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This paper discusses the implementation of the Whole Communities-Whole Health (WCWH) initiative, which is a community-based, longitudinal cohort study. WCWH seeks to better understand the impact of location on family health and child development while also providing support for families participating in the study. Implementing a longitudinal study that is both comprehensive in the data it is collecting and inclusive in the population it is representing is what makes WCWH extremely challenging. This paper highlights the learning process the initiative has gone through to identify effective strategies for implementing this type of research study and work toward building a new model for community-engaged research. Through iterative testing following the Plan-Do-Study-Act model, three main strategies for implementation were identified. These strategies are (1) creating a data collection schedule that balances participant burden and maintains temporality across data types; (2) facilitating multiple opportunities for qualitative and quantitative input from faculty, families, and nonparticipant community members; and (3) establishing an open-door policy for data analysis and interpretation. This paper serves as a guide and provides resources for other researchers wanting to implement a multidisciplinary and community-based cohort study., (©Lindsay Bouchacourt, Sarah Smith, Michael Mackert, Shoaa Almalki, Germine Awad, Amanda Barczyk, Sarah Kate Bearman, Darla Castelli, Frances Champagne, Kaya de Barbaro, Shirene Garcia, Karen Johnson, Kerry Kinney, Karla Lawson, Zoltan Nagy, Laura Quiñones Camacho, Lourdes Rodríguez, David Schnyer, Edison Thomaz, Sean Upshaw, Yan Zhang. Originally published in JMIR Formative Research (https://formative.jmir.org), 05.12.2024.)

This study presents the synthesis and characterization of a series of 13 novel acetamides. These were subjected to Ellman's assay to determine the efficacy of the AChE and BChE inhibitors. Finally, we report their antioxidant activity as an alternative approach for the search for drugs to treat AD. These studies revealed that compounds 1a-1k and 2l-2m were obtained in moderate yield. Four amides (1h, 1j, 1k, and 2l) were selective for one of the enzymes (BChE); thus, those that inhibited BChE were more active than the positive control (galantamine) and showed better IC 50 values (3.30-5.03 µM). The theoretical free binding energies calculated by MM-GBSA indicated that all inhibitors were more stable than rivastigmine, and the inhibition mechanisms involved the entire active site: peripheral anionic site, oxyanion hole, acyl-binding pockets, and catalytic site. We examined the cytotoxicity of compounds 1h, 1j, 1k, and 2l in human dermal cells and found that they did not exhibit any toxic effects under the tested conditions. Additionally, these compounds, which also inhibited BChE, displayed mixed inhibition and did not exhibit hemolytic effects on human erythrocytes. Furthermore, the ABTS and DPPH assays indicated that, although none of the compounds showed activity in the DPPH assay, the EC 50 values for radical trapping by the ABTS method showed that compounds 1a, 1d, 1e, and 1g had EC 50 values lower than 10 µg/mL, indicating their strong radical scavenging capacity. We also report the crystal structures of compounds 1c, 1d, 1f, and 1g, which are found in monoclinic crystal 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 © 2024 Elsevier Inc. All rights reserved.)

Aims: Coxiella burnetii is a highly infectious organism that is easily spread through aerosols causing Q fever in humans. Ticks can harbour and transmit C. burnetii to animals, contributing to disease maintenance. Our aim was to examine the presence of C. burnetii in ticks in Uganda., Methods and Results: In this study, ticks were collected from five Ugandan districts and tested by real-time PCR for C. burnetii (Coxiella outer membrane protein 1 gene). A total of 859 tick pools (9602 individual ticks) were tested, and pool positivity for C. burnetii was 5.5% (n = 47). Pooled prevalence differed by district; the highest was Luwero (7.3%), then Gulu (6.6%), and Kasese had the lowest (1.3%). However, district variation was not statistically significant (Fisher's exact = 0.07). Ticks collected from dogs and cats had the highest positivity rates [23/47, (48.9%)] followed by livestock (cattle, goats, sheep, and pigs) [18/47, (38.3%)] and vegetation [6/47, (12.8%)]. Haemaphysalis elliptica had the highest infection rates, followed by Rhipicephalus appendiculatus, Amblyomma variegatum and Rhipicephalus decoloratus had similar prevalence., Conclusions: Although ticks are not the primary transmitters of C. burnetii to humans, pathogen detection in ticks can be an indirect indicator of risk among animal hosts. Vulnerable populations, including occupations with close animal contact such as farming, butchery, and veterinary practice, have an increased risk of C. burnetii exposure. Veterinarians and clinicians should be aware that C. burnetii may cause human and animal illness in these regions., (© 2024 The Author(s). Zoonoses and Public Health published by Wiley‐VCH GmbH.)

By hydrogenating carbon dioxide to value-added products such as methanol, heterogeneous catalysts can lower greenhouse gas emissions and generate alternative liquid fuels. The most common commercial catalyst for the reduction of CO 2 to methanol is Cu/ZnO/Al 2 O 3 , where ZnO improves conversion and selectivity toward methanol. The structure of this catalyst is thought to be Zn oxy(hydroxyl) overlayers on the nanometer scale on Cu. In the presence of CO 2 and H 2 under reaction conditions, the Cu substrate itself can be restructured and/or partially oxidized at its interface with ZnO, or the Zn might be reduced, possibly completely to a CuZn alloy, making the exact structure and stoichiometry of the active site a topic of active debate. In this study, we examine Zn 3 clusters on Cu(100) and Cu(111), as a subnano model of the catalyst. We use a grand canonical genetic algorithm to sample the system structure and stoichiometry under catalytic conditions: T of 550 K, initial partial pressures of H 2 of 4.5 atm and CO 2 of 0.5 atm, and 1% conversion. We uncover a strong dependence of the catalyst stoichiometry on the surface coverage. At the optimal 0.2 ML surface coverage, chains of Zn(OH) form on both Cu surfaces. On Cu(100), the catalyst has many thermally accessible metastable minima, whereas on Cu(111), it does not. No oxidation or reconstruction of the Cu is found. However, at a lower coverage of Zn, Zn 3 clusters take on a metallic form on Cu(100), and slightly oxidized Zn 3 O on Cu(111), while the surface uptakes H to form a variety of low hydrides of Cu. We thus hypothesize that the 0.2 ML Zn coverage is optimal, as found experimentally, because of the stronger yet incomplete oxidation afforded by Zn at this coverage.

Background: Sedentary behavior is highly prevalent and associated with morbidity and mortality in chronic kidney disease (CKD). A Sit Less, Interact and Move More (SLIMM) sedentary activity coaching intervention can reduce sedentary duration among persons with CKD, but preliminary data suggest that effects may not persist. Prior studies have suggested that moderate/vigorous intensity physical activities are not sustainable in persons with CKD. Therefore, we aimed to determine whether guided resistance training ± oral semaglutide co-intervention improves adherence and/or persistence of the SLIMM intervention., Method/design: The SLIMM-2 is a two-center study designed with a 3-month sedentary activity coaching (SLIMM) followed by a 9-month randomized controlled trial with three arms: SLIMM + standard of care resistance training + oral placebo, SLIMM + guided resistance training + oral placebo, or SLIMM + guided resistance training + oral semaglutide. The study is recruiting persons with CKD (eGFR 20 to ≤60 ml/min/1.73 m 2 ). ActivPAL, a wearable tri-axial accelerometer, is used to assess outcomes including sedentary duration (primary outcome), stepping duration and the average number of steps per day. Additional outcomes include 6-min walk distance and body fat percentage. Persons randomized to standard of care resistance training will be encouraged to maintain individualized physical activity goals; those randomized to guided resistance training will attend guided sessions per month and be prescribed daily independent exercises., Results: Enrollment, interventions, and follow-up are ongoing., Conclusions: Results from the SLIMM-2 study are expected to inform clinical practice, with the potential to enhance physical health and functioning among persons with CKD., (Copyright © 2024. Published by Elsevier Inc.)

Plants of the subfamily Amaryllidoideae are a source of unique and bioactive alkaloids called Amaryllidaceae alkaloids. The study of their anticancer potential has intensified in recent years. This work aims to locate and characterize the profile of cytotoxic alkaloids biosynthesized and stored in different tissues of Phaedranassa lehmannii Regel using different histochemical methods and chromatographic analysis. The histochemical analysis in the bulbs revealed the presence of alkaloids at the basal edge of the scale-like leaves and bud apical zone. The GC-MS analysis indicated that the bulbs biosynthesize crinane- (9.80 µg/g DW), galanthamine- (8.04 µg/g DW), lycorine- (7.38 µg/g DW), and narciclasine-type (3.75 µg/g DW) alkaloids. The root biosynthesizes alkaloids that are mainly distributed mostly in lycorine- (225.29 µg/g DW) and galanthamine-type (72.35 µg/g DW) alkaloids. The total alkaloids biosynthesized by the root (324.93 µg/g DW) exceeded eleven times the abundance of the alkaloids identified in the bulbs (28.97 µg/g DW). In addition, the total alkaloid fractions exhibited a dose-dependent cytotoxic effect in the evaluated concentrations, with IC 50 values of 11.76 ± 0.99 µg/mL and 2.59 ± 0.56 µg/mL against human lung (A549) cancer cells and 8.00 ± 1.35 µg/mL and 18.74 ± 1.99 µg/mL against gastric (AGS) cancer cells. The present study provided evidence to locate and characterize the alkaloids of P. lehmannii grown under nursery conditions as a species producing potential antiproliferative alkaloids.

Telomeres are pivotal determinants of cell stemness, organismal aging, and lifespan. Herein, we examined similarities in telomeres of Arabidopsis thaliana, mice, and humans. We report the common traits, which include their composition in multimers of TTAGGG sequences and their protection by specialized proteins. Moreover, given the link between telomeres, on the one hand, and cell proliferation and stemness on the other, we discuss the counterintuitive convergence between plants and mammals in this regard, focusing on the impact of niches on cell stemness. Finally, we suggest that tackling the study of telomere function and cell stemness by taking into consideration both plants and mammals can aid in the understanding of interconnections and contribute to research focusing on aging and organismal lifespan determinants., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Embryonic stem cells possess the remarkable ability to self-organize into blastocyst-like structures upon induction. These stem cell-based embryo models serve as invaluable platforms for studying embryogenesis and therapeutic developments. Nevertheless, the specific intrinsic regulators that govern this potential for blastoid formation remain unknown. Here we demonstrate an intrinsic program that plays a crucial role in both blastoids and blastocysts across multiple species. We first establish metrics for grading the resemblance of blastoids to mouse blastocysts, and identify the differential activation of gene regulons involved in lineage specification among various blastoid grades. Notably, abrogation of nuclear receptor subfamily 1, group H, member 2 (Nr1h2) drastically reduces blastoid formation. Nr1h2 activation alone is sufficient to rewire conventional ESC into a distinct pluripotency state, enabling them to form blastoids with enhanced implantation capacity in the uterus and contribute to both embryonic and extraembryonic lineages in vivo. Through integrative multi-omics analyses, we uncover the broad regulatory role of Nr1h2 in the transcriptome, chromatin accessibility and epigenome, targeting genes associated with embryonic lineage and the transposable element SINE-B1. The Nr1h2-centred intrinsic program governs and drives the development of both blastoids and early embryos., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

In recent years, using orthogonal matrices has been shown to be a promising approach to improving recurrent neural networks (RNNs) with training, stability, and convergence, particularly to control gradients. While gated recurrent unit (GRU) and long short-term memory (LSTM) architectures address the vanishing gradient problem by using a variety of gates and memory cells, they are still prone to the exploding gradient problem. In this work, we analyze the gradients in GRU and propose the use of orthogonal matrices to prevent exploding gradient problems and enhance long-term memory. We study where to use orthogonal matrices and propose a Neumann series-based scaled Cayley transformation for training orthogonal matrices in GRU, which we call Neumann-Cayley orthogonal GRU (NC-GRU). We present detailed experiments of our model on several synthetic and real-world tasks, which show that NC-GRU significantly outperforms GRU and several other RNNs., (© 2024 Massachusetts Institute of Technology.)

A complete understanding of RNA biology requires methods for tracking transcripts in vivo. Common strategies rely on fluorogenic probes that are limited in sensitivity, dynamic range, and depth of interrogation, owing to their need for excitation light and tissue autofluorescence. To overcome these challenges, we report a bioluminescent platform for serial imaging of RNAs. The RNA tags are engineered to recruit light-emitting luciferase fragments (termed RNA lanterns) upon transcription. Robust photon production is observed for RNA targets both in cells and in live animals. Importantly, only a single copy of the tag is necessary for sensitive detection, in sharp contrast to fluorescent platforms requiring multiple repeats. Overall, this work provides a foundational platform for visualizing RNA dynamics from the micro to the macro scale., Competing Interests: Competing interests A.L., J.A.P., O.S., K.K.N., K.H.C., L.P.H., and C.C.C. are on a provisional patent application, filed through UCI, based on the results described here. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Morel-Lavallee Lesion (MLL) is a rare diagnosis of a closed internal degloving injury that can occur with high energy trauma. The pain, soft tissue swelling, and ecchymosis that patients describe mimic many other emergent diagnoses to include compartment syndrome and fractures. The following case highlights the importance of the role of Emergency Medicine physicians using point-of-care ultrasound (POCUS) to recognize and treat a potentially life-threatening injury. Our patient was initially managed with a bedside needle aspiration with drainage of 25cc of serosanguinous fluid that resulted in immediate pain relief. Patient was then admitted for further Interventional Radiology drainage of 160cc of serosanguinous fluid by Interventional Radiology., Competing Interests: The authors declare that they have no competing interests., (Copyright (c) 2024 Djoser Mack, Joselyn Miller, Frank Yuan, Edison Lee, Trent She.)

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by a deficiency in the phenylalanine hydroxylase (PAH) enzyme, leading to the accumulation of phenylalanine and its metabolites, which are toxic to the central nervous system. Without treatment, PKU can result in severe intellectual disability and neurological issues. This study aims to present the first cohort of clinically described Ecuadorian PKU patients, analyzing genotype-phenotype correlations and comparing these variants with global databases to improve diagnosis and treatment in Ecuador. Detailed clinical histories were collected, and an analysis of genotype versus phenotype (affected protein domain) of the variant was performed. Among the PAH genotypes identified, we found 15 distinct variants, with c.[754 C > T](p.Arg252Trp); [754 C > T](p.Arg252Trp) being the most frequent genotype (23.68%), followed by c.[1045T > C](p.Ser349Pro); [1045T > C](p.Ser349Pro) (15.79%) and c.[441 + 5G > T]; [754 C > T](p.Arg252Trp) (13.16%). Additionally, several unique genotypes were identified, such as c.[140G > A](p.Ala47Val); [140G > A](p.Ala47Val) and c.[331 C > T](p.Arg111Ter); [1243G > A](p.Asp415Asn), which are not commonly reported in other populations. Most genotypes were heterozygous (63.2%). The majority of variants were missense variants (66.6%) affecting the catalytic domain (53.3%). The highest phenylalanine levels were found in patients with c.[754 C > T](p.Arg252Trp); [754 C > T] (p.Arg252Trp) (2700 umol/L). Phenotypic data were available for 11 patients, showing 45.45% with classic PKU, 45.45% with mild hyperphenylalaninemia, and 9% with mild PKU. There was a 63.6% concordance with the BIOPKU database. Five low-frequency genotypes not reported in BIOPKU were identified, suggesting unique regional variants. Our study highlights the genetic complexity of PKU in Ecuador, with a high prevalence of unique variants not commonly found in other regions. This underscores the necessity for region-specific genetic analysis to improve PKU diagnosis and treatment. The findings emphasize the importance of tailored therapeutic strategies and continued research to enhance outcomes for PKU patients in Latin America., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the institutional review board of Universidad San Francisco de Quito (USFQ) (code 2020-038IN) and conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent. Consent for publication Written informed consent for publication was obtained from the participant. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. ecDNA renders tumours treatment resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival 1-7 . At present, there are no ecDNA-specific treatments. Here we show that enhancing transcription-replication conflict enables targeted elimination of ecDNA-containing cancers. Stepwise analyses of ecDNA transcription reveal pervasive RNA transcription and associated single-stranded DNA, leading to excessive transcription-replication conflicts and replication stress compared with chromosomal loci. Nucleotide incorporation on ecDNA is markedly slower, and replication stress is significantly higher in ecDNA-containing tumours regardless of cancer type or oncogene cargo. pRPA2-S33, a mediator of DNA damage repair that binds single-stranded DNA, shows elevated localization on ecDNA in a transcription-dependent manner, along with increased DNA double strand breaks, and activation of the S-phase checkpoint kinase, CHK1. Genetic or pharmacological CHK1 inhibition causes extensive and preferential tumour cell death in ecDNA-containing tumours. We advance a highly selective, potent and bioavailable oral CHK1 inhibitor, BBI-2779, that preferentially kills ecDNA-containing tumour cells. In a gastric cancer model containing FGFR2 amplified on ecDNA, BBI-2779 suppresses tumour growth and prevents ecDNA-mediated acquired resistance to the pan-FGFR inhibitor infigratinib, resulting in potent and sustained tumour regression in mice. Transcription-replication conflict emerges as a target for ecDNA-directed therapy, exploiting a synthetic lethality of excess to treat cancer., (© 2024. The Author(s).)

Angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are not recommended during the second and third trimester because of the significant risk of congenital anomalies associated with their use. However, data are scarce, especially regarding their use in the first trimester and about the impact of stopping just before pregnancy. Our study illustrates the profile of the women who used ACE-Is or ARBs during pregnancy and evaluates the impact on perinatal outcomes. The Registry of Pregnancy and Cardiac Disease is a prospective, global registry of pregnancies in women with structural heart disease. Outcomes were compared between women who used ACE-Is or ARBs and those who did not. Multivariable regression analysis was performed to assess the effect of ACE-I or ARB use on the occurrence of congenital anomalies. ACE-Is (n = 35) and/or ARBs (n = 8) were used in 42 (0.7%) of the 5,739 Registry of Pregnancy and Cardiac Disease pregnancies. Women who used ACE-Is or ARBs more often came from a low-or-middle-income country (57% vs 40%, p = 0.021), had chronic hypertension (31% vs 6%, p <0.001), or a left ventricular ejection fraction <40% (33% vs 4%, p <0.001). In the multivariable analysis, ACE-I use during the first trimester was associated with an increased risk of congenital anomaly (odds ratio 3.2, 95% confidence interval 1.0 to 9.6). Therefore, ACE-Is should be avoided during pregnancy, also in the first trimester, because of a higher risk of congenital anomalies. However, there is no need to stop long before pregnancy. Preconception counseling is crucial to discuss the potential risks of these medications, to evaluate the clinical condition and, if possible, to change or stop the medication., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Pregnancy involves anatomical, physiological, and metabolic changes in a woman's body. However, the effects of these changes on the voice remains unclear, particularly regarding the clinical characteristics., Objectives: We aimed to evaluate changes in vocal and speech acoustic measures and the relationship between them and clinical aspects in women during pregnancy., Method: A prospective, longitudinal study was carried out with 41 low risk, adult, pregnant women, followed for prenatal care. Demographic and anthropometric data as well as lifestyle habits and health conditions were collected. Voice recordings of sustained vowels, and automatic and spontaneous speech were held over each trimester and analyzed by PRAAT®to evaluate acoustic, aerodynamic, and articulatory measures., Results: There were no changes in fundamental frequency, jitter, shimmer, and harmony to noise ratio during pregnancy. Maximum phonation time (MPT), pause rate, and pause duration reduced at the end of pregnancy. MPT was lower in sedentary pregnant women. The fundamental frequency peak rate was higher in eutrophic participants and lower in the third trimester in women with BMI ≥25 kg/m 2 . Pause rate was higher in pregnant women with BMI ≥25 kg/m 2 . There was no relationship between sleep quality, reflux, and vocal symptoms and acoustic and aerodynamic measures., Conclusions: Differences were shown in MPT and temporal pause measurements during pregnancy. Acoustic measurements did not change. There was a relationship between acoustic and aerodynamic measures and clinical variables (BMI, physical activity, and body mass gain)., Competing Interests: DECLARATION OF COMPETING INTEREST None., (Copyright © 2022. Published by Elsevier Inc.)

Underground mines are considered one of the riskiest facilities for human activities due to numerous accidents and geotechnical failures recorded worldwide over the last century, which have resulted in unsafe labor conditions, poor health outcomes, injuries, and fatalities. One significant cause of these accidents is the inadequate or nonexistent capacity for the real-time monitoring of safety conditions in underground mines. In this context, new emerging technologies linked to the Industry 4.0 paradigm, such as sensors, the Internet of Things (IoT), and LoRaWAN (Long Range Wide Area Network) wireless connectivity, are being implemented for planning the efficient, safe, and sustainable performance of underground mine labor environments. This paper studies the implementation of an ecosystem composed of IoT sensors and LoRa wireless connectivity in a data-acquisition system, which eliminates the need for expensive cabling and manual monitoring in mining operations. Laying cables in an underground mine necessitates cable support and protection against issues, such as machinery operations, vehicle movements, mine operator activities, and groundwater intrusion. As the underground mine expands, additional sensors typically require costly cable installations unless wireless connectivity is employed. The results of this review indicate that an IoT LoRaWAN-based wireless sensor network (WSN) provides real-time data under complex conditions, effectively transmitting data through physical barriers. This network presents an attractive low-cost solution with reliable, simple, scalable, secure, and competitive characteristics compared to cable installations and manually collected readings, which are more sporadic and prone to human error. Reliable data on the behavior of the underground mine enhances productivity by improving key performance indicators (KPIs), minimizing accident risks, and promoting sustainable environmental conditions for mine operators. Finally, the adoption of IoT sensors and LoRaWAN wireless connectivity technologies provides information of the underground mine in real-time, which supports better decisions by the mining industry managers, by ensuring compliance with safety regulations, improving the productive performance, and fostering a roadmap towards more environmentally friendly labor conditions.

Edible flowers have been used since ancient times, but their potential for improving human health has not been explored. This study aimed to evaluate the profile of bioactive compounds (organic acids, phenolics, and carotenoids) and the antioxidant and antimicrobial activity of nine flower varieties with high concentrations of carotenoids or total phenolic compounds. Ninety-three edible flowers were analysed for physicochemical characteristics, total phenolic and carotenoid concentrations, and antioxidant activity (ABTS). Bioactive profiles were determined by rapid resolution liquid chromatography (RRLC), and antimicrobial activity was determined against Escherichia coli , Staphylococcus aureus , Pseudomonas aeruginosa and Streptococcus mutans , and Candida albicans and Candida tropicalis. Chrysanthemum x hybrid orange, Helianthus annuus yellow, Tagetes patula orange, Canna indica red, and Hibiscus rosa-sinensis (orange1 and yellow) showed significant concentrations of total carotenoids. In contrast, Pelargonium hortorum orange2, Hibiscus rosa-sinensis red1, and Rosa x hybrid variety medium yellow showed high levels of total phenolics. The predominant compounds in these species were citric acid (991.4 mg/g DW in Hibiscus rosa-sinensis red1), 4-hydroxybenzoic acid (936.2 mg/100 g DW in P. hortorum orange2), kaempferol (971. 9 mg/100 g DW in T. patula orange), quercetin glucoside (958.8 in C. x hybrid ), quercetin (919.3 mg/100 g DW in T. patula ), α-carotene, and β-carotene in T. patula orange (989.5 and 601.2 mg/100 g DW, respectively). Regarding antimicrobial activity, T. patula orange and P. hortorum orange2 inhibited bacterial growth, while C. x hybrid orange and P. hortorum orange2 inhibited Candida albicans, and the latter inhibited Candida tropicalis . These results indicate the potential of edible flowers as a natural source of bioactive compounds and as a tool in the fight against antimicrobial resistance.

The question of optimal timing for catheter ablation of atrial fibrillation (AF) to achieve best outcomes remains a crucial clinical issue. As AF occurs less frequently in younger patients, data regarding Diagnosis-to-Ablation Time (DAT) is especially limited in patients under the age of 55 years with persistent AF. We therefore analyzed the temporal relationship between initial AF presentation and timing of catheter ablation in this cohort. We conducted a retrospective single-centre study of patients ≤ 55 years with persistent AF who underwent first-time catheter ablation at our center. The cohort was divided into patients that underwent catheter ablation after diagnosis of persistent AF within a DAT of ≤ 12 months and patients with a DAT of > 12 months. A total of 101 patients (median age 51 years; female n = 19 (18.8%)) with persistent AF were included. Ablation was performed within 12 months ("early DAT") in 51 patients and > 12 months ("late DAT") in 50 patients. Pulmonary vein isolation was performed using high-power short-duration (HPSD) radiofrequency ablation. Median DAT was 5 months (1-12 months) in the early ablation group and 36 months (13-240 months) in the late ablation group. The median follow-up was 11.3 months (0.03-37.1 months). The rate of any atrial arrhythmia recurrence after a 30-day blanking period was significantly lower in the early DAT group (13/51 patients; 25.5%) as compared to the late DAT group (26/50 patients; 52.0%) (log rank test; p = 0.003). Catheter ablation performed > 12 months after the initial AF diagnosis was an independent predictor for the occurrence of any atrial arrythmia (OR: 2.58; (95%-CI: 1.32-5.07). Early first-time catheter ablation (DAT ≤ 12 months) in patients ≤ 55 years with persistent AF is associated with a significantly lower rate of arrhythmia recurrence., (© 2024. The Author(s).)

Recent studies indicate that central administration of oxytocin (OT) reduces body weight (BW) in high fat diet-induced obese (DIO) rodents by reducing energy intake and increasing energy expenditure (EE). Previous studies in our lab have shown that administration of OT into the fourth ventricle (4V; hindbrain) elicits weight loss and stimulates interscapular brown adipose tissue temperature (T IBAT ) in DIO rats. We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of IBAT contributes to its ability to activate BAT and reduce BW in DIO rats. To test this, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of T IBAT and reduction of BW in DIO rats. We first confirmed that bilateral surgical SNS denervation to IBAT was successful based on having achieved ≥ 60% reduction in IBAT norepinephrine (NE) content from DIO rats. NE content was selectively reduced in IBAT by 94.7 ± 2.7, 96.8 ± 1.8 and 85.9 ± 6.1% ( P <0.05) at 1, 6 and 7-weeks post-denervation, respectively, and was unchanged in liver or inguinal white adipose tissue. We then measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (1, 5 μg) to stimulate T IBAT in DIO rats. We found that the high dose of 4V OT (5 μg) stimulated T IBAT similarly between sham and denervated rats ( P =NS) and that the effects of 4V OT to stimulate T IBAT did not require beta-3 adrenergic receptor signaling. We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day) or vehicle infusion to reduce BW, adiposity, and energy intake in DIO rats. Chronic 4V OT reduced BW gain by -7.2 ± 9.6 g and -14.1 ± 8.8 g in sham and denervated rats ( P <0.05 vs vehicle treatment), respectively, and this effect was similar between groups ( P =NS). These effects were associated with reductions in adiposity and energy intake ( P <0.05). Collectively, these findings support the hypothesis that sympathetic innervation of IBAT is not required for central OT to increase BAT thermogenesis and reduce BW gain and adiposity in male DIO rats.

Introduction: The meningeal lymphatic vessels have been described as a pathway that transports cerebrospinal fluid and interstitial fluid in a unidirectional manner towards the deep cervical lymph nodes. However, these vessels exhibit anatomical and molecular characteristics typical of initial lymphatic vessels, with the absence of surrounding smooth muscle and few or absent valves. Given its structure, this network could theoretically allow for bidirectional motion. Nevertheless, it has not been assessed as a potential route for nanoparticles to travel from peripheral tissues to the brain., Methods: We employed superparamagnetic iron oxide nanoparticles (SPIONs), exosomes loaded with SPIONs, gold nanorods, and Chinese ink nanoparticles. SPIONs were prepared via chemical coprecipitation, while exosomes were isolated from the B16F10 melanoma cell line through the Exo-Spin column protocol and loaded with SPIONs through electroporation. Gold nanorods were functionalized with polyethylene glycol. We utilized C57BL/6 mice for post-mortem and in vivo procedures. To evaluate the retrograde directional flow, we injected each nanoparticle solution in the deep cervical lymph node. The head and neck were fixed for magnetic resonance imaging and histological analysis., Results: Here we show that extracellular vesicles derived from the B16F10 melanoma cell line, along with superparamagnetic iron oxide nanoparticles, gold nanorods, and Chinese ink nanoparticles can reach the meningeal lymphatic vessels and the brain of C57BL/6 mice after administration within the deep cervical lymph nodes post-mortem and in vivo, exclusively through lymphatic structures., Discussion: The functional anatomy of dural lymphatics has been found to be conserved between mice and humans, suggesting that our findings may have significant implications for advancing targeted drug delivery systems using nanoparticles. Understanding the retrograde transport of nanoparticles through the meningeal lymphatic network could lead to novel therapeutic approaches in nanomedicine, offering new insights into fluid dynamics in both physiological and neuropathological contexts. Further research into this pathway may unlock new strategies for treating neurological diseases or enhancing drug delivery to the brain., Competing Interests: The authors declare no competing interests in this work., (© 2024 Ramos-Zaldívar et al.)

An increase in the number of drug-resistant microbes is a major threat to human health. Bacterial drug resistance is mostly mediated by biofilm formation. In this study, the culture filtrate from the edible mushroom, Pleurotus ostreatus, was fractionated to isolate compounds that inhibit the biofilm formation of six pathogenic bacteria. Notably, we isolated compounds 16 using bioassay-guided chromatographic separations. Spectroscopic and X-ray diffraction analyses identified 1 as a novel fused bicyclic pyrone-furan, named pleuropyronine, whereas 2-6 were known polyketides. Pleuropyronine inhibited biofilm formation in four gram-negative bacteria, with IC50 values ranging from 5.4 to 8.7 µg/mL, whereas 2-6 exhibited IC50 values between 1.0 and 5.3 µg/mL against five bacteria. Additionally, pleuropyronine bioactivity was confirmed by the inhibition of exopolysaccharide and biofilm formation induced by C6-homoserine lactone. Thus, this may serve as a pioneering study on the pharmacological potential of isolated compounds, offering valuable insights for future research., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Recent studies have indicated that hindbrain [fourth ventricle (4V)] administration of the neurohypophyseal hormone, oxytocin (OT), reduces body weight, energy intake and stimulates interscapular brown adipose tissue temperature (T IBAT ) in male diet-induced obese (DIO) rats. What remains unclear is whether chronic hindbrain (4V) OT can impact body weight in female high fat diet-fed (HFD) rodents and whether this involves activation of brown adipose tissue (BAT). We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of interscapular brown adipose tissue (IBAT) contributes to its ability to activate BAT and reduce body weight in female high HFD-fed rats. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of T IBAT and reduction of body weight in DIO rats. We first measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (0.5, 1, and 5 µg ≈ 0.5, 0.99, and 4.96 nmol) to stimulate T IBAT in female HFD-fed rats. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) stimulated T IBAT similarly between sham rats and denervated rats ( p = NS). We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day ≈ 16.1 μg/day) or vehicle infusion to reduce body weight, adiposity and energy intake in female HFD-fed rats (N = 7-8/group). Chronic 4V OT reduced body weight gain (sham: -18.0 ± 4.9 g; denervation: -15.9 ± 3.7 g) and adiposity (sham: -13.9 ± 3.7 g; denervation: -13.6 ± 2.4 g) relative to vehicle treatment ( p < 0.05) and these effects were similar between groups ( p = NS). These effects were attributed, in part, to reduced energy intake evident during weeks 2 ( p < 0.05) and 3 ( p < 0.05). To test whether these results translate to other female rodent species, we also examined the effect of chronic 4V infusion of OT on body weight and adiposity in two strains of female HFD-fed mice. Similar to what we found in the HFD-fed rat model, we also found that chronic 4V OT (16 nmol/day) infusion resulted in reduced body weight gain, adiposity and energy intake in female DIO C57BL/6J and DBA/2J mice ( p < 0.05 vs. vehicle). Together, these findings suggest that (1) sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and weight loss in female HFD-fed rats and (2) the effects of OT to reduce weight gain and adiposity translate to other female mouse models of diet-induced obesity (DIO).

Respiratory infections account for millions of hospital admissions worldwide. The aetiology of respiratory infections can be attributed to a diverse range of pathogens including viruses, bacteria and fungi. SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2)-negative specimens from Wattansoppeng city, South Sulawesi, were analysed to study the spectrum of respiratory viruses. Samples were screened for influenza virus, enterovirus, Paramyxoviridae, Nipah virus, Coronaviridae and Pneumoviridae. Of 210 specimens, 19 were positive for respiratory syncytial virus (RSV)-A, RSV-B, human parainfluenza virus type 1 (HPIV-1), HPIV-2, human rhinovirus (HRV)-A, HRV-B, HRV-C, human metapneumovirus (HMPV), influenza A virus (IAV) and coxsackievirus A6 (CV-A6). Influenza virus was of seasonal H3N2 subtype. The HMPVs were of genotypes B1 and A2a, while one RSV-A was of the ON-1 genotype. The viruses mostly affected children with unknown severity., Competing Interests: The authors declare that there are no conflicts of interest. K.S.A. Myint receives research support from the US CDC. The findings and conclusions expressed in this report do not necessarily represent the views of the US Center for Disease Control and Prevention., (Copyright © 2024 The Authors.)

Background: Guidelines for chronic rhinosinusitis (CRS) propose total IgE and eosinophils as important biomarkers to identify type-2 inflammation. Despite the fact that specific IgE (sIgE) have been identified as a clinical predictor in some type-2 diseases for different clinical outcomes, its role in CRS has yet to be explored in detail., Objetive: To describe systemic and local sIgE in CRS and explore its possible association with clinical outcomes using nasal challenge tests (NCT)., Methods: In CRS patients, we measure total IgE, serum sIgE (SsIgE) and nasosinusal sIgE (NsIgE) against 9 allergenic sources; Der p, Der f, Blo t, Can f, Fel d, Per a, grasses, Staphylococcus enterotoxin A, and B. NCT was done using the allergen with the higher sIgE prevalence (Der p)., Results: A total of 174 patients were included. Prevalence of SsIgE was 52.8% and NsIgE 46.5%; Der p was the principal allergen for SsIgE and NsIgE. The presence of nasal polyps, asthma comorbidity, NSAID hypersensitivity, and hyposmia, were significantly associated with the presence of SsIgE and NsIgE but not with total IgE. NCT-Der p was performed in 73 CRS patients, being positive in 33 (45.2%). SsIgE have the best diagnostic accuracy (79.4%) to predict NCT results (NsIgE 67.5% total IgE 52%)., Conclusion: Specific IgE is a better biomarker in CRS than total IgE. Patients with clinically relevant SsIgE have a pheno-endotype associated with different clinical outcomes. Considering the clinical relevance of SsIgE demonstrated by NCT, interventions like allergen immunotherapy in CRS must be study., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

Telenomus remus (Hymenoptera: Scelionidae) is an efficient parasitoid of Spodoptera eggs. However, biological control programs require taxonomic, bioecological and behavioral studies of biological agents. Although the performance of T. remus in pest control has been evaluated, little is known about its behavioral aspects that can influence IPM tactics. The aim of this study was therefore to study the parameters related to the oviposition behavior of T. remus on Spodoptera frugiperda (Lepidoptera: Noctuidae) eggs. The experiment was conducted in the laboratory, where 17 females were transferred individually to arenas containing a mass of S. frugiperda eggs. Oviposition behavior was recorded for 30 minutes. The average walking speed of the females was 0.116 mm.s-1 and the total distance covered was 203.3 mm. The females remained on the egg masses for an average of 16.7 min, which corresponds to more than half of the total time. The average number of parasitized eggs was 15.1 per female in 30 minutes. Females with larger antennae had lower values for average speed and total distance covered. The results of the parameters evaluated show the standard oviposition behavior of T. remus females on S. frugiperda eggs and help us to better understand the species.

The emergence of new SARS-CoV-2 variants of concern associated with waning immunity induced by natural infection or vaccines currently in use suggests that the COVID-19 pandemic will become endemic. Investing in new booster vaccines using different platforms is a promising way to enhance protection and keep the disease under control. Here, we evaluated the immunogenicity, efficacy, and safety of the SpiN-Tec vaccine, based on a chimeric recombinant protein (SpiN) adjuvanted with CTVad1 (MF59-based adjuvant), aiming at boosting immunity against variants of concern of SARS-CoV-2. Immunization of K18-hACE-2 transgenic mice and hamsters induced high antibody titers and cellular immune response to the SpiN protein as well as to its components, RBD and N proteins. Importantly in a heterologous prime/boost protocol with a COVID-19 vaccine approved for emergency use (ChAdOx1), SpiN-Tec enhanced the level of circulation neutralizing antibodies (nAb). In addition to protection against the Wuhan isolate, protection against the Delta and Omicron variants was also observed as shown by reduced viral load and lung pathology. Toxicity and safety tests performed in rats demonstrated that the SpiN-Tec vaccine was safe and, based on these results, the SpiN-Tec phase I/II clinical trial was approved., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ricardo Tostes Gazzinelli reports financial support was provided by Rede Virus from the Ministry of Science, Technology and Innovation. Ricardo Tostes Gazzinelli reports financial support was provided by National Council for Scientific and Technological Development. Ricardo Tostes Gazzinelli reports financial support was provided by National Institute of Science and Technology of Vaccines. Ricardo Tostes Gazzinelli reports financial support was provided by State of São Paulo Research Foundation. Ricardo Tostes Gazzinelli reports financial support was provided by Ministry of Education. Ricardo Tostes Gazzinelli reports financial support was provided by Oswaldo Cruz Foundation. Ricardo Tostes Gazzinelli reports financial support was provided by Belo Horizonte City Council. Ricardo Tostes Gazzinelli reports financial support was provided by Parliamentary Amendment of State and Federal Representatives from Minas Gerais. Ricardo Tostes Gazzinelli has patent #BR1020210095733 issued to Licensee. 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 © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study, we aimed to investigate whether the abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). To this end, central venous and systemic arterial ET-1 plasma levels were simultaneously measured on Days 1 and 3 following ICU admission in mechanically ventilated COVID-19 patients with ARDS (COVID-19 ARDS, N = 18). Central venous and systemic arterial ET-1 plasma levels were also measured in two distinct SARS-CoV-2-negative mechanically ventilated critically ill patient groups, matched for age, sex, and critical illness severity, with ARDS (non-COVID-19 ARDS, N = 14) or without ARDS (non-COVID-19 non-ARDS, N = 20). Upon ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and central venous ET-1 levels compared to the non-COVID-19 ARDS and non-COVID-19 non-ARDS patients ( p < 0.05), yet a normal systemic arterial:central venous (A:V) ET-1 ratio [0.63 (0.49-1.02)], suggesting that pulmonary ET-1 clearance is intact in these patients. On the other hand, the non-COVID-19 ARDS patients demonstrated abnormal ET-1 handling [A:V ET-1 ratio 1.06 (0.93-1.20)], while the non-COVID-19 non-ARDS group showed normal ET-1 handling [0.79 (0.52-1.11)]. On Day 3, the A:V ratio in all three groups was <1. When the COVID-19 ARDS patients were divided based on 28-day ICU mortality, while their systemic arterial and central venous levels did not differ, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors [0.95 (0.78-1.34)] compared to the survivors [0.57 (0.48-0.92), p = 0.027]. Our results highlight the potential importance of ET-1 as both a biomarker and a therapeutic target in critically ill COVID-19 patients. The elevated A:V ET-1 ratio in non-survivors suggests that the early disruption of pulmonary ET-1 handling may be a key marker of poor prognosis.

Purpose: This study evaluated the safety and immunogenicity of the PIKA-adjuvanted recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein subunit vaccine as a booster dose for healthy adults who had previously received two or more doses of an inactivated coronavirus disease 2019 (COVID-19) vaccine., Materials and Methods: The study was a phase II multicenter, double-blinded, comparator-controlled, randomized trial. Participants were randomly assigned to receive either the PIKA COVID-19 vaccine booster dose or an inactivated COVID-19 vaccine (Sinovac, China). Safety was assessed based on adverse events, while immunogenicity was measured by neutralizing antibodies against SARS-CoV-2 and serum immunoglobulin G (IgG) levels. Data on safety and immunogenicity were collected in the short-term (within 14 days after the booster dose) and long-term (from 90 to 365 days after the booster dose)., Results: The PIKA-adjuvanted vaccine demonstrated a significant increase in neutralizing antibodies against the Omicron variant (geometric mean ratio [GMR]=2.0 on day 7, p-value <0.001; GMR=2.7 on day 14, p-value <0.001) and the wild type SARS-CoV-2 virus (GMR=2.3 on day 7, p-value <0.001; GMR=2.8 on day 14, p-value<0.001) in the early post-vaccination period when compared to the inactivated vaccine. Additionally, the PIKA COVID-19 vaccine showed higher seroconversion rates for neutralizing antibodies against both variants during the first 14 days post-vaccination. However, there were no significant differences in neutralizing antibody levels between the two vaccines from day 90 to day 360 post-vaccination. Serum IgG antibody levels for the PIKA COVID-19 vaccine were also higher throughout the study period. The incidence of adverse events was slightly higher in the PIKA COVID-19 group, with the most common events being pain at the injection site and headache. All adverse events were mild or moderate, with no reports of severe or life-threatening adverse events in either group., Conclusion: The PIKA COVID-19 vaccine, when administered as a booster dose, showed promising short- and long-term immunogenicity with no emergent safety issues identified. The booster dose of the PIKA COVID-19 vaccine elicited a robust immune response against various SARS-CoV-2 variants and provided some seroprotection for up to 360 days (ClinicalTrials.gov registration number: NCT05463419)., (© Korean Vaccine Society.)

Background: Non-inferiority (NI) trials require unique trial design and methods, which pose challenges in their interpretation and applicability, risking introduction of inferior therapies in clinical practice. With the abundance of novel therapies, NI trials are increasing in publication. Prior studies found inadequate quality of reporting of NI studies, but were limited to certain specialties/journals, lacked NI margin evaluation, and did not examine temporal changes in quality. We conducted a systematic review without restriction to journal type, journal impact factor, disease state or intervention to evaluate the quality of NI trials, including a comprehensive risk of bias assessment and comparison of quality over time., Methodology: We searched PubMed and Cochrane Library databases for NI trials published in English in 2014 and 2019. They were assessed for: study design and NI margin characteristics, primary results, and risk of bias for blinding, concealment, analysis method and missing outcome data., Results: We included 823 studies. Between 2014 and 2019, a shift from publication in specialty to general journals (15% vs 28%, p < 0.001) and from pharmacological to non-pharmacological interventions (25% vs 38%, p = 0.025) was observed. The NI margin was specified in most trials for both years (94% vs 95%). Rationale for the NI margin increased (36% vs 57%, p < 0.001), but remained low, with clinical judgement the most common rationale (30% vs 23%), but more 2019 articles incorporating patient values (0.3% vs 21%, p < 0.001). Over 50% of studies were open-label for both years. Gold standard method of analyses (both per protocol + (modified) intention to treat) declined over time (43% vs 36%, p < 0.001)., Discussion: The methodological quality and reporting of NI trials remains inadequate although improving in some areas. Improved methods for NI margin justification, blinding, and analysis method are warranted to facilitate clinical decision-making., (© 2024. The Author(s).)

Zinc metal anodes encounter significant challenges, including dendrite growth, hydrogen evolution, and corrosion, all of which impede the rate capability and longevity of aqueous zinc-ion batteries (AZIBs). To effectively tackle these issues, we introduced Tween-80 into the traditional ZnSO 4 electrolyte as an additive. Tween-80 possesses electronegative oxygen atoms that enable it to adsorb onto the zinc (Zn) anode surface, facilitating the directional deposition of Zn metal along the (002) orientation. The hydroxyl and ether groups within Tween-80 can displace some of the coordinated water molecules in the Zn 2+ inner solvation shell. This disruption of the hydrogen bond network regulates the solvation structure of Zn 2+ ions and suppresses the possibility of hydrogen evolution. Moreover, the long hydrocarbon chain present in Tween-80 exhibits excellent hydrophobic properties, aiding in the resistance against corrosion of the Zn anode by water molecules and reducing hydrogen evolution. Consequently, a symmetric cell equipped with the Tween-80 additive can cycle stably for over 4000 h at 1 mA cm -2 and 1 mA h cm -2 . When paired with the V 2 O 5 cathode, the full cell demonstrates a high-capacity retention rate exceeding 80 % over 1000 cycles at a current density of 2 A g -1 . This study underscores the advantages of utilizing non-ionic surfactants for achieving high-performance aqueous zinc-ion batteries., 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 Inc. All rights reserved.)

Previous studies have implicated hindbrain oxytocin (OT) receptors in the control of food intake and brown adipose tissue (BAT) thermogenesis. We recently demonstrated that hindbrain [fourth ventricle (4V)] administration of oxytocin (OT) could be used as an adjunct to drugs that directly target beta-3 adrenergic receptors (β3-AR) to elicit weight loss in diet-induced obese (DIO) rodents. What remains unclear is whether systemic OT can be used as an adjunct with the β3-AR agonist, CL 316243, to increase BAT thermogenesis and elicit weight loss in DIO rats. We hypothesized that systemic OT and β3-AR agonist (CL 316243) treatment would produce an additive effect to reduce body weight and adiposity in DIO rats by decreasing food intake and stimulating BAT thermogenesis. To test this hypothesis, we determined the effects of systemic (subcutaneous) infusions of OT (50 nmol/day) or vehicle (VEH) when combined with daily systemic (intraperitoneal) injections of CL 316243 (0.5 mg/kg) or VEH on body weight, adiposity, food intake and brown adipose tissue temperature (T IBAT ). OT and CL 316243 monotherapy decreased body weight by 8.0±0.9% ( P <0.05) and 8.6±0.6% ( P <0.05), respectively, but OT in combination with CL 316243 produced more substantial weight loss (14.9±1.0%; P <0.05) compared to either treatment alone. These effects were associated with decreased adiposity, energy intake and elevated T IBAT during the treatment period. The findings from the current study suggest that the effects of systemic OT and CL 316243 to elicit weight loss are additive and appear to be driven primarily by OT-elicited changes in food intake and CL 316243-elicited increases in BAT thermogenesis., Competing Interests: Disclosures: JEB had a financial interest in OXT Therapeutics, Inc., a company that developed highly specific and stable analogs of oxytocin to treat obesity and metabolic disease but this is no longer the case. The authors’ interests were reviewed and were managed by their local institutions in accordance with their conflict of interest policies. The other authors have nothing to report.

Objetive: Congenital heart diseases (CHD) can be found in pregnant women. Although cardiac interventions in the catheterization laboratory are considered safe and effective, it is preferable to wait 3-6 months after delivery to correct simple, uncomplicated CHD; however, this may result in follow-up losses. The objective is to present our experience in correcting CHD during the early puerperium (EP)., Materials and Methods: All cases of pregnant women with CHD, including atrial septal defect (ASD), patent ductus arteriosus (PDA), and aortic coarctation (CoA) between 2017-2023, who underwent percutaneous defect correction during the EP were collected., Results: Fifteen pregnant women were included, diagnosed with ASD (5), PDA (6), and CoA (4). Five patients (33.3%) were classified as WHO risk class IV; the procedure was successful in 80% of the cases, and only 1 patient presented complications., Conclusions: In our experience, the closure of uncomplicated congenital defects during the EP did not present major complications and could be a treatment strategy to prevent follow-up losses after delivery in pregnant women with CHD., Competing Interests: Conflictos de interés: Ninguno

Water deficiency and potential drought periods could be important ecological factors influencing cultivation areas and productivity once different crops are established. The principal supply of vegetable oil for oil crops is oil palm, and new challenges are emerging in the face of climatic changes. This study investigated the photosynthetic performance of 12 genotypes of Elaeis exposed to drought stress under controlled conditions. The assay included genotypes of Elaeis guineensis, Elaeis oleifera, and the interspecific O×G hybrid ( E. oleifera × E. guineensis ). The principal results showed that the E. guineensis genotype was the most efficient at achieving photosynthesis under drought stress conditions, followed by the hybrid and E. oleifera genotypes. The physiological parameters showed good prospects for vegetal breeding with different O×G hybrids, mainly because of their ability to maintain the equilibrium between CO 2 assimilation and stomatal aperture. We validated 11 genes associated with drought tolerance, but no differences were detected. These results indicate that no allelic variants were represented in the RNA during sampling for the validated genotypes. In conclusion, this study helps to define genotypes that can be used as parental lines for oil palm improvement. The gas exchange data showed that drought stress tolerance could define guidelines to incorporate the available genetic resources in breeding programs across the early selection in nursery stages.

The present study used the adult earthworm Aporrectodea trapezoides as a bioindicator species to look into the possible dangers of ammonium sulfate (AS) fertilizer. Two complementary toxicity tests were conducted to determine the LC50values, growth rate inhibition, morphological alterations, and histopathological texture of worms. The lethality test included four increasing concentrations of AS fertilizer (ranging from 2500 to 7500 mg/kg of dry soil weight (d.w.)), while sub-lethal concentrations were based on 10%, 30%, 40%, and 50% of the 14-day median lethal concentration (LC50), with a control group included for both tests. The LC (50) values for AS fertilizer were significantly higher at 7 days (4831.13 mg/kg d.w.) than at 14 days (2698.67 mg/kg d.w.) of exposure. Notably, earthworms exhibited significant growth rate inhibition under exposure to various concentrations and time durations (14/28 exposure days). Morphological alterations such as clitellar swelling, bloody lesions, whole body coiling and constriction, body strangulation, and fragmentation were accentuated steadily, with higher concentrations. Histopathological manifestations included severe injuries to the circular and longitudinal muscular layers, vacuolation, muscle layer atrophy, degradation of the chloragogenous tissue in the intestine, collapsed digestive epithelium of the pharynx with weak reserve inclusion, and fibrosis of blood vessels. These effects were primarily influenced by increasing concentrations of fertilizer and time exposure. The study highlights the strong relationship between concentration and exposure time responses and underscores the potential of A. trapezoides earthworms as valuable biological control agents against acidic ammonium sulfate fertilizer. Importantly, this research contributes to the use of such biomarkers in evaluating soil toxicity and the biological control of environmental risk assessment associated with chemical fertilizers.

Pupillometry is widely used to measure arousal states. The primary functional role of the pupil, however, is to respond to the luminance of visual inputs. We previously demonstrated that cognitive effort-related arousal interacted multiplicatively with luminance, with the strongest pupillary effects of arousal occurring at low-to-mid luminances (< 37 cd/m 2 ), implying a narrow range of conditions ideal for assessing cognitive arousal-driven pupillary differences. Does this generalize to other forms of arousal? To answer this, we assessed luminance-driven pupillary response functions while manipulating emotional arousal, using well-established visual and auditory stimulus sets. At the group level, emotional arousal interacted with the pupillary light response differently from cognitive arousal: the effects occurred primarily at much lower luminances (< 20 cd/m 2 ). Analyses at the individual-participant level revealed qualitatively distinct patterns of modulation, with a sizable number of individuals displaying no arousal response to the visual or auditory stimuli, regardless of luminance. Together, our results suggest that effects of arousal on pupil size are not monolithic: different forms of arousal exert different patterns of effects. More practically, our findings suggest that lower luminances create better conditions for measuring pupil-linked arousal, and when selecting ambient luminance levels, consideration of the arousal manipulation and individual differences is critical., (© 2024. The Author(s).)

Background: Efficient recanalization of occluded cerebral arteries is crucial in the treatment of acute ischemic stroke. Double stent retrievers have shown the potential to enhance the rates of recanalization on the first pass. This study aims to evaluate the efficacy and safety of the double stent retriever technique and the predictors of achieving first-pass effect in patients with acute ischemic stroke., Methods: This prospective multicenter study involved 209 patients from 16 comprehensive stroke centers in Spain. Patients with occlusions in the anterior circulation were treated using the Aperio Hybrid double stent retriever. The study examined various deployment techniques, including simultaneous and sequential deployment and stent configurations, comparing the Y-shaped and parallel configurations., Results: The double stent retriever technique achieved a first-pass effect in 72.7% of cases and a final successful recanalization rate of 99.5%. The Y-shaped configuration was significantly associated with higher recanalization rates on the first pass (OR 2.59, 95% CI 1.18 to 5.68, P=0.02). Procedural complications were mild to moderate in 6.7% and severe in 1.5% of cases, with symptomatic intracranial hemorrhage occurring in 3.3% of patients. At 3 months follow-up, 57.2% of patients achieved a good clinical outcome, with a mortality rate of 15.1%., Conclusion: The findings support the efficacy of the double stent retriever technique, particularly the Y-shaped configuration, in achieving high recanalization rates on the first pass with an acceptable safety profile. This technique may offer clinical benefits for future acute ischemic stroke treatment protocols., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Independent locomotion provides autonomy for infants, drastically changing their relationship with their surroundings. From a dynamic systems perspective, the interaction between environment, tasks, and organismic constraints leads to the emergence of new behaviors over time. This 6-month longitudinal study aimed to verify associations between the emergence of locomotor behaviors and infants' characteristics, developmental status, parental beliefs, and practices. This observational study remotely assessed 37 full-term Brazilian infants aged 5 to 15 months, divided into two groups (G1: 5 to 11 months, n = 19; and G2: 9 to 15 months, n = 18). The motor developmental status of infants was closely associated with the emergence of behaviors (p < 0.05). Infants in G2 whose parents agreed with the statement "In typically developing infants, motor development occurs naturally and there is no need to actively stimulate it" started to walk later than those whose parents disagreed. Infants whose parents expected them to walk around 10-11 months walked earlier compared to those expected to walk after 11 months (G2, p = 0.011). Infants in G2 with a high frequency of staying in the supine position started to walk, both with and without support, later than those with a low frequency (p < 0.05). For infants in G1 with a high frequency of playing on the floor, locomotion (p = 0.041) and crawling on hands-and-knees (p = 0.007) started sooner compared to those with a low frequency. Staying in the cradle more frequently was related to a later emergence of supported walk (p = 0.046) among infants in G2. The emergence of locomotor behaviors is associated with motor developmental status, the surfaces where the infant plays, and body position. Parental beliefs and expectations influence how infants are stimulated and, consequently, the emergence of independent walking., 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 Inc. All rights reserved.)

Background: The prevalence of functional impairment is increasing among middle-aged adults and is associated with adverse health outcomes. Primary care providers (PCPs) and geriatricians may have important insights about optimal approaches to caring for these patients, but little is known about their perspectives., Objective: To examine PCPs' and geriatricians' perspectives on clinical needs and optimal approaches to care for middle-aged patients with functional impairment., Design: Qualitative study using semi-structured interviews., Participants: PCPs and geriatricians from outpatient practices in the San Francisco Bay area., Approach: Interviews focused on characteristics and care needs of middle-aged patients with functional impairment and models of care to address these needs. We analyzed interviews using hybrid deductive-inductive qualitative thematic analysis., Key Results: Clinicians (14 PCPs, 15 geriatricians) described distinct characteristics of functional impairment in middle-aged versus older adults, such as different rates of onset, but similar clinical needs. Despite these similar needs, clinicians identified age-specific barriers to delivering optimal care to middle-aged patients. These included system-level challenges such as limited access to insurance and social services; practice- and clinician-level barriers including inadequate clinician training; and patient-level factors including less access to family caregivers and perceptions of stigma. To overcome these challenges, clinicians suggested clinical approaches including addressing health-related social needs within healthcare systems; implementing practice-based models that are multi-disciplinary, team-based, and coordinated; training clinicians to effectively manage functional impairment; and expanding community-based services and supports to help patients navigate the medical system. Identified needs, challenges, and solutions were generally similar across geriatricians and PCPs., Conclusions: Clinicians face challenges in delivering optimal care to middle-aged patients who have functional impairments similar to their older counterparts but lack access to services and supports available to older people. These findings suggest the importance of increasing access to care models that address functional impairment regardless of age., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Virulence pathways in pathogenic bacteria are regulated by quorum sensing mechanisms, particularly biofilm formation through autoinducer (AI) production and sensing. In this study, the culture filtrate extracted from an edible mushroom, Agaricus subrutilescens, was fractionated to isolate a compound that inhibits biofilm formation. Four gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Proteus mirabilis, and Enterobacter cloacae) and two gram-positive bacteria (Enterococcus faecalis and Staphylococcus aureus) were used for the bioassay. The bioassay-guided chromatographic separations of the culture filtrate extract resulted in the isolation of the compound. Further, spectroscopic analyses revealed the identity of the compound as 2,2'-azoxybisbenzyl alcohol (ABA). The minimum inhibitory and sub-inhibitory concentrations of the compound were also determined. Azoxybisbenzyl alcohol was significantly effective in inhibiting biofilm formation in all tested bacteria, with half-maximal inhibitory concentrations of 3-11 µg/mL. Additionally, the bioactivity of ABA was confirmed through the bioassays for the inhibition of exopolysaccharide matrixes and AI activities., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: Despite vaccination, influenza and otitis media (OM) remain leading causes of illness. We previously found that the human respiratory commensal Haemophilus haemolyticus prevents bacterial infection in vitro and that the related murine commensal Muribacter muris delays OM development in mice. The observation that M muris pretreatment reduced lung influenza titer and inflammation suggests that these bacteria could be exploited for protection against influenza/OM., Methods: Safety and efficacy of intranasal H haemolyticus at 5 × 107 colony-forming units (CFU) was tested in female BALB/cARC mice using an influenza model and influenza-driven nontypeable Haemophilus influenzae (NTHi) OM model. Weight, symptoms, viral/bacterial levels, and immune responses were measured., Results: Intranasal delivery of H haemolyticus was safe and reduced severity of influenza, with quicker recovery, reduced inflammation, and lower lung influenza virus titers (up to 8-fold decrease vs placebo; P ≤ .01). Haemophilus haemolyticus reduced NTHi colonization density (day 5 median NTHi CFU/mL = 1.79 × 103 in treatment group vs 4.04 × 104 in placebo, P = .041; day 7 median NTHi CFU/mL = 28.18 vs 1.03 × 104; P = .028) and prevented OM (17% OM in treatment group, 83% in placebo group; P = .015)., Conclusions: Haemophilus haemolyticus has potential as a live biotherapeutic for prevention or early treatment of influenza and influenza-driven NTHi OM. Additional studies will deem whether these findings translate to humans and other respiratory infections., Competing Interests: Potential conflicts of interest. P. C. R. has served on vaccine scientific advisory boards and together with L. S. K. has received institutional funding for investigator-initiated grants from GlaxoSmithKline, Pfizer, and MSD that are unrelated to this work. L. S. K., P. C. R., and C. M. G. are coinventors on patents filed in 2020 for using Pasteurellaceae species, including H haemolyticus, for prevention of respiratory infections: United States Patent and Trademark Office Application number: 17/337052 and Australian Patent Office Application number: 2020203634 (“Treating or preventing respiratory infection”; priority date: 2 June 2020; inventors: L. S. K., P. C. R., C. M. G.). K. R. S. is a consultant for Sanofi, Roche, and Novo Nordisk. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Vasconcellea x heilbornii, known as babaco, is a hybrid native to Ecuador grown in small orchards in sub-tropical highland regions. Over the last decade, several viruses have been identified in babaco using high-throughput sequencing (HTS) (Cornejo-Franco et al. 2020, (Reyes-Proaño et al. 2023). In 2021, total RNA from a babaco plant showing distinctive leaf yellowing was extracted using the PureLink RNA Mini Kit (Thermo Fischer Scientific, USA) and subjected to HTS on an Illumina NovaSeq6000 system as 150 paired-end reads (Macrogen Inc., South Korea). Library construction was done using the TruSeq Stranded Total RNA Sample kit with Plant Ribo-Zero, as described (Villamor et al. 2022). Reads were processed using BBDuk and de novo assembled using SPAdes 3.15. both implemented in Geneious 2022. Contig analysis was done by BLASTx using the NCBI viral sequence database (as of November 2022). HTS generated 54 million reads, of which 12% assembled into contigs corresponding to genomes of previously reported babaco viruses including babaco virus Q (BabVQ), babaco nucleorhabdovirus 1 (BabRV1) and babaco ilarvirus 1 (BabIV1). Interestingly, 144 reads (0.0003%) assembled into seven contigs ranging from 100 to 480 nucleotides (nt) in length. These contigs showed homology, with 97% amino acid (aa) identity (100% query coverage), to regions of the RNA-dependent-RNA-polymerase (RdRp) of beet western yellows virus (BWYV, Acc. No. NC&#95;004756), a member of the Polerovirus genus. To confirm the occurrence of BWYV in babaco, double-stranded RNA (dsRNA) was extracted from 15 g of leaf tissue from the original sample as described (Dodds et al. 1984) and used as template for reverse-transcription (RT)-PCR using overlapping primers designed to span all short contigs. RT-PCR amplified fragments were cloned into a pGEM®T-easy vector (Promega, USA) and sequenced by the Sanger method (Macrogen Inc., South Korea). The sequences were assembled into a single 2.7 kbp BWYV genome fragment comprising the complete protein 1 (P1) and partial RdRp gene (GenBank Acc. No. PP480670). Sequence alignments between the partially sequenced genome of the babaco isolate and its corresponding fragment from the closest BWYV isolate (NC&#95;004756) revealed 94% and 97% identities at the nt and aa levels, respectively. To assess the prevalence of BWYV in babaco, 30 leaf samples showing yellowing symptoms from Pichincha (n=15) and Azuay (n=15) provinces were tested by RT-PCR using total RNA. Total RNA extraction and reverse transcription were done using the methodology described by Halgren et al. (2007). For RT-PCR, the primer set BWYV&#95;Bab&#95;F: 5'-CAGTGTCCTCCAAGTGCAACAT-3' / BWYV&#95;Bab&#95;R: 5'GGTTCCTTCCCAGTTTGGTGGT-3', which amplifies a 235 nt-long P1 region, was used. Three RT-PCR products from each positive sample were purified using the GeneJET PCR clean-up kit (Thermo Scientific, USA) and sequenced. BWYV was confirmed in 9 out of 15 samples (60%) from Pichincha, and in 10 out of 15 samples (64%) from Azuay. Samples were also tested for additional babaco viruses as described (Reyes-Proaño et al. 2023). All BWYV-infected plants turned out positive for papaya ringspot virus (PRSV), babaco mosaic virus (BabMV), BabVQ, and BabIV1. Hence, the impact of BWYV infection on babaco plants in single and mixed infections warrants further investigation. To the best of our knowledge, this is the first report of BWYV in a crop in Ecuador, and the first time it has been found in a Caricaceae species.

The Tree Crickets of the genus Oecanthus Serville, 1831 are distributed across tropical and temperate regions, where they can be found in all strata of vegetation. In this work, we describe a new species of tree cricket from the Brazilian Amazon rainforest, where only one species was known until the date of this publication. This new species differs from the other 79 species in this genus by the absence of marks on the scape and pedicel of the antennae, as well as by its calling song composed of 3 to 5 chirps/s, 6 to 20 pulses per chirp, and peak frequency 3 to 3.3 kHz, at 26ºC. Photos in vivo of the individuals, as well as images of the metanotal glands and phallic sclerites, are provided.

The need for therapeutics to treat a plethora of medical conditions and diseases is on the rise and the demand for alternative approaches to mammalian-based production systems is increasing. Plant-based strategies provide a safe and effective alternative to produce biological drugs but have yet to enter mainstream manufacturing at a competitive level. Limitations associated with batch consistency and target protein production levels are present; however, strategies to overcome these challenges are underway. In this study, we apply state-of-the-art mass spectrometry-based proteomics to define proteome remodelling of the plant following agroinfiltration with bacteria grown under shake flask or bioreactor conditions. We observed distinct signatures of bacterial protein production corresponding to the different growth conditions that directly influence the plant defence responses and target protein production on a temporal axis. Our integration of proteomic profiling with small molecule detection and quantification reveals the fluctuation of secondary metabolite production over time to provide new insight into the complexities of dual system modulation in molecular pharming. Our findings suggest that bioreactor bacterial growth may promote evasion of early plant defence responses towards Agrobacterium tumefaciens (updated nomenclature to Rhizobium radiobacter). Furthermore, we uncover and explore specific targets for genetic manipulation to suppress host defences and increase recombinant protein production in molecular pharming., (© 2024 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Background: Lesion durability and transmurality are crucial for successful radiofrequency (RF) ablation. This study provides a model of real-time RF lesion visualization and insights into the role of underlying parameters, as local impedance (LI)., Methods: A force-sensing, LI-sensing catheter was used for lesion creation in an ex vivo model involving cross-sections of porcine cardiac preparations. During 60 s of RF application, one measurement per second was performed regarding lesion size and available ablation parameters. In total, 1847 measurements from n = 36 lesions were performed. Power (20-50 W) and contact force (1-5 g, 10-15 g, 20-25 g) were systematically alternated., Results: Lesion formation was most prominent in the first seconds of RF application during which nonlinear lesion growth was observed (max. 1.08 mm/s for lesion depth and 2.71 mm/s for lesion diameter). Power levels determined the extent of lesion formation in the early phase. After 20 s, lesion size growth velocity approaches 0.1 mm/s at all power levels. LI changes were also highest in the first seconds (up to - 12 Ω/s) and decreased to less than - 0.1Ω/s after prolonged application., Conclusion: Lesion formation in irrigated RF ablation is a nonlinear process. Final lesion size resulting from an RF application is mainly influenced by high rates of lesion growth in the first seconds of ablation. LI seems to be a good surrogate for differentiating changes in lesion formation., (© 2024 The Authors. Pacing and Clinical Electrophysiology published by Wiley Periodicals LLC.)

We recently reported that a novel chimeric peptide (GEP44) targeting both the glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y1- and Y2 receptor (Y1R and Y2R) reduced energy intake and body weight (BW) in diet-induced obese (DIO) rats. We hypothesized that GEP44 reduces energy intake and BW primarily through a GLP-1R dependent mechanism. To test this hypothesis, GLP-1R +/+ mice and GLP-1R null (GLP-1R -/- ) mice were fed a high fat diet for 4 months to elicit diet-induced obesity prior to undergoing a sequential 3-day vehicle period, 3-day drug treatment (5, 10, 20 or 50 nmol/kg; GEP44 vs the selective GLP-1R agonist, exendin-4) and a 3-day washout. Energy intake, BW, core temperature and activity were measured daily. GEP44 (10, 20 and 50 nmol/kg) reduced BW after 3-day treatment in DIO male GLP-1R +/+ mice by -1.5 ± 0.6, -1.3 ± 0.4 and -1.9 ± 0.4 grams, respectively ( P <0.05), with similar effects being observed in female GLP-1R +/+ mice. These effects were absent in male and female DIO GLP-1R -/- mice suggesting that GLP-1R signaling contributes to GEP44-elicited reduction of BW. Further, GEP44 decreased energy intake in both male and female DIO GLP-1R +/+ mice, but GEP44 appeared to produce more consistent effects across multiple doses in males. In GLP-1R -/- mice, the effects of GEP44 on energy intake were only observed in males and not females, suggesting that GEP44 may reduce energy intake, in part, through a GLP-1R independent mechanism in males. In addition, GEP44 reduced core temperature and activity in both male and female GLP-1R +/+ mice suggesting that it may also reduce energy expenditure. Lastly, we show that GEP44 reduced fasting blood glucose in DIO male and female mice through GLP-1R. Together, these findings support the hypothesis that the chimeric peptide, GEP44, reduces energy intake, BW, core temperature, and glucose levels in male and female DIO mice primarily through a GLP-1R dependent mechanism., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Blevins, Honeycutt, Slattery, Goldberg, Rambousek, Tsui, Dodson, Shelton, Salemeh, Elfers, Chichura, Ashlaw, Zraika, Doyle and Roth.)

Background: Pulsed field ablation (PFA) has become increasingly important in the treatment of cardiac arrhythmias. In addition to single-shot devices mainly used for pulmonary vein isolation, focal PFA may provide a treatment option that increases the versatility of the technique., Objective: The purpose of this study was to provide data on feasibility, safety, and long-term outcome of focal PFA for ablation of complex atrial tachycardia (AT)., Methods: All consecutive patients (n = 34) with complex AT treated at our department between 2022 and 2023 with a focal PFA system (CENTAURI™, Galvanize Therapeutics) were included. The majority of patients (32/34) previously had undergone at least 1 radiofrequency ablation. Established contact force-sensing catheters were used for PFA application in combination with a PFA generator. Pulsed electric field trains were conducted in a R-wave triggered manner., Results: Acute procedural success was accomplished in all patients. PFA included creation of 51 linear lesions and (re)isolation of 12 pulmonary veins. Mean procedural duration was 102.7 ± 30.3 minutes, with left atrial dwell time of 75.0 ± 24.7 minutes. Mean fluoroscopy duration was 8.7 ± 5.3 minutes. No complications occurred. After mean follow-up of 340.9 ± 130.1 days, recurrence of any AT occurred in 15 patients (44.1%). During 9 reablations, 3 gaps in previously created linear lesions were detected; the majority of recurrences (n = 6) were not related to previous PFA lesion creation., Conclusion: Focal PFA of complex AT substrates was safe and efficient. Acute procedural success was 100%. After 1 year, the majority of patients were in sinus rhythm. A minority of recurrences was caused by insufficient PFA lesion creation., Competing Interests: Disclosures Dr Bahlke participates in an educational program of Boston Scientific. Dr Erhard received travel grants from Boston Scientific and Biosense Webster. All other authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The formation of dynamic protein filaments contributes to various biological functions by clustering individual molecules together and enhancing their binding to ligands. We report such a propensity for the BTB domains of certain proteins from the ZBTB family, a large eukaryotic transcription factor family implicated in differentiation and cancer. Working with Xenopus laevis and human proteins, we solved the crystal structures of filaments formed by dimers of the BTB domains of ZBTB8A and ZBTB18 and demonstrated concentration-dependent higher-order assemblies of these dimers in solution. In cells, the BTB-domain filamentation supports clustering of full-length human ZBTB8A and ZBTB18 into dynamic nuclear foci and contributes to the ZBTB18-mediated repression of a reporter gene. The BTB domains of up to 21 human ZBTB family members and two related proteins, NACC1 and NACC2, are predicted to behave in a similar manner. Our results suggest that filamentation is a more common feature of transcription factors than is currently appreciated., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Tumor-specific CD8 + T cells are frequently dysfunctional and unable to halt tumor growth. We investigated whether tumor-specific CD4 + T cells can be enlisted to overcome CD8 + T cell dysfunction within tumors. We find that the spatial positioning and interactions of CD8 + and CD4 + T cells, but not their numbers, dictate anti-tumor responses in the context of adoptive T cell therapy as well as immune checkpoint blockade (ICB): CD4 + T cells must engage with CD8 + T cells on the same dendritic cell during the effector phase, forming a three-cell-type cluster (triad) to license CD8 + T cell cytotoxicity and cancer cell elimination. When intratumoral triad formation is disrupted, tumors progress despite equal numbers of tumor-specific CD8 + and CD4 + T cells. In patients with pleural mesothelioma treated with ICB, triads are associated with clinical responses. Thus, CD4 + T cells and triads are required for CD8 + T cell cytotoxicity during the effector phase and tumor elimination., Competing Interests: Declaration of interests M.D.H. is currently an employee and shareholder at AstraZeneca. M.D.H. current address: Early Clinical Development, Oncology R&D, AstraZeneca, New York, NY, USA. B.M.B. received funding from AstaZeneca for the clinical trial related to this project, clinical trial funding from Momatero-Gene, clinical trial funding from Novartis., (Copyright © 2024. Published by Elsevier Inc.)

Comprehending the immune defense mechanisms of new aquaculture species, such as the Chilean meagre ( Cilus gilberti ), is essential for sustaining large-scale production. Two bioassays were conducted to assess the impact of acute and intermittent hypoxia on the antibacterial activity of juvenile Chilean meagre epidermal mucus against the potential pathogens Vibrio anguillarum and Vibrio ordalii . Lysozyme and peroxidase activities were also measured. In general, fish exposed to hypoxia showed a 9-30% reduction in mucus antibacterial activity at the end of hypoxic periods and after stimulation with lipopolysaccharide. However, following water reoxygenation, the activity of non-stimulated fish was comparable to that of fish in normoxic conditions, inhibiting bacterial growth by 35-52%. In the case of fish exposed to chronic hypoxia, the response against V. anguillarum increased by an additional 19.8% after 6 days of control inoculation. Lysozyme exhibited a similar pattern, while no modulation of peroxidase activity was detected post-hypoxia. These results highlight the resilience of C. gilberti to dissolved oxygen fluctuations and contribute to understanding the potential of mucus in maintaining the health of cultured fish and the development of future control strategies.

This study evaluated the use of endemic enteric coronaviruses polymerase chain reaction (PCR)-negative testing results as an alternative approach to detect the emergence of animal health threats with similar clinical diseases presentation. This retrospective study, conducted in the United States, used PCR-negative testing results from porcine samples tested at six veterinary diagnostic laboratories. As a proof of concept, the database was first searched for transmissible gastroenteritis virus (TGEV) negative submissions between January 1st, 2010, through April 29th, 2013, when the first porcine epidemic diarrhea virus (PEDV) case was diagnosed. Secondly, TGEV- and PEDV-negative submissions were used to detect the porcine delta coronavirus (PDCoV) emergence in 2014. Lastly, encountered best detection algorithms were implemented to prospectively monitor the 2023 enteric coronavirus-negative submissions. Time series (weekly TGEV-negative counts) and Seasonal Autoregressive-Integrated Moving-Average (SARIMA) were used to control for outliers, trends, and seasonality. The SARIMA's fitted and residuals were then subjected to anomaly detection algorithms (EARS, EWMA, CUSUM, Farrington) to identify alarms, defined as weeks of higher TGEV-negativity than what was predicted by models preceding the PEDV emergence. The best-performing detection algorithms had the lowest false alarms (number of alarms detected during the baseline) and highest time to detect (number of weeks between the first alarm and PEDV emergence). The best-performing detection algorithms were CUSUM, EWMA, and Farrington flexible using SARIMA fitted values, having a lower false alarm rate and identified alarms 4 to 17 weeks before PEDV and PDCoV emergences. No alarms were identified in the 2023 enteric negative testing results. The negative-based monitoring system functioned in the case of PEDV propagating epidemic and in the presence of a concurrent propagating epidemic with the PDCoV emergence. It demonstrated its applicability as an additional tool for diagnostic data monitoring of emergent pathogens having similar clinical disease as the monitored endemic pathogens., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Serafini Poeta Silva 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.)