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Abstract A key aspect of sustainable bioeconomy is the recirculation of renewable, agricultural waste streams as substrates for microbial production of high-value compounds. One approach is the bioconversion of corn stover, an abundant maize crop byproduct, using the fungal maize pathogen Ustilago maydis. U. maydis is already used as a unicellular biocatalyst in the production of several industrially-relevant compounds using plant biomass hydrolysates. In this study, we demonstrate that U. maydis can grow using untreated corn stover as its sole carbon source. We developed a small-scale bioreactor platform to investigate U. maydis processing of corn stover, combining online monitoring of fungal growth and metabolic activity profiles with biochemical analyses of the pre- and post-fermentation residues. Our results reveal that U. maydis primarily utilizes soluble sugars i.e., glucose, sucrose and fructose present in corn stover, with only limited exploitation of the abundant lignocellulosic carbohydrates. Thus, we further explored the biotechnological potential of enhancing U. maydis´ lignocellulosic utilization. Additive performance improvements of up to 120 % were achieved when using a maize mutant with increased biomass digestibility, co-fermentation with a commercial cellulolytic enzyme cocktail, and exploiting engineered fungal strains expressing diverse lignocellulose-degrading enzymes. This work represents a key step towards scaling up the production of sustainable compounds from corn stover using U. maydis and provides a tool for the detailed monitoring of the fungal processing of plant biomass substrates. Graphical abstract

Abstract The global demand for plant oil has reached unprecedented levels and is relevant in all industrial sectors. Driven by the growing awareness for environmental issues of traditional plant oils and the need for eco-friendly alternatives, microbial oil emerges as a promising product with significant potential. Harnessing the capabilities of oleaginous microorganisms is an innovative approach for achieving sustainable oil production. To increase economic feasibility, it is crucial to explore feedstocks such as agricultural waste streams as renewable resource for microbial bioprocesses. The fungal model Ustilago maydis is one promising organism in the field of microbial triglyceride production. It has the ability to metabolize a wide variety of carbon sources for cell growth and accumulates high amounts of triglycerides intracellularly. In this study we asked whether this large variety of usable carbon sources can also be utilized for triglyceride production, using corn stover saccharides as a showcase. Our experiments revealed metabolization of the major saccharide building blocks present in corn stover, demonstrating the remarkable potential of U. maydis. The microorganism exhibited the capacity to synthesize triglycerides using the saccharides glucose, fructose, sucrose, xylose, arabinose, and galactose as carbon source. Notably, while galactose has been formerly considered as toxic to U. maydis, we found that the fungus can metabolize this saccharide, albeit with an extended lag phase of around 100 hours. We identified two distinct methods to significantly reduce or even prevent this lag phase, challenging previous assumptions and expanding the understanding of U. maydis metabolism. Our findings suggest that the two tested methods can prevent long lag phases on feedstocks with high galactose content and that U. maydis can produce microbial triglycerides very efficiently on many different carbon sources. Looking forward, exploring the metabolic capabilities of U. maydis on additional polymeric components of corn stover and beyond holds promise for innovative applications, marking a significant step toward environmentally sustainable bioprocessing technologies.

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Abstract Background Health is increasingly affected by multiple types of crises. Community engagement is recognised as being a critical element in successful crisis response, and a number of conceptual frameworks and global guideline documents have been produced. However, little is known about the usefulness of such documents and whether they contain sufficient information to guide effective community engagement in crisis response. We undertake a scoping review to examine the usefulness of conceptual literature and official guidelines on community engagement in crisis response using a realist-informed analysis [exploring contexts, mechanisms, and outcomes(CMOs)]. Specifically, we assess the extent to which sufficient detail is provided on specific health crisis contexts, the range of mechanisms (actions) that are developed and employed to engage communities in crisis response and the outcomes achieved. We also consider the extent of analysis of interactions between the mechanisms and contexts which can explain whether successful outcomes are achieved or not. Scope and findings We retained 30 documents from a total of 10,780 initially identified. Our analysis found that available evidence on context, mechanism and outcomes on community engagement in crisis response, or some of their elements, was promising, but few documents provided details on all three and even fewer were able to show evidence of the interactions between these categories, thus leaving gaps in understanding how to successfully engage communities in crisis response to secure impactful outcomes. There is evidence that involving community members in all the steps of response increases community resilience and helps to build trust. Consistent communication with the communities in time of crisis is the key for effective responses and helps to improve health indicators by avoiding preventable deaths. Conclusions Our analysis confirms the complexity of successful community engagement and the need for strategies that help to deal with this complexity to achieve good health outcomes. Further primary research is needed to answer questions of how and why specific mechanisms, in particular contexts, can lead to positive outcomes, including what works and what does not work and how to measure these processes.

Abstract Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (MM); however, drug resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, we identify, via two in vitro genome-wide CRISPR screens probing Daratumumab resistance, KDM6A as an important regulator of sensitivity to Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Loss of KDM6A leads to increased levels of H3K27me3 on the promoter of CD38, resulting in a marked downregulation in CD38 expression, which may cause resistance to Daratumumab-mediated ADCC. Re-introducing CD38 does not reverse Daratumumab-mediated ADCC fully, which suggests that additional KDM6A targets, including CD48 which is also downregulated upon KDM6A loss, contribute to Daratumumab-mediated ADCC. Inhibition of H3K27me3 with an EZH2 inhibitor resulted in CD38 and CD48 upregulation and restored sensitivity to Daratumumab. These findings suggest KDM6A loss as a mechanism of Daratumumab resistance and lay down the proof of principle for the therapeutic application of EZH2 inhibitors, one of which is already FDA-approved, in improving MM responsiveness to Daratumumab.

Abstract Osteoarthritis represents a chronic degenerative joint disease with exceptional clinical relevance. Polymorphisms of the CALCA gene, giving rise to either a procalcitonin/calcitonin (PCT/CT) or a calcitonin gene-related peptide alpha (αCGRP) transcript by alternative splicing, were reported to be associated with the development of osteoarthritis. The objective of this study was to investigate the role of both PCT/CT and αCGRP transcripts in a mouse model of post-traumatic osteoarthritis (ptOA). WT, αCGRP −/− and CALCA −/− mice were subjected to anterior cruciate ligament transection (ACLT) to induce ptOA of the knee. Mice were sacrificed 4 and 8 weeks post-surgery, followed by micro-CT and histological evaluation. Here we show that the expression of both PCT/CT and αCGRP transcripts is induced in ptOA knees. CALCA −/− mice show increased cartilage degeneration and subchondral bone loss with elevated osteoclast numbers compared to αCGRP −/− and WT mice. Osteophyte formation is reduced to the same extent in CALCA −/− and αCGRP −/− mice compared to WT controls, while a reduced synovitis score is noticed exclusively in mice lacking CALCA. Our data show that expression of the PCT/CT transcript protects from the progression of ptOA, while αCGRP promotes osteophyte formation, suggesting that CALCA-encoded peptides may represent novel targets for the treatment of ptOA.

Abstract Background Persons with opioid use disorders who inject drugs (PWID) in the United States (US) face multiple and intertwining health risks. These include interference with consistent access, linkage, and retention to health care including medication for opioid use disorder (MOUD), HIV prevention using pre-exposure prophylaxis (PrEP), and testing and treatment for sexually transmitted infections (STIs). Most services, when available, including those that address substance misuse, HIV prevention, and STIs, are often provided in multiple locations that may be difficult to access, which further challenges sustained health for PWID. HPTN 094 (INTEGRA) is a study designed to test the efficacy of an integrated, “whole-person” strategy that provides integrated HIV prevention including antiretroviral therapy (ART), PrEP, MOUD, and STI testing and treatment from a mobile health delivery unit (“mobile unit”) with peer navigation compared to peer navigation alone to access these services at brick and mortar locations. Methods HPTN 094 (INTEGRA) is a two-arm, randomized controlled trial in 5 US cities where approximately 400 PWID without HIV are assigned either to an experimental condition that delivers 26 weeks of “one-stop” integrated health services combined with peer navigation and delivered in a mobile unit or to an active control condition using peer navigation only for 26 weeks to the same set of services delivered in community settings. The primary outcomes include being alive and retained in MOUD and PrEP at 26 weeks post-randomization. Secondary outcomes measure the durability of intervention effects at 52 weeks following randomization. Discussion This trial responds to a need for evidence on using a “whole-person” strategy for delivering integrated HIV prevention and substance use treatment, while testing the use of a mobile unit that meets out-of-treatment PWID wherever they might be and links them to care systems and/or harm reduction services. Findings will be important in guiding policy for engaging PWID in HIV prevention or care, substance use treatment, and STI testing and treatment by addressing the intertwined epidemics of addiction and HIV among those who have many physical and geographic barriers to access care. Trial registration ClinicalTrials.gov NCT04804072 . Registered on 18 March 2021.

Abstract The hormone GDF15 is secreted in response to cellular stressors. Metformin elevates circulating levels of GDF15, an action important for the drug’s beneficial effects on body weight. Metformin can also inhibit mammalian respiratory complex I, leading to decreases in ATP:AMP ratio, activation of AMP Kinase (AMPK), and increased GDF15 production. We undertook studies using a range of mice with tissue-specific loss of Gdf15 (namely gut, liver and global deletion) to determine the relative contributions of two classical metformin target tissues, the gut and liver, to the elevation of GDF15 seen with metformin. In addition, we performed comparative studies with another pharmacological agent, the AMP kinase pan-activator, MK-8722. Deletion of Gdf15 from the intestinal epithelium significantly reduced the circulating GDF15 response to oral metformin, whereas deletion of Gdf15 from the liver had no effect. In contrast, deletion of Gdf15 from the liver, but not the gut, markedly reduced circulating GDF15 responses to MK-8722. Further, our data show that, while GDF15 restricts high-fat diet-induced weight gain, the intestinal production of GDF15 is not necessary for this effect. These findings add to the body of evidence implicating the intestinal epithelium in key aspects of the pharmacology of metformin action.

Abstract Background CD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved—daratumumab and isatuximab. CD38 is an ectoenzyme that degrades NAD and its precursors and is involved in the production of adenosine and other metabolites. Aim Among the various mechanisms by which CD38 antibodies can induce MM cell death is immunomodulation, including multiple pathways for CD38‐mediated T‐cell activation. Patients who respond to anti‐CD38 targeting treatment experience more marked changes in T‐cell expansion, activity, and clonality than nonresponders. Implications Resistance mechanisms that undermine the immunomodulatory effects of CD38‐targeting therapies can be tumor intrinsic, such as the downregulation of CD38 surface expression and expression of complement inhibitor proteins, and immune microenvironment‐related, such as changes to the natural killer (NK) cell numbers and function in the bone marrow niche. There are numerous strategies to overcome this resistance, which include identifying and targeting other therapeutic targets involved in, for example, adenosine production, the activation of NK cells or monocytes through immunomodulatory drugs and their combination with elotuzumab, or with bispecific T‐cell engagers.

This paper presents computer and color vision research focusing on human color perception in VR environments. A VR art gallery with digital twins of original artworks is created for this experiment. In this research, the field of colorimetry and the application of the L*a*b* and RGB color models are applied. The inter-relationships of the two color models are applied to create a color modification of the VR art gallery environment using C# Script procedures. This color-edited VR environment works with a smooth change in color tone in a given time interval. At the same time, a sudden change in the color of the RGB environment is defined in this interval. This experiment aims to record a user’s reaction embedded in a VR environment and the effect of color changes on human perception in a VR environment. This research uses lie detector sensors that record the physiological changes of the user embedded in VR. Five sensors are used to record the signal. An experiment on the influence of the user’s color perception in a VR environment using lie detector sensors has never been conducted. This research defines the basic methodology for analyzing and evaluating the recorded signals from the lie detector. The presented text thus provides a basis for further research in the field of colors and human color vision in a VR environment and lays an objective basis for use in many scientific and commercial areas.

Wavelet-based grid resolution adaptation driven by the ‘multiresolution analysis’ (MRA) of the Haar wavelet (HW) allows to devise an adaptive first-order finite volume (FV1) model (HWFV1) that can readily preserve the modelling fidelity of its reference uniform-grid FV1 counterpart. However, the MRA entails an enormous computational effort as it involves ‘encoding’ (coarsening), ‘decoding’ (refining), analysing and traversing modelled data across a deep hierarchy of nested, uniform grids. GPU-parallelisation of the MRA is needed to handle its computational effort, but its algorithmic structure (1) hinders coalesced memory access on the GPU and (2) involves an inherently sequential tree traversal problem. This work redesigns the algorithmic structure of the MRA in order to parallelise it on the GPU, addressing (1) by applying Z-order space-filling curves and (2) by adopting a parallel tree traversal algorithm. This results in a GPU-parallelised HWFV1 model (GPU-HWFV1). GPU-HWFV1 is verified against its CPU predecessor (CPU-HWFV1) and its GPU-parallelised reference uniform-grid counterpart (GPU-FV1) over five shallow water flow test cases. GPU-HWFV1 preserves the modelling fidelity of GPU-FV1 while being up to 30 times faster. Compared to CPU-HWFV1, it is up to 200 times faster, suggesting that the GPU-parallelised MRA could be used to speed up other FV1 models. HIGHLIGHTS Wavelet-based grid adaptation is parallelised on the GPU via a Z-order space-filling curve and a parallel tree traversal algorithm.; An adaptive Haar wavelet first-order finite volume shallow water model running on the GPU is developed (GPU-HWFV1).; GPU-HWFV1 is 20–300 times faster than its single-core serial CPU version 4.; GPU-HWFV1 is 1.3–30 times faster than its GPU-parallelised reference uniform-grid counterpart.;

Abstract Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2− breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.

Markers of the FRUSTRATIVE (non-realization of an expected outcome) often have a variety of uses. The Kimaragang frustrative dara also marks various related functions such as “discontinuous past”, “action narrowly averted”, frustrated intention or desire, and counterfactual conditionals. Davis & Matthewson (2022) describe a similar but not identical range of uses for the frustrative marker séna7 in St’át’imcets, and propose that the core meaning of this marker involves a type of epistemic modality. They further propose that their analysis can be extended to Kimaragang dara, suggesting that observed differences of usage may be due to differences in the tense-aspect systems of the two languages.This paper argues that the Kimaragang frustrative is different from séna7 in two respects: (1) the nature of the “frustrated expectation” inference, and (2) type of modality (epistemic vs. circumstantial). Frustrated expectation is lexically entailed in St’át’imcets, but Kimaragang dara entails only that the expected outcome cannot be asserted to be true at the time of speaking, with frustrated expectation arising as a pragmatic inference in contexts where it is reasonable to expect the speaker to know the actual outcome. Davis & Matthewson show that séna7 is purely epistemic in nature: it marks an unexpected correlation between two propositions, which need not belong to a single chain of events. Kimaragang dara is circumstantial in nature: it marks an initial situation whose expected outcome within the normal course of events is so far unrealized. It can be used to describe counterfactual situations, which are not epistemically accessible.