Geographic variation of mutagenic exposures in kidney cancer genomes.

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden1. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.

Interoception, Affect, and Cognition in Older Adults.

Interoception is the detection of signals that arise from within the body. Interoceptive sensitivity has been found to be associated with affect and cognition among younger adults, and examination of these relationships in older adult samples is beginning to emerge. Here, we take an exploratory approach to determine how demographic, affective, and cognitive variables relate to interoceptive sensitivity in neurologically normal older adults, aged 60-91 years old. Ninety-one participants completed a comprehensive neuropsychological battery, self-report questionnaires, and a heartbeat counting task to measure interoceptive sensitivity. Our findings revealed several relationships: 1) interoceptive sensitivity was inversely correlated with measures of positive emotionality: participants with higher interoceptive sensitivity tended to have lower levels of positive affect and trait extraversion; 2) interoceptive sensitivity was found to positively correlate with cognition: participants who performed better on the heartbeat-counting task also tended to perform better on a measure of delayed verbal memory; and 3) when examining the predictors of interoceptive sensitivity in a single hierarchical regression model, higher interoceptive sensitivity was related to: higher time estimation, lower positive affect, lower extraversion, and higher verbal memory. In total, the model accounted for 38% of the variability in interoceptive sensitivity (R2 = .38). These results suggest that, among older adults, interoceptive sensitivity is facilitative for aspects of cognition but perhaps disruptive for certain aspects of emotional experience.

Stubborn Predictions in Primary Visual Cortex.

Perceivers can use past experiences to make sense of ambiguous sensory signals. However, this may be inappropriate when the world changes and past experiences no longer predict what the future holds. Optimal learning models propose that observers decide whether to stick with or update their predictions by tracking the uncertainty or "precision" of their expectations. However, contrasting theories of prediction have argued that we are prone to misestimate uncertainty-leading to stubborn predictions that are difficult to dislodge. To compare these possibilities, we had participants learn novel perceptual predictions before using fMRI to record visual brain activity when predictive contingencies were disrupted-meaning that previously "expected" events became objectively improbable. Multivariate pattern analyses revealed that expected events continued to be decoded with greater fidelity from primary visual cortex, despite marked changes in the statistical structure of the environment, which rendered these expectations no longer valid. These results suggest that our perceptual systems do indeed form stubborn predictions even from short periods of learning-and more generally suggest that top-down expectations have the potential to help or hinder perceptual inference in bounded minds like ours.

Quantitative interpretation of bone marrow biopsies in MPN-What's the point in a molecular age?

The diagnosis of myeloproliferative neoplasms (MPN) requires the integration of clinical, morphological, genetic and immunophenotypic findings. Recently, there has been a transformation in our understanding of the cellular and molecular mechanisms underlying disease initiation and progression in MPN. This has been accompanied by the widespread application of high-resolution quantitative molecular techniques. By contrast, microscopic interpretation of bone marrow biopsies by haematologists/haematopathologists remains subjective and qualitative. However, advances in tissue image analysis and artificial intelligence (AI) promise to transform haematopathology. Pioneering studies in bone marrow image analysis offer to refine our understanding of the boundaries between reactive samples and MPN subtypes and better capture the morphological correlates of high-risk disease. They also demonstrate potential to improve the evaluation of current and novel therapeutics for MPN and other blood cancers. With increased therapeutic targeting of diverse molecular, cellular and extra-cellular components of the marrow, these approaches can address the unmet need for improved objective and quantitative measures of disease modification in the context of clinical trials. This review focuses on the state-of-the-art in image analysis/AI of bone marrow tissue, with an emphasis on its potential to complement and inform future clinical studies and research in MPN.

A COVID-19 Vaccination Program to Promote Uptake and Equity for People Experiencing Homelessness in Los Angeles County.

People experiencing homelessness (PEH) have been disproportionately affected by COVID-19, yet their vaccination coverage is lower than is that of the general population. We implemented a COVID-19 vaccination program that used evidence-based and culturally tailored approaches to promote vaccine uptake and equity for PEH in Los Angeles County, California. From February 2021 through February 2022, 33 977 doses of vaccine were administered at 2658 clinics, and 9275 PEH were fully vaccinated. This program may serve as a model for future service delivery in vulnerable populations. (Am J Public Health. 2023;113(2):170-174. https://doi.org/10.2105/AJPH.2022.307147).

Psychological flexibility and global health in young adults with and without a self-reported functional somatic syndrome: a preliminary investigation.

Functional somatic syndromes (FSS) are associated with functional impairments and distress. FSSs are common among young adults, and psychological flexibility may be a transdiagnostic process appropriate for treatment of FSS in this population. The objective of the current study was to compare physical and mental health in young adults with and without a self-reported FSS and examine which psychological flexibility processes are associated with better physical and mental health in the FSS subset. A total of 447 young adults participated in the current study. Individuals who reported an FSS diagnosis were coded as having a self-reported FSS. Physical and mental health and psychological flexibility were measured via self-report. FSS and non-FSS groups were compared regarding demographic characteristics and on the primary outcomes. Hierarchical regression analyses were conducted to examine the role of the psychological flexibility processes in physical and mental health in the FSS subset. Findings revealed that the FSS group scored significantly lower on measures of physical health and demonstrated less behavioral awareness than the non-FSS group. No differences regarding mental health were found. All three psychological flexibility processes were associated with physical and mental health, accounting for 26-49% of the variance in these outcomes. In conclusion, young adults with FSS experience more physical health difficulties than those without FSS. Psychological flexibility processes were related to better physical and mental health in those with FSS. These findings add to the literature and provide preliminary support for psychological flexibility as a future target for intervention development and implementation aimed at young adults with FSS.

Evaluation of Therapeutic Use of Antifibrinolytics in Cats.

Limited data are available regarding the use of the antifibrinolytic drugs tranexamic acid (TXA) and epsilon aminocaproic acid (EACA) in cats. This study aimed to evaluate the indications for the use of TXA and EACA in cats and to describe dosing regimens used, occurrence of adverse events, and patient outcomes. This was a retrospective multicenter study. Medical databases were searched for feline patients billed for TXA or EACA between 2015 and 2021. Thirty-five cats met the inclusion criteria; 86% received TXA and 14% received EACA. The most common indication was nontraumatic hemorrhage (54%), followed by traumatic hemorrhage (17%) and elective surgery (11%). The median dose was 10 mg/kg for TXA and 50 mg/kg for EACA. Overall, 52% of cats survived to discharge. Potential adverse events were noted in 7/35 (20%) patients. Of these, 29% survived to discharge. No standardized dosing regimen was identified; rather, dose, dosing interval, and duration of administration varied markedly between patients. Administration was potentially associated with severe adverse events, although the retrospective design makes it difficult to establish a causal association with antifibrinolytic use. This study provides a base for future prospective studies by giving an insight into the use of antifibrinolytic drugs in cats.

A Preliminary Investigation into the Factor Structure of Two Psychological Flexibility Measures in a Sample of Community-Dwelling Older Adults.

OBJECTIVES: Acceptance and Commitment Therapy (ACT) targets psychological flexibility and the ability to identify behavioral function in context. Properly measuring these constructs is imperative to understanding whether these processes are mechanisms of change in treatment. The current study examined the factor structure of the Comprehensive Assessment of ACT processes (CompACT) and Tacting of Function scale (TOF) in community-dwelling older adults. METHODS: Factor structure was examined with CFA. Eighty community-dwelling older adults completed questionnaires prior to an intervention. RESULTS: While the original 23-item, 3-factor structure of the CompACT demonstrated inadequate fit, a modified 15-item, 3-factor structure demonstrated adequate fit. The original 1-factor structure of the TOF demonstrated inadequate fit. A modified 2-factor structure of the TOF fit significantly better than the original 1-factor structure; however, this model also demonstrated inadequate fit. CONCLUSIONS: Examining the factor structure of the CompACT and TOF in an older adult sample contributes to the field's understanding of the constructs of psychological flexibility and tacting ability and to the clinical utility of these measures in an understudied sample. CLINICAL IMPLICATIONS: These findings provide preliminary support for the use of a short-form version of the CompACT to measure therapeutic processes of change in community-dwelling older adults.

Engaging Same-Day Peer Ambassadors to Increase Coronavirus Disease 2019 Vaccination Among People Experiencing Unsheltered Homelessness in Los Angeles County: A Hybrid Feasibility-Evaluation Study.

BACKGROUND: This study aimed to evaluate the feasibility and acceptability of engaging unhoused peer ambassadors (PAs) in coronavirus disease 2019 (COVID-19) vaccination efforts to reach people experiencing unsheltered homelessness in Los Angeles County. METHODS: From August to December 2021, vaccinated PAs aged ≥18 years who could provide informed consent were recruited during vaccination events for same-day participation. Events were held at encampments, service providers (eg, housing agencies, food lines, and mobile showers), and roving locations around Los Angeles. PAs were asked to join outreach alongside community health workers and shared their experience getting vaccinated, receiving a $25 gift card for each hour they participated. Postevent surveys evaluated how many PAs enrolled and how long they participated. In October 2021, we added a preliminary effectiveness evaluation of how many additional vaccinations were attributable to PAs. Staff who enrolled the PAs estimated the number of additional people vaccinated because of talking with the PA. RESULTS: A total of 117 PAs were enrolled at 103 events, participating for an average of 2 hours. At events with the effectiveness evaluation, 197 additional people were vaccinated over 167 PA hours ($21.19 gift card cost per additional person vaccinated), accounting for >25% of all vaccines given at these events. DISCUSSION: Recruiting same-day unhoused PAs is a feasible, acceptable, and preliminarily effective technique to increase COVID-19 vaccination in unsheltered settings. The findings can inform delivery of other health services for people experiencing homelessness.

Action Enhances Predicted Touch.

It is widely believed that predicted tactile action outcomes are perceptually attenuated. The present experiments determined whether predictive mechanisms necessarily generate attenuation or, instead, can enhance perception-as typically observed in sensory cognition domains outside of action. We manipulated probabilistic expectations in a paradigm often used to demonstrate tactile attenuation. Adult participants produced actions and subsequently rated the intensity of forces on a static finger. Experiment 1 confirmed previous findings that action outcomes are perceived less intensely than passive stimulation but demonstrated more intense perception when active finger stimulation was removed. Experiments 2 and 3 manipulated prediction explicitly and found that expected touch during action is perceived more intensely than unexpected touch. Computational modeling suggested that expectations increase the gain afforded to expected tactile signals. These findings challenge a central tenet of prominent motor control theories and demonstrate that sensorimotor predictions do not exhibit a qualitatively distinct influence on tactile perception.

Community Health Worker Perspectives on Engaging Unhoused Peer Ambassadors for COVID-19 Vaccine Outreach in Homeless Encampments and Shelters.

BACKGROUND: COVID-19 vaccination is a priority for people experiencing homelessness. However, there are barriers to vaccine access driven in part by mistrust towards clinicians and healthcare. Community health workers (CHWs) and Peer Ambassadors (PAs) may be able to overcome mistrust in COVID-19 vaccine outreach. An unhoused PA program for COVID-19 vaccine outreach by CHWs was implemented in Los Angeles using a participatory academic-community partnership. OBJECTIVE: The purpose of this study was to evaluate CHW perspectives on an unhoused PA COVID-19 vaccine outreach program in Los Angeles. DESIGN: This study used a participatory community conference and qualitative focus groups to understand CHW perspectives on the PA program. The one-day conference was held in November 2021. PARTICIPANTS: Of the 42 conference participants, 19 CHWs participated in focus groups for two-way knowledge exchange between CHWs and researchers. APPROACH: Four focus groups were held during the conference, with 4-6 CHWs per group. Each group had a facilitator and two notetakers. Focus group notes were then analyzed using content analysis to derive categories of findings. CHWs reviewed the qualitative analysis to ensure that findings represented their experiences with the PA program. KEY RESULTS: The five categories of findings from focus groups were as follows: (1) PAs were effective liaisons to their peers to promote COVID-19 vaccines; (2) CHWs recognized the importance of establishing genuine trust and equitable working relationships within CHW/PA teams; (3) there were tradeoffs of integrating unhoused PAs into the existing CHW workflow; (4) CHWs had initial misgivings about the research process; and (5) there were lingering questions about the ethics of "exploiting" the invaluable trust unhoused PAs have with unhoused communities. CONCLUSIONS: CHWs were in a unique position to empower unhoused PAs to take a leadership role in reaching their peers with COVID-19 vaccines and advocate for long-term employment and housing needs.

Predictors of posttraumatic growth among hematopoietic cell transplant recipients.

OBJECTIVE: Prior research has shown that cancer survivors often report positive psychological changes from the experience of cancer, or posttraumatic growth (PTG). However, few studies have focused on PTG in cancer patients recovering from hematopoietic cell transplantation (HCT). The present study measured PTG at specific milestones during the year following HCT and investigated psychosocial and treatment-related factors that may hinder or facilitate PTG. METHODS: Participants (N = 430) completed assessments of PTG, social support, and coping pre-transplant. Posttraumatic growth was also assessed at 1, 3, 6, and 12 months post-transplant. Information about treatment regimen and post-transplant complications was abstracted from medical records. Mixed-effects linear regression models were used to evaluate the extent to which pre-transplant social support, coping approaches, treatment intensity, and post-transplant complications predicted PTG. RESULTS: Compared to pre-transplant, PTG scores were significantly higher at 6- and 12-month post-transplant. Greater pre-transplant social support significantly predicted greater PTG across the assessment points. Use of emotional engagement coping strategies also strongly predicted post-transplant PTG. Conversely, coping styles characterized by emotional avoidance generally were not predictive of PTG. No treatment-related factors or post-transplant complications were predictive of PTG. CONCLUSIONS: Findings indicate that supportive social relationships and coping by engaging with difficult emotions may facilitate PTG following HCT. Moreover, these factors were more important than medical characteristics in explaining PTG. Findings may guide the development of interventions to enhance positive psychological outcomes after HCT.

COVID-19 Vaccine Acceptability and Financial Incentives among Unhoused People in Los Angeles County: a Three-Stage Field Survey.

Unhoused people have higher COVID-19 mortality and lower vaccine uptake than housed community members. Understanding vaccine hesitancy among unhoused people is key for developing programs that address their unique needs. A three-round, rapid, field-based survey was conducted to describe attitudes toward COVID-19 vaccination. Round 1 assessed vaccine brand preference, round 2 assessed intention to accept a financial incentive for vaccination, and round 3 measured vaccine uptake and assessed reasons for vaccine readiness during implementation of a financial incentive program. A total of 5177 individuals were approached at COVID-19 vaccination events for unhoused people in Los Angeles County from May through November 2021. Analyses included 4949 individuals: 3636 (73.5%) unsheltered and 1313 (26.5%) sheltered. Per self-report, 2008 (40.6%) were already vaccinated, 1732 (35%) wanted to get vaccinated, 359 (7.3%) were not yet ready, and 850 (17.2%) did not want to get vaccinated. Brand preference was evenly split among participants (Moderna 31.0%, J&J 35.5%, either 33.5%, p = 0.74). Interest in a financial incentive differed between those who were not yet ready and those who did not want to get vaccinated (43.2% vs. 16.2%, p < 0.01). After implementing a financial incentive program, 97.4% of participants who indicated interest in vaccination were vaccinated that day; the financial incentive was the most cited reason for vaccine readiness (n = 731, 56%). This study demonstrated the utility of an iterative, field-based assessment for program implementation during the rapidly evolving pandemic. Personal engagement, a variety of brand choices, and financial incentives could be important for improving vaccine uptake among unhoused people.

Telomere and Telomerase-Associated Proteins in Endometrial Carcinogenesis and Cancer-Associated Survival.

Risk of relapse of endometrial cancer (EC) after surgical treatment is 13% and recurrent disease carries a poor prognosis. Research into prognostic indicators is essential to improve EC management and outcome. "Immortality" of most cancer cells is dependent on telomerase, but the role of associated proteins in the endometrium is poorly understood. The Cancer Genome Atlas data highlighted telomere/telomerase associated genes (TTAGs) with prognostic relevance in the endometrium, and a recent in silico study identified a group of TTAGs and proteins as key regulators within a network of dysregulated genes in EC. We characterise relevant telomere/telomerase associated proteins (TTAPs) NOP10, NHP2, NOP56, TERF1, TERF2 and TERF2IP in the endometrium using quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). qPCR data demonstrated altered expression of multiple TTAPs; specifically, increased NOP10 (p = 0.03) and reduced NHP2 (p = 0.01), TERF2 (p = 0.01) and TERF2IP (p < 0.003) in EC relative to post-menopausal endometrium. Notably, we report reduced NHP2 in EC compared to post-menopausal endometrium in qPCR and IHC (p = 0.0001) data; with survival analysis indicating high immunoscore is favourable in EC (p = 0.0006). Our findings indicate a potential prognostic role for TTAPs in EC, particularly NHP2. Further evaluation of the prognostic and functional role of the examined TTAPs is warranted to develop novel treatment strategies.

Role of Nucleolin in Endometrial Precancerous Hyperplasia and Carcinogenesis: Ex Vivo and In Silico Study.

Endometrial cancer (EC) is the most common gynaecological malignancy. Nucleolin (NCL) is involved in rDNA transcription, cell proliferation, and apoptosis, with high expression associated with worse overall survival (OS) in other adenocarcinomas. Our aims were to assess NCL gene and protein expression and explore the differential expression of NCL-associated genes (NAGs) in endometrial carcinogenesis. Endometrial samples were obtained from 157 women to include healthy, hyperplastic (EH), EC, and metastatic groups. RT-qPCR and immunohistochemistry were employed to assess NCL gene and protein levels. In silico analysis of NAGs in TCGA and GEO datasets was performed, with the prognostic value determined via Human Protein Atlas. NCL mRNA level of EC was lower than in healthy post-menopausal endometrium (p < 0.01). EH samples had lower NCL immuno-expression scores than healthy pre-menopausal (p < 0.001), benign post-menopausal (p < 0.01), and EC (p < 0.0001) samples. Metastatic lesions demonstrated higher NCL quick scores than primary tissue (p = 0.04). Higher NCL Immuno quick scores carried a worse OS in high-grade EC (p = 0.01). Interrogating Uterine Corpus Endometrial Carcinoma (TCGA-UCEC) and Uterine Carcinosarcoma (TCGA-UCS) cohorts revealed NCL to be the most highly upregulated gene in carcinosarcoma, with S100A11, LMNB2, RERG, E2F1 and CCNA2 representing key dysregulated NAGs in EC. Since NCL is implicated in transforming hyperplastic glands into cancer, with further involvement in metastasis, it is suggested to be a promising target for better-informed diagnosis, risk stratification, and management of EC.

College student mental health: Understanding changes in psychological symptoms in the context of the COVID-19 pandemic in the United States.

The COVID-19 pandemic has altered the way higher education is structured and delivered, presenting challenges for college students that have the potential to negatively impact mental health. The current study aimed to identify potential changes in college student psychological symptoms since the onset of the pandemic. The study used analyses of covariance to examine differences in perceived stress, depression, anxiety, and obsessive-compulsive symptoms between a sample of university students collected in Fall 2016 and a sample of students from the same university collected in Spring 2020 and Fall 2020 after the onset of the pandemic. Findings indicated that college students from the 2020 sample reported significantly higher levels of stress, depressive symptoms, and anxiety symptoms than the 2016 sample. For stress and anxiety, there was a significant interaction between cohort (2016 vs. 2020 sample) and year in school (first year vs. advanced) indicating that the pandemic may have had a more prominent negative mental health impact on advanced students in comparison to first year students. There were no significant differences between samples on obsessive-compulsive symptoms. The current sample was somewhat homogenous demographically, consisting of primarily first-year students, thus limiting generalizability. Self-report measures were used. College students may be struggling with increased stress, depressive symptoms, and anxiety symptoms during the pandemic. The current study provides important information to guide the development and implementation of prevention and intervention efforts to support college student mental health in the context of the pandemic.

The micro and ultrastructural anatomy of bone spicules found in the osteochondral junction of bovine patellae with early joint degeneration.

The structural changes in the tissues of the osteochondral junction are a topic of interest, especially considering how bone changes are involved in the initiation and progression of osteoarthritis (OA). Our research group has previously demonstrated that at the cement line boundary between the zone of calcified cartilage (ZCC) and the subchondral bone, in mature bovine patellae with early OA, there are numerous bone spicules that have emerged from the underlying bone. These spicules contain a central vascular canal and a bone cuff. In this study, we use high-resolution differential interference contrast optical microscopy and scanning electron microscopy to compare the cartilage-bone junction of three groups of mature bovine patellae showing healthy to mild to moderately degenerate cartilage. The ZCC and bone junction was carefully examined to estimate the frequency of marrow spaces, bone spicules and fully formed bone bulges. The results reveal that bone spicules are associated with all grades of cartilage tissue studied, with the most occurring in the intermediate stages of tissue health. The micro and ultrastructure of the bone spicule are consistent with that of an osteon, especially those found in compression zones in long bones. Also considering the coexistence of marrow spaces and fully formed bone, this study suggests that these bone spicules arise similar to the formation of osteons in the bone remodelling process. The significance of this conclusion is in the way researchers approach the bone formation issue in the early degenerative joint. Instead of endochondral ossification, we propose that bone formation in OA is more akin to a combination of primary bone remodelling and de novo bone formation.

Long-term behavioural rewriting of maladaptive drinking memories via reconsolidation-update mechanisms.

BACKGROUND: Alcohol use disorders can be conceptualised as a learned pattern of maladaptive alcohol-consumption behaviours. The memories encoding these behaviours centrally contribute to long-term excessive alcohol consumption and are therefore an important therapeutic target. The transient period of memory instability sparked during memory reconsolidation offers a therapeutic window to directly rewrite these memories using targeted behavioural interventions. However, clinically-relevant demonstrations of the efficacy of this approach are few. We examined key retrieval parameters for destabilising naturalistic drinking memories and the ability of subsequent counterconditioning to effect long-term reductions in drinking. METHODS: Hazardous/harmful beer-drinking volunteers (N = 120) were factorially randomised to retrieve (RET) or not retrieve (No RET) alcohol reward memories with (PE) or without (No PE) alcohol reward prediction error. All participants subsequently underwent disgust-based counterconditioning of drinking cues. Acute responses to alcohol were assessed pre- and post-manipulation and drinking levels were assessed up to 9 months. RESULTS: Greater long-term reductions in drinking were found when counterconditioning was conducted following retrieval (with and without PE), despite a lack of short-term group differences in motivational responding to acute alcohol. Large variability in acute levels of learning during counterconditioning was noted. 'Responsiveness' to counterconditioning predicted subsequent responses to acute alcohol in RET + PE only, consistent with reconsolidation-update mechanisms. CONCLUSIONS: The longevity of behavioural interventions designed to reduce problematic drinking levels may be enhanced by leveraging reconsolidation-update mechanisms to rewrite maladaptive memory. However, inter-individual variability in levels of corrective learning is likely to determine the efficacy of reconsolidation-updating interventions and should be considered when designing and assessing interventions.

Metalloprotein switches that display chemical-dependent electron transfer in cells.

Biological electron transfer is challenging to directly regulate using environmental conditions. To enable dynamic, protein-level control over energy flow in metabolic systems for synthetic biology and bioelectronics, we created ferredoxin logic gates that utilize transcriptional and post-translational inputs to control energy flow through a synthetic electron transfer pathway that is required for bacterial growth. These logic gates were created by subjecting a thermostable, plant-type ferredoxin to backbone fission and fusing the resulting fragments to a pair of proteins that self-associate, a pair of proteins whose association is stabilized by a small molecule, and to the termini of a ligand-binding domain. We show that the latter domain insertion design strategy yields an allosteric ferredoxin switch that acquires an oxygen-tolerant [2Fe-2S] cluster and can use different chemicals, including a therapeutic drug and an environmental pollutant, to control the production of a reduced metabolite in Escherichia coli and cell lysates.