Global Response Research Articles

Assessing the Efficacy of Bortezomib and Dexamethasone for Induction and Maintenance Therapy in Relapsed/Refractory Cutaneous T-Cell Lymphoma: A Phase II CISL1701/BIC Study.

This multicenter, open-label, phase II trial evaluated the efficacy and safety of bortezomib combined with dexamethasone for the treatment of relapsed/refractory cutaneous T-cell lymphoma (CTCL) in previously treated patients across 14 institutions in South Korea. Between September 2017 and July 2020, 29 patients with histologically confirmed CTCL received treatment, consisting of eight 4-week cycles of induction therapy followed by maintenance therapy, contingent upon response, for up to one year. The primary endpoint was the proportion of patients achieving an objective global response. Thirteen (44.8%) of the 29 patients achieved an objective global response, including two complete responses. The median progression-free survival (PFS) was 5.8 months, with responders showing a median PFS of 14.0 months. Treatment-emergent adverse events were generally mild, with a low incidence of peripheral neuropathy and hematologic toxicities. Despite the trend toward shorter PFS in patients with higher mutation burdens, genomic profiling before and after treatment showed no significant emergence of new mutations indicative of disease progression. This study supports the use of bortezomib and dexamethasone as a viable and safe treatment option for previously treated CTCL, demonstrating substantial efficacy and manageability in adverse effects. Further research with a larger cohort is suggested to validate these findings and explore the prognostic value of mutation profiles.

FADD regulates adipose inflammation, adipogenesis, and adipocyte survival

Adipose tissue, aside from adipocytes, comprises various abundant immune cells. The accumulation of low-grade chronic inflammation in adipose tissue serves as a primary cause and hallmark of insulin resistance. In this study, we investigate the physiological roles of FADD in adipose tissue inflammation, adipogenesis, and adipocyte survival. High levels of Fadd mRNA were observed in mitochondrial-rich organs, particularly brown adipose tissue. To explore its metabolic functions, we generated global Fadd knockout mice, resulting in embryonic lethality, while heterozygous knockout (Fadd+/−) mice did not show any significant changes in body weight or composition. However, Fadd+/− mice exhibited reduced respiratory exchange ratio (RER) and serum cholesterol levels, along with heightened global and adipose inflammatory responses. Furthermore, AT masses and expression levels of adipogenic and lipogenic genes were decreased in Fadd+/− mice. In cellular studies, Fadd inhibition disrupted adipogenic differentiation and suppressed the expression of adipogenic and lipogenic genes in cultured adipocytes. Additionally, Fadd overexpression caused adipocyte death in vitro with decreased RIPK1 and RIPK3 expression, while Fadd inhibition downregulated RIPK3 in iWAT in vivo. These findings collectively underscore the indispensable role of FADD in adipose inflammation, adipogenesis, and adipocyte survival.

Enabling equitable and affordable access to novel therapeutics for pandemic preparedness and response via creative intellectual property agreements

The COVID-19 pandemic demonstrated that the current purely market-driven approaches to drug discovery and development alone are insufficient to drive equitable access to new therapies either in preparation for, or in response to, pandemics. A new global framework driven by equity is under negotiation at the World Health Organization to support pandemic preparedness and response. Some believe that the global intellectual property (IP) system itself is part of the problem and propose a purely Open Science approach. In this article, we discuss how existing IP frameworks and contractual agreements may be used to create rights and obligations to generate a more effective global response in future, drawing on experience gained in the COVID Moonshot program, a purely Open Science collaboration, and the ASAP AViDD drug discovery consortium, which uses a hybrid, phased model of Open Science, patent filing and contractual agreements. We conclude that ‘straight to generic’ drug discovery is appropriate in some domains, and that targeted patent protection, coupled with open licensing, can offer a route to generating affordable and equitable access for therapy areas where market forces have failed. The Extended Data contains a copy of our model IP policy, which can be used as a template by other discovery efforts seeking to ensure their drug candidates can be developed for globally equitable and affordable access.

Revolutionizing Antibacterial Strategies: Lipid Nanoparticles as Game-Changers in Combatting Multi-Drug-Resistant Infections.

To overcome the limits of traditional antibiotic medications, novel approaches are needed to combat the growing global epidemic of Multidrug-resistant (MDR) infections. As drug-resistant bacteria develop, the importance of innovative antimicrobial methods is underscored by antibiotic abuse and misuse. The global threat of MDR microorganisms is increasing, which calls for a coordinated global response. Lipid Nanoparticles (LNPs) possess several characteristics that make them attractive choices for managing multidrug resistant (MDR) infections, as well as potential delivery systems for antimicrobial agents. Thus, LNPs improve drug solubility, stability, and targeted delivery, thereby mitigating the drawbacks of conventional antibiotic therapy. Several characteristics of LNPs, which stop MDR bacteria from developing resistance mechanisms, serve as guidelines for precision medicine. It presents a powerful approach for combating the growing concern of MDR bacteria by increasing Anti-Microbial Peptides (AMPs) bioavailability and targeting distribution to bacterial cells. LNPs have the potential to redefine antibacterial treatments for MDR illnesses in the context of this study. Further, it discusses LNP use in larger applications, such as fighting Anti-Microbial Resistance (AMR) and MDR. A complete understanding of the unique features, many uses, and importance of collaborative efforts to overcome the global challenge of antibiotic resistance are also conveyed in the study.

Seismic behavior of high-rise modular buildings with simplified models of inter-module connections

Inter-module connections serve as crucial components, horizontally and vertically connecting individual modules to form modular buildings. This paper presents a component-based model that divides inter-module connections into vertical and horizontal connection components, facilitating the simplification of shear and axial behaviors for input into the global numerical model. Initially, experimental studies and numerical simulations were conducted to investigate the shear and axial behavior of these connection components, following which simplified connection component models were derived. Subsequently, a component-based model of inter-module connections was established, in which the shear and axial properties of the vertical and horizontal components were represented by nonlinear connector elements. Finally, the proposed component-based model was incorporated directly into the global frame models of high-rise steel modular buildings, and the seismic behavior was evaluated. The accuracy of the proposed component-based model was investigated by comparing the natural vibration characteristics and global building responses of high-rise steel modular buildings with traditional empirical models established based on assumptions of rigid or pinned fixities. The results reveal that traditional empirical models fail to accurately represent the discontinuous properties of inter-module connections, resulting in an overestimation of structural lateral stiffness. In contrast, the component-based model accounts for the actual load-transfer mechanisms of vertical and horizontal components, providing a more accurate understanding of the natural vibration characteristics and seismic response of high-rise steel modular buildings. The proposed component-based model establishes a critical link between isolated connection behavior and structural response assessment for high-rise steel modular buildings, making it well-suited for accurately predicting global building responses.

Emulating inconsistencies in stratospheric aerosol injection

Stratospheric aerosol injection (SAI) would involve the addition of sulfate aerosols in the stratosphere to reflect part of the incoming solar radiation, thereby cooling the climate. Studies trying to explore the impacts of SAI have often focused on idealized scenarios without explicitly introducing what we call ‘inconsistencies’ in a deployment. A concern often discussed is what would happen to the climate system after an abrupt termination of its deployment, whether inadvertent or deliberate. However, there is a much wider range of plausible inconsistencies in deployment than termination that should be evaluated to better understand associated risks. In this work, we simulate a few representative inconsistencies in a pre-existing SAI scenario: an abrupt termination, a decade-long gradual phase-out, and 1 year and 2 year temporary interruptions of deployment. After examining their climate impacts, we use these simulations to train an emulator, and use this to project global mean temperature response for a broader set of inconsistencies in deployment. Our work highlights the capacity of a finite set of explicitly simulated scenarios that include inconsistencies to inform an emulator that is capable of expanding the space of scenarios that one might want to explore far more quickly and efficiently.

Bacterial aggregation facilitates internalin-mediated invasion of Listeria monocytogenes

Dissemination of food-borne L. monocytogenes in the host relies on internalin-mediated invasion, but the underlying invasion strategies remain elusive. Here we use live-cell microscopy to follow single cell interactions between individual human cells and L. monocytogenes and elucidate mechanisms associated with internalin B (InlB)-mediated invasion. We demonstrate that whilst a replicative invasion of nonphagocytic cells is a rare event even at high multiplicities of invasion, L. monocytogenes overcomes this by utilising a strategy relaying on PrfA-mediated ActA-based aggregation. We show that L. monocytogenes forms aggregates in extracellular host cell environment, which promote approximately 5-fold more host cell adhesions than the non-aggregating actA-ΔC mutant (which lacks the C-terminus coding region), with the adhering bacteria inducing 3-fold more intracellular invasions. Aggregation is associated with robust MET tyrosine kinase receptor clustering in the host cells, a hallmark of InlB-mediated invasion, something not observed with the actA-ΔC mutant. Finally, we show via RNA-seq analyses that aggregation involves a global adaptive response to host cell environment (including iron depletion), resulting in metabolic changes in L. monocytogenes and upregulation of the PrfA virulence regulon. Overall, our analyses provide new mechanistic insights into internalin-mediated host-pathogen interactions of L. monocytogenes.

The efficacy and safety of monoclonal antibody therapies for interstitial cystitis/bladder pain syndrome: A meta-analysis of randomized controlled trials.

This study aimed to assess the efficacy and safety of monoclonal antibody therapies (MATs) for interstitial cystitis/bladder pain syndrome (IC/BPS). A systematic search was conducted across databases including PubMed, Embase, clinicalTrial.gov, and the Cochrane Library Central Register of Controlled Trials. Randomized controlled trials (RCTs) comparing MATs versus placebo were included. Primary outcomes comprised the Global Response Assessment (GRA) scale and the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI). Additional analyses encompassed mean daily frequency of voids, the O'Leary-Sant Interstitial Cystitis Problem Index, pain scores, and complications. Statistical analyses were performed using Review Manager 5.3. Five high-quality RCTs, comprising 263 patients with IC/BPS, were ultimately selected. MATs were generally effective in treating IC/BPS. Patients receiving MATs exhibited a higher satisfaction rate (odds ratio [OR]: 2.7, confidence interval [CI]: 1.31-5.58, p = 0.007) and lower ICSI scores (mean difference [MD]: -1.44, CI: -2.36 to -0.52, p = 0.002). Moreover, MAT recipients experienced reduced pain (MD: -0.53, CI: -0.79 to -0.26, p < 0.0001) and decreased frequency of urination (MD: -1.91, CI: -2.55 to -1.27, p < 0.00001). Importantly, there were no disparities regarding complication incidence in the MAT and control groups. The current findings indicate that MATs are effective and safe for treating IC/BPS. Nonetheless, future RCTs with larger sample sizes and long-term follow-up are warranted.

Environmental impacts of COVID-19 pandemic on selected global regions: Precursors of sustainable development

The COVID-19 pandemic prompted sweeping global responses to mitigate its spread, triggering unforeseen repercussions on the environment and the economy. These unintended consequences have cast a novel light on the intersection of pandemic control measures and their impact on environmental health and economic dynamics, consequently influencing global sustainability initiatives. This comprehensive narrative review meticulously investigates the intricate relationship between COVID-19 control measures and environmental well-being. Our study delves into key ecological dimensions, including air quality, water quality, noise pollution, soil quality, and energy demand, scrutinising their transformations during pandemic-induced lockdowns. Additionally, we assessed the pandemic’s unanticipated economic facets, particularly the rapid acceleration of digitisation and e-commerce. Our methodology hinges on an exhaustive literature review, employing rigorous comparisons between lockdown and pre-lockdown parameters. Our findings reveal a remarkable shift in environmental quality indicators during peak lockdown periods, surpassing pre-pandemic benchmarks. This transformation underscores the potential for sustainable behaviours to be seamlessly integrated into our daily lives. The pandemic has not only served as an eye-opener but also as a catalyst for sustainable practices. This review underscores the COVID-19 pandemic’s unprecedented revelation of positive environmental and economic implications. As the global community gears up to fortify health and economic resilience against future crises, the invaluable lessons learned from the pandemic’s silver linings should be the bedrock for shaping future environmental policies and targets. This synergy between health, economy, and environment presents an unprecedented opportunity to advance towards our shared sustainable development goals.

Integrated hydrodynamic-structural analysis of flexible floating structures

This paper presents a comprehensive approach for the linearized frequency-domain analysis of hydrodynamic loading and structural responses on a deformable body. The structural and hydrodynamic analyses are integrated by employing the mode superposition method. Commencing with an eigenvalue analysis on the structural model, the shapes of selected modes, mass, and structural stiffness matrices are extracted as input to the subsequent hydrodynamic analysis, where the global response is solved in the modal space. The resulting hydrodynamic and inertial loads are then transferred to the same finite element model for stress assessment. To exemplify the proposed methodology, a bottom-fixed flexible cylindrical monopile and a long box-shaped barge model are investigated. For the barge model, the sectional loads are obtained from the integral of stresses in the cuts along the structure model, which are found to be consistent with those from the hydrodynamic analysis, demonstrating the consistency of the entire workflow. In particular, this paper introduces a straightforward formulation for evaluating the generalized restoring matrices, eliminating the need for spatial derivatives of the mode shape function and thereby significantly reducing numerical uncertainties in using the flexible modes derived from finite element model for hydrodynamic analysis.

Profound loss of microbial necromass carbon in permafrost thaw-subsidence in the central Tibetan Plateau

Climate warming is causing rapid permafrost degradation, including thaw-induced subsidence, potentially resulting in heightened carbon release. Nevertheless, our understanding of the levels and variations of carbon components in permafrost, particularly during the degradation process, remains limited. The uncertainties arising from this process lead to inaccurate assessments of the climate effects during permafrost degradation. With vast expanses of permafrost in the Tibetan Plateau, there is limited research available on SOC components, particularly in the central Tibetan Plateau. Given remarkable variations in hydrothermal conditions across different areas of the Tibetan Plateau, the existing limited studies make it challenging to assess the overall SOC components in the permafrost across the Tibetan Plateau and simulate their future changes. In this study, we examined the properties of soil organic carbon (SOC) and microbial necromass carbon (MicrobialNC) in a representative permafrost thaw-subsidence area at the southern edge of continuous permafrost in the central Tibetan Plateau. The results indicate that prior to the thaw-subsidence, the permafrost had a SOC content of 72.68 ± 18.53 mg g−1, with MicrobialNC accounting for 49.6%. The thaw-subsidence of permafrost led to a 56.4% reduction in SOC, with MicrobialNC accounting for 70.0% of the lost SOC. MicrobialNC constitutes the primary component of permafrost SOC, and it is the main component that is lost during thaw-subsidence formation. Changes in MicrobialNC are primarily correlated with factors pH, plant input, and microbial properties. The present study holds crucial implications for both the ecological and biogeochemical processes associated with carbon release from permafrost, and it furnishes essential data necessary for modeling the global response of permafrost to climate warming. Based on this study and previous research, permafrost thawing in the Tibetan Plateau causes substantial loss of SOC. However, there's remarkable heterogeneity in SOC component changes across different regions, warranting further in-depth investigation.

Intratumoral Injection of mRNA Encoding Survivin in Combination with STAT3 Inhibitor Stattic Enhances Antitumor Effects

Intratumoral delivery of mRNA encoding immunostimulatory molecules can initiate a robust, global antitumor response with little side effects by enhancing local antigen presentation in the tumor and the tumor draining lymph node. Neoantigen-based mRNA nanovaccine can inhibit melanoma growth in mice by intratumoral injection. Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune responses by secreting immunosuppressive agents, such as reactive oxygen species (ROS). Suppression of STAT3 activity by stattic may reduce MDSC-mediated immunosuppression in the TME and promote the antitumor immune responses. In this study, in vitro transcribed mRNA encoding tumor antigen survivin was prepared and injected intratumorally in BALB/c mice bearing subcutaneous colon cancer tumors. In vivo studies demonstrated that intratumoral survivin mRNA therapy could induce antitumor T cell response and inhibit tumor growth of colon cancer. Depletion of CD8+ T cells could significantly inhibit survivin mRNA-induced antitumor effects. RT-qPCR and ELISA analysis indicated that survivin mRNA treatment led to increased expression of receptor activator nuclear factor-κB ligand (RANKL). In vitro experiment showed that MDSCs could be induced from mouse bone marrow cells by RANKL and RANKL-induced MDSCs could produce high level of ROS. STAT3 inhibitor stattic suppressed activation of STAT3 and NF-κB signals, thereby inhibiting expansion of RANKL-induced MDSCs. Combination therapy of survivin mRNA and stattic could significantly enhance antitumor T cell response, improve long-term survival and reduce immunosuppressive tumor microenvironment compared to each monotherapy. In addition, combined therapy resulted in a significantly reduced level of tumor cell proliferation and an obviously increased level of tumor cell apoptosis in CT26 colon cancer-bearing mice, which could be conducive to inhibit the tumor growth and lead to immune responses to released tumor-associated antigens. These studies explored intratumoral mRNA therapy and mRNA-based combined therapy to treat colon cancer and provide a new idea for cancer therapy.

Natural variation in yeast reveals multiple paths for acquiring higher stress resistance

BackgroundOrganisms frequently experience environmental stresses that occur in predictable patterns and combinations. For wild Saccharomyces cerevisiae yeast growing in natural environments, cells may experience high osmotic stress when they first enter broken fruit, followed by high ethanol levels during fermentation, and then finally high levels of oxidative stress resulting from respiration of ethanol. Yeast have adapted to these patterns by evolving sophisticated “cross protection” mechanisms, where mild ‘primary’ doses of one stress can enhance tolerance to severe doses of a different ‘secondary’ stress. For example, in many yeast strains, mild osmotic or mild ethanol stresses cross protect against severe oxidative stress, which likely reflects an anticipatory response important for high fitness in nature.ResultsDuring the course of genetic mapping studies aimed at understanding the mechanisms underlying natural variation in ethanol-induced cross protection against H2O2, we found that a key H2O2 scavenging enzyme, cytosolic catalase T (Ctt1p), was absolutely essential for cross protection in a wild oak strain. This suggested the absence of other compensatory mechanisms for acquiring H2O2 resistance in that strain background under those conditions. In this study, we found surprising heterogeneity across diverse yeast strains in whether CTT1 function was fully necessary for acquired H2O2 resistance. Some strains exhibited partial dispensability of CTT1 when ethanol and/or salt were used as mild stressors, suggesting that compensatory peroxidases may play a role in acquired stress resistance in certain genetic backgrounds. We leveraged global transcriptional responses to ethanol and salt stresses in strains with different levels of CTT1 dispensability, allowing us to identify possible regulators of these alternative peroxidases and acquired stress resistance in general.ConclusionsUltimately, this study highlights how superficially similar traits can have different underlying molecular foundations and provides a framework for understanding the diversity and regulation of stress defense mechanisms.

Dynamic and structural analyses of floating dock operations considering dock-vessel coupling loads

Floating docks are important for increasing the capacity of land-based shipyards and serve as essential platforms for vessel construction, maintenance, and repair. As the size of modern vessels increases, ensuring the structural safety of the floating docks becomes challenging. To enhance the operational safety of the floating docks, this study aims to develop an in-house code for a comprehensive global response assessment of a full-scale floating dock. The code is developed under a quasi-static assumption and enables dynamic and structural response assessments for the floating dock and docked vessel during the vessel-docking operations. The floating dock and docked vessel are represented as rigid bodies with six degrees of freedom and subjected to hydrostatic, hydrodynamic, mooring, and contact loads. The piping network of the floating dock's ballast water system is modelled to calculate the flow rates out of all ballast tanks. A modified proportional controller (P-controller) is employed to achieve automatic ballast control, regulating opening angles of ballast tank valves to minimize roll and pitch motions of the floating dock and docked vessel. For structural response assessment, a bending model is proposed to evaluate the bending deformation of the floating dock based on the load distribution along the dock's length. Results show that the present code can successfully simulate the vessel-docking process. The automatic ballast control strategy effectively minimizes roll and pitch for both the floating dock and docked vessel, ensuring stable control of the entire system. Minimal discrepancies are observed in the dynamic responses and bending of the floating dock between one- and two-way couplings. The longitudinal shift of the docked vessel's centre of gravity (CoG) increases the relative motions between the docked vessel and the floating dock, especially in surge, sway and pitch. A significant shift distance might cause the mooring rope breakage. Positioning the vessel's CoG closer to the dock's CoG proves safer for vessel-docking operations. In general, the developed code can support the decision-making for dock masters and optimize the docking plan.

How Intravesical Platelet-Rich Plasma Can Help Patients with Interstitial Cystitis/Bladder Pain Syndrome: A Comprehensive Scoping Review.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a condition characterized by chronic inflammation that affects the bladder. The study was aimed at evaluating the effectiveness of intravesical platelet-rich plasma (PRP) injections in patients with IC/BPS. We conducted a comprehensive search strategy to involve studies that investigate the efficacy of intravesical PRP injections or instillations over different time intervals. Various outcome measures were assessed, including pain scores, functional outcomes, urodynamic parameters, and surface expressions on the urothelium. Our search strategy revealed 1,125 studies. After screening, ten articles met the inclusion criteria. Intravesical PRP significantly reduced the visual analog scale (VAS) compared with baseline scores. Several clinical trials reported significant improvements in the global response rate (GRA), O'Leary-Sant Symptom (OSS) questionnaire, Interstitial Cystitis Symptom Index (ICSI), and Interstitial Cystitis Problem Index (ICPI). Urodynamic parameters such as maximum flow rate (Qmax) and post-voiding residual (PVR) showed significant improvements in some studies. The study concluded that intravesical PRP injections could be a promising effective treatment option for IC/BPS patients by their significant ability to reduce pain. However, improvement of urodynamic and functional outcomes is still not clear. Further large comparative trials are still warranted to assess the efficacy of PRP instillation.

The global impact of COVID-19 on tuberculosis: A thematic scoping review, 2020-2023.

This thematic scoping review of publications sought to understand the global impact of COVID-19 on tuberculosis (TB), interpret the scope of resonating themes, and offer policy recommendations to stimulate TB recovery and future pandemic preparedness. Publications were captured from three search engines, PubMed, EBSCO, and Google Scholar, and applicable websites written in English from January 1, 2020, to April 30, 2023. Our scoping review was limited to publications detailing the impact of COVID-19 on TB. Original research, reviews, letters, and editorials describing the deleterious and harmful--yet sometimes positive--impact of COVID-19 (sole exposure) on TB (sole outcome) were included. The objective was to methodically categorize the impacts into themes through a comprehensive review of selected studies to provide significant health policy guidance. Two authors independently screened citations and full texts, while the third arbitrated when consensus was not met. All three performed data extraction. Of 1,755 screened publications, 176 (10%) covering 39 countries over 41 months met the inclusion criteria. By independently using a data extraction instrument, the three authors identified ten principal themes from each publication. These themes were later finalized through a consensus decision. The themes encompassed TB's care cascade, patient-centered care, psychosocial issues, and health services: 1) case-finding and notification (n = 45; 26%); 2) diagnosis and laboratory systems (n = 19; 10.7%) 3) prevention, treatment, and care (n = 22; 12.2%); 4) telemedicine/telehealth (n = 12; 6.8%); 5) social determinants of health (n = 14; 8%); 6) airborne infection prevention and control (n = 8; 4.6%); 7) health system strengthening (n = 22; 13%); 8) mental health (n = 13; 7.4%); 9) stigma (n = 11; 6.3%); and 10) health education (n = 10; 5.7%). Heterogeneity of publications within themes. We identified ten globally generalizable themes of COVID-19's impact on TB. The impact and lessons learned from the themed analysis propelled us to draft public health policy recommendations to direct evidence-informed guidance that strengthens comprehensive global responses, recovery for TB, and future airborne pandemic preparedness.

Proteome signatures reveal homeostatic and adaptive oxidative responses by a putative co-chaperone, Wos2, to influence fungal virulence determinants in cryptococcosis.

The increasing prevalence of invasive fungal pathogens is dramatically changing the clinical landscape of infectious diseases, posing an imminent threat to public health. Specifically, Cryptococcus neoformans, the human opportunistic pathogen, expresses elaborate virulence mechanisms and is equipped with sophisticated adaptation strategies to survive in harsh host environments. This study extensively characterizes Wos2, an Hsp90 co-chaperone homolog, featuring bilateral functioning for both cryptococcal adaptation and the resulting virulence response. In this study, we evaluated the proteome and secretome signatures associated with wos2 deletion in enriched and infection-mimicking conditions to reveal Wos2-dependent regulation of the oxidative stress response through global translational reprogramming. The wos2Δ strain demonstrates defective intracellular and extracellular antioxidant protection systems, measurable through a decreased abundance of critical antioxidant enzymes and reduced growth in the presence of peroxide stress. Additional Wos2-associated stress phenotypes were observed upon fungal challenge with heat shock, osmotic stress, and cell membrane stressors. We demonstrate the importance of Wos2 for intracellular lifestyle of C. neoformans during in vitro macrophage infection and provide evidence for reduced phagosomal replication levels associated with wos2Δ. Accordingly, wos2Δ featured significantly reduced virulence within impacting fungal burden in a murine model of cryptococcosis. Our study highlights a vulnerable point in the fungal chaperone network that offers a therapeutic opportunity to interfere with both fungal virulence and fitness.IMPORTANCEThe global impact of fungal pathogens, both emerging and emerged, is undeniable, and the alarming increase in antifungal resistance rates hampers our ability to protect the global population from deadly infections. For cryptococcal infections, a limited arsenal of antifungals and increasing rates of resistance demand alternative therapeutic strategies, including an anti-virulence approach, which disarms the pathogen of critical virulence factors, empowering the host to remove the pathogens and clear the infection. To this end, we apply state-of-the-art mass spectrometry-based proteomics to evaluate the impact of a recently defined novel co-chaperone, Wos2, toward cryptococcal virulence using in vitro and in vivo models of infection. We explore global proteome and secretome remodeling driven by the protein and uncover the novel role in modulating the fungal oxidative stress response. Complementation of proteome findings with in vitro infectivity assays demonstrated the protective role of Wos2 within the macrophage phagosome, influencing fungal replication and survival. These results underscore differential cryptococcal survivability and weakened patterns of dissemination in the absence of wos2. Overall, our study establishes Wos2 as an important contributor to fungal pathogenesis and warrants further research into critical proteins within global stress response networks as potential druggable targets to reduce fungal virulence and clear infection.

Fostering citizen-engaged HIV implementation science.

Successful implementation of evidence-based practices depends on contextual factors like stakeholder engagement, the socio-political environment, resource availability, and stakeholders' felt needs and preferences. Nevertheless, inequities in implementation exist and undermine efforts to address HIV in marginalized key populations. Implementation science shows promise in addressing such inequities in the HIV response, but can be limited without meaningful engagement from citizens or communities. We define the concept of a citizen-engaged HIV implementation science as one that involves citizens and communities deeply in HIV implementation science activities. In this commentary, we discuss how citizen science approaches can be leveraged to spur equity in HIV implementation science. Drawing on three areas previously defined by Geng and colleagues that serve to drive impactful implementation science in the HIV response, we discuss how citizens can be engaged when considering "whose perspectives?", "what questions are being asked?" and "how are questions asked?". With respect to "whose perspectives?" a citizen-engaged HIV implementation science would leverage participatory methods and tools, such as co-creation, co-production and crowdsourcing approaches, to engage the public in identifying challenges, solve health problems and implement solutions. In terms of "what questions are being asked?", we discuss how efforts are being made to synthesize citizen or community-led approaches with existing implementation science frameworks and approaches. This also means that we ensure communities have a say in interrogating and deconstructing such frameworks and adapting them to local contexts through participatory approaches. Finally, when considering "how are questions asked?", we argue for the development and adoption of broad, guiding principles and frameworks that account for dynamic contexts to promote citizen-engaged research in HIV implementation science. This also means avoiding narrow definitions that limit the creativity, innovation and ground-up wisdom of local citizens. By involving communities and citizens in the development and growth of HIV implementation science, we can ensure that our implementation approaches remain equitable and committed to bridging divides and ending AIDS as a public health threat. Ultimately, efforts should be made to foster a citizen- and community-engaged HIV implementation science to spur equity in our global HIV response.

Isotopic study of honey documents widespread plant uptake of old carbon in North America

A comprehensive understanding of carbon cycling pathways in the soil-plant system is needed to develop models that accurately predict global carbon reservoir responses to anthropogenic perturbations. Honey is a carbon-rich natural food produced by wild and managed pollinating insects all over the world; the composition of a single sample is a function of millions of pollinator-plant interactions. We studied the 13C/12C and Δ14C of 121 honey samples sourced from the United States, and found a significant old carbon contribution. The effect is observed from 25 to 45° latitude, not correlated with 13C/12C, and consistent with a previously published study on European honeys. In specific cases, the measured values were up to 20 ‰ (Δ14C) higher than the expected atmospheric 14CO2 value for the given year, which shows a significant old carbon contribution. We hypothesize that the older carbon is from plant liquids derived in part from soil carbon or stored nonstructural carbohydrates from plants, which shifts the calibrated age of the sample by 5 years or more. Our work is the first to describe the widespread occurrence of old carbon in honey and shows that radiocarbon measurements can be a powerful tool to trace carbon allocations in terrestrial food webs and detect the atmosphere-soil-plant carbon cycle contributions.

Isotopic study of honey documents widespread plant uptake of old carbon in North America

A comprehensive understanding of carbon cycling pathways in the soil-plant system is needed to develop models that accurately predict global carbon reservoir responses to anthropogenic perturbations. Honey is a carbon-rich natural food produced by wild and managed pollinating insects all over the world; the composition of a single sample is a function of millions of pollinator-plant interactions. We studied the 13C/12C and Δ14C of 121 honey samples sourced from the United States, and found a significant old carbon contribution. The effect is observed from 25 to 45° latitude, not correlated with 13C/12C, and consistent with a previously published study on European honeys. In specific cases, the measured values were up to 20 ‰ (Δ14C) higher than the expected atmospheric 14CO2 value for the given year, which shows a significant old carbon contribution. We hypothesize that the older carbon is from plant liquids derived in part from soil carbon or stored nonstructural carbohydrates from plants, which shifts the calibrated age of the sample by 5 years or more. Our work is the first to describe the widespread occurrence of old carbon in honey and shows that radiocarbon measurements can be a powerful tool to trace carbon allocations in terrestrial food webs and detect the atmosphere-soil-plant carbon cycle contributions.