displaying 6.58- and 5.93-fold differences (P < 0.05), respectively. In contrast, similar Hco-pgp gene expression levels were recorded for FMVZ-UADY and CENID-SAI isolates except for Hco-pgp1 (P <0.1), which presented a significant upregulation (6.08-fold). The relative expression of Hco-pgp allowed confirming the IVM-resistant status of the PARAISO isolate and the IVM-susceptible status of the FMVZ-UADY isolate when compared to the CENID-SAI reference isolate. Therefore, understanding the association between the Hco-pgp genes expression of H. contortus and its IVM resistance status could help identifying the genes that could be used as molecular markers in the diagnosis of IVM resistance. However, it is important to consider the geographic origin of the nematode isolate and the deworming history at the farm of origin., Competing Interests: Declaration of competing interest Authors have no potential conflict of interest pertaining to this submission., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Though maternal diabetes effects are well described in the literature, the effects of maternal diabetes in postnatal phases are often overlooked. Diabetic individuals have higher levels of circulating glycotoxins, and there is a positive correlation between maternal-derived glycotoxins and circulating glycotoxins in their progeny. Previous studies evaluated the metabolic effects of high glycotoxin exposure during lactation in adult animals. However, here we focus on the cardiovascular system of juvenile rats., Methods: For this, we used two experimental models: 1. High Methylglyoxal (MG) environment: pregnant Wistar rats were injected with PBS (VEH group) or Methylglyoxal (MG group; 60 mg/kg/day; orally, postnatal day (PND) 3 to PND14). 2. GLO-1 inhibition: pregnant Wistar rats were injected with dimethyl sulfoxide (VEH group) or a GLO-1 inhibitor (BBGC group; 5 mg/kg/day; subcutaneously, PND1-PND5). The offspring were evaluated at PND45., Results: MG offspring presented cardiac dysfunction and subtly worsened vasomotor responses in the presence of perivascular adipose tissue, without morphological alterations. In addition, an endogenous increase in maternal glycotoxins impacts offspring vasomotricity due to impaired redox status., Conclusions: Our data suggest that early glycotoxin exposure led to cardiac and vascular impairments, which may increase the risk for developing cardiovascular diseases later in life.

Identifying the lowest energy isomers in large clusters is a major challenge. Here, we introduce the Growth Pattern Algorithm (GrowPAL), a new approach that generates initial seeds composed of n+1 atoms from the system with n atoms through an interstitial-type addition (I-type) mechanism. We evaluated the effectiveness of GrowPAL on Lennard-Jones (LJ) clusters with up to n = 80 atoms, verifying the algorithm's ability to find challenging minima such as LJ 38 and the partially icosahedral LJ 69 with fewer optimizations than existing methods. In addition, we discuss the advantages and limitations of GrowPAL using our deconstruction scheme, which identifies "forebears" structures to study growth pathways. Having evaluated the strengths and weaknesses of GrowPAL, we employed it to explore Sutton-Chen clusters containing 5 to 80 atoms, uncovering three new lowest energy forms. We then applied GrowPAL to boron clusters containing 8 to 15 atoms, successfully identifying all reported minima. Overall, GrowPAL offers a practical solution for efficiently identifying global minima in hierarchical systems, thereby reducing computational costs.

Abstract: Patients with paroxysmal nocturnal hemoglobinuria (PNH) experience complement-mediated intravascular hemolysis leading to anemia, fatigue, and potentially life-threatening thrombotic complications. Pegcetacoplan, a C3 inhibitor, demonstrated sustained improvements in hematologic and clinical parameters in the phase 3 PEGASUS trial in patients with PNH who remained anemic despite C5 inhibitor therapy. The present post hoc analysis describes 26 hemolysis adverse events (AEs) experienced in 19 patients during pegcetacoplan therapy in PEGASUS and baseline patient characteristics potentially associated with increased hemolysis risk. Lactate dehydrogenase (LDH) ≥2× the upper limit of normal (ULN) was observed in 19 events, including 2 with LDH ≥10× ULN. All patients experienced decreased hemoglobin during hemolysis (mean decrease, 3.0 g/dL). In 16 events (62%), a potential complement-amplifying condition underlying the event could be identified. Hemolysis AEs led to study discontinuation in 5 patients. However, of 26 hemolysis AEs, 17 (65%) were manageable without pegcetacoplan discontinuation. A greater proportion of patients with hemolysis AEs (n = 19) had key characteristics of higher disease activity at baseline compared to patients without hemolysis AEs (n = 61), namely higher-than-label eculizumab dose (53% vs 23%), detectable CH50 (total complement function; 74% vs 54%), and ≥4 transfusions in the previous 12 months (68% vs 51%). These characteristics may be useful predictors of potential future hemolysis events. This trial was registered at www.ClinicalTrials.gov as #NCT03500549., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

This study applied the in vitro rumen exsheathment test (IVRET) to evaluate the exsheathment kinetics of Haemonchus contortus infective larvae (L 3 ) incubated in ruminal liquor (RL) containing acetone:water extracts of Acacia pennatula (AP), Gymnopodium floribundum (GF), Havardia albicans (HA) or Lysiloma latisiliquum (LL). The role of polyphenols in the biological activity of the evaluated extracts was also determined. Larvae were incubated in RL either alone or added with a different plant extract (AP, GF, HA, or LL) at 1200 μg/mL. Polyethylene glycol (PEG) was added to block polyphenols in each treatment (RL+PEG, AP+PEG, GF+PEG, HA+PEG, and LL+PEG). After incubation times of 0, 1, 3, 6, 9, and 24 h, the exsheathment process was stopped to count the number of ensheathed and exsheathed L 3 . A Log-Logistic model was used to determine the L 3 exsheathment kinetics in the different RL treatments. The inflection point of the respective kinetic curves, which indicates the time to reach 50 % exsheathed L 3 (T 50 ), was the only parameter that differed when comparing the exsheathment models (99 % probability of difference). The T 50 values obtained for GF, HA, and LL treatments (T 50 = 7.11 - 7.58 h) were higher in comparison to the T 50 of RL (5.72 h) (≥ 70 % probability of difference). The L 3 incubated in RL added with GF, HA, and LL extracts delayed their exsheathment at 3 and 6 h of incubation (28.71 - 48.06 % exsheathment reduction) compared to the RL treatment. The T 50 value for AP, AP+PEG, GF+PEG, HA+PEG, and LL+PEG were similar to RL and RL+PEG (T 50 = 5.34 - 6.97 h). In conclusion, the IVRET can be used to identify plants with the potential to delay the exsheathment of H. contortus L 3 in the ruminal liquor. The acetone:water extracts of G. floribundum, H. albicans, and L. latisiliquum delayed the T 50 of H. contortus exsheathment, which was evident at 3 and 6 h of incubation in ruminal liquor. The observed exsheathment delay was attributed to the polyphenol content of the extracts., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: As the COVID-19 pandemic shifts to an endemic phase, an increasing proportion of patients with cancer and a preoperative history of COVID-19 will require surgery. This study aimed to assess the influence of preoperative COVID-19 on postoperative risk for major adverse cardiovascular and cerebrovascular events (MACEs) among those undergoing surgical cancer resection. Secondary objectives included determining optimal time-to-surgery guidelines based on COVID-19 severity and discerning the influence of vaccination status on MACE risk., Study Design: National COVID Cohort Collaborative Data Enclave, a large multi-institutional dataset, was used to identify patients that underwent surgical cancer resection between January 2020 and February 2023. Multivariate regression analysis adjusting for demographics, comorbidities, and risk of surgery was performed to evaluate risk for 30-day postoperative MACE., Results: Of 204,371 included patients, 21,313 (10.4%) patients had a history of preoperative COVID-19. History of COVID-19 was associated with an increased risk for postoperative composite MACE as well as 30-day mortality. Among patients with mild disease who did not require hospitalization, MACE risk was elevated for up to 4 weeks after infection. Postoperative MACE risk remained elevated more than 8 weeks after infection in those with moderate disease. Vaccination did not reduce risk for postoperative MACE., Conclusions: Together, these data highlight that assessment of the severity of preoperative COVID-19 infection should be a routine component of both preoperative patient screening as well as surgical risk stratification. In addition, strategies beyond vaccination that increase patients' cardiovascular fitness and prevent COVID-19 infection are needed., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

The influence of metal ions on the structure of amyloid- β (Aβ) protofibril models was studied through molecular dynamics to explore the molecular mechanisms underlying metal-induced Aβ aggregation relevant in Alzheimer's disease (AD). The models included 36-, 48-, and 188-mers of the Aβ 42 sequence and two disease-modifying variants. Primary structural effects were observed at the N-terminal domain, as it became susceptible to the presence of cations. Specially when β-sheets predominate, this motif orients N-terminal acidic residues toward one single face of the β-sheet, resulting in the formation of an acidic region that attracts cations from the media and promotes the folding of the N-terminal region, with implications in amyloid aggregation. The molecular phenotype of the protofibril models based on Aβ variants shows that the AD-causative D7N mutation promotes the formation of N-terminal β-sheets and accumulates more Zn 2+ , in contrast to the non-amyloidogenic rodent sequence that hinders the β-sheets and is more selective for Na + over Zn 2+ cations. It is proposed that forming an acidic β-sheet domain and accumulating cations is a plausible molecular mechanism connecting the elevated affinity and concentration of metals in Aβ fibrils to their high content of β-sheet structure at the N-terminal sequence., (© 2024. The Author(s).)

Background: The selection of primer pairs in sequencing-based research can greatly influence the results, highlighting the need for a tool capable of analysing their performance in-silico prior to the sequencing process. We therefore propose PrimerEvalPy, a Python-based package designed to test the performance of any primer or primer pair against any sequencing database. The package calculates a coverage metric and returns the amplicon sequences found, along with information such as their average start and end positions. It also allows the analysis of coverage for different taxonomic levels., Results: As a case study, PrimerEvalPy was used to test the most commonly used primers in the literature against two oral 16S rRNA gene databases containing bacteria and archaea. The results showed that the most commonly used primer pairs in the oral cavity did not match those with the highest coverage. The best performing primer pairs were found for the detection of oral bacteria and archaea., Conclusions: This demonstrates the importance of a coverage analysis tool such as PrimerEvalPy to find the best primer pairs for specific niches. The software is available under the MIT licence at https://gitlab.citius.usc.es/lara.vazquez/PrimerEvalPy ., (© 2024. The Author(s).)

Sodium overload during childhood impairs baroreflex sensitivity and increases arterial blood pressure and heart rate in adulthood; these effects persist even after high-salt diet (HSD) withdrawal. However, the literature lacks details on the effects of HSD during postnatal phases on cardiac ischemia/reperfusion responses in adulthood. The current study aimed to elucidate the impact of HSD during infancy adolescence on isolated heart function and cardiac ischemia/reperfusion responses in adulthood. Male 21-day-old Wistar rats were treated for 60 days with hypertonic saline solution (NaCl; 0.3M; experimental group) or tap water (control group). Subsequently, both groups were maintained on a normal sodium diet for 30 days. Subsequently, the rats were euthanized, and their hearts were isolated and perfused according to the Langendorff technique. After 30 min of the basal period, the hearts were subjected to 20 min of anoxia, followed by 20 min of reperfusion. The basal contractile function was unaffected by HSD. However, HSD elevated the left ventricular end-diastolic pressure during reperfusion (23.1 ± 5.2 mmHg vs. 11.6 ± 1.4 mmHg; p < 0.05) and increased ectopic incidence period during reperfusion (208.8 ± 32.9s vs. 75.0 ± 7.8s; p < 0.05). In conclusion, sodium overload compromises cardiac function after reperfusion events, diminishes ventricular relaxation, and increases the severity of arrhythmias, suggesting a possible arrhythmogenic effect of HSD in the postnatal phases.

Abstract: Angiotensin (Ang)-(1-7) is a cardioprotective peptide of the renin-angiotensin system. Prepuberty has been considered as a later susceptible window of development, and stressful factors in this life phase can induce chronic diseases in adulthood. We aimed to investigate whether the treatment with Ang-(1-7) during the prepuberty could attenuate the development of hypertension and cardiac injury in adult spontaneously hypertensive rats (SHRs). SHRs were treated with Ang-(1-7) (24 μg/kg/h) from age 4 to 7 weeks. Systolic blood pressure was measured by tail-cuff plethysmography up to 17th week. Thereafter, echocardiography was performed, and the rats were euthanized for the collection of tissues and blood. Ang-(1-7) did not change the systolic blood pressure but reduced the septal and posterior wall thickness, and cardiomyocyte hypertrophy and fibrosis in SHR. In addition, Ang-(1-7) reduced the gene expression of atrial natriuretic peptide and brain natriuretic peptide, increased the metalloproteinase 9 expression, and reduced the extracellular signal-regulated kinases 1/2 phosphorylation. Ang-(1-7) also prevented the reduction of Mas receptor but did not change the protein expression of angiotensin-converting enzyme, angiotensin-converting enzyme 2, AT1, and AT2. The treatment with Ang-(1-7) decreased the malondialdehyde (MDA) levels and increased superoxide dismutase-1 and catalase activities and protein expression of catalase. Our findings demonstrate that the treatment of SHR with Ang-(1-7) for 3 weeks early in life promotes beneficial effects in the heart later in life, even without altering blood pressure, through mechanisms involving the reduction of oxidative stress and ERK1/2 phosphorylation. In addition, this study supports the prepuberty as an important programming window., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

DNA origami nanodevices achieve programmable structure and tunable mechanical and dynamic properties by leveraging the sequence-specific interactions of nucleic acids. Previous advances have also established DNA origami as a useful building block to make well-defined micron-scale structures through hierarchical self-assembly, but these efforts have largely leveraged the structural features of DNA origami. The tunable dynamic and mechanical properties also provide an opportunity to make assemblies with adaptive structures and properties. Here the integration of DNA origami hinge nanodevices and coiled-coil peptides are reported into hybrid reconfigurable assemblies. With the same dynamic device and peptide interaction, it is made multiple higher-order assemblies (i.e., polymorphic assembly) by organizing clusters of peptides into patches or arranging single peptides into patterns on the surfaces of DNA origami to control the relative orientation of devices. The coiled-coil interactions are used to construct circular and linear assemblies whose structure and mechanical properties can be modulated with DNA-based reconfiguration. Reconfiguration of linear assemblies leads to micron scale motions and ≈2.5-10-fold increase in bending stiffness. The results provide a foundation for stimulus-responsive hybrid assemblies that can adapt their structure and properties in response to nucleic acid, peptide, protein, or other triggers., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Choosing Wisely is an initiative by the American Board of Internal Medicine (ABIM) and ABIM Foundation to deter unnecessary medical treatments and procedures. Faced with the burden of modern technologies and treatments, it is crucial to identify practices lacking value in daily care. The Latin American and Caribbean Society (SLACOM), comprising cancer control experts, deems it vital to tailor this initiative for enhancing cancer care in the region. Through a modified DELPHI methodology involving two rounds of electronic questionnaires and a hybrid meeting to discuss key points of contention, ten essential recommendations were identified and prioritised to avoid harmful oncology procedures in our region. These consensus-based recommendations, contextualised for Latin America, have been compiled and shared to benefit patients. The Scientific Committee, consisting of prominent oncologists and health experts, collaborates remotely to drive this project forward., Competing Interests: The authors declare that they have no conflicts of interest., (© the authors; licensee ecancermedicalscience.)

Abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis leading to anemia, fatigue, and potentially life-threatening thrombotic complications. Breakthrough hemolysis (BTH) was first described in patients with PNH treated with terminal complement C5 inhibitors when intravascular hemolysis reoccurred despite treatment. Pegcetacoplan, the first proximal complement C3 inhibitor, offers broad hemolysis control in patients with PNH. While experience of managing BTH on C5 inhibitors is documented, very limited guidance exists for proximal complement inhibitors. This interim analysis assessed the effect of intensive treatment with pegcetacoplan following an acute BTH event in a subset of patients enrolled in the ongoing open-label extension study of pegcetacoplan in PNH. Thirteen patients with acute BTH included in the analysis received either a single IV dose of 1080 mg (n = 4) or 1080 mg subcutaneous (SC) dosing on 3 consecutive days (n = 9). A potential, clinically-relevant complement-amplifying condition, such as infection or vaccination, was reported in approximately half of the patients experiencing an acute BTH. Lactate dehydrogenase (LDH) levels decreased between day 1 and day 2 in 8 of 12 evaluable patients and in all 13 patients at day 7 to 12. Nine of 13 patients (69%) achieved LDH <2× the upper limit of normal by day 14 to 19. All adverse events associated with the acute BTH event were considered resolved by the investigators. Overall, intensive treatment with pegcetacoplan was safe and well tolerated. These novel data support effective management of acute BTH events in patients on pegcetacoplan with intensive IV or SC pegcetacoplan dosing. This trial was registered at www.clinicaltrials.gov as #NCT03531255., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Many experimental and computational efforts have sought to understand DNA origami folding, but the time and length scales of this process pose significant challenges. Here, we present a mesoscopic model that uses a switchable force field to capture the behavior of single- and double-stranded DNA motifs and transitions between them, allowing us to simulate the folding of DNA origami up to several kilobases in size. Brownian dynamics simulations of small structures reveal a hierarchical folding process involving zipping into a partially folded precursor followed by crystallization into the final structure. We elucidate the effects of various design choices on folding order and kinetics. Larger structures are found to exhibit heterogeneous staple incorporation kinetics and frequent trapping in metastable states, as opposed to more accessible structures which exhibit first-order kinetics and virtually defect-free folding. This model opens an avenue to better understand and design DNA nanostructures for improved yield and folding performance., (© 2024. The Author(s).)

Lupins ( Lupinus spp.) are legumes with high relevance for the sustainability of agricultural systems as they improve the soil quality, namely, through the fixation of atmospheric nitrogen, and have good adaptability to different climates and soil conditions. Besides, they possess high nutritive value, especially due to the high protein content of the seeds. Nevertheless, the plants' productivity and metabolism can be influenced by the genotype, the edaphoclimatic conditions, and the sowing practices. In this work, the effect of edaphoclimatic conditions and sowing dates on the productivity, nutritional factors, and alkaloids of the seeds of L. albus cv. Estoril, L. angustifolius cv. Tango, and L. luteus cv. Cardiga was evaluated. High variability in the seeds and protein productions, nutritional traits, and alkaloid content related to the species was observed, along with a significant effect of the location. Lupinus albus cv. Estoril showed a good compromise between productivity and low alkaloid content, being an interesting genotype for food and feed use in the conditions of this trial., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

This study adapted the in vitro rumen incubation (IVRI) method to evaluate the biological activity of a Gymnopodium floribundum leaves extract against the exsheathment of Haemonchus contortus infective larvae (L 3 ), and to determine the role of plant polyphenols on the biological activity. The incubation protocol followed the IVRI method, adding polyethylene glycol (PEG) as a polyphenol-blocking agent. The L 3 were incubated in ruminal liquor (RL), ruminal liquor with PEG (RL+PEG), ruminal liquor with G. floribundum extract (RLE), and ruminal liquor with G. floribundum extract and PEG (RLE+PEG). Incubation condition controls included phosphate buffered saline (PBS), PBS with PEG (PBS+PEG), incubation medium (without ruminal liquor) (IM), and incubation medium with PEG (IM+PEG). The L 3 were recovered after incubation times of 0, 1, 3, 6, 9, and 24 h (39 °C). The respective L 3 exsheathment kinetics were estimated for the different treatments (RL, RL+PEG, RLE, and RLE+PEG) using Log-Logistic models. The parameters of the different models were compared to determine the impact of the extract, with or without PEG, on the L 3 exsheathment kinetics. The exsheathment in PBS and PBS+PEG remained < 2.71% at each incubation time. The exsheathment in IM and IM+PEG reached 13.58% and 17.18% at 24 h, respectively. The exsheathment percentages for RLE were lower than those for RL at 3, 6 and 9 h of incubation. The inflection point, indicating the time required to reach 50% of the maximal exsheathment (T 50 ), was the only parameter that differed between the ruminal liquor models. The T 50 in RLE (7.106 h) was higher than the values obtained for RL (5.385 h) and RL+PEG (4.923 h) (99.99% probability of being different). Such delay resulted in a reduction of exsheathment in RLE of 62% at 3 h, 38% at 6 h, and 12% at 9 h, relative to RL values. When PEG was added with the extract (RLE+PEG), the T 50 (5.045 h) was similar to that of RL and RL+PEG. The IVRI method was adapted as an in vitro rumen exsheathment test (IVRET). The IVRET showed that H. contortus L 3 exposed to G. floribundum extract delayed their exsheathment kinetics at different time points. The exsheathment delay was attributed to the polyphenol content of the extract., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The identification of crops that simultaneously contribute to the global protein supply and mitigate the effects of climate change is an urgent matter. Lupins are well adapted to nutrient-poor or contaminated soils, tolerate various abiotic stresses, and present relevant traits for acting as ecosystem engineers. Lupins are best studied for their seeds, but their full foraging potential needs further evaluation. This study evaluated the effects of location and sowing date on forage production, proximate composition, and the detailed mineral and alkaloid profiles of three species of Lupinus ( L. albus cv. Estoril, L. angustifolius cv. Tango, and L. luteus cv. Cardiga). Sowing date and location and their interaction with the plant species significantly affected the vast majority of measured parameters, emphasizing the effects of climate and soil conditions on these crops. The relatively high crude protein and in vitro digestibility support the potential of the lupin species studied as sustainable forage protein sources in diets for ruminant animals. The content of individual essential macro and trace elements was below the maximum tolerable levels for cattle and sheep. Lupanine, smipine, and sparteine were the most abundant quinolizidine alkaloids in L. albus cv. Estoril, lupanine, and sparteine in L. angustifolius cv. Tango, and lupinine, gramine, ammodendrine, and sparteine in L. luteus cv. Cardiga. Based on the maximum tolerable levels of total quinolizidine alkaloid intake, the dietary inclusion of forages of L. albus cv. Estoril and L . angustifolius cv. Tango does not pose a risk to the animals, but the high alkaloid content of L. luteus cv. Cardiga may compromise its utilization at high levels in the diet. Overall, the results reveal a high potential for lupins as protein forage sources well adapted to temperate regions and soils with lower fertility, with a relevant impact on livestock sustainability in a climate change era., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients., Methods: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion., Results: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan., Conclusions: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.)., (Copyright © 2024 Massachusetts Medical Society.)

To date, studies on the thermodynamic and kinetic processes that underlie biological function and nanomachine actuation in biological- and biology-inspired molecular constructs have primarily focused on photothermal heating of ensemble systems, highlighting the need for probes that are localized within the molecular construct and capable of resolving single-molecule response. Here we present an experimental demonstration of wavelength-selective, localized heating at the single-molecule level using the surface plasmon resonance of a 15 nm gold nanoparticle (AuNP). Our approach is compatible with force-spectroscopy measurements and can be applied to studies of the single-molecule thermodynamic properties of DNA origami nanomachines as well as biomolecular complexes. We further demonstrate wavelength selectivity and establish the temperature dependence of the reaction coordinate for base-pair disruption in the shear-rupture geometry, demonstrating the utility and flexibility of this approach for both fundamental studies of local (nanometer-scale) temperature gradients and rapid and multiplexed nanomachine actuation.

Biomolecular systems are dependent on a complex interplay of forces. Modern force spectroscopy techniques provide means of interrogating these forces, but they are not optimized for studies in constrained environments as they require attachment to micron-scale probes such as beads or cantilevers. Nanomechanical devices are a promising alternative, but this requires versatile designs that can be tuned to respond to a wide range of forces. We investigate the properties of a nanoscale force sensitive DNA origami device which is highly customizable in geometry, functionalization, and mechanical properties. The device, referred to as the NanoDyn, has a binary (open or closed) response to an applied force by undergoing a reversible structural transition. The transition force is tuned with minor alterations of 1 to 3 DNA oligonucleotides and spans tens of picoNewtons (pN). The DNA oligonucleotide design parameters also strongly influence the efficiency of resetting the initial state, with higher stability devices (≳10 pN) resetting more reliably during repeated force-loading cycles. Finally, we show the opening force is tunable in real time by adding a single DNA oligonucleotide. These results establish the potential of the NanoDyn as a versatile force sensor and provide fundamental insights into how design parameters modulate mechanical and dynamic properties., (© 2024. The Author(s).)

We evaluated the relationship between individual and herd GIN infection level, nutrition, production performance and anemia parameters in a tropical farm context. Fifty-four female goats were monitored to assess their body condition score (BCS, nutritional status indicator), live weight (LW) and LW gain (LWG, both used as production level indicators), FAMACHA© and hematocrit (HT, both used as anemia indicators). Goats browsed for 4 h in a tropical forest and received balanced feed and chopped grass. The eggs per gram of feces (EPG) indicated the GIN burden, with fecal samples obtained at 7:00 (AM) and 15:00 h (PM.) from each goat at six sampling points during the study. The variables and their relationship with GIN burdens were analyzed using Kruskall-Wallis, ANOVA and Friedman tests and Spearman correlations. The fecal samples obtained in the AM and PM can be equally representative of parasitic burdens (similar and highly correlated). However, the EPG of individual goats from periods of 30 days apart can be considered independent. The BCS and LWG varied between sampling times ( p < 0.05), whereas EPG, LW and HT did not ( p > 0.05). The GIN burden was negatively correlated with HT and BCS (-0.21, p = 0.01 for each one). The individual pattern of infection demonstrates the true impact of GINs on their hosts. Additionally, feeding and nutritional status may present important variations influencing the performance of the goats more than the impact of GINs under the farm conditions of the present study. However, GIN infection contributed to the variation in goat health and productivity in this tropical farm.

Background: In Colombia, the average age of first sexual intercourse is between 14 and 15, and it has one of the highest fertility rates among adolescents in Latin America, which reflects poor access to health services and a lack of knowledge about contraception. Some laws support comprehensive sex education as a learning process that families and schools should provide. The objective of this work was to assess the frequency of adequate knowledge and attitudes of acceptance towards contraception in students, their associated factors, sexual behaviours in sexually active students, and experiences with sex education., Methods: Mixed methods study consisting of an analytical cross-sectional study and a qualitative hermeneutic phenomenological study. The former included students who completed a questionnaire with sociodemographic variables, surveys on knowledge and attitudes toward contraception, and questions about sexual behaviour. Focus groups were used in the qualitative study to evaluate students' and parents' sex education experiences., Findings: 827 students were surveyed, of whom 52.3% had adequate knowledge about contraceptives and 80.1% had attitudes of acceptance. Talking with parents about sex education, receiving sex education, and being in the eleventh grade increased the likelihood of having adequate knowledge. Each year of age, being male, being a victim of forced displacement, and studying in a public school were associated with lower possibilities of attitudes of acceptance. Using condoms, compared to other contraceptives, was associated with less adequate knowledge and attitudes of acceptance (p < 0.05). Experiences with sex education, contraception, and sexual and reproductive rights were three emerging categories in the focus groups., Interpretation: In a group of Colombian high school students, half of them had adequate knowledge, eight out of 10 had attitudes of acceptance about contraception, and both were associated with having received sex education. Nevertheless, different types of barriers to sexual education were identified at home and in schools. The results will allow the generation of educational policies that modify the educational model as well as new strategies by health professionals to raise awareness about responsible sexuality., Funding: This project was financed by internal research of the Fundación Universitaria de Ciencias de la Salud-FUCS (DI-I-0392-20)., Competing Interests: None of the researchers declared any conflict of interest., (© 2024 Published by Elsevier Ltd.)

Background: Mosquito borne viruses, such as dengue, Zika, yellow fever and Chikungunya, cause millions of infections every year. These viruses are mostly transmitted by two urban-adapted mosquito species, Aedes aegypti and Aedes albopictus. Although mechanistic understanding remains largely unknown, Aedes mosquitoes may have unique adaptations that lower the impact of viral infection. Recently, we reported the identification of an Aedes specific double-stranded RNA binding protein (dsRBP), named Loqs2, that is involved in the control of infection by dengue and Zika viruses in mosquitoes. Preliminary analyses suggested that the loqs2 gene is a paralog of loquacious (loqs) and r2d2, two co-factors of the RNA interference (RNAi) pathway, a major antiviral mechanism in insects., Results: Here we analyzed the origin and evolution of loqs2. Our data suggest that loqs2 originated from two independent duplications of the first double-stranded RNA binding domain of loqs that occurred before the origin of the Aedes Stegomyia subgenus, around 31 million years ago. We show that the loqs2 gene is evolving under relaxed purifying selection at a faster pace than loqs, with evidence of neofunctionalization driven by positive selection. Accordingly, we observed that Loqs2 is localized mainly in the nucleus, different from R2D2 and both isoforms of Loqs that are cytoplasmic. In contrast to r2d2 and loqs, loqs2 expression is stage- and tissue-specific, restricted mostly to reproductive tissues in adult Ae. aegypti and Ae. albopictus. Transgenic mosquitoes engineered to express loqs2 ubiquitously undergo developmental arrest at larval stages that correlates with massive dysregulation of gene expression without major effects on microRNAs or other endogenous small RNAs, classically associated with RNA interference., Conclusions: Our results uncover the peculiar origin and neofunctionalization of loqs2 driven by positive selection. This study shows an example of unique adaptations in Aedes mosquitoes that could ultimately help explain their effectiveness as virus vectors., (© 2024. The Author(s).)

Microplastics and natural organic matter are present in the aquatic environment and their reciprocal interaction plays important roles in the transport and behavior of nutrients and contaminants. Nevertheless, we lack mechanistic understanding on these interactions, especially in the case of biodegradable plastics. Here we investigate the adsorption of a commercial humic acid onto poly (lactic acid) (PLA) microplastics in aqueous solution. While the pseudo-second order kinetic model provided a more accurate representation of the adsorption kinetics, the Elovich model also produced a good fit, suggesting that chemisorption may be the rate-limiting step. The equilibrium data was better fit by the Langmuir model, that provided a maximum adsorption capacity of 0.118 ± 0.006 mg·g -1 . The obtained values for the separation factor (R L ) and free energy (E) suggest that adsorption of humic acid onto PLA is controlled by physisorption. We studied the effects of pH, ionic strength, and PLA concentration on the adsorption of humic acid onto PLA and demonstrated that electrostatic interactions and aggregation are important. The humic acid was characterized by Fourier-transform infrared (FTIR) spectroscopy, excitation-emission matrix (EEM) fluorescence spectroscopy, and parallel factor analysis (PARAFAC), before and after interacting with PLA. This set of analyses demonstrated that PLA caused alterations in the molecular structure of humic acid, primarily attributed to modifications in hydrogen bonding and hydrophobic interactions. Therefore, we hypothesize that the carboxylic groups of humic acid formed dimers in contact with PLA. This study provides new insights into the interactions between organic matter and a biodegradable microplastic in aqueous systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Ivermectin (IVM) resistance in parasitic nematodes such as Haemonchus contortus has spurred a search for substances that help to recover its efficacy. One potential agent is the natural product curcumin (CUR). In this study, CUR was combined with polyvinylpyrrolidone (PVP) (CUR/PVP) to improve its solubility and biological applicability. This study determined the effect of CUR preincubation on the effective concentration 50% (EC 50 ) of IVM in three H. contortus isolates with different susceptibilities to IVM. The IVM EC 50 was determined for three H. contortus isolates with different IVM susceptibilities using the larval migration inhibition (LMI) test. The three isolates were (i) PARAISO (IVM resistant), (ii) FMVZ-UADY (IVM susceptible), and (iii) CENID-SAI INIFAP (reference IVM susceptible). The L 3 of each isolate were preincubated for 3 h with one of three concentrations of CUR (μg curcumin/mL): CONC-1 (3.67), CONC-2 (5.67), or CONC-3 (8.48). Corresponding controls were performed without CUR. The EC 50 of IVM was determined for each isolate after they were exposed to the different CUR concentrations. The EC 50 of IVM differed between the isolates PARAISO > FMVZ-UADY > CENID-SAI INIFAP (P < 0.05). The CUR preincubation at CONC-1 did not decrease the EC 50 of IVM for any of the three isolates, suggesting a hormetic effect. By contrast, CUR preincubation at CONC-2 or CONC-3 decreased the IVM EC 50 for the PARAISO isolate (P < 0.05) compared with the reference isolate and reduced the EC 50 of IVM for the FMVZ-UADY and CENID-SAI INIFAP isolates below the EC 50 for the CENID-SAI INIFAP isolate without CUR preincubation. In conclusion, preincubation of H. contortus L 3 with CUR reduced the EC 50 of IVM for field isolates classified as resistant and susceptible to IVM. The CUR preincubation reduced the IVM resistance factor in the different isolates tested., Competing Interests: Declaration of competing interest We declare that this is an original contribution that has not been published elsewhere in substantially the same form and it is not currently under consideration elsewhere. Furthermore, we have no financial or personal interest that could be considered a conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Marine dissolved organic matter (DOM) presents key thermodynamic properties that are not yet fully constrained. Here, we report the distribution of binding sites occupied by protons (i.e., proton affinity spectra) and parametrize the median intrinsic proton binding affinities (log K̅ H ) and heterogeneities ( m ), for DOM samples extracted from the North Atlantic. We estimate that 11.4 ± 0.6% of C atoms in the extracted marine DOM have a functional group with a binding site for ionic species. The log K̅ H of the most acidic groups was larger (4.01-4.02 ± 0.02) than that observed in DOM from coastal waters (3.82 ± 0.02), while the chemical binding heterogeneity parameter increased with depth to values ( m 1 = 0.666 ± 0.009) ca. 10% higher than those observed in surface open ocean or coastal samples. On the contrary, the log K̅ H for the less acidic groups shows a difference between the surface (10.01 ± 0.08) and deep (9.22 ± 0.35) samples. The latter chemical groups were more heterogeneous for marine than for terrestrial DOM, and m 2 decreased with depth to values of 0.28 ± 0.03. Binding heterogeneity reflects aromatic carbon compounds' persistence and accumulation in diverse, low-abundance chemical forms, while easily degradable low-affinity groups accumulate more uniformly in the deep ocean.

The increasing interest in innovative solutions for addressing bone defects has driven research into the use of Bioactive Mesoporous Glasses (MBGs). These materials, distinguished by their well-ordered mesoporous structure, possess the capability to accommodate plant extracts with well-established osteogenic properties, including bovine lactoferrin (bLF), as part of their 3D scaffold composition. This harmonizes seamlessly with the ongoing advancements in the field of biomedicine. In this study, we fabricated 3D scaffolds utilizing MBGs loaded with extracts from parsley leaves (PL) and embryogenic cultures (EC), rich in bioactive compounds such as apigenin and kaempferol, which hold potential benefits for bone metabolism. Gelatin Methacryloyl (GelMa) served as the polymer, and bLF was included in the formulation. Cytocompatibility, Runx2 gene expression, ALP enzyme activity, and biomineralization were assessed in preosteoblastic MC3T3-E1 cell cultures. MBGs effectively integrated PL and EC extracts with loadings between 22.6 ± 0.1 and 43.6 ± 0.3 µM for PL and 26.3 ± 0.3 and 46.8 ± 0.4 µM for EC, ensuring cell viability through a release percentage between 28.3% and 59.9%. The incorporation of bLF in the 3D scaffold formulation showed significant differences compared to the control in all assays, even at concentrations below 0.2 µM. Combinations, especially PL + bLF at 0.19 µM, demonstrated additive potential, with superior biomineralization compared to EC. In summary, this study highlights the effectiveness of MBGs in incorporating PL and EC extracts, along with bLF, into 3D scaffolds. The results underscore cytocompatibility, osteogenic activity, and biomineralization, offering exciting potential for future in vivo applications.

Curative bone marrow transplantation (BMT) therapies for sickle cell disease (SCD) can cause infertility. The Fertility Preservation Program (FPP) in Pittsburgh cryopreserves testicular tissues for SCD patients prior to BMT in anticipation that those tissues can be thawed in the future and matured to produce sperm. Here, we generated and validated two isogenic patient-derived induced pluripotent stem cell (iPSC) lines from testicular biopsy fibroblasts of a 12-year-old SCD patient., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kyle Orwig reports financial support was provided by National Institute of Child Health and Human Development. Kyle Orwig has patent #PCT/US2018/043948 pending to University of Pittsburgh. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

We analyzed a quantitative multiscale model that describes the epigenetic dynamics during the growth and evolution of an avascular tumor. A gene regulatory network (GRN) formed by a set of ten genes that are believed to play an important role in breast cancer development was kinetically coupled to the microenvironmental agents: glucose, estrogens, and oxygen. The dynamics of spontaneous mutations was described by a Yule-Furry master equation whose solution represents the probability that a given cell in the tissue undergoes a certain number of mutations at a given time. We assumed that the mutation rate is modified by a spatial gradient of nutrients. The tumor mass was simulated by means of cellular automata supplemented with a set of reaction diffusion equations that described the transport of microenvironmental agents. By analyzing the epigenetic state space described by the GRN dynamics, we found three attractors that were identified with cellular epigenetic states: normal, precancer and cancer. For two-dimensional (2D) and three-dimensional (3D) tumors we calculated the spatial distribution of the following quantities: (i) number of mutations, (ii) mutation of each gene and, (iii) phenotypes. Using estrogen as the principal microenvironmental agent that regulates cell proliferation process, we obtained tumor shapes for different values of estrogen consumption and supply rates. It was found that he majority of mutations occurred in cells that were located close to the 2D tumor perimeter or close to the 3D tumor surface. Also, it was found that the occurrence of different phenotypes in the tumor are controlled by estrogen concentration levels since they can change the individual cell threshold and gene expression levels. All results were consistently observed for 2D and 3D tumors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Romero-Arias et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To determine how the severity of prior history (Hx) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection influences postoperative outcomes after major elective inpatient surgery., Background: Surgical guidelines instituted early in the coronavirus disease 2019 (COVID-19) pandemic recommended a delay in surgery of up to 8 weeks after an acute SARS-CoV-2 infection. This was based on the observation of elevated surgical risk after recovery from COVID-19 early in the pandemic. As the pandemic shifts to an endemic phase, it is unclear whether this association remains, especially for those recovering from asymptomatic or mildly symptomatic COVID-19., Methods: Utilizing the National COVID Cohort Collaborative, we assessed postoperative outcomes for adults with and without a Hx of COVID-19 who underwent major elective inpatient surgery between January 2020 and February 2023. COVID-19 severity and time from infection to surgery were each used as independent variables in multivariable logistic regression models., Results: This study included 387,030 patients, of whom 37,354 (9.7%) were diagnosed with preoperative COVID-19. Hx of COVID-19 was found to be an independent risk factor for adverse postoperative outcomes even after a 12-week delay for patients with moderate and severe SARS-CoV-2 infection. Patients with mild COVID-19 did not have an increased risk of adverse postoperative outcomes at any time point. Vaccination decreased the odds of respiratory failure., Conclusions: Impact of COVID-19 on postoperative outcomes is dependent on the severity of illness, with only moderate and severe disease leading to a higher risk of adverse outcomes. Existing perioperative policies should be updated to include consideration of COVID-19 disease severity and vaccination status., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The multi-batch reanalysis approach of jointly reevaluating gene/genome sequences from different works has gained particular relevance in the literature in recent years. The large amount of 16S ribosomal ribonucleic acid (rRNA) gene sequence data stored in public repositories and information in taxonomic databases of the same gene far exceeds that related to complete genomes. This review is intended to guide researchers new to studying microbiota, particularly the oral microbiota, using 16S rRNA gene sequencing and those who want to expand and update their knowledge to optimise their decision-making and improve their research results. First, we describe the advantages and disadvantages of using the 16S rRNA gene as a phylogenetic marker and the latest findings on the impact of primer pair selection on diversity and taxonomic assignment outcomes in oral microbiome studies. Strategies for primer selection based on these results are introduced. Second, we identified the key factors to consider in selecting the sequencing technology and platform. The process and particularities of the main steps for processing 16S rRNA gene-derived data are described in detail to enable researchers to choose the most appropriate bioinformatics pipeline and analysis methods based on the available evidence. We then produce an overview of the different types of advanced analyses, both the most widely used in the literature and the most recent approaches. Several indices, metrics and software for studying microbial communities are included, highlighting their advantages and disadvantages. Considering the principles of clinical metagenomics, we conclude that future research should focus on rigorous analytical approaches, such as developing predictive models to identify microbiome-based biomarkers to classify health and disease states. Finally, we address the batch effect concept and the microbiome-specific methods for accounting for or correcting them., (© 2023 The Authors. Molecular Oral Microbiology published by John Wiley & Sons Ltd.)

Objective: To classify the staff of two reference institutions for COVID-19 care in Antioquia according to the intensity of anxiety and depression symptoms, and to determine the factors associated with these classes., Methods: Cross-sectional study in which the GAD-7, PHQ-9, fear of COVID-19, and the Copenhagen Burnout scale were used. Latent class analysis was performed to identify the classes, and the factors associated with these were determined using multinomial logistic regression., Results: 486 people participated. The three-class model had the best fit: class I with low scores on the scales; class II with mild degrees of anxiety and depression, and intermediate levels of fear of COVID-19 and perceived stress; and class III with moderate and severe degrees of anxiety, depression, and perceived stress. The factors associated with belonging to class III were age (OR = 0.94; 95%CI, 0.91-0.96), change of residence to avoid exposing relatives (OR = 4.01; 95%CI, 1.99-8.09), and a history of depressive disorder (OR = 3.10; 95%CI, 1.27-7.56), and anxiety (OR = 5.5; 95%CI, 2.36-12.90). Factors associated with class II were age (OR = 0.97; 95%CI, 0.95-0.99), history of depressive disorder (OR = 3.41; 95%CI, 1.60-7.25), living with someone at risk of death from COVID-19 (OR = 1.86; 95%CI, 1.19-2.91), family member being healthcare staff (OR = 1.58; 95%CI, 1.01-2.47), and change of residence to avoid exposing relatives (OR = 1.99; 95%CI, 1.11-3.59)., Conclusions: Three classes of participants were obtained, two of them with anxiety and depression symptoms. Younger age and a history of mental disorder were factors associated with the two classes of symptomatic patients; other factors may be causes or consequences of the symptoms., (Copyright © 2021 Asociación Colombiana de Psiquiatría. Published by Elsevier España, S.L.U. All rights reserved.)

Sphingolipids (SLs) are essential components of all eukaryotic cellular membranes. In fungi, plants and many protozoa, the primary SL is inositol-phosphorylceramide (IPC). Trypanosoma cruzi is a protozoan parasite that causes Chagas disease (CD), a chronic illness for which no vaccines or effective treatments are available. IPC synthase (IPCS) has been considered an ideal target enzyme for drug development because phosphoinositol-containing SL is absent in mammalian cells and the enzyme activity has been described in all parasite forms of T. cruzi. Furthermore, IPCS is an integral membrane protein conserved amongst other kinetoplastids, including Leishmania major, for which specific inhibitors have been identified. Using a CRISPR-Cas9 protocol, we generated T. cruzi knockout (KO) mutants in which both alleles of the IPCS gene were disrupted. We demonstrated that the lack of IPCS activity does not affect epimastigote proliferation or its susceptibility to compounds that have been identified as inhibitors of the L. major IPCS. However, disruption of the T. cruzi IPCS gene negatively affected epimastigote differentiation into metacyclic trypomastigotes as well as proliferation of intracellular amastigotes and differentiation of amastigotes into tissue culture-derived trypomastigotes. In accordance with previous studies suggesting that IPC is a membrane component essential for parasite survival in the mammalian host, we showed that T. cruzi IPCS null mutants are unable to establish an infection in vivo, even in immune deficient mice., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Dos Santos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Mechanical characterization of dynamic DNA nanodevices is essential to facilitate their use in applications like molecular diagnostics, force sensing, and nanorobotics that rely on device reconfiguration and interactions with other materials. A common approach to evaluate the mechanical properties of dynamic DNA nanodevices is by quantifying conformational distributions, where the magnitude of fluctuations correlates to the stiffness. This is generally carried out through manual measurement from experimental images, which is a tedious process and a critical bottleneck in the characterization pipeline. While many tools support the analysis of static molecular structures, there is a need for tools to facilitate the rapid characterization of dynamic DNA devices that undergo large conformational fluctuations. Here, we develop a data processing pipeline based on Deep Neural Networks (DNNs) to address this problem. The YOLOv5 and Resnet50 network architecture were used for the two key subtasks: particle detection and pose (i.e. conformation) estimation. We demonstrate effective network performance (F1 score 0.85 in particle detection) and good agreement with experimental distributions with limited user input and small training sets (~ 5 to 10 images). We also demonstrate this pipeline can be applied to multiple nanodevices, providing a robust approach for the rapid characterization of dynamic DNA devices., (© 2023. Springer Nature Limited.)

Aim: To explore the existing salivary, gingival crevicular fluid (GCF), blood, and serum biomarkers associated with grade C molar-incisor pattern (C/MIP) periodontitis in systemically healthy children and young adults., Materials and Methods: Cross-sectional, case-control, and cohort studies on stage III grade C periodontitis or former equivalent diagnosis with analysis of molecular biomarkers in saliva, GCF, blood, or serum were retrieved from six databases and screened based on the eligibility criteria. The risk of bias in included studies was evaluated. Meta-analysis was planned for biomarkers assessed using the same detection methods and sample type in at least two papers., Results: Out of 5621 studies identified at initial screening, 28 papers were included in the qualitative analysis of which 2 were eligible for meta-analysis for IgG in serum samples. Eighty-seven biomarkers were assessed with the majority being higher in cases than in controls. Only the meta-analysis of total serum IgG with low heterogeneity value revealed a significant increase in its levels in C/MIPs compared to controls (standardised mean difference: 1.08; 95% CI: 0.76, 1.40)., Conclusion: There is a paucity of data on biomarkers associated with molar-incisor pattern periodontitis. Although serum IgG levels are raised, other more specific biomarkers in saliva, GCF, and blood/serum may be promising but require further investigation., (© 2023. The Author(s).)

The development of yogurt with functional characteristics from bioactive compounds such as fiber, antioxidants, and probiotics represents a novel strategy in designing value-added dairy beverages. However, biotechnological challenges are present in these bioprocesses, such as the selection of probiotic strains, as well as the correlation with the physicochemical characteristics of the fermentative metabolism of probiotic microorganisms. Therefore, yogurt could be a vehicle for including probiotic bacteria, bioactive compounds, and phytochemicals that allow synergistic effects in the development of bioprocesses with potential benefits for the host's health. Therefore, this article aims to review the current conditions of bio-yogurt production, discuss the physicochemical and bioactive composition (sugars, fiber, vitamins), and include phytochemicals from carrots to establish synergistic relationships with probiotic microorganisms to obtain a functional dairy beverage., Competing Interests: Conflict of interestThis review article has no conflicts of interest., (© Association of Food Scientists & Technologists (India) 2022.)