Selective hydrogenation of nitro compounds to amines by coupled redox reactions over a heterogeneous biocatalyst.

Cleaner synthesis of amines remains a key challenge in organic chemistry because of their prevalence in pharmaceuticals, agrochemicals and synthetic building blocks. Here, we report a different paradigm for chemoselective hydrogenation of nitro compounds to amines, under mild, aqueous conditions. The hydrogenase enzyme releases electrons from H2 to a carbon black support which facilitates nitro-group reduction. For 30 nitroarenes we demonstrate full conversion (isolated yields 78 - 96%), with products including pharmaceuticals benzocaine, procainamide and mesalazine, and 4-aminophenol - precursor to paracetamol (acetaminophen). We also showcase gram-scale synthesis of procainamide with 90% isolated yield. We demonstrate potential for extension to aliphatic substrates. The catalyst is highly selective for reduction of the nitro group over other unsaturated bonds, tolerant to a wide range of functional groups, and exhibits excellent stability in reactions lasting up to 72 hours and full reusability over 5 cycles with a total turnover number over 1 million, indicating scope for direct translation to fine chemical manufacturing.

Service Users' Experiences of a Nationwide Digital Type 2 Diabetes Self-Management Intervention (Healthy Living): Qualitative Interview Study.

BACKGROUND: Diabetes Self-Management Education and Support programs for people living with type 2 diabetes mellitus (T2DM) can increase glycemic control and reduce the risk of developing T2DM-related complications. However, the recorded uptake of these programs is low. Digital self-management interventions have the potential to overcome barriers associated with attendance at face-to-face sessions. Healthy Living is an evidence-based digital self-management intervention for people living with T2DM, based on the Healthy Living for People with Type 2 Diabetes (HeLP-Diabetes) intervention, which demonstrated effectiveness in a randomized controlled trial. NHS England has commissioned Healthy Living for national rollout into routine care. Healthy Living consists of web-based structured education and Tools components to help service users self-manage their condition, including setting goals. However, key changes were implemented during the national rollout that contrasted with the trial, including a lack of facilitated access from a health care professional and the omission of a moderated online support forum. OBJECTIVE: This qualitative study aims to explore service users' experiences of using Healthy Living early in the national rollout. METHODS: A total of 19 participants were interviewed via telephone or a videoconferencing platform. Topics included users' experiences and views of website components, their understanding of the intervention content, and the overall acceptability of Healthy Living. Transcripts were analyzed thematically using a framework approach. RESULTS: Participants valued having trustworthy information that was easily accessible. The emotional management content resonated with the participants, prompting some to book an appointment with their general practitioners to discuss low mood. After completing the structured education, participants might have been encouraged to continue using the website if there was more interactivity (1) between the website and other resources and devices they were using for self-management, (2) with health professionals and services, and (3) with other people living with T2DM. There was consensus that the website was particularly useful for people who had been newly diagnosed with T2DM. CONCLUSIONS: Digital Diabetes Self-Management Education and Support programs offering emotional aspects of self-management are addressing an unmet need. Primary care practices could consider offering Healthy Living to people as soon as they are diagnosed with T2DM. Participants suggested ways in which Healthy Living could increase interaction with the website to promote continued long-term use.

Insights into the nucleation and growth of BiOCl nanoparticles by in situ X-ray pair distribution function analysis and in situ liquid cell TEM.

The synthesis of bismuth oxyhalides as defined nanostructures is hindered by their fast nucleation and growth in aqueous solutions. Using our recently developed single-source precursor, the formation of bismuth oxychloride in such solutions can be slowed significantly. As reported herein, this advance enables BiOCl formation to be investigated by in situ X-ray total scattering and in situ liquid cell transmission electron microscopy. In situ pair distribution function analysis of X-ray total scattering data reveals the local order of atomic structures throughout the synthesis, while in situ liquid cell transmission electron microscopy allows for tracking the growth of individual nanoparticles. Through this work, the precursor complex is shown to give rise to BiOCl upon heating in solution without the observation of structurally distinct intermediates. The emerging nanoparticles have a widened interlayer spacing, which moderately decreases as the particles grow. Mechanistic insights into the formation of bismuth oxyhalide nanoparticles, including the absence of distinct intermediates within the available time resolution, will help facilitate future design of controlled BiOX nanostructures.

Unintended consequences: college students' melatonin usage, sleep disturbance, and depressive symptoms.

With such high rates of undergraduate sleep problems, students have chosen to take melatonin, an over-the-counter supplement that can facilitate sleep. Questions remain as to the effectiveness of melatonin for sleep problems, and questions have emerged about its impact on mental health. Accordingly, the current study examined how ongoing melatonin usage might impact relative changes in college students' sleep disturbance and ultimately their depressive symptoms. The two-wave (baseline and 2-month follow-up), online sample consisted of 331 undergraduates (86% female; Mage = 21.3, SD = 2.4), who reported on melatonin usage, sleep disturbance, and depressive symptoms. Controlling for sleep hygiene, socio-economic status, and gender, our model demonstrated a significant indirect effect from ongoing melatonin usage to depressive symptoms. Specifically, melatonin consumption predicted relative increases in sleep disturbance, which, in turn, predicted corresponding increases in students' depressive symptoms. Given the increasing prevalence of melatonin usage, the potential for unforeseen consequences remains high. Results suggest that the negative consequences of melatonin use can include both college students' mental health and their sleep. Given the efficacy of addressing sleep problems with cognitive or behavioral strategies, it is essential that student support services highlight alternatives to melatonin and the potential problems associated with its use.

Flow-mediated dilation is modified by exercise training status during childhood and adolescence: preliminary evidence of the youth athlete's artery.

Chronic exercise training is associated with an "athlete's artery" phenotype in young adults and an attenuated age-related decline in endothelium-dependent arterial function. Adolescence is associated with an influx of sex-specific hormones that may exert divergent effects on endothelial function, but whether training adaptations interact with biological maturation to produce a "youth athlete's artery" has not been explored. We investigated the influence of exercise-training status on endothelium-dependent arterial function during childhood and adolescence. Brachial artery flow-mediated dilation (FMD) was assessed in n = 102 exercise-trained (males, n = 25; females, n = 29) and untrained (males, n = 23; females, n = 25) youths, characterized as pre (males, n = 25; females, n = 26)- or post (males, n = 23; females, n = 28)-predicted age at peak height velocity (PHV). Baseline brachial artery diameter was larger in post- compared with pre-PHV youths (P ≤ 0.001), males compared with females (P ≤ 0.001), and trained compared with untrained youths (3.26 ± 0.51 vs. 3.11 ± 0.42 mm; P = 0.041). Brachial FMD was similar in pre- and post-PHV youths (P = 0.298), and males and females (P = 0.946). However, exercise-trained youths demonstrated higher FMD when compared with untrained counterparts (5.3 ± 3.3 vs. 3.0 ± 2.6%; P ≤ 0.001). Furthermore, brachial artery diameter (r2 = 0.142; P = 0.007 vs. r2 = 0.004; P = 0.652) and FMD (r2 = 0.138; P = 0.008 vs. r2 = 0.003; P = 0.706) were positively associated with cardiorespiratory fitness in post-, but not pre-PHV youths, respectively. Collectively, our data indicate that exercise training is associated with brachial artery remodeling and enhanced endothelial function during youth. However, arterial remodeling and endothelium-dependent function are only associated with elevated cardiorespiratory fitness during later stages of adolescence.NEW & NOTEWORTHY We report preliminary evidence of the "youth athlete's artery," characterized by training-related arterial remodeling and elevated endothelium-dependent arterial function in children and adolescents. However, training-related adaptations in brachial artery diameter and flow-mediated dilation (FMD) were associated with cardiorespiratory fitness in adolescents, but not in children. Our findings indicate that endothelium-dependent arterial function is modifiable with chronic exercise training during childhood, but the association between FMD and elevated cardiorespiratory fitness is only apparent during later stages of adolescence.

Awake Combined Spinal Caudal Anesthesia for Longer-Duration Urologic Surgery in Infants: A Case Series.

Awake combined spinal caudal anesthesia has been used as an anesthetic technique for longer-duration infraumbilical surgeries in infants. Literature on the safety and feasibility of this technique is limited. We share our experience with 27 infants undergoing longer-duration urologic surgery using awake combined spinal and caudal anesthesia without the use of systemic sedatives or inhalational agents. We describe our technique, safety considerations, and details surrounding the optimal timing of caudal catheter activation for prolongation of surgical anesthesia.

Exploring melanoma shifts: a two-decade analysis in New Zealand.

AIMS: New Zealand melanoma incidence rates are amongst the highest in the world. The study aims to provide information on the incidence of cutaneous melanoma in New Zealand from 2000 to 2022. METHODS: De-identified data were extracted from the New Zealand Cancer Registry using the ICD-10 code for malignant melanoma (C34) and melanoma in situ (MIS) (D03) from 2000 to 2022. Statistical analysis was performed to calculate melanoma incidence rates. RESULTS: Invasive melanoma (IM) incidence rates demonstrated an increasing trend from 2000 to 2008 (+1.10 per 100,000 person-years per year), followed by an inflection point at 2008 and then a decreasing trend from 2008 to 2022 (-0.28 per 100,000 person-years per year), which was not statistically different from zero/no change. MIS incidence increased from 30.3 to 72.1 per 100,000 person-years between 2000 and 2022. CONCLUSIONS: The incidence of IM in New Zealand has plateaued in the last decade and was associated with an increase in MIS incidence over the same period. While this trend is encouraging, further research is required to investigate whether there is an actual decline in IM incidence.

In vitro evaluation of a hybrid negative pressure system for wound therapy.

OBJECTIVE: The objective of this study was to assess whether negative pressure could be maintained accurately and repeatably with a wall-suction-based hybrid negative pressure wound therapy (h-NPWT) system by comparing it with a commercial negative pressure wound therapy (NPWT) device. STUDY DESIGN: In vitro experimental study. METHODS: A commercial NPWT device (control) and three h-NPWT devices, with 0, 3, and 6 meters of additional tubing using the hospital-wall suction (groups 1, 2, and 3 respectively), were applied sequentially to a commercial NPWT dressing on a silicone skin substrate and set to run at a continuous pressure of -125 mmHg. The pressure within the wound space was monitored at 10 second intervals for 24 h. The process was repeated five times for each group. RESULTS: The commercial NPWT device produced an average pressure variance of 3.02 mmHg, and the h-NPWT produced average variances of 4.38, 4.24 and 4.20 mmHg for groups 1, 2 and 3, respectively. All groups produced an average pressure within 0.15 mmHg of -125 mmHg over the 24-hour period, and the h-NPWT systems produced the smallest range with all values remaining within a ±5% variation from -125 mmHg. CONCLUSION: The h-NPWT system achieved negative pressures that were comparable to those of a commercial control NPWT device. The addition of tubing between the skin substrate and the canister did not affect the pressure applied at the wound site. CLINICAL SIGNIFICANCE: The h-NPWT device tested in this study can be considered as an alternative for negative wound therapy when a commercial device cannot be used.

Current landscape and support for practical initiation of oncological prehabilitation translatable to thyroid cancer: A position paper.

Despite a growing body of evidence for the effectiveness of prehabilitation, the uptake of prehabilitation in Europe remains low. Contributing factors range from limited awareness and understanding of prehabilitation to a lack of supporting infrastructure and reimbursement challenges. In this position paper, the authors propose a new comprehensive definition of prehabilitation and identify differentiated thyroid cancer as a type of cancer particularly well-suited for prehabilitation. To support clinicians with the implementation of prehabilitation programs in their clinics, the authors discuss the following practical solutions: a) find the most appropriate prehabilitation program for each patient; b) raise awareness among peers; c) develop evidence to demonstrate the effectiveness of prehabilitation; d) expand the interdisciplinary team; e) expand your network and make use of existing assets; f) utilize learnings from the COVID-19 pandemic.

Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

Large walking and wellbeing behaviour benefits of co-designed sustainable park improvements: A natural experimental study in a UK deprived urban area.

There is little robust evidence of how sustainable park interventions impact on physical activity and other behaviours important for wellbeing. This controlled natural experimental study aimed to examine the effects of co-designing a sustainable park intervention, in a deprived UK urban area, on walking and other wellbeing behaviours. Behaviour observations were conducted at two intervention sites and two matched comparison sites (n = 4,783). Walking observations (primary outcome), wellbeing behaviours (vigorous, sedentary, social and take notice activities) and demographic characteristics were assessed at pre-intervention, and post-intervention (3 and 15 months). Outcomes were compared between intervention and comparison groups, controlling for pre-intervention using multilevel negative binomial regression models. Additional behaviour observations were conducted in two unchanged nearby sites to assess changes in general local activity. Intercept surveys (n = 623) assessed change in self-reported outdoor space usage at intervention and control areas. Post-intervention, walking increased 203 % at 3 months (IRR 2·03, 95 % CI 1·01-4·09) and 351 % at 15 months (IRR 3·51, 95 % CI 2·07-5·93), for intervention sites relative to comparison sites. Large increases for other wellbeing behaviours were also observed. The proportion of non-white persons increased substantially post-intervention, compared to comparison sites. Nearby unchanged sites showed little evidence of general increased activity. Self-reported outdoor usage increased more in the intervention sites (p=<0·001). Sustainable solutions can yield large increases in walking and wellbeing in deprived areas, especially where interventions are co-designed with residents. More collaborative and robust natural experimental studies like this are needed to better inform decision-makers how to maximise health and wellbeing outcomes from sustainable interventions.

Mitigating mutual coupling effects on circular polarization for improved bandwidth in MIMO systems: A novel approach.

An improved mutual coupling compensation in circularly polarized (CP) multi-input multi-output (MIMO) dielectric resonator antenna (DRA) is presented in this paper. Using trimming approach, the mutual coupling (MC) between closely spaced DRA units at 0.3λ has been significantly reduced while axial ratio performance has been maintained. Mutual coupling reduction is obtained by trimming the DRA to ensure low mutual coupling below -20dB. The exclusive features of the proposed MIMO DRA include wide impedance matching bandwidth (BW), triple band circular polarization, and suppressed MC between the radiating elements. The impedance bandwidth matches perfectly with a triple band's 3 dB axial ratio (AR). It is designed with characteristic mode analysis with good agreement of the measurement that has been obtained. Using the probe feed method, the DRA and patch strip are coupled together to allow bandwidth widening of the pro-posed DRA. An impedance bandwidth of 34% at a lower frequency to around 2% at a higher frequency was achieved in all resonance frequencies. Thus, we refer to our newly designed DRA as a proposed method for effectively reducing the mutual coupling between DRAs. Additionally, the 3 dB AR bandwidth matched at 3.3 GHz, 4.6 GHz, and 6.3 GHz with a percentage of 11.66%, 3.04%, and 2.22% obtained at the three different frequencies. Note that the proposed DRA exhibits low mutual coupling (below -20 dB) at the targeted frequencies, which is suitable for better signal reception for MIMO applications. By computing, the metrics envelop correlation coefficient, diversity gain, channel capacity loss, and total active reflection coefficient, the MIMO performance of the proposed antenna is verified. The experiments show a close result between simulated and computed validation of the proposed DRA.

Implementation of a Blended-Learning Perioperative Nursing Education Program in Canada.

Governmental COVID-19 mandates in Ontario, Canada, resulted in a backlog of perioperative procedures. Organization leaders were required to expand services after the pandemic; however, the ongoing nursing shortage and college-based structure of perioperative education programs complicated their response. In 2021, we developed an in-house perioperative education program using a blended-learning theory comprising online modules and videos, skills laboratory sessions, and clinical placement experiences. Nurses were required to apply for the program and remain employed at the facility for two years. Program evaluations showed that the novice nurses felt confident when beginning clinical experiences and preceptors believed the nurses were prepared for practice. Sixteen of 19 participants successfully completed the program, which helped resolve the staffing shortage. Novice nurses may benefit from a shadowing experience before applying for this type of program. Leaders in nonperioperative specialties should consider an in-house education program to help meet staffing needs in their areas.

Untapped Potential of Unobtrusive Observation for Studying Health Behaviors.

Improving the environment is an important upstream intervention to promote population health by influencing health behaviors such as physical activity, smoking, and social distancing. Examples of promising environmental interventions include creating high-quality green spaces, building active transport infrastructure, and implementing urban planning regulations. However, there is little robust evidence to inform policy and decision makers about what kinds of environmental interventions are effective and for which populations. In this viewpoint, we make the case that this evidence gap exists partly because health behavior research is dominated by obtrusive methods that focus on studying individual behavior and that are less suitable for understanding environmental influences. In contrast, unobtrusive observation can assess how behavior varies in different environmental contexts. It thereby provides valuable data relating to how environments affect the behavior of populations, which is often useful knowledge for effectively and equitably tackling population health challenges such as obesity and noncommunicable diseases. Yet despite a long history, unobtrusive observation methods are currently underused in health behavior research. We discuss how developing the use of video technology and automated computer vision techniques can offer a scalable solution for assessing health behaviors, facilitating a more thorough investigation of how environments influence health behaviors. We also reflect on the important ethical challenges associated with unobtrusive observation and the use of these emerging video technologies. By increasing the use of unobtrusive observation alongside other methods, we strongly believe this will improve our understanding of the influences of the environment on health behaviors.

A guide to photosynthetic gas exchange measurements: Fundamental principles, best practice and potential pitfalls.

Gas exchange measurements enable mechanistic insights into the processes that underpin carbon and water fluxes in plant leaves which in turn inform understanding of related processes at a range of scales from individual cells to entire ecosytems. Given the importance of photosynthesis for the global climate discussion it is important to (a) foster a basic understanding of the fundamental principles underpinning the experimental methods used by the broad community, and (b) ensure best practice and correct data interpretation within the research community. In this review, we outline the biochemical and biophysical parameters of photosynthesis that can be investigated with gas exchange measurements and we provide step-by-step guidance on how to reliably measure them. We advise on best practices for using gas exchange equipment and highlight potential pitfalls in experimental design and data interpretation. The Supporting Information contains exemplary data sets, experimental protocols and data-modelling routines. This review is a community effort to equip both the experimental researcher and the data modeller with a solid understanding of the theoretical basis of gas-exchange measurements, the rationale behind different experimental protocols and the approaches to data interpretation.

GradDFT. A software library for machine learning enhanced density functional theory.

Density functional theory (DFT) stands as a cornerstone method in computational quantum chemistry and materials science due to its remarkable versatility and scalability. Yet, it suffers from limitations in accuracy, particularly when dealing with strongly correlated systems. To address these shortcomings, recent work has begun to explore how machine learning can expand the capabilities of DFT: an endeavor with many open questions and technical challenges. In this work, we present GradDFT a fully differentiable JAX-based DFT library, enabling quick prototyping and experimentation with machine learning-enhanced exchange-correlation energy functionals. GradDFT employs a pioneering parametrization of exchange-correlation functionals constructed using a weighted sum of energy densities, where the weights are determined using neural networks. Moreover, GradDFT encompasses a comprehensive suite of auxiliary functions, notably featuring a just-in-time compilable and fully differentiable self-consistent iterative procedure. To support training and benchmarking efforts, we additionally compile a curated dataset of experimental dissociation energies of dimers, half of which contain transition metal atoms characterized by strong electronic correlations. The software library is tested against experimental results to study the generalization capabilities of a neural functional across potential energy surfaces and atomic species, as well as the effect of training data noise on the resulting model accuracy.

Differential metabolic responses in bold and shy sea anemones during a simulated heatwave.

As climate change-induced heatwaves become more common, phenotypic plasticity at multiple levels is a key mitigation strategy by which organisms can optimise selective outcomes. In ectotherms, changes to both metabolism and behaviour can help alleviate thermal stress. Nonetheless, no study in any ectotherm has yet empirically investigated how changing temperatures affect among-individual differences in the associations between these traits. Using the beadlet anemone (Actinia equina), an intertidal species from a thermally heterogeneous environment, we investigated how individual metabolic rates, linked to morphotypic differences in A. equina, and boldness were related across changing temperatures. A crossed-over design and a temporal control were used to test the same individuals at a non-stressful temperature, 13°C, and under a simulated heatwave at 21°C. At each temperature, short-term repeated measurements of routine metabolic rate (RMR) and a single measurement of a repeatable boldness-related behaviour, immersion response time (IRT), were made. Individual differences, but not morphotypic differences, were highly predictive of metabolic plasticity, and the plasticity of RMR was associated with IRT. At 13°C, shy animals had the highest metabolic rates, while at 21°C, this relationship was reversed. Individuals that were bold at 13°C also exhibited the highest metabolic rates at 21°C. Additional metabolic challenges during heatwaves could be detrimental to fitness in bold individuals. Equally, lower metabolic rates at non-stressful temperatures could be necessary for optimal survival as heatwaves become more common. These results provide novel insight into the relationship between metabolic and behavioural plasticity, and its adaptive implications in a changing climate.

How Would Nature See Our Corneal Triumphs? The LXXIX Edward Jackson Lecture.

PURPOSE: To describe discrepancies between clinical observation and current teachings in corneal endothelial disease, particularly in Fuchs endothelial dystrophy and its potential association with primary open angle glaucoma. DESIGN: Perspective. METHODS: A perspective is presented on Fuchs dystrophy, a disorder that commonly presents with a compromised endothelium but minimal stromal edema, indicating that the corneal imbibition pressure is relatively "too high." RESULTS: The discrepancy between the relative lack of stromal edema in the absence of an endothelial cell layer cannot be explained by the current theories involving a circulatory pumping mechanism over the endothelial cell layer, but may point to the following: (1) secondary involvement of the corneal endothelium in Fuchs dystrophy; (2) separate hydration systems for maintaining the imbibition pressure (vertical static hydration) and corneal nutrition (horizontal dynamic hydration); (3) the cornea as net contributor of aqueous humor; (4) a close relationship between the corneal imbibition and intraocular pressure, with potentially a shared regulatory system; and (5) a potential steroid-type hormone dependency of this regulatory system. CONCLUSIONS: Clinical observation shows that the stromal imbibition pressure is "too high" in Fuchs endothelial dystrophy, indicating that it may not primarily be an endothelial disease, but a type of "corneal glaucoma."

Transsphenoidal hypophysectomy for the treatment of hypersomatotropism secondary to a pituitary somatotroph adenoma in a dog.

Pituitary-dependent hypersomatotropism is rarely diagnosed in dogs and surgical treatment is not reported. A 6-year-10-month male neutered Patterdale Terrier presented with polyuria, polydipsia, progressive pharyngeal stertor, excessive hair growth and widened facial features and paws. Serum insulin-like growth factor-1 concentration via radioimmunoassay was consistent with hypersomatotropism (1783 ng/mL). A pituitary mass was identified on magnetic resonance and computed tomography imaging. Six weeks later, glucosuria, starved hyperglycemia and serum fructosamine above the reference range (467.6 µmol/L, RI 177-314) were documented, consistent with diabetes mellitus. Transsphenoidal hypophysectomy was performed under general anesthesia without complications. Pituitary histopathology identified an acidophil neoplasm, with positive immunostaining for growth hormone. Postoperatively, there was rapid resolution of clinical, biochemical and morphologic changes of hypersomatotropism with persistence of diabetes mellitus. This case demonstrates successful resolution of hypersomatotropism with ongoing diabetes mellitus in a dog after surgical treatment by transsphenoidal hypophysectomy.

Integrating Clinical Cancer and PTM Proteomics Data Identifies a Mechanism of ACK1 Kinase Activation.

Beyond the most common oncogenes activated by mutation (mut-drivers), there likely exists a variety of low-frequency mut-drivers, each of which is a possible frontier for targeted therapy. To identify new and understudied mut-drivers, we developed a machine learning (ML) model that integrates curated clinical cancer data and posttranslational modification (PTM) proteomics databases. We applied the approach to 62,746 patient cancers spanning 84 cancer types and predicted 3,964 oncogenic mutations across 1,148 genes, many of which disrupt PTMs of known and unknown function. The list of putative mut-drivers includes established drivers and others with poorly understood roles in cancer. This ML model is available as a web application. As a case study, we focused the approach on nonreceptor tyrosine kinases (NRTK) and found a recurrent mutation in activated CDC42 kinase-1 (ACK1) that disrupts the Mig6 homology region (MHR) and ubiquitin-association (UBA) domains on the ACK1 C-terminus. By studying these domains in cultured cells, we found that disruption of the MHR domain helps activate the kinase while disruption of the UBA increases kinase stability by blocking its lysosomal degradation. This ACK1 mutation is analogous to lymphoma-associated mutations in its sister kinase, TNK1, which also disrupt a C-terminal inhibitory motif and UBA domain. This study establishes a mut-driver discovery tool for the research community and identifies a mechanism of ACK1 hyperactivation shared among ACK family kinases. IMPLICATIONS: This research identifies a potentially targetable activating mutation in ACK1 and other possible oncogenic mutations, including PTM-disrupting mutations, for further study.