Institute for Learning Innovation

BackgroundMycobacterium tuberculosis resistance to standard-of-care agents is increasing. It is imperative to identify new combinations that increase the rate and depth of bacterial kill, shorten therapy and also suppress resistance. There has been little prior effort to identify combination regimens that employ new or repurposed drugs in a rational way.Methods and FindingsOur group developed a pathway to combine agents to achieve this end. This pathway starts with standard baseline evaluations (e.g., MIC), leverages information from in vitro assessments (hollow fiber infection model), then analyzes 2-agent combinations in a 96 well quantitative culture checkerboard format (Greco URSA model with simulation). Finally, development of a high dimensional mathematical model allowed evaluation of 2- and 3-drug regimens in multiple metabolic states to draw inferences regarding combination therapies. We prospectively evaluated these regimens in animal models. We showed that a prospectively chosen regimen of pretomanid, moxifloxacin plus bedaquiline performed as predicted. In the BALB/c murine model, this regimen produced sterilization in a cohort that was held for 12 weeks after therapy cessation, as it did in the C3HeB/FeJ (“Kramnik”) murine model. Finally, this and other regimens were evaluated in a cynomolgus macaque model. The decrement of the 18F-deoxyglucose signal in Positron emission tomography (PET)- computed tomography (CT) evaluations was best with this regimen. Other endpoints such as necropsy score and colony counts in lung and lymph nodes also demonstrated that this regimen behaved as predicted from our pathway/algorithm.ConclusionsWe conclude that this provides a way forward for the future to identify the most promising regimens to shorten therapy for tuberculosis and suppress emergence of resistance.

To enhance the structural rigidity of heavy atom-free room-temperature phosphorescence (RTP) materials, crystallization engineering via molecular stacking has been proposed. However, the current strategies generally rely on noncovalent interactions, which are nondirectional for structural regulation and susceptible to break under complex environmental conditions. Herein, we have proposed the B–O click reaction between boronic acid and hydroxyl groups to promote the structural rigidity of chromophores. The crystallization behaviors of chromophores with boronic acid groups have been effectively regulated with the addition of ethylene glycol, and the established B–O covalent network provided a rigid environment to suppress the nonradiative transition of chromophores. Accordingly, boosted RTP performances with prolonged lifetime as well as decent stability have been achieved for the heavy atom-free composites. Such a B–O covalent network could be applied for different chromophores, showing great potential for practical applications in information encryption.

Willixhofer, Robin, Laura Gochicoa-Rangel, Anna Apostolo, Jeness Campodonico, Elisabetta Salvioni, Ada De-Los- Santos-Martínez, Alejandro Reyes-García, Luis Torre-Bouscoulet, Sergio Harari, Federico Tagariello, and Piergiuseppe Agostoni. Improved pulmonary gas exchange at altitudes is due to pulmonary vascular adaptation to chronic hypoxia in urban residents. High Alt Med Biol. 00:00-00, 2025. Background: Chronic exposure to high altitude induces physiological adaptations in the lung, but the specific mechanisms of alveolar-capillary gas exchange adaptation in urban populations remain incompletely understood. Methods: We assessed altitude-related alveolar capillary membrane gas diffusion adaptations in Milan (lowlanders, 120 m) and Mexico City (highlanders, 2,240 m). A 1:1 nearest-neighbor matching by age and sex was performed. Results: Comparison between healthy young adults (n = 246, age <40 years) showed higher diffusing capacity for carbon monoxide (DLCO: 31.7 [27.4-39.0] vs. 28.2 [24.6-32.8] ml/min/mmHg, p < 0.0001) and pulmonary capillary blood volume (Vcap: 105 [87-113] vs. 84 [71-98] ml, p < 0.0001), but lower membrane diffusing capacity (Dm: 50 [45-60] vs. 61 [51.70] ml/min/mmHg, p < 0.0001) in highlanders. The matching procedure yielded 71 pairs (n = 142) with balanced age and sex distributions (standardized mean differences <0.1). These differences remained significant after matching: highlanders showed higher DLCO (31.7 [27.8-39.1] vs. 27.1 [23.7-32.4] ml/min/mmHg, p < 0.0001), higher Vcap (104 [85-124] vs. 78 [65-96] ml, p < 0.0001), and lower Dm (51 [46-60 vs. 57 [50-68] ml/min/mmHg, p = 0.045). Conclusions: These findings suggest vascular, rather than membrane, adaptation to chronic hypoxia in high-altitude urban residents.

Abstract The timing of initiation is critical in antiviral treatment and viral dynamic (VD) modeling is a powerful tool to study the within-host viral load changes and evaluate antiviral treatment effects using mathematical equations. Previous simulation studies have shown that early treatment initiation is critical to maximize the therapeutic response in antiviral treatment in an acute viral infection such as influenza and SARS-CoV-2. A recent experimental study demonstrated that late therapy initiation can lead to diminished antiviral potency. However, most VD model simulations with varying treatment initiation time accounted only for the effect of initiation condition (i.e., state of different cell populations when the therapy started), the loss of drug potency has been under-investigated. This may overestimate the antiviral effect, potentially resulting in suboptimal dose selection. To this end, we aimed to characterize relationship between the drug potency (EC50) and the timing of drug addition, using nirmatrelvir and GS-441524 against SARS-CoV-2 as an example. Viral load data were obtained from in vitro experiments with various drug concentrations and treatment initiated between 0 to 3 days post infection. EC50 values were fitted for each treatment initiation group and were found to vary with the timing of treatment initiation in both drugs. Also, a VD model with time-varying EC50 provided better fits than a constant EC50 model (BIC = 1667.90 vs. 1677.84). Further simulations also indicated that a constant EC50 model overestimated the antiviral efficacy when treatment started late. These findings highlighted the importance of considering EC50 shift when optimizing dosage regimens for patients presenting late.

Advanced oxidation processes (AOPs) based on peroxydisulfate (PDS) dominated by the nonradical pathway have aroused great concern in organic pollutant degradation due to the high tolerance to interference. However, secondary pollution caused by leached metal ions remains a scientific challenge for PDS activators that are mainly composed of transition metals. To develop efficient and green metal catalysts for PDS activation, we proposed a coprecipitation combined with calcination approach to prepare MgAlFe-mixed metal oxides (MMOs). MMO-700 obtained by calcination at 700 °C possesses a large specific surface area (213.14 m2/g) and atomically dispersed active sites, which synergistically facilitated the enrichment of abundant ciprofloxacin (CIP) and PDS on the catalyst surface, thereby providing a prerequisite step for PDS activation. This featured system selectively generated the MMO-700/PDS* complex, resulting in an efficient degradation efficiency of 79.7% for CIP with almost no leaching of Fe detected. Impressively, MMO-700 also exhibited excellent environmental adaptability and desirable catalytic efficiency in the PDS* complex-mediated electron transfer process. In addition, CIP degradation involved three possible pathways including the opening and oxidation of the piperazine ring, the opening of the cyclopropyl ring, and the transformation of the quinolone group. This study provides a new strategy for developing efficient and green catalysts to achieve PDS nonradical activation and contribute to wastewater treatment.

This editorial piece co-authored by the Senior Editors at Microbiome aims to highlight current challenges in the field of environmental and host-associated microbiome research. We also take the opportunity to clarify our expectations for the articles submitted to the journal. At Microbiome, we are seeking studies that provide either new mechanistic insights into the role of microbiomes in health and environmental systems or substantial conceptual or technical advances. Manuscripts need to meet high standards of language accuracy, quality of microbiome analyses, and data and protocol availability, including detailed reporting of wet-lab and in silico protocols, all of which can critically enhance transparency and reproducibility. We think that such efforts are essential to push the boundaries of our knowledge on microbiomes in a concerted, international effort.

Transfeminine people (assigned male at birth) often undergo penile inversion vaginoplasty to create vulva, a clitoris and a vaginal canal (referred to as a neovagina). After vaginoplasty, transfeminine people frequently experience gynecological concerns but their etiology is unknown due to a lack of knowledge of the neovaginal microenvironment. We characterized neovaginal microbiota and cytokines in 47 transfeminine participants. Participants self-reported sexual behaviors and symptoms, enabling correlation with bacterial (16S rRNA) and immune profiles. Four distinct clusters of co-occurring bacteria with unique immune profiles were identified. One cluster, which included Fastidiosipila , Ezakiella , and Murdochiella , was abundant, stable, and correlated with lower cytokines. Conversely, another cluster containing Howardella , Parvimonas , Fusobacterium , and Lawsonella was linked to higher cytokines. Although Lactobacillus was detected, Lactobacillus -dominance was rare. These findings underscore the need for evidence-based clinical guidelines tailored to transfeminine gynecologic care, emphasizing the vital role of the neovaginal microbiome in symptom management and sexual health.

This study analyzed metagenomic and immune marker profiles of seven individuals before, during, and after a 7-day course of metronidazole treatment for bacterial vaginosis (BV). Treatment reduced BV-associated bacteria and immune marker levels, with distinct early (days 1-4) and late (days 5-7) phases. Post-treatment, variability in microbial and immune marker profiles demonstrated a rapid resurgence of certain BV associated bacteria, highlighting the need for additional strategies like probiotics to maintain a healthy vaginal microbiome. The study found significant host and microbial influences on immune response variance, with IP-10 and sEcad highly correlated with the vaginal microbiome. The findings identify optimal timing for administering live biotherapeutics to restore D-lactic acid-producing Lactobacillus species dominance and underscore the complexity of BV infection and treatment response among different people.

Aiming at the acid selection for the industrial process of copper ore decomposition and improvement of copper recovery, we investigated the influence of different acids on the Cu2+ adsorption capacity of CaAl-Cl-LDHs fabricated by a novel atomic economic route. As-prepared materials exhibited improved removal efficiency in SO42– solution than in Cl– and NO3– ones. It was found that dissolved Ca2+ from CaAl-Cl-LDHs easily reacted with SO42– to form CaSO4 precipitation, further promoting CaAl-Cl-LDHs decomposition, thereby driving higher Cu2+ removal via generation of not only CuAl-LDH but also basic copper sulfate. Therefore, sulfuric acid was selected in actual industrial processes of iron–copper ore to improve the recovery rate in smelting wastewater. CaAl-Cl-LDHs were further produced on a larger scale with a production line of 20000 tons/year, showing satisfactory removal efficiency (∼90%), copper-containing materials (11.4%), and reusability. This work provides a new method to select acids during wet processing for ores to improve the copper recovery rate.

This article describes an effort to calculate the public and economic value of museum experiences. A significant feature of the research was its use of outcome metrics grounded in decades of visitor research on the perceived value of visiting a museum. The article lays out the underlying theoretical approach and presents data from a year-long study of visitors to eight Finnish museums. Results showed that museum users perceived that their visit experience resulted in enhanced, durable feelings of personal, social and physical well-being, with valuations of the economic benefits of these enhanced feelings of well-being in the range of €204–€641/visit. As was the case of the eight museums in the study, most museums annually serve tens to hundreds of thousands of visitors, thus annually individual museums create on the order of tens of millions of Euros of value for their communities and collectively provide value in the billions of Euros. The findings from this research make it possible for museums to make a more valid and credible case for the significant value they create and for the vital role they play in supporting the public’s well-being.