ssDNA is an allosteric regulator of the C. crescentus SOS-independent DNA damage response transcription activator, DriD.

DNA damage repair systems are critical for genomic integrity. However, they must be coordinated with DNA replication and cell division to ensure accurate genomic transmission. In most bacteria, this coordination is mediated by the SOS response through LexA, which triggers a halt in cell division until repair is completed. Recently, an SOS-independent damage response system was revealed in Caulobacter crescentus. This pathway is controlled by the transcription activator, DriD, but how DriD senses and signals DNA damage is unknown. To address this question, we performed biochemical, cellular, and structural studies. We show that DriD binds a specific promoter DNA site via its N-terminal HTH domain to activate transcription of genes, including the cell division inhibitor didA A structure of the C-terminal portion of DriD revealed a WYL motif domain linked to a WCX dimerization domain. Strikingly, we found that DriD binds ssDNA between the WYL and WCX domains. Comparison of apo and ssDNA-bound DriD structures reveals that ssDNA binding orders and orients the DriD domains, indicating a mechanism for ssDNA-mediated operator DNA binding activation. Biochemical and in vivo studies support the structural model. Our data thus reveal the molecular mechanism underpinning an SOS-independent DNA damage repair pathway.

Localization of lattice dynamics in low-angle twisted bilayer graphene.

Twisted bilayer graphene is created by slightly rotating the two crystal networks in bilayer graphene with respect to each other. For small twist angles, the material undergoes a self-organized lattice reconstruction, leading to the formation of a periodically repeated domain1-3. The resulting superlattice modulates the vibrational3,4 and electronic5,6 structures within the material, leading to changes in the behaviour of electron-phonon coupling7,8 and to the observation of strong correlations and superconductivity9. However, accessing these modulations and understanding the related effects are challenging, because the modulations are too small for experimental techniques to accurately resolve the relevant energy levels and too large for theoretical models to properly describe the localized effects. Here we report hyperspectral optical images, generated by a nano-Raman spectroscope10, of the crystal superlattice in reconstructed (low-angle) twisted bilayer graphene. Observations of the crystallographic structure with visible light are made possible by the nano-Raman technique, which reveals the localization of lattice dynamics, with the presence of strain solitons and topological points1 causing detectable spectral variations. The results are rationalized by an atomistic model that enables evaluation of the local density of the electronic and vibrational states of the superlattice. This evaluation highlights the relevance of solitons and topological points for the vibrational and electronic properties of the structures, particularly for small twist angles. Our results are an important step towards understanding phonon-related effects at atomic and nanometric scales, such as Jahn-Teller effects11 and electronic Cooper pairing12-14, and may help to improve device characterization15 in the context of the rapidly developing field of twistronics16.

Pyrazinamide Safety, Efficacy, and Dosing for Treating Drug-Susceptible Pulmonary Tuberculosis: A Phase 3, Randomized, Controlled Clinical Trial.

RATIONALE: Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/ACTG A5349 represents the largest Phase 3 randomized controlled therapeutic trial to date for such investigation. OBJECTIVES: We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure with efficacy and safety outcomes. We aimed to determine pyrazinamide dosing strategies that optimize risks and benefits. METHODS: We analyzed pyrazinamide steady-state pharmacokinetic data using population nonlinear mixed-effects models. We evaluated the contribution of pyrazinamide exposure to long-term efficacy using parametric time-to-event models and safety outcomes using logistic regression. We evaluated optimal dosing with therapeutic windows targeting ≥95% durable cure and safety within the observed proportion of the primary safety outcome. MEASUREMENTS AND MAIN RESULTS: Among 2255 participants with 6978 plasma samples, pyrazinamide displayed 7-fold exposure variability (151-1053 mg·h/L). Body weight was not a clinically relevant predictor of drug clearance and thus did not justify the need for weight-banded dosing. Both clinical and safety outcomes were associated with pyrazinamide exposure, resulting in a therapeutic window of 231-355 mg·h/L for the control and 226-349 mg·h/L for the rifapentine-moxifloxacin regimen. Flat dosing of pyrazinamide at 1000 mg would have permitted an additional 13.1% (n=96) participants allocated to the control and 9.2% (n=70) to the rifapentine-moxifloxacin regimen dosed within the therapeutic window, compared to the current weight-banded dosing. CONCLUSIONS: Flat dosing of pyrazinamide at 1000 mg daily would be readily implementable and could optimize treatment outcomes in drug-susceptible tuberculosis. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT02410772. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.

BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).

Detection of Recombinant African Swine Fever Virus Strains of p72 Genotypes I and II in Domestic Pigs, Vietnam, 2023.

African swine fever virus (ASFV) genotype II is endemic to Vietnam. We detected recombinant ASFV genotypes I and II (rASFV I/II) strains in domestic pigs from 6 northern provinces in Vietnam. The introduction of rASFV I/II strains could complicate ongoing ASFV control measures in the region.

Assessing the Efficacy of Acanthoic Acid Isolated from Acanthopanax koreanum Nakai in Male Infertility: An In Vivo and In Silico Approach.

Acanthoic acid, a diterpene isolated from the root bark of Acanthopanax koreanum Nakai, possesses diverse pharmacological activities, including anti-inflammatory, anti-diabetic, gastrointestinal protection, and cardiovascular protection. This study is the first to investigate the egg-hatching rates of Drosophila melanogaster affected by acanthoic acid. Notably, male flies supplemented with 10 µM acanthoic acid exhibited a strong increase in hatching rates compared with controls under adverse temperature conditions, suggesting a potential protective effect against environmental stressors. Molecular docking simulations revealed the binding affinities and specific interactions between acanthoic acid and proteins related to male infertility, including SHBG, ADAM17, and DNase I, with binding affinity values of -10.2, -6.8, and -5.8 kcal/mol, respectively. Following the docking studies, molecular dynamic simulations were conducted for a duration of 100 ns to examine the stability of these interactions. Additionally, a total binding energy analysis and decomposition analysis offered insights into the underlying energetic components and identified key contributing residues.

Structural basis for loading and inhibition of a bacterial T6SS phospholipase effector by the VgrG spike.

The bacterial type VI secretion system (T6SS) is a macromolecular machine that injects effectors into prokaryotic and eukaryotic cells. The mode of action of the T6SS is similar to contractile phages: the contraction of a sheath structure pushes a tube topped by a spike into target cells. Effectors are loaded onto the spike or confined into the tube. In enteroaggregative Escherichia coli, the Tle1 phospholipase binds the C-terminal extension of the VgrG trimeric spike. Here, we purify the VgrG-Tle1 complex and show that a VgrG trimer binds three Tle1 monomers and inhibits their activity. Using covalent cross-linking coupled to high-resolution mass spectrometry, we provide information on the sites of contact and further identify the requirement for a Tle1 N-terminal secretion sequence in complex formation. Finally, we report the 2.6-Å-resolution cryo-electron microscopy tri-dimensional structure of the (VgrG)3 -(Tle1)3 complex revealing how the effector binds its cargo, and how VgrG inhibits Tle1 phospholipase activity. The inhibition of Tle1 phospholipase activity once bound to VgrG suggests that Tle1 dissociation from VgrG is required upon delivery.

P T-symmetry breaking in dual-core phosphate-glass photonic crystal fibers.

We investigate the properties of a soft glass dual-core photonic crystal fiber for application in multicore waveguiding with balanced gain and loss. Its base material is a phosphate glass in a P2O5-Al2O3-Yb2O3-BaO-ZnO-MgO-Na2O oxide system. The separated gain and loss cores are realized with two cores with ytterbium and copper doping of the base phosphate glass. The ytterbium-doped core supports a laser (gain) activity under excitation with a pump at 1000 nm wavelength, while the CuO-doped is responsible for strong attenuation at the same wavelength. We establish conditions for an exact balance between gain and loss and investigate pulse propagation by solving a system of coupled generalized nonlinear Schrödinger equations. We predict two states of light under excitation with hyperbolic secant pulses centered at 1000 nm: 1) linear oscillation of the pulse energy between gain and loss core (P T-symmetry state), with strong power attenuation; 2) retention of the pulse in the excited gain core (broken P T-symmetry), with very modest attenuation. The optimal pulse energy levels were identified to be 100 pJ (first state) and 430 pJ (second state).

Target regimen profiles for tuberculosis treatment.

Simpler, shorter, safer and more effective treatments for tuberculosis that are easily accessible to all people with tuberculosis are desperately needed. In 2016, the World Health Organization (WHO) developed target regimen profiles for the treatment of tuberculosis to make drug developers aware of both the important features of treatment regimens, and patient and programmatic needs at the country level. In view of recent ground-breaking advances in tuberculosis treatment, WHO has revised and updated these regimen profiles. We used a similar process as for the 2016 profiles, including a baseline treatment landscape analysis, an initial stakeholder survey, modelling studies estimating the impact and cost-effectiveness of novel tuberculosis treatment regimens, and an extensive stakeholder consultation. We developed target regimen profiles for the treatment of rifampicin-susceptible and rifampicin-resistant tuberculosis, as well as a pan-tuberculosis regimen that would be appropriate for patients with any type of tuberculosis. We describe the revised target regimen profile characteristics, with specific minimal and optimal targets to be met, rationale and justification, and aspects relevant to all target regimen profiles (drug susceptibility testing, adherence and forgiveness, treatment strategies, post-tuberculosis lung disease, and cost and access considerations). We discuss the trade-offs of proposed characteristics for decision-making at developmental or operational levels. We expect that, following these target regimen profile revisions, tuberculosis treatment developers will produce regimens that are quality-assured, affordable and widely available, and that meet the needs of affected populations.

Des traitements de la tuberculose plus simples, plus courts, plus sûrs et plus efficaces, facilement accessibles à toutes les personnes atteintes de tuberculose, font cruellement défaut. En 2016, l'Organisation mondiale de la santé (OMS) a élaboré des profils de schéma thérapeutique cible pour le traitement de la tuberculose, afin de sensibiliser les concepteurs de médicaments aux caractéristiques importantes des schémas thérapeutiques et aux besoins des patients et des programmes au niveau national. Compte tenu des avancées récentes dans le traitement de la tuberculose, l'OMS a révisé et mis à jour ces profils de schéma thérapeutique. Nous avons appliqué un processus similaire à celui des profils de 2016, y compris une analyse de base des différentes possibilités thérapeutiques, une enquête initiale auprès des parties prenantes, des études de modélisation estimant l'impact et le rapport coût-efficacité des nouveaux schémas thérapeutiques pour la tuberculose, ainsi qu'une vaste consultation des parties prenantes. Nous avons élaboré des profils de schéma thérapeutique cible pour le traitement de la tuberculose sensible à la rifampicine ou résistant à la rifampicine, ainsi qu'un schéma multiforme qui conviendrait aux patients atteints de n'importe quel type de tuberculose. Nous décrivons les caractéristiques du profil révisé de schéma thérapeutique cible, avec les objectifs minimaux et optimaux spécifiques à atteindre, le raisonnement et les aspects pertinents pour tous les profils de schéma thérapeutique cible (tests de sensibilité aux médicaments, observance thérapeutique et manque d'observance («forgiveness¼), stratégies de traitement, maladie pulmonaire post-tuberculeuse et considérations de coût et d'accès). Nous discutons des compromis des caractéristiques proposées pour la prise de décisions au niveau du développement ou au niveau opérationnel. Nous espérons qu'à la suite de ces révisions du profil de schéma thérapeutique cible, les concepteurs de traitements antituberculeux produiront des schémas dont la qualité est assurée, qui sont abordables et largement disponibles et qui répondent aux besoins des populations touchées.

Se necesitan con urgencia tratamientos más sencillos, breves, seguros y eficaces contra la tuberculosis que sean fácilmente accesibles para todas las personas con tuberculosis. En 2016, la Organización Mundial de la Salud (OMS) elaboró perfiles objetivo de esquemas terapéuticos para el tratamiento de la tuberculosis con el fin de que los fabricantes de medicamentos conocieran tanto las características importantes de estos esquemas como las necesidades programáticas y de los pacientes en cada país. Teniendo en cuenta los recientes avances pioneros en el tratamiento de la tuberculosis, la OMS ha revisado y actualizado estos perfiles de esquemas terapéuticos. Se ha seguido un proceso similar al de los perfiles de 2016, que incluye un análisis de referencia del panorama terapéutico, una encuesta inicial a las partes interesadas, estudios de modelización para estimar el impacto y la rentabilidad de los nuevos esquemas terapéuticos para el tratamiento de la tuberculosis, y una amplia consulta a las partes interesadas. Se desarrollaron perfiles objetivo de esquemas terapéuticos para el tratamiento de la tuberculosis sensibles a la rifampicina y resistente a la rifampicina, así como un esquema farmacológico capaz de tratar todas las formas de tuberculosis que sería apropiado para pacientes con cualquier tipo de tuberculosis. Se describieron las características revisadas de los perfiles objetivo de los esquemas terapéuticos, con los objetivos mínimos y óptimos específicos que deben alcanzarse, los fundamentos y la justificación, y los aspectos relevantes para todos los perfiles objetivo de los esquemas terapéuticos (pruebas de sensibilidad a los fármacos, adherencia y olvido, estrategias de tratamiento, enfermedad pulmonar postuberculosa, y consideraciones de coste y acceso). Se discutieron las ventajas y desventajas de las características propuestas para la toma de decisiones a nivel de desarrollo u operativo. Se espera que, tras estas revisiones de los perfiles objetivo de los esquemas terapéuticos, las personas encargadas del desarrollo de tratamientos para la tuberculosis elaboren esquemas terapéuticos de calidad garantizada, asequibles y ampliamente disponibles, y que respondan a las necesidades de las poblaciones afectadas.

Modelling the spread and mitigation of an emerging vector-borne pathogen: Citrus greening in the U.S.

Predictive models, based upon epidemiological principles and fitted to surveillance data, play an increasingly important role in shaping regulatory and operational policies for emerging outbreaks. Data for parameterising these strategically important models are often scarce when rapid actions are required to change the course of an epidemic invading a new region. We introduce and test a flexible epidemiological framework for landscape-scale disease management of an emerging vector-borne pathogen for use with endemic and invading vector populations. We use the framework to analyse and predict the spread of Huanglongbing disease or citrus greening in the U.S. We estimate epidemiological parameters using survey data from one region (Texas) and show how to transfer and test parameters to construct predictive spatio-temporal models for another region (California). The models are used to screen effective coordinated and reactive management strategies for different regions.

Lateral junctions of transition metal dichalcogenides as ballistic channels for straintronic applications.

In the context of advanced nanoelectronics, two-dimensional semiconductors such as transition metal dichalcogenides (TMDs) are gaining considerable interest due to their ultimate thinness, clean surface and high carrier mobility. The engineering prospects offered by those materials are further enlarged by the recent realization of atomically sharp TMD-based lateral junctions, whose electronic properties are governed by strain effects arising from the constituents lattice mismatch. Although most theoretical studies considered only misfit strain, first-principles simulations are employed here to investigate the transport properties under external deformation of a three-terminal device constructed from a MoS2/WSe2/MoS2junction. Large modulation of the current is reported owing to the change in band offset, illustrating the importance of strain on the p-n junction characteristics. The device operation is demonstrated for both local and global deformations, even for ultra-short channels, suggesting potential applications for ultra-thin body straintronics.

Enhancing control in spatial atomic layer deposition: insights into precursor diffusion, geometric parameters, and CVD mitigation strategies.

In recent years, spatial atomic layer deposition (SALD) has gained significant attention for its remarkable capability to accelerate ALD growth by several orders of magnitude compared to conventional ALD, all while operating at atmospheric pressure. Nevertheless, the persistent challenge of inadvertent contributions from chemical vapor deposition (CVD) in SALD processes continues to impede control over film homogeneity, and properties. This research underscores the often-overlooked influence of diffusion coefficients and important geometric parameters on the close-proximity SALD growth patterns. We introduce comprehensive physical models complemented by finite element method simulations for fluid dynamics to elucidate SALD growth kinetics across diverse scenarios. Our experimental findings, in alignment with theoretical models, reveal distinctive growth rate trends in ZnO and SnO2films as a function of the deposition gap. These trends are ascribed to precursor diffusion effects within the SALD system. Notably, a reduced deposition gap proves advantageous for both diffusive and low-volatility bulky precursors, minimizing CVD contributions while enhancing precursor chemisorption kinetics. However, in cases involving highly diffusive precursors, a deposition gap of less than 100µm becomes imperative, posing technical challenges for large-scale applications. This can be ameliorated by strategically adjusting the separation distance between reactive gas outlets to mitigate CVD contributions, which in turn leads to a longer deposition time. Furthermore, we discuss the consequential impact on material properties and propose a strategy to optimize the injection head to control the ALD/CVD growth mode.

Astraoleanosides E-P, oleanane-type triterpenoid saponins from the aerial parts of Astragalus membranaceus Bunge and their ß-glucuronidase inhibitory activity.

Historically, Astragalus membranaceus Bunge has been used as a beneficial medicinal plant, particularly in the Asian traditional medical systems, for the treatment of various human diseases such as stomach ulcers, diarrhea, and respiratory issues associated with phlegm. In this study, a phytochemical characterization of the aerial parts of A. membranaceusled to the isolation of 29 oleanane-type triterpenoid saponins, including 11 new compounds named astraoleanosides E-P (6-9, 13, 14, 18-22), as well as 18 known ones. The structures of these compounds were elucidated using nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry. Among them, astraoleanoside H (9) and cloversaponin III (15) demonstrated the most potent ß-glucuronidase inhibitory activities, with IC50 values of 21.20 ± 0.75 and 9.05 ± 0.47 µM, respectively, compared to the positive control d-saccharic acid 1,4-lactone (IC50 = 20.62 ± 1.61 µM). Enzyme kinetics studies were then conducted to investigate the type of inhibition exhibited by these active compounds. In addition, the binding mechanism, key interactions, binding stability, and dynamic behavior of protein-ligand complexes were investigated through in silico approaches, such as molecular docking and molecular dynamics simulations. These findings highlight the promising potential of triterpenoid saponins from A. membranaceus as lead compounds for ß-glucuronidase inhibitors, offering new possibilities for the development of therapeutic agents targeting various diseases where ß-glucuronidase plays a crucial role.

In silico screening of Fyn kinase inhibitors using classification-based QSAR model, molecular docking, molecular dynamics and ADME study.

This study aimed to use a computational approach that combined the classification-based QSAR model, molecular docking, ADME studies, and molecular dynamics (MD) to identify potential inhibitors of Fyn kinase. First, a robust classification model was developed from a dataset of 1,078 compounds with known Fyn kinase inhibitory activity, using the XGBoost algorithm. After that, molecular docking was performed between potential compounds identified from the QSAR model and Fyn kinase to assess their binding strengths and key interactions, followed by MD simulations. ADME studies were additionally conducted to preliminarily evaluate the pharmacokinetics and drug-like characteristics of these compounds. The results showed that our obtained model exhibited good predictive performance with an accuracy of 0.95 on the test set, affirming its reliability in identifying potent Fyn kinase inhibitors. Through the application of this model in conjunction with molecular docking and ADME studies, nine compounds were identified as potential Fyn kinase inhibitors, including 208 (ZINC70708110), 728 (ZINC8792432), 734 (ZINC8792187), 736 (ZINC8792350), 738 (ZINC8792286), 739 (ZINC8792309), 817 (ZINC33901069), 852 (ZINC20759145), and 1227 (ZINC100006936). MD simulations further demonstrated that the four most promising compounds, 728, 734, 736, and 852 exhibited stable binding with Fyn kinase during the simulation process. Additionally, a web-based platform ( https://fynkinase.streamlit.app/ ) has been developed to streamline the screening process. This platform enables users to predict the activity of their substances of interest on Fyn kinase from their SMILES, using our classification-based QSAR model and molecular docking.

Comparison of substernal and posterior mediastinal route of reconstruction after minimally invasive esophagectomy for esophageal cancer.

BACKGROUND: Substernal (ST) and posterior mediastinal (PM) routes are the two most common for reconstruction after esophagectomy with cervical anastomosis. Recent evidence showed similar outcomes between the routes; thus, the superior choice remained controversial. This study aimed to compare the short-term outcomes of the ST to the PM route for reconstruction after esophagectomy for esophageal cancer (EC). METHOD: This retrospective cohort study included 132 patients who underwent McKeown minimally invasive esophagectomy (MIE) with gastric conduit for EC between March 2015 and December 2022. Among these, 89 and 43 patients received the ST route and PM route for reconstruction, respectively. Short-term outcomes including operative characteristics, postoperative morbidity, and mortality were evaluated. RESULT: There was no conversion from ST to PM route. The ST group had longer operating time (375 min vs. 341 min). Oral feeding initiation, postoperative hospital stays, and overall complication rates were comparable in the two groups. The rate and severity of anastomotic leakage were similar between the groups. The ST group had a significantly lower incidence of postoperative ICU admission and pneumonia compared to the PM group (5.6% vs. 16.3% and 19.1% vs. 37.2%, respectively). Azygos vein bleeding, obstruction at feeding jejunostomy site, and conduit-trachea fistula were severe complications that only occurred in PM route. CONCLUSION: ST route was superior to PM route in term of postoperative ICU admission and pneumonia. This route may prevent severe complications that only occur in PM route. ST route can be favorable option for reconstruction after McKeown MIE for EC.

A Standardized Approach for Collection of Objective Data to Support Outcome Determination for Late-Phase Tuberculosis Clinical Trials.

Rationale: We developed a standardized method, possible poor treatment response (PPTR), to help ascertain efficacy endpoints in Study S31/A5349 (NCT02410772), an open-label trial comparing two 4-month rifapentine-based regimens with a standard 6-month regimen for the treatment of pulmonary tuberculosis (TB). Objectives: We describe the use of the PPTR process and evaluate whether the goals of minimizing bias in efficacy endpoint assessment and attainment of relevant data to determine outcomes for all participants were achieved. Methods: A PPTR event was defined as the occurrence of one or more prespecified triggers. Each PPTR required initiation of a standardized evaluation process that included obtaining multiple sputum samples for microbiology. Measurements and Main Results: Among 2,343 participants with culture-confirmed drug-susceptible TB, 454 individuals (19.4%) had a total of 534 individual PPTR events, of which 76.6% were microbiological (positive smear or culture at or after 17 wk). At least one PPTR event was experienced by 92.4% (133 of 144) of participants with TB-related unfavorable outcome and between 13.8% and 14.7% of participants with favorable and not-assessable outcomes. A total of 75% of participants with TB-related unfavorable outcomes had microbiological confirmation of failure to achieve a disease-free cure. Conclusions: Standardized methodologies, such as our PPTR approach, could facilitate unbiased efficacy outcome determinations, improve discrimination between outcomes that are related and unrelated to regimen efficacy, and enhance the ability to conduct pooled analyses of contemporary trials.

Inhibition of Soluble Epoxide Hydrolase by Cembranoid Diterpenes from Soft Coral Sinularia maxima: Enzyme Kinetics, Molecular Docking, and Molecular Dynamics.

Soluble epoxide hydrolase (sEH) is essential for converting epoxy fatty acids, such as epoxyeicosatrienoic acids (EETs), into their dihydroxy forms. EETs play a crucial role in regulating blood pressure, mediating anti-inflammatory responses, and modulating pain, making sEH a key target for therapeutic interventions. Current research is increasingly focused on identifying sEH inhibitors from natural sources, particularly marine environments, which are rich in bioactive compounds due to their unique metabolic adaptations. In this study, the sEH inhibitory activities of ten cembranoid diterpenes (1-10) isolated from the soft coral Sinularia maxima were evaluated. Among them, compounds 3 and 9 exhibited considerable sEH inhibition, with IC50 values of 70.68 µM and 78.83 µM, respectively. Enzyme kinetics analysis revealed that these two active compounds inhibit sEH through a non-competitive mode. Additionally, in silico approaches, including molecular docking and molecular dynamics simulations, confirmed their stability and interactions with sEH, highlighting their potential as natural therapeutic agents for managing cardiovascular and inflammatory diseases.

The synthesis and properties of Ca3 Sc2 Si3 O12 :Ce3+ (CSSG) phosphor are utilized for the development of human-centric lighting light-emitting diodes (HCL-LEDs).

In this study, cerium ion (Ce3+ )-doped calcium scandium silicate garnet (Ca3 Sc2 Si3 O12 , abbreviated CSSG) phosphors were successfully synthesized using the sol-gel method. The crystal phase, morphology, and photoluminescence properties of the synthesized phosphors were thoroughly investigated. Under excitation by a blue light-emitting diode (LED) chip (450 nm), the CSSG phosphor displayed a wide emission spectrum spanning from green to yellow. Remarkably, the material exhibited exceptional thermal stability, with an emissivity ratio at 150°C to that at 25°C reaching approximately 85%. Additionally, the material showcased impressive optical performance when tested with a blue LED chip, including a color rendering index (CRI) exceeding 90, an R9 value surpassing 50, and a biological impact ratio (M/P) above 0.6. These noteworthy findings underscore the potential applications of CSSG as a white light-converting phosphor, particularly in the realm of human-centered lighting.

Oleanane-Type Triterpene Glycosides from Camellia phanii and Their α-Glucosidase Inhibitory Activity.

Three new oleanane-type triterpene saponins, named camphanosides A-C (1-3), along with five known compounds, chikusetsusaponin IVa (4), spinasaponin A 28-O-glucoside (5), (-)-epicatechin (6), (-)-epicatechin 3-O-gallate (7), and (-)-epigallocatechin 3-O-gallate (8) were isolated from the leaves Camellia phanii Hakoda & Ninh. Their structures were established by 1D and 2D-NMR and mass spectral analysis and chemical methods. Moreover, compounds 1-5 were also evaluated for α-glucosidase inhibitory activity. Compounds 1-3 exhibited moderate α-glucosidase inhibitory activity with IC50 values of 230.7±18.0, 251.4±22.7, and 421.4±25.6 µM, respectively.

Four Undescribed compounds Isolated from the Aerial Parts of Phyllanthus cochinchinensis with Antimicrobial Activity and NO Production Inhibitory Activity in LPS Activated RAW 264.7 Cells.

Four previously undescribed compounds named phyllancosides A and B (1 and 2), and phyllancochines A and B (3 and 4) together with ten known compounds (5-14) were isolated from the aerial parts of Phyllanthus cochinchinensis Spreng. Their chemical structures were elucidated on the basis of comprehensive analysis of IR, HR-ESI-MS, 1D and 2D NMR spectra. The absolute configurations of 1 and 2 were determined by electronic circular dichroism (ECD) spectra. Compounds 3, 4, and 10 showed antimicrobial activity against E. faecalis, S. aureus, and B. cereus with the MIC values in range of 32-256 µg/mL. Compound 11 inhibited E. faecalis and B. cereus, and 7 inhibited S. aureus with the MIC values in range of 64-128 µg/mL. In addition, compounds 1, 3, 4, 8, and 9 showed significantly NO production inhibitory activity in LPS activated RAW 264.7 cells with IC50 values ranging from 36.57 to 56.34 µM.